CVJA Volume 28 Issue 1 by Clinics Cardive Publishing

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CardioVascular Journal of Africa (official journal for PASCAR)

• Peripartum cardiomyopathy at Parirenyatwa Hospital, Zimbabwe • Non-dipper hypertension associated with slow coronary flow • Endothelial dysfunction and arterial stiffness in pre-eclampsia • Comparison of off- and on-pump beating-heart CABG surgery • Myocardial dysfunction in children with intrauterine growth restriction • Availability and distribution of paediatric cardiology services in Nigeria • Acute heart failure patients in sub-Saharan Africa: THESUS-HF

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Cardiovascular Journal of Africa . Vol 28, No 1, January/February 2017

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PUBLISHED ONLINE: • Abnormality of the basal interventricular septum, papillary muscle and chordae tendineae

Ă&#x; RESTORE cardiac function CARVEDILOL: - is indicated twice daily for mild to moderate stable symptomatic congestive heart failure - is indicated once daily for essential mild to moderate hypertension - has a positive effect on metabolic parameters.1

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Vol 28, No 1, JANUARY/FEBRUARY 2017

CONTENTS

Cardiovascular Journal of Africa 3

www.cvja.co.za

From the Editor’s Desk P Commerford

Cardiovascular Topics 4 Relationship between myocardial performance index and severity of coronary artery disease in patients with non-ST-segment elevation acute coronary syndrome O Abaci • Ct Kocas • V Oktay • S Arslan • Y Turkmen • C Bostan • U Coskun • A Yildiz • M Ersanlı 8 Peripartum cardiomyopathy among cardiovascular patients referred for echocardiography at Parirenyatwa Teaching Hospital, Harare, Zimbabwe ET Gambahaya • J Hakim • D Kao • N Munyandu • J Matenga 14

Non-dipper hypertension is associated with slow coronary flow among hypertensives with normal coronary angiogram E Aksit • E Gursul • F Aydin • M Samsa • F Ozcelik

19 Surgical placement of left ventricular lead for cardiac resynchronisation therapy after failure of percutaneous attempt M Ezelsoy • M Bayram • S Yazici • N Yazicioglu • E Sagbas 23 Endothelial dysfunction and arterial stiffness in pre-eclampsia demonstrated by the EndoPAT method A Meeme • GAB Buga • M Mammen • A Namugowa 30 A comparison of off- and on-pump beating-heart coronary artery bypass surgery on long-term cardiovascular events O Gurbuz • G Kumtepe • A Yolgosteren • H Ozkan • IH Karal • A Ercan • S Ener 36 Myocardial dysfunction in children with intrauterine growth restriction: an echocardiographic study K Niewiadomska-Jarosik • J Zamojska • A Zamecznik • A Wosiak • P Jarosik • J Stańczyk

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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

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Vol 28, No 1, JANUARY/FEBRUARY 2017

CONTENTS

40 Adropin as a potential marker of enzyme-positive acute coronary syndrome S Aydin • MN Eren • M Yilmaz • M Kalayci • M Yardim • OD Alatas • T Kuloglu • H Balaban • T Cakmak • MA Kobalt • A Çelik • S Aydin 48 The effects of the metabolic syndrome on coronary artery bypass grafting surgery S Özkan • F Özdemir • O Uğur • R Demirtunç • AY Balcı • M Kızılay • Ü Vural • M Kaplan • İ Yekeler 54 Audit of availability and distribution of paediatric cardiology services and facilities in Nigeria EN Ekure • WE Sadoh • F Bode-Thomas • AA Orogade • AB Animasahun • OO Ogunkunle • I Babaniyi • MU Anah • BE Otaigbe • A Olowu • F Okpokowuruk • SI Omokhodion • OC Maduka • UU Onakpoya • DK Adiele • UM Sani • M Asani • CS Yilgwan • Q Daniels • CC Uzodimma • CO Duru • MB Abdulkadir • JK Afolabi • JA Okeniyi 60 Echocardiographic predictors of outcome in acute heart failure patients in sub-Saharan Africa: insights from THESUS-HF MU Sani • BA Davison • GCotter • A Damasceno • BM Mayosi • OS Ogah • C Mondo • A Dzudie • DB Ojji • CK Kouam • A Suliman • G Yonga • SA Ba • F Maru • B Alemayehu • C Edwards • K Sliwa

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

e1 Hypertrophic angulation deformity of the basal interventricular septum combined with abnormality of the papillary muscle and chordae tendineae Y Wang • L Ye • L Yin • J Zeng

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GAUTENG CONTRIBUTOR PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month. Copyright: Clinics Cardive Publishing (Pty) Ltd.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

From the Editor’s Desk The peer-review process is a vital part of scientific publication and seeks to ensure that what is published has been effectively scrutinised for scientific integrity, validity and ethical conduct in research. No matter how good peer review may be it is inevitably, by its very nature, limited to the opinions of a small number of reviewers and editors. An important part of peer review, little mentioned, occurs after publication when the published work is exposed to a very much wider audience. This readership is often in a better position to offer critical opinions or commendations than the initial reviewers and is able to make its opinion known through letters to the editor. When these are published they offer important insights into the merit or otherwise of prior articles and serve an important educational purpose. Sadly of late there have been few such letters submitted to this journal. I encourage all readers of this journal to consider submitting letters of criticism or acclaim to the journal for consideration for publication. Ideally they should be brief and to the point, referencing the article under discussion with no more than three to five additional references. All letters will be submitted to the author of the original article, offering a right of reply. The letter and response, if forthcoming, will be published together. Letters to the editor (and the response) will not be subjected to further review but will be accepted or rejected based on the opinion of the editor. The contributions by readers criticising or commenting on published work are an important part of scientific and clinical responsibility for all of us and I encourage all readers to participate actively so as to enhance the scientific integrity and value of the CVJA. Detailed instructions for authors of letters to the editor will be added to the website shortly but in the interim I will gladly accept submissions under the conditions outlined above. In an attempt to diversify the content of the journal and to cater for the ever-growing importance of diverse imaging modalities, I plan to develop a series of ‘Images in Cardiology’. The exact requirements will be posted in the instructions

for authors on the journal website shortly. In the interim, I invite the submission of suitable images for consideration for publication. The images should be of high quality and suitable for publication, as already specified on the website. They should be accompanied by a brief clinical vignette, a report of why the imaging modality was chosen and how it contributed to patient outcome. A description of the results of imaging, suitably labelled with arrows or other markers, indicating areas of particular interest is essential. A maximum of five references may be supplied. Priority will be given to images of cardiac diseases commonly seen in Africa. Submissions will be subject to peer review by experts in the field. With the dramatic developments that have occurred in the field of imaging and that have revolutionised cardiovascular diagnosis over the last several decades, some ‘old standards’ seem to have fallen away and receive less attention than they did previously. One such is electrocardiography, which many believe, as I do, still serves as an essential aid to clinical diagnosis. It is cheap, reproducible, non-invasive and readily available. I hope to develop a series of ECG presentations to be produced on a regular basis. Other cardiovascular journals publish an ‘ECG quiz’ and I enjoy them. I sense however that some such quizzes are often difficult for the average clinician, such as myself, and therefore are avoided. My plan is to provide educational ECGs linked to clinical cases, which would be of interest to physicians and clinical cardiologists, rather than specialist electrophysiologists. I hope that these new initiatives will meet with your support and that you will continue to contribute to the journal and criticise or comment in letters to the editor when you find it necessary. Please feel free to contact me, by a letter for publication, as above, or via the journal e-mail, with suggestions as to how the journal could be improved to better meet your needs. Patrick Commerford Editor-in-Chief

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

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Cardiovascular Topics Relationship between myocardial performance index and severity of coronary artery disease in patients with non-ST-segment elevation acute coronary syndrome Okay Abaci, Cuneyt Kocas, Veysel Oktay, Sukru Arslan, Yusuf Turkmen, Cem Bostan, Ugur Coskun, Ahmet Yildiz, Murat Ersanlı

Abstract Objectives: We aimed to investigate the relationship between myocardial performance index (MPI) and severity of coronary artery disease, as assessed by the Gensini score (GS), in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Methods: Ninety patients with an initial diagnosis of NSTEMI were enrolled in our study. They were divided into tertiles according to the GS: low GS < 19; mid GS > 19 and ≤ 96; and high GS > 96. Results: The low-, mid- and high-GS groups included 24, 38 and 28 patients, respectively. Clinical features such as gender distribution; body mass index (BMI); prevalence of diabetes mellitus, hypertension and hyperlipidaemia; and smoking status were similar in the three groups. MPI and isovolumic relaxation time were significantly higher in the high-GS group than in the low- and mid-GS groups (p < 0.001 and p = 0.005, respectively). Furthermore, the high-GS group had a significantly lower ejection fraction and ejection time (p = 0.01 and p < 0.001, respectively). MPI was positively correlated with the GS (r = 0.47, p < 0.001), and multivariate regression analysis showed that MPI was an independent predictor of the GS (β = 0.358, p < 0.001). Conclusions: Patients with NSTEMI who fall within the high-risk group may be identified by means of a simple MPI measurement. Keywords: Tei index, Gensini score, acute coronary syndrome Submitted 22/10/13, accepted 3/4/16 Cardiovasc J Afr 2017; 28: 4–7

www.cvja.co.za

DOI: 10.5830/CVJA-2016-041

Department of Cardiology, Cardiology Institute of Istanbul University, Istanbul, Turkey Okay Abaci, MD, drokayabaci@hotmail.com Cuneyt Kocas, MD Veysel Oktay, MD Sukru Arslan, MD Yusuf Turkmen, MD Cem Bostan, MD Ugur Coskun, MD Ahmet Yildiz, MD Murat Ersanlı, MD

Non-ST-segment elevation myocardial infarction (NSTEMI) is one of the leading causes of morbidity and mortality, and accounts for high healthcare costs worldwide. The Gensini scoring system, based on angiographic findings, is a valuable method for estimating the severity of coronary artery disease.1,2 The severity of coronary artery lesions, as assessed by the Gensini score (GS), is associated with long-term mortality and major adverse cardiac event rates.3 Doppler-derived myocardial performance index (MPI), also known as the Tei index, is a new diagnostic method and an alternative to ejection fraction (EF) measurements. This index reflects combined systolic and diastolic function and can be defined as the sum of the isovolumic contraction time and isovolumic relaxation time, divided by the ejection time, with a reported normal mean ± standard deviation (SD) value for the left ventricle of 0.39 ± 0.05.4 Adverse outcomes are infrequently seen among patients with preserved global ventricular function.5 MPI has been identified as a powerful independent predictor of death from all causes in patients with a recent acute myocardial infarction (AMI). In this study, we aimed to determine the association between the severity of coronary atherosclerosis as assessed by the GS and MPI in patients with NSTEMI.

Methods The study was a prospective, single-centre analysis of 90 consecutive patients with an initial diagnosis of NSTEMI. Patients who had valvular heart disease, cardiomyopathy, congestive heart failure, previous cardiac surgery, history of percutaneous coronary intervention, chronic kidney disease, hepatic dysfunction, acute respiratory illness, acute infection, chronic inflammatory disease, or complex congenital heart disease were excluded from the study. Patients who were diagnosed with peripheral arterial disease or a coronary artery disease (CAD) equivalent were also excluded. Data on demographics, established cardiovascular risk factors and medical history were obtained for each patient. Written informed consent was obtained from all subjects, and the investigation conformed to the principles outlined in the Decleration of Helsinki. The local ethics committee approved the study protocol.

Echocardiographic evaluation All patients underwent echocardiographic evaluation using a standard protocol on commercially available systems (GE

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VividiVingmed Ultrasound; Horten, Norway). Comprehensive two-dimensional (2D) and Doppler echocardiographic evaluation were performed with the patient in the left lateral decubitus position before coronary angiography. Transthoracic echocardiography was performed within the first 24 hours of initial diagnosis. While performing transthoracic echocardiography all patients were monitored by ECG, and echocardiographic parameters were measured with synchronisation by ECG. In the apical four-chamber view, mitral inflow velocities were measured with the Doppler sample placed at the tip of the valve leaflets, at the left ventricular outflow tract, and below the aortic valve plane. All measurements were averaged over three consecutive cardiac cycles. Isovolumic relaxation time (IVRT) was measured from closure of the aortic valve to opening of the mitral valve. Isovolumic contraction time (IVCT) was measured from closure of the mitral valve to opening of the aortic valve. Ejection time (ET) was measured from the opening to the closure of the aortic valve on the left ventricular outflow velocity profile. MPI was calculated as the sum of the IVRT and IVCT divided by the ET. Peak velocities of early (E) and late (A) filling were determined according to the mitral inflow velocity curve.

Angiographic examination All patients underwent selective coronary angiography via the Judkins technique (IntegrisAllura 9; Philips Medical Systems, Eindhoven, the Netherlands). All angiograms were evaluated by two experienced interventional cardiologists blinded to the clinical baseline characteristics of the patients. In cases of discrepancy, the opinion of a third interventional cardiologist was obtained, and the final decision was made by consensus. The severity of coronary artery lesions was scored using a modified Gensini scoring system.1 In brief, coronary circulation was divided into eight proximal segments; the percentage by

Table 1. Baseline characteristics and laboratory findings Group 1 Group 2 Group 3 Variables (n = 24) (n = 38) (n = 28) p-value Age (years) 0.035 49.4 ± 11.1 54.7 ± 10.3 56.7 ± 9.3 Male, n (%) 18 (75) 29 (76.3) 26 (92.9) 0.15 Diabetes 6 (25) 13 (34.2) 7 (25) 0.63 mellitus, n (%) Hypertension, n (%) 12 (50) 16 (42.1) 8 (8.6) 0.27 Hyperlipidaemia, n (%) 4 (16.7) 9 (23.7) 2 (7.1) 0.20 Current smokers, n (%) 17 (70.8) 26 (68.4) 21 (75) 0.84 Glucose (mg/dl) 128.6 ± 66.2 136.0 ± 59.7 132.0 ± 54.0 0.91 (mmol/l) (7.14 ± 3.67) (7.55 ± 3.31) (7.33 ± 3.00) LDL (mg/dl) 111.1 ± 35.4 131.4 ± 38.8 132.5 ± 35.9 0.07 (mmol/l) (2.88 ± 0.92) (3.40 ± 1.00) (3.43 ± 0.93) HDL (mg/dl) 0.34 41.1 ± 16.7 36.7 ± 9.0 39.4 ± 8.5 (mmol/l) (1.06 ± 0.43) (0.95 ± 0.23) (1.02 ± 0.22) eGFR (ml/min/1.73 m2) 96.8 ± 25.5 96.5 ± 19.5 92.1 ± 21.1 0.66 Haemoglobin (g/dl) 0.31 14.2 ± 1.0 13.6 ± 1.7 13.9 ± 1.5 Leukocytes (× 103/ml) 8513 ± 2506 8826 ± 3527 8813 ± 2288 0.91 0.55 Platelet count (× 103/ 248 ±68 253 ± 81 233 ± 62 ml) LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate.

which each lesion in the proximal coronary circulation narrowed the artery was assessed according to the maximal narrowing of the diameter of the artery in all projections. The extent and severity of proximal coronary disease was assessed by assigning points to each lesion as follows: less than 50% stenosis of the luminal diameter, one point; 50 to 74% stenosis, two points; 75 to 99% stenosis, three points; and total obstruction, four points. The points for each lesion in the proximal coronary circulation were added, and a score for the severity of coronary atherosclerosis was obtained. According to the modified Gensini scoring system, the degree of coronary stenosis was classified as follows: mild lesions, one to six points; moderate lesions, seven to 13 points; and severe lesions, > 13 points. Patients were divided into tertiles according to the GS: low GS < 19; mid GS > 19 and ≤ 96; and high GS > 96 points.

Statistical analysis Statistical analysis was performed using SPSS (Statistical Package for Social Sciences) for Windows version 12 (Chicago, Illinois). Continuous variables are expressed as mean ± SD, and categorical variables are expressed as numbers and percentages. Continuous variables were compared between groups using one-way analysis of variance for normally distributed data, and the chi-squared test was used for nominal variables. Correlations between variables were calculated using the Pearson correlation coefficient. Multiple linear regression analysis was performed to identify the factors related to the GS. A p-value of < 0.05 was considered significant.

Results Of the 90 patients included in this study, 24 were assigned to the low-GS group (26.7%), 38 to the mid-GS group (42.2%) and 28 to the high-GS group (31.1%). The demographic and clinical characteristics of the 90 patients with NSTEMI according to the GS are presented in Table 1. The mean patient age was significantly higher in the highGS group than in the low- and mid-GS groups (p = 0.035). Table 2. Echocardiographic findings in the three groups Group 1 Group 2 Group 3 Variables (n = 24) (n = 38) (n = 28) p-value IVRT (ms) 0.008 88.9 ± 18.9 101.7 ± 29.1 113.1 ± 29.9 IVCT (ms) 0.18 67.3 ± 25.1 61.4 ± 31.6 74.0 ± 20.4 ET (ms) 283.0 ± 24.1 273.9 ± 31.5 241.0 ± 21.4 < 0.001 MPI 0.50 ± 0.11 0.60 ± 0.21 0.72 ± 0.12 < 0.001 E/A 0.31 1.0 ± 0.29 0.97 ± 0.46 0.91 ± 0.39 0.87 E/e′ 5.8 ± 1.5 6.1 ± 2.1 6.1 ± 1.9 EF (%) 0.01 58.2 ± 3.9 56.4 ± 5.3 53.8 ± 6.2 Left atrium (cm) 0.25 3.30 ± 0.4 3.39 ± 0.4 3.50 ± 0.4 LVEDD (cm) 0.61 4.76 ± 0.3 4.74 ± 0.4 4.84 ± 0.3 RV (cm) 0.24 2.11 ± 0.1 2.21 ± 0.2 2.2 ± 0.1 IVRT, isovolumic relaxation time; IVCT, isovolumic contraction time; ET, ejection time; MPI, myocardial performance index; E/A, ratio of peak velocities of early (E) and late (A) transmitral filling; E/e′, ratio between early mitral inflow velocity and mitral annular early diastolic velocity; EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; RV, right ventricle.

Myocardial performance index

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

1.25

r = 0.47 p < 0.001

1.00 0.75 0.50 0.25 0

100 150 Gensini score

200

250

Fig. 1. Correlation between MPI and Gensini score.

However, the groups did not differ significantly with regard to gender; BMI; prevalence of diabetes mellitus, hypertension and hyperlipidaemia; and smoking status. The echocardiographic parameters of the groups are presented in Table 2. The MPI was higher in the high-GS group of patients than in the low- and mid-GS groups (p < 0.001). IVRT was significantly higher in the high-GS group than in the other groups, and the difference was significant between the high- and low-GS groups, and between the high- and mid-GS groups (p = 0.005). Furthermore, ET was significantly lower in the high-GS group (p < 0.001), whereas the EF was similar in the low- and mid-GS groups, although the high-GS group had a significantly lower EF (p = 0.01). Correlation analysis was performed to investigate the relationship between the MPI, age and GS. MPI was positively correlated with GS (r = 0.47, p < 0.001; Fig. 1), and age and GS showed a weak positive correlation (r = 0.25, p = 0.01). Multivariate regression analysis for predictors of GS included age and MPI. MPI was identified as an independent predictor of GS (β = 0.358, p < 0.001).

Discussion In this study, we found that the risk of significant lesion complexity increased progressively with increasing MPI. According to our results, MPI is an independent predictor of GS, a measure of the severity of coronary artery disease. Assessment of systolic and diastolic function by non-invasive methods in patients with AMI is of great importance for risk stratification and prognosis.5 EF, as determined by routine 2D echocardiography, is the most widely used instrumental parameter for the evaluation of left ventricular function, but this parameter focuses only on systolic function. Both systolic and diastolic functions are frequently affected during an AMI, and therefore, a combined measurement of left ventricular performance may be more useful in assessing overall cardiac function than systolic or diastolic measures alone. MPI, also known as the Tei index, reflects both systolic and diastolic function of the left ventricle. MPI is calculated using the following formula: (IVCT + IVRT)∕ET.4 During the acute phase of an AMI, IVCT and IVRT increase, and when clinical heart failure becomes apparent, the ET decreases. As a result, MPI increases.6 MPI is rapidly increased in the early phase of MI and

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the degree of increment is associated with both mortality and morbidity.7 Several studies show that MPI tends to be significantly higher in patients with AMI,8,9 but these studies do not describe the type of AMI or the severity of coronary involvement. Sahin et al.10 showed that MPI changed in proportion to the severity of CAD in patients with stable CAD, who had an increased prevalence of risk factors such as diabetes and hypertension. However, the increased MPI in that study may have been related to these risk factors, because MPI is reported to be impaired in patients with diabetes and hypertension.11 To the best of our knowledge, our study is the first to demonstrate the relationship between MPI and GS in patients with NSTEMI. In this study, the prevalence of risk factors did not differ among groups of patients classified according to the GS, and MPI was an independent predictor of GS. There are two treatment strategies for patients with NSTEMI: invasive and conservative. Determination of the number of diseased coronary arteries is important in the decision-making process when selecting the course of treatment. The severity of coronary artery disease is associated with mortality in patients with acute coronary syndromes.12 In the early period of NSTEMI, measurement of MPI may be useful in the decisionmaking process, for selecting the course of treatment and risk stratification. Our study has some limitations. First, assessment of coronary angiographic findings was limited to visual interpretation, with inter- and intra-observer variability. Second, the sample size was small and no calculations were made to ensure that the study was adequately powered.

Conclusion MPI was an independent predictor of GS in patients with NSTEMI. Patients with NSTEMI who are at high risk may be identified by a simple MPI measurement, which can be useful in the decision-making process for treatment selection and risk stratification.

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Gensini GG. More meaningful scoring system for detemining the severity of coronary artery disease. Am J Cardiol 1983; 51(3): 606. PubMed PMID: 6823874.

Peppes V, Rammos G, Manios E, Koroboki E, Rokas S, Zakopoulos N. Correlation between myocardial enzyme serum levels and markers of inflammation with severity of coronary artery disease and Gensini score: A hospital-based, prospective study in Greek patients. Clin Interv Aging 2008; 3: 699–710. PubMed PMID: 19281062.

Zhenhong F, Yundai C, Wei D, Lian C, Luyue G, Hongbin L, et al. Correlation between coronary artery lesion severıty and long-term clinical outcomes in Chinese Han octogenarians with acute coronary syndrome. Heart 2012; 98: E191.

Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, et al. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function – a study in normal and dilated cardiomyopathy. J Cardiol 1995; 26: 357–366. PubMed PMID: 8558414.

Moller JE, Egstrup K, Kober L, Poulsen SH, Nyvad O, Torp-Pedersen C. Prognostic importance of systolic and diastolic function after acute

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myocardial infarction. Am Heart J 2003; 145: 147–153. PubMed PMID:

in acute myocardial infarction. Am J Cardiol 2000; 85: 19–25. PubMed PMID: 11078230.

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10. Sahin DY, Gür M, Elbasan Z, Uysal OK, Özaltun B, Şeker T, et al.

BS, et al. Frequency, significance and cost of recurrent ischemia after

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thrombolytic therapy for acute myocardial infarction. TAMI Study

coronary artery disease assessed with SYNTAX score in stable coronary

Group. Am J Cardiol 1995; 76: 1007–1013. PubMed PMID: 7484852.

artery disease. Echocardiography 2013; 30(4): 385–391. PubMed PMID:

Uzunhasan I, Bader K, Okçun B, Hatemi AC, Mutlu H. Correlation of

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the Tei index with left ventricular dilatation and mortality in patients

11. Turfan M, Akyel A, Bolayir HA, Vatankulu MA, Aktürk M, Yetkin I, et

with acute myocardial infarction. Int Heart J 2006; 47: 331–342.

al. Correlation of the myocardial performance index with plasma B-type

PubMed PMID: 16823239.

natriureticpeptide levels in type 2 diabetes mellitus and impaired glucose

Karatzis EN, Giannakopoulou AT, Papadakis JE, Karazachos AV,

tolerance. Kardiol Pol 2012; 70(6): 556–562. PubMed PMID: 22718370.

Nearchou NS. Myocardial performance index (Tei index): Evaluating its

12. Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, Filippatos

application to myocardial infarction. Hellenic J Cardiol 2009; 50: 60–65.

G, et al. The second Euro Heart Survey on acute coronary syndromes:

PubMed PMID: 19196622.

characteristics, treatment, and outcome of patients with ACS in Europe

Poulsen SH, Jensen SE, Nielsen JC, Møller JE, Egstrup K. Serial

and the Mediterranean Basin in 2004. Eur Heart J 2006; 27: 2285–2293.

changes and prognostic implications of a Doppler derived index of

PubMed PMID: 16908490.

combined left ventricular systolic and diastolic myocardial performance

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

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

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Peripartum cardiomyopathy among cardiovascular patients referred for echocardiography at Parirenyatwa Teaching Hospital, Harare, Zimbabwe Ellise Tapiwa Gambahaya, James Hakim, David Kao, Noleen Munyandu, Jonathan Matenga

Abstract Objectives: The main aim was to evaluate the outcome of patients with peripartum cardiomyopathy (PPCM) within six months of diagnosis. The secondary aim was to describe demographic and clinical characteristics of patients with PPCM in Harare, Zimbabwe. Methods: This was a prospective cohort study in which patients recruited into a detailed PPCM registry were followed up for six months. Echocardiograms were performed at enrolment, and three and six months after diagnosis, to determine left ventricular function. Results: From 1 August 2012 to 31 July 2013, 43 patients with a new diagnosis of PPCM were recruited at Parirenyatwa Hospital in Harare. At six months, mean ejection fraction improved from 29.7 ± 9.8 to 44.9 ± 14.9%, p < 0.001 and New York Heart Association (NYHA) functional class improved significantly (p < 0.0001). Five (11.6%) patients died. Conclusions: Left ventricular function improved in a substantial number of patients (42.9%) in this Zimbabwean cohort compared to other African cohorts. However the mortality rate remained high. Keywords: peripartum cardiomyopathy, Zimbabwe, outcomes Submitted 17/3/15, accepted 3/4/16 Cardiovasc J Afr 2017; 28: 8–13

www.cvja.co.za

DOI: 10.5830/CVJA-2016-043

Cardiovascular disease has reached epidemic proportions in sub-Saharan Africa and is a major contributor to morbidity and mortality.1 These conditions often affect young women disproportionately, particularly during pregnancy, and they may have a worse prognosis compared to other groups of patients.2 Peripartum cardiomyopathy (PPCM) is one such condition that affects previously healthy young women during

College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe Ellise Tapiwa Gambahaya, MB ChB, MMed, egambahaya@gmail.com James Hakim, MB ChB, MMed, MMedSc, FRCP Noleen Munyandu, MB ChB, MMed Jonathan Matenga, MB ChB, MSc, FRCP

Division of Cardiology, Department of Medicine, University of Colorado Denver School of Medicine, Colorado, USA David Kao MD

the most productive years of their lives. This has far-reaching consequences for the patient, children and family unit as a whole. Virchow recognised heart failure in association with pregnancy as early as the 18th century.3 However, it was not until the 1930s when Hull and Hafkesbring formally described the syndrome of heart failure following pregnancy, which they called ‘postpartum cardiomyopathy’.4 Demakis and Rahmitoola in 1971 formally defined PPCM and gave criteria for its diagnosis, the basis of which remains today.5 Since the original description by Demakis, several studies have assessed the clinical profile of patients with PPCM as well as the natural history of the condition. These studies have been done in a variety of settings with the majority emanating from the United States and South Africa. Data from these studies suggest that PPCM has a variable clinical course. Unlike many other forms of cardiomyopathy, patients with PPCM are known to recover fully from the condition. When it occurs, recovery is rapid, usually within the first six months after diagnosis.5 Series from the United States and South Africa show that 21 to 78% of patients with PPCM recover left ventricular function (LVEF ≥ 50%) within six months of diagnosis.6-9 However a proportion of patients never recovers and requires long-term management of chronic heart failure. These women often have relapses of decompensated cardiac failure that may be severe enough to require cardiac transplantation. Factors shown to be associated with recovery of left ventricular function include Caucasian race, higher New York Heart Association (NYHA) functional class, higher ejection fraction and smaller left ventricular dimensions at presentation.6,10 Typical causes of death in PPCM patients include progressive cardiac failure and sudden cardiac death, presumably due to arrhythmias and thromboembolic events.11 PPCM is known to occur more commonly in African women or those of African descent, but despite the potentially devastating consequences of PPCM, there is very little published data about its outcome in African women outside South Africa, and a few isolated historical reports from Nigeria.12 A study conducted in Haiti showed an incidence of PPCM of one in 350 live births, which is at least 10 times that of Western nations.13 In South Africa the estimated incidence is one in approximately 1 000 live births.14 Given these data, it is expected that Zimbabwe would be a setting with a relatively high prevalence of PPCM, the impact of which may be magnified by poorly resourced public hospitals that make the diagnosis and management of these patients suboptimal. Therefore, it was necessary to conduct the current study to look at the outcome of PPCM in Zimbabwe. Clinical characteristics of Zimbabwean PPCM patients were described, and change in left ventricular function, functional status, and overall survival within six months of diagnosis were evaluated.

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Methods This was a prospective cohort study conducted at Parirenyatwa Hospital, a tertiary-care teaching hospital in Harare, Zimbabwe. The study protocol was approved by the Joint Parirenyatwa Hospital and College of Health Sciences Research ethics committee as well as the Medical Research Council of Zimbabwe. Informed consent was given by all patients. Consecutive patients seen between 1 August 2012 and 31 July 2013 in the echocardiography clinic at Parirenyatwa Hospital who fulfilled the entry criteria were enrolled into a detailed PPCM registry. Inclusion criteria were: women aged 16 to 49 years; development of symptoms of heart failure one month prior to and up to five months after delivery where no obvious cause could be established; left ventricular systolic dysfunction with ejection fraction (EF) < 45% or fractional shortening (FS) < 30% on transthoracic echocardiograph. Exclusion criteria were: significant organic valvular disease; systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg. On enrolment, the following was obtained for each case: demographic data, medical and obstetric histories, drug therapy, clinical examination findings and echocardiographic profile. After the initial assessment, these patients were subsequently followed up and managed for six months at the cardiac clinic at Parirenyatwa Hospital. The two time points that were of interest for this study were three and six months after enrollment. At each time point the NYHA functional class and drug management were assessed. In addition, a thorough clinical examination was carried out and clinical data were recorded. Echocardiography to assess left ventricular function was repeated at the three- and six-month reviews. Two-dimensional and targeted M-mode echocardiography was performed using a Hitachi EVB 7500 ultrasound scanner. Echocardiograms were carried out with patients in the left lateral decubitus position. Left ventricular ejection fraction (LVEF) was calculated using left ventricular internal systolic (LVDs) and diastolic dimensions (LVDd). These were measured at the level of the mitral valve leaflet tips in the parasternal long-axis view in accordance with the American Society of Echocardiography guidelines.15 A rhythm ECG strip was recorded during echocardiography and LVDd was determined in M-mode at the beginning of the Q wave, and LVSd was determined at the end of the T wave. The valves were carefully interrogated in the four standard views to determine morphology. Echocardiography was performed by cardiologists or senior clinicians at enrolment and at the six-month review. The threemonth studies were performed by the investigator using a mobile Sonosite ultrasound machine and images were recorded and subsequently reviewed by a cardiologist or senior clinician for accuracy of measurements. Remarkable recovery was defined as an increase in the LVEF > 20% from baseline and complete recovery as LVEF > 50% after six months. The investigator assigned the NYHA functional class for each patient at baseline and at subsequent follow-up visits. Patients were defined as improvers if they were in functional class I or II or had improved by at least one class at the end of the six-month period.

Statistical analysis Study data were collected and managed using Research Electronic

Data Capture (REDCap), a secure web-based application designed to support data capture for research studies,16 hosted at the University of Zimbabwe College of Health Sciences. These data were exported and analysed using the STATA statistical package (version 10.1, College Station, TX). Discrete variables are presented as n (%), and continuous variables are presented as mean ± standard deviation. A paired ANOVA test was used to compare ejection fraction at baseline and after three and six months. Fisher’s exact test was used to compare NYHA functional class at baseline and after three and six months. Significance was defined as a two-tailed p-value < 0.05 unless otherwise specified.

Results A total of 43 patients were enrolled into the study (Fig. 1). Only one patient was lost to follow up. Left ventricular function at three months could not be assessed for one patient because she did not come for the review, although she had an echocardiogram performed at six months. Two patients missed the six-month review so clinical assessment and echocardiography could not be done. However both patients were contactable by phone and were reported to be alive and well. Table 1 shows the baseline demographic and clinical characteristics of the patients. The mean age of the cohort was 27.9 ± 6.0 years. The majority of patients (15, 34.9%) were primigravida, with seven (16.3%) having a parity of four or more. At enrolment, 23 (53.5%) of the patients were NYHA class II, with only seven (16.3%) having an NYHA class of IV. A relatively large proportion (15, 34.9%) of the cohort had been diagnosed with and managed for pregnancy-induced hypertension. Out of all 43 patients, three had twin deliveries. Only one (2.3%) patient admitted to having symptoms of heart failure two weeks prior to delivery compared to 40 (93.0%)

At baseline 43 patients enrolled 4 deaths 1 lost to follow up 1 missed 3-month follow up but contactable by phone At 3 months 37 patients returned for follow up 1 death 2 missed 6-month follow up but contactable by phone At 6 months 35 patients returned for follow up

Fig. 1. Study flow diagram of 43 participants with newly diagnosed PPCM.

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Table 1. Baseline demographic and clinical characteristics of study patients Frequency, Variable n (%) Age (years) 27.9 (6) Parity 1 15 (34.9) 28 (65.1) ≥2 NYHA functional class II 23 (53.5) III 13 (30.2) IV 7 (16.3) Pregnancy-induced hypertension 15 (34.9) Gestation type Singleton 40 (93.0) Twins 3 (7.0) Time of symptom onset Pre-partum 1 (2.3) 1–3 months post-partum 40 (9.3) 4–5 months post-partum 2 (4.7) Echocardiographic data Left ventricular end-diastolic diameter (mm, range) 56.8 (43.2–72.2) Ejection fraction (%, range) 29.7 (4.4–50)* Left ventricular thrombus 4 (9.3) *A single patient had an LVEF > 45% but fractional shortening was < 30%.

within the first three months of delivery, and two (4.7%) between four and five months postpartum. On enrolment, all the patients were already on some form of treatment for heart failure; 38 (88.4%) were on diuretics, 28 (65.1%) were on angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and 26 (60.5%) were on spironolactone. In comparison, only eight (18.6%) patients were on beta-blockers (two on atenolol, six on carvedilol). The mean ejection fraction of the cohort at baseline was 29.7 ± 9.8% and four (9.3%) patients had left ventricular thrombi. Table 2 shows the change in NYHA functional class between the three points. There was a significant improvement in NYHA

Table 2. NYHA class at baseline, and three and six months Baseline (n = 43), n (%)

Parameters NYHA class I 0 II 23 (53.5) III 13 (20.2) IV 7 (39.5) **Significant at α = 1%

3 months (n = 37), n (%)

6 months (n = 35), n (%)

20 (54.1) 13 (35.1) 2 (5.4) 2 (5.4)

23 (65.7) 9 (25.7) 2 (5.7) 1 (2.9)

p-value < 0.001**

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from baseline to each of the time endpoints (p < 0.001 for both). By three months, 20 (54.1%) patients were in NYHA class I and only two (5.4%) were in NYHA IV. Of the two patients in NYHA IV, one had completely defaulted on treatment and the other had been on suboptimal therapy. By six months, 23 (65.7%) patients had an NYHA class of I compared to only one patient with an NYHA class of IV. Table 3 summarises the changes in left ventricular function. Patients who completed six months of treatment showed a significant improvement in the ejection fraction from 29.7 ± 9.8% at baseline to 44.9 ± 14.9% after six months (p < 0.001). Increases in LVEF between all time points were statistically significant, except for those that occurred between baseline and three months (p < 0.05). There was a non-significant reduction in LVDd from 56.8 ± 6.6 mm at baseline to 53.4 ± 9.2 mm after six months. By three months after diagnosis eight (22.3%) of the patients had a normal LVEF and eight (22.3%) showed remarkable LVEF improvement. Of the 35 patients who completed six months of follow up, 15 (42.9%) had normalised left ventricular function. Remarkable improvement of LVEF was seen in 16 (45.7%) patients after six months of follow up. Of the five (11.6%) patients who died during the study period, four (9.3%) died within the first three months of diagnosis. Two (40.0%) died from progression of heart failure while still hospitalised. Of the three who died outside the hospital, one died of thromboembolic disease, based on a post mortem that showed right leg deep venous thrombosis, a left ventricular thrombus and a large pulmonary embolus. There was no reported cause of death for the other two patients, although one had an intramural thrombus on echocardiography at three months and the other had presumed upper limb deep venous thrombosis, based on clinical examination.

Discussion PPCM has never been studied before in Zimbabwe. This study looked at the natural history of this rare condition in a relatively large cohort of Zimbabwean patients with a mean age of 27.9 ± 6.0 years. The majority of the women were primigravidas and a large proportion had been diagnosed with pregnancy-induced hypertension, however none of them were hypertensive at diagnosis. The LVEF had normalised in a large proportion (42.9%) of the patients and the NYHA functional class had improved significantly after six months of follow up. Still, mortality was relatively high (11.6%), with progressive heart failure and thromboembolic disease being the main causes of death. Demakis, in his landmark study on PPCM, noted that the condition was ‘more common in the older multiparous woman and in women who have had toxemia and twins’.5 Patients who develop PPCM in Zimbabwe have a clinical profile similar to those described in previously published reports, with a few

Table 3. Left ventricular systolic function at baseline, and three and six months Baseline 3 months LVDd (mm) 56.8 ± 6.6 53.9 ± 8.2 LVEF (%) 29.7 ± 9.8 36.8 ± 13.7 *Significant at α = 5%, **significant at α = 1%.

6 months 53.9 ± 9.2 44.9 ± 14.9

0–3 months p-value 0.345 0.05

0–6 months p-value 0.204 < 0.001**

3–6 months p-value 1 0.028

All p-value 0.136 < 0.001**

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notable exceptions. Firstly, PPCM occurred at a relatively young age in our study. Traditionally, it was generally accepted that PPCM occurred with greater frequency in older compared to younger women. In the United States for example, the mean age of patients who develop PPCM is between 27 and 34 years, with the majority of studies reporting a mean age of more than 30 years.17 In the South African cohorts the mean ages ranged from 29 to 31.6 years.17 By contrast, the Zimbabwean cohort had a mean age of 27.9 years with the majority of patients (67.4%) being younger than 30 years. Low socio-economic status and poverty have been consistently linked to younger maternal age.18 In Zimbabwe the demographic health survey of 2010 to 2011 showed that the median age for women at marriage was 19.7 years and the median age at first birth was 20.2 years.19 This may account for the younger age at presentation of women with PPCM in this cohort. Secondly, the proportion of patients in their first pregnancy (34.9%) was higher than in most previously published reports. A case in point is the original report by Demakis, which showed that 29% of patients had a parity of either one or two.5 In more recent times, 24% of patients from the Haitian and 20% from a South African cohort were primigravidas.13,20 The reasons for the relatively high proportion of primigravida women in this Zimbabwean cohort is not yet established. It could be due to the relatively large number of young primigravida women in the Zimbabwean population in general. However, Elkayam et al. also reported a higher proportion of primigravidas (37%) in patients from the USA comprised predominately patients of white or Hispanic ancestry (77%).21 Lastly, a relatively large proportion (34.9%) of patients in the current study was diagnosed with pregnancy-induced hypertension (PIH). This figure is much higher than other studies of black patients from Haiti and South Africa, where the proportion of patients with PIH was reported to be 4 and 2%, respectively.13,14 This is most likely due to the fact that in the three series of patients with PPCM reported by Sliwa and colleagues in South Africa, patients with pre-eclampsia and ‘hypertension of any degree greater than mild’ were excluded from the diagnosis of the condition.7,11,20 This is in contrast to the Zimbabwean cohort in which patients with the whole spectrum of hypertensive disorders of pregnancy were included. However the proportion of patients diagnosed with hypertensive disorders of pregnancy was reported to be higher in the United States.22 Women with the whole spectrum of hypertensive disorders of pregnancy were included in the systematic review by Bello et al.22 Therefore patients who develop PPCM in Zimbabwe are younger, of lower parity and have a history of gestational hypertension when compared with patients of a similar ethnic background. Previous studies of PPCM have reported a mixed prognosis for the condition. Data from the United States showed that left ventricular function improved in 35 to 62.2% of patients with PPCM, with most patients recovering within the first six months, although some took up to two years to recover.17 The mortality rate in the United States ranged from 1.36 to 18% over variable periods of time.17 These studies enrolled mainly Caucasian patients and it was noted that black women had poorer outcomes. In the Haitian study, the rates of recovery were very low with only 24% of women achieving a normal left ventricular function after 2.2 years of follow up. The mortality during the same period of time was 15%.13 The result was

supported by data from South Africa, which showed that 21 to 23% of patients achieved normal left ventricular function within six months of diagnosis, and between 10 and 27.6% of patients died within six months.7,11,20 In this Zimbabwean cohort, 42.9% of patients had normalised left ventricular function by six months of follow up, with an overall absolute mean change in ejection fraction of 15.2 ± 13.9%. The mortality rate was 11.9%. This is more comparable to figures seen in the Western world where the majority of patients were Caucasian. There could be several reasons for the better outcome in Zimbabwean patients when compared to patients of similar ethnicity. First, the patients enrolled in the current study were not as sick as patients in the South African and Haitian studies. Only 46.5% of the patients from Zimbabwe had an NYHA functional class of III/IV compared to 69 to 98% of South African and Haitian patients at enrollment. Although not validated, it has been suggested that NYHA functional class could be an independent predictor of left ventricular recovery and is a validated predictor of prognosis.23 LVEF at baseline has also been proposed as a predictor of left ventricular recovery and mortality.6 However six-month mortality rates in the Zimbabwean cohort were relatively low compared to other South African studies, even though the baseline LVEF of the Zimbabwean cohort (29.7 ± 9.8%) was comparable to that of the South African cohorts, which had baseline ejection fractions of between 25 and 30%.6,7,11,20 Mortality rates were also higher in Haitian patients, even though left ventricular function was comparable between Haitian and Zimbabwean PPCM patients (fractional shortening 15 vs 14.3%, respectively).24 LVEF also improved by a similar magnitude in all the studies. For example, at the end of six months of follow up, LVEF in the South African patients had increased to between 42.1 and 44.1%,6,7,11,20 compared to 44.9% in the Zimbabwean patients. However NYHA functional class at baseline has been shown to more consistently predict mortality in patients with PPCM.6,7,25 The baseline NYHA functional class of patients in the Zimbabwean cohort was lower than that in South African studies. It has been proposed that patients with hypertensive disorders of pregnancy should be excluded from the definition of PPCM because cardiac dysfunction may be a result of the underlying hypertension rather than a primary cardiomyopathy resulting from the pregnancy.26 Hence series of supposed PPCM patients that include women with hypertensive disorders of pregnancy may have a better prognosis and report better outcomes than series that do not. This is because good left ventricular recovery by six months may be less likely to happen in patients with true PPCM. Although this view may hold true in some cases, it does not make for a strong argument in all cases of PPCM. Other factors such as higher LVEF, smaller left ventricular dimensions at baseline and even Caucasian race may lead to faster recovery of left ventricular function. In addition, this current group of patients was not hypertensive on enrolment, with a mean systolic blood pressure of 117.4 mmHg and mean diastolic blood pressure of 73.1 mmHg. Furthermore, most patients developed symptoms an average of five weeks after delivery, by which time their blood pressures were back to normal. The degree of recovery of left ventricular function, as measured by the mean LVEF at six months, was similar in South African

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(42.1–44.1%) and Zimbabwean patients (44.9%) despite the fact that fewer patients in Zimbabwe had access to beta-blockers. Similarly, the proportion of patients who fully recovered left ventricular function in Zimbabwe was similar to Western cohorts. Although beta-blockers have been shown to improve outcomes in patients with systolic dysfunction, their efficacy in patients of African ancestry has been questioned.27 A GRK5 polymorphism seen in black patients actually gives genetic beta-blockade and improves survival in African patients.28 A meta-analysis also confirmed no significant overall benefit of beta-blockade in black patients with NYHA class III/IV heart failure.29 Four of the patients (9%) had intramural thrombi on enrollment, and three out of the five patients who died had thrombotic complications. This is consistent with previous observations that PPCM is a prothrombotic state.30,31 This supports the recommendation by some experts that anticoagulation should be prescribed to women with PPCM with very low ejection fractions. This is in contrast to recommendations for use of anticoagulation in patients with systolic dysfunction from other causes who are in sinus rhythm.32

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to that observed in other African cohorts. These outcomes occurred despite limited access to medications such as betablockers, which have been shown to improve outcomes in heart failure. A large percentage of patients who died had a high rate of thrombotic complications, supporting the recommendation that patients with PPCM should receive anticoagulation when in the setting of a low ejection fraction. Further research to assess the differences in pathogenesis, treatment and outcomes in Zimbabwean PPCM patients is warranted.

References 1.

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Limitations

Hull E, Hafkesbring E. Toxic postpartal heart disease. New Orleans Med

This study has several limitations. Firstly, the study had a short follow-up period of only six months. In previous studies, the improvement in left ventricular function continued even after the initial six months. Sliwa et al. also showed that the mortality rate actually increased after the first six months, and a proportion of patients who recovered within the first six months still died within two years of diagnosis.11 Hence it would have been interesting to observe the long-term outcome in this group of patients. Secondly, the sample of patients in this study may not have been representative of the patients who develop PPCM in Zimbabwe. For example, only patients who presented for echocardiography were included in this study. Hence women who were not able to get an echocardiogram for various reasons, such as financial constraints, were missed. However it is important to note that Parirenyatwa Hospital was the only public institution offering echocardiography for the whole northern region of the country. The only other public institution offering echocardiography is Mpilo Hospital which is some 400 km from Harare and caters for the southern region of the country. Therefore the catchment area for the study was quite wide although the majority of patients came from in and around Harare. Lastly, patients presented at different stages in their illness after having received some form of treatment. This was largely due to the fact that most patients presented for investigation only when they had money for the echocardiogram.

Conclusion

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Surg J 1937; 89: 550–557. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy. Circulation 1971; 44(5): 964–968. 6.

Blauwet LA, Libhaber E, Forster O, Tibazarwa K, Mebazaa A, HilfikerKleiner D, et al. Predictors of outcome in 176 South African patients with peripartum cardiomyopathy. Heart Br J 2013; 99(5):308–313.

Sliwa K, Förster O, Libhaber E, Fett JD, Sundstrom JB, HilfikerKleiner D, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006; 27(4): 441–446.

Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006; 152(3): 509–513.

Safirstein JG, Ro AS, Grandhi S, Wang L, Fett JD, Staniloae C. Predictors of left ventricular recovery in a cohort of peripartum cardiomyopathy patients recruited via the internet. Int J Cardiol 2012; 154(1): 27–31.

10. Goland S, Modi K, Bitar F, Janmohamed M, Mirocha JM, Czer LSC, et al. Clinical profile and predictors of complications in peripartum cardiomyopathy. J Card Fail 2009; 15(8): 645–650. 11. Sliwa K, Forster O, Tibazarwa K, Libhaber E, Becker A, Yip A, et al. Long-term outcome of peripartum cardiomyopathy in a population with high seropositivity for human immunodeficiency virus. Int J Cardiol 2011; 147(2): 202–208. 12. Ford L, Abdullahi A, Anjorin FI, Danbauchi SS, Isa MS, Maude GH, et al. The outcome of peripartum cardiac failure in Zaria, Nigeria. Q J Med 1998; 91(2): 93–103. 13. Fett JD, Carraway RD, Dowell DL, King ME, Pierre R. Peripartum cardiomyopathy in the Hospital Albert Schweitzer District of Haiti. Am J Obstet Gynecol 2002; 186(5): 1005–1010.

In this study, Zimbabwean PPCM patients were younger and of lower parity than those in previously published studies from Africa, with a relatively high proportion of patients with pregnancy-induced hypertension. The percentage of Zimbabwean patients who recovered left ventricular function by six months was almost double that seen in other PPCM patients with similar ethnicity, although the mortality rate was similar

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single institution. Mayo Clin Proc 2005; 80(12): 1602–1606. 25. Duran N, Günes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. Int J Gynaecol Obstet 2008; 101(2): 137–140.

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26. Ntusi NBA, Mayosi BM. Aetiology and risk factors of peripartum

statement from the Heart Failure Association of the European Society

cardiomyopathy: a systematic review. Int J Cardiol 2009; 131(2):

of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010; 12(8): 767–778. 18. Serefete Molosiwa BM. Girl-pupil dropout in secondary schools in Botswana: influencing factors, prevalence and consequences. Int J Bus Soc Sci 2012; 3(7): 265–271. 19. Zimbabwe National Statistics Agency (ZIMSTAT) and ICF International. Zimbabwe Demographic and Health Survey 2010–11. Calverton, Maryland: ZIMSTAT and ICF International Inc, 2012. 20. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35(3): 701–705.

168–179. 27. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 2001; 134(7): 550–560. 28. Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, et al. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 2008; 14(5): 510–517. 29. The Beta-Blocker Evaluation of Survival trial investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344(22): 1659–1667. 30. Kane A, Mbaye M, Ndiaye MB, Diao M, Moreira P-M, Mboup C, et al. Évolution et complications thromboemboliques de la myocardiopa-

21. Elkayam U, Akhter MW, Singh H, Khan S, Bitar F, Hameed A, et

thie idiopathique du péripartum au CHU de Dakar: étude prospective

al. Pregnancy-associated cardiomyopathy: clinical characteristics and

à propos de 33 cas. J Gynécologie Obstétrique Biol Reprod 2010; 39(6):

a comparison between early and late presentation. Circulation 2005; 111(16): 2050–2055. 22. Bello N, Rendon ISH, Arany Z. The relationship between pre-eclampsia and peripartum cardiomyopathy: a systematic review and meta-analysis. J Am Coll Cardiol 2013; 62(18): 1715–1723. 23. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;

484–489. 31. Simeon IA. Echocardiographic profile of peripartum cardiomyopathy in a tertiary care hospital in Sokoto, Nigeria. Indian Heart J 2006; 58(3): 234–238. 32. Lip GYH, Shantsila E. Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database Syst Rev 2014; 3: CD003336.

Events 23rd Annual Conference of The Egyptian Society of Cardiothoracic Surgery 23rd annual conference of The Egyptian Society of Cardiothoracic Surgery in collaboration with National Heart Institute of Egypt, from 4–7 April 2017 at Mena House Hotel, Cairo, Egypt. Workshops: RV-PA conduit implantation, electrophysiology anatomy for ablation surgery, aortic repair, simulation for wire-based techniques, basic anatomy of the heart for junior staff, TEE for surgeons and anaesthetics, endoscopic vein harvesting, coronary anastomoses (hands on).

Main topics: minimal invasive surgery, aortic root surgery, TEVAR, surgery for heart failure, cardiovascular perfusion, RV-PA connections, AV valve repair in infants, staging modalities in lung cancer, woman in cardiac surgery, personal skill development for surgeons. Kindly submit abstracts before the deadline 31 December 2016. Please check the link for abstract form: www.escts2017.com

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Non-dipper hypertension is associated with slow coronary flow among hypertensives with normal coronary angiogram Ercan Aksit, Erdal Gursul, Fatih Aydin, Murat Samsa, Fatih Ozcelik

Abstract Aim: A person with a drop of more than 10% in nocturnal arterial blood pressure during the circadian rhythm is referred to as a dipper and one with a smaller decrease is referred to as a non-dipper. In our study, we aimed to compare the thrombolysis in myocardial infarction (TIMI) frame count in non-dipper and dipper hypertensive patient groups who had normal coronary artery angiography. Methods: Patients with normal coronary arteries and with ambulatory blood pressure monitoring follow ups were retrospectively investigated and 60 patients (35%, female) were included in our study. The patients were grouped as dipper (n = 30) and non-dipper (n = 30) hypertensives. Results: The TIMI frame counts in all three coronary arteries and the mean TIMI frame count in the dipper hypertensive patient group were significantly lower than those of the non-dipper hypertensives (right coronary artery TIMI frame count: 16.83 ± 3.70; 21.63 ± 3.44, p < 0.001; circumflex artery TIMI frame count: 21.28 ± 3.52; 25.65 ± 3.61, p < 0.001; left anterior descending artery TIMI frame count: 34.20 ± 2.80; 37.05 ± 3.30, p = 0.001; corrected left anterior descending artery TIMI frame count: 20.05 ± 1.63; 21.74 ± 1.95, p = 0.001; mean TIMI frame count: 19.31 ± 2.3; 22.94 ± 2.61, p < 0.001). The body mass index (BMI) was 23.79 ± 2.81 kg/m2 in the dipper patient group, while it was 25.47 ± 2.92 in the non-dippers. BMI was found to be significantly higher in the non-dipper group than in the dipper group (p = 0.027). Conclusion: In this study, TIMI frame count, which is a simple, productive, objective and reproducible method for determination of microvascular changes, was found to be higher in non-dipper hypertensive patients than in the dipper patients. Keywords: hypertension, coronary angiography, TIMI frame count, dipper, non-dipper

Department of Cardiology, Biga State Hospital, Canakkale, Turkey Ercan Aksit, MD Erdal Gursul, MD, erdalgrsul@yahoo.com.tr

Department of Cardiology, Kocaeli State Hospital, Kocaeli, Turkey

Submitted 20/10/15, accepted 3/4/16 Published online 13/5/16 Cardiovasc J Afr 2017; 28: 14–18

www.cvja.co.za

DOI: 10.5830/CVJA-2016-045

Hypertension is a significant risk factor for stroke, myocardial infarction, renal diseases and other vascular disorders. Treatment of high blood pressure may lower the incidence of complications and enable a longer life. Cardiovacular parameters such as blood pressure, heart rate and coronary tonus change with the daily circadian rhythm.1 Development of ambulatory blood pressure-monitoring (ABPM) has provided an understanding of diurnal blood pressure variations.2 According to ABPM data obtained from healthy subjects, blood pressure reaches its highest levels in the morning, decreases slowly during the day and maintains lowest levels during the night.3 This circadian rhythm in blood pressure has led to a novel classification. In this ABPM-dependent classificiation, if nocturnal blood pressure decreases more than 10% of the day-time levels, it is called dipper hypertension and if the drop is less than 10%, it is considered non-dipper hypertension.4 The mechanism of diurnal blood pressure variation disorders is not clear. At night, the balance in the autonomous nervous system probably shifts towards the sympathetic nervous system.5 If the blood pressure decrease is less than 10 to 20% during sleep, it is connected with target-organ damage. Particularly in non-dipper hypertensive patients, it is common to see left ventricular hypertrophy, congestive heart failure, myocardial infarction, stroke and renal failure (albuminuria and end-stage renal failure).6,7 The thrombolysis in myocardial infarction (TIMI) frame count is the sum of the ciné-angiographic squares obtained, after infusing opaque substance into the coronaries, from the time when the dye is seen at the level of the coronary artery ostium to when it reaches the distal part. The TIMI frame count, which is a simple, objective and reproducible method, is a quantitative predictor of coronary flow rate. A high TIMI frame count is a predictor of slow coronary flow and endothelial dysfunction.8 The aim of this study was to compare the TIMI frame count in dipper and non-dipper hypertensive patients with normal coronary artery angiography (CAG).

Fatih Aydin, MD

Department of Cardiology, Selcuk State Hospital, Izmir, Turkey

Methods

Murat Samsa, MD

This retrospective, single-centre study was performed in a tertiary healthcare centre. The study data were obtained between 15 February 2010 and 15 February 2012 from hypertensive patients aged between 18 and 80 years who had normal CAG and who had arterial blood pressure follow up with ABPM.

Department of Cardiology, Trakya University Hospital, Edirne, Turkey Fatih Ozcelik, MD

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Patients who were below 18 and above 80 years, with coronary artery disease, haemodynamic changes, congenital heart disease, left ventricular ejection fraction below 55%, and those who had severe valve disease were excluded. The study was approved by the Trakya University Ethics Board (08.02.2012, Decision Nr.05/12, Protocol Nr. 201/39). Age, gender, height, weight, hypertension and diabetes mellitus status, smoking and alcohol consumption, medications, electrocardiogram (ECG), lipid profile and creatinine levels were obtained from the patient files. Body mass index (BMI) was calculated by dividing the body weight (kg) by the square of the height (m). Echocardiogram (echo) reports were obtained from the echo laboratory, coronary artery images from the CAG laboratory, and 24-hour blood pressure levels were obtained from the effort-Holter laboratory. The echo evaluations of the patients were performed using the Vivid 7 Pro (General Electric Medical Systems, Milwaukee, Wisconsin). Left ventricular ejection fraction (EF) was calculated with the M-mode imaging method. Ambulatory blood pressure follow up was done with the tension artery Holter device (DMS 300-3A Holter Recorder) register system using the ambulatory blood pressure Spacelab 90207 device (Space Labs Inc, Richmond, Washington, USA). ABPM was performed before hospitalisation, irrespective of the type and duration of antihypertensive drug therapy. The patients were recommended to maintain daily activities and to hold the arms straight during measurement. Blood measurements were made every 15 minutes between 07:00 and 23:00, and every 20 minutes between 23:00 and 07:00. Using short time intervals, the 10:00–22:00 interval was accepted as the day-time, and the 24:00–06:00 interval as the night-time period. The recorded data were evaluated at the end of 24 hours. Systolic and diastolic blood pressure levels and heart rate measurements were evaluated for the day and night-time periods. If the mean systolic and diastolic blood pressure levels decreased by less than 10% or did not fall, the patient was considered a non-dipper, and if it decreased by more than 10%, it was considered dipper hypertension.9,10 All of the patients had undergone CAG due to a positive myocardial perfusion ischaemia test. The coronary angiography procedures had been performed up to one month after the ABPM. Coronary artery evaluation of the patients was made using the Philips Integris H 3000 (Eindhoven, The Netherlands) angiogram device. The presence or absence of coronary artery disorders was recorded. Patients who had any degree of coronary artery stenosis or plaques and those who had haemodynamic changes that may have affected the square counts during the angiogram were excluded. The TIMI frame count of patients whose coronary arteries were normal was separately calculated for all three coronary arteries. Nitrate was not administered to any patients during the CAG, as it could have affected the results of the measurements. Gibson et al. were the first to present the TIMI frame count, or the TIMI square-count method as a simple, productive, objective and quantitative technique to provide a standard index for coronary blood flow measurement. They investigated the angiographic images of the TIMI-4 study.8 The TIMI frame count was calculated by an independent operator (always the same operator), who did not know the AMBP results. To determine the TIMI frame count following

administration of the opaque material, the ciné-angiographic square counts seen between the level of the stained coronary artery ostium and its distal part were added up. The first square was taken at the moment when an opacification was seen filling the whole of the coronary artery orifice and moving forward. The last square was caught at the moment when the dye reached the standard marker point determined separately for the three arteries by Gibson et al. at the distal part of the vessel.8 The prediction points were the distal bifurcation branching point for the left anterior descending artery (LAD) (whale-tail sign at bifurcation point), the branchlet separating from the distal bifurcation at the furtherest point where the artery opacified after the lesion for the circumflex artery (Cx), and the filling moment of the posterolateral branchlet after the posterior descending artery for the right coronary artery (RCA). The best projection angle was the right anterior oblique or the left anterior oblique-caudal angle for the LAD and Cx, and the left anterior oblique-cranial angle for the RCA. In Gibson and co-workers’ study, the TIMI frame count for the RCA was 20.4 ± 3.0, the square count for the Cx artery was 22.2 ± 4.1, and for the LAD, it was 36.2 ± 2.6 (p < 0.001).8 These values were standard measurements when the coronary angiogram device could take 30 frames/s. If the coronary angiogram worked at a rate of 12.5 frame/s, to adjust to standard measurements, the value was multiplied by 2.4. If the coronary angiogram worked at a rate of 25 frame/s, to adjust to standard measurements, the value was multiplied by 1.2. If the coronary angiogram worked at a rate of 15 frame/s, to adjust to standard measurements, the value was multiplied by two. For the LAD, the correction for this difference was made by dividing the square count by 1.7. Therefore, the TIMI square count corrected for the LAD (cLAD) was determined as 21.1 ± 1.5 squares. The mean TIMI frame count was calculated by adding three coronary artery TIMI frame counts and dividing by three.

Statistical analysis For the descriptive statistics of the data, the mean, standard deviation and ratios were used. The Kolmogorov–Smirnov test was used for distribution of the data. Comparison of the means between the two groups was done using the independent samples t-test. The Chi-squared test was used for analysis of the ratios. The SPSS 20.0 program was used for the analysis. Statistical significance was set at p < 0.05 for all analyses.

Results Sixty patients (38% female), whose mean age was 52.85 ± 10.42 years, were included in the study. The demographic and clinical data of the patients are presented in Table 1. The patients were grouped as dippers (n = 30) and non-dippers (n = 30). The demographic and clinical data of the groups were compared. No significant differences were found between gender, age, smoking and alcohol consumption of the dipper and non-dipper patient groups. The BMI in the non-dipper group (25.47 ± 2.92 kg/m2) was significantly higher than that of the dippers (23.79 ± 2.81 kg/ m2) (p = 0.027). There was no significant difference between symptoms, hyperlipidaemia and diabetes mellitus between the dipper and non-dipper groups. Similarly, the use of angiotensin

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Table 1. Distribution of patients based on demographic and clinical characteristics

Table 2. Comparison of the demographic and clinical characteristics between the groups

Demographic and clinical parameters Patients (n = 60) Age (year ± SD) 52.85 ± 10.42 Female, n (%) 23 (38.3) BMI (kg/m² ± SD) 24.63 ± 2.8 Smoking, n (%) 32 (53.3) Drinking, n (%) 29 (48.3) Hyperlipidaemia, n (%) 27 (45.0) Diabetes mellitus n (%) 8 (13) Antihypertensive drugs ACEI, n (%) 21 (35.0) ARB, n (%) 20 (33.3) BB, n (%) 24 (40.0) CCB, n (%) 22 (36.6) HDL-C (mg/dl ± SD) 47.63 ± 13.21 (mmol/l) 1.23 ± 0.34 LDL-C (mg/dl ± SD) 133.55 ± 40.91 (mmol/l) 3.46 ± 1.06 FPG (mg/dl ± SD) 95.82 ± 15.04 (mmol/l) 5.32 ± 0.83 TG (mg/dl ± SD) 132.16 ± 74.34 (mmol/l) 1.49 ± 0.84 Total cholesterol (g/dl ± SD) 185.16 ± 42.7 (mmol/l) 4.80 ± 1.11 Creatinine (mg/dl ± SD) 0.79 ± 0.18 (mmol/l) 69.84 ± 15.91 Haemoglobin (g/dl ± SD) 13.6 ± 1.61 Ejection fraction (% ± SD) 66.61 ± 3.8 Continuous data are expressed as mean ± SD, categorical data are expressed as n (%). SD: standard deviation, ACEI: angiotensin converting enzyme inhibitors, ARB: angiotensin receptor blocker, BB: beta-blocker, CCB: calcium channel blockers, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, FPG: fasting plasma glucose, TG: triglycerides.

Dipper Non-dipper Demographic and clinical group group parameters (n = 30) (n = 30) p-value Age (year ± SD) 51.63 ± 12.68 54.07 ± 8.17 0.381* Gender Male, n (%) 16 (53.3) 21 (70.0) 0.184# Female, n (%) 14 (46.7) 9 (30.0) BMI (kg/m² ± SD) 23.79 ± 2.81 25.47 ± 2.92 0.027* Smoking, n (%) 14 (46.7) 18 (60.0) 0.301# Drinking, n (%) 11 (36.7) 8 (26.7) 0.405# Hyperlipidaemia, n (%) 13 (43.3) 14 (46.7) 0.895# Diabetes mellitus, n (%) 3 (10.0) 5 (16.7) 0.448# Symptoms Chest pain, n (%) 30 (100) 30 (100) 1# Palpitation, n (%) 14 (46.6) 15 (50) 0.823# Dsypnoea, n (%) 9 (30.0) 10 (33.3) 0.437# Restlessness, n (%) 8 (26.6) 14 (46.6) 0.248# Dizziness, n (%) 8 (26.6) 12 (40.0) 0.312# Antihypertensive drugs ACEI, n (%) 11 (36.7) 10 (33.3) 0.737# ARB, n (%) 10 (33.3) 10 (33.3) 1# CCB, n (%) 9 (30.0) 13 (43.3) 0.234# BB, n (%) 12 (40.0) 12 (40.0) 1# Statin, n (%) 9 (30.0) 13 (43.3) 0.234# HDL-C (mg/dl ± SD) 47.23 ± 13.51 48.03 ± 12.91 0.815* (mmol/l) (1.22 ± 0.35) (1.24 ± 0.33) LDL-C (mg/dl ± SD) 135.55 ± 42.16 131.56 ± 39.67 0.707* (mmol/l) (3.51 ± 1.09) (3.41 ± 1.03) FPG (mg/dl ± SD) 93.97 ± 15.89 97.63 ± 14.22 0.350* (mmol/l) (5.22 ± 0.88) (5.42 ± 0.79) TG (g/dl ± SD) 114.50 ± 59.67 149.83 ± 89.09 0.076* (mmol/l) (1.29 ± 0.67) (1.69 ± 1.01) Total cholesterol (g/dl ± SD) 188.00 ± 44.08 182.33 ± 41.47 0.610* (mmol/l) (4.87 ± 1.14) (4.72 ± 1.07) Creatinine (mg/dl ± SD) 0.81 ± 0.19 0.77 ± 0.18 0.404* (mmol/l) (71.60 ± 16.80) (68.07 ± 15.91) Haemoglobin (g/dl ± SD) 13.56 ± 1.82 13.70 ± 1.41 0.728* Ejection fraction (% ± SD) 66.40 ± 4.10 66.83 ± 3.61 0.666* Continuous data are expressed as mean ± SD, categorical data are expressed as n (%). *Chi-squared test, #Independent samples t-test, statistical significance level is p < 0.05 (bold values). SD: standard deviation, ACEI: Angiotensin converting enzyme inhibitors, ARB: angiotensin receptor blocker, BB: beta-blocker, CCB: calcium channel blockers, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, FPG: fasting plasma glucose, TG: triglycerides.

converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blocker (BB) and calcium channel blockers (CCB) did not demonstrate any significant dfferences between the groups. Of the laboratory parameters, no statistically significant difference was found between high-density lipoprotein (HDL-C) cholesterol, low-density lipoprotein (LDL-C) cholesterol, fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), creatinine, haemoglobin and ejection fraction (EF) levels (Table 2). None of the patients were on nitrate treatment. The 24-hour Holter data of the patients were evaluated and inter-group comparisons were performed. In the dipper group, the pulse rate (66.57 ± 4.92 bpm) was significantly lower than that of the non-dipper group (72.70 ± 4.86 bpm) (p = 0.001). No statistically significant differences were determined between the groups with regard to the mean systolic and mean diastolic blood pressures (p = 0.226, p = 0.749, respectively). Similarly, there was no significant difference between the groups regarding the day-time mean systolic and diastolic blood pressures (p = 0.802, p = 0.417, respectively). The night-time mean systolic and diastolic blood pressure levels were, however, significantly lower in the dipper group (p = 0.001, p ≤ 0.001, respectively). The percentage change in systolic and diastolic blood pressures was significantly higher in the dipper than the non-dipper group (p ≤ 0.001, p ≤ 0.001, respectively). The inter-group comparisons of ABPM are presented in Table 3. The mean TIMI frame counts of all three coronary arteries

were calculated in the dipper and non-dipper patient groups. In the dipper group, the RCA TIMI frame count (16.83 ± 3.70) was significantly lower than that in the non-dipper group (21.63 ± 3.44) (p < 0.001). In the dipper group, the Cx TIMI frame count (21.28 ± 3.52) was significantly lower than in the non-dipper group (25.65 ± 3.61) (p < 0.001). The LAD TIMI frame count in the dipper group (34.20 ± 2.80) was significantly lower than in the non-dipper group (37.05 ± 3.30) (p = 0.001). The LAD corrected TIMI frame count in the dipper group (20.05 ± 1.63) was significantly lower than in the non-dipper group (21.74 ± 1.95) (p = 0.001). In the dipper group, the mean TIMI frame count (19.31 ± 2.31) was significantly lower than in the non-dipper group (22.94 ± 2.61) (p < 0.001) (Table 4).

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Table 3. Comparison of ambulatory blood pressure data between the groups Dipper group (n = 30) 66.57 ± 4.92

Non-dipper group (n = 30) 72.70 ± 4.86

Ambulatory blood pressure p-value* 0.001 Pulse (bpm ± SD) Over 24 hours Mean systolic BP 0.226 118.93 ± 14.8 124.37 ± 19.23 (mmHg ± SD) Mean diastolic BP 0.749 68.76 ± 10.55 69.53 ± 8.64 (mmHg ± SD) Day-time Mean systolic BP 0.802 123.47 ± 16.67 124.63 ± 19.08 (mmHg ± SD) Mean diastolic BP 0.417 71.87 ± 11.49 69.67 ± 9.21 (mmHg ± SD) Night-time Mean systolic BP 0.001 108.10 ± 13.61 123.50 ± 20.49 (mmHg ± SD) Mean diastolic BP 60.60 ± 8.94 69.13 ± 8.3 < 0.001 (mmHg ± SD) Systolic BP variation 13.33 ± 4.47 1.32 ± 5.49 < 0.001 (% ± SD) Diastolic BP variation 15.57 ± 5.74 2.03 ± 6.03 < 0.001 (% ± SD) Continuous data are expressed as mean ± SD. *Independent samples t-test, statistical significance level is p < 0.05 (bold values) BPM: beat per minute, SD: standard deviation, BP: blood pressure.

Discussion Arterial blood pressure has a daily circadian rhythm. Physiologically, nocturnal blood pressure decreases by more than 10% compared to day-time levels, and this is called dipper hypertension. If the nocturnal blood pressure has a less than 10% fall from day-time blood pressure values, it is considered as non-dipper hypertension.10 The reason for such classification is due to the differences in morbidity and mortality rates between these groups. In patients who have non-dipper blood pressure, end-organ damage (ventricular hypertrophy, microalbuminuria, decreased arterial compliance) as well as cardiovascular morbidity and mortality rates are higher.11,12 In order to develop a standard index for coronary blood flow measurement, Gibson et al. presented the TIMI frame count as a simple, productive, objective and quantitative technique by investigating the angiographic images of the TIMI-4 study.8 After administration of an opaque material, the TIMI square count is the sum of the ciné-angiographic squares seen between the level of the stained coronary artery ostium and its distal part on CAG. A high TIMI frame count is related to a slow flow rate and endothelial dysfunction.13 In our study, we compared the TIMI frame count in dipper and non-dipper hypertensive patient groups who had normal CAG. According to a study by Yazici et al., the number of non-dipper patients was significantly higher than dipper patients in a patient group with slow coronary flow rates. In that study, the non-dipper patients with slow coronary flow rates had a higher percentage of unstable angina-like features, recurrent chest pain, frequency of malignant ventricular arrhythmia and sudden cardiac death rates than dipper patients.14 Evola et al. compared the TIMI frame counts of 80 hypertensive patients with normal CAG with 15 normotensive

Table 4. Comparison of TIMI frame scores between the groups Dipper Non-dipper group group TIMI fram scores (n = 30) (n = 30) p-value* RCA TIMI frame score 16.83 ± 3.70 21.63 ± 3.44 < 0.001 Cx TIMI frame score 21.28 ± 3.52 25.65 ± 3.61 < 0.001 LAD TIMI frame score 0.001 34.20 ± 2.80 37.05 ± 3.30 LAD corrected TIMI frame score 20.05 ± 1.63 21.74 ± 1.95 0.001 The average TIMI frame score 19.31 ± 2.31 22.94 ± 2.61 < 0.001 Continuous data are expressed as mean ± SD. *Chi-squared test, statistical significance level is p < 0.05 (bold values). RCA: right coronary artery, TIMI: thrombolysis in myocardial infarction, Cx: circumflex artery, LAD: left anterior descending artery.

subjects, and found higher TIMI scores in the hypertensive group. In the same study, when the hypertensive patients with negative and positive myocardial perfusion scintigraphy were compared, the TIMI frame counts were significantly higher in patients with positive scintigraphy.15 From these data, they predicted that coronary artery flow and myocardial perfusion disorders were more frequent in the group with high TIMI frame counts. They concluded that myocardial perfusion scintigraphy could be used as a non-invasive diagnostic test to determine early changes in coronary microcirculation. In our study, we found a higher TIMI frame count in all three coronary arteries in the non-dipper hypertensive patient group compared to the dipper group. In their study showing the significance of small-vessel disorder, Pekdemir et al. investigated the coronary anatomy using intravascular ultrasonography (IVUS) and epicardial resistance with fractional flow reserve (FFR).16 They stated that in patients with slow coronary flow, the increase in resistance in epicardial coronary arteries could play a role in the development of early diffuse atherosclerosis. In a patient group with slow coronary flow, Xia et al. discovered higher serum uric acid, platelet count, high-sensitivity C-reactive protein (CRP) and two-hour fasting glucose levels compared to the control group.17 In recent epidemiological and experimental studies, a high uric acid level has been proven to be a cardiovascular risk factor.18,19 Using the TIMI frame count, Turhan et al. compared coronary blood flow in 42 metabolic syndrome patients and a control group of 42 subjects without the metabolic syndrome. The TIMI frame count was statistically significantly higher in patients with higher values of waist circumference, body mass index and triglyceride levels.20 In our study, the body mass index was statistically significantly higher in the non-dipper group than in the dipper group. According to numerous robust evidence, deterioration of endothelial-dependent vasodilatation as a result of a decrease in nitric oxide release in brachial, coronary, renal and small arteries is a risk factor in cardiovascular and cerebrovascular patients.21-26 Higashi et al. compared endothelial dysfunction in 20 non-dipper and 20 dipper hypertensive patients.27 The endothelial dysfunction predictors were decreased nitric oxide final products, nitrite/nitrate and cyclic guanicine monophosphate in 24-hour urine samples. In the non-dipper patient group, nitrite/nitrate and cyclic guanicine monophosphate levels in 24-hour urine samples were statistically significantly lower. If we consider the TIMI frame count as a predictor of endothelial dysfunction, finding a higher TIMI frame count in all three coronary arteries confirms the study by Higashi et al.27

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The most important limitations of our study were its retrospective design and the small sample size, as well as the lack of testing for other biochemical and echocardiographic markers that have shown a relationship with coronary slow flow. Studies with a prospective design integrating a larger number of patients and coronary slow-flow markers would provide more valuable data. In our study, the proximal coronary artery diameters were not compared. Due to the fact that vasoconstriction, which may develop secondarily due to an increase in sympathetic tone, may have had an effect on the TIMI frame count. Measurement of proximal artery diameters and comparing them between the two groups would produce more valuable information. In our study, we found higher TIMI frame counts in all three coronary arteries and a higher mean TIMI frame count in the non-dipper hypertensive patients than in the dipper group. Microvascular bed changes and endothelial dysfunction in non-dipper hypertensive patients can be confirmed with TIMI frame count, which is a predictor of coronary slow flow rate.

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11. Ohkubo T, Hozawa A, Yamaguchi J, et al. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: The Ohasoma study. J Hypertens 2002; 20: 2183–2189. 12. Verdecchia P, Schilacci G, Borgioni C. Altered circadian blood pressure profile and prognosis. Blood Pressure Monitor 1997; 2: 347–352. 13. Cushman WC, Ford CE, Einhorn PT, et al. Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2008; 10: 751–760. 14. Yazıcı M, Demircan S, Durna K, et al. The incidence of nondipping state in normotensive patients with coronary slow flow and its relationship with prognosis. Arch Turk Soc Cardiol 2005; 33: 319–325. 15. Evola S, Cuttitta F, Evola G, et al. Early detection of coronary artery flow and myocardial perfusion impairment in hypertensive patients evidenced by Myocardial Blush Grade (MBG) and Thrombolysis in Myocardial Infarction (TIMI) Frame Count (TFC). Intern Med 2012; 51: 1653–1660. 16. Pekdemir H, Cin VG, Cicek D, et al. Slow coronary flow may be a sign

Conclusion In this study, the TIMI frame count, which is a simple, productive, objective and reproducible method for indirect determination of microvascular changes, was found to be higher in non-dipper hypertensive patients than in dipper hypertensives.

of diffuse atherosclerosis. Contribution of FFR and IVUS. Acta Cardiol 2004; 59: 127–133. 17. Xia S, Deng SB, Wang Y, et al. Clinical analysis of the risk factors of slow coronary flow. Heart Vessels 2010; 10: 81–85. 18. Niskanen LK, Laaksonen DE, Nyyssonen K, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004; 164: 1546–1551. 19. Ioachimescu AG, Brennan DM, Hoar BM, et al. Serum uric acid is

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as hypertensive subjects role of endothelium-derived nitric oxide.

Kobrin I, Oigman W, Kumar A, et al. Diurnal variation of blood pres-

Shimada K, Kawamoto A, Matsubayashi K, et al. Diurnal blood pressure variations and silent cerebrovasculer damage in elderly patients with hypertension. J Hypertens 1992; 10: 875–878. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93: 879–878.

dependent vasodilation by restoring nitric oxide activity in essential

23. Higashi Y, Sasaki S, Kurisu S. Regular aerobic exercise augments

1984; 2: 896–899.

148: 789–794. 21. Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-

nomic activity in dippers and non-dippers with coronary artery disease:

sure in elderly patients with essential hypertension. J Am Geriatr Soc 7.

(PreCIS) database cohort study. Arthritis Rheum 2008; 58: 623–630. 20. Turhan H, Erbay AR, Yasar AS, et al. Impaired coronary blood flow

tions: dippers and nondippers. Circulation 1990; 81: 700–702.

J 2002; 43: 320–328.

of cardiovascular disease: a preventive cardiology information system

Pickering TG. The clinical significance of diurnal blood pressure varia-

rate in the hypertensive subjects: dippers and non-dippers. Yonsei Med 4.

an independent predictor of all-cause mortality in patients at high risk

Roman MJ, Pickering TG, Schwartz JE, et al. Is the absence of a normal nocturnal fall in blood pressure (nondipping) associated with cardiovascular target organ damage? J Hypertens 1997; 15: 969–978.

10. O’Brien E, Sheridan J, O’Malley K. Dippers and non-dippers. Lancet 1988; 2: 397–400.

Circulation 1999; 100: 1194–1202. 24. Treasure CB, Klein JL, Vita JA, et al. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation 1993; 87: 86–93. 25. Higashi Y, Oshima T, Ozono R, et al. Effects of L-arginine infusion on renal hemodynamics in patients with mild essential hypertension. Hypertension 1995; 25: 898–902. 26. Schiffrin EL, Deng LY. Comparison of effects of angiotensin I-converting enzyme inhibition and β-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension 1995; 25: 699–703. 27. Higashi Y, Nakagawa K, Kimura M, et al. Circadian variation of blood pressure and endothelial function in patients with essential hypertension: a comparison of dippers and non-dippers. J Am Coll Cardiol 2002; 40: 2039–2043.

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Surgical placement of left ventricular lead for cardiac resynchronisation therapy after failure of percutaneous attempt Mehmet Ezelsoy, Muhammed Bayram, Suleyman Yazici, Nuran Yazicioglu, Ertan Sagbas

Abstract Objective: Cardiac resynchronisation therapy has been shown to be an effective treatment to improve functional status and prolong survival of patients in advanced chronic heart failure. This study assessed the surgical outcomes of left anterior mini-thoracotomy for the implantation of left ventricular epicardial pacing leads in cardiac resynchronisation therapy. Methods: Our study consisted of 30 consecutive patients who underwent cardiac resynchronisation therapy with a left thoracotomy between November 2010 and April 2012 in our clinic. Postoperative follow up included the assessment of New York Heart Association (NYHA) functional class, electrocardiography and echocardiography. Results: There were 22 male and eight female patients with a mean age of 68 ± 5.04 years. All patients were in NYHA class III or IV. Pre-procedure mean left ventricular ejection fraction was 28.1 ± 4.5% and post-procedural ejection fraction improved to 31.7 ± 5.1%. The pre-operative QRS duration changed from 171.7 ± 10.8 to 156.2 ± 4.4 ms after the operation. Also there was a significant reduction in left ventricular end-diastolic dimension from 6.98 ± 0.8 to 6.72 ± 0.8 mm (p < 0 .05), but no change in left ventricular end-systolic dimension and severity of mitral regurgitation. All patients had successful surgical left ventricular lead placement. There was no procedure-related mortality. The mean follow-up time was 40.4 months. Conclusion: Surgical epicardial left ventricular lead placement procedure is a safe and effective technique in patients with a failed percutaneous attempt. Keywords: cardiac resynchronisation therapy, surgically placed epicardial left ventricular lead, heart failure Submitted 6/12/15, accepted 3/4/16 Cardiovasc J Afr 2017; 28: 19–22

www.cvja.co.za

DOI: 10.5830/CVJA-2016-046

Department of Cardiovascular Surgery, Bilim University, Istanbul, Turkey Mehmet Ezelsoy, MD, mehmet_ezelsoy@hotmail.com Suleyman Yazici, MD Ertan Sagbas, MD

Department of Cardiovascular Surgery, Mehmet Akif Ersoy Hospital, Istanbul, Turkey Muhammed Bayram, MD

Cardiology, Florence Nightingale Hospital, Istanbul, Turkey Nuran Yazicioglu, MD

Cardiac resynchronisation therapy (CRT) improves the symptoms of congestive heart failure (CHF), increases exercise tolerance and decreases rates of hospital readmission. Furthermore, CRT improves ejection fraction and survival rate.1 Most of these data have been derived in large trials using a transvenous approach, placing the left ventricular lead via the coronary sinus (CS). While this approach is least invasive, it can be challenging due to restriction of the coronary sinus anatomy, epicardial scar, and unintended stimulation of the left phrenic nerve.2 Due to these restrictions, success rates of the percutaneous approach are 75 to 93%.3 We aimed to evaluate the surgical outcomes of left anterior mini-thoracotomy for the implantation of left ventricular epicardial pacing leads for CRT after failure of a percutaneous attempt.

Methods The ethics committee of Istanbul Bilim University approved this study, which consisted of 30 consecutive patients who underwent surgical placement between November 2010 and April 2012 of a left ventricular (LV) lead with a left thoracotomy after failure of the percutaneous attempt. This study included patients with New York Heart Association (NYHA) functional class III or IV heart failure, ischaemic (25%) or non-ischaemic cardiomyopathy (75%) with a left ventricular ejection fraction (LVEF) ≤ 35% and QRS duration > 120 ms. Pre- and postoperative follow up involved assessment of NYHA functional class, electrocardiography (ECG), determination of QRS duration, and echocardiographic data. LVEF, left ventricular end-diastolic dimension (LVEDD) and severity of mitral regurgitation (MR) data were collected to analyse the effect of CRT via epicardial LV lead placement on reverse ventricular remodelling. The procedures followed were in accordance with institutional guidelines. A mini-thoracotomy was performed under deep sedation with no need for selective intubation. The patients were placed in a 45° rotation to the right side. A 3- to 4-cm long left minithoracotomy was performed through the fourth intercostal space between the anterior and mid-axillary line. The pericardium was opened longitudinally anterior to the phrenic nerve and suspended with traction sutures to better expose the lateral wall. Epicardial leads were implanted posterior to an obtuse marginal branch, avoiding areas of scarred myocardium. Once a site with satisfactory pacing threshold was identified (impedance > 200 Ω and < 2 000 Ω, sensing > 5 mV and pacing threshold measured at 0.5 ms < 2.0 V), the lead was sewn with 5/0 polypropylene sutures. The connector of the lead was tunnelled submuscularly to the device pocket and the pacemaker. Patients were generally extubated in the operating room and observed in the cardiac surgery recovery unit.

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175

170

165

QRS (ms)

EF (%)

30 29 28

160 155 150 145

27 26

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Pre-procedure

Post-procedure

Fig. 1. P re- and post-procedural mean left ventricular ejection fraction.

Statistical analysis SPSS 21.0 software (SPSS Inc, Chicago, IL, USA) was used for the statistics. For data processing, besides descriptive statistical methods such as frequency, percentage, mean values and standard deviation, the Kolmogorov–Smirnov test was used to evaluate the data distribution. For comparison of the parameters in specific groups, the Wilcoxon Z-test and kappa analysis were used. Survival analysis was obtained with the Kaplan–Meier method. The results were evaluated for significance (p < 0 .05).

Results Between November 2010 and April 2012, 30 patients (75% male) with a mean age of 68 ± 5.04 years underwent epicardial LV lead placement following a failed attempt at percutaneous CRT. Table 1 summarises the baseline demographics for the patients included in this study. All patients were in NYHA functional class III or IV. Pre-procedure mean LVEF was 28.1 ± 4.5% and ejection fraction improved to 31.7 ± 5.1% post procedure (Fig. 1). The pre-surgery QRS duration reduced from 171.7 ± 10.8 to 156.2 ± 4.4 ms post surgery (Fig. 2). In addition there was a significant reduction in LVEDD, from 6.98 ± 0.8 to 6.72 ± 0.8 mm (p < 0 .05), but no change in left ventricular end-systolic dimension (LVESD) and in severity of MR (p > 0 .05) (Table 2). Patients spent an average of 1.3 ± 0.4 days in the intensive Table 1. Baseline clinical demographics of patients Variables Gender Male Female Aetiology Non-ischaemic cardiomyopathy Ischaemic cardiomyopathy Co-morbidities Diabetes mellitus Hypertension Previous myocardial infarction Chronic obstructive pulmonary disease Chronic renal failure Previous cardiac surgery Previous pacemaker/ICD

Number (%) 68 ± 5.04 2 (75) 8 (25) 8 (25) 22 (75) 13 (43) 18 (60) 17 (56) 8 (26) 9 (30) 7 (23) 10 (33)

140

Pre-procedure

Post-procedure

Fig. 2. Pre- and post-procedural mean QRS duration.

care unit post operation. Mean length of hospital stay was 4.9 ± 2.2 days. Mean duration (skin-to-skin) of procedure was 52.6 ± 12.5 minutes for left ventricular lead implantation through the mini-thoracotomy. All patients had successful surgical LV lead placement. There was no procedure-related mortality. Intravenous therapy was commonly administered, with diuretics used in 92% of patients and inotropes in 10% of patients. In total, one patient underwent heart transplantation within five months of surgical lead placement. Ten patients (30%) died during the observation period. The mean follow-up time was 40.4 months (Fig. 3).

Discussion CRT has been well-documented to improve left ventricular ejection fraction, heart failure symptoms and survival.2 A percutaneous transvenous approach for CRT depends on several factors, such as coronary sinus anatomy, and it can be time consuming.4 If there are small coronary veins, it may not be feasible, whereas in the case of large coronary veins, it is often associated with changes in pacing threshold. Furthermore, lifethreatening complications such as coronary sinus perforation may occur.5 Sub-optimal LV lead positioning may lead to unfavourable clinical outcomes following CRT. The advantage of surgical epicardial LV lead positioning is that direct visualisation helps to select the most suitable surface and avoid epicardial fat or fibrosed areas, which can cause changes in pacing thresholds. Mair et al.6 recommend that CS lead implantation should be stopped if the procedure exceeds two hours. In our cases, it took 52.6 ± 12.5 minutes from skin incision to completion of LV lead implantation. Table 2. Clinical and echocardiographic outcomes following surgical lead placement Parameters

Pre-procedural Post-procedural p-value outcome outcome 0.030 6.98 ± 0.8 6.72 ± 0.8 0.128 5.97 ± 0.8 5.90 ± 0.8 0.000 28.1 ± 4.5 31.7 ± 5.1

LVEDD (mm) LVESD (mm) EF (%) Moderate or severe MR, 6 (42) 7 (43) 0.080 n (%) 0.000 QRS (ms) 171.7 ± 10.8 156.2 ± 4.4 LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; EF, ejection fraction; MR, mitral regurgitation.

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1.0

Cumulative survival

0.8 0.6 0.4 0.2 Censored

0.0

20 40 Survival function

Fig. 3. L ong-term survival following surgical left ventricular lead placement by Kaplan–Meyer analysis (n = 30).

In terms of lead function, the pacing threshold in our patients was lower or comparable to that of CS leads.6 We acknowledge that the pacing threshold of epicardial leads may increase over time due to myocardial fibrosis, and this may lead to early battery replacement. However, there is little information on longterm follow up of LV lead threshold in CRT. Further studies with a longer follow up are essential. Transvenous insertion of LV leads is currently the route of choice for CRT. Unfortunately, its success rate is about 75 to 93%, as it is totally dependent on the inconsistent coronary venous anatomy.6 Although some centres do describe excellent success rates with percutaneous leads, this does not appear to reflect the average experience. Early and late implantation failures are reported to occur in about 15 and 10% of patients, respectively, with inability to cannulate the coronary sinus being the most frequent reason for failure of lead implantation.6 In the original reports of CRT, epicardial LV leads were placed surgically via a left thoracotomy. These procedures were associated with high apparent success rates.7 One small trial demonstrated that surgical placement of epicardial LV leads improved symptoms as well as CS lead placement at six months. It is not known if epicardial LV lead placement after a failed transvenous percutaneous approach improves survival or symptoms in the long term.8 Puglisi et al.9 reviewed their experience with epicardial LV lead placement via a limited left thoracotomy in 33 patients with failed transvenous lead implantation or who had experienced early lead dislodgement. Similar to our results, they found a larger proportion of idiopathic heart failure in patients undergoing thoracotomy compared with patients who had successful percutaneous CRT, and no significant reduction in MR. They reported no surgical complications, optimal lateral lead position in all patients, and five late deaths (15%). Similarly, we had no surgical complications. In our study we observed that 10 patients in NYHA functional class IV died at the time of percutaneous implantation. Mair et al.10 described a cohort of 80 patients who had successful LV lead implantation by thoracotomy, video-assisted thoracoscopy, or robotically enhanced manipulation. Although no serious adverse events were reported, technical failures occurred in a minority of cases. Others have reported successful

CRT with video-assisted thoracoscopic surgery and robotassisted approaches.11,12 Putnik et al.13 reviewed the reduction in QRS complex width (to 26.25 ms) and the increase in LVEF (12.2%). Similarly, in our study we also described reduction in QRS complex and LVEF improvement. We reviewed our surgical experience and found that elective epicardial LV lead placement was associated with improved functional status similar to that demonstrated with transvenous LV lead placement.2 In our study, a greater percentage of patients referred for epicardial LV lead placement after a failed coronary sinus approach had non-ischaemic heart failure, which suggests that heart failure aetiology may be predictive of failure of transvenous CRT. It is possible that a greater degree of cardiac chamber and/ or coronary sinus enlargement in patients with non-ischaemic cardiomyopathy may limit access to appropriate pacing sites via the coronary sinus, although this remains to be proven. By contrast, the presence of scarred myocardium may be more likely to lead to unacceptable pacing and sensing thresholds in patients with ischaemic cardiomyopathy. Our results of epicardial LV lead placement demonstrate a clear advantage of avoiding lead-related complications and the necessity of re-operations. Surgical LV lead placement offers the advantage of direct access to the lateral left ventricular wall. Direct visualisation provides an almost unrestricted opportunity to implant the leads at the optimal target site, so that the pre-determined lead position was achieved in all patients. Our analysis is limited by small sample size, lack of data regarding ventricular capture post implantation and the retrospective design.

Conclusion The mini-thoracotomy approach for left ventricular lead implantation is feasible and may avoid some of the limiting factors of transvenous procedures. Furthermore, our observed early functional and haemodynamic improvements show a similarity with that in the literature. This method allows optimal lead implantation under direct vision and therefore reduces the incidence of non-responders, resulting from sub-optimal lead placement. We believe that with improvement in epicardial leads, it may even have potential benefits as primary intervention in a specific subset of patients. With further development of minimally invasive surgical techniques and refinement in choice of pacing leads and lead positions, epicardial left ventricular lead placement may become a reasonable alternative for select patients with heart failure.

References 1.

Cesario DA, Turner JW, Dec GW. Biventricular pacing and defibrillator use in chronic heart failure. Cardiol Clin 2007; 25(4): 595–603.

Frattini F, Rordorf R, Angoli L, Pentimalli F, Vicentini A, Petracci B, et al. Left ventricular pacing lead positioning in the target vein of the coronary sinus: description of a challenging case. Pacing Clin Electrophysiol 2008; 31(4): 503–505.

Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. New Engl J Med 2002; 346(24): 1845–1853.

Alonso C, Leclercq C, d’Allonnes FR, Pavin D, Victor F, Mabo P, et al.

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Six year experience of transvenous left ventricular lead implantation for

nisation therapy delivery. Eur Heart J 2004; 25: 1063–1069.

technical aspects. Heart 2001; 86: 405–410. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D,

10. Mair H, Jansens JL, Lattouf OM, et al. Epicardial lead implantation

Kappenberger L, Tavazzi L. The effect of cardiac resynchronization

techniques for biventricular pacing via left lateral minithoracotomy,

on morbidity and mortality in heart failure. N Engl J Med 2005; 352:

video-assisted thoracoscopy, and robotic approach. Heart Surg Forum 2003; 6: 412–417.

1539–1549. 6.

Mair H, Sachweh J, Meuris B, Nollert G, Schmoeckel M, Schuetz A,

11. Jansens JL, Jottrand M, Preumont N, et al. Robotic-enhanced biven-

et al. Surgical epicardial left ventricular lead versus coronary sinus lead

tricular resynchronization: an alternative to endovenous cardiac resyn-

placement in biventricular pacing. Eur J Cardiothorac Surg 2005; 27:

chronization therapy in chronic heart failure. Ann Thorac Surg 2003; 76: 413–417.

235–242. 7. 8.

Puglisi A, Lunati M, Marullo AG, et al. Limited thoracotomy as a second choice alternative to transvenous implant for cardiac resynchro-

permanent biventricular pacing in patients with advanced heart failure: 5.

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Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage heart

12. DeRose JJ, Ashton RC, Belsley S, et al. Robotically assisted left ventricu-

failure: early experience. Pacing Clin Electrophysiol 1996; 19: 1748–1757.

lar epicardial lead implantation for biventricular pacing. J Am Coll Cardiol 2003; 41: 1414–1419.

Doll N, Piorkowski C, Czesla M, Kallenbach M, Rastan AJ, Arya A, et al. Epicardial versus transvenous left ventricular lead placement

13. Putnik S, Aleksic N, Matkovic M, Mikic A, Velinovic M, Jovicic VZ, et

in patients receiving cardiac resynchronization therapy: results from

al. Minithoracotomy as a primary alternative for LV lead implantation

a randomized prospective study. Thorac Cardiovasc Surg 2008; 56(5):

during coronary resynchronization therapy. J Cardiothorac Surg 2013,

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8: 104.

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

• ASD closure

• Mitral valvuloplasty

• Left atrial apendage closure

• VSD closure

• Pulmonary valve replacement

• Transseptal puncture

• How to develop structural, congenital and valvar interventions in Africa

• Echo evaluation of ASDs and VSDs

• PDA closure

• Coarctation stenting

• Pulmonary valvuloplasty

• 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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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

Endothelial dysfunction and arterial stiffness in pre-eclampsia demonstrated by the EndoPAT method A Meeme, GAB Buga, M Mammen, A Namugowa

Abstract Objectives: The EndoPAT method has been used as a noninvasive method for assessing endothelial function in several non-pregnant populations. We investigated its possible use in assessing endothelial dysfunction in pre-eclampsia. Methods: Two hundred and fifteen participants were recruited and grouped as pre-eclamptic cases (105) and normotensive controls (110). Endothelial function and arterial stiffness were measured as reactive hyperaemia index and augmentation index, respectively, using the EndoPAT 2000 machine. Results: The reactive hyperaemia index was significantly lower in the pre-eclamptic group compared to the normotensive group (p < 0.05). Augmentation index on the other hand was significantly higher in the pre-eclamptic group compared to the normotensive group (p < 0.0001). Conclusion: The EndoPAT method demonstrates endothelial dysfunction and arterial stiffness in pre-eclampsia.

Keywords: EndoPAT, reactive hyperaemia index, arterial stiffness, augmentation index, pre-eclampsia Submitted 2/2/15, accepted 5/4/16 Published online 19/5/16 Cardiovasc J Afr 2017; 28: 23–29

www.cvja.co.za

The most commonly used (gold standard) non-invasive technique in assessing endothelial function in pregnancy is the ultrasonography method called flow-mediated dilatation (FMD) of the brachial artery. The technique measures endothelial function by inducing reactive hyperaemia (which is based on nitric oxide production and bioavailability) by temporary occlusion and measuring the resultant relative increase in blood vessel diameter.5-10 This method however is user dependent, expensive and requires specialised, trained personnel to execute, and it is not readily available for routine investigational use. This means there is a need for a technique that is non-invasive, accurate, affordable and reliable to use either alone or in combination with other markers in screening patients for risk for pre-eclampsia. The EndoPAT method is non-invasive, easy to use, userindependent and immediate, and provides automatically calculated results for assessing endothelial function.11 It has been used rather extensively in recent years for assessing endothelial dysfunction in non-pregnant subjects.12-15 However, its use in pregnancy and pre-eclampsia is limited to only a few studies done in Scotland and Israel.16,17 No study has reported on its use in assessing endothelial function in a rural African population. This study set out to assess pulse-amplitude tonometry (PAT) using EndoPAT 2000 in normotensive and hypertensive pregnant women in rural Africa to determine whether it could demonstrate endothelial dysfunction associated with pre-eclampsia.

DOI: 10.5830/CVJA-2016-047

Pre-eclampsia is a pregnancy-specific multisystem disorder characterised by new-onset hypertension and proteinuria from 20 weeks’ gestation in a previously normotensive pregnant woman. It is one of the major causes of maternal and perinatal morbidity and mortality worldwide and more so in developing countries.1,2 In the complex and intriguing pathogenesis and pathophysiology of pre-eclampsia, endothelial dysfunction remains the most agreed-upon central mechanism involved, leading to clinical manifestations of the syndrome.3 Endothelial function in pregnancy has been assessed using several methods in different studies, including direct, indirect, invasive and non-invasive techniques.4

Department of Human Biology, Walter Sisulu University, Mthatha, South Africa A Meeme, MSc, PhD, allen.meeme@gmail.com M Mammen, MSc, PhD A Namugowa, MSc, PhD

Department of Obstetrics and Gynaecology, Walter Sisulu University, Mthatha, South Africa GAB Buga, MBChB, MMed, PhD

Methods The study was done with approval from the Bio-Ethics Committee of the Faculty of Health Sciences, Walter Sisulu University (bioethics clearance certificate No.045/010). It was a prospective case–control study conducted in Mthatha Hospital Complex, Eastern Cape, South Africa, between 2010 and 2013. A total of 215 participants with known HIV status were recruited into the study; 105 women had pre-eclampsia (cases) and 110 were normotensive pregnant women (controls). Selection of cases was based on persistent blood pressure of ≥ 140/90 mmHg on two occasions, at least four to six hours apart or a single reading of ≥ 160/110 mmHg, and proteinuria of ≥ 1+ on at least two random specimens collected at least four hours apart (or a 24-hour urine protein of ≥ 300 mg/l) from 20 weeks of gestation, as defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP). Controls were age-matched (within two to three years) and gestational age-matched (within two weeks) normotensive pregnant women attending the antenatal clinic or admitted for other obstetric conditions other than hypertension or diabetes. Women with severe hypertension (blood pressure of ≥ 160/110 mmHg) not responding to treatment, imminent eclampsia, foetal distress, the HELLP syndrome or eclampsia and other complications requiring immediate intervention were

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

excluded from the study. Women with known history of chronic hypertension or diabetes mellitus were also excluded from the study. Endothelial function was assessed using the EndoPAT 2000 technique, which measures PAT using the reactive hyperaemia index (RHI, arbitrary units). Briefly, after 20 minutes’ rest in a chair inclined at an angle of about 45° at room temperature, a blood pressure cuff was placed on the non-dominant upper arm (study arm), while the other arm served as the control. The hands were placed on armchair supports with the palm side down, such that the fingers hung freely. The EndoPAT probes were then placed on the tip of each index finger of both hands. The probes were prevented from touching any other finger or object, and were then electronically inflated. The PAT signal was continuously recorded on a personal computer during the test. Baseline pulse amplitude was measured from each fingertip for five minutes. After baseline recording of five minutes on each arm, arterial flow was then interrupted in the experimental arm by rapidly inflating the cuff to occlusion pressure of 200 mmHg or 60 mmHg plus systolic blood pressure (whichever was higher). After exactly five minutes’ occlusion, the cuff pressure was rapidly deflated, and post-occlusion recording continued for another five minutes in the experimental arm as well as the control arm. Pulse amplitude response to hyperaemia was automatically calculated from the hyperaemia in the finger of the experimental arm as a ratio of post-deflation average pulse amplitude to the baseline average pulse amplitude (i.e. Ah/Ah, with A representing pulse amplitude, h denoting hyperaemic finger). This result was divided by the corresponding ratio from the contralateral, control hand (i.e. Ac/Ac, with c denoting the control finger) to obtain the RH–PAT ratio or PAT ratio. The EndoPAT 2000 not only measured endothelial function with the RHI but also assessed arterial stiffness by measuring the peripheral augmentation index (PAIx) from the radial pulsewave analysis. PAIx was automatically calculated as the ratio of the difference between the early and late systolic peaks of the waveform relative to the early peak (P2–P1/P1), expressed as a percentage.

Table 1. General characteristics of the study population Controls Cases (n = 110) (n = 105) p-value 25.4 ± 0.5 27.0 ± 0.8 0.089 32.3 ± 0.4 30.8 ± 0.4 0.017* 30.7 ± 0.5 33.1 ± 0.8 0.010* 112.3 ± 1.3 140 ± 1.8 0.0000* 64.2 ± 0.9 84.2 ± 1.6 0.00008 79.1 ± 1.2 102.8 ± 1.5 0.0000* 48.2 ±1.4 55.9 ± 1.4 0.0001* 87.9 ± 1.0 81.5 ±1.5 0.0004* 0.95 ± 0.1 1.42 ± 0.2 0.033* 5 (4.5) 22 (21.4) 0.0003*

Characteristic Maternal age (years) Gestational age (weeks) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Mean arterial pressure (mmHg) Pulse pressure (mmHg) Baseline heart rate (bpm) Parity History of previous pre-eclampsia, n (%) Nulliparity, n (%) 37 (33.3) 42 (40.8) 0.3221 28 (25.2) 38 (36.9) 0.076 HIV+, n (%) Family history of HPT, n (%) 31 (28) 37 (36) 0.251 Family history of DM, n (%) 25 (23) 15 (14.6) 0.162 BMI, body mass index; HPT, hypertension; DM, diabetes mellitus.

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Statistical analysis Graphpad Prism 5 (GraphPad software Inc, San Diego, California) software was used for data analysis. Normality of the data distribution was evaluated by the Shapiro–Wilk and Kolmogorov and Smirnov normality tests. Data are summarised as means ± standard error of the mean (SEM) for normally distributed data and medians (interquartile range, IQR) for non-normally distributed data. The two-sample Student’s t-test was used to compare means, while the Mann–Whitney U-test was used to compare medians. Spearman’s correlation and multiple regression analyses were used to determine relationships between RHI, PAlx, baseline pulse-wave amplitude (BPWA) and maternal blood pressure. Secondary analysis was carried out based on whether the cases had early- or late-onset pre-eclampsia and whether cases and controls were HIV positive or negative. Kruskal–Wallis and one-way ANOVA were used to compare means between the cases and controls. Statistical significance was set at p < 0.05.

Results The general characteristics of the participants are as laid out in Table 1. As expected, the cases had significantly higher systolic, diastolic, mean arterial and pulse pressure compared with the controls. A significantly lower baseline heart rate was observed in the cases compared to the controls (81.5 ± 15.4 vs 87.9 ± 10.8 bpm; p < 0.001). There were significantly more mothers with a previous history of pre-eclampsia among the cases compared to the controls (21.4 vs 4.5%; p < 0.001). There was no difference in the percentage of nulliparous women between the cases and controls (p > 0.05). Women with pre-eclampsia were found to have significantly lower RHI [1.70 (1.04–3.61) vs 1.81 (1.18–4.62) au; p < 0.05] and log-transformed RHI [0.31 (–0.03–1.24) vs 0.48 (0.00–1.87) au; p < 0.01) compared to normotensive controls. Augmentation index at 75 bpm [12.42 (–35.79–81.76) vs 2.76 (–33.17–23.86)%; p < 0.0001] and BPWA [543.66 (23.44–1939.8) vs 450.56 (16.12– 1359.4) au; p < 0.01] were found to be higher among women with pre-eclampsia compared to the normotensive controls, as shown in Table 2.

Relationship between RHI, PAlx and BPWA with maternal risk factors On bivariate correlation analysis, there was a significant inverse relationship between RHI and diastolic blood pressure, parity and mean arterial pressure, and no relationship with maternal age, body mass index (BMI), systolic blood pressure, or total number Table 2. Vascular reactivity characteristics of the two groups Controls Cases Characteristic (n = 110) (n = 105) p-value Reactive hyperaemia index 1.81 1.70 0.0269 (RHI) (au) (1.18–4.62) (1.04–3.61) Log-transformed RHI 0.48 0.31 0.0034 (F-RHI) (0.00–1.87) (–0.03–1.24) Baseline pulse-wave 450.56 543.66 0.0021 amplitude (au) (16.12–1359.4) (23.44–1939.8) Augmentation index 2.76 12.42 0.0000 @75 (%) (–33.17–23.86) (–35.79–81.76)

of risk factors for pre-eclampsia, as seen in Table 3. On multiple regression analysis, there was a significant inverse correlation between diastolic blood pressure and RHI (r = –0.14, p < 0.05) and mean arterial blood pressure and RHI (coeff = –4.95053, SE = 2.29277; p < 0.05) as shown in Figs 1 and 2. The high diastolic blood pressure and mean arterial pressure were associated with lower RHI. Augmentation index was also positively associated with mean arterial pressure, as shown in Fig. 3. BPWA was positively related to maternal age, BMI, parity, pulse pressure, weight and systolic blood pressure on univariate correlation, as seen in Table 4. On multiple regression analysis, systolic blood pressure was the only variable independently correlated with BPWA (r = 0.22, p = 0.0166), as seen in Fig. 4. Higher systolic blood pressure was therefore significantly associated with arterial stiffness.

Differences in the study variables as per HIV status The participants were divided into four groups, namely, (1) HIV-negative normotensive (A) (n = 83); (2) HIV-positive

normotensive (B): (n = 27); (3) HIV-positive pre-eclamptic (C): (n = 38); and (4) HIV-negative pre-eclamptic (D) (n = 67) (Table 5). The Kruskal–Wallis test was used to analyse the differences between the four groups and Dunn’s multiple comparison posttest was used to check significance between the individual groups. For mean arterial pressure, significant differences were evident between HIV-positive normotensive and HIV-positive pre-eclamptic pregnant mothers (p < 0.001), HIV-positive normotensive and HIV-negative pre-eclamptic pregnant mothers (p < 0.001), HIV-negative normotensive and HIV-positive pre-eclamptic pregnant women (p < 0.0001), and between HIV-negative normotensive and the HIV-positive pre-eclamptic

130

Table 3. Relationship between RHI and maternal risk factors p-value 0.171 0.756 0.078 0.0022 0.045 0.0066 0.461 0.081 0.072

Table 4. Relationship of BPWA and maternal risk factors Factor Maternal age Baseline heart rate BMI Diastolic blood pressure Parity Mean arterial pressure Pulse pressure Weight Systolic blood pressure

Coefficient (r) 0.141 –0.137 0.238 0.079 0.192 0.123 0.169 0.209 0.170

p-value 0.0416 0.0475 0.0005 0.2556 0.0052 0.076 0.014 0.0024 0.0136

Table 5. Differences in study parameters between four HIV groups in the study population Characteristic

Normotensive HIV + (n = 27)

Normotensive HIV– (n = 83)

Pre-eclamptic Pre-eclamptic HIV+ HIV– (n = 38) (n = 67) p-value

MAP (mmHg)

76.7 (64.0– 99.3)

78.7 (0– 103.3)

103.7 (64.3– 141.7)

RHI (au)

1.79 (1.18–3.21)

1.84 (1.22–4.62)

1.67 (1.22–3.61)

102.4 < 0.0001 (73.3– 142.0) 1.70 (1.04–2.84)

0.1195

BPWA 527.08 ± 68.272 417.69 ± 34.867 593.55 ± 64.295 601.78 ± 43.92 0.0072 (au) 8.02 (–19.18–22.8)

0.82 (–50.7–23.6)

15.09 (–35.8–51.9)

10.53 < 0.0001 (–27.9–81.6)

MAP, mean arterial pressure; RHI, reactive hyperaemia index; BPWA, baseline pulse-wave amplitude; Aix, augmentation index @ 75 bpm.

100

0.8

1.6

2.4

3.2

4.0

4.8

RHI

Fig. 1. Relationship between diastolic blood pressure and RHI (p < 0.05).

Mean arterial pressure (mmHg)

Coefficient (r) –0.095 –0.022 –0.122 –0.210 –0.138 –0.187 0.051 –0.121 –0.124

150

110

0.8

1.6

2.4

3.2

4.0

4.8

RHI

Fig. 2. Relationship between mean arterial pressure and RHI (p = 0.0328).

Mean arterial pressure (mmHg)

Factor Maternal age Baseline heart rate BMI Diastolic blood pressure Parity Mean arterial pressure Pulse pressure Weight Systolic blood pressure

AIx @ 75 (%)

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Diastolic BP (mmHg)

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150

110

–50

0 50 Augmentation index @ 75 (%)

100

Fig. 3. Relationship between mean arterial pressure and augmentation index @ 75 bpm (p = 0.0372).

Baseline pulse wave amplitude (au)

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1600 1400 1200 1000 800 600 400 200 0

60 80 100 120 Systolic BP (mmHg)

140

160

Fig. 4. R elationship between systolic pressure and baseline pulse-wave amplitude.

pregnant women (p < 0.001), respectively. Significant differences were observed for BPWA (p < 0.01) and augmentation index at 75 bpm (p < 0.0001) between the four groups. For BPWA, Dunn’s multiple comparison test revealed a significant difference only between HIV-negative normotensive and HIV-negative pre-eclamptic pregnant women (p < 0.01). For augmentation index, significant differences were observed between HIV-negative normotensive and HIV-positive pre-eclamptic pregnant women (p < 0.001) and between HIV-negative normotensive and HIV-negative pre-eclamptic pregnant women (p < 0.001), as shown in Fig. 5. RHI was lower in HIV-positive normotensive and HIV-positive pre-eclamptic women than in normotensive HIV-negative women, although this did not reach statistical significance (p = 0.1195).

Discussion

Augmentation index @ 75 bpm (%)

In this study, we set out to assess whether PAT (through RHI) demonstrates endothelial dysfunction in pre-eclampsia. The RHI was found to be significantly lower in patients with pre-eclampsia compared to normotensive controls. Since RHI 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Normotensive Normotensive Pre-eclamptic Pre-eclamptic HIV+ HIV– HIV+ HIV–

Fig. 5. A ugmentation index @ 75 bpm between the four HIV groups.

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is endothelium dependent, these results indicate that there is indeed endothelial dysfunction in rural African women with pre-eclampsia, therefore confirming what has been reported in other populations. To our knowledge, this is the first report involving rural black African women. Endothelial dysfunction is known to be the central mechanism in the pathophysiology of pre-eclampsia.3 Several reports have demonstrated that FMD is significantly reduced in patients with pre-eclampsia when compared with normotensive controls,18-20 confirming that pre-eclampsia is associated with endothelial dysfunction. Although FMD measurement is still regarded as the gold standard for assessing endothelial function in pregnancy, it has several limitations, including the need for an experienced sonographer, a good-quality ultrasound machine, and the need for intra-arterial injections. It is therefore not easy to adapt the method for use in assessing endothelial function in large numbers of patients in a clinic setting. We have shown in this study that the EndoPAT 2000 can be used successfully to assess endothelial function in pregnant subjects by measuring the RHI. Although the EndoPAT 2000 itself is a fairly expensive machine, it is less invasive, much easier to use, does not require extensive training and it can be used to assess large numbers of patients rapidly and reliably, even in a clinic setting. Although not many studies have tested endothelial function in pregnancy using EndoPAT 2000, our results are in agreement with the study done by Yinon et al. in 2006, who examined 17 women at the time of diagnosis of pre-eclampsia (mean gestation 32 weeks) and compared them with 25 women with normotensive pregnancies. They found that women with pre-eclampsia had significantly lower RHI values (1.5 ± 0.1 vs 1.8 ± 0.1) compared to uncomplicated pregnancies. The results of this study with much larger number of subjects clearly indicate that RHI, as measured using the EndoPAT, can be used as an adjunct to blood pressure measurement in assessing endothelial dysfunction in pre-eclampsia. However, as endothelial dysfunction is known to precede clinical pre-eclampsia, the important question is, can the EndoPAT 2000 be used for screening and identifying patients before the onset of clinical pre-eclampsia? Carty15 followed up a cohort of patients in Scotland from the first trimester all through pregnancy to postpartum, but did not find any difference in RHI between women who went on to develop pre-eclampsia and normotensive pregnancies, both at 16 and 28 weeks’ gestation. This, however, does not rule out the possibility that RHI might still be useful in either early identification or prediction of pre-eclampsia in larger studies, as the search for predictors of pre-eclampsia continues in earnest. If it were demonstrated that RHI, as measured by the EndoPAT 2000, can be used as a predictor of pre-eclampsia, then the test would become much more cost-effective and cheaper. A prospective cohort study of normotensive pregnant women recruited in the first or early second trimester and followed until delivery is planned to determine whether RHI measurement can be used as a predictor of pre-eclampsia. When participants with early-onset pre-eclampsia were compared with those with late-onset pre-eclampsia, there was no statistically significant difference in RHI between patients with early- and late-onset pre-eclampsia (p > 0.05). Although the numbers are small, this finding suggests that endothelial dysfunction is indeed present in both early- and late-onset

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pre-eclampsia, and that this may be the central mechanism involved in the pathophysiology of both early- and late-onset pre-eclampsia. Although some authors have suggested that early-onset pre-eclampsia is a result of impaired placentation,21 while lateonset pre-eclampsia is as a result of maternal predisposition,22 both are associated with endothelial dysfunction. As no one has as yet discovered the cause of pre-eclampsia, it is difficult to attach more significance to this attempt to separate early- from late-onset pre-eclampsia. An inverse relationship observed between FMD and baseline vascular dimension has been reported from previous studies, where peak arterial dilation is a function of baseline vessel diameter and smaller vessels dilate more than larger ones.23 In our study, we found an inverse correlation between RHI and BPWA in the entire study population (normotensive and pre-eclamptics together), as well as within individual groups. Similar results were recently reported by Carty15 and Heffernan et al.24 in their studies on healthy volunteers as well as patients with coronary artery disease. The authors found that BPWA was positively related to baseline arterial diameter and in turn, inversely related to RHI. This means that smaller brachial arteries have low BPWA and subsequently a high RHI, and vice versa. It has been suggested that in individuals with variable brachial geometry, adjusting RHI for brachial artery diameter may be needed to accurately examine microvascular endothelial function using PAT.24 Although baseline artery diameters were not measured in our study, several studies have shown no difference in baseline brachial artery diameters between normotensive pregnancy and pre-eclampsia.25-27 In view of these results from other studies, it can be hypothesised that the inverse relationship between RHI and BPWA observed in this study could be due to factors other than the brachial artery diameter. Further studies will need to be done to determine the factors responsible for the inverse relationship between RHI and baseline brachial artery diameter in pregnancy. An inverse relationship was found between RHI, mean arterial pressure and diastolic blood pressure in the entire study population. No relationship was observed between RHI and systolic blood pressure. Other studies have reported conflicting relationships between RHI and mean arterial pressure, diastolic and systolic blood pressure. Truschel et al.28 showed a positive correlation (among men and non-pregnant women) between RHI and systolic blood pressure, whereas Konttinen et al.29 and Hamburg et al.11 showed no correlation between diastolic, systolic and mean arterial pressure and RHI. BPWA was, however, found to be positively correlated with systolic blood pressure. Hamburg et al. suggested that systolic blood pressure may have a limited effect on the distal microcirculation, whereas it had a predominant effect on BPWA without additional modification of the hyperaemic response, when presented as a ratio.11 Since RHI is negatively correlated with BPWA (which in turn is positively correlated with systolic blood pressure), by extrapolation, RHI would be negatively correlated with systolic blood pressure. While assessing racial differences in microcirculatory function, Morris et al. also found mean arterial pressure to be negatively associated and an independent predictor of RHI.30 In pregnancy, a similar correlation between RHI and mean arterial pressure was found in a study done in Israel assessing the relationship of pre-eclampsia with sleep-disordered breathing.17

This relationship illustrates the impact of blood pressure on microvascular function. Pre-eclampsia is characterised by generalised vasoconstriction, an increase in peripheral resistance, platelet activation, reduced plasma volume and organ hypoperfusion.31,32 The aetiology is still unclear, although evidence suggests that increments in blood pressure may reflect endothelial dysfunction, with the inability of the endothelial cells to release relaxing factors that cause vasodilatation.33,34 Endothelial dysfunction is known to lead to the widespread clinical features of pre-eclampsia. Results from our study therefore are in agreement with previous studies that found endothelial dysfunction in women with pre-eclampsia.35,36 Traditionally, PAlx is obtained from pressure waveforms via applanation tonometry of the carotid or radial arteries. Recently, it has been demonstrated that PAlx measured from digital pulse-wave volumes by peripheral PAT correlated with that from applanation tonometry14,37 in diabetes and idiopathic scleroderma associated with pulmonary arterial hypertension. Carty38 and Namugowa and Meeme39 also reported that EndoPAT augmentation index correlated with radial artery applanation augmentation index (measured using the SphygmoCor) in pregnancy. However, they cannot be used interchangeably since the actual values do not match, as they are obtained from two distinct vascular beds via two different methods. Patvardhan et al.40 found that augmentation index derived from PAT correlated with cardiovascular risk factors. In this study, we found that heart rate-corrected augmentation index (Alx@75) was higher in pre-eclampsia compared to that in normotensive pregnancy, indicating arterial stiffness. Similar results have been reported by others.41-45 Normal pregnancy is a profoundly vasodilated state.46 This vasodilated state could be due to the remarkable maternal cardiovascular adaptation to pregnancy, which is the attenuated systemic pressor response to vasoconstrictors, including angiotensin II and norepinephrine.47,48 A reduction in vascular compliance in pre-eclampsia is an indication of vascular stiffness, as is seen in non-pregnant patients with chronic hypertension, vascular disease or diabetes.49-52 It may also indicate vasoconstriction, most likely due to endothelial dysfunction, since systemic response to vasoconstrictors such as angiotensin II and norepinephrine is not attenuated but augmented in pre-eclampsia.48 The reactive hyperaemia index, as a measure of endothelial dysfunction, was lowest in HIV-positive pre-eclamptics (1.67) and highest in HIV-negative normotensive controls (1.84). In HIV-positive normotensive controls, the RHI was 1.79 and it was 1.70 in HIV-negative pre-eclamptic cases. Although these differences did not achieve statistical significance, a trend towards a lower reactive hyperaemia index can be seen in the HIV-positive patients, indicating increasing levels of endothelial dysfunction. Arterial stiffness, as measured by the augmentation index was significantly worse (p < 0.000) in the HIV-positive pre-eclamptic and normotensive women than in the HIV-negative pre-eclamptic and normotensive women. Arterial stiffness is also a measure of endothelial dysfunction, therefore indicating that HIV infection is indeed associated with endothelial dysfunction in both normotensive and pre-eclamptic patients. Considering that vasodilation, upon which the EndoPAT depends, is influenced by temperature, efforts were made to conduct the measurements in temperature-controlled rooms for

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all participants. Due to insufficient funds, we were not able to compare EndoPAT results with a blood marker of endothelial dysfunction, but such a study is planned.

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of Inﬂammation. International Scholarly Research Network ISRN Obstetrics and Gynecology 2012; 2012: 1–6. PMCID: PMC3302009. 10.

Fujita K, Tatsumi K, Kondoh E, Chigusa Y, Mogami H, Fujita M, et al. Endothelial function progressively deteriorates during normal preg-

Conclusion This study has shown that there is impaired endothelial function in rural African women with pre-eclampsia, based on the low RHI and increased arterial stiffness, as measured by the BPWA and augmentation index, compared to normotensive pregnancies. This clearly indicates that RHI, BPWA and Alx@75, as measured using the EndoPAT, can be used for assessing endothelial dysfunction in pre-eclampsia. Although PAT could be used as an adjunct to blood pressure measurement in assessing patients with pre-eclampsia, the EndoPAT is a relatively expensive piece of equipment. The EndoPAT 2000 may earn its worth if it could detect endothelial dysfunction and hence be used for screening patients before the onset of hypertension and proteinuria. This will need to be assessed in a prospective, cohort study of pregnant women from the first or early second trimester until delivery, in order to determine whether a reduced RHI can be detected before the onset of pre-eclampsia. Such a study is planned.

nancy. Hypertens Pregnancy 2013; 32(2): 129–138. PMID: 23725078. 11. Hamburg NM, Keyes MJ, Larson MG. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 2008; 117:2467–2474. PMID: 18458169. 12. Schroeter H, Heiss C, Balzer J. Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 2006; 103: 1024–1029. PMID: 16418281. 13. Aversa A, Vitale C, Volterrani M. Chronic administration of sildenafil improves markers of endothelial function in men with type 2 diabetes. Diabet Med 2008; 25: 37–44. PMID: 18199130. 14. Haller MJ, Stein J, Shuster J. Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes. Pediatr Diabetes 2007; 8: 193–198. PMID: 17659060. 15. Carty DM. Preeclampsia; early prediction and long-term consequences. PhD thesis: University of Glasgow; 2012. http://theses.gla.ac.uk/3124/. 16. Kuvin JT, Patel AR, Sliney KA. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J 2003; 146:168–174. PMID: 12851627. 17. Yinon D, Lowenstein L, Suraya S. Preeclampsia is associated with sleepdisordered breathing and endothelial dysfunction. Eur Respir J 2006;

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

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A comparison of off- and on-pump beating-heart coronary artery bypass surgery on long-term cardiovascular events Orcun Gurbuz, Gencehan Kumtepe, Atıf Yolgosteren, Hakan Ozkan, Ilker Hasan Karal, Abdulkadir Ercan, Serdar Ener

Abstract Objective: Our aim was to compare short-term outcomes and long-term major adverse cardiovascular event (MACE)-free survival and independent predictors of long-term MACE after off-pump (OPCAB) versus on-pump beating-heart (ONBHCAB) coronary artery bypass grafting (CABG). Methods: We retrospectively reviewed data of all consecutive patients who underwent elective CABG, performed by the same surgeon, from January 2003 to October 2009. A propensity score analysis was carried out to adjust for baseline characteristics and a total of 398 patients were included: ONBHCAB (n = 181), OPCAB (n = 217). Results: OPCAB was associated with significantly shorter ventilation times (p < 0.001), intensive care unit stay (p < 0.001) and hospital stay (p < 0.001). The total blood loss was significantly more in the ONBHCAB group (p < 0.001), and accordingly, the number of transfused blood units was significantly lower in the OPCAB group (p < 0.001). Incidence of peri-operative renal complications were significantly higher in the ONBHCAB group (p = 0.004). The OPCAB group showed significantly lower long-term MACE-free survival (p = 0.029). The mean number of transfused blood units was the only independent predictor of MACE (HR: 1.218, 95% CI: 1.089–1.361; p = 0.001). Conclusion: OPCAB provided better long-term MACE-free survival compared with ONBHCAB. Fewer units of blood transfused following OPCAB surgery may have been the main reason for this result. Keywords: major cardiovascular event, off-pump coronary artery bypass grafting, on-pump beating heart

Department of Cardiovascular Surgery, Faculty of Medicine, Balikesir University, Balikesir, Turkey Orcun Gurbuz, MD, gurbuzorcun@gmail.com Gencehan Kumtepe, MD Abdulkadir Ercan, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Uludag University, Bursa, Turkey Atıf Yolgosteren, MD

Department Of Cardiology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey Hakan Ozkan, MD

Department of Cardiovascular Surgery, Samsun Hospital for Education and Research, Ilkadim, Samsun, Turkey Ilker Hasan Karal, MD

Department of Cardiovascular Surgery, Doruk Yıldırım Hospital, Bursa, Turkey Serdar Ener, MD

Submitted 7/1/16, accepted 5/4/16 Published online 11/5/16 Cardiovasc J Afr 2017; 28: 30–35

www.cvja.co.za

DOI: 10.5830/CVJA-2016-049

The adverse effects of cardiopulmonary bypass (CPB), aortic cross-clamping and cardioplegic arrest have brought about growing interest in off-pump coronary artery bypass surgery (OPCAB) since the mid 1990s, as a strategy to protect high-risk patients from complications.1 Although OPCAB has advantages,2 it also carries some risks, such as intra-operative low cardiac output and inadequate revascularisation.3,4 Therefore, the debate over the optimal method of revascularisation continues. In recent years, as an alternative to both techniques, the on-pump beating-heart coronary artery bypass grafting (ONBHCAB) technique has gained acceptance in order to eliminate the harmful effects of cross-clamping, cardioplegia and unloading the heart, and it preserves both native coronary blood flow and cardiac output during surgery.5-7 Although a metaanalysis revealed better short-term outcomes and late survival rates following ONBHCAB compared with conventional CABG (CCAB),7 studies comparing the outcomes of ONBHCAB and OPCAB techniques in a similar patient population are lacking. Therefore we aimed to compare the short-term outcomes and long-term major adverse cardiovascular event (MACE)free survival after ONBHCAB versus OPCAB in a matched population.

Methods The research was conducted according to the principles of the Declaration of Helsinki, and ethical approval was granted by the local research ethics committee. In this retrospective study, we reviewed data for all patients who underwent isolated firsttime elective coronary bypass surgery at Uludag University Faculty of Medicine Hospital and Bursa Medical Park Hospital between January 2003 and October 2009. The same surgeon performed the ONBHCAB and OPCAB techniques. There were no described selection criteria between the two techniques. Exclusion criteria were as follows: critical pre-operative state [need for inotropic drug support or intra-aortic balloon pumping (IABP), acute renal failure, requiring respiratory support, history of cardiopulmonary resuscitation in the pre-operative period], myocardial infarction (MI) within three weeks [cardiac troponin I (cTnI) > 0.01 ng/ml], patients who underwent single-vessel CABG, and cases that were converted from OPCAB to ONBHCAB (12 of 339 cases, 3.5%) or ONBHCAB to conventional CABG [10 of 443 cases (2.2%)] intra-operatively.

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Finally, 760 patients were divided into two groups: ONBHCAB (group 1) or OPCAB (group 2). To adjust for baseline differences in parameters between the groups, a propensity score analysis was carried out and a total of 398 patients were included: ONBHCAB (n = 181), OPCAB (n = 217). Patients’ pre-operative characteristics, such as age and gender, smoking status, hypertension, diabetes mellitus (DM), dyslipidaemia, obesity (body mass index > 30 kg/m²), chronic obstructive pulmonary disease (COPD), history of stroke, peripheral vascular disease (PVD), history of myocardial infarction (MI), unstable angina pectoris (USAP), EuroSCORE (European System for Cardiac Operative Risk Evaluation) risk score, left ventricular dysfunction, history of percutaneous coronory intervention (PCI), number of diseased vessels, and the presence of left main coronary artery (LMCA) stenosis were recorded.

Definitions Vessel disease was defined as stenosis of more than 50% of the major epicardial coronary arteries. Estimated creatinine clearance (CrCl) rate was calculated using the Cockcroft–Gault formula: CrCl (ml/min) = [(140–age) × weight (kg)]/[serum creatinine (mg/dl) × 72] × 0.85 for women, from baseline blood samples. PVD was defined as a stenosis of 50% or more affecting any non-coronary vasculature. Left ventricular dysfunction was defined as moderate [ejection fraction (EF) 0.30–0.49%] or severe (EF < 0.30%). Complete revascularisation was defined as treatment of all major coronary arteries [left anterior descending (LAD), circumflex (Cx) and right coronary artery (RCA)] ≥ 50% diameter stenosis. Total blood loss was defined as the sum of the mediastinal and chest tube drainage in the first 48 hours. Consumed units of red blood cells (RBC) was defined as the sum of the blood units used during the hospital stay. Any inotropic support started in the peri-operative period, even low doses of dopamine infusion due to haemodynamical instability, was determined as peri-operative need for inotropic support. Peri-operative MI was defined as cTnI > 5 µg/l during the hospital stay with new ECG change or echocardiographic evidence of new regional wall motion abnormality.8 Renal complication was defined as at least 100% increase in basal serum creatinine level. Pulmonary complication was defined as pleural effusion, atelectasis, phrenic nerve paralysis, diaphragmatic dysfunction, pneumonia, acute respiratory distress syndrome, pneumothorax or chylothorax. Neurological complication was defined as any new transient ischaemic attack (TIA), stroke or encephalopathy occurring in the peri-operative period. Early rehospitalisation was defined as any hospitalisation due to CABG-related complications (such as sternal dehiscence, mediastinitis) or cardiovascular problems (such as MI, congestive heart failure, rhythm disturbance, neurological complications, pulmonary embolism). Early re-operation was defined as re-operation due to bleeding or cardiac tamponade and graft failure.

Surgical procedures All procedures were performed by the same surgeon, who made the decision to perform OPCAB or ONBHCAB surgery.

Classic median sternotomy, left internal thoracic artery (LIMA) harvesting and other conduit preparations were performed according to a standard technique. In patients undergoing OPCAB, heparin was administered to keep the activated clotting time (ACT) greater than 300 seconds. Distal anastomoses were performed by end-to-side or side-toside techniques with a running 7/0 Prolene suture, using a local myocardial stabiliser (Octopus, Medtronic Inc, Minneapolis, MN, US). Proximal coronary clamping of all target vessels was performed with Mueller atraumatic vascular clamps (0.5 Newton); distal occlusion was never performed. Insufflation of filtered room air (< 5 l/min) was used to provide better visibility during anastomosis. During distal anastomosis and reperfusion, 2 ml/kg 20% mannitol was administered. All proximal anastomoses were performed under single side clamping using 6/0 prolene sutures. At the end of surgery, heparin was neutralised with protamine, ensuring that the ACT was between 150 and 180 seconds. In the early postoperative period (6–8 hours), low molecularweight heparin and 100 mg acetylsalicylic acid were commenced routinely. In patients undergoing ONBHCAB, heparin was administered to keep the ACT above 450 seconds. CPB was established with an ascending aortic arterial cannula and a right atrial two-stage venous cannula, using a membrane oxygenator and a roller pump. All patients were cooled to 32–34°C. Mean arterial blood pressure was maintained in the range of 60–90 mmHg. Distal anastomoses were performed by end-to-side or side-to-side techniques with a running 7/0 prolene suture, using a myocardial stabiliser device (Octopus, Medtronic Inc, Minneapolis, MN, US). Proximal anastomoses were performed using a 6/0 prolene suture during the heating period with the assistance of an ascending aortic side-clamp. After the completion of CPB and cannula removal, heparin was neutralised with protamine, providing an ACT < 150 seconds. Acetylsalicylic acid at a dose of 100 mg and low molecular-weight heparin was initiated at the postoperative 24th hour. The primary endpoint of this study was to compare the early and long-term MACE rates, defined as cardiac related or sudden death, MI, the need for repeat revascularisation, and stroke following ONBHCAB versus OPCAB. The secondary endpoint was to identify independent predictors of long-term MACE in these groups of patient. Long-term follow up was obtained through out-patient clinic visits, hospital records and phone calls. All-cause mortality (patient death reported by patients’ relatives or hospital records) and MACE were determined.

Statistical analysis Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentages. A propensity score analysis was carried out to control selection based on the baseline variables. The Mann–Whitney U-test was used to compare non-parametric continuous variables, the Student’s t-test was used to compare parametric continuous variables, and the chi-squared test was used to compare categorical variables. Cumulative survival curves for long-term MACE were constructed using the Kaplan–Meier method, whereas differences between the groups were evaluated with log-rank tests. Multivariate logistic regression analysis was used to identify

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the independent predictors of MACE. All variables showing significance values (p < 0.05) on univariate analysis were included in the multivariate model. The association between variables was tested using Spearman’s or Pearson’s correlation coefficient. Two-tailed p-values < 0.05 were considered significant and the confidence interval (CI) was 95%. All statistical analyses were conducted using the Statistical Package for Social Sciences (SPSS) program (version 15.0, SPSS, Chicago, Illinois, USA). Table 1. Baseline characteristics of the study groups Overall (n = 760)

Propensity-matched patients (n = 398)

Characteristics

ONBHCAB (n = 327)

OPCAB (n = 433)

p-value

ONBHCAB (n = 181)

OPCAB (n = 217)

p-value

Age (years)

63.37 ± 9.65

59.7 ± 9.08

< 0.001 61.17 ± 9.02

60.16 ± 8.8

0.3

Males

255 (78)

359 (82.9)

0.08

147 (81.2)

179 (82.5)

0.74

Euroscore

3.9 ± 2.41

2.79 ± 1.99

< 0.001

3.06 ± 2.13

2.83 ± 2.1

0.17

Obesity (BMI ≥ 30 kg/m2)

93 (28.4)

80 (18.5)

0.001

53 (29.3)

48 (22.1)

0.1

Current smoker

142 (43.4)

234 (54)

0.004

85 (47)

113 (52.1)

0.31

Hypertension

172 (52.6)

245 (56.6)

0.27

95 (52.5)

126 (58.1)

0.26

Dyslipidaemia

114 (34.9)

181 (41.8)

0.05

62 (34.3)

89 (41)

0.16

Diabetes mellitus

102 (31.2)

125 (28.9)

0.48

58 (32)

64 (29.5)

0.58

NIDDM

74 (22.6)

98 (22.6)

0.99

44 (24.3)

46 (21.2)

0.46

IDDM

28 (8.6)

27 (6.2)

0.22

14 (7.7)

18 (8.3)

0.83

USAP

97 (29.7)

138 (31.9)

0.51

46 (25.4)

74 (34.1)

0.6

COPD

36 (11)

12 (2.8)

< 0.001

14 (7.7)

9 (4.1)

0.12

CrCl

103.3 ± 34.13 101.06 ± 38.9

0.04

102.35 ± 40.6 101.19 ± 30.58

0.21

Stroke

7 (2.1)

14 (3.2)

0.36

4 (2.2)

7 (3.2)

0.54

TIA

7 (2.1)

8 (1.8)

0.77

4 (2.2)

4 (1.8)

0.79

Peripheral vascular disease

65 (19.9)

30 (6.9)

< 0.001

29 (16)

25 (11.5)

0.19

History of MI

127 (38.8)

Normal LV function

213 (65.1)

Impaired LV function

114 (34.9)

Moderate LV function

96 (29.4)

Poor LV function

18 (5.5)

13 (3)

0.08

8 (4.4)

6 (2.8)

Previous PCI

37 (11.3)

16 (3.7)

< 0.001

15 (8.3)

9 (4.1)

Number of diseased vesssels

2.69 ± 0.56

189 (43.6)

0.18

53 (29.3)

81 (37.3)

0.91

Results Pre-operative patient characteristics for the ONBHCAB and OPCAB groups before and after matching are listed in Table 1. Peri-operative and early postoperative characteristics of the propensity-matched patients are shown in Table 2. The average number of distal anastomoses per patient was significantly higher in the ONBHCAB group (p < 0.001). The OPCAB group showed fewer grafted LAD and Cx territories (p < 0.001, p = 0.003, respectively). However, there was no significant difference between the groups in terms of incomplete revascularisation rate. Mean duration of CPB was 70 ± 35 minutes in the ONBHCAB group. OPCAB was associated with significantly shorter mean ventilation times (p < 0.001), mean lengths of intensive care unit stay (p < 0.001) and duration of hospital stay (p < 0.001). The total blood loss was significantly more in the ONBHCAB group (p < 0.001). Accordingly, the mean number of transfused RBC units was significantly lower in the OPCAB group (p < 0.001). Renal complications were significantly higher in the ONBHCAB group (p = 0.004). Postoperative characteristics of the groups were similar regarding early re-operation and rehospitalisation, in-hospital mortality rates, mediastinitis, pulmonary and neurological complications, peri-operative atrial fibrillation (AF) frequency, peri-operative MI, and the need for inotropic or IABP support. Table 2. Operative and early postoperative characteristics of the propensity matched patients Characteristics

ONBHCAB (n = 181)

OPCAB (n = 217)

p-value

Number of distal anastomoses

3.44 ± 0.85

2.84 ± 0.81

< 0.001*

41 (22.7)

55 (25.3)

0.53

Incomplete revascularisation Grafted coronary artery LAD

1.64 ± 0.5

1.39 ± 0.55

< 0.001*

0.96 ± 0.58

0.71 ± 0.56

0.003*

RCA

0.82 ± 0.58

0.79 ± 0.59

0.05

CPB time (min) 316 (73)

117 (27)

104 (24)

2.62 ± 0.54

0.02

0.09

0.01

129 (71.3)

52 (28.7)

44 (24.3)

2.69 ± 0.56

162 (74.7)

55 (25.3)

49 (22.6)

2.64 ± 0.53

0.45

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70 ± 35

Duration of ventilation (h)

11.28 ± 38.7

5.97 ± 4.01

< 0.001*

Duration in intensive care unit (h)

28.27 ± 63.9

25.48 ± 36.1

< 0.001*

Total blood loss (ml)

507.6 ± 296.8 341.9 ± 190.4 < 0.001* 1.17 ± 1.57

0.2 ± 0.58

< 0.001*

Peri-operative inotropic agent

8 (4.4)

6 (2.8)

0.37

Peri-operative IABP required

4 (2.2)

2 (0.9)

0.29

Peri-operative MI

11 (6.1)

13 (6)

0.97

0.37

Peri-operative AF

21 (11.6)

28 (12.9)

0.69

Neurological complication

11 (6.1)

6 (2.8)

0.10

0.54

Encephalopathy

4 (2.2)

1 (0.5)

0.11

TIA

6 (3.3)

4 (1.8)

0.35

Stroke

1 (0.6)

1 (0.5)

0.89

Pulmonary complications

11 (6.1)

7 (3.2)

0.17

Renal complications

24 (13.3)

11 (5.1)

0.004*

0.68

0.12

RBC (unit)

LMCA

59 (18)

45 (10.4)

0.002

30 (16.6)

24 (11.1)

0.11

Mediastinitis

Threevessel disease

246 (75.2)

285 (65.8)

0.005

135 (74.6)

146 (67.3)

0.12

Duration of hospital stay (days)

*Statistically significant difference. Values are presented as mean ± standard deviation or number (%), where appropriate. BMI, body mass index; CrCL, creatinine clearance; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; IDDM, insulin-dependent diabetes mellitus; LMCA, left main coronary artery; LV, left ventricle MI, myocardial infarction; NIDDM, non-insulin-dependent diabetes mellitus; ONBHCAB, on-pump beating heart coronary artery bypass surgery; OPCAB, off-pump coronary artery bypass surgery; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; TIA, transient ischaemic attack; USAP, unstable angina pectoris.

2 (1.1)

1 (0.5)

0.95

5.96 ± 3.51

5.41 ± 4.38

< 0.001*

Early re-operation

5 (2.8)

3 (1.4)

0.33

Early rehospitalisation (< 30 days)

13 (7.2)

14 (6.5)

0.92

Hospital mortality (< 30 days)

3 (1.7)

6 (2.8)

0.46

*Statistically significant difference. Values are presented as mean ± standard deviation or number (%), where appropriate. AF, atrial fibrillation; LAD, left anterior descending artery; Cx, circumflex coronary artery; IABP, intra-aortic balloon pump; MI, myocardial infarction; ONBHCAB, on-pump beating heart coronary artery bypass surgery; OPCAB, off-pump coronary artery bypass surgery; RBC, red blood cell; RCA, right coronary artery; TIA, transient ischaemic attack.

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Freedom from MACE

1.00

p = 0.029 OPCAB

0.90

Characteristics

95% CI

p-value

Multivariate analysis HR

95% CI

p-value

Pre-operative characteristics

0.85

Age

1.026 0.992–1.061

0.14

Males

1.519 0.77–2.998

0.22

0.75

EuroSCORE

1.299 1.140–1.479 < 0.001* 1.051 0.873–1.265

0.59

0.70

Obesity (BMI ≥ 30 kg/m2)

1.891 1.006–3.557 0.048* 1.681 0.812–3.481

0.16

CrCl

0.999 0.991–1.007

0.75

COPD

2.534 0.999–6.425

0.05

Diabetes mellitus

1.297 0.705–2.389

0.4

Cerebrovascular disease

1.439 0.446–4.641

0.54

Peripheral vascular disease

2.335 1.183–4.609

0.01*

Previous MI

ONBHCAB

0.80

40 60 80 100 Follow up (months)

120

140

Fig. 1. K aplan–Meier estimates in the propensity-matched populations. Freedom from major adverse cardiovascular events (MACE). Red lines indicate OPCAB group, black lines indicate ONBHCAB group (p = 0.029 by the log-rank test).

1.00 Freedom from mortality

Table 3. Cox proportional hazard model for MACE at the long-term follow up of propensity-matched patients Univariate analysis

0.95

OPCAB

0.90

ONBHCAB

0.85 0.80 0.75 0.70

40 60 80 100 Follow up (months)

120

140

Fig. 2. K aplan–Meier estimates in the propensity-matched populations. Freedom from mortality. Red lines indicate OPCAB group, black lines indicate ONBHCAB group (p = 0.16 by the log-rank test).

Kaplan–Meier analysis of freedom from MACE revealed significantly lower event-free survival rates in the OPCAB group (ONBHCAB, 84.9%; OPCAB, 90.3%; p = 0.029 by the log-rank test) (Fig. 1). Kaplan–Meier analysis of freedom from mortality revealed no significant difference between the two groups (ONBHCAB, 90%; OPCAB, 90.5%; p = 0.16 by the log-rank test) (Fig. 2). In the multivariable Cox proportional hazard model, the mean number of transfused RBC units was the only independent significant predictor of MACE (Table 3).

Discussion OPCAB has the potential to reduce several of the adverse effects of CCAB because of elimination of CPB, the harmful effects of cardioplegia, the cessation of coronary blood flow, and excessive aortic manipulation. Its superiority compared with CCAB in early or mid-term outcomes has therefore been reported by many authors.9-12 However, the risk of haemodynamic instability during surgery, causing incomplete revascularisation, especially in the hands of an inexperienced surgeon, remains the major limitation of this method. A third method, ONBHCAB, reduces myocardial ischaemia, maintaining coronary blood flow, preserves haemodynamic stability with the use of CPB, and permits cardiac manipulation.

1.102 0.317–3.826

0.87

0.982 0.366–2.634

0.98

2.619 1.454–4.716 0.001* 1.764 0.808–3.851

0.15

Impaired LV function 1.951 1.074–3.542

0.02*

USAP

1.446 0.796–2.625

0.22

Previous PCI

0.727 0.176–3.000

0.65

Number of diseased vessels

1.806 0.923–3.534

0.08

Number of distal anastomoses

0.921 0.658–1.288

0.63

CPB time

1.005 0.991–1.019

0.51

Total blood loss (ml) 1.001 1.000–1.002

0.18

1.186 0.529–2.659

0.68

1.435 0.664–3.099

0.35

Operative factors

RBC (units)

1.328 1.141–1.545 < 0.001* 1.218 1.089–1.361 0.001*

Postoperative inotropic support

1.847 0.913–3.733

0.08

1.047 0.584–7.825

0.25

Peri-operative MI

2.764 1.170–6.530

0.02*

1.642 0.474–5.695

0.43

Renal complications

2.131 0.951–4.778

0.06

0.836 0.269–2.597

0.75

Neurological complications

2.554 0.914–7.135

0.07

2.137 0.584–7.825

0.25

Early rehospitalisation (< 30 days)

2.852 1.273–6.387 0.011* 1.256 0.410–3.851

0.69

*Statistically significant difference. BMI, body mass index; CABG, coronary artery bypass graftıng; CI, confidence interval; CrCl, creatinine clearance; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; HR, hazard ratio; LV, left ventricle; MI, myocardial infarction; ONBHCAB, on-pump beating heart coronary artery bypass surgery; OPCAB, off-pump coronary artery bypass surgery; PCI, percutaneous coronary intervention; RBC, red blood cell, USAP, unstable angina pectoris.

Moreover, it also limits aortic manipulation and protects the heart from post-cardioplegic intimal damage, as well as OPCAB surgery. A recent meta-analysis showed that ONBHCAB was associated with significantly fewer peri-operative MIs and less IABP use, shorter CPB time, and lower total blood loss compared with CCAB. However, it was similar in terms of cerebrovascular events, renal dysfunction, pulmonary complications, re-operation due to bleeding, inotropic agent use, intensive care unit stay, hospital stay, ventilation time, number of anastomoses, early mortality and mid-term survival rates after CABG.7 Another recent meta-analysis revealed that OPCAB was associated with significantly fewer incidents of peri-operative low cardiac output (LCO) and renal dysfunction, less total blood loss, fewer RBC transfusions, shorter ventilation times and lengths of ICU or hospital stay, but similar rates of in-hospital or long-term mortality, peri-operative MIs and cerebrovascular accidents within the first 30 days compared with CCAB. Moreover, OPCAB was also associated with an increased risk of repeat revascularisation within the first month and significantly lower numbers of performed grafts.

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Studies comparing the outcomes of OPCAB versus ONBHCAB are however limited.5 Therefore we evaluated early outcomes and long-term MACE rates of ONBHCAB versus OPCAB in a matched population. All patients were operated on by the same surgeon, therefore positioning of the heart and anastomosis techniques were typically similar between the groups, except for the use of CPB. The need for inotropic agents or IABP were found to be similar between the groups. Moreover, no difference was detected in terms of incidence of peri-operative MI and AF between the two techniques. These findings indicate that both OPCAB and ONBHCAB techniques may cause similar myocardial damage, which may explain the blood loss during both procedures. Stroke is generally considered the most important coronary surgery-related morbidity. Many meta-analyses have revealed that OPCAB is associated with short- and long-term benefits in stroke prevention, especially in higher-risk patients.1,13 By contrast, Moller and co-workers’ meta-analysis revealed no significant benefit of OPCAB compared with ONCAB regarding stroke.14 In our study, no significant difference was detected among the groups in terms of peri-operative stroke, TIA or encephalopathy. These findings revealed that the avoidance of aortic crossclamping may reduce embolic particles. The duration of ventilation, and ICU and hospital stays were significantly shorter in the OPCAB group, as in previous publications.15-17 The amount of drainage in the first 48 hours was significantly lower in the OPCAB group, therefore, the mean number of transfused RBC units was significantly lower in the OPCAB group. These findings may be explained by the well-known adverse effects of extracorporeal circulation and hypothermia on the coagulation system.15-17 Chaudhry’s meta-analysis7 revealed similar renal dysfunction after ONBHCAB in comparison with CCAB. In our study, despite similar pre-operative levels of EF, CrCl and perioperative LCO, the OPCAB group showed significantly lower renal complications than the ONBHCAB group. This finding supports a previous report indicating the independent negative effect of CPB on renal function.18 Two different meta-analyses of randomised trials reported a significantly lower number of distal anastomoses performed per patient following off-pump versus on-pump surgery.7,19 Similarly, in our study, the number of distal anastomoses per patient was significantly lower in the OPCAB group. However, in terms of functionally incomplete revascularisation, no difference was detected between the groups. It is clear that the advantage of haemodynamic stability of ONBHCAB made the surgeon feel more at ease than with OPCAB and he performed better anastomoses. Two different meta-analyses of randomised trials revealed no significant differences between off-pump and on-pump CABG regarding all-cause mortality and MACE.7,8 Our study also revealed similar all-cause mortality rates between the groups, the OPCAB group showing a significantly better MACE-free period, including MI, PCI, redo CABG and stroke in the long term. Moreover, we found that the mean number of transfused RBC units was the only significant predictor of MACE following CABG. This was considered the main cause of the negative results in the ONBHCAB group. It is clear that CPB is a challenge to the haematopoietic system due to haemodilution, significant shifts in intravascular

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volume, mechanical trauma to the blood cells and hypothermia, leading to increased transfusion of RBC or blood products.2,13,15,16 Transfusion of RBC as a risk factor for early mortality following CABG has been well established, whereas the effect of RBC transfusion on late mortality or MACE is less well described. A number of studies have shown the negative impact of RBC transfusion on early cardiovascular events and late mortality rates following cardiac surgery.20-22 RBC transfusion was also found to be associated with peri-operative MI following elective isolated OPCAB.23 Additionally, a recent report showed that low-risk patients had a significantly higher long-term mortality rate when receiving RBC following cardiac surgery, compared with patients who did not receive transfusions. This effect was not seen in high-risk patients, suggesting the negative impact of the use of blood was independent of other risk factors.24 RBC transfusion was also found to be associated with a strongly increased risk of both 30-day cardiovascular events and mortality in elective vascular surgery patients.25 The reasons for such a correlation between long-term cardiovascular events and blood transfusion are unclear but the pro-inflammatory properties of transfused RBC have been suggested as a potential explanation. It has been well established that inflammation plays a major role in all stages of atherogenesis. The role of inflammation in the pathogenesis of ischaemic stroke,26 MI and neo-intimal hyperplasia leading to in-stent restenosis27 or graft failure28 has also been described. Moreover, Fransen et al. showed that blood transfusion may potentialise the inflammatory effect of CPB.29 The combined effect of RBC transfusion and CPB may therefore aggravate atherosclerosis by stimulating the ongoing inflammatory process in patients with coronary artery disease. The present study has some limitations, including its retrospective, non-randomised design and relatively small sample size. However, our population contained propensity-matched, homogeneous patients undergoing CABG surgery by the same surgeon, using the same technique, ONBHCAB. Therefore, other factors interacting with the frequency of MACE due to differences in surgical technique or patient demographics were excluded.

Conclusion Off-pump CABG provided better long-term MACE-free survival compared with on-pump beating-heart CABG. Decreased incidence of blood transfusion following OPCAB surgery may have been the main reason for this.

References 1.

Afilalo J, Rasti M, Ohayon SM, Shimony A, Eisenberg MJ. Off-pump vs on-pump coronary artery bypass surgery: an updated meta-analysis and meta-regression of randomized trials. Eur Heart J 2012; 33(10): 1257–1267.

Angelini GD, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials. Lancet 2002; 359: 1194–1199.

Saba D, Gören S, Tekin BH, Şenkaya I, Ercan A, Özkan H, et al. The effects of position, ischemia and reperfusion to hemodynamics on the beating heart coronary bypass. Turk Gogus Kalp Damar Cerrahisi Dergisi 2003; 11(1): 26-31.

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Ascione R, Angelini GD. Off-pump coronary artery bypass surgery:

16. Wijeysundera DN, Beattie WS, Djaiani G, Rao V, Borger MA, Karkouti

the implications of the evidence. J Thorac Cardiovasc Surg 2003; 125:

K, et al. Off-pump coronary artery surgery for reducing mortality and

779–781.

morbidity: meta-analysis of randomized and observational studies. J

Rastan AJ, Bittner HB, Gummert JF, Walther T, Schewick CV,

17. Reston JT, Tregear SJ, Turkelson CM. Meta‐analysis of short‐term and

artery bypass surgery-evidence of pump-induced myocardial injury. Eur

mid‐term outcomes following off‐pump coronary artery bypass grafting.

Edgerton JR, Herbert MA, Jones KK, Prince SL, Acuff T, Carter D,

Pilvinis V, et al. Cardiopulmonary bypass management and acute renal

patients undergoing coronary artery bypass grafting. Heart Surg Forum

failure: risk factors and prognosis. Perfusion 2008; 23(6): 323–327. OJ, et al. Current evidence of coronary artery bypass grafting off-pump

Ashrafian H, et al. Beating-heart versus conventional on-pump coro-

versus on-pump: a systematic review with meta-analysis of over 16 900

nary artery bypass grafting: a meta-analysis of clinical outcomes. Ann

patients investigated in randomized controlled trials. Eur J Cardiothorac Surg 2015 Aug 13. pii: ezv268. [Epub ahead of print].

Lim CC, Cuculi F, van Gaal WJ, Testa L, Arnold JR, Karamitsos T, et

20. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after

al. Early diagnosis of perioperative myocardial infarction after coronary

cardiac surgery: the TRACS randomized controlled trial. J Am Med

bypass grafting: a study using biomarkers and cardiac magnetic resonance imaging. Ann Thorac Surg 2011; 92: 2046–2053. 9.

19. Deppe AC, Arbash W, Kuhn EW, Slottosch I, Scherner M, Liakopoulos

Chaudhry UA, Harling L, Sepehripour AH, Stavridis G, Kokotsakis J,

Thorac Surg 2015; 100(6): 2251–2260. 8.

Ann Thorac Surg 2003; 76(5): 1510–1515. 18. Sirvinskas E, Andrejaitiene J, Raliene L, Nasvytis L, Karbonskiene A,

et al. On-pump beating heart surgery offers an alternative for unstable 2004; 7(1): 8–15. 7.

Am Coll Cardiol 2005; 46: 872–882.

Girdauskas E, et al. On-pump beating heart versus off-pump coronary J Cardiothorac Surg 2005; 27(6): 1057–2064. 6.

Ascione R, Lloyd CT, Gomes WJ, Caputo M, Bryan AJ, Angelini GD. Beating versus arrested heart revascularization: evaluation of myocardial function in a prospective randomized study. Eur J Cardiothorac Surg 1999; 15: 685–690.

10. Sabik JF, Gillinov AM, Blackstone EH, et al. Does off-pump coronary surgery reduce morbidity and mortality? J Thorac Cardiovasc Surg 2002; 124: 698 –707. 11. Puskas JD, Williams WH, Duke PG, et al. Off-pump coronary artery

Assoc 2010; 304: 1559–1567. 21. Surgenor SD, Kramer RS, Olmstead EM, et al. The association of perioperative red blood cell transfusions and decreased long-term survival after cardiac surgery. Anesth Analg 2009; 108: 1741– 1746. 22. Koch CG, Li L, Duncan AI, Mihaljevic T, Loop FD, Starr NJ, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg 2006; 81: 1650 –1657. 23. Biancari F, Kinnunen EM. Red blood cell transfusion is associated with troponin release after elective off-pump coronary artery bypass surgery. Ann Thorac Surg 2012; 94(6): 1901–1907.

bypass grafting provides complete revascularization with reduced

24. Jakobsen CJ, Ryhammer PK, Tang M, Andreasen JJ, Mortensen PE.

myocardial injury, transfusion requirements, and length of stay: A

Transfusion of blood during cardiac surgery is associated with higher

prospective randomized comparison of two hundred unselected patients

long-term mortality in low-risk patients. Eur J Cardiothorac Surg 2012;

undergoing off-pump versus conventional coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125: 797–808.

42(1): 114–120. 25. Valentijn TM, Hoeks SE, Bakker EJ, van de Luijtgaarden KM,

12. Al-Ruzzeh S, Nakamura K, Athanasiou T, et al. Does off-pump coro-

Verhagen HJ, Stolker RJ, et al. The impact of perioperative red blood

nary artery bypass (OPCAB) surgery improve the outcome in high-

cell transfusions on postoperative outcomes in vascular surgery patients.

risk patients? A comparative study of 1398 high-risk patients. Eur J Cardiothorac Surg 2003; 23: 50–55. 13. Edelman JJ, Yan TD, Bannon PG, Wilson MK, Vallely MP. Coronary artery bypass grafting with and without manipulation of the ascending aorta – a meta-analysis. Heart Lung Circ 2011; 20: 318–324. 14. Møller CH, Penninga L, Wetterslev J, Steinbrüchel DA, Gluud C.

Ann Vasc Surg 2015; 29(3): 511–519. 26. Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010; 87(5): 779–789. 27. Niccoli G, Montone RA, Ferrante G, Crea F. The evolving role of inflammatory biomarkers in risk assessment after stent implantation. J Am Coll Cardiol 2010; 56(22): 1783–1793.

Off-pump versus on-pump coronary artery bypass grafting for ischae-

28. Schepers A, Pires NM, Eefting D, de Vries MR, van Bockel JH, Quax

mic heart disease. Cochrane Database Syst Rev 2012; 14(3): CD007224.

PH. Short-term dexamethasone treatment inhibits vein graft thickening

15. Cheng DC, Bainbridge D, Martin JE, Novick RJ, evidence-based

in hypercholesterolemic ApoE3 Leiden transgenic mice. J Vasc Surg

perioperative clinical outcomes research group. Does off-pump coronary

2006; 43(4): 809–815.

artery bypass reduce mortality, morbidity, and resource utilization when

29. Fransen E, Maessen J, Dentener M, Senden N, Buurman W. Impact of

compared with conventional coronary artery bypass? A meta-analysis

blood transfusions on inflammatory mediator release in patients under-

of randomized trials. Anesthesiology 2005; 102: 188–203.

going cardiac surgery. Chest 1999; 116(5): 1233–1239.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

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Myocardial dysfunction in children with intrauterine growth restriction: an echocardiographic study Katarzyna Niewiadomska-Jarosik, Justyna Zamojska, Agata Zamecznik, Agnieszka Wosiak, Piotr Jarosik, Jerzy Stańczyk

Abstract Introduction: The prevalence of intrauterine growth restriction (IUGR) is about 3–10% of live-born newborns and can be as high as 20% in developing countries. It may result in the occurrence of cardiovascular diseases later in life. Methods: The aim of this study was echocardiographic evaluation, with the use of conventional and tissue Doppler parameters, of cardiac function in children born with IUGR, and comparison with healthy peers born as normally grown foetuses. Results: In the IUGR group, E wave and E/A ratio were significantly lower compared to the control group. A wave, isovolumetric relaxation time, deceleration time, myocardial performance index as well as E/E′ septal and E/E′ lateral indices were significantly higher compared to healthy peers. Conclusion: Children with IUGR presented with subclinical myocardial dysfunction. Keywords: echocardiography, intrauterine growth restriction, myocardial dysfunction, children Submitted 23/7/14, accepted 16/4/16 Published online 7/12/16 Cardiovasc J Afr 2017; 28: 36–39

www.cvja.co.za

DOI: 10.5830/CVJA-2016-053

Intrauterine growth restriction (IUGR) is a major problem in present-day medicine. It is defined as a birth weight below the 10th percentile for gestational age and involves about 5–10% of neonates.1 IUGR is one of the main causes of low birth weight and directly affects perinatal morbidity and mortality rates. It is well known that such pathology may be associated with the later occurrence of cardiovascular diseases. Barker’s hypothesis, published in 1989,2 proved increased incidence of cardiovascular diseases in adults born with IUGR, particularly

Department of Pediatric Cardiology and Rheumatology, 2nd Chair of Pediatrics, Medical University of Lodz, Poland Katarzyna Niewiadomska-Jarosik, MD, PhD, kasiajarosik@wp.pl Justyna Zamojska, MD, PhD Agata Zamecznik, MD Jerzy Stańczyk, MD, PhD

Institute of Information Technology, Technical University of Lodz, Poland Agnieszka Wosiak, PhD

Department of Pediatric Cardiosurgery, Polish Mother’s Memorial Institute, Lodz, Poland Piotr Jarosik, MD, PhD

hypertension and hyperlipidaemia. It is explained by the ‘foetal programming’ theory, which is the formation in the prenatal period of adaptive mechanisms to prevent the long-term hypoxia accompanying IUGR.3 Currently, cardiovascular dysfunction forming during the prenatal period is considered one of the main pathophysiological features of this programming.4-6 In addition, Crispi et al. suggest that this dysfunction may be one of the major mechanisms explaining increased cardiovascular mortality rates in adults who were born with IUGR.4 Due to the sparsity of reports, the increase in incidence of myocardial dysfunction in children born with IUGR remains unclear. The aim of our prospective study was echocardiographic evaluation of cardiac function in children born with IUGR, compared to children born at normal gestational age and birth weight.

Methods The analysis included 77 children (42 girls, 35 boys), aged from 5–11 years, who were randomly selected from the obstetrics and gynecology out-patient clinic. We included those born at term as small-for-gestational-age (SGA) babies (birth weight below the 10th percentile according to gestational age) with IUGR features, detected prenatally by foetal size measurements on obstetric ultrasonography. All the children were single births. The control group included 30 healthy subjects (16 girls, 14 boys), born with normal birth weight, gender and age matched to the study group. Gestational age was calculated from the mother’s last menstrual period. All patients were hospitalised at the Pediatric Cardiology and Rheumatology Department of the Medical University of Lodz between 2010 and 2013. All demographic and anthropometric data were recorded during the examination, including information about gestational age, birth weight and nutritional status [height, weight, body mass index (BMI) = weight (kg)/height (m)2] (Table 1). All subjects were well at the time of the study, none had a chronic illness or a history of medication taking. The exclusion criteria were: evidence of chromosomal or infectious aetiology for IUGR, gestational diabetes, hypothyroidism, systemic or acute disease, and the mother smoking cigarettes or using medication. This study was approved by the medical ethics committee of the Health Sciences Faculty of Lodz University (No: RNN/150/09/KB). All patients underwent a full echocardiographic study, using the Aloka Prosound α 10 device, evaluating anatomy and cardiac function. In standard projections, systolic and diastolic function of the left ventricle was estimated. • Left ventricular diameter, ejection fraction (EF) and shortening fraction (SF) were calculated in the parasternal, long-axis view, in M-mode presentation according to the Teichholz formula.

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Table 1. Patients’ characteristics Characteristics

Study group (n= 77) mean ± SD

Gender (M/F)

35/42

14/16

Age on examination

7y8m±1y4m

Birth weight (g)

2541.62 ± 218.47

Table 2. Echocardiographic parameters Parameters

Study group (n= 77) mean ± SD

Control group (n= 30) mean ± SD

p-value

LVDd (mm)

37.23 ± 4.27

37.03 ± 3.96

0.81 (NS)

7 y 7m ± 1 y 10 m

IVSd (mm)

5.40 ± 0.89

5.36 ± 0.85

0.78 (NS)

3394.33 ± 522.35

< 0.001

LVPWd (mm)

5.93 ± 0.91

5.92 ± 0.91

0.95 (NS)

39.03 ± 0.90

39.07 ± 0.74

EF (%)

69.32 ± 2.99

69.20 ± 3.14

0.86 (NS)

124.46 ± 10.40

129.30 ± 10.27

< 0.05

SF (%)

38.33 ± 2.55

38.3 ± 2.73

0.95 (NS)

Weight

25.20 ± 9.10

27.20 ± 8.10

E (cm/s)

91.71 ± 14.99

101.07 ± 10.59

0.002

BMI

15.87 ± 3.01

16.09 ± 2.60

A (cm/s)

68.37 ± 9.91

44.78 ± 9.15

< 0.001

Gestational age (hbd) Height (cm)

Control group (n= 30) mean ± SD p-value

n, number of children; SD, standard deviation; NS, not significant; M, male; F, female; y, years; m, months; hbd, weeks of gestation; BMI, body mass index.

• In the apical, four-chamber view, with the use of pulsed Doppler, evaluation of mitral inflow velocities was done. The sample volume was placed at the mitral valve annulus and the peak of early mitral inflow velocity (E wave in early diastole), the peak of atrial mitral inflow velocity (A wave in atrial systole) and the E/A ratio were assessed. • In the apical, five-chamber view, with the use of pulsed Doppler, left ventricular inflow and outflow were recorded with the sample volume placed between the aortic and mitral valves to evaluate isovolumetric relaxation time (IRT) and deceleration time (DecT). On the basis of these measurements, myocardial performance index, defined as quotient of the sum of the isovolumetric contraction time (ICT) and IRT-to-left ventricular ejection time (ET), were calculated. • In the apical, five-chamber view, with the use of pulsed Doppler, aortic flow was recorded and heart rate calculated. Each measurement was obtained for three cardiac cycles. For statistical analysis the mean value was used. Pulsed and colour tissue Doppler imaging were performed in the apical four-chamber view. The sample volume was positioned as parallel as possible with the lateral mitral annular motion. The maximal myocardial velocities during systole (S), and early (E′) and late (A′) diastole were measured at the interventricular septum (septal) and lateral annulus (lateral). The ratio of the early to late diastolic velocities was calculated for IVS (E′/A′ septal) and for the posterior wall (E′/A′ lateral). The ratio of peak transmitral E velocity to early diastolic mitral annular velocity (E/E′) was calculated for both the interventricular septum and posterior wall (E/E′ septal and E/E′ lateral, respectively).

Statistical analysis Descriptive statistics were executed by computing the mean and standard deviation (SD) for scale variables, or frequencies for nominal variables. The significance level was computed for the differences between variables in the IUGR and control groups. To evaluate the differences between the two groups, a parametric t-test and a non-parametric Mann–Whitney test were performed. Distributions were checked for normality with the Kolmogorow– Smirnov test. Statistical significance was defined as a p-value < 0.05. Pearson and Spearman correlation coefficients were computed to evaluate the degree of association between variables for either the control or study group.

Results Analysis of the medical records confirmed statistically significant differences in birth weight (IUGR group: 2 541.62

E/A ratio

1.44 ± 0.13

2.01 ± 0.29

< 0.001

IRT (ms)

102.47 ± 8.72

96.58 ± 6.08

0.002

DecT (ms)

180.81 ± 38.69

160.83 ± 25.63

0.011

0.58 ± 0.08

0.43 ± 0.09

< 0.001

85.00 ± 11.41

81.77 ± 8.94

0.095 (NS)

MPI HR/min

n, number of children; SD, standard deviation; NS, not significant; LVDd, left ventricular diameter in diastole; IVSd, interventricular septum in diastole; LVPWd, posterior wall diameter in diastole; EF, ejection fraction; SF, shortening fraction; E, E wave; A, A wave; IRT, isovolumetric relaxation time; DecT, deceleration time; MPI, myocardial performance index; HR, heart rate.

± 218.47 g versus control group: 3 394.33 ± 522.35 g; p < 0.001), while there was no significant difference for gestational age between the groups. Physical examinations did not reveal statistically significant differences between the mean values for weight and body mass index, whereas in the IUGR group, the children were significantly smaller compared to healthy subjects (Table 1). Analysis of echocardiographic left ventricular diameters did not reveal any significant differences in diastolic wall dimensions (IVSd: interventricular septum in diastole, LVPWd: posterior wall diameter in diastole) or left ventricular lumen diameters between the two groups. Left atrial diameter also did not differ significantly. The mean values of ejection fraction as well as shortening fraction were within normal limits and similar between the groups. The mean values were as follows: IUGR group: EF 69.32 ± 2.99%, SF 38.33 ± 2.55%; control group: EF 69.20 ± 3.14%, SF 38.30 ± 2.73%. According to parameters evaluating left ventricular diastolic function, there were statistically significant differences between mean values of E wave, A wave and E/A ratio. The mean values of E wave and E/A ratio were significantly lower in children with intrauterine growth retardation compared to the control group. The mean values of the A wave were significantly higher in that group of patients. The mean values of isovolumetric relaxation time and deceleration time were significantly higher in children with IUGR compared to the healthy peers (102.47 ± 8.72 vs 96.58 ± 6.08 min; 180.81 ± 38.69 vs 160.83 ± 25.63 min, respectively). The mean values of myocardial performance index obtained in the IUGR group were significantly higher than those of the control group. The heart rate was similar in both groups of patients (p = 0.095) (Table 2). Estimation of left ventricular function using tissue Doppler imaging did not reveal significant differences between the mean values of systolic myocardial velocity, either at the level of IVS, or at the posterior wall. The mean values of septal and posterior wall E′/A′ ratio were also similar. The mean values of E/E′ for the interventricular septum and E/E′ for the posterior wall were significantly higher in patients with IUGR (Table 3).

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Table 3. Tissue Doppler echocardiography parameters Parameters S septal

Study group (n= 77) mean ± SD

Control group (n= 30) mean ± SD

p-value

7.71 ± 1.20

7.88 ± 1.43

0.58 (NS)

S lateral

9.62 ± 1.37

9.90 ± 1.57

0.40 (NS)

E′ septal

15.29 ± 1.88

14.80 ± 1.83

0.22 (NS)

A′ septal

6.71 ± 1.41

6.32 ± 1.01

0.17 (NS)

E′ lateral

20.38 ± 2.94

20.85 ± 2.24

0.43 (NS)

A′ lateral

7.76 ± 1.86

7.56 ± 0.94

0.56 (NS)

E′/A′ septal

2.41 ± 0.40

2.36 ± 0.43

0.59 (NS)

E′/A′ lateral

2.82 ± 0.42

2.75 ± 0.54

0.51 (NS)

E/E′ septal

6.89 ± 1.11

4.62 ± 1.16

< 0.001

E/E′ lateral

6.10 ± 1.27

4.91 ± 0.88

< 0.001

n, number of children; SD, standard deviation; NS, not significant; S septal, myocardial velocity during systole at interventricular septum; S lateral, myocardial velocity during systole at posterior wall; E′/A′ septal, ratio of early to late diastolic velocities for the interventricular septum; E′/A′ lateral, ratio of early to late diastolic velocities for the posterior wall; E/E′ septal, ratio of peak transmitral E velocity to early diastolic mitral annular velocity for the interventricular septum; E/E′ lateral, ratio of peak transmitral E velocity to early diastolic mitral annular velocity for the posterior wall.

Discussion In recent years, more attention has been paid to changes in cardiac function in children with features of intrauterine growth retardation. Many articles describe the disorders appearing as early as in the foetus, revealing subclinical changes in the myocardium detected on echocardiographic examination.3,4,7 Changes in utero due to chronic hypoxia and malnutrition, with increased placental vascular resistance, result in pressure and volume overload of the foetal heart, which in turn induces abnormal cardiac function.8,9 In our study we evaluated the cardiac function in small-forgestational-age children with features of IUGR with the use of conventional as well as tissue Doppler echocardiographic parameters. We analysed left ventricular diameters (IVSd, LVPWd and LVDd) but did not find significant differences between the groups. This is similar to the findings of Bjarnedard et al. and Crispi et al., who studied, respectively, young adults and children the same age as our study patients.7,10 On the other hand, Turkish authors demonstrated that left ventricular diastolic dimension in neonates and infants were significantly higher in children with IUGR.11 These differences may have been due to the different age groups examined by the researchers. Other conventional echocardiographic parameters assessed in our study were shortening fraction (SF) and ejection fraction (EF) of the left ventricle. As in other reports, there were no differences between the groups.7,11,12 Altin et al. describes a significantly higher heart rate in children with growth restriction, which was not observed in our study.11 Presumably this difference may have been due to the fact that the authors evaluated neonates and infants, not older children, as in our study. These observations may indicate that predominance of the sympathetic nervous system in children with SGA tends to disappear with age. However, Crispi et al. studied children of a similar age as ours and showed similar heart rates to ours in children with IUGR.7 E/A ratio is a conventional index evaluating ventricular filling during diastole. In adults, reduced E/A ratios indicate diastolic dysfunction. Cohen et al. measured a mean E/A index of 1.9 in healthy people over 21 years of age and Eto et al. of 1.77 ± 0.53

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in children. We had similar findings in the control group, but in children with IUGR, the mean E/A ratio was lower.13,14 Other articles on children with IUGR describe different values for this index. In most recent reports in foetuses, the E/A ratio was significantly higher compared with the control group. In older children authors describe a normalisation of the E/A ratio, with no differences between a group of healthy children and those born with IUGR features.7,10,11,15,16 The lower E/A index in children with IUGR seems to be dependent on the increase in A wave and decrease in E wave in those patients. This could be explained by a lower free inflow (E wave) than active left ventricular filling (A wave), which is associated with susceptibility of the left ventricle to abnormalities, and may be one of the symptoms of diastolic dysfunction. Such abnormalities are described in children with connective tissue diseases, due to the higher content of connective tissue in cardiac muscle, which diminishes its susceptibility to stretching. The results of research on deceleration time in adults, which is an indicator of left ventricular ‘stiffness’, support this theory.17 In our study, deceleration time in the IUGR group was only slightly higher but a statistically significant difference was observed between the groups. It may indicate the start of myocardial changes in susceptibility/stiffness of the left ventricle. With regard to the IRT, results in the literature are not consistent. Sehgal et al., who studied a slightly younger group of children with growth restrictions, described a similar tendency to our results.18 By contrast, Crispi et al., in a similar age group to ours, did not report such differences.7 In our study, MPI was significantly higher in the IUGR group.11,19 Similar observations have been reported in foetuses, which may indicate that myocardial function is already impaired in utero.20 However, observations from Swedish authors who studied adults who were born with IUGR (22–25 years old) did not confirm this theory.10 These differences may have been due to the degree of restriction abnormalities, which was different in the various groups studied. There are few reports on diastolic cardiac function in children with IUGR. Altin et al. evaluated diastolic function in neonates and infants and revealed that indices that were abnormal in the foetal period (E′, A′, E′/A′, E/E′ septal and E/E′ lateral) tended to decrease with age.11 Similar findings were described by Bjarnegard et al., who estimated diastolic function in young adults. They found no differences in these indices between the IUGR and control groups.10 On the other hand, a multicentre study by Crispi et al. showed different results. Other researchers evaluated a similar age group to those in our study and, as in our analysis, some diastolic function parameters were significantly higher in IUGR children. Perhaps the observed anomalies due to intrauterine chronic hypoxia leading to cardiac volume overload and cardiac remodelling resulted in impaired cardiac function.7

Conclusion From our results, we found that diastolic function may be impaired in IUGR patients, but further studies with larger sample sizes are needed. This group of patient should be monitored long term and evaluated for cardiovascular status, due to the high risk of cardiovascular disease in adulthood.

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assessment of ventricular diastolic function using Doppler echocardiog-

Crispi F, Hernandez-Andrade E, Pelsers MM, Plasencia W, BenavidesSerralde JA, Eixarch E, et al. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet

of proB-type natriuretic peptide in human fetuses with growth restriction. Ultrasound Obstet Gynecol 2007; 29: 296–303. 16. Naujorks AA, Zielinsky P, Beltrame PA, Castagna RC, Petracco R,

Tsyvian P, Malkin K, Artemieva O, Blyakhman F, Wladimiroff JW.

Busato A, et al. Myocardial tissue Doppler assessment of diastolic

Cardiac ventricular performance in the appropriate- for-gestational age

function in the growth-restricted fetus. Ultrasound Obstet Gynecol 2009;

uniformity and peripheral resistance. Ultrasound Obstet Gynecol 2002;

34: 68–73. 17. Corrao S, Sallì L, Arnone S, Scaglione R, Pinto A, Licata G. Echo-

20: 35–41.

Doppler left ventricular filling abnormalities in patients with rheuma-

Crispi F, Bijnens B, Figueras F, Bartrons J, Eixarch E, Le Noble F, et al.

toid arthritis without clinically evident cardiovascular disease. Eur J Clin

Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation 2010; 121: 2427–2436. Verburg BO, Jaddoe VW, Wladimiroff JW, Hofman A, Witteman JC, Steegers EA. Fetal hemodynamic adaptive changes related to intrau9.

dilated cardiomyopathy. J Am Soc Echocardiogr 1999; 12: 1058–1064. 15. Girsen A, Ala-Kopsala M, Mäkikallio K, Vuolteenaho O, Räsänen J. Cardiovascular hemodynamics and umbilical artery N-terminal peptide

and small-for-gestational age fetus: relation to regional cardiac non-

global left ventricular function in normal children and in children with

Kiserud T, Ebbing C, Kessler J, Rasmussen S. Fetal cardiac output, Ultrasound Obstet Gynecol 2006; 28: 126–136.

raphy. Am Coll Cardiol 1996; 27: 1753–1760. 14. Eto G, Ishii M, Tei C, Tsutsumi T, Akagi T, Kato H. Assessment of

Gynecol 2008; 199: 254. e1-8. doi: 10.1016/j.ajog.2008.06.056. distribution to the placenta and impact of placental compromise. 6.

2009; 51: 807–811. 13. Cohen GI, Pietrolungo JF, Thomas JD, Klein ALJ. A practical guide to

fetal growth restriction. Placenta 2007; 28: 714–723.

tion of arterial stiffness with intrauterine growth retardation. Pediatr Int

infancy and death from ischemic heart disease. Lancet 1989; 2: 577–580. Meschia G. Development and mechanisms of fetal hypoxia in severe 4.

echocardiographic study. Early Hum Dev 2012; 88: 757–764. 12. Levent E, Atik T, Darcan S, Ulger Z, Gökşen D, Ozyürek AR. The rela-

Invest 1996; 26: 293–297. 18. Sehgal A, Doctor T, Menahem S. Cardiac function and arterial biophysical properties in small for gestational age infants: postnatal manifestations of fetal programming. J Pediatr 2013; 163: 1296–1300.

terine growth: the Generation R Study. Circulation 2008; 117: 649–659.

19. Cui W, Roberson DA. Left ventricular Tei index in children: comparison

Gardiner H, Brodszki J, Marsál K. Ventriculovascular physiology of

of tissue Doppler imaging, pulsed wave Doppler, and M-mode echocar-

the growth-restricted fetus. Ultrasound Obstet Gynecol 2001; 18: 47–53.

diography normal values. J Am Soc Echocardiogr 2006; 19: 1438–1445.

10. Bjarnegård N, Morsing E, Cinthio M, Länne T, Brodszki J.

20. Comas M, Crispi F, Cruz-Martinez R, Figueras F, Gratacos E. Tissue

Cardiovascular function in adulthood following intrauterine growth

Doppler echocardiographic markers of cardiac dysfunction in small-

restriction with abnormal fetal blood flow. Ultrasound Obstet Gynecol

for-gestational age fetuses. Am J Obstet Gynecol 2011; 205: 57.e1–6. doi:

2013; 41: 177–184.

10.1016/j.ajog.2011.03.010.

11. Altın H, Karaarslan S, Karataş Z, Alp H, Şap F, Baysal T. Evaluation of

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Adropin as a potential marker of enzyme-positive acute coronary syndrome Suna Aydin, Mehmet Nesimi Eren, Musa Yilmaz, Mehmet Kalayci, Meltem Yardim, Omer Dogan Alatas, Tuncay Kuloglu, Huseyin Balaban, Tolga Cakmak, Mehmet Ali Kobalt, Ahmet Çelik, Suleyman Aydin

Abstract Aim: Enzyme-positive acute coronary syndrome (EPACS) can cause injury to or death of the heart muscle owing to prolonged ischaemia. Recent research has indicated that in addition to liver and brain cells, cardiomyocytes also produce adropin. We hypothesised that adropin is released into the bloodstream during myocardial injury caused by acute coronary syndrome (ACS), so serum and saliva levels rise as the myocytes die. Therefore, it could be useful to investigate how ACS affects the timing and significance of adropin release in human subjects. Methods: Samples were taken over three days after admission, from 22 EPACS patients and 24 age- and gendermatched controls. The three major salivary glands (submandibular, sublingual and parotid) were immunohistochemically screened for adropin production, and serum and saliva adropin levels were measured by an enzyme-linked immuno-

Department of Anatomy – Cardiovascular Surgery, Elazig Education and Research Hospital, Elazig, Turkey Suna Aydin, MD, PhD, cerrah52@hotmail.com

Department of Cardiovascular Surgery, School of Medicine, Dicle University, Diyarbakir, Turkey Mehmet Nesimi Eren, MD

sorbent assay (ELISA). Salivary gland cells produce and secrete adropin locally. Results: Serum adropin, troponin I, CK and CK-MB concentrations in the EPACS group became gradually higher than those in the control group up to six hours (p < 0.05), and troponin I continued to rise up to 12 hours after EPACS. The same relative increase in adropin level was observed in the saliva. Troponin I, CK and CK-MB levels started to decrease after 12 hours, while saliva and serum adropin levels started to decrease at six hours after EPACS. In samples taken four hours after EPACS, when the serum adropin value averaged 4.43 ng/ml, the receiver operating characteristic curve showed that the serum adropin concentration indicated EPACS with 91.7% sensitivity and 50% specificity, while when the cut-off adropin value in saliva was 4.12 ng/ml, the saliva adropin concentration indicated EPACS with 91.7% sensitivity and 57% specificity. Conclusion: In addition to cardiac troponin and CK-MB assays, measurement of adropin level in saliva and serum samples is a potential marker for diagnosing EPACS. Keywords: saliva, serum, adropin, acute coronary syndrome, enzyme-positive acute coronary syndrome, myocardial infarction, immunohistochemistry

Department of Medical Biochemistry (Firat Hormones Research Group), School of Medicine, Firat University, Elazig, Turkey

Submitted 3/7/15, accepted 17/4/16

Musa Yilmaz, MD Meltem Yardim, MD Suleyman Aydin, PhD

Cardiovasc J Afr 2017; 28: 40–47

Laboratory of Medical Biochemistry, Elazig Education and Research Hospital, Elazig, Turkey Mehmet Kalayci, MD

Department of Emergency, Mugla Sitki Kocman University, Education and Research Hospital, Mugla 48000, Turkey Omer Dogan Alatas, MD

Department of Histology and Embryology, School of Medicine, Firat University, Elazig, Turkey Tuncay Kuloglu, MD

Department of Internal Medicine, 29 May State Hospital, Ankara, Turkey Huseyin Balaban, MD

Department of Cardiology, Ercis State Hospital, Van, Turkey Tolga Cakmak, MD

Department of Cardiology, School of Medicine, Firat University, Elazig, Turkey Mehmet Ali Kobalt, MD

Department of Cardiology, School of Medicine, Mersin University, Mersin, Turkey Ahmet Çelik, MD

Published online 19/5/16 www.cvja.co.za

DOI: 10.5830/CVJA-2016-055

Acute coronary syndrome (ACS) [acute myocardial infarction (AMI), enzyme-positive acute coronary syndrome (EPACS)] is the dominant cause of death and disability in children and in young,1 middle-aged and elderly adults in both developed and developing countries.2 Coronary arteriosclerosis is a chronic disease with stable and unstable periods.3 During unstable periods, increased cholesterol deposition and activated local inflammation in the vascular wall can cause atheromatous plaque rupture and thrombus formation, resulting in unstable angina (chest pain) or MI (heart attack).4,5 EPACS is currently diagnosed, according to criteria proposed by the American College of Cardiology (ACC) and European Society of Cardiology (ESC),6,7 as the presence of three or more of the following abnormalities: a history of the presenting illness, prolonged chest pain, ‘silent infarct’, pathological Q waves in the electrocardiogram (ECG), typical rise and/or fall of cardiac biomarkers (preferably troponin I) with at least one value above the 99th percentile of the upper reference limits.8

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Despite this abundance of parameters for diagnosing EPACS, a million patients annually seek care in emergency, cardiology and cardiovascular surgery departments with chest pain or other symptoms suggesting an ACS, although only around 10% are subsequently confirmed to have EPACS.9 Therefore, emergency, cardiology and cardiovascular surgery doctors need novel advance, accurate, fast, easily accessible and cost-effective cardiac markers for better patient outcomes and fewer complications. Adropin is a peptide hormone secreted from pancreatic, liver, brain and kidney tissues and from the endocardium, myocardium and epicardium of the heart.10-12 It circulates in the blood to activate the release of nitric oxide and regulate apoptosis and energy homeostasis,13,14 and could be a novel predictor of heart failure. Adropin secretion is controlled by many factors including glucose levels and myocardial infarction.10 Decreased adropin level is an independent risk factor for endothelial dysfunction, a key early event in atherogenesis, and is integral to the onset of coronary artery disease (CAD) and ACS.15 It is also an independent predictor of clinically relevant coronary atherosclerosis.16 Adropin levels are significantly lower in patients with cardiac syndrome X than in healthy subjects, so low serum adropin level could be an independent risk factor for this condition.15 It is also closely related to type 2 diabetes mellitus and gestational diabetes mellitus.16,17 In addition, a recent study revealed that adropin levels were decreased in patients with late saphenous vein graft occlusion and it could have been causally related.18 On the basis of these findings, it was hypothesised that the adropin synthesised in the endocardium, myocardium and epicardium10 could serve as a novel biological marker for the diagnosis and prognosis of myocardial ischaemia, because ischaemic injury to heart muscle cells is likely to release adropin into the bloodstream. However, there have been contradictory reports from animal studies that examined the association between adropin expression and isoproterenolinduced myocardial infarction, which indicated that the gradual increase in serum adropin levels could serve as an alternative to troponin I measurement for diagnosing EPACS,19 and human studies, showing that single-timing serum adropin levels were lower in EPACS patients than in stable angina pectoris (SAP) patients or controls.20 This conflict needs to be resolved. Therefore, the purposes of this study were: (1) to determine the changes in adropin and troponin I concentrations in sera from EPACS patients; (2) to determine whether this hormone is produced by the three major salivary glands, parotid, sublingual and submandibular; and (3) to determine whether saliva contains adropin, because obtaining saliva samples is non-invasive, making it advantageous over blood sampling.

Methods All protocols for the human studies in this work accorded with the principles set out (date 6/3/2014; issue no: 03) by the Institutional Human Ethics Committee (FUIHC) and with the ethical principles in the most recent version of the Declaration of Helsinki. Written informed consent to participate in the study was individually obtained.

A total of 46 subjects (22 EPACS patients and 24 controls) were admitted to the Emergency Department at Elazig Education and Research Hospital due to chest pain or other symptoms (within 30–40 minutes of onset). Our hospital is conveniently located in downtown Elazig so it can be reached from any part of the city within 15 minutes of the first symptoms. The heart team (cardiologists and cardiovascular surgeons) evaluated the patients admitted, as described previously.21 A diagnosis of EPACS was made by integrating the history of the presenting illness, an increase in serum troponin I concentration (1 × upper limit of the hospital normal range), and associated symptoms of ischaemia, chest pain and/or characteristic ECG signs (ST-segment–T-wave changes or development of pathological Q waves).6-8 All patients (n = 22) were screened for EPACS by coronary angiography. Healthy volunteers (n = 24) having routine annual check ups (08.00– 09.00) served as controls. The patients were treated as explained elsewhere.21 Briefly, their EPACS was treated as primary PCI (first loading dose 600 mg clopidogrel + 300 mg acetylsalicylic acid/day, and maintained on 75 mg clopidogrel + 300 mg acetylsalicylic acid/day; n = 5), thrombolytic therapy was given (10 U reteplase + 75 mg clopidogrel + 300 mg acetylsalicylic acid/day; n = 9), and routine anti-anginal therapy was provided (first loading dose 600 mg clopidogrel + 300 mg acetylsalicylic acid/day, and maintained on 75 mg clopidogrel + 300 mg acetylsalicylic acid/day; n = 8). Exclusion criteria were: over 75 or under 50 years old, surgery or trauma within two months of the study, known cardiomyopathy, and family history of cardiovascular disease (CVD) (having a father who developed CVD before 55 years of age, a mother before 65 years, or a sibling at any age). We defined CVD as coronary heart disease, hypertension (hypertension was defined as resting systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg according to WHO–ISH criteria),22 or on current antihypertensive treatment, rheumatic heart disease, known malignant diseases, febrile conditions, acute or chronic inflammatory disease, gastrointestinal diseases, suspected myocarditis or pericarditis, diabetes mellitus of any type, severe heart failure, advanced renal or hepatic disease, alcohol consumption of more than one unit per day, no regular intense exercise (> 15 min of aerobics three times per week), and use of tobacco products (former and current). All the study participants, including the control subjects, underwent a standard clinical examination. Other details relevant to the EPACS studies were described previously.8,21 The first saliva and venous blood samples were collected when patients were admitted to the Emergency Department (within 30–40 minutes of onset) and before angiography. Other samples (two, four, six, 12, 24, 48 and 72 hours) were drawn from the antecubital veins of all participants into plain sterile tubes for serum, and into sterile urine cups for whole resting saliva at 08.00 hours in the Department of Cardiology. Saliva and serum were collected simultaneously at each sampling time after thorough rinsing of the mouth with water, as previously described.21,23,24 Circadian variation in the onset of EPACS has been documented. To avoid this influence, only EPACS patients admitted in the morning were included in this study. Blood samples were divided into two aliquots, one for classical biochemical parameters and the other for measuring adropin

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levels. The plain sterile tubes for blood and sterile urine cups for saliva contained 500 kIU aprotonin to preclude proteolysis, and after clotting, the samples, were immediately centrifuged at 4 000 rpm and kept frozen (−80°C) pending analysis. All samples were subjected to conventional laboratory analyses using an autoanalyser, including determination of glucose, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. Serum troponin I concentration was measured by chemiluminescence using a Siemens IMMULITE 2000 XPi immunoassay system (Siemens Healthcare Diagnostics Inc, Flanders NJ, USA) and commercial kits (Siemens Healthcare Diagnostics Products Ltd, Llanberis, United Kingdom). Serum and saliva adropin levels were measured using the same commercial EIA kits (cat no: EK-032-35) and procedures (Phoenix Pharmaceuticals, Belmont, CA, USA). The saliva adropin assay was validated according to previously published methods.25 The lowest detectable concentration of adropin was 0.01 ng/ml, with intra- and inter-assay variations of 10 and 15%, respectively. Absorbance at 450 nm was measured with an ELX 800 ELISA reader.

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Salivary glands were obtained from the Department of Pathology. They had been removed by surgeons only because of calcification. Adropin was screened immunohistochemically using the Hsu et al. avidin–biotin peroxidase complex (ABC) method, as recently described.26 Adropin primary antibody was diluted 1/200 (rabbit polyclonal anti-adropin antibody, ab12800; Abcam, Cambridge, UK), applied and incubated for 60 min in a humid chamber at room temperature. Immunostained sections from the parotid, submandibular and sublingual glands were examined with an Olympus BX 50 photomicroscope. Immunohistochemical staining was scored for both intensity and prevalence on a scale of 0 to +3 (0: absent, +1: weak, +2: medium, +3: strong).

Statistical analysis All statistical analyses were performed using SPSS for Windows version 21.0 (SPSS Inc, Chicago, USA). Differences between groups were analysed with the Kruskal–Wallis test. The Mann–Whitney U-test was used to compare parameters within groups. Comparisons of mean values between groups were expressed as ± 2 SEM.

Fig. 1. A dropin immunohistochemistry of the intercalated duct of the parotid, striated and interlobular ducts of the submandibular, and mucous acinus of the sublingual glands. A1, parotid negative; A2: parotid adropin immunoreactivity; B1, sublingual negative; B2: sublingual adropin immunoreactivity, C1, submandibular negative; C2, submandibular adropin immunoreactivity. Red colour shows adropin immunoreactivity. Magnification ×400.

Table 1. Changes in glucose and lipid profiles with and without EPACS. All values are presented as mean ± SD. Control (n = 24) 40.57 ± 5.0 12/12 89.07 ± 6.27 (4.94 ± 0.35) 178.93 ± 42.82 (4.63 ± 1.11) 43.42 ± 9.2 (1.12 ± 0.24) 106.14 ± 31.69 (2.75 ± 0.82) 172.93 ± 57.37 (1.95 ± 0.65)

Parameters Age (years) Male/female Glucose (mg/dl) (mmol/l) Total cholesterol (mg/dl) (mmol/l) HDL-C (mg/dl) (mmol/l) LDL-C (mg/dl) (mmol/l) Triglycerides (mg/dl) (mmol/l)

EPACS (n = 22) p-value 0.000 57.75 ± 6.38 12/10 0.713 102.08 ± 19.24 0.039 (5.67 ± 1.07) 212.13 ± 44.82 0.111 (5.49 ± 1.16) 40.4 ± 7.06 0.535 (1.05 ± 0.18) 130.25 ± 37.65 0.105 (3.37 ± 0.98) 200.33 ± 86.16 0.354 (2.26 ± 0.97)

The correlation between serum adropin levels and other clinical characteristics in EPACS patients was measured as the Spearman correlation coefficient, or a chi-squared value when appropriate. Probability values were considered significant at p < 0.05.

Results Immunohistochemical studies revealed no adropin immunoreactivity in the negative controls (secondary antibody omitted or phosphate-buffered saline used) for the parotid (Fig. 1A1), sublingual (Fig. 1B1) and submandibular (Fig. 1C1) glands, but when the adropin antibody was used, there was reactivity (red colour) in all three salivary glands (Fig. 1A2, intercalated duct immunoreactive to adropin antibody; Fig. 1B2, mucous acinus immunoreactive to adropin antibody; Fig.1C2, striated duct, interlobular duct immunoreactive to adropin antibody) as distinguished histologically. Table 1 shows the differences in glucose and lipid profiles (TC, HDL-C, LDL-C and TG) in subjects with and without EPACS. Glucose levels in EPACS patients were higher than in the controls but still within the normal range. Lipid profiles were not affected by EPACS (Table 1). Validation of the EIA kit (cat no: EK-032-35) showed it to be as sensitive to saliva adropin as to serum adropin. The lowest detectable adropin concentration in saliva was 0.01 ng/ ml, with intra-assay (within day) and inter-assay (between days) variations of less than 10 and 12%, respectively. Assay recovery

Concentration (ng/ml)

12 10

Adropin Troponin I

8 6 c

c c

c Control

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c 2

6 Hours

c 72

Fig. 2. D ifferences in serum adropin and troponin I concentrations between EPACS and control subjects. ap < 0.05 and b,cp < 0.01 compared with control.

was between 98 and 106%. The response to salivary adropin was linear over the range 0.50–16.5 ng/ml. Therefore, the sensitivity and specificity of the EIA kit were the same for saliva as for serum adropin concentrations. The serum adropin concentration was slightly (insignificantly) lower in samples taken within 30 minutes (zero time) of patient admission, than the corresponding control value and stable coronary diseases (0.67–0.8 ng/ml; n = 9). It rose within two hours post infarct and peaked at six hours; the adropin concentrations at four and six hours post infarct were significantly higher than the controls. At 12 and 24 hours post infarct, the levels were also higher than the corresponding control values but not significantly so (Fig. 2). The serum troponin I concentration rose within 30 minutes (zero time: blood taken immediately after the patient was admitted to hospital), peaked at 12 hours post infarct, and remained significantly higher than the controls for up to 72 hours (Fig. 2). The time course of changes in adropin level paralleled that of troponin I. These findings demonstrate that serum adropin might help, in conjunction with troponin levels, in the early diagnosis of EPACS. The saliva adropin concentration was also slightly lower than the controls (not statistically significant) in samples taken within 30 minutes (zero time) of hospital admission. Like the serum adropin concentration, saliva adropin then rose within two hours post infarct and peaked at six hours, being significantly higher than the controls at four and six hours, and remaining elevated at 12 and 24 hours post infarct (Fig. 3). These results show that serum and saliva adropin concentrations increased and decreased in parallel in EPACS patients. Serum adropin levels were positively correlated with saliva adropin levels (r = 0.763, p ≤ 0.01) but with neither glucose level nor lipid profiles. There was also a correlation between serum adropin and cTnT levels (r = 0.68, p = 0.000). Therefore, measuring saliva adropin levels may be an alternative to measuring serum adropin concentrations for diagnosing EPACS or metabolic diseases, for example, diabetes, in which adropin regulates energy homeostasis and insulin resistance.27 Serum CK and CK-MB levels were also measured. The initial statistically significant rise in CK-MB above control concentrations occurred within 30–40 minutes (zero time) after the onset of chest pain, peaked at six hours, and returned to baseline at 72 hours. CK levels also started to increase within

Saliva adropin levels (ng/ml)

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12 10 8

6 Hours

6 4 2 0

Control

Fig. 3. Differences in saliva adropin concentrations between EPACS and control subjects. ap < 0.05 and bp < 0.01 compared with control.

800 700 600 500 400 300 200 100 0

CK CK-MB

c b

b Control

6 Hours

c 12

Fig. 4. D ifferences in serum CK and CK-MB concentrations between EPACS and control subjects. ap < 0.05 and b,c p < 0.01 compared with control.

30–40 minutes after EPACS (zero time sample: blood taken immediately on admission) and peaked at six hours, thereafter decreasing up to 72 hours. The concentration of CK was significantly higher than the controls from two hours up to 48 hours in the EPACS patients (Fig. 4). At four hours after EPACS, the serum adropin concentration measurement had a sensitivity of 91.7% and specificity of 50% at a confidence interval of 95% when the cut-off value was set at 4.12 ng/ml (Fig. 5). At six hours after EPACS, with the cut-off value set to 5.37 ng/ml adropin for serum, the sensitivity was 91.7% and the specificity 64% (Fig. 6). At four hours after EPACS, saliva adropin exhibited 91.7% sensitivity and 57% specificity at a confidence interval of 95%, when the cut-off value was 4.12 ng/ml. At six hours after EPACS, when the cut-off value was 4.12 ng/ml, the same sensitivity and specificity were found as at four hours for saliva adropin level. Serum troponin I exhibited 100% sensitivity and 100% specificity at a confidence interval of 95% when the cut-off value was 0.141 ng/ml at four hours after EPACS, and when the cut-off value was 0.226 ng/ml at six hours after EPACS (Fig. 6).

Discussion Cardiovascular diseases are the leading cause of death in both developed and developing countries. The World Health

Sensitivity

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Organisation predicts that by 2020, 37% of all deaths worldwide will be from CVDs.22 Health innovations are widely used, but ACS, a lethal manifestation of CVD, remains the leading cause of death worldwide.28 Currently, cardiac biomarkers (especially cTI and cTnT) are the most important diagnostic laboratory tests for ACS.8 Each year worldwide a million patients with suspected ACS are admitted to emergency, cardiology and cardiovascular surgery departments but only around 10% of cases are then confirmed.9 Therefore, an accurate, precise and rapid diagnostic test for EPACS is needed to save lives. In this context, recent animal studies and a human study have suggested that adropin could be useful for diagnosing EPACS in addition to other cardiac biomarkers, but these studies were controversial.19,20 Therefore the ability of adropin to identify cardiac injury earlier than is possible with current biomarkers should be re-investigated and the controversy resolved. In the present study, therefore, we measured serum cardiac marker enzymes and timed serum and saliva adropin concentrations in EPACS patients and in age- and gender-matched controls. Troponin I, CK, CK-MB and adropin concentrations gradually increased in the EPACS group from up to six hours to levels higher than in the controls (p < 0.05), and troponin I and CK-MB continued to increase for up to 12 hours after EPACS. After 12 hours, CK and adropin levels started to decrease for up to 72 hours. These findings confirmed the value of the classical parameters of troponin I, CK and CK-MB for diagnosing EPACS in clinical practice. Saliva adropin concentrations changed in parallel with serum adropin concentrations in ACS. The saliva adropin concentration was generally higher than the serum adropin, possibly because the salivary glands produce adropin (see below). Since adropin is expressed in many tissues, including the heart, all contributing to the serum pool, we had assumed that serum adropin concentration increased after EPACS, as do troponin I or CK-MB, which are released from the myocardium, mainly during EPACS and necrosis following heart injury.9 Our clinical results agree with our previous animal experiments, showing that adropin concentration gradually rose above control levels in EPACS patients. This is in contrast to Yu et al., who found that serum adropin levels were significantly lower in EPACS patients than in SAP patients or controls.20 Yu et

1,0

0,8

0,6 Serum adropin

0,4

Saliva adropin Serum troponin I Reference

0,2 0

0,2

0,4 0,6 1 – Specificity

0,8

1,0

Fig. 5. S ensitivity and specificity of serum and saliva adropin and serum troponin I for detecting EPACS at four hours. The area under the ROC curve, adropin sensitivity of 91.7% and specificity of 67%, were identified when the cut-off was set at 5.37 ng/ml adropin.

Sensitivity

Concentration (IU/l)

0,6 Serum adropin

0,4

Saliva adropin Serum troponin I Reference

0,2 0

0,2

0,4 0,6 1 – Specificity

0,8

1,0

Fig. 6. Sensitivity and specificity of serum and saliva adropin and serum troponin I for detecting EPACS at six hours. The area under the ROC curve, adropin sensitivity of 91.7% and specificity of 50%, were identified when the cut-off was set at 4.43 ng/ml adropin.

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al. argued that their result indicates deficient adropin expression in EPACS patients, and adropin deficiency could be involved in the development and progression of EPACS. The reason for the difference in results is unknown. Yu et al. measured single-time serum adropin levels in EPACS patients, while in our study we measured the time courses of serum and salivary adropin levels in patients and controls.20 In our zero-time samples, serum and saliva adropin values were slightly (insignificantly) lower in EPACS patients than in controls, and this could have corresponded to the single-time values measured by Yu et al.20 The adropin levels then started to increase and peaked at six hours after EPACS, potentially explaining the apparent conflict. Also, the mean adropin level is reported to be significantly lower in certain diseases, including in patients with late saphenous vein graft occlusion.18 Another possibiliy is that the adropin level was reduced in the baseline blood sample taken within 30 to 40 minutes of admission to hospital. Although the glucose level was within normal physiological limits in the EPACS patients, it was higher than in the controls. This could have been due to the effect of increased epinephrine secretion after EPACS, causing glycogenolysis in the liver and releasing glucose into the blood.29,30 There was an inverse relationship between adropin and glucose levels.10,12,16,17 Yu et al. reported the same glucose levels. Different drugs used to treat EPACS could also have affected the adropin levels differently.20 Here we also assumed that the increased expression of adropin in saliva and serum could indicate acute cardiac injury caused by ACS, and could be central to the development of key pathologies associated with EPACS in humans, but further studies are needed to resolve the conflict between findings. Salivary glands are now known to secrete a range of peptides/ proteins involved in regulating endocrine metabolism.21 Therefore, in this study we also investigated whether the salivary glands produce adropin. The immunochemical findings indicated that adropin is one of the most abundant proteins secreted by human salivary glands, as previously described for peptides such as irisin,21 ghrelin23,24,31 and hepcidin.32 Adropin is synthesised in the intercalated duct of the parotid, the mucous acinus of the sublingual, and the striated and interlobular ducts of the submandibular glands, and is co-localised with irisin,21 ghrelin23,24,31 and hepcidin32 in those glands. Its expression has also been demonstrated in the liver, brain, cerebellum, kidneys, heart, pancreas and vascular tissues.10 The ELISA results in this study revealed that salivary and serum adropin levels were substantially higher in EPACS patients than in the controls and stable CAD patients (0.67â&#x20AC;&#x201C;0.8 ng/ml). The adropin levels in saliva were already elevated and increasd further at four and six hours after EPACS. The origin of the high salivary adropin levels is not known but it probably comes from the plasma after saturation, or a larger amount of cardiac adropin is secreted by the salivary glands. Because there is evidence that some of these striated duct proteins are secreted basally, i.e. into the circulation,33-35 we concluded that EPACS induces the synthesis of salivary adropin, and the quantity of adropin in the saliva could be useful for early management of EPACS, in conjunction with serum adropin measurement. This research also showed that blood levels of CK-MB and CK increased within 30 to 40 minutes (zero time) after EPACS, peaked at six hours, and started to decrease after 12 hours but remained higher than control levels, even at 48 hours.

In this study, receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of serum and saliva adropin levels in EPACS patients. At four hours after ACS, serum adropin exhibited 91.7% sensitivity and 50% specificity at a confidence interval of 95% when the cut-off value was 4.43 ng/ml, while serum troponin I exhibited 100% sensitivity and 100% specificity at a confidence interval of 95% when the cut-off value was 0.141 ng/ml. At four hours after ACS, the saliva adropin concentration had a sensitivity of 91.7% and a specificity of 57% at a confidence interval of 95% when the cut-off value was 4.12 ng/ml. At six hours after ACS, the serum adropin exhibited 91.7% sensitivity and 64% specificity at a confidence interval of 95% when the cut-off value was 5.37 ng/ml, while serum troponin I exhibited 100% sensitivity and 100% specificity at a confidence interval of 95% when the cut-off value was 0.226 ng/ml. At six hours after ACS, the saliva adropin concentration had a sensitivity of 91.7% and a specificity of 57% at a confidence interval of 95% when the cut-off value was 4.24 ng/ml. ROC curve analysis indicated that serum troponin I and adropin concentrations diagnosed EPACS with over 90% sensitivity in emergency, cardiology and cardovascular surgery patients. Serum and saliva adropin measurements were not as specific as serum troponin I for diagnosing EPACS. Serum troponin I was still superior to serum or saliva adropin, even though there is the advantage of taking a salivary sample, which can be collected without a venous blood sample. Nevertheless, serum or saliva adropin could still be useful in diagnosing EPACS in the future. First-generation ELISA adropin kits, even from the same company, gave variable results, and there was even more variability among kits from different companies. More reproducible and automated adropin measurements could overcome the current shortfall in specificity, since diagnosis of EPACS by adropin is highly sensitive. Our study had other limitations, especially the small number of patients. Also, this was a single-centre study. The results should be confirmed in a prospective, multicentre study involving more patients. Moreover, adropin is expressed in many tissues, and we did not examine their possible contributions as potential confounders to our measured saliva and serum adropin concentrations. Our previous animal studies revealed that liver and kidney tissue adropin concentrations were considerably changed by isoproterenol-induced EPACS.19 The composition and production of saliva is also variable (like urine),36 and this theoretically makes the quantitative determination of any substance unreliable. However, there was a good correlation between the salivary and serum adropin concentrations in this study. This may have been due to the added protease inhibitor (aprotinin) before collection of the biological samples.25 Protease inhibitor protects the peptide of interest (adropin) from degradation.25 We also believe that a less robust correlation in a larger study could be attributed to this fact.

Conclusions Despite these limitations, this study provides novel evidence of a connection between increased saliva/serum adropin levels and EPACS. The saliva adropin concentration was higher than the serum adropin level in subjects with and without EPACS.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

Adropin is synthesised in the intercalated duct, mucous acinus and interlobular cells of human salivary glands, and this could contribute to the high concentrations in saliva. Saliva adropin levels could also be more useful than serum levels for diagnosing some metabolic conditions. Saliva offers advantages over blood, including that collection is non-invasive and therefore stress free for patients, especially children,21 making it a more suitable choice than serum for measuring adropin in diagnosing EPACS. However there are some limitations and difficulties in using ELISA on saliva, since inhibitors and/or binding proteins could be present and could negatively affect the quantitative determination of peptides/ proteins. Overall, four and six hours after EPACS, ROC curve analysis demonstrated that the saliva adropin concentration reflected EPACS with 91.7% (at four hours) and 91.7% (at six hours) sensitivity and 57% (at four hours) and 57% (at six hours) specificity. Therefore, four and six hours after EPACS, the saliva adropin concentration showed the same sensitvity and specifity for diagnosing EPACS as the serum level. All these data promise new possibilities for the diagnosis of EPACS, besides measuring other cardiac enzymes and proteins (troponins).

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Cell Metab 2008; 8(6): 468–481. 12. Aydin S. Three new players in energy regulation: preptin, adropin and irisin. Peptides 2014; 56: 94–110. 13. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, et al. Adropin is a novel regulator of endothelial function. Circulation 2010; 122(Suppl 11): S185–192. 14. Kuloglu T, Aydin S. Immunohistochemical expressions of adropin and inducible nitric oxide synthase in renal tissues of rats with streptozotocin-induced experimental diabetes. Biotech Histochem 2014; 89(2): 104–110. 15. Celik A, Balin M, Kobat MA, Erdem K, Baydas A, Bulut M, et al. Deficiency of a new protein associated with cardiac syndrome X; called adropin. Cardiovasc Ther 2013; 31(3): 174–178. 16. Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C, et al. Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and nondiabetic patients. Clin Chem Lab 2014; 52(5): 751–758. 17. Aydin S, Kuloglu T, Aydin S. Copeptin, adropin and irisin concentrations in breast milk and plasma of healthy women and those with gestational diabetes mellitus. Peptides 2013; 47: 66–70. 18. Demircelik B, Cakmak M, Nazli Y, Gurel OM, Akkaya N, Cetin M, et al. Adropin: a new marker for predicting late saphenous vein graft disease after coronary artery bypass grafting. Clin Invest Med 2014; 37(5): E338–344.

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2017

33. Lantini MS, Proto E, Puxeddu P, Riva A, Testa Riva F. Fine structure

23–25 March 2017 Century City Conference Centre Cape Town, South Africa

LIVE Centre Announcement Following the newly developed “Live How Should I Treat” format, AfricaPCR2017 will for the first time, see not only 1, but 6 Live Cases incorporated into the main programme.

Groote Schuur Hospital, Cape Town We are pleased to announce that the Live Centre for AfricaPCR2017 will be Groote Schuur, one of South Africa’s premier tertiary academic hospitals, which aligns with the PCR principles, “By and For” the African Interventional Community. The inclusion of the hospital as a Centre of Excellence for Live Cases, fittingly falls in the year of the 50th anniversary of the first South African heart transplant, allowing us to honour this cardiology milestone. Once again the course promises to facilitate transfer of skills and knowledge in a forum that takes into consideration our diverse cultures and pathologies and the unique challenges of our African region.

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Europa Organisation Africa info@eoafrica.co.za | Tel +27 (0)11 325 0020/2/3 Email: claudette@eoafrica.co.za | www.eoafrica.co.za

Your Daily Practice Companion

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

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The effects of the metabolic syndrome on coronary artery bypass grafting surgery Sevil Özkan, Fatih Özdemir, Oğuz Uğur, Refik Demirtunç, Ahmet Yavuz Balcı, Mehmet Kızılay, Ünsal Vural, Mehmet Kaplan, İbrahim Yekeler

Abstract Background: The metabolic syndrome (MS) is a clustering of factors that are associated with increased cardiovascular risk. A low-grade inflammatory process acts as the underlying pathophysiology, which suggests that the MS may have a detrimental effect on coronary interventions, including coronary artery bypass grafting (CABG) surgery performed with cardiopulmonary bypass (CPB). We aimed to evaluate the effect of the MS on morbidity and mortality rates in the early postoperative period in patients undergoing CABG. Methods: We prospectively included 152 patients (109 males and 43 females; mean age 60.1 ± 8.6 years) who underwent elective CABG on CPB between January and September 2011. Early postoperative morbidity and mortality rates were compared between subjects with and without the MS. Diagnosis of the MS was based on the American National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Results: Of the study group, 64 patients (42%) had the MS. The two groups were similar in age and gender. In the postoperative period, rates of atrial fibrillation, wound infection, pulmonary complications, and lengths of intubation, hospitalisation and intensive care unit stay were significantly higher in MS patients (p < 0.01). The MS was significantly associated with wound infection (OR 6.64, 95% CI: 1.72–25.75), pulmonary complications (OR 6.44, 95% CI: 1.58–26.33), arrhythmia (OR 5.47, 95% CI: 1.50–19.97) and prolonged intubation (OR 1.17, 95% CI: 1.05–1.32). The mortality rate was 3.1% in the MS group and 1.1% in the non-MS group, with no significant difference (p > 0.05). Conclusion: The MS was associated with a higher rate of early postoperative morbidity following CABG, without having a significant effect on the mortality rate. Keywords: coronary artery bypass grafting surgery, metabolic syndrome, postoperative morbidity and mortality Department of Internal Medicine, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey Sevil Özkan, MD, sevilfurkan@hotmail.com Refik Demirtunç, MD

Department of Cardiovascular Surgery, Dr Siyami Ersek Training and Research Hospital on Thoracic and Cardiovascular Surgery, Istanbul, Turkey Fatih Özdemir, MD Oğuz Uğur, MD Ahmet Yavuz Balcı, MD Mehmet Kızılay, MD Ünsal Vural, MD Mehmet Kaplan, MD İbrahim Yekeler, MD

Submitted 30/9/14, accepted 5/5/16 Published online 13/7/16 Cardiovasc J Afr 2017; 28: 48–53

www.cvja.co.za

DOI: 10.5830/CVJA-2016-056

The metabolic syndrome (MS) is a complex metabolic disturbance characterised by insulin resistance, central obesity, hypertriglyceridaemia, reduced high-density lipoprotein cholesterol, hypertension and glucose intolerance.1 The unifying mechanism responsible for the cluster of cardiovascular risk factors in the MS is insulin resistance, which is also a hallmark of the MS.2 It has been proposed that insulin resistance plays a major unifying role in increased ischaemic events in MS patients, but this mechanism and ensuing processes need clarification.3-5 As described by the the American National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), at least three of five criteria (Table 1) have to be met for a MS diagnosis.6 Prevalence of the MS has been reported as approximately 35–40% in industrialised countries.7 It is an inflammatory state characterised by increased levels of adipocytokines such as tumour necrosis factor-α, interleukin-6 and C-reactive protein, as well as free fatty acids, which cause vasoconstriction and endothelial dysfunction. The MS is also described as a low-grade inflammatory state manifested by increased circulating levels of inflammatory cytokines. Reduced plasma adiponectin and elevated leptin and resistin levels have been observed in MS patients. However, unlike leptin and resistin, which stimulate the immune system, adiponectin inhibits the inflammatory process in the vascular wall, mainly by inhibiting the nuclear factor kappa B pathway.2 The pro-inflammatory state associated with the MS may play a contributory role in exacerbation of the systemic inflammatory response induced by cardiopulmonary bypass (CPB) and surgical trauma, and therefore may predispose patients to peri-operative complications.8 The MS is a cluster of metabolic perturbations largely resulting from abdominal obesity, which is associated with increased risk for type 2 diabetes and cardiovascular disease.9 Although it has been shown to be a predictor of adverse events Table 1. Metabolic syndrome diagnostic criteria (NCEP ATP-III) Metabolic syndrome diagnostic criteria 1. Abdominal obesity (waist circumference) • Male > 102 cm • Female > 88 cm 2. Triglycerides > 150 mg/dl (1.7 mmol/l) 3. High-density lipoprotein cholesterol • Male < 40 mg/dl (1.04 mmol/l) • Female < 50 mg/dl (1.3 mmol/l) 4. Blood pressure > 130/85 mmHg 5. Fasting blood glucose > 110 mg/dl (6.11 mmol/l) American National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) diagnostic criteria for the metabolic syndrome.

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after cardiovascular interventions, and its association with early and late mortality and morbidity following coronary artery bypass graft (CABG) surgery has recently been reported,10 several studies failed to find such an association.11-13 We hypothesised that the MS could adversely affect the outcome in patients undergoing CABG surgery and designed a prospective study to determine the impact of the MS on postoperative morbidity and mortality rates after CABG.

Methods We prospectively enrolled 152 consecutive patients who underwent elective CABG at Siyami Ersek Thoracic and Cardiovascular Surgery Centre, Istanbul, Turkey, between January and September 2011. Diagnosis of the MS was made according to the NCEP ATP III criteria. Patients were divided into two groups (with and without the MS) depending on the MS diagnosis. Pre-operative and operative data of all patients were prospectively collected and transfered to a computerised database. Demographic features, and clinical, laboratory and intensive care unit (ICU) data of the patients were obtained by trained personnel supervised by a nurse author, as well as data on risk factors, medications and functional status. Postoperative complications were recorded prospectively by an author, and all major adverse events were simultaneously validated by an experienced cardiac surgeon according to standardised definitions. Patients undergoing emergency surgery, re-operative surgery, CABG on a beating heart, additional valve repair or replacement, having an ejection fraction of less than 45%, requiring pre-operative pacemaker implantation, and those with liver failure were excluded from the study. The study protocol was approved by the institutional review board of the hospital. Demographic and clinical features included age, gender, mean blood pressure, body mass index (BMI), waist circumference, smoking status and co-morbidities, including type 2 diabetes mellitus, systemic hypertension and obesity. Weight was measured in kilograms using a calibrated digital scale, height was measured in centimetres using a calibrated stadiometer (Seca GmbH & Co, Germany) and body mass index (BMI) was calculated. Waist circumference was measured by a trained nurse, with a cloth tape around the waist placed in a mid-axillary line at the midpoint between the highest point of the iliac crest and the lowest part of the costal margin. Diabetes mellitus was defined as the use of diabetes medications or fasting plasma glucose concentration of ≥ 110 mg/dl (6.11 mmol/l). The patients’ characteristics included the following: age, gender, height, BMI, waist circumference, duration of diabetes, alcohol consumption, use of insulin or anti-diabetic drugs, low-density lipoprotein (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglyceride and fasting blood glucose levels, smoking status, levels of postprandial blood glucose (PPBG), blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), HbA1c, haematocrit, haemoglobin, thyroid stimulating hormone (TSH) and free T4, number of grafts used during CABG, left ventricular ejection fraction, and percentage of carotid artery stenosis on Doppler ultrasonography. Blood pressure (BP) measurements were made pre-operatively using a mercury sphygmomanometer with the patient in a sitting position following at least a 10-minute rest. The average

of three measurements taken at two-minute intervals was defined as clinical BP. Hypertension was defined as BP being ≥ 140/90 mmHg from at least two measurements or the use of antihypertensive therapy. A total cholesterol level of > 200 mg/ dl (5.18 mmol/l) or a history of elevated serum total cholesterol during the past six months resulting in lipid-lowering drug use was defined as hyperlipidaemia. Current smokers and former smokers who had stopped smoking within the past three years were considered smokers. Peri-operative variables included the number of CABG surgeries, number of grafts, cardiopulmonary bypass time (min) and aortic cross-clamp time. Postoperative variables were all-cause mortality, death within one month after the operation, renal failure, postoperative creatinine level > 2.5 mg/dl (221 mmol/l), need for haemodialysis, the use of prolonged pulmonary ventilator > 24 hours, acute myocardial infarction, ST-segment changes, prolonged ventilation (more than 72 hours), re-intubation, wound infection, stroke and regional neurological dysfunctions that resolved within 24 hours with no sequela. Additional data included the length of ICU and hospital stay. Under local anaesthesia, radial and pulmonary arterial catheters were introduced. In all patients, anaesthesia induction was obtained before tracheal intubation using midazolam 0.05– 0.1 mg/kg, fentanyl 4–8 µg/kg or sufentanil 0.6–0.8 µg/kg, atracurium 0.5 mg/kg or pancuronium 0.1 mg/kg and thiopental sodium 1–2 mg/kg. All operations were performed under CPB at mild to moderate hypothermia (28–32°C). Myocardial protection was ensured by intermittent antegrade or combined antegrade and retrograde saline or blood cardioplegia. Operative outcomes included the CPB time and aortic cross-clamp time.

Statistical analysis Statistical analysis was done using the NCSS 2007 software (Number Cruncher Statistical System, LCC Statistical Software, Utah, USA). Data are expressed with descriptive statistics using mean ± standard deviation, median, frequency and percentage. The Kolmogorov–Smirnov test was used to assess the compliance of numerical variables with normal distribution. The two groups were compared with regard to pre-operative demographic data, operative data and early postoperative morbidity and mortality rates. The Student’s t-test was used for intergroup comparisons of normally distributed variables, including age, BMI, female and male waist circumference, ejection fraction, number of grafts, CPB, aortic cross-clamp time, PPBG, BUN, creatinine, total cholesterol, LDL-C, HDL-C, haematocrit, haemoglobin, free T4 and HbA1c values. Variables that did not show a normal distrubution (EuroSCORE, fasting blood glucose, AST, ALT, triglycerides, TSH, drainage, ICU stay, hospital stay, erethrocyte sedimentation rate and fresh frozen plasma) were compared using the Mann– Whitney U-test. For the comparison of categorical variables, Pearson’s chi-squared test was used when expected and observed counts were sufficient, Yates’ correction for continuity test was used when observed counts were insufficient (< 20), and Fisher’s exact test was used when expected counts were insufficient (< 5). A p-value < 0.05 was considered statistically significant. A post hoc power analysis showed the adequacy of the sample size for further analyses.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

Results There were 109 males and 43 females with a mean age of 60.1 ± 8.6 years (range 39–85 years). According to the NCEP ATP III criteria,3 64 patients (42%) had the MS, while the remaining 88 (58%) were free of the MS. The two groups were similar with regard to age and gender. All the MS parameters (BMI, waist circumference, rates of hyperlipidaemia, hypertension and diabetes) were significantly higher in the MS group. Pre-operative demographic features and operative data for each study group are shown in Table 2. When compared with patients without the MS, those with the MS had higher levels of fasting glycaemia, postprandial glycaemia, plasma total cholesterol, triglycerides and LDL-C, and a lower HDL-C concentration. Laboratory findings of the two patient groups are shown in Table 3. Overall, 102 patients (67.2%) had diabetes. Medications of the diabetic patients included oral anti-diabetic agents (58.8%), insulin (18.6%) or both (10.8%), while 11.8% had been receiving no diabetes treatment. Postoperative clinical outcomes are shown in Table 4. Postoperative mortality rates were similar in the two groups, being 3.1% (n = 2) and 1.1% (n = 1) in patients with and without the MS, respectively. However, manifestations of postoperative morbidity differed significantly, with higher rates of atrial fibrillation (AF), wound infection, pulmonary complications, prolonged intubation, and longer durations of ICU stay and hospitalisation in patients with the MS (p < 0.01). The other periand postoperative findings (postoperative revisions, incidences of renal impairment, stroke, drainage, need for erythrocytes, fresh frozen plasma replacements, cardiopulmonary bypass time and aortic cross-clamp time) were similar between the two groups. A statistically significant relationship was found between the MS and wound infection (OR 6.64, 95% CI: 1.72–25.75), pulmonary complications (OR 6.44, 95% CI: 1.58–26.33), AF (OR Table 2. Comparison of pre-operative demographic and peri-operative data of patients with and without the metabolic syndrome MS (+) (n = 64)

MS (–) (n = 88)

59.98 ± 6.89

60.55 ± 9.74

Male

44 (68.8)

65 (73.9)

Female

20 (31.3)

23 (26.1)

31.09 ± 5.56

27.58 ± 3.34

Total

106.92 ± 10.30

93.69 ± 8.21

Female

108.86 ± 9.18

95.11 ± 7.77

Male

102.65 ± 11.54

89.65 ± 8.25

Smoking, n (%)

32 (50.0)

40 (45.5)

Alcohol consumption, n (%)

11 (17.2)

15 (17.0)

Hyperlipidaemia, n (%)

41 (64.1)

31 (35.2)

Hypertension, n (%)

57 (89.1)

11 (12.5)

Carotid Doppler USG (50 and 70%), n (%)

16 (25.0)

11 (12.5)

51.25 ± 9.21

52.52 ± 10.67

0–9/4

0–11/4

3.05 ± 0.93

3.07 ± 0.84

CPB (min) (mean ± SD)

74.09 ± 16.70

71.90 ± 19.82

Aortic cross-clamp time (min) (mean ± SD)

51.08 ± 14.76

47.28 ± 17.84

Age (mean ± SD)

Table 3. Comparison of laboratory findings of the patients with and without the metabolic syndrome MS (+) (n = 64)

MS (–) (n = 88)

FBG (mg/dl) (min–max/median)

79–300/151.00

77–300/110.00

PPBG (mg/dl) (mean ± SD)

191.84 ± 51.09

157.06 ± 53.04

BUN (mg/dl) (mean ± SD)

18.25 ± 5.93

17.53 ± 5.66

Creatinine (mg/dl)(mean ± SD)

0.95 ± 0.26

0.96 ± 0.25

AST (U/l) (min–max/median)

12–62/25.00

11–51/24.00

ALT (U/l) (min–max/median)

10–97/28.00

8–61/22.00

Total cholesterol (mg/dl) (mean ± SD) (mmol/l)

226.95 ± 34.18 (2.56 ± 0.89)

185.69 ± 36.08 (4.81 ± 0.93)

LDL-C (mg/dl) (mean ± SD) (mmol/l)

134.92 ± 21.80 (3.49 ± 0.56)

121.89 ± 25.04 (3.16 ± 0.65)

HDL-C (mg/dl) (mean ± SD) (mmol/l)

36.22 ± 9.21 (0.94 ± 0.24)

38.77 ± 7.95 (1.00 ± 0.21)

71–465/160.00 (0.8–5.25/1.81)

57–482/138.00 (0.64–5.45/1.56)

Haematocrit (%) (mean ± SD)

39.90 ± 4.35

41.13 ± 4.57

Haemoglobin (g/dl) (mean ± SD)

13.32 ± 1.62

14.01 ± 1.60

Triglycerides (mg/dl) (min–max/ median) (mmol/l)

EF% (mean ± SD) EuroSCORE (min–max/median) Number of grafts (mean ± SD)

0.049*

0.098 0.010* 0.621

7.86 ± 1.59

6.61 ± 1.31

0.071 0.001**

Student’s t-test; bMann–Whitney U-test *p < 0.05 **p < 0.01. FBG: fasting blood glucose, PPBG: postprandial blood glucose, BUN: blood urea nitrogen, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, TSH: thyroid-stimulating hormone, HbA1c: haemoglobin A1c.

5.47, 95% CI: 1.50–19.97) and prolonged intubation (OR 1.17, 95% CI: 1.05–1.32). In post hoc power analysis, the observed power for wound infection, pulmonary complications, AF and prolonged intubation time were 0.944, 0.804, 0.843 and 0.715, respectively.

Discussion As MS patients have a high risk of developing coronary artery disease, they should be evaluated in line with coronary Table 4. Comparison of postoperative results of the patients with and without the metabolic syndrome

Length of ICU stay (h) (min–max/median)

MS (+) (n = 64)

MS (–) (n = 88)

6–20/11.00

4–28/9.00

400–2500/650.00 200–1500/ 650.00

p-value 0.001**

0.135

0.003**

17–168/24.00

6–96/22.00

Length of hospital stay (days) (min–max/median)

4–35/7.00

1–35/7.00

RBC replacement (units/ patient) (min–max/median)

0–5/2.00

FFP replacement (units/ patient) (min–max/median)

0–6/2.00

0–12/2.00

0.001** 0.121 0.153

Mortality, n (%)

2 (3.1)

1 (1.1)

0.076

Myocardial infarction, n (%)

4 (6.3)

1 (1.1)

0.433

Surgical revision, n (%)

5 (7.8)

5 (5.7)

0.391

Renal failure, n (%)

4 (6.3)

1 (1.1)

0.883

Wound infection, n (%)

14 (21.9)

3 (3.4)

0.174

Pulmonary complications, n (%)

11 (17.2)

3 (3.4)

0.225

Stroke, n (%)

4 (6.3)

1 (1.1)

13 (20.3)

4 (4.5)

Student’s t-test; bMann–Whitney U-Test; cYates continuity correction test; d Pearson’s chi-squared test *p < 0.05 **p < 0.01. BMI: body mass index, EF: ejection fraction, CPB: cardiopulmonary bypass (presence of the MS was significantly associated with higher prevalence). a

0.069

HbA1c (%)

0.001**

0.241

0.001**

Drainage (ml) (min–max/ median)

1.000

0.490

1.20 ± 0.19

Prolonged intubation time (h) (min–max/median)

0.579

0.775

1.26 ± 0.22

0,611

0.001**

0.447

Free T4 (ng/dl) (mean ± SD)

0.678

0.001**

Gender, n (%)

BMI (kg/m²) (mean ± SD)

p-value 0.001**

TSH (µIU/ml) (min–max/median) 0.01–11.34/1.45 0.12–19.00/1.41

p-value

Waist circumference (mean ± SD)

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Atrial fibrillation, n (%)

0.573 0.162 0.743 0.162 0.001** 0.009** 0.162 0.005**

Mann–Whitney U-Test; cYates continuity correction test; eFisher’s exact test; *p < 0.05; **p < 0.01. RBC: red blood cells, FFP: fresh frozen plasma. b

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artery disease guidelines.10-14,15 The NCEP ATP III stressed the cardiovascular risk factors associated with the MS.6 In Turkey, prevalence of the MS is as high as three out of every eight people in the adult population.16 Among coronary artery disease patients, its prevalence is 42.7% in males and 64.0% in females, with an overall prevalence of 53.0%.16 In our study, 42% of the patients had the MS, which is similar to other studies in MS patients undergoing CABG (42, 48, 47%).11,12,17 Although not statistically significant, MS patients also had a higher smoking rate, which reflected their habits and lifestyle. Patients with and without the MS did not differ in mortality rates; mortality occurred in two patients in the MS group (3.1%) and in one patient in the non-MS group (1.1%). Other studies reported similar mortality rates in the two patient groups.11,12,17 Swart et al.11 compared 370 patients with the MS (as defined by the International Diabetes Federation and NCEP ATP III criteria) and 503 patients without the MS in terms of mortality and morbidity rates following CABG. The two groups had a similar age distribution and had mortality rates of 1.9 and 1.6%, respectively (p = 0.7348). The average EuroSCORE differed significantly between the two groups, being 3.26 (median 3) in the MS group and 3.61 (median 3) in the non-MS group (p = 0.0494). The rates of re-exploration, stroke, renal insufficiency, prolonged mechanical ventilation, and the need for rewiring of sternal dehiscence were similar in the two groups. The amount of mediastinal drainage was also similar (624 vs 670 ml). The need for homologous blood transfusion was less (p = 0.0012), but hospital stay was longer (p < 0.00001) in the MS group. The authors concluded that MS did not have any detrimental clinical effects on either pre-operative risk factors or outcomes after CABG. Özyazıcıoğlu et al.12 examined the effects of the MS on postoperative mortality and morbidity rates in patients undergoing CABG. Compared with patients without the MS, those with the MS (NCEP ATP III criteria) had a higher incidence of wound infection (p < 0.05), but similar rates of atrial fibrillation, revision surgery due to haemorrhage, ventricular tachycardia, ventricular fibrillation, prolonged intubation and mortality rates. These discrepancies may have resulted from differences in the definition of postoperative morbidity and postoperative serious events, and in the duration of follow-up periods. Criteria used to define the MS may also lead to discrepant results, namely, cut-off points of criteria for the MS in various populations or even parameters of the MS (waist circumference instead of BMI) may vary. These differences may have a confounding effect on assessing the association between pre-operative MS and postoperative complications.11,12 Inhibition of adipocytes is increased in obese people, along with many proteins with immunomodulatory activity. Thromboembolic events are more commonly seen in MS patients undergoing CABG because a prothrombotic state frequently occurs postoperatively.2 Yılmaz et al.18 suggested that the MS might serve as a predictor of postoperative occlusion of saphenous vein grafts after CABG. In our study, the incidences of peri-operative myocardial infarction were similar between patients with and without the MS. It is likely that peri-operative myocardial infarction is not determined by early graft occlusion, but rather by factors related to myocardial protection strategies or unknown factors, which could explain the absence of a significant difference between patients with and without the MS.

In the present study, lengths of hospitalisation and ICU stay were significantly longer in the MS group. Brackbill et al.13 showed that female patients with the MS undergoing CABG surgery were at increased risk for longer postoperative stay as well as for in-hospital death. Bardakcı et al.19 reported that, compared with the patients without the MS, those with the MS had a significantly higher female-to-male ratio, and significantly higher rates of family history of ischaemic heart disease, and coronary artery occlusions involving the anterior descending coronary, circumflex and right coronary arteries. This difference could be noteworthy not only for increased morbidity rates, but also for treatment costs. Similar to previous studies,11,12,17,20 no significant difference was found in the occurrences of stroke and renal impairment after CABG between the MS and non-MS groups (p > 0.05). However, many parameters of morbidity, including AF, wound infection, pulmonary complications, prolonged intubation, and lengths of ICU and hospital stay were significantly higher in patients with the MS (p < 0.01). Ardeshiri et al.20 found that the MS represented an increased risk for atelectasis and that patients with the MS had a longer ICU stay following CABG. Özyazıcıoğlu et al.12 concluded that wound infection was significantly more frequent in coronary artery disease patients with the MS than in those without the MS (p < 0.05). In a multivariate analysis, the odds ratios of postoperative stroke and renal failure in MS patients were found to be 2.47 and 3.81, respectively.17 The high prevalence of postoperative events in MS patients may be associated with BMI and an increased incidence of diabetes.21 Bardakçı et al.19 found significantly prolonged intubation times, ICU and hospital stay, and a significantly higher rate of pulmonary complications in MS patients; however, in contrast with our study, they reported significant increases in the rates of mortality and peri-operative myocardial infarction. Moulton et al.22 reported that obesity was not a risk factor for adverse events after cardiac surgery, except for the increased number of superficial surgical wound infections and a higher incidence of atrial arrhythmias. Kopelman et al.23 concluded that thoracic and abdominal adipose tissue might be a cause of ventilation and perfusion mismatch, which could induce a decline in respiratory function by creating resistance to breathing exercises. In our study, pulmonary complications were significantly higher among patients with the MS (p < 0.01). This may be explained by a negative effect of the MS on postoperative respiratory function, leading to increased postoperative pulmonary complications. Concerning the relationship between pulmonary function and the MS, it was shown that male adults with the MS had decreased vital capacity.24 Bagheri et al.25 indicated that BMI was not a predictor of mortality after CABG, but pulmonary complications were independent predictors of mortality in the postoperative period. Cardiopulmonary bypass procedures are related to inflammatory response and free radical accumulation.8 It is known that MS patients have an ongoing, low-grade inflammatory process, which can be exacerbated during surgery. They also have increased systemic oxidative stress caused by oxidative transformation of LDL-C.26 The role of lipolytic activity by abdominal fat storage has been emphasised in the production of free fatty acids.26 These free fatty acids exert a significant pro-arrhythmic effect in ischaemic events. This effect has been documented for ventricular arrhythmogenicity, but it

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 1, January/February 2017

has yet to be demonstrated in the generation of AF. Therefore, further research is needed to clarify whether, like other factors, free fatty acid burden associated with hyperlipolytic visceral fat storage contributes to the generation of postoperative AF.27 It is believed that MS patients are more prone to postoperative AF through a potential pathway.28 Atrial remodelling involves two substrates: atrial architecture acting as an anatomical substrate (involved in atrial dilatation, fibrosis), and electrical inhomogeneity acting as a functional substrate (involved in shortness of effective refractory period, dispersion of refractoriness and conduction, abnormal automaticity, and anisotropic conduction).29 These latter processes have been shown to be potential substrates for postoperative AF.30 Bell and O’Keefe reported that postoperative AF was observed in 25% of patients undergoing CABG, and was associated with elevated rates of mortality and postoperative stroke, prolonged hospital stay and increased cost of hospitalisation.31 Kara et al.32 found that the incidence of AF was high (19.2%) after CABG, and they defined some independent clinical predictors. Echahidi et al.2 reported that the MS had a significant effect on clinical outcomes after cardiac surgery and was an independent predictor of postoperative AF. Girerd et al.33 showed a significant correlation between postoperative AF and increased waist circumference and/or increased C-reactive protein levels. The authors also reported that the MS was an independent risk factor for AF occurring after CABG.32 In our study, the rate of AF was significantly higher (20.9%) in MS patients compared to those without the MS (p < 0.01). Gharipour et al.34 found no significant difference in the incidence of postoperative stroke between CABG patients with and without the MS. In our study, although the rate of stroke was higher in MS patients (6.3 vs 1.1%), it was not associated with a significant difference (p = 0.162). This may be attributed to the absence of atherosclerotic plaque in the carotid arteries. In our patients, carotid Doppler ultrasound showed moderate stenosis (50–70%), which was considered insufficient to lead to haemodynamically significant conditions. Carotid stenosis is an important risk factor for stroke during CABG surgery, but neurological events may develop from other causes as well, including aortic and carotid atherosclerosis (62%), intracardiac thrombi (1%), haemorrhage (1%), hypoperfusion (11%), and other factors of unknown origin (25%).35 The severity of carotid stenoses detected in patients undergoing CABG has been reported as greater than 70% in 10% of the cases, 50–70% in 9–22% of the cases, and less than 50% in 80–91% of cases.35,36 Of interest, 50–75% of patients who suffered a stroke did not have carotid stenosis.37 Lee et al.38 reported that intracranial atherosclerosis was the main determinant of stroke, while extracranial atherosclerotic processes played a relatively smaller role. Of note, pre-operative critical risk factors for mortality after CABG were not affected by the MS. By contrast, patients without the MS required urgent operations more frequently than did those with the MS. This is not surprising because patients with the MS are normally on strict follow up to control hypertension, diabetes mellitus and dyslipidaemia, all of which are known to be underlying risk factors for coronary artery disease. Therefore, patients without the MS and with poorly controlled coronary risk factors are more likely to have urgent, non-elective interventions. The presence of factors known to increase mortality rates in MS patients may itself be a limitation to the study. These factors

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include male gender, widespread coronary artery involvement, and increased cross-clamping time. Therefore, the effect of the MS on mortality rate itself may be considered a limitation. The biggest limitation was that the study was underpowered to draw conclusions on some of the outcomes, for example, mortality. Components of the MS cannot be completely minimised by conventional pharmacological treatment modalities. It is well known that statins, angiotensin converting enzyme inhibitors, and beta-blockers have little or no effect in metabolic disturbances observed in MS cases.28

Conclusion Since MS patients already present with many cardiovascular risk factors, the MS was associated with increased morbidity rates in the early postoperative period after CABG; however, its effect on early mortality rate was similar to that seen in patients without the MS. Considering the increased postoperative morbidity rate, the MS should be taken into consideration in pre-operative assessment of CABG patients.

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Echahidi N, Pibarot P, Després J-P, Daigle J-M, Mohty D, Voisine P, et al. Metabolic syndrome increases operative mortality in patients undergoing coronary artery bypass grafting surgery. J Am CollCardiol 2007; 50(9): 843–851.

Benozzi S, Ordonez F, Polini N, Alvarez C, Selles J, Coniglio RI. Insulinresistance and metabolic syndrome in patients with coronary heart disease defined by angiography. Medicina (B Aires) 2009; 69(2): 221–228.

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Després JP. Health consequences of visceral obesity. Ann Med 2001; 33(8): 534–541.

10. Brackbill ML, Sytsma CS, Sykes K. Perioperative outcomes of coronary artery bypass grafting: effects of metabolic syndrome and patient’s sex.

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4963–4971. 27. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci 2005; 330(6): 280–289. 28. Echaidi N, Mohty D, Pibarot P, Despres JP, O’Hara G, Champagne J,

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17. Kajimoto K, Miyauchi K, Kasai T, Yanagisawa N, Yamamoto T,

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surgery. Circulation 1996; 94(9): 1187–1192. 23. Kopelman PG. Clinical complication of obesity. Clin Endocrinol Metab 1984; 13(3): 613–634. 24. Kim SK, Hur KY, Choi YK, Kim SW, Chung JH, Kim HK, et al. The relationship between lung function and metabolic syndrome in obese and non-obese korean adult males. Korean Diabetes J 2010; 34(4): 253–260. 25. Bagheri J, Rezakhanloo F, Valeshabad AK, Bagheri A. Effects of body mass index on the early surgical outcomes after coronary artery bypass grafting. Turkish J Thorac Cardiovasc Surg 2014; 22(2): 253–259. 26. Hansel B, Giral P, Nobecourt E, Chantepie S, Bruckert E, Chapman

2830–2834. 36. Venkatachalam S, Shishehbor MH. Management of carotid disease in patients undergoing coronary artery bypass surgery: is it time to change our approach? Curr Opin Cardiol 2011; 26(6): 480–487. 37. Li Y, Walicki D, Mathiesen C, Jenny D, Li Q, Isayev Y, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol 2009; 66(9): 1091–1096. 38. Lee EJ, Choi KH, Ryu JS, Jeon SB, Lee SW, Park SW, et al. Stroke risk after coronary artery bypass graft surgery and extent of cerebral artery atherosclerosis. J Am Coll Cardiol 2011; 57(18): 1811–1818.

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 1, January/February 2017

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Audit of availability and distribution of paediatric cardiology services and facilities in Nigeria Ekanem N Ekure, Wilson E Sadoh, Fidelia Bode-Thomas, Adeola A Orogade, Adeola B Animasahun, Oluwatoyin O Ogunkunle, Iretiola Babaniyi, Maxwell U Anah, Barbara E Otaigbe, Adebiyi Olowu, Frances Okpokowuruk, Samuel I Omokhodion, Ogechi C Maduka, Uvie U Onakpoya, Daberechi K Adiele, Usman M Sani, Mustapha Asani, Christopher S Yilgwan, Queennette Daniels, Chinyere C Uzodimma, Chika O Duru, Mohammad B Abdulkadir, Joseph K Afolabi, John A Okeniyi

Abstract Background: Paediatric cardiac services in Nigeria have been perceived to be inadequate but no formal documentation of availability and distribution of facilities and services has been done. Objective: To evaluate and document the currently available paediatric cardiac services in Nigeria. Methods: In this questionnaire-based, cross-sectional descriptive study, an audit was undertaken from January 2010 to December 2014, of the personnel and infrastructure, with their distributions according to geopolitical zones of Nigeria. Results: Forty-eight centres participated in the study, with 33 paediatric cardiologists and 31 cardiac surgeons. Echocardiography, electrocardiography and pulse oximetry were available in 45 (93.8%) centres while paediatric intensive care units were in 23 (47.9%). Open-heart surgery was performed in six (12.5%) centres. South-West zone had the majority of centres (20; 41.7%).

Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria Ekanem N Ekure, MB BS, FWACP Paediatric Cardiology Unit, Department of Child Health, University of Benin Teaching Hospital, Benin City, Nigeria Wilson E Sadoh, MB BS, FWACP, MPH, sadohehi@yahoo.com Department of Paediatrics, University of Jos, Nigeria Fidelia Bode-Thomas, MB BS, FWACP Christopher S Yilgwan, MB BS, FWACP Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria Adeola A Orogade, MB BS, FWACP Department of Paediatrics and Child Health, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria Adeola B Animasahun, MB BS, FWACP Division of Paediatric Cardiology, Department of Paediatrics, University College Hospital, Ibadan, Nigeria Oluwatoyin O Ogunkunle, MB BS, FWACP Samuel I Omokhodion, MB BS, FWACP, FMCP Department of Paediatrics, National Hospital, Abuja, Nigeria Iretiola Babaniyi, MB BS, FMCP Department of Paediatrics, University of Calabar Teaching Hospital, Calabar, Nigeria Maxwell U Anah, MB BS, FWACP Department of Paediatrics, College of Health Sciences, University of Port Harcourt, Nigeria Barbara E Otaigbe, MB BCh, FWACP Department of Paediatrics, Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria Adebiyi Olowu, MB BS, FWACP

Conclusions: Available paediatric cardiac services in Nigeria are grossly inadequate and poorly distributed. Efforts should be intensified to upgrade existing facilities, establish new and functional centres, and train personnel.

Keywords: audit, Nigeria, paediatric cardiac services, open-heart surgery Submitted 9/8/15, accepted 5/5/16 Published online 2/8/16 Cardiovasc J Afr 2017; 28: 54â&#x20AC;&#x201C;59

www.cvja.co.za

DOI: 10.5830/CVJA-2016-057

An estimated 70 000 children are born with congenital heart disease (CHD) in Nigeria annually, based on seven million Department of Paediatrics, University of Uyo Teaching Hospital, Uyo, Nigeria Frances Okpokowuruk, MB BS, FWACP Department of Paediatrics, Federal Staff Hospital, Abuja, Nigeria Ogechi C Maduka, MB BS, FWACP Surgery Unit, Bikets Medical Centre, Osogbo, Nigeria Uvie U Onakpoya, MB BS,FWACS, CCTh Department of Paediatrics, University of Nigeria Teaching Hospital, Enugu, Nigeria Daberechi K Adiele, MB BS, MPH, FWACP, FPedCardio Department of Paediatrics, Usmanu Danfodiyo Teaching Hosptial, Sokoto, Nigeria Usman. M Sani, MB BS, FWACP, Cert (Ped Cardiol) Department of Paediatrics, Aminu Kano Teaching Hospital, Kano City, Nigeria Mustapha Asani, MB BS, FWACP Paediatrics Unit, Zankli Hospital, Abuja, Nigeria Queennette Daniels, MB BS, FMCP, MPSCard Department of Paediatrics, Federal Medical Centres, Abeokuta, Nigeria Chinyere C Uzodimma, MB BS, FWACP Department of Paediatrics and Child Health, Niger Delta University Teaching Hospital, Wilberforce Island, Bayelsa State, Nigeria Chika O Duru, MB BS, FWACP Department of Paediatrics and Child Health, University of Ilorin, Ilorin, Nigeria Mohammad B Abdulkadir, MB BS, FWACP Joseph K Afolabi, MB BS, FMCP Department of Paediatrics, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria John A Okeniyi, MB ChB, FWACP

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annual births and a global CHD incidence of 1%.1,2 There are an estimated 300 000 school-aged children afflicted with rheumatic heart disease (RHD).3 The prevalence of RHD in a Nigerian community was 57/100 000 school children.4 The burdens of other acquired heart diseases (AHD) of childhood, although perceived to be significant, have not been quantified. In addition, most of the systemic diseases of childhood, especially infections and metabolic conditions, affect the heart in one way or another. All these constitute a huge demand for paediatric cardiac services in the country. The poor availability of paediatric cardiac services in developing countries is well documented.5 Provision of paediatric cardiac services and uneven distribution of such services in the most populous sub-Saharan African country presents a huge challenge. Currently, most of the surgical paediatric cardiac needs of Nigerian children are being met outside the country, with only a small number of affected children receiving their interventions in the country during periodic medical missions undertaken by specialists from within and outside Nigeria.6,7 It is therefore generally perceived that the number of paediatric cardiac practitioners and the facilities for paediatric cardiac care in Nigeria are grossly insufficient to meet the huge demand for such services. Although the last half decade has witnessed efforts to train personnel, establish new centres or upgrade the capacities of old centres, there has been no previous attempt to formally document the human and infrastructural resources available to provide paediatric cardiac services in Nigeria. We therefore set out to document the currently available services and resources as a baseline for future comparison, with the hope that the needs gap will be brought more sharply into focus and serve to spur more vigorous attempts at bridging the gap. It will also help improve access to care and ease referral decisions by informing practitioners on the available services that are closest to their patients.

Methods The Federal Republic of Nigeria is the most populous African nation, with an estimated population of more than 177 million people.8 There are 36 states and the Federal Capital Territory, which are grouped into six geopolitical zones. Each state has at least one government-owned designated tertiary health centre but not all of them have the capacity to investigate and definitively diagnose paediatric cardiac conditions. Fewer still have the capacity to undertake open-heart surgeries and other cardiac interventions. A few private medical centres however, have relatively advanced capabilities for paediatric cardiovascular diagnostic and interventional services. A structured questionnaire was sent to all Federal Government-owned tertiary health facilities and to large private medical centres in Nigeria in February 2015. The centres known to have a paediatric cardiologist on staff were included. This was done mainly through the platform of the Nigerian Paediatric Cardiologistsâ&#x20AC;&#x2122; network, an internet platform for disseminating information among paediatric cardiologists, interested paediatricians and paediatric cardiac surgeons in Nigeria. The questionnaire items included the number and type of personnel and the range of paediatric cardiac facilities and services available in each centre in the period between January 2010 and December 2014. Only one questionnaire was to be

returned per centre. Ethical approval was not required to use data from the audit.

Statistical analysis The information provided was coded and entered into SPSS version 20.0 (Chicago, Illinois). The proportions of centres with particular cardiac services were expressed as percentages. Available personnel and infrastructure were analysed according to geopolitical zone.

Results There was a 100% response rate from the 48 centres that participated in the study, of which 25 (52.1%) were government owned. The majority of the participating centres (20; 41.7%) were located in the South-West geopolitical zone. The distribution of centres in the other zones is shown in Fig. 1. A total of 33 paediatric cardiologists were practicing full time in 26 of the 48 centres, providing cardiac services to the 87 million population of children in Nigeria.1 The remaining 22 centres had only visiting cardiologists. All 33 physicians were able to perform echocardiography. A total of 31 cardiac surgeons were identified in this survey. In 12 centres, there were 19 (61.3%) surgeons trained in adult cardiac surgery only, while 10 centres had 12 (38.7%) surgeons trained in both adult and paediatric cardiac surgery. The distribution of the other cadres of personnel is shown in Table 1. Table 2 depicts the distribution of personnel according to geopolitical zone. Forty-seven (97.9%) centres had equipment for electrocardiography (ECG) and pulse oximetry, while echocardiography could be performed in 45 (93.8%) centres. In the three centres without an echocardiography machine, the facility had previously been available but was not functioning at the time of the survey. The centres with functional echocardiography machines had facilities for paediatric probe with transducer frequency of at least 5 MHz, two-dimensional, colour and Doppler facilities. Although defibrillators were available in 23 (47.9%) centres, paediatric paddles were only available in 11 (47.8%) of these. The distribution of the other equipment according to geopolitical zone is shown in Table 3.

North-Central 20.42%

15.31%

North-East North-West South-East

2.4% 2.4% 3.6%

South-South South-West

6.13%

Fig. 1. Distribution of the participating centres according to geopolitical zone.

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Table 1. Distribution of paediatric cardiac personnel in the centres No of centres

Personnel type

Table 3. Availability of equipment in centres according to geopolitical zone

Total number of personnel in 48 centres Total

Median

Range

Physicians with echo capability

1–4

Adult surgeons

1–6

Paediatric surgeons

1–2

Interventionists

1–1

Cardiac nurses

1.5

1–23

Cardiac anaesthetists

1–3

Perfusionists

1–2

Intensivists

1–2

NW n (%)

SE n (%)

SS n (%)

SW n (%)

Echo machines

15 (33.3) 2 (4.4) 2 (4.4)

3 (6.7)

4 (8.9)

19 (42.2)

ECG

15 (31.9) 2 (4.3) 2 (4.3)

3 (6.4)

6 (12.8) 19 (40.4)

Cardiac catheterisation was available in six (12.5%) of the 48 centres but was utilised for children in only three centres (6.3%) for diagnostic and therapeutic purposes. All six centres had single-plane equipment. The therapeutic indications included percutaneous closure of patent ductus arteriosus (PDA) and atrial septal defects (ASD). Surgical operations were performed for congenital heart diseases in 13 centres. There were 84 cardiac surgeries for congenital heart diseases performed in 13 centres with a median (range) of six (1–20) operations per centre over the study period. The average annual number of surgeries for congenital heart disease was 21. The surgeries included ligation of PDA 51 (60.7%), total repair of tetralogy of Fallot (TOF) 16 (19.0%), ASD eight (9.5%), ventricular septal defect (VSD) seven (8.3%), and BlalockTaussig shunt (B-T shunt) two (2.4%) for TOF and double-outlet right ventricle (DORV). There were a total of 21 rheumatic surgical cases performed in four centres during the study period. Of the 13 centres, only six (46.2%) had facilities for and performed open-heart surgery on children. The others did mostly PDA ligation. Pacemakers were inserted in seven (14.6%) centres. Of the six centres that had performed open-heart surgery on children, four (66.7%) were located in the South-West geopolitical zone, which also housed three (50%) of the six centres with catheterisation laboratories. The centres with open-heart surgery and cardiac catheterisation facilities and their distribution according to geopolitical zone are shown in Table 4, while the availability of echocardiography, cardiac catheterisation and open-heart surgery by state in the country is depicted in Fig. 2. Twenty-five (52.1%) of the 48 participating centres had intensive care units (ICUs), with a total of 140 ICU beds between them [median (range): 5.5 (2– 6) beds]. Only 10 (40.0%) of the 25 centres however had a dedicated paediatric ICU with

NE n (%)

Total

Holter monitor

7 (33.3) 1 (4.8) 0 (0.0)

2 (9.5)

9 (42.9)

Defibrillator

7 (29.2) 1 (4.2) 1 (4.2)

2 (8.3)

4 (16.7)

9 (37.5)

Catheterisation lab 1 (16.7) 0 (0.0) 1 (16.7)

1 (16.7) 0 (0.0)

3 (50.0)

ICU

2 (8.0)

9 (36.0)

14 (30.4)

6 (24.0) 2 (8.0) 2 (8.0)

Ventilators

Some personnel (physicians, surgeons, anaesthetiscs, perfusionists, nurses and interventionists) were working in more than one centre. Some adult surgeons also functioned as paediatric surgeons.

NC n (%)

Type of equipment

10 (21.7) 0 (0.0) 1 (2.2)

4 (16.0)

17 (40.0) 4 (8.7)

Echo = echocardiography, ICU = intensive care unit, ECG = electrocardiogram. NC = North-Central, NE = North-East, NW = North-West, SE = South-East, SS = South-South and SW = South-West.

24 beds. The median (range) number of beds in the paediatric ICU was one (1–5). Seventeen (35.4%) of the 48 centres had a total of 46 ventilators [median (range): one (1–7) ventilators]. The distribution of centres with open-heart surgery facilities, catheterisation laboratories, ICU and ventilators according to the type of hospital is shown in Table 5. All 23 private centres except one were manned by visiting cardiologists from other centres, while in three (50%) centres, the surgeons were visiting.

Discussion The study found a total of 33 paediatric cardiologists serving the country of 87.7 million children, or one paediatric cardiologists to 2.6 million children. This falls far short of the ideal requirement of a minimum of one paediatric cardiologist to serve 0.5 million of the population.9 Therefore Nigeria would need a minimum of 174 paediatric cardiologists to attend to her 87.7 million children. The available 33 paediatric cardiologists, which is about one-fifth (33/174) of the number of personnel actually required, speaks to the monumental challenge before Nigeria in providing Table 4. Centres with open-heart surgery and cardiac catheterisation facilities by geopolitical zone Open-heart surgery

Centre according to zone

Catheterisation lab

South-West zone Lagos University Teaching Hospital, Lagos

✓

Lagos State University Teaching Hospital, Lagos

✓

Redington Hospital, Lagos

✓

University College Hospital, Ibadan

✓

Biket Medical Centre, Osogbo

✓

North-Central zone Heart scan, Abuja

✓

Garki Hospital, Abuja

✓

South-East zone University of Nigeria Teaching Hospital, Enugu*

Table 2. Distribution of personnel by geopolitical zone SE n (%)

SS n (%)

Physicians that 11 (33.3) 0 (0.0) 4 (12.1) can perform echo

3 (9.1)

6 (18.2) 9 (27.3)

Adult surgeons

7 (22.6) 0 (0.0) 3 (9.7)

7 (22.6) 6 (19.4) 8 (25.8)

Paediatric surgeons

1 (8.3)

2 (16.7) 1 (8.3)

Type of personnel

Interventionists Nurses

NC n (%)

NE n (%)

NW n (%)

0 (0.0) 2 (16.7)

1 (20.0) 0 (0.0) 0 (0.0) 11 (11.6) 0 (0.0) 4 (4.2)

0 (0.0)

SW n (%)

6 (50.0)

Total

1 (20.0) 3 (60.0)

25 (26.3) 8 (8.4) 47 (49.5)

Anaesthetists

2 (11.1) 0 (0.0) 2 (11.1)

2 (11.1) 3 (16.7) 10 (55.6)

Perfusionist

1 (7.7)

2 (15.4) 1 (7.7)

0 (0.0) 1 (7.7)

8 (61.5)

✓

North-West zone

NC = North-Central, NE = North-East, NW = North-West, SE = South-East, SS = South-South and SW = South-West.

Aminu Kano Teaching Hospital, Kano*

✓

*Cardiac catheterisation for children is yet to commence in these centres.

Table 5. Distribution of number of centres with some facilities and procedures according to the type of hospital Facilities/procedures

Public n (%)

Private n (%)

Total n (%)

Open-heart surgery

4 (66.7)

2 (33.3)

6 (100.0)

Catheterisation lab

3 (50.0)

6 (100.0)

Intensive care unit

21 (84.0)

4 (16.0)

25 (100.0)

Ventilators

41 (89.1)

5 (10.9)

46 (100.0)

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Sokoto Katsina Jigawa

Kebbi

Zamfara

Yobe

Kano

Borno

Bauchi

Kaduna

Gombe

Niger Adamawa

Kwara Plateau

Abuja Nasarawa Oyo

Taraba Osun

Kogi

Ekiti

Benue Ogun

Ondo Edo Enugu

Lagos

Ebonyi Anambra

Delta

Imo Abia Rivers

Bayelsa

Cross River

Akwa Ibom

Echocardiography availability Open heart surgery Cardiac catheterisation lab availability

Less than 2 000 000 2 000 000 to 2 999 999 3 000 000 to 3 999 999 4 000 000 to 4 999 999 5 000 000 to 5 999 999 6 000 000 to 7 116 987 7 116 987 and more

Fig. 2. P opulation map of states with echocardiography, cardiac catheterisation and open-heart surgery facilities.

adequate paediatric cardiac services.9 The proportion is smaller than the 24/88 (27%) reported paediatric cardiologists serving a population of 44 million in South Africa, or one to 1.8 million people, which is also considered inadequate.10 The number of surgeons recorded in the present study is also far lower than the recommended number of at least two surgeons per centre. The reasons for the lower proportion of paediatric cardiologists per total number of children in Nigeria include poor training facilities in the country, such that residents intending to do paediatric cardiology or cardiothoracic surgery have part or all of their training in centres outside the country. Such residents may be unwilling to return to the country to pursue a career with the prospect of poor or lack of equipment and materials to work with. Furthermore, not many doctors may be interested in pursuing a career in cardiology and cardiac surgery because of the long duration of training and the ill-equipped training facilities.

The deficiency of manpower is further underscored by the fact that some of these few available personnel were also visiting physicians and surgeons to other centres, particularly private ones. This not only highlights the need to train more personnel, but in the opinion of the study group, also could point to inability of the private centres to provide adequate remuneration, tenured appointments and job security. This is against the norm in other countries where private hospital services are able to attract personnel from state-owned hospitals. This is not surprising, given the capital-intensive nature of cardiac surgery, coupled with its non-inclusion in the National Health Insurance Scheme.11 The private centres are therefore unable to generate enough income to pay highly skilled full-time staff, especially as they must rely on intermittent surgical missions to be able to generate adequate numbers of paying patients on whom to operate. These highly skilled staff therefore remain in government employment, providing low levels of cardiology

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service but willing to offer their services to those private centres that are also beginning to develop cardiac programmes whenever they organise such missions. This state of affairs leaves a lot to be desired, because practitioners require a minimum number of procedures to maintain competence and may need to periodically visit established centres outside the country to satisfy this requirement. This does not augur well for the rapid development of paediatric cardiac services in the country and creates some kind of expensive but inefficient vicious circle. Urgent intervention in terms of massive investment in the health sector and new ways of healthcare financing will be required to break the vicious circle. However, with many other competing needs in and outside the health sector, this slow pace of development of paediatric cardiac services may continue for some time. The North-Eastern geopolitical zone is particularly badly affected, with a severe dearth of paediatric cardiology services and personnel, despite having 14% of the population of Nigera.12 This may be due to the fact that it is the zone that has been particularly hit by insurgency activities in recent years. This means that parents of affected children will have to defy many odds to obtain the necessary care for their children. The other two northern zones (North-West and NorthCentral) also lag behind the south, especially the South-West, in terms of paediatric cardiac infrastructure. This finding is in tandem with a report of the paediatrician work force in Nigeria, where more than two-thirds of paediatricians practice in the South, with the lowest child:paediatrician ratio in the SouthWest.13 This trend is also consistent with observations in other aspects of socio-economic development, with the South-West historically leading the pace in terms of Western education and its attendant developments. While detailed echocardiography is adequate to prepare most patients for surgery, cardiac catheterisation is needed for the anatomical and physiological assessment of patients with CHD on whom echocardiographic evaluation is difficult.14 It is also being increasingly used for minor interventions that were hitherto surgically repaired. Only three out of the six available catheterisation laboratories in the country provided services for children during the study period, although more recently, three additional catheterisation laboratories were either in installation phase or were awaiting official opening of the centres. This again highlights inadequacy of equipment for a large population. The rudimentary paediatric cardiology and cardiac surgery services in Nigeria are being provided mainly by governmentowned centres, no doubt because of the huge capital outlays involved in setting one up. The government centres however have their peculiar challenges, such as incessant industrial action, frequent power interruption, unnecessary bureaucracy and intra-institutional conflict, resulting in loss of public confidence. One way of strengthening these centres might be regional co-operation between centres by effective referrals to one or two centres that perform open-heart surgery, considering the small number of surgeries performed in the country. As the number of surgeries outstrip the capacity of existing centre(s) to peform open-heart surgery, other centres with adequate facilities can be upgraded to referral centres. The sharing of facilities and expertise ensures sustainability of the few available centres. The small number of surgeries performed locally is the underlying reason for the thriving medical tourism for open-

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heart surgery outside Nigeria. The quest to seek medical care, including paediatric cardiac care outside Nigeria where more comprehensive cardiac services are readily available has not only led to a lot of capital flight but has also provided little opportunity for development of the fledgling cardiac services in the country. It is estimated that Nigerians spend about $20 billion on health costs annually outside Nigeria.15 The solution is the provision of cardiac services at standards close to or on par with those outside the country to convince the populace to patronise the services available in the country. The cost of cardiac care is not cheap anywhere in the world. In a single-centre study in Nigeria, the cost of open-heart surgery was found to range between US$6 230 and US$11 200 in a country where the GNI per capita income is US$2 760.16 A previous study demonstrated the catastrophic health cost to families who pay out of pocket for their children’s medical care.17 Although the cost of cardiac surgeries/interventions in Nigeria is cheaper than in many centres internationally, most Nigerian families cannot afford it. In a bid to bridge this gap, some non-governmental organisations, such as the Kanu Heart Foundation, Save a Child’s Heart Nigeria, and a number of other faith-based and non-faith-based organisations have provided full funding or have subsidised the cost of surgeries abroad for a small number of affected children.

Conclusion The available paediatric cardiac services in Nigeria are grossly inadequate and poorly distributed to cater for the teeming population. The use of periodic medical missions to accomplish intervention in a few selected cases, while marginally reducing the burden of children with uncorrected cardiac anomalies, will only serve a short-term remediation of the problem. Medium- and long-term approaches would be the upgrading of existing centres, strengthening of referral systems, coupled with the training and re-training of relevant personnel to man the centres. There is a need for better public–private partnership. It is important that efforts by government and non-governmental organisations in providing funding for surgeries abroad be continued until the cardiac services in the country are adequate for the needs of Nigerian children with structural cardiac defects. We acknowledge the contribution of Adebowale A Adeyemo in reading through the manuscript.

References 1.

Unicef. At a glance. Nigeria. Available at http://www.unicef.org/infobycountry/nigeria_statistics.html. Accessed 26072015.

Hoffman JIE. Incidence, prevalence and inheritance of congenital heart disease. In: Moller JH, Hoffman JIE, eds. Pediatric Cardiovascular Disease. New York, NY: Churchill Livingstone; 2000: 257–262.

Bode-Thomas F. Overcoming challenges in the management of structural heart diseases in Nigerian children. J Med Tropics 2011; 13: 3–10.

Sadoh WE, Omuemu VO, Israel-Aina YT. Prevalence of rheumatic heart disease among primary school pupils in mid-Western Nigeria. East Afr Med J 2013; 90: 21–25.

Global efforts for improving pediatric heart health. Report by children’s HeartLink. Available at http://www.childrensheartlink.org. Accessed March 2015.

Nwiloh J, Edaigbini S, Danbauchi S, Aminu M, Oyati A, Babaniyi I, et

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al. Cardiac surgical experience in Northern Nigeria. Cardiovasc J Afr 7.

OO, et al. Paediatrician workforce in Nigeria: Impact on child health.

Ekure EN, Okoromah CN. In-hospital outcome of children referred

Paediatric Association of Nigeria Technical Report. Niger J Paed 2013;

2009; 36: 80–86.

13. Ekure EN, Esezobor CI, Balogun MR, Woo JG, Mukhtar-Yola M, Ojo

2012; 23: 432–434. for cardiac surgery abroad from a developing country. Nig J Paediatr 8.

40(2): 112–118. 14. Feltes TF, Bacha E, Beekman RH 3rd, Cheatham JP, Feinstein

Federal Republic of Nigeria 2006 Population and Housing Census of

JA, Gomes AS, et al on behalf of the American Heart Association

Nigeria. Federal Republic Nigeria Official Gazette. Lagos 2007.

Congenital Cardiac Defects Committee of the Council on Cardiovascular

Hall R, More R, Camm J, Swanlon H, Flint J, et al. Fifth report on the

Disease in the Young, Council on Clinical Cardiology, and Council on

provision of services for patients with heart disease (United Kingdom).

Cardiovascular Radiology and Intervention. Indications for cardiac

Heart 2002; 88:(Suppl III): iii1–iii59.

catheterization and intervention in pediatric cardiac disease: a scientific

10. Hoosen EGM, Cillers AM, Hugo-Hamman CT, Brown SC, Harrisberg JR, Takawira FF, et al. Audit of paediatric cardiac services in South Africa. South Afr Heart 2010; 7: 4–9.

statement from the American Heart Association. Circulation 2011; 123: 2607–2652. 15. Connell J. Medical tourism: sea, sun, sand and surgery. Tourism Mgt

11. Federal Ministry of Health. National Health Insurance Scheme operational guidelines: 1–28. Available at http://www.nhis.gov.ng/index.php.

2006; 27: 1093–100. 16. Falase B, Sanusi M, Majekodunmi A, Ajose I, Idowu A, Oke D. The cost of heart surgery in Nigeria. Pan Afr Med J 2013; 14: 61.

(Accessed 26072015). 12. Federal Republic of Nigeria 2006 Population and Housing Census of

Doi:10.11604/pamj.2013.14.61.2162.

Nigeria. Population Distribution by Sex, State, LGA’s and Senatorial

17. Sadoh WE, Nwaneri DU, Owobu AC. The cost of out-patient manage-

District: 2006 Census Priority Tables (Vol 3). National Population

ment of chronic heart failure in children with congenital heart disease.

Commission. Abuja, 2010.

Nig J Clin Pract 2011; 14: 65–69.

African Evidence Network Survey The Africa Evidence Network (AEN) invites you to participate in a survey. Click here to access the survey https://goo.gl/forms/jDaQyLzqdxwQY7Qj2 AEN wants to know where existing capacity for evidence maps, systematic reviews, and other forms of syntheses lies across Africa. This survey takes no more than 10 minutes. The deadline is has been extended until Friday, 3 March 2017. If you have not conducted this kind of research before but you would like to, or indeed you are more interested in how systematic reviews, evidence maps and syntheses might be useful as part of research frameworks or decision-making frameworks, please complete the survey. After the initial questions, you can skip to the final section and tell us more in the comments box. If you know of others who might be interested, please feel free to forward this survey on to them. With thanks in advance for your contribution. Ruth Stewart Chairperson, Africa Evidence Network

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Echocardiographic predictors of outcome in acute heart failure patients in sub-Saharan Africa: insights from THESUS-HF Mahmoud U Sani, Beth A Davison, Gad Cotter, Albertino Damasceno, Bongani M Mayosi, Okechukwu S Ogah, Charles Mondo, Anastase Dzudie, Dike B Ojji, Charles Kouam Kouam, Ahmed Suliman, Gerald Yonga, Sergine Abdou Ba, Fikru Maru, Bekele Alemayehu, Christopher Edwards, Karen Sliwa

Abstract Background: The role of echocardiography in the risk stratification of acute heart failure (HF) is unknown. Some small studies and retrospective analyses have found little change in echocardiographic variables during admission for acute HF and some echocardiographic parameters were not found to be associated with outcomes. It is unknown which echocardiographic variables will predict outcomes in sub-Saharan African patients admitted with acute HF. Using echocardiograms, this study aimed to determine the predictors of death and re-admissions within 60 days and deaths up to 180 days in patients with acute heart failure. Methods: Out of the 1 006 patients in the THESUS-HF registry, 954 had had an echocardiogram performed within a few weeks of admission. Echocardiographic measurements were performed according to the American Society of Echocardiography guidelines. We examined the associations between each echocardiographic predictor and outcome using regression models. Results: Heart rate and left atrial size predicted death within 60 days or re-admission. Heart rate, left ventricular posterior wall thickness in diastole (PWTd), and presence of aortic stenosis were associated with the risk of death within 180 days. PTWd added to clinical variables in predicting 180-day mortality rates.

Conclusions: Echocardiographic variables, especially those of left ventricular size and function, were not found to have additional predictive value in patients admitted for acute HF. Left atrial size, aortic stenosis, heart rate and measures of hypertrophy (LV PWTd) had some predictive value, suggesting the importance of early treatment of hypertension and severe valvular heart disease. Keywords: echocardiography, acute heart failure, predictors, outcome Submitted 12/7/15, accepted 10/7/16 Cardiovasc J Afr 2017; 28: 60–67

www.cvja.co.za

DOI: 10.5830/CVJA-2016-070

Recent data clearly indicate that heart failure (HF) is an important healthcare problem in Africa, where it is estimated to constitute about 3–7% of all medical admissions.1,2 The causes of HF in Africa are different from those outside Africa. The recent THESUS-HF registry3 showed that in sub-Saharan Africa, the disease affects men and women in the most productive years of life, at an average age of 52 years. Furthermore, HF in Africa

Department of Medicine, Bayero University Kano; Aminu Kano Teaching Hospital, Kano, Nigeria

Department of Internal Medicine, Douala General Hospital and Buea Faculty of Health Sciences, Douala, Cameroon

Mahmoud U Sani, MBBS, FWACP, FACP, FACC, sanimahmoud@yahoo.com

Anastase Dzudie, MD, FESC Charles Kouam Kouam, MD

Momentum Research, Inc, Durham, North Carolina, United States of America

Department of Medicine, University of Abuja Teaching Hospital, Abuja, Nigeria

Beth A Davison, PhD Gad Cotter, MD, FACC, FESC Christopher Edwards, BS

Dike B Ojji, MBBS, PhD, FACP

Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique

Department of Medicine, Aga Khan University, Nairobi, Kenya

Albertino Damasceno, MD, PhD, FESC

Department of Medicine, GF Jooste and Groote Schuur Hospitals, University of Cape Town, Cape Town, South Africa Bongani M Mayosi, DPhil, FCP (SA)

Department of Medicine, University College Hospital, Ibadan and Ministry of Health, Abia State, Nigeria

Faculty of Medicine, University of Khartoum, Khartoum, Sudan Ahmed Suliman, MD Gerald Yonga, MD

Department of Cardiology, Faculty of Medecine, Dakar, Senegal Sergine Abdou, Ba MD, PhD

Addis Cardiac Hospital, Addis Ababa, Ethiopia Fikru Maru, MD Bekele Alemayehu, MD

Uganda Heart Institute, Kampala, Uganda

Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Charles Mondo, MB ChB, PhD

Karen Sliwa, MD, PhD, FESC, FACC

Okechukwu S Ogah, MBBS, FWACP, FACC, FESC

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is mostly caused by hypertension and not by coronary artery disease, as is seen in Western countries.4 Patients with HF are heterogeneous in terms of risk of cardiac death and re-admission for decompensated HF. Therefore assessment of prognosis is a fundamental step in individual patient management. Analysis of clinical variables has helped in identifying the most significant predictors of mortality in the HF population.5 Echocardiography has become the gold standard for the evaluation of patients with HF because it is an inexpensive, highly reproducible, widely available and relatively extensive method for assessing left ventricular systolic and diastolic function.6 In fact, the recent HF guidelines of the European Society of Cardiology state that ‘echocardiography is the method of choice in patients with suspected HF for reasons of accuracy, availability (including portability), safety, and cost’.7 More than 20 echocardiographic parameters have been proposed as predictors of outcome in HF patients in a number of clinical studies.8 However, the role of echocardiography in the assessment and risk stratification of acute HF has been less clear. Some small studies have found little correlation between echocardiographic and haemodynamic variables in acute HF, and little change in these variables from admission to follow up.9 In large registries and trials, echocardiographic parameters were not found in many cases to be associated with outcomes.10 Therefore, it is not clear which echocardiographic variables are of importance in patients with acute HF.5,11 THESUS-HF3 provided a unique opportunity to study the echocardiographic predictors of outcome in patients admitted with acute HF in this part of the world. To our knowledge, no similar study has been previously published in Africans with acute HF.

Methods THESUS-HF was a prospective, multicentre, international

observational survey of acute HF in 12 cardiology centres from nine countries in sub-Saharan Africa.3 All participating centres had a physician trained in clinical cardiology and echocardiography. Patients who were older than 12 years, were admitted with dyspnoea as the main complaint, and were diagnosed with acute HF based on symptoms and signs that were confirmed by echocardiography (de novo or decompensation of previously diagnosed HF) were enrolled consecutively. Patients excluded were those with acute coronary syndromes, severe known renal failure (patients undergoing dialysis or with a creatinine level of > 4 mg/dl), nephrotic syndrome, hepatic failure or other cause of hypoalbuminaemia. Written informed consent was obtained from each subject who was enrolled into the study. Ethical approval was obtained from the ethics review boards of the participating institutions, and the study conformed to the principles outlined in the Declaration of Helsinki. Details of data collection have been previously described.3 In brief, we collected demographic data, detailed medical history, vital signs (blood pressure, heart rate, respiratory rate and temperature) and signs and symptoms of heart failure (oxygen saturation, intensity of oedema and rales, body weight and levels of orthopnoea). Assessments were done at admission and on days 1, 2 and 7 (or at discharge if earlier). Electrocardiograms were done and read using standard reference ranges. A detailed echocardiographic assessment was performed (see below). The probable primary cause of HF was provided by the investigators, and was based on the European Society of Cardiology guidelines,7 as recently applied in the chronic HF cohort of the Heart of Soweto Study.12 Information on re-admissions and death, with respective reasons and cause, was collected throughout the six-month follow up. Outcomes of interest were re-admission or death within 60 days, and death up to 180 days.

Fig. 1. Echocardiography images depicting method of echo assessment in the study.

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Echocardiographic procedures and measurements were performed according to the American Society of Echocardiography (ASE) guidelines.13 M-mode echocardiograms were derived from two-dimensional (2D) images. The M-mode cursor on the 2D scan was moved to specific areas of the heart to obtain measurements, according to the recommendation of the committee on M-mode standardisation of the ASE. Doppler indices of left ventricular (LV) diastolic filling were obtained. Complete Doppler studies were performed according to the recommendations of the ASE (Fig. 1). From the M-mode measurements, LV dimensions and function (LV ejection fraction) were derived. LV mass was calculated using the recommended method from the ASE: 1.04 [(LVIDd + PWTd + IVSTd)3 – (LVIDd)3] – 13.6 g.14 where LVIDd is left ventricular internal diameter at end-diastole, PWTd is posterior wall thickness in diastole, and IVSTd is interventricular septal thickness in diastole. For diastolic function, left atrial (LA) size (both anteroposterior diameter and planimetry) and pulse-wave mitral-valve (MV) inflow (early and late peak diastolic velocities, which measure the E/A ratio and the deceleration time and MV A-wave duration) were measured. Echocardiography examinations also included assessment of valvular architecture, a semi-quantitative estimate of the severity of valvular regurgitation, and determination of the presence of pericardial effusion. Other abnormalities, such as evidence of pulmonary arterial hypertension, were also noted.

Statistical analysis Patients whose echocardiograph was performed within four weeks prior to and two weeks post enrollment were included in this analysis. Continuous parameters are summarised as means and standard deviation, and categorical parameters by absolute and relative frequencies. For patients who had their E/A ratios recorded, grade 1 was defined as E/A < 0.8, grade 2 as E/A between 0.8 and 1.5, and grade 3 as E/A ratio > 1.5. If a patient had a missing E/A ratio, then the grade was defined using the E-wave deceleration time as follows: grade 1 as E-wave > 200 ms, grade 2 as E-wave 160–200 ms, and grade 3 as E-wave < 160 ms. The associations between echo parameters and clinical outcomes were examined using Cox regression models. The univariate associations between each predictor and outcome were examined. The linearity of associations between continuously distributed predictors and each outcome was assessed using restricted cubic splines with four knots with a test of the significance of the non-linear terms. If the association was non-linear, a readily interpretable transformation was chosen through examination of plots of the predicted log hazard ratio against the value of the predictor and changes in Akaike’s information criterion. For the outcome of 180-day mortality, the associations with creatinine, heart rate and posterior wall thickness were all significantly non-linear. We chose to model creatinine as a quadratic polynomial, and heart rate and posterior wall thickness using linear splines with one knot where the association between predictor and outcome appeared to change.

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Table 1. Patient characteristics overall and by ejection fraction groups Patient characteristics

Overall (n = 954)

EF < 50% (n = 654)

EF ≥ 50% (n = 243)

Age, years, mean ± SD

52.3 ± 18.24

52.3 ± 17.64

53.0 ± 19.58

0.62

Male gender, n (%)

469 (49.2)

342 (52.3)

101 (41.7)

0.0050

p-value

Black Africans, n (%)

939 (99.1)

646 (99.1)

242 (99.6)

0.68

Hypertension, n (%)

532 (56.0)

369 (56.7)

138 (57.0)

0.93

Hyperlipidaemia, n (%)

84 (9.0)

58 (9.1)

23 (9.6)

0.80

History of smoking, n (%)

93 (9.8)

64 (9.8)

17 (7.1)

0.20

Malignancy, n (%)

13 (1.4)

10 (1.5)

3 (1.2)

History of cor pulmonale, n (%)

67 (7.1)

34 (5.2)

30 (12.4)

1.00 0.0002

Diabetes mellitus, n (%)

109 (11.4)

72 (11.0)

26 (10.7)

0.88

Peripheral oedema, n (%)

631 (67.1)

448 (69.6)

146 (60.8)

0.014

Rales, n (%)

533 (63.8)

382 (65.3)

130 (59.6)

0.14

BMI, kg/m2, mean ± SD

24.9 ± 5.84

24.8 ± 5.62

24.7 ± 6.10

0.82

Systolic BP, mmHg, mean ± SD Diastolic BP, mmHg, mean ± SD Heart rate, bpm, mean ± SD LVEF, %, mean ± SD Creatinine level, mg/dl, mean ± SD BUN, mg/dl, mean ± SD Sodium level, mEq/l, mean ± SD

130.7 ± 33.51 127.9 ± 32.16 137.2 ± 36.35 84.5 ± 21.04

84.0 ± 20.52

85.5 ± 22.04

104.0 ± 21.35 105.0 ± 21.02 101.1 ± 22.69

0.0006 0.34 0.016

39.4 ± 16.43

31.8 ± 10.04

60.6 ± 9.65

< 0.001

1.4 ± 0.99

1.3 ± 1.07

0.54

35.9 ± 38.35

0.79

34.7 ± 31.59 135.2 ± 6.57

35.1 ± 29.58 135.0 ± 6.72

135.5 ± 6.3

0.27

eGFR, ml/min/1.73 m2, mean ± SD

84.4 ± 47.91

81.7 ± 44.08

90.8 ± 57.97

0.032

Haemoglobin, g/dl, mean ± SD

12.1 ± 2.41

12.3 ± 2.30

11.8 ± 2.64

0.019

Glucose level, mg/dl, mean ± SD

109.8 ± 49.92 110.4 ± 51.95 106.1 ± 41.93

(mmol/l)

(6.09 ± 2.77)

(6.13 ± 2.88)

0.22

(5.89 ± 2.33)

Prior medication use, n (%) ACE inhibitor

180 (32.4)

134 (34.9)

40 (24.8)

0.022

Loop diuretics

215 (39.4)

152 (40.1)

57 (36.5)

0.44

β-blockers Digoxin Hydralazine Nitrates Aldosterone inhibitor

97 (17.9)

69 (18.3)

26 (16.7)

0.65

103 (18.9)

80 (21.1)

22 (13.9)

0.053

3 (0.6)

2 (0.5)

1 (0.6)

1.00

10 (1.8)

8 (2.1)

2 (1.3)

0.73

101 (18.5)

77 (20.4)

22 (13.8)

0.075

Statins

27 (5.0)

18 (4.8)

9 (5.7)

0.68

Aspirin

122 (22.2)

91 (24.0)

29 (18.1)

0.13

31 (5.7)

22 (5.9)

7 (4.4)

0.49

Anticoagulants Aetiology of heart failure, n (%) Hypertensive CMP

380 (40.9)

Idiopathic dilated CMP

129 (13.9)

Rheumatic heart disease

133 (14.3)

Ischaemic heart disease

71 (7.6)

Peripartum cardiomyopathy

72 (7.8)

Pericardial effusion tamponade

45 (4.8)

HIV cardiomyopathy

22 (2.4)

Endomyocardial fibrosis

11 (1.2)

Other

66 (7.1)

274 (42.5)

86 (37.6)

120 (18.6)

2 (0.9)

75 (11.6)

55 (24.0)

57 (8.8)

10 (4.4)

59 (9.2)

2 (0.9)

22 (3.4)

23 (10.0)

12 (1.9)

8 (3.5)

2 (0.3)

8 (3.5)

24 (3.7)

35 (15.3)

EF, ejaculation fraction; BMI, body mass index; LVEF, left ventricular ejection fraction; BUN, blood urea nitrogen; ACE, angiotensin converting enzyme; CMP, cardiomyopathy; eGFR, estimated glomerular filtration rate.

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Univariate associations between echo parameters and outcomes are presented for the whole analysis population as well as by key diagnosis groups. Diagnoses were grouped as hypertension, cardiomyopathy, valvular and other. Valvular was defined as having rheumatic heart disease or at least one of the following classified as severe: aortic stenosis or regurgitation, mitral stenosis or regurgitation. To assess whether an association between an echo parameter and outcomes differed by diagnosis group, we tested for the significance of the diagnosis-by-echo parameter interaction term in the Cox regression model for the outcome. The number of events in the analysis population limited development of multivariate models for 180- and 60-day mortality or re-admission. Because of this, we chose a few echo parameters in addition to predictors known to be associated with each outcome in this study population. Multiple imputations were used with a method that assumes multivariate normality (SAS PROC MI) to handle missing values. The imputation model included all covariates under consideration for the multivariate models. The ranges of imputed values were restricted to the ranges of the observed values. Seven imputation datasets were used. Parameter estimates were averaged across these datasets using Rubin’s algorithm (SAS PROC MIANALYZE). Backwards selection was used in each of the seven imputation datasets, with the criterion for staying at p < 0.10. Predictors that were significant in the majority of the imputed datasets were kept in the final model. SAS release 9.2 (SAS Institute, Cary, NC, USA) was used for analyses.

Results There was a total of 1 006 patients in the THESUS-HF registry,3 of whom 954 had an echocardiogram performed within four weeks before to two weeks after enrollment. Among these 954 patients, the mean age ± SD of the patients was 52.3 ± 18.2 years, 469 (49.2%) were men, the predominant race was black African (99.1%), 11.4% of patients had diabetes mellitus and 9.0% had

hyperlipidaemia. The mean left ventricular ejection fraction (LVEF) ± SD was 39.4 ± 16.4%, the initial systolic blood pressure was 130.7 ± 33.5 mmHg, and heart rate was 104 ± 21.4 beats per min (Table 1). Heart failure was most commonly due to hypertension (n = 380; 40.9%), followed by rheumatic valvular heart disease (n = 133; 14.3%), and idiopathic dilated cardiomyopathy (n = 129; 13.9%). Ischaemic heart failure was present in only 71 (7.6%) patients (Table 1). The distribution and proportion of missing values for each echocardiographic parameter are presented in Table 1. LVEF was available for 897 patients and was missing for 6.0% of patients. LVEF was < 50% in 654 (73%) patients and ≥ 50% in 243 (27%) patients. Patients’ characteristics according to LVEF are presented in Table 1. Patients with HF with reduced ejection fraction had higher proportions of males and peripheral oedema, and lower systolic blood pressure, higher heart rate and lower estimated glomerular filtration rate, on average. Univariate associations between the echo predictors and the outcomes by diagnosis groups (hypertensive heart disease, valvular heart disease and other) suggest that none of the associations of echo parameters with outcomes differed significantly among the diagnostic groups (Tables 2, 3). Univariate associations of echo predictors with 60-day death or re-admission and with 180-day death are shown in Tables 4 and 5, respectively. Heart rate and left atrial size were associated with death or re-admission within 60 days. Heart rate, left ventricular posterior wall thickness and presence of aortic stenosis were associated with the risk of death up to 180 days. The multivariate models suggest left ventricular end-systolic diameter, interventricular septal thickness in diastole, posterior wall thickness in diastole, left atrial size and E/A wave ratio did not add significantly to prediction of 60-day death or re-admission, while left ventricular posterior wall thickness added to clinical variables in the prediction of 180-day mortality (Tables 2, 3).

Table 2. Univariate associations between echo predictors and 60-day death or re-admission by diagnosis groups Hypertensive CMP (n = 338) Hazard ratio (95% CI) p-value 0.98 (0.95–1.01) 0.15 0.98 (0.96– 1.00) 0.087 0.98 (0.89–1.09) 0.76 1.03 (0.91–1.15) 0.68 1.00 (1.00–1.00) 0.44 1.07 (0.97–1.18) 0.16 1.02 (0.97– 1.06) 0.46 1.00 (1.00–1.00) 0.083 0.93 (0.65–1.31) 0.67 1.00 (0.99–1.00) 0.65 1.01 (1.00–1.02) 0.25

Valvular (n = 217) Hazard ratio (95% CI) p-value 1.02 (0.99–1.05) 0.29 1.01 (0.98–1.04) 0.47 0.98 (0.88– 1.10) 0.77 0.97 (0.85– 1.10) 0.59 1.00 (1.00–1.00) 0.63 0.99 (0.89– 1.11) 0.86 1.01 (0.98– 1.05) 0.57 1.00 (1.00–1.00) 0.49 1.67 (0.75– 3.75) 0.21 1.00 (0.99–1.00) 0.24 1.01 (1.00–1.01) 0.049

Other (n = 399) Hazard ratio (95% CI) p-value 1.01 (0.99–1.03) 0.49 1.00 (0.98–1.02) 0.92 0.93 (0.85–1.02) 0.12 0.93 (0.84–1.04) 0.19 1.00 (1.00–1.00) 0.59 0.99 (0.91–1.08) 0.82 1.00 (0.97– 1.03) 0.97 1.00 (1.00–1.00) 0.055 1.15 (0.85–1.55) 0.37 1.00 (0.99–1.01) 0.73 0.99 (0.99–1.00) 0.17

Interaction Echocardiographic parameter p-value LVEDD (mm) 0.17 LVESD (mm) 0.20 IVSTd (mm) 0.64 PWTd (mm) 0.47 LV mass 0.62 LVEF (%), per 5% increment 0.42 Left atrial size (A-P) (mm) 0.83 0.73 Left atrial size (planimetry) mm2 E/A ratio per doubling 0.35 E-wave deceleration time (ms) 0.77 MV A-wave duration 0.056 MV E/A ratio grades Grade 1: impaired relaxation (reference group) (reference group) (reference group) Grade 2: pseudonormal 1.63 (0.66–3.98) 0.32 – 0.78 (0.29–2.09) 0.63 0.18 Grade 3: restrictive filling 0.93 (0.39–2.18) – 1.13 (0.49–2.58) LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; IVSTd, interventricular septal thickness in diastole; PWTd, posterior wall thickness in diastole; LV, left ventricular; LVEF, left ventricular ejection fraction; A-P, antero-posterior; MV, mitral valve. Heart rates are for an increment of one unit in the predictor unless otherwise noted. Valvular group defined as rheumatic heart disease or having severe mitral stenosis/regurgitation, aortic stenosis/regurgitation.

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Table 3. Univariate associations between echo predictors and 180-day death by diagnosis groups Hypertensive CMP (n = 338) Hazard ratio (95% CI) p-value 0.98 (0.96–1.01) 0.25 0.99 (0.96–1.01) 0.28 0.95 (0.85–1.06) 0.34

Valvular (n = 217) Hazard ratio (95% CI) p-value 1.01 (0.98–1.04) 0.47 1.01 (0.99–1.04) 0.32 0.99 (0.89–1.09) 0.80

Other (n = 399) Hazard ratio (95% CI) p-value 1.02 (1.00–1.04) 0.12 1.01 (0.99–1.03) 0.19 0.91 (0.84–1.00) 0.041

Interaction Echocardiographic parameter p-value LVEDD (mm) 0.17 LVESD (mm) 0.20 IVSTd (mm) 0.50 PWTd (mm) ≤ 9 mm 0.58 (0.42–0.80) 0.79 (0.57–1.10) 0.82 (0.67–1.00) 0.0011 0.32 0.072 0.30 1.73 (1.16–2.59) 1.38 (0.91– 2.11) 1.19 (0.88–1.62) > 9 mm LV mass 1.00 (0.99–1.00) 0.097 1.00 (1.00–1.00) 0.85 1.00 (1.00–1.00) 0.62 0.36 LVEF (%), per 5% increment 1.00 (0.90–1.11) 0.99 0.95 (0.85–1.06) 0.36 0.93 (0.86–1.02) 0.11 0.59 Left atrial size (A-P) (mm) 0.99 (0.94–1.03) 0.52 1.01 (0.97–1.04) 0.79 0.99 (0.96–1.02) 0.63 0.79 1.00 (1.00–1.00) 0.70 1.00 (1.00–1.00) 0.78 1.00 (1.00–1.00) 0.34 0.72 Left atrial size (planimetry) mm2 E/A ratio, per doubling 1.03 (0.74–1.43) 0.89 2.07 (1.01–4.26) 0.049 1.13 (0.86–1.49) 0.38 0.21 E-wave deceleration time (ms) 1.00 (0.99–1.00) 0.23 1.00 (1.00–1.00) 0.42 1.00 (0.99–1.00) 0.15 0.68 MV A-wave duration 1.00 (0.99–1.01) 0.63 1.01 (1.00–1.01) 0.12 1.00 (0.99–1.01) 0.47 0.26 MV E/A ratio grades Grade 1: impaired relaxation (reference group) (reference group) (reference group) Grade 2: pseudonormal 1.63 (0.67–3.98) 0.50 0.82 (0.07–8.99) 0.14 2.71 (0.91–8.04) 0.20 0.27 Grade 3: restrictive filling 1.14 (0.50–2.61) 3.01 (0.40–22.68) 2.16 (0.76–6.15) LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; IVSTd, interventricular septal thickness in diastole; PWTd, posterior wall thickness in diastole; LV, left ventricular; LVEF, left ventricular ejection fraction; A-P, antero-posterior; MV, mitral valve. Heart rates are for an increment of one unit in the predictor unless otherwise noted. Valvular group defined as rheumatic heart disease or having severe mitral stenosis/regurgitation, aortic stenosis/regurgitation.

Discussion A thorough and complete echocardiographic examination has been shown to be a useful diagnostic test in the evaluation of patients with HF.15 Although it is widely used to evaluate cardiac structure and function in patients with HF, few data are available regarding its ability to predict outcomes.16 In the case of acute HF, the precise association of LVEF with cardiovascular outcomes in patients with acute decompensated HF is controversial.17 Because the LVEF measure is load dependent and varies with haemodynamic status, it may underestimate or overestimate true myocardial function in various pathophysiological conditions and precipitants of acute decompensation. A prospective study reported that LVEF was weakly correlated with haemodynamic measures and clinical outcomes in patients with acute HF.18 Various therapeutic interventions can reduce the risk of re-admissions and death in patients admitted with HF. Therefore, identification of patients at the highest risk of re-admission or death could help provide targeted costeffective interventions. Although several studies have assessed potential echocardiographic predictors, the results have been inconsistent.19,20 A large number of variables can be measured or calculated by echocardiographic and Doppler imaging. It is not clear which echocardiographic measurements provide independent prognostic information. In our study, echocardiographic parameters showed only limited associations between echocardiographic measures and outcomes. Heart rate (which can be obtained by simple physical examination) and left atrial size were associated with death or re-admission within 60 days, and left ventricular posterior wall thickness and presence of aortic stenosis were associated with the risk of death up to 180 days. In agreement with the results of the PROTECT study modelling,10 LVEF was not associated with 60-day death or re-admission or with 180-day mortality.

This finding contrasts with data from the ESCAPE study, where echocardiographic measures of LV size and function did change from baseline to follow up and were associated with some outcomes.21 However, the ESCAPE study enrolled patients with end-stage cardiomyopathy who had very significant LV dysfunction at baseline. These patients were different from the majority of acute HF patients, particularly those enrolled in the THESUS registry. The results of the current study confirming the preliminary findings of Gandhi et al.9 and the retrospective analysis of the PROTECT study10 raise the question of why in the general population of patients admitted for acute HF, echocardiographic measures of left ventricular function and size were not associated with outcomes. This puzzling finding suggests that the pathophysiology of acute HF may differ from that of chronic HF by being less dependent on systolic function and, as suggested by Gandhi et al.,9 more driven by factors that cause cardiac and vascular stiffening, manifesting as diastolic dysfunction. Left ventricular hypertrophy (LVH) is a recognised complication of systemic hypertension and the best-studied marker of hypertensive heart disease.22 LVH strongly predicts cardiovascular morbidity and mortality in hypertensive patients, and is an independent risk factor for overall cardiovascular mortality and morbidity.23 It is known to cause a reduction in myocardial coronary reserve, which predisposes to myocardial ischaemia and left ventricular dysfunction, thereby causing increased incidence of coronary heart disease among hypertensives.24 This finding should encourage increased efforts for screening and treatment of young hypertensive patients, in Africa and throughout the world, to prevent the progression of hypertension to LVH. The increased risk of patients with severe valvular heart disease, particularly aortic stenosis, is well documented.25 The

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Table 4. Univariate associations between echo predictors and 60-day death/re-admission

Table 5. Univariate associations between echo predictors and 180-day mortality

Echocardiographic parameter Hazard ratio (95% CI) p-value Heart rate, per increment of 5 bpm 1.07 (1.02–1.13) 0.0088 LVEDD (mm) 1.00 (0.99–1.02) 0.81 LVESD (mm) 1.00 (0.98–1.01) 0.63 IVSTd (mm) 0.96 (0.91–1.01) 0.14 PWTd (mm) 0.97 (0.91–1.03) 0.34 LV mass 1.00 (1.00–1.00) 0.63 LVEF (%), per 5% increment 1.02 (0.96–1.07) 0.58 Left atrial size (A-P) (mm) 1.01 (0.99–1.03) 0.57 1.00 (1.00–1.00) 0.030 Left atrial size (planimetry) mm2 E/A ratio, per doubling 1.07 (0.86–1.34) 0.53 E-wave deceleration time (ms) 1.00 (0.99–1.00) 0.13 MV A-wave duration 1.00 (1.00–1.01) 0.43 MV E/A ratio grades Grade 1: impaired relaxation (reference group) Grade 2: pseudonormal 1.07 (0.55–2.06) 0.61 Grade 3: restrictive filling 1.28 (0.72–2.26) Aortic stenosis None, mild (reference group) Moderate 1.83 (0.45–7.41) 0.69 Severe 0.90 (0.22–3.65) Aortic regurgitation None, mild (reference group) Moderate 1.20 (0.61–2.36) 0.072 Severe 2.42 (1.13–5.19) Mitral stenosis None, mild (reference group) Moderate 1.56 (0.58–4.22) 0.50 Severe 0.64 (0.20–2.00) Mitral regurgitation None, mild (reference group) Moderate 0.95 (0.63–1.41) 0.95 Severe 1.03 (0.60–1.76) Tricuspid regurgitation None, mild (reference group) Moderate 1.41 (0.94–2.11) 0.23 Severe 1.21 (0.66–2.21) LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; IVSTd, interventricular septal thickness in diastole; PWTd, posterior wall thickness in diastole; LV, left ventricular; LVEF, left ventricular ejection fraction; A-P, antero-posterior; MV, mitral valve. Heart rates are for an increment of one unit in the predictor unless otherwise noted.

Echocardiographic parameter Hazard ratio (95% CI) p-value Heart rate ≤ 80 bpm, per change of 5 0.90 (0.76–1.06) 0.0001 1.25 (1.03–1.52) > 80 bpm, per change of 5 LVEDD (mm) 1.01 (0.99–1.02) 0.39 LVESD (mm) 1.01 (0.99–1.02) 0.38 IVSTd (mm) 0.94 (0.89–0.99) 0.025 PWTd (mm) ≤ 9 mm 0.77 (0.67–0.89) 0.0009 1.32 (1.08–1.61) > 9 mm LV mass 1.00 (1.00–1.00) 0.22 LVEF (%), per 5% increment 0.96 (0.91–1.01) 0.12 Left atrial size (A-P) (mm) 1.00 (0.98–1.01) 0.64 1.00 (1.00–1.00) 0.50 Left atrial size (planimetry) mm2 E/A ratio, per doubling 1.13 (0.92–1.39) 0.23 E-wave deceleration time (ms) 1.00 (0.99–1.00) 0.07 MV A-wave duration 1.00 (1.00–1.01) 0.61 MV E/A ratio grades Grade 1: impaired relaxation (reference group) Grade 2: pseudonormal 1.77 (0.92–3.38) 0.19 Grade 3: restrictive filling 1.67 (0.92–3.03) Aortic stenosis None, mild (reference group) 0.039 Moderate 3.60 (1.33– 9.74) Severe 0.83 (0.21–3.36) Aortic regurgitation None, mild (reference group) 0.096 Moderate 0.93 (0.46–1.90) Severe 2.30 (1.07–4.92) Mitral stenosis None, mild (reference group) 0.89 Moderate 0.99 (0.31–3.10) Severe 0.79 (0.29–2.12) Mitral regurgitation None, mild (reference group) 0.87 Moderate 0.92 (0.62–1.34) Severe 1.05 (0.63–1.74) Tricuspid regurgitation None, mild (reference group) 0.53 Moderate 1.26 (0.85–1.86) Severe 1.04 (0.57–1.89) LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; IVSTd, interventricular septal thickness in diastole; PWTd, posterior wall thickness in diastole; LV, left ventricular; LVEF, left ventricular ejection fraction; A-P, antero-posterior; MV, mitral valve. Heart rates are for an increment of one unit in the predictor unless otherwise noted.

confirmation in our study of the increased risk of these patients when admitted for acute HF is important, adding to the evidence encouraging a low threshold for evaluation and treatment of patients with suspected aortic stenosis. Left atrial enlargement has been increasingly suggested in recent years to be an important indicator of increased risk for an adverse clinical outcome. Left atrial enlargement may serve as an indicator for persistent increased pressure within the cardiovascular system, possibly representing longerterm changes, such as the role of HbA1c in diabetes mellitus. Furthermore, the left atrium modulates left ventricular filling and cardiovascular performance by functioning as a reservoir for pulmonary venous return during ventricular systole, a conduit for pulmonary venous return during early ventricular diastole, and a booster pump that augments ventricular filling during

late ventricular diastole. Therefore, left atrial enlargement (and possibly associated dysfunction) may play an important role not only in the marking of cardiovascular dysfunction but also in its enhancement. The finding that left atrial size is associated with adverse outcomes begs the question of why measures of diastolic dysfunction were not predictive of such adverse outcomes in the current cohort. Although the reasons for that cannot be ascertained, given the limitations of the study (see below), it is possible that, as described by Gandhi et al.,9 measures of diastolic dysfunction improve rapidly after admission in patients

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with acute HF. Because the echocardiographic evaluations performed in the current study were not done close to the time of admission in many patients, the worst measures may have been missed. It is also possible that some specific characteristics of the patient population may have contributed to this lack of association. Increased resting heart rate is a known predictor for cardiovascular mortality and morbidity in a variety of cardiovascular diseases, including HF.26 In patients with reduced LVEF, with or without signs or symptoms of HF, high heart rate has predicted adverse outcomes, irrespective of other known risk factors.27 Several pathophysiological mechanisms, including blunting of the force–frequency relationship, the induction of myocardial ischaemia, precipitation of rhythm disturbances, and acceleration of atherosclerosis have been proposed to explain the association between higher heart rate and worse outcomes in patients with HF.26 Higher heart rate might also be a marker of greater neurohormonal activation. The SHIFT study showed that heart rate is important in the pathophysiology of HF with reduced LVEF, and that heart rate reduction per se is a mechanism responsible for improvement in clinical outcomes.28 The CHARM investigators also found that the value of resting heart rate in predicting worse outcomes was independent of baseline left ventricular systolic function in heart failure.29 A higher heart rate was associated with a greater risk of hospital stay for HF, both in patients with reduced and preserved LVEF in a post hoc analysis of the DIG (Digitalis Investigation Group) trial. In predicting mortality, however, higher heart rate was only significant in patients with a reduced LVEF.30 Similar to our findings, left atrial size or its surrogates have been shown to predict hospitalisation for HF and death in other studies.31 Left atrial size predicts death among high-risk groups, such as patients with dilated cardiomyopathy, LV dysfunction, atrial arrhythmias, acute myocardial infarction, as well as in in the general population.32 Left atrial size, aortic stenosis, heart rate and measures of hypertrophy had some value in predicting outcome in our cohort. This may suggest that early diagnosis and treatment of hypertension and valvular heart disease in sub-Saharan Africa should be emphasised to improve outcome.

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Consequently, these findings may not apply to older patients or to those with preserved LVEF.

Conclusions In accordance with previous studies, echocardiographic variables, especially those of left ventricular size and function, were found to have little or no additional predictive value in patients admitted for acute HF. Left atrial size was associated with death or re-admission within 60 days while left ventricular posterior wall thickness and the presence of aortic stenosis were associated with the risk of death within 180 days. There is a need for further studies of echocardiographic evaluation, especially when performed closer to the acute event, to further elucidate the pathophysiology and risk stratification of patients with acute HF. The THESUS-HF study was funded by Momentum Research Inc, Durham, North Carolina, United States of America

Reference 1.

Antony KK. Pattern of cardiac failure in northern savanna Nigeria. Trop Geogr Med 1980; 32: 118–125.

Oyoo GO, Ogola EN. Clinical and socio demographic aspects of congestive heart failure patients at Kenyatta National Hospital, Nairobi. East Afr Med J 1999; 76: 23–27.

Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries: results of the sub-Saharan Africa Survey of Heart Failure. Arch Intern Med 2012; 172: 1386–1394.

Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005; 149: 209–216.

O’Connor CM, Whellan DJ, Wojdyla D, Leifer E, Clare RM, Ellis SJ, et al. Factors related to morbidity and mortality in patients with chronic heart failure with systolic dysfunction: the HF-ACTION Predictive Risk Score Model. Circ Heart Fail 2012; 5: 63–71.

Limitations Our data should be interpreted in the context of their limitations. Unobserved variables may have confounded the results. Not all echocardiographic parameters were available in all patients, limiting the number of parameters for analysis. The variable timing of the echocardiogram and inter-observer variability may have affected the specific results obtained. Furthermore, the number of events was small. Therefore both the variable selection and the parameter estimates for the selected variables are subject to instability. We also looked at echo predictors of acute HF from various causes. Even though there was no statistically significant interaction between the echo variables, different conditions and outcomes, there could still be a dilutional effect of grouping heterogeneous conditions together. Finally, our results are drawn from a population of young acute HF patients predominantly with systolic dysfunction.

Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001; 38: 2101–2113.

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803–869.

Carluccio E, Dini FL, Biagioli P, Lauciello R, Simioniuc A, Zuchi C, et al. The ‘Echo Heart Failure Score’: an echocardiographic risk prediction score of mortality in systolic heart failure. Eur J Heart Fail 2013; 15: 868–876.

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Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin

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KM, et al. The pathogenesis of acute pulmonary edema associated with

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Medicaid-enrolled patients hospitalized with systolic heart failure. Circ

10. Cleland JG, Chiswell K, Teerlink JR, Stevens S, Fiuzat M, Givertz MM,

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et al. Predictors of postdischarge outcomes from information acquired

21. Ramasubbu K, Deswal A, Chan W, Aguilar D, Bozkurt B.

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Echocardiographic changes during treatment of acute decompensated

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Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Study. Circ Heart Fail 2014; 7: 76–87. 11. Senni M, Parrella P, De Maria R, Cottini C, Böhm M, Ponikowski P, et al. Predicting heart failure outcome from cardiac and comorbid conditions: the 3C-HF score. Int J Cardiol 2013; 163: 206–211. 12. Stewart S, Wilkinson D, Hansen C, Vaghela V, Mvungi R, McMurray

792–798. 22. Frolich E.D Cardiac hypertrophy in hypertension. N Engl J Med 1987; 317: 831–833. 23. Kannel WB, Gorden T, Offutt D. Left ventricular hypertrophy by electrocardiography: prevalence, incidence, and mortality in the Framingham Heart Study. Ann Intern Med 1969; 71: 89–105. 24. Kannel WB. Prevalence and natural history of electrocardiographic LVH. Am J Med 1983; 65: 4–11.

J, et al. Predominance of heart failure in the Heart of Soweto Study

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of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010; 23: 685–713. 14. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458.

disease. J Am Coll Cardiol 2007; 50: 823–830. 27. Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al.; SHIFT investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010; 376: 886–894. 28. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama

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1785–1795. 30. Maeder MT, Kaye DM. Differential impact of heart rate and blood pressure on outcome in patients with heart failure with reduced versus preserved left ventricular ejection fraction. Int J Cardiol 2012; 155: 249–256.

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Case Report Hypertrophic angulation deformity of the basal interventricular septum combined with abnormality of the papillary muscle and chordae tendineae Yi Wang, Luwei Ye, Lixue Yin, Jie Zeng

Abstract A Chinese woman was admitted to our hospital because of syncope. Transthoracic echocardiography revealed a hypertrophic basal interventricular septum of 15 mm with a sharp angle protruding into the left ventricular outflow tract. Moreover, an anomalous anterolateral papillary muscle (maximum width of 11 mm) was inserted into the left ventricular outflow tract, with short chordae tendineae connecting both basal interventricular septum and anterior leaflet of the mitral valve. All of these abnormalities resulted in a left ventricular outflow gradient of 136 mmHg. Surgical septal myectomy of the sharp angle combined with partial papillary muscle resection and removal of the abnormal chordae tendineae was selected to relieve the left ventricular outflow obstruction. This was a rare combination of deformity of the angulation of the focal basal interventricular septum and abnormalities of the papillary muscle and chordae tendineae, which led to left ventricular outflow obstruction.

Keywords: angulation deformity, interventricular septum, papillary muscle, hypertrophic cardiomyopathy Submitted 24/7/15, accepted 6/4/16 Cardiovasc J Afr 2017; 28: e1–e3

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DOI: 10.5830/CVJA-2016-050

Case report A 43-year-old Chinese woman was admitted to our hospital because of syncope. Physical examination showed a loud systolic ejection murmur radiating to the neck. The electrocardiogram Institute of Ultrasound Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610072, China Yi Wang, MD Luwei Ye, MD Lixue Yin, PhD

Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610072, China Jie Zeng, MD, zengjie8302@126.com; zengjie999@sina.com

was normal. Transthoracic echocardiography revealed a hypertrophic basal interventricular septum (IVS) of 15 mm with a sharp angle protruding into the left ventricular outflow tract (LVOT). Moreover, an anomalous anterolateral papillary muscle (PM) (maximum width of 11 mm) was inserted into the LVOT, with short chordae tendineae connecting both the basal IVS and anterior leaflet of the mitral valve. All these abnormalities resulted in a LVOT gradient of 136 mmHg (Fig. 1A–D). In order to verify the large gradient and exclude other associated abnormalities, cardiac catheterisation was performed. There was no stenosis of the coronary artery, but after the catheter was put into the left ventricle, it immediately went into the aorta, which indicated a large gradient of the LVOT. Left ventriculography also demonstrated a narrow LVOT with a sharp angle. Surgery was selected to relieve the LVOT obstruction. Intraoperative transoesophageal echocardiography clearly showed the presence of a focal hypertrophic IVS and malposition of the PM (Fig. 1E). Through a standard median sternotomy, cardiopulmonary bypass was instituted by aortic/bicaval venous cannulation. After aortic cross-clamping, crystalloid cardioplegia solution was administered via the aortic root. The sharp angle of the IVS and the abnormal PM were demonstrated clearly after the extended transaortic approach was used (Fig. 2A, B). The first step was septal myectomy of the sharp angle via the aortic valve. Partial PM resection was also performed to relieve the obstruction. Unfortunately, after recovery of the heart beat, transoesophageal echocardiography showed that the LVOT gradient was still about 100 mmHg because of the malposition of the PM and the short chordae tendineae (Fig. 2C). The surgeon then removed the abnormal chordae tendineae and the anomalous muscular attachments of the PM in the LVOT until a bougie of 20 mm passed through the LVOT smoothly. The saline injection test revealed trivial mitral and aortic valve regurgitation. Histological examination showed cardiomyocyte hypertrophy and disarray, as well as interstitial fibrosis and inflammation, indicating a possible diagnosis of hypertrophic cardiomyopathy (HCM) (Fig. 3A, B). Unfortunately, the patient was unwilling to do any genetic testing. At the two-month follow up, transthoracic echocardiography demonstrated a LVOT gradient of 23 mmHg and no significant mitral valve insufficiency (Fig. 3C). In addition, the patient had no syncope or other uncomfortable symptoms. Institutional review board permission was obtained to report this case.

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 1, January/February 2017

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Fig. 1. L VOT obstruction due to basal IVS hypertrophy (A) and PM malposition (A, C). B shows the narrowed blood flow of the LVOT. Pulsed Doppler demonstrated a gradient of 136 mmHg (D). Intra-operative transoesophageal echocardiography (E) showing the sharp angle of the IVS (black arrow).

Discussion The cardiac phenotype of HCM shows great diversity in the degree and pattern of hypertrophy, such as asymmetric, concentric or apical.1 Asymmetric hypertrophy is often located in the whole IVS, not in a focal site. To the best of our knowledge, there has A

been only one case reported that revealed isolated posterobasal left ventricular free wall hypertrophy, which has extended the morphological diversity of HCM.2 In our case, the basal IVS not only showed hypertrophy, but also exhibited an angulation deformity, which has never C

Fig. 2. T he sharp angle of the basal IVS (A, black arrow) and anomalous long PM (B, black arrow) were demonstrated through a transaortic approach (* aortic valve). After the first recovery of heart beat, transoesophageal echocardiography showed the LVOT gradient was still about 100 mmHg (C).

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Fig. 3. H istological examination showed inflammation (A, black arrows), cardiomyocyte hypertrophy and disarray (B, *), as well as interstitial fibrosis (B, white arrows) (haematoxylin and eosin, ×100). At the two-month follow up, transthoracic echocardiography demonstrated a LVOT gradient of 23 mmHg (C).

been reported. The second interesting abnormality was the PM. It has been suggested that isolated PM hypertrophy is a possible variant of HCM, but only a few cases have been reported in the literature.3-6 Some of these patients presented with electrocardiographic findings, such as high left precordial voltage and inverted T waves, especially those with posteromedial PM hypertrophy.3,5 In our case, hypertrophy and malposition occurred at the anterolateral PM. Treatment of HCM is based on the anatomical abnormality. In a subset of patients with HCM, LVOT obstruction will be present not only because of septal hypertrophy, but also owing to muscular apposition created by the abnormal PM. Failure to recognise this anomaly would not relieve the obstruction.7 In our case, aside from the abnormal PM and IVS, the chordae tendineae connecting them with the mitral valve also contributed to the crowded LVOT. Pre-operative identification of these three contributors to LVOT obstruction altered the surgical strategy. Therefore, this patient underwent septal myectomy of the sharp angle, partial PM resection in the LVOT, as well as removal of the abnormal chordae tendineae. Excessive PM resection could have caused mitral valve insufficiency, which may have resulted in the need for mitral valve replacement or surgical mitral leaflet manipulation. Fortunately, the saline injection test showed only trivial mitral valve regurgitation. Redaelli et al.8 proposed a procedure to reposition the anterior PM followed by adjunctive implantation of a complete semi-rigid mitral ring to abolish the systolic anterior motion and residual mitral insufficiency. If our patient had had moderate to severe mitral regurgitation, a semi-rigid mitral ring or even mitral valve replacement would have been considered.

tendineae. Although we did not have genetic evidence, this abnormal combination may represent a gap in our knowledge of HCM. Careful echocardiographic and other radiological assessment is needed before surgery, which could change the diagnosis and management of HCM.

References 1.

Arad M, Seidman JG, Seidman CE. Phenotypic diversity in hypertrophic cardiomyopathy. Hum Mol Genet 2002; 11(20): 2499–2506.

Maron BJ, Sherrid MV, Haas TS, Lindberg J, Kitner C, Lesser JR. Novel hypertrophic cardiomyopathy phenotype: segmental hypertrophy isolated to the posterobasal left ventricular free wall. Am J Cardiol 2010; 106(5): 750–752.

Kobashi A, Suwa M, Ito T, Otake Y, Hirota Y, Kawamura K. Solitary papillary muscle hypertrophy as a possible form of hypertrophic cardiomyopathy. Jpn Circ J 1998; 62(11): 811–816.

Taşdemir O, Küçükaksu DS, Kural T, Bayazit K. Hypertrophic obstructive cardiomyopathy in combination with anomalous insertion of papillary muscle directly into anterior mitral leaflet and ‘sawfish’ systolic narrowing of the left anterior descending coronary artery. Tex Heart Inst J 1994; 21(4): 317–320.

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Maron BJ, Nishimura RA, Danielson GK. Pitfalls in clinical recognition and a novel operative approach for hypertrophic cardiomyopathy with severe outflow tract obstruction due to anomalous papillary muscle.

Conclusion Different mechanisms causing LVOT obstruction may occur in subgroups of patients with HCM. The mechanism of this rare LVOT obstruction resulted from focal basal IVS hypertrophy and angulation deformity, and abnormality of the PM and chordae

Circulation 1998; 98(23): 2505–2508. 8.

Redaelli M, Poloni CL, Bichi S, Esposito G. Modified surgical approach to symptomatic hypertrophic cardiomyopathy with abnormal papillary muscle morphology: Septal myectomy plus papillary muscle repositioning. J Thorac Cardiovasc Surg 2014; 147(5): 1709–1711.

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