CVJA Volume 28 Issue 5 by Clinics Cardive Publishing

SEPTEMBER/OCTOBER 2017 VOL 28 NO 5 A Lupin Group Company

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CardioVascular Journal of Africa (official journal for PASCAR)

• Therapy for heart failure secondary to rheumatic mitral regurgitation • Echocardiographic evaluation for rheumatic valvular heart disease in Rwanda • Factors affecting interest in cardiothoracic surgery in Nigeria • Old disease: cardiac hydatid disease and surgical principles • ECG abnormalities in treatment-naïve HIV subjects in south-east Nigeria

Carzin XL, the extended release doxazosin offers: A slower onset of action vs IR formulations to allow fewer titration steps and to minimize side-effects2. Effective treatment for urinary outflow obstruction and BPH symptoms3. Safe BPH treatment for normotensive and hypertensive patients3.

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Carzin XL. Each film coated tablet contains 4 mg doxazosin. Reg. No.: RSA S3 41/7.1/0557. NAM NS2 10/34/0376. For full prescribing information, refer to the package insert approved by the Medicines Control Council, July 2009. 1) Pompeo ACL, et al. A randomised, double blind study comparing the efficacy and tolerability of controlled release Doxazosin and tamsulosin in the treatment of benign prostatic hyperplasia. Int J. Clin Pract Oct 2006;60(10):11721177. 2) Kirby RS, et al. A Combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. British Journal of Urology International 2001 Feb;87(3):192-200. 3) Carzin XL package insert. 4) Vs. Doxazosin XL originator 4 mg modified release formulation. Department of Health website.http://www.mpr.gov.za - Accessed 21/05/2015. CLXC73/01/2015

• New insights on obesity and body size perceptions in urban and rural Senegal

• Anaemia and iron deficiency in heart failure in sub-Saharan Africa Cardiovascular Journal of Africa . Vol 28, No 5, September/October 2017

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• Red cell distribution width, coronary artery disease and diabetes mellitus

PUBLISHED ONLINE: • Atrial myxoma: a rare cause of hemiplegia in children • Liddle’s syndrome in an African male: a novel mutation

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za DYNAFIL 50, 100 mg. Each tablet contains sildenafil citrate equivalent to 50, 100 mg sildenafil respectively. S4 A42/7.1.5/1071, 1072. NAM NS2 13/7.1.5/0086, 0087. For full prescribing information refer to the package insert approved by the Medicines Control Council, September 2012. DLC302/07/2017.

689

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

Vol 28, No 5, SEPTEMBER/OCTOBER 2017

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EDITORIAL 279

Who is too fat? JIE Hoffman

280

Is there a role for combination anti-remodelling therapy for heart failure secondary to chronic rheumatic mitral regurgitation? R Meel • F Peters • E Libhaber • MR Essop

285

Prevalence of rheumatic valvular heart disease in Rwandan school children: echocardiographic evaluation using the World Heart Federation criteria J Mucumbitsi • B Bulwer • L Mutesa • V Ndahindwa • E Rusingiza • P Arya • S Breakey • C Patton-Bolman • EL Kaplan

293

Factors affecting interest in cardiothoracic surgery among junior surgical residents in Nigeria EB Kesieme • U Abubakar • O Olusoji • IM Inuwa • J Kefas • N Anumenechi

298

Atorvastatin inhibits cholesterol-induced caspase-3 cleavage through down-regulation of P38 and up-regulation of Bcl-2 in the rat carotid artery R Bayatmakoo • N Rashtchizadeh • PYaghmaei • M Farhoudi • P Karimi

304

New World’s old disease: cardiac hydatid disease and surgical principles O Tanyeli • Y Dereli • I Mercan • N Gormus • T Yuksek

309

Right ventricular strain as predictor of pulmonary complications in patients with femur fracture H-J Kim • H-B Park • Y Suh • H-S Kim • Y-H Cho • T-Y Choi • E-S Hwang • D-K Cho

315

Electrocardiographic abnormalities in treatment-naïve HIV subjects in south-east Nigeria IC Okoye • EN Anyabolu

CARDIOVASCULAR TOPICS

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 Vol 28, No 5, SEPTEMBER/OCTOBER 2017

319

Red cell distribution width is correlated with extensive coronary artery disease in patients with diabetes mellitus A Celik • M Karayakali • F Altunkas • K Karaman • A Arisoy • K Ceyhan • H Kadi • F Koc

324

Prevalence of obesity and body size perceptions in urban and rural Senegal: new insight on the epidemiological transition in West Africa E Macia • E Cohen • L Gueye • G Boetsch • P Duboz

331

Anaemia and iron deficiency in heart failure: epidemiological gaps, diagnostic challenges and therapeutic barriers in sub-Saharan Africa A Makubi • J Lwakatare • OS Ogah • L Rydén • LH Lund • J Makani

338

Building and strengthening capacity for cardiovascular research in Africa through technical training workshops: a report of the joint course on health research methods by the Clinical Research Education Networking and Consultancy and the Ivorian Society of Cardiology B Dzekem • JBA Kacou • M Abanda • E Kramoh • Y Yapobi • S Kingue • AP Kengne • A Dzudie

PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed)

Atrial myxoma: a rare cause of hemiplegia in children U Onubogu • W Boma • O Boma

Liddle’s syndrome in an African male due to a novel frameshift mutation in the beta-subunit of the epithelial sodium channel gene R Freercks • S Meldau • E Jones • J Ensor • C Weimers-Willard • B Rayner

REVIEW ARTICLE

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

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Editorial Who is too fat? Julien IE Hoffman Obesity is a modern pandemic that, if not checked, will lead to increased rates of morbidity and mortality from type 2 diabetes, cardiovascular disease, cancer, osteoarthritis, hypertension, and other complications.1-3 In Tonga, a country with one of the highest percentages of obese people in the world, the recent further increase in incidence of obesity has reduced life expectancy from the mid-70s to the mid-60s.1 In the USA, older people with a body mass index (BMI) of 40 kg/m2 had an almost four-fold increased mortality rate compared with those with a BMI of 25 kg/m2.4 A well-executed study by Macia et al.,5 published in this edition of the journal, explores some of the factors involved in the obesity pandemic. They examined adults in a rural area in Senegal and compared them with adults in the capital, Dakar. One of the main findings was that there was more overweight and central obesity in the urban than the rural area, and this was attributed to the reduced amount of exercise and higher calorie intake by urban dwellers. The second important finding was based on showing the subjects silhouettes of people varying from the very obese to the very thin, and asking them what they thought about their weight. Men were more satisfied with their weight than were women. The weight selected as ideal was higher in the rural than the urban area, and for women in the rural area, their perceived ideal weight fell into the overweight category. In many parts of the world there is improved social status in being fat. This attitude is not confined to underdeveloped countries. In the United Kingdom from 1999 to 2007, the percentage of obese people increased but the proportion who identified themselves as being overweight or obese decreased.6 How should we control this pandemic? First, we need to decide who needs treatment. In 1944 Cyril Connolly wrote ‘Imprisoned in every fat man a thin one is wildly signalling to be let out’.7 This is a mantra used by many physicians as a reason for lowering weight in all who are overweight. It overlooks, however, the fact that not all fat is created equal. It has long been known that an increase in visceral and abdominal fat (appleshaped) is more deleterious than an increase of subcutaneous fat on the thighs, buttocks and shoulders (pear-shaped),8,9 and that an increase in visceral fat can occur with a relatively normal BMI. The two types of fat are functionally different.10 It would therefore be more effective to concentrate on treating appleshaped than pear-shaped obesity.

Treatment of obesity follows a simple energy balance: burn up more calories with exercise and take in fewer calories with food. Unfortunately this summation oversimplifies the problem. Changing long-standing habits regarding daily activity and diet is difficult and requires participants to want to change. Furthermore, many obese people have a low metabolic rate that remains low after they have lost weight,11 so that a higher proportion of the calories that they eat are stored rather than metabolised. This may be one reason why weight-reducing programmes seldom produce weight loss sustained over many years. Before we consider recommending weight loss we need to ask ‘Does the subject have the type of obesity that is healthy, and does not need treatment?’ And if it is unhealthy, how do we persuade people who are satisfied with their body shape to change? As physicians, we are quite good at providing care for those who want it, but quite bad at providing care for those who do not want it, such as asymptomatic hypertensives, the mentally ill, and as shown in this article, some of the obese. Treating these groups would do much to decrease morbidity and mortality rates, but we have barely scratched the surface.

References 1.

Byles J. Obesity: the new global threat to healthy ageing and longevity. Health Sociol Rev 2009; 18: 412–422.

Yaturu S. Obesity and type 2 diabetes. J Diabetes Mellitus 2011; 1: 79–95.

Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005; 366: 1640–1649.

Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006; 355: 763–778.

Macia E, Cohen E, Gueye L, Boetsch G, Duboz P. Prevalence of obesity and body size perceptions in urban and rural Senegal. New insight on the epidemiological transition in West Africa. Cardiovasc J Africa 2017; 28(4): 00–00.

Johnson F, Cooke L, Croker H, Wardle J. Changing perceptions of weight in Great Britain: comparison of two population surveys. Br Med J 2008; 337: a494.

Connolly C. The Unquiet Grave. Hesperides Press, 1944.

Hamdy O, Porramatikul S, Al-Ozairi E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diabetes Rev 2006; 2: 367–373.

Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev 1994; 74: 761–811.

10. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking

Department of Pediatrics, University of California, San Francisco, USA Julien IE Hoffman, MD (Wits) FRCP (London), jiehoffman@gmail.com

obesity to its source. Cell 2007; 131: 242–256. 11. Johannsen DL, Knuth ND, Huizenga R, Rood JC, Ravussin E, Hall KD. Metabolic slowing with massive weight loss despite preservation of fat-free mass. J Clin Endocrinol Metab 2012; 97: 2480–2496.

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Cardiovascular Topics Is there a role for combination anti-remodelling therapy for heart failure secondary to chronic rheumatic mitral regurgitation? Ruchika Meel, Ferande Peters, Elena Libhaber, Mohammed R Essop

Abstract Introduction: The value of combination anti-remodelling therapy for heart failure (HF) secondary to mitral regurgitation (MR) is unknown. We studied the effect of anti-remodelling therapy on clinical and echocardiographic parameters in patients with severe chronic rheumatic mitral regurgitation (CRMR) presenting in HF. Methods: Thirty-one patients (29 females) at Chris Hani Baragwanath Academic Hospital, treated with combination therapy for HF due to CRMR and New York Heart Association functional class II–III symptoms, underwent prospective six-month follow up. Results: Mean age was 50.7 ± 8.5 years. No patients died or were hospitalised for HF during the study period. No worsening of clinical symptoms or functional status, or left and right ventricular echocardiographic parameters (p > 0.05) was noted. Peak left atrial systolic strain improved at six months (18.7 ± 7.7 vs 23.6 ± 8.5%, p = 0.02). Conclusion: This preliminary analysis suggests that combination anti-remodelling therapy may be beneficial for HF secondary to CRMR. We had no HF-related admissions or deaths, and no deterioration in echocardiographic parameters of ventricular size and function. Keywords: heart failure, mitral regurgitation, combination therapy Submitted 5/6/16, accepted 7/12/16 Cardiovasc J Afr 2017; 28: 280–284

www.cvja.co.za

DOI: 10.5830/CVJA-2016-095

For patients with valvular disease, direct pressure or volume overload results in cardiac remodelling and eventually heart failure (HF).1-3 Changes in neuro-hormonal signalling and genotype result in abnormal structure and function of both the

myocyte and interstitial space.2-4 In chronic mitral regurgitation (MR), the persistent volume overload of the left atrium and ventricle, after a period of compensation, results in myocardial dysfunction through these mechanisms.5 This eventually culminates in atrial fibrillation, HF and death if left untreated.6 At present, surgery is the mainstay of therapy for patients with symptomatic severe MR and markers of left ventricular (LV) systolic dysfunction.7 Surgery is associated with non-negligible morbidity and mortality rates, even in established centres, especially in patients with LV dysfunction and high New York Heart Association (NYHA) functional class.8,9 The use of medical therapy for chronic MR has been largely non-conclusive and controversial.10 Most were small studies involving angiotensin converting enzyme (ACE) inhibitors and beta-blockers in degenerative MR.10-12 Guidelines on valvular heart disease recommend medical therapy for HF (ejection fraction < 50%) in chronic MR (class IIa, level of evidence B).7 No study has systematically looked at the effects of combination anti-remodelling therapy (ACE inhibitors, betablockers, aldosterone receptor antagonist) in HF secondary to MR. There is proven mortality and morbidity benefit of combination anti-remodelling therapy in systolic HF as a result of ischaemia and cardiomyopathy.13-15 We hypothesised that a similar benefit may be derived in HF secondary to CRMR. This could potentially offer an alternative option to these patients who are at high risk for surgery or are not inclined to undergo surgical intervention. Furthermore, the benefit of anti-remodelling therapy may be extended to asymptomatic patients with significant MR to prevent disease progression and delay the time to surgery. We therefore aimed to study the effect of anti-remodelling therapy, including ACE inhibitors and beta-blockers, in terms of clinical outcome, and traditional as well as newer echocardiographic parameters, such as two-dimensional strain in patients with severe CRMR who presented with HF.

Methods Division of Cardiology, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa Ruchika Meel, PhD, ruchikameel@gmail.com Ferande Peters, MD Elena Libhaber, PhD Mohammed R Essop, MD

This prospective, observational sub-study formed part of a larger study on CRMR at the Chris Hani Baragwanath Academic Hospital. Patients were enrolled between January and December 2014. The study was approved by the University of the Witwatersrand ethics committee (M140114). All patients were screened and those deemed to have severe CRMR and presented with HF were referred for possible inclusion in the study.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

HF was diagnosed as per the ACCF/AHA and ESC guideline definition.15,16 The assessment of HF was made based on a combination of the patient’s history, clinical signs as well as available clinical records. A total of 66 patients with presumed CRMR underwent clinical evaluation, resting electrocardiogram and detailed echocardiographic assessment according to a predetermined protocol. The inclusion criteria were as follows: patients aged 18 years or older with echocardiographic features of severe CRMR; symptomatic (NYHA II–III); left ventricular ejection fraction ≤ 60%; refusing or awaiting surgery; and on medical therapy [ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers or aldosterone receptor antagonist] for HF. Patients were excluded if they had significant aortic valve disease, concurrent mitral stenosis (MS) with a valve area of less than 2.0 cm2, documented ischaemic heart disease, pre-existing non-valvular cardiomyopathy, prior cardiac surgery, congenital or pericardial disease, pregnancy, severe systemic disorders such as renal failure, uncontrolled hypertension (systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg) on medication, or severe anaemia (haemoglobin < 10 g/dl). Thirty-five patients were excluded due to the following: anaemia, renal dysfunction, mild or moderate MR, MR of non-rheumatic aetiology and inadequate image quality. The final sample included 31 patients. Most HF trials conducted with anti-remodelling agents required a minimum duration of three months to demonstrate benefit.17 We therefore followed up patients in this study for a period of six months. All the patients included in the sub-study were receiving some form of medical therapy for HF. All were on the minimum dose of their respective HF medications and were up titrated at three months where indicated, based on symptoms, blood pressure, and urea and creatinine levels. All patients enrolled in this study were on a combination of at least one anti-remodelling agent in addition to a diuretic for at least one week. Therapy comprised beta-blockers (atenolol, carvedilol), ACE inhibitors/ARBs (enalapril, perindopril, telmisartan) and an aldosterone receptor antagonist (spironolactone), in addition to digitalis and diuretics. Medication was initiated at the discretion of the treating physician. All medications were either down titrated or withdrawn, or substituted on follow-up visits if side effects were reported. Patients were followed up at one, three and six months. At one and six months, a full clinical assessment was done, including the Minnesota HF questionnaire and six-minute walk test. The dose of the medication was titrated at one month and full titration was achieved at three months by the treating physician. Transthoracic echocardiography was performed on all patients in the left lateral position by experienced sonographers using a S5-1 transducer on a Philips iE33 system (Amsterdam, the Netherlands). The images were obtained according to a standardised protocol at baseline and at the six-month follow up. The data were transferred and analysed offline using the Xcelera workstation (Philips). Echocardiographic measurements were done by the researcher at baseline and the follow-up measurements were done by an experienced sonographer who was blinded to the initial results. For two-dimensional and Doppler quantification, all linear and volumetric chamber measurements were performed according to the American Society of Echocardiography (ASE)

281

chamber guidelines at baseline and at six months.18 Measurements relating to LV diastolic function were performed in accordance with the ASE guidelines on diastolic function and included pulse-wave Doppler at the mitral tips and tissue Doppler of both medial and lateral mitral annuli at baseline and at six months.19 Measurements relating to the right ventricle were based on the ASE guidelines on the right ventricle.20 MR was considered rheumatic in aetiology when the morphology of the valve satisfied the World Heart Federation (WHF) criteria for the diagnosis of chronic rheumatic heart disease.21 MR severity was assessed using qualitative, semiquantitative and quantitative methods (integrated approach) as per the ASE valvular regurgitation guideline.22,23 In equivocal cases, the echocardiographic data were integrated with the clinical evaluation by an experienced cardiologist to distinguish moderate from severe MR. For speckle tracking echocardiography, left atrial peak systolic strain and left and right ventricular peak systolic strain were measured as previously described.24-30

Statistical analysis Statistical analysis was performed with Statistica (version 12.5, series 0414 for Windows). Continuous variables are expressed as mean ± SD or median (IQR). Paired Student’s t-test or Wilcoxon’s matched-pairs test were used to compare continuous variables. Categorical variables are expressed as percentages. A p-value of < 0.05 was recognised as statistically significant.

Results The baseline clinical characteristics are summarised in Table 1. There was no change in systolic and diastolic blood pressure or heart rate from baseline to six months [125 ± 12.6 vs 120.1 ± 10.2 mmHg, p = 0.09; 76.2 ± 12.2 vs 74.2 ± 11.02 mmHg, p = 0.5; 71.5 (70–81) vs 71.0 (61–80) beats/min, p = 0.43, respectively]. The median Minnesota HF score at the start and the end of treatment at six months was 34 (18–61) and 32.5 (13–48), respectively (p = 0.3). There was no difference in the six-minute walk test at the onset of treatment and at six months (265.5 ± 103.0 vs 275.4 ± 71 m, p = 0.6). None of the patients were hospitalised for HF and all were alive at six months. Baseline and maximum therapeutic doses of

Table 1. Baseline clinical characteristics Variable Age (years) Gender (female/male) Systolic blood pressure (mmHg)

Number = 31 50.7 ± 8.5 29/2 125 ± 12.6

Diastolic blood pressure (mmHg)

76.2 ± 12.2

Heart rate (beats/min)

71.5 (70–81)

Body surface area (m2)

1.73 ± 0.16

Body mass index (kg/m2)

28.1 ± 6.1

NYHA class II–III (%)

31 (100)

Hypertension (%)

29 (93)

HIV (%)

7 (23)

Atrial fibrillation (%)

2 (6.4)

Data are presented as median (interquartile range), mean ± SD or %. HIV, human immunodeficiency virus; NYHA, New York Heart Association functional class.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

their respective medications are summarised in Table 2. There was no worsening of left and right ventricular echocardiographic indices at baseline and at six months of therapy (Table 3). Based on the integrated assessment (qualitative and quantitative parameters), MR severity did not change at the end of six months. No change in quantitative parameters of MR assessment was noted at the end of six months [(vena cava width: 6.5 ± 1.9 vs 6.0 ± 1.6 mm, p = 0.2; regurgitant fraction: 31.7 (18.9–57.7) vs 29.2% (15.7–53.5), p = 0.2)]. Left atrial peak systolic strain increased at six months (18.7 ± 7.7 vs 23.6 ± 8.5%, p = 0.02). However, no change in right and left ventricular peak systolic strain was noted at the end of combination therapy (–15.6 ± 5.0 vs –16.4 ± 5.9%, p = 0.56; –13.9 ± 4.3 vs –15 ± 4.0%, p = 0.28, respectively).

Discussion The main findings of this study were that patients with rheumatic MR and HF who were treated with optimal medical therapy had good short-term clinical outcomes. There was no deterioration in echocardiographic parameters of cardiac performance, and there was an improvement in left atrial peak systolic strain. Some older, pre-echocardiographic studies on rheumatic heart disease in Western populations demonstrated variable natural histories, ranging from CRMR being a benign lesion with a normal life expectancy, to it being a severe, progressive and ultimately fatal disease.31-33 Natural history studies in degenerative MR, with follow up ranging from seven months to 10 years, have shown increased risk of sudden cardiac death and increased postoperative morbidity and mortality rates in the presence of severe MR symptoms, arrhythmias, left ventricular end-systolic dimensions (LVESD) ≥ 45 mm and ejection fraction (EF) ≤ 60%.8,34-39 These studies, primarily pertaining to degenerative, significant MR, evaluated symptomatic and asymptomatic patients. Most of them concluded that with conservative management (medical therapy), outcomes were worse regarding cardiac death, progression to worsening NYHA functional class, left ventricular dysfunction, HF, atrial fibrillation and pulmonary hypertension. Mũnoz et al.40 compared 29 patients with MR on medical therapy alone to 45 patients who underwent mitral valve replacement. They found at five-year follow up, a lower survival rate, faster progression to higher NYHA class, and more complications such as HF and atrial fibrillation in the medical therapy group.40 The main shortcomings of all these

Table 2. Comparison between baseline and maximum medication dose of the study patients Medication

Number (%)

Baseline dose (mg)

Dose (mg) at six months

p-value

Furosemide

30 (97)

75 ± 25.9

78.3 ± 34.9

0.67

Nifedipine XL

9 (29)

34.4 ± 21.8

47.7 ± 24.3

0.23

Digoxin

7 (23)

0.125

1.0

Enalapril

11 (35)

10 (2.5–20)

20 (10–20)

0.17

Perindopril

11 (35)

2.9 ± 1

4 ± 1.7

0.003

Carvedilol

29 (94)

12.5 (3.125–12.5)

50 (37.5–50)

Spironolactone

28 (90)

25 (12.5–25)

50 (50–75)

< 0.001 0.001

Data are presented as median (interquartile range), mean ± SD or %. Two patients were on telmisartan (40 mg at baseline and six months), and one was on atenolol (12.5 mg up-titrated to 25 mg at six months).

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studies are the inclusion of mostly asymptomatic patients with significant MR, and the medication and dosages used were not systematically documented. The subset of patients we followed up had mostly stage D heart failure due to organic valvular heart disease. They were on varied combination anti-remodelling therapy as part of their management. This provided us with the opportunity of observing this subgroup. The lack of change in left and right ventricular structural and functional indices may possibly be explained by the short duration of follow up, the disease-stabilising effect of anti-remodelling therapy, and/or the relatively younger age of our patients compared to degenerative MR patients. A lack of difference in MR severity, even after controlling the systolic blood pressure in our study, may be explained by the small effect of change in pressure gradient on regurgitant volume, static left ventricular volumes, and the rheumatic nature of the disease, whereby the orifice is fixed and not dynamic, as in degenerative MR.5,12,41 There was no change in left and right ventricular longitudinal strain parameters in our study and this may be attributed to the short duration of follow up. The reason for marked improvement in left atrial peak systolic strain may be that the left atrium remodels and recovers earlier than the ventricles after an injury, as shown by Therkelsen et al.42 Additionally, left atrial reverse remodelling has been known to occur independently of left ventricular reverse remodelling, due to the direct effect of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS).4 Also, left atrial strain may be a more sensitive marker for detecting reverse remodelling than left atrial volumes, as noted in this study.

Table 3. Left and right ventricular echocardiographic parameters at baseline and six months of medical therapy Variable

Baseline (n = 31)

Six months of therapy (n = 31)

p-value

55.5 ± 8.4

55.1 ± 8.0

0.8

42.6 ± 9.4

40.7 ± 9.5

0.43

81.8 (68.9–98.1)

79.1 (64.5–99.3)

0.6

45.4 ± 17.8

42.8 ± 15.8

0.5

46.9 ± 8.7

50.4 ± 10.1

0.1

113.2 ± 47.2

112.9 ± 42.1

0.9

102.0 ± 26.5

99.4 ± 28

0.7

Left ventricular indices

LVEDD (mm) LVESD (mm) EDVi (ml/m2)† ESVi (ml/m2)† Ejection fraction (%) E wave (cm/s) A wave (cm/s) E/A wave (ratio) E´ medial (cm/s) A´ medial (cm/s) Medial E/E´(ratio) Medial S´(cm/s) LAVi (ml/m2)†

1.0 ± 0.4

1.1 ± 0.4

0.3

6.6 (4.5–8.2)

5.9 (4.7–7.8)

0.2

6.7 (5.1–8.2)

7.1 (5.9–8.3)

0.5

18.5 ± 9.5

18.9 ± 9.7

0.8

6.1 ± 1.4

6.1 ± 1.2

1.0

60.2 (47.1–89.4)

59.5 (44.2–82.4)

0.8

38.3 ± 6.25

35.8 ± 8.8

0.2

20.5 ± 2.9

20.6 ± 2.9

0.9

11.1 ± 2.7

11.6 ± 2.5

0.45

26.5 (21.7–32)

24.7 (7.4–33.8)

0.6

33.2 ± 12.4

31.4 ± 11.5

0.5

Right ventricular indices

RV base (mm) TAPSE (mm) RV S´ (cm/s) RAVi (ml/m2)† PASP (mmHg)

Data are presented as median (interquartile range), mean ± SD or %. †Values are indexed to body surface area. EDVi, end-diastolic volume index; ESVi, end-systolic volume index; LAVi, left atrial volume index; EDD, end-diastolic diameter; ESD, end-systolic diameter; LV, left ventricle; PASP, pulmonary artery systolic pressure; RAVi, right atrial volume index; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

There are a number of studies that have evaluated the effects of individual drugs in degenerative MR. Most of these involved beta-blockers or vasodilators.12,43 The results from these mostly small, non-randomised trials were inconclusive.10,44 The effect of aldosterone receptor antagonists has not been evaluated in organic MR in humans. Additionally, no trial has systematically explored the effects of combination therapy (with or without HF), secondary to CRMR. In our study, lack of benefit from individual agents may have been due to incomplete blockade of the sympathetic nervous system (SNS) or the RAAS. An example would be that of aldosterone escape during prolonged ACE inhibitor therapy.45 Other possibilities include activation of the kallikrein–kinin system due to an increase in bradykinin, which in turn activates matric metalloproteinases, resulting in collagen loss, a process that may be exacerbated by the inhibition of angiotensin II by ACE inhibitors.46 These drugs in combination have synergistic action; for example the combination of an ACE inhibitor, beta-blocker and aldosterone receptor antagonist suppresses myocardial fibrosis in systolic heart failure.3 Therefore, combination therapy with drugs that block the SNS and RAAS systems may be the answer. Most of our patients were on a combination of carvedilol, spironolactone and an ACE inhibitor. However, their effect on left ventricular function and rheumatic MR severity remains questionable. All the patients however remained stable on combined medical therapy and none was hospitalised for HF or died during the six months of follow up. This is a relevant finding as more than 50% of patients with all-cause systolic HF are re-hospitalised within six months of HF assessment.47 The lack of sudden cardiac death and HF-related deaths in this study may be attributed to medical treatment, or perhaps chance, due to the small sample size. Combined medical therapy may serve to stabilise the disease process, probably via neuro-hormonal modulation (likely the most important compensatory and deleterious mechanism in MR).48 Combination HF therapy may therefore serve as a bridge to surgery, given the long delays due to resource limitations, or as a substitute for surgery where patients decline surgery or have a high surgical risk due to severe ventricular dysfunction. There were several limitations to this observational study. We had no control arm, there was a varied combination of medications, the exact duration of therapy at baseline was not clear due to incomplete records, the study subjects and the researchers were not blinded to the treatment, it was a small sample size, and the follow-up period was short.

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Prevalence of rheumatic valvular heart disease in Rwandan school children: echocardiographic evaluation using the World Heart Federation criteria J Mucumbitsi, B Bulwer, L Mutesa, V Ndahindwa, M Semakula, E Rusingiza, P Arya, S Breakey, C Patton-Bolman, E L Kaplan

Abstract Background: Rheumatic fever (RF) and rheumatic valvular heart disease (RHD) remain important medical, surgical and public health concerns in many parts of the world, especially in sub-Saharan Africa. However, there are no published data from Rwanda. We performed a RHD prevalence study in a randomly selected sample of Rwandan school children using the 2012 World Heart Federation (WHF) criteria. Methods: Echocardiographic assessment of 2 501 Rwandan school children from 10 schools in the Gasabo district near Kigali was carried out. Resulting data were evaluated by four experienced echocardiographers. Statistical analyses were carried out by statisticians.

Results: RHD prevalence was 6.8/1 000 children examined (95% CI: 4.2/1 000–10.9/1 000). Seventeen met WHF criteria for RHD, 13 fulfilled criteria for ‘borderline’ RHD and four were ‘definite’ RHD. None of these 17 had been previously identified. Conclusion: These data indicate a significant burden of RHD in Rwanda and support a need for defined public health RF control programmes in children there. Keywords: rheumatic heart disease, rheumatic fever, echocardiography, prevalence, epidemiology Submitted 21/7/16, accepted 11/1/17 Published online 1/3/17 Cardiovasc J Afr 2017; 28: 285–292

Rwandan Heart Foundation and Department of Pediatrics, King Faisal Hospital, Kigali, Rwanda

www.cvja.co.za

DOI: 10.5830/CVJA-2017-007

J Mucumbitsi, MD

Noninvasive Cardiovascular Research, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA B Bulwer, MD

College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda L Mutesa, MD, PhD

School of Public Health, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda V Ndahindwa, MD, MSc

Rwanda Biomedical Centre, Kigali, Rwanda; Interuniversity Institute for Biostatistical and Statistical Bioinformatics, University of Hasselt, Belgium M Semakula, PhD

School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda E Rusingiza, MD

Department of Pediatric Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA P Arya, MD

Massachusetts General Hospital, Institute of Health Professions, Boston, Massachusetts, USA S Breakey, RN, PhD

Team Heart Inc, Boston, Massachusetts, USA C Patton-Bolman, RN, MSN

Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA E L Kaplan, MD, kapla001@umn.edu

The incidence of acute rheumatic fever (RF) and the prevalence of rheumatic heart disease (RHD) have decreased remarkably in industrialised countries during recent decades.1-3 Yet this disease process remains a significant health issue among socio-economically disadvantaged populations, especially in developing countries. To effectively allocate limited health resources for medical and public health planning in low- and middle-income countries, accurate assessment of the current status of RF and RHD is necessary. Echocardiography has emerged as an effective diagnostic tool for assessing cardiac pathology in patients with RHD. Recent studies have reported a wide variation in RF incidence and RHD prevalence across countries, even within different socio-economic strata and geographic regions within the same country.4-7 Several guidelines for diagnosing RHD have been published in recent years.8-12 Although some differences exist among these guidelines, they are useful in supporting rapid, non-invasive assessment of RHD status for both clinical care and epidemiological studies. Compared with clinical auscultation, echocardiography has been reported to be advantageous for demonstrating very mild (borderline) pathology or ‘silent carditis/valvulitis’ in RHD.13-15 The purpose of this project was to determine the prevalence of RHD in a sample of Rwandan school children using the 2012 World Heart Federation (WHF) echocardiographic criteria.10 There are no previously published RHD prevalence data from this sub-Saharan African country. Such determinations are important for country-based medical and public health efforts. The findings from our echocardiographic study in Rwanda are described and discussed in this report.

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Methods

Echocardiographic screening procedures

Rwanda is a small central African nation of approximately 12 million inhabitants (2013 estimate). The population is relatively young and predominantly rural. The capital city, Kigali, with a population exceeding one million people, is the location of major medical facilities. Other medical facilities such as health centres and hospitals are located at the provincial, district and sector levels. The Gasabo district, adjacent to the city of Kigali, has a population of approximately 400 000 including its own urban, suburban and rural areas. Data (2011) from the Gasabo District Education Department indicated that there were 106 schools with 67 538 registered primary and 8 989 registered secondary school students. Rwandan schools are classified by the Rwanda Education Department as rural, peri-urban public and urban private, according to their geographic location and to the socio-economic level of the adjacent population. The majority of schools are in rural areas and are considered ‘economically disadvantaged’. The included population, for the most part, lived in sub-standard housing without running water or electricity. The sample size calculated for the study was 2 940, assuming a prevalence of definite RHD at 1% in school-aged children (6–16 years), with a precision of 0.4% and an inter-cluster correlation coefficient equal to 0.001. When considering 2% non-respondents, the final sample size was increased to 3 000. Ten schools from the Gasabo district were selected for this study using a stratified two-stage cluster sampling, where the primary sampling units were schools from the three following areas with different socio-economic levels: rural public schools, middle class and urban private schools. A second stage of preparation was based on individuals, including all classes in each school where all school children were stratified by grade, class and gender to ensure an equal number of boys and girls from the grades included in the sample. Using official lists of students, children were then randomly selected, using the function RANDBETWEEN (Excel software). The majority of students in five of these 10 schools were classified by the Education Department as being economically disadvantaged. From each of the 10 selected schools, a stratified, randomised selection of 300 students was performed. Random selection of an additional 50 to 100 students from each school was also performed to constitute a reserve list. The original group of 3 000 subjects included those from rural, peri-urban and urban areas of the Gasabo district (Fig. 1). Informed parental consent, subjects’ assent (if older than eight years), and a questionnaire that included socio-demographic data, as well as personal and family health histories were obtained for each selected subject and alternate subject. The study protocol was approved by the Rwanda National Ethics Committee and the Rwandan Ministries of Health and of Education. Socio-economic status was classified as high, medium and low according to Gasabo District Education Department criteria. Educational sessions and materials about RF/RHD and the programme’s objectives were developed and distributed to school teachers, headmasters, administrators and parents of the subjects representing the selected schools. Included were didactic pamphlets, posters and banners in Kinyarwanda, the principal language spoken by most Rwandans.

The echocardiographic examinations were performed during a 10-day period by 14 experienced US-certified sonographers who were trained and followed the 2012 WHF criteria for the echocardiographic diagnosis of RHD10 (Fig. 1, Table 1). All the sonographers held a certification by either the American Registry of Diagnostic Medical Sonography (ARDMS) or Cardiovascular Credentialing International (CCI). Additionally, the mean number of years of experience exceeded 14 for the sonographers. The echocardiographic instruments, along with appropriatesized multi-Hertz, phased-array transducers, included: 11 SonoSite (five Micromaxx + five Turbo + one Nanomaxx – all SonoSite Inc, Bothell, Washington), one Philips CX50 (Philips Ultrasound, Bothell, Washington), one Acuson Cypress (Siemens, Mountain View, California) and one GE Vivid i (GE Medical Systems, Milwaukee, Wisconsin). Transthoracic echocardiographic examinations were conducted in specially prepared rooms at each school. The following views were obtained from each subject: parasternal long-axis view, parasternal short-axis views, apical three- and four-chamber views, along with colour-flow Doppler and spectral Doppler interrogation of the intracardiac valves. Two paediatric cardiologists were present during the echocardiographic screening examinations. During or following each echocardiographic examination, the sonographer and paediatric cardiologist preliminarily discussed any findings of

• Gazabo District: 67 538 primary school students; 8 989 secondary school students • Age: 6–16 years • Sites: 10 representative schools: rural, peri-urban, urban – 300 children per school • Sampling method: stratified randomised Children randomised n = 3 000 (100%) Children selected n = 2 693 (90%) Children screened n = 2 501 (83%)

WHF 2012 echocardiography criteria: definite or borderline RHD

RHD cases n = 17 (0.68%)

Definite RHD n = 4 (0.16%)

Borderline RHD n = 13 (0.52%)

Fig. 1. Summary of methodology and echocardiographic screening outcomes of the representative sample of Rwandan school children in the Gazabo district of the Rwandan capital, Kigali, and cases assessed as definite or borderline rheumatic heart disease (RHD) using the WHF 2012 criteria.9

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suspected significance. Concomitant physical examinations, including cardiac auscultation were not performed. The completed studies were uploaded to a cloud-based web server and stored using a picture archiving and communication system (PACS) (Studycast; Core Sound Imaging, Inc, Raleigh, North Carolina) and proprietary software (CoreConnect; Core Sound Imaging, Inc). The transfer of the echocardiographic images and data occurred via a secure broadband internet connection, with CoreWeb validating the integrity and confidentiality of the transmitted studies using standard secure (SSL, TLS) encryption.

Post-screening echocardiographic analysis Two certified professionals initially viewed each echocardiogram. These included an echocardiographer and a paediatric cardiologist with level III training in echocardiography (American Table 1. World Heart Federation 2012 criteria for echocardiographic diagnosis of rheumatic heart disease as applied to this study (modified from reference 10). Echo criteria for children ≤ 20 years of age Definite RHD (either A, B, C or D): A) Pathological MR and at least two morphological features of RHD of the MV B) MS mean gradient ≥ to 4 mmHg (NB – exclude congenital MV anomalies) C) Pathological AR and at least two morphological features of RHD of the AV (NB – exclude bicuspid aortic valve and dilated aortic root) D) Borderline disease of both the aortic and mitral valves as defined below Borderline RHD (either A, B or C): A) At least two morphological features of RHD of the MV without pathological MR or MS B) Pathological MR

287

Society of Echocardiography), who separately interpreted and reported on each archived echocardiographic examination using a standardised format (SmartWorksheetsTM, CoreWeb, North Carolina). During this phase of analysis the readers were blinded to individual demographic data. The echocardiographic descriptions focused on findings summarised in the WHF 2012 criteria for RHD and were categorised as definite RHD, borderline RHD, or no RHD (Table 1).10 Physiological (non-pathological) tricuspid valve and pulmonary valve regurgitation were noted, but not comprehensively assessed unless there was significant co-existing aortic and/or mitral valve pathology. Subjects who were suspected of having echocardiographic features of RHD or congenital heart disease were then referred and examined by the Kigali-based paediatric cardiologists (JM, ER) who are experienced in the diagnosis and management of RHD, for subsequent management.

Statistical analyses Data management and statistical analyses of all data were performed (LM, VN, MS) at the Rwanda Biomedical Centre in the Medical Research Centre in Kigali using STATA software (Statacorp LP. College Station, Texas). Descriptive statistics were performed; data were summarised using frequency tables and graphs. Confidence interval of RHD prevalence was computed at the 95% confidence level.

Results

C) Pathological AR Normal echocardiographic findings (all A, B and C); A) MR that does not meet all four Doppler criteria (physiological MR) B) AR that does not meet all four Doppler criteria (physiological AR) C) An isolated morphological feature of RHD of the MV or the AV (e.g. valvar thickening) without any associated pathological stenosis or regurgitation Echo criteria for adults > 20 years of age Definite RHD (either A, B, C or D): A) Pathological MR and at least two morphological features of RHD of the MV B) MS mean gradient ≥ to 4 mmHg (NB – exclude congenital MV anomalies) C) Pathological AR and at least two morphological features of RHD of the AV in those under 35 years of age only. (Bicuspid AV and dilated aortic root must first be excluded) D) Pathological AR and at least two morphological features of RHD of the MV Pathological regurgitation Mitral regurgitation (all four Doppler criteria must be met)

Aortic regurgitation (all four Doppler criteria must be met)

1. Seen in two views

2. In at least one view jet length ≥ 2 cm 2. In at least one view jet length ≥ 1 cm 3. Peak velocity ≥ 3 m/s

3. Peak velocity ≥ 3 m/s

4. Pansystolic jet for at least one envelope

4. Pandiastolic jet for at least one envelope

Morphological features of RHD Mitral valve

Aortic valve

1. AMVL thickening ≥ 3 mm (age-specific)

1. Irregular or focal thickening

2. Chordal thickening

2. Coaptation defect

3. Restricted motion

4. Excessive leaflet tip motion during systole (hypermobile or flail leaflet) resulting in abnormal coaptation

4. Prolapse

RHD, rheumatic heart disease; MR, mitral regurgitation; MV, mitral valve; MS, mitral stenosis; AR, aortic regurgitation; AV, aortic valve; AMVL, anterior mitral valve leaflet.

Of the original 3 000 school children randomly selected, 2 693 (89.7%) underwent echocardiographic evaluation. However on their scheduled day for screening, 307 were not present at school or were not available. Of these 2 693 subjects, complete demographic data from 2 501 subjects were available (92.8%; this is 83.3% of the original 3 000 selected subjects) (Fig. 1). The age distribution of the 2 501 subjects is shown in Fig. 2. The mean age of these 2 501 subjects who were completely analysed was 11.2 years. Of importance, 91% of the subjects undergoing diagnostic echocardiography were students enrolled in the first six years of primary school. Approximately 9% of those echocardiographically evaluated were somewhat older students (ages 16–20 years) enrolled in the first three years of secondary school. Therefore, the overall age distribution for the 2 501 subjects was weighted towards younger school children. Seventeen of the 2 501 children (0.68%) fulfilled the 2012 WHF echocardiographic criteria for the diagnosis of RHD, in either the definite or borderline category (Table 2, modified from reference 10). Therefore, the RHD prevalence among this sample of 2 501 Rwandan school children was 6.8/1 000 (95% CI: 4.2/1 000–10.9/1 000).

Characteristics of subjects meeting WHF criteria for RHD The age distribution of the 17 subjects with valvular RHD is shown in Fig. 3. Of the 17 subjects who met the 2012 WHF criteria, four (23.5%) were identified as definite RHD and 13 (76.5%) subjects were classified as borderline RHD (Fig. 4).

288

14 11.7

25 10.2

9.3

Percentage

8.9

11.6

12.0

10.1

9.8

10 6.8

4.6 2.3

1.6 0.7

17.7

11.8

0 0.3 0.1

10 11 12 13 14 15 16 17 18 19 20 Age

Fig. 2. A ge distribution of the 2 501 Rwandan school children studied echocardiographically.

Table 2. Summary of echocardiographic findings among the 17 subjects found to have rheumatic valvular heart disease WHF category

Valve lesion

Male

Female

0.68

Pathological MR

0.52

Pathological AR

0 4

0.16

Subjects with RHD using WHF criteria Borderline

Pathological MR

Pathological AR

Total Percentage

For complete 2012 WHF diagnostic criteria in children (and adults), refer to reference 10.

5.9

13 Age

1. AMVL ≥ 3mm n=3

1. Colour jet length = ≥ 2 cm n = 13

1. Irregular or focal thickening n=0

1. Colour jet = ≥ 1 cm n=0

2. Chordal thickening n=1

2. Seen in 2 views n = 13

2. Coaptation defect n=0

2. Seen in 2 views n=0

3. Restricted leaflet motion n=0

3. Velocity ≥ 3 m/s n = 13

3. Restricted leaflet motion n=0

3. Velocity ≥ 3 m/s n=0

4. Excessive AMVL n=1

4. Pansystolic n = 13

4. Leaflet prolapse n=1

4. Pansystolic n=0

Pathological AR: Doppler features

n = 13

n=0

1. AMVL ≥ 3mm n=3

1. Colour jet length = ≥ 2 cm n=3

1. Irregular or focal thickening n=1

1. Colour jet = ≥ 1 cm n=1

2. Chordal thickening n=3

2. Seen in 2 views n=3

2. Coaptation defect n=1

2. Seen in 2 views n=1

3. Restricted leaflet motion n=3

3. Velocity ≥ 3 m/s n=3

3. Restricted leaflet motion n=0

3. Velocity ≥ 3 m/s n=1

4. Excessive AMVL n=0

4. Pansystolic n=3

4. Leaflet prolapse n=0

4. Pansystolic n=1

n=3

The mean age of the 17 subjects found to have RHD was 12.2 years, which was slightly greater than the mean age (11.2 years) of the 2 501 evaluated group. This discrepancy in ages was not statistically significant. In fact, among the group of previously described older children, there was also a higher prevalence of RHD when compared with the younger age group. However, these age differences were not statistically significant (p = 0.856). Mean weight and height for these 17 subjects were 35.68 kg (78.5 lbs) and 139.88 cm (55.1 inches), respectively. Forty-nine per cent were male and 51% were female. While there was a higher prevalence of echocardiographic valvular findings in the

AV morphological features

n=4

Fig. 3. Age distribution of the 17 subjects diagnosed with rheumatic valvar heart disease using the WHF 2012 echocardiographic criteria.9

Pathological MR: Doppler measures

MV morphological features

Borderline cases (n = 13)

Definite

23.5 23.5

5.9

Definite cases (n = 4)

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n=1

n=0

n=1

Fig. 4. C hildren assessed as definite or borderline RHD using the morphological and Doppler criteria for RHD according to the WHF 2012 criteria.9

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males when compared with female subjects, this difference was not statistically significant (p = 0.062). The individual echocardiographic findings for the 17 subjects who fulfilled the WHF criteria are depicted in Fig. 4. As would be expected, the most frequently affected valve was the mitral valve. There was only one subject with solitary aortic valve findings. An example of definite valvular RHD (subject #06-0206) is illustrated in Fig. 5. By contrast, an example of borderline RHD (subject #06-0168) is shown in Fig. 6. The majority of the 17 subjects (76%) echocardiographically classified as having RHD were categorised as ‘economically disadvantaged students’. Additionally, 13 of the 17 subjects (76%) with echocardiographic findings compatible with RHD were students at schools that were demographically classified as rural. Although not of statistical significance, these trends are important and may have significant medical care and public health programme implications. Of the 2 501 subjects completely analysed, only two (0.03%) were found to have congenital heart disease (a 2.8-cm secundum atrial septal defect and a small pressure-restrictive patent ductus

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arteriosus). No other significant underlying chronic medical problems were identified among the subjects during these cardiac-specific evaluations. No subjects demonstrated heart failure and no subjects with acute rheumatic fever were identified.

Discussion RHD prevalence reports from echocardiographic screening studies in sub-Saharan Africa vary and high prevalence rates are not uncommon.6,7,13-15 To date, no published data exist about RHD prevalence rates among school children in urban or rural Rwanda. The geographic district of Gasabo was identified because it was socio-economically diverse, as well as being near Kigali city. Because of this, and following consultations with the Republic of Rwanda Ministry of Health and school authorities, and approval by the Rwandan National Ethics Committee, this project was initiated. If this reported sample, randomly selected from the approximately 67 000 school children in the Gasabo district, is representative, the results (the prevalence of valvular RHD was determined echocardiographically to be 6.8/1 000), suggest

Fig. 5. E xample of definite RHD consistent with WHF 2012 criteria. A. Parasternal long-axis (PLAX) view showing thickened anterior mitral leaflet exceeding 3 mm in young adult study subject. B. Colour-flow Doppler interrogation of the mitral valve shows an eccentric jet of mitral regurgitation (MR) with jet length exceeding 2 cm. C. Colour-flow Doppler interrogation of the mitral valve using the apical four-chamber (A4C) view shows eccentric jet of mitral regurgitation with jet length measuring 3.8 cm. D. Continuous-wave (CW) Doppler interrogation of the MR jet showed maximum velocities exceeding 4.7 m/s.

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Fig. 6. E xample of borderline RHD consistent with WHF 2012 criteria. A. Parasternal long-axis (PLAX) view showing thickened anterior mitral leaflet exceeding 3 mm and restricted leaflet motion in young adult study subject. B. Colour-flow Doppler interrogation of the mitral valve in the PLAX view shows a small jet of mitral regurgitation (MR) with jet length < 2 cm. C. Colour-flow Doppler interrogation of the mitral valve using the A4C view shows jet of mitral regurgitation with jet length < 2 cm. D. Continuous-wave (CW) Doppler interrogation of the MR jet showed maximum velocities exceeding < 3 m/s.

there could be more than 500 school children with established RHD in this single Rwandan district alone. Assuming a constant prevalence across the country (which may be be unjustified) extrapolating this RHD prevalence rate to Rwandaâ&#x20AC;&#x2122;s total population of school children could prove worrisome with regard to the accompanying medical, public health and economic impacts for the country. Such an extrapolation would most likely indicate that the majority of Rwandan school children with RHD are most likely undiagnosed and not receiving recommended medical care, including secondary antibiotic prophylaxis. Our data further suggest that the preponderance of RHD is most likely in rural Rwanda. Anticipated studies in additional rural areas of the country would clarify this. In extrapolating the present Gasabo data for future public health planning, the probability of higher RHD prevalence rates among adolescents and young adults must also be confirmed. If true, this would require extended coverage by public health RHD control programmes and medical facilities beyond the primary school-age population. The echocardiograms analysed here were obtained by very experienced, registered cardiac sonographers with an average of 14 years of experience and were aditionally analysed by

experienced echocardiographers (JM, BB, PA, ER) who had been given access to an advanced draft of the 2012 WHF criteria and were aware of the 2012 criteria. The RHD school-age prevalence of approximately seven per 1 000 children from this single Rwandan district is lower than, for example, recent reports from Mozambique, Kenya, Uganda, Ethiopia or South Africa.7,13-15 The reasons for these differences are not obvious although variations in prevalence rates were seen in the previously reported studies. While all of these had high prevalence rates and the prevalence rate reported here was lower, one cannot assume that prevalence rates across sub-Saharan Africa are similar. For example, this finding may be related to the fact that our study was carried out in and around the capital city, which may have benefited from better access to healthcare during the last 10 or 15 years, compared with the rest of the country. Additionally, Rwanda has been shown to have invested in primary healthcare and achieved among the best health indicators in sub-Saharan Africa.16 There appeared to be a relationship (although not statistically significant, p = 0.704) between the estimated socio-economic status and prevalence of RHD in this sample of Rwandan school children. Engle et al. have shown similar findings with

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a significantly higher RHD prevalence rate in a more socioeconomically disadvantaged community in South Africa.17 The prevalence of RHD in the small group of older school children/adolescents was higher than in the younger school children. With valvular damage becoming more evident with elapsed time, the cumulative prevalence of RHD would be expected to increase with progressing age among children and adolescents. Of note is the fact that in the report by Engle and colleagues, the population appeared somewhat older than in our present population. This may have influenced the higher prevalence reported by these workers. Increasing age would also offer more opportunities for recurrences of RF, since it appears that none of these children had been previously diagnosed and therefore were not receiving prophylactic antibiotics. In those 17 subjects found to have either ‘definite’ (n = 4) or ‘borderline’ (n = 13) valvular RHD, the mitral valve was most often affected (Table 2). Again, none of those subjects who met WHF criteria for RHD had been previously diagnosed. Therefore, none of the 17 subjects had been receiving secondary RF prophylaxis prior to this project. In fact, we were unable to elicit a history of RF from any of the 2 501 echocardiographically examined subjects as it has been found in other somewhat similar studies.7 This observation requires additional investigation. An important challenge facing the application of the WHF 2012 criteria pertains to its specificity in our presumed higher-risk Rwandan population. Evidence from a recent study in a low-risk population suggests high specificity of the morphological mitral and aortic valve features of RHD, but low specificity for the isolated pathological mitral regurgitation criteria.17 Of note, almost 95% of our borderline RHD cases were based on the mitral regurgitation criteria. Therefore the issue of specificity of the morphological and Doppler-assessed valvular regurgitation criteria is an important one, and appropriate follow up of such identified patients is mandatory. The WHF 2012 criteria used during this evaluation10 differed significantly from earlier criteria used in several other published studies conducted in the sub-Saharan region. Those studies employed earlier clinical and/or echocardiographic criteria for diagnosing valvular RHD.13-15 The present report is the second that used only the 2012 WHF echocardiographic criteria in a sub-Saharan school-age population.7 We believe that our assessment of these 2 501 subjects accurately adhered to the published WHF criteria. However, we recognise that the final conclusion will depend on long-term (prospective) follow up, which should include not only subsequent serial echocardiograms, but also documentation of adherence to secondary antibiotic prophylaxis for those subjects who initially met the criteria for valvular RHD.18 Secondary prophylaxis would help to reduce/eliminate the possibility of recurrent attacks of RF, which would confuse long-term follow-up studies. The 2015 revised Jones Criteria for the Diagnosis of ARF from the American Heart Association have been endorsed by the World Heart Federation.12 Both guidelines underscore the key advantages of using Doppler echocardiography in the diagnosis of ‘subclinical carditis’ – an important diagnostic criterion.

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Rwanda. Students in the Gasabo district were deemed by local authorities and the investigators to be representative of the socio-demographics of school children in Rwanda. Selecting a district closer to the capital was a practical consideration, but could possibly have introduced bias. Second, the smaller percentage (9%) of relatively older children in the examined sample may have (unintentionally) affected the calculated overall prevalence of RHD, as has been previously mentioned. Third, technical aspects of the echocardiographic studies require consideration. Although care was taken to standardise both equipment settings and transducer selection in an effort to minimise technical error, we used equipment from different manufacturers. The same paediatric transducers were not universally used for all subjects. Our care to include only experienced, registered sonographers as well as subsequent independent reporting by four experienced US-certified cardiologists/echocardiographers reflects the intent to minimise such potential sources of error. The absence of echocardiographic findings compatible with congenital bicuspid aortic valves (BAV) in the present study was an unexpected finding. Congenital BAV is a frequent differential when considering rheumatic aortic valvular disease. On average, approximately 1% of children have been reported to have congenital BAV. The reason(s) for the unexpectedly low prevalence of BAV among these Rwandan school children is unclear and requires confirmation.

Conclusions These data from a single geographic district of Rwanda confirm the significant prevalence of RHD, as has been reported from other sub-Saharan African countries.13-15 The feasibility of echocardiographic screening of relatively large numbers of subjects using the 2012 WHF criteria for detecting mild/‘borderline’ RHD in these populations appears to be confirmed. However, intensive and prospective long-term (years) follow up is required to support the conclusions from this sample. The present data will prove useful to health authorities in determining resource planning and allocation for control programmes for this preventable cardiovascular disease. RF and RHD remain important medical and public health issues in sub-Saharan Africa. Cost-effective public health control programmes are urgently needed.16,17 Educational efforts targeting healthcare professionals, lay populations (including school children) and public health authorities must be included. The data presented here, while informative, need to be further supported by additional comprehensive studies, including sustainable, cost-effective approaches involving less-expensive and highly portable echocardiographic instruments as well as larger study samples. These studies were designed and implemented by collaborative efforts between Team Heart, Inc, Boston, Massachusetts, and the Rwanda Heart Foundation, Kigali, Rwanda. A sincere debt of gratitude is owed to the following sonographers whose significant personal commitments and enthusiasm actually made

Limitations

this effort possible: David Adams, Lisa Bruno, Marc Couturier, Kim Fanning,

Questions may arise about whether the selected subject sample was representative of all similar-age school children in

Lauren Motola, Jennifer Neary (lead sonographer), Eva Osypiuk, MD,

Marlee Griffith, Jennifer Kane, Peggy Lospennato, Carlene McClanahan, Stephen Preiss, Lauren Skillins and Nicole Zafiris. Additionally, Mr David

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M, et al. Prevalence of rheumatic heart disease in 4720 asymptomatic

Adams gave expert advice regarding the echocardiographic techniquies. We

scholars from South Africa and Ethiopia. Heart 2015; 101: 1389-1394.

also sincerely thank Josh Goldberg and Egidia Rugwizangoga for their dedication and assistance.

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Kaplan EL, Mendis S, Bisno A, Butchart EG, Ganguly NK, Ghebrehiwet

The authors gratefully acknowledge the assistance of Agnes Binagwaho,

T, et al. Rheumatic fever and rheumatic heart disease – Report of a

MD, PhD, then Minister of Health of the Republic of Rwanda. Dr Vincent

World Health Organization Expert Consultation. WHO Technical

Biruta, then Minister of Education of the Republic of Rwanda, gave advice.

Report Series 923. World Health Organization, Geneva, Switzerland, 2004.

The Departments of Health and Education of Gasabo district were helpful in their suggestions for and facilitation of health education and parent education. We also express our appreciation to the Medical Director and the supervisory team of Kibagabaga Hospital, as well as the volunteer nurses from Gasabo

Atatoa-Carr P, Lennon D, Wilson N. Rheumatic fever. Diagnosis, management, and secondary prevention: a New Zealand guideline. N Z Med J 2008; 121: 59–69.

District Health Centres for their participation in carrying out this investigation.

10. The Australian guideline for prevention, diagnosis, and management of

We thank the Medtronic Foundation, Minneapolis, Minnesota, for

acute rheumatic fever and rheumatic heart disease. 2012. http://www.

significant financial support. Studycast, Core Sound Imaging, Inc, Raleigh,

rhdaustralia.org.au/sites/default/files/guideline_0.pdf.

NC, provided in-kind assistance in formatting images, data storage and shar-

11. Remenyi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al.

ing. The SonoSite Company (Bothell, Washington) generously provided the

World Heart Federation criteria for echocardiographic diagnosis of

majority of the echocardiographic equipment during this project. Additional

rheumatic heart disease – an evidence-based guideline. Nat Rev Cardiol

funding was provided by Team Heart, Inc, Boston, MA.

2012; 9: 297–309.

Drs Mucumbitsi and Bulwer are both first authors and put in equal

12. Gewitz MH, Baltimore RS, Tani L, Sable CM, Shulman ST, Carapetis J,

amounts of work. Dr Kaplan is corresponding author. His address is

et al. Revision of the Jones criteria for the diagnosis of acute rheumatic

Department of Pediatrics, University of Minnesota Medical School, MMC

fever in the era of Doppler echocardiography: A scientific statement

296, 420 Delaware Str SE, Minneapolis, MN 55422, USA. Tel: 612-624-4455;

from the American Heart Association Committee on Rheumatic Fever,

Fax: 612-625-7859; e-mail: kapla001@umn.edu

Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. Circulation 2015; 122; 1806–1818.

References 1.

Kaplan EL. T Duckett Jones memorial lecture: Global assessment of

14. Anabwani GM, Bonhoeffer P. Prevalence of heart disease in school

Influences and dynamics of populations and pathogens: a failure to real-

children in rural Kenya using colour-flow echocardiography. E Afr Med

Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal disease. Lancet Infect Dis 2005; 5: 685–694.

Tibazarwa, KB, Volmink JA, Mayosi, BM. Incidence of acute rheumatic fever in the world: a systematic review of population based studies. Heart 2008; 94: 1534–1540.

Echocardiographic screening for rheumatic heart disease in Ugandan schoolchildren. Circulation 2012; 125: 3127–3132. 16. Bingawaho A, Farmer PE, Nsanzimana S, et al. Rwanda 20 years on: investing in life. Lancet 2014; 384: 371-375. 17. Clark BC, Krishnan A, McCarter R, Scheel J, Sable C, Beaton A. Using

Roth SJ, et al. Resurgence of acute rheumatic fever in the intermountain

a low-risk population to estimate the specificity of the World Heart

area of the United States. N Engl J Med 1987; 316: 421–427.

Federation criteria for the diagnosis of rheumatic heart disease. J Am

Paar JA, Berrios NM, Rose JD, Caceres M, Pena R, Perez W, et al. Nicaragua. Am J Cardiol 2010; 105: 1809–1814. Essop MR, Nkomo VT. Rheumatic and non-rheumatic valvular heart disease: epidemiology, management, and prevention in Africa.

J 1996; 73: 215–217. 15. Beaton A, Okello E, Lwabi P, Mondo C, McCarter R, Sable C.

Veasy LG, Wiedmeier SE, Orsmond GS, Ruttenberg HD, Boucek MM,

Prevalence of rheumatic heart disease in children and young adults in 6.

C, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. New Eng J Med 2007; 357: 470–476.

rheumatic fever and rheumatic heart disease at the close of the century. ize prevention? Circulation 1993; 88: 1964–1972. 2.

13. Marijon E, Celermajer DS, Ferriera B, Mocumbi AO, Jani D, Paquet

Society Echocard 2016; 29: 253–258. 18. Zühlke L, Mayosi BM. Echocardiographic screening for subclinical rheumatic heart disease remains a research tool pending studies of impact on prognosis. Cur Cardiol Rep 2013; 15: 343. 19. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi B. Position state-

Circulation 2005; 112: 3584–3591.

ment of the World Heart Federation on the prevention and control of

Engle ME, Haileamlak A, Zuhlke L, Lemmer CE, Nkepu S, van der Wall

rheumatic heart disease. Nat Rev Cardiol 2013; 10: 284–292.

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Factors affecting interest in cardiothoracic surgery among junior surgical residents in Nigeria Emeka B Kesieme, Umar Abubakar, Olugbenga Olusoji, Ismail Mohammed Inuwa, John Kefas, Ndubuisi Anumenechi

Abstract Objective: A survey was undertaken to determine the factors that affect interest in cardiothoracic surgery (CTS) among junior surgical residents in Nigeria. Methods: A cross-sectional study was done using a pilottested, 56-item, semi-structured questionnaire, which was filled in by 238 junior surgical residents in accredited hospitals in Nigeria. Results: Few of the respondents (8.4%) were committed to specialising in CTS. A minority of them, 28.2 and 2.1%, had assisted in major thoracic procedures and open-heart surgeries, respectively. The relationship between the level of training, rotation in CTS in junior residency and interest in CTS were statistically significant (p < 0.05). The main important factors responsible for the low interest in CTS include the lack of equipment (92%), limited training positions (64.9%), poor or lack of exposure in CTS as a junior resident (63%) and in medical school (58.8%). Conclusion: There is a dire need to provide facilities and training opportunities to improve the cardiothoracic workforce in Nigeria. Keywords: open-heart surgery, thoracic surgery, developing countries Submitted 21/4/16, accepted 12/1/17 Published online 1/3/17 Cardiovasc J Afr 2017; 28: 293–297

www.cvja.co.za

DOI: 10.5830/CVJA-2017-004

Department of Surgery, Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria Emeka B Kesieme, MRCS, ekesieme@gmail.com

Department of Surgery, Usmanu Dan Fodio University Teaching Hospital, Sokoto, Sokoto State, Nigeria Umar Abubakar, FWACS

Department of Surgery, Lagos University Teaching Hospital, Lagos, Lagos State, Nigeria Olugbenga Olusoji, FWACS

Department of Surgery, Aminu Kano University Teaching Hospital, Kano, Kano State, Nigeria Ismail Mohammed Inuwa, FWACS

Department of Surgery, Tafawa Belawa University Teaching Hospital, Bauchi, Bauchi State, Nigeria John Kefas, FWACS

Department of Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State, Nigeria Ndubuisi Anumenechi, FWACS

In Nigeria, postgraduate training in surgery is conducted in designated hospitals approved and accredited by the West African College of Surgeons (WACS) and the National Postgraduate Medical College of Nigeria (NPMCN). Junior surgical residents who are interested in cardiothoracic surgery are required to pass Part 1 of the examination of the Faculty of Surgery, WACS or NPMCN in general clinical surgery, after completing a minimum of 24 months’ posting in core surgical specialties. The training in cardiothoracic surgery lasts for a minimum period of 48 months and involves rotations in general thoracic surgery (24 months), cardiac surgery (12 months), vascular surgery (six months), adult and paediatric cardiology (three months) and cardiopulmonary imaging (three months). There are eight centres partially accredited for cardiothoracic surgery speciality training with approximately 30 positions. These centres do mainly thoracic surgery. In the absence of a viable cardiac surgery centre in the country, cardiac surgery rotation is done in recognised centres in Ghana, South Africa, India and Western Europe. The number of candidates who sit for the exit/qualifying examination in cardiothoracic surgery of the WACS and NPMCN has remained small. In April 2015, out of the 95 candidates who attempted the exit/qualification examination (Part 2) of the WACS, only four candidates in the entire Anglophone West Africa sat for the exit examination in cardiothoracic surgery. Only two candidates sat for the exit examination in cardiothoracic surgery of NPMCN in November 2015. This shows apathy towards a career in cardiothoracic surgery among junior surgical residents and a clear preference for other surgical specialities. Cardiothoracic manpower is relatively unavailable in West Africa. In a study by Kesieme et al. in 2011, the number of active cardiothoracic surgeons serving a population of about 160 million people was about 26.1 Only 22% of cardiothoracic surgeons were active in cardiac surgery.1 The availability of cardiac surgeons per million of the population in North America and Europe is more than 10 times the figure for Africa.2 The cost of the diagnosis and treatment of heart disease is way beyond the means of the largely indigent population in Nigeria and West Africa. Hence we carried out this study to rate the interest of junior surgical residents working in Nigeria in cardiothoracic surgery, weigh up their exposure in cardiothoracic surgery, ascertain factors they consider while making decisions on speciality choice, and examine factors that may be strong points or drawbacks in choosing a career in cardiothoracic surgery.

Methods We targeted all the junior surgical residents in the 40 institutions accredited either fully or partially by the faculty of surgery, NPMCN, between April and October 2015. An active trainer was identified in these institutions to help with data collection.

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The data collection was done using the semi-structured questionnaire distributed to junior surgical residents who were doing rotations in the different surgical specialities in preparation for Part 1 of the examination of the Faculty of Surgery, NPMCN or WACS [postgraduate year (PGY) 1–3] or those who had completed their rotation but were yet to pass the examination (PGY > 3). We also used the opportunity provided by the Integrated Clinical and Revision Course in Surgery organised by WACS, between 6 and 9 September 2015 at Jos University Teaching Hospital, Jos, to collect data from some of our study population who we were unable to access. A pilot study was carried out among 15 junior residents in one of the tertiary institutions to improve reliability of the research instruments. Additional inputs were provided by two active cardiothoracic surgeons and two senior residents in cardiothoracic surgery who were not part of the study. The 56-item questionnaire was divided into four sections. The first section included socio-demographic data (age, gender, marital status, number of children and years spent in training). The second section included statements on the overall interest and exposure of the respondents in cardiothoracic surgery (CTS) as medical students and junior surgical residents and the influence of such rotation on their career. We also evaluated their active participation in major cardiothoracic procedures and the role of mentorship in their career. The relationship between the age of the respondents, their marital status, level of training, rotation in CTS in medical school and as a junior surgical resident and the different categories of interest in CTS was assessed. The third section comprised statements evaluating the importance of the following factors in decision of speciality choice. These factors included type of procedures, job and research opportunities, opportunities to teach surgery, exposure to positive role models in the speciality, advice from colleagues, length of training and one that allows time for family. In the fourth section, the respondents were asked to identify the shortcomings in practise of the different surgical specialities with regard to challenges in equipment, challenges in training, job dissatisfaction, income, unfriendly working atmosphere and time-consuming job. They were also asked to identify the factors that would most likely attract or reduce the interest of junior residents to CTS. We retrieved the questionnaires from 238 respondents, accounting for a response rate of 61%. Quantitative statistics assessment was performed using SPSS 16.0 statistical software package (SPSS Inc; Chicago, IL). Categorical data were calculated in frequencies and percentages and the chi-squared test was used to test the level of significance. The level of statistical significance was kept at p < 0.05.

Results Out of 238 respondents who returned their questionnaires, 226 (95%) were males while 10 were females. The gender was not specified in two respondents. One hundred and thirty-seven respondents (57.6%) were in the age range between 31 and 35 years. The majority of respondents (66.8%) were in PGY-2 and more than half of them (52.1%) were married (Table 1). Our respondents were grouped into four categories; 8.4% (n = 20) of the respondents were committed to specialising in CTS,

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28.6% (n = 68) had not yet chosen a speciality but were interested in CTS, 38.7% (n = 92) had considered CTS at some point in their career but would choose another speciality, and 24.4% (n = 58) would neither choose nor were interested in CTS. Among the cardiothoracic sub-specialities, the majority (37%) believed that paediatric cardiac surgery was the most exciting cardiothoracic sub-speciality. This was followed by adult cardiac surgery (21.8%) and general thoracic surgery (20.2%). A minority of respondents (8%) chose other cardiothoracic sub-specialities. Out of the 20 respondents who were committed to specialising in CTS, 15% were in PGY-1, 50% were in PGY-2, 15% were in PGY-3, while 20% were in PGY > 3. Of all the 20 respondents who believed that paediatric cardiac surgery was the most exciting sub-speciality, 13 were committed to CTS. The relationship between the different categories with regard to interest in CTS with level of training (p < 0.001) and the sub-speciality in CTS perceived as most exciting (p < 0.001) were statistically significant. Age, marital status and rotation in medical school did not have a relationship with interest in CTS (Table 2). More than half of the respondents (58%) had identified a mentor in surgery, of whom 7.6% were cardiothoracic surgeons. Those who were committed to CTS were more likely to have had a mentor than those who considered CTS but would choose another speciality (52 vs 44%) or those who would neither choose nor were interested in CTS. One hundred and ten respondents (46.2%) undertook rotation as medical students in a cardiothoracic unit/s managing minor cardiothoracic cases. The average time spent in the rotation was two weeks in 73.1% of respondents. Among those who rotated in CTS, 72% believed that the rotation had a positive influence in their surgical career generally. Only 33.2% of respondents (n = 79) had undertaken posting in CTS as junior surgical residents. In most instances, the posting Table 1. Demographic variables Demographics

Number

Percentage

Age (years) 26–30

24.8

31–35

137

57.6

36–40

14.7

41–45

2.9

Gender Male Female

226

4.1

0.9

Single

108

45.4

Married

124

52.1

2.5

19.7

12.2

6.3

3.8

0.4

PGY-1

16.8

PGY-2

119

PGY-3

20.2

PGY > 3

Not specified Marital status

Not specified Number of children

Level of training 50

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lasted for three months. Most of the junior residents who were committed to undertaking a career in CTS underwent rotation in CTS in medical school and as junior surgical residents. The relationship between the different categories with regard to interest in CTS and rotation in CTS in medical school was however not statistically significant (p = 0.17), whereas that between the different categories and posting in CTS during junior surgical residency was statistically significant (p = 0.01) (Table 2). In most instances, the cardiothoracic surgeons took an interest in the respondents during their posting. A major thoracic procedure had been observed by 50% (n = 119) of junior surgical residents, while only 13.4% (n = 32) had observed an open-heart surgical procedure. Only 28.2% (n = 67) and 2.1% (n = 5) had assisted in major thoracic procedures and open heart surgery, respectively.

Assessment of factors that influence decision of speciality choice Two hundred and nineteen respondents (92%) identified the type of procedure and the techniques involved in a speciality as the most significant factor considered in choice of surgical speciality. This was followed closely by job opportunities, which was identified by 89 respondents. Eighty-four respondents (35.3%) identified the opportunity to engage in a more financially rewarding practice as the third most popular factor (Fig. 1). The length of training and advice from colleagues were not popular factors. The relationship between all factors considered in the decision of speciality choice and the different categories of interest in CTS Table 2. The relationship between the four categories of interest in CTS with age, marital status, level of training, most exciting sub-speciality, and CTS rotation in medical school and as junior residents A

Age (years)

0.367

26–30

31–35

36–40

41–45

PGY-1

Marital status Single Married

0.361

Level of training

0.001

PGY-2

PGY-3

PGY > 3

Most exciting sub-speciality Adult cardiac

p-value

General thoracic

Other CT sub-specialities

–

Not excited by any sub-speciality

–

Yes

Have undertaken CT rotation as a junior resident

Yes

Exposure to positive role model in the speciality Research opportunity Opportunity to teach in a medical school Job opportunities Opportunity to do a more financially ... Types of procedure/techniques involved 0

50 100 150 200 250

Fig. 1. Graph showing factors considered most important in decision of surgical speciality choice.

among junior surgical residents in Nigeria were all statistically significant (p < 0.05). This is an indication that the variations across the categories of interest in CTS were not by chance. The respondents were asked about the most important shortcomings encountered in the practice of the following seven different surgical specialities (CTS, neurosurgery, plastic surgery, orthopaedics, general surgery, urology and paediatric surgery). One hundred and seventy-three respondents (72.7%) believed that the speciality with the greatest challenge with equipment was CTS. CTS was identified by 84 respondents (35.3%) to be second to neurosurgery in having the greatest challenge with training. Neurosurgery was believed to have the greatest shortcomings with regard to job dissatisfaction, unfriendly working atmosphere and being the most time consuming (Fig. 2).

Factors affecting interest in CTS Most of the respondents believed the most important factors that reduce the interest of junior residents in CTS were unavailability or lack of equipment to function as a cardiothoracic surgeon (91.2%), limited training positions (64.7%), poor or lack of exposure in CTS in medical school (58.8%) and poor or lack of exposure in CTS as junior surgical residents (63%) (Fig. 3). Among those who considered CTS but would specialise

Unfriendly working atmosphere

Job dissatisfaction Challenge with training Challenge with equipment 0% 0.176

Length of training Advice from colleagues

Income

0.007

Undertook CT posting in medical school

One that allows time for family

Time consuming 0.001

Paediatric cardiac

295

A: committed to CTS; B: not yet chosen a speciality but interested in CTS; C: considered CTS but will choose another speciality; D: will neither choose nor interested in CTS.

CTS

Neurosurgery

General surgery

20%

40%

Plastic surgery Urology

60%

80% 100% Orthopaedics

Paediatric surgery

Fig. 2. Graph showing shortcomings observed with the practice in different surgical specialties.

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Poor or lack of exposure in CTS rotation in medical school

Access/exposure to positive role models in the speciality Availability of more part-time/ flexible work schedules Evidence of job opportunities that offer workâ&#x20AC;&#x201C;life balance

Poor or lack of exposure in CTS rotation in junior residency

Evidence of long-term job security in CTS

Inadequate remuneration Long duration of training

Reduced length of training

Personalities of CT surgeons Limited training opportunities Unavailability or lack of equipment to practice as a CT surgeon 0

100

150

200

250

Fig. 3. G raph showing the most important factors that junior surgical residents believe reduce interest in cardiothoracic specialisation.

in another surgical discipline, 91.3% ticked unavailability of surgical equipment, accounting for the majority (38.7%) that identified this factor. This can be compared to those who were still to choose a surgical discipline but were interested in CTS (28.1%) and those who were already committed to specialising in CTS (7.8%). Those who considered CTS but would choose another surgical speciality also formed the majority of those who identified limited training positions (37% ), poor or lack of exposure in CTS as a junior resident (38%), and poor or lack of exposure in CTS in medical school (36%) as factors that reduced interest in CTS. Two hundred and eight respondents (87.4%) believed that making more standard training facilities available in CTS in Nigeria would bias junior surgical residents towards pursuing a career in CTS. A large majority also believed that other important factors that could create a bias towards specialising in CTS were broadening the scope of training to include open cardiac cases (71.8%), providing and sponsoring cardiac surgery training and exposure abroad (81.9%), and providing evidence of job opportunities that would offer workâ&#x20AC;&#x201C;life balance (60.9%) (Fig. 4).

Discussion This study revealed a lack of interest among junior surgical residents in Nigeria towards pursing specialisation in CTS. A study done in the USA showed a declining interest among general surgery residents in choosing a career in CTS.3 This is similar to the experience in the UK where recent studies revealed a decline in interest in CTS among UK graduates.4,5 The entry point into a CTS programme in the West African sub-region is similar to that of the UK, where the application for entry is made at the level of PGY-2, unlike in the USA, where most cardiothoracic surgeons complete an initial general surgery training. In Nigeria, no institution has been able to maintain and successfully sustain an open-heart surgery programme, despite a large number of cases requiring open-heart surgery, especially for rheumatic and congenital heart diseases.6-8 In 1974, open-heart surgery started at the University of Nigeria Teaching Hospital, Enugu (UNTH) and by 2002, about 102 surgeries had been recorded.9 The programme subsequently collapsed but fortunately it has recently been resuscitated by foreign medical missions.

Subsidising cost of cardiothoracic procedures Providing and sponsoring overseas cardiothoracic surgery... Broaden scope of training to include open cardiac surgery cases Availability of standard training facilities in the country 0

100

150

200

250

Fig. 4. Graph showing the most important factors that would bias junior surgical residents towards cardiothoracic specialisation.

Falase et al. reported 51 cases performed in Lagos State University Teaching Hospital, Ikeja (LASUTH) between August 2004 and December 2011, with the aid of a mission team. These cases were done despite gross challenges with support facilities and inadequately trained supportive staff.10 It is therefore understandable that only 13.4% of residents have observed cardiac surgery, and 2.1% have assisted in open-heart surgeries. The failure of open-heart surgery programmes in Nigeria has largely been attributed to heavy financial outlay, intensive labour requirements and high resource consumption.6 In addition, the country has headed from oil boom to oil doom. However in nearby Ghana, the National Cardiothoracic Centre, Korle-Bu, reported 464 cases performed annually back in 2008, with 25% being open-heart procedures, especially surgeries for rheumatic and congenital heart diseases.11-13 Unavailability of equipment and lack of training positions are the key or primary factors that have reduced interest in CTS in Nigeria. These have ultimately led to the lack of adequately trained personnel and a fewer number of surgeons practising this speciality. This has resulted in secondary factors, such as poor or lack of exposure in CTS as surgical residents and as medical students. Only 32.2% of residents have therefore done a CTS posting. A higher percentage (46.2%) appeared to have undertaken rotations in CTS, as some units combine general surgery with CTS. Some cardiothoracic specialists also provide services for more than one institution. More residents are also likely to have received their undergraduate training in the larger institutions where there are cardiothoracic programmes. The role of good exposure in CTS in medical school and in junior residency cannot be underestimated. A study by Lussiez et al. revealed that receiving adequate exposure in cardiothoracic procedures and disease management was significantly associated with higher satisfactory ratings in cardiothoracic procedures, especially thoracostomy incisions, empyema and pleural effusions, and lung cancer care.14 Good mentorship and absence of maltreatment were also positively correlated with good exposure.14 Good exposure in CTS in medical school may therefore play a role in biasing residents towards a career in CTS. For instance, Trehan et al. revealed that one-third of medical students who received a

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scholarship in CTS maintained their interest over time, and more than half maintained their interest in a surgical speciality.15 On account of these demographics and attitudes towards thoracic surgery, many foreign surgical societies have intensified efforts to attract medical and pre-medical students to a career in CTS. Cardiothoracic surgeons should identify and encourage those interested in CTS, and provide the necessary advice and mentorship.16 In the UK, the professional insecurity brought about by publication of surgeon-specific mortality data and the poor publicity surrounding cardiothoracic surgery is believed to be responsible for the decline in CTS among UK graduates.4 Bridgeman et al. also believed that relative lack of engagement with medical students is an additional factor.17 Vaporciyan et al. surveyed the factors affecting the interest in CTS among general surgery residents in the USA, and they noted that the dominant concern was job availability and security. Other important factors were mentorship and exposure to the CTS faculty.3 Lack of jobs, especially in the private sector, may have been responsible for the increased number of surgeons who sub-specialised in adult cardiac, paediatric cardiac, thoracic and transplantation surgery.18 The reasons for a decline in interest in CTS among junior surgical residents in Nigeria differed from those obtained from similar studies in developed countries. In the setting of a few thoracic surgeons in a densely populated country such as Nigeria, job availability is not likely to be an issue, as many university hospitals do not have a single thoracic surgeon.

lenge of congenital heart disease worldwide: epidemiologic and demographic facts. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2010; 13: 26–34. 3.

Vaporciyan AA, Reed CE, Erikson C, Dill MJ, Carpenter AJ, Guleserian KJ, et al. Factors affecting interest in cardiothoracic surgery: survey of North American general surgery residents. J Thorac Cardiovasc Surg 2009; 137: 1054–1062.

Westaby S, Baig K, De Silva R, Unsworth-White J, Pepper J. Recruitment to UK cardiothoracic surgery in the era of public outcome reporting. Eur J Cardiothorac Surg 2015; 47: 679–683.

Pepper JR, Coonar AS. High-risk surgery: the courage to fail. J R Soc Med 2015; 108: 44–46.

Adebonojo SA. Open Heart Surgery in Nigeria. In: Development of Open Heart Surgery in West Africa; A Historical Perspective. Nigeria: Acecool Medical Publishers, 2012: 35–36.

Okoromah CA, Ekure EN, Ojo OO, Animasahun BA, Bastos MI. Structural heart disease in children in Lagos: profile, problems and prospects. Niger Postgrad Med J 2008; 15: 82–88.

Omokhodoin SI, Lagunju IA. Prognostic indices in children heart failure. West Afr J Med 2005; 24: 325–328.

Eze JC, Ezemba N. Open-heart surgery in Nigeria: indications and challenges. Tex Heart Inst J 2007; 34: 8–10.

10. Falase B, Sanusi M,Majekodunmi A, Animasahun B, Ajose I, Idowu A, et al. Open heart surgery in Nigeria; a work in progress. J Cardiothorac Surg 2013; 8: 6. doi:10.1186/1749-8090-8-6. 11.

Edwin F, Tettey M, Aniteye E, Tamatey M, Sereboe L, Entsua-Mensah K, et al. The development of cardiac surgery in West Africa – the case of Ghana. Pan Afric Med J 2011; 9: 15. doi:10.11604/pamj.2011.9.15.848.

12.

Edwin F, Sereboe LA, Tettey MM, Aniteye E, Kotei D, Tamatey M, et al. Experience from a single centre concerning the surgical spectrum and

Conclusion In Nigeria, CTS is unattractive to junior surgical residents. There is a need for government to improve sponsorship and provide facilities to commence, maintain and sustain open-heart surgery programmes. There is a need for cardiothoracic societies in Africa to do more to provide opportunities to help and encourage medical students and junior residents. Cardiothoracic surgeons also need to identify and encourage those committed to pursuing a career in CTS and provide better mentorship to those who still have a chance of specialising in CTS.

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outcome of adolescents and adults with congenitally malformed hearts in West Africa. Cardiol Young 2010; 20: 159–164. 13.

Edwin F, Aniteye E, Tettey MM, Tamatey M, Frimpong-Boateng K. Outcome of left heart mechanical valve replacement in West African children – A 15-year retrospective study. J Cardiothorac Surg 2011; 6: 57.

14.

Lussiez A, Bevins J, Plaska A, Rosin V, Reddy RM. General surgery resident satisfaction on cardiothoracic rotations. J Surg Educ 2015; pii: S1931–7204(15)00224-X. doi: 10.1016/j.jsurg.2015.09.002 .

15. Trehan K, Zhou X, Yang SC. Is medical student interest in cardiothoracic surgery maintained after receiving scholarship awards? Ann Thorac Surg 2015; 100: 926–931.

The authors thank all the surgeons who assisted us in distributing and retrieving the questionnaires.

16. Merrill WH. Preparing the next generation of residents to care for patients with cardiothoracic disease. Tex Heart Inst J 2012; 39: 878–879. 17. Bridgeman A, Findlay R, Devnani A, Lim D, Loganathan K, McElnay

References 1.

Kesieme EB, Kesieme CN, Ekpe EE, Delia IZ. Attitude of cardiotho-

P, et al. Inspiring the next generation of cardiothoracic surgeons: an easily reproducible, sustainable event increases UK undergraduate interest in the specialty. Interact CardioVasc Thorac Surg 2015: 1–3.

racic surgeons in the West African subregion to the management of

18. Wheatley GH, Lee R. Where have all the cardiothoracic surgery resi-

patients with human immunodeficiency virus. J AIDS HIV Res 2011;

dents gone? Placement of graduating residents by United States thoracic

3:79–84.

surgery training programs, 1998 to 2002. Heart Surg Forum 2006; 9:

Bernier PL, Stefanescu A, Samoukovic G, Tchervenkov CI. The chal-

E618–22.

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Atorvastatin inhibits cholesterol-induced caspase-3 cleavage through down-regulation of p38 and up-regulation of Bcl-2 in the rat carotid artery Roshanak Bayatmakoo, Nadereh Rashtchizadeh, ParichehrehYaghmaei, Mehdi Farhoudi, Pouran Karimi

Abstract Aim: Atherosclerotic lesions in the carotid arteries lead to a broad range of cerebrovascular disorders such as vascular dementia and ischaemic stroke. Recent studies have verified the beneficial role of atorvastatin (AV) in atherosclerosis. Despite a large body of studies, the mechanisms underlying this effect have not been completely explained. In this study, several experiments were performed on atherosclerotic rat models to investigate the anti-inflammatory and anti-apoptotic effect of AV in the carotid artery. Methods: In this experimental study, 40 male Wistar rats (250 ± 25 g) were randomly divided into four groups: rats on a normal diet (ND; n = 10); a high-cholesterol diet (HD; n = 10); a high-cholesterol diet plus AV (HD + AV; n = 10); and the AV control group (AV; n = 10). Cleavage of caspase-3 protein, expression of B-cell lymphoma 2 (Bcl-2) as well as phosphorylation of p38 mitogen-activated protein kinase (MAPK) were determined by immunoblotting assay in the carotid artery homogenate. Plasma atherogenic indices, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured by colorimetric assay at the end of the experiment. Plasma levels of oxidised LDL (oxLDL) were measured by sandwich enzyme-linked immunosorbent assay (ELISA). Results: After eight weeks of feeding with a high-cholesterol diet, an elevated level of oxLDL was observed in the plasma in the HD group compared with the ND group [214.42 ± 17.46 vs 69.13 ± 9.92 mg/dl (5.55 ± 0.45 vs 1.78 ± 0.26 mmol/l); p < 0.01]. AV administration significantly reduced oxLDL levels in the HD + AV compared to the HD group [126.52 ± 9.46 vs 214.42 ± 17.46 mg/dl (3.28 ± 0.25 vs 5.55 ± 0.45 mmol/l); p < 0.01]. Results also showed that compared with the HC group, the HC + AV group had lower levels of p38 phosphorylation (p < 0.05) and higher levels of Bcl-2 expression (p < 0.05).

Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran Roshanak Bayatmakoo, PhD ParichehrehYaghmaei, PhD

Biotechnology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran Nadereh Rashtchizadeh, PhD, rashtchizadeh@rocketmail.com

Neurosciences Research Centre (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran Mehdi Farhoudi, MD Pouran Karimi, PhD

Lower levels of cleaved caspase-3 were observed in the HC + AV group in comparison with the HC group (p < 0.05). Conclusions: The resultant data suggest that the anti-apoptotic effect of AV could be partially mediated by the pro-inflammatory protein p38 MAPK and the anti-apoptotic protein Bcl-2 in the rat carotid artery. Atorvastatin can therefore be considered a target drug in the prevention or development of atherosclerotic events. Keywords: atherosclerosis, Bcl-2 protein, cholesterol, caspase-3, p38 mitogen-activated protein kinase Submitted 28/5/16, accepted 12/1/17 Published online 10/5/17 Cardiovasc J Afr 2017; 28: 298–303

www.cvja.co.za

DOI: 10.5830/CVJA-2017-005

Atherosclerosis is a chronic inflammatory disease involving multiple pathways. It is characterised by atheromatous plaque consisting of a lipid-core lesion located in the sub-intima of the bifurcation of large and medium-sized arteries, such as the carotid and aorta.1,2 Accumulation of low-density lipoproteins (LDLs) and their oxidised form (oxLDLs), as major carriers of cholesterol, initiate atherogenic events that are followed by the recruitment of inflammatory blood cells.1 The results of in vitro studies have revealed that oxidised LDL causes injury to the endothelial cells (EC),3 the mechanism of which is unknown, resulting in necrosis or apoptosis.4 Apoptosis refers to the morphological changes exhibited by ‘actively’ dying cells, including DNA fragmentation, chromatin condensation, membrane blebbing and cell shrinkage,5 whereas necrosis is rupture of the plasma membrane and cell lysis following cellular swelling.4 The signal transduction leading to apoptosis is characterised by a complex array of biochemical pathways, including inflammation, mitochondrial dysfunction and cell proliferation.6 Moreover, triggering of mitogen-activated protein kinase (MAPK), which is a classic inflammatory cascade, is required for oxLDL-attributed induction of apoptosis.7 Dysregulation of the MAPK pathway during atherosclerosis leads to modified gene expression, which facilitates disease processes.3 Three major members of the MAPK family that are entirely involved in atherogenic events are extracellular signal-regulated kinase (ERK), c-Jun kinase (JNK) and p38 MAPK. Among them, p38, a well-known stress kinase, controls foam cell formation and programmed cell death in macrophages, and facilitates the expression of chemokines and adhesion molecules in the endothelial cells.3

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Recent studies suggest that JNK induces apoptosis by directly phosphorylating BA, BimEL, and BimL.8-13 In addition, JNK also phosphorylates and thus inactivates the anti-apoptotic Bcl-xL and Bcl-2.14-16 In contrast to augmented studies on the regulation of Bcl-2 family members by JNK, there is no proof that p38 regulates apoptosis through direct activation/inactivation of Bcl-2 family proteins.6,17 Moreover, Bcl-2 protein is a major regulator of the intrinsic apoptosis signalling pathway. In recent years it has been elucidated that it modulates the apoptotic events in vascular cells.7,18 Activation of caspase-3 plays a unique role in apoptosis and is considered the final step prior to DNA fragmentation. Caspase-3 triggers apoptotic DNA fragmentation by cleaving DFF45 (DNA fragmentation factor 45) or ICAD (inhibitor of caspase-activated DNase), which is changed to active DFF40/ CAD (caspase-activated DNase). Statins, as classic inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, have been shown to potentiate decreased plasma levels of cholesterol and the ratio of oxLDL to native LDL, leading to attenuation of the development of atherosclerosis.19 Recently, the non-cholesterol-lowering effect of statins, including their effect on platelet adhesion,20 cytokine release,14 and anti-inflammatory effects21 have been explored. Atorvastatin (AV) is a lipophilic member of the statin family and is mainly recommended for the treatment of hypercholesterolaemia. It has been shown to have antiinflammatory benefits in the coronary arteries,3,19,22 but the effect of AV on the carotid arteries is seldom investigated. Since inflammation and apoptosis are common events in atherosclerosis, we speculated that AV may attenuate cholesterol-induced injuries in carotid tissue via its influence on inflammation and apoptosis in the carotid arteries. We therefore evaluated the effects of AV on the MAPK signalling pathway and apoptosis in this tissue.

Methods In this applied, experimental study, 40 male Wistar rats (250 ± 25 g) were obtained from the breeding colony of the Pasteur Institute, Karaj, Iran. The experiment was carried out in 2015 in the laboratories of the Neurosciences Research Centre (NSRC) located at Tabriz University of Medical Sciences, Tabriz, Iran. The study was approved by the ethics committee of Tabriz University of Medical Sciences (approval number: A125345) and conformed to the Guidelines of the National Institute of Health for the Care and Use of Laboratory Animals (NIH Publications No. 80-23). The animals were kept under controlled conditions at 22 ± 1°C with a 12-hour light:dark cycle and 50–55% relative humidity. They had free access to standard rodent chow and water, and were housed in individual cages for 96 hours before use. Atorvastatin (purity ≥ 98%) (Lipitor®; Pfizer Inc, New York, NY, USA), cholesterol (purity > 99.9%), and the protease inhibitor cocktail were purchased from Sigma-Aldrich (St Louis, MO, USA). Rabbit anti-Bcl-2, anti-phospho-p38 (antiP-p38), anti-p38, HRP-conjugated goat anti-rabbit, anti-cleaved caspase-3 and anti-B-actin polyclonal antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). All biochemical kits for colorimetric assays of plasma lipid profiles were purchased from Zist Chimi Inc (Tehran, Iran).

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We used simple randomisation by coin to divide the rats into four dietary groups: normal diet (ND; n = 10), high-cholesterol diet (HD; n = 10), high-cholesterol diet plus AV (HD + AV; n = 10) and the AV control group (AV; n = 10). HD rats received the normal chow diet plus 2% cholesterol (Sigma-Aldrich, No: C8667) whereas the ND group was fed only the normal chow diet. Rats in the AV and HD + AV groups were given AV (20 mg/kg) dissolved in 2 ml warm water before intra-gastric administration.23 All animals had access to food and water ad libitum daily during the experiment. After eight weeks of feeding the HD diet with the administration of AV, the rats were intraperitoneally anesthetised using xylazine (4 mg/kg; Sigma-Aldrich) and ketamine hydrochloride (10%, 40 mg/kg; Sigma-Aldrich). Following ligation of the left and right common carotid arteries (CCAs), blood samples were withdrawn directly from the heart of the rats and collected in a serum separator tube. The blood was allowed to coagulate for two hours at room temperature and centrifuged (Beckman model L centrifuge) at 3 000 × g for 20 minutes. The serum was saved for biochemical analyses. The CCAs were removed, put into liquid nitrogen and kept at –70°C for immunoblotting analysis. Biochemical measurement of plasma levels of triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were determined photometrically in a Vitros 5600 autoanalyser (Ortho-Clinical Diagnostics Inc, USA) in the endpoint manner using Ziest Chimi kits (Tehran, Iran). To calculate LDL-C levels, Friedewald’s formula24 was applied as follows: TC (mg/dl) – TG (mg/dl)

____________________ 25    LDL-C (mg/dl) =      5 – HDL-C (mg/dl)  .

Western blotting technique was used to evaluate the expression of bcl-2, cleaved caspase-3 and phospho-p38 proteins, based on the Santa Cruz online protocol. A 10% carotid tissue homogenate in RIPA lysis buffer (Sigma) containing protease inhibitor cocktail (Sigma-Aldrich) was prepared after being centrifuged (SW14R, Froilabo, France) at 4°C and 13 000 × g for 15 minutes. Protein concentration was measured using the Bradford assay (Bio-Rad Laboratories, CA, USA); 10 µg protein was loaded into each well of 4–10% SDS polyacrylamide gel. Following electrophoresis, proteins were blotted onto the membrane (polyvinylidene fluoride, Bio-Rad) and blocked in 3% bovine serum albumin (BSA) in phosphate-buffered saline (PBS) and 0.1% Tween 20 (PBST). Membranes were blotted overnight at 4°C with the following primary antibodies diluted in PBST containing 0.1% Tween: anti-Bcl-2 (N-19) (1:500; catalogue number sc-492), anti-cleaved caspase-3 p11 (h176)-R (1:500; catalogue number sc-22171-R) or anti-P-p38 antibody (Tyr 182) (1:500; catalogue number sc-101759) and anti-p38 antibody (1:500; catalogue number sc-535). After a rinsing step with PBST, the membrane was incubated with a secondary antibody (HRP-conjugated goat anti-rabbit) (1:5000; catalogue number sc-2004).The membranes were then rinsed in PBST containing 0.05% Tween. The immune complex was detected with a chemiluminescence method using ECL-plus kits (GE Healthcare, USA). B-actin protein expression was used as the loading control. The intensity of the bands was determined and analysed with the Spectrum multispectral imaging system by the Vision Work LS image acquisition and analysis software (UVP, Germany).

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Plasma levels of oxLDL were measured by ELISA using a specific ELISA kit (MBS729489, My BioSource Ltd, USA). The coefficient of variation for the assay was 4.4 to 5.6. The coated monoclonal antibody (mAb) was against a conformational epitope in the apolipoprotein B-100 (apoB-100) moiety of LDL. All procedures were carried out according to the manufacture’s instruction. Briefly, the mAb-coated wells were loaded with 50 µl standards or samples. In order to determine quantitative amounts of oxLDL in the sample, polyclonal antibody (conjugated to horseradish peroxidase) specific for oxLDL, was added to each well. The wells underwent washing three times with PBS following incubation for one hour at room temperature. TMB substrate solution was then added and allowed to react for 20 minutes. The chromogenic reaction was halted by adding the stop solution. The absorbance of the wells was read using a spectrophotometer (Awareness, USA) at 450 nm. The amount of oxLDL concentration in each sample was determined using a standard curve (x = concentration and y = optical density).

Statistical analysis The required sample sizes were obtained based on a previous article so no statistical methods were used to determine sample sizes.26 Resultant data are presented as means ± standard deviation (SD). The means of the variables and the differences in mean values between the groups were evaluated using the Mann– Whitney U-test. A p-value of < 0.05 was considered significant.

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200

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Results We intended to determine perturbations in the plasma lipid profile of the rats in each group to confirm the induction of hypercholesterolaemia after 20 weeks of treatment. As shown in Fig. 1, the serum total cholesterol levels of the HD group were approximately three-fold higher than those of the ND group [229.35 ± 13.26 vs 67.89 ± 5.14 mg/dl (5.94 ± 0.34 vs 1.76 ± 0.13 mmol/l); p < 0.01]. The serum levels of LDL-C in the HD group were more than 10-fold higher than those in the ND group [177.39 ± 10.38 vs 15.20 ± 2.34 mg/dl (4.59 ± 0.27 vs 0.39 ± 0.06 mmol/l); p < 0.05]. A slight but non-significant decrease was also observed in HDL-C levels [31.27 ± 4.69 vs 33.66 ± 2.90 mg/dl (0.81 ± 0.12 vs 0.87 ± 0.08 mmol/l); p = ns]. The cholesterol-lowering activity of AV was also evaluated. As shown in Fig. 1, AV displayed a strong cholesterol-lowering activity at a dose of 20 mg/kg. Serum levels of total cholesterol in the HD + AV group decreased approximately 50% in comparison with those of the HD group [119.00 ± 9.187 vs 229.35 ± 13.26 mg/dl (3.08 ± 0.24 vs 5.94 ± 0.34 mmol/l); p < 0.01]. The serum levels of LDL-C in the HD + AV group decreased 75% in comparison to those of the HD group [44.284 ± 6.905 vs 177.398 ± 10.386 mg/dl (1.15 ± 0.18 vs 4.59 ± 0.27 mmol/l); p < 0.01]. The plasma levels of oxLDL were significantly increased in the HD versus the ND group [214.42 ± 17.46 vs 69.13 ± 9.92 mg/dl (5.55 ± 0.45 vs 1.79 ± 0.26 mmol/l); p < 0.01] but AV diminished the plasma levels of oxLDL in the HD + AV group compared to the AV group [126.52 ± 9.46 vs 214.42 ± 17.46 mg/dl (3.28 ± 0.25 vs 5.55 ± 0.45 mmol/l)] (Fig. 2). The protein expression of cleaved caspase-3 and bcl-2, and phosphorylation of p38 were determined to ascertain whether cholesterol induced apoptosis. The protein expression levels of cleaved caspase-3 were measured by Western blotting analysis. Based on the results, cholesterol increased the cleavage of caspase-3

** 250

mg/dl

150 ##

200

Serum-ox (ng/dl)

100

* 0

Total serum cholesterol (mg/dl) HDL-cholesterol (mg/dl)

HD + AV

100

LDL-cholesterol (mg/dl) HDL/LDL

150

VLDL (mg/dl)

Fig. 1. B ar graph showing the attenuating effect of administration of oral atorvastatin (20 mg/kg for eight weeks) on cholesterol-induced serum lipid profiles of triglycerides (TG), total cholesterol (TC), HDL-C and LDL-C in hypercholesterolaemic rats. Data are presented as mean ± SD; n = 10. *p < 0.05, **p < 0.001 compared with normal diet group; #p < 0.05, ##p < 0.001 compared with hypercholesterolaemic rats using the ANOVA test. ND = normal diet, HD = high-cholesterol (2%) diet, HD + AV = high-cholesterol diet plus AV (20 mg/kg), and AV = AV control group.

HD + AV

Fig. 2. Box plot showing the reducing effect of administration of oral atorvastatin (20 mg/kg for eight weeks) on cholesterol-induced plasma oxLDL levels. Data are presented as mean ± SD; n = 10. **p < 0.001 compared with normal diet group; ##p < 0.001 compared with hypercholesterolaemic rats using the ANOVA test. ND = normal diet, HD = high-cholesterol (2%) diet, HD + AV = high-cholesterol diet plus AV (20 mg/kg ) and AV = AV control group.

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A Cleaved caspase 3

17 kd

Phosphor-p38

40 kd

Bc12

29 kd

Total p38

40 kd

Bactin

42 kd

B 250

200 **

150

p-p38/total p38 (% of control)

Cleaved caspase 3/Bactin (% of control)

200

100

HD + AV

100 ##

80 60

40 20

HD + AV

Fig. 4. Down-regulation of phosphor-p38 MAPK in the carotid artery of an atherosclerotic rat model after administration of oral atorvastatin (20 mg/kg for eight weeks). A. immunoblotting of phosphor-p38 MAPK, and p38 MAPK in ND, HD, HD + AV and AV groups. B. Quantitation of immunoblotting of phosphor-p38 MAPK. Values are shown as the mean ± SD of six animals in each group. *p < 0.05.

120 Bcl-2/Bactin (% of control)

100

Fig. 3. D own-regulation of cleaved caspase-3 and up-regulation of Bcl-2 in the carotid artery of an atherosclerotic rat model after administration of oral atorvastatin (20 mg/kg for eight weeks). A. Immunoblotting of cleaved caspase-3, Bcl-2, and Bactin in ND, HD, HD + AV and AV groups. B. Quantitation of immunoblotting of cleaved caspase-3. C. Quantitation of immunoblotting of Bcl-2. Values are shown as the mean ± SD of six animals in each group. *p < 0.05.

but AV attenuated the cleaved caspase-3 level in the carotid tissue of hypercholesterolaemic rats (Fig. 3B). Furthermore, to determine whether bcl-2 protein interfered in the cholesterol-induced cleavage of caspase-3, the protein expression levels of bcl-2 were evaluated in all groups. The results showed a significant decrease in bcl-2 level in the HD versus the ND group. Moreover, AV prevented this suppression (Fig. 3C). We then determined the phosphorylation state of p38, a stress kinase, after AV treatment, and found that AV significantly decreased cholesterol-induced phospho-p38 (Fig. 4).

Discussion Dysregulation of plasma metabolites and tissue apoptosis are common features of a wide range of degenerative disorders

such as atherosclerosis. Risk factors for atherosclerosis, such as oxidative stress, inflammation, hypercholesterolaemia, central obesity and abnormal levels of coagulants often co-exist. Our experimental study explored the evidence that AV therapy (20 mg/kg), besides its cholesterol-lowering effects, decreased inflammatory and apoptotic events in the carotid artery of an atherosclerotic rat model. We produced the moderate atherosclerotic rat model with the administration of 2% cholesterol [TC = 229.35 ± 13.26 mg/dl (5.94 ± 0.34 mmol/l)], compared with the study by Samout et al. of 1% cholesterol [TC = 90.71 ± 3.08 mg/dl (0.25 ± 0.08 mmol/l)] and that of Beason et al. of 4% cholesterol (TC = 595 ± 429 mg/dl (15.41 ± 11.11 mmol/l).26,27 We used this model to investigate the expression of inflammation and apoptosis-related proteins in the carotid tissue of hypercholesterolaemic rats after receiving AV. We did not carry out a histopathological study on the carotid tissue, but based on a previous study, even a 1% cholesterol-rich diet is capable of damaging the blood vessels and initiating atherosclerotic events.28 Ntchapda et al. showed extensive atherosclerotic plaques were created in almost the whole upper part of the hypercholesterolaemic rat aorta, which was not the case with the normocholesterolaemic rats.28 In our study, cholesterol-induced hyperlipidaemia was clearly attenuated after eight weeks of statin treatment. This was because of the cholesterol-lowering effect of AV,29 via inhibition of HMG-CoA reductase, the check-point step in cholesterol synthesis.14 Moreover, previous studies have shown

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that up-regulation of LDL receptors on the cell surface is another event that consequently leads to decreased plasma levels of atherogenic LDL particles.21 On other hand, based on our findings, cholesterol-induced oxidative stress in the form of plasma oxLDL could be decreased by AV administration, which was confirmed by prior studies.30 Zhang et al. indicated that AV prevented oxLDL-induced oxidative stress in cardiomyocytes via a decrease in plasma levels of oxLDL, inhibition of expression of LOX-1 as oxLDL receptors, and apoptosis.30 More recently, Mason et al. showed that in vitro eicosapentaenoic acid (EPA), a triglyceride-lowering agent, inhibited LDL oxidation, and the addition of AV at low concentrations enhanced this inhibition.31 Accumulating data from in vitro and in vivo models support the pro-atherogenic role of oxLDLs via: (1) recruitment of polymorphonuclear cells, promoting their transformation into foam cells; (2) induction of the proliferation of smooth muscle cells (SMCs) in the tunica intima; and (3) promotion of apoptosis in the endothelial cells, SMCs and macrophages.6 Therefore the oxLDL-lowering potential of AV leads to clinical benefits by attenuating cardiovascular events.32 Reduction in oxLDL levels subsequently controls its downstream effectors, such as stress kinases of p38 MAPK and JNK, which consequently reduce scavenger receptors and foam cell formation.33 Confirming previously reported evidence,14,21,32 in our experiments, AV down-regulated cholesterol-induced p38 phosphorylation, which is a pro-inflammatory marker and stress kinase, in the carotid homogenate of hypercholesterolaemic rats. In line with our results, in a concomitant study on the effects of ATO on thrombomodulin (TM), which is critical for vascular thromboresistance, Lin et al. showed in the aorta of cholesterol-fed rabbits, that statins could protect the vasculature from p38-mediated inflammatory damage and that atherosclerosis resulted from cholesterol-dependent or independent mechanisms.34 In the study by Rutishauser et al., they showed the beneficial effects of statins on hypertension-induced vascular damage by inhibition of angiotensin II-induced intracellular responses, containing p38 MAPK and RhoA/ROCK activation.19 In another study, researchers showed that oxidative stress induced NADPH oxidase production, and p38 MAPK signalling was prevented by statin treatment.35 As shown in Fig. 3, cholesterol-induced cleavage of caspase-3 in carotid tissue suggests that activation of the caspase-dependent apoptotic pathway could be negatively influenced by AV, which is similar to the results of our study. Chen et al., in an experimental rat model of acute myocardial infarction, showed that AV improved left ventricular function and decreased infarct size compared with the control group, along with reduction in the index of cell apoptosis.36 Apoptosis is a central component in the pathophysiology of atherosclerosis and is mediated by extrinsic or intrinsic signalling pathways. Bcl-2 proteins act as the major mediators of both apoptosis signalling pathways. Recently it has become clear that they regulate apoptosis in vascular cells following oxidative and inflammatory events, not only by down-regulation of antiapoptotic proteins of Bcl-2 but also by up-regulation of the pro-apoptotic protein of Bax or Bad proteins.23 Other findings in our study were that restoration of the anti-apoptotic protein of Bcl-2 occurred after administration of AV. This result is in agreement with previous studies.8,30 Kutuk

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et al. considered Bcl-2 protein an important target drug in the treatment of atherosclerosis.16 The study by Fröhlich et al. indicated that Bcl-2 had a protective role in fully differentiated ReNcell VM cells.8 However, in the study by Peng et al., inhibition of the proliferation of PC3 human prostate cancer cells has been shown via negative regulation of Bcl-2 and positive regulation of p21.9 The endoplasmic reticulum (ER), as an important cellular organelle, is implicated in various vital functions of cells,10 such as protein folding and translocation,11 lipogenesis and control of calcium balance.12 The Bcl-2 family, which is found in the ER, controls the many signalling pathways and therefore cell survival.13 ER-situated anti-apoptotic proteins such as Bcl-xL and Bcl-2 prevent the effect of a wide range of apoptosis inducers.18 Mitochondrial and ER apoptosis signalling pathways can lead to cleavage and activation of caspase-3, a major killer caspase.18 The definite output of caspase-3 cleavage is DNA fragmentation, and subsequently programmed cell death.16

Conclusion The findings of our study, including the beneficial effects of atorvastatin in the suppression of cholesterol-induced cleaved caspase-3 and the concomitant elevation of Bcl-2 and reduction of phosphorylated p38 MAPK, suggest that the anti-apoptotic effect of atorvastatin may be partially mediated by either p38 MAPK or Bcl-2.18,22 They also suggest that p38 MAPK, a pro-inflammatory protein and Bcl-2, an anti-apoptotic protein, could be targeted in the prevention of cholesterol-induced atherosclerotic events in the carotid tissue by atorvastatin. We thank Dr Farhoudi, head of the Neurosciences Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran, for providing the facilities for our experiments.

References 1.

Salvayre R, Negre-Salvayre A, Camaré C. Oxidative theory of atherosclerosis and antioxidants. Biochimie, 2016; 125: 281–296.

Conti P, Shaik-Dasthagirisaeb Y. Atherosclerosis: a chronic inflammatory disease mediated by mast cells. Central Eur J Immunol 2015; 40(3): 380–386.

Buckley ML, Ramji DP. The influence of dysfunctional signaling and lipid homeostasis in mediating the inflammatory responses during atherosclerosis. Biochim Biophys Acta 2015; 1852(7): 1498–1510.

Maiolino G, Rossitto G, Caielli P, Bisogni V, Rossi GP, Calo LA. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm 2013; 2013: 714653.

Oyinloye BE, Adenowo AF, Kappo AP. Reactive oxygen species, apoptosis, antimicrobial peptides and human inflammatory diseases. Pharmaceuticals 2015; 8(2): 151–175.

Husain K, Hernandez W, Ansari RA, Ferder L. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem 2015; 6(3): 209–217.

Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm 2013; 2013: 152786.

Fröhlich M, Jaeger A, Weiss DG, Kriehuber R. Inhibition of BCL-2 leads to increased apoptosis and delayed neuronal differentiation in human ReNcell VM cells in vitro. Int J Devel Neurosci 2016; 48: 9–17.

Peng X, Li W, Yuan L, Mehta RG, Kopelovich L, McCormick DL.

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Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21. PloS One 2013; 8(8): e70442. 10. Besbes S, Mirshahi M, Pocard M, Billard C. New dimension in therapeutic targeting of Bcl-2 family proteins. Oncotarget 2015; 6(15): 12862–12871. 11. Lindstrom R, Lindholm P, Kallijarvi J, Palgi M, Saarma M, Heino TI. Exploring the conserved role of MANF in the Unfolded protein response in Drosophila melanogaster. PloS One 2016; 11(3):e0151550.

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Toxicol 2015; 83: 36–47. 25. Sanbe T, Tomofuji T, Ekuni D, Azuma T, Irie K, Tamaki N, et al. Vitamin C intake inhibits serum lipid peroxidation and osteoclast differentiation on alveolar bone in rats fed on a high-cholesterol diet. Arch Oral Biol 2009; 54(3): 235–240. 26. Samout N, Bouzenna H, Ettaya A, Elfeki A, Hfaiedh N. Antihypercholesterolemic effect of Cleome arabica L. on high-cholesterol diet induced damage in rats. Exp Clin Sci J 2015; 14: 791–800. 27. Beason DP, Hsu JE, Marshall SM, McDaniel AL, Temel RE, Abboud

12. Xi Y, Shen W, Ma L, Zhao M, Zheng J, Bu S, et al. HMGA2

JA, et al. Hypercholesterolemia increases supraspinatus tendon stiffness

promotes adipogenesis by activating C/EBPbeta-mediated expression

and elastic modulus across multiple species. J Shoulder Elbow Surg 2013;

of PPARgamma. Bioch Biophys Res Commun 2016; 472(4): 617–623. 13. Anilkumar U, Prehn JH. Anti-apoptotic Bcl-2 family proteins in acute neural injury. Frontiers Cellr Neurosci 2014; 8: 281. 14. Van Vre EA, Ait-Oufella H, Tedgui A, Mallat Z. Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32(4): 887–893 15. Yang J, Pan Y, Li X, Wang X. Atorvastatin attenuates cognitive deficits through Akt1/caspase-3 signaling pathway in ischemic stroke. Brain Res 2015; 1629: 231–239. 16. Kutuk O, Basaga H. Bcl-2 protein family: implications in vascular apoptosis and atherosclerosis. Apoptosis 2006; 11(10): 1661–1675. 17. Rodrigues Diez R, Rodrigues-Diez R, Lavoz C, Rayego-Mateos S,

22(5): 681–686. 28. Ntchapda F, Djedouboum A, Talla E, Sokeng Dongmo S, Nana P, Adjia H, et al. Hypolipidemic and anti-atherogenic effect of aqueous extract leaves of Ficus glumosa (Moraceae) in rats. Exp Gerontol 2015; 62: 53–62. 29. Pal S, Sarkar A, Pal PB, Sil PC. Protective effect of arjunolic acid against atorvastatin induced hepatic and renal pathophysiology via MAPK, mitochondria and ER dependent pathways. Biochimie 2015; 112: 20–34. 30. Zhang L, Cheng L, Wang Q, Zhou D, Wu Z, Shen L, et al. Atorvastatin protects cardiomyocytes from oxidative stress by inhibiting LOX-1 expression and cardiomyocyte apoptosis. Acta Biochim Biophys Sinica 2015; 47(3): 174–182.

Civantos E, Rodriguez-Vita J, et al. Statins inhibit angiotensin II/Smad

31. Mason RP, Sherratt SC, Jacob RF. Eicosapentaenoic acid inhibits

pathway and related vascular fibrosis, by a TGF-beta-independent

oxidation of ApoB-containing lipoprotein particles of different size

process. PloS One 2010; 5(11): e14145.

in vitro when administered alone or in combination with atorvastatin

18. Hosomi N, Nagai Y, Kohriyama T, Ohtsuki T, Aoki S, Nezu T, et al. The Japan Statin Treatment Against Recurrent Stroke (J-STARS): a multicenter, randomized, open-label, parallel-group study. EBioMedicine 2015; 2(9): 1071–1078. 19. Rutishauser J. The role of statins in clinical medicine – LDL-cholesterol lowering and beyond. Swiss Med Weekly 2006; 136(3–4): 41–49. 20. Sacco RL, Liao JK. Drug Insight: statins and stroke. Nature Clin Prac Cardiovasc Med 2005; 2(11): 576–584. 21. Hu LH, Zhang T, Shao Q, Li DD, Jin SX, Nie P, et al. Atorvastatin suppresses oxidized LDL-induced dendritic cell-like differentiation of RAW264.7 cells regulated by the p38 MAPK pathway. Molec Cell Biochem 2012; 371(1–2): 105–113. 22. Yang JW, Hu ZP. Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress. Neural Regen Res 2015; 10(8): 1239–1244. 23. Abo El-Khair DM, El-Safti Fel N, Nooh HZ, El-Mehi AE. A comparative study on the effect of high cholesterol diet on the hippocampal CA1 area of adult and aged rats. Anat Cell Biol 2014; 47(2): 117–126.

active metabolite compared with other triglyceride-lowering agents. J Cardiovasc Pharmacol 2016; 68(1): 33–40. 32. De la Sierra A, Pinto X, Guijarro C, Miranda JL, Callejo D, Cuervo J, et al. Prevalence, treatment, and control of hypercholesterolemia in high cardiovascular risk patients: evidences from a systematic literature review in Spain. Adv Ther 2015; 32(10): 944–961. 33. Liang SJ, Zeng DY, Mai XY, Shang JY, Wu QQ, Yuan JN, et al. Inhibition of Orai1 store-operated calcium channel prevents foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 2016; 36(4): 618–628. 34. Lin SJ, Hsieh FY, Chen YH, Lin CC, Kuan, II, Wang SH, et al. Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells. Histol Histopathol 2009; 24(9): 1147–1159. 35. Qian J, Keyes KT, Long B, Chen G, Ye Y. Impact of HMG-CoA reductase inhibition on oxidant-induced injury in human retinal pigment epithelium cells. J Cell Biochem 2011; 112(9): 2480–2489. 36. Chen TL, Zhu GL, He XL, Wang JA, Wang Y, Qi GA. Short-term

24. Pal S, Ghosh M, Ghosh S, Bhattacharyya S, Sil PC. Atorvastatin

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mitochondria, calpain and caspase12 dependent pathways. Food Chem

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New World’s old disease: cardiac hydatid disease and surgical principles Omer Tanyeli, Yuksel Dereli, Ilker Mercan, Niyazi Gormus, Tahir Yuksek

Abstract Background: Hydatid cyst is a parasitic disease caused by infection with the Echinococcus granulosus tapeworm larva. It is a major public health problem in endemic regions. Cardiac involvement of the disease is rare. Methods: Between 1985 and 2015, 12 patients were admitted to our clinic with a possible diagnosis of cardiac hydatid disease. Of these patients, six (50%) were male and six (50%) were female. Mean age of the patients was 42.6 years. Results: The most common location of cardiac hydatid disease was left sided (six patients, 50%). Five (41.7%) patients had cysts located in the right heart, whereas one (8.3%) had a cyst in the interventricular septum. Eleven (91.7%) of the patients were operated on via median sternotomy and the remaining one was operated on via a left anterolateral thoracotomy. Ten (83.3%) of the patients were operated on using cardiopulmonary bypass under moderate hypothermia, whereas the remaining two (16.7%) had off-pump surgery. There was no surgical mortality in our series. All patients were discharged with medical therapy (mebendazole or albendazole) for the duration of six months. No recurrences were observed in their follow ups. Conclusion: Although cardiac hydatid disease is rare, its prevalence seems to have increased in the last decade. Any patient with suspected cardiac symptoms suggesting mass lesions should be considered for a differential diagnosis of cardiac hydatid disease, especially in developing countries. Definitive treatment is removal of the cyst, combined with medical therapy. Keywords: hydatid cyst, cardiac hydatid cyst, Echinococcus granulosus Submitted 10/6/16, accepted 12/1/17 Published online 20/2/17 Cardiovasc J Afr 2017; 28: 304–308

www.cvja.co.za

DOI: 10.5830/CVJA-2017-006

Hydatid cyst (HC) is a parasitic disease caused by infection with the Echinococcus granulosus tapeworm larva. It is a major public health problem in endemic regions such as Asia, the Middle East, the Mediterranean region, South America, New Zealand and Australia.1

Department of Cardiovascular Surgery, Meram Medicine Faculty, Necmettin Erbakan University, Konya, Turkey Omer Tanyeli, MD, otanyeli@gmail.com Yuksel Dereli, MD Ilker Mercan, MD Niyazi Gormus, MD Tahir Yuksek, MD

Hydatid disease may be seen in a variety of systems in the human body, most commonly in the liver (70%) and pulmonary region (20%). Cardiac involvement is very rare and comprises about 0.5 to 2% of all cases.2 Although there are some reports of different locations, and isolated surgical experiences are reported in the literature, large series are limited. In this article, we report our experience in surgical treatment of cardiac hydatid disease (CHD) with specific surgical steps, and we review the literature, which interestingly, shows an increase in reports of CHD over the last two decades.

Methods In the 30 years between 1985 and 2015, 12 patients were admitted to our clinic, either from the Departments of Cardiology or Emergency, with a possible diagnosis of cystic cardiac masses, which were highly suspicious for CHD. Of these patients, six (50%) were male and the remaining six (50%) were female. Mean age of the patients was 42.6 years (ranging from 12–65 years). All patients came from areas where the disease is endemic. The most common presenting symptom was dyspnoea, palpitations and chest pain resembling coronary artery disease. Among these patients, one had symptoms of pulmonary emboli and one was previously operated on because of HC of the left lung, and recurrent CHD was diagnosed five years after the first operation. She also had HCs on the right lung, liver and spleen. All the other CHDs were diagnosed incidentally. Table 1 demonstrates the clinical and demographic features of the patients. Routine tests comprising full blood count, and biochemistry and serological tests, including indirect haemagglutination (IHA) and/or enzyme-linked immunosorbent assay (ELISA) were the preferred diagnostic tools. Echocardiography was preferred to define the mass lesions with their haemodynamically active adjacent structures. Radiological tests, including plain chest X-ray, were done on all patients, and computerised tomography (CT) and/or magnetic resonance imaging (MRI) studies were performed in order to exactly define the lesion, such as the nature of the cystic lesion, location, dimensions and the relationship of the mass with the surrounding tissue or any presence of HC in the lungs. Routine abdominal ultrasonography was performed in order to exclude concomitant HC in the abdomen. After clearly defining the lesion, the patients were given information on the disease and written informed consents were received before the operation. All patients, except one who did not give consent for surgery (not included in this series), were operated on for cystectomy of CHD.

Results The most common location of CHD was left sided (six patients, 50%). Five (41.7%) patients had CHD located in the right heart,

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Table 1. Demographic data of the patients operated on due to cardiac hydatid disease (n = 12) Age (years), mean (range)

305

42.6 (12â&#x20AC;&#x201C;65)

Gender, n (%)

Male Female

6 (50) 6 (50)

Location of hydatid cyst, n (%)

Right sided Right atrium Right ventricle RVOT Left sided Left ventricle Left atrium Interventricular septum

5 (41.7) 2 (16.7) 2 (16.7) 1 (8.3) 6 (50) 5 (41.7) 1 (8.3) 1 (8.3)

Surgical procedure: cystectomy and capitonnage, n (%)

Median sternotomy with CPB Median sternotomy without CPB Left AL thoracotomy without CPB

10 (83.4) 1 (8.3) 1 (8.3)

n, number; RVOT, right ventricular outflow tract; AL, anterolateral; CPB, cardiopulmonary bypass.

whereas one (8.3%) had CHD in the interventricular septum. Eleven (91.7%) of the patients were operated on through median sternotomy and the remaining one was operated on via a left anterolateral thoracotomy. Ten (83.3%) patients were operated on using cardiopulmonary bypass (CPB) under moderate hypothermia, whereas the remaining two (16.7%) had surgery without CPB. During surgery, as previously described, right-sided cardiac hydatid cysts deserve special attention, Our technique is that, while performing the cannulation, initially a single cannula is inserted into the superior vena cava, and after clamping the pulmonary artery with the aorta, the inferior vena cava cannula is inserted in order to avoid iatrogenic HC embolisation.3 There are no special precautions regarding left-sided CHCs in terms of cannulation. After cannulation, the surgical procedure was standard. First the cyst was punctured with a wide aspiration needle connected to the suction device, and after aspiration, without removing the needle, 10% hypertonic saline was injected into the cystic cavity for sterilisation (Fig. 1). The endocyst and the remaining daughter cysts were then removed after gently opening the cystic cavity. Finally, the residual cavity was closed either with continuous or multiple interrupted prolene sutures (Fig. 2). In our series, one of the patients, a 58-year-old male, had CHD in the interventricular septum (Fig. 3). The patient had interventricular cystectomy and capitonnage surgery using standard CPB techniques under moderate hypothermia. The patient also had a bypass to the second branch of the circumflex (OM2) artery using a radial artery graft. All the resected material was sent to the Pathology Department and reports indicated either intact or degenerated HC. There was no surgical mortality in our series. Our patients had neither cardiac rhythm disturbances nor positive inotropic support postoperatively. Mean intensive care unit stay was two days (range between one and three days) after the operation, and seven days (ranging between five and nine days) to discharge from hospital. All patients were followed up with echocardiography. In the first week, the results showed no worsening of left ventricular ejection fraction, compared with pre-operative results.

Fig. 1. Surgical procedures of cardiac hydatic cystectomy. A. Cardiac hydatid cyst located on the posterior left ventricular wall. B. An aspiration needle inserted into the cyst and 10% hypertonic saline injected into the cystic cavity for sterilisation. C. Removal of the germinative membrane. D. Aspiration of the contents of the cystic cavity.

All patients were discharged with either mebendazole (in six cases) or albendazole (400 mg twice a day) treatment for six months and all patients, except one, who was operated on one year A

Fig. 2. A. Intact germinative membrane. B, C. Closure of the cystic cavity.

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ago, were followed up for a mean period of 5 ± 2 years. None of the patients had recurrence of CHD. One of our patients who had CHD in the left ventricular posterior wall (Fig. 4) had re-operation two years after cystectomy because of severe mitral insufficiency and the mitral valve was repaired using an annuloplasty ring.

Discussion Hydatid cyst is an important parasitic infection caused by the larvae of the Echinococcus granulosus tapeworm. Some carnivores (most often dogs) are the definitive hosts. Although it is believed not to be a common health problem in developed countries, the most common presentation of the disease is in endemic areas such as Asia, the Middle East, the Mediterranean region, South America, New Zealand and Australia.1 It may be seen in any organ or tissue in humans, but is most commonly seen in the liver and lung. Cardiac involvement is rare and comprises about 0.5 to 2% of all cases.2 The involvement of CHD may be either primary or secondary. Primary involvement of the heart usually occurs via the coronary circulation; the intestinal lymphatics, thoracic duct, vena cavae and patent foramen ovale may be other pathways.4 Secondary involvement occurs from dissemination of the cyst from adjacent organs, including the lungs, mediastinal structures or liver through the diaphragm.5 The most common involvement of CHD includes the myocardium, mostly in the left ventricle (50–70%), followed by the atria and free wall of the right ventricle (30%), the pericardium (15–25%) and the interventricular septum (5–15%).6 In our series, the most common location of the CHD was left sided (six patients, 50%). Five (41.7%) patients had CHD in the right heart, whereas one patient (8.3%) had one in the interventricular septum. Until the late phase of the disease, patients usually do not seek medical help, probably because it remains asymptomatic for a long period of time. Presenting symptoms of CHD are variable depending on the size, number and location of the cysts.7 As the cysts grow and reach reasonable sizes, patients may present with chest pain, palpitations and dyspnoea. Only 10% of patients,

Fig. 3. M agnetic resonance image showing the cystic mass in the interventricular septum (white arrow).

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particularly those with large HCs have clinical manifestations. Precordial pain is the most common symptom and is most often vague and does not resemble angina pectoris.8 When the cyst is located near the valvular apparatus, it may stimulate valvular stenosis or cause valvular regurgitation.9 In our series, one patient had severe mitral regurgitation after resection of the HC located over the posterior wall of the left ventricle, which may have been the cause for further mitral valve repair. Although CHD may mimic any valvular pathology, or pericardial or coronary artery disease of the heart, there are no specific symptoms regarding the diagnosis of CHD. Routine laboratory tests are not specific and may reveal both normal and abnormal results. Blood count may show eosinophilia, but it may also be completely normal. Serological tests such as IHA and ELISA can assist in the diagnosis of HC infection, but since they have a sensitivity of only 80%, false negative results should be considered.10 Usually the diagnosis starts with clinical suspicion of the disease. Plain chest X-rays may give negative results in the early phase of the disease. If the HC has a calcified outer layer or has led to an increase in cardiothoracic index, or caused a deformation over the borders of the heart, the X-ray may provide valuable data, but accurate diagnosis is made by echocardiography, CT or MRI studies. Sometimes the cyst may be found incidentally from non-specific radiological or echocardiographic evaluations. In detecting CHD, transthoracic echocardiography should be the first choice, since it is non-invasive with a high sensitivity to demonstrate the mass. CT or MRI should also be used in order to demonstrate the extent of the cyst and anatomical relationships prior to surgery. CT is superior for observing intracystic gas, minute calcifications and in anatomical mapping.11 Cysts may be identified as uni- or multilocular. Pathognomonic findings are the presence of a A

Fig. 4. A. Plain chest X-ray showing the calcified outer layer of the cardiac hydatid cyst. B. Eggshell appearance of the cardiac hydatid cyst located on the posterior left ventricular wall on computerised tomography. C, D. Surgically closed defect after removal of the highly calcified hydatid cyst.

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50 40 30 20 10 0

Fig. 5. M agnetic resonance (A) and computerised tomography (B) images of the cardiac hydatid cyst located on the left ventricular free wall.

single cyst with a wall, daughter cysts surrounded by a capsule with peripheral calcifications, and membrane detachment.12 MRI is the most reliable diagnostic modality for CHD; it depicts the exact anatomical location, and the nature of internal and external structures. A typical finding on T2-weighted images is a hypo-intense peripheral ring, representing the pericyst. More specific signs include calcification of the cyst wall, presence of daughter cysts, and membrane detachment. CT best shows wall calcification, whereas MRI depicts the exact anatomical location.12 In our clinical practice, we use either CT or MRI prior to surgery to devise a surgical plan and decide accordingly whether to carry out on- or off-pump surgery (Fig. 5). Estimates on the average increase in cyst diameter vary from about one to 1.5 cm per year.13 The disease may be silent for years or cause fatal complications, such as rupture of the HC, resulting in anaphylaxis. Whatever the location, surgical removal of the cyst is the definitive treatment for potentially lifethreatening complications, such as rupture, cardiac tamponade or pulmonary/systemic embolisation. Most surgeons prefer median sternotomy but on selected and well-defined lesions, left anterolateral thoracotomy may also be used. We performed one operation through left anterolateral thoracotomy in our series. In patients with superficially localised or pericardial CHD, the off-pump technique can be used, as in two of our patients. Using the CPB technique may be mandatory or sometimes beneficial; cross-clamping of the aorta and pulmonary artery may prevent dissemination of the parasite to the systemic or pulmonary circulation, thereby preventing possible pulmonary emboli. After cannulation, our surgical approach is to puncture and aspirate the cyst contents, sterilise with 10% saline solution and close the cavity with purse-string sutures. After surgery, close follow up of the patients is important to detect any recurrence or dissemination to other organs. Despite successful surgery, supplemental medical therapy should be administered in case of possible cyst rupture and dissemination of daughter cysts during the operation and to prevent recurrence of the cysts.14 We recommend albendazole 400 mg twice a day for a period of six months. We searched the literature in the PubMed database using the words ‘cardiac hydatid cyst’ and the number of reports is shown in Fig. 6. As can be seen, the number of reports has increased dramatically over the last decade or two. This may be explained

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60 Number of reports

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1940

1950

1960

1970

1980 1990 Year

2000

2010

2020

Fig. 6. Number of cardiac hydatid cyst reports on PubMed data search.

by more accurate diagnosis using either echocardiographic or radiological (CT or MRI) studies, and the increased numbers of open-heart surgery cases since the late 1950s. However, we should keep in mind that, as people travel more and immigrants disperse all over the world, an endemic disease will not remain endemic. Therefore a disease that we thought belonged to the Old World will also be seen in the New World.

Conclusion Although CHD is an extremely rare disease, its prevalence seems to have increased in the last decade. Any patient with suspected cardiac symptoms suggestive of mass lesions should be considered for a differential diagnosis of CHD, especially in developing countries. Definitive treatment is removal of the cyst combined with medical therapy. Surgery performed by experienced practitioners provides excellent results when combined with postoperative medical therapy. We will probably see more cases, not only in endemic regions, but also in developed countries in the near future due to the migration of populations.

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McManus DP, Zhang W, Li J, Bartley PB. Echinococcosis. Lancet 2003; 362(9392): 1295–1304.

Rein R, Niggemann B, Runge M. Echinococcosis of the heart. Herz 1996; 21(3): 192–197.

Gormus N, Yeniterzi M, Telli HH, Solak H. The clinical and surgical features of right-sided intracardiac masses due to echinococcosis. Heart Vessels 2004; 19: 121–124.

Kaplan M, Demirtas M, Cimen S, Ozler A. Cardiac hydatid cysts with intracavitary expansion. Ann Thor Surg 2001; 71: 1587–1590.

Kuruoglu S, Kizilkilic O, Ogut G, Mihmanli I, Akman C, Tanrikulu H. Primary cardiac hydatid disease: cross-sectional imaging features. South Med J 2002; 95: 1140–1144.

Urbanyi B, Rieckmann C, Hellberg K, Krakau M, Liebau G, Mayer A, et al. Myocardial echinococcosis with perforation into the pericardium. J Cardiovasc Surg 1991; 32: 534–538.

Yan F, Huo Q, Abudureheman M, Qiao J, Ma S, Wen H. Surgical treatment and outcomes of cardiac cystic echinococcosis. Eur J Cardiothorac Surg 2015; 47: 1053–1058.

Tuncer E, Turk U, Alioglu E. Cardiac hydatid cyst: An unusual cause of

Apaydin AZ, Oguz E, Ayik F, Ceylan N. Hydatid cyst confined to the

chest pain. Int Cardiovasc Res J 2013; 7(4): 150–151.

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papillary muscle: a very rare cause of mitral regurgitation. Tex Heart Inst J 2009; 36(6): 598–600.

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12. Xing Y, Bawudong D, Zhang WB, Liu WY, Pan CX, Wen H, et al. Multidetector CT and MR imaging cardiac hydatidosis: case report

10. Tabesh H, Tafti HA, Ameri S. Unusual presentation of interventricular hydatid cyst: A case report. Iran J Public Health 2015; 44(1): 130–133. 11. Nemes A, Geleijnse ML, van Geuns RJ, Caliskan K, Michels M,

and review of the literature. Int J Cardiovasc Imaging 2011; 27: 97–102. 13. Leow CK, Lau WY. Soft tissue images. Hydatid disease of the liver. Can J Surg 2000; 43: 330–332.

Soliman O, et al. Evaluation of pericardial hydatid cysts by different

14. Altas O, Sarikaya S, Sacli H, Yerlikhan O, Kirali K. Cardiac cystic

echocardiographic imaging modalities. Int J Cardiovasc Imaging 2006;

echinococcosis: Report of three cases. Asian Pac J Trop Med 2014;

22(5): 647–651.

7(11): 922–924.

CSI AFRICA 2017 CATHETER INTERVENTIONS IN CONGENITAL, STRUCTURAL AND VALVAR HEART DISEASE DECEMBER 1 – 2, 2017 | NAIROBI | KENYA

SAVE THE DATE CSI Africa 2017 will take place on December 1 – 2, 2017 in Nairobi, Kenya. Please join us for an overview of catheter interventions in congenital, structural and valvar heart disease in children and adults. CSI Africa will provide a forum for physicians from Central Africa, with an opportunity to exchange ideas and learn from each other. Read more on the congress website.

THE PROGRAM The program will include lectures, debates and recorded cases from local and international faculty and is designed to address issues and topics specific to Central Africa. Topics will include: • Paravalvar leak closure • Left atrial apendage closure • Pulmonary valve replacement • Echo evaluation of ASDs and VSDs • Coarctation stenting

• ASD closure • VSD closure • Transseptal puncture • PDA closure • Pulmonary valvuloplasty • Mitral valvuloplasty

• How to develop structural, congenital and valvar interventions in Africa • Challenging cases, problems & complications

WHO SHOULD ATTEND? The meeting is designed for adult and pediatric interventional cardiologists, cardiothoracic surgeons, anaesthetists, imaging specialists & colleagues of other disciplines, such as nursing staff, who wish to know more about this field.

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Right ventricular strain as predictor of pulmonary complications in patients with femur fracture Hyun-Jin Kim, Hyung-Bok Park, Yongsung Suh, Hyun-Sun Kim, Yoon-Hyeong Cho, Tae-Young Choi, Eui-Seok Hwang, Deok-Kyu Cho

Abstract Background: Following femur fracture, medullary fat enters the systemic circulation and altered pulmonary haemodynamics may contribute to pulmonary complications. This study evaluated the association between right ventricular (RV) function and pulmonary complications in patients with femur fracture. Methods: Patients with a femur fracture who had undergone pre-operative echocardiography that included RV peak global longitudinal strain (RV GLS) were evaluated retrospectively between March 2015 and February 2016. Pulmonary complications were defined as the development of pneumonia or pulmonary thromboembolism during the first postoperative month. Results: Among 78 patients, pulmonary complications developed in eight (10.3%). The RV GLS value of all patients was lower than the normal range. In addition, the RV GLS value of patients with pulmonary complications was significantly lower than that of patients without pulmonary complications. Multivariate regression analyses found that worse RV GLS values independently predicted pulmonary complications [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.047–4.151, p = 0.037]. Receiver operating characteristic curve analysis found that a RV GLS value of –14.85% was the best cut-off value to predict pulmonary complications; sensitivity: 75.0%; specificity: 62.9%. Moreover, patients with RV GLS values > –14.85% had significantly lower pulmonary complication-free survival. Conclusions: In patients with femur fracture, RV GLS values could help predict pulmonary complications. Therefore, patients with RV GLS values > –14.85 should be monitored closely before and after surgery for femur fracture.

Division of Cardiology, Department of Internal Medicine, Myongji Hospital, South Korea Hyun-Jin Kim, MD, titi8th@gmail.com Hyung-Bok Park, MD Yongsung Suh, MD Yoon-Hyeong Cho, MD Tae-Young Choi, MD Eui-Seok Hwang, MD Deok-Kyu Cho, MD

Department of Translational Medicine, College of Medicine, Seoul National University, South Korea Hyun-Jin Kim, MD

College of Nursing and Research Institute of Nursing Science, Seoul National University, South Korea Hyun-Sun Kim, MSN, RN

Keywords: femur fracture, RV peak global longitudinal strain, pneumonia, pulmonary thromboembolism Submitted 22/8/16, accepted 12/1/17 Published online 1/2/17 Cardiovasc J Afr 2017; 28: 309–314

www.cvja.co.za

DOI: 10.5830/CVJA-2017-011

Following femur fracture, a long-bone trauma, medullary fat enters the systemic circulation and altered pulmonary haemodynamics may contribute to pulmonary complications.1,2 Large amounts of medullary fat emboli entering the systemic circulation may produce multisystem dysfunction, more serious conditions, and pulmonary complications.3 In addition, following acute trauma, hormonal changes induce triglyceride hydrolysis and free fatty acid release, causing injury to the pulmonary capillary endothelium.4 All these changes after femur fracture, including altered pulmonary haemodynamics, hormonal changes and systemic inflammatory reactions, could worsen the clinical outcome of such patients. Accordingly, hospital stay or outcome can also be affected, not only by pulmonary complications with altered pulmonary haemodynamics but also from multisystem dysfunction. Pulmonary vascular resistance (PVR) is an important component of pulmonary haemodynamics and a critical determinant of right ventricular (RV) systolic function.5 However, because PVR can only be measured directly by invasive right heart catheterisation, a non-invasive measurement of PVR is needed to evaluate acute trauma patients. Research has demonstrated that RV myocardial strain estimates RV function accurately and is correlated with the pulmonary haemodynamics of patients with pulmonary hypertension.6-8 Consequently, RV myocardial strain, as a measure of RV function, may provide new insights into detecting altered pulmonary haemodynamics and thereby predict pulmonary complications after femur fracture. The aim of this study was to evaluate the association between pulmonary complications and RV function in patients with femur fracture.

Methods Data from 100 consecutive patients who visited a hospital for femur fracture between March 2015 and February 2016 and also underwent transthoracic echocardiography were retrospectively analysed. Among these, 22 patients were excluded from the study because the echocardiographic image quality was inadequate for quantitative analysis. The study was approved by the institutional review boards of the hospitals, and was conducted according to the Declaration

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of Helsinki. Written informed consent was exempted by the institutional review boards. Patients’ demographic and clinical characteristics were reviewed using electronic records. The following demographic and clinical characteristics were extracted: age, gender, height, weight, systolic blood pressure, diastolic blood pressure, current smoking status, and history of hypertension, diabetes, dyslipidaemia, coronary artery disease, and atrial fibrillation. Each patient’s body mass index [BMI (kg/m2)] was calculated. In addition, length of hospital stay was recorded. The following laboratory data were extracted: haemoglobin, pro-brain-type natriuretic peptide, blood urea nitrogen, creatinine, estimated glomerular filtration rate, creatine kinase MB, troponin I, C-reactive protein, and D-dimer values. In addition, we recorded the dates of the diagnosis of pneumonia, pulmonary thromboembolism and all-cause death from the medical records. Transthoracic echocardiographic images were reviewed for all patients. Transthoracic echocardiography was performed before the operation and images were obtained using the Vivid 7 or Vivid E9 echocardiography system (GE Vingmed, Horton, Norway). Left ventricular (LV) systolic function was assessed by calculation of LV ejection fraction (EF) using M-mode echocardiography. RV systolic function was assessed from the following parameters: tricuspid annular plane systolic excursion (TAPSE), tissue Doppler-derived tricuspid lateral annular systolic velocity (RVs′), and RV fractional area change (FAC).9 RV FAC was calculated by tracing end-systolic and end-diastolic areas of the RV in apical four chamber views.9 Pulmonary artery systolic pressure was calculated from the maximal velocity of the tricuspid insufficiency jet and the estimated central venous pressure. Two-dimensional images of the apical four-chamber view were collected to analyse the longitudinal RV strain using a mean frame rate of 68 ± 10 frames per second. Analyses were performed using an off-line software program (EchoPAC PC version 113, GE Vingmed Ultrasound, Horton, Norway). The endocardial border of the RV myocardium was delineated manually on an end-systolic frame, after which the software automatically drew the epicardial border. Manual adjustment was done for matching the actual borders of the regions of interest. Then the RV myocardium was traced frame by frame, and the longitudinal strain of the basal, middle and apical segments of the RV free wall and septum were obtained separately. By averaging all segmental values, RV peak global longitudinal strain (RV GLS) was calculated using this software with two-dimensional speckle-tracking echocardiography.10 Because the longitudinal myocardial fibre length decreased during systole, the myocardial shortening was interpreted in negative values. Consequently, the more negative RV GLS values indicate improved or better strain.11 In patients with atrial fibrillation, all RV GLS measurements were averaged over three cardiac cycles. The primary outcome was the development of a clinically apparent pulmonary complication during the one-month postoperative period. We defined a pulmonary complication as a composite outcome: development of either pneumonia or pulmonary embolism during the first postoperative month. Pulmonary embolism was confirmed by computed tomographic pulmonary angiogram.12 The diagnosis of pneumonia was based

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on a combination of physical signs and chest X-rays obtained by reviewing medical records.13 To assess the inter-observer variability of RV GLS, a second experienced independent investigator re-evaluated 20 randomly selected images using the same software. Intra-observer variability was evaluated: the first investigator who was blinded to the former results analysed RV GLS for each randomly selected image again at one month after the initial analysis.

Statistical analysis All categorical data are summarised as frequencies and percentages, whereas statistics for continuous variables are presented as means and standard deviations. The Pearson chi-squared test was used to compare categorical variables. The Student’s t-test was used to compare continuous variables and the Mann–Whitney U-test was used when the sample size of at least one group was less than 30. Univariate analysis was followed by multivariate logistic regression analyses to evaluate potential risk factors for pulmonary complications with adjustment for other risk factors. Variables with a p-value less than 0.1 in univariate analysis were selected for inclusion in the multivariate regression model. RV GLS was analysed as a continuous variable in univariate and multivariate models. We investigated the optimal cut-off value of RV GLS to predict pulmonary complications in patients with femur fracture using receiver operator characteristic (ROC) curve analyses. In addition, Kaplan–Meier survival analyses and log-rank tests were used to compare clinical event-free survival rates between groups stratified by the RV GLS cut-off value. Then, to evaluate the consistency of results according to the identified cut-off value, RV GLS was analysed as a dichotomous variable in univariate Cox analysis. The inter- and intraobserver agreements were described by calculating the intra-class correlation coefficient (ICC). A p-value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS 18.0 (SPSS Inc, Chicago, IL).

Results Seventy-eight patients with femur fracture were included; their mean age was 80.1 ± 9.1 years, and 59 (75.6 %) patients were female. Patients’ baseline characteristics are presented in Table 1. The mean hospital stay was 18.4 ± 7.8 days (median 17 days). All patients underwent successful surgery for femur fracture during hospitalisation. Eight patients (10.3%) developed pulmonary complications during the first postoperative month. One patient (1.3%) developed pulmonary embolism and the other seven developed pneumonia. Among these, two patients (2.6%) died. The patients who developed pulmonary complications had significantly longer hospital stays than the patients who did not develop pulmonary complications (29.8 ± 17.0 vs 17.1 ± 4.6 days, p = 0.003). Table 2 compares laboratory results and echocardiographic characteristics between the group with pulmonary complications and that with no complications. The patients in the group with pulmonary complications had significantly higher D-dimer values than the group with no complications (19 191.5 ± 16 257.0 vs 9 256.1 ± 10 304.5 ng/ml, p = 0.023). The groups did not differ significantly with regard to clinical characteristics, including previous medical history (hypertension, diabetes, dyslipidaemia,

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Table 1. Baseline characteristics

Table 3. RV strain analysis measurements according to pulmonary complications

All (n = 78)

Pulmonary complications (n = 8)

No complications (n = 70)

p-value

Age, years

80.1 ± 9.1

83.4 ± 3.2

79.7 ± 9.5

0.310

Females, n (%)

59 (75.6)

5 (62.5)

54 (77.1)

0.395

128.5 ± 20.6

126.5 ± 23.3

128.8 ± 20.5

74.7 ± 11.9

71.9 ± 8.9

Height, cm

156.0 ± 8.4

Weight, kg

54.7 ± 10.5

BMI, kg/m2

22.4 ± 3.6

Clinical variables

SBP, mmHg DBP, mmHg

All (n = 78)

Pulmonary complications (n = 8)

No complications (n = 70)

p-value

RV GLS, %

–16.66 ± 5.93

–12.40 ± 6.41

–17.14 ± 5.72

0.036

0.728

Basal septal

–15.35 ± 7.73

–14.63 ± 11.33

–15.43 ± 7.32

0.779

75.0 ± 12.3

0.488

Mid-septal

–17.47 ± 6.94

–15.88 ± 10.91

–17.66 ± 6.43

0.662

153.9 ± 5.5

156.2 ± 8.7

0.497

Apico-septal

–15.26 ± 11.87

–3.38 ± 12.98

–16.61 ± 11.04

0.010

51.9 ± 7.6

55.1 ± 10.7

0.442

Basal lateral

–14.81 ± 14.19

–10.13 ± 11.47

–15.34 ± 14.44

0.166

21.9 ± 2.5

22.5 ± 3.7

0.767

Mid-lateral

–15.78 ± 10.66

–10.63 ± 13.18

–16.37 ± 10.28

0.121

–14.36 ± 13.38

–4.5 ± 18.87

–15.49 ± 12.31

0.108

2 (2.6)

0 (0.0)

2 (2.9)

1.000

Apico-lateral

Hypertension, n (%)

59 (75.6)

7 (87.5)

52 (74.3)

0.671

RV GLS, right ventricular global longitudinal strain.

Diabetes, n (%)

20 (25.6)

2 (25.0)

18 (25.7)

1.000

Dyslipidaemia, n (%)

9 (11.5)

0 (0.0)

9 (12.9)

0.586

Coronary artery disease, n (%)

7 (9.0)

1 (12.5)

6 (8.6)

0.546

Atrial fibrillation, n (%)

2 (2.6)

0 (0.0)

2 (2.9)

1.000

18.4 ± 7.8

29.8 ± 17.0

17.1 ± 4.6

0.003

Smoking, current, n (%)

Hospital stay, days

SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index.

coronary artery disease and atrial fibrillation) (Table 1), and laboratory results, including cardiac enzymes, except for D-dimer values. In addition, echocardiographic characteristics were not significantly different between the two groups. Similarly, RV FAC, RVs′ and TAPSE values, known as measures of RV function, did not differ significantly between the two groups. Table 3 compares the RV strain values of the two groups. RV GLS values of all patients were lower than the normal range (approximately –28.0%.)14,15 RV GLS values of patients in the group with pulmonary complications were significantly lower than those of patients in the group with no complications (–12.40 ± 6.41 vs –17.14 ± 5.72 %, p = 0.036). With regard to segmental RV strain values, the apico-septal RV strain of patients in the group with pulmonary complications was Table 2. Laboratory tests and echocardiographic measurements All (n = 78)

Pulmonary complications (n = 8)

No complications (n = 70) p-value

Laboratory parameters Haemoglobin, g/dl

11.4 ± 1.8

10.3 ± 1.7

11.5 ± 1.8

0.091

Pro-BNP, pg/ml

1259.9 ± 4468.7

2375.3 ± 4237.1

1113.6 ± 4511.1

0.851

BUN, mg/dl

20.2 ± 9.0

22.7 ± 7.4

19.9 ± 9.1

0.205

Creatinine, mg/dl

1.1 ± 0.7

1.1 ± 0.2

1.1 ± 0.7

0.178

60.1 ± 22.8

52.8 ± 8.3

60.9 ± 23.8

0.140

2.0 ± 2.4

1.2 ± 1.0

2.1 ± 2.6

0.268

eGFR, ml/min/1.73 m2 CKMB, ng/ml

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Troponin I, μg/l

0.1 ± 0.2

0.0 ± 0.1

0.1 ± 0.2

0.922

CRP, mg/dl

2.9 ± 5.0

5.6 ± 7.9

2.6 ± 4.6

0.161

D-dimer, ng/ml

10460.4 ± 11500.1

19191.5 ± 16257.0

9256.1 ± 10304.5

0.023

Echocardiographic parameters LVEF, %

61.6 ± 5.9

59.9 ± 9.9

61.8 ± 5.3

0.953

RV FAC, %

39.9 ± 8.2

37.0± 13.3

40.2 ± 7.5

0.442

RVs′, cm/s

14.3 ± 3.6

13.5 ± 3.7

14.4 ± 3.6

0.313

TAPSE, mm

18.5 ± 3.1

18.1 ± 2.1

18.5 ± 3.2

0.781

PASP, mmHg

36.0 ± 12.6

40.2 ± 17.7

35.4 ± 11.9

0.705

Pro-BNP, pro-brain-type natriuretic peptide; BUN, blood urea nitrogen; CKMB, creatine kinase MB; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; RV, right ventricle; FAC, fractional area change; RVs′, tissue Doppler-derived tricuspid lateral annular systolic velocity; TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure.

Table 4. Univariate and multivariate analysis of RV GLS for predicting pulmonary complications Univariate

Multivariate

95% CI

RV GLS, %

1.17

1.007–1.369

2.09

1.047–4.151

Hospital stay, days

1.17

1.041–1.307

1.64

1.053–2.560

D-dimer, ng/ml

1.00

1.00–1.00

1.00

1.000–1.000

Haemoglobin, g/dl

0.65

0.412–1.036

0.24

0.060–0.965

CI, confidence interval; OR, odds ratio.

noticeably worse than that in the group with no complications (–3.38 ± 12.98 vs –16.61 ± 11.04%, p = 0.010). In univariate analyses (Table 4), worse RV GLS values were associated with pulmonary complications in patients [odds ratio (OR) 1.17, 95% confidence interval (CI) 1.007–1.369, p = 0.040]. Duration of hospital stay was also associated with pulmonary complications [OR 1.17, 95% CI: 1.041–1.307, p = 0.008]. Furthermore, in multivariate regression analyses, worse RV GLS values were independent predictors of pulmonary complications after adjustment for other relevant variables in patients [OR 2.09, 95% CI: 1.047–4.151, p = 0.037]. In addition, longer hospital stay was an independent predictor of pulmonary complications [OR 1.64, 95% CI: 1.053–2.560, p = 0.029]. ROC curve analysis identified RV GLS of –14.85% as the best cut-off value for predicting pulmonary complications; this value had a sensitivity of 75.0% and a specificity of 62.9% (Fig 1). Fig. 2 shows the cumulative clinical event-free survival rates of the two groups during the one-month postoperative period. The two groups were stratified by a RV GLS value of –14.85%. Patients with RV GLS values > –14.85% had a significantly higher rate of pulmonary complications during the first postoperative month than did patients whose RV GLS was ≤ –14.85% (log-rank test: p = 0.027). Based on univariate cox regression analysis, RV GLS values > –14.85% had borderline significance for the prediction of pulmonary complications [hazard ratio (HR) 7.60, 95% CI: 0.912–63.459, p = 0.061] during the one-month postoperative period (data are not shown). The inter-observer agreement of RV GLS was excellent (ICC 0.987, 95% CI: 0.966–0.995, respectively). The degree of intra-observer agreement (ICC 0.989, 95% CI: 0.973–0.996) was similar to that of the inter-observer agreement.

Discussion Pneumonia and pulmonary embolism are important complications in older patients with femur fracture. Our findings indicate that pulmonary complications develop often, at a rate

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100

80 Event-free survival (%)

Sensitivity (%)

312

40 60 80 100 – Specificity (%)

p = 0.027 60

Area under curve RV GLS: 0.728, 95% CI = 0.524–0.932

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RV GLS ≤ –14.85% RV GLS > –14.85%

100

Fig. 1. R eceiver operating characteristic (ROC) curve analysis for the detection of pulmonary complications. The best cut-off value of RV GLS for the prediction of pulmonary complications was –14.85% (area under the curve: 0.728, p = 0.036). In patients with femur fracture, this value had a sensitivity of 75.0% and a specificity of 62.9% for correctly predicting pulmonary complications. CI, confidence interval, RV GLS, right ventricular global longitudinal strain.

of 10.3%, in patients with femur fracture. Lower RV GLS values and longer hospital stay were good predictors for detecting pulmonary complications. In addition, our findings document that patients with impaired RV GLS values > –14.85% had significantly lower clinical event-free survival rates than patients with better RV GLS values. After long-bone trauma, medullary fat enters the systemic circulation and fat emboli pass through the pulmonary capillaries, causing altered pulmonary haemodynamics and a systemic inflammatory reaction.1,2 Hormonal changes after trauma can also cause damage to the pulmonary capillary beds, causing altered pulmonary haemodynamics in animal models.4 Previous studies have demonstrated that when increased pulmonary vascular resistance is caused by vascular obstruction from fat emboli, RV afterload may increase and RVEF will decline.16-18 RV function reflects not only RV myocardial contractility but also the afterload effect of pulmonary vascular pathology.19 To our knowledge, no previous study has reported on the effects of femur fracture on pulmonary haemodynamics and RV function. RV dysfunction has been shown to predict adverse clinical outcomes in patients with heart failure or myocardial infarction,5,20 therefore quantifying RV dysfunction would contribute to identifying at-risk patients, monitoring the effects of medical management and predicting clinical outcomes. However, it is difficult to assess RV function accurately using standard two-dimensional echocardiography imaging because the RV chamber has a complex shape.9 RV FAC and TAPSE have been established as echocardiographic parameters for assessing RV contractility or systolic function,9 and predicting adverse clinical events in patients with pulmonary embolism and myocardial infarction.21,22

Days

Fig. 2. Clinical event-free survival curves based on Kaplan– Meier analysis. Patients were categorised into two groups: RV GLS > –14.85% and RV GLS ≤ –14.85%. The cumulative pulmonary complication-free survival rates of the two groups were compared using Kaplan– Meier survival curves and the log-rank test. Patients with RV GLS values > –14.85% had a significantly higher rate of pulmonary complications during the first postoperative month (p = 0.027). RV GLS, right ventricular global longitudinal strain.

Although the imaging quality has improved, delineation of the endocardial border for the measurement of RV FAC has variable reliability depending on the experience of the operator. In addition, velocity and displacement-based analyses, such as TAPSE, can be affected by tethering and cardiac translation and respiratory variation.9,23 Therefore, detecting subclinical RV dysfunction may be limited using conventional two-dimensional echocardiographic measurements. In our study, echocardiographic measures of RV function, including TAPSE and RV FAC, did not differ significantly with outcome; we did not detect differences in subclinical RV dysfunction between the group with pulmonary complications and that with no complications using conventional two-dimensional echocardiographic measures. Two-dimensional strain echocardiography quantifies both regional and global myocardial function.24 Notably, detecting RV dysfunction using two-dimensional strain analysis can provide additional prognostic information and better predict outcomes than other traditional echocardiographic parameters in patients with myocardial infarction, pulmonary artery hypertension and heart failure.24,25 Because the RV muscle fibres are arranged longitudinally, most RV systolic function and RV stroke volume is generated by longitudinal shortening.26 Therefore, RV GLS is correlated with RV systolic function. A previous study demonstrated that RV GLS, including the interventricular septum and RV free wall, correlated significantly with RVEF based on cardiac magnetic resonance imaging.27 The reference value of RV GLS in normal subjects is about –28%,14,15 and the absolute values of RV GLS in our study patients were lower than the reference value. Relatively older age, altered pulmonary haemodynamics and decreased RV function due to

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acute trauma would tend to lower the absolute value of RV GLS. A previous study revealed that RV GLS value ≥ –15.5% was associated with adverse clinical events and death in patients with inferior ST-segment elevation myocardial infarction (STEMI).28 The authors suggested that RV GLS was the major predictor of long-term clinical outcome in patients with acute inferior STEMI and preserved LVEF. Similarly, RV GLS value > –14.85% was associated with adverse clinical events in our study patients with preserved LVEF who had compromised pulmonary haemodynamics due to femur fracture. It is notable from our analysis that the subclinical changes in RV function identified as decreases in RV longitudinal strain could be detected using two-dimensional strain analysis; these findings provide additional information to predict pulmonary complications in compromised pulmonary haemodynamics after acute long-bone trauma. Likewise, RV strain may help to further our understanding of pulmonary haemodynamic changes.

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Dambrauskaite V, Delcroix M, Claus P, Herbots L, D’Hooge J, Bijnens B, et al. Regional right ventricular dysfunction in chronic pulmonary hypertension. J Am Soc Echocardiogr 2007; 20: 1172–1180. PMID: 17570637.

Rajagopalan N, Simon MA, Shah H, Mathier MA, Lopez-Candales A. Utility of right ventricular tissue Doppler imaging: correlation with right heart catheterization. Echocardiography 2008; 25: 706–711. PMID: 18445057.

Naderi N, Ojaghi Haghighi Z, Amin A, Naghashzadeh F, Bakhshandeh H, Taghavi S, et al. Utility of right ventricular strain imaging in predicting pulmonary vascular resistance in patients with pulmonary hypertension. Congest Heart Fail 2013; 19: 116–122. PMID: 23121695.

Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc

Limitations Some limitations of this study should be considered. First, this study was a retrospective observational study. Moreover, it was a single-centre experience with a relatively small sample size. Because quantitative analysis could have been affected by the quality of stored images, we excluded patients with inadequate echocardiographic image quality. Although a prospective study with more patients and a longer postoperative observation period may help identify additional factors, impaired RV GLS in patients after the acute trauma of long-bone fracture was significantly associated with more short-term clinical events and may provide useful information to manage trauma patients in real-world clinical situations.

Echocardiogr 2010; 23: 685–713. PMID: 20620859. 10. Yoon SJ, Seo HS, Park S, Chung WJ. 2-Dimensional Strain analysis of regional change in right ventricular function after treadmill exercise. J Cardiovasc Ultrasound 2016; 24: 35–39. PMID: 27081442. 11. Altiok E, Neizel M, Tiemann S, Krass V, Kuhr K, Becker M, et al. Quantitative analysis of endocardial and epicardial left ventricular myocardial deformation-comparison of strain-encoded cardiac magnetic resonance imaging with two-dimensional speckle-tracking echocardiography. J Am Soc Echocardiogr 2012; 25: 1179–1188. PMID: 22951120. 12. Fedullo PF, Tapson VF. Clinical practice. The evaluation of suspected pulmonary embolism. N Engl J Med 2003; 349: 1247–1256. PMID: 14507950. 13. Lynch T, Bialy L, Kellner JD, Osmond MH, Klassen TP, Durec T, et al. A systematic review on the diagnosis of pediatric bacterial pneumonia: when gold is bronze. PLoS One 2010; 5: e11989. PMID: 20700510.

Conclusions In patients with femur fracture, the short-term pulmonary complication rate was 10.3% and this was increased by worse RV GLS values and longer hospital stays. Because of the high incidence of pulmonary complications in femur fracture, patients with RV GLS values > –14.85% should be monitored closely before and after surgery to detect pulmonary events.

14. Fine NM, Chen L, Bastiansen PM, Frantz RP, Pellikka PA, Oh JK, et al. Reference Values for right ventricular strain in patients without cardiopulmonary disease: A prospective evaluation and meta-analysis. Echocardiography 2015; 32: 787–796. PMID: 25323591. 15. Muraru D, Onciul S, Peluso D, Soriani N, Cucchini U, Aruta P, et al. Sex- and method-specific reference values for right ventricular strain by 2-dimensional speckle-tracking echocardiography. Circ Cardiovasc Imag 2016; 9: e003866. PMID: 26860970. 16. Urban MK, Sheppard R, Gordon MA, Urquhart BL. Right ventricular

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Richards RR. Pulmonary and systemic fat embolization after medullary

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12: 276–282. PMID: 20089520. 21. Nass N, McConnell MV, Goldhaber SZ, Chyu S, Solomon SD. Recovery

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26. Carlsson M, Ugander M, Heiberg E, Arheden H. The quantitative

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24. Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol 2006; 98: 699–704. PMID: 16923465. 25. Park JH, Park MM, Farha S, Sharp J, Lundgrin E, Comhair S, et al. Impaired global right ventricular longitudinal strain predicts long-term

volumetric assessment by cardiac magnetic resonance as a “gold standard”. Echocardiography 2015; 32: 956–965. PMID: 25231541. 28. Park SJ, Park JH, Lee HS, Kim MS, Park YK, Park Y, et al. Impaired RV global longitudinal strain is associated with poor longterm clinical outcomes in patients with acute inferior STEMI. J Am Coll CardiolCardiovasc Imag 2015; 8: 161–169. PMID: 25577444.

Conﬁdence Through Clinical and Real World Experience1-3 #1 Scripted Non-VKA Oral Anticoagulant by Cardiologists* Millions of Patients Treated Worldwide Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. 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 fi brillation: 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 January 2017. S4 Xarelto 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia NS2 : 12/8.2/0006; S2 Botswana: BOT1302296; Zimbabwe: PP10 Reg. 2017/10.2/5363 S4 Xarelto 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112;Namibia NS2 : 12/8.2/0007; S2 Botswana: BOT1302297; Zimbabwe: PP10 Reg. 2017/10.2/5364 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). For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM 06.2017.1808 © Bayer June 2017 *Impact RX Data 2016 NOAC: Non Vitamin K Oral Anticoagulant

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Electrocardiographic abnormalities in treatment-naïve HIV subjects in south-east Nigeria Innocent Chukwuemeka Okoye, Ernest Ndukaife Anyabolu

Abstract Background: Cardiac complications of human immunodeficiency virus (HIV) infection are important causes of morbidity and mortality. We set out to determine the electrocardiographic (ECG) abnormalities in treatment-naïve HIV-positive patients in Enugu, south-east Nigeria. Methods: This was a cross-sectional study involving 250 HIV-positive and 200 HIV-negative subjects. Demographic and anthropometric data, relevant investigations and ECG results were compared between the groups. Results: An abnormal ECG was present in 70% of the HIV-positive patients, sinus bradycardia in 64%, QTC prolongation in 48%, T-wave inversion in 21.6%, Wolf–Parkinson– White syndrome in 0.8%, abnormal P waves in 12.8%, 1st degree heart block in 2.4%, ST depression in 30%, and left-axis deviation in 1.6%. Underweight was associated with ECG abnormalities (p = 0.001). The HIV-positive patients had more ECG abnormalities than the HIV-negative subjects (p = 0.001). Conclusion: Electrocardiographic abnormalities were common in treatment-naïve HIV-positive patients in Enugu, Nigeria. The 70% prevalence of ECG abnormalities in treatment-naïve HIV-positive patients was high. There is a need to evaluate HIV-positive patients at onset for cardiac and non-cardiac abnormalities detectable by ECG. Keywords: ECG, cardiac abnormalities, non-cardiac ECG abnormalities, HIV, Enugu, Nigeria Submitted 22/6/16, accepted 26/1/17 Published online 24/3/17 Cardiovasc J Afr 2017; 28: 315–318

www.cvja.co.za

DOI: 10.5830/CVJA-2017-013

About 70% of the world’s human immunodeficiency virus (HIV)-infected persons live in sub-Saharan Africa.1 In Nigeria, the prevalence of HIV infection is 3.7%.1 Cardiac lesions have been reported in HIV-positive patients.2,3 Mpiko and Hakim showed that among the peculiar features of HIV-related cardiovascular disorders in sub-Saharan Africans, pericardial effusion may be the first manifestation of the illness. Prevalent infectious diseases were seemingly mirrored

Chukwuemeka Odumegwu Ojukwu University, Awka, Nigeria Innocent Chukwuemeka Okoye, MB BS, FWACP

Imo State University, Orlu, Nigeria Ernest Ndukaife Anyabolu, MB BS, FMCP, enhealer@yahoo.com

by the aetiology of cardiac disease, and specific cardiovascular disorders were associated with HIV infection.4 Electrocardiographic (ECG) and echocardiography abnormalities have been demonstrated in HIV-positive patients.2,3,5-7 The ECG abnormalities documented include arrhythmias, low-voltage QRS complexes, non-specific ST-segment and T-wave changes, poor R-wave progression, right bundle branch block, axis deviations, enlargement of various heart chambers and QTC prolongation.8,9 The manifestations of HIV infection in organs other than the heart mask the clinical evidence of cardiac disease in these subjects.10-13 Electrocardiography is effectively used to detect cardiac diseases.14 Cardiac diseases attributable to HIV infection are of public health importance because they are usually silent, yet have the potential to cause high mortality rates. There is a paucity of studies on ECG abnormalities in treatment-naïve HIV-positive patients emanating from southeast Nigeria, prompting us to embark on this study. This will help in identifying HIV-positive patients who may have cardiac and non-cardiac illnesses, detectable by ECG, with a view to instituting appropriate early interventions to whittle down adverse outcomes in this group of patients. In addition, ECG is cheap and readily available.

Methods This was a cross-sectional study conducted at the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria, between September and December 2015. The study subjects consisted of 250 treatment-naïve HIV-positive patients and 200 HIV-negative subjects as controls, consecutively recruited from an HIV clinic and the medical wards of the hospital. Inclusion criteria were subjects with confirmed HIV-positive tests, aged 15 years and older. Those subjects who had hypertension, pre-morbid cardiac diseases, a history of cigarette smoking and significant alcohol use, those on medications known to affect the cardiovascular system, pregnant women and puerperal women up to three months, those with diabetes mellitus, acromegaly or thyrotoxicosis were all excluded from the study. Informed consent was obtained from all the subjects who participated in this study. The ethics committee of UNTH approved the study. Demographic and other relevant data were obtained with the help of a questionnaire. Physical examination was done on each subject. Anthropometric data were obtained: height (m) and weight (kg). Body mass index (BMI) was recorded as weight/height2 (kg/m2). Blood pressure (mmHg) was measured, systolic blood pressure (SBP) at Korotkoff phase 1 and diastolic blood pressure (DBP) at phase 5 or at phase 4 when the differences between phase 4 and 5 were more than 10–20 mmHg. Body temperature (°C) was taken and evidence of cardiac decompensation determined.

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Every subject had a 12-lead surface ECG, using a long-lead V1 complex as a rhythm strip with three-channel automated Schiller ECG machine (Switzerland) AT-1. Other investigations done were standard postero-anterior chest X-rays for detecting occult cardiopulmonary lesions and for estimating cardiothoracic ratio (CTR), serum urea, creatinine, electrolyte and calcium levels, and CD4 (clusters of differentiation 4) cell count.

Statistical analysis The data were analysed using SPSS version 15.0. Descriptive statistics were used to determine the mean values of the variables and the median value of the CD4 cell counts in the study population. Chi-squared analysis was used for testing for significant differences between proportions and frequencies, while the Student’s t-test was used to compare continuous variables between the treatment-naïve HIV-positive patients and HIV-negative controls. A p-value < 0.05 was taken as statistically significant.

Results Out of 250 treatment-naïve HIV-positive subjects studied, 124 (49.6%) were female and 126 (50.4%) were male. Out of 200 HIV-negative control subjects, 107 (53.5%) were female and 93 (46.5%) were male. The HIV-positive subjects comprised Igbo 232 (92.6%), Hausa seven (3.1%), Igala five (2.0%) and other groups six (2.3%). By contrast, the HIV-negative control subjects were made up of Igbo 178 (89.0%), Hausa six (2.9%), Igala six (2.9%)

Table 1. Descriptive statistics of the study and control groups p-value

Parameters

Group

Sample size

Mean

Age (years)

HIV+ HIV–

250 200

34.89 36.04

10.58 12.61

BMI (kg/m2)

HIV+ HIV–

250 200

20.05 22.77

Sitting SBP (mmHg)

HIV+ HIV–

250 200

104.2 119.1

Sitting DBP (mmHg)

HIV+ HIV–

250 200

76.6 76.9

Standing SBP (mmHg)

HIV+ HIV–

250 200

98.96 115.0

Standing DBP (mmHg)

HIV+ HIV–

250 200

77.64 75.25

5.267 5.203

< 0.001

Temperature (°C)

HIV+ HIV–

250 200

37.54 36.67

0.60 0.45

< 0.001

1.522 2.663 10.27 9.97 4.747 4.637 10.63 5.84

0.146 < 0.001

and other groups 10 (5.2%). The majority of the study subjects (94.5%) was Christian. All the subjects were in the age range of 15–60 years. The mean age of the treatment-naïve HIV-positive subjects was 34.89 ± 10.58 years and the controls was 36.04 ± 12.61 years. There was no significant difference between the ages of the two groups (p = 0.146). Table 1 shows the descriptive statistics of the study subjects. The mean BMI, SBP and DBP were significantly lower in the treatment-naïve HIV-positive subjects than in the HIV-negative control subjects. Most (70%) of the HIV-positive subjects had a BMI < 18.5 kg/m2 (underweight). The mean body temperature was significantly higher in the HIV-positive subjects than in the HIV-negative subjects. The mean serum albumin level (22.14 g/l) was low in the treatment-naïve HIV-positive subjects (Table 2). Low CD4 cell counts (< 200 cells/ml) were present in 75 (30%) of HIV-positive subjects. All the subjects, both treatment-naïve and HIV-negative, had normal cardiac apex and normal chest X-rays. An abnormal ECG was present in 175 (70%) of the 250 treatment-naïve HIV-positive subjects, and 70 (35%) of the 200 HIV-negative subjects. Table 3 shows the various ECG abnormalities in the study population. Sinus tachycardia was present in 160 (64%) of the HIV-positive subjects, prolonged QTC in 120 (48%), ST depression in 75 (30%) and T-wave inversion in 54 (21.6%). Table 3 shows all the ECG abnormalities. Comparison of the mean ECG parameters between the study groups is shown in Table 4. The mean heart rate, axis, PR interval and QTC were significantly higher in treatmentnaïve HIV-positive subjects than in the HIV-negative subjects. Conversely, the mean QRS duration did not differ significantly between the two groups. All the subjects in the study were in sinus rhythm. Out of the 250 HIV-positive patients, 160 (64.0%) had tachycardia, while 24 (12.0%) of the 200 HIV-negative subjects had tachycardia. This difference was statistically significant (p

< 0.001 Table 3. Various ECG abnormalities in the study population

0.848 < 0.001

SD = standard deviation, BMI = body mass index, SBP = systolic blood pressure, DBP = diastolic blood pressure.

ECG abnormalities

Treatment-naïve HIV+ patients, n (%)

Sinus tachycardia

160 (64)

Sinus bradycardia Prolonged QTC Shortened PR interval (WPW)

Parameters

HIV-positive patients (mean + SD)

Non-HIV-negative controls (mean + SD)

24 (12)

p-value < 0.001

2 (0.8)

14 (7)

0.201

120 (48)

16 (8)

< 0.001

4 (2)

< 0.001

2 (0.8)

ST depression

75 (30)

T-wave inversion

54 (21.6)

16 (8)

0.011

4 (1.6)

4 (2)

< 0.001

Left atrial enlargement

32 (12.8)

16 (8)

0.048

1st degree heart block

6 (2.4)

0.005

Left anterior hemiblock

2 (0.8)

0.024

Incomplete RBBB

4 (1.6)

0.012

4 (2)

0.684

Left-axis deviation Table 2. Laboratory characteristics of the study population (n = 250)

HIV-negative subjects, n (%)

131.5 ± 4.1

134.2 ± 4.2

3.2 ± 0.2

4.2 ± 0.3

RVH

2 (0.8)

22.2 ± 0.5

23.3 ± 1.1

LVH

35 (14)

20 (10)

0.044

Urea (mmol/l)

5.8 ± 0.3

6.1 ± 0.6

Ventricular ectopics

10 (4)

2 (1)

0.019

Ca2+ (mmol/l)

2.1 ± 0.1

2.4 ± 0.2

Atrial ectopics

0.041

Albumin (g/l)

22.1 ± 0.8

3.5 ± 0.8

Low QRS in all leads

0.068

390

645

0.074

Na+ (mmol/l) K+ (mmol/l) HCO3+ (mmol/l)

CD4 cells/ml (median)

SD = standard deviation, Na+ = serum sodium, K+ = serum potassium, HCO3+ = serum bicarbonate, Ca2+ = serum calcium.

Low QRS in limb leads

2 (0.8) 10 (4) 8 (3.2)

RBBB = right bundle branch block, RVH = right ventricular hypertrophy, LVH = left ventricular hypertrophy.

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< 0.001). However, among the 160 HIV-positive patients with tachycardia, 40 (25.0%) had fever, while 120 (75.0%) did not have fever. By contrast, among the 24 HIV-negative subjects with tachycardia, 19 (79.2%) had fever while five (20.8%) did not. When fever was excluded, the prevalence of tachycardia was significantly higher in the HIV-positive patients than the HIV-negative controls. The mean axis was 45.64 ± 6.22° in the treatment-naïve HIV-positive subjects. One subject has left-axis deviation of –30° and three had left-axis deviation of –60°, while none had right axis deviation. Thirty-two (12.8%) of the 250 treatment-naïve HIV-positive subjects had abnormal P waves with P mitral in lead II with or without biphasic P wave in lead VI. By contrast, this was seen in 16 (8.0%) of the HIV-negative subjects. The mean PR interval was 0.16 ± 0.03 seconds in the treatment-naïve HIV-positive patients. Six subjects had prolonged PR intervals (1st degree heart block), while two had shortened PR intervals with associated delta waves and widened QRS complexes, evidence of Wolf–Parkinson–White (WPW) syndrome. No abnormal PR interval was seen in the HIV-negative subjects. The mean QRS duration was 0.07 ± 0.01 seconds. The two subjects with QRS > 0.01 seconds were the same patients that had WPW syndrome stated above. Thirty per cent of the subjects had ST depression in two or more leads. There was no ST elevation in either group. T-wave inversion was present in 54 (21.6%) of the 250 treatment-naïve HIV-positive subjects. Sixteen (8%) of the HIV-negative subjects had inverted T waves. The mean QTC interval was 0.44 ± 0.03 seconds in the treatment-naïve HIV-positive subjects. Of these, 48% had prolonged QTC intervals, compared to 8% of the HIV-negative subjects with same QTC intervals. This difference was significant (p < 0.001). Furthermore, among the subjects without hypocalcaemia, QTC prolongation was observed more often in the HIV-positive patients than the HIV-negative controls. This difference was statistically significant (p < 0.001). The mean serum urea level in the study group was 5.803 ± 0.227 mmol/l. Sixty-four (25.6%) of the 250 HIV-positive patients had a serum urea level > 6.5 mmol/l, and they had some level of dehydration on clinical examination. The mean serum potassium level was 3.168 ± 0.167 mmol/l. Out of the 250 treatment-naïve HIV-positive patients, 150 (60%) had serum potassium levels < 3.5mmol/l, while none had serum potassium levels ≥ 5.5 mmol/l. Table 4. Comparison of ECG parameters between treatment-naïve HIV-positive patients and HIV-negative subjects Parameter

Group

Sample size

Mean

p-value

Heart rate (beats/min)

HIV+ HIV–

250 200

99.6 84.36

11.53 5.35

< 0.001

Axis (degrees)

HIV+ HIV–

250 200

45.64 31.38

61.23 11.78

< 0.001

PR interval (s)

HIV+ HIV–

250 200

0.16 0.14

0.03 0.01

< 0.001

QRS duration (s)

HIV+ HIV–

250 200

0.07 0.06

0.04 0.01

0.068

QTC

HIV+ HIV–

250 200

0.44 0.39

0.03 0.01

< 0.001

SD = standard deviation

317

The mean serum calcium level in the study group was 2.06 ± 0.133 mmol/l. Hypocalcaemia was observed in 25% of the treatment-naïve HIV-positive patients. Forty-six per cent of the patients had hypoalbuminaemia (albumin < 2.8 g/dl). One hundred and twenty (48%) of the treatment-naïve HIV-positive patients had diarrhoea.

Discussion The prevalence of ECG abnormalities in HIV-positive patients at UNTH (70%) was significantly higher, compared to the 35% in HIV-negative subjects. This was similar to the 86% reported by Mounodji et al. in Chad,8 but higher than the 53% seen by Levy et al. in Washington, USA,15 and the 55% reported by Herst et al. in Ontario, Canada.16 These observed differences could be explained by the differences in the study design; the study population was 250 in our study, 32 in the study by Mounodji et al., and 21 in the study by Levy et al. In addition, only patients with Kaposi sarcoma were evaluated in the latter study. Cardiac abnormalities in HIV-positive patients were reported based on either autopsy findings or more advanced cardiac investigations such as echocardiography and Doppler studies. Nevertheless, the prevalence rate of ECG abnormalities in our study was within the general prevalence rate of 28 and 73% documented in some studies.3,8,16,17 The cachectic heart, a clinical pathological and ECG entity seen in chronic debilitating diseases, has been reported in HIV-positive patients.18-20 In our study, 48% of the treatment-naïve HIV-positive patients had low BMI, and ECG abnormalities were found in 80% of those patients with a low BMI (underweight). We also demonstrated that BMI had a significant effect on ECG abnormalities (p < 0.001). This shows that the ECG abnormalities observed in our study may have been contributed to by the low BMI, among various mechanisms elucidated in the pathogenesis.21,22 The prevalence of the various ECG abnormalities seen in HIV-positive patients at UNTH was in order of frequency: sinus tachycardia (64%), prolonged QTC (48%) and T-wave inversion (21.6%). This compares favourably with a similar study by Sani in Jos, Nigeria.23 Mounodji et al. reported sinus tachycardia in 31% of 55 patients studied in Chad.7 Sinus tachycardia was the second commonest ECG abnormality after low-voltage QRS complexes in their series. Heart rate is known to increase with a rise in body temperature.24 When fever was excluded in this study and tachycardia was compared between the treatment-naïve HIV-positive patients and the HIV-negative controls, the difference was statistically significant (p < 0.001). This shows that the tachycardia we noted could not be explained by pyrexia, which some of the patients had. Unexplained fever is a feature of myocarditis, and myocarditis can be caused by HIV infection.4 Some workers, however, view tachycardia as being due to excessive sympathetic stimulation, which could be caused by autonomic imbalance or stimulation of beta-receptors by the gp 120 protein of HIV.25 Emotion may be an additional contributory factor.26 However, dehydration and underweight, measures of malnutrition in developing countries, could also explain, in part, the sinus tachycardia observed in our study. QTC prolongation with no known cause was reported in 69% of AIDS patients studied by Kocheril et al.27 This rate is

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lower than the 48% found in our study. In their study, AIDS patients were evaluated, while in ours, it was treatment-naïve HIV-positive patients. This could, perhaps, account for the differences in the prevalence observed. Although QTC prolongation and torsades de pointes are known to occur with pentamidine therapy,28 none of the patients in our study was on pentamidine. Our study also showed that among subjects who did not have hypocalcaemia, QTC prolongation was observed more in HIV-positive patients than in HIV-negative controls. The QTC prolongation in this study may therefore have been due to non-specific ECG abnormalities found in HIV-positive patients.29 In the present study, 30% of the treatment-naïve HIV-positive patients had ST-segment depression while 21.6% had T-wave inversion. Non-specific ST and T-wave changes on ECG are seen in AIDS patients, caused either by pericardial disease or dilated cardiomyopathy, which are known to occur in HIV-positive patients.29,30 Low-voltage QRS complexes in all the leads may have been due to pericardial effusion. Pericardial effusion has been reported as the commonest cardiac manifestation of HIV infection.15 Low QRS complexes in only the limb leads are a feature of dilated cardiomyopathy. Other ECG abnormalities found in this study were atrial and ventricular ectopics. Although the prevalence of these ectopics did not differ significantly between the treatmentnaïve HIV-positive patients and the HIV-negative subjects, these premature contractions could be explained by possible myocarditis, abnormalities in the conduction system and derangement of the autonomic nervous system, which are all known to occur in these patients.

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and children in Thailand, Southeast Asia. J Trop Med Public Health 1997; 2: 370–374. 8.

Mouanodji M, Mbaignro D, Brendon P. Clinical outline of AIDS patients with cardiac manifestations in Africa. Int Conf AIDS 1994; 10: 266.

Lubega S, Zirembuzi GW, Lwabi P. Heart disease among children with HIV/AIDS attending the pediatric infectious disease clinic at Mulago hospital. Afr Healt Sci 2005; 3: 219–226.

10. Busari OA, Opadijo OG, Adeyemi OA. Cardiac disease in HIV and AIDS. Internet J Cardiol 2008; 5(2). 11. Okeahialam BN, Anjorin FI. Echocardiagraphic study of the heart in AIDS. The Jos Experience. Trop Cardiol 2000; 26: 3–6. 12. Danbauchi S, Sani B, Alhassan A, Oyati A. Echocardiographic features of HIV/AIDS subjects on 1–2 years of ARV drugs in Nigeria. Available at http://www. Umdnj.edu/shindler/hivecho.html. Accessed on 14/06/2016. 13. Iuginbuhl LM, Orav EJ, McIntosh K, Lipshultz SE. Cardiac morbidity and related mortality in children with HIV infectiuon. J Am Med Assoc 1993; 269: 2869–2944. 14. Carr AA, Grand BB, Neuhaus JB, EL-Sador WM, Granditis GB, Gilbert CD. Asymptomatic myocardiac ischemia in HIV-infected adults. AIDS 2008; 22: 257–267. 15. Levy WS, Simon GL, Rios JC. Prevalence of cardiac abnormalities in HIV infection. Am J Cardiol 1989; 63: 86–89. 16. Herst JA, Shepherd FA, Liu P. Prospective assessment of cardiac function in patients with Kaposi sarcoma and AIDS. Clin In Med 1991; 14: 21–27. 17. Rosales-Guzman I, Rosales L, Zghaib A. The autopsy of 51 cases of AIDS with cardiovascular damage. Arch Inst Cardiol Mex 1994; 65: 485–490. 18. Anker SD1, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol. 2002; 85(1): 51–66. 19. Anker SD1, Coats AJ. Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation. Chest 1999; 115(3): 836–847.

Conclusion

20. Buchanan N, Cane RD, Kinsley R, Eyberg CD. Gastrointestinal absorp-

Cardiac and non-cardiac abnormalities, detectable by ECG, were common in treatment-naïve HIV-positive patients in Enugu, Nigeria. The 70% prevalence of ECG abnormalities in treatmentnaïve HIV-positive patients was high. There is a need to evaluate this group of patients at onset for cardiac and non-cardiac abnormalities detectable by ECG. Further research could explore how some of these abnormalities are generated in HIV infection.

21. Herskowitz A, Willoughby S, Wu TC. Immunopathogenesis of HIV-1

tion studies in cardiac cachexia. Intens Care Med 1977; 3(2): 89–91 associated cardiomyopathy. Clin Immunol Immunopathol 1993; 68: 234–241. 22. Sonnenblick M, Rosenmann D, Rosin A. Reversible cardiomyopathy induced by interferon. Br Med J 1990; 300: 1174–1175. 23. Sani MU, Okeahialam BN. QTc interval prolongation in patients with HIV and AIDS. J Nat Med Assoc 2005; 97(12): 1657. 24. Davies P1, Maconochie I. The relationship between body temperature,

References 1.

UNAIDS. Global Report: Annexes. UNAIDS Report on the global AIDS epidemic. http://aidsinfo.unaids.org, accessed on July 18, 2015.

Pairoj R, Nattawat W, Larry E, Morris NK. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 2000; 160: 602–608.

Commarosano C, Lewis W. Cardiac lesions in AIDS. J Coll Cardiol 1985; 5(3): 703–706.

Mpiko N, Hakim J. Impact of immunodeficiency virus infection on cardiovascular disease in Africa. Circulation 2005; 112: 3602–3607.

Longo-Mbenza B, Sehersa KV, Phuatic M, Bikangib FN, Mubagwac K. Heart involvement and HIV infection in African patients; Determinants of survival. Int J Cardiol 1998; 64: 63–73.

Okeahialam BN, Sani MU. Heart disease in HIV/AIDS. Afr J Med Sci 2006; 35: 99–102.

heart rate and respiratory rate in children. Emerg Med J 2009; 26(9): 641–643. doi: 10.1136/emj.2008.061598. 25. Glulio PT, Patriziom BA. HIV envelope glycoprotein (gp 120) interacts with astroglial beta adrenergic receptors . International Conference on AIDS, Florence 1998. Abstract MA. 1037. 26. Peter T, Mark R, Sunil J, Logantha RJ, Pier DL. Anger, emotion, and arrhythmias: from brain to heart. Front Physiol 2011; 2: 67. 27. Kocheri AG, Bokhari SAJ, Bastford QP, Sinusas AJ. Role of antiretroviral treatment in prolonging QTC interval in HIV-positve patients. J Infec Dis 2007; 54(6): 597–602. 28. Eisenhauer MD1, Eliasson AH, Taylor AJ, Coyne PE Jr, Wortham DC. Incidence of cardiac arrhythmias during intravenous pentamidine therapy in HIV-infected patients. Chest 1994; 105(2): 389–395. 29. Woods GL, Goldsmith JC. Fatal pericarditis due to mycobacterium avium intracellulare in AIDS. Chest 1989; 85: 1355–1359. 30. Decastro S, D’Ameti G, Gallo P. Frequency of development of acute

Pathmancend C, Anuroj K, Thisyakom C, Sueblinwong V. Cardiovascular

global left ventrivular dysfunction in HIV infection. J Am Coll Cardiol

manifestations and left ventricular functions in HIV infection in infants

19944; 24: 1018–1024.

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Red cell distribution width is correlated with extensive coronary artery disease in patients with diabetes mellitus Atac Celik, Metin Karayakali, Fatih Altunkas, Kayihan Karaman, Arif Arisoy, Koksal Ceyhan, Hasan Kadi, Fatih Koc

Abstract Introduction: Previous studies have predicted an independent relationship between red cell distribution width (RDW) and the risk of death and cardiovascular events in patients with coronary artery disease (CAD). The aim of this study was to investigate the relationship between RDW and extensiveness of CAD in patients with diabetes mellitus (DM). Methods: Two hundred and thirty-three diabetic patients who underwent coronary angiographies at our centre in 2010 were included in the study. All of the angiograms were re-evaluated and Gensini scores were calculated. Triple-vessel disease was diagnosed in the presence of stenosis > 50% in all three coronary artery systems. Result: RDW was significantly higher in diabetic CAD patients (p < 0.001). Patients with CAD who had a RDW value above the cut-off point also had higher Gensini scores, higher percentages of obstructive CAD and triple-vessel disease (p ≤ 0.001 for all). According to the cut-off values calculated using ROC analysis, RDW > 13.25% had a high diagnostic accuracy for predicting CAD. RDW was also positively correlated with Gensini score, obstructive CAD and triple-vessel disease (r < 0.468 and p < 0.001 for all). Conclusion: RDW values were found to be increased in the diabetic CAD population. Higher RDW values were related to more extensive and complex coronary lesions in patients with DM. Keywords: red cell distribution width, coronary artery disease, diabetes mellitus, Gensini score Submitted 27/5/16, accepted 8/3/17 Published online 23/8/17 Cardiovasc J Afr 2017; 28: 319–323

www.cvja.co.za

DOI: 10.5830/CVJA-2017-015

Department of Cardiology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey Atac Celik, MD, dretaci@yahoo.com Metin Karayakali, MD Fatih Altunkas, MD Kayihan Karaman, MD Arif Arisoy, MD Koksal Ceyhan, MD

Department of Cardiology, Faculty of Medicine, Balikesir University, Balikesir, Turkey Hasan Kadi, MD

Department of Cardiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey Fatih Koc, MD

Red cell distribution width (RDW) is widely accepted as a measure of anisocytosis and is routinely reported during automated complete blood counts.1 It is commonly used to narrow the differential diagnosis of anaemia.2 Many studies have reported that higher RDW values are associated with a worse prognosis in coronary artery disease, heart failure, peripheral artery disease, and even in the unselected population.3-6 Diabetes mellitus (DM) is one of the major risk factors for atherosclerosis.7 Coronary artery disease (CAD) is more common among patients with DM.8 CAD is the main cause of death in DM, and DM is associated with a two- to four-fold increased mortality risk from heart disease.9 Moreover, it has a worse prognosis and is usually more advanced at the time of diagnosis.10 Previous studies have shown an association between RDW value and the severity of CAD, but there were no data on the diabetic population.11-13 The aim of this study was to investigate the relationship between RDW and the extensiveness of CAD in patients with DM.

Methods The study group was formed retrospectively from our catheterisation laboratory registries. Two hundred and thirtythree diabetic patients who underwent coronary angiography at our centre in 2010 were included in the study. The diagnosis of DM was based on a previous history of diabetes treated with or without drug therapies. Patients with acute or chronic inflammatory disease, severe liver or renal insufficiency, morbid obesity, malignancy, valvular heart disease, heart failure, prior coronary intervention, or who had experienced acute coronary syndrome within 30 days prior to coronary angiography were excluded from the study. In addition, subjects were also excluded if they had a history of anaemia and blood transfusion. Patient age, gender, past history of disease, smoking habits and current medications were carefully ascertained. Hypertension was defined as blood pressure ≥ 140/90 mmHg or if the subject was taking antihypertensive medications. Dyslipidaemia was defined as low-density lipoprotein cholesterol ≥ 100 mg/dl (≥ 2.59 mmol/l) or if they were taking a hypolipidaemic drug. Anaemia was defined as haemoglobin concentration < 13 mg/dl in men and < 12 mg/dl in women. Body mass index (BMI) was calculated as weight/height2 (kg/m2). This investigation was a single-centre study. Informed consent was obtained from all participants, and the study protocol was approved by the ethics committee at our institution. The study was in accordance with the Declaration of Helsinki. Blood samples were drawn from each patient after overnight fasting, during admission for routine chemistry. Haemoglobin, white blood cell count, mean platelet volume (MPV) and RDW values were measured with a Pentra DX 120 analyser

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(ABX, Montpellier, France). Neutrophil/lymphocyte (N/L) ratio was calculated by dividing the total neutrophil count by the lymphocyte count. High-sensitivity C-reactive protein (hs-CRP) analyses were done using the immunonephelometry method (Dade Behring, Inc, BN Prospect, Marburg, Germany). Serum levels of creatinine, fasting blood glucose, triglycerides, total cholesterol, and low- and high-density lipoprotein cholesterol were measured using conventional methods. A conventional angiography device (Artis zee; Siemens, Erlangen, Germany) was used for coronary angiography. Angiograms were evaluated qualitatively by two different experts, and mean values were used to assess the rate of stenosis. Patients with atherosclerotic lesions in any of the coronary arteries were diagnosed as having CAD. Obstructive CAD was defined as stenosis of ≥ 50% of the diameter of a major epicardial or branch vessel > 2.0 mm in diameter. Gensini scores were calculated for each patient as previously defined.14 Triple-vessel disease was defined as stenosis of ≥ 50% in each of the major vessels or their major branches. Patients were evaluated and treated according to the current guidelines.

included in the low RDW group. The rest formed the high RDW group. There were no significant differences between the low and high RDW groups with regard to age, gender, hypertension, hyperlipidaemia, smoking, BMI, systolic and diastolic blood pressure and medications (Table 2). There were also no differences between the low and high RDW groups with regard to serum levels of glucose, uric acid, lipid profile, WBC and haemoglobin (Table 2). Serum levels of creatinine, hs-CRP, MPV and N/L ratio were significantly higher in the high RDW group (p < 0.005 for all) (Table 2). RDW was positively correlated with hs-CRP, MPV and N/L ratio (r = 0.248, r = 0.240 and r = 0.281, respectively and p = 0.033 for hs-CRP, p < 0.001 for MPV and N/L ratio). Patients with CAD who had a RDW value above the cut-off point also had higher Gensini scores, higher percentages of obstructive CAD and triple-vessel disease (p ≤ 0.001 for all) (Table 3). According to the cut-off values calculated using ROC curve analysis, RDW > 13.25% had a high diagnostic accuracy for predicting CAD (area under the ROC curve = 0.742, p < Table 1. Baseline characteristics and laboratory findings of the study groups

Statistical analysis Statistical analysis was performed using commercial software (IBM SPSS Statistics 22, SPSS Inc, Chicago, IL, USA). After performing the Kolmogorov–Smirnov normality test, two independent-sample t-tests were used to compare the normally distributed independent variables, and the Mann–Whitney U-test was used to compare the non-normally distributed independent variables between the two groups. For normally distributed variables, mean and standard deviation (SD) are listed, otherwise, median values are given. To analyse the categorical data, a chi-squared test was used. Categorical data are expressed as numbers and percentages. A receiver operating characteristic (ROC) curve was constructed for RDW to test the effectiveness of various cut-off points in predicting CAD. The area under the ROC curve was calculated; the sensitivity and specificity for the RDW of the most appropriate cut-off point were calculated for predicting CAD. Correlations were determined using the Spearman test. A p-value < 0.05 was considered statistically significant.

Results The study group was divided into two, according to angiographic results (CAD negative and CAD positive). There were no significant differences between the two groups with regard to age, gender, hypertension, hyperlipidaemia, smoking, BMI, systolic and diastolic blood pressure, and medications, including aspirin, renin–angiotensin system (RAS) blockers and statins (Table 1). Clopidogrel and calcium channel blocker use was higher in the CAD-positive group (p < 0.001 and p = 0.001, respectively) (Table 1). There were no differences between the two groups in serum levels of glucose, creatinine, uric acid, hs-CRP, lipid profile, WBC, haemoglobin, MPV and N/L ratio (Table 1). RDW was significantly higher in the CAD-positive group (12.5 ± 1.5 vs 13.8 ± 1.7%, p < 0.001) (Table 1). The most appropriate cut-off point calculated for predicting CAD was 13.25%. The patients who had a RDW ≤ 13.25% were

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Variables

CAD– (n = 109)

CAD+ (n = 124)

p-value

58.6 ± 8.0

57.7 ± 9.0

Gender (male)

61 (56)

68 (55)

0.895

Hypertension

93 (85)

104 (84)

0.856

Dyslipidaemia

61 (56)

77 (62)

0.353

Smoking

14 (13)

24 (20)

0.215

Aspirin

72 (66)

93 (75)

0.150

0 (0)

23 (19)

< 0.001

RAS blockers

70 (64)

93 (75)

0.086

β-blockers

34 (31)

66 (53)

0.001

Calcium channel blockers

20 (18)

23 (19)

1.000

Age (years)

Clopidogrel

Statins

0.387

30 (28)

43 (38)

0.260

Body mass index (kg/m2)

28.7 ± 5.0

28.3 ± 4.5

0.536

Systolic blood pressure (mmHg)

130 ± 13

132 ± 14

0.144

Diastolic blood pressure (mmHg)

78 ± 9

79 ± 8

0.627

166 ± 75

174 ± 78

0.416

[9.21 ± 4.16]

[9.66 ± 4.33]

Glucose (mg/dl) [mmol/l] Creatinine (mg/dl) [μmol/l]

0.73 ± 0.18

0.71 ± 0.28

[64.53 ± 15.91]

[62.76 ± 24.75]

0.630

4.5 ±1.4

4.9 ± 1.7

hs-CRP (mg/l)

5.12 ± 2.93

6.07 ± 4.83

0.348

Total cholesterol (mg/dl)

197 ± 40

199 ± 49

0.726

[5.10 ± 1.04]

[5.15 ± 1.27]

Uric acid (mg/dl)

[mmol/l] Triglycerides (mg/dl) [mmol/l] LDL cholesterol (mg/dl) [mmol/l] HDL cholesterol (mg/dl) [mmol/l]

187 ± 86

191 ± 138

[2.11 ± 0.97]

[2.16 ± 1.56]

120 ± 36

122 ± 44

[3.11 ± 0.93]

[3.16 ± 1.14]

46 ± 11

45 ± 13

[1.19 ± 0.28]

[1.17 ± 0.34]

0.081

0.786 0.688 0.283

7.0 ± 1.9

7.2 ± 2.0

Haemoglobin (g/dl)

13.1 ± 1.1

13.1 ± 1.6

0.757

RDW (%)

12.5 ± 1.5

13.8 ± 1.7

< 0.001

MPV (fl)

8.43 ± 1.10

8.59 ± 1.02

0.265

Neutrophil/lymphocyte ratio (%)

2.26 ± 1.37

2.52 ± 1.94

0.457

WBC (103 cells/µl)

0.407

CAD: coronary artery disease, CAD–: patients with normal coronary arteries, CAD+: patients with coronary artery disease, RAS: renin–angiotensin system, hs-CRP: high-sensitivity C-reactive protein, LDL: low-density lipoprotein, HDL: high-density lipoprotein, WBC: white blood cells, RDW: red cell distribution width, MPV: mean platelet volume. Data are shown as n (%) or mean ± SD

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Table 3. Severity of coronary artery disease between low and high RDW groups

Table 2. Baseline characteristics and laboratory findings of low and high RDW groups

Variables

Low RDW (≤ 13.25) (n = 46)

High RDW (> 13.25) (n = 78)

Age (years)

p-value

56.7 ± 8.0

58.2 ± 9.5

0.381

Gender (male)

27 (59)

41 (53)

0.318

Hypertension

38 (83)

66 (85)

0.478

Dyslipidaemia

29 (63)

48 (61)

0.511

5 (11)

19 (24)

0.052

33 (72)

60 (77)

0.331

Smoking Aspirin Clopidogrel

11 (24)

12 (15)

0.173

RAS blockers

32 (70)

61 (78)

0.195

β-blockers

28 (61)

38 (49)

0.130

9 (20)

14 (18)

0.501

Calcium channel blockers Statins

13 (28)

30 (39)

0.169

Body mass index (kg/m2)

28.8 ± 4.5

28.0 ± 4.5

0.363

Systolic blood pressure (mmHg)

131 ± 13

133 ± 15

0.328

Diastolic blood pressure (mmHg)

78 ± 8

79 ± 8

0.196

163 ± 77

181 ± 79

0.207

[mmol/l]

[9.05 ± 4.27]

[10.05 ± 4.38]

Creatinine (mg/dl)

0.63 ± 0.17

0.76 ± 0.31

[55.69 ± 15.03]

[67.18 ± 27.40]

Glucose (mg/dl)

[μmol/l] Uric acid (mg/dl) hs-CRP (mg/l) Total cholesterol (mg/dl) [mmol/l] Triglycerides (mg/dl) [mmol/l] LDL cholesterol (mg/dl) [mmol/l] HDL cholesterol (mg/dl) [mmol/l] WBC (103 cells/µl) Haemoglobin (g/dl)

4.6 ± 1.5

5.1 ± 1.7

0.213

7.12 ± 5.58

0.043

195 ± 44

202 ± 52

0.481

[5.05 ± 1.14]

[5.23 ± 1.09]

197 ± 173

188 ± 114 [2.12 ± 1.29]

114 ± 33

127 ± 48

[2.95 ± 0.85]

[3.29 ± 1.24]

46 ± 15

44 ± 12

[1.19 ± 0.39]

[1.14 ± 0.31]

Low RDW (≤ 13.25) (n = 46)

High RDW (> 13.25) (n = 78)

p-value

Total

11 [4–31]

43 [16–73]

< 0.001

LAD

5 [3–12]

18 [5-30]

0.001

3 [1–5]

7 [3–19]

< 0.001 < 0.001

Variables Gensini score

RCA Obstructive CAD

2 [1–3]

7 [2–18]

23 (50)

63 (81)

0.001

2 (4)

26 (33)

< 0.001

Triple-vessel disease

RDW: red cell distribution width, LAD: left anterior descending coronary artery, Cx: circumflex coronary artery, RCA: right coronary artery, CAD: coronary artery disease. Data are shown as n (%) or median [interquartile range].

Table 4. Diagnostic accuracy of red cell distribution width for coronary artery disease Cut-off value AUC 95% CI of AUC Sensitivity Specificity p-valuea

Variable RDW (%)

> 13.25

0.742

0.679–0.806

0.629

0.771

< 0.001

AUC: area under the receiver operating characteristic curve, CI: confidence interval, RDW: red cell distribution width. aSignificance level of AUC.

0.008

4.11 ± 1.88

[2.23 ± 1.95]

321

0.736 0.088 0.461

7.1 ± 1.9

7.3 ± 2.2

0.516

13.3 ± 1.5

13.0 ± 1.6

0.454

RDW (%)

12.9 ± 0.7

14.3 ± 1.4

0.001

MPV (fl)

8.35 ± 1.13

8.72 ± 0.93

0.049

Neutrophil/lymphocyte ratio (%)

1.92 ± 0.07

2.89 ± 2.33

0.009

RDW: red cell distribution width, RAS: renin–angiotensin system, hs-CRP: high-sensitivity C-reactive protein, LDL: low-density lipoprotein, HDL: highdensity lipoprotein, WBC: white blood cells, MPV: mean platelet volume. Data are shown as n (%) or mean ± SD

from Felker et al., which concluded that there was a strong and independent association between RDW and the risk of adverse outcomes in heart failure patients.16 Subsequently, Tonelli et al. predicted an independent relationship between RDW and the risk of cardiovascular death in patients with CAD.3,16 Following the direction of these studies, researchers reported that higher RDW values were also associated with a worse prognosis in peripheral artery disease and even in the unselected population.5,6 Several explanations could be postulated in order to explain the underlying mechanisms that may contribute to a worse prognosis among patients with cardiovascular disease. However the reason for the poor prognosis remains unclear. It has not been determined yet whether RDW is a marker of the severity of various disorders or if there is direct link between anisocytosis and poor prognosis in patients with CAD. Factors

1.0

0.001) (Table 4, Fig. 1). RDW was positively correlated with Gensini score, obstructive CAD and triple-vessel disease (r = 0.468, r = 0.409 and r = 0.332, respectively and p < 0.001 for all).

This study showed an association between RDW and CAD in diabetic patients. RDW values were found to be higher in the diabetic CAD population and higher RDW values were related to more extensive and complex coronary lesions. RDW is a marker of the variation in size of red blood cells circulating in the body, which reflects the value of anisocytosis.1 It is routinely reported during automated complete blood counts. An elevation in RDW values may be seen in patients with ineffective erythropoiesis (iron, vitamin B12 or folic acid deficiency and various haemoglobinopathies), recent blood transfusions and haemolysis.15 In daily practice it is commonly used to narrow the differential diagnosis of anaemia.2 The growing attention given to the relationship between RDW and cardiovascular events was first spurred on by the report

Sensitivity

Discussion

0.8

0.6

0.4

0.2 – : RDW (%) 0.0

0.0

0.2

0.4 0.6 1 – Specificity

0.8

1.0

Fig. 1. Receiver operating characteristic curve showing the relationship between sensitivity and false positivity at various cut-off points for red cell distribution width to predict coronary artery disease.

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impairing bone marrow haematopoiesis are probably identical to those that worsen the prognosis in CAD. These factors are anaemia, iron deficiency, lipid disorders, chronic inflammation, neurohumoral activation, glycaemic disturbance, vitamin D3 deficiency, oxidative stress and renal failure.17,18 Additionally, red cell deformability diminution may result in impaired flow through the microcirculation.17 Previous studies have shown an association between RDW and the severity of CAD.11-13 Akin et al. investigated the association of RDW with the severity of CAD in acute myocardial infarction and showed that higher RDW values were correlated with higher Syntax scores, which means more complex coronary lesions. They found that after multiple logistic regression analysis, RDW remained a significant predictor for the severity of CAD.11 Isik et al. evaluated this relationship in patients with stable angina pectoris and found an independent association between RDW and the complexity of CAD, which was determined with Syntax scores.12 A large Chinese cohort study with 677 subjects showed significantly elevated RDW values in CAD patients and a positive correlation between RDW and the Gensini score.13 They also found that a RDW value of 12.85% was an effective cut-off point for predicting CAD, with a sensitivity of 50% and a specificity of 65%. Recently, Sahin et al. concluded that RDW values were independently associated with a high Syntax score but were not associated with long-term mortality in patients with non-ST-elevation myocardial infarction.19 In agreement with the current literature, we found that elevation in RDW values was associated with both the presence and complexity of CAD. Furthermore, we found that an RDW value of 13.25% was an effective cut-off point in order to determine the presence of CAD. Moreover, our study is the first to show an association between RDW and CAD severity in a diabetic population. Chronic inflammation and neurohumoral activation are thought to be the key factors for both a worse cardiovascular prognosis and more complex coronary lesions.17,18 In our study, hs-CRP levels were similar in the two CAD groups, but there was a positive correlation between RDW and hs-CRP. Unfortunately, we did not measure brain natriuretic peptides, which are markers of the neurohumoral pathway. Some researchers demonstrated that elevated mean platelet volume (MPV) was associated with acute coronary syndromes, thrombosis and inflammation.20,21 We also found a positive relationship between RDW and MPV. It is well known that there is a link between glycaemic disturbance and high RDW values. Two different studies showed a relationship between glycosylated haemoglobin and RDW in an unselected elderly population and in healthy adults.22,23 Garg et al. demonstrated that glycosylated haemoglobin was an independent predictor of CAD severity in a non-diabetic population.24 Our findings support the results of previous studies. This study has some limitations. First, we did not measure some factors that might have influenced RDW levels, such as vitamin B12, folate and iron levels. Second, cardiovascular events were not analysed due to the cross-sectional nature of the study. Third, the relationship between RDW, glycaemic disturbance and the severity of CAD could have been better understood if we had analysed glycosylated haemoglobin levels. Lastly, the diagnosis of DM was based on a previous history instead of biochemical results.

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Conclusion RDW values were significantly higher in diabetic than non-diabetic patients with CAD. Higher RDW values were related to more extensive and complex coronary lesions, suggesting that RDW may be a marker for predicting CAD severity in patients with DM.

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19. Sahin O, Akpek M, Sarli B, Baktir AO, Savas G, Karadavut S, et al.

129–132. PubMed PMID: 22813786.

Association of red blood cell distribution width levels with severity

24. Garg N, Moorthy N, Kapoor A, Tewari S, Kumar S, Sinha A, et al.

of coronary artery disease in patients with non-ST elevation myocar-

Hemoglobin A(1c) in nondiabetic patients: an independent predictor

dial infarction. Med Princ Pract 2015; 24(2): 178–183. PubMed PMID:

of coronary artery disease and its severity. Mayo Clin Proc 2014; 89(7):

25531370.

908–916. PubMed PMID: 24996234.

Marijuana associated with three-fold risk of death from hypertension Marijuana use is associated with a three-fold risk of death from hypertension, according to research published recently in the European Journal of Preventive Cardiology. ‘Steps are being taken towards legalisation and decriminalisation of marijuana in the United States, and rates of recreational marijuana use may increase substantially as a result’, said lead author Barbara A Yankey, a PhD student in the School of Public Health, Georgia State University, Atlanta, US. ‘However, there is little research on the impact of marijuana use on cardiovascular and cerebrovascular mortality.’ In the absence of longitudinal data on marijuana use, the researchers designed a retrospective follow-up study of NHANES (National Health and Nutrition Examination Survey) involving participants aged 20 years and older. In 2005–2006, participants were asked if they had ever used marijuana. Those who answered ‘yes’ were considered marijuana users. Participants reported the age when they first tried marijuana and this was subtracted from their current age to calculate the duration of use. Information on marijuana use was merged with mortality data in 2011 from the National Centre for Health Statistics. The researchers estimated the associations of marijuana use and duration of use with death from hypertension, heart disease and cerebrovascular disease, controlling for cigarette use and demographic variables including gender, age and ethnicity. Death from hypertension included multiple causes such as primary hypertension and hypertensive renal disease. Among a total of 1 213 participants, 34% used neither marijuana nor cigarettes, 21% used only marijuana, 20% used marijuana and smoked cigarettes, 16% used marijuana and were past-smokers, 5% were past-smokers and 4% only smoked cigarettes. The average duration of marijuana use was 11.5 years. Marijuana users had a higher risk of dying from hypertension. Compared to non-users, marijuana users had a 3.42-times higher risk of death from hypertension and a 1.04 greater risk for each

year of use. There was no association between marijuana use and death from heart disease or cerebrovascular disease. Ms Yankey pointed out that there were limitations to the way marijuana use was estimated. For example, it cannot be certain that participants used marijuana continuously since they first tried it. She said: ‘Our results suggest a possible risk of hypertension mortality from marijuana use. This is not surprising since marijuana is known to have a number of effects on the cardiovascular system. Marijuana stimulates the sympathetic nervous system, leading to increases in heart rate, blood pressure and oxygen demand. Emergency rooms have reported cases of angina and heart attacks after marijuana use.’ ‘We found higher estimated cardiovascular risks associated with marijuana use than cigarette smoking’, said Ms Yankey. ‘This indicates that marijuana use may carry even heavier consequences on the cardiovascular system than that already established for cigarette smoking. However, the number of smokers in our study was small and this needs to be examined in a larger study.’ ‘Needless to say, the detrimental effects of marijuana on brain function far exceed that of cigarette smoking’, she added. Ms Yankey said it was crucial to understand the effects of marijuana on health so that policy makers and individuals could make informed decisions. She said: ‘Support for liberal marijuana use is partly due to claims that it is beneficial and possibly not harmful to health. With the impending increase in recreational marijuana use it is important to establish whether any health benefits outweigh the potential health, social and economic risks. If marijuana use is implicated in cardiovascular diseases and deaths, then it rests on the health community and policy makers to protect the public.’ Source: European Society of Cardiology Press Office

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Prevalence of obesity and body size perceptions in urban and rural Senegal: new insight on the epidemiological transition in West Africa Enguerran Macia, Emmanuel Cohen, Lamine Gueye, Gilles Boetsch, Priscilla Duboz

Abstract Background: The objectives of this study were to assess the prevalence of obesity in Dakar and in Tessekere, a rural municipality in northern Senegal, and to compare ideal body size between these populations. Methods: A cross-sectional survey was carried out in 2015 on a representative sample of 1 000 adults, aged 20 years and older in Dakar, and 500 adults of the same age in Tessekere. Results: The prevalence of obesity and overweight was higher in Dakar than in Tessekere. However, overweight and obesity rates of young women living in this rural area were close to those of young women in Dakar. At a body mass index of 27.5 kg/m², less than 40% of the men in Dakar and Tessekere found themselves too fat, compared to 50% of urban women and 30% of rural women. Conclusion: This study explains how and why obesity is becoming a rural health problem in Senegal. Keywords: Africa, biological anthropology, epidemiological transition, nutrition transition, overweight Submitted 4/11/16, accepted 13/7/17 Published online 25/10/17 Cardiovasc J Afr 2017; 28: 324–330

www.cvja.co.za

DOI: 10.5830/CVJA-2017-034

Overweight and obesity are important risk factors for cardiovascular disease.1,2 The increasing prevalence of obesity during the last few decades in a number of countries3 has been reported as a global pandemic and a major public health issue worldwide.4-7 Sub-Saharan Africa (SSA) is not immune to this Faculty of Medicine, Pharmacology and Odontology, University of Cheikh Anta Diop, Dakar, Senegal; National Centre for Scientific Research, University of Bamako, Mali; and National Centre for Scientific and Technological Research, Burkina Faso Enguerran Macia, PhD, enguerranmacia@gmail.com Emmanuel Cohen, PhD Lamine Gueye, PhD Gilles Boetsch, PhD

Department of Eco-Anthropology and Ethnobiology, National Museum of Natural Science, University of Paris, France Emmanuel Cohen, PhD

Department of Anthropology, Ethics and Health, Santé, Aix-Marseille University, Marseille, France Priscilla Duboz, PhD

epidemic.8,9 In urban West Africa, the prevalence of obesity more than doubled from 7.0% in 1990–94 to 15.0% in 2000–04.10 However, over this 15-year period, Abubakari and colleagues noted that obesity rates seemed to remain unchanged in rural West Africa, possibly due to the small number of studies retrieved from these populations.10 Despite the threat posed by obesity in West Africa, there are very few studies addressing this issue in Senegal and none in the rural areas. To our knowledge, few studies have evaluated the prevalence of obesity among both men and women in Dakar,11 the political and economic capital of the country. In terms of body mass index (BMI), the prevalence of overweight and general obesity in 2009 was 22.3 and 8.3%, respectively, in Dakar, whereas using waist circumference (WC), the prevalence of central obesity was 21.2%.11 Only by monitoring prevalence over time can the evolution of the obesity epidemic in the Senegalese capital be understood.1 Various factors contribute to the high prevalence of obesity in SSA.8,9 More precisely, numerous macrosocial (e.g. urbanisation,12 globalisation9), genetic,13 behavioural (mainly diet and physical activity14), sociodemographic,15 and culturally underlying16 factors have been reported as determinants of obesity in West Africa. In the context of this comparative urban–rural study in Senegal, a focus on urbanisation, sociodemographics and perception of body size is fundamental. It is now well established that urbanisation is a major driving force in obesity, by reducing physical activity and increasing consumption of energy-dense diets.17 In West Africa, urban residents have three times the odds of being obese than rural residents.10 Among sociodemographic factors, age and gender have regularly been shown to be associated with obesity in SSA8 and West Africa.10 Beyond these recurrent and robust predictors, the role of socio-economic status (SES) seems more complex in SSA. Indeed, while studies regularly report that obesity is significantly more likely to occur in the highest SES group,8 Ziraba and colleagues observed that the increase in obesity was higher among the poorest than among the richest African urban dwellers during the period 1995 to 2005.18 In line with the epidemiological transition occurring in SSA,19,20 the relationship between obesity and SES is likely to change in the coming years and gradually affect the lowest SES groups more than the highest. In SSA, positive traditional representations of stoutness – the social validation of the big belly for men and large hips for women21 – may also contribute to the gradual development of obesity. Obesity is a concept that is viewed differently across cultures.22 In SSA, where HIV and other diseases associated with wasting away are prevalent, overweight and obesity have been associated with health.16,23 Moreover, once married, extra weight is seen as an indicator that the spouse is well cared for.24

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In Pikine, a suburb of Dakar, these positive perceptions of stoutness have been observed among women.25 However, no study has been conducted from this perspective among urban men, or among the rural population. Therefore, the objectives of this study were (1) to assess and compare the prevalence of obesity, general and central, in Dakar and in Tessekere, a rural municipality in northern Senegal, and to analyse trends in obesity in Dakar; (2) to determine sociodemographic risk factors for obesity in both environments; and (3) to compare ideal body size between urban and rural areas.

Methods The study was approved by the National Ethics Committee for Health Research of Senegal (protocol SEN13/67, no 0272). The research was conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from participants. This study was conducted from February to August 2015 on a sample of 1 000 individuals, aged 20 years and older in Dakar, and on a sample of 500 adults of the same age bracket in the Tessekere municipality. The samples were constructed using the combined quota method (cross-section by age, gender and town of residence in Dakar; only by age and gender in Tessekere municipality) in order to strive for representativeness of the population aged 20 years and older living in the department of Dakar and in Tessekere municipality. Data from the Agence Nationale de la Statistique et de la Démographie dating from the last census (2013) were used. The quota variables used were gender (male/female), age (20–29, 30–39, 40–49, 50–59, and 60 years and over, with an upper age limit of 100 years) and, for Dakar, town of residence. In Dakar, the towns were grouped by the four arrondissements making up the department: Plateau-Gorée (five towns), Grand Dakar (six towns), Parcelles Assainies (four towns) and Almadies (four towns). In practical terms, this method requires constructing a sample that reflects the proportions observed in each target population. For example, according to the last census, men aged 20–29 years living in the town of Medina (arrondissement of Plateau-Gorée) represented 1.9% of the population aged 20 years and over living in the department of Dakar. The sample was constructed to reflect this proportion and it included 19 men aged 20–29 living in this town. Inclusion criteria were individuals 20 years old or older, living in the department of Dakar. Pregnant women were excluded from the study. Eight trained investigators (PhD students in Medicine, Pharmacy and Sociology) started out each day from different points in each town (Dakar) or camp (Tessekere) to interview individuals in Wolof, Haalpulaar or French in every third home. Investigators had a certain number of individuals to interview to meet the quotas. Only one person was selected as a respondent in each home. Investigators went to the house, inquired about the inhabitants and then chose the first person they saw who met the characteristics needed for the quotas. In-person interviews were conducted. They ranged from 45 minutes to more than one hour and 30 minutes, depending on respondent availability and desire to talk. Weight was measured using a digital scale (measurement accuracy of 100 g), with subjects dressed in minimal clothing

325

and barefoot. To measure height, the subject was to stand ‘at attention’, arms at the sides, heels together, without shoes. Following World Health Organisation (WHO) recommendations, BMI was calculated by dividing the weight (kg) by the square of the height (m2). Underweight was defined as BMI < 18.5 kg/m2; overweight was defined as 25 ≤ BMI < 30 kg/m2; and obesity corresponded to a BMI of ≥ 30 kg/m2.26 Waist circumference (WC) was measured at the narrowest point of the abdomen at the end of a normal expiration. WC was measured using a measuring tape with 1-mm accuracy. WC of ≥ 102 cm in men and ≥ 88 cm in women was considered central obesity.27 Waist-to-hip ratio (WHR) was also used as a criterion of central obesity: a WHR of ≥ 0.9 in men and ≥ 0.8 in women was considered central obesity.28 Among the sociodemographic data collected during the interviews, three variables were taken into account for this study: age, gender and educational level. Four age groups were defined: 20–29, 30–39, 40–49 and 50 years and over. Gender was coded as follows: 1 for women, 0 for men. In Dakar, five levels of education were defined based on the Senegalese school system: none, primary (one to five years of schooling), intermediate (six to eight years), secondary (nine to 12 years), and university (13 years and over). In the Tessekere municipality, given the large proportion of persons who have never attended school (76%), the educational level was dichotomised: no schooling/one or more years of schooling. Satisfaction with body weight was assessed in one question, with five possible responses: ‘Do you think you are: too thin, a little too thin, average, a little too fat, too fat?’ To determine ideal body size, we took the BMI at which the same percentage of individuals believed they were too heavy as those who felt they were too thin.29 We also used the body size scale (BSS), developed and validated by Cohen et al. in Senegal,30 to assess ideal body size (IBS) of women and men, to obtain a complementary representation of body image assessed from the questionnaire. This tool has two advantages: (1) it consists of a gender-specific scale of nine models; and (2) it represents real black models with their anthropometric characteristics to assess specific body weight perceptions in African populations. One model represents the underweight category, three models the normal-weight category, two models the overweight category, and one model each class of obesity level as defined by the WHO (30.0 < BMI ≤ 34.9 kg/m², 35.0 < BMI ≤ 39.9 kg/m², and ≥ 40 kg/m²). BSS was considered a numerical variable, as each human picture ranged from 1 to 9 according to increasing BMI categories to measure ideal body size.

Statistical analysis To answer our research questions, we used the Student’s t-test, ANOVA, chi-squared test and logistic regressions. Results are expressed as mean ± standard deviation for continuous variables or as percentages for categorical variables. Bivariate comparisons were performed using the Student’s t-test, ANOVA for continuous variables, and chi-squared tests for categorical variables. Multivariate analyses were performed using binary logistic regression and results are expressed as odds ratios with 95% confidence intervals (CIs). The software used for the statistical analysis was SPSS Statistics 22 for Windows.

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Table 1. Demographic and anthropomatic characteristics of the sample Dakar Total (n = 984)

Characteristics Age (years)

35.70 ± 13.16

Height (cm)

172.56 ± 9.87

Tessekere

Male (n = 494) 35.89 ± 13.27 178.96 ± 8.07

Female (n = 490)

p-value

35.51 ± 13.07 166.11 ± 6.88

Weight (kg)

69.28 ± 14.44

70.21 ± 16.67

68.34 ± 16.00

BMI (kg/m²)

23.33 ± 4.89

21.91 ± 3.54

24.76 ± 5.59

General obesity, n (%)

95 (9.7)

WC (cm)

84.31 ± 13.02

Central obesity by WC, n (%)

256 (26)

WHR

0.836 ± 0.081

Central obesity by WHR, n (%)

14 (2.8) 81.51 ± 10.65

393 (39.9)

83 (16.8)

208 (21.1)

84 (27)

< 0.001

169.63 ± 10.38

0.043

235 (48)

< 0.001

0.834 ± 0.092

0.579

37.26 ± 15.45 175.85 ± 8.09

p-value

37.40 ± 15.08 163.75 ± 8.77

0.917 < 0.001

60.25 ± 12.32

62.38 ± 11.26

58.23 ± 12.96

< 0.001

20.15 ± 3.24

21.74 ± 4.60

< 0.001

14 (2.8)

2 (0.8)

77.25 ± 10.59

12 (4.7)

76.13 ± 9.31

59 (11.9)

56 (22.?)

0.847 ± 0.075

0.009

78.32 ± 11.59

3 (1.2)

0.839 ± 0.079

< 0.001

310 (63.3)

Female (n = 255)

20.97 ± 4.07

< 0.001 < 0.001

0.021 < 0.001

0.831 ± 0.082

117 (23.6)

17 (7.1)

100 (39.2)

124 (25.3)

373 (75.2)

168 (69.7)

205 (80.4)

185 (37.8)

123 (24.8)

73 (30.3)

50 (19.6)

0.019 < 0.001

< 0.001

Educational level (Dakar/Tessekere), n (%) None/none

37.33 ± 15.25

87.14 ± 14.51

21 (4.3) 0.837 ± 0.069

0.652

< 0.001

81 (16.5)

Male (n = 241)

Total (n = 496)

Primary/1 year or +

348 (35.5)

163 (33)

Intermediate

197 (20)

109 (22.1)

0.006

88 (18)

Secondary

91 (9.2)

51 (10.3)

40 (8.2)

University

140 (14.2)

87 (17.6)

53 (10.8)

BMI: body mass index, WC: waist circumference, WHR: waist–hip ratio.

Among the 1 000 individuals included in the Dakar sample, 16 women were excluded because they reported pregnancy. Similarly, four women of the Tessekere sample were also excluded for pregnancy. Analyses were finally performed on a sample of 984 Dakarites and 496 Tessekere dwellers. The distributions of height, weight, BMI, WC, WHR, general and central obesity, sociodemographic variables, and comparisons between males and females in both environments are summarised in Table 1. The results show that men and women differed for all the factors studied except for age in both environments, and for WHR in Dakar. In Dakar, the prevalence of underweight, overweight and general obesity in terms of BMI was 12.6% (95% CI: 10.5–14.7), 19.2% (95% CI: 16.7–21.7) and 9.7% (95% CI: 7.9–11.5), respectively. The prevalence of central obesity was 26.0% (95% CI: 23.3–28.7) using WC, and 39.9% (95% CI: 36.8–43.0) using WHR (Table 2). In Tessekere, the prevalence of underweight, overweight and general obesity in terms of BMI was 29.6% (95% CI: 25.6– 33.6), 13.3% (95% CI: 10.3–16.3) and 2.8% (95% CI: 1.3–4.3), respectively. The prevalence of central obesity was 11.9% (95% CI: 9.1–14.7) using WC, and 23.6% (95% CI: 19.9–27.3) using WHR (Table 2). Dakar residents were more often overweight and obese and less often thin than the Tessekere inhabitants [χ² (3 df) = 80.9; p < 0.001]. Likewise, they showed higher central obesity rates than the Tessekere inhabitants [WC: χ² (1 df) = 39.3, p < 0.001; WHR: χ² (1 df) = 39, p < 0.001]. Table 2. Prevalence (%) of underweight, overweight, general obesity and central obesity by place of residence Criterion

Category

Dakar

Tessekere

Underweight

12.6 (10.5–14.7)

29.6 (25.6–33.6)

Overweight

19.2 (16.7–21.7)

13.3 (10.3–16.3)

General obesity

9.7 (7.9–11.5)

2.8 (1.3–4.3)

Central obesity

26.0 (23.3–28.7)

11.9 (9.1–14.7)

WHR

Central obesity

39.9 (36.8–43.0)

23.6 (19.9–27.3)

BMI

BMI: body mass index, WC: waist circumference, WHR: waist-hip ratio. In brackets: 95% confidence limits.

In Dakar as in Tessekere, bivariate analyses showed that all the sociodemographic factors studied were associated with general and central obesity (Table 3). The prevalence of general and central obesity rose gradually with age in both environments, except for obesity based on WC in Tessekere, which reached its highest rate among people between the ages of 40 and 49 years. In the urban and rural areas studied, general obesity affected women six times more often than men, and their WC exceeded the threshold of obesity 11 times and 18 more often than men in Dakar and Tessekere, respectively. As shown in Fig. 1, the prevalence of overweight/obesity (using BMI) rose with age among men and women in Dakar. The same pattern was observed among men in Tessekere. However, among rural women, the prevalence of overweight/obesity reached its highest rate between the ages of 30 and 39 years. Multivariate analyses showed that age and gender were the primary risk factors for overweight/obesity in Dakar and Tessekere (Table 4). Educational level also showed significant associations with BMI ≥ 25 kg/m², but only in the urban area, where people with between one and eight years of schooling had greater chances of being overweight or obese than people

80 % of overweight/obesity

Results

67.5

48.2

50 40

30.0

30 20 10 0

53.9

22.3 15.0 10.6 4.0

16.1

30.7 28.3 19.6

21.4 20.5 14.3

7.3

20–29

30–39

Women in Dakar Men in Dakar

40–49

50 and over

Women in Tessekere Men in Tessekere

Fig. 1. Age- and gender-specific prevalence (%) of overweight/obesity in Dakar and Tessekere.

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Table 3. Prevalence (%) of underweight, overweight, obesity and central obesity by age, gender and educational level in Dakar and Tessekere Obesity based on BMI Variable

Underweight

Overweight

Obesity based on WHR

Obese

p-value

< 0.001

Obese

p-value

26.2

< 0.001

Obesity based on WC Obese

p-value

12.6

< 0.001

Dakar Age (years) 20–29

413

18.6

12.8

3.6

30–39

266

11.3

22.6

9.8

37.6

25.9

40–49

156

5.1

20.5

16.7

54.5

37.2

≥ 50

149

29.5

18.8

67.1

51.7

Male

494

15.4

Female

490

9.8

Gender 14 24.5

< 0.001

2.8 16.5

< 0.001

16.8 63.3

4.3

< 0.001

Educational level < 0.01

Illiterate

208

8.7

21.6

Primary

348

10.9

21.6

10.3

Intermediate

< 0.001

51.9 40.8

32.2

< 0.001

29.9

197

13.2

20.8

10.2

25.4

Secondary

19.8

15.4

9.9

41.8

25.3

University

140

17.1

3.6

25.7

8.6

Tessekere Age (years) 20–29

200

30–39

115

30.4

40–49 ≥ 50

77 104

9.5 17.4

< 0.01

0 1.7

< 0.001

14 20

4.5

< 0.001

9.6

27.3

11.7

6.5

28.6

23.4

17.3

6.7

42.3

20.2

Gender Male

241

34.4

8.7

0.8

Female

255

25.1

17.6

4.7

< 0.001

7.1 39.2

1.2

< 0.001

Educational level None

373

30.6

12.9

2.9

1 year and +

123

26.8

14.6

2.4

< 0.01

26.5 14.6

13.1

8.1

BMI: body mass index, WC: waist circumference, WHR: waist-hip ratio.

who attended university. Gender was the primary risk factor for central obesity (WC and WHR) in both environments (Table 4). In Dakar, 50% of the study participants were satisfied with their weight, 27% thought they were too thin and 23% too fat. Men were more often satisfied with their weight than women (57 vs 43%), who in turn more often thought themselves too heavy (33 vs 13%; p < 0.001). In Tessekere, the majority found themselves too thin (53%), 8% believed they were too fat, and 39% were satisfied with their weight. Men were more often satisfied with their weight than women (45 vs 34%; p < 0.01). Fig. 2 shows that ideal BMI for men and women in Dakar was found to be 23.5 kg/m². In Tessekere, ideal BMI for men was 25.5 kg/m². For women in this rural area, the tendency was not as clear, but the ideal BMI for rural women could nevertheless be situated in the overweight category. We should note that at a BMI of 27.5 kg/m², only 42% of the men in Dakar felt too fat, as opposed to 49% of the women. In Tessekere, for the same BMI, 41% of the men felt too heavy as opposed to only 30% of the women. In Tessekere, 10 people were unable to judge ideal body size by the BSS. Analyses concerning this scale were therefore done on 486 participants in the rural area and 984 in the urban area (Fig. 3). First, we observed that for both male and female scales, averages of IBS for oneself and the opposite sex were lower in urban Senegalese than in rural Senegalese. The ideal male and female bodies fell within the normal range in Dakar, and in the overweight category in Tessekere. Second, there were no significant differences between men and women from each environment on each scale, except for the female scale in Dakar;

urban women perceived the ideal female body size as heavier than their male counterparts (t = 5.45; p < 0.001). Table 4. Adjusted odds ratio (OR) for overweight/obesity and central obesity in Dakar (n = 984) and Tessekere (n = 496) Overweight/obesity Obesity based on WHR Obesity based on WC Variables

95 % CI

1.32–2.92

95 % CI

Dakar Age (20–29) 30–39

2.39*** 1.62–3.52

1.96**

40–49

3.17*** 2.03–4.95

5.34*** 3.29–8.66

2.89*** 1.82–4.60

≥ 50

5.38*** 3.42–8.45

12.40*** 7.35–20.93 29.51*** 14.79–58.90

3.85*** 2.81–5.29

13.24*** 9.21–19.05 49.33*** 26.74–91.01

7.47*** 4.24–13.18

Gender (men) Women

Educational level (university) None

1.47

0.80–2.72

1.23

0.70–2.18

1.43

0.65–3.16

Primary

1.85*

1.05–3.26

1.1

10.65–1.85

2.58*

1.24–5.40

Intermediate

1.96*

1.07–3.58

0.94

0.53–1.66

2.58*

1.17–5.68

0.77–3.25

1.59

0.81–3.12

2.91*

1.17–7.21

0.89–5.89

Secondary 1.59 Tessekere Age (20–29) 30–39

2.35*

1.19–4.65

1.55

0.81–2.96

2.29

40–49

2.49*

1.13–5.46

2.53**

1.25–5.13

8.74*** 3.34–22.83

≥ 50

3.89*** 1.93–7.86

6.03*** 3.13–11.60

7.67*** 3.02–19.45

Gender (men) Women

2.93*** 1.71–5.02

10.08*** 5.59–18.18 27.16*** 8.15–90.55

Educational level (1 year or +) None

0.57

0.31–1.05

1.07

0.57–2.00

0.56

0.23–1.34

*p < 0.05; **p < 0.01; ***p < 0.001. BMI: body mass index, WC: waist circumference, WHR: waist-hip ratio.

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Women in Dakar 85.7

77.8 67.2

41.1

40.0 28.7 15.9

0 BMI < 16

5.8

11.1

12.1

Men in Dakar 100 90 80 70 60 50 40 30 20 10 0

45.8 8.3

0 BMI > 30

16 ≤ 18.5 ≤ 20 ≤ 22.5 ≤ 25 ≤ 27.5 ≤ BMI BMI BMI BMI BMI BMI < 18.5 < 20 < 22.5 < 25 < 27.5 < 30 % feel too lean % feel too fat

100 90 80 70 60 50 40 30 20 10 0

100 81.6 69.0 60.4

28.4 23.1 2.4

0 BMI < 16

69.6 52.0

44.4 35.0

BMI < 16

5.0

3.2

12.7

6.3

9.7

17.7

5.2

1.2 BMI > 30

16 ≤ 18.5 ≤ 20 ≤ 22.5 ≤ 25 ≤ 27.5 ≤ BMI BMI BMI BMI BMI BMI < 18.5 < 20 < 22.5 < 25 < 27.5 < 30 % feel too lean % feel too fat Women in Tessekere

100 64.3

55.2 40.2

Men in Tessekere 100 90 80 70 60 50 40 30 20 10 0

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33.3

50.0

13.5

0 BMI > 30

16 ≤ 18.5 ≤ 20 ≤ 22.5 ≤ 25 ≤ 27.5 ≤ BMI BMI BMI BMI BMI BMI < 18.5 < 20 < 22.5 < 25 < 27.5 < 30 % feel too lean % feel too fat

100 90 80 70 60 50 40 30 20 10 0

69.1

63.2

66.7

66.6 55.6 37.8

33.3

30.8

29.6 5.3 BMI < 16

2.3

6.1

3.3

22.2

15.4

13.5

BMI > 30

16 ≤ 18.5 ≤ 20 ≤ 22.5 ≤ 25 ≤ 27.5 ≤ BMI BMI BMI BMI BMI BMI < 18.5 < 20 < 22.5 < 25 < 27.5 < 30 % feel too lean % feel too fat

Fig. 2. S atisfaction with weight by BMI among men and women in Dakar and Tessekere.

Discussion This study is to our knowledge the first to evaluate the prevalence of obesity among both men and women in urban and rural Senegal. Moreover, it is also the first study to assess perception of body size in both genders in this country. In Dakar, the prevalence of general obesity was 9.7%, and that of overweight, 19.2%. These prevalence rates place Dakar among the West African cities that are least affected by problems of excess weight.31,32 Comparison of our results with those of a study carried out among men and women in Dakar in 200911

1 Scientific Averages Norms

Ideal body size

Underweight

Normal weight

6 Overweight

8 Obesity levels

Men 4.5 ± 1.3 5.1 ± 1.7 ***

suggests that prevalence of general obesity may have increased in the Senegalese capital in five years (17%), but this difference was not statistically significant. However, since 2009, the prevalence of central obesity by WC has increased significantly, by 23% (p < 0.05). In Tessekere, the prevalence of overweight and obesity were 13.3 and 2.8%, respectively. Despite the difficulty of making comparisons with other West African rural areas due to the lack of current data,10 these results tend to indicate that Tessekere is also one of the rural areas in the sub-region that is least affected by the obesity epidemic.33-35

1 Scientific Averages Norms

Ideal body size

Women 4.6 ± 1.4 5.1 ± 1.8 *** Urban Senegalese

Women 4.7 ± 1.7 5.5 ± 1.8 *** Men 4.2 ± 1.4 5.3 ± 1.7 ***

Rural Senegalese

Fig. 3. P erceptions of ideal body size on masculine and feminine body size scale.

Underweight

Normal weight

6 Overweight

8 Obesity levels

***

Urban Senegalese

Rural Senegalese

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As indicated in the literature on West Africa,10 problems of excess weight affect the urban environment more than the rural environment, therefore showing just how environmentally dependent the nutritional transition is in Senegal. In Dakar, the modern lifestyle36 is combined with a decrease in physical activity and a higher calorie content diet. In Tessekere, where there is no running water or electricity, a pastoral lifestyle still protects the population from the obesity epidemic, particularly by obliging people to travel long distances daily to feed and water their herds. However, our results show that such differences between the urban and rural environment may not last, as overweight and obesity rates among women born after the great drought of 1973–1974, hitande bonde [the worst year in Pulaar], are now approaching those of their urban counterparts. The gradual closing of the gap between urban and rural populations is also borne out by results concerning the ideal body size. In the rural environment, the ideal body type for both men and women is in the overweight category, whereas it is in the normal range in Dakar. The social value placed on the overweight body undeniably acts as a factor in the development of excess weight in rural areas.16 At the same time, it is important to note the considerable tolerance that both rural and urban Senegalese show toward overweight. At a BMI of 27.5 kg/m², less than 40% of the men in Dakar and Tessekere saw themselves as too fat, compared to 50% of urban women and 30% of rural women. By comparison, in France, for the same BMI, 60% of the men and 85% of women saw themselves as too fat.29 Therefore, not only are body weight norms higher in Senegal than in France, but they are also less strict, which can only foster development of the obesity epidemic.16 A tightening of these body weight norms is conceivable in the years to come, both pro-actively, through public health messages issued by the Senegalese government, and also through globalisation and the media, which convey beauty standards that emphasise a slimmer body, particularly in the urban environment.37,38 Our investigation has several limitations. First, the study design was cross-sectional, which does not allow us to explore causation. To overcome this limitation, it would be necessary to conduct a longitudinal study in Dakar in the future. Second, due to insufficient numbers of older adults in the study, we were unable to survey the evolution of body weight after 50 years of age, which should be analysed in the future, given the significant rise in weight-related problems with age, and the aging population on the continent.39

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Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et al. Obesity and the risk of myocardial infarction in 27000 participants from 52 countries: a case-control study. Lancet 2005; 366: 1640–1649.

Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766–781.

Chiolero A, Paccaud F. An obesity epidemic booga booga. Eur J Public Health 2009; 19: 568–569.

Roth J, Qiang X, Marbán SL, Redelt H, Lowell BC. The obesity pandemic: where have we been and where are we going? Obes Res 2004; 12: 88S–101S.

Popkin BM, Adair LS, Ng SW. Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev 2012; 70: 3–21.

Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011; 378: 804–814.

Steyn NP, Mchiza ZJ. Obesity and the nutrition transition in subSaharan Africa. Ann NY Acad Sci 2014; 1311: 88–101.

Scott A, Ejikeme CS, Clottey EN, Thomas JG. Obesity in sub-Saharan Africa: development of an ecological theoretical framework. Health Promot Int 2013; 28: 4–16.

10. Abubakari AR, Lauder W, Agyemang C, Jones M, Kirk A, Bhopal RS. Prevalence and time trends in obesity among adult West African populations: a meta-analysis. Obes Rev 2008; 9: 297–311. 11. Macia E, Duboz P, Gueye L. Prevalence of obesity in Dakar. Obes Rev 2010; 11: 691–694. 12. Popkin BM. Urbanization, lifestyle changes and the nutrition transition. World Dev 1999; 27: 1905–1916. 13. Yako YY, Echouffo-Tcheugui JB, Balti EV, Matsha TE, Sobngwi E, Erasmus RT, et al. Genetic association studies of obesity in Africa: a systematic review. Obes Rev 2015; 16: 259–272. 14. Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide obesity dynamics and their determinants. Int J Obes 2004; 28: 2–9. 15. Dinsa GD, Goryakin Y, Fumagalli E, Suhrcke M. Obesity and socioeconomic status in developing countries: a systematic review. Obes Rev 2012; 13: 1067–1079. 16. Cohen E, Boëtsch G, Palstra FP, Pasquet P. 2013. Social valorisation of stoutness as a determinant of obesity in the context of nutritional transition in Cameroon: the Bamiléké case. Soc Sci Med 2013; 96: 24–32. 17. WHO. Diet, nutrition and the prevention of chronic diseases. Geneva:

Conclusion This study shows that the prevalence of obesity is bound to rise quickly among Senegalese women living in a rural environment, partly due to high body weight norms and a large tolerance towards overweight and obesity. To combat problems of obesity in Senegal at present, public health messages should be geared towards the population category most at risk, in other words mature women living in urban areas. However, to limit the scope of the epidemic over the entire country, health centres, which are the only local health structures in rural areas, must begin to raise awareness of the problems that arise with excess body weight.

World Health Organization, 2003. 18. Ziraba AK, Fotso JC, Ochako R. Overweight and obesity in urban Africa: a problem of the rich or the poor? BMC Public Health 2009; 9: 465–473. 19. WHO Regional Office for Africa. The health of the people: the African regional health report (2006). Geneva: World Health Organization, 2006. 20. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998; 97: 596–601. 21. Brown PJ, Konner M. (1987). An anthropological perspective on obesity. Ann NY Acad Sci 1987; 499: 29–36. 22. Brown P. Culture and the evolution of obesity. Human Nature 1990; 2: 31–57.

The authors received funding for this research from the National Center for Scientific Research, France (PEPS ‘Ecological Health’).

23. Renzaho A. Fat, rich and beautiful: changing sociocultural paradigms associated with obesity risk, nutritional status and refugee children from

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sub-Saharan Africa. Health Place 2004; 10: 105–113. 24. Puoane T, Bradley H, Hughes G. Obesity among black South African women. Human Ecology Special 2005; 13: 91–95. 25. Holdsworth M, Gartner A, Landais E, Maire B, Delpeuch F. Perceptions of healthy and desirable body size in urban Senegalese women. Int J Obes 2004; 28: 1561–1568. 26. WHO. Obesity: preventing and managing the global epidemic. Report of the WHO consultation. WHO Technical Report Series 894. Geneva: World Health Organization, 2000. 27. Lean ME, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. Br Med J 1995; 311:158–161.

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review. J Hypertens 2014; 32: 464–472. 32. Ouédraogo HZ, Fournet F, Martin-Prevel Y, Gary J, Henry MC, Salem G. Socio-spatial disparities of obesity among adults in the urban setting of Ouagadougou, Burkina-Faso. Public Health Nutr 2008; 11: 1280–1287. 33. Agyemang C. Rural and urban differences in blood pressure and hypertension in Ghana, West Africa. Public Health 2006; 120: 525–533. 34. Addo J, Amoah AG, Koram KA. The changing patterns of hypertension in Ghana: a study of four rural communities in the Ga District. Ethn Dis 2006; 16: 894–899. 35. Oladapo OO, Salako L, Sodiq O, Shoyinka K, Adedapo K, Falase

28. Dobbelsteyn CJ, Joffres MR, MacLean DR, Flowerdew GA.

AO. A prevalence of cardiometabolic risk factors among a rural

Comparative evaluation for waist circumference, wais to hip ration

Yoruba southwestern Nigerian population: a population-based survey.

and body mass index as indicators of cardiovascular risk factors, the Canadian Health Heart Survey. Int J Obes 2001; 25: 652–661. 29. De Saint Pol T. (2009). Surpoids, normes et jugements en matière de poids: comparaisons européennes. Population et Sociétés 2009; 455.

Cardiovasc J Afr 2010; 21: 26–31. 36. Werner J.-F. Itinéraires individuels à la marge. Etudes de cas sénégalais. In: Marie A (ed). L’Afrique des individus. Paris: Karthala, 1997: 367–403. 37. Malete L, Motlhoiwa K, Shaibu S, Wrotniak BH, Maruapula SD,

30. Cohen E, Bernard JY, Ponty A, Ndao A, Amougou N, Saïd-Mohamed

Jackson J, et al. Body image dissatisfaction is increased in male and

R, et al. Development and validation of the Body Size Scale for assess-

overweight/obese adolescents in Botswana. J Obesity 2013; Article ID

ing body weight perception in African Populations. PLoS One 2015; 10: e0138983. 31. Commodore-Mensah Y, Samuel LJ, Dennison-Himmelfarb CT, Agyemang C. Hypertension and overweight/obesity in Ghanaians and Nigerians living in West Africa and industrialized countries: a systematic

763624; doi.org/10.1155/2013/763624. 38. Szabo CP, Allwood CW. Body figure preference in South African adolescent females: a cross cultural study. Afr Health Sci 2006; 6: 201–206. 39. Golaz V, Nowik L, Sajoux M. L’Afrique, un continent jeune face au défi du vieillissement. Population et Sociétés 2012: 491.

Nearly one-quarter of patients say mechanical heart valve disturbs sleep ‘For some patients, the closing sound of their mechanical heart valve reduces their quality of life, disturbs their sleep, causes them to avoid social situations, and leads to depression and anxiety’, said lead author Dr Kjersti Oterhals, a nurse researcher at Haukeland University Hospital in Bergen, Norway. He was speaking at EuroHeartCare 2017 in Sweden. This study investigated how the noise of a mechanical heart valve affected patients’ lives, in particular their sleep, and whether there were any differences between women and men. In April 2013 all 1 045 patients who had undergone aortic valve replacement at Haukeland University Hospital between 2000 and 2011 were invited to participate in a postal survey. Of the 908 patients who responded, 245 had received a mechanical valve and were included in the current analysis. Patients were asked if the valve sound was audible to them or others, if they sometimes felt uneasy about the sound, if the sound disturbed them during daytime or during sleep, and whether they wanted to replace the mechanical valve with a soundless prosthetic valve if possible. Patients ranked the noise on a scale of 0 (does not disturb them at all) to 10 (causes maximum stress). The Minimal Insomnia Symptom Scale, which consists of three questions about sleep, was used to give patients a score of 0 to 12 for insomnia. Patients were 60 years old on average and 76% were men. Nearly one-quarter (23%) said the valve sound disturbed them during sleep and 9% said it disturbed them during the day. Some 28% wanted to replace their valve with a soundless prosthetic valve if possible. Over half (51%) said the noise was often or sometimes audible to others, but only 16% said they sometimes felt uneasy about others hearing it. The researchers found that 87% of men and 75% of women said that they were able to hear the closing sound of their

mechanical valve. Women were more disturbed by the valve sound than men. Some 53% of the respondents had no insomnia, 31% had subclinical insomnia, and 17% had moderate to severe insomnia. Valve noise perception was the strongest predictor of insomnia, followed by age and female gender. There was a linear association between insomnia and valve noise perception, and the more patients considered the valve noise a disturbance in daily life, the more insomnia they reported. Dr Oterhals said ‘Almost one-fourth of patients said that the sound of their mechanical heart valve makes it difficult for them to sleep. Most of us need a quiet environment when we are going to sleep and these patients found it hard to ignore the noise from the valve.’ Not all patients are aware before surgery that they may hear their mechanical valve, and while most get used to it, for some it is troublesome for many years. ‘One female patient said to me, “I will never have silence around me again” when she realised she would hear the noise 24 hours a day for the rest of her life’, said Dr Oterhals. The most common ways patients coped with the noise when trying to sleep were to sleep on their right side, which reduced the valve noise, put the duvet around their bodies to isolate the sound, listen to music and do relaxation exercises. Ear plugs were not effective and made the valve noise louder. Dr Oterhals said: ‘We are not very proactive about this issue at the moment. It would improve many patients’ quality of life if we asked them about valve noise and provided advice to those who find it distressing.’ Source: European Society of Cardiology Press Office

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Review Article Anaemia and iron deficiency in heart failure: epidemiological gaps, diagnostic challenges and therapeutic barriers in sub-Saharan Africa Abel Makubi, Johnson Lwakatare, Okechukwu S Ogah, Lars Rydén, Lars H Lund, Julie Makani

Abstract Anaemia and iron deficiency (ID) are common and of prognostic importance in heart failure (HF). In both conditions the epidemiology, diagnosis and therapies have been extensively studied in high-income countries but are still largely unexplored in sub-Saharan Africa (SSA). The lack of adequate and robust epidemiological data in SSA makes it difficult to recognise the significance of anaemia and ID in HF. From a clinical perspective, less attention is paid by clinicians to screening for anaemia in HF, and as far as interventions are concerned, there are no clinical trials in SSA that provide guidance on the appropriate interventional approach. Therefore studies are needed to provide more insight into the burden and peculiarities of and intervention for anaemia and ID in HF in SSA, where the pathophysiology might be different from that in high-income countries.

There is increasing appreciation that targeting ID may serve as a useful additional treatment strategy for patients with chronic HF in high-income countries. However, there is limited information on the diagnosis of and therapy for ID in HF in SSA, where infections and malnutrition are more likely to influence the situation. This article reviews the present epidemiological gap in knowledge about anaemia and ID in HF, as well as the diagnostic and therapeutic challenges in SSA.

Keywords: heart failure, anaemia, iron deficiency, review, epidemiology, therapy, sub-Saharan Africa Submitted 4/6/16, accepted 2/1/17 Cardiovasc J Afr 2017; 28: 331–337

www.cvja.co.za

DOI: 10.5830/CVJA-2017-001

School of Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania Abel Makubi, MD, MMed, MSc, PhD, makubi55@gmail.com Johnson Lwakatare, MD, MRCP, FESC Julie Makani, MD, FRCP, PhD

Cardiology Unit, Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden Abel Makubi, MD, MMed, MSc, PhD Lars Rydén, MD, PhD, FESC, FACC Lars H Lund, MD, PhD

Muhimbili National Hospital, Dar es Salaam, Tanzania Abel Makubi, MD, MMed, MSc, PhD Johnson Lwakatare, MD, MRCP, FESC Julie Makani, MD, FRCP, PhD

Division of Cardiology, Department of Medicine, University College Hospital, Ibadan, Nigeria Okechukwu S Ogah, MBBS, FESC

Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden Lars H Lund, MD, PhD

Nuffield Department of Clinical Medicine, University of Oxford, London, United Kingdom Julie Makani, MD, FRCP, PhD

The importance of anaemia in heart failure (HF) has attracted considerable interest over the past two decades. Recently, iron deficiency (ID) with or without anaemia has been recognised as an emerging therapeutic target with prognostic implications.1-5 In both conditions, the epidemiology, diagnosis and therapies have been extensively studied in developed countries but are largely unexplored in sub-Saharan Africa (SSA), where infections and malnutrition are common and may influence the situation.1 This article focuses on the present epidemiological gap in knowledge about anaemia and ID in HF, as well as the diagnostic and therapeutic challenges in SSA. No formal search of Medline or other search engines was performed; however, PubMed and Cochrane were checked for all relevant articles. The criterion to include an article was clinical relevance. Full versions of articles rather than abstracts were assessed for inclusion.

Defining anaemia in the setting of HF in SSA and its clinical relevance The definition of anaemia has a definite impact on the burden of anaemia in patients with HF, which also varies according to the setting and population in which anaemia is being considered. The precise cut-off values to define anaemia in HF are arbitrary and there is no consensus as to the definition of anaemia specific to patients with chronic diseases such as HF.

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The historical cut-off points put forward by the World Health Organisation (WHO), namely a haemoglobin (Hb) concentration < 13 g/dl for men or < 12 g/dl for women have been under debate regarding their relevance when it comes to SSA, where haemoglobin values have been reported to be relatively low in the normal general population.6,7 This difference might be related to a high prevalence of infections, haemoglobinopathies and nutritional deficiencies. Furthermore, genetic factors may also be implicated.6,7 In SSA, the concept of clinically relevant Hb cut-off points has been applied in some settings, leading to the use of more stringent cut-offs when reporting anaemia in HF in SSA compared to studies from high-income countries.2,8 For example, a Hb cut-off value of < 10 g/dl in HF for both genders was used in the Tanzania Heart Failure (TaHeF) study,2 the SSA Survey of Heart Failure (THESUS) study,8 and by Ogah et al.,9 while in the Heart of Soweto,10 a cut-off value of < 11 g/dl for men and < 10 g/dl for women was defined as clinically relevant anaemia (Table 1). This further complicates the comparability and potential criteria for interventions versus what has already been reported from high-income countries. Accordingly, there is a need for standardised and uniform cut-off points that are relevant to and applicable in SSA.

Epidemiological gap in knowledge of anaemia burden in HF in SSA The available data suggest that there are limited reports about the epidemiology of anaemia in SSA compared to a large number of studies in high-income countries. Using the WHO cut-off point, the small amount of scattered information available reveals that the prevalence of anaemia in HF in SSA ranges from 14 to 64% (45% on average) (Table 1), compared to 36% in the general population. In high-income countries, the prevalence ranges from 10 to 49% (34% on average), compared to 8% in the general population.11,12 Higher rates of prevalence are therefore seen in SSA than in high-income countries, and in both populations, the prevalence of anaemia in HF is higher than the global burden of anaemia in the general population. Less attention is paid by clinicians in SSA to screening for anaemia in HF in a clinical perspective, which may be explained by the scarcity of epidemiological data. Table 1. Studies in SSA reporting on adult HF patients with anaemia

Authors, country and year

Sample Anaemia size (%)

Definition of anaemia by haemoglobin (g/dl) or packed cell volume (%)

Makubi et al.2 Tanzania, 2015 452

8.8

< 10

Damasceno et al.8 9 African countries, 2012

1006

15.2

< 10

Stewart et al.10 South Africa, 2008.

699

10.0

Male < 11, female < 10

Karaye et al.13 Nigeria, 2008

Kuule et al.14 Uganda, 2009

Ogah et al. Nigeria, 2014 9

< 39% in male and < 36% in female

157

64.3

Male ≤ 12.9, female ≤ 11.9

Inglis et al.15 South Africa, 2007

163

13.5

World Health Organisation

Dzudie et al.16 Cameroon, 2008

140

15.7

Not available

Oyoo et al.17 Kenya, 1999

13.2

Not available

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As far as interventions are concerned, there are no clinical trials in SSA that provide guidance on the appropriate approach to manage anaemia in HF. Due to the relatively recent attention given to the importance of iron deficiency in HF in SSA, guidelines do not provide help in this regard. Studies are therefore needed to provide more insight into the burden, peculiarities and possible interventions for anaemia in HF in SSA.

Epidemiological gap in knowledge of ID burden in HF The prevalence of ID in HF populations in SSA is largely unknown. To our knowledge the TaHeF study, reporting a prevalence of 67%, was the only study providing data on the prevalence of ID in HF in SSA.2 This should be seen in the perspective of more than 12 studies from high-income countries (Table 2). Since the only study so far conducted indicates that iron-deficiency anaemia is a very common condition in SSA, further studies should aim to see whether active detection and correction of ID are warranted.

Challenges in biochemical diagnosis of ID in HF Absolute ID is conventionally defined by a serum ferritin level of < 30 mg/l.29,30 As the ferritin is elevated in HF due to the inflammatory state, in their 2012 guidelines, the European Society of Cardiology introduced the definition of ID in HF as either serum ferritin < 100 mg/l for absolute ID or 100–299 mg/l and transferrin saturation < 20% for functional ID.31 The criteria have been used in several clinical trials.32-34 These diagnostic criteria for ID in HF used in high-income countries may not be feasible in SSA due to the lack of diagnostic facilities and the presence of co-existing malnutrition, haemoglobinopathies and infections. Serum ferritin/transferrin saturation (TSAT) has commonly been used in several observational and clinical trials (Table 2) to Table 2. Studies reporting on the magnitude of ID in HF Number

% with ID

Makubi et al.2 Tanzania, 2014

411

MCV < 80 fl

Jankowska et al.20 Poland, 2014

165

Low hepcidin and high sTfR Serum ferritin and TSAT

Rangel et al.3 Portugal, 2014

127

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

Parikh et al.21 United States, 2014

574

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

Enjuanes et al.22 Europe, 2014

1278

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

Ijsbrand et al.4 Europe, 2014

1506

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

443

SF < 100 µg/l OR SF 100–300 µg/l +TSAT < 20%

Authors, country and year

Jankowska et al.23 Poland, 2013

Definition of ID

Nanas et al.24 Greece, 2006

Bone marrow

Cohen-Solal et al.25 France, 2014

832

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

Yeo et al.26 Singapore, 2014

751

SF < 100 µg/l OR SF 100–299 µg/l +TSAT < 20%

De Silva et al.27 UK, 2006

955

Lower limit for serum iron and SF

296

Low SF

Ojji et al.18 Nigeria, 2013

475

8.0

Not available

Klaus et al.28 UK, 2004

Onwuchekwa et al.19 Nigeria, 2009

423

6.2

Not available

sTfR: soluble transferrin receptor, TSAT: transferrin saturation, SF: serum ferritin, TR: transferrin receptor.

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diagnose ID in HF in high-income countries. The unavailability of biochemical iron markers in many SSA countries may limit the use of these diagnostic criteria as applied in high-income countries and this may underestimate the magnitude of iron deficiency in this population. Red cell indices such as mean corpuscular volume and the degree of hypochromia, which are used in many SSA countries, cannot distinguish between the presence or absence of sufficient bone marrow iron in patients with chronic disease, thereby offering a relatively low sensitivity (Table 3).35 This information gap warrants serious attention if ID is to be intervened in by the provision of diagnostic resources, allowing the use of serum ferritin, which provides a considerably higher specificity and sensitivity compared to haematological indices (Table 3).

Absolute ID and serum ferritin < 60–100 µg/l in HF It has been suggested that cut-off levels of the order of 60–100 µg/l of ferritin rather than the normal < 30 µg/l, or indeed previously reported 12–15 µg/l, should be used when screening for absolute ID in people with co-existing inflammation, infection and malignant conditions.29,30,41 This recommendation is based on the fact that patients with acute or chronic disease usually have elevated ferritin levels as a result of intracellular iron Table 3. Sensitivity and specificity of iron measures in chronic diseases Study, year Punnonen et al.36 1996

% hypochromia

Punnonen et al.36 1996

Mean corpuscular volume

Means et al.37 1999

42 % transferrin saturation

Means et al. 1999 37

Van Tellingen et al.38 2001

Serum ferritin

Treatment approaches with regard to iron therapy in HF Utility and beneficial effect of iron therapy in HF In a series of controlled and uncontrolled clinical trials of HF and ID (Table 5), all conducted in high-income countries,

Sensitivity Specificity (%) (%)

Iron marker

Punnonen et al.36 1996

accumulation and the inflammatory response. The explanation is that serum ferritin is an acute-phase reactant. Even these higher levels only slightly improve the sensitivity (Table 3). The combined use of serum ferritin with inflammatory markers such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) in a discriminant analysis provide only marginal improvement in sensitivity/specificity.42 Serum ferritin < 100 µg/l has been widely used as a cut-off in high-income countries when looking for absolute ID in patients with HF in most clinical trials. Studies supporting its use in SSA are limited.34,43,44 Serum ferritin levels such as < 150 µg/l offer a better balance between sensitivity and specificity than < 100 µg/l (Table 4).29,39 Afro-Americans and black Africans tend to have a high level of serum ferritin.45,46 It is not clear whether this is genetic or due to environmental changes as a result of common chronic infection. In view of this, high cut-off values such as < 150 µg/l (rather than < 100 µg/l) may be more appropriate but this requires further study and validation. Such studies will pave the way to clinical trials of relevance to SSA.

90 83

Table 4. Sensitivity and specificity of serum ferritin Author, year

Ferritin cut-off value (ng/ml)

Sensitivity (%)

Specificity (%)

< 50

< 100

< 150

< 200

Tessitore et al.48 2001

< 100

Kalantar-Zadeh et al.49 2004

< 200

100

Lockhat et al.47 2004

Lee et al.39 2001

Punnonen et al.36 1996

Joosten et al.40 2001

Table 5. Studies on parental iron therapy in HF Author, year

Study design

Sample size

Type of parental iron

Dose/duration

Ben-Assa et al.54 2015

Uncontrolled

Ferric sucrose

200 mg, 6 weeks

↑Hb

Reed et al.53 2015

Uncontrolled

Ferric gluconate

250 mg bd/day, 3 days

↑Hb, ↑SF, ↑TSAT

Gaber et al.55 2011

Uncontrolled

Ferric dextran

200 mg/week, 4–8 weeks

↑NYHA, ↑6MWD, ↑SF, ↑TSAT, ↑exercise capacity, ↑renal function, ↑QoL

Benefits

Usmanov et al.52 2008

Uncontrolled

Ferric sucrose

100 mg 3×/week, then once/week, 26 weeks

↑Hb, ↑NYHA, ↑LV diameters

Bolger et al.56 2006

Uncontrolled

Ferric sucrose

1 g daily, 12 days

Hb 12.55, ↑TSAT, ↑6MWD ↑NYHA

Toblli et al.57 2015

Controlled

Ferric sucrose

200 mg/week, 5 weeks

↑Hb, ↑SF, ↑TSAT, ↑LV diameters, ↑LVEF, ↑ CrCl, ↑NT-proBNP

Ponikowski et al.33 2014

Controlled

304

Terrovitis et al.58 2012

Controlled

Ferric sucrose

300 mg weekly, 6 weeks

↑Hb

Anker et al.32 2009

Controlled

459

Ferric carboxymaltose

200 mg, 24 weeks

↑Hb, ↑SF, ↑TSAT, ↑PGA, ↑NYHA, ↑6MWD, trend ↓hospitalisation

Ferric carboxymaltose Total dose 500–2000 mg, in correction phase ↑6MWD, ↑NYHA, ↑exercise capacity, ↑PGA, 500 mg, in maintenance 52 weeks ↑QoL, ↑ hospitalisation, ↑fatigue score

Drakos et al.59 2009

Controlled

Ferric sucrose

300 mg/week, 6 weeks

↑Hb

Arutyunov et al.60 2009

Controlled

30 27

Ferric carboxymaltose Ferric sucrose

200 mg weekly to calculated dose, then 200 mg every 4 weeks, 12 weeks

Not applicable

Okonko et al.50 2008

Controlled

Ferric sucrose

200 mg weekly, 16 weeks

↑Hb, ↑SF, ↑VO2, ↑exercise capacity, ↑NYHA, ↑PGA

Toblli et al.61 2007

Controlled

Ferric sucrose

200 mg/week, 5 weeks

↑Hb, ↑NT-proBNP, ↑LVEF, ↑NYHA, ↑exercise capacity, ↑renal function: ↑QoL

Hb: haemoglobin, SF: serum ferritin, TSAT: transferrin saturation, NYHA: New York Heart Association, 6MWD: six-minute walking distance, QoL: quality of life, LV: left ventricular, LVEF: left ventricular ejection fraction, NT-proBNP: N-terminal pro B-type natriuretic peptide, CrCl: creatine clearance rate, PGA: patient’s global assessment, pVO2: peak oxygen consumption, ↑: improved.

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parental iron showed clear short- to medium-term benefits, leading to improved symptoms and quality-of-life measures and less hospitalisation.32,33,50-53 In the FAIR-HF study, patients were randomised to parental iron or placebo and 50 versus 28%, and 47 versus 30% reported improved quality of life and New York Heart Association (NYHA) class, respectively.32 Similarly in the FERRIC-HF study, 35 patients with congestive heart failure were put on 16 weeks of intravenous iron or no treatment in a 2:1 ratio.50 The NYHA functional class improved in eight patients (44%) in the iron group versus no patients in the control group (p = 0.03). In all these trials, parental iron was used as a supplement, added to standard therapy on optimal pharmacological treatment, which included a diuretic, a beta-blocker and/or an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) as determined by the investigator (unless contra-indicated or not tolerated). Data on the efficacy of parental iron remain undisclosed in SSA.

Dosage for parental iron therapy in HF Table 5 provides the dosage for various types of parental iron used in clinical trials, nine of which used parental ferric sucrose (FSC),24,52,54,56,57,61-63 two used parental ferric carboxymaltose (FCM),32,33 one study used both ferrics,60 one used ferric gluconate,53 and one iron dextran.55 In most of the studies, the 200-mg weekly dose for parental FSC was applied in the correction phase, with a maintenance period in some studies. However, for parental FCM, it was given either as a total loading dose to correction or a 200-mg weekly dose. There is therefore a need to have a standardised dose for both parental FSC and FCM, and to determine whether the same doses apply in SSA.

Treatment targets of parental iron therapy in HF The target treatment levels are variable, ranging from replenishment through maintenance to a predetermined period of study or haemoglobin level. From the clinical perspective, this needs to be carefully determined from additional studies, for guideline implementation. The levels of haemoglobin for initiation and cessation should also be properly studied, as well as the period of maintenance or monitoring for those who receive iron replenishment.

Long-term effects after parental iron therapy in HF During treatment, intravenous iron seems to be relatively safe with only a few side effects or adverse events, which can usually be tolerated by the patients.33,44 However, data are limited on the long-term effects after this therapy is ended, such as undesirable complications (iron overload or myocardial changes) several years after therapy. It is also not known how long the replenished iron store and improved clinical symptoms of HF are sustained following parental iron therapy. A close follow up of patients who received iron therapy, several months or years after therapy may shed some light on the matter.

Excluded populations in parental iron therapy trials Despite the significant progress made in the use of parental iron in patients with HF and ID, most of the trials included patients

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with heart failure with reduced ejection fraction (HFrEF) (EF < 40 or 45%) and no data are available for patients with heart failure with preserved ejection fraction (HFpEF). It is also unclear whether this therapy could benefit patients with HF due to valvular heart disease, obstructive cardiomyopathy, those with Hb levels < 9.5g/dl or > 13.5g/dl and iron deficiency. The findings from these trials therefore cannot be generalised and must be applied with caution in SSA populations.

Possible limitation of parental iron therapy in SSA The high level of iron deficiency in a setting where infections, haemoglobinopathies and malnutrition are common requires special attention.2 The role of parental iron therapy (and other potential options) in SSA requires further justification before implementation measures are considered. The TaHeF study, along with a few other reports from SSA, have locally quantified the magnitude of anaemia, as shown in Table 2.2 TaHeF was the only study that characterised ID, which resulted in a poor prognosis in HF patients. With this limited regional data, further studies are needed to identify the peculiarities of ID and other types of anaemia or nutritional deficiencies (folate, vitamin B12) in HF in SSA and determine whether the consequences are the same as in high-income countries before any interventions (whether parental or oral) are conducted or adopted. Apart from epidemiological challenges, as explained above, the other important limitation may be related to acceptance of and adherence to parental iron. Across all studies done in high-income countries, none looked at the level of adherence. Even with oral therapy and other HF medication, the problem of compliance in SSA is high and is mainly related to financial constraints, limited access to health facilities, as well as limited health education/awareness. Proper measures should therefore be put in place to address this. This approach also imposes a burden on the patient, with increased clinic appointments and transportation costs, and absence from work of people with already reduced mobility and functional capacity. This may complicate the already compromised health system with overloading of clinics and administrative logistics. There is possibly a need to have an accelerated iron-supplementation regimen, which would shorten the duration, or look into the possibility of providing parental iron for replenishment in the hospital ward, while maintenance with oral iron is taken at home, with more widely scheduled appointments.53 Finally, parental iron is expensive and administration to large populations of HF patients may not be feasible, particularly in countries with limited healthcare resources.

Possible role of oral iron therapy in SSA Oral iron supplementation is an established therapy for treating iron deficiency in a range of medical conditions but it has not been widely tested in HF patients. It remains promising in resource-limited settings because (1) newer ferrous sulphate preparations may be better absorbed than the older ferrous sucrose; (2) the pathophysiology or iron deficiency may differ geographically; and (3) oral iron supplementation is inexpensive. Preliminary studies (Table 6) on randomised clinical trials

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Table 6. Study reporting oral iron therapy as an interventional drug or placebo in HF Study design

Sample size

Type of iv iron

Dose

Niehau et al.64 2015

Observational

105

Oral iron (NS)

NS, 180 days

Tay et al.65 2010

Observational

Ferrous fumarate

200 mg 3×/day, Iron 12 weeks repletion

Beck-da-Silva et al.62 2013

Controlled

Ferrous sulphate

200 mg 3×/day, 8 weeks

Parissis et al.66 2008

Controlled

Ferrous sulphate

Van Velduisen et al.63 2007

Controlled

165

Palazzuoli et al.67 2006

Controlled

Author, year

Target dose

Benefits

Adverse effect/toxicity

↑Hb, ↑SF, ↑TSAT, ↑Iron, ↑TIBC

Hb, ferritin, TSAT, 6MWT

No adverse effect

↑Hb, ↑Ferritin, ↑TSAT, ↑peak VO2, ↑NHYA

250 mg twice a day, 12 weeks

No change in QoL, Hb, significant deterioration in exercise capacity

1 TIA, 1 constipation

Oral iron

200 mg/day, 26 weeks

No change in exercise capacity, Hb, ferritin, TSAT, minor improvement in QoL, NYHA class

Adverse effect comparable to ESA including discontinuation, HF, HT, DVT

Ferrous gluconate

300 mg/day 12 weeks

No changes in NYHA, exercise capacity, Hb, BNP, creatinine

Iron repletion

iv: intravenous, NS: not specified, NR: not reported, Hb: haemoglobin, SF: serum ferritin, TSAT: transferrin saturation, NYHA: New York Heart Association, 6MWD: six-minute walking distance, VO2: oxygen consumption, QoL: quality of life, TIBC: total iron-binding capacity, TIA: transient ischaemic attack, ESA: erythropoiesis stimulating agent, DVT: deep-vein thrombosis, HT: hypertension, BNP: B-type natriuretic peptide.

on erythropoiesis-stimulating agents (ESA) versus oral iron supplementation showed no improvement in exercise capacity or Hb and ferritin levels with oral therapy. However in a recent non-randomised clinical trial,64 the researchers found that replenishment of Hb, TSAT and ferritin produced similar results to giving parental iron in the FAIR trial32 in patients with HF. A randomised trial62 also showed ferritin and Hb levels increased when using both parental and oral iron, although the study was underpowered. In a prospective study of 25 patients with cyanotic congenital heart disease, the researchers demonstrated a significant improvement in serum ferritin and Hb levels and the six-minute walking test (6MWT) distance after 90 days of oral iron supplementation with 200 mg iron fumarate three times per day.65 The recently completed TaHeF-ID study has also shown similar findings, with additional improvement in left ventricular ejection fraction from 37.8 ± 12.2% to 44.5 ± 10.7% (+17%; p < 0.001) and N-terminal pro B-type natriuretic peptide (NT-proBNP) from 986 ± 774 ng/l to 582 ± 503 ng/l (–41%; p < 0.001) from baseline after 90 days of a similar dosage of iron sulphate.68 These findings are promising and justify randomised clinical trials to address this area of uncertainty by comparing parental and oral iron supplementation, particularly in SSA. Results from the IRONOUT trial (NCT02188784), which is being conducted by the National Heart, Lung, and Blood Institute’s Heart Failure Network are also awaited.69

Conclusions The accumulating data on HF and anaemia/ID anaemia continue to be largely of studies conducted in high-income countries, with very limited information for SSA. Creating awareness and identification of these co-morbidities in HF, both in the hospital setting and at the population level, should be a priority. Diagnostic dilemmas and therapeutic challenges require further exploration in SSA, in which the pathophysiology of ID in HF and the healthcare system may differ from that of high-income countries.

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Congress News Building and strengthening capacity for cardiovascular research in Africa through technical training workshops: a report of the joint course on health research methods by the Clinical Research Education Networking and Consultancy and the Ivorian Society of Cardiology Bonaventure Suiru Dzekem, Jean Baptiste Anzouan Kacou, Martin Abanda, Euloge Kramoh, Yves Yapobi, Samuel Kingue, Andre Pascal Kengne, Anastase Dzudie

Abstract Africa bears a quarter of the global burden of disease but contributes less than 2% of the global research publications on health, partially due to a lack of expertise and skills to carry out scientific research. We report on a short course on research methods organised by the Clinical Research Education Networking and Consultancy (CRENC) during the third international congress of the Ivorian Cardiac Society (SICARD) in Abidjan, Cote d’Ivoire. Results from the pre- and post-test evaluation during this course showed that African researchers could contribute more to scientific research and publications, provided adequate support and investment is geared towards the identification and training of motivated early-career scientists. With about 17% of the global population, Africa bears 25% of the global burden of disease, yet it contributes less than 2% of the world’s health research publications.1 This negligible contribution of African scientific health knowledge is partially explained by the lack of adequate training in research across most universities in the region.2,3 Clinical Research Education Networking and Consultancy, Douala, Cameroon Bonaventure Suiru Dzekem, MD Martin Abanda, MD Anastase Dzudie, MD, PhD, FESC, aitdzudie@yahoo.com

It is vital for any African institution to develop a critical mass of clinicians that can effectively carry out research and publish their findings. The Clinical Research Education Networking and Consultancy (CRENC), a Cameroon-based research organisation, was established to improve skills acquisition in research in Africa by developing research priorities and training African clinical researchers in partnership with stakeholders with a similar vision.4 The international short course on human health research methods titled ‘Fostering dissemination of research findings in routine clinical practice’ was organised by the CRENC during the third international congress of the Ivorian Cardiac Society (SICARD) held at Afrikland Hotel, Abidjan, from 9 to 11 May 2017. This half-day training session brought together a selected group of 50 participants, most of whom were cardiologists. It included a pre-test, lectures on how to ask a research question, study designs, and how to write and publish a scientific article, as well as a post-test. Here we provide a report on this course.

Course introduction and pre-test evaluation The course began at 14:00 with an opening speech from the Chair, Professor Yves Yapobi. Dr M Abanda then coordinated the administration of pre-test multiple-choice questions. These comprised six questions on how to ask a research question, five questions on research study designs and 15 questions on how to write and publish a scientific article.

Société Ivoirienne de Cardiologie (SICARD) and Institut de Cardiologie d’Abidjan, Abidjan, Cote d’Ivoire Jean Baptiste Anzouan Kacou, MD Euloge Kramoh, MD Yves Yapobi, MD

Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Cameroon Samuel Kingue, MD Anastase Dzudie, MD, PhD, FESC

South African Medical Research Council, Cape Town, South Africa Andre Pascal Kengne, MD, PhD

Fig. 1. Participants during the post-test evaluation.

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Course objectives After administration of the pre-test, Anastase Dzudie presented the objectives of the course, which included equipping clinicians and other health professionals with the methodological skills needed to conduct clinical research, from asking a research question and choosing the best study design, to publishing their research findings in a peer-reviewed journal. He also presented the CRENC as an international organisation, made up of medical researchers and clinicians with the vision of enhancing the practice of evidence-based medicine in Africa via research.

How to ask a research question Dr Dzudie, in his presentation on how to ask a research question, reiterated that a research question is the starting point of every study. The key message from this presentation was that a research question must be one that is relevant, feasible, specific, ethical, and whose answers will add to existing knowledge on the topic in question.

Study designs In his presentation on study designs focused on how a research question dictates the study design, Dr Dzekem enlightened participants on what a study design is, various types of study designs, and why choosing the correct study design is important. Using popular studies such as the May measurement month (MMM), the INTERHEART, Framingham and PAPUCO studies, and the INVICTUS and CREOLE trials as illustration, he showed how a research question can be used to select the appropriate study design, as well as their advantages and disadvantages. He concluded that the choice of study design depends on the research goals, the researchers’ beliefs, values and skills, availability of time and resources, and research questions.

How to write and publish a scientific article Building on his experience as editor of several journals, this presentation by Dr Dzudie focused on how to avoid pitfalls in preparing manuscripts, the natural lifecycle of a scientific manuscript and how to get a scientific article published in a medical journal. His key messages were the following: • An unpublished work has no value, and is unethical. • Publishing begins as early as when the protocol is written, and not after the study has been completed. • Patience and perseverance are the keys for the success of a manuscript. He concluded by insisting on the relevance of team building and leadership in research and offering a word of thanks to participants and the SICARD.

100 post-test

pre-test 60 40 20 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

Fig. 2. Trends in overall performance. Table 1. Comparison of median scores for performance in pre- and post-tests Pre-test: median Post-test: median p-value (25th – 75th percentile) (25th – 75th percentile) (Mann– ISCReM performance (n = 49) (n = 43) Whitney) Research question

50.0 (37.5–83.30)

50.0 (33.3–66.67)

Research design

60.0 (40.0–80.0)

80.0 (50.0–80.0)

0.29

How to publish

53.3 (40.0–66.7)

66.7 (60.0–73.3)

0.07

Total score

57.7 (39.4–68.2)

61.5 (50.0–73.1)

0.35

0.14

Out of 50 participants, 49 (98%) took the pre-test and 43/45 (95.5%) took the post-test. Overall, the trend in performance was better in the post-test compared to the pre-test, although this was not statistically significant (Fig. 2). The course had its greatest influence on participants’ performance in the ‘How to publish’ section (Table 1). The real impact of this course however can only be assessed by an increase in the number and quality of publications from course participants.

Conclusion Africa’s needs for research capacity building are huge but with a good vision, clear objectives and support for a multi-level team driving the strategy, change is possible. CRENC’s belief is that if identified earlier in their career and appropriately trained, talented individuals will lead research programmes at their institutions, resulting in increased research productivity. This is fundamental to generate research evidence that will guide policy, strengthen good medical practice and maximise the use of resources to improve healthcare on the continent.

References 1.

The next pandemic? Non-communicable diseases in developing countries. [Internet] [cited 2017 May 20]. Available from: http://accessaccelerated.economist.com/reports/thenextpandemic/.

Dzudie A, Aminde L, Sliwa K. The way forward for clinical research in Cameroon: first scientific and research day in Douala, 2014. Cardiovasc

Post-test and results Following the presentations, the CRENC team answered several questions from the audience, not only on presented topics, but on research as a whole. Dr M Abanda coordinated the administration of the post-test with the same questions that were initially administered. In his closing speech, the chair of the session acknowledged the CRENC team and all the participants in the training session.

339

J Afr 2014; 25(5): 250. 3.

Knowledge gap. In: Encyclopedia of Survey Research Methods [Internet]. Sage Publications, Inc, 2008 [cited 2017 May 16]. Available from: http://methods.sagepub.com/reference/encyclopedia-of-survey-researchmethods/n263.xml.

Dzudie A, Sliwa K. Addressing the shortage of research capacity in cardiovascular disease in Africa via leadership training. Heart Asia 2017; 9(1): 96–98.

ECG rhythms CPD CPD developed by Prof Rob Scott Millar, Cardiac Clinic, UCT/Groote Schuur Hospital CPD overview: Following the introductory “Approach to Rhythms”, this online educational CPD quiz will consist of a series of ECGs with a variety of important cardiac rhythms. Each will be accompanied by a series of questions, followed by a detailed analysis and explanation. Target audience: Cardiologists, physicians, emergency unit doctors and anaesthetists. Including those studying for FCP and certificate in cardiology. Total time commitment: ± 30 to 60 minutes. Assessment information: A pass mark of 70% is required. A candidate has 60 days to complete the CPD after registration. CPD certificate: A PDF certificate of completion will be issued on successful completion the CPD. CPD enrollment fee: Free / no charge. Important notice: The CPD was made possible by an unrestricted educational sponsorship from Bayer Pharmaceuticals South Africa, which had no control over the content. Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.

For more information please visit www.cvja.co.za

Cardiovascular Journal of Africa

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

Case Report Atrial myxoma: a rare cause of hemiplegia in children Uchenna Onubogu, Boma West, Boma Orupabo-Oyan

Abstract Background: Atrial myxoma is an uncommon cause of hemiplegia in children. However hemiplegia is the commonest manifestation of atrial myxoma in the paediatric age group. Case report: An 11-year-old girl presented with left hemiplegia and palpitations. Three months later she had a deepvein thrombosis of the right common iliac vein. MRI of the brain showed a subacute right thalamic infarct, and an ECG showed left atrial and left ventricular hypertrophy. Transthoracic echocardiography revealed a left atrial myxoma impinging on the mitral valve. A diagnosis of left atrial myxoma with multiple thromboembolic events was made. She was placed on anticoagulants until she died while awaiting surgical tumour resection. Conclusion: Echocardiography should be done early in children presenting with ischaemic thromboembolic diseases in order to reduce morbidity and mortality rates resulting from cardiac pathology.

Keywords: atrial myxoma, hemiplegia, thromboembolic, cardiac, children Submitted 17/5/16, accepted 30/10/16 Published online 9/12/16 Cardiovasc J Afr 2016; 27: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2016-093

Cardiac myxoma is a rare cause of cerebrovascular disease (CVD), especially in children. The common cause of CVD in African children is sickle cell disease.1 Other common causes are cyanotic congenital heart diseases, arrhythmias, coagulopathies and systemic infection (meningitis, sepsis).1,2 The term myxoma is the Latin translation of a Greek word ‘muxa’, which literally means mucus. A cardiac myxoma is a benign tumour of the heart arising from primitive mesenchyme. Cardiac myxoma is the most common primary tumour of the heart in adults but is very infrequent in the paediatric population.3 Among primary cardiac tumours in children, the rhabdomyomas are the commonest.4 Braithwaite Memorial Specialist Hospital, Portharcourt, Rivers, Nigeria Uchenna Onubogu, MB BS, FWACP, utchayonubogu@yahoo.co.uk Boma West, MB BS, FWACP Boma Orupabo-Oyan, MB BS, FWACP

Cardiac myxomas can be seen in any of the cardiac chambers but rarely on the heart valves. The atria are more affected than the ventricles, therefore cardiac myxomas are said to be predominantly intra-atrial. About 90% of cardiac myxomas are located in the atria with a left-to-right ratio of about 4:1.5 Our patient had a left atrial cardiac myxoma. The size of a cardiac myxoma can range from small (unnoticeable) to as large as 8 cm in length.

Case report An 11-year-old girl was referred to the cardiology clinic on account of left hemiplegia of one month duration. The hemiplegia was of sudden onset and was associated with headache, dizziness and vomiting at onset. She had also been having intermittent episodes of palpitations and had just been discharged from hospital two weeks earlier after being managed for an intracranial space-occupying lesion, with raised intracranial pressure, left hemiplegia and multiple cranial nerve palsy. She had a positive history of sudden death in her family (an uncle and her grandmother). On examination, she had a hemiplegic gait, a left CN V1, VII palsy and decreased power, tone and reflexes in the left upper and lower limb. A regular pulse and wide blood pressure difference was noted in both right and left upper limbs (right 120/50 mmHg, left 60 mmHg/unrecordable). Previous tests had been done when she was admitted. MRI of the brain showed subacute right thalamic infarct, and her blood lipid profile and random blood glucose results were normal. Her genotype was AA, mantoux was negative, chest radiograph was normal, and PT/PTTK was also normal. A diagnosis of peripheral artery disease was entertained and magnetic resonance angiography of both carotid arteries was done, which was normal. The ECG showed sinus rhythm with evidence suggestive of left atrial and left ventricular hypertrophy. An echocardiography could not be done immediately but was requested. She was subsequently placed on aspirin, encephabol and regular physiotherapy while angiography was being awaited. She defaulted from follow up and was seen in hospital three months later when she collapsed at school after complaining of heaviness of the right side of the body and inability to walk. Her history revealed that she had stopped her aspirin two days earlier. On examination, she was conscious, and the blood pressure in both upper limbs was equal and normal (110/70 mmHg). Her pulse was a good volume but irregularly irregular, both legs were cold to the touch, and the dorsalis pedis was barely palpable. A diagnosis of deep-vein thrombosis was entertained.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017

Fig. 1. I ntra-atrial mass measuring 3.9 × 2.6 cm impinging on the mitral valve, and a dilated left atrium.

She was rehydrated and recommenced on aspirin tablets, while vascular ultrasound of both legs showed a deep focal vein clot in the right common iliac vein. A transthoracic echocardiography was finally done and it revealed a mobile mass in the left atrium (myxoma) measuring 3.9 × 2.6 cm impinging on the mitral valve, a dilated left atrium and multiple ectopic beats (Fig. 1). A diagnosis of left atrial myxoma with intermittent arrhythmia and multiple thromboembolic events was made. Anticoagulation was commenced with heparin and warfarin tablets. She was also referred for surgical resection of the atrial myxoma. Due to financial constraints, surgery could not be done and she died 10 months later while awaiting resection of the cardiac tumour.

Discussion Cardiac myxoma accounts for 30% of all primary cardiac tumours, with a male-to-female ratio of 2:7.6 The mean age of presentation is 56 years for sporadic cases and 25 years for familial cases.3,7 It is very rarely reported in children; about three case have been reported in Nigerian children.8,9 A surgical incidence of 0.5 atrial myxomas per million population per year was reported in Ireland.10 Myxomas may be associated with several syndromes, namely Carney complex (multiple cardiac and extra-cardiac myxoma, pigmented skin lesions and endocrine hyperactivity), LAMB complex (lentigenosis, atrial myxoma, mucocutaneous myxoma and blue nevi), NAME complex (nevi, atrial myxoma, neurofibromatosis and ephelides-freckles) and a complex with lentigenosis, myxoid fibroma of the breast, skin myxomas and nodular adrenal disease. Single or multiple gene mutations have been implicated in the aetiology of cardiac myxoma. They are PRKAR1 on chromosomes 17 and 2p16. Autosomal dominant transmission is seen in Carney complex. Atrial myxomas usually occur as a single

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lesion and rarely as multiple lesions of varying sizes. They may be pedunculated lesions or freely mobile and able to move through the AV valves, as in our patient, or sessile with a broad base. Cardiac myxomas can be asymptomatic in 20% of cases and present as sudden death in 15% of cases.11,12 When symptomatic, symptoms may be due to intra-cardiac obstruction to blood inflow and outflow. Our patient’s tumour was causing some obstruction in the mitral valve. Symptoms can also be due to mechanical interference with cardiac function, leading to signs of left- or right-sided heart failure, arrhythmias and syncope, depending on the location. Our patient had syncope and intermittent arrhythmias, which were captured clinically by the irregular pulse; unfortunately when her ECG was done she had converted to normal rhythm. Patients may also present with symptoms of systemic or pulmonary embolisation due to fragmentation of the tumour cells. Our patient had multiple systemic embolic phenomena affecting the common iliac vein and cerebral vessels. There may also be constitutional symptoms in 50% of patients due to overproduction of interleukin 6 by the tumour cells. These symptoms include fever, weight loss, lightheadedness and arthralgia. A review of nine paediatric cases with atrial myxoma shows that right hemiparesis was the commonest clinical presentation in the paediatric age group, occurring in eight (89%) of the children. Other common symptoms documented were red spots on the limbs (44%), aphasia (44%), lethargy (22%), seizures, headache, blindness, slurred speech, dizziness and diplopia (11%).13 Pridie also described three children with cardiac myxoma; all had systemic emboli involving the central nervous system.14 A full blood count and blood film may show normochromic or hypochromic anaemia. They can also have haemolytic anaemia due to mechanical destruction of the erythrocytes by the tumour. Serum interleukin 6 levels may be high and can be used as a marker of recurrence. Chest radiography can show abnormal cardiac silhouette, mimicking mitral stenosis, tumour calcification and pulmonary oedema. Echocardiography will show an intra-cardiac mass. Transoesophageal echocardiography has better specificity and sensitivity compared to transthoracic echocardiography. We did a transthoracic echocardiograph for our patient. The point of attachment of the tumour is best visualised by MRI or CT scanning. Electrocardiography will show left atrial enlargement, atrial fibrillation, atrial flutter or other conduction disturbances. Our patient had left atrial enlargement. Molecular genetic testing for PRKAR1 may be positive. Histology shows lipidic cells embedded in a vascular myxoid stroma, polygonal to stellate shaped, with scanty eosinophilic cytoplasm. Surgical resection is the treatment of choice; open heart or endoscopic resection. Drug therapy is used only for complications such as congestive heart failure or cardiac arrhythmias. Post-surgery survival is good, however there is an unusual recurrence risk of 1–3% in sporadic cases and 20% in familial cases.3,15 Biannual echocardiograms are useful for early detection of recurrent tumors post surgery. Relatives of a child with the familial type of atrial myxoma should undergo echocardiography for early detection.

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Conclusion Atrial myxoma is an uncommon cause of hemiplegia in children. However hemiplegia is the commonest manifestation of atrial myxoma in the paediatric age group. Echocardiography should be done early in children presenting with ischaemic thromboembolic diseases in order to reduce morbidity and mortality rates resulting from cardiac pathology.

presentation and investigation findings in cardiac myxomas: new insights from the developing world. Am Heart J 2007; 154(6): 1102–1107. 8.

Animasahun AB1, Kushimo OY, Fajuyile FA, Njokanma OF. Atrial myxoma in 2 Nigerian children: case reports and review of the literature. World J Pediatr Congenit Heart Surg 2010; 1(3): 397–399.

Aliyu I, Gambo S. Right atrial mass: An accidental echocardiographic finding. Heart India 2015; 3: 27–29.

10. MacGowan SW, Sidhu P, Aherne T, Luke D, Wood AE, Neligan MC, et

References 1.

11. Lone RA, Ahanger AG, Singh S, Mehmood W, Shah S, Lone GN, et al.

Moohr JW, et al. Cerebrovascular accidents in sickle cell disease: rates

Atrial myxoma: trends in management. Int J Health Sci (Qassim) 2008;

12. Weiner SD, Homma S. Tumors/masses. In: Klein AL, Asher CR (eds).

hood arterial ischemic stroke in a population-based cohort: the impor-

Clinical Echocardiography Review: A Self-Assessment Tool. Philadelphia: 13. Al-Mateen M, Hood M, Trippel D, Insalaco SJ, Otto RK, Vitikainen

Available from: http://emedicine.medscape.com/article/151362-overview.

KJ. Cerebral embolism from atrial myxoma in pediatric patients.

Wang JN, Yao CT, Chen JS, Yang YJ, Tsai YC, Wu JM. Cardiac tumors Markel ML, Waller BF, Armstrong WF. Cardiac myxoma: A review. Medicine (Baltimore) 1987; 66(2): 114–125.

Wolters Kluwer Lippincott Williams & Wilkins, 2011: 458.

Gyanendra KS, Park WW. Atrial myxoma [cited 2015 Sept 22].

in infants and children. Acta Paediatr Taiwan 2003; 44(4): 215–219. 5.

2(2): 141–151.

Fullerton HJ, Wu YW, Sidney S, Johnston SC. Risk of recurrent childtance of cerebrovascular imaging. Pediatrics 2007; 119(3): 495–501.

ment. Ir J Med Sci 1993; 162(6): 223–226.

Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, and risk factors. Blood 1998; 91(1): 288–294.

al. Atrial myxoma: national incidence, diagnosis and surgical manage-

Pediatrics 2003; 112(2) : 162–167. 14. Pridie RB. Left atrial myxomas in childhood: presentation with emboli – diagnosis by ultrasonics. Thorax 1972; 27: 759–763. 15. Sheng WB, Luo BE, Liu Y, Zhang H, Zou LJ, Xu ZY, et al. Risk

Sakamoto H, Sakamaki T, Kanda T, Tsuchiya Y, Sato M, Sato H.

factors for postoperative recurrence of cardiac myxoma and the clinical

Vascular endothelial growth factor is an autocrine growth factor for

managements: a report of 5 cases in one center and review of literature.

cardiac myxoma cells. Circ J 2004; 68(5): 488–493.

Chin Med J (Engl) 2012; 125(16): 2914–2918.

Aggarwal SK, Barik R, Sarma TC, Iyer VR, Sai V, Mishra J. Clinical

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Case Report Liddle’s syndrome in an African male due to a novel frameshift mutation in the beta-subunit of the epithelial sodium channel gene Robert Freercks, Surita Meldau, Erika Jones, Jason Ensor, Clarise Weimers-Willard, Brian Rayner Case report

Abstract Resistant hypertension is a common clinical problem in South Africa and is frequently associated with low renin and aldosterone levels, especially in black Africans. In South Africa, novel variants in the epithelial sodium channel (ENaC) have been described to be associated with varying degrees of hypokalaemia and hypertension due to primary sodium retention. We report here a case of Liddle’s syndrome due to a novel c.1709del11 (p.Ser570Tyrfs*20) deletion in the beta-subunit of the ENaC in a young black African male. We discuss the likely pathogenesis of hypertension in this setting as well as the treatment options available in South Africa aimed at the ENaC. This case highlights the need for vigilance in detecting and appropriately treating low-renin and low-aldosterone hypertension in view of the frequency of the described variants of the ENaC channel in our country. Specific therapy such as amiloride should be made more widely available.

Keywords: hypertension, Liddle’s, Africa, amiloride, resistant hypertension, hypokalaemia, low renin Submitted 2/11/16, accepted 12/1/17 Cardiovasc J Afr 2017; 28: e4–e6

www.cvja.co.za

DOI: 10.5830/CVJA-2017-012

Division of Nephrology and Hypertension, Livingstone Hospital, Port Elizabeth, South Africa

An 18-year-old Xhosa-speaking South African male was referred to the Livingstone Hospital renal unit for evaluation. He first presented at the age of 17 years to a nearby hospital emergency unit with a headache. He was not on any chronic or over-thecounter medications, did not consume liquorice, ethanol or traditional medications and was a non-smoker. He was noted to be hypertensive, with a blood pressure of 216/114 mmHg and hypokalaemic, with a serum potassium level of 2.9 mmol/l (see Table 1), but he left without treatment. Eight months later he was seen at the same unit with a similar presentation and was admitted for further investigations and treatment. Despite multiple antihypertensive interventions, his blood pressure remained uncontrolled. At discharge he was commenced on the following medications: enalapril 10 mg 12 hourly, amlodipine 10 mg daily, furosemide 40 mg twice daily, atenolol 25 mg daily, hydrallazine 50 mg twice daily and hydrochlorothiazide 25 mg daily. He was referred to our unit, and one month later his blood pressure was 179/118 mmHg in the left arm and 182/113 mmHg in the right arm, despite adherence to the treatment regime. He looked well, had a regular pulse rate of 59 beats/min and weighed 68 kg. The patient gave a history of experiencing frequent headaches associated with muscle fatigue, but no myalgias. The muscle fatigue was worse at times when the headache was present. He also described exertional dyspnoea but no spells suggestive of phaeochromocytoma. Both his parents were hypertensive and his father had died of an uncertain cause before the age of 50 years. On cardiovascular examination, all pulses were present. There was no radiofemoral delay or any bruits. The cardiac apex beat

Robert Freercks, MB ChB, FCP (SA), Cert Neph, MPhil, FRCP (Lon) Jason Ensor, MB ChB, FCP (SA), Cert Neph Clarise Weimers-Willard, MB ChB

Division of Chemical Pathology, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa

Table 1. Blood results and blood pressure readings Test

02/2014 10/2015 11/2015 01/2016 03/2016 06/2016 08/2016

Sodium, mmol/l

142

139

136

2.9

3.4

2.7

3.5

3.3

3.7

Department of Medicine, Division of Nephrology and Hypertension, University of Cape Town, Cape Town, South Africa

Potassium, mmol/l Creatinine, umol/l

220

150

144

134

153

128

Robert Freercks, MB ChB, FCP (SA), Cert Neph, MPhil, FRCP (Lon), robert.freercks@uct.ac.za Erika Jones, MB BCh, PhD, FCP (SA), Cert Neph Jason Ensor, MB ChB, FCP (SA), Cert Neph, Brian Rayner, MB ChB, FCP (SA), MMed, PhD

Renin, mIU/l (9.2–69.7)

6.0

Aldosterone, pmol/l (94–757)

48.6

Surita Meldau, BSc Med (hons), MSc (Med)

Office BP, mmHg

140

Amiloretic added 03/2016

216/114 220/120 179/118 173/101 181/121

162/91

142/100

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was forceful and laterally displaced with an associated fourth heart sound. He had normal secondary sexual characteristics, and retinal examination revealed markedly reduced arteriolar diameter and arteriovenous nicking. The urine dipstick was normal as was an ultrasound of the kidneys, ureters and bladder. Chest radiography showed a bulky heart shadow and electrocardiogram confirmed left ventricular hypertrophy with a Sokolow–Lyon score of 88 mV. Laboratory investigations confirmed the hypokalaemia and his serum potassium level was now 2.7 mmol/l, associated with a supressed renin level of 6.0 mIU/l and aldosterone of 48.6 pmol/l (Table 1). Unfortunately, arterial blood gas analysis was not performed prior to treatment. Based on this presentation, genetic testing for the locally prevalent c.1815G>A (p.R563Q)1 Liddle’s syndrome-associated genetic variant in the SCNN1B gene was requested, and his treatment was intensified to include doxazosin as no amiloridecontaining medications were available at the time. His blood pressure remained uncontrolled and the c.1815G>A (p.R563Q) variant screen was negative. Due to his persistent hypokalaemia, hypertension and supressed renin and aldosterone levels, sequencing of exon 13 of the beta-chain of the epithelial sodium channel was pursued. A novel heterozygous 11bp deletion in the SCNN1B gene was detected (Fig. 1A, case and 1B, control). The mutation causes a frame shift in exon 13 of the gene, resulting in a premature stop codon and truncated protein product.

His family was called in for screening. We have been unable to see his mother who lives in a rural area distant from our clinic. He has two brothers and one sister who are from the same parents. His younger brother (11 years) and his older sister (21 years) were both well and had normal blood pressures. His older brother (25 years) was found to have a raised blood pressure of 141/77 mmHg on ambulatory monitoring but was overweight with signs of insulin resistance and he had a body mass index of 35.1 kg/m2. All three siblings tested negative for the mutation seen in this patient and had potassium, renin and aldosterone levels in the normal range. As amiloride is not registered in South Africa and is only available in combination with hydrochlorothiazide (5 mg amiloride; 50 mg hydrochlorothiazide) (Amiloretic, Aspen Pharmacare, South Africa), he was started on the latter. Over the next few months his blood pressure improved significantly, with office readings of 162/91, 139/84, 190/113 and 142/100 mmHg. He still requires concomitant treatment with enalapril 10 mg daily, amlodipine 10 mg daily, atenolol 50 mg daily, doxazosin XL 8 mg daily and potassium replacement. On one occasion, after running out of tablets for three days, his blood pressure was 221/157 mmHg. His creatinine level has remained elevated but he has had no further headaches. However, potassium levels remain low and we suspect that higher doses of amiloride are needed. This will be introduced, pending local regulatory approval.

Fig. 1. S equence electropherogram showing the deletion in exon 13 of the SCNN1B gene (A), compared to a control sequence (B).

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Discussion Low-renin hypertension has been found to be more common in people of black African origin.2 Furthermore, in South Africa, low renin was found to be associated with low aldosterone levels in patients with resistant hypertension. The epithelial sodium channel is the final and rate-limiting step in sodium reabsorption. Liddle’s syndrome was described in a family that presented with hypertension and hypokalaemia associated with metabolic alkalosis.3 The genetic variant was found to be a truncating mutation of the beta-subunit of the epithelial sodium channel. Truncation of the carboxy terminal of the betasubunit results in impaired internalisation of the channel with ongoing sodium and water reabsorption, resulting in hypertension. Aberations due to activating mutations within the carboxyl terminal region of the epithelial sodium channel (ENaC) betaor alpha-subunits are known to cause Liddle’s syndrome. Such mutations negatively affect targeting of the protein products for endocytic degradation, which in turn leads to increased sodium reabsorption and resultant hypertension.4 The mechanism is thought to be due to interference with PPPY-targeting motifs needed for recognition by NEDD4 ubiquitin ligases. Multiple variants in the SCNN1B gene have been reported, many causing complete Liddle’s syndrome. Some mutations affect the PY motif, others truncate the carboxy terminal. In the case of single-nucleotide polymorphisms that do not affect the PY motif, the full Liddle’s phenotype is not usually present.5,6 A variant (R563Q, c.1815G>A) of the beta-subunit of the epithelial sodium channel was found frequently in patients with resistant hypertension and with low renin and aldosterone levels.7 This variant was described to result in the full Liddle’s phenotype during pregnancy;8 and in black South African hypertensive patients, the prevalence was 5.9% versus 1.7% in normotensives.1 Unlike the c.1815G>A (p.R563Q) variant, which affects a single amino acid in the protein product, the c.1709del11 (p.Ser570Tyrfs*20) deletion, seen in our patient (Fig. 1A), causes a frame shift, resulting in complete mistranslation from this point onwards and ultimately resulting in a premature stop codon 20 amino acids downstream. This mutation results in loss of the PPPY motif, impairing ENaC degradation, and resulting in unopposed sodium and water reabsorption. As neither parent could be tested and no siblings were found to carry this variant, it is impossible to say whether this is a new or inherited variant. However, both parents were hypertensive and it is likely that one of them are/were affected. Ideally the mother of this patient and/or any living paternal siblings should be tested. The mild hypertension present in the older brother can be explained on the basis of him having the metabolic syndrome phenotype. In patients with Liddle’s syndrome, treatment requires inhibition of the sodium channel. There are two agents available for this: triamterene and amiloride. In the intial stages of hypertension, inhibition of the sodium channel can completely reverse the clinical effects. After prolonged uncontrolled hypertension, the vascular consequences can result in hypertension that is more difficult to treat.

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Neither amiloride nor triamterene are licenced in South Africa, which impacts negatively on treatment. Amiloride is only available in combination with large doses of hydrochlorothiazide (5 mg amiloride/50 mg hydrochlorothiazide), which is not ideal in the setting of hypokalaemia. Our patient has responded well to this treatment, although he is not yet fully controlled and most likely requires a higher dose of amiloride. Amiloride 10 mg can be issued on an individualised basis under section 21 drug use but availability is limited and extremely expensive. Due to the frequency of described variants of the SCNN1B gene in South Africa, specific therapy targeting the epithelial sodium channel should be made more widely available.

Conclusion We have described a novel c.1709del11 (p.Ser570Tyrfs*20) deletion in the beta-subunit of the ENaC associated with Liddle’s syndrome in a young black African male. Due to this frameshift mutation, the defect is likely causative of the hypertension and therapy should be targeted at inhibition of ENaC. Unfortunately, this is not easily achievable in our context and treatment of such patients is therefore severely hampered in South Africa.

References 1.

Jones ES, Owen EP, Rayner BL. The association of the R563Q genotype of the ENaC with phenotypic variation in Southern Africa. Am J Hypertens 2012; 25(12): 1286–1291.

Rayner BL, Myers JE, Opie LH, Trinder YA, Davidson JS. Screening for primary aldosteronism – normal ranges for aldosterone and renin in three South African population groups. S Afr Med J 2001; 91(7): 594–599.

Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 1994; 79(3): 407–414.

Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, Rossier BC. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J 1996; 15(10): 2381–2387.

Baker EH, Dong YB, Sagnella GA, Rothwell M, Onipinla AK, Markandu ND, et al. Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London. Lancet 1998; 351(9113): 1388–1392.

Persu A. The epithelial Na+ channel: progressing from Liddle’s syndrome to essential hypertension. J Hypertens 2003; 21(5): 855–857.

Rayner BL, Owen EP, King JA, Soule SG, Vreede H, Opie LH, et al. A new mutation, R563Q, of the beta subunit of the epithelial sodium channel associated with low-renin, low-aldosterone hypertension. J Hypertens 2003; 21(5): 921–926.

Dhanjal MK, Owen EP, Anthony JA, Davidson JS, Rayner BL. Association of pre-eclampsia with the R563Q mutation of the betasubunit of the epithelial sodium channel. Br J Obstet Gynaecol 2006; 113(5): 595–598.

“I can’t believe we broke the bed again.” Some problems are worth having.

SILDENAFIL 50 mg •100 mg

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za DYNAFIL 50, 100 mg. Each tablet contains sildenafil citrate equivalent to 50, 100 mg sildenafil respectively. S4 A42/7.1.5/1071, 1072. NAM NS2 13/7.1.5/0086, 0087. For full prescribing information refer to the package insert approved by the Medicines Control Council, September 2012. DLC302/07/2017.

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