CVJA Volume 27 Issue 3 by Clinics Cardive Publishing

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CardioVascular Journal of Africa (official journal for PASCAR)

• Techniques for balloon sizing in percutaneous mitral valvuloplasty • Hypertrophic cardiomyopathy in South Africans • Fat distribution, insulin resistance and dyslipidaemia in SA women • Actions to eradicate rheumatic heart disease in Africa • Cardiology–cardiothoracic training in South Africa • Patterns of collaboration in research in sub-Saharan Africa • Report of the PASCAR Hypertension Task Force

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Cardiovascular Journal of Africa . Vol 27, No 3, May/June 2016

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ISSN 1995-1892 (print) ISSN 1680-0745 (online)

Vol 27, No D, MAY/JUNE 2016

CONTENTS

Cardiovascular Journal of Africa

127

www.cvja.co.za

From the Editor’s Desk P Commerford

Cardiovascular Topics

128 Iloprost as an acute kidney injury-triggering agent in severely atherosclerotic patients ME Uyar • P Yucel • S Ilin • Z Bal • S Yildirim • AS Uyar • T Akay • E Tutal • S Sezer 134

Changes in cardiac structure and function in a modified rat model of myocardial hypertrophy W Dai • Q Dong • M Chen • L Zhao • A Chen • Z Li • S Liu

143 Subclavian artery cannulation provides better myocardial protection in conventional repair of acute type A aortic dissection: experience from a single medical centre in Taiwan P-S Hsu • J-L Chen • C-S Tsai • Y-T Tsai • C-Y Lin • C-Y Lee • H-Y Ke • Y-C Lin 147

Comparison of two different techniques for balloon sizing in percutaneous mitral balloon valvuloplasty: which is preferable? A Tastan • A Ozturk • O Senarslan • E Ozel • S Uyar • EE Ozcan • O Kozan

152

Clinical features, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy in South Africans NAB Ntusi • G Shaboodien • M Badri • F Gumedze • BM Mayosi

159 Administration of perivascular cyanoacrylate for the prevention of cellular damage in saphenous vein grafts: an experimental model N Kahraman • G Yumun • A Gücü • KK Özsin • T Taner • E Şener • MT Göncü 164 Effects of a PPAR-gamma receptor agonist and an angiotensin receptor antagonist on aortic contractile responses to alpha receptor agonists in diabetic and/or hypertensive rats I Tugrul • T Dost • O Demir • F Gokalp • O Oz • N Girit • M Birincioglu 170

Tabula viva chirurgi: a living surgical document MJ Swart • G Joubert • J-A van den Berg • GJ van Zyl

177 Associations between body fat distribution, insulin resistance and dyslipidaemia in black and white South African women D Keswell • M Tootla • JH Goedecke INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS

184 Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué D Watkins • L Zuhlke • M Engel • R Daniels • V Francis • G Shaboodien • M Kango • A Abul-Fadl • A Adeoye • S Ali • M Al-Kebsi • F Bode-Thomas • G Bukhman • A Damasceno • DY Goshu • A Elghamrawy • B Gitura • A Haileamlak • A Hailu • C Hugo-Hamman • S Justus • G Karthikeyan • N Kennedy • P Lwabi • Y Mamo • P Mntla • C Sutton • AO Mocumbi • C Mondo • A Mtaja • J Musuku • J Mucumbitsi • L Murango • G Nel • S Ogendo • E Ogola • D Ojji • TO Olunuga • MM Redi • KE Rusingiza • M Sani • S Sheta • S Shongwe • J van Dam • H Gamra • J Carapetis • D Lennon • BM Mayosi 188

Cardiology–cardiothoracic subspeciality training in South Africa: a position paper of the South Africa Heart Association K Sliwa • L Zühlke • R Kleinloog • A Doubell • I Ebrahim • M Essop • D Kettles • D Jankelow • S Khan • E Klug • S Lecour • D Marais • M Mpe • M Ntsekhe • L Osrin • F Smit • A Snyders • JP Theron • A Thornton • A Chin • N van der Merwe • E Dau • A Sarkin

Review Article

194 Patterns of international collaboration in cardiovascular research in sub-Saharan Africa R Ettarh

Vol 27, No 3, MAY/JUNE 2016

Meeting Report

200 Development of the roadmap for reducing cardiovascular morbidity and mortality through the detection, treatment and control of hypertension in Africa: report of a working group of the PASCAR Hypertension Task Force A Dzudie • A Kane • E Kramoh • JB Anzouan-Kacou • JM Damourou • L Allawaye • J Nzisabira • L Mousse • D Balde • O Nouhom • JL Nkoa • K Kaki • A Djomou • A Menanga • CN Nganou • JB Mipinda • L Nebie • LM Kuate • S Kingue • SA Ba

PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) Cardiovascular Topics

e1 L’echographie trans-oesophagienne (ETO) a l’Institut de cardiologie d’Abidjan: indications, resultats et rentabilite diagnostique (Transoesophageal echocardiography (TEE) at the Institute of Cardiology in Abidjan: indications, results and diagnostic accuracy) J-B Anzouan-Kacou • C Konin • C-P Zobo • D Bamba-Kamagaté • M-P N’cho-Mottoh • B Bok

Case Reports

e5 A case of enoxaparin-induced thrombocytopaenia during treatment of acute myocardial infarction SY Lim • SR Lee • YH Kim • JS Kim • SH Kim • JC Ahn • WH Song e9 Transcatheter intervention in a child with scimitar syndrome Z Wang • X Cai e12 Short-term warfarin treatment for apical thrombus in a patient with Takotsubo cardiomyopathy A İcli • H Akilli • M Kayrak • A Aribas • K Ozdemir e15 Unexpected complication of oesophagoscopy: iatrogenic aortic injury in a child O Tezcan • M Oruc • M Kuyumcu • S Demirtas • C Yavuz • O Karahan

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AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016

127

From the Editor’s Desk This issue carries several important messages for those interested in cardiovascular heath in Africa. In the landmark Addis Ababa communiqué, Watkins and colleagues (page 184) describe seven essential actions aimed at eliminating rheumatic heart disease (RHD) in Africa. The distinguished group of authors are widely representative of Africans knowledgeable and active in both research and clinical service in this field and they are supported by international experts. Most importantly, this third All-Africa Workshop on Acute Rheumatic Fever and Rheumatic Heart Disease was hosted by the social cluster of the African Union Commission, and the communiqué has since been endorsed by African Union heads of state. Therefore the political will and support so necessary for successful implementation seems to be available and will be essential in the years ahead. The communiqué identifies that one of the barriers to eradicating RHD in Africa is that there are few centres capable of providing cardiac surgery, and action five aims to ‘Establish centres of excellence for cardiac surgery, which will sustainably deliver state-of-the-art surgical care, train the next generation of African cardiac practitioners, and conduct research on endemic cardiovascular diseases, including RHD’. Against the background of that statement it is disturbing to read the position paper of the South African Heart Association by Sliwa and colleagues (page 188) on training in cardiology and cardiothoracic surgery in South Africa. The authors, all experienced in their fields of expertise and many are responsible for providing training in these fields, document the lack of training opportunities, the lack of adequate facilities and the failure of the state to expand and enlarge facilities so as to keep up with the population expansion. For the majority of South Africans who lack medical insurance or the funds to access private healthcare and who have heart disease, the situation has worsened over the last decade, with longer waiting lists for cardiac surgery at some tertiary centres than were seen previously, and a lack of simple monitoring tools such as echocardiography at many secondary level facilities. As the authors point out, clinicians have limited powers to alter the situation, and urgent action at government level is needed. So we have the paradoxical situation where we publish two conflicting statements on the state of cardiovascular care in Africa. One is an encouraging, visionary message that the need for improved facilities for such care is recognised by both healthcare professionals and politicians, the other sketches the existing situation in South Africa where there has been no progression and in fact retrogression in provision of such care for the majority of the population. Which of the two scenarios play out in the future will depend on the continued involvement of the cardiovascular healthcare community and its active and successful interaction with politicians and governments. An interesting review of research output in sub-Saharan Africa (SSA) and international collaboration in that research is provided by Ettarh (page 194). This study provides a picture over 10 years of the volume and scientific impact of international collaboration in cardiovascular research in SSA. This may be the first study of its kind and encouragingly demonstrates that

research output is increasing and collaboration appears to be improving. Unfortunately, the extent of collaboration within SSA is very limited compared to the level of collaboration with other non-SSA countries. This pattern has been observed with data for all of the scientific output of the region. The potential benefits of increased collaboration in the region are described and should be an encouragement to junior researchers to widen collaboration in SSA. Research into ethnic differences in risk factors for cardiac and other non-communicable diseases may provide insight into possible strategies to stem the predicted increase in these diseases in Africa. Keswell and co-authors (page 177) examined associations between body fat distribution, insulin resistance and dyslipidaemia in black and white South African women. The novel finding of this study was that central and peripheral fat depositions were independently associated with insulin resistance in both black and white women, and with triglyceride levels in the black women. By contrast, fasting glucose concentrations were associated with centralisation of body fat in black, but not white women, whereas total cholesterol and low-density lipoprotein cholesterol concentrations were associated with centralisation of body fat in white, but not black women. Hypertrophic cardiomyopathy (HCM) was historically thought to be rare among Africans but as Ntusi and colleagues point out (page 152), recent echocardiographic studies from the continent have dispelled that myth. They examined a consecutive series of patients with HCM (30.2% black African), prospectively enrolled from a tertiary referral centre and characterised them clinically, echocardiographically and genetically. They found HCM to occur more in men, and with a younger age of onset. Major symptoms and complications were similar to those reported in North American, Middle Eastern and Asian studies. Known and novel disease-causing mutations were identified in the MYH7 and MYBPC3 genes, with a lower yield of mutation screening of about 30%, compared to the expected 40 to 70% found elsewhere. The mortality rate in this contemporary African HCM series was, however, higher than reported elsewhere, although comparable to age- and gender-matched members of the South African population. Survival was predicted by NYHA functional class at last clinic visit. Balloon mitral valvuloplasty (BMV) revolutionised the management of many patients with rheumatic mitral stenosis, and the advent of the innovative Inoue balloon in the early eighties further popularised the technique, which was remarkably successful in alleviating symptoms and improving the mitral valve area. The method of selecting the size of balloon to use, based on the height of the patient, always seemed unusual, to say the least, but produced good results. Tastan and co-workers (page 147) describe the use of echocardiography to select balloon size and their results seem to indicate that this may be a more preferable method. PJ Commerford Editor-in-Chief

128

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016

AFRICA

Cardiovascular Topics Iloprost as an acute kidney injury-triggering agent in severely atherosclerotic patients Mehtap Erkmen Uyar, Piril Yucel, Sena Ilin, Zeynep Bal, Saliha Yildirim, Ahmet Senol Uyar, Tankut Akay, Emre Tutal, Siren Sezer

Abstract Background: Iloprost, a stable prostacyclin analog, is used as a rescue therapy for severe peripheral arterial disease (PAD). It has systemic vasodilatory and anti-aggregant effects, with severe vasodilatation potentially causing organ ischaemia when severe atherosclerosis is the underlying cause. In this study, we retrospectively analysed renal outcomes after iloprost infusion therapy in 86 patients. Methods: Eighty-six patients with PAD who received iloprost infusion therapy were retrospectively analysed. Clinical and biochemical parameters were recorded before (initial, Cr1), during (third day, Cr2), and after (14th day following the termination of infusion therapy, Cr3) treatment. Acute kidney injury (AKI) was defined according to KDIGO guidelines as a ≥ 0.3 mg/dl (26.52 μmol/l) increase in creatinine levels from baseline within 48 hours. Results: Cr2 (1.46 ± 0.1 mg/dl) (129.06 ± 8.84 μmol/l) and Cr3 (1.53 ± 0.12 mg/dl) (135.25 ± 10.61 μmol/l) creatinine levels were significantly higher compared to the initial value (1.15 ± 0.6 mg/dl) (101.66 ± 53.04 μmol/l). AKI was observed in 36 patients (41.86%) on the third day of iloprost infusion. Logistic regression analysis revealed smoking and not using acetylsalicylic acid as primary predictors (p = 0.02 and p = 0.008, respectively) of AKI during iloprost treatment. On the third infusion day, patients’ urinary output significantly increased (1813.30 ± 1123.46 vs 1545.17 ± 873.00 cm3) and

Department of Internal Medicine, Baskent University, Ankara, Turkey Mehtap Erkmen Uyar, MD, mehtap94@yahoo.com Piril Yucel, MD Sena Ilin, MD Zeynep Bal, MD Saliha Yildirim, MD

Department of Anesthesiology, Ulucanlar Eye Education and Research Hospital, Ankara, Turkey Ahmet Senol Uyar, MD

Department of Cardiovascular Surgery, Baskent University, Ankara, Turkey Tankut Akay, MD

Department of Nephrology, Baskent University, Ankara, Turkey Emre Tutal, MD Siren Sezer, MD

diastolic blood pressure significantly decreased (70.07 ± 15.50 vs 74.14 ± 9.42 mmHg) from their initial values. Conclusion: While iloprost treatment is effective in patients with PAD who are not suitable for surgery, severe systemic vasodilatation can cause renal ischaemia, resulting in nonoliguric AKI. Smoking, no acetylsalicylic acid use, and lower diastolic blood pressure are the clinical risk factors for AKI during iloprost treatment. Keywords: iloprost, acute kidney injury, severe atherosclerosis Submitted 20/11/14, accepted 14/6/15 Cardiovasc J Afr 2016; 27: 128–133

www.cvja.co.za

DOI: 10.5830/CVJA-2015-051

Iloprost is a stable epoprostenol (prostacyclin, PGI2) analog that mimics the effects of prostacyclin in the microvascular blood flow, namely, inhibition of platelet aggregation, leukocyte–vessel interaction and vasodilatation.1,2 A superior chemical stability confers iloprost with a longer half-life than that of prostacyclin, giving it an advantage as a therapeutic agent for the treatment of many cardiovascular and pulmonary diseases.3 Iloprost also inhibits platelet aggregation and leukocyte activation, and leads to vasodilatation in ischaemic tissue after ischaemia/reperfusion (I/R) injury.4,5 Iloprost is used as a rescue therapy for patients with severe obstructive peripheral arterial disease (PAD) who cannot tolerate surgery. Renoprotective effects of iloprost have been reported in contrast-induced nephropathy and I/R injury.6 In these cases, iloprost infusion was administered either at a low dose or for a short duration, causing vasodilation without systemic hypotension.7,8 On the other hand, during rescue therapy for severe atherosclerosis, its use may lower blood pressure,9 leading to tissue ischaemia, renal hypoperfusion and acute kidney injury.10 Because of iloprost’s hypotension-inducing potent systemic vasodilatory effect, several potential safety issues should be considered in these patients.11 This ischaemia-triggering hypoperfusion effect of iloprost may cause organ dysfunction, such as acute kidney injury, especially in patients with co-morbidities. On the basis of the systemic hypotensive effect of iloprost and our clinical experience of patients with acute kidney injury under iloprost treatment, we retrospectively analysed the effects of iloprost infusion therapy on renal outcomes in 86 patients.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016

Methods We retrospectively analysed patients with severe PAD who received iloprost infusion therapy at a dose of 1 ng/kg/min between January 2011 and January 2012 at Baskent University Hospital, Ankara, Turkey. Severe PAD was detected with non-invasive tests, including ankle–brachial index < 0.40 and absent blood flow on duplex ultasonography. Among these, 86 patients were selected according to the following exclusion criteria: (1) malignant disease, (2) rheumatological or chronic inflammatory disease of unknown origin, (3) history of systemic vasculitis, (4) unstable heart failure (ejection fraction < 50%) during infusion therapy, (5) chronic liver failure, (6) systemic infective or non-infective inflammatory diseases, (7) evidence of end-stage renal disease (ESRD), (8) younger than 18 years of age. An informed consent was obtained from all subjects of the study. According to the treatment protocol, patients received iloprost infusion at a dose of 1 ng/kg/min for 10–14 days. Iloprost in a 100-ml isotonic solution was infused during a six-hour period via the intravenous route. Nausea, flushing, headache and thrombophlebitis were recorded as drug-related side effects. In accordance with the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, acute kidney injury (AKI) was defined as ≥ 0.3 mg/dl (26.52 μmol/l) increase in creatinine levels from baseline within 48 hours.12 The following parameters were collected retrospectively from clinical charts: (1) age; (2) gender; (3) smoking status; (4) presence of diabetes, hypertension, dyslipidaemia [serum highdensity lipoprotein cholesterol (HDL-C) < 40 mg/dl (1.04 mmol/l) and/or low-density lipoprotein cholesterol (LDL-C) > 130 mg/dl (3.37 mmol/l) and/or triglycerides > 300 mg/dl (3.39 mmol/l)], or ischaemic heart disease; (4) urinary output; (5) use of statins, acetylsalicylic acid (ASA), clopidogrel, low-molecularweight heparin (LMWH), angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB); (6) daily systolic, diastolic and mean arterial (2 × diastolic pressure + systolic pressure)/3) blood pressure measurement data; (7) haemoglobin, sodium, potassium, calcium, phosphorus, albumin, blood urea nitrogen (BUN), creatinine, and estimated glomerular filtration rate (eGFR) (MDRD equation) values.

Table 1. Clinical features of the patients Whole study group (n = 86)

Patients with AKI (n = 36)

65.82 ± 16.7

69.77 ± 12.9

64.24 ± 17.0

0.109

Male gender, n (%)

56 (66.2)

21 (58.3)

35 (70)

0.186

Diabetes mellitus, n (%)

48 (55.8)

22 (61.1)

26 (52)

0.221

Hypertension, n (%)

84 (97.6)

36 (100)

48 (96)

0.196

Ischaemic heart disease, n (%)

40 (46.5)

17 (47.2)

23 (46)

0.542

Dyslipidaemia, n (%)

24 (27.9)

10 (27.8)

14 (28)

0.589

Smoking habbit, n (%)

43 (50)

14 (38.9)

29 (58)

0.063

ASA, n (%)

57 (66.2)

20 (55.6)

37 (74)

0.045

Clopidogrel, n (%)

26 (30.2)

12 (33.3)

14 (28)

0.340

LMWH, n (%)

43 (50)

16 (44.4)

27 (54)

0.265

Statin, n (%)

18 (20.9)

8 (22.2)

10 (20)

0.354

ACEI, n (%)

32 (37.2)

14 (38.9)

18 (36)

0.469

ARB, n (%)

5 (5.8)

2 (5.5)

3 (6)

0.657

Mortality rate at 30 days’ follow up, n (%)

9 (10.4)

8 (22.2)

1 (2)

0.003

Age (years)

Patients without AKI (n = 50) p-value

ASA, acetylsalicylic acid; LMWH, low-molecular-weight heparin; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blocker.

Clinical and biochemical parameters were collected before (baseline), during (third day of infusion therapy) and after (two weeks after cessation of infusion therapy; 28th day) iloprost treatment, and mean values were determined as arithmetic means. Baseline values were defined as those measured at admission to the in-patient clinic. Office blood pressure levels were recorded.

Statistical analysis Statistical analyses were performed using SPSS software (Statistical Package for the Social Sciences, version 15.0, SPSS Inc, Chicago, IL, USA). Subjects were grouped according to the absence of AKI, as the normal renal function group (n = 50), and presence of AKI, as the AKI group (n = 36). Normality of data was analysed using the Kolmogorov– Smirnov test. All numerical variables with normal distributions were expressed as means ± standard deviations (SD), while variables with skewed distributions were expressed as medians and interquartile ranges (IR). Categorical variables were expressed as percentages and compared using the chi-squared test. Normally distributed numerical variables were analysed by the independent samples t-test, one-way ANOVA (post-hoc Tukey), or paired samples t-test. Numerical variables with a skewed distribution were compared using the Mann–Whitney U- and Kruskal– Wallis tests. Spearman and Pearson correlation tests were used for correlation analyses. A binary logistic regression analysis was performed to assess the major determinant of AKI between correlated variables. A Kaplan–Meier survival analysis was used Table 2. The laboratory parameters of the whole study group Laboratory parameters Glucose (mg/dl) (mmol/l) BUN (mg/dl) Creatinine (mg/dl) (μmol/l) Haemoglobin (g/dl) Sodium (mmol/l)

Initial

Third day of infusion

143.9 ± 69.7 (7.99 ± 3.87)

135.65 ± 49.39 (7.53 ± 2.74)

23.6 ± 13.7

30.0 ± 20.7

1.15 ± 0.60 1.53 ± 0.12 (101.66 ± 53.04) (135.25 ± 10.61)

Two weeks after infusion p-value 141.55 ± 66.2 (7.86 ± 3.67) 24.9 ± 13.5

0.062* 0.289§ 0.014* 0.458§

1.46 ± 0.10 (129.06 ± 8.84)

0.001* 0.001§

12.7 ± 2.1

11.8 ± 1.9

11.7 ± 1.6

0.236*§

134.9 ± 14.8

137.4 ± 4.9

137.1 ± 15.7

0.228* 0.117§

Potassium (mmol/l)

4.76 ± 0.78

4.11 ± 0.68

4.42 ± 0.92

0.406* 0.606§

Phosphorus (mg/dl)

3.45 ± 0.78

3.80 ± 2.18

3.87 ± 1.38

0.865* 0.185§

Calcium (mg/dl)

8.9 ± 0.6

8.8 ± 0.8

8.9 ± 1.4

0.307* 0.587§

Albumin (g/dl)

3.6 ± 0.7

3.4 ± 0.8

3.2 ± 0.7

0.339* 0.047§

52.48 ± 4.85

81.12 ± 4.67

67.05 ± 5.15

0.009* 0.125§

CRP (mg/dl) Urinary output (cm3/24 h)

1545.17 ± 873.00 1813.30 ± 1123.46 1447.32 ± 934.63

0.012* 0.406§

76.98 ± 35.57

71.16 ± 43.43

72.84 ± 53.39

0.01* 0.04§

122.97 ± 16.51

118.16 ± 26.41

121.71 ± 19.72

0.606* 0.117§

Diastolic blood pressure (mmHg)

74.37 ± 9.09

70.29 ± 14.94

71.20 ± 12.65

0.011* 0.025§

Mean arterial pressure (mmHg)

90.57 ± 10.5

86.25 ± 17.9

88.04 ± 14.3

0.024* 0.112

eGFR (MDRD) (ml/min/1.73 m2) Systolic blood pressure (mmHg)

p-value for initial vs at the third day of infusion; §p-value for initial vs two weeks after infusion. BUN, blood urea nitrogen; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate.

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to compare 30-day patient survival between the two groups. A p-value < 0.05 was considered statistically significant.

Results The clinical features of the patients are summarised in Table 1. According to KDIGO criteria, 36 (41.86%) patients were diagnosed with AKI on the third day of iloprost infusion therapy. Co-morbidities and drug use (ASA, clopidogrel, LMWH, statin, ACEI) rates were similar in those with and without AKI (Table 1). When the entire study group was analysed, serum creatinine levels recorded on the third and 28th day of treatment (1.53 ± 0.12 and 1.46 ± 0.1 mg/dl, respectively) (135.25 ±10.61 and 129.06 ± 8.84 μmol/l) were significantly higher than the baseline level [1.15 ± 0.6 mg/dl (101.66 ± 53.04 μmol/l), p = 0.001 for both]. The BUN level recorded on the third day (30.0 ± 20.7 mg/ dl) was significantly higher than the baseline level (23.6 ± 13.7 mg/dl, p = 0.014), as was the serum C-reactive protein (CRP) level (81.12 ± 4.67 vs 52.48 ± 4.85 mg/dl, p = 0.009). On the third day of the infusion, urinary output was significantly increased from the baseline value (1 813.30 ± 1 123.46 vs 1 545.17 ± 873.0 cm3, p = 0.012) while eGFR values were significantly lower compared to baseline levels (71.16 ± 43.43 vs 76.98 ± 35.57 ml/ min/1.73 m2, p = 0.01) (Table 2). All patients had a significant decrease from baseline in diastolic blood pressure on the third day of infusion therapy (70.29 ± 14.94 vs 74.37 ± 9.09 mmHg, p = 0.011). Patients’ mean arterial pressures were significantly

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decreased on the third day of therapy (90.57 ± 10.5 vs 86.25 ± 17.9 mmHg, p = 0.024). On the 28th day, eGFR values were significantly lower than baseline values (72.84 ± 53.39 vs 76.98 ± 35.57 ml/min/1.73 m2, p = 0.01) (Table 2). All patients had a significant decrease in diastolic blood pressure on the 28th day compared to baseline values (71.20 ± 12.65 vs 74.37 ± 9.09 mmHg, p = 0.025). A non-significant trend towards a lower blood pressure on the third and 28th days was observed (p > 0.05) (Table 2). According to data from the 28th day, renal function improved as BUN levels decreased to baseline values, while the creatinine level was high and eGFR was significantly lower (Table 2). Patients who developed AKI had significantly higher serum creatinine (p = 0.032) and CRP (p = 0.012) levels and significantly lower eGFR values (p = 0.05) at baseline compared to patients without AKI (Table 3). Those who developed AKI had significantly higher serum BUN (p = 0.001) and creatinine (p = 0.001) levels and lower eGFR (p = 0.001) and systolic (p = 0.015), diastolic (p = 0.014) and mean arterial (p = 0.039) blood pressure values on the third day of infusion compared to patients without AKI (Table 3). Serum glucose levels of patients with AKI were significantly higher both compared to their own baseline value (p = 0.042) and to the value of the third day of patients without AKI (p = 0.037) (Table 3). Patients who developed AKI had significantly higher serum creatinine (p = 0.001), BUN (p = 0.012), CRP (p = 0.001) and urinary output (p = 0.005) levels on the third day of infusion

Table 3. Laboratory parameters of the whole group Initial Laboratory parameters

Patients with AKI (n = 36)

Glucose (mg/dl) (mmol/l)

146.32 ± 67.9 (8.12 ± 3.77)

Third day of infusion

Patients without AKI (n = 50) p-value 141.21 ± 72.3 (7.84 ± 4.01)

Patients with AKI (n = 36)

Patients without AKI (n = 50) p-value

Patients with AKI (n = 36)

Patients without AKI (n = 50) p-value

120.46 ± 41.7 (6.69 ± 2.31)

146.20 ± 47.3 (8.11 ± 2.63)

0.037

133.17 ± 61.3 (7.39 ± 3.40)

147.10 ± 72.0 (8.16 ± 4.00)

> 0.05

44.88 ± 21.6

19.40 ± 8.28

0.001

33.08 ± 15.5

18.4 ± 9.1

0.001

0.012* 0.001§†

2.37 ± 1.26 (209.51 ± 111.38)

0.94 ± 0.3 (83.10 ± 26.52)

0.001

2.14 ± 1.11 (189.18 ± 98.12)

0.87 ± 0.3 (76.91 ± 26.52)

0.001

0.001* > 0.05§ 0.001†

22.4 ± 14.7

Creatinine (mg/dl) (μmol/l)

1.28 ± 0.60 (113.15 ± 53.04)

1.05 ± 0.5 (92.82 ± 44.20)

Haemoglobin (g/dl)

12.09 ± 2.1

13.04 ± 2.0

> 0.05

11.33 ± 1.8

12.06 ± 1.8

136.91 ± 4.0

0.032

> 0.05

11.88 ± 1.1

12.30 ± 1.6

> 0.05

p-values within the AKI group

> 0.05

26.0 ± 12.1

BUN (mg/dl)

Two weeks after infusion

> 0.05

0.042* > 0.05§†

> 0.05*§†

133.74 ± 19.1

> 0.05

138.05 ± 6.2

136.91 ± 3.4

> 0.05

139.16 ± 5.6

135.20 ± 20.3

> 0.05

> 0.05*§†

Potassium (mmol/l)

4.34 ± 0.5

4.19 ± 0.9

> 0.05

4.17 ± 0.6

4.07 ± 0.7

> 0.05

4.16 ± 0.8

4.17 ± 0.2

> 0.05

> 0.05*§†

Phosphorus (mg/dl)

3.72 ± 0.8

3.22 ± 0.6

> 0.05

4.28 ± 2.9

3.28 ± 0.5

> 0.05

4.60 ± 1.6

3.23 ± 0.7

> 0.05

> 0.05*§†

Calcium (mg/dl)

8.84 ± 0.5

8.93 ± 0.7

> 0.05

8.98 ± 1.09

8.67 ± 0.6

> 0.05

9.21 ± 1.9

8.78 ± 0.7

> 0.05

> 0.05*§†

Albumin (g/dl)

3.53 ± 0.6

3.73 ± 0.8

> 0.05

2.62 ± 1.0

3.42 ± 0.6

> 0.05

2.91 ± 0.7

3.62 ± 0.6

67.62 ± 7.7

40.38 ± 4.3

0.012 102.85 ± 9.7

70.67 ± 6.6

90.62 ± 8.7

52.80 ± 9.3

> 0.05

0.001* > 0.05§ 0.01†

1632.96 ± 648.2

> 0.05

0.005*§ > 0.05†

Sodium (mmol/l)

CRP (mg/dl)

Urinary output (cm3/24 h)

1242.91 ± 990.15 1663.37 ± 736.3

> 0.05 1503.20 ± 1267.09 1918.18 ± 827.1

0.012

0.004 1259.63 ± 986.0

0.001 > 0.05*§†

eGFR (MDRD)

70.22 ± 41.7

84.83 ± 34.3

0.05

36.04 ± 23.4

93.10 ± 40.2

0.001

40.68 ± 25.9

101.03 ± 52.84

Systolic blood pressure (mmHg)

121.6 ± 19.5

123.78 ± 14.5

> 0.05

106.8 ± 31.7

125.0 ± 10.8

0.015

116.2 ± 28.6

124.92 ± 20.1

71.8 ± 10.5

75.90 ± 7.8

> 0.05

61.2 ± 17.5

74.64 ± 8.2

0.014

65.4 ± 16.4

75.71 ± 9.9

0.001

0.023* > 0.05§ 0.002†

88.40 ± 12.5

91.86 ± 8.9

> 0.05

76.0 ± 21.6

91.42 ± 8.0

0.039

82.36 ± 19.9

92.11 ± 12.1

0.002

0.003* > 0.05§ 0.04†

Diastolic blood pressure (mmHg) Mean arterial pressure (mmHg)

p-value for initial vs on the third day of infusion; §p-value for initial vs two weeks after infusion; †p-value for third day vs two weeks after infusion. BUN, blood urea nitrogen; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate.

0.001 > 0.05

0.0001*† > 0.05§ 0.002* > 0.05§ 0.023†

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Table 4. Drug-related side effects Patients with AKI (n = 36)

Side effects

Patients without AKI (n = 50) p-value

Nausea, n (%)

9 (25)

3 (6)

0.172

Flushing, n (%)

1 (2.7)

1 (2)

0.660

Headache, n (%)

1 (2.7)

3 (6)

0.448

Thrombophylebitis, n (%)

compared to baseline values. Among patients who developed AKI, systolic (p = 0.002), diastolic (p = 0.023) and mean arterial pressures (p = 0.003) as well as eGFR (p = 0.0001) values were significantly lower on the third day of infusion compared to the baseline value (Table 3). Drug-related side effects were similar in both patient groups (Table 4). A binary logistic regression analysis of co-morbidities and drugs revealed that smoking, diastolic hypotension, and no ASA use were significant independent predictors (p = 0.02, p = 0.003 and p = 0.008, respectively) for the development of AKI during iloprost treatment. We also evaluated factors associated with 30-day mortality and compared survival ratios between the patient groups. The Cox regression analysis revealed that diabetes mellitus (p = 0.005) and AKI (p = 0.012) are significant determinants of mortality in patients undergoing iloprost infusion therapy. The Kaplan– Meier analysis revealed a significant difference in survival between patients with AKI and those without AKI (at 30-day follow up: 22.2 vs 2%, p = 0.001) (Fig. 1).

Discussion AKI refers to a rapid and reversible decrease in kidney function that develops within a period of hours or days. In this retrospective study, we assessed the relationship between laboratory and clinical parameters and subsequent changes in kidney function in patients with PAD who developed AKI after iloprost infusion therapy. We observed that iloprost infusion therapy led to hypotension (systolic, diastolic and mean arterial pressure) and a significant decline in eGFR. Patients who developed AKI were more likely to have worse renal function at the initiation of therapy than other patients. In the multivariate analysis, diastolic hypotension, smoking and lack of ASA treatment were independently associated with an increased risk of developing AKI. In addition, AKI was associated with a higher mortality rate at the 30-day follow up.

Cum survival

1.0

No AKI AKI

0.8

0.6 0.4 0.2 0.0

100

150

200

250

300

Days

Fig. 1. T he Kaplan–Meier survival analysis between patients with AKI and those without AKI (at 30-day follow up: 22.2 vs 2%, p = 0.001).

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In the kidney, prostaglandins uphold the balance between vasodilation and vasoconstriction to maintain homeostasis and physiological kidney function.13,14 Vasodilator prostaglandins have clinically important side effects that underscore their potential efficacy in the treatment of severe PAD.15 In experimental animal studies, iloprost preserved kidney function against anoxia in rabbits,16 and had beneficial effects in I/R-induced renal injury in a rat model.17 Furthermore, in a clinical study by Spargias et al., iloprost was successfully used to prevent contrast-mediated nephropathy.9 However, in these studies that reported iloprost to be a renoprotective agent, the selected doses were as low as 1–2 ng/kg/min and the infusion period lasted approximately four to six hours to avoid systemic hypotension, and dosing was not repeated.9,17-19 Hypotension is the principal, dose-dependent side effect of iloprost. There is evidence that such hypotension is a risk factor for the development of AKI and it is a commonly encountered problem in elderly patients with AKI,20-22 patients with pre-existing renal insufficiency,23,24 and patients with low cardiac output states such as myocardial infarction and congestive cardiac failure.24-26 We observed that patients who received iloprost had a significant decrease in systolic, diastolic and mean arterial pressure compared to baseline, and that relative diastolic hypotension was a significant risk factor for the development of AKI. In their study, Liu et al. showed an independent association between the relative decrease in systolic blood pressure and the development of AKI.27 Sutton et al.28 used an ischaemic rat model to demonstrate that the ‘initiation’ phase of AKI, during which renal blood flow is reduced, is the primary determinant of GFR.6 Similarly to these studies, our AKI patients had significantly lower diastolic blood pressure, causing decreased renal blood flow and leading to a decline in GFR. In patients with chronic kidney disease (CKD), the risk of developing AKI is significantly increased.29 Co-morbidities such as diabetes, hypertension and proteinuria in hospitalised patients were independently associated with an increased risk of AKI, requiring dialysis.29,30 Our patients with AKI showed significantly reduced renal function with significantly higher serum creatinine levels and lower eGFR at the initiation of iloprost treatment. These patients were more prone to develop AKI because of the kidney’s sensitivity to disrupted microperfusion or hypotensive ischaemia. Consistent with these findings, smoking and the lack of ASA use were significant independent predictors for the development of AKI in our patients. Smoking is a major preventable risk factor for atherosclerosis. Exposure to cigarette smoke activates a number of mechanisms predisposing to atherosclerosis, including thrombosis, vascular inflammation, abnormal vascular growth and angiogenesis.31-33 ASA, the fundamental therapy given for PAD, reduces the risk of cardiovascular events and arterial occlusion. The use of ASA for primary and secondary prevention of cardiovascular events in most patients with PAD is supported by excellent clinical evidence.34 Based on these data, we can speculate that the presence of smoking and absence of ASA use were associated with microvascular ischaemia, which made these patients more prone to hypotensive AKI. The mortality rate in AKI patients with CKD was 3.3 times higher than that of patients without CKD.35 In our study, patients with AKI had significantly higher mortality rates over

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30 days of follow up. In addition, according to our findings, diabetes mellitus and AKI were significant determinants of mortality in patients undergoing iloprost infusion therapy. This study has several limitations, many of which are inherent in its retrospective design, including the possibility of missing risk factors that could contribute to a confounding bias. In addition, renal imaging studies were unavailable for all patients. However, the association between iloprost-induced hypotension and AKI was independent and clear. Our results clearly illustrate that relative hypotension may play a key role in the development of AKI during iloprost infusion therapy in patients with altered renal function.

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1749–1751. 8.

Sketch MH Jr, Whelton A, Schollmayer E, et al for the Prostaglandin E1 Study Group. Prevention of contrast media-induced renal dysfunction with prostaglandin E1: a randomized, double-blind, placebo-controlled study. Am J Ther 2001; 8: 155–162.

Spargias K, Adreanides E, Giamouzis G, et al. Iloprost for prevention of contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure. Results of a randomized pilot study. Eur J Clin Pharmacol 2006; 62(8): 589–595.

10. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007; 357(8): 797–805. 11. Spargias K, Adreanides E, Demerouti E, et al. Iloprost prevents contrast-induced nephropathy in patients with renal dysfunction under-

Conclusion We conducted a retrospective study to evaluate the risk factors for AKI development and mortality in patients with severe PAD treated with iloprost. We found that patients who developed AKI were more likely to have relative decreases in systolic, diastolic and mean arterial pressures and worse baseline renal function than unaffected patients. We suggest that patients with a smoking habit and those not using ASA are at an increased risk for AKI. In this group of patients we advise iloprost dose reduction and close follow up for evidence of AKI, and discontinuation of iloprost in patients with severe hypotension. As patients with AKI have a higher mortality risk, we suggest that iloprost treatment should be given to selected patients. From our findings, we advise that iloprost should be avoided as it is very likely to cause AKI in patients with CKD or low blood pressure. In addition, we recommend iloprost dose reduction or possible discontinuation for patients receiving iloprost who show evidence of AKI or hypotension. Ultimately, prospective, randomised studies will be needed to address the effects of iloprost infusion therapy on renal outcomes in patients with severe PAD.

going coronary angiography or intervention. Circulation 2009; 120(18): 1793–1799. 12. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2012; 2(Suppl): 1–138. 13. Johannes T, Ince C, Klingel K, Unertl KE, Mik EG. Iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat. Crit Care Med 2009; 37(4): 1423–1432. 14. Nasrallah R, Nusing RM, Hebert RL. Localization of IP in rabbit kidney and functional role of the PGI(2)/IP system in cortical collecting duct. Am J Physiol Renal Physiol 2002; 283: F689–F698. 15. Rozhkov V, Wilson D, Vinogradov S. Phosphorescent Pd porphyrindendrimers: Tuning core accessibility by varying the hydrophobicity of the dendritic matrix. Macromolecules 2002; 35: 1991–1993. 16. Turker RK, Demirel E, Ercan ZS. Iloprost preserves kidney function against anoxia. Prostaglandins Leukot Essent Fatty Acids 1988; 31: 45–52. 17. Mizutani A, Okajima K, Uchiba M, et al. Antithrombin reduces ischemia/ reperfusion induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood 2003; 101: 3029–3036. 18. Isobe H, Okajima K, Uchiba M, Harada N, Okabe H. Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of

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Nephrol Dial Transplant 2000; 15: 212–217. 21. Santacruz F, Barreto S, Mayor MM, Cabrera W, Breuer N. Mortality in elderly patients with acute renal failure. Ren Fail 1996; 18: 601–605. and prognosis of acute renal failure in the very old. J Am Geriatr Soc 1998; 46: 721–725.

Kiris I, Tekin I, Yilmaz N, Sutcu R, Karahan N, Ocal A. Iloprost down-

23. Liano F, Pascual J. Madrid Acute Renal Failure Study Group.

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Ozcan AV, Sacar M, Aybek H, et al. The effects of iloprost and vitamin C on kidney as a remote organ after ischemia/reperfusion of lower extremities. J Surg Res 2007; 140: 20–26. Tumlin JA. Impaired blood flow in acute kidney injury: pathophysiology and potential efficacy of intrarenal vasodilator therapy. Curr Opin Crit Care 2009; 15(6): 514–519.

acute renal failure in the elderly: a hospital-based prospective study.

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induced by abdominal aortic ischemia-reperfusion. Ann Vasc Surg 2009; 5.

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Fink AN, Frishman WH, Azizad M, Agarwal Y. Use of prostacyclin 1999; 1: 29–40.

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McCullough PA, Tumlin JA. Prostaglandin-based renal protection against contrast-induced acute kidney injury. Circulation 2009; 120(18):

nity based study. Kidney Int 1996; 50: 811–818. 24. Fonarow GC, Heywood JT. The confounding issue of comorbid renal insufficiency. Am J Med 2006; 119: S17–S25. 25. Zanchetti A, Stella A. Cardiovascular disease and the kidney: an epidemiologic overview. J Cardiovasc Pharmacol 1999; 33(Suppl 1): S1–S6; discussion S41–S43. 26. Wencker D. Acute cardio-renal syndrome: progression from congestive heart failure to congestive kidney failure. Curr Heart Fail Rep 2007; 4: 134–138. 27. Liu YL, Prowle J, Licari E, Uchino S, Bellomo R. Changes in blood

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Conﬁdence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 References: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). S4 XARELTO ® 10 (Film-coated tablets). Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. S4 XARELTO ® 15 and XARELTO ® 20 (Film-coated tablets). Reg. No.: XARELTO ® 15: 46/8.2/0111; XARELTO ® 20: 46/8.2/0112. Each film coated tablet contains rivaroxaban 15 mg (XARELTO ® 15) or 20 mg (XARELTO ® 20). PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM.01.2016.1265 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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Changes in cardiac structure and function in a modified rat model of myocardial hypertrophy Wenjun Dai, Qi Dong, Minsheng Chen, Luning Zhao, Ailan Chen, Zhenci Li, Shiming Liu

Abstract Aim: In this study we designed a modified method of abdominal aortic constriction (AAC) in order to establish a stable animal model of left ventricular hypertrophy (LVH). We also evaluated cardiac structure and function in rats with myocardial hypertrophy using echocardiography, and provide a theory and experimental basis for the application of drug interventions using the LVH animal model. We hope this model will provide insight into novel clinical therapies for LVH. Methods: The abdominal aorta of male Wistar rats (80–100 g) was constricted between the branches of the coeliac and anterior mesenteric arteries, to a diameter of 0.55 mm. Echocardiography, using a linear phase array probe, combined with histology and plasma BNP concentration, was performed at three, four and six weeks post AAC. Results: The acute (24-hour) mortality rate was lower (8%) than in previous reports (15%) using this modified rat model. Compared with shams, animals who underwent AAC demonstrated significantly increased interventricular septal (IVS), LV posterior wall (LVPWd), LV mass index (LVMI), crosssectional area (CSA) of myocytes, and perivascular fibrosis; while the ejection fraction (EF), fractional shortening (FS) and cardiac output (CO) were consistently lower at each time interval. Notably, differences in these parameters between the AAC and sham groups were significant by three weeks and reached a peak at four weeks. Following AAC, plasma B-type natriuretic peptide (BNP) level was gradually elevated, compared with the sham group, between three and six weeks. Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Wenjun Dai, MD Shiming Liu, MD

Department of Physiology, Guangzhou Medical University, Guangzhou, China Qi Dong, MD

Guangzhou Institute of Cardiovascular Disease, Guangzhou, China Minsheng Chen, MM, gzminsheng@vip.163.com Wenjun Dai, MD Shiming Liu, MD

Department of Medical Experimental Centre, Guangzhou Medical University, Guangzhou, China Luning Zhao, MB BS

Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Ailan Chen, MD

Department of Cardiology, The First Municipal People’s Hospital of Guangzhou affiliated to Guangzhou Medical College, Guangzhou, China Zhenci Li, MD

Conclusion: This modified AAC model induced LVH both stably and safely by week four post surgery. Echocardiography was accurately able to assess changes in chamber dimensions and systolic properties in the rats with LVH. Keywords: AAC, myocardial hypertrophy, echocardiography, rat Submitted 20/1/13, accepted 2/7/15 Cardiovasc J Afr 2016; 27: 134–142

www.cvja.co.za

DOI: 10.5830/CVJA-2015-053

The development of left ventricular hypertrophy (LVH) is an adaptive response to pressure overload. Clinically, sustained hypertrophy is correlated with an increase in incidence of cardiovascular disease (CVD)-mediated mortality, and is often the initial step in the progression to congestive heart failure. Cardiac hypertrophy is also a risk factor for arrhythmia and sudden cardiac death. In order to develop therapeutic approaches to prevent LVH, it is important to elucidate the precise mechanisms and time course of the development of LVH. Animal models of hypertrophy are critically important for studies on the pathogenesis of LVH, its pathological processes and therapeutic strategies for treatment and/or prevention of LVH. Abdominal aortic constriction (AAC) is the most widely used strategy to induce pressure overload leading to compensatory myocardial hypertrophy. Several important factors may affect the time course and progression of myocardial hypertrophy caused by pressure overload, such as species and age of animals, anatomical sites of constriction, overload duration, and the degree of stenosis.1,2 In previous studies, most investigators constricted the abdominal aorta above the left renal artery in adult rats. Based on the anatomy of the abdominal aorta in rats, there are two large arterial branches anterior to the left renal artery, the coeliac and anterior mesenteric arteries. The constriction site relative to these arterial branches may affect progression to myocardial hypertrophy.3-6 Recent reports have noted that younger animals fare better than adults following the AAC procedure,2 since younger animals may have a narrower abdominal aorta, leading to suboptimal restriction and less myocardial hypertrophy and AAC-mediated surgical mortality. In this study, we modified the traditional methods of AAC to evaluate banding severity, banding location, age and time course. We also explored an optimal method to induce myocardial hypertrophy in rats. To date, most studies have used smallanimal echocardiographic systems or clinical echocardiography instruments coupled with miniature transducers to detect ventricular structural and functional changes in rats. This specialised equipment increases the cost of experiments.2-4,7 In order to reduce these costs, we evaluated the possibility of using a standard human ultrasound probe, which is commonly

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found in hospitals, to investigate cardiac changes in sham rats or rats with ACC-induced myocardial hypertrophy by using an extensive analysis, including echocardiography, heart and left ventricular mass, cardiomyocyte area, plasma B-type natriuretic peptide (BNP) concentration, and interstitial and perivascular fibrosis. BNP is a circulating hormone produced in the heart, primarily by ventricular cells. This hormone is mainly secreted in response to increases in ventricular wall stress, such as ventricular hypertrophy, and it is detectable at high concentrations in a number of circumstances, including cardiac ischaemia and severe heart failure.8 In addition, the expression of BNP is significantly increased in animal models of chronic haemodynamic overload. Therefore, we measured blood BNP concentrations to enhance our understanding of BNP secretion in both AAC and sham rats sequentially, as a marker to evaluate the extent of cardiac hypertrophy. The primary goals of this study were to modify the AAC procedure in order to establish a safer and more stable LVH model in rodents, evaluate the utility of standard human ultrasound probes to detect structural and functional changes in rats with cardiac hypertrophy, and provide a theoretical and experimental foundation for the application of novel drug interventions aimed at interfering with clinical LVH.

Methods Fifty male Wistar rats (80–100 g) were used in all experiments. They were allowed standard laboratory chow and tap water ad libitum and housed in stable conditions at 22°C with a 12-hour light/dark cycle for one week prior to AAC surgery. All procedures were performed in accordance with institutional guidelines for animal research. After a one-week acclimatisation, the AAC surgery was performed. All experimental rats were weighed prior to surgery, and at three, four and six weeks post surgery. Echocardiographic studies were conducted at three, four and six weeks post surgery. For LV weight and histological measurements, rats were sacrificed following echocardiography, and blood samples were collected from the right carotid artery for enzyme-linked immunosorbent assay (ELISA) analyses of plasma BNP concentrations. AAC was induced in outbred male rats, as previously described.9 In brief, the animals were anesthetised with sodium pentobarbital (45 mg/kg, i.p.). The abdominal aorta proximal to the left renal artery was exposed and separated from the vena cava. A 2-0 silk suture was tied, using a blunt 24-G probe (the external diameter was 0.55 mm), beside the aorta between the branches of the coeliac and anterior mesenteric arteries. The probe was removed, leaving the vessel constricted to a diameter of 0.55 mm. Saline (1 ml) was administered into the peritoneal cavity in order to replenish any fluid loss, and the abdominal wall and skin were sutured closed. All rats were allowed to recover on a warming pad. The same procedure was performed in the sham animals except that the silk suture around the aorta was pulled through and not tied. Following surgery, 50 mg/kg, i.m. ampicillin was administered once daily for three days after surgery to prevent infection. The day following surgery, the sham and AAC animals were randomly divided into six groups as follows: (1) sham for three weeks (n = 8); (2) sham for four weeks (n = 8); (3) sham for six

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weeks (n = 8); (4) AAC for three weeks (n = 8); (5) AAC for four weeks (n = 8); (6) AAC for six weeks (n = 10).

Echocardiographic studies Echocardiographic studies were performed between 16:00 and 20:00, with the animals in the left lateral decubitus position, using sodium pentobarbital (45 mg/kg, i.p.) for anaesthesia. The IE 33 echocardiographic system (Philips Medical Systems, Nederland BV) was used to perform two-dimensional (2D) guided M-mode echocardiography and pulse-wave Doppler echocardiography with a linear-phase array probe (L15-7io; frequency range 7–15 MHz), which was placed on the shaved left hemithorax. 2D images of the heart were obtained in the parasternal long-axis view, followed by the short-axis and apical four-chamber views. M-mode echocardiography is useful for assessing LVH, allowing accurate measurements of wall thickness and LV dimensions during systole and diastole. For M-mode recordings, the parasternal long-axis view was used to image the heart in 2D, with a depth setting of 2 cm. M-mode recordings were then analysed at a sweep speed of 66 mm/s, with the axis of the probe aligned near the posterior leaf mitral valve. The following parameters were measured: LV posterior wall (LVPW) dimensions during both diastole and systole (LVPWd and LVPWs, respectively), interventricular septal (IVS) dimensions during both diastole and systole (IVSd and IVSs, respectively), LV internal dimensions (LVID) during both diastole and systole (LVIDd and LVIDs, respectively), LV end-diastolic volume (EDV), LV end-systolic volume (ESV), percentage LV fractional shortening (FS), LV ejection fraction (EF), cardiac output (CO), and heart rate (HR). LV mass (LVm) was obtained from echocardiography and derived from the cubic equation at the end of diastole: LVm = 1.04 × [(LVIDd + LVPWd + IVSd)3 – LVIDd3] × 0.8 + 0.14.10 All data are means of three consecutive cardiac cycles. 2D guided M-mode recordings were obtained from the parasternal short-axis view of the left ventricle at the level of the papillary muscles. The angle of the M-mode beam was focused on the middle of the LV, and aligned at the anteroposterior axis, perpendicular to the LV walls. Parameters and methods were the same as in the parasternal long-axis view, except that the thickness of the LV anterior wall (LVAW) was obtained instead of IVS. To assess inflow and outflow of the left ventricle, Doppler recordings were acquired in the apical four-chamber view to obtain inflow values parallel to the sample volume. Pulse-wave Doppler (PWD) recordings were acquired with the sample volume placed midway between the mitral and aortic valves to determine the velocity of mitral inflow and aortic outflow. PWD spectra of mitral inflow were recorded with the sample volume placed at the tips of the mitral valve leaflets and adjusted to the position at which velocity was maximal, with the sample volume set to the smallest size available (1 mm). Due to the high heart rates of rodents, which caused fusion of the E and A waves, diastolic function was not evaluated using Doppler imaging. LV outflow velocity was recorded from the apical long-axis view, with the sample volume positioned just below the aortic

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valve. The Doppler beam was set within 30° of the incident angle, to the aortic direction. Values for statistical analyses were averaged data collected from three to five cardiac cycles. Colour-flow Doppler images were obtained by centering the sampling area in the region of interest, thus making it possible to evaluate valvular dysfunction. The same method was used to measure diameters of the abdominal aorta via the aortic longaxis view. All measurements were performed in accordance with the leading-edge method of the American Society of Echocardiography.11 Images were stored digitally on magnetooptical discs (DICOM).

Morphological analyses Rat hearts were harvested by cardiectomy and perfused in 30 ml of ice-cold phosphate-buffered saline to wash out any remaining blood. The total mass of the hearts and mass of the right and left ventricles were obtained. Heart mass index (HMI) and LV mass index (LVMI) were determined as the ratio of LVm (in mg) to body weight (in g). The left ventricle was then cut into four pieces along the longitudinal axis. Three sections were immediately frozen in liquid nitrogen and one was fixed in 10% formalin for histological analysis. Tissues were dehydrated through serial alcohol immersions, cleared in xylene and embedded in paraffin. They were then cut into three to five 5-μm-thick sections for each animal. For cardiomyocyte size measurements, the samples were stained with haematoxylin/eosin (HE) and Masson trichrome (MT), as previously described,12 for the evaluation of interstitial and perivascular fibrosis. To quantify cardiomyocyte hypertrophy, about 30 myocytes were selected randomly per section, at 400 × magnification, and digitally imaged. The cross-sectional area of the cardiomyocytes was measured using Image Pro Plus software (Media Cybernetics, Carlsbad, CA). Quantitative measurement of the perivascular fibrosis area was calculated as the ratio of the fibrosis area surrounding the vessel wall to the total vessel area using Image Pro Plus software. At least 10 arterial cross sections were examined per heart. The area of interstitial fibrosis was identified, after excluding the vessel area from the region of interest, as the ratio of interstitial fibrosis to the total tissue area. At least three sections were examined per heart. A

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For ELISA analyses, blood was collected into tubes containing heparin from the right carotid artery of the rats and immediately centrifuged at 1 000 × g for 15 minutes. The plasma supernatant was collected and maintained at −80°C for BNP concentration determinations, using ELISA assays with a specific BNP kit (Cusabio).

Statistical analyses All data are expressed as mean ± SD. One-way analysis of variance (ANOVA) was performed to compare the AAC and sham groups. When the probability value was statistically significant, a least-significant-difference (LSD) t-test was applied for multiple comparisons. Linear regression analysis was used to evaluate correlations between LVm by echocardiography and the actual weights from sacrificed rats. SPSS V19 was used for statistical analyses. A probability value of p < 0.05 was considered statistically significant.

Results Fifty rats were initially enrolled in this study. After the surgery (same day as surgery), the mortality rate for the experimental pressure overload was 8% (two rats died), and there were no fatalities in the sham groups. Three days after surgery, 41 rats remained in the study, including 22 sham controls and 19 AAC rats. No additional fatalities occurred over the duration of the experiment. Following AAC surgery, the abdominal aortas were constricted in diameter by 37% (~ 0.06 ± 0.01 cm) relative to the aorta, measured using echocardiography (Fig. 1). Fig. 2 shows a typical 2D echocardiogram of the heart obtained via the parasternal long-axis view of the LV to compare cardiac structures between the sham and AAC groups at three, four and six weeks. Fig. 3 demonstrates the M-mode changes that occurred in the LVID, IVS and LVPW dimensions during both diastole (Fig. 3A, C, E) and systole (Fig. 3B, D, F), as well as in EDV and ESV (Fig. 3G, H). IVS (Fig. 3C, D) was significantly increased A

Fig. 1. A bdominal aortic constriction. A: sham rats, B: AAC rats, C: sham rats using colour Doppler, D: AAC rats using colour Doppler.

Fig. 2. Parasternal long-axis view of the left ventricle. A: sham rats at six weeks, B: AAC rats at three weeks, C: AAC rats at four weeks, D: AAC rats at six weeks.

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in AAC rats as early as three weeks post surgery, compared to the controls. This trend continued to four weeks, when the AAC rats exhibited wall thickening of 193% at diastole (137% at systole) compared to the sham values. In addition, the AAC rats A

exhibited significant thickening of LVPWd at three weeks, which progressed to 143% of the control values at four weeks. In the AAC rats, IVS and LVPWd were significantly increased at all time points, reaching a maximum at four weeks. At six B

0.60

0.40

0.55

0.30 LVIDs (cm)

LVIDd (cm)

0.35

0.50 0.45 0.40 **

0.35 0.30

0.20 0.15 Sham

0.05

AAC 2

0.25

0.10

Sham

0.25 0.20

0.00

AAC 2

Weeks

0.30

** ** IVSs (cm)

IVSd (cm)

0.25 0.20 0.15 0.10

Sham

0.05

AAC 2

0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00

Sham AAC 2

LVPWs (cm)

LVPWd (cm)

0.25 0.20 0.15 Sham

0.05 0.00

Sham AAC 2

0.60 0.40 AAC 4 Weeks

0.06 0.04 0.02

Sham

0.08 ESV (ml)

IVS/LVPW

0.80

0.10

1.00

0.00

4 Weeks

0.20

0.00

1.20

0.30

Weeks

0.40

0.10

AAC 2

0.50

0.10

0.60

0.30

Weeks

0.40 0.35

Weeks

4 Weeks

0.35

0.00

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0.00

Sham AAC 2

4 Weeks

Fig. 3. M -mode echocardiographic examination of diastolic dimensions (A, C, E, G) and systolic dimensions (B, D, F, H) in sham and AAC rats; *p < 0.05 vs sham control, **p < 0.01 vs sham control. The n values are given for each group at three, four and six weeks in sequential order. ANOVA was used to compare the AAC and sham groups, when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

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100

40 30

EF (%)

FS (%)

20 Sham

10 0

40 20

AAC 2

Sham AAC 2

Weeks

0.10

430 HR (bpm)

CO (l/min)

440

0.08 0.06 ** Sham

0.02

420 410 400 390

** 5

Sham

380

AAC 2

450

0.12

0.04

4 Weeks

0.14

0.00

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370

AAC 2

Weeks

4 Weeks

Fig. 4. F S (A), EF (B), CO (C) and HR (D) of AAC models. *p < 0.05 vs sham control, **p < 0.01 vs sham control. The n values are given for each group at three, four and six weeks in sequential order. ANOVA was performed to compare the AAC and sham groups when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

weeks post AAC, IVSd and LVPWd were decreased to 177% and 141% of the sham values, respectively. IVSs remained at the same level at four and six weeks post AAC, which was 137% of the control values. In the AAC rats, LVPWs were significantly increased (112–129% of the sham values) four weeks post surgery, a trend that continued to six weeks. Subsequently, the AAC rats had no marked chamber dilatation; however, some time points showed statistically significant yet marginal increases in ESV and IVIDs (at four weeks), and EDV and LVIDd were decreased significantly at three weeks post AAC. Fig. 4 shows the changes in FS, EF, CO and HR that occurred

PFVA (cm/s)

140

120

100

80 60 **

40 Sham

20 0

80 **

4 Weeks

40 Sham

AAC 2

E wave (cm/s)

over the six-week time course in both sham and AAC rats. In the AAC rats, reduced systolic function was first noted at three weeks post surgery, with significant reductions in FS and EF (Fig. 4A, B). Both of these trends continued to four weeks, where these parameters in the AAC group were markedly decreased (FS: 54.9 ± 6.5% for sham vs 32.3 ± 10.9% for AAC; EF: 89.4 ± 4.0% for sham vs 65.3 ± 15.2% for AAC). FS and EF had slightly recovered at six weeks, but were still decreased compared with the sham values (FS: 46.6 ± 5.0% for sham vs 43.7 ± 14.5% for AAC; EF: 83.0 ± 4.8% for sham vs 77.9 ± 14.2% for AAC). These differences did not reach statistical significance.

AAC 2

Weeks

Fig. 5. T ime course of velocity parameters obtained using Doppler echocardiography in both sham and AAC rats. PFVA, peak flow velocity of aorta; E wave, peak early diastolic filling velocity. *p < 0.05 vs sham control, **p < 0.01 vs sham control. The n values are given for each group at three, four and six weeks in sequential order. ANOVA was performed to compare the AAC and sham groups, when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

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Table 1. General characteristics of the sham and AAC rats Three weeks

Four weeks

Six weeks

Sham (n = 7)

AAC (n = 6)

Sham (n = 8)

AAC (n = 6)

Sham (n = 7)

AAC (n = 7)

LV weight (g)

0.47 ± 0.04

0.62 ± 0.08**

0.46 ± 0.04

0.86 ± 0.04**

0.53 ± 0.03

0.81 ± 0.17**

Heart weight (g)

0.58 ± 0.04

0.71 ± 0.09**

0.57 ± 0.05

1.02 ± 0.07**

0.65 ± 0.03

0.95 ± 0.19**

Body weight (g)

189 ± 17

216 ± 17

201 ± 5

246 ± 17

217 ± 30

LVMI (mg/g)

2.46 ± 0.16

2.13 ± 0.06

4.28 ± 0.13**

2.15 ± 0.10

3.72 ± 0.65**

Parameter

HMI (mg/g) LV weight (g)a

173 ± 13 3.55 ± 0.23**

3.07 ± 0.16

4.11 ± 0.22**

2.65 ± 0.07

5.07 ± 0.26**

2.65 ± 0.13

4.40 ± 0.71**

0.496 ± 0.099

0.625 ± 0.160*

0.464 ± 0.085

0.849 ± 0.081**

0.513 ± 0.100

0.810 ± 0.359**

LV mass was calculated in vivo using echocardiography. *p < 0.05 vs sham control, **p < 0.01 vs sham control.

CO was measured in order to differentiate between highand low-output failure (Fig. 4C). In the AAC rats, CO was significantly decreased at the three-week time point, and was less than half (55% of sham values) by six weeks. HR was not significantly different between the two groups (Fig. 4D). Using Doppler echocardiography, as shown in Fig. 5, peak flow velocity of the aorta (PFVA) was significantly decreased compared to the sham group from four to six weeks in the AAC rats. Additionally, the E wave was significantly decreased in the AAC rats at all time points, beginning as early as three weeks post surgery (Fig. 5B). As shown in Table 1, LVMI in the AAC animals was significantly increased as early as three weeks post surgery, and remained elevated compared to the sham controls. The same trend was observed in HMI (p < 0.01). By four weeks post AAC, the ratio of LVMI and HMI were markedly increased, reaching 201 and 191% of the sham values, respectively. At all time points, the AAC model caused no significant difference in body weight compared to their respective sham controls. In this pressure overload model, LVm values obtained using echocardiography were consistent with the actual tissue weights, with a correlation coefficient of 0.997 (Table 1, Fig. 6). Fig. 7 shows morphometric images and data from three, four and six weeks post surgery, comparing myocyte crosssectional area (CSA) between the sham and AAC animals with H&E-stained sections. Pressure overload induced a profound cardiomyocyte hypertrophy in the ACC rats compared with the shams, with a 376% increase in CSA at three weeks, 515% at four weeks, and 294% at six weeks.

Calculated LVm (g)

0.9 0.8 0.7 0.6 0.5 0.4

0.4

0.5

0.6

0.7

0.8

0.9

Interstitial and perivascular fibrosis measurements are presented in Figs 8 and 9. The degree of interstitial fibrosis was elevated in the AAC group compared to the control group at all time points, but did not reach statistical significance (Fig. 8). In the AAC group, perivascular fibrosis was significantly increased at all time points, especially at four weeks (269% of sham values) (Fig. 9). Plasma BNP levels were significantly increased in a timedependent manner in the AAC group compared to the sham group (p < 0.01, Table 2). BNP plasma concentrations in the AAC group at six weeks post AAC surgery were 1.37-fold the level observed at four weeks. However, there were no significant differences in the sham groups between BNP concentrations at four and six weeks post surgery.

Discussion LV pressure overload can be induced by constricting the ascending aorta, aortic arch or the abdominal aorta in rats, mice or dogs.13 AAC is a model of chronic pressure overload that promotes LVH. In previous studies, adult rats weighing 200–300 g3,4,14 were typically used to create the AAC model; however, younger rats weighing 80–100 g were used in our study. The main advantage of using young animals is to produce overload pressure gradually via aortic constriction as the animals age, which is similar to the chronic process of cardiac hypertrophy caused by hypertension.2 Our preliminary study confirmed that constricting the abdominal aorta between the branches of the coeliac and anterior mesenteric arteries was more effective than constricting the aorta above the coeliac artery, and was associated with lower mortality rates and no difference in the timing and progression to myocardial hypertrophy. Both methods are better than constricting the abdominal aorta above the left renal artery for the development of myocardial hypertrophy. In the present study, we constricted the abdominal aorta between the branches of the coeliac and anterior mesenteric arteries to a diameter of 0.55 mm, rather than constriction above the left renal artery to a diameter of 0.80 mm, as in most previous studies.3-6 Pressure-overload LVH has previously been induced using AAC for six weeks.15 However, in our experiment, after three weeks, the rats developed significant cardiac hypertrophy with

Actual LVm (g)

Fig. 6. L inear regression analyses of actual heart weights versus LVm values calculated in vivo using echocardiography at all points. Data at each point are the average weights of AAC and sham groups at three, four and six weeks, respectively.

Table 2. BNP plasma concentration in sham and AAC rats Groups

Three weeks

Four weeks

Sham (pg/ml)

117.23 ± 10.49

116.34 ± 8.03

113.72 ± 10.71

AAC (pg/ml)

477.69 ± 22.76**

577.22 ± 24.31**

653.29 ± 25.99**

**p < 0.01 vs sham control

Six weeks

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1000

G Sham

AAC

800 600

400 200 0

Weeks

Interstitial fibrosis (%)

Cell CSA (mm2)

Sham

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AAC

8 6 4 2 0

Weeks

Fig. 7. A ssessment of cardiomyocyte cross-sectional area (CSA). (A–F) H&E staining (× 400) and myocyte cross-sectional area. Data are presented as mean ± SEM. **p < 0.01 vs sham control. A: sham rats at three weeks, B: sham rats at four weeks, C: sham rats at six weeks, D: AAC rats at three weeks, E: AAC rats at four weeks, F: AAC rats at six weeks, G: comparison of cardiomyocyte CSA between the sham and AAC groups. ANOVA was performed to compare the AAC and sham groups when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

Fig. 8. Comparison of interstitial fibrosis between sham and AAC groups using Masson trichrome staining (A–F) (× 200). Data are presented as mean ± SEM. All p-values are > 0.05 vs sham control. A: sham rats at three weeks, B: sham rats at four weeks, C: sham rats at six weeks, D: AAC rats at three weeks, E: AAC rats at four weeks, F: AAC rats at six weeks, G: quantitative analysis of interstitial fibrosis between the sham and AAC groups. ANOVA was performed to compare the AAC and sham groups when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

a lower acute (24-hour) mortality rate (8% compared with 15%) than in previous reports.3,5 Furthermore, the length of the abdominal aorta between the branches of the coeliac and anterior mesenteric arteries is short, therefore the constriction site is circumscribed. Our approach was favourable compared with the traditional method, which defined the constriction site above the left renal artery branch of the abdominal aorta, because there are two major branches here (coeliac and anterior mesenteric arteries), and the constriction site relative to these branches could impact on the progression to myocardial hypertrophy, as describe above.

Therefore, development of myocardial hypertrophy in our study was more stable than in traditional methods. For monitoring changes in hearts subjected to dynamic pressure overload, we used echocardiographic measurements. Echocardiography is a non-invasive method routinely used to investigate changes in cardiac structure and function in various disease states. Echocardiography allows repetitive, non-invasive evaluation in a single live animal, as well as serial determination of cardiac structure and function to follow disease progression and response to therapeutic interventions. This method is far superior and more physiologically relevant than invasive

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Perivascular fibrosis (PVF/VA)

Sham

AAC

3 2 1 0

Weeks

Fig. 9. C omparison of perivascular fibrosis between the sham and AAC groups using Masson trichrome staining (A–E) (× 200), (E) (× 100). Data are presented as mean ± SEM. *p < 0.05 vs sham control, **p < 0.01 vs sham control. A: sham rats at three weeks, B: sham rats at four weeks, C: sham rats at six weeks, D: AAC rats at three weeks, E: AAC rats at four weeks, F: AAC rats at six weeks, G: quantitative analysis of perivascular fibrosis between the sham and AAC groups. ANOVA was performed to compare the AAC and sham groups when the probability value was statistically significant. An LSD t-test was applied for multiple comparisons.

techniques that require open-chest procedures and intubation of vessels, offering no opportunity for time-course studies, since they require time-consuming surgeries, with subsequent euthanasia. The Sonos 5500 echocardiographic system,2-4,7 a universal type of echocardiography instrument used in clinics, is commonly equipped with a high-frequency transducer that can be used for rodent studies. This study is the first report to use a standard echocardiographic system (IE 33) to assess cardiac structure and function in rats with myocardial hypertrophy. The IE 33 system

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can clearly show parasternal long-axis and short-axis views, apical four-chamber views of the LV, and the abdominal aorta in rats without requiring an extra transducer. This reduces the cost of investigation in small animals. Concentric myocardial hypertrophy is a hallmark of chronic pressure overload. Increased ventricular wall thickness induced by overload pressure is initially beneficial to maintain normal cardiac function. However, the heart could convert to heart failure with LV dilatation if the hypertrophic stimulus is maintained. In our study, significant increases in LVPW and IVS with only small decreases in LVIDs were indicative of pure concentric hypertrophy, which is often observed during the early stages of pure pressure overload. Most previous studies have shown late-stage chamber dilatation, signifying the end of the compensatory response and the start of heart failure.16 However, in this study, even at six weeks post surgery, there was little change in LVIDs, LVIDd, EDV and ESV, indicating chamber dilatation and dysfunction in ventricular relaxation were not present at this stage of hypertrophy. FS and EF are commonly used parameters to evaluate systolic function, which is determined by measuring LV end-diastolic and end-systolic diameters with M-mode echocardiography. Since increased afterload may depress stroke volume (SV) in AAC rats, FS and EF were lower in the AAC rats compared to sham rats from three to six weeks. Accordingly, significant decreases in CO were observed in AAC rats, especially at the four-week time point, since CO may be affected by HR and EF (both reduced in the AAC groups). In this study, we measured PFVA and E waves using echocardiography to evaluate ventricular relaxation and diastolic function. Significant decreases in PFVA and E-wave values in the AAC rats suggested restrictive filling, which may result from the combined effect of elevated ESV and impaired compliance due to wall thickening and/or fibrosis.17 Although E/A ratio is a marker for ventricular relaxation, it could not be obtained in this study since the E and A waves were fused in the rats due to their extremely fast heart rates. To distinguish E and A waves, Kokubo et al.7 used ketamine hydrochloride and xylazine anaesthesia in the animals in order to decrease the HR to 70–80% of normal levels in conscious animals, however control of HR is difficult. In rats, the heart generally gains ~ 1 g in weight with each 2-mm increase in LV wall thickness. Progressive increases in heart weight, HMI and LVMI, and increased cross-sectional areas of the myocytes (determined using histological analysis) were observed in the ACC rats. Elliott et al.3 found that echocardiographic determination of LVm is relatively accurate, yet highly overestimated in rats. As LVm increases, a greater degree of LVm overestimation occurs. However, a strong correlation between LVm determined using echocardiography and the actual heart weights of sacrificed rats was observed in the present study, indicating that the parameters measured using echocardiography were closer to the actual values. Fibrosis is a common response to pressure overload or infarction, to overcome elevated ventricular wall stress. Excessive fibrotic deposits around the small vessels may reduce oxygen and nutrient exchange rates between the blood supply and the surrounding myocardium. Additionally, extensive interstitial fibrosis impedes myocardial relaxation, increasing stiffness in the ventricular wall and reducing LV compliance.

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Our data suggest that hypertrophic indices decline from four to six weeks post surgery, with myocardial hypertrophy reaching its peak at four weeks in rats. This observation may be associated with acute pressure overload within four weeks post surgery, and then LV pressure decreases slightly (data not shown), leading to alleviation of myocardial hypertrophy, as previously shown.18 As an important biological marker, BNP concentrations in the plasma may increase in line with increased haemodynamic stress, or ventricular cavity expansion in the case of cardiac hypertrophy and heart failure.14,19-21 In the present study, plasma BNP concentrations were associated with the duration of AAC. As the duration extended, BNP levels were progressively elevated, for example, 307, 396 and 474% higher than in the sham groups at three, four and six weeks, respectively. Some limitations of this study should be considered. E and A waves were not isolated due to the high heart rates of rodents. In addition, the longest time point studied (six weeks) was not long enough to observe the transition from concentric to eccentric hypertrophy. Echocardiographic measurements were performed under anaesthesia, which is known to alter cardiac and respiratory function, even if the doses used were the minimum necessary.

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involved in reverse remodeling of the hypertrophic rat heart after pressure unloading. Int J Cardiol 2010; 143(3): 414–423. 5.

Kompa AR, Wang BH, Phrommintikul A, et al. Chronic urotensin II receptor antagonist treatment does not alter hypertrophy or fibrosis in a rat model of pressure-overload hypertrophy. Peptides 2010; 31(8): 1523–1530.

Shah KB, Duda MK, O’Shea KM, et al. The cardioprotective effects of fish oil during pressure overload are blocked by high fat intake: role of cardiac phospholipid remodeling. Hypertension 2009; 54(3): 605–611.

Kokubo M, Uemura A, Matsubara T, Murohara T. Noninvasive evaluation of the time course of change in cardiac function inspontaneously hypertensive rats by echocardiography. Hypertens Res 2005; 28(7): 601–609.

Pandey KN. Biology of natriuretic peptides and their receptors. Peptides 2005; 26(6): 901–932.

Phrommintikul A, Tran L, Kompa A, et al. Effects of a rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction. Am J Physiol Heart Circ Physiol 2008; 294(4): H1804–1814.

10. Ono K, Masuyama T, Yamamoto K, et al. Echo Doppler assessment of left ventricular function in rats with hypertensive hypertrophy. J Am Soc Echocardiogr 2002; 15(2): 109–117. 11. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regard-

Conclusion

ing quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58(6): 1072–1083.

This study demonstrated that constriction of the abdominal aorta between the branches of the coeliac and anterior mesenteric arteries, to a diameter of 0.55 mm in young rats represents an excellent experimental animal model of pressure overload-induced myocardial hypertrophy. This model induces hypertrophy that occurs at three weeks or earlier, developing to a peak at four weeks, and recovering slightly at six weeks. Changes in cardiac structure and function during the development of cardiac hypertrophy were monitored using a standard ultrasound probe. LVm was determined using echocardiography and was consistent with the actual tissue weights. By using this animal model, we aim to provide a theoretical and experimental foundation for the application of novel drugs, for example, highspecificity and high-affinity receptor antagonists or agonists to intervene in the pathogenesis of clinical LVH.

12. Doser TA, Turdi S, Thomas DP, Epstein PN, Li SY, Ren J. Transgenic

This study was supported by grants from the National Natural Science

17. Namba T, Tsutsui H, Tagawa H, et al. Regulation of fibrillar collagen

Foundation of China (No.30440053) and the Natural Science Foundation of

gene expression and protein accumulation involume-overloaded cardiac

overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation 2009; 119(14): 1941–1949. 13. Shen YT, Malik FI, Zhao X, et al. Improvement of cardiac function by a cardiac myosin activator in conscious dogswith systolic heart failure. Circ Heart Fail 2010; 3(4): 522–527. 14. Nader L, Lahoud L, Chouery E, Aftimos G, Bois P, Fares NA. B-type natriuretic peptide receptors in hypertrophied adult rat cardiomyocytes. Ann Cardiol Angiol (Paris) 2010; 59(1): 20–24. 15. Ruetten H, Dimmeler S, Gehring D, Ihling C, Zeiher AM. Concentric left ventricular remodeling in endothelial nitric oxide synthaseknockout mice by chronic pressure overload. Cardiovasc Res 2005; 66(3): 444–453. 16. Heyen JR, Blasi ER, Nikula K, et al. Structural, functional, and molecular characterization of the SHHF model of heartfailure. Am J Physiol Heart Circ Physiol 2002; 283(5): H1775–1784.

Guang Dong Province, China (No. S2011010004269 and 9151018201000029).

hypertrophy. Circulation 1997; 95(10): 2448–2454. 18. Cantor EJ, Babick AP, Vasanji Z, Dhalla NS, Netticadan T. A compara-

References 1.

Boluyt MO, Robinson KG, Meredith AL, et al. Heart failure after longterm supravalvular aortic constriction in rats. Am J Hypertens 2005; 18(2 Pt 1): 202–212.

Molina EJ, Gupta D, Palma J, et al. Novel experimental model of pressure overload hypertrophy in rats. J Surg Res 2009; 153(2): 287–294.

Cantor EJ, Babick AP, Vasanji Z, Dhalla NS, Netticadan T. A comparative serial echocardiographic analysis of cardiac structure and functionin rats subjected to pressure or volume overload. J Mol Cell Cardiol

tive serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload. J Mol Cell Cardiol 2005; 38(5): 777–786. 19. Beeri R, Chaput M, Guerrero JL, et al. Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricularremodeling in ischemic mitral regurgitation. Circ Heart Fail 2010; 3(5): 627–634. 20. Yoon PO, Lee MA, Cha H, et al. The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophyand fibrosis. J Mol Cell Cardiol 2010; 49(2): 294–303. 21. Nader L, Smayra V, Jebara V, Bois P, Potreau D, Fares N. Brain natriu-

2005; 38(5): 777–786.

retic peptide secretion in adult rat heart muscle cells: the role of calcium

Xu R, Lin F, Zhang S, Chen X, Hu S, Zheng Z. Signal pathways

channels. Arch Cardiovasc Dis 2008; 101(7–8): 459–463.

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Subclavian artery cannulation provides better myocardial protection in conventional repair of acute type A aortic dissection: experience from a single medical centre in Taiwan Po-Shun Hsu, Jia-Lin Chen, Chien-Sung Tsai, Yi-Ting Tsai, Chih-Yuan Lin, Chung-Yi Lee, Hong-Yan Ke, Yi-Chang Lin

Abstract Background: Although many reports have detailed the advantages and disadvantages between femoral and subclavian arterial cannulations for acute aortic dissection type A (AADA), the confounding factors caused by disease severity and surgical procedures could not be completely eliminated. We compared femoral and subclavian artery cannulation and report the results for reconstruction of only the ascending aorta. Methods: From January 2003 to December 2010, 51 AADA cases involving reconstruction of only the ascending aorta were retrospectively reviewed and categorised on the basis of femoral (n = 26, 51%) or subclavian (n = 25, 49%) artery cannulation. Bentall’s procedures, arch reconstruction and hybrid operations with stent-grafts were all excluded to avoid confounding factors due to dissection severity. Surgical results, postoperative mortality, and short- and mid-term outcomes were compared between the groups. Results: Subclavian cannulation had a lower incidence of cerebral and myocardial injury and lower hospital mortality than femoral cannulation (8 vs 34%, p = 0.04). Ventilation duration as well as intensive care unit (ICU) and hospital stay were also shorter with subclavian cannulation. Risk factors for hospital mortality included pre-operative respiratory failure (odds ratio: 12.84), peri-operative cardiopulmonary bypass (CPB) time > 200 minutes (odds ratio: 13.49), postoperative acidosis (pH < 7.2, odds ratio: 88.63), and troponin I > 2.0 ng/ml (odds ratio: 20.08). The overall hospital mortality rate was 21%. The 40 survivors were followed up for three years with survival of 75% at one year and 70% at three years. Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan Po-Shun Hsu, MD Chien-Sung Tsai, MD, sung1500@mail.ndmctsgh.edu.tw Yi-Ting Tsai, MD Chih-Yuan Lin, MD Chung-Yi Lee, MD Hong-Yan Ke, MD Yi-Chang Lin, MD

Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, National Defense Medical Centre, Taoyuan, Taiwan Chien-Suang Tsai, MD

Department of Anesthesia, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan Jia-Lin Chen, MD

Conclusions: Our results show that subclavian cannulation had a lower incidence of cerebral and myocardial injury as well as better postoperative recovery and lower hospital mortality rates for reconstruction of only the ascending aorta. Keywords: acute aortic dissection, axillary artery cannulation, femoral artery cannulation, T-graft peripheral cannulation Submitted 5/3/15, accepted 2/7/15 Cardiovasc J Afr 2016; 27: 143–146

www.cvja.co.za

DOI: 10.5830/CVJA-2015-056

Surgical repair of acute aortic dissection type A (AADA) is always a significant challenge to cardiovascular surgeons. The key issues involved in this type of procedure include establishing adequate extracorporeal circulation, repairing the torn intima and friable aortic wall, and protecting vital organs, especially the brain, from ischaemia. In the past two decades, there have been many debates regarding the use of femoral or axillary artery cannulation.1 Methods used may vary according to the extent of dissection, which may introduce a major statistical error when comparing cannulation sites. In this retrospective study, we excluded cases involving the arch and Bentall’s procedure and identified 51 patients in whom reconstruction of only the ascending aorta was performed. We analysed short- and mid-term results between the groups formed on the basis of femoral and subclavian cannulation. In addition, we predicted risk factors for mortality based on Kaplan–Meier survival curve results.

Methods Our study included 51 patients who were diagnosed with uncomplicated AADA, including DeBakey type I and II, via computerised tomography (CT) angiography, and had undergone simple reconstruction of the ascending aorta between 2003 and 2010. Bentall’s or David’s procedure was excluded if the intimal tear extended into the coronary ostium or aortic valve. Arch reconstruction was also excluded if any intimal tear was detected over the greater curve after aortotomy or if dissection of any one of the arch branches was confirmed on computerised tomography (CT) angiography. In total, we excluded three cases of David’s procedure, seven cases of Bentall’s procedure, and nine cases of arch reconstruction, as well as two patients who underwent combined Bentall’s procedure and arch reconstruction. In other words, if

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no intimal tear was discovered over the aortic root or the arch, simple reconstruction of the ascending aorta was done and the patient was enrolled in our data set. In total there were 21 cases of DeBakey type I and 30 of DeBakey type II (Table 1). Of these 51 cases, seven patients underwent concomitant re-suspension of the aortic valve due to mild aortic regurgitation, noted during pre-operative echocardiography. The patients were divided into two groups based on their arterial cannulation site. We collected the data retrospectively and focused on mortality rate and short- and mid-term results between the two cannulation groups. Operative mortality was defined as death within 30 days after surgery. Of the survivors, we compared ventilator-dependent days, intensive care unit (ICU) stay, and hospital stay between the two subgroups. The patients were scheduled for follow-up CT angiography every three months in the first year and then every year for the next two years. Demographics and pre-operative characteristics of all 51 patients (38 men and 13 women) are summarised in Table 1. The mean age of the patients was 59.0 ± 14.0 years (median: 60.5; range: 33–87). All surgeries were performed on an emergency basis within 12 hours of the onset of symptoms. Forty-two patients (82%) had hypertension, 13 (25%) had congestive heart failure, and seven (13%) had diabetes. With regard to clinical presentations (Table 1), 12 patients (23%) were in shock (systolic blood pressure < 90 mmHg), 14 (27%) had haemopericardium, and 11 (21%) had respiratory failure with ventilator support. Two patients developed cerebral ischaemia (4%), six developed visceral ischaemia (12%), 11 developed renal ischaemia (21%), and four developed lower limb ischaemia (8%). Table 1. Disease characteristics, clinical presentation and intra-operative variables Parameters

Total, n (%)

Femoral Subclavian group, n (%) group, n (%) p-value

Total number

26 (100)

DeBaykey type I

21 (41)

12 (46)

9 (36)

DeBaykey type II

30 (59)

14 (54)

16 (64)

Age (mean ± SD)

59.0 ± 14.0

60.9±13.7

57.0 ± 14.4

38 (74)

20 (77)

18 (72)

0.687

Cerebral vascular accident

1 (2)

1 (4)

0 (0)

1.00

Coronary artery disease

8 (15)

4 (15)

4 (16)

1.00

Diabetes

7 (13)

4 (15)

3 (12)

1.00

42 (82)

23 (88)

19 (76)

0.24

1 (2)

0 (0)

1 (4)

0.98

13 (25)

8 (30)

5 (20)

0.37

Gender (male)

Hypertension PAOD Congestive heart failure

25 (100)

0.33

COPD

6 (11)

2 (7)

4 (16)

0.62

Shock

12 (23)

7 (27)

5 (20)

0.56

Haemopericardium

14 (27)

10 (38)

4 (16)

0.138

Aortic regurgitation

7 (13)

6 (23)

1 (4)

0.11

Cerebral ischaemia

2 (4)

2 (7)

0 (0)

0.48

Respiratory failure

11 (21)

6 (23)

5 (20)

0.78

Visceral ischaemia

6 (12)

3 (11)

3 (12)

0.95

Renal ischaemia

11 (21)

6 (23)

5 (20)

0.78

Limb ischaemia

4 (8)

2 (7)

2 (8)

0.96

Operation time (h) Cardiopulmonary bypass time (min)

6.72 ± 1.39

0.07

184.9 ± 57.1 177.9 ± 62.1 192.2 ± 51.6

7.13 ± 1.60

0.37

Heart ischaemic time (min)

95.9 ± 33.6

Circulatory arrest time (min) Brain ischaemic time (min)

7.53 ± 1.72

97.0 ± 34.5

94.8 ± 33.3

32.2 ± 5.4

33.8 ± 5.1

30.6 ± 5.3

–

33.8 ± 5.1

0.81 0.03 0.00

PAOD, peripheral arterial occlusion disease, COPD, chronic obstructive pulmonary disease.

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Surgical technique Before 2005, our cannulation strategy for repairing AADA tended towards more use of femoral artery cannulation. After 2005, the strategy switched to more use of subclavian artery cannulation because of developing familiarity with this technique. We routinely used 8- or 10-mm T-grafts for cannulation to avoid compromise of perfusion distally, and then performed median sternotomy and dual-stage venous cannulation over the right atrium. Once cardiopulmonary bypass (CPB) was initiated, profound hypothermia was induced until the bladder or oesophageal temperature was less than 18°C. At the same time, protective adjuncts, such as barbiturates, steroids, ice packed around the head, and steep Trendelenburg positioning, were employed for cerebral protection. Aortic clamping was abandoned to avoid injury to the fragile intima. Once the temperature was below 18°C, hypothermic circulatory arrest without retrograde cerebral perfusion was used in the femoral cannulation group, while antegrade selective cerebral perfusion with arterial flow of 8–10 ml/kg/min was used in the subclavian cannulation subgroup. Aortotomy approximately 3 cm above the sinus of Valsalva was performed, and the aortic root and arch were carefully inspected to determine the optimal procedure for each case. If arch reconstruction, Bentall’s procedure or David’s procedure was required, these patients were excluded from the study. St Thomas cardioplegic solution was directly infused via both coronary ostia for myocardial protection. Distal anastomosis with a Hemashield graft and sandwich procedure with Teflon felt strips for reinforcement of the diseased aorta was performed first, after which the perfusion was converted through the ascending graft and was initiated to minimise systemic ischaemic time. Proximal anastomosis was subsequently performed, followed by rewarming, adequate de-airing, and weaning of the extracorporeal circulation. The intra-operative variables are summarised in Table 1. Overall, the mean CPB time was 184.9 ± 57.1 min, the mean heart ischaemic time was 95.9 ± 33.6 min, and the mean circulatory arrest time was 32.2 ± 5.4 min. In the femoral group, without selective antegrade cerebral perfusion, the mean brain ischaemic time was 33.8 ± 5.1 min.

Statistical analysis All statistical analyses were performed using SPSS software version 12 (SPSS, Chicago, IL, USA). Categorical variables are expressed as percentages and were evaluated with the χ2 test or Fisher’s exact test. Continuous variables are expressed as mean ± standard deviation and were evaluated using the Student’s t-test. Stepwise logistic regression analysis was used to determine the independent predictors of 30-day hospital mortality. Survival was calculated by the Kaplan–Meier method.

Results There were 11 (21%) deaths after surgery (Table 2), the causes of which included cardiac failure in six, visceral ischaemia in three, aortic re-dissection in one, and respiratory failure complicated by adult respiratory distress syndrome (ARDS) in one. Five patients (9%) had postoperative neurological complications, including transient neurological dysfunctions in three and permanent

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Table 2. Post-operative general data and short-term outcomes

Total

Subclavian group (n = 25)

p-value

7.26 ± 0.15

7.35 ± 0.05

0.01

PaO2 (mmHg)

115 ± 92

136 ± 75

0.37

HCO3- (mEq/dl)

20.5 ± 4.5

22.6 ± 3.1

0.06

Amylase (U/l)

316 ± 482

101 ± 159

0.04

Lipase (U/l)

98 ± 158

41 ± 57

0.09

GOT (U/l)

391 ± 1078

70 ± 113

0.14

GPT (U/l)

286 ± 890

33 ± 29

0.16

Troponin I (ng/ml)

7.5 ± 11.9

0.1 ± 0.3

0.003

10.9 ± 8.0

5.4 ± 3.5

0.003

2.9 ± 0.4

3.3 ± 0.4

0.001

CRP (mg/dl) Albumin (g/dl) Short-term outcomes Total number, n (%)

26 (100)

25 (100)

Transfusion > 500 ml, n (%)

26 (51)

15 (57)

11 (44)

Resternotomy, n (%)

4 (8)

2 (7)

2 (8)

1.00

Mediastinitis, n (%)

2 (4)

2 (7)

0 (0)

0.01

5 (9)

5 (19)

0 (0)

0.001

12 (23)

8 (27)

4 (16)

0.36

Neurological dysfunction, n (%) Pneumonia, n (%) ARDS, n (%)

0.32

5 (9)

3 (11)

2 (8)

0.67

Acute renal failure, n (%)

22 (43)

15 (57)

7 (28)

0.03

Mortality, n (%)

11 (21)

9 (34)

2 (8)

0.04

The biochemical tests were recorded 24 hours after surgery. GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; CRP, C-reactive protein; ARDS, acute respiratory distress syndrome.

strokes in two. All five patients with neurological complications survived and were released from hospital. One stroke patient died of pneumonia with sepsis within three years. Twenty-six (51%) patients required transfusions of more than 500 ml packed red blood cells after surgery, and four (8%) underwent re-sternotomy for haemostasis. Furthermore, 12 (23%) had pneumonia, five (9%) had ARDS, and 22 (43%) developed acute renal failure. The subclavian group showed a significantly lower incidence of mediastinitis (p = 0.01), neurological dysfunction (p < 0.001), acute renal failure (p = 0.03), and mortality (p = 0.04) (Table 2). In the 24-hour postoperative biochemistry data (Table 2), we found metabolic acidosis and hyperamylasaemia to be significantly higher (p < 0.05) in the femoral artery group. In addition, higher troponin I and C-reactive protein and lower albumin levels were also noted in the femoral artery group (p < 0.05). The survivors in the subclavian artery group had a shorter mean ventilator-dependent duration (6.0 ± 4.8 vs 6.4 ± 3.5 days) as well as ICU (8.9 ± 5.8 vs 13.3 ± 9.1 days) and hospital stay (18.8 ± 9.8 vs 34.1 ± 22.6 days) than those in the femoral artery group. The compared Kaplan–Meier survival curve for the two groups is shown in Fig. 1. All 40 survivors were followed up for three years with annual CT angiography. Two patients died within one year of surgery, one of sudden death and the other of a cerebral vascular accident. Two more patients died within the next two years, one of pneumonia with severe sepsis and the other following recurrent dissection of the aortic root. According to the outcomes of the annual CT angiography (Fig. 2), three root re-dissections were found; two underwent re-do Bentall’s operation and the other died of sudden death without re-operation. Four arch dissections without branch involvement were found and all four adopted conservative treatment. Two arch aneurysms were found and one underwent re-do arch reconstruction due to impending rupture. Three dissecting aneurysms of the descending aorta were found and all

1.0 Cum survival

Postoperative data pH

Femoral group (n = 26)

0.8

Subclavian canulation

0.6

Femoral canulation

+ +

0.4 0.2 0.0

100

150

200

250

300

350

Days

Fig. 1. Kaplan–Meier survival curve in relation to the two groups.

three underwent thoracic endovascular aortic repair (TEVAR). The other 28 were diagnosed with type B dissection and adopted conservative treatment. Overall survival was 75% at one year and 70% at three years. Results of univariate and multivariate analysis are shown in Table 3. Logistic regression analysis revealed independent risk factors for hospital death as pre-operative respiratory failure, peri-operative CPB > 200 min, postoperative severe acidosis (pH < 7.2), and troponin I > 2.0 ng/ml.

Discussion There is a trend towards cannulation of the axillary artery for extracorporeal circulation in patients with AADA,1-4 but the debate is ongoing and several possible reasons could explain this deficiency, including the following: (1) the urgency of AADA does not allow for complicated surgical techniques but instead requires a simple, rapid and safe approach to achieve rapid extracorporeal circulation; (2) the different individual situations demand an individual approach, and it is difficult to relate outcome to the cannulation site; (3) the number of procedures performed at each centre is rather small, especially in Asia, while a multicentre approach is not practicable owing to the different strategies practiced at different centres; and (4) most important of all, the severity of the AADA hinges on the location of the torn intima and the extent of the dissection, which also demands different types of procedures. In this study, we enrolled only cases involving ascending aorta reconstruction to avoid major

40 survivors

3 root re-dissection

2 re-do Bentall’s procedure

4 arch dissection

Conservative treatment

2 arch aneurysm

1 re-do arch reconstruction

3 dissecting aneurysm of descending aortic

3 TEVAR

28 type B dissection

Conservative treatment

Fig. 2. Outcomes of the annual CT angiography and follow-up intervention.

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Table 3. Significant risk factors associated with hospital mortality Univariate analysis

Variables Total number

Survival group

Mortality group

n (%)

40 (100)

11 (100)

< 0.001

p-value

Pre-operative Respiratory failure Peri-operative Cardiopulmonary bypass time > 200 mins Post-operative pH < 7.2

< 0.001

Troponin I > 2.0 ng/dl

< 0.001

Acute renal failure

< 0.001

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which reached statistical significance in the multivariate analysis. The significance could be confirmed if more patients are enrolled in the future. This study has several limitations. First, the cohort was relatively small, but despite this, we still identified an advantage in subclavian cannulation, which suggests a significant benefit for simple reconstruction of the ascending aorta. Second, the data were collected from 2003 to 2010. Surgical techniques and general postoperative care may have improved in the latter part of the study, which could explain the unusually high mortality rate of femoral cannulation in the earlier phase. Third, the study was retrospective and not randomised. More prospective, randomised, controlled trials should be designed to support our hypothesis.

Multivariate analysis OR

95% CI

p-value

12.84

1.48–111.0

0.020

13.49

1.29–140.1

0.029

pH < 7.2

88.63

1.178–4.39

0.003

Troponin I > 2.0

20.08

1.37–293.4

0.013

Variables Pre-operative Respiratory failure Peri-operative CPB time > 200 min Post-operative

AR, aortic regurgitation; CRP, C-reactive protein; CI, confidence interval; OR, odds ratio; CPB, cardiopulmonary bypass.

statistical error that could have been introduced because of disease severity and procedure differences. In this study, fewer postoperative complications and lower mortality rate were detected in the subclavian artery group (Table 2). Undoubtedly, the lower incidence of neurological dysfunction could be attributed to selective cerebral perfusion through subclavian cannulation.5 We also found that subclavian artery cannulation provided better perfusion for other visceral organs (Table 2). Two possible hypotheses may elucidate why. First, according to the Hagen–Poiseuille law,6 the pressure drops in a fluid flowing through a long cylindrical pipe. So under constant blood flow, cardiac and sternal perfusion may not be adequate with femoral cannulation, especially when the aorta is dissected. Inevitably, sternitis and myocardial injury would be higher in the femoral cannulation group. Second, we assume that subclavian cannulation would pump major blood flow into the true lumen, while femoral cannulation pumps more blood into the false lumen. Based on our evaluation, femoral cannulation introduced more retrograde dissection and exacerbated perfusion of the visceral organs. Survivors who underwent subclavian cannulation had better recovery during the postoperative hospital course, which might be attributed to better perfusion of the visceral organs. In other words, subclavian rather than femoral cannulation could achieve a lower incidence of visceral malperfusion during surgeries for AADA. Our univariate analysis of hospital mortality revealed many risk factors, including pre-operative respiratory failure, perioperative CPB time > 200 min, postoperative acidosis, troponin I > 2.0 ng/dl, and acute renal failure (Table 3). Myocardial injury has been thought to be a risk factor during major aortic surgery, particularly when the thoracic aorta is involved.7-8 Although femoral cannulation was eliminated as a risk factor by multivariate analysis, it seemed to have a trend towards increased mortality because it resulted in a higher postoperative troponin I level, which leads to increased peri-operative cardiac injury,

Conclusion Cardiac failure and visceral malperfusion are both fatal complications of AADA surgery.9,10 In Christian and co-workers’ study, antegrade perfusion to the true lumen appeared to be associated with superior long-term survival after hospital discharge.11 Based on our evaluation, we believe subclavian cannulation could provide better perfusion, not only for the brain but also for the myocardium and other visceral organs, leading to lower mortality rates and better recovery following AADA procedures.

References 1. Gulbins H, Pritisanac A, Ennker J. Axillary versus femoral cannulation for aortic surgery: enough evidence for a general recommendation? Ann Thorac Surg 2007; 83:1219–1224. 2. Wong DR, Coselli JS, Palmero L, et al. Axillary artery cannulation in surgery for acute or subacute ascending aortic dissections. Ann Thorac Surg 2010; 90:731–737. 3. Neri E, Massetti M, Capannini G, et al. Axillary artery cannulation in type A aortic dissection operations. J Thorac Cardiovasc Surg 1999; 118: 324–329. 4. Numata S, Ogino H, Sasaki H, et al. Total arch replacement using antegrade selective cerebral perfusion with right axillary artery perfusion. Eur J Cardiothorac Surg 2003; 23: 771–775. 5. Zierer A, El-Sayed Ahmad A, Papadopoulos N, et al. Selective antegrade cerebral perfusion and mild (28°C–30°C) systemic hypothermic circulatory arrest for aortic arch replacement: results from 1002 patients. J Thorac Cardiovasc Surg 2012; 144: 1042–1049. 6. Pozrikidis C. Fluid Dynamics: Theory, Computation, and Numerical Simulation, 2nd edn. New York, London: Springer Science, 2009: 362–383. 7. Hafez HM, Berwanger CS, McColl A, et al. Myocardial injury in major aortic surgery. J Vasc Surg 2000; 31: 742–750. 8. Haggart PC, Adam DJ, Ludman PF, Bradbury AW. Comparison of cardiac troponin I and creatine kinase ratios in the detection of myocardial injury after aortic surgery. Br J Surg 2001; 88: 1196–1200. 9. Girdauskas E, Kuntze T, Borger MA, et al. Surgical risk of preoperative malperfusion in acute type A aortic dissection. J Thorac Cardiovasc Surg 2009; 138: 1363–1369. 10. Deeb GM, Patel HJ, Williams DM. Treatment for malperfusion syndrome in acute type A and B aortic dissection: a long-term analysis. J Thorac Cardiovasc Surg 2010; 140(Suppl 6): S98–S100; discussion; S142–S146. 11. Christian DE, Konstantin VA, Jaqueline da RS, et al. Impact of perfusion strategy on outcome after repair for acute type A aortic dissection. Ann Thorac Surg 2014; 97: 78–86.

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Comparison of two different techniques for balloon sizing in percutaneous mitral balloon valvuloplasty: which is preferable? Ahmet Tastan, Ali Ozturk, Omer Senarslan, Erdem Ozel, Samet Uyar, Emin Evren Ozcan, Omer Kozan

Abstract Background: Percutaneous balloon mitral valvuloplasty (BMV) is an important option for the treatment of mitral valve stenosis. The crux of this process is choosing the appropriate Inoue balloon size. There are two methods to do this. One is an empirical formula based on the patient’s height, and other is to choose according to the maximal inter-commissural distance of the mitral valve provided by echocardiography. Methods: The study, performed between January 2006 and December 2011, included 128 patients who had moderate to severe mitral stenosis and whose valve morphology was suitable for BMV. Patients were randomised into two groups. One group was allocated to conventional height-based balloon reference sizing (the HBRS group) and the other was allocated to balloons sized by the echocardiographic measurement of the diastolic inter-commissural diameter (the EBRS group). Results: BMV was assessed as successful in 60 (92.3%) patients in the HBRS group and in 61 (96.8%) in the EBRS group (p = 0.03). The mean of the calculated balloon reference sizes was significantly higher in the HBRS than in the EBRS group [26.3 ± 1.2 mm, 95% confidence interval (CI): 26.1–26.6 vs 25.2 ± 1.1, 95% CI: 25.0–25.4, respectively; p = 0.007). Final mitral valve areas (MVA) were larger and mitral regurgitation (MR) > 2+ was less in the EBRS group (p = 0.02 and p = 0.05, respectively). Conclusions: EBRS is a method that is independent of body structure. Choosing Inoue balloon size by measuring maximal diastolic annulus diameter by echocardiography for BMV may be an acceptable method for appropriate final MVA and to avoid risk of significant MR. Keywords: mitral balloon valvuloplasty, balloon size, echocardiography Submitted 16/3/15, accepted 26/7/15 Published online 26/1/16 Cardiovasc J Afr 2016; 27: 147–151

www.cvja.co.za

DOI: 10.5830/CVJA-2015-062

Department of Cardiology, Sifa University Faculty of Medicine, Izmir, Turkey Ahmet Tastan, MD Ali Ozturk, MD Omer Senarslan, MD, dromersen@yahoo.com Erdem Ozel, MD Samet Uyar, MD Emin Evren Ozcan, MD

Department of Cardiology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey Omer Kozan, MD

Although both the incidence and prevalence of rheumatic heart disease have seen a dramatic decrease in recent years, it is still the leading cause of mitral valve stenosis. It is known that rheumatic changes are present in 99% of stenotic mitral valves excised at the time of mitral valve surgery.1 Mitral valve stenosis is the most serious sequel of rheumatic fever and it has unfavourable effects on survival rates and quality of life. The disease is endemic in developing countries, including Middle Eastern countries.2 Long-term left heart obstruction causes unwanted structural and haemodynamic deterioration. Medical therapy neither treats the disease nor modifies its course.1 In addition medical therapy is routinely given to reduce symptoms and to prevent thromboembolic complications, or to avoid recurrent rheumatic fever. Since the first publication of the Inoue balloon in 1984, balloon mitral valvuloplasty (BMV) has become the procedure of choice all over the world because of its lower cost and morbidity rate.3 Successfully applied BMV improves the haemodynamics and symptoms related to mitral valve stenosis, and has favourable impacts on early and long-term survival of patients.4,5 According to recently published valvular heart disease guidelines, BMV is recommended for symptomatic patients with moderate to severe mitral valve stenosis. Candidate patients for BMV should have a suitable valve structure with no mitral regurgitation (MR). BMV should not be administered to a patient with thrombus in the cardiac chambers. The main purpose of BMV is to provide an adequate mitral valve area (MVA) of > 1.5 cm2 with no significant MR (MR not more than 2/4 in over 80% of patients).6 Despite high technical expertise in BMV, MR remains a major procedure-related complication.7 Many studies have shown that acute procedural results, including final MVA and post-procedural MR, independently predict the long-term outcome after BMV.8 The incidence of severe MR after BMV reported in the literature varies between 1.4 and 7.5%.9,10 BMV is recommended for symptomatic patients with suitable valvular morphology who have moderate to severe mitral stenosis (MVA < 1.5 cm2) and also for asymptomatic patients with pulmonary artery systolic pressure of > 50 mmHg at rest or > 60 mmHg with exercise.11 The aim of this procedure is to provide adequate valve area while protecting the mitral valve apparatus. For this purpose, selection of the appropriate balloon size is one of the most critical factors for BMV.12 There are two basic methods to decide the size of the Inoue balloon. One is the use of an empirical formula to calculate inflated balloon catheter diameter based on the height of the patient [size = 0.1 × height (cm) + 10].13,14 Differences between body habitus, heart orientation and configuration of the cardiac skeleton are combined to calculate balloon diameter using a height-based formula. Therefore, different results can be obtained, even in patients with the same height.

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A reasonable alternative approach is choosing balloon size according to the maximal inter-commissural distance of the mitral valve as provided by echocardiography. This is a more direct and conservative method of balloon sizing to avoid possible mistakes when determining the size of the balloon, and to prevent possible complications in the procedure. The aim of this study was to assess the early haemodynamic and echocardiograhic results of BMV according to these two different types of Inoue balloon selection strategy.

Methods Between 1 January 2006 and 31 December 2011, 128 consecutive symptomatic patients were seen with moderate to severe mitral stenosis (MVA < 1.5 cm2), whose valve morphology was suitable for BMV and who had no contraindications for BMV. Symptomatic and asymptomatic patients were included who had a pulmonary artery systolic pressure of > 50 mmHg at rest or 60 mmHg with exercise in the presence of favourable morphological criteria of the mitral valve, derived from the echocardiographic Wilkins scoring system.11 Patients were considered eligible if they were aged 18 years or older. Exclusion criteria were mild mitral stenosis, a Wilkins score of > 10, moderate or severe mitral regurgitation, any moderate or severe valvular heart disease other than mitral stenosis, a history of coronary artery disease, heart failure, pulmonary embolism, congenital heart disease, chronic kidney disease and current pregnancy. Patients were randomised into two groups. One group was allocated to conventional height-based balloon reference sizing (the HBRS group) and the other was allocated to balloons sized by the echocardiographic measurement of the diastolic intercommissural diameter (the EBRS group). BMV was performed in all patients. All patients were informed about the study, and written consent was obtained. The study was approved by the institution’s ethics committee and performed in accordance with the Helsinki Declaration.

Echocardiography In accordance with the recommendations of the American Society of Echocardiography, all transthoracic echocardiographic (TTE) examinations were performed with the patient lying in the left lateral decubitus position, and two-dimensional images were recorded and measured in the apical four-chamber, two-chamber, and parasternal long- and short-axis views.15 Echocardiographic examinations were performed by two independent cardiology specialists, blinded to the outcome of BMV, in the echocardiography laboratory before and one month after BMV. B-mode, two-dimensional Doppler and colour-flow Doppler echocardiographic evaluations were performed using a Siemens Acuson CV70 system (Siemens AG Medical Solutions, Erlangen, Germany) with a 2.5–4.0-MHz transducer with second harmonic capabilities. Transoesophageal echocardiographic (TEE) examinations were performed on all patients with a 5-MHz multiplane endoscopic probe. MVAs were calculated using the direct planimetry and pressure half-time method. Diastolic trans-mitral gradients

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were measured by continuous-wave Doppler echocardiography. Systolic pulmonary artery pressure (sPAP) was measured with continuous-wave Doppler. Tricuspid regurgitation velocity (V) was recorded from any view and used to determine sPAP (sPAP = 4V2 + right atrial pressure). V is the maximum velocity of the tricuspid valve regurgitant jet, measured by continuous-wave Doppler, added to the estimated right atrial pressure. Right atrial pressure was calculated using the caval respiratory index, as described by Kircher et al.16 Finally, the maximal inter-commissural distance was measured on the parasternal short-axis view from the anterolateral to posteromedial commissures in mid-diastole. The degree of mitral regurgitation and the presence of concomitant valvular heart disease and left atrial clot were also determined.

Catheterisation and valvuloplasty Cardiac catheterisation was performed using Siemens AXIOM Artis dFC equipment (Siemens AG, Medical Solutions, Erlangen Germany). The right and left heart haemodynamic study was performed to evaluate sPAP and mitral valve pressure gradients. In the HBRS group, balloons were selected using the heightbased reference size by calculating according to the standard height-based formula [0.1 × height (cm) + 10]. In the EBRS group, balloons were selected according to the echocardiographic inter-commissural distance measurement in mid-diastole. The classic antegrade Inoue balloon technique was used for BMV by two experienced cardiologists in a standard and similar fashion. Procedures were performed with TEE guidance. After the atrial septostomy and appropriate septal dilation, 100 IU/kg of heparin was administered to achieve an activating clotting time of > 250 seconds. Left ventriculography was performed before and after BMV to evaluate mitral regurgitation. A successful BMV was defined as an uncomplicated procedure yielding a final mitral valve area of > 1.5 cm2 and post-valvuloplasty mitral regurgitation of < 3+.

Statistical analysis Continuous variables are given as mean ± SD. Categorical variables were defined as percentages and compared with the chi-square test to compare the measurements before and after BMV, and a Student’s paired t‑test was used. A probability value of p < 0.05 was considered significant, and two-tailed p-values were used for all statistics.

Results In this study, 128 patients participated. In 65 patients, Inoue balloon sizes were calculated according to HBRS, while in the remaining 63 patients, sizes were provided by EBRS. The study patients’ baseline clinical, echocardiographic and catheterisation characteristics are shown in Tables 1, 2 and 3. The mean age of the patients was 32 years in the HBRS group and 31 in the EBRS group, and there was no statistically significant difference (p = 0.16) between the groups; 72.7% of the patients were female. There was no difference between the groups in terms of weight and height (p = 0.64 and p = 0.62, respectively). Therefore it can be considered that both groups were similar in terms of body mass index.

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Table 3. Pre-procedural catheterisation data of study participants

Table 1. Background characteristics of study patients

Age (years)

HBRS (n = 65)

EBRS (n = 63)

35.4 ± 6.2

31.4 ± 5.1

0.12

18 (27.7)

17 (27)

p-value

HBRS (n = 65)

EBRS (n = 63)

p-value

PA pressure (mmHg)

49 ± 15

51 ± 16

0.91

0.67

RV pressure (mmHg)

48 ± 14

49 ± 15

0.82

7.5 ± 2 9.9 ± 4.1

Gender, n (%) Male

9.1 ± 2.4

0.14

10.4 ± 4.4

0.32

Female

47 (72.3)

46 (73)

0.58

RA pressure (mmHg)

Weight (kg)

66.2 ± 10.9

70.1 ± 11.1

0.14

MV mean pressure (mmHg)

Height (cm)

162 ± 9

163 ± 9

0.62

0.09

CVD

Atrial fibrillation

0.53

0.62

NYHA

EBRS, echocardiographic balloon reference sizing; HBRS, height-based balloon reference sizing; F, female; M, male; CVD, cerebrovascular disease; NYHA, New York Heart Association functional classification.

Echocardiographic and catheterisation assessment of patients before the procedure showed no significant differences between the basic features of the two groups. The degree of mitral valve stenosis, mitral valve scores and MR (2+) were similar between the two groups (p = 0.73, p = 0.58 and p = 0.74, respectively). BMVs were performed successfully on both groups. Adequate mitral valve area and a decrease in MVG were obtained. BMV was assessed as successful in 60 (92.3%) patients in the HBRS group and in 61 (96.8%) in the EBRS group (p = 0.03). The mean of the calculated balloon reference sizes was significantly higher in the HBRS than in the EBRS group [26.3 ± 1.2 mm, 95% confidence interval (CI): 26.1–26.6 vs 25.2 ± 1.1, 95% CI: 25.0– 25.4, respectively; p = 0.007]. The final inflated balloon sizes were similar between the groups (25.6 ± 0.9 mm, 95% CI: 25.3–25.9 vs 25.9 mm ± 1.0 mm, 95% CI: 25.1–25.8, respectively; p = 0.34). The post-procedural results of the patients are presented in Table 4. A greater decrease in the trans-mitral mean gradient was observed in the EBRS group but it was not statistically significant (p = 0.06). In the EBRS group, larger MVAs were achieved than in the HBRS group (1.6 ± 0.3 cm2, 95% CI: 1.56–1.69 vs 1.7 ± 0.3 cm2, 95% CI: 1.57–1.74, respectively; p = Table 2. Pre-procedural echocardiographic data of study participants HBRS (n = 65)

EBRS (n = 63)

p-value

LVDD (mm)

46 ± 2.4

47 ± 2.5

0.81

LVSD (mm)

29 ± 1.5

29 ± 1.4

0.78

LA (mm)

49 ± 6

47 ± 6

0.51

LVEF (%)

64 ± 5

65 ± 5

0.54

MVA (cm2)

1.1 ± 0.2

1.0 ± 0.3

0.13

MV Wilkins score

8.7 ± 1.1

9.1 ± 1.4

0.38

22.4 ± 5.5

21 ± 5.3

0.34

9.5 ± 4.2

9.7 ± 4.5

0.69

MV max gradient (mmHg) MV mean gradient (mmHg) MR 0

0.52

EBRS, echocardiographic balloon reference sizing; HBRS, height-based balloon reference sizing; LVDD, left ventricular end-diastolic diameter; LVSD, left ventricular end-systolic diameter; LA, left atrium; LV EF, left ventricular ejection fraction; MVA, mitral valve area; MV, mitral valve; MR, mitral regurgitation.

0.69

EBRS, echocardiographic balloon reference sizing; HBRS, height-based balloon reference sizing; PA, pulmonary artery; RV, right ventricle; RA, right atrium; MV, mitral valve; MR, mitral regurgitation.

0.02). The incidence of significant MR (3–4+) was lower than in the HBRS group (p = 0.05 by echocardiography and p = 0.03 by ventriculography). Also, 2+ degree MR was significantly less developed in the EBRS patients (p = 0.01).

Discussion In recent years, Inoue balloon mitral commissurotomy has become the treatment of choice in many patients with rheumatic mitral stenosis. The main target of this procedure is to resolve the stenotic mitral orifice without causing extensive damage to the commissures, leaflets and subvalvular apparatus, thus leading to excessive mitral regurgitation. The most common serious complication is haemopericardium, with an incidence of 0 to 2.0%.17 Severe MR is another important and common serious complication after BMV.18 Many studies have shown that acute procedural results, including final MVA and post-procedural MR, independently predict the long-term outcome after BMV.8 When severe mitral regurgitation occurs after BMV, surgical treatment is required at some point. Most mild but significant cases of MR are caused by commissural split, chordal rupture or leaflet laceration. Table 4. Post-procedural catheterisation data of study participants HBRS (n = 65)

EBRS (n = 63)

Estimated reference MBS (mm)

26.3 ± 1.2

25.2 ± 1.1

0.02

Final balloon size

25.6 ± 0.9

25.9 ± 1.0

0.34

p-value

MVA (cm2)

1.6 ± 0.2

1.7 ± 0.3

0.02

Transmitral mean gradient (mm Hg)

3.2 ± 0.3

3.0 ± 0.3

0.04

PAP (mmHg)

28 ± 8

29 ± 7

0.81

0.03

MR severity, n (%) Echocardiography 0

3–4+ Catheterisation 0

3–4+

0.04

EBRS, echocardiographic balloon reference sizing; HBRS, height-based balloon reference sizing; MBS, mitral balloon size; MVA, mitral valve area; PAP, pulmonary artery pressure; MR, mitral regurgitation.

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Although there are many data for MBV, there is no consensus in determining the optimal size of the balloon.19 Appropriate balloon catheter sizing is the most important step for successful MBV procedure, as well as in reducing complications.20 Routine balloon sizing based on the conventional height-based formula has been validated in many studies.21 However, empirical selection of balloon size by the height-based formula has no correlation with variables such as cardiac structure, MVA and orifice. This mismatch can prevent the success of the process required and can lead to inappropriate consequences, even though perfect procedures are carried out by trained surgeons. Also, the relationship of a person’s height to the diameter of the mitral valve orifice is not necessarily linear.12 As a result of these findings, more effective methods have been investigated to determine the appropriate size of the balloon to maximise success and efficiency and to minimise complication rates.22 Nobuyoshi and colleagues recommended selecting the balloon size by directly measuring the mitral annular diameter using two-dimensional echocardiography to avoid undesirable extensive injury to the mitral valve apparatus.12 When maximal diastolic annulus diameter is used for balloon sizing, the balloon reference sizes are smaller than those obtained with the heightbased formula.22 In this way, balloons with a smaller diameter can be used to achieve sufficient mitral valve area, and with smaller balloons, procedures might be performed with less damage to the chordal structure and the leaflets. Less damage to the mitral valve apparatus results in less MR. In our study we have shown that selecting Inoue balloon size according to echocardiographic maximal diastolic diameter is as efficient as using the height-based formula. Final balloon sizes were similar between the HBRS and EBRS groups but were smaller in the EBRS group. There was a significant difference between calculated and final balloon sizes in the HBRS group. We achieved sufficient MVAs by echocardiography-derived balloon sizing in this study, associated with lesser degrees of MR change. Sanati and colleagues had the same clinical results with the EBRS method. Their final balloon sizes were similar between the two groups, and they achieved better valve areas with less MR.22 We believe that if calculated and final balloon sizes are similar, the success of MBV will be higher. Using the correct size of balloon and inflation pressure will cause less damage to the mitral valve apparatus. Considering the fact that severe MR is also infrequent with the height-based method, but in our study severe MR was seen less in the EBRS group, we believe that applying invasive treatments for heart diseases using imaging methods could be better than using empirical methods. So in order to achieve effective MVA without severe MR, we suggest the EBRS method to select Inoue balloon size. In the future, the importance and correlation of MR developing after MBV with prognosis of patients will be better understood.

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Conclusion EBRS is a method that is independent of body structure. Some patients are tall, some are short, and some are obese or asthenic, so patients who have discordance between heart size and body structure may benefit from this method. Choosing Inoue balloon size for BMV by measuring maximal diastolic annulus diameter using echocardiography is a reasonable method with acceptable final MVAs to avoid the risk of significant MR. Echocardiographic balloon sizing for BMV should be used, especially in patients with discordance between height and heart size. We believe that all types of invasive procedures may be planned according to the dimensions of cardiac structures. Our study sheds some light on this issue.

References 1.

Essop MR, Nkomo VT. Rheumatic and nonrheumatic valvular heart disease: epidemiology, management, and prevention in Africa. Circulation 2005; 112(23): 3584–3591.

Wood P. An appreciation of mitral stenosis: II. Investigations and results. Br Med J 1954; 1(4871): 1113–1124.

Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984; 87(3): 394–402.

Hernandez R, Banuelos C, Alfonso F, et al. Long-term clinical and echocardiographic follow-up after percutaneous mitral valvuloplasty with the Inoue balloon. Circulation 1999; 99(12): 1580–1586.

Song JK, Song JM, Kang DH, et al. Restenosis and adverse clinical events after successful percutaneous mitral valvuloplasty: immediate post-procedural mitral valve area as an important prognosticator. Eur Heart J 2009; 30(10): 1254–1262.

Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33(19): 2451–2496.

Kaul UA, Singh S, Kalra GS, et al. Mitral regurgitation following percutaneous transvenous mitral commissurotomy: a single-center experience. J Heart Valve Dis 2000; 9(2): 262–266; discussion 266–268.

Jneid H, Cruz-Gonzalez I, Sanchez-Ledesma M, et al. Impact of preand postprocedural mitral regurgitation on outcomes after percutaneous mitral valvuloplasty for mitral stenosis. Am J Cardiol 2009; 104(8): 1122–1127.

Hernandez R, Macaya C, Banuelos C, et al. Predictors, mechanisms and outcome of severe mitral regurgitation complicating percutaneous mitral valvotomy with the Inoue balloon. Am J Cardiol 1992; 70(13): 1169–1174.

10. Feldman T. Hemodynamic results, clinical outcome, and complications of Inoue balloon mitral valvotomy. Cathet Cardiovasc Diagn 1994; Suppl 2: 2–7. 11. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of

Study limitations The participants in this study were all suitable for MBV, and we did not include patients who had a borderline Wilkins score. The number of patients in our study was higher than in other studies in the literature; however, the number of patients should perhaps have been greater. Also, long-term follow-up results, especially those concerning MR, are yet to be published.

dilatation. Br Heart J 1988; 60(4): 299–308. 12. Nobuyoshi M, Arita T, Shirai S, et al. Percutaneous balloon mitral valvuloplasty: a review. Circulation 2009; 119(8): e211–219. 13. Lau KW, Hung JS. A simple balloon-sizing method in Inoue-balloon percutaneous transvenous mitral commissurotomy. Cathet Cardiovasc Diagn 1994; 33(2): 120–129; discussion 130–131. 14. Hung JS, Lau KW, Lo PH, Chern MS, Wu JJ. Complications of Inoue balloon mitral commissurotomy: impact of operator experience and

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evolving technique. Am Heart J 1999; 138(1 Pt 1): 114–121. 15. Gottdiener JS, Bednarz J, Devereux R, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17(10): 1086–1119. 16. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990; 66(4): 493–496. 17. Martinez-rios MA, Tovar S, Luna J, Eid-Lidt G. Percutaneous mitral commissurotomy. Cardiol Rev 1999; 7(2): 108–116. 18. Padial LR, Freitas N, Sagie A, et al. Echocardiography can predict which patients will develop severe mitral regurgitation after percutane-

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valvuloplasty: the when (timing for intervention), what (choice of valve), and how (selection of technique). Cathet Cardiovasc Diagn 1995; 35(2): 91–100. 20. Chen CG, Wang X, Wang Y, Lan YF. Value of two-dimensional echocardiography in selecting patients and balloon sizes for percutaneous balloon mitral valvuloplasty. J Am Coll Cardiol 1989; 14(7): 1651–1658. 21. Lau KW, Gao W, Ding ZP, Hung JS. Immediate and long-term results of percutaneous Inoue balloon mitral commissurotomy with use of a simple height-derived balloon sizing method for the stepwise dilation technique. Mayo Clin Proc 1996; 71(6): 556–563. 22. Sanati HR, Kiavar M, Salehi N, et al. Percutaneous mitral valvuloplasty

ous mitral valvulotomy. J Am Coll Cardiol 1996; 27(5): 1225–1231.

– a new method for balloon sizing based on maximal commissural diam-

19. Lau KW, Hung JS, Ding ZP, Johan A. Controversies in balloon mitral

eter to improve procedural results. Am Heart Hosp J 2010; 8(1): 29–32.

What procedures must any cath lab in Africa offer? Answering this question, Dr Francois Bourlon from Monaco named these as some of the key procedures any African cath lab should offer: • right- and left-sided pressure studies • coronary angiography • percutaneous coronary intervention (notably with radial access) • mitral/pulmonary valvuloplasty • PDA closure • atrial septostomy • pacing, both permanent and temporary • pericardiocentesis • bilateral iliac intervention. This is an ideal scenario and Africa as a whole is still a long way from achieving it. As Dr Bourlon pointed out, facilities vary greatly across the continent. ‘There are a few cath labs that are well equipped and manned by well-trained staff. Many others have extremely limited resources, however, requiring interventional cardiologists to be versatile and skilful. And in many parts of Africa, a cath lab is just a dream.’

A Tanzanian success story But dreams can be achieved. Dr Robert Mvungi, from Tanzania, shared an inspiring update on what his cath lab has accomplished in the past year since AfricaPCR 2015. Established in Dar-es-Salaam in 2013, it is the country’s first cath lab. Its first procedure, a permanent pacemaker implantation, took place on 19 November 2013 and the first coronary angiogram was performed on 25 June 2014. Dr Mvungi noted that there were challenges in equipping the facility and training the team. The cath lab nurses had to be trained in India, and returned with good skills. To date

the laboratory has undertaken 365 adult procedures and 85 paediatric ones, most of the latter being PDA closures. Overall, many more procedures were undertaken in 2015 than in 2013/2014 – these included pacemaker procedures, stenting, right heart studies and fluoroscopies. ‘We’ve also done eight percutaneous mitral balloon valvuloplasties to date’, he told delegates at AfricaPCR 2016. Coronary artery bypass grafting procedures are now performed onsite. There are many plans in view to ensure the laboratory goes from strength to strength. ‘We’re establishing a database registry to monitor ongoing quality improvement and focusing on building human resource capacity. I’m also looking forward to our acquiring new equipment that will enable us to undertake more complex procedures in the future.’ He believes the following are critical elements for establishing a cath lab in Africa: • government support (73% of the laboratory’s work is funded by Tanzania’s national health insurance) • human resource capacity • adequate funding • a continuous supply of consumables • a fluoroscopy and haemodynamic system • supporting equipment • maintenance services. He concluded by underscoring the importance of institutional relationships. These will allow African cardiologists to train with recognised leaders internationally and then return to their own countries with the skills necessary to run an autonomous African cath lab. Source: AfricaPCR 2016.

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Clinical features, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy in South Africans Ntobeko AB Ntusi, Gasnat Shaboodien, Motasim Badri, Freedom Gumedze, Bongani M Mayosi

Abstract Background: Little is known about the clinical characteristics, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy (HCM) in Africans. The objective of this study was to delineate the clinical and genetic features and outcome of HCM in African patients. Methods: Information on clinical presentation, electrocardiographic and echocardiographic findings, and outcome of cases with HCM was collected from the Cardiac Clinic at Groote Schuur Hospital over a mean duration of follow up of 9.1 ± 3.4 years. Genomic DNA was screened for mutations in 15 genes that cause HCM, i.e. cardiac myosinbinding protein C (MYBPC3), cardiac β-myosin heavy chain (MYH7), cardiac troponin T2 (TNNT2), cardiac troponin I (TNNI3), regulatory light chain of myosin (MYL2), essential light chain of myosin (MYL3), tropomyosin 1 (TPM1), phospholamban (PLN), α-actin (ACTC1), cysteine and glycine-rich protein 3 (CSRP3), AMP-activated protein kinase (PRKAG2), α-galactosidase (GLA), four-and-a-half LIM domains 1 (FHL1), lamin A/C (LMNA) and lysosomeassociated membrane protein 2 (LAMP2). Survival and its predictors were analysed using the Kaplan–Meier and Cox proportional hazards regression methods, respectively. Results: Forty-three consecutive patients [mean age 38.5 ± 14.3 years; 25 (58.1%) male; and 13 (30.2%) black African] were prospectively enrolled in the study from January 1996 to December 2012. Clinical presentation was similar to that reported in other studies. The South African founder mutations that cause HCM were not found in the 42 probands. Ten of 35 index cases (28.6%) tested for mutations in 15 genes had disease-causing mutations in MYH7 (six cases or 60%) and MYBPC3 (four cases or 40%). No disease-causing mutation was found in the other 13 genes screened. The annual mortal-

Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa and The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa Ntobeko AB Ntusi, MB ChB, FCP (SA), DPhil, MD, ntobeko.ntusi@ gmail.com Gasnat Shaboodien, PhD Motasim Badri, PhD Bongani M Mayosi, MB ChB, FCP (SA), DPhil

King Saud Bin Abdulaziz University for Medical Sciences, Riyadh, Kingdom of Saudi Arabia Motasim Badri, PhD

Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa Freedom Gumedze, PhD

ity rate was 2.9% per annum and overall survival was 74% at 10 years, which was similar to the general South African population. Cox’s proportional hazards regression showed that survival was predicted by New York Heart Association (NYHA) functional class at last visit (p = 0.026), but not by the presence of a disease-causing mutation (p = 0.474). Conclusions: Comprehensive genetic screening was associated with a 29% yield of causal genetic mutations in South African HCM cases, all in MYH7 and MBPC3 genes. A quarter of the patients had died after a decade of follow up, with NYHA functional class serving as a predictor of survival. Keywords: hypertrophic cardiomyopathy, genetics, clinical characteristics, outcome, South Africa Submitted 2/5/14, accepted 15/9/15 Cardiovasc J Afr 2016; 27: 152–158

www.cvja.co.za

DOI: 10.5830/CVJA-2015-075

Hypertrophic cardiomyopathy (HCM) is defined by the presence of myocardial hypertrophy in the absence of haemodynamic stresses sufficient to account for the degree of hypertrophy (e.g. arterial hypertension and aortic stenosis), and without other secondary causes of cardiac hypertrophy, such as amyloidosis and glycogen storage disease.1 HCM was historically thought to be rare among Africans.2 This impression was reinforced by a study that found HCM to occur in 0.2% of 6 680 unselected echocardiograms performed in Tanzania.3 However, recent echocardiographic studies from the continent have dispelled that myth.4 For example, in Ghana, HCM has been reported to be the third commonest cardiomyopathy after dilated cardiomyopathy (DCM) and endomyocardial fibrosis (EMF).5 Similarly, in Ethiopia, HCM accounts for 34% of all cardiomyopathies diagnosed on echocardiography.6 However, there is a dearth of information on the clinical features, genetics and outcome of HCM from the African continent, with a few publications reporting on HCM-causing mutations in South Africans of northern European descent and mixed ancestry.7-10 To the best of our knowledge, there are no data on the genetics of HCM in black Africans. HCM is a diverse disease with variable phenotypic expression; a substantial proportion of patients live a normal life with minimal risk of sudden cardiac death.11 However, some patients with or without symptoms may die suddenly, even without having clinical features of severe left ventricular hypertrophy (LVH).9 The pattern of LVH in HCM is variable and associated with differences in morbidity and mortality. For instance, apical HCM in the Japanese and North American populations is

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associated with a benign outcome.12 The clinical pattern and outcome of HCM in Africans is not known. The aim of this study was to delineate the clinical features, spectrum of diseasecausing mutations and outcome of HCM in African patients.

Methods Consecutive patients diagnosed with HCM at the Cardiac Clinic, Groote Schuur Hospital (GSH), Cape Town, South Africa were prospectively enrolled into a longitudinal cohort study of familial cardiomyopathy, from 1 February 1996 to 31 August 2012. The diagnosis of HCM was based on the presence of a hypertrophied, non-dilated left ventricle in the absence of other diseases capable of producing the degree of observed LVH (i.e. left ventricular wall thickness > 14 mm on echocardiography).13 Clinical data were collected at six-monthly visits during the study period. The study was designed in keeping with the principles of the Helsinki Declaration, and was approved by the University of Cape Town Human Research Ethics Committee. All participants gave informed, written consent to participate in the study. All patients had comprehensive clinical assessment, complemented by chest radiography, electrocardiography, detailed two-dimensional and Doppler colour-flow echocardiography, and cardiac catheterisation, when appropriate. The primary imaging modality used for diagnosis in all patients was transthoracic two-dimensional and Doppler echocardiography. Patients found to have outflow tract gradients below 40 mmHg underwent Valsalva manoeuvre. Patients with cardiovascular risk factors, angina or subjects over 40 years old frequently underwent coronary angiography, at the discretion of the attending clinician. A comprehensive database that incorporated patient demographic details, medical history, co-morbidity, medical therapy, clinical, electrographic and echocardiographic details was utilised. Normal values for echocardiographic measurement were based on age and body-surface area, as described by Lauer et al.14

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included adding molecular identifiers to each sample. Samples were pooled and then sequenced using the Roche 454 FLX nextgeneration sequencing platform. Samples were processed and analysed using NextGENe version 2.2.0 (SoftGenetics). Prior to analysis, reads were trimmed and low-quality reads were removed. Reads were aligned to .gbk files and variants seen in < 20% were annotated. Variants were filtered, taking into account coverage, read balance, allele balance and homopolymers. Samples with coverage below 10 were considered failures. Unclassified variants were Sanger sequenced to confirm their presence; known polymorphisms were not Sanger sequenced. The Cape Town population controls were used to determine the population frequencies of all novel variants identified in the 15 genes. One hundred and ninety-five anonymous blood donors from the Western Province Blood Transfusion Service provided consent for blood samples to be taken for DNA extraction. The control DNA consisted of samples from 95 persons of mixed ancestry, 50 black Africans and 50 white South Africans.

Statistical analysis Simple descriptive statistics were used for data interpretation and to draw inferences about the population of patients studied. Results of continuous variables are given as means ± SD. Categorical variables are represented as number and percentage. Pearson’s chi-squared or Fisher’s exact test were used to compare the relative frequency of characteristics between individuals. All p-values were two-sided, and p ≥ 0.05 was considered not to indicate statistical significance. Survival analysis testing between groups was compared using log-rank testing, and the Kaplan–Meier survival curves were constructed using the product-limit method. Age-, gender- and race-adjusted survival curves for the general South African population were derived and compared with the Kaplan–Meier survival rates for the patients with HCM. Analysis included

Table 1. List of genes that were subjected to mutation screening in this study

Genotyping Peripheral blood was collected from HCM probands for DNA extraction using standard methods. Mutation screening was undertaken by pyrosequencing of the coding regions and exon/ intron boundaries of the following 15 genes that are associated with HCM: cardiac myosin-binding protein C (MYBPC3), cardiac β-myosin heavy chain (MYH7), cardiac troponin T type 2 (TNNT2), cardiac troponin I type 3 (TNNI3), regulatory light chain of myosin (MYL2), essential light chain of myosin (MYL3), tropomyosin 1 (TPM1), phospholamban (PLN), α-actin (ACTC1), cysteine and glycine-rich protein 3 (CSRP3), AMP-activated protein kinase (PRKAG2), α-galactosidase (GLA), four-and-a-half LIM domains 1 (FHL1), lamin A/C (LMNA) and lysosome-associated membrane protein 2 (LAMP2) (Table 1).15 Exons and intron/exon boundaries (± 10 base pairs) of the 15 cardiomyopathy-related genes were amplified by microdroplet polymerase chain reaction (PCR) using RDT 1000 technology (Rain Dance Technologies, Billerica, MA 01821, USA). Libraries were prepared using the Rapid Library 454 FLX protocol, which

Genes

Ensemble gene number

Chromosome: base range

MYBPC3

ENSG00000134571

chr11:47352958–47374253

MYH7

ENSG00000092054

chr14:23881948–23904870

TNNT2

ENSG00000118194

chr1:201328143–201346805

TNNI3

ENSG00000129991

chr19:55663137–55669100

TPM1

ENSG00000140416

chr15:63334838–63364111

MYL2

ENSG00000111245

chr12:111348626–111358404

MYL3

ENSG00000160808

chr3:46899357–46904973

ACTC1

ENSG00000159251

chr15:35080297–35087927

PLN

ENSG00000198523

chr6:118869442–118881586

CSRP3

ENSG00000129170

chr11:19203578–19223589

FHL1

ENSG00000022267

chr X:135229559-135293518:1

PRKAG2

ENSG00000106617

chr 7:151253197-151574210

GLA

ENSG00000102393

X:100652791-100662913

LMNA

ENSG00000160789

chr1:156084461–156109878

LAMP2

ENSG00000005893

chr X:119561682-119603220

MYBPC3, myosin-binding protein 3; MYH7, beta-myosin heavy chain; TNNT2, troponin T; TNNI3, troponin I; MYL2, essential myosin light chain; MYL3, regulatory myosin light chain; TPM1, tropomyosin 1 alpha; PLN, phospholamban; ACTC1, actin; CSRP3, cysteine- and glycine-rich protein 3; PRKAG2, 5′-AMP-actvated protein kinase; GLA, alpha-galactosidase; FHL1, four-and-a-half LIM domains 1; LMNA, lamin A/C; LAMP2, lysosome-associated membrane protein.

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univariate and multivariate regression analysis, with a focus on mortality rather than time to death, therefore justifying the use of Cox’s proportional hazards model rather than logistic regression analysis.

Results The study cohort comprised 43 patients with HCM. The clinical characteristics and co-morbid status of the study population at the initial evaluation are shown in Table 2. The mean age of HCM patients studied was 38.5 ± 14.3 years; 25 (58.1%) were male. Thirteen (30.2%) were black Africans, and the majority (62.8%) were of mixed ancestry. Twenty-six (60.5%) had firstdegree relatives with HCM and five (11.6%) had a family history of sudden cardiac death (SCD) in a first-degree relative. Symptoms of palpitations (79.1%), angina (65.1%), fatigue (58.1%) and effort-related breathlessness (55.8%) were frequently reported by the patients. Ten (23.3%) had a New York Heart Association (NYHA) functional capacity of class III at the initial assessment. An ejection systolic murmur was reported in 18 (41.9%) of patients. The electrocardiographic and echocardiographic characteristics of the study population are shown in Table 2. Four (9.3%) of the HCM patients had atrial fibrillation at diagnosis. On echocardiography, the mean left ventricular (LV) septal thickness in diastole, LV ejection fraction (LVEF) and left atrial diameter were 1.9 ± 0.7 cm, 71.5 ± 8.3% and 3.5 ± 0.8 cm, respectively. Left ventricular outflow tract (LVOT) obstruction, with a resting gradient of greater than 10 mmHg was found in 12 (27.9%) patients. Evidence of diastolic dysfunction was present in the majority of patients, and the mean E/A ratio was 1.2 ± 0.4.

Spectrum of mutations that cause HCM in South Africans Of the 43 patients diagnosed with HCM, 42 were screened for the common founder mutations previously described in the South African population, and all 42 were found to be negative for these variants.10 Further molecular genotypic analysis was undertaken in 35 of these HCM patients for 15 cardiomyopathyassociated genes. Of these 35 probands, mutation screening yielded disease-causing mutations in 10 unrelated individuals (28.6%) (Table 3). The disease-causing mutations were found in two out of the 15 genes screened, with the majority in MYH7 (n = 6 probands; 60%) and the rest in MYBPC3 (n = 4 probands; 40%). Two of the MYH7 mutations were novel, and diseasecausing mutations were found in all ethnic groups tested. No single disease-causing mutation occurred in more than one study subject. There were three genetic variants of unknown significance found in MYBPC3, which were not observed in 195 population controls: c.1224-19G>A, c.1790+5G>A, and c.133G>A. In addition, a large number of known polymorphisms were found in 16 probands in MYBPC3 (tmp_esp_11_47355301, rs113941605 and rs113658284), MYH7 (rs149439730, rs45523835, rs145738465, rs202205780, rs61737803, rs146858930, rs36211714, rs45501694, and rs111626355), TNNT2 (rs113471285, and rs115805892), TPM1 (tmp_esp_15_63356347), MYL3 (rs199474709), CSRP3 (rs112848043), FHL1 (rs182106777), PRKAG2 (rs116605521, and rs113234987), GLA (rs151195362), and LMNA (rs12117552,

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Table 2. Demographic, clinical, electrocardiographic and echocardiographic features at presentation in patients with hypertrophic cardiomyopathy compared to three large contemporary international reports from North America, Taiwan and Saudi Arabia South North Africa America Taiwan (n = 43) (n = 277) (n = 163) 38.5 ± 14.3 47 ± 22 60.9 ± 12.1 25 (58) 152 (55) 84 (52)

Saudi Arabia (n = 69) 42 ± 16 43 (71)

Medical history Age at diagnosis (years) Males Ethnicity (%) Black/African 13 (30) White/Caucasian 2 (5) 277 (100) Coloured/mixed ancestry 27 (63) Indian ancestry 1 (2) Taiwanese 163 (100) Arab 69 (100) First-degree relative with HCM 26 (61) 21 (8) – 2 (5) Second-degree relative with HCM 7 (16) – – – Has family history of SCD 5 (12) – – 4 (9) NYHA functional class I and II 33 (77) – – – III and IV 10 (23) Symptoms 174 (63) Fatigue 25 (58) – – Dyspnoea 24 (56) 121 (74) 31 (65) Palpitations 34 (79) 28 (17) 5 (7) Angina 28 (65) 111 (68) – Presyncope/syncope 12 (28) 20 (12) 2 (4) Smoking 19 (31) – – – Hypertension 12 (28) – 28 (17) – Diabetes 0 (0) – 29 (18) – Alcohol consumption 9 (21) – – – Dyslipidaemia 6 (14) – – – Coronary artery disease 3 (7) – 29 (18) – COPD 2 (5) – – – HIV infection 2 (5) – – – Medical examination Heart rate – – – 71.3 ± 12.7 BPsys – – – 125.8 ± 19.2 BPdia – – – 75.8 ± 11.3 Pedal oedema 5 (11.6) – – – Ejection systolic murmur 18 (41.9) – – – Electrocardiographic findings Sinus rhythm 39 (90.7) – – – Atrial fibrillation 4 (9.3) – 34 (21) – QRS abnormalities present 12 (28) – – – Voltage criteria for LVH 22 (51) – 137 (84) 60 (87) Presence of pathological Q waves 12 (28) – – – T-wave inversion 34 (79) – 108 (66) – Left atrial hypertrophy 10 (23) – – – LBBB 4 (9) – – – RBBB 2 (5) – – – PR prolongation 2 (5) – – – Echocardiographic findings LVEDD (cm) – – 4.1 ± 0.8 4.5 ± 0.5 LVESD (cm) – – 2.7 ± 0.6 2.4 ± 0.4 IVSdia (cm) 2.2* 1.9 ± 0.7 1.9 ± 0.4 –2.1 ± 0.7 IVSsys (cm) – – – 2.1 ± 0.7 LVPFWdia (cm) – 1.2 ± 0.4 1.1 ± 0.3 1.3 ± 0.4 LVEF (%) – – 71.5 ± 8.3 68 ± 13 Left atrial size (cm) – – 3.5 ± 0.8 3.8 ± 0.7 SAM 9 (21) – 80 (49) 39 (57) LVOT obstruction 12 (28) – 78 (48) 28 (41) E/A ratio – – 1.5 (0.9–2.1) 1.2 ± 0.4 Pattern of hypertrophy Sigmoid 13 (30) 75 (27) – 8 (12) Catenoid 23 (53) 92 (33) 29 (42) Neutral 6 (14) 65 (23) 25 (36) Apical 1 (2) 5 (2) 7 (10) All results are means ± standard deviation, unless otherwise indicated. *No standard deviation given. BPdia, diastolic blood pressure; BPsys, systolic blood pressure; COPD, chronic obstructive pulmonary disease; E/A, ratio of early (E) to late (A) ventricular filling velocities on Doppler echocardiography; IVSdia, interventricular septal thickness in diastole; IVSsys, interventricular septal thickness in systole; HCM, hypertrophic cardiomyopathy; HIV, human immunodeficiency virus; LBBB, left bundle brunch block morphology on electrocardiography; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; LVH, left ventricular hypertrophy; LVPFWdia, left ventricular posterior free-wall thickness in diastole; LVOT, left ventricular outflow tract; NYHA, New York Heart Association functional classification for severity of breathlessness; RBBB, right bundle brunch block morphology on electrocardiography; SAM, systolic anterior motion of the anterior mitral valve leaflet; SCD, sudden cardiac death.

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Table 3. Disease-causing mutations found in 10 unrelated index cases with hypertrophic cardiomyopathy Ethnicity

Reported previously?

Gene

Exon

Nucleotide and amino acid change

Type of mutation

Reference

HCM1.1

Indian

Yes

MYH7

c.611G>A (p.R204H)

Missense

Richard, et al. 200318

HCM4.1

Mixed ancestry

MYH7

c.2282C>A (p.T761N)

Missense

Novel

HCM7.1

Mixed ancestry

Yes

MYH7

c.4258C>T (p.R1420W)

Missense

Zou, et al. 201322

HCM11.1

Mixed ancestry

Yes

MYBPC3

c.1000G>A (p.E334K)

Missense

Bahrudin, et al. 200823

HCM14.1

European

MYH7

c.2167C>T (p.R723C)

Missense

Novel

HCM16.1

European

Yes

MYH7

c.746G>A (p.R249Q)

Missense

Zou, et al. 201322

HCM21.1

Black African

Yes

MYBPC3

c.772G>A (p.E258K)

Missense

Andersen, et al. 200424

HCM33.1

Mixed ancestry

Yes

MYBPC3

c.530G>A (p.R177H)

Missense

University of Stellenbosch thesis25

Index case ID

HCM34.1

Black African

Yes

MYH7

c.1357C>T (p.R453C)

Missense

Zou, et al. 201322

HCM38.1

Black African

Yes

MYBPC3

c.1246G>A (p.G416S)

Missense

Tanjore, et al. 200826

HCM, hypertrophic cardiomyopathy; MYBPC3, cardiac myosin-binding protein C; MYH7, cardiac β-myosin heavy chain.

and rs117939448). Two novel single-nucleotide polymorphisms were found in MYH7 (c.1368C>T) and PRKAG2 (c.828C>A) in two different probands. The total number of variants in the 15 genes per HCM patients (regardless of whether it was disease causing or not) ranged from six to 20 (mean: 12.8, SD 3.2; median 12). The patient who died had a higher number of variants (14.8 ± 3.9) compared to survivors (12.5 ± 3.1), although this difference was not statistically significant (p = 0.47).

Outcome of HCM in South Africans The mean duration of follow up was 9.1 ± 3.4 years. Of the 43 patients studied, eight died during the period of follow up. The

1.00

Cumulative proportion surviving

overall Kaplan–Meier survival estimate is shown in Fig. 1A; the cumulative proportion of patients who survived to 10 years was 74%. Complications of chronic heart failure, atrial fibrillation, stroke and evolution to dilated cardiomyopathy with systolic dysfunction were observed in 11 (25.6%), eight (18.6%), four (9.3%) and four (9.3%), respectively. Therapeutic interventions, including surgical myomectomy, alcohol septal ablation and orthotopic heart transplantation were performed on three (7.0%), one (2.3%) and one (2.3%) patients, respectively. At the last visit, 12 (27.9%) reported NYHA functional class III and IV performance status (Table 4). The most frequently prescribed drugs were beta-blockers and calcium channel blockers, used by 33 (76.7%) and 17 (39.5%) patients, respectively (Table 5).

0.75 0.50 0.25 0.00

1.00 0.75 0.50 0.25

NYHA I, II NYHA III, IV

p = 0.026

0.00

Survival time (years)

1.00 0.75 0.50 0.25

Mutation identified No mutation

p = 0.474

0.00

10 Survival time (years)

Cumulative proportion surviving

Survival time (years)

1.00 0.75 0.50 0.25

Cohort survival SA population survival

p = 0.531

0.00

Survival time (years)

Fig. 1. K aplan–Meier survival estimates in HCM. A. Kaplan–Meier plot showing the survival of HCM patients; B. Kaplan–Meier plot showing the survival of HCM patients when stratified by NYHA functional class; C. Kaplan–Meier plot showing the survival of HCM patients when stratified by the presence or absence of HCM-causing mutation(s); D. Kaplan–Meier plot showing the survival of HCM patients when compared to age-, gender- and race-matched members of the South African population.

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Table 4. Follow-up and outcome data n (%)

Outcome data

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Table 6. Cox’s proportional hazards regression model analysis of predictors of mortality in hypertrophic cardiomyopathy Univariate Cox regression

Mean duration of follow up (years ± SD)

9.1 ± 3.4

Total number of mutations per person

12.8 (3.2)

Variables

Regular

37 (86.0)

Lost to follow up

6 (14.0)

Hazard ratio (95% CI)

p-value

Age at diagnosis

1.0 (1.0–1.1)

0.561

Mutation positive

1.8 (0.4–8.9)

0.474

Sarcomeric mutations

1.3 (0.5–3.5)

0.585

1.12 (0.91–1.3)

0.412

IVS

1.6 (0.8–3.4)

0.169

LVEF

1.1 (1.0–1.2)

0.060

Family history of SCD

0.8 (0.1–6.6)

0.840

E/A ratio

2.0 (0.4–10.0)

0.370

6 (14.0)

Loop recorder

3.5 (0.8–14.6)

0.088

Chronic heart failure

4.4 (1.0–18.3)

0.044

No arrhythmia

32 (74.4)

NYHA functional class at last visit

6.2 (1.2–30.6)

0.026

Atrial fibrillation

8 (18.6)

Atrial flutter

1 (2.3)

Ventricular tachycardia

2 (4.7)

Follow-up observation

Death

8 (18.6)

Chronic heart failure

11 (25.6)

ICD insertion

0 (0)

PPM insertion

0 (0)

CRT/biventricular pacing

0 (0)

Loop recorder Arrhythmia present

Myomectomy

3 (7.0)

Alcohol septal ablation

1 (2.3)

Evolution to DCM

4 (9.3)

Orthotopic heart transplantation

1 (2.3)

NYHA functional class at last visit I and II

31 (72.1)

III and IV

12 (27.9)

Stroke

4 (9.3)

All values are number (percentage), unless otherwise stated. ICD, implantable cardioverter defibrillator; PPM, permanent pacemaker; CRT, cardiac resynchronisation therapy; DCM, dilated cardiomyopathy; NYHA, New York Heart Association functional classification for evaluation of severity of dyspnoea.

Cox’s proportional hazards regression showed that survival was predicted by NYHA functional class at last visit (p = 0.026), but not by presence of a disease-causing mutation (p = 0.474), as shown in Figs 1B and 1C, respectively. Survival in this cohort was similar to that of an age- and gender-matched general South African population (Fig. 1D). The presence of chronic heart failure [hazard ratio (HR) 4.4, 95% CI: 1.0–18.3; p = 0.044] and NYHA functional class at last visit (HR: 6.2, 95% CI: 1.2–30.6; p = 0.026) were found to be predictors of mortality on univariate regression analysis. On multivariate analysis, both chronic heart failure and NYHA functional class were not significant as predictors of mortality, as they may be proxies for LVEF (Table 6).

Table 5. Medical therapy at follow up Therapy

n (%)

β-blocker

33 (76.7)

Calcium channel blocker

17 (39.5)

Warfarin

12 (27.9)

ACEI or ARB

9 (20.9)

Furosemide

8 (18.6)

Aspirin

8 (18.6)

Disopyramide

4 (9.3)

Spironolactone

4 (9.3)

Amiodarone

3 (7.0)

Digoxin

2 (4.7)

Nitrates

1 (2.3)

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; β-blocker, beta-blocker.

Total number of mutations per person

Multivariate Cox regression Hazard ratio (95% CI)

p-value

LVEF

1.1 (1.0–1.2)

0.100

Loop recorder

0.8 (0.1–5.3)

0.828

Chronic heart failure

1.6 (0.2–16.2)

0.684

NYHA functional class at last visit

4.2 (0.4–41.3)

0.218

Variables

E/A, ratio of early (E) to late (A) ventricular filling velocities on Doppler echocardiography; IVS, interventricular septal thickness in diastole; HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional classification for severity of breathlessness; SCD, sudden cardiac death. In the univariate and multivariate regression analysis, NYHA was correlated as a binary variable (NYHA FC I–II vs NYHA FC III–IV).

Discussion To our knowledge this is the first prospective study of the clinical profile, spectrum of disease-causing gene mutations and outcome in HCM from the African continent, including black Africans. Age at onset of symptoms (38.5 ± 14.3 years), male preponderance (58%), and major symptoms were similar to those reported in North American, Middle Eastern and Eastern series (Table 2).11,16,17 Nearly 30% of the patients bear mutations in the MYH7 and MYBPC3 genes, which are the commonest genetic causes of HCM.15 While the annual mortality rate of 2.9% was high and the overall survival of 74% at 10 years was low compared to other series of patients with HCM,11 the survival rate was comparable to age- and gender-matched members of the South African population. Survival was predicted by NYHA functional class at last visit. We have found that HCM occurs predominantly in men, with a young age of onset, including black Africans, and with a positive family history of HCM in the majority. Fatigue, breathlessness and palpitations were the commonest symptoms. Atrial fibrillation was found in 9%, left ventricular outflow tract obstruction in 28%, and diastolic dysfunction in most. In a study of the natural history of HCM in non-hospitalised Americans, Maron and others found that 55% of patients were men, the mean age was 47 years, and cardiac symptoms were present in 63% of patients.11 Similarly, in a study from Taiwan, Lee and colleagues found 52% HCM patients to be male, and that men had a younger age of onset of HCM compared to women.16 In this study, the prevalence of apical HCM was three times higher in men, and interestingly, men had a lower prevalence of LVOT obstruction. Thirty-six per cent of Taiwanese HCM patients had pulmonary oedema or paroxysmal atrial fibrillation. More recently, in the first report on the clinical

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characteristics of HCM in Saudi Arabia, Ahmed and co-authors found the population of HCM patients to be 71% male, and with a mean age of 42 years.17 Dyspnoea and palpitations were the commonest symptoms, and LVOT obstruction was found in 28%. To date, over 1 400 mutations have been reported to cause HCM in genes encoding eight sarcomere proteins: beta-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYPBC3), cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), cardiac actin (ACTC), alpha-tropomyosin (TPM1), essential light chain of myosin (MYL3) and regulatory light chain of myosin (MYL2).15,18 Mutations in MYH7 and MYPBC3 occur most often, and account for approximately 50% of HCM cases,19,20 while mutations in TNNT2, TNNI3, ACTC, TPM1, MYL3 and MYL2 collectively account for less than 20% of HCM cases.21 In our study, mutations in MYH7 and MYPBC3 were the commonest causes of HCM. Moolman-Smook and colleagues have done pioneering work on the genetics of HCM in two South African sub-populations: those of European descent and those of mixed ancestry, and have previously reported on common HCM-causing mutations that arose independently and demonstrated clear founder effects in the South African population. These mutations included the MYH7 Ala797Thr (25% prevalence),8 TNNT2 Arg92Trp (15%),9 MYH7 Arg403Trp (5%),7 MYH7 Arg717Gln and the MYH7 Glu499Lys10 mutations, which collectively accounted for 47.5% of cases of HCM from the Eastern and Western Cape provinces of South Africa. To save money and to improve efficiency, a strategy was proposed to first screen for these five founder mutations before undertaking an extensive molecular genetic screening for other HCM mutations in South Africa.10 However, in our study of 42 South African HCM patients, these founder mutations were absent. The mutation yield of screening 15 sarcomeric and non-sarcomeric genes that are associated with HCM was relatively low in this study. Disease-causing mutations in any one of the sarcomeric protein genes are found in up to two-thirds of patients with HCM, and the yield of screening-associated causal genes ranges from 40–70%.15 The indications for molecular genetic testing in cardiomyopathy vary according to the yield of molecular testing, the cost of molecular analyses, and the impact of genetic testing on the medical management of the individual and the family. Given the relatively low yield of screening in this study, molecular genetic testing in Africans with HCM should probably not be carried out routinely as yet, until studies on the full spectrum of causal mutations and the impact of genetic testing on outcome are available. In our study, the mean duration of follow up was 9.1 years, with an annual mortality rate of 2.9%. Complications included heart failure, atrial fibrillation, stroke and evolution to DCM. Myomectomy, alcohol septal ablation and heart transplantation were performed in a small number of patients; however no implantable cardioverter defibrillators (ICDs) were used. The high rates of mortality observed in our study may reflect, in part, the higher mortality rate of the South African population, as well as the skewed nature of tertiary-centre experience with many symptomatic patients. In the USA, HCM was found to have an annual mortality rate of 1.3% and to be associated with stroke, atrial fibrillation, sudden cardiac death, congestive heart failure and the need for

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heart transplantation.11 In Taiwan, HCM was reported to have an annual mortality rate of 0.8%, and the mortality rate could be predicted by LVOT obstruction, atrial fibrillation and female gender.16 In Saudi Arabia, HCM had an annual mortality rate of 0.7%, with five ICDs inserted over seven years of follow up, and a single patient progressing to end-stage dilated cardiomyopathy.17 This study has a number of important limitations. First, the small sample size is a major weakness. This may account for the failure to detect the effect of known predictors of mortality in HCM, such as history of syncope and magnitude of left ventricular hypertrophy. Second, we screened for 15 genes that are commonly associated with HCM. However, there are several important HCM-causing mutations in other genes that were not included in our genetic panel, such as titin (TTN), myosin heavy chain gene (MYH6) and cardiac troponin C (TNNC). Therefore, there is a need for larger, prospective studies of HCM in Africa that encompass all the important genetic causes of the disease.

Conclusions We report on the first prospective investigation of the clinical characteristics, genetics and outcome of HCM in Africans. We found HCM to occur more in men, and with a younger age of onset. Major symptoms and complications were similar to those reported in North American, Middle Eastern and Asian studies. Known and novel disease-causing mutations were identified in the MYH7 and MYBPC3 genes, with a lower yield of mutation screening of about 30%, compared to the expected 40–70% found elsewhere. The mortality rate in this contemporary African HCM series was, however, higher than reported elsewhere, although comparable to age- and gender-matched members of the South African population. Survival was predicted by NYHA functional class at last visit. We are grateful to the patients and families who participated in this study. We acknowledge the assistance of Carolina Lemmer and Sisters Maitele Tshifularo, Unita September and Veronica Francis in the execution of this study. The authors of this article were funded in part by research grants from the Lily and Ernst Hausmann Trust, the International Centre for Genetic Engineering and Biotechnology, University of Cape Town, the Medical Research Council of South Africa, the Discovery Foundation, the National Research Foundation, and the Wellcome Trust (UK).

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Moolman JC, Brink PA, Corfield VA. Identification of a new missense

Clinical and echocardiographic characteristics and outcome analysis. J Saudi Heart Assoc 2014; 26: 7–13.

mutation at Arg403, a CpG mutation hotspot, in exon 13 of the betamyosin heavy chain gene in hypertrophic cardiomyopathy. Hum Mol 8.

18. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, et

Genet 1993; 2: 1731–1732.

al, EUROGENE Heart Failure Project. Hypertrophic cardiomyopathy:

Moolman JC, Brink PA, Corfield VA. Identification of a novel

distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107: 2227–2232.

Ala797Thr mutation in exon 21 of the beta-myosin heavy chain gene in hypertrophic cardiomyopathy. Human Mutation 1995; 6: 197–198. 9.

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19. Konno T, Chang S, Seidman JG, Seiman CE. Genetics of hypertrophic cardiomyopathy. Curr Opin Cardiol 2010; 25: 205–209.

Moolman JC, Corfield VA, Posen B, et al. Sudden death due to troponin T mutations. J Am Coll Cardiol 1997; 29: 549–555.

20. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years. J Am Coll Cardiol 2012; 60: 705–715.

10. Moolman-Smook JC, De Lange WJ, Bruwer EC, Brink PA, Corfield VA. The origins of hypertrophic cardiomyopathy-causing mutations in

21. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and thera-

two South African subpopulations: a unique profile of both independ-

peutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009; 54: 201–211.

ent and founder events. Am J Hum Genet 1999; 65: 1308–1320. 11. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli

22. Zou Y, Wang J, Liu X, Wang Y, Chen Y, Sun K, et al. Multiple gene

DM. Clinical course of hypertrophic cardiomyopathy in a regional

mutations, not the type of mutation, are the modifier of left ventricle

united states cohort. J Am Med Assoc 1999; 281: 650–655.

hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep 2013; 40(6): 3969–3976.

12. Eriksson MJ, Sonnenberg B, Woo A, et al. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol

23. Bahrudin U, Morisaki H, Morisaki T, Ninomiya H, Higaki K, Nanba

2002; 39: 638–645.

E, et al. Ubiquitin-proteasome system impairment caused by a missense

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cardiac myosin-binding protein C mutation and associated with cardiac

the diagnosis and treatment of hypertrophic cardiomyopathy: executive

dysfunction in hypertrophic cardiomyopathy. J Mol Biol 2008; 384(4): 896–907.

summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines.

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Circulation 2011; 124: 2761–2796.

AK, et al. Genetic and phenotypic characterization of mutations in

14. Lauer MS, Larson MG, Levy D. Gender-specific reference M-mode

myosin-binding protein C (MYBPC3) in 81 families with familial hyper-

values in adults: population-derived values with consideration of the

trophic cardiomyopathy: total or partial haploin sufficiency. Eur J Hum Genet 2004; 12(8): 673–677.

impact of height. J Am Coll Cardiol 1995; 26: 1039–1046. 15. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N

25. De Lange WJ. An Investigation of myosin binding protein C mutations in South Africa and a search for ligands binding to myosin binding

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protein C. PhD thesis, University of Stellenbosch, 2004.

16. Lee CH, Liu PY, Lin LJ, Chen JH, Tsai LM. Clinical characteristics and outcomes of hypertrophic cardiomyopathy in Taiwan – a tertiary center

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experience. Clin Cardiol 2007; 30: 177–182.

MYBPC3 gene variations in hypertrophic cardiomyopathy patients in India. Can J Cardiol 2008; 24(2): 127–130.

17. Ahmed W, Akhtar N, Bech-Hanssen O, Mahdi BA, Otaibi TA, Fadel

Risk of cardiac death in diabetic haemodialysis patients increased due to thyroid problems A prospective study found that diabetic haemodialysis patients’ sub-clinical hyperthyroidism and euthyroid sick syndrome may increase the risk of sudden cardiac-related deaths. Dr Christiane Drechsler, of University Hospital Würzburg in Würzburg, Germany, and colleagues conducted a study that included 1 000 patients undergoing haemodialysis for diabetes. Of those patients, 78.1% had euthyroidism, 13.7% had sub-clinical hyperthyroidism, 1.6% had sub-clinical hypothyroidism and 5.4% had euthyroid sick syndrome. Patients with euthyroidism were compared with those who had sub-clinical hyperthyroidism and euthyroid sick syndrome with regard to which group showed an increased short-term (within a 12-month period) risk of sudden cardiac death. It showed that patients who had euthyroidism had a 2.0-fold increased short-term risk of sudden cardiac death, and those who had sub-clinical hyperthyroidism and

euthyroid sick syndrome had a 2.7-fold increase. The results showed that euthyroid sick syndrome was associated with a three-fold increased risk of short-term mortality, but in the long term (two to four years) it showed no increased risk. The study revealed that sub-clinical hypothyroidism was not associated with cardiovascular events or all-cause mortality, which indicated that thyroid disorders had no influence on the risks of myocardial infarction and stroke. This study led researchers to conclude, ‘Regularly assessing a patient’s thyroid status may help estimate the cardiac risk of dialysis patients.’

Reference 1.

http://www.renalandurologynews.com/thyroid-problems-up-cardiac-death-risk-in-diabetic-hd-patients/article/348571/

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Administration of perivascular cyanoacrylate for the prevention of cellular damage in saphenous vein grafts: an experimental model Nail Kahraman, Gunduz Yumun, Arif Gücü, Kadir Kağan Özsin, Temmuz Taner, Ebru Şener, Mehmet Tuğrul Göncü

Abstract Objective: The saphenous vein is the most commonly used graft in coronary artery bypass surgery, since no suitable arterial graft is available. However, the frequency of late graft failure is a cause for research into graft protection. The objective of this study was to investigate the effect of synthetic adhesive cyanoacrylate administration on the saphenous vein graft for preventing vascular damage due to internal pressure on the graft. Methods: In this study we enrolled 20 volunteer subjects who had undergone coronary artery bypass surgery and who had excess saphenous vein grafts. Perivascular cyanoacrylate was administered to one of two saphenous vein grafts explanted from each patient. The other saphenous vein graft from each patient was not treated and was used as the control. A model of the arterial system was created using a saphenous vein cardiopulmonary bypass system. Circulation was maintained at 120 mmHg for 45 minutes. Afterwards, the grafts were subjected to histopathological examination. Results: The cyanoacrylate group of grafts did not develop severe vascular damage compared with many instances of moderate and severe damage due to compression in the control group of grafts (p = 0.003). Conclusion: Perivascular administration of cyanoacrylate appeared to be successful in the prevention of early saphenous vein graft injury. No in vivo study has been performed to date to assess endothelial damage in the saphenous vein, in order to demonstrate the long-term effect of cyanoacrylate. Further investigations are needed in this regard. Keywords: cyanoacrylate, saphenous vein graft, vascular damage, arterial pressure

Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey Nail Kahraman, MD

Namik Kemal University, Tekirdag, Turkey Gunduz Yumun, MD, gunduzyumun@gmail.com

Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey Arif Gücü, MD Kadir Kağan Özsin, MD Temmuz Taner, MD Mehmet Tuğrul Göncü, MD

Department of Pathology, Erzurum Education and Research Hospital, Erzurum, Turkey Ebru Şener, MD

Submitted 13/2/15, accepted 4/10/15 Published online 28/10/15 Cardiovasc J Afr 2015; 26: 159–163

www.cvja.co.za

DOI: 10.5830/CVJA-2015-078

Coronary artery bypass surgery (CABG) in coronary artery disease affords a longer lifespan for patients and higher patency rates of grafts than with percutaneous procedures.1,2 At present, the saphenous vein is the most commonly used graft, as no suitable arterial graft can be prepared for all vessels. At the end of 10-year follow-up studies, it was reported that up to 40% of the saphenous vein grafts had undergone occlusion.3,4 Stenosis in up to half of the patent vessels is a significant negative factor with regard to long-term results after CABG. Therefore, a wide range of investigations has been conducted to investigate protection of saphenous vein grafts. Increases in pulsatile flow and wall tension occur in venous grafts exposed to post-operative arterial pressure. Therefore injuries develop in the wall layers of the blood vessels, particularly the endothelium. Consequently, proliferation and migration of cells, vascular smooth muscle hyperplasia, and the formation of myofibroblasts, as well as neo-intimal development occur.5-7 Numerous studies have been performed involving the use of rigid and elastic supports or fibrin glue for the outside of the venous grafts in order to reduce the stress on them.8-11 The objective of this study was to investigate the protective effect of perivascular cyanoacrylate administration against saphenous vein damage due to blood pressure in patients after CABG.

Methods The study included 20 of the patients who underwent on-pump CABG operations between 2011 and 2012 in our clinic, who agreed to participate in the study, and who had sufficient saphenous vein grafts for use in this study. Two graft samples were taken from each patient to ensure standardisation between the groups. Then each patient’s two grafts were divided into two groups, one with and one without perivascular cyanoacrylate application, to ensure each group had 20 grafts. Patients who had undergone off-pump surgery, those who had had an emergency operation, those with insufficient saphenous vein grafts, those who did not agree to participate, those with known malignancies, and those with haematological problems were excluded from the study. An arterial system model was created using redundant saphenous vein grafts in a cardiopulmonary bypass system (CPB). A device with two 3-cm-long saphenous vein grafts was created during CPB using a new line from the arterial

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line of the pump (Fig. 1). Cyanoacrylate was sprayed on the outer surface of one of the saphenous vein grafts and allowed to dry for five minutes. The other saphenous vein graft was not subjected to any process and both grafts were exposed to pump flow at 120 mmHg for approximately 45 minutes. At the end of the procedure, both saphenous veins were placed into containers with 10% formaldehyde solution and dispatched to the laboratory for histopathological examination.

Histopathological examination The removed grafts were fixed in 10% buffered formaldehyde solution for 24 hours. After routine tissue processing, 5-µm sections were cut from the paraffin-embedded blocks. These sections were stained with haematoxylin and eosin (H&E), histochemically with Masson’s Trichrom, and immunohistochemically with CD34, which is an endothelial marker. All sections were coded and the endothelium was examined under a light microscope by a pathologist who was unaware of the treatment protocol applied (Olympus CX 51, Tokyo, Japan). The histomorphological classification of endothelial injury was as follows: • No injury: endothelial cells are in contact with each other, the cell has no change in contents or reduction in diameter. Platelets and other blood cells may or may not have adhesions to the endothelium (Fig. 2). • Type 1 injury: while the integrity of endothelial cells is maintained on the entire endothelial surface and endothelial cells are in contact with each other, there is a change in contents and reduction in diameter (flattening) of the cell. There is adhesion of the platelets and other blood cells to the endothelium (Fig 2). • Type 2 injury: there is detachment of the cells from the junctions and lack of endothelial cells in places (Fig. 3). • Type 3 injury: there is endothelial cell peeling and the subsequent formation of sub-endothelial tissue (Fig. 4).

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was used to evaluate the analysis of categorical data. SPSS 18 (SPSS Inc, Chicago, IL, USA) software was used for statistical evaluations.

Results Endothelial injury was determined from the diameter of the saphenous vein, which remained unchanged in the group supported with cyanoacrylate, whereas severe distention of the saphenous vein occurred in the control group. Endothelial injury was examined by H&E staining and immunohistochemically with CD34 staining, which is an endothelial marker. On first impression, no severe damage was seen in the saphenous vein grafts from the cyanoacrylate group,

Statistical analysis The variables obtained were classified into categories and indicated as numbers and percentages. The chi-squared test C

Fig. 1. P erivascular cyanoacrylate applied to one of the saphenous vein grafts, prepared from the same patient, for the purpose of external support.

Fig. 2. A shows mild endothelial cell loss (black arrows) with no oedema and no minimal intimal separation (white arrow). B shows CD34-labelled endothelial cell loss (black arrows). C shows minimal separation of the tunica media and intima but no loss of organelles.

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B B

Fig. 3. A shows moderate endothelial cell loss (black arrows). B shows moderate loss of CD34-labelled endothelial cells (black arrows). C shows significant separation between the tunica media and intima (black arrows), and oedema (white arrow). Additionally, there is mild loss in the organelle distribution in the collagen fibres.

Fig. 4. A shows severe endothelial cell loss (black arrows). B shows nearly total loss of CD34-labelled endothelial cells (black arrows). C shows significant separation between the tunica media and intima (black arrows), and oedema (white arrow). Additionally, there is loss in the organelle distribution in the collagen fibres.

whereas severe endothelial injury and tunica media defects were seen in the control group. Within the frame of classification of endothelial injury, in the control group, no significant injury was observed in three samples, whereas type 1, type 2 and type 3 vascular endothelial injury was seen in six, six and five grafts, respectively. In the

cyanoacrylate group, no endothelial injury was observed in seven grafts, type 1 and type 2 endothelial injury was seen in 10 and two grafts, respectively, and there was no type 3 injury in the grafts. Endothelial injury was significantly less in the cyanoacrylate group, as shown by the assessment of intergroup results (Table 1). The cyanoacrylate group did not exhibit any significant change in the medial layer of the saphenous vein grafts, whereas Massonâ&#x20AC;&#x2122;s Trichrom staining demonstrated significant separation and oedema between the tunica media and intima in the untreated saphenous vein graft group.

Table 1. Distribution of saphenous vein injury in the groups as per classification Group 1 (perivascular cyanoacrylate)

Group 2 (control)

No injury

Type 1 injury

Type 2 injury

Type 3 injury

Class of vascular damage

p-value

0.003

Discussion In this study, a model of the arterial system was established and the saphenous vein graft was exposed to internal pressure.

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Perivascular administration of cyanoacrylate onto the saphenous vein graft to prevent vascular injury due to extreme stress in group 1 proved to be protective in vitro. CABG remains the superior method for promoting quality of life and lifespan in the treatment of coronary artery disease affecting multiple vessels. Long-term success is determined by graft success. Atherosclerosis and early occlusions may be seen in a short period of time, particularly in venous grafts. Increased rates of atherosclerosis and rapid neo-intimal hyperplasia in venous grafts are described as endothelial injury and endothelial dysfunction as a result of exposure of the vein to the arterial system in peri-operative graft preparations.3-5 In recent years, pharmacological, genetic and physical protective methods have been described to provide protection against early injury to saphenous vein grafts.3-15 Ip et al. classified coronary endothelial injury into three types and reported that particularly type 3 injury may result in stenosis and occlusion of the coronary artery.16 Endothelial injury was defined as: type 1 injury: normal morphology despite functional changes in the endothelial layer; type 2 injury: maintenance of internal elastic lamina and medial layer despite separation, local peeling and intimal damage in the endothelial layer; type 3 damage: peeling of the endothelial layer and subsequent formation of sub-endothelial tissue, and intimal and medial damage in the respective classification. Okazaki et al.17 classified endothelial injury into five stages. The classification includes stage 1: normal morphology; stages 2 and 3: minor or diffuse adhesion of blood cells (corresponding to type 1 injury); stage 4: rare isolated separation in endothelial cells (corresponding to type 2 injury); stage 5: generalised lack of endothelial cells (corresponding to type 3 injury). In particular, development of type 3 (stage 5) injury and widespread formation of a sub-endothelial layer will lead to platelet aggregation and the formation of thrombus as a result of contact between blood components and this layer. This will trigger smooth muscle proliferation and migration with mitogen factors; hence this may result in early or late stenosis or occlusion in the anastomosis area.16-17 Stooker et al. exposed saphenous veins to an arterial systemlike pressure atmosphere using a non-pulsatile cardiopulmonary device. The study indicated that endothelial injury of the saphenous vein graft was prevented by fibrin glue.10 Fibrin and fibrinogen degradation products proved to be potent chemotactic agents for saphenous vein grafts.14 However, in a report by Nomura et al. regarding the use of perivascular fibrin glue, they state it may direct the cellular stimulus and migration to the adventitial level, preventing intimal thickening.15 Perivascular fibrin glue and losartan administration were demonstrated by Moon et al. to prevent neo-intimal hyperplasia following saphenous vein graft angioplasty.18 Absorbable (vicryl) and non-absorbable (polyester) loose stents significantly reduced neo-intimal thickening, as shown by the examination of saphenous vein grafts at one and six months.6,9 Looseness of the support was reported as the potential reason.7 However, the space between the graft and these loose grafts was filled with fibrin after a short time and the loose structure disappeared, stimulating new microvascular growth in that area.9,19 It has therefore been suggested to cause development of the vasa vasorum and protection against vascular hypoxia, not intimal thickening.

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However, in an in vivo study by Wan et al., saphenous vein graft intimal thickening could not be reduced by fibrin glue in the long term.5 The reason is that the chemotactic effects of fibrin cannot be controlled and it will stimulate late intimal thickening. We did not discover any other studies on this topic, apart from cyanoacrylate-related vascular embolism and arterial intervention-site repair.20,21 These resources specify the superior adhesion characteristic of cyanoacrylate and its low fibrosis rate during the follow-up period. Dai et al. showed reduced intimal and medial thickening of the vein graft and inflammatory responses in their rabbit model study.22 However, it is not known whether the use of cyanoacrylate in vivo will cause graft restriction and related problems. This is because previously used supportive stents were loose or absorbable, whereas cyanoacrylate is a strong adhesive expected to have long-term durability.

Conclusion This study demonstrated that cyanoacrylate provided external support to the graft without any chemotactic effect, and primary protection of the graft against damage due to extreme stress. However, in vivo studies are required to investigate the effects on the graft in the long term.

References 1.

Kajimoto K, Miyauchi K, Yamamoto T, Daida H, Amano A. Metaanalysis of randomized controlled trials on the treatment of unprotected left main coronary artery disease: one-year outcomes with coronary artery bypass grafting versus percutaneous coronary artery intervention with drug-eluting stent. J Card Surg 2012; 27(2): 152–157.

Oh EH, Imanaka Y, Hayashida K, Kobuse H. Meta-analysis comparing clinical effectiveness of drug-eluting stents, bare metal stents and coronary artery bypass surgery. Int J Evid Based Healthcare 2007; 5(3): 296–304.

Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation 1998; 97: 916–931.

Shah PJ, Gordon I, Fuller J, Seevanayagam S, Rosalion A, Tatoulis J, et al. Factors affecting saphenous vein graft patency: clinical and angiographic study in 1402 symptomatic patients operated on between 1977 and 1999. J Thorac Cardiovasc Surg 2003; 126: 1972–1977.

Wan S, Arifi AA, Chan MC, Yip JH, Ng CS, Chow LT, et al. Differential, time-dependent effects of perivenous application of fibrin glue on medial thickening in porcine saphenous vein grafts. Eur J Cardiothorac Surg 2006; 29(5): 742–746.

Mehta D, George SJ, Jeremy JY, Izzat MB, Southgate KM, Bryan AJ, et al. External stenting reduces long-term medial and neointimal thickening and platelet derived growth factor expression in a pig model of arteriovenous bypass grafting. Nat Med 1998; 4: 235–239.

Angelini GD, Lloyd C, Bush R, Johnson J, Newby AC. An external, oversized, porous polyester stent reduces vein graft neointima formation, cholesterol concentration, and vascular cell adhesion molecule 1 expression in cholesterol-fed pigs. J Thorac Cardiovasc Surg 2002; 124: 950–956.

Stooker W, Niessen HW, Baidoshvili A, Wildevuur WR, van Hinsbergh VW, Fritz J, et al. Perivenous support reduces early changes in human vein grafts: studies in whole blood perfused human vein segments. J Thorac Cardiovasc Surg 2001; 121: 290–297.

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Jeremy JY, Bulbulia R, Johnson JL, Gadsdon P, Vijayan V, Shukla N, et

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al. A bioabsorbable (polyglactin), nonrestrictive, external sheath inhibits

smooth muscle cell proliferation. J Am Coll Cardiol 1990; 15: 1667–1687.

porcine saphenous vein graft thickening. J Thorac Cardiovasc Surg 2004;

17. Okazaki Y, Takarabe K, Murayama J, Suenaga E, Furukawa K, Rikitake

127: 1766–1772. 10. Stooker W, Niessen HW, Wildevuur WR, van Hinsbergh VW, Fritz J, Jansen EK, et al. Perivenous application of fibrin glue reduces early injury to the human saphenous vein graft wall in an ex vivo model. Eur J Cardiothorac Surg 2002; 21: 212–217. 11. Wan S, Yim APC, Johnson JL, Shukla N, Angelini GD, Smith FCT,

K, et al. Coronary endothelial damage during off-pump CABG related to coronary-clamping and gas insufflation. Eur J Cardiothorac Surg 2001; 19: 834–839. 18. Moon MC, Molnar K, Yau L, Zahradka P. Perivascular delivery of losartan with surgical fibrin glue prevents neointimal hyperplasia after arterial injury. J Vasc Surg 2004; 40: 130–137.

et al. The endothelin-1A receptor antagonist BSF 302146 is a potent

19. Vijayan V, Shukla N, Johnson JL, Gadsdon P, Angelini GD, Smith FC,

inhibitor of neointimal and medial thickening in porcine saphenous

et al. Long-term reduction of medial and intimal thickening in porcine

vein-carotid artery interposition grafts. J Thorac Cardiovasc Surg 2004;

saphenous vein grafts with a polyglactin biodegradable external sheath. J

127: 1317–1322.

Vasc Surg 2004; 40: 1011–1019.

12. Shukla N, Angelini GD, Ascione R, Talpahewa S, Capoun R, Jeremy JY.

20. Del Corso A, Bargellini I, Cicorelli A, Perrone O, Leo M, Lunardi A,

Nitric oxide donating aspirins: novel drugs for the treatment of saphen-

et al. Efficacy and safety of a novel vascular closure device (Glubran

ous vein graft failure. Ann Thorac Surg 2003; 75: 1437–1442.

2 seal) after diagnostic and interventional angiography in patients with

13. Wan S, George SJ, Nicklin SA, Yim APC, Baker AH. Overexpression of p53 increases lumen size and blocks neointima formation in porcine interposition vein grafts. Mol Ther 2004; 9: 689–698. 14. Jeremy JY, Dashwood MR. Microvascular repair. In: Shepro AM, ed. Encyclopaedia of the Microvasculature. Elsevier Science, 2005: 903–911.

peripheral arterial occlusive disease. Cardiovasc Intervent Radiol 2013; 36(2): 371–376. 21. Kull S, Martinelli I, Briganti E, Losi P, Spiller D, Tonlorenzi S, et al. Glubran 2 surgical glue: in vitro evaluation of adhesive and mechanical properties. J Surg Res 2009; 157(1): e15–21.

15. Nomura H, Naito M, Iguchi A, Thompson WD, Smith EB. Fibrin gel

22. Dai L, Gao M, Gu C, Zhang F, Yu Y. Perivenous application of

induces the migration of smooth muscle cells from rabbit aortic explants.

cyanoacrylate tissue sealants reduces intimal and medial thickening of

Thromb Haemost 1999; 82: 1347–1352.

the vein graft and inflammatory responses in a rabbit model of carotid

16. Ip JH, Fuster V, Badimon L, Badimon J, Taubman MB, Chesebro JH.

artery bypass grafting. Eur J Cardiothorac Surg 2015, Apr 2. pii: ezv111.

SHARE: Sustain Health development in Africa through Responsible Education Founded nine years ago by Prof Jean Marco (France) and Dr Francois Bourlon (Monaco), who has been largely instrumental in driving it, SHARE is a non-profit organisation that provides essential training to African cath lab staff by linking them with experienced teams in Europe, the USA and Asia Pacific. It’s aimed at those African cardiologists who wish to build a local diagnostic and interventional practice and need to develop their skills. ‘Africa has 1.1 billion people in 54 countries, only 20 of which have a cath lab’, said Dr Bourlon. ‘We therefore saw a need for a training organisation, which is funded by the private sector and industry partners.’ SHARE’s first initiative was the establishment of a medicosurgical centre in Nouakchott, Mauritania, North Africa. ‘We started from nothing, which makes it a significant achievement. The centre comprises one cath lab, two operating theatres, one recovery room, one sterilisation unit and one in-patient unit. With the assistance of the Europa Organisation, we have trained four cardiologists and four allied health professionals, who committed to return to Mauritania once their training was finished and submit written activity reports every three months. The unit is now autonomous, undertaking angiography, percutaneous interventions and cardiac surgery. It has even organised its own congress.’

Now SHARE is facilitating the training of an interventional cardiologist in mitral valvuloplasty. He is currently based in Morocco, further to a year of training in Italy. ‘We’re also developing training material for nurses and allied professionals in the form of short educational films that will be made available on YouTube’, said Dr Bourlon. With its Mauritanian initiative successfully completed, SHARE has turned its attention to Mali in West Africa with a view to duplicating the Mauritanian experience. ‘There is currently no such facility in the capital, Bamako, so we are looking to design and build a cath lab there. The initial steps are under way, including one cardiologist currently being trained in Monaco.’ SHARE’s vision for the future is to consolidate its actions in Mauritania and Mali, and extend this vision to other African countries. ‘We’re looking to find new training centres in both Europe and Africa and facilitate the participation of trained personnel in educational activities. We wish to create a community of learners who are united in a shared experience. We accept that progress is slow, but we keep moving forward step by step’, concluded Dr Bourlon. Source: AfricaPCR 2016.

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Effects of a PPAR-gamma receptor agonist and an angiotensin receptor antagonist on aortic contractile responses to alpha receptor agonists in diabetic and/or hypertensive rats Ibrahim Tugrul, Turhan Dost, Omer Demir, Filiz Gokalp, Ozlem Oz, Necip Girit, Mustafa Birincioglu

Abstract Aim: The aim of this study was to investigate the effects of pioglitazone and losartan pre-treatment on the aortic contractile response to the alpha-1 agonist, phenylephrine, and the alpha-2 agonist, clonidine, in L-NAME-induced hypertensive, STZ-induced diabetic, and hypertensive diabetic rats. Methods: Male Wistar rats were randomly allocated to four groups: control, diabetic (DM), hypertensive (HT) and hypertensive diabetic (HT + DM) groups. Three weeks after drug application, in vitro dose–response curves to phenylephrine (Phe) (10-9–10-5 M) and clonidine (Clo) (10-9–10-5 M) were recorded in aortic rings in the absence (control) and presence of pioglitazone (10 μM) and/or losartan (10 μM). Results: Pioglitazone and losartan caused a shift to the right in contractile response to phenylephrine in all groups. The sensitivity of the aortic rings to phenylephrine was decreased in the presence of pioglitazone and/or losartan in all groups. The contractile response of clonidine decreased in the presence of pioglitazone and/or losartan in the control, HT and DM groups. Conclusion: The sensitivity of aortic rings to alpha-1 and alpha-2 adrenoceptors was decreased in the presence of pioglitazone and/or losartan in diabetic and hypertensive rats. Concomitant use of PPAR-gamma agonists, thiazolidinediones, and angiotensin receptor blockers may be effective treatment for diabetes and hypertension. Keywords: diabetes, hypertension, pioglitazone, losartan, alpha adrenoceptors Submitted 27/3/15, accepted 4/10/15 Published online 4/5/16 Cardiovasc J Afr 2016; 27: 164–169

www.cvja.co.za

DOI: 10.5830/CVJA-2015-080

Hypertension and diabetes mellitus are both common diseases worldwide and they co-exist frequently, resulting in significant rates of morbidity and mortality. Diabetes mellitus Department of Medical Pharmacology, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey Ibrahim Tugrul, MD, ibrahimtugrul@yahoo.com Turhan Dost, MD Omer Demir, MD Filiz Gokalp, MD Ozlem Oz, MD Necip Girit, MD Mustafa Birincioglu, MD

and hypertension have been identified as risk factors for cardiovascular disease and cause altered vascular responsiveness to several vasoconstrictors and vasodilators.1-3 Endotheliumdependent vasodilation is reduced in diabetes, largely due to excessive oxidative stress and the bio-availability of nitric oxide. Endothelium-derived nitric oxide (NO) is a potent endogenous nitrovasodilator and plays a major role in modulation of vascular tone.4 NG-nitro-L-arginine methyl ester (L-NAME)induced hypertension has been one of the most frequently used models of experimental hypertension since 1990.5 Thiazolidinediones (TZDs) such as pioglitazone are a class of oral antidiabetic agent that act primarily by decreasing insulin resistance. Drugs in this class act as potent and highly selective agonists for peroxisome proliferator-activated receptor gamma (PPARg).6 Pioglitazone repairs blunted endothelium-dependent vasodilatation, protects against oxidative stress and lowers blood pressure.7-11 The vascular endothelium mediates relaxant responses to a wide range of vasodilators and modulates the constrictor responses to alpha agonists such as phenylephrine and clonidine. The streptozotocin (STZ)-induced diabetic rat model has been widely used to study changes in vascular reactivity to alpha adrenoceptor agonists.12 Hyperglycaemia is likely to modulate physiological responses to angiotensin II and may contribute to the pathogenesis of vascular dysfunction in diabetes.13 Angiotensin type 1 receptor (AT1R) blockers (ARBs) such as losartan are widely used in the treatment of hypertension.14,15 It is not clear how concomitant use of medication in the treatment of hypertension and diabetes has effects on vascular contractility. Hence the aim of this study was to investigate the effect of pioglitazone and losartan pre-treatment on the aortic contractile response to the alpha-1 agonist, phenylephrine (Phe), and the alpha-2 agonist, clonidine (Clo), in L-NAME-induced hypertensive, STZ-induced diabetic, and hypertensive diabetic rats.

Methods Male Wistar rats (250–300 g) were obtained from the experimental animal centre of Adnan Menderes University and all experiments were performed according to the principles and guidelines of the Adnan Menderes University animal ethics committee. Male Wistar rats were randomly allocated to four groups: a control group (Cont) (n = 15), a diabetic group (DM) (n = 20), a hypertensive group (HT) (n = 20), and a hypertensive diabetic group (HT + DM) (n = 20). All rats were housed at 22–24°C on a 12-hour dark–light cycle and received food and water (or L-NAME solution in

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drinking water in the hypertensive groups) ad libitum. Diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ in the DM group. Hypertension was induced by giving L-NAME (50 mg/kg) in the drinking water for three weeks in the HT group. Hypertension plus diabetes were induced by a single intraperitoneal injection of 50 mg/kg STZ and providing L-NAME (50 mg/kg) in the drinking water for three weeks in the HT + DM group. Body weights of the treated groups were measured at weekly intervals. In vitro experiments were started three weeks after the drug injections. Systolic blood pressure (SBP) of the rats was measured before the in vitro experiments using the tail-cuff method. Blood was obtained from a tail vein in conscious rats. At least five readings were done at every session and the mean of four values was used to obtain the SBP of each rat. Glucose concentrations were determined using an International Medical Equipment Diabetes Care (IME-DC) blood glucose meter (Oberkotzau, Germany).

Preparation of aortic rings and in vitro experiments The rats were anaesthetised with ketamine and xylasine (50 and 5 mg/kg intraperitoneal, respectively). A thoracotomy was performed and the thoracic aorta was removed from the diaphragm to the heart. The aorta was then placed in ice-cold Krebs’ solution where it was cleaned and any adhering fat was removed. The composition of the Krebs’ solution (mmol/l) was 118.0 NaCl; 25.0 NaHCO3; 4.7 KCl; 1.2 KH2PO4; 1.2 MgSO4·7H2O; 2.5 CaCl2; and 10.1 glucose. The aorta was then cut into small rings (4–5 mm in width). The rings were suspended horizontally between two stainless steel wires and mounted in a 20-ml organ bath filled with warmed (37°C) and oxygenated (95% O2 and 5% CO2) Krebs’ solution. One end of the ring was connected to a force transducer (MAY FDT 05, Commat Ltd. Ankara, Turkey). The rings were equilibrated for 60 min under a resting tension of 2 g with the bath fluids being changed every 15 min. Measurement of the isometric force was recorded on a data-acquisition system (MP 36, Biopac Systems, Inc). After the equilibration period, the rings were sub-maximally contracted with Phe (10-7 M), and the cumulative concentration– response curve to acetylcholine (10-9–10-5 M) was then obtained to test their contractile capacity. Intact vessels failing to achieve at least 60% relaxation to acetylcholine were assumed to be damaged and were discarded. Cumulative responses to Phe (10-9–10-5 M) and Clo (10-9–10-5 M) were recorded in the aortic Table 1. Body weight, blood glucose levels and systolic blood pressure before the in vitro experiments

Parameters Body weight (g)

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Control group (n = 15)

DM group (n = 20)

HT group (n = 20)

HT+DM group (n = 15)

275.1 ± 6.1

279.1 ± 5.9

309.4 ± 9.5

201.1 ± 7.2a

177.6 ± 15.4

395.4 ± 14.1b

187.9 ± 3.9c

161.5 ± 7.1c

Blood glucose 120.3 ± 6.6 371.7 ± 18.1b level (mg/dl) Systolic blood 96.4 ± 2.9 155.2 ± 5.2c pressure (mmHg)

Values are expressed as mean ± SEM. a p < 0.05, compared to control group. b p < 0.05, compared to control group. Blood glucose levels > 250 mg/dl (13.88 mmol/l) indicated diabetes. c p < 0.05, compared to control group.

rings in the absence (control) and presence of pioglitazone (10 μM) and/or losartan (10 μM), which was added to the bathing solution 15 min prior to the contractile responses of Phe or Clo. Pioglitazone hydrochloride was obtained as a gift sample from Sandoz (Istanbul, Turkey). Streptozotocin, phenylephrine, clonidine, L-NAME and the other chemicals were purchased from Sigma Chemicals. Losartan potassium was purchased from Fluka China (Interlab, Izmir, Turkey).

Statistical analysis The results are expressed as mean ± SEM. Statistical evaluation of the data was performed by analysis of variance (ANOVA) and the Student’s t-test. Results were considered significant when p < 0.05. The agonist pD2 value (–log EC50 ) was calculated from the concentration–response curve by non-linear regression analysis of the curve, using a base-fitting program (Prism, Graphpad).

Results STZ-injected animals developed diabetes in the DM and HT + DM groups. In the HT + DM group, five rats died in the first week after the STZ injection. The body weights, blood glucose levels and SBP are shown in Table 1. There was a significant increase in blood glucose levels in the STZ-injected groups (DM and HT + DM groups). The daily intake of L-NAME was calculated from the daily water intake and was approximately 21–23 mg/kg/day for the HT and HT + DM groups. There was a significant increase in SBP in the L-NAME-treated groups (HT and HT + DM groups) Table 1. Phe induced a concentration-dependent contractile response in the aortic rings from all four groups. These curves are shown in Figs 1–4. There was no significant change in maximum contractile response (Emax) to Phe in all groups due to the presence of pioglitazone and/or losartan; these drugs shifted the contractile response to Phe to the right. The sensitivity of the aortic rings to Phe was however decreased in the presence of pioglitazone and/or losartan in all groups [Table 2 (pD2 value)]. There was significant decrease in maximum contractile response (Emax) to Clo in the control group due to the presence Table 2. Acute effects of pioglitazone and losartan on vascular sensitivity (pD2) to pheylephrine in segments of thoracic aorta from Wistar rats Control group pD2 (n = 15)

HT group pD2 (n = 7)

DM group HT+DM group pD2 (n = 19) pD2 (n = 12)

Control

7.26 ± 0.08

7.53 ± 0.04

7.29 ± 0.07

7.27 ± 0.07

Pioglitazone

6.80 ± 0.08a

7.04 ± 0.07a

7.10 ± 0.06a

7.23 ± 0.07

Losartan 6.95 ± 0.13b 7.03 ± 0.06b 7.13 ± 0.10 6.76 ± 0.10b Pioglitazone 6.61 ± 0.08c 6.81 ± 0.08c,d 6.97 ± 0.05c 6.97 ± 0.09c,d + losartan n is the number of aortic segments in each group. Values are expressed as mean ± SEM. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Control group: aCont vs pio (p < 0.001); bCont vs los (p < 0.001); cCont vs pio+los (p < 0.001). HT group: aCont vs pio (p < 0.001); bCont vs los (p < 0.001); cCont vs pio+los (p < 0.001); dPio vs pio+los (p = 0.046). DM group: aCont vs pio (p = 0.037); bCont vs los (p = 0.005); cCont vs pio+los (p = 0.001). HT + DM group: cCont vs pio+los (p = 0.013); dPio vs pio+los (p = 0.030).

2000

1500

1000

Cont Pio Los Pio + Los

500

7 6 -log M Phenylephrine

Contraction (mg)

2000

1000

2000

1500

Cont Pio Los Pio + Los

500 0

7 6 -log M Phenylephrine

Fig. 3. Effects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of phenylephrine in DM group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM.

2000

1000

Cont Pio Los Pio + Los

500 0

Fig. 1. E ffects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of phenylephrine in the control group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM.

Contraction (mg)

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Contraction (mg)

166

1000

Cont Pio Los Pio + Los

500 0

7 6 -log M Phenylephrine

Fig. 2 E ffects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of phenylephrine in the HT group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM.

Fig. 4. Effects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of phenylephrine in the HT + DM group. Cont: control, Pio: pioglitazone, Los : losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM.

of pioglitazone and/or losartan (Fig 5). In the absence of pioglitazone and losartan (control), Clo induced contraction. In the presence of pioglitazone and/or losartan, Clo induced relaxation in the control aortic rings (Fig. 5). In the HT group, Clo did not cause relaxation. The contractile response to Clo was decreased in the presence of pioglitazone and/or losartan (Fig. 6). In the DM group, the contractile response to Clo was significantly decreased in the presence of pioglitazone and losartan, but not in the presence of either pioglitazone or losartan alone (Fig. 7). In the HT + DM group, the decrease in contractile response to Clo was not significant in the presence of pioglitazone and losartan (Fig. 8).

the contractile responses to phenylephrine and decreased the maximum clonidine contraction. Various authors have reported on the blood pressurelowering effects of PPAR-gamma agonists such as pioglitazone in rats and monkeys, and in patients with type 2 diabetes and hypertension.9,16-18 Majithiya et al. noted an increase in SBP in STZ-induced (55 mg/kg, intravenous) diabetic Sprague-Dawley rats, and also reported that pioglitazone administration to these rats lowered their blood pressure.10 Diep et al. showed that treatment with pioglitazone (10 mg/kg/day) or rosiglitazone (5 mg/kg/day) for seven days attenuated the development of hypertension, improved endothelial dysfunction induced by angiotensin II infusion, and corrected vascular structural abnormalities.19 Nomura and co-workers reported their findings regarding the effect of pioglitazone on the contractility of isolated blood vessels.20 Buchanan and colleagues showed that the addition of pioglitazone to vascular preparations decreased KCl- and norepinephrine-induced vasoconstriction in vitro.11 Accordng to Majithiya and co-workers, administration of pioglitazone for four weeks restored elevated blood pressure to normal, reduced the enhanced contractility to phenylephrine, and restored acetyl choline-induced relaxation.10

Discussion This study investigated the effects of pioglitazone and losartan on aortic contractile responses to alpha adrenoceptors in diabetic and/or hypertensive rats. We examined the effects of pioglitazone and losartan on vascular contractility in control, L-NAME-induced hypertensive, STZ-induced diabetic, and hypertensive diabetic rats. The major findings of this study were that pre-treatment of rat aortic rings with pioglitazone (10 μM) and/or losartan (10 μM) decreased the sensitivity of

400 300 200 100 0 –100 –200 –300 –400

Cont Pio Los Pio + Los

* *#

400

7 6 -log M Clonidine

200 100

Fig. 5. E ffects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of clonidine in the control group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM (n = 14). *Cont vs Pio (p = 0.001); *Cont vs Los (p = 0.011); #Cont vs Pio+Los (p < 0.001).

Cont Pio Los Pio + Los

300

0 9

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Contraction (mg)

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* 9

7 6 -log M Clonidine

Fig. 7. Effects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of clonidine in DM group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM (n = 16). *Cont vs Pio+Los (p = 0.005).

Contraction (mg)

400 300 200 100

* **

0 –100

7 6 -log M Clonidine

Contraction (mg)

400 Cont Pio Los Pio + Los

Fig. 6. E ffects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of clonidine in the HT group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM (n = 5). *Cont vs Pio (p = 0.004); *Cont Clo vs Los (p = 0.014); *Cont Clo vs Pio+Los (p = 0.001).

The endothelium is involved in the beneficial vascular action of the glitazones.21 Various authors have shown that pioglitazone directly dilates blood vessels by blocking the calcium channels.11,22 It has been reported that a decrease in blood pressure due to pioglitazone is due to direct dilation of the vascular smooth muscles by blocking the calcium channels or reducing total peripheral resistance.11,22,23 In vivo PPAR-alpha and -gamma agonists have been shown to reduce superoxide generation, restore endothelial dysfunction and improve vasorelaxation to acetyl choline in the aorta of diabetic rats.10,24 Majithiya and colleagues reported that treatment with pioglitazone reduced blood pressure, reduced oxidative stress and restored endothelial function in STZ-induced diabetic rats. The fact that pioglitazone reduced oxidative stress may have been a cause of the reduction in blood pressure. The protective effect of pioglitazone against oxidative stress may prevent the breakdown of NO, which may improve vascular function. Similar observations were made by Bagi and co-workers that pioglitazone increased NO bio-availability and reduced

Cont Pio Los Pio + Los

300 200 100 0 –100

7 6 -log M Clonidine

Fig. 8. Effects of pioglitazone and losartan on the response of aortic segments to increasing concentrations of clonidine in the HT + DM group. Cont: control, Pio: pioglitazone, Los: losartan, Pio+Los: pioglitazone + losartan. Values are expressed as mean ± SEM (n = 13).

oxidative stress in coronary arterioles of mice with type 2 diabetes.25 Matsumoto and colleagues reported that chronic treatment with pioglitazone restored impaired NO-mediated, endotheliumdependent relaxation in diabetic rat aortae.26 It has been shown that reduction in blood pressure in the case of STZ-induced diabetic rats was NO mediated.4 Calnek and co-workers reported that PPARgamma agonists increased NO bioavailability in cultured cells.27 Pioglitazone was shown to directly induce a relaxation of rat aortae pre-contracted with phenylephrine, which was inhibited by L-NAME.10 Similarly, indomethacin-treated vessels incubated with pioglitazone markedly reduced the phenylephrine contractions.3 Although most researchers agree that the sensitivity to phenylephrine was unchanged during the early stage of diabetes (up to 12 weeks in STZ-induced diabetic rats), they disagree on the response to phenylephrine. Agrawal and McNeill reported an increase in contractility in response to phenylephrine,28 Pfaffman and co-workers reported a decrease,29 and Scarborough and Carrier and White and Carrier reported no change.30,31 In contrast, studies that extended the diabetic duration up to 43–52 weeks have demonstrated a consistent increase in sensitivity to noradrenaline in rat aortae32 and mesenteric arteries33 from STZ-induced diabetic rats.

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In our study, we suggest that our diabetic rats did not have enough time to develop a sufficiently severe degree of vascular dysfunction to manifest an effect to phenylephrine. From our results, acute pioglitazone/losartan pre-treatment did not significantly change the maximum contractile responses to phenylephrine in the control, diabetic or hypertensive rats. We attempted to determine whether these drugs affected the endothelial modulatory responses to vasoconstriction produced by phenylephrine. Sensitivity of the aortic rings to phenylephrine was decreased in the presence of pioglitazone and/or losartan. The glitazones have been shown by Asano et al. to decrease smooth muscle cell contractility,34 and by Dormandy et al. to cause improvement in vascular function.35 We believe, however, that the blunted adrenergic responses observed in the presence of glitazones were mediated by the action of these drugs on the endothelial cells, since the effect disappeared when the endothelium was removed in a study Mendizabal and co-workers.21

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azone on L-NAME induced hypertension in diabetic rats. Vascul Pharmacol 2005; 43: 260–266. 5.

Gardiner SM, Compton AM, Bennett T, Palmer RM, Moncada S. Regional haemodynamic changes during oral ingestion of NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester in conscious Brattleboro rats. Br J Pharmacol 1990; 101: 10–12.

Martens FM, Visseren FL, Lemay J, de Koning EJ, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62: 1463–1480.

Dorafshar AH, Moodley K, Khoe M, Lyon C, Bryer-Ash M. Pioglitazone improves superoxide dismutase mediated vascular reactivity in the obese Zucker rat. Diab Vasc Dis Res 2010; 7: 20–27.

Kotchen TA, Reddy S, Zhang HY. Increasing insulin sensitivity lowers blood pressure in the fructose-fed rat. Am J Hypertens 1997; 10: 1020–1026.

Grinsell JW, Lardinois CK, Swislocki A, et al. Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat. Am J Hypertens 2000; 13: 370–375.

10. Majithiya JB, Paramar AN, Balaraman R. Pioglitazone, a PPAR-gamma

Conclusion In this study, in vitro experiments were carried out to investigate the direct effect of pioglitazone and/or losartan on aortic rings of control, diabetic, hypertensive and hypertensive diabetic rats. Our results demonstrate that vascular sensitivity to an alpha adrenoceptor agonist was decreased in the presence of pioglitazone and/or losartan in diabetic and/or hypertensive rat aortic rings. We postulate that these results explain at least in part the beneficial effects of pioglitazone and losartan for hypertension and diabetes. The mechanism of action of pioglitazone and losartan to improve vascular reactivity may be as a result of intracellular protection from oxygen free radicals. Our findings suggest a possible beneficial combination of thiazolidinediones and angiotensin receptor blockers for treatment of diabetes and hypertension. Further studies are required to elucidate the effects of pioglitazone and losartan on alpha receptors and on the mediators of NO metabolism. It is also remains unclear how pioglitazone and losartan inhibited alpha-2 receptor activities in our rat aortic rings. Further investigation is needed to clarify these underlying mechanisms.

agonist, restores endothelial function in aorta of streptozotocin-induced diabetic rats. Cardiovasc Res 2005; 66: 150–161. 11. Buchanan TA, Meehan WP, Jeng YY, et al. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995; 96: 354–360. 12. Chang KS, Stevens WC. Endothelium-dependent increase in vascular sensitivity to phenylephrine in long-term streptozotocin diabetic rat aorta. Br J Pharmacol 1992; 107: 983–990. 13. Gaikwad AB, Viswanad B, Ramarao P. PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance. Pharmacol Res 2007; 55: 400–407. 14. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptorgamma activity. Circulation 2004; 109: 2054–2057. 15. De Gasparo M, Catt KJ, Inagami T, Wright J, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000; 52: 415–472. 16. Kotchen TA, Reddy S, Zhang HY. Increasing insulin sensitivity lowers blood pressure in the fructose-fed rat. Am J Hypertens 1997; 10: 1020–1026. 17. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Meglasson MD. Pioglitazone increases insulin sensitivity, reduces blood glucose,

This study was supported by research funding from ADU (TPF09019). We thank Santek Medikal (Izmir, Turkey) for generously donating the IME-DC® Glucometer (GmbH, Germany) and Sandoz (Istanbul, Turkey) for the pioglitazone.

insulin, and lipid levels, and lowers blood pressure, in obese, insulinresistant rhesus monkeys. Diabetes 1994; 43: 204–211. 18. Uchida A, Nakata T, Hatta T, et al. Reduction of insulin resistance attenuates the development of hypertension in sucrose-fed SHR. Life Sci 1997; 61: 455–464.

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Overcoming the radial learning curve in the cath lab: the African journey In addition to its sessions tailored to the needs of specialists, AfricaPCR also includes workshops specifically designed for allied health professionals. One of the highlights of this year’s programme was a lively interactive debate around the pros, cons, challenges and benefits of introducing a radial programme in African cath labs. The meeting was facilitated by registered nurse Sr Diane Kerrigan, radiographer Kerry Moir, and cardiologists Dr Mark Abelson (South Africa) and Dr Jacques Monsegu (France). Accessing the coronary arteries via the radial artery has been increasing in popularity over the past approximately two decades, as an alternative to the femoral and brachial routes. The first radial interventional programme in South Africa commenced more than 10 years ago. While the left radial artery is usually used for bypass grafting procedures, the right radial is the preferred route for angiography and percutaneous coronary intervention. Patient selection is highly dependent on operator experience, so repetition of the procedure is key. ‘The more you practise, the better you get’, said Sr Kerrigan. There are many good reasons for going the radial route. The procedure is more comfortable for the patient. The artery is close to the surface and has a dual blood supply. It’s associated with fewer renal, and nerve and vascular complications. Transfusion requirements are less. Reduced staff utilisation translates into reduced hospital-related costs, as does a shorter hospital stay. Patients can be mobilised earlier. Radial access is also associated with lower mortality

rates than with the femoral access. However, for radial access to be undertaken successfully, it is important for the cath lab team to be ready. It requires trained allied professionals, lots of experience, a supportive, quiet and relaxed environment, and good communication. It is also imperative that all the correct equipment be available. Sr Kerrigan highlighted the four key areas/learning steps necessary to ensure a successful radial programme: • preparation and comfort of the patient, including sedation • accessing the radial artery • management of complications • haemostasis. As previously noted, using the right radial artery is the default practice in South Africa, but there might be a case for using the left radial as it is a more direct route to the coronary arteries. Also, left radial access is more similar to femoral access, something that may be an advantage in the earlier stages of the radial learning curve. Offsetting this, however, is that using the right radial is more comfortable for the cardiologist and exposes the patient to less radiation. Summing up, Sr Kerrigan underscored these take-home messages. ‘Be aware of the learning curve. Make sure the patient has a good pulse and is comfortable. Use the appropriate cocktail of medications. Choose the catheter carefully and ensure good haemostasis.’ Source: AfricaPCR 2016.

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Tabula viva chirurgi: a living surgical document Marius J Swart, Gina Joubert, Jan-Albert van den Berg, Gert J van Zyl

Abstract Aim: The purpose of this article is to present the results of a private cardiac surgical practice. This information could also serve as a hermeneutical text for new wisdom. Methods: A personal database of 1 750 consecutive patients who had had coronary artery bypass graft (CABG) surgery was statistically analysed. Mortality and major morbidity figures were compared with large registries. Risk factors for postoperative death were determined. Results: Over a period of 12 years, 1 344 (76.8%) males and 406 (23.2%) females were operated on. The observed mortality rate was 3.03% and the expected mortality rate (EuroSCORE) was 3.87%. After stepwise logistic regression, independent risk factors for death were urgency (intra-aortic balloon pump), renal impairment (chronic kidney disease, stage III), re-operation and an additional procedure. Apart from the 53 deaths, another 91 patients had major complications. Conclusion: Mortality and morbidity rates compared favourably with other international registries. Mortality was related to co-morbidities. This outcome contributes to a hermeneutical understanding focusing on new spiritual wisdom and meaning for the surgeon. Keywords: auto-ethnography, CABG, spirituality, surgery Submitted 29/5/15, accepted 4/10/15 Cardiovasc J Afr 2016; 27: 170â&#x20AC;&#x201C;176

www.cvja.co.za

DOI: 10.5830/CVJA-2015-081

Cardiac surgical risk models for postoperative mortality in the South African context do not exist. An effort to set up a registry or database for cardiac surgery was unsuccessful.1 Local surgeons have to rely on results from outside South Africa to compare their results. Risk models established in Europe or the

Bloemfontein Mediclinic; Health Sciences Education, Faculty of Health Sciences, and Department of Practical Theology, Faculty of Theology, University of the Free State, Bloemfontein, South Africa Marius J Swart, MB ChB, FCS (SA), PhD, mjswart@ktc.bfnmcc.co.za

Department of Biostatistics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Gina Joubert, BA, BSc, BSc (Hons), MSc

Department of Practical Theology, Faculty of Theology, University of the Free State, Bloemfontein, South Africa Jan-Albert van den Berg, BD, MDiv, MPhil, PhD

Dean, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Gert J van Zyl, MB ChB, MFam Med, MBA, PhD

United States of America cannot necessarily be applied.2 Patient profiles differ from region to region. As an alternative, one can use the published results from South African units as a yardstick. However, the reporting of outcome after coronary artery bypass graft surgery (CABG) is not common in South Africa. Between 1961 and 2009, five articles informed on general outcome after CABG surgery.3 In 1972 Wentworth Hospital, Durban, described 20 patients who had CABG surgery.4 In 1979 the Department of Cardiothoracic Surgery at the University of the Free State published their results on the first 50 CABG cases,5 and followed it up with the first 100 patients in 1983.6 Groote Schuur Hospital contributed with 204 patients that were operated on between 1976 and 1978.7 In 1982, Tygerberg Hospital added their 118 cases operated on between 1978 and 1980.8 None of these publications referred to mortality risk. After the literature search was repeated in 2014, a further two reports on CABG outcome were found. Both were small in number and both emphasised a specific subset of patients and not CABG in general.9,10 One other author also contributed with published results after CABG. A randomised, double-blind study from a single centre, on the effect of aprotonin on cardiac surgery (50 CABG cases and 50 valve cases), was conducted in the early 1990s at Groote Schuur Hospital.11 This study had exclusion criteria and was not representative of a cardiac surgical practice. The first local comparison of outcome with a risk score (EuroSCORE) appeared in the European Journal of Cardiothoracic Surgery as a letter to the editor in 2004.12 Only 574 cases were involved, compared to the much larger numbers of most European or American studies. The impact of impaired renal function as calculated by the simplified modification of diet in renal disease (sMDRD) and the metabolic syndrome on CABG outcome was reported in two separate articles.13,14 These studies excluded additional procedures in conjunction with CABG and did not signify a true registry type of database. Evaluating surgical outcome is common among cardiac surgeons.15 Looking at mortality and morbidity rates is one way of assessing outcome; however, a new interpretation of such data could also lead to a different form of knowledge or wisdom. As part of a spiritual reflection on negative outcomes after CABG in an auto-ethnographic study, the database of one of the authors (MJS) was presented as a personal document or text for re-interpretation.16 The science of text interpretation is also known as hermeneutics. Each human being can be read as a living document, similar to a historical text or piece of art. According to Gerkin, this reading of a living document could be an effort to reconcile experience with theological language,17 hence the title of this article: Tabula viva chirurgi: a living surgical document. Theological language has a spiritual undertone. In the words of Henri Nouwen, this spirituality should be a movement from the restlessness of loneliness to the restfulness of solitude.18 The aim of this article was to acknowledge the negative

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outcomes of some patients after CABG, to articulate it and to interpret it. This should present insight into a private cardiac surgical practice in South Africa where there is generally a lack of published data, but also accentuate the possibility of a spiritual gain from such an endeavour by obtaining new wisdom.

Methods All patients who had CABG surgery done consecutively by one surgeon (MJS) between November 2000 and November 2012 in the Mediclinic Hospital, Bloemfontein, were included. The information was obtained from a personal and ongoing database. Almost all the patients were operated with conventional cardiopulmonary bypass and cardiac arrest. The Ethics Committee at the Faculty of Health Sciences, University of the Free State, approved the study as part of a thesis. Mortality was defined as death while in hospital. This is in line with the EuroSCORE II as well as the Cleveland Clinic.19,20 Pre-operative renal function was determined with the sMDRD formula. Impairment was defined as a calculated glomerular filtration rate (GFR) of less than 60 ml/l/1.73 m2 or chronic kidney disease stage III (CKD III). Major postoperative morbidity as reported by the Society of Thoracic Surgeons (STS) implies re-exploration, prolonged ventilation (> 48 hours), permanent stroke, renal failure and deep sternal infection.21 For this study, renal failure after surgery was not defined on the basis of a doubling in serum creatinine value, but as new dialysis. The STS has subsequently adjusted its definitions for prolonged ventilation and renal failure.22 All patients who had rewiring after dehiscence of the sternum while in hospital, as well as within six weeks after discharge, were considered to have deep mediastinal infection. In addition, gastrointestinal complications, postoperative bleeding, the use of homologous blood products and length of hospital stay (LOS) were also investigated. Postoperative care was done by the surgeon in conjunction with the nursing staff. In general the physicians get involved once the patient develops multi-organ failure.

Aorta dissection (intra-operative complication)

Statistical analysis The statistical analysis was done by the Department of Biostatistics of the Faculty of Health Sciences at the University of the Free State. Results were summarised by calculating means with standard deviations or percentiles (numerical variables), and frequencies and percentages (categorical variables). Individual possible risk factors’ relationship with mortality was investigated using chi-squared or Fisher’s exact tests. Significant univariate risk factors were included in a logistic regression.

Results A total of 1 750 patients had a CABG done. Of these patients, 122 (7.0%) had an additional procedure (Table 1). Males were in the majority at 76.8%, with females at 23.2%. The age range was between 20 and 87 years old. The median age for males was 61 years and for females 64 years. Table 2 depicts a profile of this population of CABG patients. During hospitalisation, 53 patients (3.03%) died. A one-word cause of death was given for each patient who died (Table 3). The expected mortality rate was 3.87% (69 patients). The observed/expected mortality rate (O/E) was 0.78. In the original EuroSCORE population the mortality rate was 4.80%.23 Risk-adjusted mortality (RAM) allows individual surgeons to compare their results within a larger group of patients.24 The RAM for this series was therefore 3.74% (0.78 × 4.80%), which is less than the EuroSCORE cohort. Isolated CABG (no additional procedure done with the CABG) had an observed mortality of 2.21% and an expected mortality of 3.63% with an O/E of 0.61. More than a quarter (26.3%) of the patients was considered high risk for operative mortality, i.e. EuroSCORE ≥ 6.0.

Univariate analysis The Working Group Panel on the Cooperative CABG Database Project was used as a reference point.25 Seven core risk factors

Table 1. Additional procedures to the CABG Additional procedure

The additive EuroSCORE of 1999 was used to calculate the risk for operative mortality for each patient.23 Towards the end of the study time period, the EuroSCORE II became available and was introduced into the practice, but this was not applied to this study.19

Number

Percentage (n = 1 750)

0.1

2.9

0.2

Aortic valve + mitral valve replacement + Maze

0.1

Females

ASD

0.1

Males

Aortic valve replacement Aortic valve + mitral valve replacement

Table 2. Profile of CABG patients Profile

Number

Percentage of total

406

23.2

1 344

78.8

ASD + Maze

0.1

≤ 39 years

Biopsies for carcinoma

0.2

40–49 years

Left ventricular aneurysm

0.1

50–59 years

505

28.9

Left ventricular aneurysm + Maze

0.1

60–69 years

604

34.5

Left ventricular rupture

0.1

70–79 years

363

20.7

Maze

0.3

≥ 80 years

0.9

Diabetes mellitus

0.1

Urgent (IABP/ventilator)

312

17.8

1.7

Renal impairment (CKD III)

376

21.7

Mitral valve repair Mitral valve repair + Maze Mitral valve replacement

2.2

204

11.7

2.0

442

25.3

Mitral valve replacement + Maze

0.2

Re-operation (2nd, 3rd, 4th operation)

196

11.2

VSD (ischaemic)

0.1

Additional procedure

122

7.0

ASD, atrio-septal defect; VSD, ventriculo-septal defect.

CKD, chronic kidney disease; IABP, intra-aortic balloon pump.

172

Table 3. Reason for death Reason for death

Table 5. Cardiologist’s mortality/risk and contribution to the cohort Number of deaths (%)

Cardiac (death in theatre)

5 (9.4)

Surgical bleed

1 (1.9)

Sudden and unexplainable

5 (9.4)

Stroke

2 (3.8)

Brain dead

1 (1.9)

Inflammatory conditions (DIC, IE, sepsis, SIRS)

7 (13.2)

Gastrointestinal

3 (5.7)

Organ failure (cardiac, respiratory, renal, MOF)

1 (1.9)

DIC, diffuse intravascular coagulopathy; IE, infective endocarditis; MOF, multiorgan failure; SIRS, systemic inflammatory response syndrome.

for mortality were identified during the mid-1990s. These risk factors were age (younger than 70 years, and 70 years or older were arbitrarily selected by the surgeon), gender, re-operation, left main stem, low ejection fraction (40% was applied as the cut-off point), urgency, and number of coronary artery systems involved. Data on the last factor are not available for this series. From Table 4 it is clear that of these factors, the female gender was not significantly associated with operative mortality rate. As expected, patients with chronic obstructive pulmonary disease (COPD) were at higher risk (223 patients with 5.8% mortality rate, compared to 2.6% for the other patients) (p = 0.0090). About one-fifth (21.7%) of the patients had renal impairment (CKD III) based on the calculated GFR. Their mortality rate was 6.7% compared to 2.1% for the rest (p < 0.0001). Other potential risk factors that were not significantly associated with operative mortality included hypertension, diabetes mellitus and body mass index (BMI ≥ 30 kg/m2), not even in combination, as in the metabolic syndrome. A perception that the patients of some referring cardiologists are at higher risk was tested (Table 5). Six cardiologists are or were involved at the Mediclinic, Bloemfontein, at some point. One of the six ‘cardiologists’ actually represents a number of cardiologists, each with only a small number of cases. Cardiologist B had a higher risk score and therefore also a higher mortality rate than A, D and E. Cardiologists B and C (the latter had only 58 cases) did not differ significantly regarding mortality rate. Table 4. Core risk factors25 Mortality/total

Mortality (%)

< 70 years

31/1 352

2.3

Female

22/398

5.5

46/1 344

3.4

7/406

1.7

1st sternotomy

35/1 554

2.3

2nd sternotomy

14/179

7.8

3rd sternotomy

4/15

26.7

4th sternotomy

0/2

0.0

34/1 420

2.4

19/330

5.8

LVEF ≥ 40%

41/1 652

2.5

LVEF < 40%

12/98

12.2

Home/ward

14/570

2.5

CCU

21/868

2.4

IABP

12/299

4.0

6/13

46.2

No left main stem Left main stem

Ventilator/lab

Mortality/ total

Mortality (%)

EuroSCORE

Contribution to the total (%)

12/484

2.5

3.57

27.6

19/335

5.7

4.76

19.1

0/58

0.0

4.36

3.1

5/309

1.6

3.69

17.7

11/431

2.6

3.55

24.6

6/133

4.5

4.17

7.6

Stepwise logistic regression All the significant risk factors were used to establish a model of factors that are significantly associated with mortality in a multivariate logistic regression. Four risk factors could be considered independent risk factors: urgency (intra-aortic balloon pump; IABP), renal impairment (CKD III), re-exploration, and an additional procedure (Table 6).

Morbidity Besides the 53 deaths, 115 patients had a major complication during their initial stay in hospital; however, 31 of these patients also had a major complication after the operation and then died (22 patients died without an official major complication). A further seven patients were included as morbidity after they had been discharged, but were re-admitted with sternal dehiscence. The combined mortality and major morbidities involved 144 patients (8.2%). Table 7 illustrates the prevalence of major morbidities. Some patients (23 + 5) had more than one major complication and their mortality rate was 50%. The low mortality rate (1.0%) associated with no major complication is obvious (Table 8). Gastrointestinal complications are not often regarded as major complications, yet some are very serious. Twenty-one such patients (1.2%) were identified, of whom 11 had a gastroscopically diagnosed peptic ulcer; four presented with active bleeding and six had laparotomies. This finding was despite the routine use of a proton pump inhibitor. The laparotomies were done for bowel ischaemia (three), bowel obstruction (two) and ulcer perforation (one). There were four (19.0%) deaths among these 21 patients, two with bleeding and two with ischaemia. Table 6. Significant risk factors in logistic regression with odds ratio

Risk factor

Male

Cardiologist

28 (52.8)

Pining away

≥ 70 years

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p-value 0.0009 0.0801

Risk factor

95% CI

Urgency (IABP)

2.21

1.13–4.32

Renal impairment (CKD III)

2.58

1.44–4.65

Re-operation

4.31

2.32–8.00

Additional procedure

7.14

3.60–14.18

CI, confidence interval; CKD, chronic kidney disease; OR, odds ratio; IABP, intra-aortic balloon pump. < 0.0001 Table 7. Major morbidities 0.0013 < 0.0001

< 0.0001

CCU, coronary care unit; IABP, intra-aortic balloon pump; lab, catheter laboratory; LVEF, left ventricular ejection fraction.

Complication

Number of patients (%)

Re-exploration

32 (1.8)*

Prolonged ventilation

36 (2.1)

Renal failure

32 (1.8)

Permanent stroke

20 (1.1)

Sternal dehiscence

17 (1.0)

The percentage was calculated from 1 745 patients as five died in theatre. *31 for bleeding and one instrument that was left behind. 28 patients had more than one major complication (Table 8).

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Table 8. Patients with associated major complications Number of patients

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Table 11. Length of stay and age Total group (n = 1 697)

With major complication

Mortality (%)

Single

17 (18.1)

Age (years)

Double

12 (52.2)

≤ 39 (n = 39)

Triple

2 (40.0)

40–49 (n = 203)

1 623*

None

50–59 (n = 495)

60–69 (n = 584)

70–79 (n = 346)

≥ 80 (n = 30)

17 (1.0)

*Five patients died in theatre and had no major complications. The number of patients was 1 750 (5 + 94 + 23 + 5 + 1 623). The number of deaths was 53 (5 + 17 + 12 + 2 + 17).

Re-exploration for mediastinal bleeding is considered a major complication and was necessary in 31 patients (1.8%). Mediastinal drainage was measured over 48 hours. The average bleeding plus one standard deviation was considered major bleeding. A calculated volume of 1 070 ml per 48 hours was therefore considered important. There were 180 (10.3%) such patients. Table 9 illustrates the association between bleeding and mortality. The significant difference between 9.4 and 2.0% had a p-value of < 0.0001. Cardiac surgery is an important consumer of homologous blood products. Of these 1 750 patients, only 404 (23.2%) patients actually received blood products. Almost a quarter of this surgical population depended on the blood bank for red blood cells (RBC), plasma and/or platelets. The close association between risk, mortality and blood bank usage is demonstrated in Table 10. The risk and outcome between the group with three and more units of RBC and those with less differed considerably (p < 0.0001).

Length of stay The average length of stay (LOS) of the 1 697 patients who left hospital was 6.0 days (2–83 days, median 5). LOS is an indication of recovery and that should correlate with age and risk for mortality. Tables 11 and 12 confirmed this. For isolated CABG (n = 1 628 patients) 63.8% of patients stayed five days and less in hospital, whereas only 2.2% stayed longer than two weeks.

Discussion The exposition of such surgical outcome data might appear like basic auditing of a practice, yet one should always be attuned to more wisdom. The scientist looks for wisdom of theoria and

the surgeon evaluates for wisdom of technē. A practical wisdom obtained with a process of hermeneutics against a certain traditional background, such as faith, is referred to as phronēsis.26 Mortality rate is one way of assessing outcome, but favourable mortality rates could also indicate limited morbidity and even long-term survival.27 Registries provide a more accurate picture of mortality as an outcome. In fact, published articles underrepresent mortality rate up to 50% lower than a database.27 A statistical comparison between the local outcome and records from both sides of the Atlantic Ocean and Japan was not possible and the reader is left with a visual comparison. Table 13 displays such a comparison with other databases. Mortality could also be defined as death within 30 days, even if the patient had been discharged. Locally, the majority of patients are from outside the city where surgery is performed and follow up is limited. To balance the odd patient who might have died at home within 30 days are those cases where the patient died after several weeks in hospital with, for example, respiratory failure or after a second operation. They were all considered as primary cardiac surgical mortalities. Decanting refers to transferring a critical patient to a second facility and so the mortality or morbidity is erased.28 This was not and is still not the practice in Bloemfontein. The determination of the aetiology of death is not simple and could differ from surgeon to surgeon. In the Tabula viva chirurgi it seems most patients died due to a non-cardiac system failure (Table 3). A post mortem is done only in cases of death in theatre or in cases where the patient has not woken up. That being said, a routine post mortem is not always clarifying.29 The phase-of-care mortality analysis (POCMA) identifies an identifiable trigger for a fatal course.30 These five phases are pre-operative, the operation itself, while the patient is in intensive care, in the ward, and during the discharge phase. Such a seminal event leading

Table 9. Outcome associated with mediastinal drainage Drainage

Number (%)

Mortality (%)*

Re-exploration (%)

≥ 1 070 ml

180 (10.3)

17 (9.4)

29 (16.1)

< 1 070 ml

1 565 (89.7)

31 (2.0)

3 (0.2)**

*Five patients died in theatre (total mortality 53). **The re-explorations were in two patients who drained 950 and 975 ml and the third patient had to be re-opened to remove a surgical instrument.

Table 10. Risk, mortality and blood bank usage Blood bank usage*

Median (days)

Table 12. Length of stay and EuroSCORE Total group (n = 1 697)

Median (days)

EuroSCORE

≤ 2 (n = 630)

3–5 (n = 644)

6–9 (n = 365)

≥ 10 (n = 58)

Table 13. Comparison of isolated CABG mortality with other databases

EuroSCORE

Mortality (%)

No bank blood (n = 1 346)

3.43

23 (1.7)

Tabula viva chirurgi

Bank blood (n = 404)

5.33

30 (7.4)

EuroSCORE23

Only 1–2 units RBC (n = 222)

4.95

6 (2.7)

≥ 3 units RBC (n = 123)

6.05

20 (16.3)

RBC, red blood cells. *Bank blood includes red blood cells, plasma and/or platelets.

Databases

Year

Number

2000–2012

1 628

Mortality (%) 2.21

1998

12 103

3.40

STS22

2000–2006

774 881

2.30

JACVSD35

2000–2005

7 133

2.72

JACVSD, Japan Adult Cardiovascular Surgery Database; STS, Society of Thoracic Surgeons.

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to death was found in 35% during the pre-operative phase by Shannon et al.30 For the local study, a POCMA was not done. In practice, it means an error in selection, an error in procedure or an error in care. Hence co-morbidities and mortality risk factors are part of the selection criteria. Determining those factors was important for the surgeon, as every death or major complication emphasises the surgeon’s feeling of responsibility or loneliness. This is an emotional response, but it could progress to spiritual reflection. Some of the risk factors of the 1990s are even now important contributors to the risk for death. In this particular study, female gender was not a risk for mortality, although female patients had a higher EuroSCORE than the males (4.7 vs 3.6). In fact, male gender was almost a mortality hazard (p = 0.0801). In the EuroSCORE II, female gender still contributes to death after surgery, although this contribution is small.19 Others claim that it is not the gender per se, but rather the associated co-morbidities associated with the female gender.31 The finding that the referring cardiologist contributes to the risk and therefore mortality rate was expected (Table 5); however, it was not significant in the stepwise logistic regression. Cardiologist B referred more patients with an additional procedure (40.2% of the total of 122). Cardiologist C had only one such patient, but then C presented 11.0% of patients with an IABP, whereas C’s contribution to the total number of cases was only 3.1%. In the EuroSCORE, IABP is a significant factor for risk/mortality. It could be argued that Cardiologist B had a lower threshold to refer patients with a higher risk for surgery in an attempt to treat the patient. It could also mean that Cardiologist B has a more aggressive interventional approach towards lowerrisk patients. It is hoped that this also attests to confidence in the surgical team. The significant risk factors from the Tabula viva chirurgi after logistic regression differed from the original Working Group Panel on the Cooperative CABG Database Project.25 Only re-operation and urgency remained as risk factors. Three of the five theatre deaths were re-operations and the patient who bled to death also had a second operation. The other deaths among the re-operation group of patients had the same mixture of reasons for death as the rest (Table 3). In a large series of 1 521 re-operations, the mortality rate was 9.7% (in the Tabula viva chirurgi re-operations had a mortality rate of 9.2%).32 Pre-operative renal impairment (CKD III in particular) and an associated procedure were not investigated in the Working Group during the 1990s. If all the patients with one or more of these four significant risk factors were excluded, the mortality rate would drop to seven of 963 patients (0.73%), with an expected mortality rate of 2.40% (EuroSCORE). Another way of confirming the contribution of risk factors is to look at the observed mortality rate of those patients with an expected mortality rate of 0% (i.e. EuroSCORE 0). One individual of 237 patients died (0.42%). In the recent EuroSCORE II, the lowest possible risk of mortality is in any case 0.5%. The impact of major morbidity on mortality is illustrated in Table 8. Not all patients who bleed more than expected require re-exploration, nevertheless excessive drainage is stressful to the surgeon. To take patients back to theatre for bleeding/ tamponade puts severe strain on the surgeon. It is not only a

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utilisation of resources (human and financial), but the bleeding, re-opening of the chest and subsequent blood transfusion put the patient at further risk. It is comforting to realise that a unit such as Cleveland takes 3.0% of patients back to theatre.33 A Swedish study reported on 2 000 CABG patients,34 with a re-exploration rate of 4.9% and, interestingly enough, 10.0% (similar to the Tabula viva chirurgi) drained more than 1 000 ml, measured over 12 hours. In the Tabula viva chirurgi, the measurement was done over 48 hours. Although 36 patients were ventilated for longer than 48 hours, 15 patients were ventilated for respiratory reasons and 21 because of a suppressed level of consciousness. Renal failure in particular needs to be addressed. As an isolated complication, renal failure was found in 14 patients, and another 15 had renal failure combined with mechanical ventilation. Three patients had a third complication. Of these 32 (1.8%) patients, 25 required dialysis (seven patients died before renal intervention). Prolonged mechanical ventilation with renal failure (dialysis) is a lethal combination as 11 of 15 such patients died. Only one of 10 patients who required postoperative dialysis as an isolated major complication, died. Two-thirds of the patients with renal failure were pre-operatively CKD III. Both Cleveland Clinic34 and the Japan Adult Cardiovascular Surgery Database (JACVSD)35 consider renal failure as new dialysis. The prevalence of renal failure (new dialysis) in the JACVSD was 3.18%. The STS defines renal failure as a critical rise in serum creatinine.21,22 In the Tabula viva chirurgi, 144 (8.2%) patients increased their basal creatinine level by 50% or higher postoperatively. This remains a sign of renal damage. It is important to realise that three-quarters of patients (Tabula viva chirurgi) are operated on in hospital directly after their coronary angiogram and were therefore exposed to contrast medium. The referring cardiologist is usually concerned about unstable angina and critical coronary artery anatomy. These patients are all at risk for renal injury and even more so after the surgery that might follow.36 Surgery within five days of angiography has an odds ratio of 1.82 to lead to renal impairment.37 This is regardless of a pre-operative glomerular filtration rate < 60 ml/l/1.73 m2, and cardiopulmonary bypass duration, which also affects renal performance.37 Stroke is a shattering complication. Apart from it being a blow to the patient and to those caring for him/her, a stroke in particular contributes to this burden of liability surgeons might experience, not only from a medico-legal perspective, but also from a spiritual viewpoint. Stroke occurred in 20 patients (1.1%), 11 as an isolated complication, but in another nine as an associated major adverse event (Table 6). Four patients died, therefore a mortality rate of 20%. This stroke rate is also in accordance with the STS and JACVSD, 1.4% and 1.5%, respectively, but both registries were for isolated CABG.22,35 The unit at Emory University reports a prevalence of 2.2% with an almost similar mortality rate of 22.5%.38 Deep sternal sepsis is another major complication of the STS. The Centres for Disease Control and Prevention provide criteria for the diagnosis of deep sternal sepsis.39 In the local series, dehiscence of the sternum was documented for deep sternal sepsis. Ten patients were taken back to theatre for rewiring during the initial hospital stay and another seven were discharged, but were re-admitted within six weeks. Two of the patients were also mechanically ventilated and one of them had

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a stroke as a third major complication. None of these 17 (1.0%) patients died. Their median BMI was 29.4 kg/m2 and those with intact sternums had a BMI of 28.4 kg/m2. The presence of COPD was found in 29% of patients with sternal dehiscence compared with 12% among those with a sternum in one piece. In a large Finnish study, 70% of patients with deep sternal sepsis were taken to theatre. This represents a prevalence of 0.8%.39 Patients are under the impression that the chest bone does not heal. A South African study investigated the general picture of post-CABG patients after six weeks and found six patients of 179 with no healing of the chest bone. Two of them had already had a second attempt in hospital to approximate the sternum.40 At least three others had risk factors such as prolonged mechanical ventilation and heart failure with pneumonia. Most patients in our series were not from Bloemfontein, where the operation was done. They had to be well enough to travel back to whence they came, where health facilities are often limited. In general, patients are discharged only when the risk of re-admission is low. According to the STS registry, 51.2% of patients had an LOS of less than six days and 5.6% were hospitalised for more than two weeks.22 As far as isolated CABG is concerned, the hospital LOS compared well with the STS.

also bring a new wisdom to the fore, which allows the surgeon to move from loneliness to solitude as a spiritual movement. The disappointments of negative surgical outcomes should move on to make the surgeon’s responsibilities a vocation instead of a burden. This allows the surgeon to provide hospitality as an alternative to hostility towards the patient.18 Such a spiritual experience should also have spiritual transformation as an outcome.43 As part of creation, physiological limits exist and surgical outcome is based on these limits. Mortality and morbidity are time and again linked to co-morbidity and surgical risk. This has implications for the pastoral and spiritual care of the sick. We thank Prof Christoff (JC) Zietsman, head of the Department of Latin at the University of the Free State, Bloemfontein, who assisted with the title, Tabula viva chirurgi.

References 1.

Larger numbers have more statistical power, but smaller numbers are the reality of a typical South African cardiac unit. In the private sector one finds units with a single surgeon and many with only a few surgeons per unit. Although the surgeon used transparent definitions, there was still a personal interpretation. The additive EuroSCORE was used but this probably underestimated the real mortality risk. The logistic EuroSCORE was perhaps more accurate for the higher-risk patient, especially in a low-volume practice.41 It has been stated before that 26.3% of patients fell into a higher-risk category. Low-risk patients did very well, with an O/E of < 0.61 and even less. To determine a unit’s care of patients with major complications is a good way of assessing performance. The fewer the number of patients that die with a major complication, the better the unit performs. Those are the patients who failed to be rescued (FTR). A Canadian unit reported on 5 000 various open cardiac surgical cases over five years,42 where the mortality rate was 3.6%. Ten important complications were associated with 92% of the deaths. Their calculated FTR was 19.8%. In other words, in spite of major complications, 80.2% of patients survived. A FTR for the Tabula viva chirurgi would have been a good indication of how Mediclinic, Bloemfontein, fares as far as the care of patients with major complications is concerned, but we lacked data for this to be calculated. Table 8 might give some indication of the outcome of the patients with one or more of the five major complications. Of the patients with one or more major complications, 25% died.

Linegar AG, Smit F, Stroebel A, Schaafsma E. A South African national database in cardiothoracic surgery. Cardiovasc J Afr 2010; 21: 153–154.

Prins C, Jonker I de V, Botes L, Smit FE. Cardiac surgery risk-stratification models. Cardiovasc J Afr 2012; 23: 160–164.

Limitations

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Linegar AG. Visiting lecturer Department Cardiothoracic Surgery, University of the Free State. E-mail communication, 1 September 2011.

Robers NMA, Bakst A, Lewis BS, Moyes DG, Gotsman MS. Early results of surgery for coronary artery disease. S Afr Med J 1972; 46: 1247–1253.

Meyer JM, Kleynhans PHT, Verwoerd CA, Steyn JG. Coronary artery bypass surgery at the University of the Orange Free State Medical School. S Afr Med J 1979; 56: 93–98.

Verwoerd CA, Meyer JM, Neethling WML, Kleynhans PHT, Marx JD. Coronary artery bypass at the University of the Orange Free State Medical School. Medium-term follow-up of the first 100 cases. S Afr Med J 1983; 64: 813–815.

Curcio CA, Barnard MS, Berloco P, Barnard CN. [The aorta-coronary by-pass. Personal clinical experience (author’s translation)]. Giornale Italiano Di Cardiologia 1981; 11(3): 297–302.

Barnard PM, Lubbe JJ de W, Rossouw JJ, Weich HFH. Aortakoronêre omleidingschirurgie te Tygerberg-hospitaal, 1978-1980. S Afr Med J 1982; 62: 756–758.

Harris DG, Coetzee AR, Augustyn JT, Saaiman A. Repeat surgery for coronary artery bypass grafting: The role of the left thoracotomy approach. Heart Surg Forum 2009; 12(3): E163–E167.

10. Von Oppell UO, Stemmet F, Brink J, Commerford PJ, Heijke SAM. Ischemic mitral valve repair surgery. J Heart Valve Dis 2000; 9(1): 64–73. 11. Swart MJ, Gordon PC, Hayse-Gregson PB, Dyer RA, Swanepoel AL, Buckels NJ, Schall R, Odell JA. High-dose aprotinin in cardiac surgery – a prospective randomized study. Anaesth Intensive Care 1994; 22(5): 529–533. 12. Swart MJ, Joubert G. The EuroSCORE does well for a single surgeon outside Europe. Letter to the Editor. Eur J of Cardiothorac Surg 2004; 25: 145.

Conclusion It was not the intention to present these data as a benchmark for the South African context, but it opens a window on a private cardio-surgical practice in South Africa. The outcomes are in line with those of established units and databases all over the world. This is wisdom related to the scientific and technical aspects associated with cardiac surgery and care. These findings

13. Swart MJ, Bekker AM, Malan JJ, Meiring AM, Swart Z, Joubert G. The simplified modification of diet in renal disease equation as a predictor of renal function after coronary artery bypass graft surgery. Cardiovasc J of Afr 2010; 21: 9–12. 14. Swart MJ, De Jager WH, Kemp JT, Nel PJ, Van Staden SL, Joubert G. The effect of the metabolic syndrome on the risk and the outcome of coronary artery bypass graft surgery. Cardiovasc J Afr 2012; 23: 400–404.

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15. Treasure T, Valencia O, Sherlaw-Johnson C, Gallivan S. Surgical performance measurement. Health Care Manag Sci 2002; 5: 243–248. 16. Swart MJ. 2014. ‘n Narratiewe refleksie op negatiewe koronêre vatomleidingsoperasie-uitkomste: die spirituele belewenis van ‘n chirurg. (Unpublished PhD thesis). University of the Free State, South Africa. 17. Gerkin CV. The Living Human Document. Nashville: Abingdon Press, 1984: 37. 18. Nouwen HJM. Reaching out. Great Britain: Fount Paperbacks, 1998: 17, 38, 39. 19. Nashef SAM, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur J Cardiothorac Surg 2012; 41: 1–12.

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Virchows Arch 2003; 443: 528–535. 30. Shannon FL, Fazzalari FL, Theurer PF, Bell GF, Sutcliffe KM, Prager RL. A method to evaluate cardiac surgery mortality: Phase of care mortality analysis. Ann Thorac Surg 2012; 93: 36–43. 31. Ried M, Lunz D, Kobuch R, Rupprecht L, Keyser A, Hilker M, et al. Gender’s impact on outcome in coronary surgery with minimized extracorporeal circulation. Clin Res Cardiol 2012; 101(6): 437–444. 32. Launcelott S, Ouzounian M, Buth KJ, Légaré J-F. Predicting in-hospital mortality after redo cardiac operations: Development of a preoperative scorecard. Ann Thorac Surg 2012; 94: 778–784. 33. Vivacqua A, Koch CG, Yousuf AM, Nowicki ER, Houghtaling PL,

20. Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD,

Blackstone EH, et al. Morbidity of bleeding after cardiac surgery: Is it

et al. Morbidity and mortality risk associated with red blood cell and

blood transfusion, reoperation for bleeding, or both? Ann Thorac Surg

blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006; 34(6): 1608–1616. 21. Shroyer ALW, Coombs LP, Peterson ED, Eiken MC, DeLong, ER, Chen A, et al. The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk models. Ann Thorac Surg 2003; 75: 1856–1865.

2011; 91: 1780–1790. 34. Waldén K, Jeppsson A, Nasic S, Backlund E, Karlsson M. Low preoperative fibrinogen plasma concentration is associated with excessive bleeding after cardiac operations. Ann Thorac Surg 2014; 97: 1199–1206. 35. Motomura N, Miyata H, Tsukihara H, Okada M, Takamoto S. First

22. Shahian DM, O’Brien SM, Filardo G, Ferraris VA, Haan CK, Rich

report on 30-day and operative mortality in risk model of isolated

JB, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk

coronary artery bypass grafting in Japan. Ann Thorac Surg 2008; 86:

models: Part 1 – Coronary artery bypass grafting surgery. Ann Thorac Surg (Supplement) 2009; 88(1): S1–S62. 23. Roques F, Nashef SAM, Michel P, Gauducheau E, De Vincentiis C, Baudet E, et al. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999; 15: 816–823. 24. Miyata H, Motomura N, Murakami A, Takamoto S. Effect of bench-

1866–1872. 36. Garcia S, Ko B, Adabag S. Contrast-induced nephropathy and risk of acute kidney injury and mortality after cardiac operations. Ann Thorac Surg 2012; 94: 772–777. 37. Duca DD, Iqbal S, Rahme E, Goldberg P, De Varennes B. Renal failure after cardiac surgery: Timing of cardiac catheterization and other perioperative risk factors. Ann Thorac Surg 2007; 84(4): 1264–1271.

marking projects on outcomes of coronary artery bypass graft surgery:

38. Puskas JD, Winston AD, Wright CE, Gott JP, Brown WM, Craver

Challenges and prospects regarding the quality improvement initiative.

JM, et al. Stroke after coronary artery operation: Incidence, correlates,

J Cardiovasc Surg 2012; 143: 1364–1369.

outcome, and cost. Ann Thorac Surg 2000; 69: 1053–1056.

25. Jones RH, Hannan EL, Hammermeister KE, DeLong ER, O’Connor

39. Eklund AM, Lyytikäinen O, Klemets P, Huotari K, Anttila V-J,

GT, Luepker RV, et al. Identification of preoperative variables needed

Werkhala KA, et al. Mediastinitis after more than 10 000 cardiac surgi-

for risk adjustment of short-term mortality after coronary artery bypass graft surgery. J Am Coll Cardiol 1996; 28(6): 1478–1487. 26. Browning DS. A Fundamental Practical Theology: Descriptive and Strategic Proposals. Minneapolis: Fortress Press, 1996: 11. 27. Anyanwu AC, Treasure T. Unrealistic expectations arising from mortality data reported in the cardiothoracic journals. J Thorac Cardiovasc Surg 2002; 123: 16–20. 28. Burack JH, Impellizzeri P, Homel P, Cunningham JN. Public reporting of surgical mortality: A survey of New York state cardiothoracic surgeons. Ann Thorac Surg 1999; 68: 1195–1202. 29. Glasz T, Frenken M, Knieriem H-J, Krian A. Mechanisms of death in the early postoperative period following coronary artery bypass grafting for acquired heart disease. A clinicopathological study of 32 cases.

cal procedures. Ann Thorac Surg 2006; 82: 1784–1789. 40. Swart MJ, Arndt J, Badenhorst P, Langenhoven L, van der Walt J, Joubert G. Die sesweke-ondersoek ná koronêre vatchirurgie: Bevindinge by Bloemfontein Medi-Clinic Hospitaal. S Afr Fam Pract 2005; 47(3): 61–64. 41. Gogbashian A, Sedrakyan A, Treasure T. EuroSCORE: a systematic review of international performance. Eur J Cardiothorac Surg 2004; 25: 695–700. 42. Ahmed EO, Butler R, Novick RJ. Failure-to-rescue as a measure of quality of care in a cardiac surgery recovery unit: a five-year study. Ann Thorac Surg 2014; 97: 147–152. 43. Waaijman K. Spirituality. Forms, Foundations, Methods. Leuven: Peters, 2002: 456, 457.

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Associations between body fat distribution, insulin resistance and dyslipidaemia in black and white South African women Dheshnie Keswell, Mehreen Tootla, Julia H Goedecke

Abstract Aim: The aim was to examine differences in body fat distribution between premenopausal black and white South African (SA) women and explore the ethnic-specific associations with cardiometabolic risk. Methods: Body composition, using dual-energy X-ray absorptiometry (DXA) and computerised tomography, insulin resistance (HOMA-IR) and lipid levels were assessed in 288 black and 197 white premenopausal SA women. Results: Compared to the white women, black women had less central and more peripheral (lower-body) fat, and lower serum lipid and glucose concentrations, but similar homeostasis models for insulin resistance (HOMA-IR) values. The associations between body fat distribution and HOMA-IR, triglyceride and high-density lipoprotein cholesterol concentrations were similar, while the associations with fasting glucose, total and low-density lipoprotein cholesterol levels differed between black and white women. Conclusion: Ethnic differences in body fat distribution are associated, in part, with differences in cardiometabolic risk between black and white SA women. Keywords: body fat distribution, ethnicity, cardiometabolic risk, dual X-ray absorptiometry, visceral adipose tissue, subcutaneous adipose tissue Submitted 9/9/15, accepted 14/11/15 Published online 25/5/16 Cardiovasc J Afr 2016; 27: 177–183

www.cvja.co.za

DOI 10.5830/CVJA-2015-088

Recent studies have shown that non-communicable diseases (NCDs) account for the majority of deaths globally (65.5%), and that 80% of the deaths attributed to NCDs each year are in lowmiddle-income countries.1 Within South Africa (SA), NCDs, such as cardiovascular disease (CVD) and type 2 diabetes (T2D) were the second highest cause of death in 2000.2 Obesity, a major

Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, South Africa Dheshnie Keswell, PhD Mehreen Tootla, MSc Julia H Goedecke, PhD

Non-communicable Disease Research Unit, South African Medical Research Council, Cape Town, South Africa Julia H Goedecke, PhD, Julia.goedecke@mrc.ac.za

risk factor for CVD and T2D,3,4 is extremely common in SA women, particularly in black women.5 However, fat distribution rather than the amount of body fat has been shown to be a greater predictor of CVD and T2D risk factors, such as insulin resistance (IR) and dyslipidaemia.6-8 There is growing evidence indicating that not all fat stores contribute equally to CVD and T2D risk factors.9 Studies in predominantly white populations have shown that central fat mass (FM) [measured as trunk fat on the dual-energy X-ray absorptiometry (DXA) scan] or waist circumference,9-11 and more specifically visceral adipose tissue (VAT),12,13 is positively associated with IR and dyslipidaemia. Conversely, lower-body (gluteo-femoral) subcutaneous adipose tissue (SAT) has been shown to be negatively associated with these cardiometabolic risk factors.9-11,14 Some, but not all of these studies have demonstrated that central and lower-body fat have independent effects on metabolic risk.9-11 The relationship between fat distribution and IR appears to be altered by ethnicity. Studies in the USA and SA have shown that compared to white women, black women have less VAT and more gluteo-femoral FM, but are more insulin resistant.15-19 Less VAT in the black women may, however, explain their more favourable lipid profile compared to white women.20 However, SA studies have been performed in only small samples of women (n = 10–15) and focused only on abdominal fat distribution. To date, most studies that have explored ethnic-specific associations between whole-body fat distribution (central and peripheral) and cardiometabolic risk have been undertaken in the USA or Europe, with no studies to our knowledge, examining the independent associations between central and peripheral fat distribution and cardiometabolic risk in African women. Therefore, the aim of this study was to examine differences in whole-body fat distribution between premenopausal black and white women and to explore the ethnic-specific associations with cardiometabolic risk. We also set out to determine whether central versus peripheral fat were independently associated with cardiometabolic risk, and to examine which body composition variable was most closely associated with cardiometabolic risk in black and white women, taking into account other lifestyle factors that have been shown to alter body composition, such as physical activity, use of contraception, smoking and alcohol consumption.

Methods The study population consisted of 288 black and 197 white SA women who were recruited by advertisement and from local church groups, community centres and universities in Cape Town, as previously described.21 Inclusion criteria were: age 18–45 years; no known diseases or not taking any medication

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for metabolic disorders; not currently pregnant, lactating or postmenopausal; and being of SA ancestry. This study was approved by the Human Research Ethics Committee of the Faculty of Health Science, University of Cape Town. Procedures and risks were explained to participants, all of whom gave written informed consent, prior to participation. The testing procedures and biochemical analyses have been described previously,21 but are described briefly below. A demographic questionnaire22 was administered and included measures of socio-economic status, including housing density, family history of T2D and behavioural/lifestyle factors. Contraceptive use was recorded, and women were categorised as using hormonal contraception (oral and injection) or not. Smoking was recorded and women were categorised as current smokers or not. Alcohol consumption in grams/day was also recorded using dietary recall. Physical activity energy expenditure was characterised using the global physical activity questionnaire (GPAQ).23 Moderateto vigorous-intensity physical activity (MVPA) was calculated as minutes of physical activity per week. Anthropometric measurements of participants were taken, including height, weight in light clothing, waist circumference (at the level of umbilicus) and hip circumference (at the largest gluteal area). Body composition (FM and fat-free mass) was measured using DXA (Discovery-W, Software version 4.40; Hologic). Fat mass index (FMI) was calculated as total body fat (kg)/height (m2). DXA-derived measures of body fat distribution included trunk, arm and leg FM. Trunk FM included the region between the neck (line below the bottom of the jaw) and waist cut-offs (line above the iliac crest), with the lateral boundaries positioned to achieve separation of the upper arm and trunk at the glenoid fossa, and the inclusion of vertical lines on either side of the spine were positioned to exclude the spine. The arms included the region below the line through the glenoid fossa. Vertical lines extending downward from the waist cut-off were positioned to separate thigh from hands, and oblique lines were positioned to pass through the femoral neck and join the central vertical line between the legs, in order to isolate the legs.24 A CT scan (Toshiba X-press Helical Scanner; Toshiba Tokyo, Japan) at the level of the L4–L5 vertebrae was used to determine VAT and SAT areas. After an overnight fast (10–12 hours), a blood sample was drawn from the antecubital vein for the subsequent determination of plasma glucose, serum insulin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), total cholesterol (TC) and triglyceride (TG) concentrations. Plasma glucose concentrations were determined using the glucose oxidase method (YSI 2300 Stat Plus; YSI Life Sciences, Yellow Springs, OH). Serum insulin concentrations were determined by immunochemiluminometric assays using the ADVIA Centaur (Bayer Diagnostics, Tarrytown, NJ). Blood lipids were measured using the Roche modular autoanalyser (Roche Diagnostics GmbH, Mannheim, Germany). LDL-C was calculated using the Friedewald formula.25 HOMA-IR was calculated from fasting glucose and insulin levels (glucose (mmol/l) × insulin (mU/l)/22.5).26

Statistical analysis Results were analysed using Statistica version 10 (Statsoft Inc, Tulsa, Oklahoma, USA). Results are presented as median and

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interquartile range (IQR). All skewed variables were normalised by log transformation where required. Ethnic differences in body composition, IR and lipid levels were determined using one-way ANCOVA, adjusting for age. Pearson’s chi-squared was used to determine differences in categorical variables between the black and white women. Partial correlations were used to determine the associations between the various body fat distribution variables and cardiometabolic outcomes in the black and white women, adjusting for age and FMI. FMI was chosen as the covariate because it takes into account both the total body fat and the height of an individual (which differs significantly between black and white women). Multiple regression analysis was used to determine the independent associations between body fat distribution and IR and serum lipid levels, adjusting for age and FMI. In addition, the effect of ethnicity on these relationships was tested by including ethnicity × body fat distribution interaction term in the model. Backward stepwise regression was used to determine the model that accounted for most of the variance for each cardiometabolic outcome. In each model, trunk FM and leg FM were included in the model, with age, FMI, contraception use, MVPA, alcohol consumption and smoking. The analyses were then repeated including VAT and SAT in the model (due to the smaller sample size).

Results The black women were younger than the white women [median (IQR): 22 (22–33) vs 32 (24–39] years, p < 0.01] and consequently, all subsequent analyses were adjusted for age. Black women had higher levels of MVPA compared to white women [335 (90–855) vs 240 (120–480) min/week, p = 0.01], and fewer black women smoked (10.1 vs 17%, p = 0.04), whereas alcohol consumption did not differ between the groups [0 (0–2.8) vs 61 (0.5–14.7), p = 0.95]. There was no significant difference in the proportion of women who used contraceptives (32.0 vs 31.1%, p = 0.74), but more black women used injectable contraceptives (25.7 vs 5.1%, p < 0.01), while more white women used oral contraceptives (26.0 vs 6.3%, p < 0.01). Ethnic differences in body composition and fat distribution are summarised in Table 1. Black women were significantly shorter, heavier, had a higher body mass index (BMI) and greater FM (absolute and %) compared to white women. Black women had greater absolute measures of trunk, leg and arm FM compared to white women. However, as a percentage of total FM, black women had less trunk FM and more leg FM. Accordingly, the trunk FM/leg FM ratio was greater in white than black women. As a percentage of total body FM, there was no significant difference in arm FM between black and white women. Black women had less abdominal VAT and more SAT and a lower VAT/SAT ratio compared to white women. Cardiometabolic risk factors for black and white women are summarised in Table 2. Although there were no ethnic differences in fasting plasma glucose concentrations, black women had higher fasting insulin concentrations and HOMAIR than white women. However, after adjusting for differences in age and FMI, glucose concentrations were significantly lower in the black compared to the white women, but the differences in fasting serum insulin concentrations and HOMA-IR were no longer significant. Black women had lower TC, TG, HDL-C

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Table 1. Body composition and body fat distribution of black and white women Black women median (IQR)

White women median (IQR)

p-value adjusted for age

Table 3. Correlations between body fatness and its distribution and cardiometabolic risk factors in black and white women and the combined sample

FMI (kg/m2)

Body composition Height (m)

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288

1.60 (1.56–1.64)

197 1.67 (1.60–1.70)

< 0.001

Glucose

Insulin

HOMAIR

0.26∆

0.53∆

0.54∆

0.23∆

0.035 –0.31∆

0.15*

0.23∆

0.61∆

0.35∆

0.26∆

–0.39∆

0.36∆

All

0.25∆

0.59∆

0.60∆

0.30∆

0.13∆$ –0.34∆

0.25∆$

0.34∆

0.30∆

0.34∆

0.30∆

HDL-C LDL-C

Weight (kg)

288

80.4 (60.9–96.2)

197 73.9 (62.0–94.1)

0.02

BMI (kg/m2)

288

31.7 (23.6–37.2)

197 26.6 (22.4–33.2)

< 0.001

Fat (kg)

288

33.7 (19.4–44.3)

197 26.7 (17.1–40.3)

< 0.001

0.069

0.29∆

0.099

Fat (%)

288

42.1 (32.7–46.9)

197 36.5 (28.9–43.9)

< 0.001

All

1.04∆$

1.16∆

1.23∆

0.92∆

FMI (kg/m2)

288

13.3 (7.6–17)

197

< 0.001

0.12

0.24∆

0.27∆

0.078 –0.034 –0.099 0.0011

Body fat distribution

9.9 (6.4–14.5)

Trunk FM (kg)

VAT (cm2)

0.19*

0.21*

0.10

–0.25∆

0.17*

0.33∆

0.20∆

–0.04$

–0.28∆

0.05$

0.094

–0.023

0.019 –0.11

–0.0002

–0.017 –0.016

Trunk FM (kg)

288

14.1 (7.4–20.6)

197

12.2 (7.4–20.3)

0.01

Trunk FM (% FM) 288

42.1 (36.7–46.7)

197 45.5 (40.7–49.7)

< 0.001

W –0.25∆ All

0.13$

13.7 (9.3–18.01)

197

10.7 (7.5–15.9)

< 0.001

288

44.3 (39.5–49.4)

197 41.4 (37.5–45.7)

< 0.001

Trunk FM/leg FM

288

0.95 (0.74–1.2)

197

1.1 (0.90–1.3)

< 0.001

Arm FM (kg)

288

3.8 (1.9–4.9)

197

2.9 (1.8–4.6)

< 0.001

Arm FM (%)

288

10.7 (9.3–12.3)

197

10.8 (9.7–11.9)

VAT (cm2)

222

71 (47–102)

153

80 (60–124)

SAT (cm2)

220

442 (212–577)

150

297 (169–460)

VAT/SAT

220

0.20 (0.14–0.27)

150 0.31 (0.23–0.42)

0.9 0.04 < 0.001 < 0.001

Values presented as median and interquartile range (IQR); p-values for one-way ANCOVA adjusting for age. BMI, body mass index; FMI, fat mass index; WC, waist circumference; FM, fat mass; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue.

and LDL-C concentrations than white women, which remained significant after adjusting for age and FMI. Table 3 shows the partial correlations (adjusted for age and FMI) between body fatness and its distribution and cardiometabolic risk factors for the black and white women individually and combined. In summary, age-adjusted total body fat, as defined by FMI, was positively associated with plasma glucose concentrations, measures of IR (fasting insulin and HOMA-IR), TG and LDL-C concentrations, and negatively associated with HDL-C concentrations in both black and white women. FMI was positively associated with TC concentrations in white women only. In black and white women, increased central FM and reduced lower-body fat correlated with measures of IR (fasting insulin and HOMA-IR). In black women only, greater trunk FM and lower leg FM were associated with increased fasting plasma glucose concentrations. Notably these associations Table 2. Cardiometabolic risk factors of black and white women p-value White women p-value adjusted median adjusted for age (IQR) for age and FMI

Black women median (IQR)

Glucose (mmol/l)

280

4.5 (4.2–4.9)

4.7 (4.4–4.9)

0.08

< 0.001

Insulin (mU/l)

287 9.8 (5.6–16.6) 197 6.9 (4.6–10.8)

< 0.001

0.27

HOMA-IR

279

2.1 (1.1–3.4)

196

1.5 (1.0–2.2)

< 0.001

0.59

TC (mmol/l)

274

3.9 (3.3–4.5)

197

4.7 (4.1–5.3)

< 0.001

TG (mmol/l)

274

0.7 (0.5–1.0)

197

0.9 (0.6–1.2)

< 0.001

HDL-C (mmol/l)

273

1.2 (1.0–1.6)

197

1.6 (1.4–1.9)

< 0.001

LDL-C (mmol/l)

273

2.2 (1.7–2.8)

197

2.6 (2.1–3.3)

< 0.001

n 196

Values presented as median and interquartile range (IQR); p-values for one-way ANCOVA adjusting for age and age and FMI. HOMA-IR, homeostasis model for insulin resistance; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Leg FM (kg)

0.09$

0.21∆

< 0.001

288

0.12

0.10$

88 (78–101.5)

Leg FM (% FM)

–0.87∆

W –0.039

288 94.8 (77.3–108.6) 197

Leg FM (kg)

0.043 –0.18∆ –0.09$

All

Waist (cm)

SAT (cm2)

–0.060 –0.23∆ –0.039

–0.039 0.15

0.18

0.20

–0.06

–0.20$

0.15* –0.071 0.16

0.079

–0.06 –0.19$

–0.16∆

–0.33∆

–0.34∆

–0.23∆

–0.011

0.15* –0.015

W –0.12

–0.25∆

–0.26∆

–0.16*

–0.097

0.19∆ –0.15*

All –0.38∆

–0.67∆

–0.69∆

–0.52∆

–0.09

0.39∆ –0.15

Values are presented as partial correlation coefficients adjusted for age and FMI (except for FMI); ∆p < 0.01 and *p < 0.05. ‘All’ values are presented as beta-coefficients adjusted for age, FMI and ethnicity. $Ethnic × body composition interaction. FMI, fat mass index; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; FM, fat mass; HOMA-IR, homeostasis model of insulin resistance; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

with glucose concentrations and trunk FM were significantly different between black and white women. In white women only, increased abdominal SAT was associated with reduced fasting glucose concentrations, and this association differed significantly between black and white women. In both black and white women, reduced lower-body FM, characterised by leg FM, was associated with TG concentrations. In the black women, higher trunk FM, and in the white women, higher VAT was associated with TG concentrations. In addition, in both the black and white women, trunk FM was associated with reduced HDL-C concentrations. By contrast, higher leg FM was associated with increased HDL-C concentrations in both the black and white women. In white women only, increased VAT and lower-leg FM were associated with increased LDL-C concentrations. There were no associations between arm FM and any metabolic risk factor in both black and white women. We further explored the confounding effects of various lifestyle factors, including contraceptive use, smoking, physical activity and alcohol consumption on metabolic risk. In summary, in black women, IR [2.3 (1.3–3.7) vs 1.8 (1–3.2) mU/l, p = 0.04] was higher and HDL-C concentrations [1.1 (0.9–1.4) vs 1.3 (1.1– 1.6) mmol/l, p < 0.01] were lower in women on contraception than those not on it. Despite few black women consuming alcohol, consumption was positively associated with serum HDL-C concentrations (r = 0.20, p < 0.05) in black women. In white women, TC [5 (4.5–5.5) vs 4.5 (4.1–5.2) mmol/l, p = 0.01], TG [1 (0.7–1.4) vs 0.8 (0.6–1.2) mmol/l, p < 0.01] and HDL-C [1.7 (1.5–2) vs 1.5 (1.3–1.8) mmol/l, p < 0.01] concentrations were higher in women on contraception than those not on it, while lower MVPA was associated with higher fasting insulin concentrations (r = –0.19, p < 0.05) and HOMA-IR (r = –0.18, p < 0.05). In separate models for black and white women, we then used backward stepwise regression to determine the factors that accounted for the greatest variance in cardiometabolic risk

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factors, including the following variables in the initial model: age, FMI, trunk FM and leg FM. Based on the results relating to the covariates described above, we also included the covariates contraceptive use and alcohol consumption into the appropriate models (Table 4). We then repeated the regression analyses including VAT and SAT in the models. In black women, FMI and trunk FM accounted for 21% of the variance in fasting glucose concentrations, whereas in white women, age and FMI contributed significantly to the model, accounting for only 12% of the variance. In both black and white women, trunk FM and leg FM were independently associated with fasting serum insulin concentrations and HOMA-IR, and together with age, and in the case of black women, contraceptive use accounted for 40–45% of the variance in the models. The addition of VAT and SAT to the models did not contribute independently or significantly to the models for fasting plasma glucose and measures of IR in the black and white women. For the black women, trunk FM and leg FM were independently associated with TG concentrations, whereas only FMI and leg FM, as well as contraceptive use were associated Table 4. Multivariate analysis for black and white women, separately Black women Variable

p-value Variable

Glucose (mmol/l) FMI (kg/m2) Trunk FM (kg)

White women

Age (years)

0.18

0.01

1.47 < 0.01

FMI (kg/m2)

0.24

0.00

r = 0.45 r2 = 0.21 < 0.01

Trunk FM (kg) Leg FM (kg) Contraception

–1.11 < 0.01

Insulin (mU/l) Age (years)

r = 0.34 r2 = 0.12 < 0.01 Insulin (mU/l)

–0.33 < 0.01 1.09 < 0.01 –0.53 < 0.01

Age (years)

–0.25

0.00

Trunk FM (kg) 1.02

0.00

Leg FM (kg)

0.00

–0.37

0.11 < 0.01 r = 0.64 r2 = 0.40 < 0.01

HOMA-IR

r = 0.67 r2 = 0.45 < 0.01 HOMA-IR

Age (years) Trunk FM (kg) Leg FM (kg) Contraception

–0.29 < 0.01 1.14 < 0.01 –0.57 < 0.01 0.11

–0.21

0.00

Trunk FM (kg) 1.03

0.00

–0.38

0.00

Age (years) Leg FM (kg)

0.02

r = 0.65 r2 = 0.42 < 0.01 TG (mmol/l)

r = 0.67 r2 = 0.45 < 0.01 TG (mmol/l)

Age (years)

0.12

0.04

FMI (kg/m2)

0.90

0.00

Trunk FM (kg)

0.84

0.00

Leg FM (kg)

–0.51

0.00

–0.59

0.00

Contraception

0.26

0.00

Leg FM (kg)

r = 0.48 r2 = 0.23 < 0.01 HDL-C (mmol/l) Age (years) FMI (kg/m ) 2

Leg FM (kg) Contraception Alcohol consumption

r = 0.49 r2 = 0.24 < 0.01 HDL-C (mmol/l)

0.20

0.07

–1.20 < 0.00 0.77

0.01

–0.23

0.02

0.23

0.02

VAT (cm2)

–0.45

0.00

0.18

0.01

Contraception

r = 0.51 r2 = 0.26 < 0.01

TC (mmol/l)

r = 0.51 r2 = 0.26 < 0.01 TC (mmol/l)

Age (years)

0.22

0.0021

Age

0.22

0.00

FMI (kg/m2)

0.38

0.025

FMI (kg/m2)

0.29

0.00

–0.36

0.029

Contraception

0.29

0.00

SAT (cm2)

r = 0.30 r2 = 0.10 < 0.01 LDL-C (mmol/l)

r = 0.44 r2 = 0.19 < 0.01 LDL-C (mmol/l)

Age (years)

0.19

0.0071

Age

0.16

0.02

FMI (kg/m2)

0.46

0.0073

Trunk FM (kg) 0.38

0.00

–0.33

0.049

SAT (cm2)

p-value

Glucose (mmol/l)

r = 0.33 r2 = 0.11 < 0.01

r = 0.46 r2 = 0.21 < 0.01

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with TG concentrations in the white women. The addition of VAT and SAT did not contribute significantly to the model in both black and white women. In the black women, HDL-C concentrations were independently associated with age, FMI, leg FM, contraceptive use and alcohol consumption, whereas in white women, only VAT and contraceptive use contributed to the model. Notably, the associations between HDL-C concentrations and contraceptive use were opposite in the black and white women, showing a negative association in black women and a positive association in white women. The model that explained the greatest variance in TC and LDL-C concentrations in the black women included age, FMI and abdominal SAT, the latter being negatively associated with TC and LDL-C concentrations. This contrasts with the findings for white women, where age, FMI and contraceptive use accounted for the greatest variance in TC concentrations, and age and trunk FM contributed to the model for LDL-C concentrations.

Discussion The main findings of this study were that compared to white women, black women had less central and more lower-body fat, and lower fasting glucose and lipid concentrations, but had similar levels of IR. Despite these differences, the associations between body fat distribution and measures of IR, as well as TG and HDL-C concentrations were similar in black and white women. The novel finding of this study was that central and peripheral fat depositions were independently associated with IR in both the black and white women, and with TG concentrations in the black women. By contrast, fasting glucose concentrations were associated with centralisation of body fat in black, but not white women, whereas TC and LDL-C concentrations were associated with centralisation of body fat in white, but not black women. Black women in this study had more total body fat compared to their white counterparts. This is in accordance with recent national SA prevalence data, which reported that black women had a higher prevalence of obesity than other ethnic groups.5 However, when adjusting for total body fat, black women had a greater peripheral distribution of fat, characterised by less central FM and more lower-body FM than their white counterparts. Furthermore, within the abdominal depot, black women had less VAT and more SAT compared to white women, which is commensurate with both SA and American studies.15-19 Less central FM, and to a lesser extent, more peripheral FM in black women, associated with their lower fasting glucose concentrations, suggesting that accumulation of central FM may play a vital role in determining fasting plasma glucose concentrations, and hence the development of T2D in black women. By contrast, despite the differences in body fat distribution, fasting insulin levels and HOMA-IR values were not significantly different between black and white women. Numerous studies have shown that compared to white women, black women have a higher prevalence of IR and T2D for the same BMI or waist circumference.17,19 These results are surprising, given that greater central and reduced peripheral FM were similarly associated with higher fasting insulin and HOMAIR values in both black and white women, a finding supported by similar studies in the USA.15,27 These findings suggest that

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other factors, in addition to body fat distribution, are important determinants of IR in black women. Another important finding of this study was that central and peripheral FM were independently associated with fasting insulin and HOMA-IR values in both the black and white women. To our knowledge, this is the first study to demonstrate independent associations among ethnically diverse women, a finding that has been demonstrated in mostly white men and women.9-11 Differences in the contribution of abdominal and gluteo-femoral fat to IR may be due to phenotypic differences in adipose tissue depots. Indeed, studies from our laboratory and others have shown that in white women, inflammatory gene expression, especially in the abdominal depot, was significantly associated with higher IR.28-30 However, despite black women having a higher SAT inflammatory gene expression profile than white women, SAT inflammatory gene expression was not significantly associated with IR in black women.28 In contrast to abdominal fat, lower-body fat has been suggested to act as a metabolic sink, storing excess free fatty acids (FFA) when there is an energy surplus, due to its lower lipolytic activity and higher lipoprotein lipase (LPL) activity, compared to upper-body fat stores.31-34 Lower-body fat has been suggested to protect against ectopic fat deposition and therefore protect against risk for CVD and T2D. However, when the capacity to store excess fat in the periphery is exceeded, peripheral fat is no longer protective. A small SA study demonstrated reduced adipogenesis and lipogenesis in obese black women, and this was associated with increased IR.18 Furthermore, a recent study from our laboratory has shown that with increasing weight gain, black women accumulated more central relative to peripheral FM, which was associated with the development of IR.35 These findings imply that the prevention of an increase in centralisation of body fat is vital for the prevention of metabolic risk in black women, and it is important to determine the point at which peripheral FM is no longer protective. In addition to body fat distribution, other lifestyle factors also influenced IR, but these differed between black and white women. In black women only, contraceptive use, which was predominantly in the form of injectable contraceptives, was associated with increased IR, which is supported by previous studies.36 In addition, physical activity was differentially associated with IR in the black and white women. Despite white women having lower MVPA than black women, MVPA was associated with IR in white women only. Previous research from our laboratory has demonstrated that white women mainly perform leisure activity, typically undertaken at a higher intensity, whereas black women mainly perform physical activity for travel, typically undertaken at a lower intensity.17,37 This may suggest that the intensity of exercise is an important determinant of IR. HDL-C and TG concentrations are often used as markers for IR.38,39 Despite similar levels of IR, HDL-C and TG concentrations were lower in the black compared to the white women. Notably, similar to the findings for IR, higher HDL-C and lower TG concentrations were associated with reduced central and increased peripheral FM, and these associations were similar in black and white women, a finding supported by studies in the USA.40,41 The lower HDL-C concentrations of black women must therefore be explained by other factors. HDL-C in black women was associated with alcohol consumption, independent of body fat distribution. Alcohol

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consumption may raise HDL-C concentrations by increasing the transport rate of the major HDL apolipoproteins Apo-I and Apo-II.42 Contraceptive use was another significant determinant of HDL-C levels in both black and white women and TG levels in the white women. Notably, contraceptive use was negatively associated with HDL-C concentrations in the black women and positively associated in the white women, which could be explained by the type of contraception used. Studies have demonstrated that women using injectable contraception had lower HDL-C and TG concentrations compared to those who were on oral contraception.36 In our study, we also demonstrated that independent of body fat, TC and LDL-C concentrations were lower in the black compared to the white women, which is in agreement with similar SA studies.22,43,44 Additionally, we demonstrated that increased TC and LDL-C concentrations were associated with increased central FM in white women only. Hosain et al.45 also demonstrated that the association between central FM and lipid levels was stronger in white compared to black women. It is important to note that increased trunk FM was significantly associated with increased LDL-C concentrations in the white women, whereas in the black women, abdominal SAT area was negatively associated with LDL-C and TC concentration, suggesting a protective effect of SAT in the black women. There have been a number of studies demonstrating that SAT is protective against IR and increased lipid levels, more specifically TG in women with higher BMI.46 Additionally, lipodystrophic loss of SAT results in increased IR and dyslipidaemia.47 By contrast, other studies in women have demonstrated that loss of abdominal SAT did not produce the same beneficial results as VAT in terms of reduced IR and dyslipidaemia.48 This is the first study of which we are aware, that has demonstrated a protective effect of abdominal SAT on cardiometabolic risk in black women. A possible mechanism for the protective role of SAT is that it is an alternative depot for excess FFA, potentially reducing ectopic fat deposition in VAT and the liver, thereby preventing lipotoxicity and reducing dyslipidaemia.49 Notably, we found no associations between arm FM and any metabolic risk factor in black and white women. A few previous studies have examined the independent effects of arm vs leg FM on cardiometabolic risk, but the results have been contradictory.11,50 Although arm FM is regarded as ‘peripheral fat mass’, this is from the upper body and therefore may not exhibit the same protective effects as leg FM. Further studies are required to understand these disparate findings. The strengths of this study include the state-of-the-art measures of body fat distribution, DXA and CT scans, and the examination of ethnic-specific associations with cardiometabolic risk. Possible limitations of the study were the inclusion of a convenient sample of women, which was not representative of the total population. The black women were more obese that the white women but this may be reflective of the population, according to a recent population survey.5 The cross-sectional design of the study limits one to derive conclusions in terms of causality. The number of women in which CT scans were conducted was low (76% of total sample) and this may have created type II error. Furthermore, we did not measure other lifestyle factors such as diet, and this has been shown to affect body fat and cardiometabolic risk. More objective measures of physical activity, using accelerometers, should be used, as

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this may provide further insight into possible differences in non-exercise thermogenesis within these populations. Future studies should also include subjects with a wider age range, as cardiometabolic risk factors differ with age.

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disease in older women. Austr J Pharm: Endocrinol Metab 2002; 282(5): E1023–1028. 9.

Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CDA, Yudkin JS, et al. Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study.

Conclusion This study showed that black women had lower central and greater peripheral fat compared to white women, which was associated with lower fasting glucose concentrations in the black women and higher TC and LDL-C concentrations in the white women. Increased central and reduced peripheral FM were independently associated with measures of IR in both the black and white women. In addition to body fat distribution, modifiable risk factors were identified, including MVPA, which were associated with reduced IR in the white women, and contraceptive use, which was associated with IR and lipid levels in the black and white women. Intervention studies aimed at reducing centralisation of body fat, increasing physical activity and changing contraceptive use are required to verify these findings in order to provide evidence-based guidelines for the prevention and management of cardiometabolic risk.

Diabetes Care 2004; 27(2): 372–377. 10. Snijder M, Dekker J, Visser M, Bouter L, Stehouwer C, Kostense P, et al. Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study. Am J Clin Nutr 2003; 77(5): 1192–1197. 11. Williams MJ, Hunter GR, Kekes-Szabo T, Snyder S, Treuth MS. Regional fat distribution in women and risk of cardiovascular disease. Am J Clin Nutr 1997; 65(3): 855–860. 12. Després JP. Abdominal obesity as important component of insulinresistance syndrome. Nutrition 1993; 9(5): 452–459. 13. Neeland IJ, Ayers CR, Rohatgi AK, Turer AT, Berry JD, Das SR, et al. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity 2013; 21(9): E439–E447 14. Rocha PM, Barata JT, Teixeira PJ, Ross R, Sardinha LB. Independent and opposite associations of hip and waist circumference with metabolic syndrome components and with inflammatory and atherothrombotic risk factors in overweight and obese women. Metabolism 2008;

This work was funded by the National Research Foundation of South Africa

57(10):1315–1322.

(Grant No: FA2004051800040), the South African Medical Research Council

15. Lovejoy JC, Smith SR, Rood JC. Comparison of regional fat distribu-

and the University of Cape Town. Opinions expressed and conclusions

tion and health risk factors in middle-aged white and African American

arrived at are those of the authors and are not necessarily to be attributed to

women: the Healthy Transitions study. Obes Res 2001; 9: 10–16.

the NRF. The authors acknowledge the excellent clinical and technical assis-

16. Perry AC, Martin L. Race differences in obesity and its relationship

tance of Yael Joffe, Juliet Evans, Courtney Jennings and Hendriena Victor.

to the sex hormone milieu. Horm Mol Biol Clin Investig 2014; 19(3):

Nandipha Sinyanya is thanked for subject recruitment and translation.

151–161. 17. Goedecke JH, Levitt NS, Lambert EV, Utzschneider KM, Faulenbach

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Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué David Watkins, Liesl Zuhlke, Mark Engel, Rezeen Daniels, Veronica Francis, Gasnat Shaboodien, Mabvuto Kango, Azza Abul-Fadl, Abiodun Adeoye, Sulafa Ali, Mohammed Al-Kebsi, Fidelia BodeThomas, Gene Bukhman, Albertino Damasceno, Dejuma Yadeta Goshu, Alaa Elghamrawy, Bernard Gitura, Abraham Haileamlak, Abraha Hailu, Christopher Hugo-Hamman, Steve Justus, Ganesan Karthikeyan, Neil Kennedy, Peter Lwabi, Yoseph Mamo, Pindile Mntla, Chris Sutton, Ana Olga Mocumbi, Charles Mondo, Agnes Mtaja, John Musuku, Joseph Mucumbitsi, Louis Murango, George Nel, Stephen Ogendo, Elijah Ogola, Dike Ojji, Taiwo Olabisi Olunuga, Mekia Mohammed Redi, Kamanzi Emmanuel Rusingiza, Mahmoud Sani, Sahar Sheta, Steven Shongwe, Joris van Dam, Habib Gamra, Jonathan Carapetis, Diana Lennon, Bongani M Mayosi

Abstract Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted

Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa David Watkins, MD, MPH Liesl Zuhlke, MB ChB, PhD Mark Engel, PhD Rezeen Daniels Veronica Francis, BA Gasnat Shaboodien, PhD Bongani M Mayosi, MB ChB, DPhil, bongani.mayosi@uct.ac.za University of Washington, USA David Watkins, MD African Union Commission, Ethiopia Mabvuto Kango, MBBS Association Friends of Children with RHD, Egypt Azza Abul-Fadl, MD University College Hospital, Ibadan, Nigeria Abiodun Adeoye, MBBS University of Khartoum and Sudan Heart Centre, Sudan Sulafa Ali, MD University of Sana’a, Yemen Mohammed Al-Kebsi, MD, PhD University of Jos, Nigeria Fidelia Bode-Thomas, MBBS Harvard Medical School/ Partners in Health, USA Gene Bukhman, MD, PhD Mozambican Heart Association (AMOCOR), Mozambique Albertino Damasceno, MD, PhD

Addis Ababa University, Ethiopia Dejuma Yadeta Goshu, MD Ministry of Health, Rheumatic Heart Disease Programme, NCDs, Egypt Alaa Elghamrawy, MD Kenyatta National Hospital, Kenya Bernard Gitura, MB ChB, MMed (Int Med) Jimma University, Ethiopia Abraham Haileamlak, MD Mekelle University, Ethiopia Abraha Hailu, MB ChB

a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a ‘roadmap’ of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards Sefako Makgatho Health Sciences University, South Africa Pindile Mntla, MB ChB Chris Sutton, MB BCh Instituto Nacional de Saúde, Mozambique and PASCAR Vice President South Ana Olga Mocumbi, MD, PhD Mulago Hospital, Uganda Charles Mondo, MB ChB, PhD University Teaching Hospital, Zambia Agnes Mtaja, MBBS John Musuku, MBBS, MMed (Paeds)

Ministry of Health and Social Services, Namibia Christopher Hugo-Hamman, MB ChB

Rwanda Heart Foundation, Rwanda Joseph Mucumbitsi, MD

Touch Foundation, Tanzania Steve Justus, MD

East African Community, Burundi Louis Murango, BSc

All India Institute of Medical Sciences, India Ganesan Karthikeyan, DM College of Medicine, University of Malawi, Malawi Neil Kennedy, MB ChB Uganda Heart Institute, Uganda Peter Lwabi, MB ChB, MMed (Int Med) Technical Adviser, NCD directorate, Federal Ministry of Health of Ethiopia, Ethiopia Yoseph Mamo, MD

PASCAR Secretariat, South Africa George Nel, MSc Bongani M Mayosi, MB ChB, DPhil

Federal Medical Centre, Abeokuta, Nigeria Taiwo Olabisi Olunuga, MB ChB Common Market for Eastern and Southern Africa, Ethiopia Mekia Mohammed Redi University of Rwanda, Rwanda Kamanzi Emmanuel Rusingiza, MD Bayero University Kano and Aminu Kano Teaching Hospital, Nigeria Mahmoud Sani, MBBS Cairo University Children Hospital, Faculty of Medicine, Egypt Sahar Sheta, MD, MSc WHO Regional Office in Africa, Congo Steven Shongwe, MB ChB, MBA Novartis, USA Joris van Dam, PhD African Heart Network, Tunisia Habib Gamra, MD

University of Nairobi, Kenya Stephen Ogendo, MB ChB, MMed (Surg) Elijah Ogola, MB ChB, MMed (Int Med)

Telethon Kids Institute, University of Western Australia, Princess Margaret Hospital for Children, Australia Jonathan Carapetis, MBBS, PhD

University of Abuja Teaching Hospital, Nigeria Dike Ojji, MBBS, PhD

University of Auckland, New Zealand Diana Lennon, MD

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the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organsations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime. Keywords: rheumatic heart disease, prevention Submitted 8/10/15, accepted 14/11/15 Published online 12/1/16 Cardiovasc J Afr 2016; 27: 184–187

www.cvja.co.za

DOI: 10.5830/CVJA-2015-090

While acute rheumatic fever (ARF) essentially vanished from industrialised countries during the latter half of the 20th century,1 the condition and its major sequel, rheumatic heart disease (RHD) remain important public health concerns in Africa. Poverty and inadequate primary healthcare systems are major contributors to the persistence of ARF/RHD in Africa.2 On the other hand, improving economic conditions and enhanced health system investments during the HIV/AIDS era offer an opportunity to address this neglected disease of poverty in a co-ordinated fashion.3,4 Over the past decade, there has been a renewed global interest in RHD as well as a proliferation of scientific and public health work led by African investigators and practitioners.5 At the same time, the World Heart Federation (WHF) non-communicable disease action plan, developed for the World Health Assembly in 2013, called for a 25% reduction in premature mortality from RHD by the year 2025 (‘25 by 25’).6 Prior to 2015, two workshops on ARF/RHD in Africa were held, with resultant position statements on the necessary steps to address ARF/RHD on the continent. The first statement, the ‘Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa’, was issued in 2005 after the meeting in South Africa,7 and the second, the ‘Mosio-tunya Call to Action’, was issued in 2014 after the meeting in Zambia.8 This was followed by the publication of a key dataset, enumerating key characteristics, gaps in implementation of evidence-based practices and shortfalls in the management of RHD in African communities.9 From 21 to 22 February 2015, the Social Cluster of the African Union Commission (AUC) hosted the Third All-Africa Workshop on ARF and RHD, which was an expert consultation

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of RHD clinicians and researchers affiliated with the Pan-African Society of Cardiology (PASCAR). This meeting was intended to develop a roadmap that could be adopted by ministries of health and governments in order to eliminate ARF and control RHD in their home countries. This article outlines the Addis Ababa communiqué that emerged from the consultative meeting, and also provides a brief report of the objectives and proceedings of the meeting, as well as the outcomes of the meeting in the first six months thereafter.

The Addis Ababa communiqué on eradication of RHD in Africa Motivation The communiqué began by recalling that RHD is both preventable and common in Africa, affecting 1.5 to 3% of school-aged children.10,11 Because severe RHD is lethal in the absence of surgical treatment,12 the total economic cost of premature mortality in Africa is staggering,13 and hampers the achievement of the Millennium Development Goals and forthcoming Sustainable Development Goals on health. The problem has been made worse by a lack of comprehensive, integrated prevention and control programmes in most African Union (AU) member states that carry a heavy burden of ARF/RHD. The AU recognised several mandates to convene this meeting and discuss a roadmap for ARF/RHD in Africa. These included the following: • The 6th ordinary session of the Conference of AU Ministers of Health (CAMH6; 22–26 April 2013), adopted under the AU Executive Council Declaration EX.CL/Dec.795(XXIV): this requested the AU commission (AUC) to develop a mechanism to control NCDs in Africa. • The first joint AU and World Health Organisation (WHO) ministerial meeting, convened under AU Assembly Decision Assembly/AU/Dec.506(XXII): this pledged action towards controlling NCDs in Africa under the AUC–WHO joint work plan (14–17 April 2014). • The Drakensberg Declaration and the Mosi-o-Tunya Call to Action, mentioned above, which were endorsed by the WHO Regional Office for Africa and called for the eradication of ARF/RHD ‘in our lifetime’.

Barriers to action The foundation of the recommendations of the communiqué was a recent publication of baseline characteristics of patients with RHD from 12 African countries.9 Several of the key barriers to control of RHD in Africa are listed in Table 1. Notably, despite the lack of progress on RHD control in Africa, there are several examples of countries, such as Cuba,14 Costa Rica,15 and Tunisia,16 that have realised the eradication of ARF and control of RHD over several years by implementing co-ordinated and comprehensive public health programmes.

Meeting objectives and proceedings The objectives of the Third All-Africa Workshop on ARF and RHD were as follows: • develop approaches on how to eradicate RHD in Africa • develop milestones for the eradication of RHD

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Table 1. Barriers to ARF/RHD eradication in Africa 1. Lack of RHD surveillance efforts at the local, regional and national level. 2. Variable supply and use of high-quality benzathine penicillin G. 3. Low use of reproductive health services among women with RHD. 4. Overly centralised diagnostic and treatment services for RHD. 5. Few facilities capable of providing cardiac surgery for advanced RHD. 6. Lack of national RHD prevention programmes. 7. Absence of multi-sectoral RHD initiatives.

• identify key stakeholders for collaboration in eradication of RHD. The meeting was officially opened on 21 February by His Excellency the AU Commissioner for Social Affairs, Dr Mustapha Kaloko. Opening comments were provided by representatives from the Government of the Federal Democratic Republic of Ethiopia, the African Union Commission Department of Social Affairs, the WHO Regional Office in Africa, and Novartis/ Sandoz Pharmaceuticals. Three main activities comprised the meeting: • Formal presentations on successful ARF/RHD control programmes in Africa and Oceania. • Breakout sessions on the minimal datasets that are needed, key investments that will be required, and stakeholder participation that should be sought in order to develop ARF/RHD programmes in African countries. • A group deliberation on the final set of expert recommendations and key principles to be enumerated in the communiqué. At the close of the meeting, the principles of the communiqué, reproduced in Table 2, were assented to, and the document was sent by the AUC to the April 2015 Ministerial Conference on Health, Population and Drug Control for consideration.

Recommendations 1. Establish prospective RHD registers. These would occur at sentinel sites in AU member states affected by ARF/RHD. The major objective of these registers will be to monitor progress towards RHD-related health outcomes, which include a 25% reduction in premature mortality from RHD by the year 2025. 2. Ensure adequate supplies of benzathine penicillin G (BPG). The WHO recognises BPG as an essential medication. In order to achieve adequate coverage of primary and secondary prevention measures for ARF/RHD, BPG must be readily available at all primary care facilities in AU member states, and training of providers on effective and safe use of BPG should be part of supply-side efforts. BPG can also be used for the treatment of other endemic diseases in Africa, such as syphilis, yaws and sickle cell disease. 3. Guarantee universal access to reproductive health services for women with RHD. RHD greatly increases a woman’s risk of mortality and foetal demise during pregnancy. Reproductive health services, including contraception, are currently underutilised among women with RHD in Africa and this contributes to the high maternal mortality rates on the continent. Comprehensive care for RHD and other NCDs should include access to reproductive health services for all women at risk. 4. Decentralise diagnostic services for ARF/RHD to district hospitals. Primary healthcare services and district hospitals need appropriate technical expertise in the diagnosis of ARF and RHD. Key point-of-care technologies that should be

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considered for provision at district and community levels include ultrasound of the heart (echocardiography), anticoagulation testing, and antigen tests for the rapid diagnosis of group A streptococcal pharyngitis. 5. Establish cardiac surgery centres of excellence. Such facilities could sustainably deliver state-of-the-art surgical care as well as train the next generation of African cardiac specialists. They could also be centres of research on endemic cardiovascular diseases (including RHD). 6. Foster multi-sectoral and integrated national RHD control programmes led by ministries responsible for health. These programmes would oversee the implementation of national RHD action plans and progress towards the ‘25-by-25’ targets. 7. Cultivate partnerships that can implement the actions above. A partnership needs to be developed between the AU commission, ministries responsible for health, international agencies, governments, industry, academia, civil society and other relevant stakeholder to monitor and evaluate progress related to the implementation of the key actions and achievement of the outcome of 25% reduction in premature mortality from RHD by the year 2025. In addition to these recommendations, important and specific roles for international stakeholders (Table 3) were identified. Finally, the communiqué requested the AU to mandate PASCAR and other stakeholders to work with the AU commission to develop a detailed implementation plan of the key actions. This would include roles and responsibilities, timelines, estimates of costs, and a communication framework for the roadmap.

Adoption and next steps On 14 April 2015, the Addis Ababa communiqué was presented to the African Union Specialised Technical Committee on Health, Population and Drug Control (a platform of ministers Table 2. The Third All-Africa Workshop on ARF and RHD: recommendations to the AU commission and member states 1. Establish prospective RHD registers at sentinel sites in affected member states in order to monitor RHD-related health outcomes, including the achievement of a 25% reduction in mortality from RHD by the year 2025. 2. Ensure adequate supplies of high-quality benzathine penicillin that can be administered in the most effective manner, in order to achieve primary and secondary prevention of RHD. 3. Guarantee universal access to reproductive health services for women with RHD and other NCDs, in whom pregnancy carries specific and often fatal risks, and for whom contraception can reduce maternal and foetal mortality. 4. Decentralise appropriate technical expertise to the primary and district levels in order to improve the diagnosis of ARF (which is under-diagnosed in Africa) and early detection, diagnosis, secondary prevention and treatment of RHD using cross-cutting point-of-care technologies such as cardiac ultrasound, anticoagulation testing and rapid antigen tests for group A streptococcal pharyngitis. 5. Establish centres of excellence for cardiac surgery, which will sustainably deliver state-of-the-art surgical care, train the next generation of African cardiac practitioners, and conduct research on endemic cardiovascular diseases, including RHD. 6. Foster multi-sectoral and integrated national RHD control programmes led by the Ministry of Health, which will oversee the implementation of national RHD action plans in order to achieve the goal of reducing mortality from RHD and other NCDs by 25% by the year 2015. 7. Cultivate, through a strong communication framework, partnerships between the AUC, ministries responsible for health, international agencies, governments, industry, academia, civil society and other relevant stakeholders, in order to ensure the implementation of the above actions, and the connection of African RHD control measures with the emerging global movement towards RHD control.

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Table 3. The Third All-Africa Workshop on ARF and RHD: Recommendations to international stakeholders (WHO, UNICEF, WHF and others) 1. Provide open-access resources to develop and strengthen ARF/RHD country programmes.

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3. Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM. Rheumatic fever: neglected again. Science 2009; 324(5923): 37. 4. Robertson KA, Volmink JA, Mayosi BM. Towards a uniform plan for the control of rheumatic fever and rheumatic heart disease in Africa – the Awareness Surveillance Advocacy Prevention (A.S.A.P.) Programme. S

2. Raise the profile of RHD in the context of strengthening and equity of health systems.

Afr Med J 2006; 96(3 Pt 2): 241.

3. Partner with AU member states to address the supply of high-quality benzathine penicillin G.

5. Maurice J. Rheumatic heart disease back in the limelight. Lancet 2013;

4. Support development of an ARF vaccine that would be affordable and effective in Africa.

6. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM, World Heart

382(9898): 1085–1086. Federation. Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease. Nature Rev Cardiol

of health, population and drug control) where it was adopted unanimously and referred for further consideration to the African Union Heads and Government Summit.17 In their meeting held from 7 to 12 June 2015 in Johannesburg, South Africa, the 27th ordinary session of the Executive Council (Ministers of Foreign Affairs) adopted the document under declaration number EX.CL/Dec.876(XXVII), and it was endorsed by the 25th AU Heads of State and Government Summit that was held from 14 to 15 June 2015 in Johannesburg, South Africa. Following on the formal adoption of the principles of the expert consultation, it is now incumbent on ministries of health of AU member states to develop local implementation plans. The PASCAR ARF/RHD task force is developing principles for implementation of ARF/RHD action plans at the local level, which will include an analysis of the key financial and human resource investments required in order to accomplish the objectives of the Addis Ababa communiqué. To this end, PASCAR and the AUC plan to convene a workshop in March 2016 on the implementation of the Addis Ababa communiqué at country level.

2013; 10(5): 284–292. 7. Mayosi B, Robertson K, Volmink J, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006; 96(3 Pt 2): 246. 8.

Mayosi BM, Gamra H, Dangou J-M, Kasonde J. Rheumatic heart disease in Africa: the Mosi-o-Tunya call to action. Lancet Global Health 2014; 2: e438–e439.

9. Zuhlke L, Engel ME, Karthikeyan G, et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur Heart J 2015; 36(18): 1115–1122. 10. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5(11): 685–694. 11. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet 2012; 379(9819): 953–964. 12. Gunther G, Asmera J, Parry E. Death from rheumatic heart disease in rural Ethiopia. Lancet 2006; 367(9508): 391. 13. Watkins D, Daskalakis A. The economic impact of rheumatic heart disease in developing countries. Lancet Global Health 2015; 3: S37. 14. Nordet P, Lopez R, Duenas A, Sarmiento L. Prevention and control of rheumatic fever and rheumatic heart disease: the Cuban experience

Conclusions Over the past 25 years, ARF and RHD have endured on the African continent despite dramatic progress in the control of many other important childhood, adolescent and maternal conditions.18-20 The partnership between the African Union Commission and the Pan-African Society of Cardiology, and the subsequent political commitment to the principles for the eradication of ARF/RHD in Africa, promises to change this situation. It is hoped that the implementation of action plans on ARF/RHD will, through a concerted and multi-sectoral effort, rapidly improve cardiovascular health and strengthen health systems for chronic non-communicable diseases in Africa.

(1986–1996–2002). Cardiovasc J Afr 2008; 19(3): 135–140. 15. Arguedas A, Mohs E. Prevention of rheumatic fever in Costa Rica. J Pediatr 1992; 121(4): 569–572. 16. Ben Romdhane H, Haouala H, Belhani A, et al. [Epidemiological transition and health impact of cardiovascular disease in Tunisia]. La Tunisie Medicale 2005; 83(Suppl 5): 1–7. 17. African Union. Development of a roadmap for the eradiation of rheumatic heart disease in Africa. 2015. http://sa.au.int/en/sites/default/files/ Dev’t of Road map to eradicate RHD - English- SA14501.pdf. 18. Wang H, Liddell CA, Coates MM, et al. Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384(9947): 957–79. 19. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, et al. Global, regional,

References 1. Gordis L. The virtual disappearance of rheumatic fever in the United States: lessons in the rise and fall of disease. T. Duckett Jones memorial lecture. Circulation 1985; 72(6): 1155–1162. 2. Robertson KA, Mayosi BM. Rheumatic heart disease: social and economic dimensions. S Afr MedJ 2008; 98(10): 780–781.

and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384(9947): 980–1004. 20. Murray CJ, Ortblad KF, Guinovart C, et al. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384(9947): 1005–1070.

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Cardiology–cardiothoracic subspeciality training in South Africa: a position paper of the South Africa Heart Association Karen Sliwa, Liesl Zühlke, Robert Kleinloog, Anton Doubell, Iftikhar Ebrahim, Mohammed Essop, Dave Kettles, David Jankelow, Sajidah Khan, Eric Klug, Sandrine Lecour, David Marais, Martin Mpe, Mpiko Ntsekhe, Les Osrin, Francis Smit, Adriaan Snyders, Jean Paul Theron, Andrew Thornton, Ashley Chin, Nico van der Merwe, Erika Dau, Andrew Sarkin

Abstract Over the past decades, South Africa has undergone rapid demographic changes, which have led to marked increases in specific cardiac disease categories, such as rheumatic heart disease (now predominantly presenting in young adults with advanced and symptomatic disease) and coronary artery disease (with rapidly increasing prevalence in middle age). The lack of screening facilities, delayed diagnosis and inadequate care at primary, secondary and tertiary levels have led to a large burden of patients with heart failure. This leads to suffering of the patients and substantial costs to society and the healthcare system. Hatter Institute for Cardiovascular Research in Africa, MRC Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town; Soweto Cardiovascular Research Unit, University of the Witwatersrand, Johannesburg, South Africa Karen Sliwa, MD, PhD, FESC, FACC, Karen.Sliwa-Hahnle@uct.ac.za Departments of Paediatric Cardiology and Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Liesl Zühlke MB ChB, DCH, FCPaeds, Cert Cardiology (SA), MPH, FESC, PhD Cardiothoracic Surgery, Ethekwini Hospital and Heart Centre, Durban, South Africa Robert Kleinloog, BSc Hons, BSc Pharm, MB ChB, FCS (SA) Division of Cardiology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Tygerberg, South Africa Anton Doubell, MB ChB, MMed, FCP (SA), BSc Hons, PhD Netcare Unitas Hospital, Lyttleton Manor, Pretoria, South Africa Iftikhar Ebrahim, MB BCh, MMed (Int Med), Cert Cardiology (SA) Division of Cardiology, Baragwanath Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Mohammed Essop, MB BCh, MRCP, FCP, FRCP, FACC St Dominic’s Hospital, and Frere Hospital, East London, South Africa David Kettles, MB ChB, FCP (SA), MMed Netcare Linksfield Hospital, Linksfield West, Johannesburg, South Africa David Jankelow, MB BCH, FCP(SA), FACC Department of Cardiology, Faculty of Health Sciences, University of KwaZulu Natal, Durban, South Africa Sajidah Khan, MB ChB, PhD Netcare Sunninghill Hospital, Sunninghill, Johannesburg, South Africa Eric Klug, MB BCh, FCP (SA), MMed Andrew Thornton, MB BCh, PhD, FCA (SA)

In this position paper, the South African Heart Association (SA Heart) National Council members have summarised the current state of cardiology, cardiothoracic surgery and paediatric cardiology reigning in South Africa. Our report demonstrates that there has been minimal change in the number of successfully qualified specialists over the last decade and, therefore, a de facto decline per capita. We summarise the major gaps in training and possible interventions to transform the healthcare system, dealing with the colliding epidemic of communicable disease and the rapidly expanding epidemic of non-communicable disease, including cardiac disease.

Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Sandrine Lecour, DPharm, PhD Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa David Marais, MB ChB, FCP (SA) Mediclinic Heart Hospital, Arcadia, Pretoria, South Africa Martin Mpe, MB ChB, FCP (SA), MMed Department of Cardiology, Faculty of Health Sciences, University of Cape Town, South Africa Mpiko Ntsekhe, MD, PhD, FACC Ashley Chin, MB ChB, FCP (SA), MPhil, FHRS Zuid-Afrikaans Hospital, Muckleneuk and Department of Cardiology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa Les Osrin, MMed, MB ChB, BSc Department of Cardiothoracic Surgery, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Francis Smit, MB ChB, FC Cardio (SA), PhD, FACC Wilgers Medical Consortium, Die Wilgers, Pretoria, South Africa Adriaan Snyders, MB ChB, MMed (Int Med), FACC, FESC Interventional Cardiology Unit, Netcare Union Hospital, Alberton, South Africa Jean Paul Theron, MB ChB, MMed, Cert Cardiology (SA) Mediclinic Bloemfontein, Bloemfontein, South Africa Nico van der Merwe, MB ChB, MMed (Int Med), FCP (SA) South African Heart Association, Tygerberg, South Africa Erika Dau Department of Cardiology, Faculty of Health Sciences, Steve Biko Academic Hospital and University of Pretoria, South Africa Andrew Sarkin, MB ChB, FCP (SA)

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Keywords: cardiology training in South Africa, cardiothoracic surgery training in South Africa Submitted 3/2/16, accepted 18/5/16 Cardiovasc J Afr 2016; 27: 188–193

www.cvja.co.za

DOI: 10.5830/CVJA-2016-063

Why is it important to train specialists in cardiovascular care and heart health in South Africa? The Global Burden of Disease study has highlighted that South Africa has an unacceptably high proportion of premature mortality1 and disability-adjusted life-years (DALYs) lost from cardiovascular disease. This is largely in part due to marked increases in hypertensive, rheumatic as well as ischaemic heart disease, and heart failure due to cardiomyopathy from 1990– 2010.2 Rapid demographic changes and adaptation to the so-called Western lifestyle, which includes low physical activity and high intake of processed high-caloric food, has led to more than one-third of the population being obese and hypertensive.3 In South Africa and sub-Saharan Africa (SSA), the spectrum and manifestation of cardiovascular disease is complex and markedly different compared to high-income countries, as rheumatic heart disease (RHD), tuberculous pericarditis and the cardiomyopathies remain common and often present at an advanced stage due to cardiac failure.4 Furthermore, over half of the patients hospitalised with heart failure are under 52 years of age.5 Patients with myocardial infarction are typically two decades younger than patients in the USA and Europe6 (Table 1), and RHD becomes symptomatic in adulthood. The onset of serious heart disease before the sixth decade of life has important economic and other implications for South African society.7 A study from the Heart of Soweto cohort, reporting on the incidence and clinical characteristics of newly diagnosed RHD in adulthood from an urban African community, found an

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estimated incidence of new cases of RHD for those over 14 years of age to be in the region of 23.5 cases/100 000 per annum.8 Due to undetected RHD in the early years, many of those patients presented late, with left or right heart failure. Subsequently, one-quarter of this cohort of 344 cases needed valve replacement or repair within one year, with a further 26% being admitted for initial diagnosis of suspected bacterial endocarditis within 30 months. The severity of disease was further corroborated in a recent study from 12 African countries, including South Africa, India and Yemen. Patients with RHD were young (median age 28 years), largely female and mostly severely affected.9 A further burden of late diagnosis of RHD is the fact that women often present with symptomatic RHD only when pregnant. A fouryear audit of cardiac disease in pregnancy in a South African hospital found an aetiology of 63.5% of RHD and 20.1% of prosthetic valvular heart disease (probably of RHD origin) among these women.10 A recent single-centre cohort study of 225 consecutive women presenting with cardiac disease in pregnancy at a dedicated cardiac disease in maternity clinic at Groote Schuur Hospital, Cape Town, highlighted the complex burden of symptomatic RHD (26%), congenital heart disease (32%) and severe cardiomyopathy (27%), among other cardiac conditions.11 Mortality occurred typically in the postpartum period beyond the standard date of recording maternal death, as also highlighted in a recent publication in the Lancet.12 The confidential inquiry into maternal deaths in South Africa reported that, of the 4 867 deaths reported over two years, 14% were due to hypertensive disorders, with another 8.8% due to medical and surgical conditions.13 Medical disorders, in particular cardiac disease complicating pregnancy, were the fourth most common cause of maternal death during pregnancy. How well is South Africa prepared to transform our healthcare system to meet the demands of two colliding and interacting epidemics: a communicable disease epidemic of HIV/AIDS and tuberculosis, and a rapidly expanding second epidemic of non-communicable cardiovascular diseases?

Table 1. Comparison of age at first myocardial infarction Region

Medium age, women

Medium age, men

Western Europe

Central and Eastern Europe

North America

South America and Mexico

Australia and New Zealand

Middle East

South Asia

Africa

China

South-east Asia and Japan

European

Chinese

South Asian

Other Asian

Arab

Latin American

Black African

Coloured African

Other

Overall

Ethnic origin

Training of doctors and healthcare personnel in South Africa Between 2000 and 2012, the number of medical students enrolling per annum increased by 34%, with a major and deliberate demographic shift towards more female students and African blacks.14,15 Subsequently, the number of graduating doctors has increased by 18% in the same time period. However, the ratio of physicians per 1 000 population remained the same (0.77 in 2004 vs 0.76 in 2011) and is failing to keep up with the growth of the population.15 In response to the fact that the academic health workforce in South Africa is aging, numbers are shrinking, and there is a decline in clinical research capacity and output, two new research training tracks within the professional MB ChB programme have been created. These are the intercalated BSc (Med) Hons/MB ChB track and the integrated MB ChB/PhD track.16 Furthermore, the Ministry of Health has pledged to train 1 000 clinician PhDs though the National Health Scholars Programme over the next 10 years, providing scholarships equivalent to the salaries of health professionals employed by the Department of Health.16

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Cardiology training in South Africa is not keeping up with demand What has changed in the training of cardiologists in the past decade? In South Africa, cardiology training is a three year subspecialist degree following the four-year training as a general physician (after being a house officer and having completed the community service time, bringing the total number of years for training to 15 years). Fig. 1 highlights cardiologists successfully qualified per annum with minimal change over the last decade and, therefore, a de facto decline per capita. The number of registered cardiologists in the country is currently about 200 for 52 million South Africans (one for 260 000). How does that compare with, for example, Brazil or one of the other BRICs countries with similar cardiovascular health issues to South Africa? Brazil has 8 000 board-certified specialists in cardiology for a population of 185 million (1:23 000) or 10 times more cardiologists and, even with that number, is not adequately equipped for the enormous cardiovascular challenges.17 If we use a conservative estimate based on the Brazilian numbers, we still require at least 2 000 cardiologists in this country. Furthermore, there is an unequal distribution of South African cardiologists servicing the private sector, as opposed to those servicing the public sector, where the greatest need for service delivery exists. In order to equalise or rectify this discrepancy, there needs to be ongoing political involvement in creating posts in the public service sector and equalisation of remuneration. This has a number of serious consequences. There are inadequate or even no services at many tertiary and regional hospitals, as well as no pacing facilities in several provinces in the government set up. This is clearly linked to untimely death due to easily treatable medical conditions â&#x20AC;&#x201C; patients may succumb from heart block without insertion of a pacemaker, have inadequate therapy without reperfusion with thrombolytic agents in acute ST-elevation myocardial infarction or suffer inadequate management of acute heart failure. Rheumatic heart disease is not diagnosed timeously due to poor access to advanced diagnostic facilities, such as echocardiography practiced by a cardiologist.

Paediatric cardiology training in South Africa The story of congenital heart disease is one of the major successes of medicine in the last 50 years, with the vast majority

of congenital lesions now being amenable to surgery.18 However, the situation in SSA is startlingly different.19 There are only a handful of specialised cardiothoracic centres in SSA, and the majority of children requiring congenital heart surgery do not have access to these centres.20 Furthermore, cardiac catheterisation laboratories that are able to perform procedures such as ductal closures, pulmonary valvotomies and mitral valvuloplasties on children are also limited in SSA. In South Africa, we appear fortunate in that we have the expertise to manage almost all of the congenital lesions, with the training institutions for surgeons and cardiologists consistently preforming over 300 cases in certain centres and over 1 500 per year in the country. However, the reality on the ground is that, as our primary healthcare services improve and awareness of congenital lesions increase, more patients will be referred with congenital heart disease requiring intervention. Despite many medical advances in the field, we remain critically understaffed, with increasing waiting lists and inadequate numbers of operations per year for our population.21,22 It is estimated that one paediatric cardiologist is required for every 500 000 population. If we use a conservative estimate based on half that number (one per million), we still require at least an additional 10 paediatric cardiologists in the public service in this country. Audits performed in 2010 and 2013 revealed that the number of paediatric cardiologists in the public service has increased by only one since 2010. In addition, as there is no subspecialist training for paediatric cardiothoracic surgeons, no significant increase had occurred in the number of children being operated on each year (Fig. 2). Only two of the six national units consistently do over 150 operations per year. This has resulted in waiting lists in all the public service centres that exceed 100 patients, with many dying while waiting for surgery. A particular concern is the fact that several provinces do not have any regular paediatric cardiac services. This implies that referrals between provinces are the only option for these patients, which involves significant logistical, economic and transport difficulties. We know that certain critical congenital heart disease (CCHD) lesions are rarely seen in these provinces, suggesting early demise of those affected, without a definitive cardiac diagnosis. The importance of paediatric cardiology training is not only for tertiary institutions but also to increase awareness

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Adult

Paediatric

Surgical

Fig. 1. N umber of cardiologists, paediatric cardiologists and cardiothoracic surgeons qualified in South Africa between 2003 and 2014.

Western Cape

Eastern Cape

Durban

Paediatric cardiologists

Bloemfontein

Chris Hani Pretoria Complex Academic

Total posts required

Surgeons

Fig. 2. Consultant paediatric cardiology and cardiac surgery staff in the Public Service.

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among secondary and primary-level institutions. The inadequate number of public service paediatric cardiologists affects training and outreach programmes to our neighbouring provinces and countries. Several novel approaches have been attempted to remedy this. The Walter Sisulu Centre of Africa previously attempted to fill this gap, the African Paediatric Fellowship Programme (APFP, http:// www.paediatrics.uct.ac.za/scah/apfp) serves to train paediatricians from across Africa, including paediatric cardiologists and surgeons, and collaborations between countries such as South Africa and Ethiopia have used task shifting to build capacity.23 Paediatric cardiac services in several provinces, such as Limpopo, rest on the shoulders of paediatricians with an interest in paediatric cardiology in order to diagnose patients, refer timeously and continue post-operative management and treatment.

Cardiothoracic surgery training in South Africa Currently, training in cardiothoracic surgery requires entry into a four-year programme post qualification. The four-year training programme encompasses a three-part examination in General Surgical Principles Part I, Intensive Care Principles Part II and Cardiothoracic Surgical Adult and Congenital Surgery Part III. Entry into the discipline is dictated by a single exit examination, which can be sat after acquiring Part I and II. The exit examination needs to be supported by a case load report, verified by the head of department prior to, or at the time of, sitting the Part III examination. Further requirements are competency in the practice of cardiothoracic surgery, which needs to be evaluated and confirmed by the head of department where the individual has undergone training. To enable the country to satisfy its need for surgeons in the discipline, there are currently seven academic departments with a staff compliment of 28. Currently there are 21 surgeons-intraining at various residency levels. The number of registered cardiothoracic surgeons in the country is 103. The need for cardiothoracic surgical expertise is estimated to be one surgeon per 800 000 population. Currently, the number of surgeons per population equals one per 4.5 million. Furthermore, there is an unequal distribution of surgeons servicing the private sector, as opposed to those servicing the public sector where the greatest need for service delivery exists. In order to equalise or rectify this discrepancy, there needs to be ongoing political involvement in equalisation of remuneration. The current College of Cardiothoracic Surgeons of the College of Medicine of South Africa is in the process of reviewing the training period and instituting a recommendation and requirements for the training period to be extended to a total of six years. The Society of Cardiothoracic Surgeons of South Africa is involved in coordinating additional training of residents by having established a Residents’ Forum in 2000. This Residents’ Forum has now been embellished by the involvement of the European Association of Cardiothoracic Surgeons education programme, which has contributed to this meeting in the past years. The Society is also currently involved in establishing an exchange programme between the Israeli Society and the South African Society, whereby a number of registrars and/or consultants will be exchanged on an annual basis in order to further enhance the training of South African surgeons and vice versa.

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The subspeciality of cardiac electrophysiology The subspeciality of cardiac electrophysiology (EP) and pacing has become one of the more popular subspecialities in cardiology worldwide. However, EP in South Africa and SSA has long been considered to be a ‘niche’ subspeciality. Over the past 20 years, Groote Schuur Hospital in Cape Town has attracted several full-time EPs, and currently has the only full-time academic EP in South Africa. Fortunately, there are two part-time EPs performing sessions at Chris Hani Baragwanath Hospital in Johannesburg and Albert Luthuli Hospital and Grey’s Hospital in Durban and Pietermaritzburg, respectively. The legacy of having a full-time EP service at Groote Schuur Hospital has stimulated interest in the field and has led to a further seven Groote Schuur Hospital cardiology registrars subspecialising in EP, mostly in North America and Europe, over the past 10 years. No training post for an aspiring EP exists in South Africa and all will need to perform an overseas fellowship (usually two years in duration). There are currently 13 CASSAaccredited EPs registered in South Africa, with a rough estimate of one EP per 21 million people in the public sector, compared to one EP per 800 000 people in the private sector. It is not surprising that EP does not form a significant part of the core cardiology curriculum of cardiology training in South Africa. Cardiology registrars need to observe 15 EP cases to complete the logbook for the certificate in cardiology. This is inadequate to teach and understand the principles and practices of EP and does little to stimulate interest in the field. Most of the cardiology registrars outside of Cape Town observe cases in private hospitals around South Africa. Cardiac pacing for bradyarrhythmias is considered a core skill in the training of cardiologists in South Africa. Cardiology registrars need to implant a minimum of 30 cardiac pacemakers (including five dual-chamber pacemakers) before being considered for the written and oral examination. The practical training of cardiac pacing at academic institutions is highly variable and mostly taught by general cardiologists. Many institutions are dependent on industry for device interrogation and troubleshooting. The current implantation rate in South Africa is 60 per million people, which is much lower compared to European countries such as Germany, where the implantation rate is much higher. There is still a lack of cardiac pacing in four out of 11 provinces in South Africa. There is also a severe shortage of pacemaker implanters in the rest of SSA. In order to address this urgent need for cardiac pacing, the PASCAR Fellowship in Cardiac Pacing has been established. Doctors will be able to learn the principles and practices of cardiac pacing at Groote Schuur Hospital for a six-month period – the first fellow started in March 2016. Implantable cardioverter defibrillators (ICDs) and biventricular pacemakers are limited in most academic institutions because of financial constraints and a lack of skilled expertise to implant them. Cardiology fellows need to observe 10 ICD and 10 biventricular implants for the logbook. Further additional training is often needed before cardiologists feel competent to implant them. CASSA has identified the need to improve the management and implantation of ICDs and has proposed an additional accreditation examination for non-EPs. Currently, all aspiring electrophysiologists need to seek overseas training, usually in North America or Europe. Compared to

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the United States, which has one EP per 127 500 people, it is estimated that South Africa needs a further 400 EPs for the equivalent population!

The way forward Having identified the profound deficiencies in the training of cardiologists, cardiothoracic surgeons and paediatric cardiologists in our country, the SA Heart Executive Committee, at three National Council face-to-face meetings held in 2015, identified the need to prepare a position paper summarising the facts and exact training deficiencies in South Africa over the past decade. It was generally felt that specialists in academia and private practice need to work more closely together and endeavour to engage with members of the Departments of Health and Education. In addition, the pharmaceutical, device and private hospital groups should be encouraged to sponsor more training posts in academic institutions. To facilitate earlier disease detection (e.g. RHD in young adults, including pregnant women) in a country and continent with so few specialists per capita, capacity for screening will have to be increased. This could be achieved by training a larger Table 2. Summary of the gaps identified and suggested next steps Gaps identified

Suggested next steps

• Create more posts for cardiovascular Low rates of graduates from health professional schools due to inadequate academics, promote career developtraining posts ment and other incentives for teaching roles Inadequate pool of trained cardiovascular specialists

• The establishment of a private training centre for cardiologists following the same curriculum they follow in the state, based at a centre of excellence

Internal and external brain drain

• Close engagement of specialists in academic hospitals and private practice

Specialists not used optimally, considering low number of specialists in South Africa and therefore late or inappropriate referral from the community level

• Use of non-physician technicians, medical officers in the use of handheld echocardiography for early cardiac disease detection, facilitating early referral to cardiologist/cardiothoracic surgeon

Specific training needs in cardiol• Training of obstetricians in the detecogy in pregnancy, heritable disorders tion of cardiac disease, facilitating predisposing to cardiomyopathy and early referral to cardiologist/cardiothoarrhythmia, and metabolic disorders, racic surgeon. including especially familial hypercho- • Registrar rotation through special lesterolaemia clinics

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group of healthcare workers in the appropriate use of simple, hand-held ultrasound devices. The screening for relevant diseases requiring referral to secondary and tertiary facilities could then, to some extent, be performed by general practitioners and medical technologists.24 In cases of women presenting with cardiac symptoms in pregnancy, the obstetricians could receive training in screening for cardiac diseases, as is currently already in practice via a dedicated clinic at Groote Schuur Hospital. Obstetricians have good ultrasound skills and the detection of turbulence over a rheumatic valve, a myopathic heart or a pericardial effusion would lead to quicker referral to cardiologists or cardiothoracic surgery for appropriate intervention. SA Heart is cognisant of the fact that the health authorities face tremendous challenges. Mismanagement and a burgeoning layer of bureaucracy have had a catastrophic effect on the delivery of healthcare. This deficiency is evident at all levels, including the training of nurses and specialists, and the provision of an adequate infrastructure for the practice of an acceptable level of medicine. Fundamental to this issue is the failure by the government to recognise that academic and tertiary health facilities are not a burden to the economy but underpin a strong and effective health system. In particular, provincial government has abrogated its responsibility to support and promote tertiary medicine, which has culminated in poor service delivery to the indigent patient and plummeting morale among the academic community. In the setting of very limited resources and previously poorly investigated sectors of the population, it is very important that cardiologists are trained to deal with a broader range of disorders so that they are recognised and appropriately managed away from the few teaching hospitals. In such hospitals, it is important to have good support for emerging subspecialities within cardiology to integrate service, teaching and research that is relevant to this country. Specific areas that need attention include cardiology in pregnancy, heritable disorders predisposing to cardiomyopathy and arrhythmia, and metabolic disorders including especially familial hypercholesterolaemia, in which much progress in treatment has been made. Rumours that management of tertiary hospitals will be taken over by the national government seem promising but unlikely to occur any time soon. The committee has summarised gaps and possible interventions in Table 2. In addition, Fig. 3 depicts the number

Health system weaknesses in CVD area Lack of strategies for increased specialist training for cardiovascular disease in South Africa

• Closer engagement with Departments of Health and Education to increase training posts

Insufficient epidemiological data on CVD and its medical and surgical management in South Africa

• Improve science and technology infrastructure, acquiring better epidemiological data on CVD as part of health system-strengthening strategies

Overall low CVD scientific output, making healthcare planning difficult

• Progressive increase in the percentage of GDP allocated to research and development, better recognition of the role of the clinician–scientist and subsequent increase in scientific output related to cardiac disease

Health policy decision makers and cardiovascular specialist inertia to increase training opportunities

• Invest in regulation that promotes public–private partnerships on research

Low investment in research and devel- • Facilitate translational research opment infrastructure and lack of • Facilitate training in cardiovascular science and technology culture research in South Africa and collaborations with international research entities

55.7

6.8%

3.84

30%

0.6

Adult cardiologists

1.03

Paediatric cardiologists

Number per million

50%

Adult surgeons

Needed per million

Fig. 3. Registered specialists in South Africa versus number of specialists needed per million population.

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of specialists registered currently in South Africa versus the specialists needed to serve the country.

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Hospital. Sth Afr Med J 2008; 98(7): 553–556. PubMed PMID: 18785398. 11. Sliwa K, Libhaber E, Elliott C, Momberg Z, Osman A, Zuhlke L, et

Conclusion SA Heart is deeply concerned that the government has reduced and frozen training posts, progressively whittled down the number of tertiary hospital beds, and has failed to provide an environment conducive to the delivery of healthcare that would comply with internationally acceptable standards.

al. Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa. Heart 2014; 100(24): 1967–1974. PubMed PMID: 25227705. Pubmed Central PMCID: 4251204. 12. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, Shackelford KA, Steiner C, Heuton KR, et al. Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384(9947): 980–1004. PubMed PMID: 24797575. Pubmed Central

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Death. (NCCEMD). Saving Mothers 2008–2010. Fifth report on the

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Cape Town: models for a national medical student research training

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programme. Sth Afr Med J 2014; 104(2): 111–113. PubMed PMID:

Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et

PubMed PMID: 22945249. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect

2010; 31(13): 1541–1542. PubMed PMID: 20595222. 18. Williams RG. Increased survival of congenital heart disease: How did we get here and now what? J Am Coll Cardiol 2015; 66(1): 45–46. PubMed PMID: 26139057. 19. Zühlke L, Mirabel M, Marijon E. Congenital heart disease and rheu-

tion in 52 countries (the INTERHEART study): case–control study.

matic heart disease in Africa: recent advances and current priorities.

Lancet 2004; 364(9438): 937–952. PubMed PMID: 15364185.

Heart 2013; 99(21): 1554–1561. PubMed PMID: 23680886. Pubmed

Ogah OS, Stewart S, Onwujekwe OE, Falase AO, Adebayo SO, Olunuga

Central PMCID: 3812860.

T, et al. Economic burden of heart failure: investigating outpatient

20. Mocumbi AO. The challenges of cardiac surgery for African children.

and inpatient costs in Abeokuta, Southwest Nigeria. PloS one 2014;

Cardiovasc J Afr 2012; 23(3): 165–167. PubMed PMID: 22555641.

4240551. Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S. Incidence and characteristics of newly diagnosed rheumatic heart disease in urban African adults: insights from the heart of Soweto study. Eur Heart J 2010; 31(6): 719–727. PubMed PMID: 19995873. 9.

24893538. 17. Taylor J. Cardiology in Brazil: a country in development. Eur Heart J

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PubMed PMID: 25265493. 16. Katz AA, Futter M, Mayosi BM. The intercalated BSc (Med) Honours/ MB ChB and integrated MB ChB/PhD tracks at the University of

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Pubmed Central PMCID: 3721936. 21. Hoosen E, Hugo Hamman C, Brown S, Harrisberg J, Takkawira F, et al. Audit of paediatric cardiac services in South Africa. S A Heart J 2010; 7: 4–7. 22. Hoosen EG, Cilliers AM, Hugo-Hamman CT, Brown SC, Lawrenson JB, Zuhlke L, et al. Paediatric cardiac services in South Africa. Sth Afr Med J 2011; 101(2): 106–107. PubMed PMID: 21678733.

B, et al. Characteristics, complications, and gaps in evidence-based

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Review Article Patterns of international collaboration in cardiovascular research in sub-Saharan Africa Remare Ettarh

Abstract The rising prevalence of cardiovascular disease in subSaharan Africa (SSA) constitutes a significant health and socio-economic challenge for the countries in the region. This study examines the patterns and scientific impact of international collaboration in cardiovascular research (CVR) in SSA. Bibliographic data from 2005 to 2014 were obtained from the Web of Science for cardiovascular-related publications with at least one author affiliated to an SSA country. The number of publications involving multiple SSA countries over this period accounted for less than 10% of the total number of multicountry publications that included at least one SSA country. Collaboration patterns reflected dominance by countries in Europe and North America, with South Africa accounting for the bulk of scientific collaboration in CVR within SSA. The findings indicate that pro-active strategies are needed to strengthen collaboration in CVR across SSA for the region to derive health and socio-economic benefits from locally conducted research. Keywords: cardiovascular research, Africa, collaboration, co-authorship analysis, academic impact Submitted 15/6/15, accepted 4/10/15 Cardiovasc J Afr 2015; 26: 194–200

www.cvja.co.za

DOI: 10.5830/CVJA-2015-082

The increasing burden of cardiovascular diseases (CVD) in sub-Saharan Africa has been reported in recent studies on the global burden of disease.1 The epidemiological transition in the region from a predominantly infectious disease burden to one that includes a high prevalence of non-communicable conditions, such as cardiovascular diseases, poses significant challenges, not only for the economies and health systems of the countries, but also for the local health research sector, which often lacks the capacity to drive knowledge advancement and innovation leading to positive health impacts.2 Over the last decade, there have been efforts to develop capacity in developing countries. These strategies have included promoting international collaboration through the joint development of projects by research groups in developed and

Alberta Innovates – Health Solutions, Edmonton, Canada Remare Ettarh, PhD, remare.ettarh@aihealthsolutions.ca

developing countries.3,4 The value of this collaborative approach for the developing country partner lies in the availability of financial and technical resources for research, opportunities to develop and nurture institutional research capacity, and the potential impact of locally focused research on the health system. The negligible contribution of Africa to global scientific knowledge and impact is well documented.5 However, there has been a gradual increase in the volume of scientific publications that include authorship from Africa in recent years, albeit with a substantial dominance by non-African co-authors.5,6 Some of the reasons for this pattern of scientific output include: (1) low budgetary funding for research by African countries; (2) lack of investment in scientific infrastructure and research equipment; (3) emphasis on personnel development within the higher education system rather than on support for research; and (4) the dearth of skilled research scientists in the region, partly associated with the brain drain phenomenon. There are suggestions that these challenges can be partly addressed by increased international collaboration, which reduces research cost and time, enhances knowledge transfer across borders, and improves scientific impact.7 The extent of research collaboration across SSA has been the subject of a few recent publications,5,8,9 although little is known about the patterns of collaboration within the area of CVR in this region. Additional studies are required to understand the extent of scientific output as well as the patterns and impact of collaboration in CVR among countries in SSA. The evidence from such studies would be valuable in developing strategies to advance knowledge in cardiovascular disease prevention and care in the region. The use of co-authorship networks for analysing research collaboration at the individual or micro-level is well established,10,11 although there is an upward trend in its application for studying macro-level or international collaboration.12 Network analysis offers possibilities for visualising and understanding the relationships between the collaborating research entities. The methodologies allow for the identification of hubs, boundary spanners, clusters and the strength of relationships.13 Temporal analysis of the collaborative patterns is also possible using timesliced data.14 In a macro-level network, the vertices represent countries and the edges between them represent the presence of collaboration in the form co-authorship by one or more research groups. The weight of the edge reflects the number of publications by a pair of vertices or countries. This study examines the indexed scientific output of cardiovascular research conducted solely or in part by researchers in sub-Saharan Africa over the last 10 years in order

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to analyse macro-level collaboration in the region. Specifically, the study uses citation and network analyses to: (1) examine the trends in scientific output and collaborative research patterns in CVR in SSA; (2) identify the top countries in SSA involved in collaborative CVR within the region and globally; and (3) assess the scientific impact of collaborative CVR in SSA.

Methods Bibliographic data were sourced from the Web of Science of Thompson Reuters. A search procedure was developed to retrieve the relevant publications for analysis. The databases included in the search included: Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index – Science (CPCI-S), Conference Proceedings Citation Index – Social Science & Humanities (CPCI-SSH) and Arts & Humanities Citation Index (A&HCI). The publication period was restricted to 2005 to 2014. A set of key words for cardiovascular research was used for the search of the title, keyword and abstract fields.15 The list of the 47 countries that constitute sub-Saharan Africa was obtained from the World Bank16 and used as part of the advanced search protocol. Citation data were obtained for all the retrieved records by using the Create Citation Report function in Web of Science. Pre-processing of the Web of Science data was done in Microsoft Excel. Country names were extracted from each author’s affiliation and saved with accompanying attribute data, such as year and type of publication. The resulting flat file was merged with citation data from Web of Science using unique identifiers for each publication. Duplicate country names, which occurred where co-authors were from the same country, were eliminated for each publication using macros within Microsoft Excel. After cleaning, a total of 1 569 publications from 2005–2014 were available for analysis. The dataset was then split into two for subsequent citation and network analyses: one with single SSA country publications (n = 783) and another with multicountry publications (n = 786). The multi-country dataset was filtered to show only countries within SSA, to enable analysis of collaboration patterns within the region. For network analysis using this SSA-specific dataset, all publications with only one SSA country were excluded. A total of 75 publications were obtained, which included collaborations between multiple SSA countries.

Data analysis Research output was assessed using number of publications, disaggregated by region or country and by single or joint country authorship. The trend in research output was determined and illustrated over the 10-year period. The instances of collaboration were determined from adjacency matrices and used to determine the top 10 SSA countries involved in cardiovascular research collaboration and the top six countries outside the SSA with which these collaborations occurred. Citation analysis was done by examining the trend in citation rates in single-country- and multi-country-authored publications across the 10-year period. Patterns of international collaboration in cardiovascular research involving SSA countries were analysed using traditional network analysis methodologies. The co-occurrence of countries

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in the affiliation field of publications was considered an instance of collaboration between the two countries. Co-authorship at the macro level is considered an effective approach to the analysis of research collaboration between countries.10 Preparation of datasets for network analysis involved creating adjacency matrices of countries reflecting instances of collaboration. Adjacency matrices were created using Visual Basic scripts run in Microsoft Excel, and used in the analysis of instances of collaboration within SSA. NodeXL, an open-source network analysis and visualisation application, was used for creating the network graph.17 Network data were uploaded into NodeXL as edge lists, i.e. a two-column list of country pairs that collaborated in publications. The network graph used to visualise international collaboration in CVR within SSA was created using the Harel-Koren fast multiscale algorithm.

Results Cardiovascular research output A total of 88 cardiovascular research publications with authorship in SSA were indexed in the Web of Science in 2005. There was a gradual increase to 225 publications in 2014. The trend for the fraction of CVR publications that involved multiple countries was from 37 in 2005 to 124 in 2014. There were eight CVR publications that involved multiple SSA countries in 2005, with a slight increase to 16 in 2014. Overall, the number of publications involving multiple SSA countries over the 10-year period accounted for less than 10% of the total number of multicountry publications that included at least one SSA country. The number of publications in the field with authorship from a single SSA country rose from 51 in 2005 to 101 in 2014 (not shown in Fig. 1). These data reflect minimal country-level collaboration in CVR in SSA and very limited growth in co-authorships across country borders over the last decade. The trend in cardiovascular research output in SSA is shown in Fig. 1. Table 1 shows the cardiovascular research output by the top 10 countries in SSA and the percentage of publications that involved collaboration with other countries within or

Number of publications

AFRICA

250 200 150 100 50 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Year SSA + International (single and multi) SSA + International (multi) SSA (multi)

Fig. 1. Trend in the number of publications in CVR with authorship from countries in SSA, 2005–2014. Single refers to publications with only one SSA country in its affiliations; multi refers to publications with more than one country in its affiliations but including at least one SSA country. International is used to refer to all countries outside SSA.

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Table 1. Number of cardiovascular research publications by the top 10 countries in sub-Saharan Africa, 2005–2014

Country South Africa

Total number of articles published

Number of articles that involved international collaboration

Percentage of articles that involved international collaboration

1016

507

Nigeria

228

Kenya

Cameroon

Uganda

Mozambique

Ghana

Senegal

Tanzania

100

1494

745

Zimbabwe Total

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outside SSA. Eight of the 10 SSA countries had international collaborations on more than 50% of their publications. South Africa had the largest output over the decade with 1 016 publications, which was more than all the other SSA countries combined. Collaboration with other countries accounted for 50% of the output from South Africa, compared with 23% from Nigeria, which was the lowest in SSA. All of the publications from Zimbabwe involved collaboration with other countries.

International collaboration in CVR in sub-Saharan Africa Table 2 presents the extent of collaboration in CVR between the countries in SSA and the most frequent partner countries outside the region. The data reflect instances of collaboration between pairs of countries based on their co-occurrence in the author affiliations of a given publication. In network analysis terms, this is equivalent to the number of edges that any two countries share. The numbers in parentheses represent the percentage of the SSA country’s total instances of collaboration that involved the non-SSA country or all of SSA. South Africa recorded the highest instances of collaboration in SSA, with 15% of those occurring with the USA. Countries in SSA accounted for 4% of South Africa’s instances of collaboration in CVR. Nigeria had the second highest instances of collaboration in CVR, with the majority of these occurring with the USA. Cameroon and Senegal had most of their collaborations outside SSA with France, and the two countries also had the highest percentages of collaboration instances with SSA, at 37 and 41%, respectively. Table 3 presents the instances of collaboration between the top 10 SSA countries in CVR. The numbers in parentheses represent the percentage of an SSA country’s collaborations within SSA that occurred with the paired SSA country. The highest number of instances of collaboration occurred between South Africa and Nigeria,15 and this accounted for 27% of South Africa’s SSA collaborations and 58% of Nigeria’s SSA collaborations. South Africa accounted for the majority of instances of collaboration for eight of the countries, with the exception of Senegal, which collaborated mostly with Cameroon. The network of collaboration in CVR between countries in SSA can be visualised in Fig. 2. The network is based on the subset of publications in which more than one SSA country was

Table 2. Number of instances of cardiovascular research collaboration between the top 10 countries in sub-Saharan Africa and the most frequent non-SSA partner countries, 2005–2014 USA (%)

Total South Africa

England Italy (%) (%)

1379 208 (15) 116 (8)

Nigeria

France Germa- Canada SSA (%) ny (%) (%) (%)

78 (6) 56 (4)

84 (6) 52 (4)

55 (4)

112

16 (14)

8 (7)

2 (2)

4 (4)

2 (2)

26 (23)

Cameroon

7 (8)

3 (3)

4 (5)

9 (10)

5 (6)

–

32 (37)

Uganda

7 (9)

4 (5)

3 (4)

12 (15)

Zimbabwe

1 (1)

5 (7)

2 (3)

1 (1)

–

4 (5)

16 (21)

Mozambique

5 (8)

6 (10)

–

14 (23)

1 (2)

2 (3)

9 (15)

Kenya

15 (28)

7 (13)

1 (2)

2 (4)

1 (2)

10 (19)

Ghana

8 (16)

4 (8)

–

2 (4)

5 (10)

–

16 (31)

Tanzania

4 (11)

6 (17)

1 (3)

–

8 (22)

Senegal

2 (6)

1 (3)

–

8 (24)

–

14 (41)

17 (21) 10 (12)

The numbers in parentheses represent the percentage of the SSA country’s total instances of collaboration that involved a non-SSA country or all of SSA.

present from authors’ affiliations. A total of 34 SSA countries were involved in at least one instance of collaboration out of the 47 countries in the region. The size of any vertex is proportional to the degree centrality, i.e. the number of countries with which that country has an instance of collaboration. Cameroon had the highest degree centrality18 and eigenvector centrality (0.087), indicating a high degree of collaboration with other countries in the region, and playing a role as a boundary spanner linking the French-speaking countries with most of the English-speaking countries. The width of the edges connecting pairs of countries is proportional to the frequency of co-authorship or collaboration between these countries. The thickest edge occurs between South Africa and Nigeria, indicating the highest level of collaboration in CVR in the region. South Africa also has strong collaboration in CVR with Zimbabwe, Ghana and Mozambique.

Burkina Faso

Gabon

Benin

Mauritania Mali Cote Ivoire DR Congo

Guinea Chad Togo

Angola Sudan

Congo

Senegal Cameroon

Tanzania

Ghana Nigeria Gambia Uganda Seychelles Namibia

Rwanda Malawi Zambia Mauritius

South Africa

Madagascar Ethiopia Mozambique Eritrea

Zimbabwe Botswana Kenya

Fig. 2. Network of cardiovascular research collaboration among countries in SSA. The 10 countries in red are those with the highest number of publications in cardiovascular research from 2005 to 2014. The width of the edges between countries reflects the extent of collaboration between the pair based on co-authorship.

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Table 3. Number of instances of cardiovascular research collaboration between the top 10 countries in sub-Saharan Africa, 2005–2014 South Africa (%)

Nigeria (%)

South Africa

Cameroon (%)

15 (27)

Nigeria

15 (58)

Uganda (%)

Zimbabwe (%)

Mozambique (%)

Kenya (%)

Ghana (%)

Tanzania (%)

Senegal (%)

All SSA (%)

5 (9)

2 (4)

8 (15)

3 (5)

6 (11)

1 (2)

2 (8)

1 (4)

–

1 (4)

2 (8)

Cameroon

5 (16)

2 (6)

Uganda

2 (17)

1 (8)

1 (3)

–

3 (9)

1 (3)

4 (13)

1 (8)

–

1 (8)

–

1 (8)

–

1 (6)

–

2 (20)

–

Zimbabwe

8 (50)

1 (6)

Mozambique

8 (89)

–

Kenya

3 (30)

–

1 (10)

–

Ghana

6 (38)

1 (6)

3 (19)

–

2 (13)

Tanzania

1 (13)

–

Senegal

1 (7)

2 (14)

4 (29)

–

Numbers in parentheses are row percentages using the total number of instances of collaboration with all countries in SSA as denominator.

International collaboration and citation impact Table 4 presents the 10-year trend in bibliometric outcomes for publications in CVR with authorship involving SSA. The table also compares research output and citation impact for publications with single-country authorship (SCP) and those with multi-country authorship (MCP). Overall, there was a consistent increase in the total number of publications and total number of citations each year from 2005 to 2014. The total number of publications over the 10-year period was similar for SCP and MCP, as shown by the publication ratio, with a slight increase from 0.7 in 2005 to 1.2 in 2014. Total citations rose from 20 in 2005 to 2 973 in 2014. There were substantial differences between the SCP and MCP in the citation frequency and citation rate (CR, number of citations per publication) throughout the period of analysis. On average, the annual citation frequency for MCP was 3.4 times higher than the annual citation frequency for SCP. Over 10 years, the total number of citations for the MCP was 10 116, compared to 3 117 for the SCP. Comparisons of citation rates for the two categories using the annual CR ratio showed that the CR for MCP was on average 3.6 times higher than that for SCP.

Discussion This study provides a 10-year picture of the range, volume and scientific impact of international collaboration in cardiovascular research in sub-Saharan Africa. The absence

of published literature on this issue suggests that this is the first study that evaluates the comparative output of SSA countries in cardiovascular research and examines the patterns of co-authorship involving country-level affiliations within and outside SSA. A study in 2005 on estimates of the global production in CVR showed that the scientific productivity of Africa (which included SSA and countries in North Africa) over the period 1995 to 2002 was the lowest of all the world regions, accounting for 0.3% of the global output in the field.18 Over the eight-year period, Africa produced 212 articles in the 38 journals included in the study, with a fairly constant average annual output of 27 articles per year. In the present study, the annual output for SSA increased constantly from 88 in 2005 to 225 in 2014. The higher annual output in this study may be due to the difference in search methodology, in which published articles were not restrictively drawn from the 38 journals in the ‘Cardiac and Cardiovascular Systems’ category of ‘Journal Citation Report’ as was done in the study mentioned above.18 In general, there appears to be a gradual increase in research output in this field in SSA, although the contribution of the region to the global output remains very low. Some of the reasons for the lower research productivity in SSA were mentioned above – lack of resources for research, the fewer number of research institutions, weak government support, and the dearth of skilled researchers in many fields of

Table 4. Comparison of annual count and citations for single-country (SSA) authored and multi-country (international) authored cardiovascular research publications All publications

Single-country publications (SCP)

2005

0.1

0.4

0.7

4.0

5.5

2006

101

247

0.9

195

4.2

0.8

3.8

4.5

2007

108

547

122

2.1

425

8.5

0.9

3.5

4.0

2008

149

702

150

2.3

552

6.7

1.3

3.7

2.9

2009

156

1008

231

2.6

777

11.4

0.8

3.4

4.4

2010

163

1247

325

3.9

922

11.7

0.9

2.8

3.0

2011

164

1762

425

5.2

1337

16.3

1.0

3.1

2012

197

2104

498

5.2

101

1606

15.9

1.1

3.2

3.1

2013

218

2623

105

581

5.5

113

2042

18.1

1.1

3.5

3.3

2014

225

2973

101

729

7.2

124

2244

18.1

1.2

3.1

2.5

Total

1569

13233

786

3117

4.0

783

10116

12.9

1.0

3.2

3.3

157

1,323

312

3.5

1012

11.1

1.0

3.4

3.6

Publications

Citations

Citation rate (CR) Publications

Comparisons (MCP/SCP)

Year

Average

Total citations

Multi-country publications* (MCP)

Total publications

Citations

Citation rate (CR)

Publication ratio

Citation ratio

CR ratio

*This refers to all multi-country publications that included at least one SSA country among the author affiliations.

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study.5,6 In addition, the pressure to publish in these countries is enormous, as promotion and tenure, institutional performance and external funding are strongly tied to publication counts.19,20 Collaboration in CVR between SSA and non-SSA countries shows similarities with the patterns reported for international collaborations across all scientific disciplines in Africa.5 South Africa remains the leading country both in terms of research output and the extent of collaboration with countries outside SSA. The top non-SSA countries involved in co-authorships in CVR with SSA countries are: USA, England, Italy, France, Germany and Canada. Most of these countries are reported in the top 10 of the worldâ&#x20AC;&#x2122;s leading countries in terms of scientific output in cardiovascular research.15 The reasons underlying this pattern of collaboration in CVR are numerous. The strength of the national economies measured as gross domestic product has been shown to be positively associated with national research output.18 Although data on GDP was not utilised in the study, this association may partly explain the position of South Africa and Nigeria as the leading countries in CVR in the region. Historical and political ties between countries may influence the extent of collaboration in research,21 as well as the dominant language of use in research. France is well known to be a critical partner with regard to international research collaboration in French-speaking Africa.12 The high degree centrality of Cameroon in the CVR network of SSA countries can be attributed to the presence of anglophone and francophone populations within the country. This unique characteristic of Cameroon makes it strategically important in creating and expanding collaborative research networks within SSA, essentially co-developing joint research projects with groups of cardiovascular researchers in both English- and French-speaking countries in the region. Such networks are critically important for improved rigour and cost-effectiveness of research endeavours in SSA, with the advantage of multi-country study designs and the possibility of concurrent policy engagement strategies in different countries using common evidence to influence health policy and practice aimed at reducing cardiovascular morbidity and mortality rates in the region. International collaborations in SSA are strongly linked to the source of research funding from countries outside the region. A large number of research articles in public health with African authorship can be linked to the grants awarded for projects in specific countries from the major funding agencies, such as USAID, the UK Medical Research Council, and the Wellcome Trust.5 In addition, research training opportunities for students from SSA in developed countries provide avenues for collaboration with researchers in the host universities.22 Nigeria presents a unique case of low international collaboration in spite of a relatively high CVR output compared to most countries in the region. This may be due to the availability of greater local funding for CVR and the relatively higher number of universities with medical faculties compared to most other SSA countries. The motivation for researchers in Nigeria to publish for career advancement purposes may positively influence the national research output in this field without a significant influence from international funding and collaboration.23 The extent of collaboration within SSA is very limited compared to the level of collaboration with other non-SSA

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countries. This pattern has been observed with data for all of the scientific output of the region.5,8,9,24 Some studies have found lower levels of collaboration between countries in West Africa compared with their individual levels of collaboration with France.25,26 South Africa and Nigeria, which account for the bulk of the cardiovascular research output in SSA, partly due to the size of their cardiovascular research communities, are best placed to serve as strategic hubs for promoting and coordinating collaboration in this field. In South Africa, the Hatter Institute of Cardiovascular Research in Africa, located at the University of Cape Town, is working to facilitate national and international research collaborations to combat cardiovascular disease in Africa.27 Two key multinational collaborative projects underway at the institute include: (1) the Pan-African Pulmonary Hypertension Cohort (PAPUCO) study, which aims to describe the epidemiology of pulmonary hypertension in patients from 10 African countries,28 and (2) the THESUS-HF survey, which focuses on the causes, treatment and outcome of acute heart failure in patients across nine African countries.29 These large, collaborative studies reflect real intent and progress in building regional networks that fosters international collaboration in cardiovascular research. In the last few years, there has been a revival of the Pan-African Society of Cardiology (PASCAR), leading to improved networking among researchers and clinicians involved in cardiovascular research across Africa.30 Some of the major multinational collaborative research projects that involve PASCAR include: the Awareness Surveillance Advocacy Prevention (ASAP) programme,31 the ASTRAL study targeted at controlling hypertension,32 the IMPI trial for the management of tuberculous pericarditis,33 and the Human Heredity and Health in Africa (H3Africa) initiative.34 These large initiatives are transforming the landscape of cardiovascular research in Africa, and the resulting enhanced capacity of African scientists will be evident from increased research productivity in this field and the contributions to knowledge that will ultimately benefit the continent. A benefit of international collaboration in CVR is seen in the greater citation impact that resulted from publications with multi-country authorship compared with that from publications with single-country authorship. Despite similar research outputs over the 10-year period, the multi-country publications resulted in over three times the number of citations garnered by the single-country publications. While no analysis was done on the range of journals in which the articles were published and how these could influence citation rates, this finding likely reflects the greater possibilities for dissemination and utilisation of the knowledge generated through the networks associated with the multiple authors and affiliated institutions in the countries involved. These results are similar to those reported by other authors.35,36

Limitations This study has a number of limitations. First, the analysis involved publications contained in the Web of Science and therefore excludes the numerous journals not indexed, particularly journals in countries in SSA. Web of Science was used in this study because it provided the affiliations of all the authors listed in each record for the time period under consideration,

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without which the study would not have been possible. Second, the use of co-authorship as a form of collaboration is limited by the assumption of interaction between all pairs of authors. The impact of co-authorship on future collaboration is not well understood and requires further study. Lastly, the use of citation measures as evidence of scientific impact has its limitations, particularly with regard to the journals and databases used, self-citation issues, and the unequal access to articles in different journals due to the use or otherwise of an open-access policy. In spite of these limitations, this study utilised a reliable data source and methodologies that provided valuable evidence on connectedness of countries involved in cardiovascular research in SSA.

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10. Glänzel W, Schubert A. Analysing Scientific networks through co-authorship. In: Moed HF, Glänzel W, Schmoch U, eds. Handbook of Quantitative Science and Technology Research. Dordrecht, NLD: Kluwer Academic, 2005: 257–276. 11. Adams J. Collaborations: The rise of research networks. Nature 2012; 490(7420): 335–336. 12. Leydesdorff L, Wagner CS. International collaboration in science and the formation of a core group. J Informetr 2008; 2(4): 317–325. 13. Wasserman S, Faust K. Social Network Analysis, Methods and Analysis. Cambridge, UK: Cambridge University Press, 1994. 14. Weingart S, Guo H, Bo¨rner K, et al. Science of Science (Sci2) Tool User Manual. 2010 [cited 22 May 2015]; Available from: http://sci2.wiki. cns.iu.edu. 15. Bolaños-Pizarro M, Thijs B, Glänzel W. Cardiovascular research in

Conclusion This study provides evidence on the state and scientific impact of national-level collaboration in cardiovascular research in SSA. It reveals the very low, but growing, research output and collaboration in this field from the region, even as the burden of cardiovascular disease continues to rise in SSA. Research institutions and national governments in SSA need to pro-actively work to build effective cardiovascular research networks that include multiple countries in the region, as a means of developing capacity in this field and improving the quality and volume of research in cardiovascular disease prevention and care. Creating and strengthening international research networks in SSA is critical if the growing challenge of a rising cardiovascular disease burden in the region is to be addressed effectively.

Spain. A comparative scientometric study. Scientometrics 2010; 85(2): 509–526. 16. The World Bank. Data: Sub-Saharan Africa. 2015 [cited 2015 22 May]; Available from: http://data.worldbank.org/region/SSA. 17. Hansen D, Shneiderman B, Smith MA. Analyzing Social Media Networks with NodeXL: Insights from a Connected World. Burlington, MA: Morgan Kaufmann, 2009. 18. Rosmarakis ES, Vergidis PI, Soteriades ES, et al. Estimates of global production in cardiovascular diseases research. Int J Cardiol 2005; 100(3): 443–449. 19. Wadesango N. Publish or perish: Impediments to research output and publication. Int J Educat Sci 2014; 6(1): 57–63. 20. Kyvik S. Changing trends in publishing behaviour among university faculty, 1980–2000. Scientometrics 2003; 58: 35–48. 21. Georghiou L. Global cooperation in research. Res Policy 1998; 27: 611–626. 22. Demeritt D, Lees L. Research relevance, ‘knowledge transfer’ and the

This article was prepared by the author in his personal capacity. The opinions expressed in this article are the author’s own and do not reflect the views of Alberta Innovates – Health Solutions.

geographies of CASE studentship collaboration. Area 2005; 37(2): 127–137. 23. Anunobi CV, Emerole N. Motivation and encumbrances to research and publication: The case of Nigerian library and information science (LIS)

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Mocumbi AO. Lack of focus on cardiovascular disease in sub-Saharan Africa. Cardiovasc Diagn Ther 2012; 2(1): 74–77.

Nchinda TC. Research capacity development for CVD prevention: the role of partnerships. Ethn Dis 2003; 13(2 Suppl 2): S40–44.

Whitworth JAG, Kokwaro G, Kinyanjui S, et al. Strengthening capacity for health research in Africa. Lancet 2008; 372(9649): 1590–1593.

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Africa. Scientometrics. 2009; 81(2): 413–434. 26. Jeenab M, Pouris A. South African research in the context of Africa and globally. S Afr J Sci 2008; 104(9–10): 351–355. 27. Hatter Institute for Cardiovascular Research in Africa. Heart of Africa 2015 [25 May 2015]; Available from: http://african-heart.org/research/ heart-of-africa/. 28. Thienemann F, Dzudie A, Mocumbi AO, et al. Rationale and design of the Pan African Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary registry on pulmonary hypertension in

Leydesdorff L, Carley S, Rafols I. Global maps of science based on the Onyancha O, Ocholla D. Country-wise collaborations in HIV/AIDS 239–24. Onyancha O, Maluleka J. Knowledge production through collaborative research in sub-Saharan Africa: how much do countries contribute to each other’s knowledge output and citation impact? Scientometrics 2011;

2010; 84: 481–503. 25. Boshoff N. Neo-colonialism and research collaboration in Central

in Africa. Scientometrics 2014; 98(1): 547–556.

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Adams J, Gurney K, Hook D, et al. International collaboration clusters

new Web-of-Science categories. Scientometrics 2013; 94(2): 589–593. 7.

practitioners. Educat Res Rev 2008; 3(2): 66–72. 24. Bishoff N. South–South research collaboration of countries in the

Africa. Br Med J Open 2014; 4(10): e005950. 29. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012; 172(18): 1386–1394. 30. Pan-African Society of Cardiology (PASCAR). Pan-African Society of Cardiology. PASCAR; 2015 [20 July 2015]; Available from: http://www. pascar.org. 31. Robertson KA, Volmink JA, Mayosi BM. Towards a uniform plan for

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34. Owolabi MO, Mensah GA, Kimmel PL, et al. Understanding the rise

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epidemiological teams and tools. Cardiovasc J Afr 2014; 25(3): 134–136. 35. Sooryamoorthy R. Do types of collaboration change citation? Collaboration and citation patterns of South African science publications. Scientometrics 2009; 81(1): 177–193.

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Meeting Report Development of the roadmap for reducing cardiovascular morbidity and mortality through the detection, treatment and control of hypertension in Africa: report of a working group of the PASCAR Hypertension Task Force Anastase Dzudie, Abdoul Kane, Euloge Kramoh, Jean-Baptiste Anzouan-Kacou, Jean Marie Damourou, Lucien Allawaye, Jolis Nzisabira, Latif Mousse, Dadier Balde, Ouane Nouhom, Jean Louis Nkoa, Kimbally Kaki, Armel Djomou, Alain Menanga, Christ Nadege Nganou, Jean Bruno Mipinda, Lucie Nebie, Liliane Mfeukeu Kuate, Samuel Kingue, Serigne Abdou Ba, on behalf of the PASCAR task force on hypertension

Abstract The fourth Pan-African Society of Cardiology (PASCAR) hypertension taskforce meeting was held at the Yaoundé Hilton Hotel on 16 March 2016. Its main goals were to update and facilitate understanding of the PASCAR roadmap for the control of hypertension on the continent, to refine the PASCAR hypertension algorithm, and to discuss the next steps of the PASCAR hypertension policy, including how the PASCAR initiative can be customised at country level. The formation of the PASCAR coalition against hypertension, the writing group and the current status of the PASCAR hypertension policy document as well as the algorithm were presented to delegates representing 12 French-speaking countries. The urgency to finalise the continental policy was recognised and consensus was achieved by discussion on the main points and strategy. Relevant scientific issues were discussed and comments were received on all points, including how the algorithm could be simplified and made more accessible for implementation at primary healthcare centres.

Keywords: hypertension, policy, PASCAR, roadmap, Africa In sub-Saharan Africa, the high prevalence of hypertension is coupled with poor rates of detection, treatment and control.1 The disease is a major threat to achievement of the World Health Organisation Global Action Plan 2013–2020 for non-communicable disease (NCD) reduction, specifically focused on heart attacks, strokes and other cardiovascular diseases. As the leading continental organisation, the Pan-African Society of Cardiology (PASCAR), including all hypertension experts and stakeholders, embarked on the development of a continental hypertension policy to help reduce heart disease and stroke on the continent by the year 2025. To achieve its goal, this coalition started working in 2014,2 achieving consensus on a majority of points by group discussion during conference calls and three face-to-face meetings, as well as by iterative revisions of the written document. This document, which is a customisation of the World Heart Federation (WHF) global roadmap3 to the Africa-specific context, was discussed and reviewed on several occasions in opportunistic and scheduled meetings.

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The Cameroon Cardiac Society (CCS) meeting held in Yaoundé from 16 to 18 March 2016 was a unique occasion to review the progress so far and discuss the next steps with national cardiac societies from French-speaking African countries, some of which were unable to fully participate physically in the previous steps. This opportune meeting welcomed together a large number of delegates representing 12 French-speaking African countries.

Welcome address Prof Abdou Serigne BA (Senegal), vice president of the PASCAR West region and chair of the meeting, welcomed the participants and thanked them for their time and the effort made to attend the meeting, and for their enthusiasm in contributing to this unique opportunity to develop a clear policy against hypertension in Africa. He expressed gratitude to the CCS for convening this meeting, which would serve as a call to all other African national cardiac societies to join the continental organisation. He also set out the agenda, presented an update on the PASCAR hypertension roadmap, and made a presentation on the PASCAR hypertension algorithm, which was followed by friendly, open discussion. As president of the CCS and co-chair of the meeting, Prof Samuel Kingue (Cameroon) followed Prof Ba, welcoming the delegates and wishing the group a fruitful working session. The second co-chair, Prof Jean Louis Nkoua (Congo) joined his peers in welcoming participants and wished them a successful meeting.

Update on the PASCAR roadmap for hypertension Dr Anastase Dzudie, chair of the PASCAR Task Force on Hypertension, presented an update on the PASCAR hypertension roadmap thus far and an evidence-based review on clinical trials

Douala General Hospital and Buea Faculty of Health Sciences, Douala, Cameroon; Soweto Research Group and National Institute of Health Millennium Fogarty Chronic Disease Leadership programme, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa Anastase Dzudie, MD, PhD, FESC, aitdzudie@yahoo.com

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and guidelines for hypertension management in Africa. The work to date has consisted of three face-to-face meetings (Nairobi: 27 October 2014, London: 30 August 2015, and Mauritius: 3 October 2015) and several conference calls, during which the situation analysis was done, the WHF policy document was presented and discussed, and the continental policy was drafted, taking into consideration the specific African context. During these working sessions, relevant scientific issues were discussed, comments were received on all points, and consensus was achieved by discussion. The following key stakeholders have collaborated with PASCAR in the developmental process: International Forum for Hypertension Control in Africa, African Heart Network, International Society of Hypertension (low- and middle-income countries), and several national cardiac societies.

PASCAR algorithm for the diagnosis and management of hypertension Prof Abdoul Kane (Senegal) presented the PASCAR algorithm for the diagnosis and management of hypertension in the African population. Prof Kane concluded his talk by expressing the willingness of the writing group to receive feedback in order to improve the algorithm.

Discussion The delegates were from 12 African countries, including Cameroun, Togo, Cote D’Ivoire, Mali, Gabon, Chad, Senegal, Burkina Faso, Togo, Congo, Benin and Burundi. The audience acknowledged that the lack of evidence on drug trials on the continent, as well as the small number of active hypertension policy programmes on the continent were a real concern needing an urgent response.

Centre Hospitalier et Universitaire de Bamako, Mali Ouane Nouhom, MD

Centre Hospitalier et Universitaire, Brazaville, Congo Jean Louis Nkoa, MD Kimbally Kaki, MD

Service de cardiologie, Hôpital Général de Grand Yolf, Dakar, Senegal

Hôpital Laquintinie de Douala, Cameroon

Abdoul Kane, MD

Institut cardiologique d’Abidjan, Cote d’Ivoire

Cardiology Unit, Department of Internal Medicine, Yaoundé Central Hospital, Yaoundé, Cameroon

Euloge Kramoh, MD Jean-Baptiste Anzouan-Kacou, MD

Alain Menanga, MD Samuel Kingue, MD

Service de cardiologie, Centre Hospitalier et Universitaire de Lomé, Togo

Service de cardiologie, Hôpital Central de Yaoundé, Yaoundé, Cameroon

Jean Marie Damourou, MD

Hôpital Général de Djamena, Chad

Christ Nadege Nganou, MD Liliane Mfeukeu Kuate, MD

Lucien Allawaye, MD

Hôpital Universitaire du Centre de Libreville, Gabon

Hôpital militaire de Bujumbura, Burundi

Jean Bruno Mipinda, MD

Jolis Nzisabira, MD

Polyclinique internationale de Ouagadougou, Burkina Faso

Centre Hospitalier de Cotonou, Benin

Lucie Nebie, MD

Latif Mousse, MD

Centre Hospitalier et Universitaire, Conakry, Guinee Conakry

Service de cardiologie, Université Cheikh Anta DIOP, Dakar, Senegal

Dadier Balde, MD

Serigne Abdou Ba, MD

Armel Djomou, MD

202

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Delegates at the conference. Front (left to right): Ouane Nouhom (Mali), Jean Louis Nkoua (Congo), Abdoul Kane (Senegal), Seringne Abdou Ba (PASCAR council, Senegal), Anastase Dzudie (chair, PASCAR task force on hypertension), Samuel Kingue (president, Cameroon Cardiac Society), Findibe Damourou (president, Togolese Society of Cardiology). Middle (left to right): Adama Kane (Senegal), Edwige Siransy (Côte d’Ivoire), Goeh Akue Edem (Togo), Mariam Béavogui (Guinée), Dadhi Balde (Guinée), Yves Moukam (Cameroon). Back (left to right): Roland N’guetta (Côte d’Ivoire), Aime Bony (Cameroon), Lucien Allawaye (Tchad), Jolis Nzisabira (Burundi), Latif Mousse (Benin), Jerome Boomhbi (Cameroon), Jean-Baptiste Anzouan-Kacou (Côte d’Ivoire), Xavier Jouven (France), Moustapha Sarr (Senegal).

The PASCAR response was therefore recognised as a timely and most appropriate one to the challenge of management and prevention of hypertension in the region. The algorithm was welcomed and discussed, and the audience was advised to make it simple and widely available, especially at primary healthcare centres where a substantial proportion of hypertensive patients are managed. Comments on the algorithm were received and feedback will be sent by e-mail.

We acknowledge support from the Cameroon Cardiac Society and all other francophone colleagues for the organisation of this PASCAR working session.

References 1.

Ataklte F, Erqou S, Kaptoge S, Taye B, Echouffo-Tcheugui JB, Kengne AP. Burden of undiagnosed hypertension in sub-Saharan Africa: a systematic review and meta-analysis. Hypertension 2014; 65(2): 291–298.

Dzudie A, Ojji D, Anisiuba BC, Abdou BA, Cornick R, Damasceno

Conclusion

A, et al. Development of the roadmap and guidelines for the preven-

The delegates acknowledged the importance of advocacy to continental organisations such as the African Union. Experts recognised that strong government leadership and policy are mandatory to making hypertension a priority in the region, and adopting and implementing a minimum standard for the health system to achieve hypertension control.

the PASCAR Hypertension Task Force meeting: Nairobi, Kenya, 27

tion and management of high blood pressure in Africa: Proceedings of October 2014. Cardiovasc J Afr 2015; 26(2): 82–85. 3.

Adler AJ, Prabhakaran D, Bovet P, Kazi DS, Mancia G, Mungal-Singh V, et al. Reducing cardiovascular mortality through prevention and management of raised blood pressure: a World Heart Federation roadmap. Global Heart 2015; 10(2): 111–122.

Novo Nordisk South Africa

How can we overcome barriers to effective glycaemic control in type 2 diabetes? Diabetes is a global epidemic. Worldwide, it is a leading cause of cardiovascular disease, blindness, kidney failure and lower limb amputation.1. p8a; 11a; 28a In SubSaharan Africa, the majority of people with diabetes will die before the age of 60. Furthermore, diabetes accounts for almost one out of every three 1 out of every deaths among the economically active age 3 deaths in group of 30 to 40 years.1 p71a,73 30-40 year olds

Diabetes is a global epidemic

Physicians may be afraid of causing harm and be overly cautious when prescribing so as to avoid weight gain and hypoglycaemia, especially in patients who already have comorbidities.5,8 5.p39a; 8. p17a They may be concerned about patient non-compliance, or merely not know how to manage a patient who simply refuses to entertain the thought of escalating treatment.8 p17-18a Accordingly, oral therapies are continued for as long as possible, in the hope that patients will implement lifestyle changes.9 p370 Physicians overly cautious when prescribing so oral therapies are continued for as long as possible

Insulin is an effective diabetes treatment Careful control of blood glucose can help prevent or delay micro- and macrovascular complications of diabetes. Initially this may be adequately achieved with lifestyle changes and oral medication, but because of the progressive nature of diabetes, characterised by gradual decline in ß-cell function and density, most patients will eventually require insulin to achieve glycaemic goals.2 p72a Nevertheless, the benefits of control achieved early in the disease remain for many years, despite it becoming more difficult to maintain target glucose levels.3 p1577a Insulin is an effective treatment to control blood glucose. With appropriate doses it is possible to achieve any level of glycaemic control depending on the target set for an individual patient.4 p197a However, in practice, achieving and sustaining these targets is very difficult, because patients do not always adhere to their treatment regimen, and doctors may be overly cautious, so that treatment is not intensified when it needs to be.5 p38a, b

Patient considerations In fact, a substantial proportion of patients with type 2 diabetes do not achieve internationally recognised glycaemic targets.5 p38a Even in some South African Adequate glycaemic control specialist clinics, adequate glycaemic control is achieved in no more than is achieved in no more than about 1 in every about 1 in every 4 patients 4 patients with diabetes!6 p154a with diabetes Of course, nonadherence to therapy is an important problem associated with chronic diseases. Nevertheless, there are also specific reasons why diabetic patients may be reluctant to initiate or intensify antihyperglycaemic medication. Some of these include feelings of failure about suboptimal glycaemic control, anxiety about hypoglycaemia or weight gain, and fear of injections. Poor education about type 2 diabetes and the importance of treatment can exacerbate nonadherence.5 p38b Nonadherence through anxiety of weight gain fear of injections

In addition to consideration of their patients’ concerns, clinicians themselves may have reasons to delay initiation or intensification of insulin therapy in a patient who needs it. This is a worldwide phenomenon, sometimes referred to as ‘clinician inertia’.5,7 5.p38b; 7.p2675a Causes range from time and resource constraints to underestimation of the patient’s needs, and failure to identify and manage comorbidities.

Physician-related barriers to timely initiation of insulin8 • • • • • •

Concerns over patients with comorbidities Excess weight gain in already overweight patients Concerns about patient non-compliance Risk of severe hypoglycaemia/adverse effects on quality of life Lack of resources Patient refusal

Novo Nordisk seeks to dismantle barriers to insulin prescribing In response to these complex challenges, Novo Nordisk is leading the way in developing new molecules and delivery devices to change the way people with diabetes, and their healthcare providers, think about insulin. Novo Nordisk understands that if treatment regimens can be made simpler and more comfortable, and concerns over side effects no longer get in the way of efficient glycaemic management, then life with diabetes will be simpler, less scary and of a much better quality than it has ever been before.

References 1. International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. http://www.idf.org/diabetesatlas. Accessed 11 May 2016. 2. Henske JA, Griffith ML, Fowler MJ. Initiating and titrating insulin in patients with type 2 diabetes. Clin Diab 2009; 27(2): 72-76. 3. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-1589. 4. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the study of Diabetes. Diabetes Care 2009; 32(1): 1-11. 5. Ross SA. Breaking down patient and physician barriers to optimize glycemic control in type 2 diabetes. Am J Med 2013; 126(9 Suppl 1): S38-S48. 6. Pinchevsky Y, Butkow W, Raal FJ, et al. The implementation of guidelines in a South African population with type 2 diabetes. JEMDSA 2013; 18(3): 154-158. 7. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among patients and providers. Results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005; 28: 2673-2679. 8. Kumar A, Kalra S. Insulin initiation and intensification: insights from new studies. JAPI 2001; 50(Suppl): 17-22. 9. Wallace TM, Matthews DR. Poor glycaemic control in type 2 diabetes: A conspiracy of disease, suboptimal therapy and attitude. QJM 2000; 93: 369-374.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016

Cardiovascular Topics Transoesophageal echocardiography (TEE) at the Institute of Cardiology in Abidjan: indications, results and diagnostic accuracy Jean-Baptiste Anzouan-Kacou, Christophe Konin, Charles-Philippe Zobo, Djenamba Bamba-Kamagaté, Marie-Paule N’cho-Mottoh, Bénédicte Boka Abstract Objective: The aim of the study was to define the indications for and results and diagnostic accuracy of transoesophageal echocardiography (TEE) in the Abidjan Cardiology Institute. Methods: A retrospective analysis was carried out of 103 TEE reports from February 2007 to January 2011. The analysis focused on the clinical characteristics of the patients, quality of the prescribers, and indications and diagnostic accuracy (proportion of confirmed diagnoses, which is the ratio of ‘anomaly found/number of examinations made for the indication’). Results: There were 47 women (45.6%) and 56 men (54. 4%) in the study, with an average age of 37.9 ± 16.4 years. Prescribers were mostly cardiologists (n = 57; 55.4%). The indications were predominantly evaluation for atrial septal defect (ASD,

Cardiology Institute of Abidjan, Abidjan, Ivory Coast Jean-Baptiste Anzouan-Kacou, MD, jb_anzouan@yahoo.fr; anzouan@hotmail.com Christophe Konin, MD Charles-Philippe Zobo, MD Djenamba Bamba-Kamagaté, MD Marie-Paule N’cho-Mottoh, MD Bénédicte Boka, MD

34.9%), investigation for thrombus due to rhythm disturbance before cardioversion (18.4%), aetiological evaluation of ischaemic stroke (13.5%), and assessment for mitral regurgitation (lesion assessment, mechanism and/or quantification, 9.7%). In the evaluation for an ASD, TEE was contributory in 17.3% and for thrombus, it was 21%. No embolic aetiology was found in the ischaemic strokes. Three examinations were done during cardiac surgery to assess the mechanical valves or quality of mitral plasty. There were no incidents or accidents reported during those 103 examinations. Conclusion: Because of the high number of congenital heart disease cases discovered in adulthood involving arrhythmias and valvular heart disease, TEE is likely to become more important as a means of diagnosis, and should be used correctly so as to achieve optimal diagnostic advantage. TEE should be provided by specialists not cardiologists. Keywords: transoesophageal echocardiography, congenital heart disease, valvular disease, Africa Submitted 23/7/13, accepted 2/7/15 Cardiovasc J Afr 2016; 27: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2015-054

L’echographie trans-oesophagienne (ETO) à l’Institut de cardiologie d’Abidjan: indications, resultats et rentabilité diagnostique Jean-Baptiste Anzouan-Kacou, Christophe Konin, Charles-Philippe Zobo, Djenamba Bamba-Kamagaté, Marie-Paule N’cho-Mottoh, Bénédicte Boka Institut de cardiologie d’Abidjan, Abidjan, Cote d’Ivoire

Abstract

Jean-Baptiste Anzouan-Kacou, MD, jb_anzouan@yahoo. fr;anzouan@hotmail.com Christophe Konin, MD Charles-Philippe Zobo, MD Djenamba Bamba-Kamagaté, MD Marie-Paule N’cho-Mottoh, MD Bénédicte Boka, MD

Objectifs: Préciser les indications, les principaux résultats et la rentabilité diagnostique de l’échographie trans-oesophagienne (ETO) à l’Institut de Cardiologie d’Abidjan (ICA). Méthode: Analyse rétrospective de 103 compte-rendus d’ETO réalisés consécutivement de février 2007 à janvier 2011 à l’ICA. L’analyse a porté sur les caractéristiques d’âge, de sexe,

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016

la qualité des médecins prescripteurs, les indications et la rentabilité diagnostique (proportion de diagnostics confirmés soit le ratio anomalie retrouvée/nombre d’examen réalisés dans l’indication). Résultats: La série se composait de 47 femmes (45.6%) et de 56 hommes (54.4%) d’âge moyen 37.9 ± 16.4 ans. Les médecins prescripteurs étaient majoritairement des cardiologues (n = 57 soit 55.4%). Les indications étaient dominées par la recherche ou l’évaluation d’une communication inter-auriculaire (34.9%), la recherche de thrombus dans un trouble du rythme supra-ventriculaire avant cardioversion (18.4%), le bilan étiologique d’un accident vasculaire cérébral ischémique (13.5%) et l’évaluation d’une insuffisance mitrale (bilan lésionnel, mécanisme et/ou quantification 9.7%). Dans la recherche d’une CIA, l’ETO était contributive dans 17.3% et dans la recherche de thrombus dans 21% des cas. Aucune étiologie embolique n’a été retrouvée dans les accidents vasculaires cérébraux ischémiques. Trois examens ont été réalisés en per opératoire pour évaluation du fonctionnement des valves mécaniques et de la qualité de plasties mitrales. Aucun incident ni accident n’a été signalé au cours des 103 examens. Conclusion: Du fait du nombre élevé des cardiopathies congénitales découvertes à l’âge adulte, des troubles du rythme et des valvulopathies, l’ETO est appelée à se développer. Les indications doivent être bien posées de façon obtenir une rentabilité diagnostique optimale. Les prescriptions devraient toucher un plus grand nombre de spécialistes non cardiologues.

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période d’étude. Critères de non inclusion: Compte-rendu incomplets du point de vue de l’âge, du sexe, des indications et/ ou de la conclusion de l’examen. Pendant la période d’étude, 116 examens ont été réalisés. Treize examens ont été exclus, ce qui nous a permis de retenir 103 compte-rendus. Pour chaque compte rendu, les caractéristiques d’âge, de sexe, la qualité du médecin prescripteur, l’indication de l’examen et les résultats obtenus ont été répertoriés et analysés. Les indications ont été classées par groupe nosologique. Dans chaque groupe ont été précisées les différentes pathologies et leurs proportions respectives. Nous avons évalué la rentabilité diagnostique de l’examen comme étant la proportion de diagnostics confirmés (ratio anomalie retrouvée /nombre d’examens réalisés). Cette évaluation a été réalisée lorsque la réponse technique à la question était binaire (oui/non, présence ou absence).

Traitement des donnees La saisie et l’analyse des données ont été effectuées grâce aux logiciels EPI info version 6.04 et Microsoft Excel 2010. Les variables continues ont été présentées sous forme de moyenne ± écart type. Le test t de Student apparié a permis la comparaison des moyennes avec un seuil de significativité statistique à 0.05.

Resultats Mots clés: echographie trans-oesophagienne, communication inter auriculaire, trouble du rythme, valvulopathie, rentabilité diagnostique Submitted 23/7/13, accepted 2/7/15 Cardiovasc J Afr 2016; 27: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2015-054

L’échographie trans-oesophagienne (ETO) est un examen d’imagerie diagnostique et thérapeutique indispensable en cardiologie.1 L’ETO est de pratique extrêmement courante en Europe et en Amérique.1,2 L’usage de cette technique semiinvasive est formalisé par de nombreuses recommandations de sociétés savantes en ce qui concerne ses indications, leur pertinence et les résultats attendus.1-4 A Abidjan (Côte d’Ivoire), cette technique est pratiquée en routine depuis 2007. L’objectif de ce travail était de préciser les indications, relever les principaux résultats et dégager la rentabilité diagnostique de l’ETO à l’Institut de Cardiologie d’Abidjan (ICA).

Methode Il s’agit d’une étude observationnelle et rétrospective réalisée à l’Institut de Cardiologie d’Abidjan sur une période de 48 mois, entre février 2007 et janvier 2011. Compte-rendu des patients ayant bénéficié d’une ETO à l’Institut de Cardiologie d’Abidjan. Tous les examens ont été réalisés grâce à un Echographe General Electrics (GE) Vivid 3 avec une sonde transoesophagienne multi plan 5T. Critères d’inclusion: Comptes rendus des patients admis consécutivement pour la réalisation d’une ETO pendant la

L’âge moyen de l’ensemble des 103 patients était de 37.9 ± 16.4 ans. La série se composait 47 femmes (45.6%) et de 56 hommes (54.4%) avec un sex ratio H/F de 1.19. La répartition de la qualité des médecins prescripteurs était la suivante: cardiologues (n = 57 soit 55.4%), cardio-pédiatres (n = 29, soit 19.4%), neurologues (n = 10 soit 9.7%), chirurgiens cardiaques (n = 10 soit 9.7%), internistes (n = 6 soit 5.8%). Les examens ont été divisés en 2 grands groupes: examens demandés en dehors d’un contexte chirurgical aigu (n = 99 soit 96.1%); examens demandés en contexte péri-opératoire de chirurgie cardiaque programmée (n = 4 soit 3.9%).

Examens demandés en dehors d’un contexte chirurgical aigu (n = 99) Les indications retrouvées étaient: • la recherche ou l’évaluation d’une cardiopathie congénitale (n = 40 soit 40.4%) • l’évaluation d’une valvulopathie (n = 24 soit 24.2%) • le bilan de troubles du rythme supra ventriculaires (TDR) (n = 19 soit 19.2%) • le bilan étiologique d’un accident vasculaire cérébral ischémique (AVCI) (n = 14 soit 14.2%) • la recherche de masse intra-auriculaire gauche suspectée à l’échographie trans – thoracique (n = 1 soit 1%) • la suspicion de dissection aortique (n =1 soit 1%). Les détails des indications dans le groupe des cardiopathies congénitales apparaissent dans le tableau 1. L’évaluation dans le cadre de communications inter-auriculaires (CIA) représentait 36 examens soit 90% des examens demandés pour cardiopathie congénitale et 34.9% (36/103) de l’ensemble des indications. L’aide au diagnostic positif d’une CIA constituait la principale question technique.

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Tableau 1. Détail des indications dans la recherche et l’évaluation des cardiopathies congénitales (n = 40)

Tableau 3. Rentabilité diagnostique en fonction de l’indication

72.5

CIA connue, bilan anatomique

7.5

Réévaluation d’une CIA

Bilan pré cathétérisme d’une CIA

2.5

CIA opérée, dilatation des cavités droites

2.5

CIV connue, anatomie d’une membrane sous aortique

Recherche de CIV

2.5

CIV opérée, appréciation d’un shunt résiduel sur patch

2.5

Indications Recherche de CIA, ETT non-contributive

Total

100

Les communications inter-ventriculaires (CIV) représentaient 4 examens soit 10% des examens demandés pour cardiopathie congénitale et 3.9% (4/103) de l’ensemble des indications. Les détails des indications dans le groupe des valvulopathies apparaissent dans le tableau 2. L’évaluation d’une insuffisance mitrale (quantification et/ou bilan lésionnel) représentait 10 examens soit 41.7% des examens demandés pour valvulopathie et 9.7% (10/103) de l’ensemble des indications. Parmi les 5 demandes pour suspicion d’endocardite infectieuse (tableau 2), il s’agissait 4 fois de recherche de végétation mitrale, 1 fois de recherche de végétation tricuspidienne, et 1 fois de recherche de végétation sur prothèse mécanique en position mitrale. Dans le groupe des troubles du rythme (19/103 soit 18.4% du total des indications), la recherche de thrombus avant cardioversion pour arythmie complète par fibrillation auriculaire représentait 16 demandes soit 84.2% des examens demandés pour TDR et 15.5% (16/103) de l’ensemble des indications. La recherche de thrombus avant cardioversion pour flutter auriculaire représentait 3 demandes soit 15.8% des indications pour TDR. Le bilan étiologique d’un accident vasculaire cérébral AVCI représentait 14/103 soit 13.5% de l’ensemble des indications. Le tableau 3 permet de récapituler la rentabilité diagnostique de l’ETO en fonction des indications, lorsque la réponse technique à la question était binaire (oui/non, présence ou absence). Cette analyse a concerné 73 examens.

Examens demandés en contexte chirurgical aigu Trois patients ont bénéficié d’une ETO per opératoire. Il s’agissait dans tous les cas de valvulopathies opérées soit par remplacement valvulaire soit par plastie. Les ETO étaient indiquées dans tous les cas pour évaluation du fonctionnement des valves mécaniques et de la qualité de plasties. Une patiente a bénéficié d’une ETO en post-opératoire immédiat pour établissement du mécanisme d’un état de choc. Aucun incident ni accident n’a été signalé au cours des 103 examens. Tableau 2. Détail des indications dans l’évaluation des valvulopathies acquises (n = 24) Indication

Insuffisance mitrale sévère: anatomie valvulaire et sous valvulaire

33.3

Quantification d’une insuffisance mitrale

4.2

Analyse d’une insuffisance mitrale par perforation mitrale

4.2

Rétrécissement mitral: anatomie valvulaire et sous valvulaire

12.5

Insuffisance aortique: recherche de mécanisme

16.6

Suspicion d’endocardite infectieuse: recherche de végétations

20.9

Suspicion de dysfonction de prothèse mécanique

Total

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8.3 100

Proportion sur l’ensemble des demandes d’examen (%) 28.1

Rentabilité diagnostique (%) 17.3

Recherche d’une CIV (n = 1) CIV opérée, appréciation du shunt résiduel sur patch (n = 1) Suspicion d’endocardite infectieuse: recherche de végétations (n = 5) Recherche de dysfonction de prothèse mécanique (n = 2) AC/FA, et flutter auriculaire recherche de thrombus (n = 19)

0.9

100

4.8

1.8

3.9

Recherche de MIAG (n = 1)

0.9

Recherche de dissection aortique (n = 1) Recherche d’une cause cardiaque d’embolie dans le cadre d’un AVC ischémique (n = 14)

0.9

100

13.6

Indications (n = 73) Recherche de CIA, ETT non-contributive (n = 29)

Discussion Notre travail permet de rapporter l’activité d’ETO à l’ICA, d’en préciser les principales indications et la rentabilité diagnostique en fonction des indications. Les indications étaient dominées par la recherche ou l’évaluation d’une communication interauriculaire (34.9% de l’ensemble des indications), la recherche de thrombus dans un trouble du rythme supra-ventriculaire avant cardioversion (18.4% de l’ensemble des indications), le bilan étiologique d’un AVC ischémique (13.5 % de l’ensemble des indications) et l’évaluation d’une insuffisance mitrale (bilan lésionnel, mécanisme et/ou quantification 9.7% de l’ensemble des indications). La plupart des examens (96.1%) étaient réalisés en dehors du contexte aigu de chirurgie cardiaque programmée. Dans la littérature médicale en Afrique sub-saharienne, en dehors de l’Afrique du Sud, il est fait très peu mention des activités d’ETO. Une étude gabonaise5 rapporte une expérience de 146 examens sur 81 mois, de 2000 à 2006. Les examens ont été réalisés grâce à une sonde monoplan, donc de technologie plus ancienne. Les patients ont un âge moyen de 55 ans (plus élevé que celui des patients de notre série qui était de 27.9 ans). Une équipe béninoise rapporte 24 ETO sur une période de 29 mois5 dans l’indication unique de l’aide à la stratégie de réduction d’une fibrillation auriculaire. Cette indication représentait 16 demandes soit 15.5% des indications dans notre série. Des auteurs Dakarois6 rapportent 33 cas d’examens per-opératoires dans le cas de plasties mitrales, indication retrouvée 4 fois dans notre pratique. Dans l’expérience gabonaise,7 les indications se répartissent différemment: recherche étiologique dans les AVC ischémiques (37.6%), recherche de mécanisme de valvulopathie avant chirurgie réparatrice (20.5%), aide à la stratégie de réduction de troubles du rythme (16.4%), recherche d’endocardite infectieuse 11.6%. Dans cette série aucun examen n’a été réalisé dans l’indication d’une cardiopathie congénitale. Dans une série américaine récente, évaluant la pertinence des indications de 202 ETO réalisées sur une période de 3 mois,4 les 3 indications principales étaient l’aide à la stratégie de réduction des troubles du rythme (49%), la recherche d’endocardite infectieuse (13%) et les procédures de cardiologie interventionnelle non coronariennes (9%). Il faut donc conclure que la pratique des examens est liée non seulement au spectre des cardiopathies dans le milieu de travail, mais certainement à l’orientation des pratiques par établissement.

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Les spécialistes en cardiologie (cardiologues 55.4%, cardiopédiatres 19.4%, chirurgiens cardiaques 9.7%), représentaient les principaux prescripteurs des examens, comme dans la plupart des séries.3,4 Les neurologues représentent pour Mansour aux Etats-unis3 8.9% des prescripteurs, à l’identique de nos résultats. L’ETO a des avantages certains sur l’ETT du fait de l’utilisation de sondes de haute fréquence à proximité des structures cardiaques, avec une résolution élevée des images.8,9 Evaluer la rentabilité diagnostique est importante du fait du caractère semiinvasif de l’ETO et donc non dénué de complications, posant le problème de la pertinence des indications et des résultats attendus.3,4 Dans notre série nous n’avons noté aucun incident. Les complications sérieuses de l’ETO sont rarissimes, estimées à 1/10 000 examens.10 La rentabilité des examens est variable en fonction de l’indication. L’examen a été le plus rentable dans la recherche de dissection aortique et dans la recherche d’un shunt résiduel sur patch de CIV (100%, tableau 3). Cependant ces indications ne comptaient chacune qu’un seul examen. Dans la recherche de CIA (29 demandes soit 28.1% des demandes sur l’ensemble des indications, tableau 3), l’ETO n’a mis en évidence l’anomalie recherchée que dans 17.3% des cas. La justesse de l’indication conditionne la qualité du résultat. A l’ETT dans la coupe apicale 4 cavités il apparait un semblant de défaut dans un septum normal, donnant l’illusion d’une fausse CIA, lié au faible signal écho reflété par le septum inter-auriculaire.11 La faible rentabilité diagnostique de l’ETO dans les CIA dans notre série pourrait s’expliquer par des indications mal posées. Dans l’endocardite infectieuse (4.8% des indications) la rentabilité diagnostique était de 20%. La supériorité de l’ETO sur l’ETT dans le domaine de l’endocardite infectieuse est bien établie, les critères échographiques faisant partie des critères diagnostiques.12 L’ETO est particulièrement intéressante pour la mise en évidence des végétations de petite dimension, inférieures à 5 mm, et offre ainsi la possibilité d’un diagnostic plus précoce de l’endocardite, permettant une mise en route rapide du traitement.12 La sensibilité de l’ETO sur une série de 96 patients dans la détection des végétations serait de 100% contre 63% pour l’ETT.13 Malgré cette faible rentabilité, toute suspicion d’endocardite infectieuse doit faire réaliser une ETO devant une ETT non-contributive.12 Dans l’indication d’un AVCI dans notre série aucun examen n’a permis de retrouver des arguments pour une cardiopathie emboligène. La taille de notre échantillon pourrait aisément l’expliquer. Ailleurs,14,15 dans les AVCI, chez 15 à 25% des patients, l’ETO permet de mettre en évidence une source cardiaque d’embolie.

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inter-auriculaires. Les prescriptions devraient provenir d’un plus grand nombre de spécialistes non cardiologues, notamment les neurologues, du fait de l’importance des AVCI dans notre milieu.

References 1.

Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ ASE 2003 Guideline Update for the Clinical Application of Echocardiography: Summary Article. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (ACC/AHA/ASE committee to update the 1997 guidelines for the clinical application of echocardiography). J Am Soc Echocardiogr 2003; 16: 1091–1110.

Flachskampf FA, Badano L, Daniel WG, et al. Recommendations for transoesophageal echocardiography: update 2010. Eur J Echocardiogr 2010; 11: 557–576.

Mansour NI, Lang MR, MD, Kathy T. Furlong KT, et al. Evaluation of the application of the ACCF/ASE appropriateness criteria for transesophageal echocardiography in an academic medical center. J Am Soc Echocardiogr 2009; 22: 517–522.

Bhatia RS, Carne DM, Picard MH. Comparison of the 2007 and 2011 appropriate use criteria for transesophageal echocardiography. J Am Soc Echocardiogr 2012; 25: 1170–1175.

Houenassi M, Tchabi Y, Sacca-Véhounkpé J, et al. Etude échographique de la thrombose et du contraste spontané intra-auriculaire chez les patients en fibrillation auriculaire. Cardiol Trop 2012; 33: 13–17.

Cissé AG, Diarra O, Dieng PA, et al. La plastie mitrale sur valve rhumatismale chez l’enfant au Sénégal: 100 observations. Med Trop 2009; 69: 278–280.

Mipinda JB, Ecke NJE, Allognon C, Kombila P. Pratique de l’échocardiographie transoesophagienne au Centre Hospitalier de Libreville. Cardiol Trop 2008; 23: 52–56.

Roelandt JR, Fraser AG. Transesophageal echocardiography: clinical applications and prospect. Curr Opin Cardiol 1990; 5: 783–794.

Matsukaki M, Toma Y, Kusukawa R. Clinicals applications of transeophageal echocardiography. Circulation 1990; 82: 709–722.

10. Daniel WG, Erbel R, Kasper W, et al. Safety of transeoesophageal echocardiography. A multicenter survey of 10,419 examinations. Circulation 1991; 83: 817–821. 11. Schiller NB, Maurer G, Ritter SB, et al. Transesophageal echocardiography. J Am Soc Echocardiogr 1989; 2: 354–357. 12. Durack D, Lukes A, Bright D, New criteria for diagnosis of infective endocarditis: utilisation of specific echocardiographic finding. Am J Med 1994; 96: 200–209. 13. Erbel R, Rohmonn S, Drexler M, Mohr-kahalys S, Gerharz C D, Iversen S, et al. Improved diagnostic value of echocardiography in patient with infective endocarditic by transesophageal approach. A prospective study. Eur Heart J 1988; 9: 43–53.

Conclusion L’ETO est un examen indispensable dans l’aide au diagnostic et à l’évaluation de plusieurs affections cardiovasculaires. Les indications doivent être bien posées de façon obtenir une rentabilité diagnostique optimale notamment dans les communications

14. Amarenco P, Cohen A, Baudrimont M, et al. Transesophageal echocardiographic detection of aortic arch disease in patients with cerebral infarction. Stroke 1992; 23: 1005–1009. 15. Cujec B, Polasek P, Voll C et al: Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke 1991; 22: 727–733.

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Case Report A case of enoxaparin-induced thrombocytopaenia during treatment of acute myocardial infarction Snag Yup Lim, Se Ryeon Lee, Yong Hyun Kim, Jin Seok Kim, Seong Hwan Kim, Jeong Chun Ahn, Woo Hyuk Song

Abstract Heparin-induced thrombocytopaenia is a life-threatening complication, affecting the morbidity and mortality of the patient if not properly treated. We report a case of a 75-year-old female patient who experienced enoxaparininduced thrombocytopaenia during medical treatment of acute ST-segment elevation myocardial infarction due to thrombotic total occlusion in the large right coronary artery. Keywords: heparin, thrombocytopaenia, myocardial infarction

to 75% of patients, and about 10 to 20% of patients suffer disseminate intravascular coagulation (DIC).3 The mortality rate associated with the HIT syndrome (HITS) is approximately 5 to 10%, usually secondary to thrombotic complications.4 The risk of HITS is higher in women and surgical patients compared with medical patients, and five- to 10-fold higher in patients receiving UHF compared to LMWH.5 Although rare, LMWH-induced thrombocytopaenia can occur and some cases have been reported in acute coronary syndrome. Here, we report a case of a patient who experienced enoxaparininduced thrombocytopaenia during medical treatment of acute myocardial infarction.

Submitted 12/9/15, accepted 17/2/16 Published online 12/4/16 Cardiovasc J Afr 2016; 27: e5–e8

www.cvja.co.za

DOI: 10.5830/CVJA-2016-010

Thrombocytopaenia often occurs in critically ill patients. While there are many reasons for it, heparin-induced thrombocytopaenia (HIT) is one of the most fatal complications, characterised by the occurrence of thrombocytopaenia in conjunction with thrombotic manifestations after exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).1 The incidence of the HIT syndrome in patients exposed to heparin varies widely, depending on the preparation of the heparin and its concentration, varying from 0.2 to 5%.2 Clinical presentation of the HIT syndrome ranges from asymptomatic thrombocytopaenia to a variety of intravascular thromboses and embolisms after exposure to heparin. Thrombosis can affect both the arterial and venous system, however, venous thromboembolic complications are much more serious than arterial thrombotic events. Without alternate anticoagulation, the risk of thromboembolic complications can be seen in 30

Department of Internal Medicine, Ansan Hospital, Korea University, Dan Won-Gu, Ansan, GyoungGi-Do, Korea Snag Yup Lim, MD, PhD Se Ryeon Lee, MD Yong Hyun Kim, MD Jin Seok Kim, MD Seong Hwan Kim, MD Jeong Chun Ahn, MD Woo Hyuk Song, MD, cardiologist@hanmail.net

Case report A 75-year-old female visited the emergency department with chest pain of 12 hours’ duration. She had no other significant medical or family history except mild arthritis in both knees. Her initial electrocardiogram showed a normal sinus rhythm with Q wave and ST-segment elevation in leads II, III and aVF. The echocardiogram demonstrated hypokinesia of the inferior wall of the left ventricle. In the laboratory tests, the haemoglobin level was 12.7 g/dl, white blood cell count was 13.4 × 103 cells/μl and the platelets were 302 × 103 cells/μl. Initial coagulation studies showed a normal range. The initial level of CK-MB was 85.4 U/l and troponin-I was 20.2 ng/ml. Her clinical diagnosis was acute ST-segment elevation myocardial infarction of the inferior wall. An emergent coronary angiogram (CAG) revealed total thrombotic occlusion of the proximal right coronary artery (RCA) (Fig. 1). The RCA was engaged with a 7-Fr guiding catheter (AL1, Cordis, Miami Lakes, Florida, USA) and predilatation was carried out with a Sprinter 3.0 × 20-mm balloon (Medtronic, Minneapolis, MN, USA) after a loadingdose injection of intracoronary abciximab. After the procedure, the total thrombotic occlusion was still present, so we repeated thrombus aspiration with a thrombus extraction catheter (Thrombuster, Kaneka Medical Corp, Japan) and repeated the ballooning. The thrombotic occlusion did not improve and we decided on the second-stage procedure after one week of enoxaparin therapy in the intensive care unit. The patient was treated with aspirin, clopidogrel, statin and enoxaparin for one week. A follow-up CAG (Fig. 2) and intravascular ultrasound (IVUS) were done after seven days of enoxaparin therapy, and it still revealed thrombi in the large RCA, despite the enoxaparin

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Fig. 1. E mergent coronary angiogram (CAG) revealed total thrombotic occlusion of the proximal right coronary artery (RCA).

Fig. 3. Intravascular ultrasound (IVUS) revealed thrombi still present in the large RCA. The reference diameter of the RCA was 6.2 mm.

therapy. The reference diameter of the RCA was 6.2 mm (Fig. 3). The patient received repeated thrombus aspiration, but large thrombi still remained in the RCA. We decided to continue the enoxaparin therapy for several days instead of stenting, due to the large diameter of the RCA. After 10 days of enoxaparin therapy, the patient complained of epistaxis and her platelet count was 11 000 cells/μl. We stopped the enoxaparin injection and checked the coagulation profile and

heparin–platelet factor 4 antibody. The anti-factor Xa activity was not measured. The coagulation profiles were normal, but the heparin–platelet factor 4 antibody was strongly positive and she was a heparin-naïve patient. After discontinuation of enoxaparin, the platelet count recovered to 49 000 cells/μl on the first day and 117 × 103 cells/μl on the second day. Fortunately, there were no adverse cardiac events. The second follow-up CAG and IVUS were performed on the

Fig. 2. T he follow-up CAG revealed thrombi still present in the large RCA, even after seven days of enoxaparin therapy.

Fig. 4. The follow-up CAG was performed on the 15th day after admission and revealed resolution of the thrombi in the RCA, with improved distal flow.

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15th day after admission and revealed resolution of the thrombi in the RCA (Fig. 4). The patient was discharged and received medical therapy, including aspirin, clopidrogel and a statin instead of stent implantation. She had an uneventful recovery and there were no cardiac events during clinical follow-up of one year.

Discussion For over 80 years, heparin has been used clinically as an anticoagulant.6 Thrombocytopaenia as a result of heparin therapy was first described in the late 1960s.7 The HIT syndrome is characterised by thrombocytopaenia and thrombotic manifestations after exposure to heparin.4 Administration of heparin products is often in the setting of thrombosis or pro-thrombotic stimuli. The initial steps of HITS involve patient exposure to heparin, followed by initial formation of the IgM antibody, and development of IgG antibodies over four to 14 days.8 IgG antibodies activate the platelets and release the contents of platelet granules. When platelet factor 4 (PF4) is released, it binds to heparin, resulting in a conformational change in PF4. The IgG antibodies and PF4–heparin become a ‘foreign antigen’, which can be immunogenic.8,9 The activated platelets secrete more PF4, feeding back to create more antigen and aggregate, which become procoagulant. Thrombin is then generated and platelet–fibrin thrombi are formed.10 When HITS appears to present with bleeding, this is usually the result of a thrombotic complication.11 For example, cerebral venous thrombosis causes increased venous congestion, and it may similarly manifest as intracranial haemorrhage. The thrombotic complications of HIT manifest as arterial or venous thromboses. Venous thrombotic events predominate over arterial events, and less common manifestations are necrotising skin lesions at the heparin injection sites.12 The severity of thrombocytopaenia is associated with higher risk of HIT-related thrombosis. In some HIT cases, there may be life-threatening complications, such as deep-vein thrombosis, pulmonary embolus, myocardial infarction, cerebral sinus thrombus, stroke, adrenal vein thrombosis, limb gangrene and acute limb ischaemia.8,12 The diagnosis of HITS includes a 50% fall in platelet count, beginning between five and 14 days after initial exposure to heparin of any dose or type, and detection of the HIT antibody against the PF4–heparin complex is necessary.13 PF4–heparin antibodies have been widely used for the diagnosis of HITS. The diagnostic criteria of HIT include thrombocytopaenia during heparin therapy, resolution of thrombocytopaenia after cessation of heparin, exclusion of other causes of thrombocytopaenia and confirmation of heparin-induced antibodies.14 There are two types in HITS.15 HIT type 1 is non-immunological and causes activation and aggregation of platelets, and eventually results in thrombocytopaenia. The degree of thrombocytopaenia does not fall below 100 000 cells/μl. It appears during the first hours of heparin administration and thrombosis is not observed. HIT type 2 is usually defined as a relative decrease in platelet counts to less than 50% of baseline or an absolute decrease to less than 100 000 cells/μl, typically five to 10 days after initiation of heparin therapy, a pattern indicative of the immunological aetiology of the condition.16

Compared to UFH, LMWH shows better outcomes, not only in thromboembolic events but also in complications such as HITS. Although antithrombotic therapy with LMWH is known to be safer than therapy with UFH, enoxaparin-induced thrombocytopaenia can occur.5 Even though enoxaparin-induced thrombocytopaenia occurred less often than HITS in one study, the clinical manifestations of both were similar.17 It is a general principle that for patients with suspected or confirmed HITS, all forms of heparin should be stopped and transfusion of platelet concentrate should not be considered unless thrombocytopaenia is life-threatening, or when the patient undergoes invasive procedures with high risk of bleeding, because the administered platelets would cause thromboembolic complications to develop or it would aggravate them.13,14,18 Anticoagulation with an alternative non-heparin anticoagulant should be commenced. The direct thrombin inhibitors (DTIs) such as argatroban, bivalirudin and lepirudin are effective in the treatment of HIT-induced thromboembolism and as alternative anticoagulants for thrombosis prophylaxis in patients diagnosed with HIT.15,16,18 When DTIs are not available, factor Xa inhibitors such as fondaparinux should be administered. The binding of factor Xa inhibitors to antithrombin inhibits factor Xa, thus decreasing the rate of thrombin generation.19 In this case, we did not recognise any of these pathognomonical signs of enoxaparin-induced thrombocytopaenia, except a drop in platelet count and nasal bleeding after 10 days of anticoagulation therapy. The platelet count was normalised within days of discontinuation of enoxaparin. Both the clinical situation of the patient and the medical treatment, including intracoronary abciximab, aspirin and clopidogrel could have been a cause of thrombocytopaenia, but the fact that the platelet count normalised after stopping enoxaparin, and the presence of anti-PF4–heparin antibodies suggested HITS. We diagnosed enoxaparin-induced thrombocytopaenia because of the clinical features, the patient’s heparin-naïve state and the laboratory finding of antibodies against PF4 and heparin complexes. Another factor was the administration of aspirin and clopidogrel, which changed the activation of platelet aggregation in response to the stimulus of anti-PF4–heparin antibodies, although dual antiplatelet therapy with aspirin and clopidogrel neither treats HITS, nor aggravates HIT to form a thrombotic complication. This may explain why there was only nasal bleeding with the absence of any thrombotic complications in this patient, and it may have affected her prognosis. We treated this patient with medication instead of stenting because of her large RCA diameter of more than 6 mm. The patient received dual antiplatelet agents, including 100 mg of aspirin and 75 mg of clopidogrel per day, and there were no other major adverse cardiac events during clinical follow up. There are a few reports of enoxaparin-induced thrombocytopaenia in the literature but no reports however on enoxaparininduced thrombocytopaenia during medical treatment of acute myocardial infarction.

Conclusion We report our experience with enoxaparin-induced thrombocytopaenia during medical treatment of acute

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ST-segment elevation myocardial infarction. Although rare, LMWH such as enoxaparin may induce thrombocytopaenia, which could be a life-threatening complication. Physicians should always pay attention to complications such as thrombocytopaenia, even when using LMWH.

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of microparticle generation in heparin-induced thrombocytopenia. Blood 2000; 96: 188–194. 11. Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 1973; 136: 409–416. 12. Warkentin TE, Sheppard JL, Horsewood P, et al. Impact of the patient

References 1. 2.

Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia: a

tion of heparin-induced thrombocytopenia: American College of Chest

Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr

Physicians Evidence-Based Clinical Practice Guidelines. 8th edn. Chest

14. Watson H, Davidson S, Keeling D, et al. Guidelines on the diagnosis and

density values in hospitalized patients with heparin-induced thrombo-

management of heparin-induced thrombocytopenia: second edition. Br

Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia:

Hematology Am Soc Hematol Educ Program 2013; 2013: 668−674.

Yeh RW, Wiviott SD, Giugliano RP, et al. Effect of thrombocytopenia

16. Linkins LA, Dans AL, Moores LK, et al. Treatment and preven-

on outcomes following treatment with either enoxaparin or unfraction-

tion of heparin-induced thrombocytopenia: antithrombotic therapy

ated heparin in patients presenting with acute coronary syndromes. Am

and prevention of thrombosis, 9th edn. American College of Chest

J Cardiol 2007; 100: 1734–1738.

Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;

Crafoord C. Preliminary Report on post operative treatment with 79: 407–426. Natelson EA, Lynch EC, Alfrey CP, et al. Heparin-induced thrombocytopenia. An unexpected response to treatment of consumption coagulopathy. Ann Intern Med 1969; 71: 1121–1125.

Bambrah RK, Pham DC, Zaiden R, et al. Heparin-induced thrombocytopenia. Clin Adv Hematol Oncol 2011; 9: 594–599.

J Haematol 2012; 159: 528–540. 15. Lee GM, Arepally GM. Heparin-induced thrombocytopenia.

diagnosis and management update. Postgrad Med J 2007; 83: 575–582.

heparin as a preventative of thrombosis. Acta Chirurgica Scand 1936; 7.

2008; 133: 340S–380S.

Zwicker JI, Uhl L, Huang WY, et al. Thrombosis and ELISA optical cytopenia. J Thromb Haemost 2004; 2: 2133–2137.

2000; 96: 1703–1708. 13. Warkentin TE, Greinacher A, Koster A, et al. Treatment and preven-

historical perspective. Blood 2008; 112: 2607–2616. Opin Hematol 2011; 18: 315–322. 3.

population on the risk for heparin-induced thrombocytopenia. Blood

141: e495S–e530S. 17. Famularo G, Gasbarrone L, Minisola G, et al. Systemic bleeding in a patient with enoxaparin-induced thrombocytopenia. Am J Emerg Med 2009; 27: 756. e1–2. 18. Coventry DA, Webster NR. Heparin-induced thrombocytopenia and the health economic analysis of argatroban. Br J Anaesth 2014; 112: 964–967. 19. Ratuapli SK, Bobba B, Zafar H. Heparin-induced thrombocytopenia

Thachil J. Heparin induced thrombocytopenia with thrombosis: a two-

in a patient treated with fondaparinux. Clin Adv Hematol Oncol 2010;

step process? Hematology 2008; 13; 181–182.

8: 61–65.

10. Hughes M, Hayward CP, Warkentin TE, et al. Morphological analysis

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Case Report Transcatheter intervention in a child with scimitar syndrome Zhouping Wang, Xiaoyi Cai

Abstract Scimitar syndrome is a rare congenital heart disease characterised by anomalous pulmonary venous drainage to the inferior vena cava, aortopulmonary collaterals, hypoplasia of the right lung and intracardiac defects. Surgical correction remains the gold-standard therapy. However, non-surgical intervention has been reported effective in selected cases with scimitar syndrome. We report on a one-year-old boy with scimitar syndrome who underwent stepwise transcatheter intervention as an alternative treatment. Embolisation of the aortopulmonary collaterals and occlusion of the atrial septal defect were performed using detachable coils and an Amplatzer septal occluder, respectively. The patient’s postcathetherisation course was uneventful. The right cardiac chamber and pulmonary arterial pressure returned to normal during follow up. Keywords: scimitar syndrome, congenital heart disease, transcatheter intervention Submitted 1/7/15, accepted 17/1/16 Published online 8/6/16 Cardiovasc J Afr 2016; 27: e9–e11

www.cvja.co.za

DOI: 10.5830/CVJA-2016-004

two types. One is the adult form, which is usually asymptomatic and not associated with other cardiac disorders. The other type is the infantile form, presenting with signs and symptoms of severe pulmonary hypertension, associated cardiac malformations, and large systemic collateral arteries feeding the right lung in the first weeks of life. Transcatheter embolisation of the APC and repair of co-existing cardiac defects may improve symptoms and decrease pulmonary arterial pressure in symptomatic patients.7-8 Herein we describe a boy with scimitar syndrome who had obvious clinical improvement and pulmonary arterial pressure drop after transcatheter embolisation of the APC and atrial septal defect closure.

Case report A one-year-old, 9.5-kg male was admitted to our hospital (Guangzhou Women and Children Medical Centre, China) with tachypnoea. He had a history of recurrent pneumonia, sweating and growth retardation. On admission, a physical examination revealed grade II/VI systolic murmur at the left sternal border. Moreover, cardiac dextroposition and a radiopaque right hemithorax were confirmed on a chest X-ray examination (Fig. 1). Echocardiography showed an enlarged right cardiac chamber, partially anomalous pulmonary venous drainage, an 8-mm secundum atrial septal

Scimitar syndrome is a rare congenital anomaly consisting of anomalous pulmonary venous drainage from the right lung to the inferior vena cava (IVC), hypoplasia of the right lung, cardiac dextroposition, and malformation of the right pulmonary artery and aortopulmonary collaterals (APC) supplying the lower lobe of the right lung.1-3 Its prevalence is low and is estimated at two out of every 100 000 live births.4 The clinical presentations are quite diverse, ranging from severe congestive heart failure in infancy to mild symptoms in childhood, and depend greatly on the extent of left-to-right shunting from partially anomalous pulmonary venous drainage and aortopulmonary collateral flow.5,6 Scimitar syndrome has

Department of Cardiology, Guangzhou Women and Children’s Medical Centre, Guangzhou, Guangdong Province, China Zhouping Wang, MD, freebirdwzp@sohu.com Xiaoyi Cai, MSc

Fig. 1. Chest X-ray showing cardiac dextroposition and radiopaque right hemithorax.

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Fig. 4. Catheterisation showing complete occlusion of the atrial septal defect by the Amplatzer septal occluder.

Fig. 2. C TA showing right pulmonary vein drainage to the inferior vena cava.

defect (ASD). The systolic pulmonary arterial pressure was 63 mmHg, calculated from tricuspid regurgitation velocity. The computerised tomography angiography (CTA) revealed partially anomalous pulmonary venous drainage to the IVC, APC originating from the abdominal aorta, and hypoplasia of the right lung (Fig. 2), which confirmed the diagnosis of scimitar syndrome. The patient’s parents refused conventional surgical intervention, considering the high risk of postoperative events. As an alternative, stepwise transcatheter intervention and coil embolisation of the APC and closure of the ASD were selected to decrease the left-to-right shunt and reduce pulmonary arterial hypertension. The patient proceeded to A

have cardiac catheterisation under general anaesthesia. A 4-F Cobra cathether (Cook, Bloomington, IN) was delivered to the APC via the femoral artery and then two 8 × 50-mm MReye embolisation coils (Cook, Bloomington, IN), five 5 × 30-mm MReye embolisation coils and two 5 × 30-mm Cook coils (Cook, Bloomington, IN) were deployed for occlusion (Fig. 3A, B). After percutaneous entry of the femoral vein, a sizing balloon 8-F MPA2 catheter was introduced over an extra-stiff guide wire positioned in the left upper pulmonary artery to measure the pulmonary arterial pressure (pathway: IVC→RA: right atrium→RV: right ventricule→MPA: main pulmonary artery). Using an exchange 260-cm Cordis guidewire, an occlusion balloon catheter was introduced into the left atrium to determine the stretched diameter of the ASD (pathway: MPA→RV→RA→ASD→LA). A 10-mm Amplatzer septal occluder (AGA Medical, MN) was implanted after balloon sizing the defect (diameter: 8 mm) (Fig. 4). The procedure was successful. C

Fig. 3. ( A) Catheterisation showing systemic arterial collaterals arising from the abdominal aorta and supplying the right lung. (B) and (C) Catheterisation showing coil embolisation of the systemic arterial collaterals supplying the right lung.

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The total surgical time was 150 min; fluoroscopy time was 45 min. Pulmonary-to-systemic flow ratio (Qp/Qs) dropped from 2 to 1.2 and pulmonary arterial pressure decreased from 70/41 (50) mmHg to 45/14 (24) mmHg. After intervention, the patient improved clinically and was treated with asprin and frusemide. Three months later he was asymptomatic, and he was clinically well at the 12-month follow-up assessment. The indicators of right cardiac chamber and pulmonary arterial pressure estimated by echocardiography were normal.

Discussion Scimitar syndrome has a wide complex of anomalies, including drainage of all or part of the right lung to the inferior caval vein, hypoplasia of the right lung, pulmonary hypertension, dextroposition of the heart and anomalous systemic arterial supply.9 The anomaly was first described by Cooper in London in 1836 during autopsy of an infant.4 The aetiology of scimitar syndrome is not clear. Clinical presentation of patients with scimitar syndrome depend on the degree of pulmonary arterial hypertension, which is often secondary to left-to-right shunt from the pulmonary vein, co-existing intracardiac shunt, pulmonary hypoplasia, resulting in reduction of the vascular bed, and systemic arterial supply to the right lung. A surgical approach has been recognised as the goldstandard therapy for scimitar syndrome, including rerouting of the aberrant pulmonary vein and repair of the other cardiac defects.2,10 However, a two-staged strategy with catheter-based embolisation of the APC, followed later by correction of the anomalous veins, has also been recommended in some cases. There is no consensus on which is the best option. Recently, multiple reports have shown transcatheter intervention, including embolisation of the APC and closure of the cardiac defects, may improve symptoms, decrease pulmonary arterial pressure,11,12 and postpone or even eliminate the need for surgical correction.7,8,13 Instead of a surgical approach, patients with scimitar syndrome who have significant left-to-right shunt due to APC and other cardiac defects are largely suitable for transcatheter intervention. In our case, the patient’s pulmonary arterial hypertension was attributed to the ASD and APC, which could be improved by decreased pulmonary arterial pressure after transcatheter intervention. We opted for embolisation of the APC and closure of the ASD. The patient had satisfactory clinical improvement and no surgery was performed during follow up. No pulmonary infarction was observed during the follow-up period. Many kinds of devices, such as detachable coils, AVPII and AVPIV have been reported to be appropriate for embolisation of the APC. In this case, we used detachable coils due to their ease of deployment, extractability, small size of catheter required, low metal content and affordability. Besides the therapies mentioned above, others have also been used in scimitar syndrome. Pneuomonectomy or lobectomy is performed cautiously in patients with persistent haemoptysis, thrombosed intra-atrial baffle, obvious hypoplasia of the

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right lung,14 or right pulmonary vein obstruction at risk of scoliosis post operation2, and respiratory insufficiency post pneuomonectomy.10,12,15

Conclusion Although the traditional surgical approach is still the gold standard in symptomatic patients, transcatheter intervention of embolisation of the aortopulmonary collaterals and repair of co-existing cardiac defects may be an option for selected patients with scimitar syndrome. We thank Yingyi He and Xiaomeng Wang for the language editing in this report.

Reference 1.

Gao YA, Burrows PE, Benson LN, Rabinovitch M, Freedom RM. Scimitar syndrome in infancy. J Am Coll Cardiol 1993; 22: 873–882.

Najm HK, Williams WG, Coles JG, Rebeyka IM, Freedom RM. Scimitar syndrome: twenty years’ experience and results of repair. J Thorac Cardiovasc Surg 1996; 112: 1161–1168; discussion 8–9.

Canter CE, Martin TC, Spray TL, Weldon CS, Strauss AW. Scimitar syndrome in childhood. Am J Cardiol 1986; 58: 652–654.

Gudjonsson U, Brown JW. Scimitar syndrome. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 2006: 56–62.

Dupuis C, Charaf LA, Breviere GM, Abou P. “Infantile” form of the scimitar syndrome with pulmonary hypertension. Am J Cardiol 1993; 71: 1326–1330.

Dupuis C, Charaf LA, Breviere GM, Abou P, Remy-Jardin M, Helmius G. The “adult” form of the scimitar syndrome. Am J Cardiol 1992; 70: 502–507.

Aslan E, Tanidir IC, Saygi M, Onan SH, Guzeltas A. Simultaneous transcatheter closure of intralobar pulmonary sequestration and patent ductus arteriosus in a patient with infantile scimitar syndrome. Turk Kardiyol Dern Ars 2015; 43: 192–195.

Parappil H, Masud F, Salama H, Rahman S. Scimitar syndrome with absent right pulmonary artery and severe pulmonary hypertension treated with coil occlusion of aortopulmonary collaterals in a term neonate. Br Med J Case Rep 2015; 2015: 1–4.

Hayashi S, Hirai S, Naito M, et al. Scimitar vein descending from the right inferior lobe to the inferior vena cava beneath the diaphragm: a rare case. Anat Sci Int 2015; 90: 123–125.

10. Wang CC, Wu ET, Chen SJ, et al. Scimitar syndrome: incidence, treatment, and prognosis. Eur J Pediatr 2008; 167: 155–160. 11. Dusenbery SM, Geva T, Seale A, et al. Outcome predictors and implications for management of scimitar syndrome. Am Heart J 2013; 165: 770–777. 12. Midyat L, Demir E, Askin M, et al. Eponym. Scimitar syndrome. Eur J Pediatr 2010; 169: 1171–1177. 13. Brink J, Yong MS, d’Udekem Y, Weintraub RG, Brizard CP and Konstantinov IE. Surgery for scimitar syndrome: the Melbourne experience. Interact Cardiovasc Thorac Surg 2015; 20: 31–34. 14. Huddleston CB, Exil V, Canter CE, Mendeloff EN. Scimitar syndrome presenting in infancy. Ann Thorac Surg 1999; 67: 154–159; discussion 60. 15. Korkmaz AA, Yildiz CE, Onan B, Guden M, Cetin G, Babaoglu K. Scimitar syndrome: a complex form of anomalous pulmonary venous return. J Card Surg 2011; 26: 529–534.

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Case Report Short-term warfarin treatment for apical thrombus in a patient with Takotsubo cardiomyopathy Abdullah İcli, Hakan Akilli, Mehmet Kayrak, Alpay Aribas, Kurtulus Ozdemir Case report

Abstract Takotsubo cardiomyopathy (TCMP) is characterised by a temporary aneurysm of the left ventricular apex in individuals without significant stenosis of the coronary arteries. It is extremely rare to see it combined with a thrombus. In this case report, we present a 57-year-old female patient with TCMP in whom apical thrombus was treated with short-term warfarin use. Keywords: Takotsubo cardiomyopathy, apical thrombus, warfarin Submitted 20/10/15, accepted 17/2/16 Published online 19/5/16 Cardiovasc J Afr 2016; 27: e12–e14

www.cvja.co.za

DOI: 10.5830/CVJA-2016-011

Takotsubo cardiomyopathy (TCMP) is characterised by a temporary aneurysm of the left ventricular apex in individuals without significant stenosis of the coronary arteries. Mostly seen in postmenopausal women, it is also called ampulla cardiomyopathy, human stress cardiomyopathy or broken heart syndrome.1 It is extremely rare to see it combined with a thrombus. The Mayo Clinic diagnostic criteria for TCMP include reversible left ventricular dysfunction, newly emerging ECG changes and/or increased troponin levels, intracranial haemorrhage, pheochromocytoma and hypertrophic cardiomyopathy, absence of head trauma, and angiographic exclusion of occlusive coronary artery disease or plaque rupture.2 In this case report, we present a 57-year-old female patient with TCMP in whom apical thrombus was treated with short-term warfarin use.

Department of Cardiology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey Abdullah İcli, MD, abdullahicli@yahoo.com, aicli@konya.edu.tr Hakan Akilli, MD Mehmet Kayrak, MD Alpay Aribas, MD Kurtulus Ozdemir, MD

A 57-year-old postmenopausal female patient was admitted to the emergency department with a four-day history of chest pain and dyspnoea. Her past medical history included hypertension. Electrocardiography performed in the emergency department showed symmetrical T-wave negativity in V1–V6 and DI–avL (Fig. 1). With ongoing chest pain, the patient underwent coronary angiography, which detected normal coronary anatomy (Fig. 2). During the follow up, the troponin level was 0.83 ng/ ml. Transthoracic echocardiography revealed a dyskinetic left ventricular apex, with an ejection fraction of 35% and a 2.3 × 3.3-cm thrombus (Fig. 3). In the light of the typical ECG, coronary angiography and echocardiography findings, the patient was diagnosed with TCMP. The patient was informed about the risks and benefits of anticoagulation with warfarin, surgical thrombectomy and other treatment options, including beta-blockers and angiotensin converting enzyme inhibitor. Warfarin was commenced. The patient was discharged with a recommendation to visit a week later for measurement of the prothrombin time international normalised ratio (PT-INR) and warfarin dose arrangement. Fifteen days later, the patient was admitted with bruising on her body, and her PT-INR level was 6.5. The echocardiographic examination was repeated, which showed that the apical dyskinesia and thrombus in the left ventricle had disappeared, and the ejection fraction was normal (Fig. 4).

Discussion The vast majority (90%) of patients with TCMP are hypertensive postmenopausal women.3 In addition to ST-segment elevation, other ECG changes such as T-wave inversion and QT prolongation may be seen. Cardiac enzymes are generally moderately elevated. For these reasons, TCMP is often misdiagnosed as myocardial infarction with ST elevation. A definitive diagnosis is made with the detection of hypokinetic and aneurysmal images of the left ventricular apex in echocardiography or ventriculography, with coronary angiography showing an absence of stenosis in the coronary arteries.4 Cardiac magnetic resonance imaging may be highly beneficial in differentiating between various types of cardiomyopathy and myocarditis.5 Diverse factors have been proposed for the pathophysiology of TCMP, including stress, increased adrenergic activity, prolonged stunned myocardium, hypertension, chronic obstructive lung disease, decreased oestrogen levels, small-vessel disease, myocarditis and insufficient fatty acid metabolism in

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Fig. 1. Admission ECG showing ST–T changes.

the myocardium.6 The mortality rate from TCMP is lower than that of acute myocardial infarction. In-hospital mortality is quite low, at 1–2%.1,4 The complications include apical thrombus formation, cardiac rupture, embolism and conduction defects.7 De Gregorio et al. (2008) reported intracavitary thrombus in 2.5% of the patients with TCMP, and stated that 33% of these patients may have thromboembolic complications.8 However, thromboembolic events may occur even in patients receiving anticoagulant treatment.7 Myocardial necrosis and haemorrhage are feared limitations in treatment decisions.9 Surgical thrombectomy has drawbacks, such as decreasing the ejection fraction in the early post-surgical period, and the increased risks of anaesthesia and operational stress for patients with TCMP.10,11

Conclusion

Fig. 2. C oronary angiography with normal coronary angiographic findings.

This patient’s outcome shows that anticoagulant treatment with warfarin is an effective, conservative treatment option. Despite ongoing debate, it would be beneficial to consider warfarin in individualised treatment, and the decision should be made with consideration of the features of intracavitary thrombus.

Diastole

Systole

Fig. 3. I nitial echocardiography showing apical ballooning and apical thrombus in the diastolic and systolic phase.

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Diastole

Systole

Fig. 4. A fter warfarin treatment, echocardiography showing improved left ventricle and resolved thrombus in the diastolic and systolic phase.

References 1.

or takotsubo cardiomyopathy: A systematic review. Eur Heart J 2006;

e37–e38.

Prasad A. Apical ballooning syndrome: An important differential diagnosis of acute myocardial infarction. Circulation 2007; 115: e56–59.

syndrome: A systematic review. Int J Cardiol 2008; 131(1): 18–24.

significance of left ventricular thrombus in tako-tsubo cardiomyopathy 4.

Prasad A, Dangas G, Srinivasan M, et al. Incidence and angiographic characteristics of patients with apical ballooning syndrome (takotsubo/

Sacha J, Masełko J, Wester A, Szudrowicz Z, Pluta W. Left ventricular apical rupture caused by takotsubo cardiomyopathy comprehensive pathological heart investigation. Circ J 2007; 71(6): 982–985.

stress cardiomyopathy) in the HORIZONSAMI trial: An analysis from

10. Jensen JB, Malouf JF. Takotsubo cardiomyopathy following cholecys-

a multicenter, international study of ST-elevation myocardial ınfarction.

tectomy: a poorly recognized cause of acute reversible left ventricular

Catheter Cardiovasc Interv 2014; 83(3): 343–348. 5.

De Gregorio C, Grimaldi P, Lentini C. Left ventricular thrombus formation and cardioembolic complications in patients with Takotsubo-like

Haghi D, Papavassiliu T, Heggemann F, et al. Incidence and clinical assessed with echocardiography, Q J Med 2008; 101(5): 381–386.

Nerella N, Lodha A, T´ıu CT, Chandra PA, Rose M. Thromboembolism in Takotsubo syndrome: A case report. Int J Cardiol 2008; 124(2):

27: 1523–1529. 2.

Nef HM, Mollmann H, Akashi YJ, Hamm CW. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 2010; 7: 187–193.

Gianni M, Dentali F, Grandi AM, et al. Apical ballooning syndrome

dysfunction. Int J Cardiol 2006; 106(3): 390–391.

Fernandez-Perez GC, Aguilar-Arjona JA, de la Fuente GT, et al.

11. Niino T, Unosawa S. Surgical extirpation of apical left ventricular

Takotsubo cardiomyopathy: Assessment with cardiac MRI. Am J

thrombus in takotsubo cardiomyopathy. Case Rep Surg 2015; 1–3. ID

Roentgenol 2010; 195: W139–145.

387037.

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Case Report Unexpected complication of oesophagoscopy: iatrogenic aortic injury in a child Orhan Tezcan, Menduh Oruc, Mahir Kuyumcu, Sinan Demirtas, Celal Yavuz, Oguz Karahan

Abstract Introduction: Oesophagoscopy is usually a safe procedure to localise and remove ingested foreign bodies, however, unexpected complications may develop during this procedure. In this case report we discuss iatrogenic aortic injury, which developed during oesophagoscopy, and its immediate treatment. Case report: A six-year-old male patient was admitted to hospital with symptoms of having ingested a foreign body. Oesophagoscopy was carried out and the foreign body was visualised at the second constriction of the oesophagus. During this procedure, profuse bleeding occurred. Subsequently, a balloon dilator was placed to control bleeding in the oesophagus. Thoracic contrast tomography revealed thoracic aortic injury. Open surgical aortic repair was immediately carried out on the patient and the oesophageal hole was primarily repaired. The patient was discharged on postoperative day 15 with a total cure. Conclusion: Although oesophagoscopy is a safe, easily applied method, it should be kept in mind that fatal complications may occur during the procedure. This procedure should be done in high-level medical centres, which have extra facilities for managing complications. Keywords: oesophagoscopy, complication, aortic injury Submitted 14/1/16, accepted 17/2/16 Cardiovasc J Afr 2016; 27: e15â&#x20AC;&#x201C;e17

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DOI: 10.5830/CVJA-2016-015

Department of Cardiovascular Surgery, Medical School of Dicle University, Diyarbakir, Turkey Orhan Tezcan, MD, dr.orhantezcan@gmail.com Sinan Demirtas, MD Celal Yavuz, MD

Department of Chest Surgery, Medical School of Dicle University, Diyarbakir, Turkey Menduh Oruc, MD Oguz Karahan, MD

Department of Anesthesiology, Medical School of Dicle University, Diyarbakir, Turkey Mahir Kuyumcu, MD

Oesophagoscopy is an effective diagnostic and treatment method for oesophageal pathologies, with 0.03 to 17% complication rates.1,2 Perforation and bleeding are the most important complications of this procedure. Previous reports have claimed that therapeutic interventions with oesophagoscopy present more risks with regard to complications, than other diagnostic procedures.1,2 Ingestion of a foreign body into the oesophagus has serious potential for perforation.3 Oesophagoscopy strategies can be used both for detecting the location of the foreign body and for removal of it. However, it should be borne in mind that treatment with oesophagoscopy has the potential for further aortic injury if sufficient pre-operative evaluation of the anatomical and pathological status is not done.3 In this study, we present a case of aortic injury during oesophagoscopy in a patient with foreign body ingestion.

Case report A six-year-old male patient was admitted to hospital with dysphagia. Chest radiograms revealed the image of a coin at the second constriction of the oesophagus (Fig. 1A). Rigid oesophagoscopy was carried out on the patient under general anaesthesia. Copious bleeding was noted during removal of the foreign body, so flexible oesophagoscopy was used. The injury site could not be determined due to severe haemorrhage. Because the blood pressure was dropping rapidly (60/30 mmHg), an achalasia balloon (polyethylene balloon) dilator (Figs 1B, 2A) was placed in the oesophagus to control the bleeding. The haemoglobin level was 5 g/dl and three units of erythrocyte suspension replacement were administered immediately. After controlling the bleeding with the balloon dilator, contrast tomography (CT) was carried out. The coin was visualised in the stomach during the chest radiography (Figs 1B, 2A). Contrast extravasation revealed it near the descending aorta (crossing site of oesophagus) (Fig. 2A, B, C). We consulted with a cardiovascular surgeon and immediate surgery on the descending aorta was planned. The patient was taken to the theatre for aortic repair. A left posterolateral thoracotomy was carried out on the patient for surgical exploration of the descending aorta. The injured site of the aorta was detected (Fig. 3A) and then repaired primarily with pledgeted sutures (Fig. 3B). Just below the damaged aorta, a 1-cm oesophageal injury was detected. After dissection of the parietal pleura, the oesophagus was primarily repaired to avoid development of an aortooesophageal fistula. The patient was taken to the intensive care unit after the operation.

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Fig. 1. A . Chest radiography showing the first position of the ingested coin. B. Reposition of the coin in the stomach and visualisation of the achalasia balloon. C, D. Oesophageal radiographs on postoperative day 12.

Fig. 2. A . Achalasia balloon placed in the oesophagus. B. Contrast extravasation (red arrow) from aortic rupture (axial view). C. Contrast extravasation (red arrow) from aortic rupture (sagittal view). D. Contrast extravasation (red arrow) from aortic rupture (coronal view).

A graph of oesophageal passage was done on postoperative day 12 with iohexol (Omnipaque®, Nycomed, Oslo, Norway) contrast agent and no leakage was observed (Fig. 1C, D). The patient was discharged uneventfully on the 15th day after the operation.

Discussion We could not find any cases in the literature reporting aortic rupture during rigid oesophagoscopy. Therefore we report on this case with a view to preventing such complications in other patients. Foreign body ingestion is frequently seen in early childhood. Peristaltic transmission of these foreign bodies to the stomach A

Fig. 3. A . Adventitial haematoma from the aortic injury. B. Aortic injury repaired with pledgeted suture.

may be challenging due to anatomical constriction of the oesophagus.4,5 In these cases, endoscopic (10–20%) or surgical (1%) removal may be required.4,5 However, both the foreign body and the endoscope used for removal of the object could lead to aortic wall injury.3,5 Incidence of oesophageal rupture is reported at 0.1 to 1.9% during rigid oesophagoscopy.6 Aorto-oesophageal fistula is a rare but fatal (40–60%) complication of foreign body ingestion. The common site of aortic injury is at the second constriction of the oesophagus, which has a relatively narrow lumen due to the cross-over of the left primary bronchus and aortic arch.3 Aortic rupture of the oesophagus usually has a fatal course, particularly with spontaneous rupture of the aorta. He et al. reported sudden death due to ruptured pseudo-aneurysms into the oesophagus.7 However, iatrogenic injuries of the aorta can be more easily controlled than unforeseen events. Therefore, pre-operative staging of the condition and planning of the procedure is important to avoid fatal outcomes. Similar injuries have been reported with other thoracic interventions, such as spinal instrumentation and surgical and endovascular aortic repair techniques described for treatment of complications.8 However, direct aortic injury during oesophagoscopy is not reported as frequently as other complications. The majority of reports mention oesophageal rupture due to foreign body removal with oesophagoscopy.1,2 Oesophageal perforations may cause fatal outcomes due to mediastinitis and fulminant sepsis, which could prevent oesophageal repair.1,2 However, in combination with aortic rupture, this may become an emergency situation. An aortooesophageal fistula will usually occur after neglect of an ingested foreign body, as the oesophagus compresses the object, which irritates the oesophageal wall. This condition may develop over

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time, but iatrogenic aorto-oesophagial rupture occurs suddenly and progresses quickly to haemorrhagic shock.7,9 Therefore 80 to 90% of aortic injuries are fatal, and immediate aortic repair is important for survival.7 In our case, immediate aortic surgery was carried out after controlling the bleeding with a polyethylene balloon and CT detection of the injury. Contrast CT scan is a suggested imaging technique for detecting the site of aortic injury and its relationship with surrounding structures.3 However, angiography can be undertaken for determining aortic pathology and treatment of the injury with endovascular techniques.3,8 Repair with an endovascular graft is a safer option for acute aortic injury. However, there is limited experience with this procedure in the paediatric population and natural progression of the stent is not fully known. Therefore, open surgical repair is the preferred technique for paediatric patients with aortic injury.8,10 In accordance with the therapeutic opportunities of the surgical centre, an appropriate method should be chosen and an immediate treatment protocol should be determined. In our case, we decided on open repair with simultaneous intervention on the aortic injury and oesophageal rupture.

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References 1.

Majeski J, Lynch W, Durst G. Esophageal perforation during esophagogastroduodenoscopy. Am J Surg 2009; 198(5): e56–57.

Bhatia NL, Collins JM, Nguyen CC, Jaroszewski DE, Vikram HR, Charles JC. Esophageal perforation as a complication of esophagogastroduodenoscopy. J Hosp Med 2008; 3(3): 256–262.

Wei Y, Chen L, Wang Y, Yu D, Peng J, Xu J. Proposed management protocol for ingested esophageal foreign body and aortoesophageal fistula: a singlecenter experience. Int J Clin Exp Med 2015; 8(1): 607–615. eCollection 2015.

Cheng W, Tam PK. Foreign-body ingestion in children: experience with 1,265 cases. J Pediatr Surg 1999; 34: 1472–1476.

Wyllie R. Foreign bodies in the gastrointestinal tract. Curr Opin Pediatr 2006; 18: 563–564.

Eroglu A, Turkyilmaz A, Aydin Y, Yekeler E, Karaoglanoglu N. Current management of esophageal perforation: 20 years’ experience. Dis Esophagus 2009; 22: 374–380.

He S, Chen X, Zhou X, Hu Q, Ananda S, Zhu S. Sudden death due to traumatic ascending aortic pseudoaneurysms ruptured into the esophagus: 2 case reports. Medicine (Baltimore). 2015; 94(15): e716.

Minor ME, Morrissey NJ, Peress R, Carroccio A, Ellozy S, Agarwal G, et al. Endovascular treatment of an iatrogenic thoracic aortic injury after spinal instrumentation: case report. J Vasc Surg 2004; 39(4): 893–896.

Conclusion Aortic wall injury may occur during oesophagoscopy. Balloon dilatators may be helpful to control bleeding and secure time for surgical repair. Open aortic repair may ensure patient survival and it allows simultaneous oesophageal repair.

Aronberg RM, Punekar SR, Adam SI, Judson BL, Mehra S, Yarbrough WG. Esophageal perforation caused by edible foreign bodies: a systematic review of the literature. Laryngoscope 2015; 125(2): 371–378.

10. Gunabushanam V, Mishra N, Calderin J, Glick R, Rosca M, Krishnasastry K. Endovascular stenting of blunt thoracic aortic injury in an 11-year-old. J Pediatr Surg 2010; 45(3): E15–18.

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• Enoxaparin-induced thrombocytopaenia • Short-term warfarin treatment for apical thrombus