CVJA Volume 29 Issue 5 by Clinics Cardive Publishing

SEPTEMBER/OCTOBER 2018 VOL 29 NO 5 A Lupin Group Company

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Lone atrial fibrillation at Groote Schuur Hospital • Rheumatic heart disease in Sudanese school children • Comparison of quantitative and qualitative coronary angiography • Microalbuminuria and left ventricular dysfunction in type 2 diabetes • Pregnant women on anticoagulation for mechanical heart valves

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• Ellisras Longitudinal Study conference 2017

• Cystatin C levels and mortality rates in acute decompensated heart failure Cardiovascular Journal of Africa . Vol 29, No 5, September/October 2018

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• Severity of valvular involvement in acute rheumatic carditis

• Prognostic significance of MPI in stable placental-mediated disease • Rheumatoid arthritis and risk of cardiovascular disease • Gender difference in atherosclerosis markers in peripheral artery disease? • PASCAR: certificate course in the management of hypertension in Africa

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Cardiovascular Journal of Africa

AFRICA

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

Vol 29, No 5, SEPTEMBER/OCTOBER 2018

CONTENTS

Cardiovascular Journal of Africa 267

www.cvja.co.za

FROM THE EDITOR’S DESK CARDIOVASCULAR TOPICS

268 Clinical characteristics and outcome of lone atrial fibrillation at a tertiary referral centre: the Groote Schuur Hospital experience V Thomas • S Schulein • RN Scott Millar • BM Mayosi 273

Echocardiographic screening for rheumatic heart disease in 4 515 Sudanese school children: marked disparity between two communities S Ali • S Domi • B Abbo • R Abbas • T Bushari • K Al Awad • A Elhassan • ME Abdel-Rahman

278

Comparison of quantitative and qualitative coronary angiography: computer versus the eye T Sen • C Kilit • MA Astarcioglu • LD Asarcikli • T Aksu • H Kafes • A Parspur • G Gozubuyuk • BA Masyali

283

Association of microalbuminuria with left ventricular dysfunction in Nigerian normotensive type 2 diabetes patients TT Shogade • IO Essien • UE Ekrikpo • IO Umoh • CT Utin • BC Unadike • JJ Andy

289

Haemorrhage and other complications in pregnant women on anticoagulation for mechanical heart valves: a prospective observational cohort study S Kariv • F Azibani • J Baard • A Osman • P Soma-Pillay • J Anthony • K Sliwa

296

The neutrophil-to-lymphocyte ratio and mean platelet volume can be associated with severity of valvular involvement in patients with acute rheumatic carditis SF Çelik • E Çelik

301

Ellisras Longitudinal Study 2017: The relationship between dietary intake and body mass index among young rural adults in South Africa aged 18 to 30 years (ELS 18) JTM Mashiane • KD Monyeki • AP Kengne • NM Rosina • MS Monyeki

INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

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

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

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

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

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

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 29, No 5, SEPTEMBER/OCTOBER 2018

305

The impact of admission cystatin C levels on in-hospital and three-year mortality rates in acute decompensated heart failure H Selcuk • MT Selcuk • O Maden • KG Balci • MM Balci • S Tekeli • EH Çetin • A Temizhan • M Balci • N Karabiber

310

The clinical prognostic significance of myocardial performance index (MPI) in stable placental-mediated disease I Bhorat • M Pillay • T Reddy

317

Rheumatoid arthritis and risk of cardiovascular disease PWA Meyer • R Anderson • JA Ker • MTM Ally

322

The role of novel atherosclerosis markers in peripheral artery disease: is there a gender difference? H Comşa • D Zdrenghea • SC Man • D Pop

331

Development of the certificate course in the management of hypertension in Africa (CCMH-Africa): proceedings of the first continental faculty meeting, Nairobi, Kenya, 25–26 February 2018 A Dzudie • D Ojji • A Damasceno • MU Sani • E Kramoh • JBA Kacou • B Anisiuba • E Ogola • M Awad • G Nel • H Otieno • AI Toure • A Kane • AP Kengne • C Ngwasiri • H Ba • S Kingue • B Mipinda • BE Mbolla • A Weldehana • F Bukachi • B Gitura • B Kitio • B Rayner • AE Shutte • AO Mocumbi • B Mayosi • A Jose • B Sandeep • M Weber • C Delles • F Cappuccio • H Gamra • D Prabhakaran • N Poulter • S Subhani • on behalf of the PASCAR task force on hypertension

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

REVIEW ARTICLES

PASCAR REPORT

financial & production co-ordinator ELSABÉ BURMEISTER Tel: 021 976 8129 Fax: 086 664 4202 Cell: 082 775 6808 e-mail: elsabe@clinicscardive.com

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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 29, No 5, September/October 2018

267

From the Editor’s Desk It is a great pleasure to invite you as readers to enjoy the content of this issue of the Journal and to reflect on its impact on our continent. As always we try to ensure that the articles submitted and accepted for publication are illustrative of the health-related issues of the people of the continent and also the efforts of individuals, organisations and professional societies to resolve outstanding issues. Ali and collaborators report on a large echocardiographic screening programme of school children in Sudan (page 273) for rheumatic heart disease (RHD). They used hand-held echo and modifications of the World Heart Federation protocol to examine children in Khartoum and Darfur. The examinations were performed by operators with different levels of expertise and they used different protocols. Despite criticisms that can be raised on these methodological aspects, acknowledged by the authors, the results are of importance. Firstly, RHD remains very common in children in parts of Africa. Secondly, there is an ‘economic gradient’, with RHD being more prevalent in areas with poor socioeconomic conditions. Thirdly, surveillance screening such as this allows for health planners to target programmes for secondary prevention, which need to be instituted urgently. Lastly and most importantly, politicians and society as a whole need to target the improvement of living conditions of marginalised communities if societal health is to be improved. The number of children diagnosed with definite RHD in Darfur poses a huge potential burden for the healthcare environment of the future. Very few, if any, African countries have the requisite skilled personnel or financial resources to cope with this potential future demand. Bearing in mind that for most patients with chronic RHD, the only relief of intractable symptoms is valve-replacement surgery (rarely repair), it is relevant to examine the complications resulting from necessary anticoagulation of such patients. Kariv and co-investigators (page 289) examined the very difficult issue of managing young, pregnant female patients who had undergone valve-replacement surgery (the majority for RHD). They conclude ‘Complication rates were high despite centralised care’. These results are from a tertiary-level hospital with a dedicated maternity/obstetric clinic. I have no idea how this relates to secondary and primary levels of care, but they may be the best we can achieve. They indicate that young women with prosthetic valve replacements who are on anticoagulants such as warfarin are at high risk during pregnancy. The newer oral anticoagulants are unproven for valve replacement and are untested in pregnancy.

Professor PJ Commerford

A personal view, which may well be controversial, has been to advise young women with RHD to complete their families before valve-replacement surgery is necessary and then to adopt a form of effective and life-long contraception that will permit them to see their children grow and enjoy the benefits of a mother. Few subjects elicit as much controversy as the influence of diet on health. Monyeki and colleagues (page 301) report on the Ellisras study and confirm a concerning high prevalence of overweight and obesity in a rural community. The future implications for the over-stretched healthcare sector remain unresolved. The Journal is the official journal of PASCAR and is happy to publish the report (page 331) of the development of the certificate course in the management of hypertension in Africa. Pat Commerford Editor-in-Chief

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CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 29, No 5, September/October 2018

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Cardiovascular Topics Clinical characteristics and outcome of lone atrial fibrillation at a tertiary referral centre: the Groote Schuur Hospital experience Vinod Thomas, Simone Schulein, Robert N Scott Millar, Bongani M Mayosi

Abstract Introduction: Atrial fibrillation (AF) is a relatively common arrhythmia. When AF represents an electrophysiological phenomenon in structurally normal hearts, it is termed lone AF. This study was a retrospective, case-based analysis of patients attending the Cardiac Clinic at Groote Schuur Hospital (GSH) and describes the clinical characteristics and outcomes of patients classified as having lone atrial fibrillation. To the best of our knowledge there are no such studies reported from Africa. Methods: This was a retrospective, descriptive study in which 289 medical records of patients with AF at the GSH Cardiac Clinic were reviewed from 1992 to 2006. The clinical data were interrogated to exclude identifiable causes of AF. Information on clinical characteristics and outcomes were entered into a data-entry form. Baseline descriptive statistics were expressed as means and range for continuous variables, and counts with percentages for categorical variables. Results: Fifteen per cent (n = 42) of patients were identified as having lone AF, with a mean follow-up time of 5.8 years. Males comprised 57% (n = 24) and females 43% (n = 18). Fifty per cent (n = 21) of the patients had paroxysmal AF, 29% (n = 12) had persistent AF, and 12% (n = 5) progressed from paroxysmal to permanent AF. Subsets of lone AF included concomitant atrial flutter (17%) (n = 7) and sick sinus syndrome (21%) (n = 9). Complications were stroke (10%) (n = 4), tachycardia-related cardiomyopathy (17%) (n = 7) and bleeding complications on warfarin (11%) (n = 3). Conclusion: Lone AF is not an uncommon arrhythmia, with a preponderance in thin, middle-aged males. The symptoms of lone AF can be debilitating. It has associated morbidity, including tachycardia-related cardiomyopathy and thromboembolism. Rate control and appropriate anticoagulation are the cornerstones of patient management.

The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa Vinod Thomas, MB ChB (Wits), FCP (SA), vndthomas21@gmail.com Simone Schulein MB ChB, FCA (SA) Robert N Scott Millar MB ChB, FCP (SA) Bongani M Mayosi MB ChB, FCP (SA), DPhil (Oxford)

Keywords: lone atrial fibrillation, paroxysmal atrial fibrillation, persistent atrial fibrillation, tachycardia-related cardiomyopathy, stroke, anticoagulation, sick sinus syndrome, atrial flutter Submitted 25/5/17, accepted 14/1/18 Cardiovasc J Afr 2018; 29: 268â&#x20AC;&#x201C;272

www.cvja.co.za

DOI: 10.5830/CVJA-2018-005

Atrial fibrillation (AF) is a common and obstinate arrhythmia that represents a growing epidemic, with significant health consequences. It is often difficult to manage. The classical risk factors for developing AF include hypertension, valvular heart disease, thyroid disease and cardiomyopathies, including those related to ischaemia.1 In some patients with AF, no underlying cardiovascular pathology is present and the aetiology remains unknown. This is known as lone atrial fibrillation. Lone AF accounts for three to 20% of cases of atrial fibrillation.2,3. The concept of lone AF is arbitrary and negative: the absence of detectable structural heart disease. There is increasing evidence that from a pathophysiological point of view, the underlying mechanism of lone AF is different from that of AF in the setting of underlying structural heart disease. The latter is more substrate related, showing diseased and dilated atria due to stretch and fibrosis. By contrast, lone AF is probably more related to electrophysiological phenomena in apparently structurally normal atria. This explains why patients with lone AF have a normal life expectancy compared with individuals without arrhythmia, a lower risk of heart failure, and why paroxysmal lone AF has a lower risk of progression to persistent or permanent AF.3-5 By contrast, AF in the setting of underlying cardiac pathology usually progresses from paroxysmal to persistent and/or permanent AF and is associated with an increased incidence of stroke, heart failure and death. Although lone AF follows a relatively benign course, it adversely affects the quality of life and exercise capacity of affected individuals.6 Regular follow up of lone AF patients is essential, as in time, risk factors such as hypertension, diabetes and ischaemic heart disease may develop, thereby altering the prognosis.2,4,6 Recurrent paroxysms of AF in patients with lone AF may also predispose to the formation of an atrial structural substrate, which in time leads to left atrial dilatation.7-9 This in turn increases the risk of progression to persistent or permanent AF, with its attendant increased risk of stroke and tachycardia-

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018

related cardiomyopathy.7-9 Recently, in addition to the classical risk factors, there is an increasing body of evidence linking lone AF to several novel genetic, molecular and pathophysiological mechanisms, thereby making it a ‘not-so-lone AF’.10,11 The autonomic nervous system plays an integral role in the onset and offset of AF. Triggers for AF include adrenergicmediated states such as the alcohol-associated ‘holiday heart’,12,13 caffeine14 and dehydration.15 This can be contrasted with vagallymediated states such as sleep, postprandial and post-exercise situations that tend to be triggers for AF in tall, lean and physically fit middle-aged males involved in endurance sports.16-19 On the other hand, the pathophysiology of AF noted in overweight patients has been linked to the inflammatory state associated with the metabolic syndrome.20,21 There are several subsets of lone AF, including familial AF22-24 and AF associated with conduction system disorders, such as sick sinus syndrome (SSS) or the bradycardia–tachycardia syndrome.25 In the near future it is hoped that elucidating the aetiology of lone AF will lead to a more tailored and therapeutic approach to the management of AF. To the best of our knowledge, there are no studies to describe the clinical characteristics and outcomes of patients with lone AF in Africa and other developing regions of the world. The purpose of this study was to describe the clinical characteristics and outcomes of patients with lone AF attending Groote Schuur Hospital (GSH) in Cape Town.

Methods This study was a retrospective, descriptive study of the clinical characteristics and outcomes of patients with lone AF who attended GSH from January 1992 to December 2006. All medical records of patients with AF over this 15-year period were reviewed to identify those with lone AF. The patients had presented to GSH Emergency Department, had already been attending the Cardiac Clinic or had been referred to the Cardiac Clinic from day hospitals or private medical institutions. The medical records were reviewed for findings of their clinical examinations, electrocardiograms, echocardiograms, chest X-rays, laboratory results and, if clinically indicated, the 24-hour Holter, exercise stress test and coronary angiograms. Our inclusion and exclusion criteria were comparable to the Mayo Clinic series,2,3 the exception being the subset of patients who had AF and concomitant SSS, which we included in the study. Patients with any of the following at the initial diagnosis of AF were excluded from the study: hypertension treated with medication, or systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg on two or more consecutive occasions; coronary artery disease according to clinical or laboratory data; hyperthyroidism as per laboratory data; left bundle branch block or pre-excitation on electrocardiogram; valvular heart disease; chronic obstructive airway disease; idiopathic dilated cardiomyopathy; and patients who developed atrial fibrillation in the context of an acute medical or surgical condition. We included patients with systolic blood pressures recorded between 140 and 160 mmHg or diastolic pressures between 80 and 90 mmHg on fewer than two consecutive occasions, as long as there was no evidence of left ventricular hypertrophy on the electrocardiogram or echocardiogram; elderly patients over 60 years, to assess their clinical characteristics and outcomes;

269

patients with documented AF and concomitant flutter or SSS; and those with documented echocardiograms. More inclusion criteria than those used in previous studies were chosen, to investigate a population without any evidence of organic heart disease at the first presentation, which may reflect what is commonly found in clinical practice. Although the Mayo Clinic series2,3 did not include patients with AF/SSS, a subsequent study25 did include these subjects. Patients who had symptoms and signs of heart failure and/ or a dilated left ventricle on echocardiogram in the absence of classical risk factors or metabolic causes and with a normal QRS duration and morphology at the initial diagnosis of AF (normal apart from the AF) were included only if they demonstrated a subsequent improvement of their symptoms and signs of heart failure and left ventricular function on repeat echocardiogram, once their rate was controlled. The following baseline characteristics were entered into a data-entry form: age at diagnosis, follow-up time, gender and race (white, black or mixed race). The height and weight of patients were noted and a body mass index of < 25 kg/m2 was considered normal and > 25 kg/m2 was considered to be overweight. The type of AF (paroxysmal or persistent) and the number of patients who progressed from paroxysmal to permanent AF, and subsets of patients with atrial flutter and conduction system disease were noted. Family history was reviewed. Presenting symptoms, their duration and possible triggering factors were noted. Mortality rate and complications, including tachycardiarelated cardiomyopathy and thromboembolism were recorded. Therapy instituted to control or terminate the AF was reviewed. The indications and therapy chosen for prevention of thromboembolism were reviewed. The number of patients who developed bleeding complications while on anticoagulants was also reviewed. Baseline descriptive statistics were expressed as means and range for continuous variables. Counts with percentages were used for categorical variables.

Results Of the 289 patients with AF in the period under review, 42 were identified as having lone AF (15% of all patients with AF). The mean follow-up time of these patients was 5.8 years. Males comprised 57% (n = 24), and 43% (n = 18) were females. The mean age of the males at diagnosis was 46 years with no males being older than 60 years. The mean age of the females was 62.4 years; 55% (n = 10) were less than 65 years of age at the time of diagnosis and they had a mean age of 45 years. The remaining 45% (n = 8) were older than 65 years. The racial composition was 50% (n = 21) white, 36% (n = 15) mixed race, 7% (n = 3) black and 7% (n = 3) not having their race specified. Forty three per cent (n = 18) of patients were of normal weight, 36% (n = 15) were overweight and 21% (n = 9) were not specified. At the time of diagnosis, 50% (n = 21) of the patients had paroxysmal AF, 29% (n = 12) had persistent AF and 12% (n = 5) progressed from paroxysmal to permanent AF over the followup period. Subsets of AF included those with concomitant atrial flutter (17%) (n = 7) and those with SSS (21%) (n = 9). A family history of AF or palpitations was poorly documented in the medical records.

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The reasons for seeking medical attention at the time of diagnosis varied. These included palpitations (71%) (n = 30), dizziness (64%) (n = 27), dyspnoea (45%) (n = 19), near blackouts (40%) (n = 17), chest pain (21%) (n = 9) and fatigue (21%) (n = 9). The mean duration of symptoms prior to presentation was 7.7 years. Triggers included exertion 26% (n = 11) and alcohol consumption (17%) (n = 7). Other triggers such as stimulant use, caffeine, postprandial states and sleep were not well elucidated on history in the medical records. Complications of lone AF included stroke (10%) (n = 4) and tachycardia-related cardiomyopathy (17%) (n = 7). No deaths were recorded. Therapy instituted included atrioventricular nodal blocking agents, such as beta-blockers (60%) (n = 25), digoxin (29%) (n = 12) and verapamil (14%) (n = 6). Often a combination of beta-blockers and digoxin was used. Twenty one per cent of patients (n = 9) required amiodarone. Twelve per cent (n = 5) had radiofrequency ablation of the concomitant AF and one patient had radiofrequency ablation of the atrial ectopic foci arising from the pulmonary veins. Ten per cent of patients (n = 4) went on to have an atrioventricular nodal ablation and permanent pacemaker insertion because of inadequate rate control with drugs. One patient was put onto flecainide and another onto propafenone. Cardioversion was attempted at least once in 29% (n = 12) of the patients. Eighty per cent of patients (n = 34) were on anticoagulant therapy. Sixty-seven per cent (n = 28) of our subjects were on warfarin and 26% (n = 11) were on aspirin. Eleven per cent (n = 3) had bleeding complications while on anticoagulation therapy with warfarin. There was a 12% (n = 5) crossover between the anticoagulants. Indications for warfarin included age over 75 years (n = 2); age between 60 and 75 years (n = 8); tachycardia-related cardiomyopathy (CHADS2 score 1) (n = 3); post stroke (CHADS2 score 2) (n = 3); possible or probable hypertension that developed during follow up (CHADS2 score 1) (n = 6); and myocardial infarction with heart failure (CHADS2 score 1) (n = 1) during follow up. Two patients had no clear indication for warfarin. Indications for aspirin included age over 75 years and patient reluctance to be on warfarin (n = 1); tachycardia-related cardiomyopathy (n = 1) (could not tolerate warfarin); and possible or probable hypertension that developed over time (n = 1). Three patients who had bleeding complications on warfarin were placed on aspirin. Two were placed on aspirin for lessrobust indications, such as dilated left atria. Three patients had no clear indications for aspirin

Discussion Fifteen per cent of the patients with AF presenting to the Cardiac Clinic at GSH over a 15-year period had lone AF. This finding is similar to other studies in which lone AF accounted for three to 20% of cases of AF.2,3 As opposed to most studies, our study included patients with lone AF over the age of 60 years at the time of diagnosis, as this is more reflective of what we see in our clinical practice. The male-to-female ratio of 1.3:1 was lower than that reported in most studies. Those studies did not however include patients over 60 years.2,4,9 If we excluded patients over the age of 60 years, males comprised 70% (n = 24) and females 30% (n = 10). The

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higher male-to-female ratio of 2.3:1 in patients under 60 years is in keeping with that found in other studies.2,4,9 If we excluded patients over the age of 60 years, the mean age for male patients at diagnosis was 46 years, and 45 years for females. The mean age for all patients under 60 years at diagnosis was 45.5 years, which is comparable to the mean age of 44 years found at the Mayo Clinic.2 This study is unique in that it included patients of various racial backgrounds. Fifty per cent (n = 21) were white, 36% (n = 15) were of mixed race and 7% (n = 3) were black. Seven per cent (n = 3) did not have their race specified. The differences mirror access to tertiary healthcare afforded to the various racial groups. Forty-three per cent (n = 18) of the patients were of normal weight (body mass index < 25 kg/m2), 36% were overweight (body mass index > 25 kg/m2) and 21% did not have their weight specified. This is of interest as there are epidemiological studies linking atrial fibrillation to obesity.20-22 Postulated mechanisms include the inflammatory state associated with the metabolic syndrome, neurohormonal activation, autonomic dysfunction associated with sleep apnoea, and increased left atrial size.10,11,16,20,21 It is intriguing to speculate that weight reduction may lower the risk of atrial fibrillation in this group of patients. As found in other studies, the majority of patients (50%) (n = 21) had paroxysmal AF and 29% (n = 12) had permanent AF. Twelve per cent (n = 5) progressed from paroxysmal to permanent AF, which is slightly higher than the 7.8% reported in the study by Patton et al.25 We also report on a subset of patients with lone AF and concomitant atrial flutter. Seventeen per cent of these patients (four males and three females) had one or more episodes of documented atrial flutter at diagnosis or during follow up. This is comparable to the 19.7% reported in the study by Patton et al.25 There was another subset of patients with structurally normal hearts, AF and associated SSS (SSS/AF) or the bradycardia– tachycardia syndrome. Twenty one per cent (n = 9) of our patients had SSS/AF in comparison to the 6% reported in the study by Patton et al.25 Seven of the nine patients had a permanent pacemaker inserted. Five patients were female, of whom three were older than 60 years. Interestingly, all three patients suffered a thromboembolic event. Four patients were males, all younger than 60 years. Traditionally, the bradycardia–tachycardia syndrome (SSS/ AF) is considered to be a degenerative, age-related disorder. Interestingly, it has recently been shown that AF and conductionsystem disorders tend to run in families and mutations in both the lamin A/C and the ankyrin 2 genes have been associated with this condition,26 therefore prioritising these genes to be potential candidates for further investigation into the likely aetiology of this subtype of AF. Triggers for symptoms of AF in our cohort included exertion (27%) and alcohol consumption (17%). Our figures are lower than that reported in the study by Paton et al.25 where patients reported their episodes to be triggered by adrenergic states such as alcohol consumption (34%) and exercise (36%). Seventeen per cent (n = 7) of patients developed a tachycardiarelated cardiomyopathy. This is comparable with the 18% reported in the study by Jahingir et al.4 Four of these patients presented with symptoms and signs of heart failure, rapid AF (otherwise normal ECG), left ventricular dilatation (otherwise normal echo), and normal metabolic screen. Their symptoms and signs resolved

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with rate control and there was a marked improvement in left ventricular function. The remaining three started with good left ventricular function that deteriorated due to poor rate control, thereby necessitating more drastic measures to achieve rate control. The mean age of our cohort of patients with heart failure was 45 years (range 28–73 years), which is less than the mean age of 74 years that was reported in the Jahingir et al. study.4 Ten percent of patients (n = 4) developed thromboembolic complications. One patient was a male who had developed hypertension over time. He consequently developed an ischaemic stroke that necessitated anticoagulation therapy with warfarin. This highlights the importance of constant vigilance for thromboembolic risk factors in lone AF patients during follow up. The remaining three patients with thromboembolic complications were females over the age of 60 years who were part of the subset of patients with AF and SSS or the bradycardia–tachycardia syndrome. They were not on any anticoagulation therapy prior to the stroke. Intriguingly, in the study by Rubenstein et al.,27 there was a high incidence of systemic embolisation in the SSS/AF patients, and they recommended anticoagulation in this group regardless of age or the CHADS2 score. They hypothesised that the fibrillating atria predispose to thrombus formation, and the sudden cessation of fibrillation predisposes to a thromboembolic event. This leaves scope for a study to assess whether young patients with frequent, recurrent episodes of paroxysmal lone AF are at higher risk of thromboembolism compared to the young general population and young patients with persistent/chronic lone AF. There were no deaths recorded in our series. This could have been due to the relatively short follow-up period of each individual patient (mean follow up of 7.7 years). The study by Kopecky et al.2 recorded a death rate of 20% over a 30-year follow-up period. Seventy per cent of the deaths were due to cardiovascular causes (coronary artery disease, heart failure, stroke and aortic aneurysms). Sixteen per cent of these deaths resulted directly from embolic events.2 At the GSH Cardiac Clinic, to improve symptoms, therapy is aimed at achieving rate or rhythm control, which can significantly improve quality of life and prevent complications such as tachycardia-related cardiomyopathy. Timely anticoagulation with aspirin or warfarin is instituted (if bleeding risk is low) to prevent thromboembolic complications. Cardioversion was attempted at least once in 29% (n = 12) of patients in an attempt to achieve rhythm control. Two patients who could afford the drugs were placed on class IC antiarrhythmics (flecainide/propafenone) in an effort to maintain sinus rhythm because of severe symptoms during AF. These agents may be used in young patients with structurally normal hearts, however due to various constraints in the public health sector, the use of class IC anti-arrhythmic drugs was limited. For rate control, 60% (n = 25) of patients were on betablockers, 29% (n = 12) were on digoxin and 14% (n = 6) on verapamil. Often beta-blockers were used in combination with digoxin. Rate control was considered adequate if the resting ventricular rate was < 80 beats/min. If patients failed to respond to rate-controlling agents or could not tolerate the side-effect profile of these atrioventricular nodalblocking agents, they were put on a class III anti-arrhythmic drug, such as amiodarone, in an attempt to maintain sinus rhythm. Twenty-two per cent (n = 9) progressed on to amiodarone. Of

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these patients, 67% (n = 6) developed complications related to the long-term use of amiodarone, including hypothyroidism (n = 2), hyperthyroidism (n = 2), interstitial pneumonitis (n = 1) and chronic inflammatory demyelinating polyneuropathy (n = 1). This emphasises the non-benign nature of this agent, and that the decision to place patients on long-term amiodarone should not be taken lightly. Sotalol was avoided due to its potential QT-prolonging effect and subsequent risk of torsades des pointes, which has been documented in patients with structurally normal hearts.28,29 Twelve per cent of patients (n = 5) had radiofrequency ablation of the concomitant atrial flutter and one patient had radiofrequency ablation of the atrial ectopic foci in the pulmonary veins. This form of AF ablation became available only late in the course of the study period. Ten percent of patients (n = 4) did not respond or developed an adverse side-effect profile on medical therapy and went on to have an atrioventricular nodal ablation and permanent pacemaker insertion. In patients who are refractory to medical management, options include atrioventricular nodal (AVN) ablation and pacemaker insertion, aso known as the ‘ablate and pace’ strategy. It is considered an extreme form of rate control. There is lifelong pacemaker dependency after this procedure. A recent meta-analysis by Chatterjee et al.30 compared AVN ablation with pharmacotherapy in patients with drug-refractory AF. Of the five studies included in the efficacy analysis, four were randomised trials, comprising 314 subjects in total. The efficacy analysis demonstrated that AVN ablation improved symptoms and quality of life significantly in patients with medically refractory disease, compared with pharmacotherapy alone.30 The GSH Cardiac Clinic policy is to assess the thromboembolic risk using the CHADS2 scoring system in patients who have AF without underlying structural heart disease, and balance this against the bleeding risk so that an anticoagulation strategy can be tailored for each patient. Patients considered to be at high risk for thromboembolism are those with congestive heart failure, hypertension, age above 75 years, diabetes mellitus and previous stroke. A CHADS2 score of 1 is at intermediate thromboembolic risk and aspirin is recommended. A CHADS2 score ≥ 2 is a high thromboembolic risk and warfarin is recommended.

Limitations Although the subjects in our study were identified retrospectively, the history of events was analysed prospectively from the time of diagnosis. The importance of these observational studies is determined by the paucity of patients with lone AF in randomised studies and their relatively short follow-up time. The sample size was relatively small but this was a consequence of strictly adhering to a clinical definition of lone AF in a geographically defined population. Our follow-up time of each individual patient was relatively short and this may have resulted in underestimation of certain events. Groote Schuur Hospital is a tertiary referral centre in the public sector and as a result, there may have been a referral bias in our cohort of patients. The number of subjects in some subsets was small and it may be premature to extrapolate the associations observed in this study to the general population with AF and no underlying organic heart disease. Additionally, these subjects were largely symptomatic, and there may be

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an under-representation of asymptomatic individuals in this cohort. The medical records were also lacking in information in certain areas, such as family history of lone AF. Despite careful attention to exclusion criteria, it is possible that occult cardiovascular disease may have been present in some patients, therefore overestimating the events.

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atrial fibrillation: hunting for the underlying causes and links. Int J Cardiol 2009; 131: 180–185. 12. Ettinger PO, Wu CF, De La Cruz C Jr, Weisse AB, Ahmed SS, Regan TJ. Arrhythmias and the “holiday heart”: alcohol-associated cardiac rhythm disorders. Am Heart J 1978; 95: 555–562. 13.

Frost L, Verstergaard P. Alcohol and risk of atrial fibrillation or flutter. Arch Int Med 2004; 164: 1993–1996.

Conclusions This is the first study to describe the clinical characteristics and outcomes of patients with lone AF in a racially diverse population in Africa. The clinical characteristics of the patients with lone AF who attended GSH were similar to those described in other studies. Lone AF occurs in all racial groups. Further phenotypic subsets of lone AF were characterised in the study and included lone AF with concomitant atrial flutter, and lone AF with concomitant SSS, which seems to be a strong risk factor for stroke. Additionally, a few patients who were initially characterised as having lone AF, developed risk factors for stroke with time, therefore emphasising the importance of constantly reviewing the indications for anticoagulation during the follow-up period.

14. Rashid A, Hines M,

Scherlag BJ, Yamanashi WS,

Lovallo W.

The effects of caffeine on the inducibility of atrial fibrillation. J Electrocardiol 2006; 39: 421–425. 15. Edwards JD, Wilkins RG. Atrial fibrillation precipitated by acute hypovolemia. Br Med J 1987; 294: 283–284. 16. Coumel P, Attuel P, Lavallée J, Flammang D, Leclercq JF, Slama R. The atrial arrhythmia syndrome of vagal origin. Arch Mal Coeur Vaiss 1978; 71(6): 645–656. 17. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial fibrillation in vigorously exercising middle-aged men: a case-control study. Br Med J 1998; 316: 1784–1785. 18. Mont L, Tamborero D, Elosua R, Molina I, Coll-Vinent B, Sitges M, et al; GIRAFA (Grup Integrat de Recerca en Fibril-lació Auricular) investigators. Physical activity, height and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals.

We thank Dr Lethukuthula Khanyi who contributed to this article as a medical student rotating in internal medicine.

Europace 2008; 10: 15–20. 19. Elosua R, Arquer A, Mont L, Sambola A, Molina L, García-Morán E, et al. Sport practice and the risk of lone atrial fibrillation: a case–control

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Kopecky SL, Gersch BJ, McGoon MD, et al. The natural history of lone atrial fibrillation: A population-based study over three decades. N Engl J Med 1987; 317: 669–674.

Kopecky SL, Gersch BJ, McGoon MD. Lone atrial fibrillation in elderly persons. Arch Intern Med 1999; 159: 1118–1122.

Jahangir A, Lee V, Friedman PA, Trusty JM, Hodge DO, Kopecky SL, et al. Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study. Circulation 2007; 115: 3050–3056.

Falk G, Fahey T. Patients with lone atrial fibrillation had low risk of progression to permanent atrial fibrillation, death, congestive heart failure and stroke. Evid Based Med 2008; 13: 24.

Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with atrial fibrillation: A systematic review. Am J Med. 2006; 119(448): e1–19.

1255–1260. 21. Aviles RJ, Martin DO, Apperson-Hansen C. Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108: 3006–3010. 22. Hodgson-Zingman DM, Karst ML,

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Darbar D, Herron KJ, et al. Atrial natriuretic peptide frameshift mutation in familial AF. New Engl J Med 2008; 359: 158–165. 23. Fatkin D, Otway R, Vandenberg JI. Genes and atrial fibrillation: A new look at an old problem. Circulation 2007; 116: 782–792. 24. Darbar D, Herron KJ, Ballew JD, Jahangir A, Gersh BJ, Shen WK, et al. Familial atrial fibrillation is a genetically heterogeneous disorders. J Am Coll Cardiol 2003; 41: 2185–2192. 25. Patton KK, Zacks ES, Chang JY, Shea MA, Ruskin JN, Macrae CA, Ellinor PT. Clinical subtypes of lone atrial fibrillation. PACE 2005; 28: 630–638.

Lloyd-Jones DM, Wang TJ, Leip AP. Lifetime risk for development of

26. Lévy S, Maarek M, Coumel P, Guize L, Lekieffre J, Medvedowsky JL,

atrial fibrillation: the Framingham Heart study. Circulation 2004; 110:

Sebaoun A. Characterization of different subsets of atrial fibrillation

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in general practice in France: the ALFA study. Circulation 1999; 99:

Osranek M, Bursi F, Bailey KR, Grossardt BR, Brown RD Jr, Kopecky SL, et al. Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up. Eur Heart J 2005; 26: 2556–2561.

study. Int J Cardiol 2006; 108: 332–337. 20. Watanabe H, Tanabe N, Watanabe T, Darbar D, Roden DM, Sasaki

Scardi S, Mazzone C, Pandullo C, Goldstein D, Poletti A, Humar F. Lone atrial fibrillation: prognostic differences between paroxysmal and chronic forms after 10 years of follow-up. Am Heart J 1999; 137: 686–689.

3028–3035. 27. Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of sick sinus syndrome. Circulation 1972; 46: 5–13. 28. Chatterjee NA, Upadhyay GA, Ellenbogen KA, et al. Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis and systematic review. Circ Arrhythmia Electrophysiol 2012; 5(1): 68–76. 29. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990; 65(Suppl): 74A–81A

10. Schoonderwoerd BA, Smit MD, Pen L, Gelder IC. New risk factors for

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Echocardiographic screening for rheumatic heart disease in 4 515 Sudanese school children: marked disparity between two communities Sulafa Ali, Sara Domi, Bahja Abbo, Rabab Abbas, Tajudeen Bushari, Khalid Al Awad, Abdelrahman Elhassan, Manar E Abdel-Rahman

Abstract Introduction: Echocardiographic (echo) screening has unmasked a high prevalence of subclinical rheumatic heart disease (RHD) in many countries, and it can be used as a surveillance tool to control the disease. Methods: School children of 10 to 15 years of age were selected in two areas of Sudan, Khartoum, the capital, and Niyala in western Sudan. Echo screening using a hand-held echo (HHE) was conducted in Khartoum using a three-view protocol, and in Niyala, a one-view protocol, both modified from the World Heart Federation protocol. Suspected cases were referred for standard echo study. Training of health personnel was conducted and health education sessions were delivered to the public. Results: In Khartoum, a total of 3 000 school children were screened; seven cases were positive for RHD using HHE and one case was confirmed by standard echocardiography. The prevalence of RHD using echocardiography was 0.3 per 1 000 children. In Niyala, a total of 1 515 school children were screened. Using HHE, 59 cases were positive for RHD; 44 had definite and 15 borderline disease. Out of 34 who underwent standard echocardiography, 29 (85.2%) were found to have RHD; 22 had definite and seven borderline disease. The prevalence using echocardiography was 19 per 1 000 children. A total of 779 health workers were trained in South Darfur and 50 000 posters and pamphlets were distributed.

Department of Paediatrics, Faculty of Medicine, University of Khartoum; and Department of Paediatric Cardiology, Sudan Heart Centre, Khartoum, Sudan Sulafa Ali, MD, FRCPCH, FACC, sulafaali2000@gmail.com

Department of Paediatric Cardiology, Sudan Heart Centre, Khartoum, Sudan Sara Domi, MD Rabab Abbas Tajudeen Bushari, MD Abdelrahman Elhassan, MD

Department of Paediatrics, Niyala Hospital, South Darfur, Sudan Bahja Abbo, MD Khalid Al Awad

Department of Statistics, Faculty of Mathematical Sciences, University of Khartoum, Sudan; and Department of Public Health, College of Health Sciences, Qatar University, Doha, Qatar Manar E Abdel-Rahman, PhD

Conclusion: Using echocardiography, there was a significant disparity in RHD prevalence between the two communities in Sudan. Efforts to control RHD should be directed to this area, and other rural communities should be investigated. Keywords: rheumatic heart disease, echocardiography, Sudan Submitted 24/3/17, accepted 15/3/18 Published online 16/4/18 Cardiovasc J Afr 2018; 29: 273–277

www.cvja.co.za

DOI: 10.5830/CVJA-2018-022

Rheumatic heart disease (RHD) is an immune response to group A beta-haemolytic streptococcal infection and is considered a leading cause of acquired heart disease in young people globally.1 Sudan is the third largest country in Africa with a population of 34 million, poverty rate of 46.4%, per capita income of US$1 270, and human development index of 0.414. Political conflict has resulted in social divides that caused internal displacement of thousands of families in the Darfur area.2 In Sudan, the last epidemiological study on RHD was conducted in 1992 and showed a clinical prevalence of 11 per 1 000 in Khartoum’s school children.3 In recent years, echocardiographic (echo) screening has documented a prevalence of RHD that is several fold higher than clinical auscultation.4,5 The availability from the World Heart Federation (WHF) of defined echo criteria for diagnosing subclinical RHD has enabled many investigators to objectively study subclinical carditis in different settings.6 Hand-held echo (HHE), a small and less costly machine, was proven to have a sensitivity of up to 97% for definite RHD, therefore it can be used as a surveillance tool in resource-limited settings.7 In Sudan, a World Health Organisation-based RHD control programme ended in 1998 and since then, there has been no active programme until 2012, when a national programme was established.8,9 A hospital-based register has shown that most RHD patients come from a belt localised to Kordofan, Darfur, White Nile and Gezira states in western and central Sudan.10 This study aimed to measure the prevalence of RHD in Khartoum using echo for diagnosis, compare it to that of South Darfur, and initiate a sentinel site for RHD control in the latter area.

Methods Phase 1 of the study was conducted in Khartoum inner city, Mayo area, from September 2015 to February 2016, and phase 2 in Niyala city, South Darfur state from July to September 2016. The gap of four months was due to the school holidays. Schools

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were chosen from inside the camps of people who were internally displaced because of Darfur political conflict. Table 1 details the features of the communities in Khartoum and Niyala (data obtained from local authorities). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the research ethics committee of the University of Khartoum. Approval was obtained from the school health department of the Ministry of Health as well as the school and camp authorities. Informed consent forms were given to the children’s families and only those who consented were screened. A sample size of 3 000 subjects was calculated for each site based on an estimated echo prevalence of 3%10 and non-respondent rate of 5%. In both study areas, all the primary schools were listed. Fifteen schools were selected randomly in Khartoum and eight in Niyala, Darfur, with equal numbers of girls’ and boys’ schools. In both areas, school grades four to eight were chosen (age 10 to 15 years). All the pupils were invited to participate. Two HHE machines (V scan, General Electric) were used. This machine has a single probe with a frequency of 1.7 to 3.4 MHz. It has storage capacity and a battery that lasts about 2.5 hours. For the Khartoum study, four paediatric cardiology fellows were trained in using the V scans based on the WHF guidelines, with the exception of continuous-wave Doppler, which is not available in the HHE.6 Three views were used (parasternal long-axis, four-chamber and four-chamber with aorta), all done without and then with colour Doppler. The fellows took the measurements and recorded abnormal echo studies for offline review by another cardiologist. For the Niyala, Darfur study, two medical officers were trained in using the V scan. A simplified ‘one-view’ protocol utilising the parasternal long-axis view was adopted following the publication of an article that showed its high diagnostic ability.11 Four images were recorded, two without and two with colour Doppler. All the studies were recorded and stored to be reviewed offline by two paediatric cardiologists. An abnormal result was defined by the modified WHF criteria as follows: • Definite RHD: –– If there is pathological regurgitation plus two morphological criteria Table 1. Demographic features of the two sites Demographic features Location

Khartoum site

Niyala site

Mayo area 9 km south of Khartoum

Ottash and Deraig camps for displaced people, 6 km south of Niyala, South Darfur

Population

37 000

128 460

Average income (US$/month)

Type of work

Marginal business

Seasonal farmers

Average number of 11 family members

10 100% non-brick

Type of house

50% non-brick

Piped water

Available

Not available

Electricity

Available

Not available

Number of health facilities

20 units

6 units

Population/health facility ratio

1 850:1

21 410:1

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–– If there is borderline disease of both mitral and aortic valves • Pathological regurgitation is defined as: –– mitral regurgitation (MR) jet ≥ 2 cm –– aortic regurgitation (AR) jet ≥ 1 cm • Morphological criteria are defined as: –– For the mitral valve: anterior mitral valve leaflet > 3 mm, chordal thickening, restricted leaflet motion and excessive leaflet tip motion in systole –– For the aortic valve the morphological criteria include irregular thickening, coaptation defect, restricted leaflet motion and prolapse. The main difference between this method and the original WHF criteria is that we do not use continuous Doppler as the HHE does not have this feature. • Borderline RHD: –– Pathological regurgitation without morphological criteria –– Two of the above morphological criteria without pathological regurgitation. School children with abnormal results were called through their school administrators and the families were informed. Transportation was arranged to the hospital where a standard echo (SE) study was performed for each child. Echo machines used for SE were the Esaote My Lab 50 in Khartoum and the Mandray machine in Darfur. Two paediatricians from Niyala Hospital were trained in RHD prevention, according to the national guidelines.12 Lectures were integrated into the routine training activities of the primary healthcare personnel. Posters and pamphlets were distributed to the health workers. Local radio and television programmes were provided with a promotional video.13

Statistical analysis Data were analysed using percentages. Bias-adjusted kappa = 2 (Agreement 1) was used to assess agreement between HHE and SE. The same test was used to determine the inter-observer variation on a randomly selected sample of 28 echo studies.14 Data were analysed using Stata version 14.15

Results In Khartoum, 3 000 school children were screened using HHE. Seven cases were found to have RHD, six were borderline and one was definite (ratio of definite-to-borderline RHD of 0.16:1). Using SE, two cases were found to have congenital heart disease (partial atrioventricular septal defect in both), one had mitral valve prolapse, one physiological MR and two were normal. One was found to have definite RHD (pathological MR plus two morphological criteria). The prevalence of RHD in Khartoum was 0.3/1 000 children. The average time to complete the HHE study was 10 minutes. In Niyala, Darfur, due to technical problems with electricity supply (see limitations), we managed to screen only 1 515 school children. On reviewing the echo studies, 17 were excluded because of inadequate imaging quality. Out of the remaining 1 498 studies, 59 cases were positive for RHD; 44 had definite and 15 borderline RHD. The ratio of definite-to-borderline RHD was 2.9:1. The average time to complete the echo study was four minutes.

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Out of 59 children with positive HHE results, 34 were available for a SE study while 15 were unable to attend due to social reasons and 10 were travelling. Of the 34 children who underwent SE, 29 were found to have RHD (85.2%); 22 had definite and seven borderline disease. The ratio of definite-toborderline RHD by SE was 3.1:1, with females representing 72% of the definite cases. The echo prevalence was 19/1 000 children. The bias-adjusted kappa test showed good agreement between the two echo readers of 92.9% (= 2, Agreement 1 = 2 × 0.9643 – 1). All the cases with definite and borderline RHD were asked to come for a follow-up study by SE after six months. Definite RHD cases were started on benzathine penicillin prophylaxis. Table 2 and Figs 1 and 2 summarise these findings. Table 3 details the echo findings of 29 cases found positive using SE. MR was present in all the cases detected by SE and in 58/59 of those by HHE (Fig. 3). AR was present in seven cases using HHE (11.8%) and in four with SE. Of those with AR detected by HHE, only four came for SE. Two children had aortic valve morphological abnormalities detected by HHE but did not come for SE. These included irregular thickening in one, and in another case it was associated with leaflet prolapse and asymmetry (Fig. 4). No cases of mitral or aortic stenosis were identified. The agreement between HHE and SE on the assessment of mitral valve morphological criteria as well as the diagnosis of RHD were calculated. Bias-adjusted kappa showed a fair agreement of anterior mitral valve leaflet thickness > 3 mm, chordal thickening and excessive leaflet tip motion in systole (28, 28 and 32%, respectively) and good agreement (66%) with the diagnosis of definite versus borderline RHD.

Discussion This is the first study that has measured the echo-diagnosed prevalence of RHD in Sudan. This was coupled with the initiation of a control programme based on training of health personnel, and raising public awareness in South Darfur. Compared with the 1992 clinical prevalence of 11 per 1 000,3 RHD prevalence in Khartoum has dropped significantly, which could be attributed to the relative improvement of health services and living conditions in urban areas. On the other hand, this study unmasked a huge burden of asymptomatic patients living in a poor rural community. In sharp contrast to Khartoum, the prevalence in South Darfur camps was over 60 times higher. This prevalence may have been underestimated due to the smaller sample size and the high number of children who could not attend the SE study in Niyala. The Khartoum study was conducted by paediatric cardiology fellows who were experienced in echo and were using three echo views as per the modified WHF protocol, therefore the accuracy of the echo studies was expected to be high. Moreover, the interobserver agreement was 92%, indicating the reliability of echo interpretation. This disparity in prevalence could be attributed to many factors, including the availability of more health centres within Khartoum compared to the Darfur area, and a relatively better socio-economic status and more secure living conditions in the Mayo area, which is only 9 km from the Khartoum centre. The ratio of definite-to-borderline RHD cases of 3:1 further supports the notion that the disease is well established in Darfur Table 3. Features of patients who were found to have RHD by standard echo (total = 29) Patient characteristics

No (%)

Type of RHD

Table 2. Summary of the clinical and echo findings of children in Khartoum and Niyala, Darfur Characteristics

Niyala, Darfur

Number of school children

3 000

1 515

Number of echo studies analysed

3 000

1 498

10.5 (0.4)

10.8 (0.2)

Mean age in years (± SD) Echo findings Positive by HHE

Positive by SE

29/34

0.16/1

2.9/1

0.3/1 000

19/1 000

Definite-to-borderline ratio using HHE RHD prevalence using echo

45 40 35 30 25 20 15 10 5 0

22 (76)

Borderline

7 (24)

Female:male ratio

Khartoum

Female gender (%)

Definite

3:1

Echo features

Definite

Borderline

Pathological MR

22 (100)

7 (100)

AML thickening

18 (81)

4 (57)

Chordal thickening

22 (100)

4 (57)

Restricted leaflet motion

1 (0.04)

Excessive anterior leaflet tip motion

13 (59)

Pathological AR

4 (18)

3 (14)

Morphological aortic valve criteria Borderline disease in both mitral and aortic valves

MR: mitral regurgitation, AML: anterior mitral valve leaflet, AR: aortic regurgitation.

HHE Total number screened = 1515

Khartoum

Niyala-Darfur

Fig. 1. P revalence of RHD in Khartoum and Niyala, Darfur (per 1 000 population) by hand-held echo (HHE) and standard echo (SE).

Total number analysed = 1498

Positive by HHE = 59 Definite = 44 Borderline = 15

Those who had SE = 34

Positive cases by SE = 29 Definite = 22 Borderline = 7

Fig. 2. Total subjects screened in Darfur and their results.

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Fig. 3. A : Hand-held echo in parasternal long-axis view with colour Doppler showing mitral regurgitation. B: Standard echo in parasternal long-axis view with colour Doppler of the same patient, showing mitral regurgitation.

school children. By contrast, in Khartoum the definite-toborderline ratio was 0.16:1, in accordance with other studies done in urban communities.4,16-18 The definite-to-borderline ratio in Darfur was much higher than the 1.2:1 that was reported in Ethiopia.18 The high RHD prevalence in Darfur is comparable to that found in Cambodia and South Africa but less than that found in Ethiopia and Mozambique.16,18 Similar to our findings, Engel et al. found a disparity between two areas within South Africa, which was attributed to lower socio-economic status.18 These findings emphasise the importance of improving medical services in the most vulnerable rural communities within the same country and call for effort to be directed to RHD control programmes in these areas. It is desirable to have a simplified approach to RHD screening

in remote areas. In this study we documented that the ‘one-view’ protocol decreased screening time, as has been reported by Zühlke et al.11 We have shown that HHE identified 85.2% of cases of RHD that were detected by SE, with a good agreement between HHE and SE in diagnosing definite versus borderline RHD. These findings support the usefulness of HHE in resourcelimited areas in order to improve RHD surveillance, as well as being a potential mode for early diagnosis and management of patients in remote, high-risk settings when SE is not immediately available. Although there is no consensus regarding the management of echo-diagnosed borderline RHD, there is preliminary agreement to start prophylaxis for definite cases and arrange follow-up echo for both definite and borderline cases. For mitral valve morphological criteria, HHE showed only a fair agreement with SE. Lu et al.19 reported similar findings

Fig. 4. A : Hand-held echo in parasternal long-axis view showing irregularity and prolapse of the aortic valve cusp. B: Hand-held echo in parasternal long-axis view with colour Doppler for the same patient, showing aortic regurgitation.

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that morphological criteria diagnosed by HHE had poor sensitivity for definite RHD, therefore these parameters should be interpreted with caution when diagnosed with HHE. A prevention programme for RHD was initiated in South Darfur using scanty resources. Training and raising the awareness of a large number of health workers can be achieved. A regional register for RHD as well as an echo clinic were established, which serves South Darfur and nearby states. There were some limitations to this study. Electricity was not available in most of the schools so we had to use generators. In Darfur, the generator electricity was unstable and the chargers of the V scans were damaged, which led to a premature ending of the study. When asked to come for the SE, many families were not available, but we are in contact with those who did not attend as we realise that there are probably many cases of RHD among them. Lastly, the roads to the camps were not paved in an area experiencing heavy rains, which led to the cancellation of many trips.

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Beaton A, Okello E, Lwabi P, Mondo C, McCarter R, Sable C. Echocardiography screening for rheumatic heart disease in Ugandan schoolchildren. Circulation 2012; 125: 3127–3132.

Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease – an evidence-based guideline. Nat Rev Cardiol 2012; 9: 297–309.

Godown J, Lu JC, Beaton A, Sable C, Mirembe G, Sanya R, et al. Handheld echocardiography versus auscultation for detection of rheumatic heart disease. Pediatrics 2015; 135: e939–944.

Rheumatic fever and rheumatic heart disease. Report of a World Health Organization study group. World Health Organization, Geneva, 1988

Conclusion RHD prevalence in Khartoum has dropped significantly in the last 23 years. However we found a high prevalence of RHD in Niyala, Darfur camps, reflecting the vulnerability of this community. HHE using a single view was reliable and performed well in screening for RHD. We initiated a control programme despite limited resources, which needs to be consolidated in this area and in similarly affected rural Sudanese communities. In order to have an impact on clinical practice, mapping of RHD cases within the country must be carried out. HHE screening is a cheap and fast tool to identify hot spots of RHD and this study will be replicated in other areas. Control programmes must be implemented in high-prevalence areas. The reliability of HHE obviates the need to do an SE, therefore definite cases can immediately be started on penicillin prophylaxis.

(technical report series No. 764) updated November 2001. 9.

Ali SK. Rebuilding the Rheumatic Heart Disease Program in Sudan: Global Heart 2013; 3: 285–286.

10. Khalid E, El Banna H, Mahmoud R, Hassan H, El Mahdi L, Ali S. Clinical and echocardiographic features of 370 children with rheumatic heart disease seen in Khartoum. Sudan Med J 2014; 50: 151–154. 11. Zühlke LJ, Engel ME, Nkepu S, Mayosi BM.Evaluation of a focused protocol for hand-held echocardiography and computer-assisted auscultation in detecting latent rheumatic heart disease in scholars. Cardiol Young 2016; 26: 1097–1106. 12. Ali S, Alkhalifa MS, Khair SM. Acute rheumatic fever and rheumatic heart disease, Sudan’s guidelines for diagnosis, management and control. http://sudankidsheart.org/images/rhd/ARF_RHD%20Book.pdf. 13. Training and awareness materials. http://sudankidsheart.org/index.php/ component/content/article/90-home/148-new-training-and-awarenesstools.html. 14. Cunningham M. More than just the kappa coefficient: a program to

Two HHE machine V scans were donated by the Sudanese American Medical Association (https://www.sama-sd.org/), which obtained special permission from the United States government to purchase General Electric V scans for use in Sudan. Special thanks go to Drs Ameena Adam and Kawther Yusuf,

fully characterize inter-rater reliability between two raters. In: SAS global forum 2009; Mar: 242. 15. StataCorp 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.

who conducted the echo screening in Niyala. The study was funded by a

16. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et

Ministry of Higher Education research grant. The funders had no role in the

al. Prevalence of rheumatic heart disease detected by echocardiographic

execution, analysis or writing of this study.

screening. N Engl J Med 2007; 357: 470–476. 17. Kane A, Mirabel M, Touré K, et al. Echocardiographic screening for

References 1.

Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the auto-

M, Daniel W, King MS, Mayosi BM. Prevalence of rheumatic heart

immune pathogenesis of rheumatic heart disease. Autoimmunity 2006;

disease in 4720 asymptomatic scholars from South Africa and Ethiopia.

39: 31–39. 2. 3.

rheumatic heart disease: age matters. Int J Cardiol 2013; 168: 888–891. 18. Engel ME, Haileamlak A, Zühlke L, Lemmer CE, Nkepu S, van de Wall

United Nations Development Program, 2013. About Sudan. (http://

Heart 2015; 101: 1389–1394. 19. Lu JC, Sable C, Ensing GJ, Webb C, Scheel J, Aliku T, et al. Simplified

www.sd.undp.org/content/sudan/en/home/countryinfo.htm.

rheumatic heart disease screening criteria for handheld echocardiogra-

Ibrahim-Khalil S, Elhag M, Ali E, Mahgoub F, Hakiem S, Omer N, et

phy. J Am Soc Echocardiogr 2015; 28: 463–469.

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Comparison of quantitative and qualitative coronary angiography: computer versus the eye Taner Sen, Celal Kilit, Mehmet Ali Astarcioglu, Lale Dinc Asarcikli, Tolga Aksu, Habibe Kafes, Afsin Parspur, Gokhan Gozubuyuk, Basri Amasyali

Abstract Objective: Since visual estimation of the extent of vessel stenosis may vary between operators, we aimed in this study to investigate both inter-observer variability and consistency between the estimation of an operator and quantitative coronary analysis (QCA) measurements. Methods: A total of 147 elective percutaneous coronary intervention patients with 155 lesions between them were consecutively enrolled in the study. These patients were evaluated for visual estimation of lesion severity by three operators. The lesions were also evaluated with QCA by an operator who was blinded to the visual assessments. Reference diameter, minimal lumen diameter, percentage diameter of stenosis, percentage area of stenosis and diameter of lesion length from the proximal lesion-free segment to the distal lesion-free segment were calculated using a computerised QCA software program. Results: There was a moderate degree of concordance in the categories 70–89% (kappa: 0.406) and 90–99% (κ: 0.5813), whereas in the categories < 50% and 50–69% there was a low degree of concordance between the visual operators (κ: 0.323 and κ: 0.261, respectively). There was a low to moderate grade of concordance between visual estimation and percentage area of stenosis by QCA (κ: 0.30) but there was no concordance between visual estimation and percentage diameter of stenosis by QCA (κ: –0.061). Also, there was a statistically significant difference between QCA parameters of percentage diameter of stenosis and percentage area of stenosis (58.4 ± 14.5 vs 80.6 ± 11.2 %, p < 0.001).

Department of Cardiology, Dumlupinar University, Kutahya Evliya Celebi Education and Research Hospital, Dumlupinar, Turkey Taner Sen, MD, medicineman_tr@hotmail.com Celal Kilit, MD Mehmet Ali Astarcioglu, MD Afsin Parspur, MD Basri Amasyali, MD

Department of Cardiology, Dıskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey Lale Dinc Asarcikli, MD

Department of Cardiology, Derince Education and Research Hospital, Derince, Turkey Tolga Aksu, MD

Department of Cardiology, Yuksek Ihtisas Hospital, Ankara, Turkey

Conclusion: Visual estimation may overestimate a coronary lesion and may lead to unnecessary coronary intervention. There was low concordance in the categories < 50% and 50–69% between the visual operators. Percentage area of stenosis by QCA had a low to moderate grade of concordance with visual estimation. Percentage area of stenosis by QCA more closely reflected the visual estimation of lesion severity than percentage diameter of stenosis. Keywords: coronary stenosis, quantitative coronary analysis, coronary angiography Submitted 10/7/15, accepted 2/4/18 Cardiovasc J Afr 2018; 29: 278–282

www.cvja.co.za

DOI: 10.5830/CVJA-2018-024

Standard coronary angiography is the gold standard in the diagnosis of coronary artery disease. Most laboratories use visual estimation to predict the severity of coronary lesions. Many patients undergo coronary revascularisation according to visual estimation of their coronary stenosis. Unfortunately, visual estimation may vary between operators. In 1971, Gensini et al. first introduced a new electronic measurement system by drawing the vessel contour with a cursor.1 From the early 80s, many computer-based quantitative coronary assessment (QCA) programs have been developed and embedded in angiographic devices. Nowadays, modern QCA programs enable more accurate assessment and more reproducible measurement of coronary stenosis in an operatorindependent way. Many studies have shown inter-operator variation and discrepancy between visual estimation and QCA analysis. Most of these studies were performed before 2000.2-8 In a recent study performed by Nallamothu et al., the authors found that many operators tend to estimate coronary lesions more severely than QCA measurement.9 This is consistent with older studies. In the light of this study, many patients who did not have severe lesions according to QCA have undergone unnecessary revascularisation procedures based on visual estimation. In this retrospective study, we aimed to investigate both inter-observer variability and consistency between the visual estimation of a primary operator and QCA measurement in a blinded manner in patients who had had elective percutaneous coronary intervention (PCI) in our clinic.

Habibe Kafes, MD

Department of Cardiology, Malatya State Hospital, Malatya, Turkey Gokhan Gozubuyuk, MD

Methods A total of 147 consecutive patients who had had elective PCI between January and June 2015 were enrolled in the study.

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We obtained the data for these patients from the records of our catheterisation laboratory. Patients who had had acute myocardial infarction and totally occluded coronary lesions were excluded from the study. A total of 147 patients with 155 lesions between them were identified and retrospectively enrolled in the study in a consecutive manner. These patients’ records were evaluated for visual estimation of their lesion severity by two other operators who were blinded to the previous primary operator’s visual estimation. We also categorised the lesions as percentages according to their severity: < 50, 50–69, 70–89 and 90–99%. Three visual estimations (qualitative evaluation) were therefore obtained for each lesion. For QCA analysis, first, the lesion was evaluated in multiple views for quality of the images, excessive foreshortening, sidebranch overlap and severity of stenosis. The frame demonstrating the most severe narrowing with the best image quality and least foreshortening was selected in end-diastole and then calibration was done using the tip of the catheter. Disease-free segments of proximal and distal coronary segments were used as reference segments. Thereafter, the software automatically detected the contour after manually tracing a central line through the lesion. The proximal and distal coronary segments should be relatively free of disease and were referred to as the reference diameter. Vessel contour was automatically detected by the software and edge detection was corrected if necessary. In cases of multi-lesion intervention, each lesion was evaluated separately (Fig. 1). Complete QCA analysis of the lesions of each patient was performed by another operator who was blinded to the visual assessment of the lesions. Reference diameter (the diameter of the disease-free segments of the proximal and distal vessels), minimal lumen diameter, percentage of stenosis, percentage area of stenosis and lesion length from the proximal lesionfree segment to the distal lesion-free segment in diameter were calculated using a computerised QCA software program (Axiom Artis Zee, Siemens, Germany). One QCA (quantitative evaluation) measurement was thus obtained for each lesion.

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Statistical analysis Continuous variables are expressed as mean ± SD and categorical variables as numbers and percentages. All data were evaluated by IBM SPSS (Statistical Package for Social Sciences, version 22). Kappa analysis was used for evaluation for concordance of visual assessments between operators. The difference between visual assessment and QCA was determined using the paired Student’s t-test. Concordance between visual assessment and QCA was tested with kappa analysis. The difference between percentage diameter of stenosis and percentage area of stenosis was assessed with the paired Student’s t-test.

Results The study population was composed of 147 patients who underwent PCI for 155 lesions between them. Table 1 shows the characteristics of the patients and the 155 lesions. Mean age of the patients was 64.7 years (range 28–95). There were 107 men (72.8%) and 42 women (27.2%). The mean percentage of stenosis of the 155 lesions determined visually by the primary operator was 84% (range 55–99). The most commonly reported category for percentage of stenosis by the primary operator was 70–90%. The most treated vessel was the left anterior descending artery (LAD) (68, 46.4%), followed by the right coronary artery (RCA) (42, 27.1%), the circumflex artery (Cx) (39, 25.2%) and the intermediate artery (two, 1.3%). In total, 159 stents were implanted. Five patients underwent balloon dilatation only, 92 underwent bare-metal stent implantation, whereas 56 had drug-eluting stent implantation. Both bare-metal and drug-eluting stents were implanted in two patients. Mean stent length was 19.1 ± 6.6 mm (range 8–54). Mean stent diameter was 3.13 ± 0.49 mm (range 2.0–4.75). Mean percentages of stenosis determined by the primary, second and third operator by visual estimation were 84.0, 80.4 and 80.4%, respectively (Table 2). Concordance between the operators was evaluated with kappa (κ) analysis. There was a moderate degree of concordance in the categories 70–89% (κ: 0.406) and 90–99% (κ: 0.5813), while in the categories < 50 and

Fig. 1. Q uantitative coronary analysis of a lesion in the left circumflex coronary artery.

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Table 1. Characteristics of the patients and lesions Characteristics

Total: 147 patients/155 lesions

Mean age, years

64.7 ± 11.3

Table 3. Evaluation of concordance between operators with kappa analysis Group

Kappa

Concordance

< 50%

0.261

low–moderate

107 (72.8)

50–69%

0.406

moderate

70–89%

0.581

moderate

LAD, n (%)

68 (46.4)

90–99%

0.323

low–moderate

Cx, n (%)

39 (25.2)

Total

0.458

moderate

RCA, n (%)

42 (27.1)

Female, n (%)

40 (27.2)

Male, n (%) Vessel

Intermediate, n (%)

2 (1.3)

Percentage stenosis Mean (range)

84 (55–99)

Intervention, n Stent

159

Balloon

Stent type, n BMS

DES

BMS + DES

Stent size (mm) Length (mean)

19.1 ± 6.6

Diameter (mean)

3.13 ± 0.49

QCA Minimal lumen diameter (mm) Mean

1.19 ± 0.48

Range

0.09–2.53

Reference diameter (mm) Mean

2.90 ± 0.58

Range

1.75–5.22

LAD, left anterior descending artery; Cx, circumflex artery; RCA, right coronary artery; BMS, bare-metal stent; DES, drug-eluting stent; QCA, quantitative coronary analysis.

50–69%, there was a low degree of concordance between the operators (κ: 0.323 and κ: 0.261, respectively) (Table 3). QCA was performed on all PCI-treated lesions by another operator who was blinded to the results of the visual assessment. The mean minimal lumen diameter was 1.19 ± 0.48 mm (range 0.09–2.53). The mean reference diameter was calculated as 2.90 ± 0.58 mm (range 1.75–5.22) and the mean length of the lesions

Table 2. Visual estimations of three operators Operators

Visual estimation, n (%)

Primary operator Percentage stenosis (mean)

84.0

was 17.3 ± 8.1 mm (range 6.7–45.1). Mean percentage diameter of stenosis was 58.4 ± 14.5% (range 29–97). Mean percentage area of stenosis was 80.6 ± 11.2% (range 50–99). The most commonly calculated category, mean percentage area of stenosis was 70–90%. There was a statistically significant difference between the QCA parameters percentage diameter of stenosis and percentage area of stenosis (58.4 ± 14.5% vs 80.6 ± 11.2%, p < 0.001). The difference between the primary operator’s visual assessment and the QCA measurement was evaluated with the Student’s t-test. There was a statistically significant difference between the visual estimation of percentage of coronary stenosis, and the percentage diameter of stenosis and percentage area of stenosis determined by QCA (p < 0.01). Visual estimation of percentage of stenosis was higher than percentage diameter of stenosis and percentage area of stenosis calculated by QCA. A statistically significant difference was found between the stent size and reference diameter measured by QCA, and there was also a significant difference between stent length and lesion length determined by QCA (p < 0.001) (Table 4). Concordance between visual estimation and QCA was investigated with kappa analysis. There was a low to moderate grade of concordance between the categories of visual estimation and the percentage area of stenosis (κ: 0.30) (Table 5) but there was no concordance between the categories of visual estimation and percentage diameter of stenosis on QCA (κ: –0.061) (Table 6). Of the 155 lesions considered above 70% on visual estimation, 23 were found by QCA not to be significant.

Discussion Many catheterisation laboratories still depend on visual estimation of lesion severity rather than quantitative analysis when deciding on PCI. Unfortunately, visual estimation may not be accurate and may vary between operators. Moreover, it has many limitations. The error with visual estimation may exceed

> 50%

0 (0)

50–69%

68 (3.9)

70–89%

75 (48.4)

Table 4. Comparison between visual estimation and quantitative analysis

90–99%

74 (47.7)

Visual analysis QCA estimation

Mean

Std deviation

Percentage visual

84.01

10.846

Percentage minimum lumen area

80.61

11.229

2nd operator Percentage stenosis (mean)

80.4

< 50%

3 (1.9)

50–69%

12 (7.7)

Percentage visual

84.01

10.846

70–89%

82 (52.9)

Percentage minimum lumen diameter

58.42

14.513

90–99%

58 (37.4)

Stent diameter (visual)

3.13

0.491

Reference diameter

2.91

0.586

Stent length (visual)

19.15

6.647

Lesion length

17.36

8.135

3rd operator Percentage stenosis (mean)

80.4

< 50%

3 (1.9)

50–69%

20 (12.9)

Percentge area of stenosis (visual)

80.61

11.229

70–89%

73 (47.1)

Percentage diameter of stenosis

58.42

14.513

90–99%

59 (38.1)

**p < 0.01.

t-value

p-value

3.996

0.000**

25.440

0.000**

6.611

0.000**

3.891

0.000**

60.500

0.000**

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Table 5. Comparison of concordance between visual estimation and percentage area of stenosis with kappa analysis Percentage area of stenosis by QCA, n (%) Visual percentage Total of stenosis 50–69% 70–89% 90–99% Kappa 50–69% 70–89% 90–99% Total

2 (33.3)

4 (66.7)

17 (22.7) 53 (70.7) 6 (8.1)

0 (0) 5 (6.7)

32 (43.2) 36 (48.6)

p-value

6 (100) 75 (100) 74 (100)

Table 6. Comparison of concordance between visual estimation and percentage diameter of stenosis with kappa analysis Visual percentage of stenosis < 50%

0.300

0.000**

25 (15.6) 89 (57.8) 41 (26.6) 155 (100)

**p < 0.01.

35%.10 Operators tend to overestimate severe stenosis, whereas modest stenosis is underestimated.11 In our study, we found a moderate degree of concordance between visual operators in the categories 70–89 and 90–99%. There was a low degree of concordance between visual operators in the categories < 50 and 50–69%. These results show that especially in cases of moderate and low degree of stenosis, interobserver variability increases. QCA of coronary stenosis eliminates inter-observer bias and enables reproducible measurements. QCA is also useful for prediction of coronary restenosis after different coronary interventional techniques.12 It may also be used to follow the natural course of atherosclerosis. A decrease in the minimal lumen diameter and an increase in the percentage diameter of stenosis determined by QCA in follow-up coronary angiography was associated with increased coronary events. Change in minimal lumen diameter was the strongest predictor of coronary events.13 When we compared the results of visual estimation with QCA, we found significant differences between visual estimation and QCA in percentage diameter of stenosis and percentage area of stenosis. We also found differences between implanted stent diameter and reference diameter calculated by QCA and between stent length and lesion length derived from QCA. That means there is variability between implanted stent diameter and length and true size of the lesion. Physicians tended to implant larger and longer stents. The difference between mean diameter of implanted stent and mean reference diameter was 0.22 mm and the difference in mean length of the implanted stent and the lesion was 1.79 mm. Although statistically significant, this difference was not so great as to cause clinically important consequences. The important point is to cover the whole atherosclerotic segment with an optimal sized stent. Theoretically, choosing a longer stent size may increase the risk of stent restenosis in the future. Twenty-three lesions considered significant according to visual estimation were found not to be significant when determined by QCA. This means that approximately 15% of patients, or one in seven, underwent unnecessary intervention. When comparing the difference between percentage diameter of stenosis and percentage area of stenosis in determining the severity of stenosis, there was a statistically significant difference between the QCA-derived parameters (58.4 ± 14.5 vs 80.6 ± 11.2%). Percentage area of stenosis had a low to moderate grade of concordance with visual estimation, whereas there was no concordance between percentage diameter of stenosis and visual estimation. Percentage diameter of stenosis may underestimate the lesion. In a study by Gottsauner-Wolf et al., it was shown that

281

Percentage diameter of stenosis by QCA, n (%) < 50%

50–69%

0 (0)

70–89%

90–99%

0 (0)

4 (38.7)

0 (0)

50–69%

3 (50)

70–89%

29 (53)

42 (56)

90–99%

11 (14.9) 31 (41.9) 27 (36.5)

5 (6.8)

Total

43 (27.7) 76 (49.0) 31 (20.0)

5 (3.2)

Kappa

p-value

–0.061

0.000**

**p < 0.01.

percentage area of stenosis more closely reflected the visual estimation of lesion severity than percentage diameter of stenosis.14 In another study, the authors used dobutamine stress echocardiography to determine the cut-off values of QCA parameters in estimation of the functional significance of coronary lesions. Angiographic cut-off values were determined as ≤ 1.07 mm, ≥ 75% and ≥ 52% for minimal lumen diameter, percentage area of stenosis and percentage diameter of stenosis, respectively. The cut-off value for percentage diameter of stenosis was much less than the cut-off value for percentage area of stenosis.15 Similar to the results of our study, percentage area of stenosis was prone to underestimate the lesion if the cut-off value was accepted as 70%. If percentage diameter of stenosis is used as QCA parameter, it may be more suitable to accept the cut-off value as 50%. There are a few early trials comparing visual assessment with QCA. Older QCA software systems did not have the technology that we have today.2-8 Modern QCA software systems have advanced digital technology enabling more accurate and complex assessment. There is only one recent study comparing visual assessment of severity of coronary lesions and QCA measurement. In this study, similar to our study, Nallamothu et al. showed that visual assessment tended to overestimate the lesion more than QCA. Inconsistency between QCA and visual assessment was high, especially in cases of moderately severe coronary lesions.9 QCA is a non-invasive and cheap method of quantification of coronary stenosis and measurement of reference vessel diameter for deciding the size of the stent. Despite its limitations, such as vessel foreshortening, it enables well-correlated measurements of lesion length, minimal lumen diameter and reference diameter. It also may prevent unnecessary PCI.

Conclusion Visual estimation may overestimate a coronary lesion and may lead to unnecessary coronary intervention. There was low concordance in the categories < 50% and 50–69% between the operators. Percentage area of stenosis had a low to moderate grade of concordance with visual estimation. Percentage area of stenosis more closely reflected the visual estimation of lesion severity than percentage diameter of stenosis.

References 1.

Gensini GG, Kelly AE, Da Costa BCB. Quantitative angiography: the measurement of coronary vasomobility in the intact animal and man. Chest 1971; 60: 522–530.

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F, et al. Comparison of clinical interpretation with visual assessment and quantitative coronary angiography in patients undergoing percu-

al. Reproducibility of coronary arteriographic reading in the coronary

taneous coronary intervention in contemporary practice: the Assessing

Goldberg RK, Kleiman NS, Minor ST, Abukhalil J, Raizner AE. of lesion severity pre and post PTCA. Am Heart J 1990; 119: 178–184. Fleming RM, Kirkeeide RL, Smalling RW, Gould KL. Patterns in visual interpretation of coronary arteriograms as defected by quantitative coronary arteriography. J Am Coll Cardiol 1991; 18: 945–951.

Desmet W, Willems J, Lierde JV, Piessens J. Discrepancy between visual estimation and computer-assisted measurement of lesion severity before and after coronary angioplasty. Cathet Cardiovasc Diagn 1994; 31: 192–198.

Angiography (A2) project. Circulation 2013; 127(17): 1793–1800. 10. De Rouen TA, Murray JA, Owen W. Variability in the analysis of coronary arteriograms. Circulation 1977; 55: 324. 11. Fleming RM, Kirkeeide RL, Smalling RW, Gould KL. Patterns in visual interpretation of coronary arteriograms as detected by quantitative coronary arteriography. J Am Coll Cardiol 1991; 18: 945 12. Serruys PW, Foley DP, Kirkeeide RL, King SB 3rd. Restenosis revisited: insights provided by quantitative coronary angiography. Am Heart J 1993; 126: 1243. 13. Mack WJ, Xiang M, Selzer RH, Hodis HN. Serial quantitative coronary angiography and coronary events. Am Heart J 2000; 139(6): 993–999.

Folland ED, Vogel RA, Hartigan P, Bates ER, Beauman GJ, Fortin

14. Gottsauner-Wolf M, Sochor H, Moertl D, Gwechenberger M,

T, et al. Relation between coronary artery stenosis assessed by visual,

Stockenhuber F, Probst P. Assessing coronary stenosis. Quantitative

caliper, and computer methods and exercise capacity in patients with

coronary angiography versus visual estimation from cine-film or phar-

single-vessel coronary artery disease. The Veterans Affairs ACME Investigators. Circulation 1994; 89: 2005–2014. 8.

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Am Heart J 2000; 139: 106–113.

Galbraith JE, Murphy ML, de Soyza N. Coronary angiogram interpretation. Interobserver variability. J Am Med Assoc 1978; 240(19):

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macological stress perfusion images. Eur Heart J 1996; 17(8): 1167–1174. 15. Baptista J, Arnese M, Roelandt JR, Fioretti P, Keane D, Escaned J, et al.

Leape LL, Park RE, Bashore TM, Harrison JK, Davidson CJ, Brook

Quantitative coronary angiography in the estimation of the functional

RH. Effect of variability in the interpretation of coronary angiograms

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pine stress test. J Am Coll Cardiol 1994; 23: 1434–1439.

Losing weight can reverse atrial fibrillation in obese patients Australian research shows for the first time that obese people who are suffering from atrial fibrillation can reduce or reverse the effects of the condition by losing weight. The researchers found that a 10% loss in weight along with management of associated risk factors can reverse the progression of the disease. They studied 355 overweight or obese people who lost varying amounts of weight. The research was led by the Centre for Heart Rhythm Disorders at the University of Adelaide and the South Australian Health and Medical Research Institute (SAHMRI). ‘This is the first time that evidence has been found that if people who are obese and are suffering from atrial fibrillation the disease can be alleviated by losing weight and treating lifestyle factors,’ says lead author Dr Melissa Middeldorp, researcher from the University of Adelaide’s Centre for Heart Rhythm Disorders. Atrial fibrillation (AF), Australia’s most common heart rhythm disorder, is a leading cause of stroke and can lead to heart failure. Millions of people around the world are diagnosed with this condition every year. Chest pain, a ‘racing’ or unusual heart beat and shortness of breath are all symptoms of AF. ‘AF is a progressive disease in which initial short, intermittent symptoms develop into more sustained forms of the condition. Obesity and lifestyle factors are associated with its progression,’ says Middeldorp. The number of overweight and obese adults has doubled

over the past two decades, with Australia now being ranked as one of the fattest developed nations. ‘The study showed that if obese people lose more than 10% of their weight and subsequent management of other risks to their lifestyle, they can reverse the progression of the disease. People who lost weight experienced fewer symptoms, required less treatment and had better outcomes. Those who previously had sustained symptoms experienced only intermittent symptoms or indeed stopped experiencing AF entirely,’ says Middeldorp. ‘Progression of the disease is shown to have a direct link with the degree of weight loss. Without weight loss, there is a progression of AF to more persistent forms of AF.’ The Centre for Heart Rhythm Disorders is led by Professor Prash Sanders, world leader in atrial fibrillation research. ‘This study shows that weight loss and treating lifestyle factors is an essential component for effectively managing AF, in many instances being an alternative to surgery or drug intervention. Melissa’s work has widespread implications for the management of this disease globally and is good news for people with the condition,’ says Sanders. ‘With record levels of obesity in Australia and in most high-income countries, this study gives hope that obese people can have a better quality of life as well as reducing their dependence on health-care services if they lose weight.’ Source: Medical Brief 2018

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Association of microalbuminuria with left ventricular dysfunction in Nigerian normotensive type 2 diabetes patients TT Shogade, IO Essien, UE Ekrikpo, IO Umoh, CT Utin, BC Unadike, JJ Andy

Abstract Background: Diabetes mellitus (DM) is a risk factor for left ventricular (LV) dysfunction, and microalbuminuria is frequently associated with DM. This study aimed to compare LV function among normotensive type 2 diabetes (T2DM) patients with normoalbuminuria, those with microalbuminuria, and healthy controls. Methods: This was a cross-sectional study conducted at the diabetes and cardiology clinics of the University of Uyo Teaching Hospital, Uyo, Akwa-Ibom State, Nigeria, from January 2013 to March 2014. Microalbuminuria was tested for using Micral test strips, and echocardiography-derived indices of LV function were compared among the three groups. Results: Sixty-three normoalbuminuric, 71 microalbuminuric T2DM patients and 59 healthy controls were recruited. Mean age of participants was 50 ± 8 years and the three groups were age and gender matched (p = 0.23, p = 0.36, respectively). LV diastolic dysfunction (LVDD) showed a stepwise increase from the healthy controls to the normoalbuminuric to the microalbuminuric T2DM patients (16.9 vs 61.9 vs 78.9%, respectively) (p < 0.001), while E/A ratio and fractional shortening showed a significant stepwise decrease (both p < 0.001). LV systolic dysfunction was rare among the three groups. Microalbuminuria showed a strong direct association with LVDD (OR 3.58, 95% CI: 1.99–6.82, p < 0.001). Age remained independently associated with LVDD (OR 1.10, 95% CI: 1.03–1.17, p = 0.003). Conclusions: LV diastolic function was altered in Nigerian normotensive T2DM patients, and the presence of microalbuminuria with DM had additional effects on this abnormality. Early screening for DM and microalbuminuria could identify individuals with high cardiovascular risk and possibly abnormal LV function. Keywords: diabetes mellitus, microalbuminuria, left ventricle, diastolic dysfunction

Department of Medicine, College of Health Sciences, University of Uyo, and University of Uyo Teaching Hospital, Uyo, Akwa-Ibom, Nigeria TT Shogade, MB ChB, FMCP (Cardiol), docttaiwo@yahoo.com IO Essien, MB BCh, FMCP (Cardiol) UE Ekrikpo, MB BS, MSc (Med) (Epidemiology & Biostat), FMCP (Nephrol) IO Umoh, MB BCh, FWACP (Cardiol) BC Unadike, MB BS, FMCP (Endo) (deceased) JJ Andy, MB BS, FWACP, FMCP

Cleno Health Ultrasound Institute, Uyo, and University of Uyo Teaching Hospital, Akwa-Ibom, Nigeria CT Utin, MBA, DCR, RDMS, RDCS

Submitted 19/2/17, accepted 10/4/18 Published online 13/6/18 Cardiovasc J Afr 2018; 29: 283–288

www.cvja.co.za

DOI: 10.5830/CVJA-2018-026

Diabetes mellitus (DM) is associated with diverse cardiovascular conditions such as myocardial infarction, heart failure (HF), stroke and diabetic cardiomyopathy (DMCMP), which are the leading causes of diabetes-related morbidity and mortality.1,2 Previous studies elsewhere3,4 and in Nigeria5 have demonstrated left ventricular diastolic dysfunction (LVDD) in normotensive diabetics, supporting the existence of DMCMP. The Framingham Heart Study showed that the frequency of HF is twice as high in diabetic men and five times higher in diabetic women compared with age-matched controls, and that this increased incidence of HF persisted despite correction for age, hypertension, obesity, hypercholesterolaemia and coronary artery disease (CAD).6 An increased risk for developing HF in prospective analyses after correction for confounding variables has also been reported.7 Therefore screening for the presence of DMCMP at the earliest stage is appropriate for the early detection and prevention of HF. The most sensitive non-invasive test for detection of LV dysfunction is a two-dimensional echocardiogram with pulsedwave Doppler.8 As the cost of echocardiography is high, a less expensive pre-screening test for monitoring further deterioration in cardiac function in normotensive type 2 diabetes (T2DM) patients is needed. Microalbuminuria (MCA), a known marker of glomerular endothelial dysfunction, is also associated with microangiopathy in T2DM patients.9 It is suggested here that detection of MCA may also serve as an inexpensive pre-screening test for monitoring further deterioration in cardiac function in normotensive T2DM Nigerian patients. This study was designed to determine whether the presence of MCA in T2DM Nigerian subjects could demonstrate further deterioration in cardiac function in these patients.

Methods The study was done in accordance with the Declaration of Helsinki and the protocol was approved by the University of Uyo Teaching Hospital, Uyo Institutional Health Ethical Research Committee (IHREC) reference number UUTH/AD/S/96/VOL.XII/38. The study was conducted in the diabetes and cardiology clinics of UUTH between January 2013 and March 2014. Two hundred participants were recruited; 134 consecutive diabetic patients, diagnosed according to the American Diabetes Association,10 or who were on oral antidiabetic drugs, and 59 non-diabetic age- and gender-matched controls completed the study.

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Exclusion criteria were hypertension (blood pressure ≥ 140/90 mmHg or use of antihypertensive drugs), age above 65 years, macroalbuminuria, serum creatinine of ≥ 1.5 mg/ dl, chest deformity or long-standing chest disease evidenced on chest X-ray, sickle cell disease, urinary tract infection, pregnancy, cardiac conditions such as arrhythmia, heart failure, valvular heart disease, pericardial disease, congenital heart disease, and ischaemic heart disease as evidenced by clinical, electrocardiographic and echocardiographic features. Age, gender and duration of diabetes were recorded for each subject. Weight was determined in kilograms (kg) using a weighing scale, height using a stadiometer, and waist and hip circumferences (WC and HC) were measured in centimetres (cm) using a tape measure. Body mass index (BMI), body surface area (BSA) and waist:hip ratio (WHR) were calculated. Blood pressure was measured using an Accosson mercury sphygmomanometer with appropriate sized cuff at the brachial artery, Korotkoff phase 1 was used for systolic (SBP) and phase 5 for diastolic blood pressure (DBP) after at least 15 minutes of rest in a sitting position. Pulse rate (PR) was measured at the radial artery. The mean of three consecutive measurements, taken at five-minute intervals, was recorded. An overnight fasting venous blood sample was collected for measurement of levels of plasma glucose, creatinine and urea, and lipid profile using standard protocols. A two-step microalbuminuria screening process was conducted. Combur 10 test strip (Roche Diagnostics, Mannheim, Germany), a visual colorimetric semi-quantitative urine test strip, was used to test for protein, blood, nitrite and leucocyte levels. If all were absent then detection of microalbuminuria was performed on the same urine sample. Microalbuminuria was determined using Micral test strips, an optically read semi-quantitative immunoassay method (Roche Diagnostics, Australia) with a sensitivity and specificity of 80 and 88%, respectively.11 There are four colour blocks on the test strip corresponding to negative (or 0), 20, 50 and 100 mg/l of albumin. The test was done on two occasions; the first was random urine samples (RUS) and the second was first morning void (FMV) urine samples of the subjects. Microalbuminuria was considered to be present when the two urine samples produced a reaction colour corresponding to 20 mg/l or more. The result from the FMV urine sample was recorded as the MCA status of the subject. It has been suggested that MCA detected in the FMV urine sample corresponds better with 24-hour urinary albumin excretion (UAE) than microalbuminuria measured in a RUS, because it is less influenced by physical exercise and diet.12 Echocardiographic examination was performed with the patient in the left lateral decubitus position using a HewlettPackard Sonos 4500 echocardiography machine with a 3.5-MHz transducer. Measurements were taken under two-dimensional guided M-mode, as recommended by the American Society of Echocardiography (ASE).13 Endocardial fractional shortening (FS) was calculated automatically by the echocardiography machine using the formula:14 LVIDd – LVIDs

_____________ FS =        × 100 LVIDd

where LVIDd is left ventricular internal dimension in diastole and and LVIDs is left ventricular internal dimension in systole.

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Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) were calculated automatically by the echocardiography machine from M-mode-derived LV dimensions, using Teicholz’s formula: 7.0 × LVID3

LVEDV or LVESV =   __________ 2.4 + LVID   Ejection fraction (EF) was calculated using the formula: EDV – ESV

EF =   __________   × 100 EDV    The LV systolic function was considered normal if the EF was greater than 50% and/or FS was greater than 25%.14 The LV diastolic function was assessed using Doppler modalities. Early (E) and atrial (A) velocities as well as deceleration time (DT) were measured using pulsed-wave Doppler by placing the sample volume at the tips of the mitral leaflets in apical four-chamber view. Isovolumic relaxation time (IVRT) was measured as the time interval from the end of LV outflow and start of LV inflow, as indicated by simultaneous registration of outflow and inflow signals by high-frequency pulsed-wave Doppler. Pulmonary venous flow (PVF), systolic (S), diastolic (D) and atrial reversal (Ar) velocities were obtained by placing a pulsedwave Doppler sample volume 1–2 cm into the pulmonary vein, proximal to its insertion into the left atrium. E/A and S/D were calculated. Diastolic function (DF) was categorised into grades according to its progression to diastolic dysfunction (DD): • normal DF: E/A between 1 and 2, IVRT 60–100 ms and DT 160–240 ms • grade 1 DD: E/A < 1, IVRT > 100 ms, DT > 240 ms • grade 2 DD: E/A 1– 2, IVRT 60–100 ms, DT 150–220 ms, PVFS/D < 1 • grade 3 DD: E/A > 2, IVRT < 60 ms, DT < 160 ms.15 where DT is deceleration time and PVFS is pulmonary venous flow S velocity. Pulmonary artery systolic pressure (PASP) was estimated from peak tricuspid regurgitant flow using continuous-wave Doppler. Tissue Doppler echocardiography was not used because, at the time the study was conducted, the echo machine used did not have the facility.

Statistical analysis Data obtained were analysed using STATA 10. Continous variables are expressed as mean (± standard deviation) and categorical variables as percentages. Categorical variables were analysed using the chi-squared test. Student’s t-test and analysis of variance (ANOVA) were used to analyse continuous variables. Correlates of LV function were determined using Pearson’s rank correlation and predictors were assessed using logistic regressions. A p-value ≤ 0.05 was considered statistically significant.

Results One hundred and ninety-three participants comprising 63 T2DM patients with normoalbuminuria, 71 T2DM with microalbuminuria and 59 controls were studied. The mean age for all participants was 50 years and the three groups were age and gender matched. Table 1 shows the clinical characteristics of the three study groups. The duration since diagnosis of DM was significantly longer in the microalbuminuric than in the

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normoalbuminuric diabetics (p = 0.02). WC, SBP and PR showed a significant stepwise increase from control to microalbuminuric group (p < 0.001, p = 0.03, p = 0.03, respectively). Weight, BMI, WHR, DBP and PP were comparable among the three groups. Renal function, as assessed by estimated glomerular filtration rate (eGFR) using the Cockcroft Gault formula, was reasonably preserved among the three groups. It was highest in the control group but not statistically significantly different. The mean values of all lipid components were normal and comparable, except for the low-density lipoprotein (LDL) cholesterol level and atherogenic ratio, which showed a significant stepwise increase from control to microalbuminric group (p = 0.0008 and p = 0.01, respectively). FBS was also significantly higher in the diabetic groups compared to the controls (p = 0.001). Table 2 shows the echocardiographic parameters of LV function among the three groups. Mean values of EF and FS were normal in the three groups, but FS showed a significant stepwise decrease from control to microalbuminuric group (p = 0.0002). Doppler echocardiographic parameters showed some degree of LV diastolic dysfunction, which was more pronounced in the diabetic groups. A velocity (p = 0.0034), IVRT (p = 0.0001) and PASP (p = 0.02) showed a significant stepwise increase from control to microalbuminuric group, with a reverse trend for E velocity (p < 0.001) and E/A ratio (p < 0.001). Fig. 1 shows the prevalence and pattern of LVDD among the three groups. The prevalence of LVDD showed a Table 1. Sociodemographic, anthropometric and laboratory data (mean ± SD) variations among healthy controls, and normotensive diabetics with normoalbuminuria or microalbuminuria Normoalbuminuric No = 63

Characteristics

Controls (n = 59)

Age (years)

47 ± 10.0

50 ± 7.5

Microalbuminuric (n = 71) 51 ± 7.0

F-test

p-value

0.87

0.43

Gender (% male)

2.05

0.36

DMdur (years)

4.7 ± 2.8

6.1 ± 4.1

2.38

0.02

Weight (kg)

66 ± 11

68 ± 13

69 ± 12

1.00

0.37

Height (cm)

162 ± 8

161 ± 9

0.62

0.54

BMI (kg/m )

24.93 ± 4.4

26.4 ± 5.2

26.5 ± 3.8

2.14

0.12

BSA (m2)

1.71 ± 0.17

1.74 ± 0.18

1.75 ± 0.18

0.64

0.53

89 ± 10

91 ± 10

11.19

< 0.001

2.96

0.05

Waist (cm)

83 ± 10*†

WHR

0.89 ± 0.08

0.93 ± 0.07

0.93 ± 0.13

SBP (mmHg)

116 ± 11

118 ± 9

120 ± 8

3.51

0.03

DBP (mmHg)

74 ± 8

74 ± 6

76 ± 6

2.62

0.08

PP (mmHg)

42 ± 9

42 ± 6

43 ± 7

1.42

0.25

PR (beats/min)

79 ± 12*

83 ± 10

83 ± 8

3.55

0.03

†

Creatinine (mg/dl)

0.9 ± 0.19

1.0 ± 0.31

1.01 ± 0.24

2.64

0.08

Urea (mmol/l)

2.6 ± 0.8*†

4.2 ± 1.7

4.0 ± 1.7

4.3

0.02

eGFR (ml/min)

102 ± 20

79 ± 31

86 ± 30

2.38

0.10

TC (mmol/l)

4.0 ± 0.6

4.6 ± 1.1

4.5 ± 1.2

1.17

0.32

0.9 ± 0.4

1.3 ± 0.8

1.1 ± 0.5

2.33

0.10

HDL-C (mmol/l)

1.73 ± 0.3

1.45 ± 0.5

1.37 ± 0.5

2.81

0.07

LDL-C (mmol/l)

1.74 ± 0.6†

2.38 ± 1

2.64 ± 0.8

5.14

0.008

TG (mmol/l)

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2.3 ± 0.4*

3.5 ± 1.6

3.6 ± 1.0

4.67

0.01

FBS (mmol/l)

5.0 ± 0.5*†

8.1 ± 4

9.3 ± 4

3.72

0.001

†

F-test for ANOVA or student’s t-test. *p < 0.05 compared to normoalbuminuria by ANOVA. † p < 0.05 compared to microalbuminuria by ANOVA. BMI: body mass index, BSA: body surface area, DMdur: duration of diabetes mellitus, WHR: waist:hip ratio, SBP: systolic blood pressure, DBP: diastolic blood pressure, PR: pulse rate, PP: pulse pressure, AR: atherogenic ratio, eGFR: estimated glomerular filtration rate, TC: total cholesterol, TG: triglycerides, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, FBS: fasting blood sugar level.

stepwise increase from 16.9% in the control to 78.9% in the microalbuminuric group. The most common grade of DD was grade 1, which occurred in 70.4 and 55.5% of microalbuminuric and normoalbuminuric groups, respectively, compared to 16.9% in the controls. Grade 1 was the only type of DD found in the control group; 3.2% of the normoalbuminuric group and 8.5% of the microalbuminuric group had grade 2 pattern of DD. None of the microalbuminuric group had grade 3 but 3.2% of the normoalbuminuric group did. These observed differences were statistically significantly different (χ2 = 50.05, p < 0.01). Table 3 shows clinical and biochemical parameters that correlated significantly with indices of LV diastolic function (E/A ratio and IVRT) among the normotensive diabetics. The strongest correlate of E/A ratio in the model was age (p < 0.001). Serum creatinine level (p = 0.009) and eGFR (p = 0.009) also correlated significantly with E/A, but the other parameters did not. Table 4 shows univariate and multivariate regression models used to determine predictors of LVDD in the normotensive diabetics. At the univariate level, age and MCA status were significantly associated with the occurrence of LVDD. Those with microalbuminuria had about a four-fold increased risk of developing LVDD compared to those with normoalbuminuria (95% CI: 1.99–6.82, p < 0.001). Also, for every one year increase in age, the risk of developing DD increased by 11% (95% CI: 4–17%, p ≤ 0.001). After adjusting for all the other factors in the multivariate model, only age remained an independent predictor of DD. The model shows that for every one year increase in age, there was

Table 2. Comparison of echocardiographic parameters (mean ± SD) of left ventricular systolic and diastolic function among healthy controls, and normotensive diabetics with normoalbuminuria or microalbuminuria Normoalbuminuric (n = 63)

Microalbuminuric (n = 71)

Echo parameters

Control (n = 59)

LVIDd (mm)

42 ± 4.4†

40 ± 4.9

38 ± 4.3

7.84

0.0006

LVIDs (mm)

27 ± 3.2

26 ± 2.8

26 ± 3.2

0.81

0.45

EDV (ml)

82 ± 19†

76 ± 20

68 ± 16

8.13

0.0004

ESV (ml)

27 ± 8

26 ± 8

25 ± 7

0.82

0.44

F-test

p-value

Stroke volume (ml)

54 ± 20†

51 ± 19†

45 ± 17

9.28

0.0002

Cardiac output (l)

4.3 ± 0.9†

4.2 ± 1.1†

3.6 ± 1.0

10.05

0.0002

Ejection fraction (%)

62 ± 7.3

63 ± 8

60 ± 6.2

1.99

FS (%)

36 ± 5.5†

34 ± 6.1†

31 ± 4.1

11.39 < 0.001 20.65 < 0.001

Mitral E velocity (m/s)

77 ± 21*†

65 ± 18

61 ± 12

Mitral A velocity (m/s)

67 ± 17†

69 ± 13

74 ± 13

E/A ratio

1.2 ± 0.3†

1.0 ± 0.3

0.8 ± 0.2

5.9

0.14

0.0034

31.51 < 0.001

IVRT (s)

79 ± 13†

84 ± 16

90 ± 18

9.65

0.0001

Deceleration time (s)

199 ± 29

192 ± 42

192 ± 33

0.03

0.9658

PVF S velocity (m/s)

56 ± 11†

47 ± 14

52 ± 11

4.57

0.0123

PVF D velocity (m/s)

49 ± 8*

42 ± 7

47 ± 11

5.11

0.0074

S/D ratio

1.2 ± 0.2

1.1 ± 0.2

1.1 ± 0.3

0.38

0.685

PVF Ar velocity (m/s)

31 ± 4.4

33 ± 4.0

34 ± 3.0

2.72

0.069

PASP (mmHg)

30 ± 8

30 ± 7†

33 ± 9

4.22

0.0165

LADs (mm)

35 ± 3.3

34 ± 3.5†

36 ± 3.6

4.5

0.0125

*p < 0.05 compared to normoalbuminuria by ANOVA followed by Bonferroni post hoc test. † p < 0.05 compared to microalbuminuria by ANOVA followed by Bonferroni post hoc test. F-test for ANOVA. PVF: pulmonary venous flow, LADs: left atrial end-systolic dimension, IVRT: isovolumic relaxation time, E: transmitral early-to-late inflow velocity ratio, A: transmitral late atrial velocity, PASP: pulmonary artery systolic pressure.

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90 χ2 = 50.15, p < 0.001

Proportion of subjects (%)

80 70 60 50 40 30 20 10 0

Normal

Control

Impaired relaxation

Pseudonormalisation

Normalalbuminuria

Restrictive pattern

Microalbuminuria

Fig. 1. C omposite bar chart showing the prevalence and pattern of left ventricular diastolic dysfunction among the three groups.

a 10% increased risk of developing DD (OR = 1.10, 95% CI: 1.03–1.17, p = 0.003). The area under the receiver operating curve of this model was 0.76, suggesting a good model.

Discussion In this study, LVDD occurred significantly more frequently in the diabetic groups with or without MCA compared with the controls (p < 0.001) and the prevalence of LVDD in both diabetic groups were within the range of 40 to 75% reported by studies done on normotensive diabetics within16 and outside the country.17 Grade 1 LVDD was the commonest, which was significantly Table 3. Correlation coefficient of clinical and biochemical variables compared with E/A ratio and IVRT in normotensive diabetic subjects (p < 0.05) E/A ratio

IVRT

Parameters

Rho

p-value

Rho

Age (years)

–0.45

< 0.001

0.06

p-value 0.55

DM duration (years)

–0.06

0.51

0.14

0.15 0.39

Weight (kg)

0.11

0.24

0.08

Body surface area (m2)

0.13

0.16

0.09

0.34

Body mass index (kg/m2)

0.06

0.49

–0.03

0.77

Waist circumference (cm)

–0.03

Hip circumference (cm)

0.004

0.77

0.15

0.12

0.97

0.06

0.55

0.35

0.05

0.61

Waist:hip ratio

–0.09

Systolic BP (mmHg)

–0.04

0.65

–0.01

0.91

Diastolic BP (mmHg)

0.14

0.15

–0.06

0.53

Pulse pressure

–0.14

0.12

0.02

0.86

Pulse rate (beat/min)

–0.11

0.22

–0.26

0.005

Creatinine (mg/dl)

–0.32

0.009

0.19

0.13

eGFR (ml/min) Total cholesterol (mmol/l) Trigylcerides (mmol/l)

0.33

0.008

–0.09

0.47

–0.16

0.25

–0.13

0.36

0.01

0.91

0.32

0.01

HDL-C (mmol/l)

0.02

0.87

–0.08

0.57

LDL-C (mmol/l)

–0.07

0.60

–0.04

0.76

Rho: correlation coefficient, DM: diabetes mellitus, eGFR: estimated glomerular filtration rate, HDL-C: high-density lipoprotein cholesterol, LD-C: lowdensity lipoprotein cholesterol.

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more in the microalbuminuric than the normoalbuminuric group and was the only grade seen in the controls (p < 0.01). Aigbe et al.16 and Patil et al.17 reported similar findings. Higher grades (2 and 3), although rare, were commoner in the microalbuminuric (8.5%) than the normoalbuminuric group (6.4%). Lower rates of LVDD were reported by Liu et al.18 among American Indians with T2DM, 16% in normo-, 26% in microand 31% in the macroalbuminuric groups, because diastolic function assessment was based on only transmitral flow parameters, with no distinctions made between normal and grade 2 DD. Therefore, patients with a pseudo-normalised pattern were not included in their analysis. Systolic dysfunction was rare among the normotensive T2DM patients, which is similar to a previous report.3 A higher value of 15.56% reported by Dodiyi-Manuel et al.5 may be due to the higher EF cut-off value of 55% used to define systolic dysfunction, thus suggesting that systolic dysfunction detected by conventional echocardiography is not an early feature of DMCMP. This supports the assumption that alteration of both relaxation and filling usually precede marked changes in chamber systolic function, although more sophisticated imaging technology such as speckle-tracking imaging (STI), used to assess myocardial strain and strain rate, have permitted the detection of subtle systolic dysfunction in the diabetic myocardium.19 The significant correlation of E/A ratio with age (p < 0.001), creatinine level (p = 0.009) and eGFR (p = 0.008) in the normotensive T2DM patient suggests a worsening of LVDD as the patient grows older and serum creatinine level rises as a result of decline in renal function. Danbauchi et al.20 reported a significant correlation of LVDD with age, fasting blood glucose and two-hour postprandial glucose level in T2DM patients. Likewise, Yazici et al.21 in their study on 76 T2DM patients of Turkish origin documented that E/A ratio correlated significantly with age, glycated haemoglobin (HbA1c) level and duration of diabetes. These observations suggest that aging and impairment of renal function correlate with LVDD in normotensive diabetics. The relationship between microalbuminuria and asymptomatic LVDD in T2DM patients has been a subject of much debate. In this study, a worsening of diastolic function as evidenced by significantly higher A velocity, lower E velocity and E/A ratio, larger left atrial dimension and longer IVRT were observed in the microalbuminuric compared to normoalbuminuric group. Baykan et al.22 also reported significantly longer deceleration time and IVRT in the microalbuminuric than the normoalbuminuric group. Table 4. Logistic regression model to determine predictors of left ventricular diastolic dysfunction in the normotensive diabetic subjects Univariate analysis Odds ratio (95% CI)

Age

1.11 (1.04–1.17)

Microalbuminuria Gender

Variable

Multivariate analysis

p-value

Odds ratio (95% CI)

p-value

< 0.001*

1.10 (1.03–1.17)

0.003*

3.58 (1.99–6.82)

< 0.001*

1.81 (0.70–4.68)

0.222

0.69 (0.31–1.55)

0.309

0.56 (0.21–1.48)

0.240

BMI

0.98 (0.90–1.07)

0.719

0.91 (0.79–1.06)

0.227

Waist

1.01 (0.98–1.06)

0.452

1.04 (0.97–1.12)

0.263

DM duration

1.10 (0.96–1.24)

0.142

1.04 (0.90–1.19)

0.599

Systolic BP

1.01 (0.95–1.05)

0.824

0.98 (0.91–1.06)

0.694

Diastolic BP

0.96 (0.89–1.03)

0.234

0.97 (0.87–1.08)

0.598

Receiver operating curve 0.76, CI: confidence interval, DM: diabetes mellitus, BP: blood pressure.

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Liu et al.18 was the first to report that albuminuria status was independently associated with systolic and diastolic dysfunction in patients with T2DM. Akiyama et al.23 reported that the odds of having LVDD in Japanese T2DM patients with albuminuria was about eight times more than those without albuminuria (OR 7.95, 95% CI: 1.74–21.6, p = 0.005). By contrast, Alwis et al.4 noted in their study on 28 T2DM patients without any cardiovascular disease that 73.7% of those without microalbuminuria and 66.7% of those with microalbuminuria had LVDD. Likewise, Yildirimturk et al.24 found among 50 diabetics, no significant differences in LV systolic and diastolic function between patients with or without MCA. The relatively smaller sample sizes may explain the lack of significant difference in diastolic function between diabetic patients with or without MCA in these studies. In our study, the univariate model showed a strong direct association of LVDD with microalbuminuria (OR 3.58, 95% CI: 1.99–6.82, p < 0.001) and age (OR 1.1, 95% CI: 1.04–1.17, p < 0.001), which is similar to a previous study.22 Only age remained as an independent predictor of LVDD (OR 1.10, 95% CI: 1.03– 1.17, p < 0.003) after controlling for other confounders, including microalbuminuria. It is commonly believed that grade 1 LVDD in patients above 65 years may represent a relaxation abnormality associated with the aging process. However patients younger than 65 years may represent impaired relaxation due to other conditions, which may be a precursor to more advanced diastolic impairment if not treated. In our study, subjects older than 65 years were excluded. The negative prevalence of grade 2 and 3 LVDD in the control group and the fact that pseudo-normal and restrictive LV filling patterns are usually pathological phenomenona25 suggest that the higher proportion of LVDD seen in the diabetic groups was linked not only to aging but also to DM with or without MCA. We included both micro- and macroalbuminuric patients in our study, as this increased the chances of detecting albuminuria as an independent predictor of LVDD, as reported by Liu et al.18 in their study. Although the association between MCA and LVDD in normotensive T2DM patients was weak, it was stronger than the association of T2DM without albuminuria with LVDD. The limitation in this study was lack of glycated haemoglobin values of the subjects studied.

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Alwi I, Harun S, Waspadji S, Rahman A, Ismail D. Left ventricular diastolic dysfunction in type 2 diabetes mellitus patient without cardiovascular disease: the association with microalbuminuria. Med J Indones 2005; 14(3): 169–173.

Dodiyi-Manuel S, Akpa M, Odia O. Left ventricular dysfunction in normotensive type II diabetic patients in Port Harcourt, Nigeria. Vasc Health Risk Manag 2013; 3(9): 529–533.

Kannel W, Mc Gee D. Diabetes and Cardiovascular Risk Factors: The Framingham Study. Circulation 1979; 59: 8–13.

Aaron M, Scott C, Chen H. The development of heart failure in patients with diabetes mellitus and preclinical diastolic dysfunction: A population based study. J Am Coll Cardiol 2010; 55(4): 1–12.

Nagueh S, Appleton C, Gillebert T, et al. Recommendation for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22(2): 107–133.

Kalaitzidis R, Bakris G. Pathogenesis and treatment of microalbuminuria in patients with diabetes: The road ahead. J Clin Hypertens 2009; 11(11): 636–643.

10. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011; 34(1): 62–69. 11. Parikh C, Fischer M, Estacio R, Schrier R. Rapid microalbuminuria screening in type 2 diabetes mellitus: simplified approach with Micral test strips and specific gravity. Nephrol Dial Transpl 2004; 19(7): 1881–1885. 12. Chavan V, Durgawale P, Sayyed A, et al. A comparative study of clinical utility of spot urine samples with 24-h urine albumin excretion for screening of microalbuminuria in type 2 diabetic patients. Indian J Clin Biochem 2011; 26(3): 283–289. 13. Sahn D, De Mario A, Kisslo J, Weyman A. The committee on M-mode standardization of the American Society of Echocardiography: recommendations regarding quantitation in M-mode echocardiography, results of a survey of echocardiography method. Circulation 1978; 58: 1072–1083. 14.

Lang R, Bierig M, Devereux R. Recommendation for chamber quantification. Eur J Echocardiogr 2006; 7(2): 79–108.

15. Oh J, Park S, Nagueh S. Advances in cardiovascular imaging: established and novel clinical applications of diastolic function assessment by echo-

Conclusion Our study showed that the prevalence of LVDD was significantly higher in normotensive T2DM patients with or without microalbuminuria. This study was also confirmatory of the strong direct association of microalbuminuria with LVDD and the direct and independent association of age with LVDD in normotensive diabetic patients. Therefore periodic screening for microalbuminuria, especially in patients with risk factors such as hypertension or diabetes, could allow early identification of cardiovascular disease and help in stratifying overall cardiovascular risk.

cardiography. Circ Imaging 2011; 4: 444–455. 16. Aigbe I, Kolo P, Omotoso A. Left ventricular structure and function in black normotensive type 2AAM diabetes mellitus patients. Ann Afr Med 2012; 11(2): 84–89. 17.

Patil V, Patil H, Shah K, Vasani J, Shetty P. Diastolic dysfunction in asymptomatic type 2 diabetes mellitus with normal systolic function. Cardiovasc Dis Res 2011; 2(4): 213–222.

18. Liu J, Robbins D, Palmieri V. Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes. J Am Coll Cardiol 2003; 41(11): 2022–2028. 19. Aneja A, Tang W, Bansilal S, Garcia M, Me F. Diabetic cardiomyopathy: insight into pathogenesis, diagnostic challenges, and therapeutic

References 1.

Bos M, Agyemang C. Prevalence and complications of diabetes mellitus in Northern Africa, a systematic review. BMC Public Health 2013; 13: 387–344.

options. Am J Med 2008; 121(9): 748–757. 20. Danbauchi S, Anumah F, Alhassan M, David S, Onyemelukwe G, Oyati I. Left ventricular function in type 2 diabetic patients without cardiac symptoms in Zaria Nigeria. Ethn Dis 2005; 15(4): 635–640. 21. Yazici M, Ozdemir K, Gonen M et al. Is there any relationship between

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metabolic parameters and left ventricular functions in type 2 diabetic patients without evident heart disease? Echocardiography 2008; 25(7): 675–682. 22. Baykan M, Erdogan T, Erem C, et al. The relationship between flowmediated dilatation and left ventricular function in type 2 diabetic patients with microalbuminuria. Endocrine 2006; 30(2): 197–202. 23. Akiyama T, Eto Y, Matsuda H, Kimura Y, Yanagawa T. Albuminuria and left ventricular mass index are associated with left ventricular dias-

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5(2): 129–133. 24. Yildirimturk O, Kilicgedik M, Tugcu A, Aytekin V, Aytekin S. The relationship of microalbuminuria with left ventricular functions and silent myocardial ischaemia in asymptomatic patients with type 2 diabetes. Arch Turk S 2009; 37: 91–97. 25. Khali S, Kamal A, Hashim F, Olaish M. Study of left ventricular diastolic function in patients with diabetes mellitus. Sudan J Med Sci 2007; 2(2): 85–90.

tolic dysfunction in type 2 diabetes mellitus patients. Diabetol Int 2014;

Ten-year fall in blood cholesterol of Malaysia heart attack patients suggests statin impact A 10-year decline in the blood cholesterol of heart attack patients in Malaysia suggests that statins are having a positive impact, according to an observational study in nearly 49 000 patients presented at the ASEAN Federation of Cardiology Congress 2017 (AFCC2017). AFCC2017 was hosted by the Brunei Cardiac Society, with the support of the ASEAN Federation of Cardiology, on 3 to 5 November in Brunei Darussalam. Experts from the European Society of Cardiology (ESC) presented a special programme. ‘Lifestyle changes appear to be responsible for falls in blood cholesterol in the general populations of developed nations while statins have reduced cholesterol in patients with heart disease,’ said lead author Dr Sazzli Kasim, Chair, Malaysian Society of Atherosclerosis and Associate Professor of Medicine, University Technology MARA, Shah Alam, Malaysia. ‘Blood cholesterol is still on the rise in the general population of developing countries like Malaysia,’ he continued. ‘This study investigated trends in cholesterol levels in Malaysian patients with acute coronary syndromes.’ The study included 48 851 patients who had an acute coronary syndrome between 2006 and 2015 in Malaysia and were enrolled in the National Cardiovascular Disease Database Acute Coronary Syndrome (NCVD-ACS) registry. This ongoing registry is maintained by the National Heart Association Malaysia with the support of the Ministry of Health Malaysia. Total cholesterol was assessed on entry to the registry. The researchers examined trends in cholesterol levels of ACS patients over the 10-year period and compared them to previously published values for the entire population. They found a significant trend for declining total cholesterol from 2006 to 2015 in the ACS population (p = 0.012). This was opposite to the total cholesterol trend in the Malaysian population. ACS patients with a history of coronary heart disease had almost twice the declining rate in cholesterol as those with

no history of coronary heart disease. When the researchers examined total cholesterol by type of ACS, they found that patients with unstable angina had the lowest total cholesterol level but the steepest rate of decline, followed by patients with non-ST-elevation myocardial infarction and then patients with ST-elevation myocardial infarction. Dr Kasim said: ‘We found that blood cholesterol levels have been falling in Malaysian patients with acute coronary syndromes, which is the opposite of the national trend.’ ‘Since cholesterol levels have increased significantly in the Malaysian population as a whole, it is highly doubtful that lifestyle change is the reason for the declining cholesterol trend we observed in the ACS population,’ he continued. Dr Kasim said: ‘While this was an observational study and we cannot infer causality, it seems likely that cholesterol levels decreased as a result of lipid-lowering medication such as statins. ACS patients with a history of coronary heart disease, who were more likely to be taking statins, had a more rapid decline in cholesterol levels than those without a history of coronary heart disease.’ He concluded: ‘These results appear to mimic findings from developed countries in previous years and show that the Malaysian population is reaching similar health milestones. The findings also highlight the need to increase awareness of the harm of raised lipid values and the treatment available.’ Dr Ezam Emran, scientific chair of AFCC 2017, said: ‘This large study suggests that statins are being effectively used by heart attack patients in Malaysia. Rising lipid levels in the general population need to be tackled by promoting healthier lifestyles.’ Professor Michel Komajda, a past president of the ESC and course director of the ESC programme in Brunei, said: ‘The benefits of statins for preventing a second heart attack are unequivocal, as highlighted by the 2017 ESC guidelines. Patients should also be encouraged to quit smoking, adopt a healthier diet and be physically active.’ Source: European Society of Cardiology Press Office

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Haemorrhage and other complications in pregnant women on anticoagulation for mechanical heart valves: a prospective observational cohort study S Kariv, F Azibani, J Baard, A Osman, P Soma-Pillay, J Anthony, K Sliwa

Abstract Objective: To document maternal and foetal morbidity and mortality in anticoagulated, pregnant patients with mechanical heart valves until 42 days postpartum. Methods: In a tertiary single-centre, prospective cohort, 178 consecutive patients at the cardiac-obstetric clinic were screened for warfarin use between 1 July 2010 and 31 December 2015. Of 33 pregnancies identified, 29 were included. Patients received intravenous unfractionated heparin from six to 12 weeks’ gestation and peripartum, and warfarin from 12 to 36 weeks. Maternal outcomes including death, major haemorrhage and thrombosis, and foetal outcomes were documented. Results: There were two maternal deaths, five returns to theatre post-delivery, eight patients transfused, six major haemorrhages, one case of infective endocarditis and three ischaemic strokes. Ten pregnancies had poor foetal outcomes (six miscarriages, three terminations, one early neonatal death). Twenty patients required more than 30 days’ hospitalisation, and 15 required three or more admissions. HIV positivity was associated with surgical delivery (p = 0.0017). Conclusions: Complication rates were high despite centralised care. Keywords: warfarin, heparin, pregnancy, anticoagulation, mechanical heart valves, Africa

Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa S Kariv, MB BCh, Sarah.kariv@gmail.com

The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and University of Cape Town F Azibani, PhD J Baard, MB BCh K Sliwa, PhD

Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences and IDM, University of Cape Town, Cape Town, South Africa F Azibani, PhD J Baard, MB BCh K Sliwa, PhD

Department of Obstetrics and Gynaecology, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa A Osman, MB BCh, FCOG J Anthony, MB BCh, FCOG

Department of Obstetrics and Gynaecology, Steve Biko Academic Hospital and University of Pretoria, Pretoria, South Africa P Soma-Pillay, MB BCh, FCOG

Submitted 4/2/18, accepted 22/5/18 Published online 13/6/18 Cardiovasc J Afr 2018; 29: 289–295

www.cvja.co.za

DOI: 10.5830/CVJA-2018-029

Rheumatic heart disease (RHD) is common in urban Africans, with an estimated yearly incidence of 23.5 cases per 100 000 population aged over 14 years.1 Mechanical prosthetic heart valves (MHVs) require lifelong, uninterrupted anticoagulation treatment, therefore, many female patients require anticoagulation during childbearing years. This anticoagulation is essential during pregnancy as without it, up to 25% of pregnant women will experience a thrombotic event.2 Cardiac disease is the most important non-obstetric cause of maternal deaths,3 and RHD is an important contributor.4 Mortality and serious morbidity are higher in patients with MHVs than in those with tissue valves, or those who have cardiac disease without prosthetic valves. It has been reported that only 58% of women with MHVs survive pregnancy without any serious adverse events.5 Although warfarin is the most effective anticoagulant in preventing thrombotic complications,2,6,7 its use in pregnancy remains problematic. It is associated with warfarin embryopathy if administered between six and 12 weeks’ gestation,2,8 and with foetal loss and stillbirth later in pregnancy.7,9,10 Warfarin crosses the placenta, placing the vitamin K-deficient foetus at risk of haemorrhage.6 Some findings suggest that certain foetal complications of warfarin may be dose dependent,11,12 but not all studies have replicated these findings.13 In some patients, low doses may also result in sub-therapeutic anticoagulation. Heparin, an alternative to warfarin, does not cross the placenta14 but results in higher rates of thromboembolic complications.6 The challenge of administering anticoagulation to pregnant women with valve replacements includes management of the underlying cardiac condition and its complications, as well as the obstetric risks of the anticoagulant regimen. A low-resource setting (such as South Africa) may further exacerbate these difficulties, although there are limited data available to inform local practice. The objective of this study was to characterise the clinical course of patients with MHVs needing anticoagulation in pregnancy, and to document antenatal, intra-partum and postpartum morbidity and mortality rates as well as foetal outcomes.

Methods In the ongoing, single-centre, prospective Cardiac Disease in Maternity (CDM) cohort study, 178 women with heart disease

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(WHO risk group class II–IV) presenting at the dedicated cardiac-obstetric clinic between 1 July 2010 and 31 December 2015, were screened for warfarin use. The research was approved by the University of Cape Town Human Research Ethics Committee (261/2015). Of the 33 pregnancies identified, 29 (in 23 patients) were included, with four excluded due to incomplete data. Additional information, particularly maternal post-partum bleeding, ischaemic and thrombotic events, and time hospitalised were collected retrospectively from maternity folders stored at Groote Schuur Hospital. Preconception counselling in patients attending tertiary care included advice to conceive on warfarin and to attend a maternity clinic as soon as a period was missed or pregnancy was suspected. Echocardiography was not routinely performed pre-conception. Antenatal anticoagulation comprised warfarin up to six weeks’ gestation, unfractionated, intravenous heparin (heparin sodium–fresenius) from six to 12 weeks’ gestation, warfarin from 12 to 36 weeks’ gestation, and unfractionated heparin from 36 weeks’ gestation. During periods of heparin infusion, the activated partial thromboplastin time (aPTT) target was 2.5 to 3.5 times the control value for all patients, achieved through regular monitoring and adjustment of the infusion rate. International normalised ratio (INR) levels were used to monitor and adjust the warfarin dose to achieve an INR value between 2.5 and 3.5. Patients found to be sub-therapeutic while on warfarin were admitted for heparin infusion concurrent with warfarin until INR levels were again therapeutic. Peripartum anticoagulation involved stopping warfarin at 36 weeks’ gestation and admitting for heparinisation. Heparin was omitted from the onset of labour and reinitiated six hours post-partum in the absence of clinical concern of haemorrhage. Warfarin was restarted at the consultant’s discretion, usually the day after delivery, with concurrent heparin until warfarin was therapeutic. Induction of labour and caesarean sections were performed only for obstetric indications. Parameters collected included baseline characteristics such as age, gravidity, HIV status and warfarin dosage, as well as occurrence of bleeding, thrombotic and ischaemic complications. Gestational age was calculated by the obstetrician and measured either from the last normal menstrual period if the date was certain, or by early foetal ultrasound dating. Failing either of these methods, a late ultrasound was used. In patients who had more than one pregnancy, all pregnancies occurring during the study period were included. Major haemorrhage was defined as bleeding necessitating return to theatre or bleeding associated with both transfusion as well as a drop in haemoglobin of ≥ 2.0 g/dl. Minor bleeding was Table 1. Maternal and foetal outcomes recorded Maternal, bleeding

Antepartum haemorrhage, postpartum haemorrhage, haemorrhagic stroke, need for transfusion, other bleeding complications

Maternal, Valve thrombosis, ischaemic or embolic stroke, other thrombotic thrombotic complications Maternal, other

Foetal/ infant

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Maternal mortality rates, maternal days in hospital, rates of caesarian section and indication (obstetric or medical), new-onset atrial fibrillation, infective endocarditis, new-onset or worsening heart failure Warfarin embryopathy, analysed according to warfarin dosages; other congenital anomalies; rates of miscarriage; rates of stillbirth

defined as all other bleeding including gum bleeding, epistaxis or troublesome bleeding from drip sites. Table 1 outlines the parameters recorded.

Statistical analysis Data were analysed using GraphPad Prism version 5.00 for Windows (GraphPad Software, La Jolla California, USA). Results are expressed as mean ± SD and percentages. Unpaired t-tests with Welch correction were used to establish whether differences in maternal outcome according to the HIV status were statistically significant.

Results Demographic data for the 23 patients are shown in Table 2. The majority of patients were black (78%) and spoke isiXhosa (61%). Most (78%) had reached high school but none had tertiary education. Sixty-five per cent of patients declared a monthly income of < ZAR 300 and none had a monthly income > ZAR 10 000. Table 3 shows baseline maternal characteristics. All patients had baseline effort tolerance of NYHA I or II. The mean heart rate was 90 beats per min, mean systolic blood pressure (SBP) was 111 mmHg and mean diastolic blood pressure (DBP) was 72 mmHg. The left ventricular mean ejection fraction was 54.4%. Seven patients had abnormal cardiac rhythms. Twenty-eight of 29 patients had rheumatic valve disease, while just one patient had a valve replacement for Takayasu’s disease. Nine patients (10 pregnancies) were HIV infected. Other co-morbidities included syphilis, psoriasis and hearing impairment. Just two patients presented prior to six weeks’ gestation and five presented after 24 weeks’ gestation. No patient was known to have had a thrombotic event (deep-vein thrombosis, pulmonary embolus, stroke) prior to her pregnancy. In this cohort there were two deaths, both occurring postpartum. The first was an 18-year-old, HIV-negative patient with a double valve replacement (mitral and aortic). In the third

Table 2. Demographic data of 23 patients Demographics

Number (%)

Ethnicity African or black

18 (78)

Mixed

4 (18)

White

0 (0)

Other (Arab, Indian, other)

1 (4)

Language isiXhosa

14 (61)

Afrikaans

4 (17)

English

3 (13)

Other

2 (9)

Education level Year 1–5

5 (22)

Year 6–10

18 (78)

Year > 10

0 (0)

Income per month (ZAR) < 300

15 (65)

300–999

3 (13)

1 000–9 999

5 (22)

> 10 000

0 (0)

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trimester, she had required treatment for infective endocarditis, complicated by acute kidney injury and disseminated intravascular coagulation. She was discharged after this episode and readmitted a week later at 36 weeks, as per protocol. Normal vaginal delivery followed and she was discharged six days later in a satisfactory condition. She returned to casualty 41 days post-delivery and complained to the prehospital crew that she was unable to hear her valve clicks. Her INR was 3.73 (supra-therapeutic). She then suffered a cardiorespiratory arrest and could not be resuscitated. The cause of death was unclear, however it was suspected to be a valve thrombosis on the basis that she complained that she was unable to hear her valve clicks. She had had no INR monitoring between discharge post-partum and her presentation in cardiac arrest. Table 3. Baseline maternal characteristics (n = 29) Characteristics

Mean ± SD or n (%)

Age at delivery (years)

27.9 ± 7.9

Weight (kg) (n = 26)

70.2 ± 13.8

NYHA FC, n (%) I/II

29 (100)

III

0 (0)

Vital signs Heart rate (bpm)

90 ± 18

SBP (mmHg)

111 ± 16

DBP (mmHg)

72 ± 11

Echocardiogram (n = 25) LVEDD (mm)

50.1 ± 9

LVESD (mm)

35.8 ± 9.8

EF (%)

54.4 ± 13.7

ECG (n = 27), n (%) Sinus rhythm

22 (81)

Atrial fibrillation

5 (19)

Atrial flutter

1 (4)

RBBB

1 (4)

Medical history HIV

10 (34)

Syphilis

2 (7)

Other (psoriasis, hearing impairment)

2 (7)

Reason for valve replacement, n (%) Rheumatic heart disease Takayasu’s

22 (97) 1 (3)

Position of valves, n (%) Mitral

18 (62)

Aortic

3 (10)

Mitral and aortic

8 (28)

Warfarin dose, n (%) ≤ 35 mg/week

10 (35)

> 35 mg/week

14 (48)

Undocumented

5 (17)

Obstetric history, n (%) Primigravida

6 (21)

Multigravida

23 (79)

Gestation age at presentation, n (%) < 6 weeks

2 (7)

< 12 weeks

14 (48)

12–24 weeks

8 (28)

≥ 24 weeks

5 (17)

kg: kilogram, NYHA FC: New York Heart Association functional class, bpm: beats per minute, SBP: systolic blood pressure, DBP: diastolic blood pressure, LVESD: left ventricular end-systolic diameter, LVEDD: left ventricular enddiastolic diameter, EF: ejection fraction, ECG: echocardiogram, RBBB: right bundle branch block.

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The second death occurred in a 36-year-old patient with a double valve replacement (mitral and aortic) necessitated by Takayasu’s disease. She had tight aortic stenosis with pulmonary hypertension using standard criteria and was assessed as high risk for surgical revision, although this was considered ‘semiurgent’. There was extensive vascular involvement, including total occlusion of the left carotid and of both subclavian vessels as well as severe stenosis of other head and neck vessels. She was also HIV infected (CD4 count was 321 cells per mm3) and had defaulted on antiretroviral therapy. This was restarted late in pregnancy. Additionally, she was rhesus negative. There was also a history of previous tuberculosis, which had been fully treated. Due to the very high-risk nature of the pregnancy, the patient was offered a termination of pregnancy, which she declined. At 31 weeks’ gestation, she had spontaneous rupture of the membranes and two days thereafter required a caesarean section. She was discharged seven days postpartum but represented two days later requiring intubation for pneumonia and ICU admission. Her clinical course was complicated by acute kidney injury, supraventricular tachycardia requiring cardioversion, pneumonia and a brainstem infarct. Intensive care was subsequently withdrawn and the patient died. There were three cases of stroke and one patient with a clot on a prosthetic valve. One HIV-negative patient developed a left middle cerebral artery infarct while on a heparin infusion at nine weeks’ gestation, presumably after a thrombotic event. At the time, her PTT was 2.4 times that of the control. Despite the risks of warfarin in the first trimester, she was changed to warfarinbased anticoagulation after this event. A second patient developed a brainstem infarct post-partum while intubated. On the four days preceding confirmation of the infarct on CT brain scan, her INR measurements ranged between 2.8 and 6.04. This patient, who died following her infarct and is described in more detail above, had multiple risk factors for stroke, including Takayasu’s arteritis and HIV. A third patient developed an ischaemic stroke in the first trimester, prior to diagnosis of pregnancy. At the time, her INR was 1.35. The stroke resulted in right hemiplegia and aphasia. This patient was also HIV positive and attended the maternity clinic for the first time in the third trimester. The aetiology of the stroke remains unclear and may not have been embolic or thrombotic in nature, but rather an ischaemic stroke due to HIV infection. A fourth, HIV-negative patient, was noted to have a ‘small clot on her valve’ at routine echo while receiving a sub-therapeutic dose of heparin. This resulted in no adverse sequelae. The first death, described above, may have been due to a valve thrombosis but this was unproven. No deep-vein thromboses or pulmonary emboli were detected. Major haemorrhage occurred in six pregnancies (Table 4). These included four major haemorrhages in term deliveries and two major haemorrhages in pregnancies terminating at 11 and 19 weeks, respectively. Of the four term deliveries, there were two episodes of haemorrhage related to sepsis and two wound haematomas requiring return to theatre. Sepsis contributed to two major haemorrhages. One patient with puerperal sepsis, who delivered by caesarean section, needed total abdominal hysterectomy and bilateral salpingo-oophorectomy as well as massive transfusion for post-operative bleeding. Another patient with puerperal sepsis

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required evacuation of retained products of conception six days post normal vaginal delivery. This procedure led to postpartum haemorrhage of two litres, massive blood transfusion, bilateral uterine artery embolisation and vaginal packing to control bleeding. There were two cases of wound haematomas requiring evacuation in theatre. In patients delivering before 20 weeks’ gestation, two major haemorrhages occurred. The first patient underwent a hysterotomy at 19 weeks. She required a second laparotomy for post-operative intraperitoneal bleeding of more than one litre. The lowest documented haemoglobin was 3.9 g/dl and she received a massive transfusion. One episode of serious haemorrhage occurred following a first-trimester termination of pregnancy, performed as the patient did not wish to continue with a high-risk pregnancy. Following evacuation of the products of conception, this patient bled to a haemoglobin of 3g/dl and required fluid resuscitation. Eight patients received blood transfusions. In five cases, blood products were given after bleeding. In three cases blood and/or fresh frozen plasma was given to increase a low haemoglobin level or to avoid bleeding prior to a procedure. Minor bleeding was common. One episode of haematemesis following assault occurred, eight patients experienced epistaxis on one or more occasion, four patients experienced gum bleeding, one patient had a drip-site haematoma and another had problematic bleeding at a drip site. Nine (45%) of 20 term pregnancies were delivered by caesarean section. There was an additional hysterotomy carried out to deliver a previable infant. The hysterotomy was performed as the mother had had two previous caesarean sections. HIV infection was more likely to be associated with surgical delivery (p = 0.0017). Eleven pregnancies had episodes of arrhythmia, most commonly atrial fibrillation. However, in seven cases, the arrhythmia had been documented prior to pregnancy. Nine pregnancies were associated with worsening of New York Heart Association functional class, with three patients developing pulmonary oedema. The average hospital stay was 41.0 days. Five (17.2%) patients spent 60 or more nights in hospital. The average number of admissions per patient was 3.0. Fourteen (48%) patients had four or more admissions.

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Four or more admissions refused hospital treatment. There were 57 admissions between weeks 12 and 36, the period in which admission was not mandated, equating to an additional two admissions per patient, most commonly for sub-therapeutic INR requiring ‘heparin cover’. In one case this occurred on five separate occasions, when the patient was repeatedly found to be sub-therapeutic on warfarin at antenatal visits and offered in-patient intravenous heparin. Additionally, two patients absconded. Three spontaneous first-trimester miscarriages and three second-trimester miscarriages occurred (Table 5). Three pregnancies were terminated, one in the first trimester because the patient did not wish to continue a high-risk pregnancy. There were two terminations for foetal malformations not attributed to warfarin (Table 6). One of these had confirmed Dandy–Walker syndrome and was delivered by hysterotomy at 19 weeks. The other delivered vaginally at 22 weeks because of suspected anomalies based upon the presence of echogenic bowel. One infant was born alive with multiple anomalies, including features consistent with warfarin embryopathy, together with other abnormalities. This patient had been taking 5 mg of warfarin daily. Antenatal ultrasound showed an absent nose and abnormal face with close-set eyes, low-set ears and a bossed forehead. Brain abnormalities were also noted and included dilated anterior horns of the lateral ventricle fusing in the midline and a dilated fourth ventricle. This patient refused early termination of pregnancy and the baby, born alive by caesarean section, died on day five of life.

Discussion In this study, a high rate of serious adverse events was observed in maternal and foetal outcomes (Table 5). Maternal morbidity included major haemorrhage, cardiac failure and sepsis, as well as ischaemic stroke. There were three instances of pulmonary oedema, an approximately 20% risk of major haemorrhage, three ischaemic strokes and one case of infective endocarditis. Both deaths occurred post-partum. One was in a patient with significant vascular disease caused by Takaysu’s arteritis, further complicated by HIV infection. Adverse perinatal outcome was evident as a high rate of miscarriage in the first and second trimesters, two cases of

Table 4. Details of major haemorrhage Patient No.

Timing of bleeding

Transfusion

Drop in Hb pre- and postdelivery (g/dl)

Peripartum C/S

1 100 ml lost during C/S. Wound continued to bleed. Day 5 post C/S had relook laparotomy but only required cauterisation of fat

2 units RBCs

3.4

Peripartum C/S

Required repeat laparotomy for evacuation of haematoma and TAH and BSO. Patient was septic

2 RBCs, 4 FFPs

Not available

1.6

Delivery

Gestation (weeks) Details

Peripartum C/S

Wound haematoma, required return to theatre for evacuation

Peripartum NVD + forceps

On day 6 post-delivery required evacuation of RPOC in theatre. Post 3 units in pregnancy. Perievacuation found in shock requiring resuscitation and massive transfu- partum 11 RBCs + other sion. Bilateral uterine artery embolisation attempted. This failed and products patient had further surgery to pack vaginal bleeders. Patient was septic

6.6

Peripartum Medical termination

Patient had termination of pregnancy. Later found in shock with Hb of 3 g/dl

2 units RBCs

7.0

Peripartum Hysterotomy

1 litre intraperitoneal bleed post hysterotomy. Lowest Hb 3.9 g/dl. Required repeat laparotomy 2 days post hysterotomy.

Massive transfusion. 7 units RBCs, 6 units FFPs, cryoprecipitate and haemo-solvex

7.1

Hb: haemoglobin, RBCs: red blood cells, FFPs: fresh frozen plasma, C/S: caeserean section, TAH: total abdominal hysterectomy, BSO: bilateral salpingo-oophorectomy, RPOC: retained products of conception.

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Table 5. Maternal and foetal outcomes Outcomes

Table 6. Congenital abnormalities including warfarin embryopathy

Number (%)

Maternal outcomes NYHA FC (n = 13) I/II

III

Deaths

GA at 1st AnticoPatient Maternal antenatal agulant no age visit Parity and dose Sonography 25

ENND Warfarin, Polyhydramnios, abnormal facies, 5 mg close-set eyes, absent nose, lowset ears, bossed forehead, abnormal ventricles, short spine, fat puffy hands and feet

17’5

Warfarin Dandy–Walker 5 mg in malformation T1 then defaulted

Termination at 19 weeks

19’1

Warfarin Echogenic bowel 7.5 mg daily

Termination at 22 weeks

19 (66)

Caesarean

9 (31)

Hysterotomy

1 (3)

Reasons for surgical delivery Foetal distress

Previous caesarian section

SROM

Other

Bleeding complications

Foetal outcomes

Delivery Vaginal

293

GA: gestational age, ENND: early neonatal death, T1: first trimester.

Major bleeding

7 (24)

Blood transfusion

8 (28)

Thrombotic complications

4 (14)

Arrhythmias

11 (38)

Time in hospital 41 ± 28

Hospital stay (days)

3 ± 1.8

Admissions Foetal outcomes Healthy

19 (66)

Birth weight (g) (n = 19)

< 2 kg: 2 2–2.5 kg: 4 2.5–4 kg: 13

Apgar score at 5 min (n = 18)

Apgars 9–10: 17 Apgars 7: 1 Born before arrival: 1

ENND

1 (3)

Pregnancy loss

6 (21)

Termination

3 (10)

NYHA FC: New York Heart Association functional class, SROM: spontaneous rupture of membranes, ENND: early neonatal death.

suspected unrelated foetal anomalies and a third case of a complex foetal anomaly probably attributable to warfarin. Only 20 pregnancies (69%) had a normal neonatal outcome. The women in this cohort had lengthy hospitalisations, with 20 patients (69%) requiring more than 30 days in hospital and 15 (52%) requiring three or more admissions. The mortality rate (6.9%) in our cohort compares unfavourably with similar local cohorts9,13,15 and with a large meta-analysis showing a 2.9% rate,2 but favourably with UKOSS, a recent United Kingdom population-based study.16 Both mortalities occurred postpartum after discharge and in patients with double valve replacements, which have been associated with worse maternal outcomes.16 Inducing an anticoagulated state opposes the pro-thrombotic milieu of normal pregnancy.17 Obstetric haemorrhage is known to be a major contributor to maternal deaths.18 Haemorrhage rates were significantly high with 21% of patients having major haemorrhagic complications. This rate is comparable with other cohorts of women with mechanical prosthetic heart valves.5,16 Another study15 reported post-partum haemorrhage in only 5.8% of patients. These variable rates may reflect differing practice in the timing of anticoagulation reintroduction. The anticoagulation protocol used prescribes heparin rather than warfarin from 36 weeks’ gestation, allowing rapid reversal of anticoagulation if required during delivery. Delivery takes

place during an anticoagulation-free ‘window’ to minimise risk of post-partum haemorrhage. There is a need to identify the optimal duration of this ‘window’ to balance the risks of haemorrhage and thrombosis. Heparin is usually reinstated six hours after delivery unless there is clinical concern of haemorrhage. Of the 19 pregnancies delivered after viability, and consistent with other literature,19-21 post-operative haemorrhage (3/9 caesarean sections, 33%) was more frequent than major haemorrhage post-vaginal delivery (1/10 normal vaginal deliveries, 10%), indicating that a longer anticoagulation window may be appropriate after operative delivery. The data suggest that caesarean sections should be performed only when clearly indicated, with meticulous haemostasis, and in anticipation of possible haemorrhage. Despite the risk of major bleeding, neither death occurred as a direct result of bleeding. However, cases of major haemorrhage would have resulted in deaths had resuscitation, including transfusion not been available. Only one patient had a suspected thrombo-embolic event. Two further patients had ischaemic strokes in the setting of HIV positivity. Protocols used called for intravenous unfractionated heparin from six to 12 weeks’ gestation and peripartum, according to relevant guidelines.14 However, more recent guidelines22 recommend subcutaneous low-molecular-weight heparin (LMWH) (enoxaparin, Clexane) in preference to unfractionated heparin (UFH), dose adjusted according to peak anti-Xa levels. LMWH has more predictable pharmacokinetics and less risk of allergic reactions, heparin-induced thrombocytopenia and osteoporosis compared to UFH.22,23 However, there is concern that the use of subcutaneous UFH may lead to unacceptably high rates of treatment failure and valve thrombosis.24 Consequently, intravenous UFH is generally recommended and may remain the only alternative to warfarin where access to anti-Xa monitoring is limited, such as in our setting. Intravenous heparin infusions are, however, resource intensive, requiring frequent monitoring and prolonged hospitalisation. The single suspected thrombotic event occurred in a patient receiving UFH while in a sub-therapeutic range. However, even ideal anticoagulation can lead to treatment failure. In general, heparin use avoids the pregnancy loss and embryopathy associated with warfarin but carries a higher risk

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of valve thrombosis.25 Women at particularly high thrombosis risk may be offered warfarin throughout pregnancy, except at peripartum. Factors conferring higher risk of thrombosis include older-generation mechanical heart valves, valves in the mitral position, and previous history of thrombosis on heparin. Improvements in prosthetic valve thrombogenicity over time have reduced the risk of thrombosis.12 Among live births in the cohort, the rate of caesarean section was 45%. While above the national average rate of 23.1%,26 it did not differ from the background rate for all high-risk pregnancies receiving care at the tertiary hospital. HIV-positive patients were more likely to have caesarean delivery (p = 0.0017), perhaps reflecting the local policy of offering caesarean section to HIV-infected mothers with persistent viraemia. Eleven (38%) patients had episodes of arrhythmia, of which seven (24%) had been documented prior to pregnancy, most commonly atrial fibrillation. This rate is high relative to both the developed5 and developing9 world. Nine (31%) pregnancies were complicated by worsening New York Heart Association functional class, and three patients developed pulmonary oedema. This compares unfavourably with the cohort described by van Hagen et al.,5 where 7.5% of pregnancies were complicated by heart failure, and may reflect more advanced disease or the effects of co-morbidities present in a low-resource setting. Long hospital stays are costly and contribute negatively to patient quality of life. Out-patient regimens such as selfadministered subcutaneous heparin as per newer guidelines22,27 could reduce length of admissions. Pregnancy loss occurred in nine pregnancies (31%), comparable with similar South African cohorts.9,13 Congenital abnormalities were seen in three pregnancies (10%), however, only one (3.4%) was considered to be due to warfarin embryopathy, a rate lower than reported elsewhere.2,9,13 Warfarin embryopathy is caused by foetal exposure to warfarin between six and 12 weeks’ gestation and is avoided by using heparin during this period. Only two patients presented prior to six weeks’ gestation, enabling timeous switching from warfarin to heparin. Eleven patients presented between six and 12 weeks and received heparin from presentation to 12 weeks. The patient whose foetus may have been affected by warfarin embryopathy presented at 24 weeks’ gestation and therefore was on warfarin throughout the vulnerable period.

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by a longer anticoagulation-free ‘window’ peripartum. More studies are needed to identify the optimal window to balance haemorrhagic and thrombotic risk but it is likely to be longer than six hours. Heightened vigilance is required post-partum. Contraception should be offered routinely at out-patient cardiac clinics. Preconception counselling should emphasise the importance of early presentation. Prolonged intravenous heparin is likely to be a risk factor for infective endocarditis. Subcutaneous out-patient LMWH should be considered. The Hatter Institute for Cardiovascular Research is supported by the National Research Foundation South Africa, the Medical Research Foundation South Africa, the Maurice Hatter Foundation and SERVIER.

References 1.

Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S. Incidence and characteristics of newly diagnosed rheumatic heart disease in Urban African adults: insights from the Heart of Soweto Study. Eur Heart J 2010; 31: 719–727.

Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med 2000; 160: 191–196.

Mocumbi AO, Sliwa K, Soma-Pillay P. Medical disease as a cause of maternal mortality : the pre-imminence of cardiovascular pathology. Cardiovasc J Afr 2016; 27(2): 84–88.

Soma-pillay P, Seabe J, Sliwa K. Cardiovascular Topics The importance of cardiovascular pathology contributing to maternal death: Confidential Enquiry into Maternal Deaths in South Africa, 2011–2013. Cardiovasc J Afr 2016; 27(2): 60–65.

Van hagen IM, Roos-Hesselink JW, Rhys TPE, Merz WM, Goland S, Gabriel H, et al. Pregnancy in women with a mechanical heart valve. Circulation 2015; 132: 132–142.

Mclintock C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. Thromb Res [Internet] 2011; 127: S56–60. Available from: http://dx.doi.org/10.1016/S00493848(11)70016-0.

Nishimura RA, Warnes CA. Anticoagulation during pregnancy in women with prosthetic valves: evidence , guidelines and unanswered questions. Heart 2015; 101: 430–435.

Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med 2003; 164: 694–698.

Mazibuko B, Ramnarain H, Moodley J. An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: a five-

Stengths and limitations Comparison of this cohort with previously published literature shows some differences in mortality rate and perinatal outcome, which is likely spurious owing to the small sample size, and is further skewed by the death related to complicated Takayasu’s arteritis.

year experience. Cardiovasc J Afr 2012; 23(4): 216–221. 10. Basude S, Hein C, Curtis SL, Clark A, Trinder J. Low-molecularweight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study. Br J Obstst Gynaecol 2012; 119: 1008–1013. 11. Vitale N, Feo M De, Santo LS De, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999; 33(6): 1637–1641.

Conclusion Pregnancies in patients on anticoagulation carry additional risks due to both the underlying condition for which the patient is anticoagulated and the anticoagulation itself. In this small study, ischaemic events occurred intrapartum, while haemorrhagic events occurred peri- or post-partum. Avoidance of post-partum haemorrhage, particularly post-operatively, may be achieved

12. De Santo L, Romano G, Della Corte A, D’Oria V, Nappi G, Giordano S, et al. Mechanical aortic valve replacement in young women planning on pregnancy. J Am Coll Cardiol [Internet] 2012; 59(12): 1110–1115. Available from: http://dx.doi.org/10.1016/j.jacc.2011.10.899. 13. Soma-Pillay P, Nene Z, Mathivha T. The effect of warfarin dosage on maternal and fetal outcomes in pregnant women with prosthetic heart valves. Obstet Med 2011; 4: 24–27. 14. Elkayam U, Singh H, Irani A, Akhter MW. Anticoagulation in pregnant

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women with prosthetic heart valves. J Cardiovasc Pharmacol Ther 2004; 9(2): 107–115. 15. Elliot C. Complications of anticoagulation in pregnant women with mechanical heart valves [Internet]. University of Cape Town; 2012. Available from: https://open.uct.ac.za/bitstream/item/2815/thesis_ hsf_2012_elliott_c.pdf ?sequence=1. 16. Vause S, Clarke B, Tower CL, Hay CRM, Knight M. Pregnancy

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delivery: A national emergency. S Afr Med J 2016; 106(5): 472–476. 21. Van den Berg K, Bloch EM, Aku AS, Mabenge M, Creel D, Hofmeyr G, et al. A cross-sectional study of peripartum blood transfusion in the Eastern Cape , South Africa. S Afr Med J 2016; 106(11): 1103–1109. 22. Schapkaitz E, Jacobson BF, Manga P, Chitsike RS, Benade E, Jackson S, et al. Recommendations for the anticoagulation of pregnant patients with mechanical heart valves. S Afr Med J 2015; 105(9): 733–738.

outcomes in women with mechanical prosthetic heart valves: a prospec-

23. Saeed CR, Jacobson BF, Manga P, Aziz RH, Moodley S, Toweel GD.

tive descriptive population based study using the United Kingdom

A prospective trial showing the safety of adjusted-dose enoxaparin for

Obstetric Surveillance System (UKOSS ) data collection system. Br J

thromboprophylaxis of pregnant women with mechanical prosthetic

Obstet Gynaecol 2016: 1–9.

heart valves. Clin Appl Thromb 2011; 17(4): 313–319.

17. Goland S, Zilberman L, Elkayam U. Clinical considerations on anti-

24. Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted

coagulation management in cardiovascular diseases during pregnancy.

doses of subcutaneous heparin to prevent thromboembolic phenomena

Drug Dev Res 2013; 74: 541–552.

in pregnant patients with mechanical cardiac valve prostheses. J Am Coll

18. National Committee for the Confidential Enquiry into Maternal

Cardiol 1996; 27(7): 1698–1703.

Deaths. Saving Mothers 2011–2013: Sixth report on the Confidential

25. James AH, Brancazio LR, Gehrig TR, Wang A, Ortel TL. Low-molecular-

Enquiries into Maternal Deaths in South Africa [Internet]. 2013.

weight heparin for thromboprophylaxis in pregnant women with

Available from: http://www.kznhealth.gov.za/mcwh/Maternal/SavingMothers-2011-2013-short-report.pdf.

mechanical heart valves. J Matern Neonatal Med 2006; 19(9): 543–549. 26. Gebhardt GS, Fawcus S, Moodley J, Farina Z. Maternal death and

19. Fawcus S, Moodley J. Postpartum haemorhage associated with caesar-

caesarean section in South Africa: Results from the 2011–2013 Saving

ean section and caesarean hysterectomy. Best Pract Res Clin Obstet

Mothers Report of the National Committee for Confidential Enquiries

Gynaecol [Internet] 2013; 27: 233–249. Available from: http://dx.doi. org/10.1016/j.bpobgyn.2012.08.018 20. Fawcus S, Pattinson RC, Moodley J, Moran NF, Schoon MG, Mhlanga RE, et al. Maternal deaths from bleeding associated with caesarean

into Maternal Deaths. S Afr Med J 2015; 105(4): 287–291. 27. Bates S, Greer I, Middeldorp S, Veenstra D, Prabulos A-M, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy. Chest 2012: 691–736.

Dangerously high blood pressure spikes more prevalent in black adults Black American adults experience a hypertensive crisis at a rate that is five times the national average, according to a study presented at the American Heart Association’s Joint Hypertension 2018 scientific sessions, an annual conference focused on recent advances in hypertension research. Hypertensive crisis is a complication of high blood pressure in which blood pressure quickly and severely soars to life-threatening levels. People often can avoid this dangerous blood pressure escalation by keeping their blood pressure under control with medications and lifestyle modifications. ‘We studied an inner-city population to find that being black is a risk factor for progressing from hypertension to hypertensive crisis,’ said study author Dr Frederick A Waldron, an emergency medicine physician at Newark Beth Israel Medical Centre, New Jersey. ‘Now that we have effective anti-hypertensive medications available, hypertensive crisis and hypertensive emergency, a rare but further progression of hypertensive crisis in which organ damage occurs, should not exist to this degree among black or other patients.’ In what Waldron said is the largest case–control study to date on hypertensive-crisis patients, researchers looked back at emergency department medical records of more than 15 000 patients from 2013 to 2016. They defined hypertensive crisis as blood pressure at or above 200/120 mmHg. They found: nearly 1 800, or 11.4% of the 15 631 hypertensive patients that came through the emergency department in the three-year study were in hypertensive

crisis; nearly 90% of those in hypertensive crisis were black; one in four, or 25%, of patients with hypertensive crisis went on to develop catastrophic organ failure, including stroke, congestive heart failure, kidney failure or heart attack. Being older than 65 years or male, as well as having anaemia, chronic kidney disease or a history of stroke and cardiovascular diseases, including high cholesterol levels, predicted higher risk for hypertensive emergencies. Anaemia has not been identified before as a hypertensive emergency risk factor, according to Waldron. Insurance status and access to primary care did not affect patients’ odds of having a hypertensive crisis. ‘There is no good treatment for organ damage, so the best way to address this is to develop a preventative strategy,’ Waldron said. He suggests efforts to help patients take their medicine properly could help reduce hypertensive crises. The numbers in the study may be underestimated due to differing definitions of hypertensive crisis. For example, the American Heart Association defines it as blood pressures at or above 180/120 mmHg. This study defined hypertensive crisis as above 200/120 mmHg. Waldron said future studies should determine rate of adherence to blood pressure medications, and follow patients in hypertensive crisis longer to determine true incidence of hypertension emergency. Source: Medical Brief 2018

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The neutrophil-to-lymphocyte ratio and mean platelet volume can be associated with severity of valvular involvement in patients with acute rheumatic carditis Serkan F Çelik, Elif Çelik

Abstract Objectives: The aim of the study was to investigate the association between the severity of acute rheumatic carditis (ARC) and the neutrophil–lymphocyte ratio (NLR) and mean platelet volume (MPV). Methods: Paediatric patients diagnosed with ARC between 2010 and 2016 and age- and gender-matched controls were retrospectively analysed. At the time of diagnosis, we reviewed the demographic features obtained: echocardiographic data, complete blood count reports, acute-phase reactants, including C-reactive protein, and erythrocyte sedimentation rate values. The patient group was further divided into two subgroups according to the degree of valvular regurgitation, which included those with severe and those with mild-tomoderate valvular regurgitation. Results: The number of cases with ARC and age- and gendermatched controls were 120 and 50, respectively. The mean age of the patients was 12.25 ± 2.89 (range: 7–18) years. NLR, MPV, anti-streptolysin-O, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haemoglobin level, and white blood cell (WBC) and neutrophil count were significantly higher in patients with acute carditis compared with the controls (p < 0.001). NLR was found to have a significantly positive correlation with CRP (r = 0.177, p = 0.001), ESR (r = 0.81, p = 0.03) and WBC count (r = 0.47, p = 0.001). Moreover, we found a positive correlation between NLR and severity of valvular regurgitation (r = 0.34, p < 0.001), and a negative correlation between MPV and severity of valvular regurgitation (r = –0.38, p < 0.05) in our patients. In multiple linear regression analysis, severe valvular regurgitation was associated with NLR (0.51; 95% CI: 0.32–0.68; p = 0.006) and MPV (–0.78; 95% CI: –0.72 to –0.98; p = 0.008). Conclusion: NLR and MPV are novel inflammatory markers and simple, rapid and easily accessible prognostic parameters that can be associated with severity of valvular involvement in patients with ARC.

Keywords: neutrophil-to-lymphocyte ratio, mean platelet volume, acute rheumatic carditis

Division of Paediatric Cardiology, Department of Paediatrics, Adnan Menderes University Hospital, Aydın, Turkey Serkan F Çelik, MD, docser2003@yahoo.com

Department of Paediatrics, Adnan Menderes University Hospital, Aydın, Turkey Elif Çelik, MD

Submitted 11/10/17, accepted 19/6/18 Published online 10/9/18 Cardiovasc J Afr 2018; 29: 296–300

www.cvja.co.za

DOI: 10.5830/CVJA-2018-031

Acute rheumatic fever (ARF) results from the body’s autoimmune response to a throat infection caused by Streptococcus pyogenes, also known as group A Streptococcus bacteria. The most serious manifestation is carditis (> 50% of patients) because it can lead to chronic rheumatic heart disease, whereas all other clinical features resolve fully, often within weeks. The most commonly affected valves in rheumatic heart disease are the mitral and aortic valves.1 The pathogenic mechanisms of ARF are not completely understood.2 Activation of the innate immune system begins with a pharyngeal infection that leads to the presentation of S pyogenes antigens to the T and B cells. CD4+ T cells are activated and results in the production of specific IgG and IgM antibodies by the B cells.3 Tissue injury ensues through an immune-mediated mechanism that is initiated via molecular mimicry.4 Structural similarity between the infectious agent and human proteins leads to cross-activation of antibodies and/or T cells directed against the human proteins.3 Leukocytes are the main mediators of inflammation, and changes in their populations reflect the response of the immune system to systemic inflammation.5 In general, neutrophils are considered a marker of ongoing non-specific inflammation, while lymphocytes are a marker of the immune regulatory response.6 The neutrophil-to-lymphocyte ratio (NLR) therefore represents the balance between inflammation and immune regulation. It has been shown to predict mortality and major adverse cardiac events in acute coronary syndromes,7 degenerative aortic stenosis,8 acute rejection after heart transplantation,9 and acute myocardial infarction. Also, platelet activation has a very important role in inflammation; it has been observed to secrete mediators such as chemokines and cytokines.10 Mean platelet volume (MPV) is a marker of platelet activation that is associated with serious inflammation.11 In previously reported studies, MPV values were shown to be significantly lower in rheumatoid arthritis and inflammatory bowel disease patients with active disease, compared to controls.12,13 Furthermore, lower MPV values have been shown in patients with acute rheumatic carditis (ARC).14 However, there is no study evaluating the correlation between valve involvement and MPV, NLR and other full blood count parameters during the ARC period. The aims of this study were to compare full blood count parameters in children with ARC with healthy children, and to

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evaluate these parameters in terms of heart valve involvement during the acute phase.

Methods The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The study was approved by the institutional committee of Erciyes University. Detailed consent forms were signed by the parents of all subjects before participating in the study. In this matched case–control study, 120 consecutive patients diagnosed with ARC at the Department of Paediatric Cardiology between February 2010 and March 2016, were enrolled in the study. As the Jones criteria for the diagnosis of ARF were modified in 2015,15 older criteria had been used for the diagnosis of earlier patients. A diagnosis of ARF was established when the last Jones criteria were fulfilled for acute cases. All patients underwent echocardiographic examination before starting anti-inflammatory treatment. The Vivid 7 Pro Ultrasound System (GE Medical Systems, NE) was used for two-dimensional, M-mode and colour-flow Doppler imaging. A paediatric cardiologist experienced in rheumatic heart disease performed all echocardiographic examinations following the guidelines of the American Society of Echocardiography and European Society of Cardiology.16 The severity of mitral and aortic regurgitation detected by colour Doppler was defined as mild, moderate and severe when the length of the jet was > 1.5, 1.5–2.9 and > 3 cm, respectively.17 The patient group was further divided into two subgroups according to the degree of regurgitation, which included those with severe and those with mild-to-moderate regurgitation. Patients who had taken non-steroidal anti-inflammatory drugs within the last four weeks before blood sampling, and those with abnormal renal function or liver tests and malignancies were excluded. Arthritis and mild-to-moderate carditis were treated with salicylate, whereas patients with severe carditis were treated with oral prednisolone. Also, oral steroid therapy was started in patients without discriminating between moderate and severe carditis. Initially prednisolone (2 mg/kg/d) was given for two weeks, which was then tapered off, and aspirin was started at 75–100 mg/kg/d (maximum dose 3.5 g/d) to prevent rebound. Fifty age- and gender-matched healthy children were recruited from the local population. They were referred to our hospital because of cardiac murmur and underwent electrocardiography. They had a negative medical history and no signs or symptoms of acute or chronic disease. All participants in the control group were examined by the same paediatrician and the results of the physical examination were normal. Full blood count parameters, anti-streptolysin-O (ASO), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) titres and echocardiographic examinations of all subjects were recorded from the same computerised database. Blood samples were drawn from the peripheral veins and collected in plastic tubes (Vacutainer-Becton, Dickinson and Co, USA), containing dipotassium ethylene diamine tetra-acetic acid (EDTA-K2). The full blood count analysis was done by flow cytometry using the Abxpentra model 120 DX analyser in the laboratory

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of our institution. NLR was calculated using the absolute count method. ESR was determined with the Westergren method. ASO (Rapitex ASL) and CRP titres were determined using standard reagents on the Beckman-Coulter DXC 800 systems analyser in the same laboratory.

Statistical analysis Data are reported as mean ± standard deviation. If not normally distributed, parameters are presented as median (range). The distribution pattern of data was assessed with the Shapiro– Wilks test. Differences between quantitative groups with normal distribution were evaluated with the Student’s t-test. The Mann– Whitney U-test was used for abnormally distributed data. The associations between parameters were assessed using Pearson’s or Spearman’s correlation tests. Statistical Package for Social Sciences (SPSS) version 22.0 (SPSS Inc, Chicago, IL, USA) was used for all statistical calculations. Beta- and p-values were assessed for each independent factor in multiple linear regression analysis; p-values < 0.05 were considered to be statistically significant.

Results One hundred and twenty patients (72 female), who were diagnosed with ARC, and 50 age- and gender-matched healthy children were included in this study. The mean age of the patients was 12.25 ± 2.89 (range: 7–18) years. Baseline clinical and laboratory characteristics of patients and control subjects are shown in Table 1. Compared with the controls, ASO, CRP, ESR, haemoglobin, white blood cell count (WBC), neutrophil count, MPV and NLR values were significantly higher in patients with acute carditis compared with the controls (p < 0.001) (Table 1). Also, platelet counts (p = 0.002) and MPV (p = 0,049) values were significantly higher in the patients. NLR was found to have a significantly positive correlation with CRP (r = 0.177, p = 0.001), ESR (r = Table 1. Demographic and laboratory characteristics of the patient and control groups Characteristics Age (years) Males, n (%) WBC count (× 103 cells/mm3) Haemoglobin (g/dl) ESR (mm/hour)

Control (n = 50) 12.96 ± 2.55 12 7.02 ± 1.86

ARF (n = 120) 12.25 ± 2.89 48 10.58 ± 3.76

p-value 0.48 0.86 < 0.01

13.60 ± 1.09

12.35 ± 1.03

< 0.01

3.83 ± 2.57

37.12 ± 27.63

< 0.001

CRP (mg/l)

3.34 ± 0.54

46.37 ± 48.78

< 0.001

ASO (U/ml)

244.91 ± 239.62

995.24 ± 1023.69

< 0.001

Platelet count (× 103 cells/mm3)

291.30 ± 67.80

355.22 ± 103.3

MPV (fl)

10.21 ± 1.25

9.01 ± 1.35

RDW (%)

0.002 < 0.003

13.65 ± 1.30

12.88 ± 0.89

0.26

Neutrophil count (× 103 cells/mm3)

3.64 ± 1.20

7.21 ± 3.56

< 0.001

Lymphocyte count (× 103 cells/mm3)

2.64 ± 0.84

2.55 ± 0.84

0.67

NLRa

1.35 (1.02–1.94)

3.73 (2.02–4.07)

< 0.001

MCV (fl)

82.95 ± 5.04

80.15 ± 6.01

0.06

ARF: acute rheumatic fever, ASO: anti-streptolysin-O, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, MPV: mean platelet volume, WBC: white blood cell, RDW: red blood cell distribution width, NLR: neutrophil-tolymphocyte ratio, MCV: mean corpuscular volume (fl). Parametric values are expressed as means with standard deviation. Significance is determined by p < 0.05 and shown in bold. aIf not normally distributed, values are presented as median and range in parentheses.

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ESR

120.00

CRP

250.00

100.00 80.00

WBC

25.00

200.00

20.00

150.00

15.00

100.00

10.00

60.00 40.00 r = 0.81 p = 0.03

20.00 0.00

6 8 NLR

50.00 0.00

r = 0.377 p = 0.001 0

6 8 NLR

5.00 0.00

r = 0.47 p = 0.001 0

6 8 NLR

Fig. 1. T he relationship between neutrophil-to-lymphocyte ratios (NLR) and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell (WBC) count. The same numerical valves are shown once on the figures.

0.81, p = 0.03) and WBC count (r = 0.47, p = 0.001) (Fig. 1). However, there was no significant difference in lymphocyte count and red blood cell distribution width between the groups (p > 0.05). Mitral regurgitation (MR) existed in 68 patients, aortic regurgitation (AR) in 16, and combined valve involvement in 36 patients. There were 38 patients with severe valve regurgitation. Twenty-eight patients had severe MR, six had severe AR, and four had severe combined valve regurgitation. We found a positive correlation between NLR and the severity of valvular regurgitation (r = 0.34, p < 0.001), and a negative correlation between MPV and the severity of valvular regurgitation (r = –0.38, p < 0.05). The MPV and NLR values according to valve involvement in the groups are shown in Fig. 2. Clinical and echocardiographic variables, which were correlated with NLR and MPV values in the Student’s t-test (severe valvular regurgitation), were included in multiple linear regression analysis to detect the determinants of possible platelet volume decrease and NLR increase in the patient group. In regression analysis, NLR (OR = 0.51, 95% CI: 0.32–0.68, p = 0.006) and MPV (OR = –0.78, 95% CI: –0.72–0.98, p = 0.008)

were found to be independent predictors for the presence of severe valvular regurgitation (Table 2).

Discussion To the best of our knowledge, this study showed for the first time that increased NLR and decreased MPV levels can be associated with severity of valvular involvement in patients with ARC. Furthermore, NLR values were correlated with WBC count, ESR and CRP during ARF. In the case of ARF, several inflammatory cells such as neutrophils, macrophages, and T and B lymphocytes infltrate both the myocardium and the valves. Activated lymphocytes and macrophages secrete tumour necrosis factor cytokines, and interleukins play an important role in the pathogenesis of ARC. The healing process of rheumatic carditis results in varying degrees of fibrosis and valve damage. Kumar et al. reported that macrophages and neutrophils, which infiltrate the myocardium, may through the generation of oxygen free radicals, play a role in the pathogenesis of cardiac damage seen in patients with rheumatic heart disease. Also, they showed that the enzymatic

12.00

14.00

10.00

12.00

8.00 MPV

NLR

10.00 6.00

8.00 4.00 6.00

2.00 0.00

Severe MR/AR

MR/AR

Control

4.00

Severe MR/AR

MR/AR

Control

Fig. 2. B ox plot showing neutrophil-to-lymphocyte ratios (NLR) and mean platelet volume (MPV) in the controls and in acute rheumatic carditis patients (the severity of mitral and aortic regurgitation was defined as mild and moderate or severe). MR: mitral regurgitation, AR: aortic regurgitation.

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Table 2. Independent predictors of severity of valve regurgitation Univariate logistic regression Independent variables WBC count (×103 cells/mm3)

OR (95% CI)

p-value

0.79 (0.53–2.86)

0.034

Haemoglobin (g/dl)

1.53 (1.26–1.87)

0.042

ESR (mm/h)

0.38 (0.21–0.76)

0.50

CRP (mg/l)

0.92 (0.88–0.97)

0.22

Platelet count (× 103 cells/mm3)

0.26 (0.18–0.52)

0.035

MPV (fl)

0.44 (0.24–0.94)

< 0.001

Neutrophil count (× 103 cells/mm3)

0.85 (0.54–1.89)

0.042

NLR

0.42 (0.27–0.66)

< 0.001

MCV

0.36 (0.26–0.64)

0.024

Multiple logistic regression OR (95% CI)

p-value

0.78 (0.72–0.98)

0.008

0.51 (0.32–0.68)

0.006

Dependent variable: severe valve regurgitation cases with or without two-valve regurgitation (n = 38). OR: odds ratio, CI: confidence interval, WBC: white blood cell, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, MPV: mean platelet volume, NLR: neutrophil-to-lymphocyte ratio, MCV: mean corpuscular volume (fl).

response of neutrophils and monocytes was similar although the magnitude of NADPH oxidase activity was significantly higher in neutrophils than in monocytes of patients with ARF.18 In recent years, there has been a focus on WBC subtypes, such as neutrophils, lymphocytes, and NLR as predictors of cardiovascular risk. Many studies have shown that high ratios are associated with increased inflammation in various cardiovascular diseases. Öztürk et al. reported that higher NLR was associated with spontaneous echocardiographic contrast in rheumatic mitral valve stenosis.19 Increased neutrophil count was found to be associated with infarct size and adverse angiographic outcomes in patients with myocardial infarction,6 while low lymphocyte count was related to adverse outcomes in patients with myocardial infarction and chronic heart failure.20 Akboga et al. evaluated adult patients with rheumatic mitral valve stenosis (RMS) and found median NLRs to be significantly higher in patients with RMS compared with the control group. Moreover, they also showed NLRs to increase with the severity of mitral stenosis.21 Baysal et al. revealed that high levels of NLR were an independent predictor of severe RMS.22 In a recent study, it was reported that patients with severe RMS had significantly higher NLRs than those with mild-to-moderate RMS.23 In addition, higher NLRs were associated with an increased risk of long-term mortality in patients admitted with acute decompensated heart failure.24 In our study, we found that there was a significant positive correlation between CRP, ESR and NLR in ARC, indicating that NLR was associated with inflammation in this group of patients. Kucuk et al. demonstrated a strong association of CRP and ESR levels in children with ARC.17 Similarly, Ozdemir et al. showed higher CRP and ESR levels in ARF.25 The NLR may be the more preferable marker owing to three factors. First, although some conditions such as exercise and dehydration may increase the absolute number of neutrophils and lymphocytes, NLR is less commonly affected.26 Second, NLR is calculated from the counts of products of two different but complementary immune pathways.6 Third, the reason for the increased NLR was probably increased apoptosis of the lymphocytes, associated with the increased inflammatory status in ARF.

299

We also discovered increasing platelet counts and decreasing MPV values in patients with ARC, which reflect the inverse relationship between changes in platelet count and size. The mechanism of increase in platelet volume is thought to be that inflammatory cytokines stimulate the production of large, reactive platelets, which have a shorter life span.27 Sert et al. showed lower MPV levels in ARF patients.14 They speculated that lower MPV values during ARF may be related to the effect of interleukin 6 (IL-6). In a previously reported study, administration of IL-6 was shown to cause an increase in platelet number as well as a decrease in MPV values.28 Previous studies showed that serum IL-6 levels were significantly elevated during attacks of ARF.29 Regarding the effect of IL-6 on thrombocytes, low MPV values during ARF may be related to the effect of IL-6. Similarly, in a prospective study, MPV values significantly decreased together with CRP and IL-6 values and platelet counts in response to two-year anti-rheumatic treatment, questioning the inverse correlation between MPV and thrombocytosis.30 Since 2015, there have been changes in the diagnosis of ARF due to the revised Jones criteria. Changing the criteria may have led to an increase in our patient numbers. However, at least one extra major criterion or at least two minor criteria were definitely identified besides clinical carditis in the patient group prior to 2015. Therefore none of the ARC patients were excluded from the study. Although conducted with a relatively large ARC patient cohort, the retrospective design represents this study’s main limitation. Also we could not find follow-up full blood count values for the majority of patients due to their lack of adherence. Therefore the study was conducted using pre-treatment blood values.

Conclusion NLR and MPV are simple, rapid and easily accessible inflammatory markers that could be prognostic parameters associated with the severity of valvular involvement in ARC. However, prospective studies with larger numbers of patients are needed to evaluate the role of NLR and MPV values in ARC.

References 1.

Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5(11): 685–694.

Sika-Paotonu D, Beaton A, Raghu A, Steer A, Carapetis J. Acute rheumatic fever and rheumatic heart disease. In: Ferretti JJ, Stevens DL, Fischetti VA, eds. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016–2017 Mar 10 [updated 2017 Apr 3].

Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000; 13(3): 470–511.

Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity 2006; 39(1): 31–39.

Zahorec R. Ratio of neutrophil to lymphocyte counts-rapid and simple parameter of systemic inflammation and stress in critically ill. Bratislavske Lekarske Listy 2001; 102(1): 5–14.

Azab B, Zaher M, Weiserbs KF, Torbey E, Lacossiere K, Gaddam S, et

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al. Usefulness of neutrophil to lymphocyte ratio in predicting short- and long-term mortality after non-ST-elevation myocardial infarction. Am J Cardiol 2010; 106(4): 470–476. 7.

Dong C-H, Wang Z-M, Chen S-Y. Neutrophil to lymphocyte ratio predict mortality and major adverse cardiac events in acute coronary syndrome: A systematic review and meta-analysis. Clin Biochem 2017;

matic mitral stenosis as an indicator of spontaneous echocardiographic contrast. Kardiologia Polska (Polish Heart J) 2014; 72(10): 969–976. 20. Avanzas P, Quiles J, de Sá EL, Sánchez A, Rubio R, Garcı́a E, et al. Neutrophil count and infarct size in patients with acute myocardial infarction. Int J Cardiol 2004; 97(1): 155–156. 21. Akboğa M, Abacı A, Canpolat U, Yayla Ç, Şahinarslan A, Açıkgöz

57: 131–136. https://doi.org/10.1016/j.clinbiochem.2017.11.008

K, et al. Association of red blood cell distribution width with pres-

Küçükseymen S, Çağırcı G, Güven R, Arslan Ş. Is neutrophyl to

ence and severity of rheumatic mitral valve stenosis. Turk Kardiyoloji

lymphocyte ratio really a useful marker for all grades of degenerative

Dernegi Arsivi: Turk Kardiyoloji Derneginin Yayin Organidir 2015; 43(3):

aortic stenosis? Turk Kardiyol Dern Ars 2017; 45(6): 506–513. 9.

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227–233.

Choi D-H, Kobayashi Y, Nishi T, Luikart H, Dimbil S, Kobashigawa J,

22. Baysal E, Burak C, Cay S, Aksu T, Altıntaş B, Yaylak B, et al. The

et al. Change in lymphocyte to neutrophil ratio predicts acute rejection

neutrophil to lymphocyte ratio is associated with severity of rheumatic

after heart transplantation. Int J Cardiol 2018; 251: 58–64. 10. Bath P, Butterworth R. Platelet size: measurement, physiology and vascular disease. Blood Coagulation Fibrinol 1996; 7(2): 157–61. 11. Pitchford S, Page C. Platelet activation in asthma: integral to the inflammatory response. Clin Exp Allergy 2006; 36(4): 399–401.

mitral valve stenosis. J Blood Med 2015; 6: 151. 23. Polat N, Yildiz A, Yuksel M, Bilik MZ, Aydin M, Acet H, et al. Association of neutrophil–lymphocyte ratio with the presence and severity of rheumatic mitral valve stenosis. Clin Appl Thromb/ Hemostasis 2014; 20(8): 793–798.

12. Kapsoritakis AN, Koukourakis MI, Sfiridaki A, Potamianos SP,

24. Uthamalingam S, Patvardhan EA, Subramanian S, Ahmed W, Martin

Kosmadaki MG, Koutroubakis IE, et al. Mean platelet volume: a useful

W, Daley M, et al. Utility of the neutrophil to lymphocyte ratio in

marker of inflammatory bowel disease activity. Am J Gastroenterol 2001;

predicting long-term outcomes in acute decompensated heart failure.

96(3): 776–781.

Am J Cardiol 2011; 107(3): 433–438.

13. Gasparyan AY, Stavropoulos-Kalinoglou A, Toms TE, Douglas KM,

25. Özdemir R, Güzel O, Küçük M, Karadeniz C, Katipoglu N, Yılmaz Ü,

Kitas GD. Association of mean platelet volume with hypertension in

et al. The effect of the ketogenic diet on the vascular structure and func-

rheumatoid arthritis. Inflam Allergy-Drug Targets 2010; 9(1): 45–50. 14. Sert A, Aypar E, Odabas D. Mean platelet volume in acute rheumatic fever. Platelets 2013; 24(5): 378–382. 15. Gewitz MH, Baltimore RS, Tani LY, Sable CA, Shulman ST, Carapetis J, et al. Revision of the Jones criteria for the diagnosis of acute rheu-

tions in children with intractable epilepsy. Pediat Neurol 2016; 56: 30–34. 26. Demir F, Karadeniz C, Özdemir R, Yozgat Y, Çelegen K, Karaaslan U, et al. Usefulness of neutrophil to lymphocyte ratio in prediction of coronary artery lesions in patients with Kawasaki disease. Balkan Med J 2015; 32(4): 371.

matic fever in the era of Doppler echocardiography: a scientific state-

27. Endler G, Klimesch A, Sunder‐Plassmann H, Schillinger M, Exner

ment from the American Heart Association. Circulation 2015; 131(20):

M, Mannhalter C, et al. Mean platelet volume is an independent risk

1806–1818.

factor for myocardial infarction but not for coronary artery disease. Br

16. Pellikka FFFE, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7(79): 108. 17. Kucuk M, Ozdemir R, Karadeniz C, Celegen K, Demirol M, Yilmazer

J Haematol 2002; 117(2): 399–404. 28. Van Gameren MM, Willemse P, Mulder NH, Limburg P, Groen H, Vellenga E, et al. Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood 1994; 84(5): 1434–1441.

M, et al. Red blood cell distribution width: can it be a predictive marker

29. Settin A, Abdel-Hady H, El-Baz R, Saber I. Gene polymorphisms of

for long‐term valvular involvement in children with acute rheumatic

TNF-α(-308), IL-10(-1082), IL-6(-174), and IL-1Ra(VNTR) related

carditis? Int J Lab Hematol 2016; 38(5): 569–575.

to susceptibility and severity of rheumatic heart disease. Pediat Cardiol

18. Kumar V, Ganguly N, Anand I, Wahi P. Release of oxygen free radicals by macrophages and neutrophils in patients with rheumatic fever. Eur Heart J 1991; 12(suppl D): 163–165. 19. Öztürk D, Erturk M, Celık O, Ozyılmaz S, Akturk F, Cakmak HA, et al. The role of the neutrophil/lymphocyte ratio in patients with rheu-

2007; 28(5): 363–371. 30. Milovanovic M, Nilsson E, Järemo P. Relationships between platelets and inflammatory markers in rheumatoid arthritis. Clin Chim Acta 2004; 343(1–2): 237–40.

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Ellisras Longitudinal Study 2017: The relationship between dietary intake and body mass index among young rural adults in South Africa aged 18 to 30 years (ELS 18) Julia TM Mashiane, Kotsedi D Monyeki, Andre P Kengne, Nkwana M Rosina, Mafoloa S Monyeki

Abstract Aim: To assess the relationship between dietary intake and adiposity in young rural South African adults. Methods: A total of 728 young adults participated and dietary intake was assessed using the 24-hour recall method. Linear regression models were used to determine the association between dietary intake and body mass index (BMI) before and after adjustment for age and gender. Results: Females showed higher mean BMI values than males in all age groups. An age group of 27- to 30-year-old females had a mean value of 28.1 kg/m2 while males had a mean value of 21.9 kg/m2. The distribution of BMI categories (underweight, normal weight, overweight, obese) was 20.5, 61.7, 9.3 and 3.1% in males, and 8.6, 42.5, 23.1 and 25.8% in females (p ≤ 0.05). Cholesterol intake was significantly (p ≤ 0.05) associated with BMI (beta = 0.002, 95% CI: 0.00–0.004) as well as overweight and obesity (odds ratio = 1.734; 95% CI: –1.09–2.75) after adjustment for age and gender. Conclusion: There was a high prevalence of overweight and obesity among rural Ellisras females. Moreover, increasing cholesterol intake was associated with overweight and obesity in the overall sample. Keywords: dietary intake, body mass index, adults, overweight and obesity Submitted 12/4/18, accepted 19/6/18

Methods

Published online 24/10/18 Cardiovasc J Afr 2018; 29: 301–304

www.cvja.co.za

DOI: 10.5830/CVJA-2018-033

The prevalence of obesity continues to increase at an alarming rate worldwide, with approximately two billion people being overweight and one-third of them obese.1 Over-consumption of Department of Physiology and Environmental Health, University of Limpopo, Sovenga, South Africa Julia TM Mashiane, BSc (Hons) Kotsedi D Monyeki, PhD, MPH, kotsedi.monyeki@ul.ac.za Nkwana M Rosina, BSc (Hons) Mafoloa S Monyeki, MPhil

Non-Communicable Diseases Research Unit, South African Medical Research Council and University of Cape Town, Cape Town, South Africa Andre P Kengne, MD, PhD, CRENC

macronutrients contributes to overweight and obesity among the adult population.2 A diet characterised by a decrease in dietary fibre and an increase in saturated fats, accompanied by a lack of physical activity, results in weight gain.3,4 This is the result of a positive energy balance, where energy intake is higher than energy expenditure.2 Traditional eating habits of South Africans residing in rural areas consist mostly of a prudent diet, which is associated with a low prevalence of overweight and obesity.5-8 However, the shift towards a Western diet has become apparent among rural Africans, increasing their likelihood of having modifiable risk factors for chronic diseases of lifestyles, which include physical inactivity, increased alcohol consumption, stress and smoking.5 Preliminary results from the Ellisras cohort study showed a significant association between intake of mono-unsaturated fats and body mass index (BMI) among rural Ellisras children.9 Furthermore, Sekgala et al.10 reported a potential link between dietary fibre intake and fasting blood glucose and high-density lipoprotein cholesterol levels with both systolic and diastolic blood pressure among young rural Ellisras adults. With the Ellisras sample reaching the young adult stage, the relationship between BMI and dietary intake has received little attention. This cross-sectional study aimed to investigate the relationship between dietary intake and BMI among young rural Ellisras adults aged 18 to 30 years.

This study is part of the ongoing Ellisras longitudinal study (ELS), of which the details of the sampling procedure and geographical area were reported elsewhere.11 The subjects participating in this cross-sectional study included 728 young adults (356 males and 372 females), aged 18 to 30 years, who are part of the Ellisras longitudinal study (ELS). The ethics committee of the University of Limpopo granted ethical approval prior to the survey. The participants were provided with informed consent forms and signed the form after receiving verbal assent from the project leader. All participants underwent a series of anthropometric measurements according to the standard procedures recommended by the International Society for the Advancement of Kinanthropometry (ISAK).12 Weight was measured on an electronic scale to the nearest 0.1 kg, with light clothing and without shoes. Martin anthropometric was used to measure height, to the nearest 0.1 cm, with no shoes. BMI was defined as weight (kg)/height (m2). All participants were classified as underweight, normal, overweight and obese, according to World Health Organisation cut-off points for adults.13

302

Statistical analysis Variables were summarised as descriptive statistics. Linear regression models were used to assess the continuous association between dietary intake and BMI, while logistic regression models were used to assess the association between low/high dietary intake and prevalent overweight and obesity, both in invariable analyses and after adjusting for age and gender. All data were analysed using the statistical package for social sciences (SPSS) version 23 and a p-value < 0.05 was used to characterise statistically significant results.

Results The mean BMI was 20.3–21.9 kg/m2 in males and 23.2–28.1 kg/ m2 in females (p ≤ 0.05). Mean BMI increased from 20.3 kg/m2 in the age group 18–20 years to 21.9 kg/m2 in the age group 27–30 years in males, and from 23.2 to 28.1 kg/m2 in females (Fig. 1). The distribution of BMI categories in the overall sample was 8.6–20.5% for underweight, 9.3–23.1% for overweight and 3.1–25.8% for obesity. Equivalent figures were 20.5, 61.7, 9.3 and 3.1% in males, against 8.6, 43.5, 23.1 and 25.8% in females (p ≤ 0.05 for the difference in the distribution of BMI categories in males and females) (Fig. 2). Males had a higher incidence of underweight (20.5%) than females. However, females (23.1 and

35 30 25

23.2 20.3

21.5

28.1

26.8

2 21.7

61.7

42.5

Prevalence (%)

Diet was measured using the 24-hour recall method, which is a valid method to determine group dietary intake.14 In December 2015, senior Northern Sotho-speaking dietetics students of the University of Limpopo, specifically trained in using the 24-hour recall method, interviewed the parent/caregiver at home regarding the dietary intake of the young adults over the previous 24 hours. For each participant, an interview took place on one weekday and one weekend day. An average of two days of 24-hour dietary intake was then taken for each participant. Estimated portion sizes of foods consumed were recorded in as much detail as possible, using a pre-tested questionnaire and food models simulating average portions of local foods.15,16 Dietary data were analysed using local food tables and Food Finder dietary software, and compared with recommended intakes.15-18

BMI (kg/m2)

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20.5 9.3

8.6

25.8

23.1

3.1

0 –20

Underweight

Normal Overweight Nutritional status Males

Obese

Females

Fig. 2. The prevalence of malnutrition by gender among young rural Ellisras adults aged 18–30 years.

25.8%) showed a higher incidence than males (9.3 and 3.1%) of overweight and obesity, respectively. Fried chicken (23.8%), pap (22.6%), cold drink (16.9%) and white sugar (14%) were the foods most frequently consumed by the young Ellisras adults, while samp (2.6%), yogurt (2.4%) and spinach (2.0%) were the least frequently consumed foods (Table 1). Carbohydrates ranged between 78.2 and 84.5% while total fats and saturated fats ranged between 31.6 and 42%, and 4.1 and 6.0%, respectively, for all BMI categories for the overall population (Fig. 3). In linear regression analyses, there was a borderline positive association between cholesterol intake and BMI (p = 0.058), with further enhancement after adjustment for age and gender (beta = 0.002, p = 0.035) (Table 2). Table 3 presents logistic regression for the association between overweight/obesity and low dietary intake. In logistic regression analyses, there was a positive association between cholesterol intake and overweight and obesity (p = 0.084), and after adjustment for age and gender, the association of cholesterol intake with overweight and obesity was significant (p = 0.020) (Table 3).

Discussion This study aimed to investigate the relationship between dietary intake and BMI among young rural Ellisras adults aged 18 to 30 years. There was a significant association between cholesterol intake and BMI. Furthermore, a high prevalence was reported of overweight and obesity among females compared to males in the Ellisras population. These findings were in line with previous

21.9

Table 1. The most frequent food items in the diets for the overall sample, from the most common food liked to the least liked

Variables

Percentage

Fried chicken with skin

23.8

Pap

22.6

Cold drink

16.9

White sugar

18–20

21–23 24–26 Age group Males

27–30

Females

Fig. 1. D escriptive statistics of mean body mass index by age group and gender among young rural Ellisras adults aged 18–30 years.

Vetkoek

5.8

Fried beef

4.7

Peanut butter

4.4

Samp

2.6

Yoghurt

2.4

Spinach

2.0

Pilchards

0.5

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90 80

84.5

78.2

79.1

Macronutrients (%)

70 60 50

33.7

32.8

31.6

30 20 4.8

10 0

Underweight

4.7

4.1

Normal Overweight Nutritional status

Carbohydrates

Total fat

Obese Saturated fat

Fig. 3. D escriptive statistics for 24-hour recall of dietary intake by nutritional status of young rural Ellisras adults aged 18–30 years.

studies conducted in rural black communities in the Limpopo province.3 This may be due to culture-related attitudes, physical inactivity, poor nutritional value of food, and high intake of calorie-dense food in rural populations.3 Obesity is a risk factor for cardiovascular diseases such as hypertension and type 2 diabetes, and it is a global public health concern.13 Van Den Ende et al.9 reported a low prevalence of overweight and obesity among the same sample at a younger age (7–15 years). The present study revealed a high prevalence of obesity (3–26%) and overweight (9–23%) as the ELS sample grew older. This is a serious concern. The findings are in line with other studies in Africa and the prevalence of overweight and obesity continues to increase, with from 25 to 60% of urban females being overweight.3,4 The influence of a Western diet together with low levels of physical activity, particularly among women, as reported by Sekgala et al.,10 Mchiza et al.6 and Jaffer et al.7 among the South African population, could be contributing to this escalating high prevalence of obesity and overweight. Table 2. Linear regression coefficient, 95% CI and p-value in the association with body mass index and dietary intake Unadjusted BMI variables Total fat Animal protein Plant protein

95% CI

p-value

Adjusted (age and gender) β

95% CI

p-value

–0.002 –0.011 0.007 0.665 –0.001 –0.010 0.007 0.738 0.000 –0.016 0.015 0.988

0.004 –0.010 0.018 0.538

–0.001 –0.041 0.038 0.951

0.008 –0.028 0.044 0.667

Total sugar

0.009 –0.010 0.028 0.366 –0.002 –0.019 0.015 0.827

Carbohydrates

0.001 –0.002 0.004 0.545

0.001 –0.002 0.004 0.459

Total dietary fibre

0.016 –0.040 0.073 0.570

0.019 –0.032 0.071 0.460

Total protein

0.000 –0.013 0.014 0.972

0.005 –0.007 0.017 0.451

0.002

Cholesterol intake

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0.000 0.004 0.058

0.000 0.004 0.035*

Mono-unsaturated fatty acids

–0.008 –0.032 0.016 0.527 –0.005 –0.027 0.016 0.634

Polyunsaturated fatty acids

–0.002 –0.033 0.028 0.876 –0.002 –0.029 0.026 0.899

Saturated fatty acids

–0.007 –0.033 0.019 0.600 –0.007 –0.030 0.017 0.583

CI: confidence interval, β: beta-coefficient. *Significant at p < 0.05.

Furthermore, several studies have reported the overconsumption of macronutrients to be one of the leading causes of the high prevalence of overweight and obesity among the adult Saudi population.19,20 An increase in urbanisation, in terms of social, political and economic factors, explains the dietary transition in South Africa among females.21 It is projected that the population of overweight and obesity worldwide will increase to 2.3 billion for overweight and 700 million for obesity.3 According to the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaboration Group, 9.1 million adults are affected with overweight and obesity.22 This has caused the tendency of overweight and obesity to double worldwide. The intake of carbohydrates and fats in the present study was higher than that reported by Van Den Ende et al.9 in the same sample at a younger age. Singh et al.2 recommended 60% carbohydrate, 30% total fats and 10% protein as the total daily kilocalories for an individual. The high consumption of fats in our study therefore reveals that there is a peak in the nutritional transition, and weight status has therefore changed among Ellisras females. The high intake of saturated fat reported in this study is in agreement with that in healthy young adults in Saudi Arabia.23 The significant association between dietary intake and BMI predicts that the higher the percentage of kilojoules, the higher the risk of overweight and obesity. This finding is consistent with Van Den Ende et al.9 Sengwayo et al.3 found a significant association of dyslipidaemia with high BMI among females in Limpopo. This is associated with a shift in the nutritional pattern, which predisposes to the development of atherosclerosis due to a high cholesterol intake. A limitation of this study is the cross-sectional design, which does not allow an analysis of cause and effect regarding the association between BMI and dietary intake. Also we did not consider blood sample analysis to support the findings of dietary intake. However, Steyn et al.21 confirm that dietary intake can be reliably evaluated by assessing the macronutrient intake. All anthropometric data were measured, not self-reported by the participants, which allows the comparison of our study with other studies in South Africa to be accurate.4,21 Furthermore, we used intervieweradministered questionnaires, which are more effective than a self-administered questionnaire.5

Conclusions There was a high prevalence of overweight and obesity among rural Ellisras females. Cholesterol intake was associated with a Table 3. Logistic regression for the association between overweight/obesity and low dietary intake Unadjusted Variable

95% Cl

Adjusted for age and gender p-value

95% CI

p-value

Overweight/obesity Total fat

0.78

0.56

1.10

0.154

0.86

0.59

1.22

0.430

Total sugar

1.18

0.67

2.08

0.561

0.96

0.52

1.78

0.900

Saturated fat

1.23

0.89

1.69

0.215

1.32

0.924

1.894 0.127

Mono-unsaturated fat 0.61

0.20

1.88

0.388

0.48

0.14

Polyunsaturated fat

1.48

0.25

8.93

0.668

1.46

0.20

10.81

0.708

Cholesterol intake

1.43

0.95

2.16

0.084

1.73

1.09

2.75

0.020*

OR: odds ratio; CI: confidence interval. *Significant at p < 0.05.

1.694 0.255

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raised BMI in the overall sample. Therefore, dietary knowledge and access to resources are important to improve health and nutrition in a sustainable way. The need to assess the changes that occur over time in serum levels of a variety of biochemical and haematological parameters related to cardiovascular diseases and/or diabetes in rural African settings is vital.

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701–706. 10. Sekgala MD, Mchiza ZJ, Parker W, Monyeki KD. Dietary Fiber Intake and Metabolic Syndrome Risk Factors among Young South African Adults. Nutrients 2018; 10(4). pii: E504. 11. Monyeki KD, Cameron N, Getz B. Growth and nutritional status of rural South African children 3–10 years old: the Ellisras Growth Study. Am J Hum Biol 2000; 12: 42– 49.

The financial support received from Vrije University, Amsterdam, the Netherlands (grant: UNIN Health Project under VUA Foundation funds),

12. Norton K, Olds T. Anthropometric: A Textbook of Body Measurements for Sports and Health Courses. Australia: NSW Press, 1996.

the University of Limpopo, South Africa (grant no. 1404), the National

13. World Health Organisation (WHO). Obesity: preventing and managing

Research Foundation of South Africa (grant no. URD2002050400168), and

the global epidemic: Report of a WHO Consultation (WHO Technical

the Medical Research Council for the Ellisras Longitudinal Study is acknowl-

Report Series894). http://www.who.int/nutrition/publications/obesity/

edged with gratitude. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and therefore the funding sources do not accept any liability in regard thereto. The authors are indebted to ELS administrators (PS Seleka, TT Makata, W Makata, S Seleka) for providing technical support in the preparation of this manuscript.

WHO_TRS_894/en/ (accessed 27 June 2014) 2000. 14. Trustwell S, Mann J (eds). Essentials of Human Nutrition. Oxford: Oxford University Press, 1998. 15. Langenhoven ML, Conradie PJ, Wolmarans P, Faber M. MRC Food Quantities Manual (2nd edn). Parow: Research Institute for Nutritional Diseases. Cape Town: South African Medical Research Council, 1991:

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Nel JH, Steyn NP. Report on South African food consumption studies

trends in body mass index since 1980: Systematic analysis of health

undertaken amongst different population groups (1983–2000): average

examination surveys and epidemiological studies with 960 country-years

intakes of foods most commonly consumed. Pretoria: Department of Health, 2002. 9.

Town: South African Medical Research Council, 2004: 14–32. 19. El-Hazmi MA, Warsy AS. Prevalence of obesity in the Saudi population.

Mchiza ZJ, Steyn NP, Hill J, Kruger A, Schönfeldt H, Nel J, Wentzeltion from 2000 to 2015. Nutrients 2015; 7: 8227–8250.

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Sengwayo DG, Moraba MM, Motaung SCKM. Prevalence of obesity

bigger picture. Lancet 2015; 385: 2510–2520.

Town: South African Medical Research Council, 1991: 75–108. 17. Food Finder Dietary Software, Parow. Research Institute for Nutritional

Swinburn BA, McPherson K. Child and adolescent obesity: part of a 5.

Table (3rd edn). Parow: Research Institute for Nutritional Diseases. Cape

Singh A, Bennett TL, Deuster PA. Force and Health Protection Nutrition press, 1999.

117–200. 16. Langehoven ML, Kruger M, Gouws E, Faber M. MRC Food Composition

and 9.1 million participants. Lancet 2011; 377(9765): 557–567. 23. Alissa EM, Bahijri SM, Al-Ama N, Ahmed WH, Feras GA. High cardio-

Van Den Ende C, Twisk JW, Monyeki KD. The relationship between

vascular risk in young Saudi males; cardiovascular risk factors, diet and

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inflammatory markers. Clin Chim Acta 2006; 365: 288–296.

South Africa: The Ellisras Longitudinal Study. Am J Hum Biol 2014; 26:

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The impact of admission cystatin C levels on in-hospital and three-year mortality rates in acute decompensated heart failure Hatice Selcuk, Mehmet Timur Selcuk, Orhan Maden, Kevser Gülcihan Balci, Mustafa Mücahit Balci, Sebahat Tekeli, Elif Hande Çetin, Ahmet Temizhan, Mustafa Balci, Nihal Karabiber

Abstract Background: Although tremendous advances have been made in preventative and therapeutic approaches in heart failure (HF), the hospitalisation and mortality rates for patients with HF is high. The aim of this study was to investigate the association between cystatin C and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and in- and out-of-hospital mortality rates in acute decompensated HF (ADHF). Methods: Between February 2008 and November 2011, 57 consecutive patients who were admitted with ADHF were included in this prospective study. These patients were clinically followed up every three months by means of visits or telephone interviews. The primary clinical endpoint of this study was any death from heart failure rehospitalisation and/or other causes. Results: The subjects who died during the in-hospital follow up were younger than the survivors (47.4 ± 17.5 vs 60.8 ± 15.8, p = 0.043). There was a notable correlation between plasma cystatin C and NT-proBNP levels (r = 0.324, p = 0.014) and glomerular filtration rate (GFR) (r = –0.638, p < 0.001). Multivariate logistic regression analysis revealed that only cystatin C level [odds ratio (OR): 12.311, 95% confidence interval (CI): 1.616–93.764, p = 0.015] and age [OR: 0.925, 95% CI: 0.866–0.990, p = 0.023] were linked to in-hospital mortality rate. In the multivariate Cox proportional hazard model, only admission sodium level appeared as a significant independent predictor of death during the 36-month follow up [hazard ratio: 0.937, 95% CI: 0.880–0.996, p = 0.037]. Conclusion: Evaluation of admission cystatin C levels may provide a reliable prediction of in-hospital mortality, compared to estimated GFR or NT-proBNP levels among patients with ADHF. However, in this trial, during long-term follow up, only admission sodium level significantly predicted death. Department of Cardiology, Turkiye Yuksek Ihtisas Research and Education Hospital, Ankara, Turkey Hatice Selcuk, MD Mehmet Timur Selcuk, MD Orhan Maden, MD Kevser Gülcihan Balci, MD, kevs84@gmail.com Mustafa Mücahit Balci, MD Sebahat Tekeli, MD Elif Hande Çetin, MD Ahmet Temizhan, MD

Department of Immunology, Turkiye Yuksek Ihtisas Research and Education Hospital, Ankara, Turkey Mustafa Balci, MD

Department of Microbiology, Turkiye Yuksek Ihtisas Research and Education Hospital, Ankara, Turkey Nihal Karabiber, MD

Keywords: cystatin C, heart failure, in-hospital mortality Submitted 5/5/17, accepted 20/6/18 Published online 13/7/18 Cardiovasc J Afr 2018; 29: 305–309

www.cvja.co.za

DOI: 10.5830/CVJA-2018-035

Worldwide, chronic heart failure (HF) syndrome is increasing in prevalence. Despite advances in preventative and therapeutic approaches, mortality and hospitalisation rates in this population remain high. Impaired renal function often accompanies HF, and co-existence of these diseases is correlated with an increased rate of cardiovascular risk and death.1 The exact mechanism underlying the complex interaction between HF and renal disease remains unclear. Recently, cystatin C, an inhibitor of cysteine proteases of the cathepsin family has gained valuable recognition, being a more reliable measure of renal function than serum creatinine-based calculations. Cystatin C is created by all nucleated cells and is simply drained at the glomerulus and not secreted from the tubules. Unlike creatinine, it does not seem to be affected by gender, race or muscle volume, which makes it a more definite marker of glomerular capacity.2,3 Increased levels of cystatin C are related to impaired renal function and correlated with a decline in estimated glomerular filtration rate (eGFR).4 In both acute and chronic stages of HF, cystatin C level is a better predictor of mortality and unfavourable cardiovascular outcome, compared to serum creatinine-based assessments.5-7 HF causes volume overload, which results in myocardial stretch and excretion of cardiac peptides such as N-terminal pro-B-type natriuretic peptide (NT-proBNP).8 NT-proBNP is not only useful for diagnostic purposes, but also provides relevant information about clinical responses to HF regimens and prognosis of the HF.9,10 In a previous report, a combination of cystatin C and NT-proBNP level was used as a predictor of unfavourable results in subjects with acute decompensated HF (ADHF).11 The authors reported that combination of the two parameters was useful in predicting patients who had the highest risk for worse outcomes. However, in the literature, there are no data about the relationship between hospital admission cystatin C levels and mortality on an annual basis. We intended to assess the association between in-hospital mortality rate among patients with ADHF and both cystatin C and NT-proBNP levels. Another aim was to evaluate whether out-of-hospital mortality rate was associated with in-hospital levels of cystatin C during regular follow up (36 months).

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Methods Between February 2008 and November 2011, 57 consecutive patients (mean age 54.1 ± 16.3 years, male 68.4%) with typical symptoms and signs of ADHF and with low left ventricular ejection fraction (LVEF < 40%) were enrolled in this study.12 During the hospital stay, all of the patients received appropriate HF treatment measures in accordance with contemporary guideline recommendations.13 Patients with concomitant unstable ischaemic diseases, those presenting with shock, severe renal failure [GFR estimated by Modification of Diet in Renal Disease (MDRD) equation < 30 ml/min/1.73 m2] or hepatobiliary dysfunction, anaemia or haematological disease, acute or chronic infection and inflammation, malignant neoplasms and patients with echocardiographic LVEF values ≥ 40% were excluded. A genderand age-matched control group (n = 31) with normal LVEF and renal function was included to compare plasma NT-proBNP and cystatin C levels with the patient group. Surviving participants were clinically followed up every three months for three years by means of visits or telephone interviews. In the case of death during the follow-up period, follow-up duration was calculated in months (time interval from admission to death) for that subject. Mean follow-up duration for the entire group was 17.2 months. The primary clinical endpoint of this study was determined as all-cause mortality. From each patient, oral informed permission for the study was obtained by one of the investigators, and the study protocol was approved by the local ethics committee of our hospital. Blood samples for biochemical parameters, including haemoglobin, blood urea nitrogen (BUN), creatinine, electrolytes, cystatin C and NT-proBNP were drawn at admission for ADHF. GFR was determined using two different contemporary formulae: the MDRD and the Cockroft–Gault formulae.14,15 For cystatin C assessment, an immediate centrifugate of the collected sample was obtained. Aliquot serum samples were stored in microcentrifuge tubes at −80°C until assayed. Measurements of cystatin C levels were performed using a particle-enhanced immune nephelometric method (Dade Behring GmbH, Liederbach, Germany). Intra-assay and interassay coefficients were 2.5 and 2.0%, respectively. NT-proBNP was measured by ARCHITECT i2000 platform (Abbott Laboratories, Abbott Park, Illinois). All patients underwent standard echocardiographic imaging in the left lateral decubitus position with a commercially available device (Vivid 7 Ultrasound System; GE, Horten, Norway) on admission. The echocardiographic assessments were based on the criteria proposed by the American Society of Echocardiography. A modified Simpson’s method was used for LVEF calculation.16

Statistical analysis Statistical analyses were performed using SPSS for Windows, version IBM 11.5 (SPSS Inc, Chicago, IL, USA). Continuous variables are presented as the mean ± standard deviation (SD) or median (min–max), where applicable. Categorical variables are presented as percentages. The Student’s t-test was used to analyse mean differences between two independent groups. The Mann– Whitney U-test was employed for identification of medians

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between two independent groups. As both plasma cystatin C and NT-proBNP levels were normally distributed. Correlation coefficients and their significance were calculated with Pearson’s correlation test. To define the predictors that changed in-hospital mortality, multiple logistic regression analyses were used. Odds ratios (OR) and 95% confidence intervals (CI) for the different independent variables were also determined. Univariate and multivariate Cox regression analyses were performed to delineate independent predictors of mortality during 36 months of follow up. A p-value < 0.05 was considered statistically significant.

Results In this study, 57 subjects who met the inclusion criteria constituted the final research group. Plasma NT-proBNP and cystatin C levels were determined among patients with ADHF and the control subjects (n = 31). Plasma NT-proBNP concentrations of the patients were greater than in the control group (641.6 ± 31.7 vs 23.2 ± 31.7 pg/ml, p < 0.001). However, there were no notable differences in plasma cystatin C levels between the patient and control groups (1.27 ± 0.48 mg/l in the patients vs 1.11 ± 0.43 mg/l in the controls, p = 0.095). Baseline demographic characteristics of the patients are reviewed in Table 1. During the in-hospital period, seven (12.3%) patients died. Comparisons of variables were made between survivors and those who died during the hospital stay. There were no notable differences regarding gender, hypertension, diabetes mellitus, smoking and myocardial infarction between the groups (p > 0.05). However, the subjects who died during the in-hospital period were younger than the survivors (47.4 ± 17.5 vs 60.8 ± 15.8 years, p = 0.043). Also, the rate of prior cerebrovascular accident was significantly higher in patients who died (28.6 vs 6.0%, p = 0.048). Moreover, among patients who died during the hospital stay, lower sodium concentrations, and higher cystatin C and NT-proBNP levels were observed (p = 0.003, p = 0.023, p = 0.001, respectively) (Table 2). Baseline echocardiographic characteristics of the patients are reviewed in Table 3. There were no differences between the two groups regarding echocardiographic parameters (p > 0.05). Table 1. Baseline demographic characteristics of the study population Variables

In-hospital survivors In-hospital deaths (n = 50) (n = 7) p-value

Age (years)

60.8 ± 15.8

47.4 ± 17.5

0.043

Male gender, n (%)

34 (68.0)

5 (71.4)

0.855

Diabetes mellitus, n (%)

15 (30.0)

4 (57.1)

0.154

Hypertension, n (%)

24 (48.0)

5 (71.4)

0.246

Hyperlipidaemia, n (%)

12 (24.0)

1 (14.3)

0.566

Cigarette smoking, n (%)

6 (12.0)

1 (14.3)

0.863

History of MI, n (%)

9 (18.0)

2 (28.6)

0.507

History of CVA, n (%)

3 (6.0)

2 (28.6)

0.048

History of PCI, n (%)

5 (10)

1 (14.3)

0.729

History of CABG, n (%)

6 (12.0)

1 (14.3)

0.863

New diagnosis of HF, n (%)

7 (14)

0 (0.0)

0.291

BMI (kg/m²)

26.1 ± 4.9

22.4 ± 3.8

0.062

Hospitalisation length (days)

15.2 ± 22.2

23.6 ± 27.2

0.345

3.2 ± 4.9

3.4 ± 5.6

0.237

NYHA functional class

BMI: body mass index, CABG: coronary artery bypass grafting, CVA: cerebrovascular accident, HF: heart failure, MI: myocardial infarction, NYHA: New York Heart Association, PCI: percutaneous coronary intervention.

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Table 2. Baseline laboratory characteristics of the study population In-hospital survivors In-hospital deaths (n = 50) (n = 7) p-value

Variables

113.6 ± 48.7

124.7 ± 49.1

(mmol/l)

6.30 ± 2.70

6.92 ± 2.73

Urea (mg/dl)

69.5 ± 33.7

93.9 ± 51.7

0.100

Creatinine (mg/dl)

1.15 ± 0.43

1.27 ± 0.61

0.784

136.5 ± 35.8

127.0 ± 38.9

0.518

(mmol/l)

3.54 ± 0.93

3.29 ± 1.01

Triglycerides (mg/dl)

85.6 ± 34.5

106.6 ± 35.2

(mmol/l)

0.97 ± 0.39

1.20 ± 0.40

Fasting glucose (mg/dl)

Total cholesterol (mg/dl)

0.559

0.138

135.5 ± 5.1

128.9 ± 7.6

0.003

Potassium (mmol/l)

4.3 ± 0.6

4.2 ± 0.7

0.794

Haemoglobin (g/dl)

12.4 ± 1.9

11.5 ± 1.2

0.218

Cystatin C (mg/l)

1.22 ± 0.39

1.62 ± 0.62

0.023

577.2 ± 585.5

1101.6 ± 228.7

0.001

GFR (ml/min/1.73 m2)

72.8 ± 30.0

74.3 ± 44.8

0.907

Cockcroft (ml/dk)

74.5 ± 33.2

78.2 ± 54.1

0.803

Sodium (mmol/l)

NT-proBNP (pg/ml)

GFR: glomerular filtration rate, NT-proBNP: N-terminal pro-B-type natriuretic peptide.

Multivariate logistic regression analysis confirmed that only cystatin C level (OR: 12.311, 95% CI: 1.616–93.76, p = 0.015) and age (OR: 0.925, 95% CI: 0.866–0.990, p = 0.023) were linked to in-hospital deaths. Also there was a notable correlation between plasma cystatin C and NT-proBNP levels (r = 0.324, 95% CI: 0.069–0.539, p = 0.014) and GFR (r = –0.638, 95% CI: –0.770 to –0.453, p < 0.001) (Table 4). During the 36-month follow-up period, the primary endpoint (death) occurred in 38 subjects. When we compared the admission cystatin C levels among survivors and those who died, we did not observe any significant difference between the two groups (p > 0.05) (Table 5). Univariate and multivariate analyses were performed to examine independent predictors of mortality for the entire 36-month follow-up period. When univariate Cox proportional regression analysis was applied to baseline parameters, cystatin C level was found to have no effect on mortality rate during the 36-month follow-up period [hazard ratio (HR): 1.531, 95% CI: 0.696–3.371, p = 0.290], but age (HR: 0.978, 95% CI: 0.960–0.997, p = 0.023) and sodium level (HR: 0.927, 95% CI:

Variables

0.874–0.982, p = 0.010) were found to be related to mortality rate. In the multivariate Cox proportional hazard model including age, cystatin C, NT-proBNP and sodium levels, LVEF and GFR variables, only admission sodium level was a significant independent predictor of death during the 36-month follow up (HR: 0.937, 95% CI: 0.880–0.996, p = 0.037) (Table 6, Fig. 1).

Discussion This study showed that higher admission cystatin C levels among patients with ADHF were related to in-hospital mortality rates, and in multivariate analysis, both cystatin C level and age were regarded as independent predictors of in-hospital death. However, during long-term follow up, when the two groups were compared in terms of mortality assessed on an annual basis, sodium level was the only independent predictor of death. The combination of acute cardiac and renal dysfunction, termed cardiorenal syndrome,17 is associated with unfavourable consequences in patients with acute HF.18 Possible mechanisms for renal dysfunction in HF are low cardiac output, higher central blood pressure, renin–aldosterone–angiotensin axis dysfunction, activation of sympathetic tone, oxidative damage, and impaired renal perfusion.19 Therefore, assessing renal function may simply show haemodynamic and neurohormonal perturbations in the setting of heart failure hospitalisations but may predict unfavourable consequences.20 Although markers such as eGFR, BUN and creatinine level are easily available in routine blood tests, they may not always represent renal function properly.21 In this context, using cystatin C levels may provide a more reliable assessment of renal function.22 In some subsets of patients with chronically impaired renal function, volume overload and haemodilution at the time of ADHF hospitalisation may mask underlying dysfunction, while patients with previously preserved renal function may present with worsening renal function due to accompanying low cardiac output and resultant low renal perfusion.23 Therefore, since small changes in GFR can be detected by cystatin C level,22 it may be preferred over standard renal function tests and may also be Table 5. Comparison of admission cystatin C levels according to survival, assessed on an annual basis Cystatin C (mg/l)

Table 3. Baseline echocardiographic characteristics of the study population In-hospital survivors (n = 50)

307

Survivor (n)

Deceased (n)

p-value

In hospital

1.22 ± 0.39 (50)

1.62 ± 0.62 (7)

0.023

p-value

12 months

1.24 ± 0.35 (30)

1.31 ± 0.52 (27)

0.373

Follow up

In-hospital deaths (n = 7)

6.3 ± 1.0

6.1 ± 0.4

0.607

24 months

1.21 ± 0.39 (22)

1.31 ± 0.47 (35)

0.393

EF (%)

25.6 ± 7.0

20.7 ± 8.9

0.101

36 months

1.21 ± 0.40 (19)

1.30 ± 0.46 (38)

0.491

sPAP (mmHg)

43.0 ± 11.5

40.9 ± 10.2

0.638

LVEDD (cm)

EF: ejection fraction, LVEDD: left ventricular end-diastolic diameter, sPAP: systolic pulmonary artery pressure.

95% CI

Table 4. Correlation analysis of the variable

NT-proBNP

r-value

Lower

Upper

p-value

0.324

0.069

0.539

0.014

MDRD

–0.638

–0.770

–0.453

< 0.001

Cockcroft

–0.486

–0.663

–0.258

< 0.001

0.179

–0.086

0.420

0.183

–0.007

–0.267

–0.331

0.957

Age Hospitalisation time

Wald

p-value

Lower

Age

0.975

2.599

0.107

0.944

1.006

Cystatin C

0.959

0.005

0.946

0.287

3.201

Independent variables

Cystatin C (95% CI) Variables

Table 6. Multivariate analysis of predictors of mortality during 36-month follow up

CI: confidence interval, MDRD: Modification of Diet in Renal Disease, NT-proBNP: N-terminal pro-B-type natriuretic peptide.

Upper

NT-proBNP

1.000

0.512

0.474

1.000

1.001

Sodium

0.937

4.336

0.037

0.880

0.996

LVEF

0.952

2.697

0.101

0.897

1.010

GFR

0.984

3.509

0.061

0.967

1.001

CI: confidence interval, LVEF: left ventricular ejection fraction, GFR: glomerular filtration rate, HR: hazard ratio, NT-proBNP: N-terminal pro-B-type natriuretic peptide.

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follow up of subjects with ADHF and raised cystatin C levels. Although our study had a prospective design and followed patients for a considerable period, the number of recruited patients was relatively small, which probably lowered the statistical power of the study. Also, the recruited patients represent a relatively young population compared to previous studies. Because our centre is a tertiary referral hospital, the patient characteristics may not represent the whole HF population. Finally, we did not analyse GFR, cystatin C and plasma NT-proBNP levels according to heart failure aetiology, and only admission levels were evaluated rather than follow-up values. The costeffectiveness of serial measurements of cystatin C levels in the prognostication of HF patients should be confirmed in large prospective studies.

1.0

Cumulative survival

0.8

0.6

0.4

0.2

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20 Months

Fig. 1. P lot of the survival curve for patients with acutely decompensated heart failure.

useful in outcome measures. Inazumi et al. found that cystatin C levels were more accurate for mortality prediction than eGFR in patients with ADHF.23 They showed that even without a decrease in eGFR, increases in cystatin C level were associated lower long-term, event-free survival (180 days). Also, Rafouli-Stergiou et al. reported that in-hospital rise in cystatin C and NT-proBNP levels was useful in predicting 60-day cardiac death and rehospitalisation.24 Similarly, we found that, rather than estimated GFR calculations, in-hospital mortality rate was related to higher cystatin C and NT-proBNP levels. However, during long-term follow up, only sodium level was an independent predictor of death, which affirms that hyponatraemia is a surrogate marker for mortality.25 Interestingly, we found that younger patients were more prone to suffer a cardiac death than older subjects. The possible reason for this finding may be that our hospital is a tertiary referral centre for heart transplant candidates, and younger patients with a worse clinical condition are mostly referred to our centre for advanced therapies. When we looked at similar studies evaluating mortality differences in ADHF patients, they principally included older subjects (60 years or more),11,23,24 with an absence of younger patients, which might have limited data on differences in mortality rates in such patients. Compared to the above studies, including younger patients may add further information about the association between cystatin C levels and mortality rates in such populations. Furthermore, among patients who died during their hospital stay, the rate of prior cerebrovascular accident was significantly higher than among survivors. The presence of cerebrovascular accident is a risk factor for HF,26 but the co-existence of these conditions may be related to increased mortality rate. In the ASCEND trial, 180-day follow up of patients with ADHF showed that baseline cystatin C level was a strong predictor of adverse events.27 However, increase in cystatin C levels did not predict adverse outcomes. In contrast to the ASCEND trial, we did not observe differences in mortality rate with regard to baseline cystatin C levels during the 36-month follow-up time. Despite the fact that the sample size of our study was small, our results provide complementary data for long-term

Conclusion In subjects with ADHF, evaluation of admission cystatin C levels may provide a reliable prediction of death compared to eGFR or NT-proBNP levels. Higher cystatin C levels provided important prognostic data about unfavourable in-hospital outcomes. For the post-discharge follow-up period, sodium level was the marker that had prognostic significance. The preliminary results of this study (in-hospital mortality) were accepted as an oral presentation at the American College of Cardiology congress in 2013 (http://dx.doi.org/10.1016/j.cardfail.2013.06.088). The three-year follow-up results were accepted as an abstract presentation at the European Society of Cardiology Heart Failure congress (21–24 May 2016) in Florence, Italy.

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19. Damman K, Voors AA, Navis G, van Veldhuisen DJ, Hillege HL. The cardiorenal syndrome in heart failure. Prog Cardiovasc Dis 2011; 54:

results from the ASCEND-HF trial. J Am Coll Cardiol Heart Fail 2015; 3: 40–49.

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The clinical prognostic significance of myocardial performance index (MPI) in stable placental-mediated disease I Bhorat, M Pillay, T Reddy

Abstract Aim: To determine whether a single elevated myocardial performance index (MPI) value in the third trimester of pregnancy is a marker for later adverse obstetric outcomes in stable placental-mediated disease, defined as well-controlled pre-eclampsia (PE) on a single agent and/or uncompensated intra-uterine growth restriction (IUGR). Methods: Fifty-five foetuses whose mothers had stable placental-mediated disease, either mild pre-eclampsia controlled on a single agent, and/or uncompensated IUGR in the third trimester, attending the Foetal Unit at Inkosi Albert Luthuli Hospital, Durban, South Africa were prospectively recruited with 55 matched controls. Recorded data for the subjects included demographic data of maternal age and parity, sonographic data of estimated foetal weight (EFW) and amniotic fluid index (AFI), myocardial performance index (MPI), and foetal Doppler data of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV). Results: The mean gestational age in the controls, the IUGR and any PE cases was 31.4, 31.8 and 31.0 weeks, respectively. The distribution of MPI values was significantly lower in the controls compared to all other groups. The highest standardised MPI values were observed in the PE–IUGR group, where a median of 5.62 was observed. The only significant differences observed between the PE and IUGR groups was the UA resistance index (p = 0.01), where the IUGR cases tended to have higher UA values compared to the combined PE group. Borderline statistical significance was observed for the MCA resistance index values (p = 0.05) between these groups. The overall adverse event rate in the cases was 49%. The highest rate was observed in the PE + IUGR group, where eight out of 12 (67%) experienced adverse events. MPI z-scores served as a good marker of adverse events, as evidenced by the total area under the curve (AUC) of 0.90 on the ROC curve. A cutoff value of 4.5 on the MPI z-score conferred a sensitivity of 89% and specificity of 68% for an adverse event later in pregnancy. In univariate logistic regression, MPI z-score, AFI, EFW, UA Doppler, CPR category, DV Doppler and MCA Doppler were assessed separately as potential predictors of adverse outcome. The only significant predictor of adverse outcome was MPI z-score.

Department of Obstetrics and Gynaecology, Sub-Department of Foetal Medicine, University of Kwa-Zulu Natal, Durban, South Africa I Bhorat, MB ChB, FCOG, PhD, bhorat@worldonline.co.za M Pillay, MB ChB, FCOG

Biostatistics Unit, South African Medical Research Council of South Africa, Durban, South Africa T Reddy, MSc

Conclusion: A single elevated value of the MPI (z-score > 4.5) in the third trimester in stable placental-mediated disease was a strong indicator of adverse obstetric outcomes later in pregnancy. This has the potential to be incorporated in conjunction with standard monitoring models in stable placental-mediated disease to predict an adverse event later in pregnancy and thus to reduce perinatal morbidity and mortality. Keywords: myocardial performance index, intra-uterine growth restriction, pre-eclampsia, foetal cardiac Doppler, Doppler ultrasonography Submitted 31/10/16, accepted 21/6/18 Published online 15/8/18 Cardiovasc J Afr 2018; 29: 310–316

www.cvja.co.za

DOI: 10.5830/CVJA-2018-036

The myocardial performance index (MPI) is a potentially useful predictor of global cardiac function.1-3 Our previous study established normal reference ranges of modified MPI in the second half of pregnancy and interpreted the findings in the context of cardiac physiological principles.4 Our previous studies have also suggested cut-off MPI values for adverse neonatal outcome in both growth restriction and pre-eclampsia,5,6 and shown it to be a useful predictor of adverse foetal outcomes in other high-risk obstetric conditions.7 MPI is defined as the sum of the isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) divided by the ejection time (ET). The equation is MPI = ICT + IRT/ET. Placental-mediated disease, which is an umbrella term for describing different clinical phenotypes, including intra-uterine growth restriction (IUGR), pre-eclampsia (PE) and abruptio placentae, arises from a single pathophysiological event in the first trimester relating to placental maladaptation and lack of vascular remodelling of the spiral arterioles.8,9 In early-onset pre-eclampsia (EO-PE), interstitial trophoblastic invasion is downregulated while endovascular trophoblastic invasion is limited to the decidua. The clinical phenotype of PE represents a worse placental pathological state than IUGR, with combined phenotypes representing, in addition, obstructive vascular lesions in the placental vasculature. The sentinel event for EO-PE, EO-IUGR and combined phenotypes relates to placental maladaptation in the first trimester.8 Therefore EO-PE, IUGR and combined phenotypes can be considered as the same pathophysiological process with differing degrees of pathological severity. The heart plays a central role in the foetal adaptive mechanisms to placental insufficiency and hypoxia. Significant alterations

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in echocardiographic parameters and elevated levels of atrial and B-type natriuretric peptides have been reported in smallfor-date foetuses.10-13 Our previous study has shown significant impairment of cardiac function in growth-restricted foetuses, with the myocardial performance deteriorating with the severity of growth restriction, as evidenced by increasing MPI values.5 The MPI was noted to be abnormal before hypoxia or acidosis set in and can therefore be regarded as a ‘warning’ parameter of impending compromise. In severe pre-eclampsia it has been shown that foetal cardiac function was significantly impaired and deteriorated with worsening degrees of placental vascular resistance.6 This project is a continuation of our group’s quest to further define the clinical use of the MPI in high-risk obstetric conditions and find its appropriate place in antenatal foetal surveillance, in the context of present standard foetal-monitoring models. With this background, the study sought to establish whether a single elevated MPI value in the third trimester in what can be deemed stable placental-mediated disease, that is, uncompensated IUGR or well-controlled pre-eclampsia (single agent and no multisystemic manifestation) is a predictor of adverse obstetric outcome later in the pregnancy.

Methods Fifty-five foetuses with mothers having stable placental-mediated disease, either mild pre-eclampsia controlled on a single agent and/or uncompensated IUGR in the third trimester, attending the Foetal Unit at Inkosi Albert Luthuli Hospital, Durban, South Africa were consecutively prospectively recruited. There were 55 matched controls. This study was approved by the Biomedical Research Ethics Committee of the University of Kwa-Zulu Natal, Durban, South Africa (BE228/12). Uncompensated IUGR was defined as follows: abdominal circumference < 10th percentile for gestational age, positive flow in the umbilical artery but resistance index more than two standard deviations (2SD) above the mean with no arterial redistribution, and normal venous Doppler, that is, a non-hypoxic, non-acidotic growth-restrictive state. Foetuses with absent or reversed end-diastolic flow in the umbilical artery were excluded. Mild pre-eclampsia was defined by the criteria as set out by the American College of Obstetricians and Gynaecologists14 as systolic blood pressure ≥ 140 mmHg and < 150 mmHg, or diastolic blood pressure ≥ 90 mmHg and < 100 mmHg on two occasions at least six hours apart in a woman on bed rest. This is accompanied by a proteinuria reading of 1–2+ on dipstick testing on two random samples at least six hours apart. All cases of oliguria (< 500 ml of urine in 24 hours), cerebral or visual disturbances, pulmonary oedema, epigastric pain, impaired liver function and thrombocytopaenia representing unstable/severe pre-eclampsia at the time of assessment were excluded. Other exclusion criteria were congenital malformations, multiple pregnancies, foetuses of diabetic mothers, foetuses of mothers treated with a tocolytic agent, and foetuses with abnormal heart rates (tachycardia or bradycardia). Data recorded for subjects included demographic data of maternal age and parity, sonographic data of foetal weight and amniotic fluid index, cardiac Doppler data of MPI, and foetal Doppler data of umbilical artery (UA), middle cerebral

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artery (MCA) and ductus venosus (DV). The cerebro-placental ratio (CPR) was calculated and plotted on the Ebbing graph to determine the percentile.15 Foetal echocardiography using the E8 Voluson General Electric ultrasound system (GE Medical Systems, WI, USA) or Siemens Antares ultrasound system (Siemens Medical Systems, Malvern, PA, USA) was performed in each woman. The four-chamber view, outflow-tract views, triple-vessel view, longitudinal view of the aortic and ductal arch, and colourflow mapping were used to screen for cardiac malformations. The MPI was calculated in the foetal left ventricle4,16 (Fig. 1). Our previous study established reference intervals and trends of the MPI in normal pregnancies and the methodology of obtaining the MPI has been described in detail in the article.4 A cross-sectional image of the foetal thorax at the level of the four-chamber view with an apical projection of the heart was obtained. The Doppler sample was opened to 3 mm and placed in the internal leaflet of the mitral valve (MV). In this location, owing to its closeness to the aortic valve (AV), the opening and closing AV clicks were registered. The angle of insonation was always < 30 degrees. E/A waveform was always displayed as positive flow. The Doppler gain was lowered as far as possible to clearly visualise the echoes corresponding to the opening and closing clicks of the two valves at the beginning and end of the E/A (mitral valve) and aortic waveforms. Cruz-Martinez et al.17 suggested using the beginning of the mitral and aortic valve clicks as the landmarks for measurement but this can lead to poorer variability and varying results due to variation in valve click widths. Measurement of the time intervals at the peak of the valve clicks was used as it overcomes this problem, and is more precisely definable than the base, as was performed in our normal reference values study, showing excellent reproducibility,4 and also as suggested by Meriki et al.18 This is a clearer landmark and overcomes variations in valve click width and has a better reproducibility. The Doppler sweep velocity was set at 5 cm/s and the wall motion filter at 300 Hz. The three time periods were estimated as follows: ICT – from the beginning of the MV closure to the AV opening; ET – from the AV opening to closure; IRT – from AV closure to MV opening. The modified MPI (Mod-MPI) = (ICT + IRT)/ET. The peak of the click was used as the landmark, as suggested by Meriki et al.,18 as this results in better reproducibility.

10 MPI z-score

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–5

Control

IUGR

PE all

Fig. 1. MPI z-score versus controls, IUGR and PE group.

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Table 1. Foetal parameters stratified by group Controls (n = 55)

IUGR (n = 32)

PE (n = 23)

0.67 (0.66–0.69)

0.76 (0.745–0.79)

0.68 (0.66–0.75)

31.44 (1.88)

31.77 (1.65)

MPI

0.38 (0.37–0.39)

MPI z-score MCA

Parameters UA Gestation age (weeks), mean (SD)

AFI EFW (mg)

p-value any PE vs IUGR

PE-only (n = 11)

PE–IUGR (n = 12)

0.0108

0.67 (0.66–0.69)

0.715 (0.665–0.78)

31.01 (1.90)

0.231

31.70 (1.53)

30.37 (2.04)

0.535 (0.485–0.595)

0.50 (0.47–0.59)

0.3556

0.48 (0.45–0.49)

–0.01 (–0.38–0.38)

5.00 (4.37–5.58)

4.57 (4.07–6.32)

0.7200

0.83 (0.82–0.86)

0.80 (0.78–0.83)

0.83 (0.80–0.86)

13 (12–14.5)

12.1 (10.7–13)

2005 (1717–2210)

1561.5 (1344–1676)

p-value IUGR vs controls

p-value PE-only vs controls

p-value PE–IUGR vs controls

< 0.0001

0.8189

0.0639

0.4079

0.6670

0.0831

0.55 (0.50–0.60)

< 0.0001

4.29 (3.54–4.57)

5.62 (4.71–7.82)

< 0.0001

0.0538

0.83 (0.81–0.85)

0.82 (0.79–0.86)

0.0008

0.4940

0.2752

12 (11.1–13)

0.6944

11.8 (11.1–12.3)

12.65 (11.35–13.1)

0.007

0.0019

0.2324

1767 (1305–1989)

0.1105

1989 (1655–2012)

1600.5 (1076.5–1800.5)

< 0.0001

0.3482

0.0010

UA = umbilical artery, MPI = myocardial performance index, MCA = middle cerebral artery, AFI = amniotic fluid index, EFW = estimated foetal weight. Data are reported as median (IQR) unless otherwise stated.

All the pre-eclamptic mothers were controlled on single agents and none had magnesium sulphate therapy before our examination. Steroids were not administered to the patients at the time of the assessment. At least three measurements were taken once a clear and consistent Doppler trace had been obtained, and the measurement taken from the clearest waveform was included in the final analysis. Adverse obstetrical outcome later in the pregnancy was defined as: development of significant oligohydramnios (AFI < 5 cm), antenatal decelerative cardiotocography, intrauterine death, development of imminent eclampsia or HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome, abruption placentae, and deterioration of foetal Dopplers (arterial redistribution or venous Doppler anomalies). We have previously documented high levels of inter- and intraobserver variability agreement for the MPI and its components in our article establishing reference intervals of the MPI in normal pregnancies.4

Statistical analysis MPI values were transformed to z-scores using the standards proposed by Bhorat et al.4 Continuous variables are reported as means with standard deviations for normally distributed variables, and medians with interquartile ranges for variables with skewed distributions. The Shapiro–Wilk test was used to test for normality. The Wilcoxon rank sum test was used to perform comparisons of the foetal parameters between the study groups. To compare the adverse event rate and CPR categories between the study groups, Fisher’s exact test was used. The overall diagnostic accuracy of the MPI z-score for adverse outcomes was assessed through computation of the area under the receiver operating characteristics (ROC) curve. To determine whether the MPI was an independent predictor of adverse outcome, while adjusting for other foetal parameters, logistic regression was used; p-values less than 0.05 were considered statistically significant. All analysis was performed in Stata version 14 (Stata Corp, College Station, TX, USA).

Results A total of 55 subjects, comprising 32 IUGR cases, 11 PE-only

cases and 12 PE with IUGR cases (total PE cases: 23) were included in the analysis. Controls were matched to cases in a 1:1 ratio by gestational age rounded off to the nearest week. The mean gestational age in the controls, IUGR and any PE cases was 31.4, 31.8 and 31.0 weeks, respectively. The UA resistance index (UA RI) values were significantly lower in the controls compared to the IUGR cases (p < 0.0001). There was no significant difference in the median UA RI between the controls and PE-only cases (p = 0.819). The amniotic fluid index (AFI) was significantly higher in the controls compared to the IUGR and PE-only group (p = 0.007 and 0.002, respectively). MCA resistance index (MCA RI) values were significantly higher in the controls compared to the IUGR-only cases, however no significant difference was observed between the controls and PE-only and PE–IUGR cases, respectively. The lowest estimated foetal weight (EFW) was observed in the IUGR cases, followed by the PE–IUGR cases. No significant differences were observed between the EFW in the controls and PE-only cases (p = 0.348). The distribution of the standardised MPI values between the groups of interest is presented in Table 1 and Figs 1 and 2. It is clear that the distribution of MPI values was significantly lower in the controls compared to all other groups. This is affirmed by the analysis in Table 1, with all differences statistically significant. The highest standardised MPI values were observed in the PE–IUGR group, where a median of 5.62 was observed (Fig. 2). All foetal parameters were compared between the PE group combined (n = 23) and IUGR cases (n = 32). The only significant differences observed between these two groups was the UA (p = 0.01), where the IUGR cases tended to have higher UA values compared to the combined PE group. Borderline statistical significance was observed for the MCA values (p = 0.05) between these groups. The overall adverse event rate in the cases was 49%, which is shown in Fig. 3 and Table 2. The highest rate was observed in the PE–IUGR group where eight out of 12 (67%) experienced adverse events. There was no significant difference in the adverse event rate between the three groups (0.197). Foetuses were also categorised according to their CPR percentile for gestational age; 81, 9 and 58% were observed to have CPR values less than the fifth percentile in the IUGR,

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100

CPR categorisation (%)

MPI z-score

80 70 60

Control

IUGR

PE-only

PE-only and PE–IUGR groups, respectively (Fig. 4). This difference was statistically significant (p < 0.001). The utility of MPI in predicting adverse outcomes was assessed. We found that the MPI z-scores served as a good marker of an adverse obstetric event later in pregnancy, as evidenced by the total area under the curve (AUC) of 0.90. The ROC curve is presented in Fig. 5. A cut-off value of 4.5 on the MPI z-score conferred a sensitivity of 89% and specificity of 68% (Table 3). We also assessed the accuracy of a CPR value less than the fifth percentile in predicting adverse outcomes. Fig. 4 demonstrates CPR categorisation between the groups. Table 4 demonstrates the utility of CPR in predicting adverse outcomes. Of the 54 cases with CPR values, 33 (61%) had values less than

30 20 6 IUGR

PE-only

PE–IUGR

< p5

Fig. 2. M pi z-score versus controls, IUGR, PE-only and PE + IUGR groups.

PE–IUGR

7 26

10 –5

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Total

> p5

Fig. 4. CPR categorisation between groups.

the fifth percentile (p5). The sensitivity of CPR < p5 in predicting adverse events was 66% and the specificity was estimated at 42% (Table 4). Logistic regression was performed to evaluate predictors of adverse events after adjusting for all other foetal parameters. In univariate logistic regression, MPI z-score, AFI, EFW, UA Doppler, CPR category, DV Doppler and MCA Doppler were assessed separately as potential predictors of adverse outcomes. The only significant predictor of adverse outcome was the MPI z-score. Treating this as a continuous variable, the odds ratio was 7.8 (95% CI: 2.3–26.1), which can be interpreted as follows: for a one unit higher Mod-MPI z-score, there is an approximately eight-times higher risk of an adverse outcome.

Discussion Table 2. CPR versus adverse events Adverse events, n (%)

IUGR

PE-only

PE–IUGR

Total

16 (50)

3 (27)

8 (67)

27 (49)

p-value 0.197 < 0.001

CPR > p5

6 (19)

10 (91)

5 (42)

21 (38)

< p5

26 (81)

1 (9)

7 (58)

34 (62)

CPR = cerebro-placental ratio, IUGR = intra-uterine growth restriction, PE = pre-eclampsia.

We have previously shown that mainly in severe IUGR, that is, compensated and critical-status IUGR and in severe earlyonset pre-eclampsia, an elevated MPI was a good predictor of adverse neonatal outcome, and cut-off MPIs were suggested.5,6 This study now focused on whether an elevated MPI in milder forms of placental-mediated disease was a predictor of adverse obstetric outcome later on in the pregnancy. This study has shown that a cut-off value of 4.5 on the MPI z-score is a strong indicator of adverse obstetric outcome later in pregnancy, with

100 80 70

1.00

3 16

60 50 40 30 20

8 28

0.50 0.25

10 0

0.75

8 Sensitivity

Adverse event rate (%)

Area under ROC curve = 0.8981

0.00 IUGR

PE-only

Adverse event

PE–IUGR

Total

0.00

0.25

0.50 1 – Specificity

0.75

1.00

No adverse event

Fig. 3. Adverse-event rate between groups.

Fig. 5. ROC curve depicting diagnostic accuracy of MPI z-scores.

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Table 3. MPI z-score cut-off points for predicting adverse outcomes Cut-off point

Sensitivity (%)

Specificity (%)

Correctly classified (%)

LR+

LR–

(≥ 2.98 )

100.00

0.00

49.09

1.0000

(≥ 3.23 )

100.00

3.57

50.91

1.0370

0.0000

(≥ 3.27 )

100.00

7.14

52.73

1.0769

0.0000

(≥ 3.53 )

100.00

10.71

54.55

1.1200

0.0000

(≥ 3.54 )

100.00

14.29

56.36

1.1667

0.0000

(≥ 4.07 )

96.30

25.00

60.00

1.2840

0.1481

(≥ 4.15 )

96.30

32.14

63.64

1.4191

0.1152

(≥ 4.16 )

96.30

39.29

67.27

1.5861

0.0943

(≥ 4.29 )

96.30

42.86

69.09

1.6852

0.0864

(≥ 4.31 )

96.30

53.57

74.55

2.0741

0.0691

(≥ 4.45 )

96.30

57.14

76.36

2.2469

0.0648

(≥ 4.49 )

92.59

60.71

76.36

2.3569

0.1220

(≥ 4.5 )

88.89

67.86

78.18

2.7654

0.1637

(≥ 4.58 )

85.19

67.86

76.36

2.6502

0.2183

(≥ 4.64 )

85.19

71.43

78.18

2.9815

0.2074

(≥ 4.67 )

85.19

75.00

80.00

3.4074

0.1975

(≥ 4.83 )

85.19

78.57

81.82

3.9753

0.1886

(≥ 4.89 )

81.48

78.57

80.00

3.8025

0.2357

(≥ 4.97 )

81.48

82.14

81.82

4.5630

0.2254

(≥ 5.11 )

77.78

82.14

80.00

4.3556

0.2705

(≥ 5.23 )

74.07

85.71

80.00

5.1852

0.3025

(≥ 5.24 )

74.07

89.29

81.82

6.9136

0.2904

(≥ 5.29 )

70.37

89.29

80.00

6.5679

0.3319

(≥ 5.35 )

66.67

92.86

80.00

9.3333

0.3590

(≥ 5.48 )

62.96

96.43

80.00

17.6296

0.3841

16.5926

(≥ 5.54 )

59.26

96.43

78.18

(≥ 5.62 )

55.56

100.00

78.18

0.4225 0.4444

(≥ 5.69 )

51.85

100.00

76.36

0.4815

(≥ 5.76 )

48.15

100.00

74.55

0.5185

(≥ 5.77 )

44.44

100.00

72.73

0.5556

(≥ 6.32 )

40.74

100.00

70.91

0.5926

(≥ 6.96 )

37.04

100.00

69.09

0.6296

(≥ 7.08 )

33.33

100.00

67.27

0.6667

(≥ 7.69 )

29.63

100.00

65.45

0.7037

(≥ 7.95 )

25.93

100.00

63.64

0.7407

(≥ 8.15 )

22.22

100.00

61.82

0.7778

(≥ 8.98 )

18.52

100.00

60.00

0.8148

(≥ 9.84 )

14.81

100.00

58.18

0.8519

(≥ 10.19 )

11.11

100.00

56.36

0.8889

(≥ 10.33 )

7.41

100.00

54.55

0.9259

(≥ 11.36 )

3.70

100.00

52.73

0.9630

(> 11.36 )

0.00

100.00

50.91

1.0000

LR+ = likelihood ratio positive, LR– = likelihood ratio negative.

Table 4. The utility of CPR in predicting adverse outcomes Adverse outcome

No adverse outcome

CPR < p5

CPR > p5

Sensitivity (%)

66.7

Specificity (%)

42.9

PPV (%)

52.9

NPV (%)

57.1

CPR = cerebro-placental ratio, PPV = positive predictive value, NPV = negative predictive value.

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a sensitivity of 89% and specificity of 68% (AUC on the ROC curve of 0.9). In univariate logistic regression, MPI z-score, AFI, EFW, UA Doppler, CPR category, DV Doppler and MCA Doppler were assessed separately as potential predictors of adverse outcome. The only significant predictor of adverse outcome was MPI z-score. Treating this as a continuous variable, the odds ratio was 7.8 (95% CI: 2.3–26.1), which can be interpreted as follows: for a one unit higher MPI z-score, there is an approximately eight times higher risk of adverse outcomes. This study suggests that even in stable placental-mediated disease, an elevated MPI can be a predictor of adverse outcome later in the pregnancy. Our previous study and other studies5,19,20 have shown that the MPI becomes abnormal much earlier than arterial redistribution, and DV anomalies and MPIs deteriorated with worsening grades of growth restriction. This study expands the notion that cardiac dysfunction is probably the initial quantitative parameter to become abnormal in placental-mediated disease and tracks the severity of it. It is the first study to have shown that a single elevated MPI in the context of a perceived mild/stable placentalmediated disease scenario can be predictive of deterioration later in the pregnancy. In the study group (across all groups), adverse outcomes were reported in 49% of cases, including three intra-uterine deaths, 11 cases eventually having decelerative tococardiography, four who subsequently developed imminent eclampsia, two with HELLP syndrome, five who developed severe oligohydramnios later in the pregnancy, and two abruptios, with the highest number recorded in the PE + IUGR group (67%). This would be consistent with a more advanced placental maladaptive process. The question is why would this be the case? Intrinsic cardiac function plays a pivotal role in the compensatory mechanisms of the growth-restricted foetus. Cardiac flow and cardiac contractility may be directly impaired by early hypoxaemia before Doppler changes in MCA can occur, while polycythaemia resulting from blood viscosity changes may alter preload.21,22 Elevated MPIs beyond ‘buffer coping zones’ may be reflecting early hypoxaemia and therefore could predict adverse obstetric outcome.5 Pre-eclampsia on the other hand affects foetal cardiac function by causing an increase in afterload. This is due to the abnormal placental remodelling process and reduced placental perfusion, causing placental vessel injury and placental vasoconstriction, leading to increased placental vascular resistance and thus increased foetal cardiac afterload. This process can certainly impact on cardiac function. Our initial study investigating MPI in severe pre-eclampsia demonstrated that MPIs deteriorate, with worsening placental vascular resistance in severe pre-eclampsia and this was linked to adverse neonatal outcomes.6 This is probably on the basis of angiogenic disparity, tipped in favour of anti-angiogenic substances such as soluble fms-like tyrosine kinase (sFlt-1), which are able to block the effects of vascular endothelial growth factor and placental growth factor (PLGF) by inhibiting interactions with its receptors, leading to widespread vasoconstriction.23-26 Therefore elevation of MPI would reflect these pathophysiological mechanisms, which would directly impact on the foetal heart. An abnormal CPR (< p5) for gestational age has been reported to be an indicator of foetal hypoxaemia and impaired long-term neurological outcome.27 Foetuses were therefore also

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categorised according to their CPR percentile for gestational age and we assessed the accuracy of a CPR value less than the fifth percentile in predicting adverse outcome. Of the 54 cases with CPR values, 33 (61%) had values less than the fifth percentile. The sensitivity of CPR < p5 in predicting an adverse event was 67% and the specificity was estimated at 43%, which cannot be regarded as a good predictor for adverse outcome. The possible explanation for this is that an abnormal CPR probably reflects an established hypoxaemic state and is probably not a predictive parameter, as we were trying to establish in this study. The patients we investigated were stable/mild placental-mediated conditions, i.e. uncompensated IUGR (non-hypoxaemic, non-acidotic) and well-controlled pre-eclamptics (stable control on a single agent). The clinical phenotypes of IUGR and PE depend on the degree of placental maladaptation and degree of lack of vascular remodelling. Both conditions can be grouped as ischaemic placental disease or placental-mediated disease. In EO-PE there is down-regulation of the interstitial trophoblastic invasion, while endovascular trophoblastic invasion is limited to the decidua. The combined IUGR and PE clinical phenotypes are the result of a more advanced degree of placental maladaptation,9 and the high number of adverse outcomes in the PE–IUGR group is consistent with this pathophysiology. This is therefore a dynamic process and, depending on the clinical phenotype and placental lesion, will in worse outcomes, result in hypoxia, oligohydramnios (due to decreased foetal perfusion), maternal multi-systemic organ affectation (such as HELLP or eclampsia), foetal acidosis and death. From whatever clinical phenotype is realised, the path to deterioration can be foetal and/or maternal, depending on levels of placental ischaemia and the associated production of increased levels of toxic factors such as sFLt-1 and endoglin. Present standard monitoring models, done in the early third trimester, may not be predictive of later adverse outcomes. For example, UA RI becomes abnormal only if more than 30 to 40% of the placenta is non-functional,28,29 MCA RI becomes abnormal only at the onset of hypoxia,29 and DV changes are late changes in the cascade of cardiovascular deterioration, already reflecting acidosis and myocardial necrosis.30 Furthermore, the vast majority (> 72%) of ‘unexplained’ stillbirths at term are so-called appropriate for gestational age, that is between p10 and p50, so biometry is also not entirely helpful.31 As early hypoxia and increasing afterload both impact on cardiac function, the MPI is well placed to become a predictor of adverse obstetric outcome, as demonstrated in this study. The use of MPI together with biochemical markers, such as sFlt-1 and PLGF,32 may further improve its sensitivity. This project is a continuation of our group’s quest to further define the clinical use of MPI in high-risk obstetric conditions and find its appropriate place in antenatal foetal surveillance, in the context of present standard foetal monitoring models. The main limitation of the study is the limited numbers in the groups under investigation, but the results nonetheless highlight the great potential of cardiac Doppler as an important adjunct to standard monitoring models in placental-mediated disease. It makes the case to further corroborate these findings in larger trials and to fine-tune the place and implementation of cardiac Doppler in mainstream monitoring of cases with placental-mediated disease. Another limitation is that it requires

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training and experience to obtain a reliable MPI result and it can be confounded by user bias. However this parameter shows good reproducibility when the valve-click method of establishing landmarks is used, as we have demonstrated in our study, establishing reference intervals of the MPI in normal pregnancies.4

Conclusion A single elevated value of the MPI (z-score > 4.5) in the third trimester in stable placental-mediated disease is a strong indicator of adverse obstetric outcome later in pregnancy. This has the potential to be incorporated, in conjunction with standard monitoring models, in stable placental-mediated disease to predict an adverse event later in pregnancy and thus to reduce perinatal morbidity and mortality.

References 1.

Tei C, Ling C, Hodge DO. 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.

Tei C. New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995; 26: 135–136.

Tei C, Dujardin KS, Hodge DO. Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr 1996; 9: 838–847.

Bhorat IE, Bagratee JS, Reddy T. Gestational age-adjusted trends and reference intervals for the modified myocardial performance index (Mod-MPI) with its interpretation in the context of established cardiac physiological principles. Prenat Diag 2014 DOI: 10.1002/pd. 4414.

Bhorat IE, Bagratee J, Pillay M, Reddy T. Determination of the myocardial performance index in deteriorating grades of intrauterine growth restriction and its link to adverse outcomes. Prenat Diag 2014 DOI;10.1002/ pd 4537.

Bhorat IE, Bagratee J, Reddy T. Assessment of fetal myocardial performance in severe early onset pre-eclampsia (EO-PET) across deteriorating stages of placental vascular resistance and links to adverse outcomes, as well as to assess if coexistent intrauterine growth restriction influences cardiac function in severe EO-PET: a prospective cross-sectional study. Unpublished, 2016.

Bhorat IE, Bagratee JS, Pillay M, Reddy T. Use of the myocardial performance index as a prognostic indicator of adverse fetal outcome in poorly controlled gestational diabetic pregnancies. Prenat Diag 2014 DOI:10.1002/pd.4471.

Khong TY, de Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 1986; 93: 1049–1059.

Brosens I, Pijnenborg R, Vercruysse L, Romero R. The ‘Great Obstetrical Syndromes’ are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204(3): 193–201.

10. Rizzo G, Arduini D, Romanini C, et al. Doppler echocardiographic assessment of atrio-ventricular velocity waveforms in normal and small for gestational age foetuses. Br J Obstet Gynecol 1988; 95: 65–69. 11. Groenenberg IA, Baerts W, Hop C, et al. Relationship between fetal cardiac and extracardiac Doppler flow velocity waveformes and neonatal outcome in intrauterine growth retardation. Early Hum Dev 1991; 26: 185–192

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12. Rizzo G, Arduini D,Romanini C, et al. Doppler echocardiographic evaluation of time to peak velocity in the aorta and pulmonary artery of small for gestational age foetuses. Br J Obstet Gynecol 1990; 97: 603–607.

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Br Med J 1987; 294: 1051–1053. 22. Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth restriction. Am J Obstet Gynecol 1991; 165: 876–882. 23. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-

13. Al-Ghazaii W, Chita SK, Chapman MG, et al. Evidence of redistribu-

like tyrosine kinase 1(sFlt1) may contribute to endothelial dysfunction,

tion of cardiac output in asymmetrical growth retardation. Br J Obstet

hypertension and proteinurea in pre-eclampsia. J Clin Invest 2003; 111:

Gynecol 1989; 96: 697–704. 14. ACOG Committee on Practice Bulletins – Obstetrics. ACOG Practice Bulletin. Diagnosis and management of pre-eclampsia and eclampsia. Obstet Gynecol 2002; 99: 159–167.

649–658. 24. Schlembach D, Beinder E. Angiogenic factors in pre-eclampsia. J Soc Gynecol Invest 2003; 10: 316A. 25. Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble

15. Ebbing C, Rasmussen S, Kiserud T. Middle cerebral artery blood veloci-

vascular endothelial growth factor receptor in pre-eclamptic patients:

ties and pulsatility index and the cerebroplacental pulsatility ratio: longi-

pathophysiological consequences. J Clin Endocrinol Metab 2003; 88:

tudinal reference ranges and terms for serial measurements. Ultrasound Obstet Gynecol 2007; 30; 287–296. 16. Hernandez-Andrade E, Figuero-Diesel H, Kottman C, et al. Gestational-

5555–5563. 26. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of pre-eclampsia. N Engl J Med 2004; 350: 672–683.

age adjusted reference values for the modified myocardial performance

27. Morales-Rosello J, Khalil A. Fetal cerebral redistribution – a marker

index for evaluation of left fetal cardiac function. Ultrasound Obstet

of fetal compromise regardless of fetal size. Ultrasound Obstet Gynecol

Gynecol 2007; 29: 321–325.

2015; 46: 385–388.

17. Cruz-Martinez R, Figueras F, Bennasar, et al. Normal reference ranges

28. Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal

from 11–14 week gestation of fetal left modified myocardial perfor-

outcome in early onset placental dysfunction. Obstet Gynecol 2007; 109:

mance index by concentional Doppler with the use of stringent criteria for delimitation of time periods. Fetal Diagn Ther 2012; 32: 79–86.

253–261. 29. Ferazzi E, Bozzo M, Rigano S, et al. Temporal sequence of abnormal

18. Meriki N, Izurieta A,Welsh AW. Fetal left modified myocardial perfor-

Doppler changes in the peripheral and central circulatory systems of

mance index: technical refinements in obtaining pulse Doppler wave-

the severely growth restricted fetus. Ultrasound Obstet Gynecol 2002;

forms. Ultrasound Obstet Gynecol 2012; 39: 421–429.

19: 140–146.

19. Cruz-Martinez R, Figueras F, Benavides-Serralde A, et al. Sequence

30. Kiserud T, Kessler J, Ebbing C, et al. Ductus venosus shunting in growth

of changes in myocardial performance index in relation with the aortic

restricted foetuses and effect of umbilical circulatory compromise.

isthmusand ductus venosus Doppler in fetuses with early onset intrau-

Ultrasound Obstet Gynecol 2006; 28: 143–149.

terine growth restriction. Ultrasound Obstet Gynecol 2011; 38: 179–184.

31. Vasak B, Koenen SV, Koster MPH, et al. Human fetal growth is

20. Crispi F, Hernandez-Andrade E, Pelsers MAL, et al. Cardiac dysfunc-

constrained below optimal for perinatal survival. Ultrasound Obstet

tion and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 2008; 199: 254.e1–e8. 21. Soothill PW, Nicolaides KH, Campbell S. Prenatal asphyxia, hyperlacticaemia, hypoglycaemia and erthroblastosis in growth retarded foetuses.

Gynecol 2015; 45: 162–167. 32. Gomez-Arriaga PI, Herraiz I, Lopez-Jemenez EA. Uterine artery Doppler and sFlt/PLGF ratio: usefulness in diagnosis of pre-eclampsia. Ultrasound Obstet Gynecol 2013: 41: 530–537.

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Review Articles Rheumatoid arthritis and risk of cardiovascular disease Pieter WA Meyer, Ronald Anderson, James A Ker, Mahmood TM Ally Overall mortality in rheumatoid arthritis (RA)

Abstract In developing countries, rheumatoid arthritis (RA) remains a seriously under-prioritised disease, particularly among the underprivileged, often resulting in presentation of patients late in the course of their disease, further complicated by limited therapeutic options and inconsistent follow up. The consequences are often severe with irreversible disability, increased frequency of co-morbidities, especially cardiovascular disease (CVD), and higher mortality rates, relative to developed countries. Despite addressing traditional cardiovascular risk factors, the impact of subclinical or ‘residual’ inflammation from uncontrolled RA needs to be considered. This narrative review explores the prevalence and pathogenesis of CVD in RA, including the impact of tobacco use. It discusses pitfalls in the risk assessment of CVD in patients with RA, and the effect of disease-modifying anti-rheumatic therapy on cardiovascular co-morbidity.

Keywords: cardiovascular risk, chronic inflammation, rheumatoid arthritis, tobacco usage, effects of drug treatment Submitted 28/6/17, accepted 11/3/18 Published online 27/3/18 Cardiovasc J Afr 2018; 29: 317–321

www.cvja.co.za

DOI: 10.5830/CVJA-2018-018

Department of Immunology, Faculty of Health Sciences, University of Pretoria, and Tshwane Academic Division of the National Health Laboratory Service of South Africa, Pretoria, South Africa Pieter WA Meyer, PhD, Pieter.Meyer@up.ac.za

Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa Ronald Anderson, PhD

Department of Internal Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa James A Ker, MB ChB, MD

Division of Rheumatology, Department of Internal Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa Mahmood TM Ally, PhD

Despite innovative advances made in the management of patients with RA, premature mortality from co-morbid diseases remains a significant challenge. The disease is not only more common in females (gender ratio of 3:1), but they also tend to have more active disease and impaired function than males.1 A systematic review and meta-analysis of 11 longitudinal studies published in 2013, which covered the period 1955–1995, encompassing five different developed countries (the Netherlands, Spain, Sweden, UK and USA) and a total of 51 819 patients with RA, concluded that ‘mortality has decreased among RA patients over the past decades but remained higher than in the general population as assessed by the incident mortality rate and the standardised mortality over time’.2 This trend has continued in developed countries according to more recent studies from Canada,3 France4 and the UK,5 all confirming a sustained increased mortality rate in RA sufferers relative to the general population.6 According to the findings of the aforementioned systematic review and a meta-analysis reported by Dadoun et al., the standardised mortality ratio is 1.47, meaning that patients with RA have a 47% higher risk of premature mortality relative to the general population when matched for age and gender,2 with a decreased life expectancy of three to 10 years or more.7 A recent study from Spain covering the period 1994–2013 identified the following major independent risk factors for poor survival in RA: male gender, older age at diagnosis, the presence of rheumatoid factor (RF), [testing for anti-cyclic citrullinated peptide antibodies (ACPA) was unavailable in the early years of the study], higher number of hospital admissions, greater disease activity, and more severe radiographic joint damage.8 In addition, genetic predisposition in Caucasian populations contributes significantly to the development and severity of, as well as mortality from, RA, this being conferred by the susceptibility genes known as the HLA-DRB1 shared epitope (SE) alleles.9 The influence of genetic susceptibility is particularly evident in RA patients who smoke, increasing the propensity for the development of ACPA-seropositive disease.9 Indeed cigarette smoking, and possibly exposure to other types of inhaled irritants/toxicants, particularly in the context of expression of SE alleles, appears to promote the formation of ACPA by mechanisms that have been reviewed in detail.10,11

Causes of mortality in RA Cardiovascular disease (CVD) is well recognised as the most common cause of mortality in patients with RA, being associated with endothelial dysfunction and arterial stiffness due to inflammation-associated loss of elasticity of the vascular wall. This results from alterations in the structural proteins,

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collagen and elastin, leading to accelerated atherosclerosis, usually detected by the measurement of carotid intima–media thickness.12–15 One meta-analysis of observational studies undertaken by a Canadian group concluded that the CVD mortality rate was increased by approximately 50% in RA patients compared with the general population,16 with neoplastic disease and respiratory disease, particularly pneumonia, being other significant contributors.4 Notwithstanding traditional risk factors for CVD common among RA patients in developed countries (smoking, obesity, type 2 diabetes mellitus, dyslipidaemia and others), those specifically associated with RA include the presence of extraarticular manifestations and erosions, as well as prolonged disease duration with accompanying systemic inflammation and endothelial dysfunction.12-18 Given that increased risks for the development of myocardial infarction, heart failure/sudden death and stroke in patients with RA have been estimated to be two- to three-fold, two-fold and 1.7-fold, respectively,19 it is hardly surprising that the European League Against Rheumatism advocates ‘that early detection and pre-emptive treatment of high-risk (RA) patients is of great importance in reducing the excess risk of CVD in RA’.20 In this context, RA-related CV screening in the developed world setting is considered to be a cost-effective strategy.21 The current methods used to assess cardiovascular risk do not accommodate long-term exposure to inflammation and tend to underestimate the risk. Different scoring mechanisms are used and under-estimations of risk as large as two-fold have been observed with the Framingham Risk Score (FRS) when applied to RA patients.22 The European League Against Rheumatism (EULAR) working group has suggested that the Systematic Coronary Risk Evaluation (SCORE) scoring system risk value be multiplied by 1.5 in RA patients who show at least two of the following: (1) RA disease of more than 10 years, (2) positive RF, (3) positive ACPA, and (4) presence of extraarticular manifestations.23 It is, however, possible that even with the modified SCORE, a large number of RA patients still may not be identified and are at high risk for CVD.24 In addition to ultrasound measurement of carotid intima– media thickness13 and high-resolution ultrasound measurement of flow-mediated vasodilation in the branchial artery (measures arterial response to hypoxia) to evaluate endothelial function as a ‘surrogate marker of subclinical atherosclerosis’,25 several systemic biomarkers of inflammation and cardiac dysfunction have also been reported to predict CVD risk and mortality in RA patients. Currently, the most promising of these is N-terminal pro-brain natriuretic peptide (NT-proBNP), a well-recognised, sensitive predictor of future CVD and mortality in general healthy populations, as well as in RA patients, according to the limited studies undertaken to date.26-28 Measurement of cardiac troponin T may also have predictive potential in RA,28 but interpretation of data is complicated by the influence of age and/ or the presence of other co-morbidities.

Pathogenesis of CVD in RA Chronic, low-grade systemic inflammation leading to prolonged endothelial activation and an accompanying pro-thrombotic/ pro-coagulant state is believed to be the major contributor to the increased risk of CVD in RA.19 Some of the most prominent

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proposed immunopathogenic processes underpinning these events are summarised as follows: • increased systemic levels, presumably synovium-derived, of the endothelial-activating cytokines interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and interferon (IFN)-γ19,29-31 • binding and activation of neutrophils, monocytes and platelets to cytokine-activated, pro-adhesive vascular endothelium, potentiated by the neutrophil and monocyte chemokines, CXCL8 (IL-8) and CCL2, respectively19,29,30 • systemic activation of platelets, not only via interaction with cytokine-sensitised vascular endothelium and proximal neutrophils/monocytes, which may trigger further platelet activation via protease-activated receptors (PARs) 1 and 4, but also by exposure to ACPA32 • activation of vascular endothelium PAR-1 by adherent neutrophils/monocytes, thereby exacerbating systemic inflammation and endothelial dysfunction33 • creation of a pro-inflammatory milieu conducive to the formation of pro-atherogenic oxidised low-density lipoprotein29 • intra-vascular formation of neutrophil extracellular traps (NETs) via exposure of these cells to activated platelets34 • NETs, in turn, contribute to the intravascular, pro-inflammatory/pro-thrombotic/pro-coagulant environment via expression of endothelium-activating proteases33 and histones,35 as well as the expression and presentation of functional tissue factor.36 Although partially controlled by endogenous anti-inflammatory mechanisms,30 this chronic, low-grade activation and dysfunction of vascular endothelium, triggered and sustained by synovialderived mediators of inflammation, is likely to underpin the pro-atherogenic, pro-thrombotic changes that favour accelerated development of CVD in patients with untreated RA.

Smoking, smokeless tobacco use, RA and CVD Smoking is a well-recognised risk factor for the development of both RA and CVD, and in a recent study from the US, smoking was found to be an independent predictor, albeit somewhat weaker than age (p < 0.05 vs p < 0.001, respectively), of the presence of atherosclerotic plaques in patients with RA.37 As with RA, these atherothrombotic effects of smoking are also associated with ‘multiple pathological effects in the endothelium’, as well as activation of platelets and the coagulation cascade.38 However, less attention has been focused on the possible pro-atherogenic effects of usage of smokeless tobacco products, which is common among black South African females, with a recorded prevalence of 48% among RA participants in the Gauteng Rheumatoid Evaluation and Assessment Trial (GREAT).39 Indeed, on the African continent, only Botswana and Mauritania have a higher prevalence of smokeless tobacco use than South Africa.40 In a recently reported analysis of the global burden of disease, usage of smokeless tobacco products was estimated to account for 4.7 million disability-adjusted life years lost and 204 309 deaths, based on data from the benchmark 52-country INTERHEART study,40 the risk being statistically significant with an adjusted odds ratio of 1.57.41 In this context, it is noteworthy that blood levels of the nicotine metabolite, cotinine, in South African female users of inhaled snuff products were found to be comparable with those of active smokers.39 In the past, nicotine has been a

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somewhat neglected component of tobacco usage with regard to pro-inflammatory activity. Recently, however, nicotine has been reported to possess endothelial disruptive, pro-inflammatory activity,42 while exposure of isolated human blood neutrophils to nicotine in vitro has been reported to activate NETosis, which was augmented by the combination of nicotine with either TNF-α or APCA.43 In this same study, administration of nicotine to mice was found to accelerate collagen-induced arthritis, which was accompanied by increased systemic levels of myeloperoxidase-DNA complexes, an in vivo surrogate of NETosis.43 Moreover, chronic inhalation of nicotine by mice has been found to cause pulmonary injury associated with increased expression of pulmonary cytokines and proteases, mimicking the features of chronic obstructive pulmonary disease.44 Notwithstanding a high content of heavy metal toxicants, cured tobacco also contains high levels of pro-inflammatory microbial products, particularly bacterial endotoxins.10,45 Endotoxins, which are potent activators of vascular endothelium, neutrophils, monocytes/macrophages and platelets, as well as other types of immune/inflammatory and structural cells, have also been implicated in the pathogenesis of atherosclerosis.46,47 In this context, users of smokeless tobacco products may be particularly vulnerable to the pro-atherogenic effects of tobaccoderived endotoxins, since these are inhaled or ingested without modification by the combustion of tobacco. The impact of tobacco use in the context of RA disease progression and associated co-morbidity is often neglected by both patient and clinician, even though globally, a high percentage of patients with RA continue to smoke.10,48

Effects of disease-modifying anti-rheumatic drug and cytokine-targeted therapies on clinical and systemic indices of CVD in patients with RA Methotrexate (MTX) is the pivotal traditional disease modifying anti-rheumatic drug (DMARD) and has a proven track record for the cost-effective management of RA. In addition, MTX increases total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride levels in RA, which might be attributed to the decrease in inflammation.24 MTX treatment has been found to reduce mortality rate in RA patients by 70% and showed a decrease of 21% in total cardiovascular risk, including myocardial infarctions, congestive cardiac failure and strokes.49 This information confirms the belief that if systemic inflammation in RA is reduced, the risk for CVD is also reduced. It is therefore important to achieve remission or low disease activity as soon as possible, not only to achieve better structural and functional outcomes, but also to reduce the risk of CVD in these patients.49 As alluded to above, TNF-α is pivotally involved in the pathogenesis of RA and is one of the main targets in the treatment of the disease. Anti-TNF biologics are now standard in the treatment of refractory RA. The main agents used in this group are etanercept, adalimumab, infliximab and golimumab. Treatment of RA with anti-TNF biologics may decrease CVD risk by inhibiting endothelial dysfunction, and the progression of atherosclerosis by decreasing the expression of pro-inflammatory cytokines and endothelial adhesion molecules.

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No changes in the levels of LDL-C or the ratio between HDL-C and TC were found with long-term treatment of RA patients with these immunotherapies. However, evidence derived from clinical studies shows that TNF inhibitors can reduce the risk for cardiovascular events between 30 and 70% in RA patients. Non-TNF biologics such as tocilizumab (TCZ), tofacitinib, rituximab, abatacept and anakinra act on different arms of the immune system and also demonstrate clinical efficacy in RA, but little is known about the effects of these drugs on CVD morbidity and mortality rates. In this context, evidence from a limited number of clinical studies has indicated that lipid profiles tend to alter when RA patients are treated with these drugs, but results are inconclusive and more research is needed.50 An important albeit unanswered question is ‘can the remarkable advances in the management of RA be used to manage patients with non-RA associated CVD?’ In this context, an unmet need in the management of patients with CVD is subclinical or ‘residual’ inflammatory risk, despite addressing other cardiovascular risk factors, in the management of patients with CVD. The identification of inflammatory mediators or other biomarkers associated with cardiovascular risk has the potential to stratify at-risk patients and develop novel therapies for CVD in general.51 In this context, it is noteworthy that studies in cholesterol-fed rats have demonstrated anti-atherosclerotic effects of MTX,52,53 while several clinical trials are currently exploring the role of anti-rheumatic drugs such as MTX and IL-1 antagonists as novel therapies for non-RA CVD.54,55

Conclusion Cardiovascular co-morbidity has a significant impact on overall prognosis in the management of patients with RA. It is important to emphasise that classical risk factors for CVD are common in RA patients and their treatment is as important as in the general population. Controlling disease activity with aggressive and early introduction of conventional DMARDs with escalation to targeted or biologic therapies if required will enable control of inflammation and lower the CVD burden.

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17. Steyers CM III, Miller FJ Jr. Endothelial dysfunction in chronic inflammatory diseases. Int J Mol Sci 2014; 15(7): 11324–11349. 18. Yang X, Chang Y, Wei W. Endothelial dysfunction and inflammation:

platelets. J Leukoc Biol 2016; 99(1): 153–162. 35. Zhang Y, Guan L, Yu J, Zhao Z, Mao L, Li S, et al. Pulmonary endothelial activation caused by extracellular histones contributes to neutrophil acti-

immunity in rheumatoid arthritis. Mediators Inflamm 2016; 2016: 6813016.

vation in acute respiratory distress syndrome. Respir Res 2016; 17(1): 155.

19. Ku IA, Imboden JB, Hsue PY, Ganz P. Rheumatoid arthritis: model of

36. Stakos DA, Kambas K, Konstantinidis T, Mitroulis I, Apostolidou E,

systemic inflammation driving atherosclerosis. Circ J 2009; 73(6): 977–985.

Arelaki S, et al. Expression of functional tissue factor by neutrophil extra-

20. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien

cellular traps in culprit artery of acute myocardial infarction. Eur Heart J

TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69(2): 325–331. 21. Kievit W, Maurits JS, Arts EE, van Riel PL, Fransen J, Popa CD. Costeffectiveness of cardiovascular screening in patients with rheumatoid arthritis. Arthritis Care Res 2017; 69(2): 175–182. 22. Liao KP. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc Med 2017; 27(2): 136–140. doi: 10.1016/j. tcm.2016.07.006 23. Martin-Martinez MA, González-Juanatey C, Castañeda S, Llorca J,

2015; 36(22): 1405–1414. 37. Dalbeni A, Giollo A, Tagetti A, Atanasio S, Orsolini G, Cioffi G, et al. Traditional cardiovascular risk factors or inflammation: which factors accelerate atherosclerosis in arthritis patients? Int J Cardiol 2017; 236: 488–492. 38. Csordas A, Bernhard D. The biology behind the atherothrombotic effects of cigarette smoke. Nat Rev Cardiol 2013; 10(4): 219–230. 39. Govind N, Ally MM, Tikly M, Anderson R, Hodkinson B, Meyer PW. Pitfalls in the assessment of smoking status detected in a cohort of South African RA patients. Rheumatol Int 2016; 36(10): 1365–1369.

Ferraz-Amaro I, Fernández-Gutiérrez B, et al. Recommendations for the

40. Siddiqi K, Shah S, Abbas SM, Vidyasagaran A, Jawad M, Dogar O, et al.

management of cardiovascular risk in patients with rheumatoid arthritis:

Global burden of disease due to smokeless tobacco consumption in adults:

scientific evidence and expert opinion. Semin Arthritis Rheum 2014; 44(1): 1–8.

analysis of data from 113 countries. BMC Med 2015; 13: 194. 41. Teo KK, Ounpuu S, Hawken S, Pandey MR, Valentin V, Hunt D, et

24. Choy E, Ganeshalingam K, Semb AG, Szekanecz Z, Nurmohamed

al. Tobacco use and risk of myocardial infarction in 52 countries in the

M. Cardiovascular risk in rheumatoid arthritis: recent advances in the

INTERHEART study: a case-control study. Lancet 2006; 368(9536):

understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology 2014; 53(12): 2143–2154.

647–658. 42. Schweitzer KS, Chen SX, Law S, Van Demark M, Poirier C, Justice MJ,

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et al. Endothelial disruptive proinflammatory effects of nicotine and

49. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P,

e-cigarette vapour exposures. Am J Physiol Lung Cell Mol Physiol 2015;

et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-

309(2): L175–L187.

steroidal anti-inflammatory drugs and corticosteroids on cardiovascular

43. Lee J, Luria A, Rhodes C, Raghu H, Lingampalli N, Sharpe O, et al.

events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a system-

Nicotine drives neutrophil extracellular traps formation and acceler-

atic review and meta-analysis. Ann Rheum Dis 2015; 74(3): 480–489.

ates collagen-induced arthritis. Rheumatology 2017; 56(4): 644–653. doi:

50. Shen J, Shang Q, Tam LS. Targeting inflammation in the prevention of

10.1093/rheumatology/kew449. 44. Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, et al. Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax 2016; 71(12): 1119-1129. doi: 10.1136/thoraxjnl-2015-208039.

cardiovascular disease in patients with inflammatory arthritis. Transl Res 2016; 167(1): 138–151. 51. Ridker PM. How common is residual inflammatory risk? Circ Res 2017; 120: 617–619. Doi: 10.1161/CIRCRESAHA.116.310527. 52. McPherson JA, Barringhaus KG, Bishop GG, Sanders JM, Rieger JM,

45. Feldman C, Anderson R. Cigarette smoking and mechanisms of suscepti-

Hesselbacher SE, et al. Adenosine A(2A) receptor stimulation reduces

bility to infections of the respiratory tract and other organ systems. J Infect

inflammation and neointimal growth in a murine carotid ligation model.

2013; 67(3): 169–184.

Arterioscler Thromb Vasc Biol 2001; 21(5): 791–796.

46. Stoll LL, Denning GM, Weintraub NL. Potential role of endotoxin as a

53. Bulgarelli A, Martins Dias AA, Caramelli B, Maranhão RC. Treatment

proinflammatory mediator of atherosclerosis. Arterioscler Thromb Vasc

with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J

Biol 2004; 24(12): 2227–2236.

Cardiovasc Pharmacol 2012; 59(4): 308–314.

47. Schrottmaier WC, Kral JB, Zeitlinger M, Salzmann M, Jilma B, Assinger

54. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis:

A. Platelet activation at the onset of human endotoxemia is undetectable

scientific rationale for the cardiovascular inflammation reduction trial

in vivo. Platelets 2016; 27(5): 479–483.

(CIRT). J Thromb Haemost 2009; 7(suppl 1): 332–339.

48. Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, Douglas KM,

55. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and

Nevill AM, Jamurtas AZ, et al. Cigarette smoking associates with body

the prevention of recurrent cardiovascular events: rationale and design

weight and muscle mass of patients with rheumatoid arthritis: a cross-

of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study

sectional, observational study. Arthritis Res Ther 2008; 10(3): R59.

(CANTOS). Am Heart J 2011; 162(4): 597–605.

Mortality outcomes of original ASCOT trial reported In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressurelowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. Professor Peter Sever at the National Heart and Lung Institute, Imperial College London writes in The Lancet that the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow up of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15.7 years (IQR 9.7–16.4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressurelowering treatment. Of these patients, those who had total cholesterol of 6.5 mmol/l or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death. Of 8 580 UK-based patients in ASCOT, 3 282 (38.3%) died, including 1 640 (38.4%) of 4 275 assigned to atenolol-based treatment and 1 642 (38.1%) of 4 305 assigned to amlodipinebased treatment; 1 768 of the 4 605 patients in the LLA died, including 903 (39.5%) of 2 288 assigned placebo and 865 (37.3%) of 2317 assigned atorvastatin. Of all deaths, 1 210

(36.9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments [adjusted hazard ratio (HR) 0.90, 95% CI: 0.81–1.01, p = 0.0776], although significantly fewer deaths from stroke (adjusted HR 0.71, 95% CI: 0.53–0.97, p = 0.0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3 975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0.79, 95% CI: 0.67–0.93, p = 0.0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p = 0.022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0.85, 95% CI: 0.72–0.99, p = 0.0395) occurred among patients assigned to statin than among those assigned placebo. Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes. Source: Medical Brief 2018

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The role of novel atherosclerosis markers in peripheral artery disease: is there a gender difference? Horațiu Comşa, Dumitru Zdrenghea, Sorin Claudiu Man, Dana Pop

Abstract Peripheral arterial disease (PAD) represents a major public health problem due to its high and increasing prevalence, worldwide distribution, and significant morbidity and mortality rate. Female gender is a risk factor for PAD globally and especially in low-income countries. In this review, we summarise the present knowledge regarding the role of novel atherosclerosis markers in the development of PAD in women. We discuss inflammatory markers, cytokines, cellular adhesion molecules, markers of oxidative stress and other circulating markers, and their role in the prediction of presence, severity and complications of PAD, with particular emphasis on gender. Although many PAD biomarkers are indicative of PAD in both males and females, some are strongly correlated with the disease in females. These gender differences could be useful for the early identification and management of PAD in women. Keywords: peripheral arterial disease, biomarkers, risk factors, gender Submitted 11/4/17, accepted 15/3/18 Published online 20/4/18 Cardiovasc J Afr 2018; 29: 322–330

www.cvja.co.za

DOI: 10.5830/CVJA-2018-023

Peripheral arterial disease (PAD) represents a major public health problem due to its high and increasing prevalence, worldwide distribution and significant morbidity and mortality rates.1 The prevalence of PAD increases with age, especially in individuals over 75 years of age, in males, and subjects of African-American ethnicity.2 Figures regarding prevalence of the disease and gender distribution vary from one study to another, depending on the criteria used to diagnose PAD and geographical variations. However, global data on trends in PAD prevalence between 2000 and 2010, published by Fowkes and collaborators, show that in

Department of Internal Medicine, Faculty of Medicine, University of Medicine and Pharmacy; and Department of Cardiology, Rehabilitation Clinical Hospital, Cluj-Napoca, Romania Horațiu Comşa, MD Dumitru Zdrenghea, MD, PhD Dana Pop, MD, PhD

Department of Mother and Child, Faculty of Medicine, University of Medicine and Pharmacy, Cluj-Napoca, Romania Sorin Claudiu Man, MD, PhD, claudiu.man@umfcluj.ro

high-income countries, PAD prevalence is reported to be higher in men than in women, whereas in low- and middle-income countries, rates are slightly higher in women.1 This is coupled with the fact that in developing countries the disease generally tends to affect younger age groups.1 Female gender is a risk factor for PAD globally, especially after the age of 65 years, with apparently higher rates in low- and middle-income countries, whereas in high-income countries, the male gender tends to be an independent risk factor for PAD, as data from the same analysis show.1 This difference, although unlikely to stem from an excess of conventional atherosclerotic risk factors in females, may be related to other unidentified factors or even a diagnostic bias due to smaller body mass index, atypical symptoms or longer life expectancy in women. Geo-economical differences may stem from lifestyle differences between developing countries and the industrialised world, with women in the former being more exposed to smoking and uncontrolled diabetes at a younger age. We also have to take into consideration that major differences in healthcare expenditure, and healthcare access between high- and low/middle-income countries, coupled with atypical symptoms and particular anthropometric characteristics, lead to delayed diagnosis and ill-treatment of this disease in women from less-developed countries. Unfortunately, all these factors contribute to female patients worldwide referring to the physician in more advanced stages of the disease, often presenting with critical limb ischaemia.3 In terms of ethno-racial distribution, several studies have shown that the highest prevalence of PAD of all ethnic groups is in African-American individuals, even after adjusting for other cardiovascular risk factors.2,4,5 Ethnic differences are therefore unlikely to be caused by only lifestyle differences between individuals.6 During the first year after diagnosis, patients with intermittent claudication have a mortality rate ranging from 20 to 25%, with a five-year survival rate of less than 30%.7,8 This is the reason why understanding and identifying the risk factors for the development of this disease are of utmost importance. Although atherosclerotic disease does not become clinically apparent until adult life, studies have shown that the onset of the atherosclerotic process is in childhood,9 even in prenatal life.10,11 The two main risk factors for the development of PAD in both genders are diabetes mellitus and smoking.12 As is the case for other cardiovascular conditions, female subjects have been under-represented in PAD clinical trials. Despite this, it was shown that women who developed PAD were older than their male counterparts and were more frequently obese and dyslipidaemic.13-15 Other research has demonstrated the involvement of endothelial dysfunction in the pathogenesis of PAD in women. Gardner and co-workers have shown that during physical exercise, peripheral microcirculation is more deficient and the arterial elasticity indices are much lower in females with PAD compared to male subjects.16

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In this review, we summarise the present knowledge regarding the involvement of novel markers of atherosclerosis in the development of PAD in women.

Inflammatory markers Although not a novel marker, fibrinogen, an important acutephase protein, is responsible for increasing blood viscosity, with secondary prothrombotic effects.6 Regardless of the presence of PAD symptoms, various studies have demonstrated the presence of elevated fibrinogen levels in subjects with marked peripheral atherosclerosis.17,18 The association between high levels of fibrinogen and PAD is stronger in men than in women, while for the latter it seems to be positively correlated with smoking.19 The Multi-Ethnic Study of Atherosclerosis (MESA), which included individuals without a known history of cardiovascular disease, demonstrated that women of all ethnic groups had higher median levels of C-reactive protein (CRP) than men.20 Numerous clinical trials have shown that there is a robust and independent association between CRP and the presence of PAD, regardless of gender.17,21-23 In a recent study, Gardner et al. found a direct relationship between CRP levels and the progression of PAD,23 while Pradhan’s study demonstrated a strong association between CRP, soluble intracellular adhesion molecule-1 (sICAM-1), high-density lipoprotein cholesterol (HDL-C) levels, triglyceride/ HDL-C ratio and symptomatic PAD in women.22 Female subjects with high levels of CRP enrolled in the Women’s Health Study had a significantly greater risk of developing PAD over time.17 CRP is also a marker associated with an increased risk of developing PAD-related complications, as shown by the European Prospective Investigation into Cancer and Nutrition (EPIC): Norfolk cohort.24 High serum levels of CRP before endovascular therapy in haemodialysis-requiring PAD patients were independently associated with increased risk of re-intervention, amputation and even overall mortality.25 Similar to data obtained in adults, CRP is probably the most studied inflammatory biomarker in children. Jarvisalo et al. found that healthy young children with higher CRP levels had higher carotid intima–media thickness (CIMT) and lower brachial artery flow-mediated dilatation.26 The Pathobiological Determinants of Atherosclerosis in Youth Study (PDAY), which included subjects aged 15 to 34 years, demonstrated a direct relationship between CRP levels and abdominal aorta or right coronary artery atherosclerotic lesions.27 As in older adults, CRP levels were higher in young women.27 Other studies, such as the Cardiovascular Risk in Young Finns study, 28 and Giannini and colleagues’ work,29 did not find an association between childhood CRP levels and adult CIMT. These findings are in line with current knowledge that high levels of inflammatory markers are independent predictors of adverse cardiovascular outcomes, and this seems to be true irrespective of gender or age.

Homocysteine Thirty per cent of young patients with PAD have increased blood levels of homocysteine compared to 1% in the general population, as it may be a stronger risk factor for PAD than for coronary artery disease.8 In the MESA study, homocysteine

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along with high levels of interleukin-6, fibrinogen and D-dimers, were significantly correlated with the presence of PAD, even after adjustment for traditional cardiovascular risk factors.5 A meta-analysis published in 2009, comprising 14 studies, found that homocysteine levels were elevated in PAD patients compared to healthy controls.30 Even among the PAD group, blood levels increased with age, being higher in elderly subjects.31 Along with other traditional atherosclerosis risk factors such as smoking, diabetes, arterial hypertension and dyslipidaemia, homocysteine is thought to be an important predisposing factor for the development of PAD in women.32 Several older studies showed an association between high homocysteine levels and PAD in women.33-35 On the other hand, more recent studies give different results. Elevated levels of homocysteine had been found only in male subjects with PAD in a Japanese-Brazilian population.36 Pradhan et al. found no correlation between homocysteine levels and the presence of PAD in female subjects.22 Using data from two large cohort studies (72 348 female participants from the Nurses’ Health Study and 44 504 males from the Health Professionals Follow-Up Study), of whom only subjects with clinically manifested PAD were selected, Bertoia et al. showed that homocysteine levels were positively associated with the risk of developing PAD only in men, not in women.37 In children, elevated plasma homocysteine levels correlated significantly with increased CIMT and decreased flow-mediated dilatation, but only in young girls,38 as opposed to findings of recent adult studies. Another study enrolling adolescents with multiple risk factors for atherosclerosis proved that individuals with CIMT in the upper quartile had significantly higher mean plasma homocysteine levels than those of subjects in the lower quartile. Unfortunately, gender differences were not analysed.39

Lipoprotein (a) In the Invecchiare in Chianti (inCHIANTI) study, performed on a cohort from Tuscany, Italy, there was a strong correlation between high levels of lipoprotein (a) and lower-limb PAD in both men and women over 60 years of age.40 In the MESA study, which included 4 618 participants, significantly elevated levels of lipoprotein (a) were detected only in Hispanic Americans (men and women) with PAD.41 High circulating levels of lipoprotein (a), along with other inflammatory markers, were also associated with a reduced ankle–brachial index (ABI) and the presence of clinically significant PAD in an African-American cohort,42 confirming this is an establised risk factor for atherosclerosis, regardless of vascular teritory involved, ethnicity or gender. Its inherent procoagulant effects via its apolipoprotein (a) component, which can inhibit fibrinolysis, makes it an independent marker of acute vascular thrombotic complications.43

Interleukin-6 (IL-6) IL-6 is the main interleukin that exerts procoagulant effects. It is also involved in the inflammatory process by stimulating macrophages and contributing greatly to arterial smooth muscle cell proliferation, thus promoting atherosclerotic plaque formation.44 Two large studies, the Edinburgh Artery Study22 and the Walking and Leg Circulation (WALCS) II cohort44

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demonstrated significantly elevated IL-6 levels, along with higher levels of D-dimer, homocysteine, CRP and soluble vascular cellular adhesion molecule-1 (sVCAM-1) in PAD subjects, which were also related to adverse calf muscle characteristics.45 This suggests higher levels of inflammation may correlate with functional impairment and functional decline in PAD patients. The association between IL-6 and PAD was stronger in African-American women than in non-Hispanic whites,42 proving that in addition to gender differences, there are also ethnic dissimilarities.

Tumour necrosis factor-alpha (TNF-α) TNF-α pro-inflammatory effects range from mediating cellular activation and proliferation to inducing acute-phase responses and destructive cellular outcomes such as apoptosis or cellular necrosis.46 TNF-α is therefore a pro-angiogenic cytokine. In one study performed on 91 healthy volunteers, serum TNF-α concentrations were inversely correlated with age, but only in men; in females, no distinct age-related changes were observed.47 Circulating TNF-α was increased in PAD patients (both men and women) in several studies,47-49 with additional increases noticed after treadmill stress testing.48 Gender differences were not assessed48,49 or were not significant.50

Cellular adhesion molecules Cellular adhesion molecules (CAMs) are integral membrane proteins that mediate cell-to-cell binding. Some of them, such as the selectins and integrins, are involved in leukocyte extravasation and the inflammatory response.51 A rise in sICAM and sVCAM-1 levels was associated with the progression of PAD in some studies.52,53 In both male and female subjects included in the Edinburgh Artery Study, high initial circulating levels of ICAM were correlated with a decrease in the ABI at one-year follow up.22 Recent research has shown that elevated levels of ICAM-1 were associated with a slower walking pace and a shorter stride length [along with the rise in high-sensitivity CRP (hs-CRP) and reactive oxygen species (ROS) levels], which may suggest that chronic inflammation and oxidative stress can influence walking pace and distance in elderly PAD patients.23 McDermott et al. demonstrated that high levels of hs-CRP, IL-6, VCAM-1, ICAM-1 and homocysteine were associated with difficulties in completing the six-minute walk test (SMWT) by patients with PAD.54 In another research published by Gardner et al., African-American women with PAD had higher levels of serum ICAM-1 and leptin than their male counterparts.3 The same study found that Caucasian women had higher levels of VCAM-1 than men.3 Cellular adhesion molecules were also assessed as markers of arterial disease in children. In one paediatric study, ICAM-1 was positively related to CIMT in obese, hypertensive adolescents,55 while another study performed in healthy young children found that higher plasma levels of the chemokine CCL5, also known as RANTES (regulated on activation, normal T cell expressed and secreted) were positively correlated with arterial stiffness, but not with CIMT.56 In the same article, monocyte chemo-attractant protein 1 (MCP-1), VCAM and ICAM did not correlate with any of the studied vascular characteristics, namely CIMT,

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common carotid distensibility or Young’s elastic modulus.56 These conflicting results suggest more research is needed for a better understanding of the role of adhesion molecules in vascular ageing and remodelling.

Markers of oxidative stress Oxidative stress, a disturbance in the pro-oxidant–antioxidant balance in favour of the former, plays a major role in the development of atherosclerosis57 and PAD.58 Numerous studies have shown a rise in ROS,59,60 alongside a decrease in serum nitric oxide (NO) levels in individuals with PAD.61 NO (a vasoprotective factor) decrease is partly explained by NO removal secondary to oxidation by excess ROS.57 In comparison with controls, PAD subjects (both males and females) had increased urinary isoprostanes (a marker of oxidative stress) and NOX2 (one isoform of NADPH oxidase, a major producer of ROS) activation, contributing to reduced flow-mediated dilatation observed in these patients; these effects were reversed by administration of an antioxidant.62 High serum levels of myeloperoxidase, an enzyme involved in inflammation and oxidation,63 were associated with PAD; the association was stronger in African-Americans compared to non-Hispanic whites, and it was independent of gender.64 Another study indicated a predictive value for major adverse cardiovascular events, such as myocardial infarction, stroke or death in males or smokers with PAD.65 In the same way, elevated levels of galectin-3, a lectin involved in inflammation, oxidative stress and angiogenesis, were significantly associated with an increased risk of cardiovascular mortality in PAD subjects.66 It seems that endothelial oxidative stress is more important for the development of symptomatic PAD in African-American women, so the effect is gender and race specific. Gardner et al. found that African-American females with symptomatic PAD had significantly higher levels of both inflammatory and oxidative stress biomarkers compared to their male counterparts.3 In the same study, women also had a poorer peripheral circulation than men, especially concerning the smaller distal vessels, with a markedly reduced exercise capacity and daily activity compared to men.3

Other markers Serum beta-2 microglobulin (β2M), one of the major histocompatibility complex class I molecules, is a risk factor for increased CIMT67 and a predictor of total mortality in older adults.68 Kals et al. had shown that levels of β2M were significantly higher in patients with PAD and correlated with aortic pulse-wave velocity, a measure of arterial stiffness.69 In a nested case–control study performed in two cohorts, β2M was identified as a risk factor for developing PAD, but only in the male cohort.70 Other markers such as leptin and apolipoprotein CIII were found to be higher in women than in men diagnosed with PAD.3 In a case–control study, adiponectin was significantly lower in women developing PAD compared to healthy controls.71 Similar to adult data, paediatric observational studies had shown an inverse correlation between plasma adiponectin levels and CIMT,72 establishing it as a marker of vascular ageing. Circulating levels of the N-terminal prohormone of brain natriuretic peptide (NT-proBNP), a marker of haemodynamic

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stress, were significantly higher in male patients with PAD,73 but lower than in patients (men and women) with poorly compressible arteries (the latter being defined as having an ABI > 1.4 or an ankle blood pressure > 255 mmHg).74 Higher NT-proBNP levels were associated with lower functional capacity in individuals with PAD. In this study by Fan and collaborators, female gender was another independent predictor of lower functional capacity.75 It was also noted that elevated NT-proBNP levels were linearly related to the risk of complications in PAD subjects, including overall cardiovascular mortality, independent of gender.76 We may speculate that this might be caused by associated heart failure due to concomitant coronary artery disease in these patients, but we cannot completely rule out PAD from the pathophysiological chain. The soluble receptor for advanced glycation end-products (sRAGE) was found to be lower in patients with coronary artery disease compared to healthy controls.77 Individuals with associated PAD (82% were males) had even lower levels of sRAGE.77 sRAGE has protective effects against the harmful interaction of advanced glycation end-products (AGEs) with RAGE.78 This interaction increases the production of ROS and arterial stiffness,79 leading to accelerated atherosclerosis and an increased risk of developing symptomatic PAD. The transforming growth factor-beta (TGF-β) is another cytokine with pro-fibrotic and pro-inflammatory effects.80,81 Studies showed discordant results regarding TGF-β plasma levels in PAD patients; decreased,53 increased,80 or no significant differences82 versus controls. Gender variations were not reported53 or not statistically significant.80,82 These data could be explained by the mixed effects of TGF-β, both as a pro-inflammatory and fibrotic cytokine on the one hand, and as a major orchestrator of vascular repair on the other. Vascular endothelial growth factors (VEGFs) are essential signalling proteins and key regulators of angiogenesis.83 In a study in which women and African-Americans were well represented, VEGF-A serum levels were decreased in PAD patients compared to controls.50 The lower levels of VEGF-A in patients with PAD and claudication suggest that they had lower levels of neo-angiogenesis.50 Paradoxically, serum VEGF-A levels were increased in several studies on PAD patients.83-86 Recent studies demonstrated that there are splice variants of VEGF-A: VEGF-A165a, with pro-angiogenic activity, which was decreased in patients with clinically manifested PAD, and VGFA-A165b, with anti-angiogenic properties, which were increased.83 This might explain the discrepancies found in studies in which total VEGF-A was measured. CD163 is a scavenger receptor for the tumour necrosis factor-like weak inducer of apoptosis (TWEAK).87 TWEAK, a member of the tumour necrosis factor superfamily of structurally related cytokines, determines an increase in pro-inflammatory cytokine secretion, which is associated with the development of atherosclerosis.88 In one study, performed on white males, the ratio between plasma levels of CD163 and TWEAK was increased in patients with more severe PAD.89 The results were confirmed in another study performed on both males and females, which did not reveal any gender differences.90 Plasma thrombospondin-1 (TSP-1) level, an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions, was increased in a study that included only white male patients with PAD.91 Another study, in which 31% of the

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subjects were females and 62% African-Americans, revealed no significant differences in TSP-1 levels.92 TSP-1 is a potent inhibitor of angiogenesis by enhancing endothelial colonyforming cell (ECFC) adhesion,91 and elevated levels may restrict capillary growth in PAD patients,93 leading to deficient collateral circulation and worsening of PAD symptoms. Matrix metalloproteinases (MMPs) are a family of endopeptidases that contribute extensively to tissue remodelling by degrading extracellular matrix components.94 PAD is a manifestation of systemic atherosclerosis and MMPs have been involved in all stages of plaque development.94 It seems that MMP-9 plays a major role in the process of new blood vessel formation, its deficit compromising ischaemia-induced neovascularisation by decreasing the mobilisation and migration of circulating endothelial progenitor cells (EPC), but also by affecting vasculogenesis.95 Other results indicate that MMP-10 activity may contribute to plaque rupture and its associated complications.94 Recent case–control studies showed an association between PAD and elevated circulating levels of MMP-2,53,96 MMP-8,97 MMP-9,53,96,98 and MMP-10.96 In some studies, levels of MMPs (MMP-996 and MMP-1094) were positively correlated with the severity of PAD. These cited works included both males and females, but gender differences were not assessed. Gardner’s study demonstrated that Caucasian women had higher levels of MMP-9, along with higher VCAM-1 and lower hepatocyte growth factor (HGF) levels than Caucasian men. African-American women with clinically manifested PAD also had evidence of increased endothelial oxidative stress compared to their male counterparts.3 These findings point towards women being a more vulnerable group of PAD subjects, exibiting a more pronounced pro-inflamatory profile of circulating biomarkers than men, and thus requiring stricter lifestyle intervention and medical management.

Novel biomarkers and conventional risk factors Smoking was for decades considered to be the main risk factor for developing clinically manifested PAD, and recent data confirm its leading pathogenic role along with diabetes mellitus.12 Cigarette smoking increases oxidative stress at the level of the vascular endothelium and promotes vascular inflammation.99 In PAD patients, fibrinogen levels are higher as the disease is more extensive, but in female subjects there was a more pronounced increase with smoking status.19 Research by Rom et al. conducted on a cohort of heavy smokers showed a positive association between CRP levels and smoking history after adjustment for possible confounders.100 Among over 1 800 participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), current smokers had an array of significantly increased inflammatory markers compared to former or non-smokers, ranging from acute-phase proteins (CRP), to chemokines (C-C motif ligands), interleukins and soluble receptors such as soluble vascular endothelial growth factor receptor 3 (sVEGFR-3).101 However, these values seemed to normalise in time after smoking cessation, approximating those of never smokers after some years. No gender-specific differences were reported in any of these studies. This proves that smoking effects on vascular inflammation are reversible with cessation, and that its consequences are equally harmful in both genders.

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Diabetes mellitus (DM), the other major conventional risk factor for PAD, has been shown in multiple research studies to induce a pro-inflammatory state that leads to accelerated atherosclerosis. The proposed mechanism is that of increased expression of adhesion molecules, leading to inflammatory cells crossing the endothelium and forming foam cells, thus initiating and perpetuating the vicious circle of atherosclerotic plaque formation.102 A study on patients with diabetic foot showed markedly elevated levels of IL-6 and resistin, coupled with reduced adiponectin plasma levels,103 suggesting an important antiinflammatory and anti-atherosclerotic role for this glucoseregulating protein. Tuttle et al. reported higher levels of circulating IL-6 and TNF-a in diabetic women, irrespective of clinically manifested cardiovascular disease.104 Similar results were found in a study on Indian subjects with type 2 DM (which had higher plasma levels of hs-CRP and lower levels of adiponectin compared to healthy controls),105 confirming the pro-inflammatory state that diabetes mellitus induces, one that transcends gender or age. Dyslipidaemia has also been related to increased systemic inflammation in several trials. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study showed that in healthy women with high levels of low-density lipoprotein cholesterol (LDL-C) (> 130 mg/dl; 3.37 mmol/l) and a value of hs-CRP above 2 mg/ dl, the overall risk of developing adverse cardiovascular events, even PAD related, increased greatly.106 Elevated serum levels of CRP in women have been related to the presence of diabetes, the metabolic syndrome and collagen vascular disease,107 all of these conditions being known for their predisposition to accelerated atherosclerosis. Multiple other associations between lipid components and inflammatory status have been revealed. For example, in men with established cardiovascular disease, including PAD, a clear association between lipoprotein (a), LDL-C, arterial hypertension and elevated fibrinogen levels has been found,108 suggesting that the novel biomarkers of atherosclerosis and inflammation are strongly related to traditional risk factors for the disease in a pathophysiological continuum that reveals some gender-specific peculiarities.

review and analysis. Lancet 2013; 382: 1329–1340. doi: 10.1016/S01406736(13)61249-0. 2.

Although many of the above biomarkers represent a hallmark of atherogenesis in both genders [lipoprotein (a), TNF-α, sRAGE, VEGF, CD163/TWEAK, thrombospondin-1, galectin-3], some tend to correlate positively and strongly with the presence of PAD in females (CRP, IL-6, ICAM-1, VCAM-1, ROS, leptin, apolipoprotein CIII, adiponectin, MMP-9), while others, such as homocysteine, seem to be associated with the disease only in male individuals. Acknowledging these gender differences could be useful for the early identification and optimal management of patients with PAD.

Allison MA, Ho E, Denenberg JO, Langer RD, Newman AB, Fabsitz RR, et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med 2007; 32: 328–333. doi: 10.1016/j. amepre.2006.12.010.

Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra AI, Ungvari Z, et al. Gender and racial differences in endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease. J Vasc Surg 2015; 61: 1249–1257. doi: 10.1016/j. jvs.2014.02.045.

Kullo IJ, Bailey KR, Kardia SL, Mosley TH, Jr., Boerwinkle E, Turner ST. Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study. Vasc Med 2003; 8: 237–242. doi: 10.1191/1358863x03vm511oa.

Allison MA, Criqui MH, McClelland RL, Scott JM, McDermott MM, Liu K, et al. The effect of novel cardiovascular risk factors on the ethnicspecific odds for peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006; 48: 1190–1197. doi: 10.1016/j.jacc.2006.05.049.

Fowkes FG, Aboyans V, Fowkes FJ, McDermott MM, Sampson UK, Criqui MH. Peripheral artery disease: epidemiology and global perspectives. Nat Rev Cardiol 2017; 14: 156–170. doi: 10.1038/nrcardio.2016.179.

Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113: e463–654. doi: 10.1161/CIRCULATIONAHA.106.174526.

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45(Suppl S): S5–67. doi: 10.1016/j.jvs.2006.12.037.

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PASCAR Report Development of the certificate course in the management of hypertension in Africa (CCMH-Africa): proceedings of the first continental faculty meeting, Nairobi, Kenya, 25–26 February 2018 Anastase Dzudie, Dike Ojji, Albertino Damasceno, Mahmoud U Sani, Euloge Kramoh, Jean Baptiste Anzouan Kacou, Benedict Anisiuba, Elijah Ogola, Mohamed Awad, George Nel, Harun Otieno, Ali Ibrahim Toure, Abdoul Kane, Andre Pascal Kengne, Calypse Ngwasiri, Hamadou Ba, Samuel Kingue, Bruno Mipinda, Bertrand Ellenga Mbolla, Amha Weldehana, Fred Bukachi, Bernard Gitura, Brice Kitio, Brian Rayner, Aletta E Shutte, Ana Olga Mocumbi, Bongani Mayosi, Arun Jose, Bhalla Sandeep, Michael Weber, Christian Delles, Francesco Cappuccio, Habib Gamra, Dorairaj Prabhakaran, Neil Poulter, Saad Subhani, on behalf of the PASCAR task force on hypertension

Department of Physiology, Yaoundé Faculty of Medicine and Biomedical Sciences, Yaoundé, Cameroon

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

Centre Hospitalier et Universitaire de Libreville, Libreville, Gabon

Anastase Dzudie, MD, PhD, FESC, aitdzudie@yahoo.com Hamadou Ba, Samuel Kingue

Benedict Anisiuba, MD

Department of Clinical Medicine and Therapeutics, University of Nairobi, Nairobi, Kenya

Centre Hospitalier et Universitaire de Brazaville, Brazaville, Congo

Clinical Research Education Networking and Consultancy, and Cardiology Unit, Douala General Hospital, Douala, Cameroon

Elijah Ogola, MD

Anastase Dzudie, MD, PhD, FESC Andre Pascal Kengne, MD, PhD Calypse Ngwasiri, MD

Hatter Institute for Cardiovascular Research, University of Cape Town, South Africa Anastase Dzudie, MD, PhD, FESC

Department of Medicine, Faculty of Health Sciences, University of Abuja; Cardiology Unit, Department of Medicine, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria Dike Ojji, MD, PhD

Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique Albertino Damasceno, MD, PhD Ana Olga Mocumbi, MD, PhD, FESC

Department of Medicine, Bayero University and Aminu Kano Teaching Hospital, Kano, Nigeria Mahmoud Sani, MD, PhD, FWACP, FACC

Institut cardiologique d’Abidjan, Abidjan, Cote d’Ivoire Euloge Kramoh, MD Jean Baptiste Anzouan Kacou, MD

Division of Cardiology, University of Khartoum, Khartoum, Sudan Mohamed Awad, MD Saad Subhani, MD

Pan-African Society of Cardiology (PASCAR), Cape Town, South Africa George Nel

Section of Cardiology, Department of Medicine, Aga Khan University Hospital, Nairobi, Kenya Harun Otieno, MD

Cardiovascular Department, Faculty of Medical Sciences, University Teaching Hospital, Niamey, Niger

Bruno Mipinda

Bertrand Ellenga Mbolla

Guidelines Advisory Network for Africa Brice Kitio, MBA

Public Health Foundation of India, New Delhi, India Arun Jose, MD Bhalla Sandeep, MD Dorairaj Prabhakaran, MD, PhD

Division of Cardiovascular Medicine, State University of New York, Downstate Medical Center, New York, USA Michael Weber, MD

Mental Health and Wellbeing, University of Warwick, Coventry, UK Francesco Cappuccio, MD

Ali Ibrahim Toure, MD

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland

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

Christian Delles, MD

International Centre for Circulatory Health, Imperial College, London, UK

Abdoul Kane, MD

Neil Poulter, MD, PhD

Medical Research Council, Cape Town, South Africa

University of Cape Town, Cape Town, South Africa

Andre Pascal Kengne, MD, PhD

Addis Ababa University Medical School, Addis Ababa, Ethiopia

Brian Rayner, MD, PhD Bongani Mayosi, MD, PhD

Ministry of Public Health, Kenya

Hypertension in Africa Research Team (HART); MRC Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa

Fred Bukachi, MD

Aletta E Schutte, PhD

Cardiorenal Centre, Nairobi, Kenya

African Heart Network

Bernard Gitura, MD

Habib Gamra, MD

Amha Weldehana, MD

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Abstract Background: In response to the call by the World Health Organisation to reduce premature deaths from non-communicable diseases by 25% by the year 2025 (25×25), the Pan-African Society of Cardiology (PASCAR), in partnership with several organisations, including the World Heart Federation, have developed an urgent 10-point action plan to improve detection, treatment and control of hypertension in Africa. Priority six of this action plan is to promote a task-shifting/task-sharing approach in the management of hypertension. Aim: This capacity-building initiative aims to enhance the knowledge, skills and core competences of primary healthcare physicians in the management of hypertension and related complications. Methods: In a collaborative approach with the International Society of Hypertension, the British and Irish Hypertension Society, the Public Health Foundation of India and the Centre for Chronic Disease Control, the PASCAR hypertension taskforce held a continental faculty meeting in Kenya on 25 and 26 February 2018 to review and discuss a process of effective contextualisation and implementation of the Indian hypertension management course on the African continent. Results: A tailored African course in terms of evidence-based learning, up-to-date curriculum and on-the-job training was developed with a robust monitoring and evaluation strategy. The course will be offered on a modular basis with a judicious mix of case studies, group discussions and contact sessions, with great flexibility to accommodate participants’ queries. Conclusions: Hypertension affects millions of people in Africa and if left untreated is a major cause of heart disease, kidney disease and stroke. CCMH-Africa will train in the next 10 years, 25 000 certified general physicians and 50 000 nurses, capable of adequately managing uncomplicated hypertension, thereby freeing the few available specialists to focus on severe or complicated cases. Keywords: hypertension, roadmap, certified course, primary care physicians, Africa Cardiovasc J Afr 2018; 29: 331–334

www.cvja.co.za

DOI: 10.5830/CVJA-2018-055

Hypertension is a rapidly growing epidemic in Africa. This increasingly high prevalence is coupled with very poor awareness, and low treatment and control rates, putting affected persons at highest risk for stroke, heart and renal diseases.1-3 African Union member states described hypertension as the continent’s greatest health challenge after HIV/AIDS. An urgency was recognised to develop and share best practices, including affordable and effective community-based programmes to detect, treat and control hypertension. As the leading continental association, the Pan-African Society of Cardiology (PASCAR), supported by the World Heart Federation roadmap to Africa and all continental hypertension and cardiac societies, published the 10-point action plan to significantly improve control of hypertension, in an attempt to reduce heart disease and stroke on the continent by the year 2025.4 Target six of this action plan aims to shift the paradigm

Group photo. Front left to right: Arun Jose (PHFI), Mahmoud Sani (PASCAR), Euloge Kramoh (PASCAR), Dike Ojji (PASCAR), Fred Burachi (Kenyan Ministry of Public Health), Benedick Anisiuba (PASCAR), Habib Gamra (African Heart Network), Amha Weldehana (Ethiopian Cardiac Society). Middle left to right: George Nel (PASCAR), Francesco Cappuccio (BISH), Saad Subhani (PASCAR), Bhalla Sandeep (PHFI), Christian Delles (BISH), Bernard Gitura (Kenyan Cardiac Society), Calypse Ngwasiri (CRENC). Back left to right: Ibrahim Toure (PASCAR), Awad Mohamed (PASCAR), Elijah Ogola (PASCAR), Neil Poulter (ISH), Albertino Damaceno (PASCAR), Anastase Dzudie (PASCAR), Andre-Pascal Kengne (PASCAR), Brice Kitio (GANEO).

in hypertension management via promoting a task-shifting/tasksharing approach, with adequate training of non-specialists. The certificate course in the management of hypertension will be the educational cornerstone and training guide needed to ultimately control hypertension in Africa. It aims to enhance the knowledge, skills and core competencies of primary care physicians in the management of hypertension and related complications. This course is a joint certification programme to be issued by PASCAR, in collaboration with the Public Health Foundation of India (PHFI), British and Irish Hypertension Society (BIHS), International Society of Hypertension (ISH) and Centre for Chronic Disease Control (CCDC), supported by local governments and academics. This unique capacity-building initiative will provide exceptional education and address several issues that arise in the management of hypertension, such as the very low doctor-to-patient ratios, concentration of the few specialists in urban areas, and inadequate training in the management of hypertension at graduate level. It is in this regard that the continental faculty meeting was held at Nairobi, Kenya, on 25 and 26 February 2018. The event witnessed the gathering of six esteemed international experts and 20 representatives from PASCAR, PHFI, BIHS, the African Heart Network (AHN) and the Kenyan Ministry of Health. These experts reviewed the course in terms of evidence-based learning with an up-to-date curriculum contextualised to the African setting, aimed at training 50 000 nurses and 25 000 certified general physicians who would adequately manage uncomplicated hypertension, thereby freeing the few available specialists to focus on severe or complicated cases.

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Welcome address and review of draft modules Prof Elijah Ogola (Kenya), the chairperson for the meeting, welcomed the audience to Nairobi and congratulated the PHFI for their marvellous work and relentless effort to share their ideas with other partners. Dr Saad Subhani (Sudan), president of PASCAR, welcomed the delegates and thanked all the stakeholders for their support of and commitment to this inaugural meeting. In his opening address, he gave a brief overview of PASCAR (founded by Prof Ayodele Falase), explaining it as an organisation of physicians and surgeons across Africa, involved in the prevention and treatment of cardiovascular diseases. He further spoke briefly on the organogram of PASCAR, its governing council task forces, with representation from key role players in cardiovascular sub-specialties. Dr Subahi’s address was followed by a short speech by Prof Anastase Dzudie (Cameroon), chair of the hypertension task force, who set the pace for the meeting. He gave a brief overview of the burden of hypertension in Africa and the roadmap to achieving 25% control by 2025. In his remarks, he highlighted target six of the 10-point action plan, identified by the PASCAR hypertension task force, which includes a shifting of the paradigm of hypertension management by promoting a task-sharing approach, and the certificate course in the management of hypertension in Africa (CCMH-Africa) will be one such initiative. He informed the gathering about the vast coverage of this course, with enormous success in India, and explained how a similar approach will be customised to the African context. In the African context, such a project has the potential to build on the existing health systems and strengthen a direct referral linkage for the management of hypertension between nurses, general practitioners and specialists. Prof Neil Poulter, president of the ISH, expressed how proud they were to be part of the collaboration between PHFI and PASCAR in extending the reach of a certified course in the management of hypertension from India to the African continent. He also illustrated how ISH is committed to promoting/encouraging the advancement of scientific research and its application for the prevention and management of cardiovascular diseases around the world. His two key aspirations are to support younger members (organisation members) and reach out to as many countries globally as possible. He highlighted the May Measurement Month survey as an example of such aspiration. Prof Francesco Cappuccio, president of the BIHS, presented opening remarks on behalf of his organisation, highlighting briefly the partnership between BIHS and CCMH, and the journey in making this initiative possible. He warmly welcomed this new initiative, which would provide access to valuable specialist training to many doctors and health professionals in Africa, sorely needed on a continent where the double burden of disease (communicable and non-communicable) is projected to cause high mortality and morbidity rates and long-term disabilities. Dr Sandeep Bhalla (India), programme director, Centre for Control of Chronic Conditions and Injuries (CCCI), gave the programme overview of CCMH-Africa. He mentioned that the journey of this capacity-building initiative was started by the PHFI in the year 2015 and how the programme had received

an overwhelming response from its participants. He also graded the compliance rate a success in India and stated how several government institutions are adopting the programme for the training of their medical officers. Salient features of the course were outlined and the audience was briefed on the various models. In his second presentation, he gave a rundown of the course implementation, and proposed methods to facilitate this task. Finally, Dr Arun Jose (India), programme manager CCMHIndia, apprised the gathering about the CCMH-Africa course design protocol and group working guidelines, followed by the release of the course brochure.

Overall discussion and way forward The group recognised the urgent need to develop a course that will empower and improve the core competencies of primary care physicians in the management of hypertension. To accomplish the objectives of the meeting, four group experts were formed to review the modules, with one rapporteur from each group to facilitate the discussion and record notes/comments. Each group of experts then reviewed the designated module and suggested changes in that particular module. In the final session, one representative from each group presented the modules they had reviewed and their suggested changes to the rest of the audience for their feedback. The session witnessed intense discussions, and general consensus was achieved on each topic. After the in-depth brainstorming sessions, the curriculum was reviewed meticulously and the active participation of the experts was noteworthy.

Roll-out plan for CCMH-Africa

African key opinion leaders meeting

PASCAR regional high impact [train the trainer (T3)] × 3 trainers per country aligned per region

French Africa

English Africa

Arabic Africa

Portuguese Africa

Local language adaptation

Country high-impact course [T3] Train the trainer at “regional and national congresses”

In country: full prescriber certificate courses – 10 contacts over 10 months [national trainers train prescriber (GP)]

Full non-prescriber course – 5 contact over 5 months [GP train referral non-prescribers]

Fig. 1. Roll-out plan for CCMH-Africa (ideal model).

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The course will be valid, reproducible, clear, simple and concise enough to be easily adopted by various African countries and monitored regularly. For the roll-out plan of the course (Fig. 1), the consensus was that different language versions of the course will be produced and implementation will be done by PASCAR’s organisational structure through the various national cardiac societies. There was a consensus that under PASCAR leadership, funds should be raised both at international and national levels to support the running of the course. The following key stakeholders will be involved in the developmental process: PASCAR, PHFI, BIHS, ISH, CCDC, African Union and WHO-AFRO. Finally the group adopted a timeline of activities for the finalisation and implementation of the suggestions relevant to the African context and a regional faculty meeting was planned for two month’s time.

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Ideally, the total duration of the course is 10 months with a once-a-month contact session scheduled on a designated weekend at regional centres. The course will be offered on a modular basis with a judicious mix of case studies, group discussions and contact sessions, with great flexibility to accommodate participants’ queries. The course content will be delivered by trained faculty, all of whom are eminent cardiologists/medicine specialists.

Eligibility criteria • MB BS (or country-specific equivalent) with a minimum of three years of clinical experience. • MD/DNB (medicine/internal medicine/family medicine) or country-specific equivalent.

Conclusion

Certification criteria

The curriculum of the Indian CCMH course was customised to a tailored African version that met the needs of the urgent paradigm shift in hypertension management in Africa. The key next steps are implementation of the course in all African countries, with translated versions into French, Portuguese, Arabic and local languages. National cardiac societies, all professional and non-professional organisations (including the African Heart Network and the International Forum for Hypertension Prevention and Control in Africa) and various stakeholders (including the African Union, ministries of health and the WHO) will be called upon to support this course that has been designed to significantly improve the management of hypertension in Africa.

The criteria for successful completion of the programme are as follows: • Participation in at least nine out of 10 monthly contact sessions (including the pre-test of each module). • Completion of assigned course work. • Passing of the final written examination in the form of 50 multiple-choice questions, with a minimum pass mark of 70%.

African CCMH in brief The primary objective of this capacity-building initiative is to enhance the knowledge, skills and core competencies of primary care physicians in the management of hypertension and related complications. In addition, there are three secondary objectives: • to develop/update a standard teaching protocol and module for evidence-based learning in hypertension • to build a network of primary care physicians and specialists in the field of hypertension • to regularly update the primary care physicians with the latest advancements in the field of hypertension.

Contact details Mr George Nel PASCAR Executive, CCMH (Africa) Cell: +27834585954 e-mail: info@pascar.org Website: www.pascar.org Skype: george.nel68

References 1.

Atakite F, Erqou S, Kaptoge S, Taye B, Echouffo-Tcheugui JB, Kegne AP. Burden of undiagnosed hypertension in sub-Saharan Africa: A systematic review and meta-analysis. Hypertension 2015; 65(2): 291–298.

Adeloye D, Basquill C. Estimating the prevalence and awareness rates of hypertension in Africa. A systematic analysis. Schnabel RB (ed). PLoS One 2014; 9(8): e104300.

Dzudie A, Kegne AP, Muna WFT, Ba H, Menanga A, kouam Kouam C, et al. Prevalence, awareness, treatment and control of hypertension in a self-selected sub-Saharan Africa urban population; a cross-sectional

Course design and duration CCMH-Africa is a unique course in terms of evidence-based learning, an up-to-date curriculum with inputs from international experts and regional faculty, on-the-job training, and robust monitoring and supervision strategy.

study. Br Med J Open 2012; 2(4): 1–10. 4.

Dzudie A, Rayner B, Ojji D, Schutte AE, Twagirumukiza M, Damasceno A, et al., on behalf of the PASCAR task force on hypertension Roadmap to achieve 25% hypertension control in Africa by 2025. Cardiovasc J Afr 2017; 28(4): 261–72.

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