CVJA Volume 30 Issue 1 by Clinics Cardive Publishing

JANUARY/FEBRUARY 2019 VOL 30 NO 1

Need endurance when treating CVS disease?

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Right-sided hearts in South Africa • Pulmonary hypertension and heart failure in Lagos • Management of LDL-C levels in South Africa: ICLPS • The Ellisras Longitudinal Study 2017 • Acute coronary syndrome in sub-Saharan Africa

the endurance ACE-inhibitor For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za PEARINDA 4, 8. Each tablet contains 4, 8 mg perindopril tert-butylamine respectively. S3 A41/7.1.3/0649, 0650. NAM NS2 10/7.1.3/0476, 0477. For full prescribing information, refer to the professional information approved by SAHPRA, April 2009. PEARINDA PLUS 4. Each tablet contains 4 mg perindopril tert-butylamine and 1,25 mg indapamide. S3 A41/7.1.3/0633. NAM NS2 10/7.1.3/0611. For full prescribing information, refer to the professional information approved by SAHPRA, April 2010. 1) The EUROPA study Investigators. “Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study)”. The Lancet 2003;362:782-788. 2) The PREAMI study Investigators. “Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodelling and clinical outcome. Results of the randomized perindopril and remodelling in elderly with acute myocardial infarction (PREAMI) study”. Arch Intern Med 2006;166:659-666. 3) PROGRESS Collaborative Group. “Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack”. The Lancet 2001;358:1033-41. 4) Guerin AP, et al. “Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure”. Circulation 2001;103;987-992. PAH515/06/2018.

• Surrogate measures of sympathetic activity: SABPA • Cardiovascular risk factors with HIV in rural Kenya

Cardiovascular Journal of Africa . Vol 30, No 1, January/February 2019

Perindopril has proven outcomes in: • Coronary Artery Disease1 • Acute Myocardial Infarction2 • Stroke3 • End-stage Renal Failure4

• Diagnostic algorithm for pulmonary hypertension

Published online: • Pulmonary thromboendarterectomy in a thrombophilia patient

Africa STEMI Live! 2019 9

April 25 - 27, 2019 The Radisson Blu Hotel, Nairobi, Kenya

CALL FOR ABSTRACTS AND CASES Africa STEMI Live!2019- submit your clinical case or research abstract for publication in the Cardiovascular Journal of Africa! Submit now and become a speaker at Africa STEMI Live! 2019. All abstracts accepted for the conference will be fast-track published in the April edition AfricaSTEMI supplement issue of the Cardiovascular Journal of Africa. CATEGORIES FOR SUBMISSION Original research in the following fields will be considered for presentation and publication at the meeting. 1. Acute Coronary Syndromes and Myocardial Infarction 2. Systems of care in STEMI 3. Heart failure 4. Prevention (Hypertension and Diabetes) 5. Case reports and case series 6. Resuscitation

Kindly refer to the website www.africastemi.com for submission guidelines Stand a chance to win a complimentary registration to Africa STEMI Live! 2019.

IMPORTANT INFORMATION

WHEN ALL THE PARTS FIT...

PERFECTLY. EFFICACY

All abstracts must be submitted via the Cardiovascular journal of Africa submission portal http://cvja.co.za/abstract-submissions/ Case submission deadline - 11.59pm March 1st 2019 (SA time)

SAFETY 2

PROVEN OUTCOMES 3

For additional information Heart & Life Medical Conferences Tel: +254 721 575 483 Address: P.O. Box 34172, Oval Building, Nairobi Kenya. Email: heartandlifeconferences@gmail.com

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za AMLOC 5, 10 mg. Each tablet contains amlodipine maleate equivalent to 5, 10 mg amlodipine respectively. S3 A38/7.1/0183, 0147. NAM NS2 06/7.1/0011, 0012. BOT S2 BOT 0801198, 0801199. For full prescribing information, refer to the professional information approved by SAHPRA, 25 November 2011. 1) IMS MAT UNITS March 2018. 2) Dahlof B, Sever PS, Poulter NR, et al. for the Ascot investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906. 3) Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: A randomised controlled trial. JAMA 2004;292:2217-2226. ACG528/07/2018.

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

Vol 30, No 1, JANUARY/FEBRUARY 2019

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EDITORIAL 3

Right-sided hearts C Greig • DG Buys • SC Brown

A retrospective review of right-sided hearts at a South African tertiary hospital N Beringer • A Cilliers

Clinical and echocardiographic correlates of pulmonary hypertension among heart failure patients in Lagos, south-western Nigeria OA Kushimo • AC Mbakwem • JNA Ajuluchukwu • CE Amadi

Management of low-density lipoprotein cholesterol levels in South Africa: the International ChoLesterol management Practice Study (ICLPS) DJ Blom • F Raal • A Amod • P Naidoo • Y-y (E) Lai • for the ICLPS SA study group

Ellisras Longitudinal Study 2017: The relationship between waist circumference, waist-to-hip ratio, skinfolds and blood pressure among young adults in Ellisras, South Africa (ELS 14) RB Sebati • KD Monyeki • MS Monyeki • B Motloutsi • AL Toriola • MJL Monyeki

Outcomes in patients with acute coronary syndrome in a referral hospital in sub-Saharan Africa MH Varwani • M Jeilan • M Ngunga • A Barasa

Aldosterone and renin in relation to surrogate measures of sympathetic activity: the SABPA study LF Gafane-Matemane • JM van Rooyen • R Schutte • AE Schutte

The value of community outreach for a University: a synthesis of trends in higher education. The case of the University of Limpopo (ELS 45) H Siweya • KD Monyeki

CARDIOVASCULAR TOPICS

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

EDITORS

SUBJECT EDITORS

EDITORIAL BOARD

Editor-in-Chief (South Africa) PROF PAT COMMERFORD

Nuclear Medicine and Imaging DR MM SATHEKGE

PROF PA BRINK Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

DR MT MPE Cardiomyopathy

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 DP NAIDOO PROF MR ESSOP Haemodynamics, Heart Failure Echocardiography & Valvular Heart Disease PROF B RAYNER Hypertension/Society DR OB FAMILONI Clinical Cardiology PROF MM SATHEKGE Nuclear Medicine/Society DR V GRIGOROV Invasive Cardiology & Heart PROF YK SEEDAT Failure Diabetes & Hypertension PROF J KER (SEN) PROF H DU T THERON Hypertension, Cardiomyopathy, Invasive Cardiology Cardiovascular Physiology DR J LAWRENSON Paediatric Heart Disease

INTERNATIONAL ADVISORY BOARD PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery) PROF PETER SCHWARTZ Italy (Dysrhythmias) PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

CONTENTS Vol 30, No 1, JANUARY/FEBRUARY 2019

Intracoronary or intravenous abciximab after aspiration thrombectomy in patients with STEMI undergoing primary percutaneous coronary intervention A Bedjaoui • K Allal • MS Lounes • CE Belhadi • A Mekarnia • S Sediki • M Kara • A Azaza • J-J Monsuez • S Benkhedda

Cardiovascular risk factors among people living with HIV in rural Kenya: a clinic-based study K Juma • R Nyabera • S Mbugua • G Odinya • M Ngunga • D Zakus • G Yonga

Long-segment patchplasty of diffuse left anterior descending artery disease on the beating heart E Kaya • O Isik

A diagnostic algorithm for pulmonary hypertension due to left heart disease in resource-limited settings: can busy clinicians adopt a simple, practical approach? A Dzudie • AP Kengne • K Lamont • BS Dzekem • LN Aminde • MH Abanda • F Thienemann • K Sliwa

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

Delayed left ventricular pseudo-aneurysm after post-infarction repair of ventricular septal defect Y-S Song • S-H Seol • S-H Kim • D-K Kim • K-H Kim • D-I Kim • H-J Jun

Pulmonary thromboendarterectomy in a combined thrombophilia patient H Akbayrak • H Tekumit

REVIEW ARTICLE

CASE REPORTS

FINANCIAL & PRODUCTION CO-ORDINATOR ELSABÉ BURMEISTER Tel: 021 976 8129 Fax: 086 664 4202 Cell: 082 775 6808 e-mail: elsabe@clinicscardive.com

PRODUCTION EDITOR

SHAUNA GERMISHUIZEN Tel: 021 785 7178 Cell: 083 460 8535 e-mail: shauna@clinicscardive.com

CONTENT MANAGER

MICHAEL MEADON (Design Connection) Tel: 021 976 8129 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

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.

All submissions to CVJA are to be made online via www.cvja.co.za

Subscriptions for 6 issues:

Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances.

your postal address, e-mail

Postal address: PO Box 1013, Durbanville, RSA, 7551 Tel: 021 976 8129 Fax: 0866 644 202 Int.: +27 21 976 8129

To subscribe to the journal or change elsabe@clinicscardive.com South Africa: R490 (incl VAT) Overseas: $135 Online subscription: R300 The views and opinions expressed in the articles and reviews published are those

LAYOUT: Martingraphix

e-mail: info@clinicscardive.com

PRINTER: Tandym Print/Castle Graphics

Electronic abstracts available on Pubmed

reflect those of the editors of the Journal

Audited circulation

or its sponsors. In all clinical instances,

ONLINE PUBLISHING & CODING SERVICES: Design Connection & Active-XML.com

Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact elsabe@clinicscardive.com

of the authors and do not necessarily

medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Editorial Right-sided hearts C Greig, DG Buys, SC Brown The discovery of a right-sided heart (RSH) can result in a very simple to an extremely complex work-up that may require multiple investigations and interventions. As associated lesions are very common and sometimes multifaceted, it is essential for any clinician to recognise this and target investigations towards a comprehensive diagnosis. This is very important as the ultimate prognosis will depend on the complexity of the cardiac lesion and associated abnormalities.1,2 The outcome may range from incidental RSH as the only finding, to early morbidity and mortality in more complex cases. For these reasons, early identification of this condition is important. The incidence of RSH is reported as low, ranging from 0.4 to 0.8 per 10 000 pregnancies. The prevalence of true dextrocardia is described as 1/12 000 pregnancies.1,3,4 Common to most statistics in Africa, the reported incidence of RSH is lacking. As RSH is relatively uncommon, understanding the possible complexity and incidence in Africa remains important. The classification of RSH may be puzzling due to multiple conflicting views and terminologies. The terminology used includes: dextrocardia, dextroversion, dextroposistion and mirror-image dextrocardia. Since the early 1960s there have been many reviews and updates to the different classifications. Simplifying the approach and describing structures as they are found may avoid these difficulties. The most simple and logical way to classify RSH would be to make use of the sequential segmental approach, which includes cardiac position within the thorax, abnormalities of atrial and visceral situs, and associated cardiac abnormalities (ACA).2,3 We suggest a logical approach to patients with RSH, starting with confirmation of the cardiac malposition and then proceeding to rule out any extra-cardiac causes for this malposition, such as hypoplastic/collapsed lung, large pleural effusion and intra-thoracic mass. The next step will be to establish atrial and visceral situs, caval position and connections. Once atrial situs is determined, this should be followed by an assessment of atrioventricular (AV) connections and AV valve morphology, including commitment and chordal insertion. This follows ventricular situs and morphology, and their relationship with the great arteries as well as their extra-cardiac course (including aortic arch location, branching pattern and other arch abnormalities). Cardiac position is divided into levocardia (left sided), mesocardia (midline) and dextrocardia (right sided) irrespective Department of Paediatric Cardiology, University of the Free State, Bloemfontein, South Africa C Greig, MMed (Paed), Cert cardiology DG Buys, MMed, Cert cardiology, DCH (SA), buysdg@ufs.ac.za SC Brown, DMed, FCPaed, DCH

of the base–apex orientation. When evaluating patients with cardiac malposition, it is important that the sonographer maintains left–right conventions and not be tempted to make the images look familiar.3 RSH can then be subdivided into: • dextroposition: base–apex orientation to the left and caused by extra-cardiac processes • dextroversion: atrial situs solitus and ventricular inversion • true dextrocardia: base–apex orientation to the right and caused by intrinsic defect of the normal lateralisation process. The relationship between the cardiac position and situs is important to establish. Situs is primarily determined by the atria. Further investigation into the visceral situs (tracheobronchial tree and abdominal organs) is also necessary.3 This is usually most important in cases of true dextrocardia. Situs is classified as: • situs solitus: morphological right atrium to the right of morphological left atrium • situs inversus: mirror image of situs solitus and most common in cases of true dextrocardia; both atrial and visceral involvement is known as situs inversus totalis • situs ambiguous: difficult to accurately determine situs. Situs ambiguous has a very low prevalence (1/20 000 pregnancies) and is usually associated with complex cardiac anatomy and requires further investigation into the heterotaxy syndromes. Heterotaxia is also referred to as isomerism of the atrial appendages and is defined as abnormal arrangement of the abdominal and thoracic organs, caused by disruption of the left–right axis orientation during early embryonic development. Heterotaxia syndromes can be associated with considerable morbidity and mortality.1,3 Isomerism is defined as: • left isomerism: both atria morphologically left, multiple spleens, midline liver and two-lobed lungs • right isomerism: both atria morphologically right, absent spleen, midline liver and three-lobed lungs. In all instances, associated cardiac abnormalities should be excluded. These are most commonly found in true dextrocardia with situs solitus and in all cases of situs ambiguous. Associated syndromes to consider with RSH include: CHARGE (coloboma, heart defects, choanal atresia, growth retardation, genital hypoplasia and ear abnormalities), and scimitar and Kartagener syndromes. Scimitar syndrome includes the combination of dextroposition, hypoplastic right pulmonary artery, anomalous pulmonary venous drainage of the right pulmonary veins and sub-diaphragmatic collaterals from the aorta to the right lung. Kartagener syndrome comprises a triad of sinusitis, situs inversus and bronchiectasis.3 The more complex the ACAs and visceral abnormalities, the more likely the patient will require percutaneous and/or surgical intervention.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

The article by Beringer and Celliers in this edition (page 5) highlights the rarity of RSH but also the importance of an early diagnosis to ensure optimal planning and good long-term outcomes.5 Their local experience correlates with international data. Mortality rate, as expected, increased with the complexity of the cardiac and associated lesions. As noted in the article, it is important to do a complete work-up, including chest roentgenography, echocardiography, electrocardiography, cardiac catheterisation and foetal ultrasonography, and to have a high index of suspicion of associated lesions and syndromes (e.g. Kartagener and scimitar) to determine the prognosis and treatment options. An accurate diagnosis is essential for surgical planning and possible correction.

AFRICA

References 1.

Bohun CM, Potts JE, Casey BM, Sandor GS. A population-based study of cardiac malformations and outcomes associated with dextrocardia. Am J Cardiol 2007; 100 (2): 305–309.

Calcaterra G, Anderson RH, Lau KL, Shinebourne EA. Dextrocardia – value of segmental analysis in its categorization. Br Med J 1979; 42: 497–507.

Maldjiian PD, Saric M. Approach to dextrocardia in adults: Review. Am J Roentgen 2007; 188: S39–S49.

Offen S, Jackson D, Caniffe C, Choudhary P, Celermajer DS. Dextrocadia in adults with congenital heart disease. Heart Lung Circ 2015; 25: 352–357.

Beringer N, Cilliers A. A retrospective review of right-sided hearts at a South African tertiary hospital. Cardiovasc J Afr 2019; 30: 4–7.

Women under-treated for heart attack die at double the rate of men A study of 2 898 patients (2 183 men, 715 women) reveals that six months after hospital discharge, death rates and serious adverse cardiovascular events in women presenting with ST-elevation myocardial infarction (STEMI) in the past decade were more than double the rates seen in men. Gender differences in the management and outcomes of patients with acute coronary syndromes such as STEMI have been reported in the medical literature, but most studies fail to adjust for ‘confounding’ factors that can affect the accuracy of findings. This new study, authored by leading cardiac specialists and researchers from across Australia, offers robust insights into this life-threatening condition by adjusting for factors that could affect treatment and health outcomes. ‘We focused on patients with STEMI because the clinical presentation and diagnosis of this condition is fairly consistent, and patients should receive a standardised management plan,’ said the University of Sydney’s Professor Clara Chow, who is a cardiologist at Westmead Hospital, the study’s senior author. ‘The reasons for the under-treatment and management of women compared to men in Australian hospitals aren’t clear. It might be due to poor awareness that women with STEMI are generally at higher risk, or by a preference for subjectively assessing risk rather than applying more reliable, objective risk prediction tools. Whatever the cause, these differences aren’t justified. We need to do more research to discover why women suffering serious heart attacks are being underinvestigated by health services and urgently identify ways to redress the disparity in treatment and health outcomes.’ Professor David Brieger, co-author of the study and leader of the CONCORDANCE (Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events) registry from which the findings were extracted, agrees: ‘While we have long recognised that older patients and those with other complicating illnesses are less likely to receive evidence-based treatment, this study will

prompt us to refocus our attention on women with STEMI.’ A STEMI (heart attack) happens when a fatty deposit on an arterial wall causes a sudden and complete blockage of blood to the heart, starving it of oxygen and causing damage to the heart muscle. A STEMI diagnosis is typically made initially by administering an ECG that reveals a tell-tale ECG signature. These heart attacks can cause sudden death due to ventricular fibrillation (a serious heart rhythm disturbance) or acute heart failure (when the heart can’t pump enough blood to properly supply the body). STEMI represents about 20% of all heart attack presentations. In 2016, an average of 22 Australians died from a heart attack each day. Researchers collected data from 41 hospitals across all Australian states and territories between February 2009 and May 2016. Twenty-eight hospitals (68%) are in metropolitan regions and 13 are in rural locations. Data was sourced from the CONCORDANCE registry, intended for use by clinicians to help improve the quality of patient care in line with treatment guidelines. Main outcome measures: the primary outcome was total revascularisation, a composite endpoint encompassing patients receiving PCI (percutaneous coronary intervention), thrombolysis, or coronary artery bypass grafting (CABG) during the index admission. Secondary outcomes: timely vascularisation rates; major adverse cardiac event rates; clinical outcomes and preventive treatments at discharge; mortality in hospital and six months after admission. The average age of women presenting with STEMI was 66.6 years; the average age of men was 60.5 years. More women than men had hypertension, diabetes, a history of prior stroke, chronic kidney disease, chronic heart failure, or dementia. Fewer had a history of previous coronary artery disease or myocardial infarction, or of prior PCI or CABG. Source: Medical Brief 2018

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Cardiovascular Topics A retrospective review of right-sided hearts at a South African tertiary hospital Nadia Beringer, Antoinette Cilliers

Abstract Background: A right-sided heart (RSH) has three main causes: dextrocardia, dextroposition and dextroversion. It may be associated with cardiac malformation, extra-cardiac abnormalities and adverse patient outcomes. The aim of this study was to determine the prevalence, demographics, associated cardiac malformations (ACM) and outcome of paediatric patients diagnosed with a RSH at a South African tertiary hospital. Methods: A retrospective review was performed over a 22-year period. Results: RSH comprised 1% of the paediatric cardiology referrals. Dextrocardia was the most frequent cause (58.1%) and the majority of these patients had ACM (81.5%). More than a third (40.9%) were diagnosed with dextroposition, secondary to extra-cardiac factors. Dextroversion was the least common cause (1.1%). Over a quarter of all patients were confirmed dead at the time of the study; most had been diagnosed with dextrocardia. Two-thirds of the patients were lost to follow up. Conclusion: A RSH is an unusual occurrence. Dextrocardia, the most common cause, is frequently associated with ACM and extra-cardiac abnormalities. It is therefore important to timeously elucidate the cause of a RSH. Keywords: right-sided hearts, dextrocardia, dextroposition, dextroversion Submitted 25/5/17, accepted 22/10/18 Published online 21/11/18 Cardiovasc J Afr 2019; 30: 5–8

www.cvja.co.za

DOI: 10.5830/CVJA-2018-051

Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa Nadia Beringer, MB ChB, MMed, DCH, FCPaed, nadia.beringer@ gmail.com

Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Paediatric Cardiology Division, Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Antoinette Cilliers, MB BCh, DCH (SA), FCPaed (SA)

A right-sided heart (RSH) is a cardiac malposition that is predominantly caused by dextrocardia, dextroversion or dextroposition. Each cause has a different aetiology, associated cardiac malformations (ACM) and outcome.1 ACM range from severe cyanotic congenital heart defects to sub-clinical ductal lesions2 Dextrocardia is the most common cause of a RSH. The reported incidence ranges from 0.01% of all live births in highincome countries2,3 to a slightly higher incidence of 0.35% in low-income countries.4,5 It occurs when the base–apex of the heart is displaced to the right.3,4 Factors intrinsic to the heart are responsible for this malformation, which occurs during foetal embryogenesis. However, no specific genetic cause or inheritance pattern for dextrocardia has been identified.6 Dextrocardia is often accompanied by ACM.3,7 Dextroposition is the displacement of the heart to the right hemi-thorax, secondary to extra-cardiac causes.1 It is not usually associated with ACM.1,7,8 Dextroversion results from a congenital malrotation of the ventricular part of the heart about its long axis with the atria remaining in the normal position.1 It is essentially dextrocardia with normally related atria and viscera.4 ACM are very common and mostly involve the cono-truncal region of the heart.1 The term situs is not only used to describe the atrial position, but also the anatomical position of the abdominal and thoracic organs.9,10 There are three types of situs described associated with a RSH: situs solitus, situs inversus and situs ambiguous.9-11 Situs solitus refers to the normal position of the atria, thoracic and abdominal organs.3,10 The complete mirror image of this relationship is situs inversus.10 When situs cannot be determined anatomically, it is referred to as situs ambiguous.3,10 This is also known as heterotaxy or isomerism and is invariably coupled with severe cardiac and non-cardiac malformations. Situs ambiguous is further divided into right atrial isomerism (RAI) and left atrial isomerism (LAI).3,7,10 Non-cardiac malformations include: asplenia in RAI and polysplenia and biliary atresia in LAI. Malrotation of the gut can occur in both.11,12 The incidence and severity of complex cardiac anomalies are directly proportional to the failure of shift of the cardiac apex with regard to the abdominal and thoracic organs. In other words, situs solitus dextrocardia is more likely to be associated with cardiac malformations, compared to situs inversus dextrocardia.10,13,14 Failure to diagnose a RSH and its associations may impact on patient outcomes. To date, there are no publications from the African continent describing RSH: its overall prevalence,

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

underlying causes, ACM, therapeutic interventions, and morbidity and mortality rates. Thus follows a retrospective review of all the children with RSH presenting to a large tertiarycare hospital in southern Africa.

Methods A retrospective review of children diagnosed with RSH at the Chris Hani Baragwanath Academic Hospital (CHBAH) was undertaken. The study spanned a 22-year period and patient records were obtained from the electronic database of the CHBAH cardiology department. Data collected included age at diagnosis, gender, underlying cause of the RSH, prevalence, ACM, extra-cardiac abnormalities, situs, interventions and patient outcome at the time of the study. We used chest roentgenogram, echocardiography, electrocardiogram, cardiac catheterisation and foetal ultrasonography either alone or in combination to diagnose the RSH. ACM were grouped according to the diagnostic categories described by DC Fyler and published in the New England Regional Infant Cardiac Program in 1980.15 Permission to conduct retrospective analyses was obtained from the Human Research Ethics Committee of the University of the Witwatersrand.

Statistical analysis Descriptive statistical analysis was performed. The Chi-squared test, unpaired Student’s t-test and Mann–Whitney U-test were employed. A p-value < 0.05 was used as the level of significance. Data were collected and managed using REDCap (Research Electronic Data Capture)16 and were analysed using Microsoft Excel and Graphpad Prism. REDCap is a secure, web-based application designed to support data capture for research studies, hosted at the University of the Witwatersrand.16

AFRICA

Results There were 18 870 paediatric patients referred for cardiac assessment between 1 January 1991 and 2 November 2012. One hundred and eighty-six children were found to have RSH. This comprised 1% of the total paediatric cardiology referrals seen during the study period. Of the 186 patients with RSH, 108 were diagnosed with dextrocardia as the underlying cause. A further 76 patients had dextroposition and only two had a confirmed diagnosis of dextroversion. The extra-cardiac causes of dextroposition are described in Fig. 1. The median age at diagnosis of a RSH was two months (range, prenatal to 16 years). The majority of diagnoses were made before one year of age (144 out of 186 patients, 77.4%). There were 97 male patients and 83 female patients. The gender of six neonates was not documented. The male-to-female ratio (180 patients) was 1:0.86 (53.9% male, 46.1% female).

ACM Eighty-eight out of the 108 patients (81.5%) with dextrocardia demonstrated ACM. The various ACM are listed in Table 1. Of the 76 patients with dextroposition, four demonstrated ACM (5.3%). An atrial septal defect secundum was diagnosed in one patient and a large patent ductus arteriosus (PDA) in another. A further two patients in this subgroup demonstrated a small PDA in association with a hypoplastic right lung and Scimitar syndrome. There were 11 patients with dextroposition secondary to congenital diaphragmatic hernias (14.5%), none of whom had documented ACM. One out of the two patients in this subgroup had transposition of the great arteries (TGA).

Situs Fifty-two patients with dextrocardia (Fig. 2) exhibited situs inversus (48.1%) and ACM was diagnosed in 32 of them (61.5%). Situs solitus was found in a further 24 patients (22.2%), 15 of whom demonstrated ACM (62.5%). There was

30 Table 1. Dextrocardia: associated cardiac malformations15 Associated cardiac malformations

Number of patients

18 (16.7)

Single ventricle

17 (15.7)

Hypoplastic left ventricle

Tricuspid atresia

Collapsed Hypoplastic SpaceScimitar Unrecorded right lung lung occupying syndrome lesion A space-occuping lesion was defined as a mass or tumour that causes local pressure leading to displacement of the heart to the right hemi-thorax

Fig. 1. Extra-cardiac causes of dextroposition.

6 (5.6) 13 (12)

D-transposition of great arteries

15 (13.9)

Endocardial cushion defect

2 (1.9)

Double-outlet right ventricle L-transposition of great arteries

Number of patients (%)

Heterotaxias

2 (1.9) 10 (9.3)

Total anomalous pulmonary venous return

4 (3.7)

Tetralogy of Fallot

3 (2.8)

Coarctation of the aorta

2 (1.9)

Ventricular septal defect

26 (24.1)

Pulmonary stenosis

19 (17.6)

Atrial septal defect secundum

10 (9.3)

Patent ductus arteriosus

11 (10.2)

No significant heart disease

36 (33.3)

Lung disease

8 (7.4)

Other (all other diagnoses)

8 (7.4)

Most patients demonstrated more than one ACM at the time of echocardiography

AFRICA

Table 2. Gastrointestinal surgical procedures performed in patients with dextrocardia

Number of patients

Surgical procedure 45

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

Situs inversus

Situs solitus

Situs ambiguous

Undefined

Fig. 2. Dextrocardia: situs arrangements.

no statistical difference between the two situs arrangements and their associated cardiac malformations (p = 1.000). Eighteen patients demonstrated situs ambiguous, with an incidence of 16.7%. In this subgroup, 17 had documented ACM (94.4%), five were found to have RAI and eight to have left LAI. The remaining five patients with situs ambiguous did not have their atrial isomerism defined. Fourteen patients in the dextrocardia subgroup had unknown situs arrangements (13%). All of the 76 patients with dextroposition demonstrated situs solitus. This is in keeping with the underlying aetiology of dextroposition and involves external forces that may either be compressive or pulling in nature. Of the two patients with dextroversion, one had situs solitus and one had situs inversus with TGA.

Ventricular arrangements The majority of patients with dextrocardia had two ventricles (84.3%), while 17 had a univentricular heart (15.7%). Over two-thirds of the patients demonstrated atrioventricular (AV) concordance, 10 had AV discordance, and the AV relationship of 25 patients was not recorded. Sixty-three patients demonstrated ventriculo-arterial (VA) concordance, 11 had VA discordance, 13 had double-outlet right ventricle (DORV) and the VA relationship of 22 patients was not recorded. All the patients with dextroposition had normal AV and VA relationships. Both the patients diagnosed with dextroversion had two ventricles and AV concordance. One had VA discordance (TGA) while the other patient had a normal heart.

No. of patients

Kasai for biliary atresia (situs inversus, 1)

Tracheo-oesophageal fistula repair (heterotaxy: undefined, 1)

Jejunal atresia (heterotaxy: undefined, 1, situs solitus, 1)

Duodenal atresia (left atrial isomerism, 1)

Gastric outlet obstruction (right atrial isomerism, 1)

Omphalocele (situs inversus, 2, situs solitus, 1)

Total

Surgery Cardiac surgery was performed in 25 of the patients with dextrocardia (23.1%). Eight of these procedures were corrective (32%), while 17 were palliative (68%). Corrective surgeries included ligation of a PDA, closure of a ventricular septal defect (VSD) and/or pulmonary artery (PA) banding. Palliative procedures included Blalockâ&#x20AC;&#x201C;Taussig or Glenn shunts. Nine patients with dextrocardia underwent general gastrointestinal (GIT) surgeries (Table 2). Four patients in this subgroup demonstrated isomerism (44.4%). Twenty-nine patients with dextroposition underwent surgical procedures. Seven were diagnosed with Scimitar syndrome and had percutaneous occlusion of the anomalous feeder arteries from the descending aorta. A wide variety of non-cardiac surgeries were undertaken in the remaining patients with dextroposition (Table 3).

Patient outcomes Twenty-one (19.4%) of the patients with dextrocardia were reported dead at the time of the study. All had complex ACM, which included: hypoplastic left ventricle, tricuspid atresia, double-outflow right ventricle, and single atrium and ventricle. Five had previously undergone cardiac surgery. Nine out of the 21 patients had situs inversus (42.9%), six had situs solitus (28.6%) and five had situs ambiguous (23.8%). In two patients the situs was undefined. Infection was the documented cause of death in seven patients (33.3%). Twenty-two patients (20.4%) were confirmed alive, and 65 (60.2%) had been lost to follow up. Eight patients with dextroposition had died at the time of the study (10.5%), two of whom had Scimitar syndrome. Eleven were found to be alive (14.5%), while the majority of patients were lost to follow up (75%). In the dextroversion subgroup, neither of the patients underwent surgery and both were alive at the time of the study.

Extra-cardiac abnormalities A total of 48 patients with dextrocardia had associated extracardiac abnormalities (44.4%), eight of whom (16.7%) were diagnosed with Kartagener syndrome (situs inversus totalis, chronic sinusitis and bronchiectasis). Two out of the five patients diagnosed with dextrocardia and RAI were confirmed to have asplenia on computerised tomography of the abdomen, and one patient had gastric outlet obstruction. There were eight patients diagnosed with LAI, three had an interrupted inferior vena cava, one patient had heart block, while duodenal atresia was diagnosed in one other.

Table 3. General (non-cardiac) surgical procedures performed in patients with dextroposition Surgical procedure Congenital diaphragmatic hernia repair Space-occupying lesion

No. of patients 11 3

Mass excision (thorax), 2 Cyst drainage (left thorax), 1 Tracheo-oesophageal fistula repair

Duodenal atresia

Omphalocele Total

2 20

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Discussion The study results are in keeping with published literature that describes a RSH as an uncommon entity.1,3 RSH comprised only 1% of the total number of paediatric patients referred for cardiac assessment at CHBAH over a 22-year period. The majority of patients were diagnosed with dextrocardia. There was no statistical significance between dextrocardia, the two most common situs arrangements and their ACM. This differs from other published data that have demonstrated an association between dextrocardia, situs arrangements and ACM.10,13 As this was a retrospective audit, pertinent patient information was not obtainable in some cases. Therefore it is possible that some of the study patients had undocumented ACM. Eight of the study patients with situs inversus dextrocardia without ACM were confirmed to have Kartagener syndrome.8,9 This highlights the importance of including a ciliopathy in the differential diagnosis of patients with recurrent respiratory infections and dextrocardia. In this study, 7% of patients with situs inversus dextrocardia and 22% of patients with situs ambiguous dextrocardia underwent GIT surgery. Patients with situs inversus totalis can present with abdominal signs and symptoms that differ from patients with situs solitus. For example, appendicitis in patients with situs inversus totalis and midgut rotation can present with left lower-quadrant pain. Patients with situs ambiguous are at risk of malrotation of the bowel and consequently bowel ischaemia.11 This highlights the importance of timeous recognition of different situs arrangements. Furthermore, as seen in the study, RAI is associated with asplenia, placing these patients at an increased risk for serious bacterial infections.12 The prevalence of situs ambiguous dextrocardia (16.7%) was found to be similar to that previously reported.3,4,17 In the study, both the RAI and LAI groups demonstrated some of the more common serious cardiac and non-cardiac anomalies (in particular GIT defects) requiring specialised paediatric surgical services. These anomalies are in keeping with previously published literature.12 The mortality rate was also in keeping with published data, and was higher in the RAI group compared to the LAI group.7,10,12 The risk for congenital heart lesions in patients with dextroposition is reportedly the same as for the general population.1,15,18 This was supported in the study results. Over a quarter of the patients were diagnosed with Scimitar syndrome, which is an unusual cause of dextroposition and is often associated with cardiac lesions.19,20 The diagnosis of dextroversion is sometimes missed and erroneously interchanged with dextroposition.

AFRICA

Bohun CM, Potts JE, Casey BM, Sandor GG. A population-based study of cardiac malformations and outcomes associated with dextrocardia. Am J Cardiol 2007; 100(2): 305–309. http://dx.doi.org/10.1016/j. amjcard.2007.02.095.

Evans WN, Acherman RJ, Collazos JC, Castillo WJ, Rollins RC, Kip, KT, et al. Dextrocardia: practical clinical points and comments on terminology. Pediatr Cardiol 2010; 31(1):1–6. http://dx.doi.org/10.1007/ s00246-009-9516-0.

Garg N, Agarwal BL, Modi N, Radhakrishnan S, Sinha N. Dextrocardia: an analysis of cardiac structure in 125 patients. Int J Cardiol 2003; 88(2–3):143–155.

Khan MA, Almasham Y, Almoukirish A, Galal O, Momenah T. Dextrocardia and associated cardiac malformations: Experience from a tertiary centre in Saudi Arabia. 2013; Available at: http://livestreamsa. co.za/wcpccs/eposter/?option=view&id=308&page=24&sortby=title. Accessed December 17, 2013.

Rare diseases: Genetic and Rare Diseases Information Centre. Dextrocardia with situs inversus. (No date); Available at: https:// rarediseases.info.nih.gov/diseases/6268/dextrocardia-with-situs-inversus. Accessed March 14, 2018.

Maldjian PD, Saric M. Approach to dextrocardia in adults: review. Am J Roentgenol 2007; 188(6 Suppl): S39–S49; quiz S35–8. http://dx.doi. org/10.2214/AJR.06.1179.

Bharati S, Lev M. Positional variations of the heart and its component chambers. Circulation 1979; 59(5): 886–887.

Wilhelm A. Situs inversus imaging. 2011; Available at http://emedicine. medscape.com/article 413679-overview. Accessed November 13, 2012.

10. Ghosh S, Yarmish G, Godelman A, Haramati LB, Spindola-Franco H. Anomalies of visceroatrial situs. Am J Roentgenol 2009; 193(4): 1107–1117. http://dx.doi.org/10.2214/AJR.09.2411. 11. Akbulut S, Ulku A, Senol A, Tas M, Yagmur Y. Left-sided appendicitis: Review of 95 published cases and a case report. World J Gastroenterol 2010; 16(44): 5598–5602. http://dx.doi.org/10.3748/wjg.v16.i44.5598. 12. Applegate KE, Goske MJ, Pierce G, Murphy D. Situs revisited: Imaging of the heterotaxy syndrome. Radiographics 1999; 19(4): 837–852. http:// dx.doi.org/10.1148/radiographics.19.4.g99jl31837. 13. Kim SJ. Heterotaxy syndrome. Korean Circ J 2011; 41(5): 227–232. http://dx.doi.org/10.4070/kcj.2011.41.5.227 14. Abdullah NL, Quek SC, Seto KY, Teo LLS. Clinics in diagnostic imaging (160). Singapore Med J 2015; 56(4): 198–202. http://dx.doi. org/10.11622/smedj.2015059. 15. Fyler DC. Report of the New England regional infant cardiac program. Pediatrics 1980; 65(suppl): 375–461. 16. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42(2): 377–381. 17. Roodpeyma SH, Abarashi M. Dextrocardia in children: Review of 15

Conclusion This study confirms the rarity of RSH, which are associated with both cardiac and non-cardiac anomalies and requires a high index of suspicion to make the diagnosis. Appropriate assessment will allow for a streamlined approach and correct management.

cases. Iran J Pediatr 1999; 9(1): 41–47. 18. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote, L. Congenital heart disease in the general population. Changing prevalence and age distribution. Circulation 2007; 115(2): 163–172. http://dx.doi. org/10.1161/CIRCULATION.AHA.106.627224. 19. Gao Y, Burrows PE, Benson LN, Rabinovitch M, Freedom RM. Scimitar syndrome in infancy. J Am Coll Cardiol 1993; 22(3): 873–882.

References 1.

20. Dusenbery SM, Geva T, Seale A, Valente AM, Zhou J, Sena L, et al. Outcome predictors and implications for management of scim-

Grant RP. The syndrome of dextroversion of the heart. Circulation

itar syndrome. Am Heart J 2013; 165(5): 770–777. http://dx.doi.

1958; 18(1): 25–36. http://dx.doi.org/10.1161/01.CIR.18.1.25.

org/10.1016/j.ahj.2013.01.016.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Clinical and echocardiographic correlates of pulmonary hypertension among heart failure patients in Lagos, south-western Nigeria OA Kushimo, AC Mbakwem, JNA Ajuluchukwu, CE Amadi

Abstract Background: Pulmonary hypertension (PH) is very prevalent among heart failure (HF) subjects and is now recognised as an independent predictor of poor prognosis. There is a paucity of data in our environment about the frequency and correlates of PH in HF. We aimed to determine the frequency of PH in HF patients in an academic hospital and assess its correlates using echocardiography. Methods: A total of 219 heart failure patients in NYHA functional class II to IV, and without co-morbidities that could cause PH, were consecutively recruited. Demographic, clinical and echocardiographic data were obtained from all subjects. Results: The frequency of PH was 38.8%, using an estimated pulmonary artery systolic pressure (PASP) cut-off value of > 36 mmHg. HF subjects with PH tended to be male with a worse NYHA functional class compared with subjects without PH. HF subjects with PH also had significantly higher left ventricular (LV) filling pressures (higher left atrial volume index and E/e′ ratio), more severe mitral regurgitation (MR), poorer LV systolic function, and worse parameters of right ventricular (RV) structure and function compared with those without PH. Echocardiographic variables that correlated significantly with PASP include LV filling pressures (p < 0.001 for all), mitral regurgitant volume (r = 0.269, p < 0.001) and LV ejection fraction (r = –0.239, p > 0.001). On multivariate analysis, the left atrial volume index and E/e′ ratio were independently associated with PASP. Conclusion: PH is common among HF subjects in our environment and is associated with higher LV filling pressure, more severe MR, poorer LV systolic function and worse RV remodelling. Routine screening for PH among HF patients is recommended for better risk stratification and management.

Submitted 16/4/18, accepted 22/10/18 Published online 5/11/18 Cardiovasc J Afr 2019; 30: 9–14

www.cvja.co.za

DOI: 10.5830/CVJA-2018-053

Pulmonary hypertension (PH) is very prevalent among heart failure (HF) subjects and is now recognised as an independent predictor of poor prognosis.1,2 PH develops initially from passive congestion of the pulmonary venous circulation, secondary to elevated filling pressures of the left cardiac chambers. Later, functional and structural changes may occur in the pulmonary venous and distal arterial circulation, resulting in a fixed or reactive form of PH.3 The key correlates of PH in HF are factors associated with increased pulmonary venous pressure.4 These include elevated left ventricular (LV) filling pressures and mitral regurgitation (MR), which have been demonstrated by several studies.1,2,5-7 The role of other factors, such as clinical parameters and LV systolic function is less clear. Right heart catheterisation is the goldstandard method for making a definitive diagnosis in selected patients.8,9 Echocardiography is a convenient, non-invasive investigation widely used in clinical practice to screen for PH, as suggested by the guidelines.8,9 Not much is known presently about the frequency and correlates of PH in HF in our environment. We therefore evaluated the frequency of PH in an academic hospital in southwestern Nigeria, and its correlates using echocardiography. It is expected that results from this study will help improve risk stratification, management and prognostication in our patients with HF.

Methods Keywords: pulmonary hypertension, heart failure, correlates, echocardiography

Cardiology Unit, Department of Medicine, Lagos University Teaching Hospital, Nigeria OA Kushimo, MB BS, MWACP, FMCP, wolekushimo@gmail.com AC Mbakwem, MB BS, FWACP, FESC, FACC JNA Ajuluchukwu, MB BS, M.MED, FMCP, FESC CE Amadi, MBBS, MSc, FMCP

College of Medicine, University of Lagos, Nigeria AC Mbakwem, MB BS, FWACP, FESC, FACC JNA Ajuluchukwu, MB BS, M.MED, FMCP, FESC CE Amadi, MB BS, MSc, FMCP

This was a cross-sectional study carried out at the Lagos University Teaching Hospital in south-western Nigeria. We consecutively recruited 219 HF patients of 18 years or older, who were in New York Heart Association (NYHA) functional class II to IV and were referred to the emergency unit, medical wards and the cardiology out-patient clinic of our hospital. Heart failure was diagnosed using the Framingham criteria. We excluded patients with a known history of co-existing conditions that can cause PH, besides left heart disease. These included patients with sickle cell disease, chronic parenchymal lung disease, human immunodeficiency virus infection, chronic liver disease with portal hypertension, congenital heart disease, obstructive sleep apnoea, chronic kidney disease, chronic exposure to high altitude, and use of anorexigenic agents. Approval for this study was obtained from the Health Research and Ethics Committee of the Lagos University

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Teaching Hospital. Subjects were duly counselled about the aims and objectives of the study. Written informed consent was obtained prior to recruitment. The bio-data of the subjects were obtained. A history was taken and physical examination performed to ascertain the diagnosis and aetiology of HF, to determine the patient’s functional class and duration of illness, measure various anthropometric indices, and screen for the exclusion criteria mentioned above. Transthoracic echocardiography was done with a Sonoscape SSI-8000 machine and 3.5-MHz transducer probe. Two-dimensional (2D) directed M-mode and Doppler transthoracic echocardiography were performed in the parasternal, apical and subcostal views on all 219 subjects. The 2D directed M-mode measurements were done in accordance with recommendations of the American Society of Echocardiography (ASE) to determine LV chamber dimensions and LV ejection fraction (LVEF). Right ventricular (RV) longitudinal systolic function was assessed by the tricuspid annular plane systolic excursion (TAPSE).10 2D parameters of RV structure were also assessed. These included RV basal diameter, right atrial area, RV wall thickness and eccentricity index.11 Doppler echocardiography was performed to determine pulmonary artery systolic pressure (PASP), LV diastolic function and the severity of MR. PASP was determined by the tricuspid regurgitant (TR) jet method, using the ASE guidelines for assessment of the right heart.11 The peak TR jet velocity (V) was measured by colour Doppler guided continuous-wave Doppler in the apical fourchamber view, parasternal RV inflow view and parasternal shortaxis view at aortic valve level. The highest velocity obtained from any of these views was selected. Right atrial pressure (RAP) was estimated from the size and collapsibility of the inferior vena cava (IVC) by assigning standardised values, recommended by the guidelines.11 The estimated PASP was then calculated using the modified Bernoulli equation: PASP = 4V2 + RAP A cut-off value of PASP > 36 mmHg, suggesting PH, was employed in this study, based on the 2009 European Society of Cardiology (ESC)8 and 2010 ASE11 recommendations. These were the prevailing guidelines during the planning and execution of this study. LV diastolic function was assessed according to the ASE guidelines,12 using transmitral Doppler velocities, left atrial volume index, and tissue Doppler of the septal and lateral mitral annulus. All Doppler measurements were taken at the end of expiration, using the average of measurements obtained during three consecutive cardiac cycles. LV filling pressure was assessed using the E/e′ ratio (ratio of the pulsed-wave transmitral E velocity and average tissue Doppler e′ velocities). Diastolic dysfunction was graded as normal, grade 1 (impaired LV relaxation), grade 2 (pseudonormal filling pattern with mild elevation in LV filling pressure) or grade 3 (restrictive LV filling pattern and marked elevation in LV filling pressure). Severity of MR was assessed by calculating the mitral regurgitant volume (MRvol) using the formula: MRvol = SVmitral – SVLV outflow tract13 where SVmitral is the mitral valve stroke volume and SVLV outflow tract

AFRICA

is the LV outflow tract stroke volume. MR severity was graded according to the ASE guidelines13 as follows: mild (< 30 ml), moderate (30–60 ml) and severe (> 60 ml).

Statistical analysis Data were analysed using the Statistical Package for Social Sciences version 17.0 (SPSS, Inc, Chicago, IL, USA). Normally distributed numerical data are presented as means and standard deviations, while the skewed ones are expressed as medians and ranges. Categorical variables are presented as proportions. Means were compared using the Student’s t-test. Categorical variables were compared using the chi-squared test or Fisher’s exact test when cell counts were less than five. Correlation analyses were done to demonstrate associations between pulmonary pressures and specific clinical and echocardiograhic parameters. Pearson’s correlation was done for normally distributed variables while Spearman’s rank correlation was used for variables that did not meet normality assumptions. Forward stepwise multiple linear regression analyses were performed in order to determine the clinical and echocardiographic parameters that were independently associated with PASP in the study population.

Results A total of 219 subjects with heart failure were recruited for this study, comprising 132 males (60.3%) and 87 females (39.7%). Mean age of the study population was 56 ± 15 years. Other clinical characteristics of the study population are summarised in Table 1. The most common aetiology of HF in the overall study population was hypertensive heart disease, which was found in 107 (48.9%) subjects, followed by idiopathic dilated cardiomyopathy, which occurred in 74 (33.8%) subjects. One hundred and forty-six subjects (66.7%) had heart failure with reduced ejection fraction (HFrEF), while 73 (33.3%) had heart failure with preserved ejection fraction (HFpEF). The frequency Table 1. Clinical characteristics of the study population (n = 219) Parameters

Mean ± SD/n (%)

Overall mean age in years Male Female Males Females Body mass index (kg/m2)

56 ± 15 58 ± 14 54 ± 15 132 (60.3) 87 (39.7) 27.2 ± 5.6

Systolic blood pressure

117.0 ± 20.3

Diastolic blood pressure

75.0 ± 13.3

NYHA functional class II

131 (59.8)

III

68 (31.1)

20 (9.1)

Median NYHA functional class

2 (2–4)*

Median duration of HF (weeks)

52 (1–579)*

Previous hospitalisations None

103 (47.0)

73 (33.3)

≥2

43 (19.7)

*Median (range); NYHA, New York Heart Association.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 2. Comparison of the clinical characteristics of subjects with and without pulmonary hypertension Parameters Gender (M/F, %)

PH group (n = 85)

Non-PH group (n = 134)

69/31

55/45

p-value

Table 4. Comparison of echocardiographic characteristics of subjects with and without pulmonary hypertension PH group (n = 85)

Parameters

Non-PH group (n = 134)

0.028

LV diastolic diameter (cm)

6.3 ± 1.1

5.7 ± 1.3

p-value < 0.001

Age (years)

55.0 ± 13.9

57.2 ± 14.9

0.28

LV systolic diameter (cm)

5.2 ± 1.2

4.4 ± 1.4

< 0.001

BMI (kg/m2)

25.8 ± 5.1

28.1 ± 5.7

0.002

LA volume index (ml/m2)

89.8 ± 72.9

54.7 ± 25.9

< 0.001

Pulse (beats/min)

85.2 ± 14.6

80.9 ± 13.7

0.03

Fractional shortening (%)

17.3 ± 8.4

22.6 ± 10.0

< 0.001

SBP (mmHg)

114 ± 19.9

119 ± 20.3

0.05

Ejection fraction (%)

35.4 ± 15.0

44.1 ± 16.7

< 0.001

DBP (mmHg)

75.7 ± 14.0

74.5 ± 12.8

0.52

LV mass index (g/m2)

172 ± 54.9

138.5 ± 53.4

< 0.001

TAPSE (cm)

1.6 ± 0.4

2.0 ± 0.5

< 0.001

NYHA class, n (%) II

29 (34.1)

102 (76.1)

RV basal diameter (cm)

5.0 ± 0.8

4.2 ± 0.8

< 0.001

III

41 (48.2)

27 (20.1)

RV wall thickness (cm)

0.37 ± 0.16

0.33 ± 0.09

< 0.04

15 (17.6)

5 (3.7)

RA area (cm2)

28.8 ± 7.7

19.4 ± 6.2

< 0.001

Eccentricity index*

1.12 ± 0.18

1.03 ± 0.11

< 0.001

65 (48.5)

Presence of D-sign, n (%)

26 (30.6)

7 (5.2)

< 0.001

15.9 ± 5.4

11.7 ± 5.5

< 0.001

3 (3.6)

55 (41.0)

Previous admissions, n (%) None

0.74 38 (44.7)

31 (36.5)

42 (31.3)

E/e′ ratio

≥2

16 (18.8)

27 (20.1)

Diastolic dysfunction grade

Duration of heart failure (weeks)*

0.26

1 or normal

< 0.001

1–25

25 (32.9)

38 (33.3)

13 (15.7)

36 (26.9)

26–104

31 (40.8)

35 (30.7)

67 (80.7)

5 (32.7)

105–579

20 (26.3)

41 (36.0)

11 (12.9)

30 (22.4)

< 0.001

MR severity, n (%)

*Grouped as tertiles; PH, pulmonary hypertension; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; NYHA, New York Heart Association.

mild moderate

20 (23.5)

41 (30.6)

severe

51 (60.0)

44 (32.8)

85.8 ± 64.7

67.4 ± 59.3

Mitral regurgitant volume (ml)

of PH using an estimated PASP cut-off value of > 36 mmHg was present in 85 (38.8%) subjects. Clinical characteristics of HF subjects with and without PH are summarised in Table 2. HF subjects with PH tended to be male (p = 0.03) with a lower body mass index (BMI) (p = 0.002) and higher NYHA functional class (p < 0.001) compared with those without PH. However, there was no significant difference in the frequency of previous hospitalisations (p = 0.74) and duration of HF (p = 0.26) between the groups. The presence of PH was significantly associated with a HF aetiology of dilated cardiomyopathy (p = 0.02) and valvular heart disease (p = 0.015), while the absence of PH was associated with hypertensive heart disease (p = 0.008) (Table 3). Comparison of the echocardiographic characteristics of HF subjects with and without PH is summarised in Table 4. HF subjects with PH had significantly higher left atrial and LV chamber dimensions (p < 0.001). They also had poorer LV systolic function, higher LV diastolic dysfunction grade (Fig. 1) and LV filling pressures, assessed by E/e′ ratio (p < 0.001 for all). Table 3. Comparison of heart failure aetiologies among subjects with and without PH

The presence of PH was associated with more severe MR (Fig. 2). The subjects with PH had significantly worse parameters of right heart structure and function, compared with the non-PH group. The age and BMI of the study population correlated negatively with PASP (p = 0.02, p < 0.001, respectively). The pulse of the subjects had a significant but weak positive correlation with PASP (r = 0.138, p = 0.04). Other clinical parameters did not show significant correlations with PASP (Table 5). PASP correlated significantly with all selected echocardiographic parameters of left heart structure and function, such as left atrial volume index (LAVI), LV mass index, LVEF and E/e′ ratio (Table 5). The mitral regurgitant volume correlated positively with PASP (r = 0.269, p < 0.001). All parameters of RV structure and function correlated significantly with PASP.

Parameters

PH group (n = 85) n (%)

Non-PH group (n = 134) n (%)

p-value

Hypertensive heart disease

32 (37.6)

75 (56.0)

0.008

Idiopathic dilated cardiomyopathy

Percent

PH group (PASP > 36 mmHg) non-PH group

37 (43.5)

37 (27.6)

0.02

Peripartum cardiomyopathy

3 (3.5)

11 (8.2)

0.26

Valvular heart disease

8 (9.4)

2 (1.5)

0.02

RCM/amyloid heart disease*

4 (4.7)

1 (0.7)

0.08

Ischaemic heart disease

1 (1.2)

3 (2.2)

0.96

Obesity-related heart disease**

0 (0)

4 (3.0)

0.16

PH, pulmonary hypertension, RCM, restrictive cardiomyopathy. *This was diagnosed by suggestive echo findings of severe LV wall thickening, myocardial speckled appearance and normal or low-voltage limb lead voltages on 12-lead ECG. ** This was a diagnosis of exclusion made in subjects with a BMI > 30 kg/m2 and no other other identifiable cause or explanation of heart failure.

< 0.04

PH, pulmonary hypertension; LA, left atrium; LV, left ventricle; TAPSE, tricuspid annular plane systolic excursion; RVWT, right ventricular wall thickness; E velocity, mitral inflow E velocity; e′, early mitral annular diastolic velocity; MR, mitral regurgitation. *Eccentricity index is the ratio of the LV anteroposterior and septolateral diameters measured in the parasternal short-axis view.

30 20

No MR Mild MR Moderate MR Severe MR Mild MR (MRvol < 30 ml), moderate (MRvol 30–59 ml), severe MR (MRvol > 60 ml)

Fig. 1. Severity of mitral regurgitation in the PH and non-PH subgroups.

Table 6. Stepwise multivariate linear regression model identifying determinants of estimated pulmonary artery systolic pressure

PH group (PASP > 36 mmHg)

non-PH group

Variables

Percent

Standardised β-coefficient

p-value

Model with PASP as dependent variable

60 50

Left atrial volume index

0.432

< 0.001

E/e′ ratio

0.188

0.006

R2 = 0.288

PASP, pulmonary artery systolic pressure; mPAP, mean pulmonary artery pressure; E, mitral inflow E velocity; e′, early mitral annular diastolic velocity; R2, coefficient of determination.

20 10 0

None

Grade 1

Grade 2

Grade 3

Fig. 2. D iastolic dysfunctional grade in the PH and non-PH subgroups.

Multivariate analyses were performed in order to determine the clinical and echocardiographic parameters that were independently associated with PASP in the study population (Table 6). A model was derived by forward stepwise multiple linear regression analysis with PASP as the dependent variable. The independent/predictor variables included in the analysis were relevant clinical and left heart echocardiographic parameters with statistically significant correlations on univariate analysis with p-values < 0.05. These were age, gender, pulse rate, BMI, LAVI, LV mass, LVEF, E/e′ ratio and mitral regurgitant volume. Right heart echo parameters were not included in the models because they can be deranged as a consequence of PH and therefore are not predisposing factors. The analysis revealed that only LAVI and E/e′ ratio were independently associated with PASP. Table 5. Correlation between selected clinical and echo parameters with estimated pulmonary artery systolic pressure PASP Parameters

p-value

Clinical variables Age

–0.163

0.02

BMI

–0.298

< 0.001

Pulse

0.138

0.04

SBP

–0.105

0.12

DBP

0.083

0.22

Previous admissions

0.037†

0.59

–0.048†

0.51

Duration of HF Echocardiographic variables LV diastolic diameter

0.237

0.002

LV systolic diameter

0.229

0.003

LV ejection fraction

–0.239

< 0.001

Fractional shortening

–0.240

< 0.001

LA volume index

0.565

< 0.001

LV mass index

0.269

< 0.001

TAPSE RV wall thickness

–0.428

< 0.001

0.267

< 0.001

RV basal diameter

0.472

< 0.001

Right atrial area

0.550

< 0.001 < 0.001

Eccentricity index

0.481

E/e′ ratio

0.415

< 0.001

Mitral regurgitant volume

0.269

< 0.001

Spearman’s ranked correlation coefficient. r, Pearson’s correlation coefficient; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LA, left atrium; LV, left ventricle; TAPSE, tricuspid annular plane systolic excursion; RV, right ventricle; E, early mitral inflow velocity; e’, early mitral annular diastolic velocity.

†

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Discussion This study showed that pulmonary hypertension was fairly common among the HF subjects and was significantly associated with clinical and echo indices of worsening HF severity. The frequency of PH varies widely in the literature, with a reported range of 7–83%.1,2,5,14-22 This is likely due to differences in assessment methods and cut-off values. We found a PH frequency of 38.8%, which is quite close to that of some studies17,18 that employed a similar cut-off value but much lower than in two community studies1,2 carried out in the USA. Our reported PH frequency is also lower than in two earlier local studies done in Nigeria by Karaye et al.14 and Amadi et al.,22 reporting an occurrence of 66 and 70.4%, respectively. This was probably due to the differences in PH estimation methods employed. The clinical characteristics of the HF subjects with and without PH were compared. Significant differences were noted with gender, BMI, pulse rate, systolic blood pressure and NYHA functional class. The PH group in this study had a significantly lower BMI than the non-PH group. This finding was also reported by some investigators,2,6 although other studies1,5 did not find any significant difference. A lower BMI in HF has been associated with increased disease severity and higher mortality risk, most likely due to the effects of TNF-alpha and catecholamine excess, which lead to cachexia and depressed LV function.23,24 Therefore HF patients with a lower BMI are likely to have poorer LV function and higher LV filling pressures, which are associated with elevated PASP. This finding differs from what is described in the normal population, where subjects with higher BMI have slightly higher PASP.25 In this study, a significantly higher proportion of the HF subjects with PH were in NYHA class III and IV, compared with the non-PH subgroup. This suggests that PH in HF patients is associated with worsening HF severity, which has also been reported by other studies.2,5 This is an expected finding, bearing in mind that decompensated HF patients usually present with an increased level of pulmonary venous congestion as a result of higher LV filling pressures.3,4,26,27 A comparison of HF aetiologies between subjects with and without PH was done in this study. Significant differences were observed in the occurrence of hypertensive heart disease, idiopathic dilated cardiomyopathy (DCM), and valvular heart disease (VHD). The PH group had a significantly lower frequency of hypertensive heart disease (37.6%) compared with the non-PH group (56%). This was also reported among hospitalised HF patients in a study done in northern Nigeria.14 In our study, PH was associated with a HF aetiology of DCM and VHD. Amadi et al.22 found a similar association

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

between PH and DCM among HF subjects in south-western Nigeria. However, in a similar study, Karaye et al.14 did not find a significant association between PH and both HF aetiologies, perhaps due to the smaller sample of 80 patients enrolled in their study. The frequency of subjects with a DCM echo pattern was also significantly higher in the PH group compared with the non-PH group. The higher frequency of DCM or a DCM echo morphology observed in PH subjects might have been due to the restrictive diastolic physiology associated with high LV filling pressures commonly seen in these patients.28 Among our HF population, we did not find an independent relationship between clinical parameters and PASP. This was also reported in a similar study among a mixed HF population.5 The key echocardiographic factors implicated in the development of PH in HF patients are left heart variables associated with increased pulmonary venous pressure.4 These factors include markers of elevated LV filling pressure and parameters of MR, as demonstrated by most studies.1,2,5-7 This has been further confirmed in the present study in which echocardiographic markers of elevated LV filling pressures and diastolic function, LAVI and E/e′ ratio correlated significantly and positively with PASP on both univariate and multivariate analyses. This suggests that worsening LV diastolic function and increasing LV filling pressures are independently associated with increasing PASP. Mitral regurgitant volume correlated positively with PASP. This suggests that worsening MR in the study population was associated with increasing pulmonary artery pressures. However, this finding was not significant on multivariate analysis. Chronic mitral regurgitation results in maladaptive increases in LV dimension, increase in systolic wall stress, progressive decline in LV contractile function, elevation of left atrial pressure, and therefore worsening PH.29 The relationship between LVEF and PH is less clear in view of the conflicting data reported in various studies.1,2,5,6,14,30 In this study, LVEF correlated negatively with PASP. This suggests that worsening LV systolic function was associated with increasing PASP. The association of worsening LVEF and PH is likely to be seen in studies of isolated or predominant HFrEF populations.5,6,30 The present study had a predominant HFrEF frequency of 66.7%. Other studies5,6 that did not find a significant association had isolated or a significant number of HFpEF subjects. PH of any cause is associated with compensatory and maladaptive changes of the right heart.4,31 In this study, all the parameters of RV structure (RV basal and RV wall thickness dimensions) and function (TAPSE and eccentricity index) correlated significantly with PASP. This finding highlights the importance of properly assessing the right side of the heart, which can help to characterise patients with borderline Dopplerderived pulmonary artery pressure measurements.8,9

identify those at high risk who require aggressive optimisation of standard therapy, as recommended by guidelines. The authors thank our cardiovascular laboratory nurses, Matron Phil-Enemosa and Sister Eke, for their assistance in preparing patients for echocardiography.

References 1.

Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53(13):1119–1126.

Bursi F, McNallan SM, Redfield MM, Nkomo VT, Lam CSP, Weston SA, et al. Pulmonary pressures and death in heart failure: a community study. J Am Coll Cardiol 2012; 59(3): 222–231.

Guazzi M, Galie N. Pulmonary hypertension in left heart disease. Eur Respir Rev 2012; 21(126): 338–346.

Kalogeropoulos AP, Vega JD, Smith AL, Georgiopoulou VV. Pulmonary hypertension and right ventricular function in advanced heart failure. Congest Heart Fail Greenwich Conn 2011; 17(4): 189–198.

Damy T, Goode KM, Kallvikbacka-Bennett A, Lewinter C, Hobkirk J, Nikitin NP, et al. Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J 2010; 31(18): 2280–2290.

Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997; 29(1): 153–159.

Patel JB, Borgeson DD, Barnes ME, Rihal CS, Daly RC, Redfield MM. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail 2004; 10(4): 285–291.

Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-L, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30(20): 2493–2537.

Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37(1): 67–119.

10. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16(3): 233–270. 11. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assess-

Conclusion

ment of the right heart in adults: a report from the American

PH is a fairly common condition among HF subjects, occurring in over a third of this study. Its presence in our HF population was significantly associated with higher LV filling pressures, more severe MR, poorer LV systolic function and worse RV remodelling. Echocardiographic screening for pulmonary hypertension should be done in all HF patients in order to

of Echocardiography, a registered branch of the European Society of

Society of Echocardiography endorsed by the European Association Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010; 23(7): 685–713; 786–788. 12. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

10(2):165–193.

AFRICA

187–193.

13. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD,

23. Shah R, Gayat E, Januzzi JL, Sato N, Cohen-Solal A, diSomma S, et al.

Levine RA, et al. Recommendations for evaluation of the severity of

Body mass index and mortality in acutely decompensated heart failure

native valvular regurgitation with two-dimensional and Doppler echo-

across the world: a global obesity paradox. J Am Coll Cardiol 2014;

cardiography. J Am Soc Echocardiogr 2003; 16(7): 777–802.

63(8): 778–785.

14. Karaye KM, Saidu H, Bala MS, Yahaya IA. Prevalence, clinical charac-

24. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ,

teristics and outcome of pulmonary hypertension among admitted heart

et al. Hormonal changes and catabolic/anabolic imbalance in chronic

failure patients. Ann Afr Med 2013; 12(4): 197–204.

heart failure and their importance for cardiac cachexia. Circulation 1997;

15. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, et al.

96(2): 526–534.

Independent and additive prognostic value of right ventricular systolic

25. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates

function and pulmonary artery pressure in patients with chronic heart

and reference intervals for pulmonary artery systolic pressure among

failure. J Am Coll Cardiol 2001; 37(1): 183–188.

echocardiographically normal subjects. Circulation 2001; 104(23): 2797–

16. Butler J, Chomsky DB, Wilson JR. Pulmonary hypertension and exercise intolerance in patients with heart failure. J Am Coll Cardiol 1999; 34(6): 1802–1806.

2802. 26. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a

17. Merlos P, Núñez J, Sanchis J, Miñana G, Palau P, Bodí V, et al.

report of the American College of Cardiology Foundation/American

Echocardiographic estimation of pulmonary arterial systolic pressure

Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol

in acute heart failure. Prognostic implications. Eur J Intern Med 2013; 24(6): 562–567.

2013; 62(16): e147–239. 27. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS,

18. Ghio S, Temporelli PL, Klersy C, Simioniuc A, Girardi B, Scelsi L, et

et al. 2016 ESC guidelines for the diagnosis and treatment of acute and

al. Prognostic relevance of a non-invasive evaluation of right ventricular

chronic heart failure: The Task Force for the diagnosis and treatment of

function and pulmonary artery pressure in patients with chronic heart

acute and chronic heart failure of the European Society of Cardiology

failure. Eur J Heart Fail 2013; 15(4): 408–414.

(ESC). Developed with the special contribution of the Heart Failure

19. Grigioni F, Potena L, Galiè N, Fallani F, Bigliardi M, Coccolo F, et

Association (HFA) of the ESC. Eur J Heart Fail 2016; 18(8): 891–975.

al. Prognostic implications of serial assessments of pulmonary hyper-

28. Pinamonti B, Di Lenarda A, Sinagra G, Camerini F. Restrictive

tension in severe chronic heart failure. J Heart Lung Transplant 2006;

left ventricular filling pattern in dilated cardiomyopathy assessed by

25(10): 1241–1246.

Doppler echocardiography: clinical, echocardiographic and hemody-

20. Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and risk factors of pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved ejection fraction. Am J Cardiol 2010; 106(2): 284–286.

namic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol 1993; 22(3): 808–815. 29. Patel H, Desai M, Tuzcu EM, Griffin B, Kapadia S. Pulmonary hypertension in mitral regurgitation. J Am Heart Assoc 2014; 3(4): e000748.

21. Khush KK, Tasissa G, Butler J, McGlothlin D, De Marco T. Effect of

30. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics,

pulmonary hypertension on clinical outcomes in advanced heart fail-

and outcomes of pulmonary hypertension due to chronic heart failure

ure: analysis of the Evaluation Study of Congestive Heart Failure and

with reduced ejection fraction: pulmonary hypertension and heart fail-

Pulmonary Artery Catheterization Effectiveness (ESCAPE) database. Am Heart J 2009; 157(6): 1026–1034.

ure. J Am Coll Cardiol Heart Fail 2013; 1(4): 290–299. 31. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular

22. Amadi VN, Ajayi OE, Akintomide AO, Abiodun OO, Bamikole OJ,

function in cardiovascular disease, part I: Anatomy, physiology, aging,

Balogun MO. Pulmonary Hypertension in heart failure patients present-

and functional assessment of the right ventricle. Circulation 2008;

ing at OAUTHC, Ile-Ife, Nigeria. Clin Med Insights Cardiol 2016; 10:

117(11): 1436–1448.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Management of low-density lipoprotein cholesterol levels in South Africa: the International ChoLesterol management Practice Study (ICLPS) Dirk J Blom, Frederick Raal, Aslam Amod, Poobalan Naidoo, Yen-yu (Evelyn) Lai, for the ICLPS SA study group

Abstract The International Cholesterol Management Practice Study (ICLPS) South Africa investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in real-world clinical practice. Demographic data, clinical characteristics, cardiovascular risk factors, lipidmodifying medications, lipid values and investigator’s assessment of cardiovascular risk were recorded for 396 patients on stable lipid-modifying therapy. Most (98.7%) patients received statins; 25.1% of statin-treated patients were receiving highintensity statins. Overall, 41.4% of patients achieved their LDL-C target; among 354 (89.4%) patients in whom cardiovascular disease risk, based on ESC Systematic Coronary Risk Estimation (SCORE) was calculated, achievement rate was 14.3% for moderate-risk (n = 7), 59.3% for high-risk (n = 123) and 32.3% for very high-risk patients (n = 223). Half of Asian (54.7%) and black African (53.2%) patients were at LDL-C target compared with 29.8% of European/Caucasian and 27.3% of ‘other’ patients. Improved guideline adherence and greater use of combination therapy may increase LDL-C goal achievement. Keywords: LDL-C goal, lipid-modifying therapy, cardiovascular risk, statin

Department of Medicine, Division of Lipidology and Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa Dirk J Blom PhD, MB ChB, FCP (SA), MMed (Int Med), Dirk.blom@uct.ac.za

Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa Frederick Raal, FRCP, FRCPC, FCP (SA), Cert Endo, MMED, PhD

The Centre for Diabetes and Endocrinology, Life Chatsmed Garden Hospital, Woodhurst, Chatsworth, South Africa Aslam Amod, MB ChB, FCP (SA), Cert Endocr&Metab (SA), FRCP (London)

Sanofi-Aventis, Midrand, South Africa Poobalan Naidoo, BPharm (Hons), MB BCh, MMed Sci (Pharmacol) Yen-yu (Evelyn) Lai, MB BCh

Submitted 9/7/18, accepted 22/10/18 Published online 16/1/19 Cardiovasc J Afr 2019; 30: 15–23

www.cvja.co.za

DOI: 10.5830/CVJA-2018-054

Despite improvements in its identification, prevention and treatment, cardiovascular disease (CVD) remains the world’s leading cause of morbidity and mortality.1 Furthermore, Africa in general, and South Africa specifically, are experiencing an increasing burden of CVD.2,3 Dyslipidaemia is a major risk factor for atherosclerotic CVD and the primary goal of dyslipidaemia treatment is to reduce levels of low-density lipoprotein cholesterol (LDL-C) to targets recommended by clinical practice guidelines.4,5 Statins are the preferred choice of lipid-modifying therapy (LMT) because of their proven efficacy and safety, and their relatively low cost.6,7 Addition of another LMT, such as ezetimibe or bile-acid sequestrant, to statin therapy is an option for patients who are not at target LDL-C on statins alone; however, these non-statin therapies have limited efficacy in lowering LDL-C.5 More effective LMTs, such as the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab8 and evolocumab,9 are not yet approved for use in South Africa. Large studies conducted predominantly in Western Europe and North America have shown that LDL-C levels remain elevated in many patients at high cardiovascular risk, despite the wide availability of statins.10-12 Similar results were reported for the CEntralised Pan-South African survey on tHE Undertreatment of hypercholesterolaemia (CEPHEUS SA)13 and the DYSlipidaemia International Study (DYSIS),14 which found that less than half of patients treated for dyslipidaemia achieved their LDL-C goals. Several factors may contribute to the under-treatment of dyslipidaemia in South Africa, including limited availability and lack of affordability of statins, use of low doses, frequent use of low-potency statins, statin intolerance, non-adherence to therapy and inadequate response to treatment. In the public health sector, treatment is limited by restrictive formularies that allow for only modest statin doses to be prescribed for most patients. In the private sector, restrictions imposed by medical funders make it difficult for many patients to access high-intensity statins. Many funders require titration from low-dose to high-dose statins for reimbursement; however, dose titration is infrequent in practice. For example, in CEPHEUS SA, of 2 996 patients with dyslipidaemia treated with LMT for three months or longer, 63.5% had remained on their initial starting treatment and dose at the time of assessment, and only 8.7% had had their dose increased.13 Medical funders frequently

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

impose co-payments on certain statins or ezetimibe, thus, in effect making them unavailable to many patients if they cannot afford the co-payments. The International Cholesterol Management Practice Study (ICLPS) was a multinational observational study that investigated the achievement of European Society of Cardiology (ESC)/ European Atherosclerosis Society (EAS) guideline LDL-C targets5 and their determinants in real-world clinical practice in countries outside of Western Europe.15 In this article, we report the findings from ICLPS participants in South Africa and assess whether the management of patients with dyslipidaemia has improved since reporting of the CEPHEUS SA13 and DYSIS14 studies.

Methods This cross-sectional, observational study was conducted in 19 centres in South Africa. The study was conducted according to the principles laid out by the 18th World Medical Assembly in the Declaration of Helsinki (Helsinki, 1964) and all subsequent amendments, the guidelines for Good Epidemiology Practice, and according to local regulations. Ethics approval was obtained from university ethics committees for academic sites (Universities of Cape Town and the Witwatersrand) and from a central ethics committee (Pharma Ethics) for all other sites. All patients provided written informed consent. Patients (≥ 18 years of age) who had been receiving a stable dose and type of LMT for at least three months before enrolment, and who had their LDL-C value measured on stable LMT in the previous 12 months, were eligible to participate. Patients participating in a clinical trial or who had received a PCSK9 inhibitor in the previous six months were excluded. The first patient was enrolled in August 2015 and the last patient in February 2016. A national expert advised on the relative contribution of each medical speciality to the management of patients with dyslipidaemia in South Africa. This information, together with a feasibility study, was used to identify suitable physician investigators and to ensure the results would adequately reflect the real-world management of patients with dyslipidaemia. Bias in the selection of study sites was limited by independently selecting participating centres and physicians in a randomised manner from pre-established lists, aiming to ensure a balanced representation of each speciality. To limit bias in patient selection, investigators were instructed to approach all eligible patients consecutively and recruit all patients who provided consent (minimum of five patients recruited per site) during a predefined two-week interval at each site. Physicians completed a questionnaire collecting demographic data, medical speciality, years of practice, type of practice and its location, main workplace, mean number of patients consulted per day, choice of and adherence to practice guidelines for lipid disorders [that is, ESC/EAS,5 American College of Cardiology/ American Heart Association (ACC/AHA),7 other international guidelines or local/national guidelines], and the definition of statin intolerance used in their practice (that is, intolerance to one, two or three or more statins). For each patient, the investigator completed a case-report form during a single visit. Data collected included demographic data, physical examination findings, cardiovascular risk factors, medical history, type of hypercholesterolaemia (primary or familial),

AFRICA

LDL-C and other lipid values (calculated or measured directly at the site’s local laboratory, on current treatment and untreated if available), current LMTs, socio-economic profile and the investigator’s assessment of the patient’s cardiovascular risk level. Data quality control was performed at a randomly selected sample (≥ 10%) of sites by trained personnel.

Statistical analysis Baseline characteristics are presented as descriptive statistics with mean ± standard deviation (SD) or median (interquartile range) for continuous variables, and as counts (percentages) for categorical data. The primary outcome was the proportion of patients taking LMT who had failed to achieve their appropriate LDL-C targets at enrolment, as defined by the 2011 ESC/EAS guidelines: < 1.8 mmol/l (∼70 mg/dl) or 50% LDL-C reduction (for those patients for whom baseline untreated LDL-C was available) when target levels could not be reached for very highrisk patients, < 2.5 mmol/l (∼100 mg/dl) for high risk, and < 3.0 mmol/l (∼115 mg/dl) for moderate risk.5 The Systematic Coronary Risk Estimation (SCORE) chart5 for high-risk countries was used to retrospectively risk stratify patients in whom the relevant data were available. The high-risk chart was used owing to the increasing rate of CVD in non-European countries. The SCORE algorithm16 assesses 10-year risk of fatal CVD, based on gender, age, smoking status, systolic blood pressure and total serum cholesterol. In the ICLPS SA, pre-treatment total serum cholesterol values were used; consequently, not all patients could be classified according to risk level. Low-risk patients were those with a SCORE value < 1% and moderate risk was a SCORE value ≥ 1% and < 5%. Patients with a SCORE value ≥ 5% or with systolic blood pressure ≥ 180 mmHg and diastolic blood pressure ≥ 110 mmHg, or with familial hypercholesterolemia as per the Dutch Lipid Clinic Network algorithm (definite or probable), or with diabetes without target-organ damage were classified in the high-risk group. The very high-risk group included patients with a 10-year risk of fatal CVD ≥ 10% or with at least one of the following conditions: documented coronary artery disease (CAD), cerebrovascular disease or peripheral artery disease, type 2 diabetes with target-organ damage, and history of chronic kidney disease (glomerular filtration rate < 60 ml/min/1.73 m²). Patients without a serious pathology classifying them as very high or high cardiovascular risk, and in whom the SCORE could not be calculated owing to missing data (most commonly baseline LDL-C) were categorised as non-assessable.

Results A total of 19 physicians participated in the study as investigators (age 50.6 ± 8.4 years; 63.2% men). (A full list of participating physician investigators is provided at the end.*) More than half (57.9%) were general practitioners or family physicians, and the rest included specialists in endocrinology (10.5%), cardiology, lipidology, internal medicine (each 5.3%) or another field (15.8%). Participating physicians had been in practice for a mean ± SD of 22.9 ± 8.3 years. Most physicians (57.9%) were in practices that treated mostly private patients, 21.1% were in practices that treated mostly public patients, and 21.1% were in mixed practices that treated both public and private patients. Overall, 78.9% of practices were

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

100

427 patients screened 31 patients ineligible 396 patients enrolled

354 (89.4%) patients cardiovascular risk assessable

42 (10.6%) patients cardiovascular risk not assessable

Fig. 1. P atient flow chart.

in urban areas. All physicians reported adhering to dyslipidaemia guidelines: 57.9% to ESC/EAS, 31.6% to ACC/AHA and 5.3% to other international guidelines. In addition, 42.1% stated that they adhered to the local South African guidelines, which are closely aligned with the ESC/EAS guidelines. Statin intolerance was defined as intolerance to one, two or three statins by 15.8, 47.4 and 36.8% of physicians, respectively. Of 427 patients assessed, 31 were ineligible for enrolment (Fig. 1). Therefore, the study population comprised 396 patients (mean ± SD age, 60.0 ± 10.2 years; 56.3% men) (Table 1). Patient demographic and clinical characteristics, lipid values and LMTs are shown according to cardiovascular risk level in Tables 1 and 2. Overall, 36.4% were Caucasian/European, 24.7% were Asian (including South Asian) and 24.2% were black African. Most (n = 367, 92.7%) patients were from urban/suburban areas, and 81.1% (n = 317) had completed secondary education or higher. A total of 279 (70.5%) patients had private medical insurance. Most patients (81.8%) had healthcare cover (public or private) that included drug reimbursement (private medical insurance) or drug supply (public sector). Most (87.1%) were overweight or obese [defined as a body mass index (BMI) of 25 to < 30 kg/m2 and ≥ 30 kg/ m2, respectively], 57.3% were physically inactive, 53.9% had the metabolic syndrome (Adult Treatment Panel III), 13.4% were current smokers and 22.0% reported regular alcohol consumption. Diabetes mellitus was present in 65.2% and hypertension in 81.3% of patients. A total of 135 (34.1%) patients had documented CAD: previous acute coronary syndrome (88/135, 65.2%), percutaneous coronary intervention (75/135, 55.6%) or coronary artery bypass graft surgery (57/135, 42.2%). Median time since dyslipidaemia diagnosis was 6.0 (interquartile range 3.0–12.0) years. The LDL-C value at the time of first diagnosis was available in 130 (32.8%) patients; mean untreated LDL-C was 3.9 ± 1.4 mmol/l (151.7 ± 52.7 mg/dl) and the LDL-C range was 0.7–9.0 mmol/l (27.0–347.5 mg/dl). At first diagnosis, 63.8% (83/130) of patients had an LDL-C value > 3.4 mmol/l (130 mg/dl) and 18.5% (24/130) had LDL-C > 4.9 mmol/l (190 mg/dl). Definite or probable familial hypercholesterolaemia was reported in 6.2% of patients. Of the 354 (89.4%) patients in whom SCORE cardiovascular risk could be calculated, 63.0% were at very high risk, 34.7% at high risk, 2.0% at moderate risk and 0.3% (one patient) was at low risk. Physician-estimated risk correlated poorly with calculated risk (Fig. 2); physicians underestimated risk in 54.7% of patients at very high calculated risk and 38.2% of those at high risk.

Physician-estimated cardiovascular risk (%)

AFRICA

14.2

23.6

45.3

70 60

57.1

38.2

100

50 40

40.4

30 20 28.6

10 0

38.2

29.3

8.9 Low (n = 1)

Moderate (n = 7)

High (n = 123)

54.7

11.7 2.7 Very high (n = 223)

Calculated cardiovascular risk level (SCORE) Low

Moderate

High

Very high

Fig. 2. Physician-estimated assessment of patient cardiovascular risk versus calculated risk (calculated using SCORE16).

Tables 3 and 4 show patient demographic and clinical characteristics, lipid values and LMTs by patient ethnicity. A smaller proportion of black African patients were male (35.4%) compared with other ethnic groups (53.4–72.2%). In the black African patient group, the incidences of obesity and hypertension were 63.5 and 89.6%, respectively. Corresponding figures in the other ethnic groups ranged from 32.7 to 54.2% for obesity and 71.5 to 87.9% for hypertension. Rates of documented CAD were 10.4% in black Africans compared with 28.6 to 50.0% in other ethnic groups. At study enrolment, 98.7% of patients were receiving statin therapy; 90.7% were receiving statin monotherapy, 3.3% were receiving statin plus a fibrate, and 2.6% were receiving a statin plus a cholesterol-absorption inhibitor (Table 1). One-quarter of patients treated with statins were receiving high-intensity statin therapy (that is, atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) and 17.7% were on the highest-dose regimen available in South Africa at the time of the study. Mean LDL-C value at enrolment was 2.6 ± 1.0 mmol/l (98.7 ± 39.6 mg/dl) (Table 2). Overall, 41.4% of patients were at or below their LDL-C target at enrolment (Figs 3A and 4). Among patients for whom SCORE cardiovascular risk could be assessed, achievement rates were 14.3, 59.3 and 32.3% for those at moderate, high and very high risk, respectively (Fig. 3A). Around half of Asian (54.7%) and black African (53.2%) patients achieved their LDL-C target compared with 29.8% of European/Caucasian patients and 27.3% of patients of ‘other’ ethnicity (Fig. 3B); achievement rates ranged from 65.0% in patients seen by physicians with several specialities to 6.3% in patients under the care of a cardiologist (Fig. 3C).

Discussion This observational study in patients on stable LMT indicated that achievement of LDL-C goals in South Africa is inadequate,

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Table 1. Demographics, presenting characteristics and medical history of the study population overall and by cardiovascular risk level Risk level Variables

Total (n = 396)

Low (n = 1)

Moderate (n = 7)

High (n = 123)

Very high (n = 223)

Not assessablea (n = 42)

Demographics Age (years), mean (SD)

60.0 (10.2)

43.0

43.4 (13.9)

57.8 (10.0)

62.4 (9.1)

56.9 (11.2)

Men, n (%)

223 (56.3)

1 (100.0)

6 (85.7)

52 (42.3)

142 (63.7)

22 (52.4)

Asian/South Asian/Indian

98 (24.7)

0 (0.0)

2 (28.6)

34 (27.6)

59 (26.5)

3 (7.1)

Black African

96 (24.2)

0 (0.0)

1 (14.3)

46 (37.4)

32 (14.3)

17 (40.5)

Caucasian/European

144 (36.4)

1 (100.0)

4 (57.1)

26 (21.1)

94 (42.2)

19 (45.2)

Other

58 (14.6)

0 (0.0)

17 (13.8)

38 (17.0)

3 (7.1)

367 (92.7)

0 (0.0)

6 (85.7)

117 (95.1)

208 (93.3)

36 (85.7)

29 (7.3)

1 (100.0)

1 (14.3)

6 (4.9)

15 (6.7)

6 (14.3)

Illiterate

7/391 (1.8)

0 (0.0)

3 (2.5)

1 (0.5)

3 (7.1)

Primary

67/391 (17.1)

0 (0.0)

24 (19.8)

34 (15.5)

9 (21.4)

Secondary

197/391 (50.4)

0 (0.0)

5 (71.4)

59 (48.8)

117 (53.2)

16 (38.1)

University/higher

120/391 (30.7)

1 (100.0)

2 (28.6)

35 (28.9)

68 (30.9)

14 (33.3)

Yes

279 (70.5)

1 (100.0)

7 (100.0)

85 (69.1)

161 (72.2)

25 (59.5)

117 (29.5)

0 (0.0)

38 (30.9)

62 (27.8)

17 (40.5)

301/368 (81.8)

1 (100.0)

5 (71.4)

97/113 (85.8)

174/216 (80.6)

24/31 (77.4)

Full time

159 (40.2)

1 (100.0)

5 (71.4)

56 (45.5)

74 (33.2)

23 (54.8)

Part time

13 (3.3)

0 (0.0)

3 (2.4)

9 (4.0)

1 (2.4)

224 (56.6)

0 (0.0)

2 (28.6)

64 (52.0)

140 (62.8)

18 (42.9)

25 to < 30 kg/m2

145/395 (36.7)

1 (100.0)

3 (42.9)

37 (30.1)

91/222 (41.0)

13 (31.0)

≥ 30 kg/m2

199/395 (50.4)

0 (0.0)

2 (28.6)

71 (57.7)

101/222 (45.5)

25 (59.5)

Metabolic syndrome (ATP III), n or n/n (%)

205/380 (53.9)

0 (0.0)

1 (14.3)

62/121 (57.2)

125/210 (59.5)

17/41 (41.5)

Physical inactivity,b n (%)

227 (57.3)

1 (100.0)

3 (42.9)

65 (52.8)

134 (60.1)

24 (57.1)

Current smoker,c n (%)

53 (13.4)

0 (0.0)

13 (10.6)

39 (17.5)

1 (2.4)

Regular alcohol consumption, n (%)

87 (22.0)

1 (100.0)

2 (28.6)

20 (16.3)

56 (25.1)

8 (19.0)

SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg, n (%)

196 (49.5)

0 (0.0)

3 (42.9)

56 (45.5)

120 (53.8)

17 (40.5)

Diabetes mellitus (type 1 or 2), n (%)

258 (65.2)

0 (0.0)

109 (88.6)

149 (66.8)

0 (0.0)

253/395 (64.1)

0 (0.0)

106 (86.2)

147/222 (66.2)

0 (0)

Dyslipidaemia (diagnosis or history) (physician defined), n (%)

390 (98.5)

1 (100.0)

7 (100.0)

122 (99.2)

219 (98.2)

41 (97.6)

Ethnicity, n (%)

Residence location, n (%) Urban/suburban Rural Educational level, n (%)

Private health insurance, n (%)

Insurance includes drug reimbursement, n or n/n (%) Employment status, n (%)

Not employed/retired Presenting characteristics BMI, n or n/n (%)

Diabetes mellitus (type 2), n or n/n (%) Family history of CVD,d n (%)

151 (38.1)

1 (100.0)

3 (42.9)

30 (24.4)

100 (44.8)

17 (40.5)

Hypertension (diagnosed/history of), n (%)

322 (81.3)

0 (0.0)

2 (28.6)

99 (80.5)

190 (85.2)

31 (73.8)

Familial hypercholesterolaemia,e n/n (%)

8/130 (6.2)

0 (0.0)

0/6 (0.0)

1/56(1.8)

7/67 (10.4)

CAD (documented), n (%)

135 (34.1)

0 (0.0)

135 (60.5)

0 (0.0)

ACS/MI, n (%)

88 (22.2)

0 (0.0)

88 (39.5)

0 (0.0)

Stroke (any), n (%)

15 (3.8)

0 (0.0)

15 (6.7)

0 (0.0)

Peripheral artery disease, n (%)

18 (4.5)

0 (0.0)

18 (8.1)

0 (0.0)

Congestive heart failure, n (%)

13 (3.3)

0 (0.0)

1 (0.8)

12 (5.4)

0 (0.0)

Chronic kidney disease (GFR < 60 ml/min/1.73 m2), n (%)

27 (6.8)

0 (0.0)

27 (12.1)

0 (0.0)

Medical history

ACS: acute coronary syndrome; ATP: Adult Treatment Panel; BMI: body mass index; CAD: coronary artery disease; CVD: cardiovascular disease; DBP: diastolic blood pressure; GFR: glomerular filtration rate; MI: myocardial infarction; NA: not available; SBP: systolic blood pressure; SD: standard deviation. Patients without a serious pathology, classifying them as very high or high cardiovascular risk, and in whom the SCORE could not be calculated owing to missing data. b Subject is not regularly involved in moderate (walking/cycling/gardening) or strenuous exercise (jogging/football/vigorous swimming) for ≥ four hours each week. c Individuals who smoked any tobacco in the previous 12 months or who quit during past year. d Coronary and/or vascular disease < 55 years of age in male and < 60 years in female first-degree relatives. e Dutch Lipid Clinics criteria: definite or probable. a

despite the availability of local and international dyslipidaemia management guidelines with well-publicised LDL-C targets. Fewer than half of patients (41.4%) were at or below their LDL-C target, and target achievement rates were lower (32.3%) for those patients at very high cardiovascular risk and moderate risk (14.3%). These results are consistent with the overall findings of the ICLPS study, which demonstrated that lipid management

remains suboptimal in countries outside of Western Europe.15 Similar rates of LDL-C goal achievement (∼50%) were reported for previous studies conducted in South Africa,13,14 demonstrating a lack of improvement in dyslipidaemia management over recent years. Factors that may contribute to low LDL-C goal achievement rates include prescription of inadequate statin doses, use of moderate- or low-potency statins,

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 2. Laboratory values and lipid-modifying therapies at enrolment in the study population overall and by cardiovascular risk level Risk level Total (n = 396)

Low (n = 1)

Moderate (n = 7)

High (n = 123)

Very high (n = 223)

Not assessablea (n = 42) 3.1 (0.9)

Lipid values LDL-C, mmol/l, mean (SD)

2.6 (1.0)

2.0

3.6 (0.7)

2.5 (1.0)

Total cholesterol, mmol/l, mean (SD)

n = 382

n=1

n=7

n = 121

n = 212

n = 41

4.5 (1.1)

4.0

5.5 (1.0)

4.5 (1.1)

4.3 (1.1)

5.2 (1.0)

n = 375

n=1

n=7

n = 120

n = 206

n = 41

1.2 (0.5)

1.2

1.3 (0.3)

1.3 (0.8)

1.2 (0.4)

1.3 (0.3)

HDL-C, mmol/l, mean (SD) Triglycerides, mmol/l, median (IQR) Mixed dyslipidaemia,b n/n (%)

n = 373

n=1

n=7

n = 120

n = 204

n = 41

1.5 (1.1–2.2)

0.7 (0.7–0.7)

1.5 (1.5–2.2)

1.5 (1.2–2.1)

1.6 (1.1–2.2)

1.6 (1.2–2.3)

98/331 (29.6)

3 (42.9)

24/120 (20.0)

71/204 (34.8)

Other laboratory values Fasting glucose, mmol/l, mean (SD) Serum creatinine, μmol/l, mean (SD)

n = 110

n=0

n=3

n = 25

n = 75

n=7

7.7 (3.4)

5.2 (0.9)

8.1 (3.4)

7.9 (3.6)

5.5 (0.5)

n = 252

n=1

n=4

n = 77

n = 153

n = 17

85.7 (30.2)

78.0

89.2 (12.9)

74.3 (16.8)

91.8 (34.7)

81.4 (21.6)

LMT Any statin, n (%)

391 (98.7)

1 (100.0)

7 (100.0)

120 (97.6)

221 (99.1)

42 (100.0)

High-intensity statin (in statin-treated patients),c n/n (%)

98/391 (25.1)

0 (0.0)

1/7 (14.3)

14/120 (11.7)

76/221 (34.4)

7/42 (16.7)

On highest dose (in statin-treated patients),d n/n (%)

69/389 (17.7)

0/1 (0.0)

1/7 (14.3)

15/120 (12.5)

50/220 (22.7)

3/41 (7.3)

359 (90.7)

1 (100.0)

7 (100.0)

111 (90.2)

201 (90.1)

39 (92.9)

Statin + fibrate ± other LMT, n (%)

13 (3.3)

0 (0.0)

5 (4.1)

8 (3.5)

0 (0.0)

Statin + cholesterol-absorption inhibitor ± other LMT, n (%)

10 (2.6)

0 (0.0)

9 (4.0)

1 (2.4)

Statin monotherapy, n (%)

HDL-C: high-density lipoprotein cholesterol; IQR: interquartile range; LDL-C: low-density lipoprotein cholesterol; LMT: lipid-modifying therapy; NA: not available; SD: standard deviation. a Patients without a serious pathology classifying them as very high or high cardiovascular risk, and in whom the SCORE could not be calculated owing to missing data. b Total serum triglycerides ≥ 1.7 mmol/l (150 mg/dl) and LDL-C > target. c Atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg. d Marketed in South Africa.

failure to titrate statin dosages, failure to use combination therapy, poor adherence and limited effectiveness of current LMTs, particularly for achieving the lower LDL-C goals recommended for patients at very high cardiovascular risk. There was poor agreement between physician-estimated cardiovascular risk and risk assessed using SCORE; in general, physicians underestimated risk. As a patient’s LDL-C goal depends on assessment of their cardiovascular risk, this underestimation may result in a lack of intensification of LMT, leaving many patients undertreated. There may be a need for better dissemination of local lipid-management guidelines to improve physicians’ understanding of risk assessment and to promote adherence to guideline recommendations. Funder barriers and affordability may also limit the use of appropriate doses and intensity of statin therapy, as well as the use of combination therapy with ezetimibe. IMPROVE-IT demonstrated that the addition of ezetimibe to statin therapy resulted in an incremental lowering of LDL-C and improved cardiovascular outcomes in patients with acute coronary syndrome (ACS).17 The proportion of patients on a statin plus ezetimibe in the current study was low, and greater use of this combination may improve LDL-C goal attainment. Cost and lack of access are major reasons for the low use of ezetimibe. It is envisaged that generic ezetimibe will enter the market in South Africa soon. Its lower cost, together with the findings of IMPROVE-IT,16 may increase access and uptake of ezetimibe, at least for patients at very high risk of atherosclerotic CVD. In addition, the introduction of novel LMT combinations, not yet available in South Africa, may further improve dyslipidaemia management and reduce the risk of cardiovascular events.

Recent studies have demonstrated the efficacy of the PCSK9 inhibitors in high-risk patients treated with statins.8,9 In FOURIER, evolocumab reduced LDL-C levels by 59% and cardiovascular events by 15% compared with placebo in patients treated with statins who had atherosclerotic CVD and LDL-C ≥ 70 mg/dl (1.8 mmol/l).9 ODYSSEY OUTCOMES examined the effect of alirocumab in patients with a recent ACS and elevated cholesterol level despite intensive or maximum-tolerated statin therapy.8 Rates of major adverse cardiovascular events and all-cause mortality were reduced by 15% with alirocumab versus placebo. The findings of the present study revealed socio-economic differences between ethnic groups, which may reflect a legacy of the previous political system that limited opportunities for black South Africans. For example, 57.9% of black African patients had completed secondary or university education compared with 86.7% of Asian and 99.4% of Caucasian/European patients. In addition, rates of private health insurance cover were lower in black African patients (50.0%) than in Asian (77.6%) and Caucasian/Europeans (93.1%). Rates of obesity (63.5%) and hypertension (62.5%) were high in black African patients. It should be noted that obesity was defined as BMI ≥ 30 kg/m2 for all patients; however, a lower cut-off point may be more appropriate in Asian patients.18 Consequently, the true rate of obesity in Asian patients may be higher than that observed in this group (32.7%). Diabetes mellitus, a major risk factor for CVD, was also highly prevalent in both black African (78.1%) and Asian (87.8%) patients compared with Caucasians/Europeans (42.4%). These differences between ethnic groups contrast with those from the South African National Health and Nutrition Examination Survey (SANHANES-1), which examined the prevalence of

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Table 3. Demographics, presenting characteristics and medical history of the study population overall and by ethnicity Ethnicity Total (n = 396)

Asian (n = 98)

Black African (n = 96)

Caucasian/European (n = 144)

Other (n = 58)

Age (years), mean (SD)

60.0 (10.2)

61.5 (8.9)

57.3 (9.9)

61.4 (10.9)

58.5 (10.2)

Men, n (%)

223 (56.3)

54 (55.1)

34 (35.4)

104 (72.2)

31 (53.4)

367 (92.7)

98 (100.0)

88 (91.7)

124 (86.1)

57 (98.3)

29 (7.3)

0 (0.0)

8 (8.3)

20 (13.9)

1 (1.7)

Demographics

Residence location, n (%) Urban/suburban Rural Educational level, n or n/n (%) Illiterate

7/391 (1.8)

0 (0.0)

7/95 (7.4)

0 (0.0)

Primary

67/391 (17.1)

13 (13.3)

33/95 (34.7)

1 (0.7)

20 (37.0)

Secondary

197/391 (50.4)

60 (61.2)

32/95 (33.7)

80 (55.6)

25 (46.3)

University/higher

120/391 (30.7)

25 (25.5)

23/95 (24.2)

63 (43.8)

9 (16.7)

Yes

279 (70.5)

79 (77.6)

48 (50.0)

134 (93.1)

21 (36.2)

117 (29.5)

22 (22.4)

48 (50.0)

10 (6.9)

37 (63.8)

301/368 (81.8)

55/96 (57.3)

74/79 (93.7)

131/140 (93.6)

41/53 (77.4)

Full time

159 (40.2)

31 (31.6)

44 (45.8)

69 (47.9)

15 (25.9)

Part time

13 (3.3)

3 (3.1)

4 (2.8)

3 (5.2)

224 (56.6)

64 (65.3)

49 (51.0)

71 (49.3)

40 (69.0)

Low

1 (0.3)

0 (0.0)

1 (0.7)

0 (0.0)

Moderate

7 (1.8)

2 (2.0)

1 (1.0)

4 (2.8)

0 (0.0)

High

123 (31.1)

34 (34.7)

46 (47.9)

26 (18.1)

17 (29.3)

Very high

223 (56.3)

59 (60.2)

32 (33.3)

94 (65.3)

38 (65.5)

Not assessablea

42 (10.6)

3 (3.1)

17 (17.7)

19 (13.2)

3 (5.2)

25 to < 30 kg/m2

145/395 (36.7)

47 (48.0)

27 (28.1)

51 (35.4)

20/57 (35.1)

≥ 30 kg/m2

199/395 (50.4)

32 (32.7)

61 (63.5)

78 (54.2)

28/57 (49.1)

Metabolic syndrome (ATP III), n/n (%)

205/380 (53.9)

52/91 (57.1)

56/92 (60.9)

64/140 (45.7)

33/57 (57.9)

Physical inactivity,b n (%)

227 (57.3)

65 (66.3)

63 (65.6)

64 (44.4)

35 (60.3)

Current smoker,c n or n/n (%)

53 (13.4)

15 (15.3)

3 (3.1)

25 (17.4)

10 (17.2)

Regular alcohol consumption, n (%)

87 (22.0)

20 (20.4)

10 (10.4)

51 (35.4)

6 (10.3)

SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg, n (%)

196 (49.5)

42 (42.9)

60 (62.5)

66 (45.8)

28 (48.3)

Private health insurance, n (%)

Insurance includes drug reimbursement, n or n/n (%) Employment status, n (%)

Not employed/retired CVD risk level, n (%)

Presenting characteristics BMI, n/n (%)

Diabetes mellitus (type 1 or 2), n (%)

258 (65.2)

86 (87.8)

75 (78.1)

61 (42.4)

36 (62.1)

253/395 (64.1)

85/97 (87.6)

71 (74.0)

61 (42.4)

36 (62.1)

Dyslipidaemia (diagnosis or history) (physician defined), n (%)

390 (98.5)

98 (100.0)

92 (95.8)

143 (99.3)

57 (98.3)

Family history of CVD,d n (%)

151 (38.1)

43 (43.9)

18 (18.8)

71 (49.3)

19 (32.8)

Hypertension (diagnosed/history of), n (%)

322 (81.3)

82 (83.7)

86 (89.6)

103 (71.5)

51 (87.9)

Familial hypercholesterolaemia,e n/n (%)

8/130 (6.2)

0/46 (0.0)

1/41 (2.4)

1/27 (3.7)

6/16 (37.4)

Diabetes mellitus type 2, n/n (%)

Medical history CAD (documented), n (%)

135 (34.1)

28 (28.6)

10 (10.4)

72.0 (50.0)

25 (43.1)

ACS/MI, n (%)

88 (22.2)

16 (16.3)

6 (6.3)

47 (32.6)

19 (32.8)

Stroke (any), n (%)

15 (3.8)

1 (1.0)

4 (4.2)

7 (4.9)

3 (5.2)

Peripheral artery disease, n (%)

18 (4.5)

3 (3.1)

4 (4.2)

8 (5.6)

3 (5.2)

Congestive heart failure, n (%)

13 (3.3)

0 (0.0)

6 (6.3)

7 (4.9)

0 (0.0)

Chronic kidney disease (GFR < 60 ml/min/1.73 m2), n (%)

27 (6.8)

9 (9.2)

5 (5.2)

12 (8.3)

1 (13.8)

ACS: acute coronary syndrome; ATP: Adult Treatment Panel; BMI: body mass index; CAD: coronary artery disease; CVD: cardiovascular disease; DBP: diastolic blood pressure; GFR: glomerular filtration rate; MI: myocardial infarction; SBP: systolic blood pressure; SD: standard deviation. a Patients without a serious pathology classifying them as very high or high cardiovascular risk, and in whom the SCORE could not be calculated owing to missing data. b Subject is not regularly involved in moderate (walking/cycling/gardening) or strenuous exercise (jogging/football/vigorous swimming) for ≥ four hours each week. c Individuals who smoked any tobacco in the previous 12 months or who quit during past year. d Coronary and/or vascular disease < 55 years of age in male and < 60 years in female first-degree relatives. e Dutch Lipid Clinics criteria: definite or probable.

non-communicable diseases and their risk factors in the general population in South Africa in 2012.19 SANHANES-1 noted a lower rate of self-reported diabetes in black African participants than with Asian (13.6%) and white (6.9%) participants, and similar or lower levels of obesity and hypertension compared with other ethnic groups. However, SANHANES-1 was a

general population study, whereas this study examined a highly selected population receiving LMT. Changes in the political system have now made access to cities possible for black South Africans, and many have migrated from rural to urban areas. This has likely resulted in a greater adoption of a sedentary lifestyle and increased consumption of refined

AFRICA

100

90 80 70 60 50 40 30

59.3

32.3

10 0

14.3 Moderate risk (n = 7)

High risk (n = 123)

Very high (n = 223)

Patient’s cardiovascular risk level

Proportion of patients achieving LDL-C goal (%)

80 70 60 50 40 30

54.7

53.2

29.8

27.3

Caucasian European (n = 124)

Other (n = 55)

10 Asian (n = 95)

Black African (n = 79)

100 90 80 70 60 50 40 44.4

15.0

Speciality of treating physician*

Several specialities (n = 20)

General practitioner (n = 193)

Cardiologist (n = 16)

6.3

Endocrinologist (n = 40)

65.0 47.4

Other (n = 45)

40.9

Lipidologist (n = 20)

52.5

Internal medicine (n = 19)

Fig. 3. P atients who achieved the 2011 ESC/EAS LDL-C goals at enrolment,5 according to (A) calculated cardiovascular risk level (calculated using SCORE16), (B) ethnicity, and (C) speciality of physician. EAS: European Atherosclerosis Society; ESC: European Society of Cardiology; LDL-C: low-density lipoprotein cholesterol; SCORE: Systemic Coronary Risk Estimation. *n refers to the number of patients not the number of physicians.

4.9

6.7

11.4

10.3

8.9

8.1

15.4

11.7

28.6

33.6

35.0

7.1

21.4

100

11.9

28.6 20 14.3 Low (n = 1)

Moderate (n = 7)

29.6

24.4

23.8 7.1

Very high Not (n = 223) assessable (n = 42) Calculated cardiovascular risk level (SCORE)

Patient’s ethnicity

Proportion of patients achieving LDL-C goal (%)

28.6

100

Patients within each LDL-C level category at enrolment (%)

Proportion of patients achieving LDL-C goal (%)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

High (n = 123)

≥ 4.1 mmol/l (160 mg/dl)

≥ 3.4 to < 4.1 mmol/l (130–160 mg/dl)

≥ 3.0 to < 3.4 mmol/l (115–130 mg/dl) ≥ 1.8 to < 2.6 mmol/l (70–100 mg/dl)

≥ 2.6 to < 3.0 mmol/l (100–115 mg/dl) < 1.8 mmol/l (70 mg/dl)

Fig. 4. Percentage of patients in each LDL-C value category at enrolment (on lipid-modifying treatment), according to calculated cardiovascular risk level (calculated using SCORE16). LDL-C: low-density lipoprotein cholesterol; SCORE: Systemic Coronary Risk Estimation.

foods, which may have contributed to a rise in cardiovascular risk factors relative to other ethnic groups. Despite the lower level of education and private health cover, and high rates of cardiovascular risk factors in black African patients, LDL-C target attainment rate was 53.2% in this group compared with 54.7% in Asians and 29.8% in Caucasian/Europeans. Better LDL-C target achievement in black African patients may partially be due to the high prevalence of diabetes mellitus in the black African patients included in our sample, as LDL hypercholesterolaemia is characteristically not very severe in patients with diabetes. In addition, familial hypercholesterolaemia is relatively common in Caucasian/European individuals, and to a lesser extent in Asian South Africans, due to founder effects. Achieving LDL-C goals in patients with familial hypercholesterolaemia is more difficult, owing to very high baseline LDL-C values. A very low proportion of patients attained their LDL-C goal when treated by a cardiologist or lipidologist. This may be due to the higher proportion of patients with severe dyslipidaemia, such as familial hypercholesterolaemia, managed by these specialities. Patients with familial hypercholesterolaemia are unlikely to reach LDL-C goal with LMTs that are currently available in South Africa, and novel agents, such as PCSK9 inhibitors, would be required to manage these patients.

Limitations This study was subject to limitations that may influence its findings. The study population is not fully representative of all patients treated with LMT in South Africa. The participants

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Table 4. Laboratory values and lipid-modifying therapies at enrolment in the study population overall and by ethnicity Ethnicity Total (n = 396)

Asian (n = 98)

Black African (n = 96)

Caucasian/European (n = 144)

Other (n = 58)

LDL-C, mmol/l, mean (SD)

2.6 (1.0)

2.3 (0.8)

2.5 (0.9)

2.6 (1.1)

2.9 (1.2)

Total cholesterol, mmol/l, mean (SD)

n = 382

n = 96

n = 95

n = 134

n = 57

4.5 (1.1)

4.2 (1.0)

4.6 (1.2)

4.5 (1.0)

4.9 (1.4)

Lipid values

HDL-C, mmol/l, mean (SD) Triglycerides, mmol/l, median (IQR) Mixed dyslipidaemia,a n/n (%)

n = 375

n = 90

n = 92

n = 137

n = 56

1.2 (0.5)

1.1 (0.3)

1.3 (0.8)

1.2 (0.4)

n = 373

n = 90

n = 92

n = 134

n = 57

1.5 (1.1–2.2)

1.5 (1.1–2.4)

1.6 (1.2–2.2)

1.6 (1.1–2.0)

1.5 (1.0–2.1)

98/331 (29.6)

23/88 (26.1)

18/96 (24.0)

40/114 (35.1)

17/54 (31.5)

Other laboratory values Fasting glucose, mmol/l, mean (SD) Serum creatinine, μmol/l, mean (SD)

n = 110

n = 16

n = 20

n = 41

n = 33

7.7 (3.4)

7.4 (3.6)

9.5 (4.1)

7.4 (3.2)

7.1 (2.9)

n = 252

n = 74

n = 63

n = 74

n = 41

85.7 (30.2)

86.6 (35.6)

79.0 (24.2)

90.3 (28.4)

85.9 (30.5)

LMT Any statin, n (%)

391 (98.7)

98 (100.0)

96 (100.0)

141 (97.9)

56 (96.6)

98/391 (25.1)

9/98 (9.2)

9/96 (9.4)

69/141 (48.9)

11/56 (19.6)

69/389 (17.7)

5/98 (5.1)

12/96 (12.5)

43/139 (30.9)

9/56 (16.1)

359 (90.7)

95 (96.9)

92 (95.8)

120 (83.3)

52 (89.7)

Statin + fibrate ± other LMT, n (%)

13 (3.3)

1 (1.0)

2 (2.1)

7 (4.9)

3 (5.2)

Statin + cholesterol-absorption inhibitor ± other LMT, n (%)

10 (2.6)

2 (2.0)

0 (0.0)

8 (5.6)

0 (0.0)

High-intensity statin (in statin-treated patients),b n/n (%) On highest dose (in statin-treated patients),c n/n (%) Statin monotherapy, n (%)

HDL-C: high-density lipoprotein cholesterol; IQR: interquartile range; LDL-C: low-density lipoprotein cholesterol; LMT: lipid-modifying therapy; SD: standard deviation. a Total serum triglycerides ≥ 1 .7 mmol/l (150 mg/dl) and LDL-C > target. b Atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg. c Marketed in South Africa.

comprised mainly educated patients residing in urban areas with a high rate of private healthcare insurance, in contrast with the general population, in which most patients are treated in the public health sector. In addition, the study only included patients on stable LMT; therefore, patients with untreated dyslipidaemia are not represented. We were therefore unable to estimate what proportion of patients with an indication for LMT was receiving treatment. Owing to the observational nature of the study, and in accordance with the study design, LMTs and doses varied according to site/physician preference, and patient adherence to LMTs was not assessed. SCORE was used to assess cardiovascular risk; however, its validity in non-European populations has not been established. Only one patient was classified as at low risk; therefore, the findings are not representative of this group. In addition, missing data may have limited some analyses, including LDL-C values at first diagnosis, and the diagnosis of familial hypercholesterolaemia based upon genetic/family history data.

The authors thank the patients, their families and all investigators involved

Conclusion

References

Achievement of LDL-C goals is suboptimal in South Africa, particularly in patients at moderate and very high cardiovascular risk. Physicians’ assessment of cardiovascular risk was poor, and the use of high-dose statin or combination therapy was low, highlighting a gap between guideline recommendations and clinical practice. Sociodemographic differences between ethnic groups may also influence the management of dyslipidaemia. Improving adherence to guidelines, increasing the use of combination therapy, and the introduction of novel LMTs are important strategies for improving LDL-C goal achievement.

in this study. Medical writing assistance and editorial support, under the direction of the authors, were provided by Fiona Van, PhD, and Ian Norton, PhD, both of Prime (Knutsford, UK), funded by Sanofi, according to Good Publication Practice guidelines (link to guidelines: https://www.ismpp.org/ gpp3). Sanofi was involved in the study design, collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors. ICLPS SA investigators* Aslam Amod, Durban; Dirk Blom, Cape Town; Neville Chelin, Umbilo; Kathleen Coetzee, Paarl; Clive Corbett, Cape Town; Leon Fouche, Thabazimbi; Nyda Fourie, Bloemfontein; Uttarn Govind, Durban; Shaifali Joshi, Pretoria; Ilse Kapp, Johannesburg; Hester Johanna Kotze, Centurion; Hemant Makan, Lenasia; Akbar Anvar Mahomed, Moloto South; Nomangesi Judith Ngcakani, Port Elizabeth; Trevenesan Padayachee, Durban; Frederick Raal, Johannesburg; Saadiya Seedat, Port Elizabeth; Hans H Snyman, Brits; Julien Trokis, Cape Town.

World Health Organization. The top 10 causes of death, Fact Sheet 2018.http://www.who.int/mediacentre/factsheets/fs310/en/

(2018,

accessed 21 June 2018). 2.

Keates AK, Mocumbi AO, Ntsekhe M, Sliwa K, Stewart S. Cardiovascular disease in Africa: epidemiological profile and challenges. Nat Rev Cardiol 2017; 14: 273–293.

Maredza M, Hofman KJ, Tollman SM. A hidden menace: Cardiovascular disease in South Africa and the costs of an inadequate policy response. SA Heart 2011; 8: 48–57.

Klug E, South African Heart Association (S A Heart), Lipid and

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Atherosclerosis Society of Southern Africa (LASSA). South African

on the lifestyle, risk factor and therapeutic management of coronary

dyslipidaemia guideline consensus statement. S Afr Med J 2012; 102:

patients from 24 European countries. Eur J Prev Cardiol 2016; 23:

178–187. 5.

13. Raal F, Schamroth C, Blom D, Marx J, Rajput M, Haus M, et al.

Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipi-

CEPHEUS SA: a South African survey on the under-treatment of 14. Raal FJ, Blom DJ, Naidoo S, Bramlage P, Brudi P. Prevalence of

al. National Lipid Association recommendations for patient-centered

dyslipidaemia in statin-treated patients in South Africa: results of the

management of dyslipidemia: part 1 – executive summary. J Clin Lipidol

DYSlipidaemia International Study (DYSIS). Cardiovasc J Afr 2013; 15. Danchin N, Almahmeed W, Al-Rasadi K, Azuri J, Berrah A, Cuneo

Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood

CA, et al. Achievement of low-density lipoprotein cholesterol goals in

cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report

18 countries outside of Western Europe: the International ChoLesterol

of the American College of Cardiology/American Heart Association Task

management Practice Study (ICLPS). Eur J Prev Cardiol 2018; 25(10): 1087–1094.

Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R,

16. Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer

et al. Alirocumab and cardiovascular outcomes after acute coronary

G, et al. Estimation of ten-year risk of fatal cardiovascular disease in

syndrome. N Engl J Med 2018; 379: 2097–2107. 9.

24: 330–338.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB,

Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2889–2934. 8.

hypercholesterolaemia. Cardiovasc J Afr 2011; 22: 234–240.

Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et

2014; 8: 473–488. 7.

636–648.

Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, daemias. Eur Heart J 2011; 32: 1769–1818.

Europe: the SCORE project. Eur Heart J 2003; 24: 987–1003.

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD,

17. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA,

Murphy SA, et al. Evolocumab and clinical outcomes in patients with

Theroux P, et al. Ezetimibe added to statin therapy after acute coronary

cardiovascular disease. N Engl J Med 2017; 376: 1713–1722.

syndromes. N Engl J Med 2015; 372: 2387–2397.

10. Hermans MP, Castro Cabezas M, Strandberg T, Ferrieres J, Feely J,

18. World Health Organization Western Pacific Region, IASO international

Elisaf M, et al. Centralized Pan-European survey on the under-treat-

Association for the Study of Obesity, International Obesity Taskforce.

ment of hypercholesterolaemia (CEPHEUS): overall findings from eight

The Asia-Pacific perspective: Redefining obesity and its treatment,

countries. Curr Med Res Opin 2010; 26: 445–454.

http://www.wpro.who.int/nutrition/documents/docs/Redefiningobesity.

11. Banegas JR, López-García E, Dallongeville J, Guallar E, Halcox JP,

pdf (2000, accessed 25 June 2018).

Borghi C, et al. Achievement of treatment goals for primary preven-

19. Shisana O, Labadarios D, Rehle T, Simbayi L, Zuma K, Dhansay A, et

tion of cardiovascular disease in clinical practice across Europe: the

al. South African National Health and Nutrition Examination Survey

EURIKA study. Eur Heart J 2011; 32: 2143–2153.

(SANHANES-1). Cape Town: HSRC Press.http://www.hsrc.ac.za/

12. Kotseva K, Wood D, De Bacquer D, De Backer G, Rydén L, Jennings C, et al. EUROASPIRE IV: A European Society of Cardiology survey

uploads/pageNews/72/SANHANES-launch%20edition%20(online%20 version).pdf (2013, accessed 25 June 2018).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Ellisras Longitudinal Study 2017: The relationship between waist circumference, waist-to-hip ratio, skinfolds and blood pressure among young adults in Ellisras, South Africa (ELS 14) RB Sebati, KD Monyeki, MS Monyeki, B Motloutsi, AL Toriola, MJL Monyeki

Abstract Background: Obesity and hypertension are major risk factors for non-communicable diseases in the world today. The relationship between indicators of obesity and blood pressure needs attention in the rural South African population. Aim: This study examined the relationship between anthropometric parameters and blood pressure (BP) among young adults in the Ellisras rural area of South Africa. Methods: A total of 742 (365 females and 377 males) young adults aged 22 to 30 years, who were part of the Ellisras Longitudinal Study (ELS), participated in the research. Anthropometric and BP measurements were taken using the protocol of the International Society for the Advancement of Kinanthropometry (ISAK). Linear regression was used to determine the relationship between anthropometric parameters and BP. The risk of developing hypertension among young Elisras adults was evaluated using logistic regression. Results: The results indicted a higher but non-significant prevalence of hypertension in men (2.7%) than women (2.4%). Linear regression showed a significant positive (p < 0.05) association between waist circumference and systolic BP (beta = 0.273, 95% CI: 0.160–0.386), even after being adjusted for age and gender (beta = 253, 95% CI: 0.127–0.343). The risk for developing hypertension was significant (p < 0.05) for waist circumference (OR = 2.091, 95% CI: 1.129–3.871) after adjustment for age and gender. Conclusion: Of all anthropometric parameters, waist circumference was most significantly associated with BP (p < 0.05). Anthropometric indicators of obesity were strong predictors of hypertension among young adults in the Ellisras rural area. Keywords: hypertension, skinfolds, waist circumference, waist-tohip ratio, central obesity, adults

Department of Physiology and Environmental Health, University of Limpopo, Sovenga, South Africa RB Sebati, BSc Hons KD Monyeki, PhD, MPH, kotsedi.monyeki@ul.ac.za MS Monyeki, MPhil B Motloutsi, BSc Hons MJL Monyeki

Department of Sport, Rehabilitation and Dental Sciences, Tshwane University of Technology, Pretoria, South Africa AL Toriola, PhD

Submitted 10/4/18, accepted 24/10/18 Published online 18/9/18 Cardiovasc J Afr 2019; 30: 24–28

www.cvja.co.za

DOI: 10.5830/CVJA-2018-056

Hypertension is a significant global challenge that contributes to high risk of cardiovascular and kidney disease.1 The prevalence of hypertension continues to increase in low- and middle-income countries,2 and is mainly due to population growth, aging and behavioural risk factors such as unhealthy diet, which lead to obesity.3 Obesity usually refers to excessive storage of energy in the form of adipose tissue,4 and remains a strong predictor for the risk of developing hypertension.5 Moreover, a high prevalence of hypertension is found in individuals who are more obese or overweight than normal individuals, thus further increasing the risk for cardiovascular disease.6 Studies have also shown that obesity increases fatty tissue, which heightens vascular resistance and overworks the heart to pump blood throughout the body, thereby elevating blood pressure.7 Studies have established that anthropometry is an easy and reliable method to use for predicting cardiovascular diseases (CVDs), including hypertension.8,9 However, such studies were mostly conducted in children and fewer in adults, especially in rural areas.10,11 In the same rural population, Monyeki et al.12 reported skinfold thickness, waist circumference (WC) and body mass index (BMI) to have a significant positive association with blood pressure at a younger age (seven to 13 years). However, little is known about the association between WC, waist-to-hip ratio (WHR) and skinfold thickness with BP in young adults. Therefore, the aim of this study was to assess the relationship between anthropometric (WC, skinfold thickness, WHR) parameters and BP among young Ellisras adults aged between 22 and 30 years.

Methods Ellisras, now known as Lephalale, is a rural area based in Limpopo province, South Africa. Ellisras has approximately 42 settlements, with a population of about 5 000 people.13 Ellisras village (23° 40’S, 27° 44’W) is about 70 km from the nearest settlement on the Botswana border. In Ellisras, the Iscor coal mine and Matimba electricity station are the main sources of employment for the people, while other sources of livelihood include crop farming and cattle rearing, as few individuals are educated. Unemployment and

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

poverty appear to be a major concern in South African rural areas, including Ellisras.14 Details of the Ellisras Longitudinal Study (ELS) research design and sampling procedure have been reported elsewhere.15,16 For the purpose of this analysis, a total of 742 young adults aged 22 to 30 years (365 females and 377 males), who were part of the ELS, participated in this survey. The ethics committee of the University of the North, now known as the University of Limpopo, granted approval prior to the survey. Participants read and signed informed consent forms. All subjects went through a series of anthropometric measurements based on the standard procedures recommended by the International Society for the Advancement of Kinanthropometry (ISAK).17 Skinfold (triceps, biceps, subscapular and supraspinale) and height were measured using both the Martin anthropometer and Slim Guide skinfold calliper. Height was rounded off to the nearest 0.1 cm and skinfolds were measured three times, where the values were rounded off to the nearest 0.1 mm. A flexible steel tape was used to measure WC in centimetres as participants assumed a standing position. WC was measured sideways from midway between the lowest portion of the rib cage and iliac crest and anteriorly, midway between the xiphoid process of the sternum and the umbilicus. Measurements for both systolic (SBP) and diastolic blood pressure (DBP) were taken at least three times with the electronic Micronta monitoring kit at an interval of five minutes, after the participants had been sitting for at least 15 minutes in a well-ventilated room.18,19 The device contained an infrasonic transducer that keeps records of BP and pulse rate on the display screen. The device has been used for research and clinical purposes.20 Readings taken with a conventional mercury sphygmomanometer and an automated device showed a high correlation (r = 0.93), based on a pilot study conducted before the actual survey. Readings for intra- and inter-tester technical errors of measurement (% TEM) for height, skinfolds and WC ranged from 0.04 to 4.16 cm (0.2–5.01%), 0.2 to 6 mm (0.4–6.8%) and 0 to 3.4 cm (0–4%), respectively.12

Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, according to WHO.21 Central obesity was assessed based on WC and WHR as follows: WC in men ≥ 102 cm and in women ≥ 88 cm, and WHR ≥ 0.5 cm in both men and women.22 The sum of four skinfold measurements (triceps, biceps, subscapular and supraspinale), categorised as above the 85th percentile, was used to determine general obesity, where young adults were characterised as normal or excessively fat.23 The association between BP, WHR, WC and skinfolds, adjusted for age and gender, was assessed using a linear regression model. The risk of developing hypertension among young Ellisras adults who were obese or overweight was assessed with multinomial logistic regression analysis. Data were analysed using the Statistical Package for the Social Sciences (SPSS) (version 23), with the level of significance set at p < 0.05.

Results Table 1 presents descriptive statistics for anthropometric parameters, skinfolds and BP among young Ellisras adults aged 22 to 30 years. Women showed significantly (p < 0.05) higher mean average WC (82.49 ± 14.73 cm) than men (74.74 ± 9.56 cm) (p < 0.000). Men showed a significantly higher mean SBP (125.33 ± 2.60 mmHg) than women (114.32 ± 10.23 mmHg). Presented in Table 2 are the summary data on the prevalence of hypertension, overweight and central obesity among the participants as evaluated using anthropometric parameters (WC, WHR and skinfold thickness). There was a higher significant (p < 0.000) prevalence of central obesity in women (69.6%) than in men (1.4%), while the prevalence of overweight was higher in men (15.4%) than women (15.1%), although not significant. High SBP was significantly (p < 0.05) more prevalent in men (14.0%) than in women (1.9%). Table 3 indicates the Pearson correlation coefficients between anthropometric parameters, skinfold thickness and BP measurements. There were significant (p < 0.05) correlations

Table 2. Prevalence of central obesity, overweight and hypertension among young rural Ellisras adults

Statistical analysis

Men, n (%)

Women, n (%)

p-value*

5 (1.4)

134 (35.4)

0.000

High WHR

110 (30.2)

263 (69.6)

0.000

Overweight

56 (15.4)

57 (15.1)

0.142

High SBP

51 (14.0)

7 (1.9)

0.013

High DBP

11 (3.0)

9 (2.4)

0.312

8 (2.2)

5 (1.3)

0.003

Variable

Descriptive statistics for WC, WHR and skinfold thickness were computed. Independent t-tests were calculated to examine whether there were any significant gender differences in the participants’ anthropometric and haemodynamic measurements.

High WC

Hypertension Table 1. Descriptive statistics for anthropometric parameters, skinfold thickness and blood pressure among young Ellisras adults Men (n = 364)

Women (n = 375)

p-value

25.44 ± 2.60

25.52 ± 2.53

0.636

SBP, mmHg

125.33 ± 12.95

114.32 ± 10.23*

0.000

DBP, mmHg

Variable Age, years

WC, waist circumference; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 3. Pearson’s correlation coefficient between blood pressure and anthropometric parameters (skinfold thickness, WC and WHR)

71.67 ± 10.11

69.43 ± 9.12*

0.002

Variable

Biceps skinfold, cm

3.62 ± 2.10

10.70 ± 6.44*

0.000

Women

Triceps skinfold, cm

6.46 ± 4.30

12.41 ± 7.20*

0.000

Subscapular skinfold, cm

8.71 ± 3.28

12.59 ± 6.80*

0.000

Supraspinale skinfold, cm

5.11 ± 3.57

12.34 ± 7.19*

0.000

Waist-to-height ratio

0.434 ± 0.082

0.509 ± 0.122*

0.000

SBP

0.012**

Waist circumference, cm

74.74 ± 9.56*

82.49 ± 14.73*

0.000

DBP

0.059

Mean ± SD; *p < 0.05. SBP, systolic blood pressure; DBP, diastolic blood pressure.

Triceps

Biceps

Subscapular Supraspinale WHR

Waist

SBP

0.022**

0.021**

0.053**

0.140

0.175

0.237

DBP

0.046**

0.007**

0.013**

0.093

0.136

0.684

0.015**

0.120

0.016

0.231

0.303

0.017**

0.054**

0.068

0.171

0.211

Men

**Correlation is significant at the 0.05 level (two-tailed). SBP, systolic blood pressure; DBP, diastolic blood pressure.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 4. Liner regression analysis for the association of WC, WHR and skinfold thickness with blood pressure Unadjusted (for age and gender) β

Variable

p-value

95% CI

p-value

95% CI

Variable

p-value

95% CI

Adjusted (for age and gender) p-value

95% CI

High systolic blood pressure 0.229

0.171

Abdominal obesity (WC)

0.952 0.983

0.163–0.378

Overweight

0.045 1.634

0.143–0.064

0.025–0.059

Abdominal (WHR)

0.080 0.660

16.654–8.327

9.419–14.301

0.556–0.099 0.397

0.013

0.854

0.000

0.709–0.085

0.527–1.182

0.010–0.647

1.420–0.697

0.603–0.160

0.465–0.088

0.160–0.386 Subscapular

Unadjusted (for age and gender)

Adjusted (for age and gender)

Systolic blood pressure Triceps

Table 5. Logistic regression analysis of association of anthropometric variables with hypertension among young Ellisras adults

0.318

0.127–0.343 0.057

0.566–1.707

0.019 2.091

1.129–3.871

0.460

1.229

0.712–2.122

0.830

1.061

0.621–1.812

0.273 1.543

0.711–3.343

1.012–2.801 0.415–1.051

High diastolic blood pressure Abdominal obesity (WC)

0.989 1.005

0.491–2.059 0.741–2.590 0.592–2.009

Biceps

1.058

0.000

0.222

0.254

Supraspinale

0.188

0.181

0.108

0.435

Overweight

0.308 1.385

0.676

1.147

0.604–2.177

Sum of 4 skinfolds

0.103

0.000

0.017

0.433

0.782 1.090

0.308

1.396

0.735–2.653

WHR

4.163

0.513

2.441

0.686

Abdominal obesity (WHR)

0.273

0.000

0.253

0.000

Abdominal obesity (WC)

0.041 2.775

0.891–8.585

Overweight

0.987 1.012

0.532

0.548

0.068–4.175

Abdominal obesity (WHR)

0.416 1.596

1.906

0.314

0.543–6.699

Hypertension

Diastolic blood pressure Triceps

0.377

0.004

0.633–0.122 0.412

Biceps

0.669–0.155 0.137–0.404

0.392–0.172

0.216–0.412

0.225–0.207

0.165–0.218

0.053–0.006

0.037–0.031

7.766–11.726

6.243–13.286

0.053–0.230 Subscapular

0.002

0.013–0.525

6.186 0.049 1.0073–7.993

0.221–4.614 0.514–4.896

Dependent variables: DBP, SBP, hypertension. WC, waist circumference; WHR, waist-to-hip ratio.

0.036–0.213

0.269

0.039

0.133

0.333

110

0.443

0.098

0.541

Supraspinale

0.009

0.935

0.058

0.608

Sum of 4 skinfolds

0.024

0.118

0.003

0.856

WHR

1.980

0.690

3.522

0.479

0.141

0.002

0.124

Dependent variables: DBP and SBP. WC, waist circumference; WHR, waist-to-hip ratio.

between triceps (r = 0.022), biceps (r = 0.021) and subscapular (r = 0.053) skinfolds and SBP in women, while DBP in women was significantly (p < 0.05) associated with triceps (r = 0.046), biceps (r = 0.007) and subscapular (r = 0.013) skinfolds. In men, SBP significantly (p < 0.05) correlated with triceps (r = 0.012) and biceps (r = 0.015) skinfolds, while DBP was substantially (p < 0.05) correlated with biceps (r = 0.017) and subscapular (r = 0.054) skinfolds. Table 4 presents linear regression coefficients for the association between anthropometric parameters and BP. The results exhibited a significant positive (p < 0.000) relationship between WC and SBP (beta = 0.273; 95% CI: 0.053–0.230), even after being adjusted for age and gender (beta = 2.091; 95% CI: 1.129–3.871). There was a significant positive (p < 0.002) association between WC and DBP (beta = 0.141; 95% CI: 0.053–0.230) when the data were unadjusted for age and gender. Triceps skinfold (p < 0.004) was significantly associated with DBP (beta = 0.377; 95% CI: 0.633–0.122), even after the data were adjusted for age and gender (p < 0.002) (beta = 0.412; 95% CI: 0.669–0.155). Table 5 presents logistic regression analyses to determine the risk of developing hypertension among young Ellisras adults. High SBP was associated with abdominal obesity (WC) after adjusting for age and gender (OR = 2.091, 95% CI: 1.129–3.871). There was a significant association between high SBP and overweight (OR = 1.634, 95% CI: 1.012–2.801).

Discussion The purpose of the study was to determine the association between anthropometric parameters and BP among young Ellisras adults aged 22 to 30 years. In this study, WC was significantly associated with both SBP and DBP. This confirms the results of previous studies in which a significant positive association between WC and both SBP and DBP was reported among adults aged 23 to 40 years.24,25 Although studies have been conducted in different parts of the world, subjects of similar ages were targeted, therefore resulting in similar findings. Furthermore, a study carried out in adolescents aged 13 to 19 years found similar results.9 However, Ashwell et al.22 found that WHR was positively associated with SBP among adults. The study focused on individuals aged 60 years and older, therefore making the age difference a plausible explanation for the disparity in published research findings. Our study also found that there was no significant association between both SBP and DBP and WHR. Contrary to this, Barbosa et al.26 found WHR to be significantly associated with both SBP and DBP. Regarding skinfold thickness, the present study found that both SBP and DBP were significantly correlated with triceps, biceps and subscapular skinfolds among young Ellisras adults. Similarly, Birmingham et al.27 reported a significant positive correlation between subscapular, triceps and biceps skinfolds and both SBP and DBP in individuals aged 18 to 40 years. Furthermore, the results agree with those of Dua et al.28 and Timpson et al.,29 which indicated a significant positive association between triceps, biceps and subscapular skinfolds and BP in adults. In our study, men (1.9%) had a higher prevalence of hypertension compared to women (1.3%). Tesfaye et al.30 also found the prevalence of hypertension to be higher in men (21.0%) than in women (16.4%). It has been reported that gender differences in the association between anthropometric variables and blood pressure could be influenced by both biological

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

and behavioural risks.31 Biological factors include chromosome differences and sex hormones, which serve as a mechanism of protection against hypertension in most young women until they reach menopause.32 In contrast to our study, Luz et al.33 reported the prevalence of hypertension to be 54.6 and 71.3% in men and women, respectively. The study focused more on older adults rather than young adults. As women grow older, their oestrogen levels decrease while the pituitary hormones increase, thus putting older women at a greater risk of developing hypertension than men.34 In our study, the prevalence of central obesity was found to be higher in women (35.4–69.6%) than in men (1.4–30.2%). Barbosa et al.26 also found a higher prevalence of central obesity in women (65.1%) than men (40.1%), as did Munaretti et al.35 (women 63.2%; men 18.7%). Women have a larger amount of body fat compared to men.36 In addition, lifestyle risks such as excessive consumption of diets rich in refined fats, oil and carbohydrates contribute to the elevation of central obesity.37 Most studies are in agreement with our study as they have also reported the incidence of general obesity to be higher in women than in men.38,39 Al-Hazzaa et al.40 reported that general obesity can be high in either men or women, taking into account their behavioural risk factors such as smoking and alcohol consumption. We found that WC and overweight were significantly associated with hypertension and can best be used to predict the risk of hypertension in individuals who are obese. Sakurai et al.25 also reported a strong association between WC and hypertension among Asians aged 19 to 33 years. Furthermore, Zhu et al.24 found that WC, overweight and hypertension were significantly correlated in white Americans living in an urban setting. However, our findings contradict those reported by Munaretti et al. 35 in which WHR was shown to be a significant predictor of hypertension. The contradiction between the two studies is probably because WHR is considered to have greater accuracy because of the nature of the measurements required, compared to WC and participants’ age categories. The study setting was also different.22 Individuals with high WC in our study were at a greater risk of developing hypertension. Although the current study found WC and overweight to be the best predictors for hypertension, Hou et al.41 reported that the prediction of individuals who are at a greater risk of developing CVD, specifically hypertension, can be improved by combining WC, WHR and BMI. These findings are consistent with those published previously.24,42 However, Hans et al.43 reported that the WC parameter has several advantages compared to other parameters because of its ease of measurement and interpretation in most clinical settings. The present study did not include predisposing factors such as diet, lifestyle and level of physical activity for central obesity. Other important factors associated with hypertension, such as medical history, family history, alcohol intake and smoking, were not assessed. The study had a low sample size therefore its findings cannot be representative of all young adults in South Africa.

overweight (the sum of four skinfolds). It is vital to investigate the relationship between lifestyle and biological risk factors for cardiovascular disease over time. The financial support received from University of Limpopo, South Africa, and the National Research Foundation of South Africa, for the Ellisras Longitudinal Study is gratefully acknowledged. Any opinions, findings and conclusions or recommendations expressed in this report are those of the authors and therefore the above funding sources do not accept any liability in regard thereto. The authors are indebted to ELS administrators, Seleka Simon, Makata William and Jan Mabote, for providing technical support in the preparation of this manuscript.

References 1.

He H, Kimura S, Fujisawa Y, Tomohiro A, Kiyomoto K, Aki Y, Abe Y. Dietary L-arginine supplementation normalizes regional blood flow in Dahl-Iwai salt-sensitive rats. Am J Hypertens 1997; 10(S4): 89S–93S.

Fuentes R, Ilmaniemi N, Laurikainen E, Tuomilehto J, Nissinen A. Hypertension in developing economies: a review of population‐based studies carried out from 1980 to 1998. J Hypertens 2000; 18(5): 521–529.

Gersh BJ, Sliwa K, Mayosi BM, Yusuf S. Novel therapeutic concepts the epidemic of cardiovascular disease in the developing world: global implications. Eur Heart J 2010; 31(6): 642–648.

Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15(4): 6184–6223.

Montani JP, Antic V, Yang Z, Dulloo A. Pathways from obesity to hypertension: from the perspective of a vicious triangle. Int J Obes 2002; 26(S2): S28.

Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr 2004; 79(3): 379–384.

Richard N. Obesity-related hypertension. Ochsner J 2009; 9(3): 133–136.

Sanchez-Viveros S, Barquera S, Medina-Solis CE, Velazquez-Alva MC, Valdez R. Association between diabetes mellitus and hypertension with anthropometric indicators in older adults: results of the Mexican Health Survey, 2000. J Nutr Health Aging 2008; 12(5): 327–333.

Silva SM, Facchini LA, Tomasi E, Piccini R, Thume E, Silveira DS, et al. Advice for salt, sugar and fat intake habits among adults: a nationalbased study. Rev Bras Epidemiol 2013; 16: 995–1004.

10. Nafiu OO, Zepeda A, Curcio C, Prasad Y. Association of neck circumference and obesity status with elevated blood pressure in children. J Hum Hypertens 2014; 28(4): 263. 11. Idler EL, Benyamini Y. Self-rated health and mortality: a review of twenty-seven community studies. J Health Soc Behav 1997: 21–37. 12. Monyeki KD, Kemper HCG, Makgae PJ. Relationship between fat patterns, physical fitness and blood pressure of rural South African children: Ellisras Longitudinal Growth and Health Study. J Hum Hypertens 2008; 22: 311–319; advance online publication, February 14, 2008; doi:10.1038 /jhh. 2008.3 13. Sidiropoulos E, Jeffery A, Mackay S, Gallocher R, Forgey H, Chips C. South Africa Survey 1995/1996. Johannesburg: South African Institute of Race and Relations 1996: 234–360. 14. Statistics South Africa. Cause of death in South Africa 1997–2001.

Conclusion The prevalence of hypertension was high in men compared to women. Hypertension was significantly related to WC and

Advance Release of Records of Death. Pretoria: Statistics South Africa, 2002: 18–42. 15. Monyeki KD, Van Lenthe FJ, Steyn NP. Obesity: does it occur in African children in a rural community in South Africa?. Int J Epidemiol

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

1999; 28(2): 287–292.

AFRICA

relates to blood pressure among adults. N Am J Med Sci 2014; 6(2): 89.

16. Monyeki KD, Cameron N, Getz B. Growth and nutritional status of

29. Timpson NJ, Harbord R, Smith GD, Zacho J, Tybjærg-Hansen A,

rural South African children 3–10 years old: The Ellisras growth study.

Nordestgaard BG. Does greater adiposity increase blood pressure and

Am J Hum Biol 2000; 12(1): 42–49.

hypertension risk? Mendelian randomization using the FTO/MC4R

17. Norton K, Olds T (eds). Anthropometrica: A Textbook of Body Measurement for Sports and Health Courses. UNSW Press, 1996. 18. National high blood pressure education program (NHBPEP) working group on hypertension control in children and adolescents. Update on the 1987 task force report on high blood pressure in children and adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics 1996; 98: 649–658. 19. National High Blood Pressure Education Program Working Group on

genotype. Hypertension 2009; 54(1): 84–90. 30. Tesfaye F, Byass P, Wall S. Population based prevalence of high blood pressure among adults in Addis Ababa: uncovering a silent epidemic. BMC Cardiovasc Disord 2009; 9(1): 39. 31. Sandberg K, Ji H. Sex differences in primary hypertension. Biol Sex Differ 2012; 3(1): 7. 32. Rosano GM, Vitale C, Fini M. Cardiovascular aspects of menopausal hormone replacement therapy. Climacteric 2009; 12(sup1): 41–46.

High Blood Pressure in Children and Adolescents. The fourth report

33. Luz RH, Barbosa AR, d’Orsi E. Waist circumference, body mass index

on the diagnosis, evaluation, and treatment of high blood pressure in

and waist-height ratio: Are two indices better than one for identifying

children and adolescents. Pediatrics 2004; 114: 555–576. 20. Monyeki KD, Kemper HC. The risk factors for elevated blood pressure and how to address cardiovascular risk factors: a review in paediatric populations. J Hum Hypertens 2008; 22(7): 450. 21. Higgins JR, de Swiet M. Blood-pressure measurement and classification in pregnancy. Lancet 2001; 357(9250): 131–135.

hypertension risk in older adults? Prev Med 2016; 93: 76–81. 34. Zaitunel M. Survey on nutritional and health status. Prev Med 2006; 19: 1–2. 35. Munaretti DB, Barbosa AR, Marucci MD, Lebrão ML. Self-rated hypertension and anthropometric indicators of body fat in elderly. Rev Assoc Med Bras 2011; 57(1): 25–30.

22. Ashwell M, Gunn P, Gibson S. Waist‐to‐height ratio is a better screen-

36. Fares D, Barbosa AR, Borgatto AF, Coqueiro RD, Fernandes MH.

ing tool than waist circumference and BMI for adult cardiometabolic

Factors associated with nutritional status of the elderly in two regions

risk factors: systematic review and meta‐analysis. Obes Rev 2012; 13(3): 275–286. 23.

Twisk JW, Kemper HC, Van Mechelen W, Post GB. Tracking of risk factors for coronary heart disease over a 14-year period: a comparison between lifestyle and biologic risk factors with data from the Amsterdam

of Brazil. Rev Assoc Med Bras 2012; 58(4): 434–441. 37. Kruger J, Ham SA, Prohaska TR. Peer reviewed: Behavioral risk factors associated with overweight and obesity among older adults: the 2005 National Health Interview Survey. Prev Chronic Dis 2009; 6(1): A14. 38. Moges B, Amare B, Fantahun B, Kassu A. High prevalence of over-

Growth and Health Study. Am J Epidemiol 1997; 145(10): 888–898.

weight, obesity, and hypertension with increased risk to cardiovascular

24. Zhu S, Heshka S, Wang Z, Shen W, Allison DB, Ross R, Heymsfield SB.

disorders among adults in northwest Ethiopia: a cross sectional study.

Combination of BMI and waist circumference for identifying cardiovascular risk factors in whites. Obesity 2004; 12(4): 633–645. 25. Sakurai M, Miura K, Takamura T, Ota T, Ishizaki M, Morikawa Y,

BMC Cardiovasc Disord 2014; 14(1): 155. 39. World Health Organization. Noncommunicable Diseases Country Profiles. Geneva: World Health Organization, 2011.

et al. Gender differences in the association between anthropometric

40. Al-Hazzaa HM, Abahussain NA, Al-Sobayel HI, Qahwaji DM,

indices of obesity and blood pressure in Japanese. Hypertens Res 2006;

Musaiger AO. Lifestyle factors associated with overweight and obesity

29(2): 75.

among Saudi adolescents. BMC Public Health 2012; 12(1): 354.

26. Barbosa PV, Makhlouf AA, Thorner D, Ugarte R, Monga M. Optimal

41. Hou X, Lu J, Weng J, Ji L, Shan Z, Liu J, et al. Impact of waist circum-

cut-off points for obesity: using simple anthropometric indices for

ference and body mass index on risk of cardiometabolic disorder and

prediction for the risk of hypertension. Int J Obes Relat Metab Disord

cardiovascular disease in Chinese adults: a national diabetes and meta-

2011; 26: 1232–1238. 27. Birmingham B, Dyer AR, Shekelle RB, Stamler J. Subscapular and triceps skinfold thicknesses, body mass index and cardiovascular risk factors in a cohort of middle-aged employed men. J Clin Epidemiol 1993; 46(3): 289–302. 28. Dua S, Bhuker M, Sharma P, Dhall M, Kapoor S. Body mass index

bolic disorders survey. PLoS One 2013; 8(3): e57319. 42. Barreto M. Prevalence of risk factors for hypertension and waist circumference in Brazil. J Hypertens 2015; 20:14–20. 43. Han S, Chen X, Cox B, Yang CL, Wu YM, Naes L, Westfall T. Role of neuropeptide Y in cold stress-induced hypertension. Peptides 1998; 19(2): 351–358.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Outcomes in patients with acute coronary syndrome in a referral hospital in sub-Saharan Africa Mohamed Hasham Varwani, Mohamed Jeilan, Mzee Ngunga, Anders Barasa

Abstract Background: Coronary artery disease and its acute presentation are being increasingly recognised and treated in subSaharan Africa. It is just over a decade since the introduction of interventional cardiology for coronary artery disease in Kenya. Local and regional data, and indeed data from subSaharan Africa on long-term outcomes of acute coronary syndromes (ACS) are lacking. Methods: A retrospective review of all ACS admissions to the Aga Khan University Hospital, Nairobi (AKUHN) between January 2012 and December 2013 was carried out to obtain data on patient characteristics, treatment and in-patient outcomes. Patient interviews and a review of clinic records were conducted to determine long-term mortality rates and major adverse cardiovascular events. Results: A total of 230 patients were included in the analysis; 101 had a diagnosis of ST-segment myocardial infarction (STEMI), 93 suffered a non-ST-segment myocardial infarction (NSTEMI), and 36 had unstable angina (UA). The mean age was 60.5 years with 81.7% being male. Delayed presentation (more than six hours after symptom onset) was common, accounting for 66.1% of patients. Coronary angiography was performed in 85.2% of the patients. In-hospital mortality rate was 7.8% [14.9% for STEMI and 2.3% for non-ST-segment ACS (NSTE-ACS, consisting of NSTEMI and UA)], and the mortality rates at 30 days and one year were 7.8 and 13.9%, respectively. Heart failure occurred in 40.4% of STEMI and 16.3% of NSTE-ACS patients. Re-admission rate due to recurrent myocardial infarction, stroke or bleeding at one year was 6.6%. Conclusion: In our series, the in-hospital, 30-day and one-year mortality rates following ACS remain high, particularly for STEMI patients. Delayed presentation to hospital following symptom onset is a major concern. Keywords: acute coronary syndromes, myocardial infarction, outcomes, Kenya, sub-Saharan Africa

Department of Medicine, the Aga Khan University Hospital, Nairobi, Kenya Mohamed Hasham Varwani, MB ChB, MMed, mhvarwani@gmail.com Mohamed Jeilan, MD, MRCP Mzee Ngunga, MB ChB, MMed Anders Barasa, MD, PhD

Department of Clinical and Molecular Medicine, University of Gothenburg, Gothenburg, Sweden Anders Barasa, MD, PhD

Submitted 26/9/17, accepted 31/10/18 Published online 4/12/18 Cardiovasc J Afr 2019; 30: 29–33

www.cvja.co.za

DOI: 10.5830/CVJA-2018-066

The burden of cardiovascular diseases (CVD) in sub-Saharan Africa (SSA) is rapidly increasing, with a rising prevalence of cardiovascular risk factors.1-3 In SSA, CVD occurs in younger patients who are often in the working age group, thereby having a significant economic bearing.4 Coronary artery disease (CAD), once thought to be rare among native Africans, is increasingly being diagnosed.5,6 In a recent prospective survey carried out at an urban hospital in Kenya, acute coronary syndromes (ACS) contributed to 5.1% of all admissions to the critical care units.7 An autopsy study by Ogeng’go et al. reported that cardiovascular deaths comprised 13.2% of all autopsies performed during the study period.8 Among these, the leading aetiology was myocardial infarction (18.7%). The findings of these more recent studies contrast with reports from the 1960s that suggested a very low prevalence of CAD.9 It is nearly a decade since the introduction of coronary interventions and coronary surgery in Kenya. The supporting infrastructure for emergency response and intervention, however, lags behind. Most cardiovascular specialists and catheterisation laboratories (cathlabs) in the country are disproportionately located in Nairobi, the capital city. Following an ACS, a patient remains at elevated risk of death and major adverse events such as heart failure, recurrent myocardial infarction, stroke and bleeding, compared to the general population.10 Over the last three decades, both shortterm (in-hospital and 30-day) and long-term survival following myocardial infarction has been improving worldwide.11 This is thought to be due to improved response infrastructure, availability of better drugs and interventions for the acute phase, and use of secondary preventative therapies such as statins and beta-blockers. Little is known about the outcomes of patients following an ACS in SSA.5 Apart from a report based on South African data from the ACCESS registry, no published studies were found that looked at out-of-hospital outcomes following ACS in SSA.12 A few local reports have described the management and in-hospital outcomes in patients with ACS.7,13,14 Long-term outcomes in the country and region however remain unknown. The Aga Khan University Hospital, Nairobi, is a private teaching hospital, serving as a referral centre for patients within Kenya and the broader region of East and Central Africa. A heterogenous cohort of patients is therefore served at the facility. The cathlab operates during the daytime, but is available for emergencies after that, with an on-call interventional cardiologist and cathlab team.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Methods The primary study objective was to determine the in-hospital and long-term (30-day and one-year) mortality rates of ACS patients treated at the Aga Khan University Hospital, Nairobi (AKUHN). Secondary objectives were to determine the rate of in-hospital non-fatal events, specifically heart failure, recurrent myocardial infarction (MI), need for repeat revascularisation, stroke and major bleeding, and to determine the rate of rehospitalisation in the first year owing to major adverse events (recurrent MI, stroke and major bleeding). This was a cross-sectional, retrospective review of chart and electronic health records for all patients admitted with ACS between 1 January 2012 and 31 December 2013. To confirm our findings, and where chart data were ambiguous, telephone interviews were conducted with the patients and documented relatives to determine the long-term outcomes following discharge. Ethical approval was obtained from the Ethical and Scientific Review Committee of the AKUHN. Verbal consent was obtained from the participants prior to initiating the telephone interview. The study included patients who received a discharge diagnosis of ACS and its subcategories: ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina (UA) (ICD 10 codes I20.0, I21, I22, respectively). Patients with suspected type 2 MI were excluded. MI was defined by the third universal definition of MI;15 major bleeding was defined as per the TIMI bleeding criteria,16 and the diagnosis of stroke was based on the American Heart Association/American Stroke Association updated definition.17 Other outcome definitions were based on accepted definitions used in cardiovascular trials.18

Statistical analysis IBM Statistical Package for Social Sciences (SPSS) version 21 was used to analyse the data. All patients were grouped into Table 1. Demographic and clinical characteristics of patients Patient characteristics

STEMI (n = 101 )

Age, years

58.7 ± 13.8

61.9 ± 12.0

0.063

Male gender, %

81.2

82.2

0.865

Diabetes, %

43.6

31.0

0.054

Hypertension, %

52.5

64.3

0.080

22.8

23.3

1.0 < 0.001

Prior myocardial infarct, % Creatinine clearance (Cockcroft–Gault), ml/min/1.73 m2

5.9

28.7

108.6 ± 60.7

103.8 ± 45.3

0.135

84.2 ± 38.4

82.7 ± 37.1

0.555

Total cholesterol, mmol/l

4.6 ± 1.4

4.5 ± 1.4

0.588

HDL, mmol/l

1.1 ± 0.3

0.348 0.683

2.9 ± 1.3

2.8 ± 1.2

BMI, kg/m2

27.6 ± 4.1

28.1 ± 5.1

0.188

Systolic BP, mmHg

127 ± 28

140 ± 24

0.128

88 ± 19

79 ± 17

0.021

33.7

34.9

LDL, mmol/l

Pulse rate per minute Ethnicity Black African, % Caucasian, % Asian Indian, %

4.0

9.3

62.4

55.8

Results During the 24-month period, 230 patients were admitted with ACS. Of these, 101 had a STEMI, 93 suffered an NSTEMI, and 36 had UA. Demographic and clinical characteristics of the patients are summarised in Table 1. Fewer than 10% of patients presented within one hour of symptom onset, while more than 35% took longer than 24 hours to arrive at the hospital, some taking as long as two weeks (Fig. 1). Patients with STEMI tended to present earlier, compared to those with NSTE-ACS, with 46.6 and 23.3% presenting within six hours of symptom onset, respectively. Of the 101 patients admitted with STEMI, 49 received thrombolytic therapy while 19 patients underwent primary percutaneous intervention (PCI). Thirty-three patients presented outside the acute phase and did not receive acute reperfusion therapies. The mean time to thrombolysis and PCI was 49 (± 42) and 137 (± 63) minutes, respectively. Target door-to-needle time for thrombolysis of 30 minutes was met in 26 of the 49 patients thrombolysed (53.1%), and door-to-balloon time of 90 minutes in five of the 19 patients taken for primary PCI (26.3%). One hundred and ninety-six of 230 (85.2%) patients underwent coronary angiography. The left anterior descending

p-value

Smoker, % Creatinine, μmol/l

either STEMI or non-ST-elevation ACS (NSTE-ACS, consisting of NSTEMI or UA) for comparison of demographic and clinical characteristics, and outcome variables of interest. Continuous variables are expressed as mean ± standard deviation and comparisons between means were performed using independent samples Student’s t-test. Categorical variables are expressed as percentages, and comparisons between subgroups were performed using Fisher’s exact test. Survival analysis was performed using Kaplan–Meier estimates. The duration from event to death was calculated for patients who died. Patients were censored at the date of last contact based on the medical records or on the date of the telephone interview, whichever was latest.

STEMI, ST-elevation myocardial infarction, NSTE-ACS, non-ST-elevation acute coronary syndrome; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; BMI, body mass index.

Diagnosis STEMI NSTE-ACS

Percent

NSTE-ACS (n = 129 )

AFRICA

<1 hour

1–3 hours

3–6 6–12 hours hours Presentation

12–24 hours

> 24 hours

Fig. 1. Duration from symptom onset to presentation in patients with acute coronary syndrome.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 2. In-hospital events STEMI (n = 101 )

NSTE-ACS (n = 129)

p-value

Death, n (%)

15 (14.9)

3 (2.3)

< 0.001

Heart failure, n (%)

40 (40.4)

21 (16.3)

< 0.001

Events

Stroke, n (%)

1 (1)

3 (2.3)

0.64

Major bleed, n (%)

2 (2)

2 (1.6)

Repeat revascularisation, n (%)

STEMI, ST-elevation myocardial infarction, NSTE-ACS, non-ST-elevation acute coronary syndrome.

artery was the most common culprit vessel, accounting for 51.6% of STEMI and 37.8% of NSTE-ACS. Non-occlusive coronary artery disease was found to be the underlying cause of ACS in two patients with STEMI and three with NSTE-ACS. Of the 196 patients, 64 (32.8%) were found to have multi-vessel disease. Of the 230 patients, 219 had documented left ventricular function assessment done by two-dimensional echocardiography. Left ventricular ejection fraction (LVEF) of patients with STEMI was significantly lower than that of NSTE-ACS patients (42.2 vs 50.3%, p < 0.001). In-hospital outcomes are summarised in Table 2. Fifteen patients with STEMI (14.9%) and three with NSTE-ACS (2.3%) died while in hospital. The mean duration of event to death in hospital was 11 days (± 16.9) for STEMI patients and 21.3 days (± 19.3) for patients with NSTE-ACS. Heart failure was the most common in-hospital complication and was more likely to occur in STEMI patients (40.4 vs 16.3%, p < 0.001). One patient with STEMI and three with NSTE-ACS suffered a stroke, while two patients in each category developed a major bleed. Survival status and out-of-hospital outcome data were obtained in 184 of 212 patients (86.8%) discharged alive from hospital. At the end of 30 days, 7.8% of the patients had died, and at the end of one year after the event, 13.9% had died. The

1.0

Cumulative survival

0.8

0.6

0.4

0.2

0.0

0.00

10.00

20.00

30.00

40.00

50.00

60.00

Duration (months) Diagnosis STEMI NSTE-ACS STEMI-censored NSTE-ACS-censored

Chi-Square DF

Breslow

6.915

0.009

Tarone-Ware

5.726

0.017

Log Rank

4.188

0.041

Fig. 2. Kaplan–Meier curves for survival.

mortality rate at both 30 days (13.7 vs 3.1%) and one year (20.8 vs 8.5%) was higher in patients with STEMI compared to those with NSTE-ACS. Kaplan–Meier survival curves for STEMI and NSTE-ACS are displayed in Fig. 2. There was an early and significant separation of the curves, and while this reduced over the course of time, the difference remained significant at the end of 50 months of follow up (Fig. 2). A total of 14 of the 212 patients discharged alive (6.6%) were readmitted during the first year following the event. Of these, 10 patients suffered a recurrent myocardial infarction; one patient was readmitted with a stroke, and three patients were admitted due to major bleeding.

Discussion With increasing awareness of the problem and access to expertise and facilities, management of ACS in East and Central Africa has seen some evolution in the past decade. In 2006, there were only two functioning cathlabs in the region, both located in Kenya. By 2012 this number grew to five, and in 2017 there were 12 cathlabs located within three countries in the region. A few reports have described management practices and in-hospital outcomes. However this is the first study in the region that reports on both in- and out-of-hospital outcomes in patients who have suffered ACS. The mean age of patients was 60.5 (± 12.8) years. This is comparable to the mean age in the South African cohort in the ACCESS-SA study,12 but about four years younger than that reported in a European registry, the EHS-ACS-II.19 This supports the notion that ACS is occurring at a younger age in patients from SSA compared to western countries. Notably in both the ACCESS-SA and EHS-ACS-II studies, STEMI patients were significantly younger than patients with NSTEACS (54.5 vs 60.5 years, and 62.5 vs 66.1 years, respectively). This difference was however much less pronounced in our study (58.7 and 61.9 years, respectively, p = 0.063). As in other studies, an overwhelming male predominance was noted in both subgroups. There were no significant differences between the two groups with regard to other patient characteristics, and these were comparable to those noted in other studies. In this study, 230 patients had a confirmed diagnosis of ACS in the two-year period from January 2012 to December 2013. This is more than twice the number of ACS admissions reported at the same facility between April 2008 and May 2010, reflecting the growing number of ACS patients seen and managed at the centre. STEMI comprised 44% of the patients presenting with ACS in this study. This is comparable to data from both the EHS-ACS-II and ACCESS-SA registries, in which STEMI accounted for 47 and 41% of the patients’ diagnosis, respectively. The most prominent major modifiable risk factor in our population was hypertension, present in nearly 60% of the patients. This is consistent with data from other regional and international series. Diabetes appeared more prevalent (36.5%) in our series than in other series (23.9% in ACCESS-SA and 14.1% in EHS-ACS-II). By contrast, smokers accounted for less than a quarter of the ACS cases in our series, compared to nearly double that in both of the above series.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

In our study, we considered established atheroscletic coronary disease as either prior MI or a revascularisation procedure. It was notable that this was significantly higher in patients with NSTEACS compared to the STEMI group (28.7 vs 5.9%, p < 0.001). ACS registries and other prospective surveys have looked at MI, PCI and coronary artery bypass grafting (CABG) separately. In the EHS-ACS-II series, a prior MI was reported in 15.7% of patients with STEMI and nearly double that with NSTE-ACS. Similarly, a revascularisation procedure had been performed in only 8.9% of STEMI and 21.5% of NSTE-ACS patients. This suggests that patients who have pre-existing coronary artery disease are more likely to present with NSTE-ACS than STEMI. These data need to be understood in the context of the relatively recent availability of facilities for diagnosis and coronary intervention in our region. In this study, fewer than 10% of the patients presented within one hour of symptom onset and more than 35% presented more than 24 hours later. The median time to presentation was more than 12 hours. By contrast, the median time to presentation in the the EHS-ACS-II series was less than three hours, while in the ACCESS-SA study, the median time to presentation was 3.6 and 7.4 hours for STEMI and NSTE-ACS, respectively. Prompt treatment from symptom onset, especially in STEMI, is a key determinant of patient outcomes in ACS.20 There is a significant delay in presentation to hospital in our set-up and this is an important factor to address. STEMI systems of care are rudimentary or non-existent in SSA and outcomes can be expected to be poor in this group of patients where delays to reperfusion occur. Reasons contributing to late presentation are probably multifactorial and must be studied systemically in SSA, given the unique challenges faced by patients. In many cases, a lack of appreciation for the significance of the symptoms by the patient and/or their initial point of medical contact, or a lack of ACS diagnostic facilities (ECG or cardiac enzymes) will result in a significant delay between onset of symptoms and arrival at a facility capable of managing STEMI. Public education and awareness programmes have been effective in tackling this in countries with developed ACS infrastructure. Heightened sensitivity within the healthcare fraternity targetting such facilities may facilitate early diagnosis. Moreover, a structured referral system that intergrates treatment strategies, such as pre-referral thrombolysis and emergency medical technician (EMT) services, would help to reduce delays in treatment and improve outcomes. In the study, 48.5% of patients with STEMI received thrombolysis, 15.8% were subjected to primary PCI, and no acute reperfusion was performed in nearly 35% of patients, primarily due to delayed presentation. This contrasted with the strategies employed in the EHS-ACS-II series in which, of the 63.9% of patients who received primary revascularisation treatment, a greater proportion (51.8%) of patients was treated with primary PCI. The low rate of primary PCI compared to thrombolysis might reflect the absence of a 24-hour on-site team, and a perceived delay in arrival of the on-call team. Given the low volume of pimary PCI in most cathlabs in the region, it is not yet cost effective to have an on-site team. However, when considering the temporal trends within our unit, the rate of primary PCI has increased nearly two-fold from that reported by Shavadia et al. in the 2008–2010 series. This

AFRICA

reflects the increased availability of interventional expertise and may also reflect established processes to facilitate delivery of these services within the unit. STEMI patients in our series had a higher mortality rate compared to other series.12,19 As discussed, a large proportion of patients in our series had a significant delay from onset of symptoms to hospital presentation, with more than half presenting more than 12 hours after symptom onset. It is well known that outcomes in STEMI are strongly related to the promptness of acute reperfusion therapy, therefore delayed presentation of patients may account for the increased in-hospital and long-term mortality rates compared to other series. The STEMI group had a significantly lower LVEF and were also more likely to develop heart failure while in hospital compared to NSTE-ACS patients. This implies that significant myocardial damage had occurred in a significant proportion of these patients. In a series that reported on long-term outcomes, early mortality rate was often higher in STEMI patients, but by the end of one year, this was usually similar to or lower than in NSTE-ACS patients.21 In our series, we noted a higher STEMI mortality rate, even at the end of one year. Also, the Kaplan–Meier survival estimates suggest a significantly higher STEMI mortality rate even beyond one year. Again, this may be associated with significant myocardial damage that occurs in patients with STEMI, predisposing them to long-term mortality. Heart failure or cardiogenic shock was the most common in-hospital complication occurring in 26.5% of patients, with STEMI patients twice as likely to develop this. In the EHS-ACSII series, this occurred in a significantly lower proportion of patients (12.4%). Delays in presentation and revascularisation could explain this. Patient-reported readmissions due to the pre-specified major adverse events at one year occurred in 14 of the 212 (6.6%) patients discharged alive. Recurrent MI occurred in 10 patients, stroke in one and bleeding requiring hospitalisation in three patients. In the ACCESS registry, 15.6% of patients were readmitted due to a cardiac-related event in the first year. Of these, nearly two-thirds were admitted due to recurrent ACS, 15% due to heart failure, 1.8% due to bleeding and 6.6% due to stroke or transient ischaemic attack. We acknowledge that our series was subject to reporting bias and the common limitations of retrospective analysis. However, our response rate of 86.8% would indicate that a representative group completed follow up. The study was conducted in an urban, private, tertiary-level referral facility and therefore the patient population seen here is vastly different from the general population in Kenya. The results of this study should be interpreted with this in mind. However, the facility is one of the few hospitals in the region that has a well-developed cardiology programme and this study provides previously unavailable data on the short- and long-term outcomes of ACS in the region.

Conclusions This single-centre report from an urban referral hospital in SSA suggests that in-hospital and long-term mortality rates following ACS, particularly STEMI, remain high. Delayed presentation following symptom onset apppears to be an important contributing factor. This needs to be studied systemically and

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

tackled, keeping in mind local challenges. STEMI preparedness strategies and innovative homegrown solutions should become an area of focus for healthcare providers coming to terms with the expected epidemic of coronary artery disease in SSA.

Africa: insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry: cardiovascular topics. Cardiovasc J Afr 2012; 23(7): 365–370. 13. Ogeng’o JA, Olabu BO, Ong’era D, Sinkeet SR. Pattern of acute myocardial infarction in an African country. Acta Cardiol 2010; 65(6):

References 1.

World Health Organization. Projections of mortality and burden of disease, 2004–2030.

2Onen CL. Epidemiology of ischaemic heart disease in sub-Saharan Africa. Cardiovasc J Afr 2013; 24(2): 34–42.

3. 4.

Omran AR. The epidemiologic transition: A theory of the epidemiology

a consensus report from the Bleeding Academic Research Consortium.

A, et al. An updated definition of stroke for the 21st century: A state-

AT, Bloomfield GS, et al. Acute myocardial infarction in sub-Saharan

ment for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2013; 44(7): 2064–2089.

Jablonski-Cohen MS, Kosgei RJ, Rerimoi AJ, Mamlin JJ. The emerg-

18. Hicks K, Hung H, Mahaffey KW, Mehran R, Nissen SE, Stockbridge

ing problem of coronary heart disease in Kenya. East Afr Med J 2003;

NL, et al. Standardized definitions for endpoint events in cardiovascular trials. CDISC 20 Oct 2010.

Shavadia J, Yonga G, Otieno H. A prospective review of acute coronary

19. Mandelzweig L. The second Euro Heart Survey on acute coronary

syndromes in an urban hospital in sub-Saharan Africa. Cardiovasc J Afr

syndromes: characteristics, treatment, and outcome of patients with

2012; 23(6): 318–321.

ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J 2006;

Ogeng’o J., Gatonga P, Olabu BO. Cardiovascular causes of death in an east African country: An autopsy study. Cardiol J 2011; 18(1): 67–72.

Circulation 2011; 123(23): 2736–2747. 17. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras

Hertz JT, Reardon JM, Rodrigues CG, De Andrade L, Limkakeng

80(6): 293–297.

Biochem 2013; 46(1–2): 1–4. 16. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials:

Africa: The need for data. PLoS One 2014; 9(5): 1–7.

with practice guidelines? Afr J Emerg Med 2013; 3(4): S10. 15. Jaffe AS. Third universal definition of myocardial infarction. Clin

Steyn K, Sliwa K, Hawken S, Commerford P, Onen C, Damascene A, INTERHEART Africa Study. Circulation 2005; 112(23): 3554–3561.

myocardial infarction in a tertiary hospital in Kenya: Are we complying

of population change. Milbank Q 2005; 83(4): 731–757. et al. Risk factors associated with myocardial infarction in Africa: The 5.

613–618. 14. Wachira B, Owuor A, Otieno H. Emergency management of ST-elevation

27(19): 2285–2293. 20. Gibson CM, Murphy SA, Kirtane AJ, Giugliano RP, Cannon CP,

Shaper AG. Cardiovascular studies in the Samburu tribe of Northern

Antman EM, et al. Association of duration of symptoms at presenta-

Kenya. Am Heart J 1962; 63: 437–42.

tion with angiographic and clinical outcomes after fibrinolytic therapy

10. Simpson CR, Buckley BS, McLernon DJ, Sheikh A, Murphy A, Hannaford PC. Five-year prognosis in an incident cohort of people

in patients with st-segment elevation myocardial infarction. J Am Coll Cardiol 2004; 44(5): 980–987.

presenting with acute myocardial infarction. PLoS One 2011; 6(10): 1–7.

21. Alnasser SMA, Huang W, Gore JM, Steg PG, Eagle KA, Anderson

11. Smolina K, Wright FL, Rayner M, Goldacre MJ. Long-term survival

FA, et al. Late consequences of acute coronary syndromes: Global

and recurrence after acute myocardial infarction in England, 2004 to

Registry of Acute Coronary Events (GRACE) follow-up. Am J Med

2010. Circ Cardiovasc Qual Outcomes 2012; 5(4): 532–540.

2015; 128(7): 766–775.

12. Schamroth C. Management of acute coronary syndrome in South

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Aldosterone and renin in relation to surrogate measures of sympathetic activity: the SABPA study Lebo F Gafane-Matemane, Johannes M van Rooyen, Rudolph Schutte, Aletta E Schutte

Abstract Introduction: Hypertension, particularly in black populations, is often accompanied by augmented sympathetic nervous system activity and suppressed renin activity, indicative of possible blood pressure (BP) dysregulation. The potential role of the interrelationship between the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system in the context of low-renin conditions is unclear. We therefore explored whether surrogate measures of sympathetic activity [noradrenaline, 24-hour heart rate (HR) and percentage (%) dipping of night-time HR] relate to renin, aldosterone and aldosterone-to-renin ratio (ARR) in black and white South Africans. Methods: We included black (n = 127) and white (n = 179) males and females aged 20–63 years. We measured 24-hour BP and HR, and calculated night-time dipping. We determined renin and aldosterone levels in plasma and calculated ARR. Noradrenaline and creatinine levels were determined in urine and the noradrenaline:creatinine ratio was calculated. Results: More blacks had low renin levels (80.3%) compared to whites (58.7%) (p < 0.001). In univariate and after multivariate analyses the following significant associations were evident in only the black group: HR dipping was associated negatively with aldosterone level (β = –0.18, p = 0.024) and ARR (β = –0.20, p = 0.011), while 24-hour HR was associated positively with renin level (β = 0.20, p = 0.024). Additionally, there was a borderline significant positive association between noradrenaline:creatinine ratio and aldosterone level (β = 0.19, p = 0.051). Conclusion: The observed associations between surrogate measures of sympathetic nervous system activity and components of the RAAS in the black group suggest that the adverse effects of aldosterone and its ratio to renin on the cardiovascular system may be coupled to the effects of the sympathetic nervous system.

Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa Lebo F Gafane-Matemane, PhD Johannes M van Rooyen, DSc Rudolph Schutte, PhD Aletta E Schutte, PhD, alta.schutte@nwu.ac.za

Department of Medicine and Healthcare Science, Faculty of Medical Science, Anglia Ruskin University, Chelmsford, United Kingdom Rudolph Schutte, PhD

Research Unit for Hypertension and Cardiovascular Disease, Medical Research Council, North-West University, Potchefstroom, South Africa Lebo F Gafane-Matemane, PhD Johannes M van Rooyen, DSc Aletta E Schutte, PhD

Keywords: heart rate, blood pressure, dipping, renin–angiotensin–aldosterone system, noradrenaline Submitted 6/12/17, accepted 31/10/18 Published online 22/1/19 Cardiovasc J Afr 2019; 30: 34–40

www.cvja.co.za

DOI: 10.5830/CVJA-2018-065

Hypertension is the most common risk factor for cardiovascular events and its prevalence continues to increase in sub-Saharan Africa.1,2 A suppressed renin–angiotensin–aldosterone system (RAAS) and increased nocturnal blood pressure (BP) (non-dipping) are among the prominent features of hypertension in black populations.3-6 Low-renin hypertension may reflect a physiological response to increased BP and sodium/volume overload attributable to aldosterone.7 Even modest increases in aldosterone levels, as indicated by a high aldosterone-to-renin ratio (ARR),8,9 particularly in the presence of high sodium intake, result in high BP in black populations.10,11 In salt-sensitive blacks on sodium loading, blockade of angiotensin II receptors increased renin activity and reduced plasma aldosterone level, resulting in reduced night-time BP.12 It is therefore probable that sympathetic drive and blunted decrease in aldosterone level may be the driving force for increases in night-time BP. The detrimental effects of aldosterone in black populations may be augmented by increased mineralocorticoid receptor sensitivity,4,13 rather than increased aldosterone levels resulting from stimulation of the RAAS. Aldosterone also influences the autonomic nervous system by, for example, blunting the baroreflex response and potentiating the vasoconstrictor effects of noradrenaline.14,15 Blockade of aldosterone improves 24-hour heart rate (HR) variability and reduces HR, particularly in the early morning hours when sympathetic nervous system activity is high.16 Additionally, HR is associated with muscle sympathetic nervous system activity, which is the gold standard for assessing sympathetic nervous system outflow and plasma noradrenaline levels,17 while reduced HR dipping or a higher night-time HR can also represent a state of sympathetic nervous system overdrive.18 However, it is not clear if the interplay of aldosterone and its ratio to renin (ARR) with the sympathetic nervous system is evident in black populations who are predisposed to low-renin hypertension. To address this, we determined whether surrogate measures of sympathetic activity [noradrenaline, 24-hour HR and percentage (%) dipping in HR] related to renin and aldosterone levels, and ARR in black and white South Africans.

Methods The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was conducted between February 2008

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

and May 2009. The study originally included 409 school teachers aged 20–65 years of age from the North West Province of South Africa. Exclusion was based on the following criteria: ear temperature > 37.5°C, vaccinated or donated blood within three months before the study commenced, pregnancy, lactation, diabetes, any acute/chronic medication (excluding hypertension treatment) and psychotropic substance abuse or dependence.19 For this sub-study we further excluded 62 participants on antihypertensive medication and 41 participants without renin values, with data therefore being available for 127 black and 179 white participants. Participants were fully informed about the objectives and procedures of the study before enrolment. Assistance was given to any participant who requested conveyance of information in their home language. All participants signed an informed consent form. The study complied with all applicable requirements of the international regulations, in particular, the Helsinki Declaration of 1975 (as revised in 2008) for investigation of human participants. The Health Research Ethics Committee of North-West University (Potchefstroom campus) approved this study (NWU-00036-07-S6). We administered validated general health and sociodemographic questionnaires, as described previously by Malan et al.19 Weight, height, waist and hip circumferences were measured in triplicate by anthropometrists with calibrated instruments according to standardised methods (Precision Health Scale, A & D Co, Tokyo, Japan; Invicta Stadiometer, IP 1465, London, UK; Holtain non-stretchable metal flexible measuring tape). Body mass index (BMI) was calculated and expressed as kg/m2.20 The 24-hour ambulatory BP (ABPM) and HR measurements were conducted during the working week. The ABPM apparatus (Meditech CE120® Cardiotens, Budapest, Hungary) was attached on the participant’s non-dominant arm and programmed to measure BP at 30-minute intervals during the day (08:00–22:00) and every hour during the night (22:00–06:00). Percentage dipping for BP and HR, respectively were calculated for each participant as follows: mean daytime BP – mean night-time BP

_______________________________       × 100 % dipping BP =       mean daytime BP

mean daytime HR – mean night-time HR

________________________________ % dipping HR =              × 100 mean daytime HR

We therefore included 24-hour HR and its dipping as well as noradrenaline level as surrogate measures of sympathetic nervous activity. Hypertension was defined as ABPM ≥ 130/80 mmHg, according to the European Society of Hypertension (ESH) guidelines. The validated Finometer device21,22 (FMS, Finapres Measurement Systems, Amsterdam, Netherlands) and Beatscope® software were used to measure and calculate resting cardiac output (CO), HR and stroke volume (SV), and total peripheral resistance (TPR).

Biological sampling and biochemical analyses Participants were requested to be in a fasted state by not eating or drinking anything except water for approximately eight to 10 hours prior to sample collection in the mornings. An eight-hour morning spot urine sample was collected, from which creatinine, sodium, potassium and noradrenaline levels were measured

(Cobas Integra 400 plus, Roche, Basel, Switzerland & 3-Cat Fast Track kit, LDN, Nordhorn, Germany). Microneurography and regional noradrenaline spill-over are the gold standards for studying sympathetic outflow23 and were not used in this study. However noradrenaline and its metabolites are still used to assess sympathetic activity,24 and therefore the noradrenaline:creatinine ratio was used in the present study. Plasma noradrenaline level was not obtained in the SABPA study due to the complexity of the SABPA protocol and the short catecholamine half-life of approximately three minutes. We therefore obtained only saliva and urinary noradrenaline. In addition, using the noradrenaline:creatinine ratio instead of only urinary noradrenaline corrects/compensates for urine volume. The blood sample was obtained with a sterile winged infusion set from the antebrachial vein branches while the participant was in a supine position for a period of 30 minutes. Samples were prepared according to appropriate methods and stored at –80°C in the laboratory. Sequential multiple analysers (Konelab 20i, ThermoScientific, Vantaa, Finland; and Cobas Integra 400 plus, Roche, Basel, Switzerland) were used to analyse levels of total and high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (CRP), creatinine, serum sodium, potassium, gammaglutamyltransferase (GGT) and glycosylated haemoglobin (HbA1c). Tumour necrosis factor-alpha (TNF-α) l was analysed with a Quantikine high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN USA). Serum cotinine was analysed with a homogeneous immunoassay (Automised Modular, Roche, Basel, Switzerland). The modification of diet in renal disease (MDRD) formula was used to estimate glomerular filtration rate (eGFR) as a measure of renal function (serum creatinine was used in the formula). We analysed active plasma renin using the high-sensitivity radioimmunometric assay (Renin III Generation, CIS Biointernational, Cedex, France) with cross-reaction with prorenin being 0.4%. The source of reagents was mouse anti-human-active renin monoclonal antibody (IBL Lab, 38T501, USA). Plasma aldosterone was analysed using a competitive radioimmunoassay (Beckman Coulter, Brea, CA). We used the age-specific expected normal reference values (20–40 years, mean 8.11 pg/ml, SD 3.66; 40–60 years, mean 6.18 pg/ml, SD 3.42) from the renin III CISBIO kit to divide our study population into low- and high-renin groups (Renin III Generation, CIS Biointernational, Cedex, France). The mean age for this study population was 44.4 years (SD 9.60). We therefore used 6.18 pg/ ml as a cut-off value to determine the number of participants with low versus high renin levels.

Statistical analysis We used Statistica Version 12 for all statistical analyses (Statsoft Inc, Tulsa, OK). Data were categorised and analysed according to black and white ethnicity, based on the interaction with ethnicity on the association between 24-hour HR and renin activity (β = –0.56, p = 0.019). No gender interactions were observed. The distribution of renin, aldosterone, ARR, HbA1c, GGT, cotinine, total cholesterol, HDL-C, CRP, creatinine and noradrenaline were normalised by logarithmic transformation. The central tendency and spread of these variables were represented by the geometric mean and the 5th and 95th percentile intervals.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Means and proportions were compared using independent t-tests and chi-squared tests, respectively. We performed single, partial and forward stepwise multiple regression analyses to investigate associations between relevant cardiovascular variables and renin, aldosterone and ARR, as well as between aldosterone and noradrenaline:creatinine ratio. In partial regression analyses we adjusted for age, body mass index (BMI) and gender. Covariates included in the models were age, waistto-hip ratio, gender, GGT, cotinine, urinary Na+:K+ ratio, total cholesterol:HDL-C ratio, HbA1c, TNF-α, eGFR and TPR.

Table 1. Comparison between black and white groups Variables

Blacks (n = 127)

Whites (n = 179)

p-value

Age (years)

43.0 ± 7.33

44.0 ± 10.8

0.35

Women, n (%)

64 (50.4)

93 (52.0)

0.78

Hypertensive, n (%)

77 (60.6)

66 (36.9)

< 0.001

Body mass index (kg/m2)

30.2 ± 7.26

27.5 ± 6.01

0.001

Waist-to-hip ratio

0.87 ± 0.11

0.87 ± 0.10

0.51

Cardiac output (l/min)

6.72 ± 1.88

6.44 ± 1.94

0.21

Heart rate (bpm)

67.9 ± 10.3

66.3 ± 10.7

0.17

Stroke volume (ml)

100 ± 27.2

97.9 ± 24.5

0.43

Total peripheral resistance (mmHg/ml/s)

1.03 ± 0.42

1.03 ± 0.53

0.93

Anthropometric measurements

Resting cardiovascular measurementsa

Results Table 1 compares the black and white groups in which the frequency of low renin level was higher in the black group compared to whites (80.3% vs 58.7%, p < 0.001).The ethnic groups had similar mean ages (p = 0.35) and gender distribution (p = 0.78). Twenty-four-hour, day- and night-time systolic BP (SBP) and diastolic BP (DBP) as well as HR were higher in the black group (all p < 0.001), while percentage dipping in SBP, DBP or HR was lower in the black group compared to the white group (all p ≤ 0.042). Aldosterone (p = 0.015) and noradrenaline:creatinine ratio (p =0.044) were higher in the white group compared to the black group, while blacks had lower renin level (p < 0.001) and a higher ARR (p = 0.007) compared to whites. We performed Pearson and partial correlations (adjusting for age, gender and BMI) to investigate the associations of surrogate measures of sympathetic activity (noradrenaline:creatinine ratio, 24-hour HR and night-time dipping in HR) with renin, aldosterone and ARR (Fig. 1, Tables 2, 3). In blacks, before and after full adjustment in multiple regression analysis, 24-hour HR associated positively with renin (β = 0.20, p = 0.024), while night-time dipping in HR associated negatively with aldosterone (β = –0.18, p = 0.024) and ARR (β = –0.20, p = 0.011) (Table 4). Percentage dipping in SBP was positively associated with aldosterone (β = 0.23, p = 0.008) and ARR (β = 0.18, p = 0.038), while dipping in DBP was positively associated with aldosterone level (β = 0.24, p = 0.007) (Table 4). In whites, the renin level was positively associated with dipping in DBP (β = 0.16, p = 0.033) (Table 4). Table 5 indicates the following associations in the black group: 24-hour SBP (β = –0.22, p = 0.006) and 24-hour DBP (β = –0.20, p = 0.009) associated negatively with renin level. There was also a borderline significant association of noradrenaline:creatinine ratio with aldosterone (β = 0.19, p = 0.051) (Table 5). In the white group, 24-hour SBP (β = –0.15, p = 0.021) and 24-hour DBP (β = –0.16, p = 0.019) associated negatively with renin level (Table 5).

Discussion The main finding of this study is that in the black group, which consisted mainly of participants with low renin levels, 24-hour HR and its dipping as surrogate measures of sympathetic nervous system activity related independently and adversely to renin, aldosterone and ARR. Furthermore, there was a tendency towards a positive association between aldosterone and noradrenaline levels (p = 0.051). Previous observations in the SABPA cohort indicated a blunted baroreceptor sensitivity and

AFRICA

Systolic BP 24-hour (mmHg)

132 ± 15.4

124 ± 11.9

< 0.001

Daytime (mmHg)

137 ± 15.4

129 ± 11.8

< 0.001

Night-time (mmHg)

123 ± 16.1

113 ± 13.8

< 0.001

Diastolic BP 24-hour (mmHg)

82.5 ± 10.5

73.8 ± 9.94

< 0.001

Daytime (mmHg)

87.7 ± 11.4

81.4 ± 8.70

< 0.001

Night-time (mmHg)

73.4 ± 11.7

66.4 ± 9.01

< 0.001

24-hour (bpm)

79.3 ± 9.70

73.7 ± 10.2

< 0.001

Daytime (bpm)

84.2 ± 10.4

78.7 ± 10.7

< 0.001

Night-time (bpm)

71.0 ± 12.0

64.9± 10.3

< 0.001

Heart rate

% Dipping Systolic BP (mmHg)

10.1 ± 6.34

12.2 ± 6.33

0.003

Diastolic BP (mmHg)

15.9 ± 11.9

18.2 ± 7.90

0.042

14.6 ± 8.78

17.2 ± 9.25

0.015 0.015

Heart rate (bpm) Biochemical measurements Aldosterone (pg/ml)

43.7 (10.5; 170)

55.0 (21.8; 219)

Renin (pg/ml)

3.47 (0.95; 9.33)

5.75 (2.24; 12.3) < 0.001

Low renin status, n (%)

< 0.001

102 (80.3)

105 (58.7)

Aldosterone-to-renin ratio

12.5 (2.95; 67.6)

9.55 (2.88; 33.1)

Glycosylated haemoglobin (%)

6.03 (5.25; 8.71)

5.50 (5.01; 6.31) < 0.001

0.007 0.0002

Total cholesterol:HDL-C

4.07 (2.29; 7.41)

4.68 (2.82; 7.94)

C-reactive protein (mg/l)

3.80 (0.28; 26.3)

2.04 (0.99; 8.91) < 0.001

Cotinine (ng/ml)

2.75 (1.00; 148)

1.86 (1.00; 209)

Gamma-glutamyltransferase (U/l)

43.6 (20.4; 138)

18.6 (7.08; 74.1) < 0.001

Tumour necrosis factor-α (IU/ml)

3.00 ± 2.13

1.90 ± 2.00

< 0.001

Estimated glomerular filtration rate (ml/min/1.73 m2)

114 ± 27.8

94.5 ± 17.1

< 0.001

0.043

5.47 ± 4.11

4.09 ± 2.73

0.0004

1.45 (0.95; 2.51)

1.55 (0.85; 2.69)

0.044

Self-reported smoking, n (%)

22 (17.3)

26 (14.6)

0.52

Self-reported alcohol use, n (%)

29 (22.8)

91 (51.1)

< 0.001

Urinary Na+:K+ ratio Urinary noradrenaline:creatinine ratio Lifestyle factors

Obtained from the Finometer device. Values are arithmetic mean ± standard deviation; geometric mean (5th and 95th percentile interval) for logarithmically transformed variables. BP, blood pressure; HDL-C, high-density lipoprotein cholesterol. Bold text indicates p < 0.05. a

depressed HR variability, supporting the possibility of higher sympathetic activity in this population group.25,26 A novel finding of this study was that despite higher aldosterone levels in whites compared to blacks, aldosterone and its ratio to renin were associated with less dipping of night-time HR in blacks only. A higher HR is associated with total mortality rate, and night-time HR predicts cardiovascular mortality rate in the general population.27 In blacks, a more pronounced sympathetic drive, as shown by an exaggerated cardiovascular reactivity to

AFRICA

Nordadrenaline:creatinine ration

3.5

Black

3.0

2.5

Nordadrenaline:creatinine ration

2.0

1.5

1.0

White

2.0

1.5

1.0

r = 0.23; p = 0.017 0.5

1.2

1.6 2.0 2.4 Log aldosterone (pg/ml)

r = –0.07; p = 0.37 0.5

2.8

% Dipping heart rate

0.8

1.2

1.6 2.0 2.4 Log aldosterone (pg/ml)

2.8

r = –0.19; p = 0.038 –10

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

0.8

1.2

1.6 2.0 2.4 Log aldosterone (pg/ml)

2.8

r = 0.008; p = 0.92 –10

0.8

1.2

1.6 2.0 2.4 Log aldosterone (pg/ml)

2.8

Fig. 1. A ssociations between (A) log noradrenaline:creatinine ratio and log aldosterone; (B) night-time dipping in heart rate and aldosterone level in black and white groups. Solid and dashed lines represent the regression line and 95% CI boundaries, respectively.

stress compared to whites, contributed to elevation of BP through increased TPR and HR.28 The positive association between 24-hour HR and renin level may indicate β-adrenergic receptor stimulation at both the heart and kidney, resulting in increases in HR and renin secretion at the juxtaglomerular apparatus, respectively.29 Previous findings in the same population under study indicated that even at suppressed renin levels, sympathetic stimulation by exposure to an acute stressor resulted in a positive association between TPR reactivity and renin reactivity in blacks, but not in whites.30 The observed association of aldosterone and ARR with attenuated HR dipping may not only be an indication of possible synergy between aldosterone and sympathetic drive, but also the direct effects of aldosterone on the cardiovascular system

via high-density mineralocorticoid receptors.31,32 The increased aldosterone sensitivity in blacks13 may also explain the observed negative association with HR dipping, despite having lower mean aldosterone levels compared to whites. In the present study we also found blacks to have lower noradrenaline levels, which showed a borderline significant relationship with aldosterone. Experimental studies indicated that aldosterone prevents extraneuronal and myocardial uptake of noradrenaline and therefore may enhance its effects,15,33 albeit at lower levels. The higher frequency of low renin and aldosterone levels in blacks compared to whites is consistent with previous studies.34,35 However, blacks exhibited a higher ARR. A relatively higher

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 2. Pearson and partial correlations of BP, HR and noradrenaline with renin, aldosterone and ARR in black and white groups Blacks (n = 127)

Pearson correlations Variables Log renin Log aldosterone Log ARR

Log renin Log aldosterone Log ARR Adjusted for age, gender and BMI

Log renin Log aldosterone Log ARR

24-hour SBP r p –0.18 0.039 0.05 0.55 0.17 0.052

24-hour DBP 24-hour HR r p r p –0.18 0.039 0.24 0.006 0.07 0.43 0.14 0.11 0.18 0.034 –0.04 0.64 Whites (n = 179)

24-hour SBP r p –0.05 0.51 –0.05 0.53 –0.01 0.92

24-hour DBP 24-hour HR r p r p –0.07 0.34 0.06 0.41 –0.02 0.82 0.12 0.12 –0.01 0.92 0.06 0.41 Blacks (n = 127)

24-h SBP r p –0.23 0.011 –0.04 0.64 0.12 0.18

24-h DBP 24-h HR r p r p –0.25 0.005 0.26 0.004 –0.02 0.82 0.14 0.13 0.16 0.084 –0.06 0.50 Whites (n = 179)

Table 3. Pearson and partial correlations of percentage dipping in night-time BP and HR with renin, aldosterone and ARR in black and white groups Blacks (n = 127)

Pearson correlations NA:creatinine ratio r p 0.07 0.44 0.23 0.017 0.14 0.12 NA:creatinine ratio r p –0.06 0.44 –0.07 0.37 –0.02 0.81 NA:creatinine ratio r p 0.08 0.42 0.22 0.022 0.14 0.15

NA:creatinine 24-h SBP 24-h DBP 24-h HR ratio r p r p r p r p Log renin –0.15 0.042 –0.15 0.034 0.07 0.37 0.09 0.23 Log aldosterone –0.08 0.27 –0.03 0.70 0.10 0.21 –0.04 0.093 Log ARR 0.03 0.65 0.09 0.24 0.04 0.61 –0.11 0.17 SBP, systolic blood pressure; DBP, diastolic blood pressure, HR, heart rate; NA, noradrenaline; ARR, aldosterone-to-renin ratio; BMI, body mass index. Bold text indicates p < 0.05.

aldosterone level for a given level of plasma renin points to the possibility of excess aldosterone secretion, which has a significant role in salt/volume-related hypertension.36-38 Higher ARR has been linked to a non-dipping pattern of BP in the presence of high dietary sodium levels in the general Japanese population.39 In our study, we showed that aldosterone and its ratio to renin were associated with an increase in BP dipping and a decrease in HR dipping. The favourable association of aldosterone and ARR with BP dipping may possibly be as a result of a compensatory mechanism for the reduced dipping in HR to maintain haemodynamic balance. Our study should be interpreted within the context of its strengths and limitations. We did not collect 24-hour urine in order to assess noradrenaline level, and we did not assess salt intake, salt sensitivity or angiotensin II levels. Even though the use of catecholamines is not regarded as the gold standard, catecholamines and their metabolites are still used to assess sympathetic activity24 and therefore the noradrenaline:creatinine ratio was used in our study. This was a cross-sectional study therefore causality could not be inferred. This homogenous sample cannot be regarded as representative of the general South African population.

Conclusion We found in blacks only that aldosterone level and its ratio to renin was associated with less dipping in night-time HR. Our findings suggest that low-renin hypertension in black populations may be partly mediated by the direct effects of

% SBP

% DBP

% HR

Variables

Log renin

0.05

0.59

0.03

0.72

0.13

0.14

Log aldosterone

0.23

0.010

0.28

0.002 –0.19

0.038

Log ARR

0.16

0.065

0.22

0.013 –0.25

0.004

Whites (n = 179) % SBP

% HR

0.13

0.091

0.19

0.009

0.07

0.39

0.09

0.22

–0.03

0.64

–0.06

0.42

Log renin Log aldosterone Log ARR

% DBP

0.12

0.11

0.001

0.92

–0.08

0.26

Blacks (n = 127)

Adjusted for age, gender and BMI

% SBP

% DBP

% HR

Log renin

0.06

0.51

0.05

0.61

0.11

0.24

Log aldosterone

0.26

0.004

0.31

< 0.001 –0.19

0.025

Log ARR

0.19

0.23

0.24

0.008 –0.25

0.006

Whites (n = 179) % SBP r

% HR

0.14

0.062 –0.17

0.021

0.08

0.28

0.09

0.24

–0.03

0.72

–0.05

0.55

Log renin Log aldosterone Log ARR

% DBP p

0.10

0.19

0.001

0.99

–0.07

0.34

SBP, systolic blood pressure; DBP, diastolic blood pressure, HR, heart rate; ARR, aldosterone-to-renin ratio; BMI, body mass index. Bold text indicates p < 0.05.

Table 4. Independent associations of 24-hour HR, night-time dipping in HR and BP with renin, aldosterone and ARR in black and white groups Blacks (n = 127) 24-h HR

% HR Adjusted p-value R2

Adjusted R2

β (95% CI)

0.15

0.20 (0.93; 12.1)

0.024

0.19

–

Log aldosterone 0.13

0.09 (–2.12; 6.66)

0.31

0.29

–0.18 (–7.83; –0.61)

0.024

–

0.30

–0.20 (–7.28; –0.99)

0.011

Log renin Log ARR

0.13

% SBP

β (95% CI)

p-value

% DBP

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

0.10

–

0.12

0.10 (–2.91; 11.2)

0.25

Log aldosterone 0.14

0.23 (1.07; 6.73)

0.008

0.16

0.24 (2.14; 12.8)

0.007

Log ARR

0.18 (0.18; 5.23)

0.038

0.12

0.15 (0.83; 8.95)

0.11

Log renin

0.12

p-value

Whites (n = 179) 24-h HR

% HR Adjusted p-value R2

Adjusted R2

β (95% CI)

p-value

0.22

–

0.13

0.10 (–1.62; 9.42)

0.17

Log aldosterone 0.22

–

0.13

–

Log ARR

0.22

–

0.13

–0.09 (–6.63; 1.67 )

0.24

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

0.01

Log renin

% SBP

% DBP p-value

0.12 (–0.54; 7.27)

0.09

0.06

0.16 (0.46; 10.3)

0.033

Log aldosterone 0.0001

–

0.05

0.08 (–1.36; 6.48)

0.20

Log ARR

–

0.04

–

Log renin

0.0001

–, log renin, log aldosterone and log ARR did not enter the forward stepwise model. Independent variables included in the model: age, waist-to-hip ratio, gender, gamma-glutamyltransferase, cotinine, urinary Na+:K+ ratio; total cholesterol:high-density lipoprotein cholesterol ratio, glycosylated haemoglobin, tumour necrosis factor-α, estimated glomerular filtration rate and total peripheral resistance. Associations with % dipping variables were additionally adjusted for daytime measurements. ARR, aldosterone-to-renin ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. Values in bold indicate p < 0.05.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 5. Independent associations of 24-hour BP and noradrenaline:creatinine ratio with renin, aldosterone and ARR in black and white groups Blacks (n = 127) 24-h SBP

24-h DBP

Log noradrenaline:creatinine ratio

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

Log renin

0.31

–0.22 (–19.3; –3.44)

0.006

0.37

–0.20 (–12.4; –1.88)

0.009

0.10

–

Log aldosterone

0.28

–

0.34

–

0.12

0.19 (0.0005 ; 0.16)

0.051

Log ARR

0.28

0.11 (–1.59; 9.53 )

0.16

0.35

0.14 (–0.23; 6.89)

0.070

0.10

0.10 (–0.03 ; 0.10)

0.31

Independent variables

p-value

Whites (n = 179) 24-h SBP

24-h DBP

Log noradrenaline:creatinine ratio

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

p-value

Adjusted R2

β (95% CI)

p-value

Log renin

0.29

–0.15 (–13.9; –1.20)

0.021

0.28

–0.16 (–9.71; –0.93)

0.019

0.34

0.08 (–0.03; 0.13)

0.22

Log aldosterone

0.28

–0.11 (–9.52; 0.96)

0.11

0.27

–0.07 (–5.61; 1.69)

0.29

0.34

–

Log ARR

0.27

–

0.26

–

0.34

–0.09 (–0.10 ; 0.02)

0.16

–, log renin, log aldosterone and log ARR did not enter the forward stepwise model. Independent variables included in the model: age, waist-to-hip ratio, gender, gamma-glutamyltransferase, cotinine, urinary Na+:K+ ratio; total cholesterol: high-density lipoprotein cholesterol ratio, glycosylated haemoglobin, tumour necrosis factor-α, estimated glomerular filtration rate, total peripheral resistance. ARR, aldosterone-to-renin ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure. Values in bold indicate p < 0.05.

aldosterone and its relationship with the sympathetic nervous system.

J, et al. Aldosterone-to-renin ratio and the relationship between urinary

This work was supported by HART, North-West University, South Africa;

11. Huan Y, DeLoach S, Keith SW, Goodfriend TL, Falkner B. Aldosterone

the Metabolic Syndrome Institute, France; Medical Research Council, South

and aldosterone: renin ratio associations with insulin resistance and blood

salt excretion and blood pressure in a community of African ancestry. Am J Hypertens 2011; 24: 951–957.

Africa; Roche Diagnostics, South Africa; and the North West Department

pressure in African Americans. J Am Soc Hypertens 2012; 6: 56–65.

of Education. The financial assistance of the National Research Foundation

12. Polonia J, Diogo DI, Caupers P, Damasceno A. Influence of two

(NRF) towards this research is hereby acknowledged. Opinions expressed and

doses of irbesartan on non-dipper circadian blood pressure rhythm

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

in salt-sensitive black hypertensives under high salt diet. J Cardiovasc

attributed to the NRF.

Pharmacol 2003; 42: 98–104. 13. Tu W, Eckert GJ, Hannon TS, Liu H, Pratt LM, Wagner MA, et

References 1.

Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013; 380: 2224–2260.

Danaei G, Finucane MM, Lin JK, Singh GM, Paciorek CJ, Cowan MJ, et al. National, regional, and global trends in systolic blood pressure

ity: a review with a focus on non-Hispanic blacks and Hispanics. J Am

K, Kario K. Nocturnal non-dipping of heart rate predicts cardiovascu-

Funder JW. Sensitivity to aldosterone plasma levels are not the full story.

lar events in hypertensive patients. J Hypertens 2009; 27: 2265. 19. Malan L, Hamer M, Frasure-Smith N, Steyn HS, Malan NT. Cohort profile: Sympathetic activity and Ambulatory Blood Pressure in Africans

Murphy MB, Fumo MT, Gretler DD, Nelson KS, Lang RM. Diurnal

(SABPA) prospective cohort study. Int J Epidemiol 2015; 44: 1814–1822.

blood pressure variation: differences among disparate ethnic groups. J

20. Marfell-Jones T, Olds T, Carter A. International standards for anthro-

Mayet J, Chapman N, Li CK, Shahi M, Poulter NR, Sever PS, et al.

Gordon RD, Laragh JH, Funder JW. Low renin hypertensive states: perspectives, unsolved problems, future research. Trends Endocrinol

pometric assessment. International Society for the Advancement of Kinanthropometry (ISAK), 2006. 21. Imholz BP, Wieling W, van Montfrans GA, Wesseling KH. Fifteen years’ experience with finger arterial pressure monitoring: assessment of the technology. Cardiovasc Res 1998; 38: 605–616. 22. Guelen I, Westerhof BE, van der Sar GL, van Montfrans GA,

Metabol 2005; 16: 108–113.

Kiemeneij F, Wesseling KH, Bos WJW. Validation of brachial artery

Gordon RD. Mineralocorticoid excess syndromes. In: Margerison, AN

pressure reconstruction from finger arterial pressure. J Hypertens 2008;

& Chrousos, GP (eds). Adrenal Disorders. New York: Springer, 2001: 355–377. 9.

1998; 16: 1635–1639. 18. Eguchi K, Hoshide S, Ishikawa J, Pickering TG, Schwartz JE, Shimada

profile. Hypertension1998; 31: 1190–1194.

congestive heart failure. J Am Coll Cardiol 2001; 37: 1800–1907.

Richardson SI, Freedman BI, Ellison DH, Rodriguez CJ. Salt sensitiv-

Ethnic differences in the hypertensive heart and 24-hour bloos pressure 7.

of aldosterone blockade on heart rate variability and QT dispersion in

Mancia G. Heart rate as marker of sympathetic activity. J Hypertens

Hypertens 1991; 9: S45–S47. 6.

aldosterone on vascular smooth muscle. Life Sci 1982; 30: 2009–2017. 16. Yee K-M, Pringle SD, Struthers AD. Circadian variation in the effects

miological studies with 786 country-years and 5.4 million participants.

Hypertension 2014; 63: 1168–1170. 5.

Clin Sci 1998; 95: 687–692. 15. Weber MA, Purdy RE. Catecholamine-mediated constrictor effects of

17. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell’Oro R,

Soc Hypertens 2013; 7: 170–179. 4.

Hypertension 2014; 63: 1212–1218. 14. Yee K, Struthers A. Aldosterone blunts the baroreflex response in man.

since 1980: systematic analysis of health examination surveys and epideLancet 2011; 377: 568–577. 3.

al. Racial differences in sensitivity of blood pressure to aldosterone.

Pilz S, Tomaschitz A, März W. Diagnostic procedures for primary aldosteronism. Lab Medizin 2009; 33: 202–209.

10. Scott L, Woodiwiss AJ, Maseko MJ, Veliotes DG, Majane OH, Paiker

26: 1321–1327. 23. Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur Heart J 2012; 33: 1058–1066. 24. Hildebrandt DA, Irwin ED, Cates AW, Lohmeier TE. Regulation of renin secretion and arterial pressure during prolonged baroreflex activa-

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

tion influence of salt intake. Hypertension 2014; 64: 604–609. 25. Van Lill L, Malan L, van Rooyen J, Steyn F, Reimann M, Ziemssen T. Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: the SABPA study. Blood Press 2011; 20: 355–361. 26. Malan L, Hamer M, Schlaich M, Lambert G, Ziemssen T, Reimann M, et al. Defensive coping facilitates higher blood pressure and early sub-clinical structural vascular disease via alterations in heart rate variability: the SABPA study. Atherosclerosis 2013; 227: 391–397.

AFRICA

32. Cachofeiro V, Miana M, de las Heras N, Martín-Fernández B, Ballesteros S, Fernández-Tresguerres J, Lahera V. Aldosterone and the vascular system. J Ster Biochem Mol Biol 2008; 109: 331–335. 33. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995; 76: 1259–1265. 34. Rayner BL, Myers JE, Opie LH, Trinder YA, Davidson JS. Screening for primary aldosteronism--normal ranges for aldosterone and renin in

27. Hansen TW, Thijs L, Boggia J, Li Y, Kikuya M, Björklund-Bodegård K,

three South African population groups. S Afri Med J 2001; 91: 594–599.

et al. Prognostic value of ambulatory heart rate revisited in 6928 subjects

35. El-Gharbawy AH, Nadig VS, Kotchen JM, Grim CE, Sagar KB,

from 6 populations. Hypertension 2008; 52: 229–235. 28. Huisman HW, Schutte AE, Schutte R, van Rooyen JM, Fourie CM,

Kaldunski M, et al. Arterial pressure, left ventricular mass, and aldosterone in essential hypertension. Hypertension 2001; 37: 845–850.

Mels CM, et al. Exploring the link between cardiovascular reactivity and

36. Satoh M, Kikuya M, Ohkubo T, Mori T, Metoki H, Hara A, et al.

end-organ damage in African and Caucasian men: the SABPA study.

Aldosterone-to-renin ratio as a predictor of stroke under conditions

Am J Hypertens 2013; 26: 68–75.

of high sodium intake: the Ohasama study. Am J Hypertens 2012; 25:

29. Anderson NB. Racial differences in stress-induced cardiovascular reactivity and hypertension: current status and substantive issues. Psychol Bull 1989; 105: 89. 30. Gafane LF, Schutte R, van Rooyen JM, Schutte AE. Plasma renin

777–783. 37. Fisher ND, Hurwitz S, Ferri C, Jeunemaitre X, Hollenberg NK, Williams GH. Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension. Hypertension 1999; 34: 388–394.

and cardiovascular responses to the cold pressor test differ in black

38. Lim PO, Struthers AD, MacDonald TM. The neurohormonal natural

and white populations: The SABPA study. J Hum Hypertens 2016; 18:

history of essential hypertension: towards primary or tertiary aldoster-

396–404.

onism? J Hypertens 2002; 20: 11–15.

31. Lombès M, Alfaidy N, Eugene E, Lessana A, Farman N, Bonvalet J-P.

39. Satoh M, Kikuya M, Ohkubo T, Mori T, Metoki H, Hashimoto T,

Prerequisite for cardiac aldosterone action mineralocorticoid receptor

et al. Aldosterone-to-renin ratio and nocturnal blood pressure decline

and 11β-hydroxysteroid dehydrogenase in the human heart. Circulation

in a general population: the Ohasama study. J Hyptertens 2011; 29:

1995; 92: 175–182.

1940–1947.

Cardiac magnetic resonance’s potential for predicting potentially fatal cardiovascular disease The use of magnetic resonance imaging (MRI) to determine heart function has been slow to catch on, but a study from Duke Health researchers shows that stress cardiac MRI not only diagnoses disease, but can also predict which cases are potentially fatal. Results from a large, multi-centre study suggest that cardiac magnetic resonance, or CMR, has potential as a non-invasive, non-toxic alternative to stress echocardiograms, catheterisations and stress nuclear examinations in identifying the severity of coronary artery disease. ‘We’ve known for some time that CMR is effective at diagnosing coronary artery disease, but it’s still not commonly used and represents less than 1% of stress tests used in this country,’ said senior author Dr Robert Judd, co-director of the Duke Cardiovascular Magnetic Resonance Centre. ‘One of the impediments to broader use has been a lack of data on its predictive value – something competing technologies have,’ Judd said. ‘Our study provides some clarity, although direct comparisons between CMR and other technologies would be definitive.’ Judd and colleagues analysed data from more than 9 000 patients who underwent CMR at seven US hospitals, encompassing up to 10 years of follow up. For patients without any history of heart disease and at low risk, based

on traditional clinical criteria, those with an abnormal CMR scan were 3.4 times more likely to die compared to patients with a normal CMR scan. For the entire patient population, the researchers found a strong association between an abnormal stress CMR and mortality, even after adjusting for patient age, gender and cardiac risk factors. ‘Non-invasive cardiac stress testing is a cornerstone in the clinical management of patients with known or suspected coronary artery disease,’ Judd said, noting that CMR works as well as or better than other examinations at identifying heart wall motion, cell death and the presence of low blood flow. In addition, the technology does not require any radiation exposure, which is essential in nuclear stress tests that are by far the most commonly used in the USA. ‘There are a number of reasons for the limited use of stress CMR, including availability of good-quality laboratories, exclusion of patients who cannot undergo magnetisation, and a lack of data on patient outcomes,’ Judd said. ‘With the findings from this study suggesting that stress CMR is effective in predicting mortality, we provide a strong basis for a head-to-head study between stress CMR and other modalities.’ Source: Medical Brief 2019

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

The value of community outreach for a university: a synthesis of trends in higher education The case of the University of Limpopo (ELS 45) Hlengani Siweya, Kotsedi D Monyeki

Abstract Background: The South African National Development Plan (SANDP) vision for 2030 highlights key recommendations for reducing the prevalence of non-communicable diseases (NCDs) by 28% by 2030. These are mirrored by the World Heart Federation, although it focuses on reducing the NCD prevalence by 25% by 2025. The targeted diseases include, among others, cardiovascular diseases, diabetes, cancer and chronic respiratory diseases. Objectives: The aim was to contribute to discussion on the social responsibility, public good and community development functions of a university in South Africa, as derived from the Higher Education Act 101 of 1997 (as amended). Methods: The researcher’s ontology links with this notion of the existence of multiple realities that exist among universities in South Africa, and provides the basis for a social construction epistemology. Different realities exist for the University of Limpopo. Results: The Dikgale Health and Demographic Surveillance System and the Ellisras Longitudinal Study, which both started in 1996 within the University of Limpopo, provide ample bush university outreach models on social responsibility, public good and community development. Community participation was central to the dissemination of research results. Conclusion: Social responsibility, public good and community development are core functions for a university, which should be treated as stand-alone roles, such as teaching, learning and research. The University of Limpopo has distinguished itself by being true to its vision of ‘being a leading African university focused on the developmental needs of its communities and epitomising academic excellence and innovativeness’. Keywords: community development, public good and social responsibility Submitted 10/4/18, accepted 31/10/18 Published online 7/2/19 Cardiovasc J Afr 2019; 30: 41–44

www.cvja.co.za

DOI: 10.5830/CVJA-2018-059

Faculty of Science and Agriculture, University of Limpopo, Sovenga, South Africa Hlengani Siweya, PhD, hlengani.siweya@ul.ac.za

Department of Physiology and Environmental Health, University of Limpopo, Sovenga, South Africa Kotsedi D Moyeki, PhD

Social responsibility, public good and community development are three functions of a university that are less spoken about by any university outside the traditional roles of teaching, learning and knowledge generation through research. However, the understanding and interplay between these functions are often confused with community engagement, which many scholars are still grappling with as another university core function. Teaching and learning are geared towards preparing and equipping learners with skills necessary for entry into the job market, and to a lesser extent, towards fulfilment of social roles in society. On its own, research could be classified into that which is meant to advance a discipline in the form of new findings on the one hand, and that which is meant to benefit the public on the other. The extent to which university research achieves its objective(s) manifests itself in policy formulation by the state or the advent of new products in the commercial industry. Yet non-communicable diseases (NCDs), which are rooted in lifestyle modification, are rooted in the community, despite the numerous research projects conducted by universities in Africa. The fundamental importance of full community participation, as rooted in the South African National Development Plan,1 received little attention from universities in Africa in perusing research to improve the lives of people in society. This was evident from the highest increase in NCD-related mortality rates, with about 46% of all those expected mortalities attributed to NCDs by 2030 in Africa.2,3 Therefore the culture of valuing and respecting the needs of the community has faded in universities for their pursuit of community outreach programmes. The main objective of this article is to contribute to discussions on the social responsibility, public good and community development functions of a university in South Africa, as derived from the Higher Education Act 101 of 1997 (as amended).

Strategic plans and quality-assurance directorates In the past two decades, many universities in South Africa came up with strategic plans for establishing quality-assurance directorates to drive their academic activities: in essence, higher education management has become mission driven. However, the pursuit/desire of every higher education management to achieve its strategic objectives, as enunciated in its strategic goals, should not be at the expense of a university fulfilling public expectations on community development, social responsibility and public good. In addition, Saleem Badat4 lifted out some of the social purposes the new higher education terrain was expected to serve, which include: • production, acquisition and application of new knowledge • contributing to the creation, sharing and evaluation of knowledge

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

• addressing the developmental needs of society • contributing to the social–cultural and intellectual life of a rapidly changing society • socialisation of enlightened, responsible and constructively critical citizens • helping to lay the foundations of a critical civil society with a culture of public debate and tolerance. Furthermore, public good and social responsibility as functions of universities, are closely related and often difficult to differentiate. Here is an example of public good: under the inspirational leadership of Prof Jakes Gerwel, the University of (the) Western Cape (UWC) created a community legal centre [which was recently renamed the Dullar Omar Institute of Constitutional Law (DOI)], whose mandate was (to the public benefit of South Africa): ‘the engine room of committed thought towards the new constitution’. Its contribution to the South African dispensation will be remembered for a long time. The Institute was instrumental in the inclusion and phrasing of some sections of the South African Constitution that deal with the National Council of Provinces, socio-economic rights, enforceable rights to housing, health, food and basic education.5 In fact, UWC had declared itself ‘the intellectual home of the left’.6 Our Constitution (as amended) has enshrined in it a number of civil rights, among which the right to education and the right to academic freedom are of interest in higher education. The two are interrelated in the sense that ‘if a person does not have access to (basic or higher) education, the person is also deprived of academic freedom’.7 Academic institutions are better placed to promote the understanding of this right to education and academic freedom. The University of the Witwatersrand (commonly known as Wits University), during the erstwhile leadership of the respected and leading mathematician-cum-manager of our time, Loyiso Nongxa, was in the public spotlight through its Targeting Talent project. Through it, Wits would search for talented matriculants and help them find admission spaces at higher education institutions in the country.8 South Africa is known for its social inequalities; it is not uncommon that some of her brightest learners are based at rural villages, often without access to the internet, let alone information about academic offerings at South African universities. When such learners graduate from secondary education, having passed with distinction in critical subjects such as mathematics, physical science and accountancy, they would be unable to enter higher education. These are the learners Loyiso would target: this is public goodness. In November 2017, Nongxa’s successor, well-known political commentator, Adam Habib volunteered his university’s expertise to assess the status of numerous bridges in Gauteng and advise the provincial government on whose responsibility it is to maintain these bridges. This is an example of social responsibility: providing the community with the expertise to find solutions to a social challenge. The success of universities in the three areas that this article centres on depends on the role of their vice-chancellors; however, a university community is also at the centre of the visibility of the university in the public sphere. It is not surprising that at the University of Zululand, Charles Dlamini noted: ‘When the transformation committee was established at the University of Zululand, I was excluded from it. I pointed out that the people constituting the committee might not have the necessary experience and expertise to lead the process …, but was told

AFRICA

to give these people a chance … When the process failed, I got the blame’.9 While university leaders are undoubtedly the face and chief spokespersons of their institutions, their constituent communities are the foot soldiers.

Contextual framework In this article, community development derives from a form of practice in the sense of it being inclusive. Some scholars refer to this as a community of practice where interest groups come together to share ideas on a specific activity; so, it is based on the principles of equality and social inclusion.10 Inclusion can also take the form of selected variables that the targeted population is expected to satisfy, as was the case with Kayama et al.,11 where the community was (hospital) patients who had dropped out of out-patient care for more than three months. Analogously, a group of small-scale farmers in a village is a community, and their development could involve management of maize varieties or dinawa recipes (as is the case in examples that are discussed below). Being inclusive, community development is necessarily collaborative in that there ought to be a mutual understanding of community needs as well as availability of resident resources, which will inform the ‘what’ and ‘how’ of interaction between a university and the targeted community. Our conception of the value and nature of a university is best summed up by Chris Brink when, in reference to the nature of a university, he says: ‘The first, which is a matter of quality, is to ask what we are good at. The second, which is a matter of equality, or more broadly, our role in civil society, is to ask what we are good for’.6 It is the reference to civil society that this article leans on: to advance that which a university is good at for the benefit of society. After all, Aasen7 argues that a university should contribute towards a better life for all. Creating and sharing knowledge with communities is the social responsibility of every higher education institution. For centuries, universities have also been at the centre of social change and development. The demise of apartheid in South Africa and the collapse of communism in Eastern Europe resulted from many African and East European countries in which universities played pivotal roles to dismantle the two philosophies. In South Africa, while the contribution of universities as centres of apartheid resistance was immense and well documented, perhaps the contribution of white universities, in particular the Universities of Cape Town (UCT) and the Witwatersrand need acknowledgement. Even though Hendrik Verwoerd had wanted the black child not to be taught mathematics, and in consequence science, engineering and accounting, UCT started the Academic Support Programme (ASP) and Alternative Admissions Research Project (AARP) as a ‘…means of access for educationally disadvantaged students whose school results do not necessarily reveal their potential to succeed in higher education’.6 This is the highest form (and example) of social responsibility: creating opportunities to and helping those who were not meant to enter higher education to succeed! A university should be able to elevate its research to inform its teaching mission and reinforce its historical commitment to helping communities meet their needs.12 In addition Bender also argues that the pedagogy of engagement can be used to advance social responsibility.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

Experiences from the University of Limpopo The commitment of the University of Limpopo to a societal reconstruction and development programme is evidenced through a number of initiatives that have come about post 1994. In the current classification, some of the social responsibilityorientated activities are (the) university crĂ¨che, Meal-a-Day initiative and Student Disability Unit (SDU); the CSIR White Spaces project falls on the public good side, while the dinawa project falls in the category of community development. Universities are communities of a kind, and so is the University of Limpopo. The University has designated divisions whose responsibilities include provision of legal advice/services on a small scale, protection of life and property and ensuring that the University community behaves within certain minimum agreed standard and policies, access to health services, and provision of professional counselling to its community. All these are sufficient evidence that the University of Limpopo complies with the expectations on social justice and responsibility.

Dikgale Health and Demographic Surveillance System (DHDSS) The project started in 1996 under the leadership of Prof Marriane Alberts, now emeritus professor in medical sciences, when the first census was conducted, and covered approximately 8 000 people. However, DHDSS was expanded in 2010 and it currently has in the region of 38 000 people under surveillance. The main aim of the project was to monitor NCDs and associated risk factors in a rural area that is undergoing rapid changes in lifestyle. An annual census update has been conducted since 1996 to capture life events such as births, deaths and residence status, education status and migration; but since 2011, causes of deaths have been included. Fieldworkers are used to interview adults in each household on health surveys covering prevalence of and risk factors for chronic diseases, therefrom developing intervention strategies for better management of chronic diseases and reduction of attendant risk factors. Of significance in this project is the added fact that regular meetings are held with the Dikgale tribal authority at which the main research findings are discussed, as well as informing the community about any future research that is being planned in the DHDSS. Beneficiaries are also University masters and doctoral students whose projects are based at Dikgale village.

Ellisras Longitudinal Study project The desire of the South African government to improve the health of rural peoples requires that adequate baseline data be made available to combat the emerging chronic diseases of lifestyle, as they are becoming a major health burden in our communities today. In November 1996, the Ellisras Longitudinal Study (ELS) was initiated to monitor the growth, health and lifestyle of a group of children in the Ellisras rural area over time. Table 1 presents the data collected from then to date. It is clear that the NCD profile is changing rapidly over time among the Ellisras rural community children as they grow older. For example, under-nutrition among Ellisras children was over 50% in the period 1996 to 2003, with most children in the ectomorphâ&#x20AC;&#x201C;mesomorph category.13,14 The prevalence of

type 2 diabetes mellitus was non-existent in the same population during the same period. However, the level of physical fitness and physical activity was extremely low for girls compared to boys and other children of the same age studied in urban areas.15 The prevalence of tobacco smoking in the ELS increased from 4.9 to 17%.16 Today, from the same ELS sample measured from November to December 2015, the prevalence of obesity is high, particularly among the females.17 Furthermore, it was clear from the previous analysis of this population that the prevalence of hypertension was emerging and low.13,18 Currently, the prevalence of diabetes and hypertension are escalating in this Ellisras population.19 The well-characterised ELS provides a unique opportunity for mapping some of these changes, particularly in vulnerable adolescents and young adults over time. The fact that ELS subjects migrate to urban areas and sporadically return to Ellisras rural areas provides a further unique opportunity for investing the influence of urbanisation on the changing magnitudes of NCD risk-factor profiles in the South African population. The overall performance of the health system in South Africa since 1994 has been poor despite the development of good policy and relatively high spending in proportion to the GDP. Long-term health outcomes are shaped by factors largely outside the health system: lifestyle, nutrition, education, diet, sexual behaviour and exercise. Universities should play a central role in uplifting the standard of living.

Conclusion Social responsibility, public good and community development are core functions for a university, which should be treated as stand-alone roles, such as teaching, learning and research. They are important functions for any university, not because they are implied in the Higher Education Act 101 of 1997 but because they can be used to advance social cohesion in communities and improve health awareness and lifestyles. Table 1. Research question data collected in the Ellisras Longitudinal Study sample from 1996 to 2008/9 Survey Anthropometrical measurement

1996 1997 1998 1999 2000 2001 2002 2003 2005 2008/9 *

Blood pressure

Diet

Socio-economic status

Glucose tolerance

Learning environment

Educational achievement (maths and English)

Aptitudes tests (IQ test)

Tanner scale

Questionnaire on menarche

Smoking Alcohol and drugs *One survey, **two surveys.

* *

Physical activity Fitness

* *

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Certainly the University of Limpopo has distinguished itself by being true to its vision of ‘being a leading African university focused on the developmental needs of its communities and epitomising academic excellence and innovativeness’. Not only has its researchers conducted research in neighbouring villages, but the University also continues to feed back into these communities. When the need arises, communities look up to the University for intervention and help, so, the communities see the University as a strategic partner. However, there are still many other areas of possible intervention and partnership that require substantial funding, which the current government funding model does not cover.

AFRICA

tion in strategic planning. In: Leadership and Institutional Change in Higher Education. CHET and UNCF, 2000. 10. Hart CS. Professionalisation of Community Development in South Africa: Process, Issues and Achievements. Unisa Press: Africanus 2012; 42(2): 55–66. 11. Kayama M, Kido Y, Setoya N, Tsunoda A, Matsunaga A, Kikkawa T, et al. Community outreach for patients who have difficulties in maintaining contact with mental health services: longitudinal retrospective study of the Japanese outreach model project, MBC Psychiatry 2014; 14(311): 1–10. 12. Bender CJG. Engagement and social responsibility in the core curriculum: how engaged and responsible are our academics? https://www.cetl. hku.hk/conference2010/pdf/Bender.pdf. 13. Monyeki KD, Kemper HCG. The risk factors for elevated blood pres-

References 1.

South African Government (2012). A vision for 2030: South Africa’s National Development Plan.

WHO. Non-communicable diseases country profiles. Geneva: World Health Organization, 2014.

tion, and physical fitness in rural children of South Africa: The Ellisras 16. Mashita RJ, Themane MJ, Monyeki KD, Kemper HC. Current smoking

training institutions in South Africa. A study commissioned by the

behaviour among rural South African children: Ellisras Longitudinal

The Constitution (Reflecting on 20 years). University of Limpopo

Study. BMC Paediatric 2011; 11: 58. 17. Matshipi M, Monyeki KD, Kemper H. the Relationship between physi-

Strategic Plan 2020. Financial Mail/Business Day 2017.

cal activity and plasma glucose level amongst Ellisras rural young adult

Brink C. Two tales of quality and equality. In: Reflections of South

males and females: Ellisras Longitudinal Study. Int J Environ Res Public Health 2017; 14(2): 198. 18. Sekgala MD, Monyeki KD, Mogale MA, Ramoshaba NE. Performance

Aasen HS. Academic freedom and education in a human rights perspec-

of blood pressure to height ratio as a screening tool for elevated blood

tive – experiences from Norway. In: Constituting Higher Education.

pressure in rural children: Ellisras Longitudinal Study. J Hum Hypertens

Kagisano: 2017; 11: 51–80.

longitudinal study. Am J Hum Biol 2007; 19(4): 551–558.

Saleem B. The challenges of transformation in higher education and

(2016). 2014: 93–118.

rural South African girls. Ann Hum Biol 2002); 29(1): 37–49. 15. Monyeki MA, Koppes LLJ, Monyeki KD, Kemper HCG, Twisk JWR. Longitudinal relationships between nutritional status, body composi-

African University Leaders (1981 to 2014), African Minds and CHE 7.

Nthangeni ME, Lenthe FV. Stability of somatotypes in 4 to 10-year-old

M, et al. Non-communicable diseases in sub-Saharan Africa: what we

Development Bank of Southern Africa, 2010. 5.

atric population. J Human Hypertens 2008; 22: 450–459. 14. Monyeki KD, Toriola AL, Ridder JD, Kemper HCG, Steyn NP,

Dalal S, Beunza JJ, Volmink J, Adebamowo C, Bajunirwe F, Njelekela know now. Int J Epidemiol 2011; 40(4): 885–901.

sure and how to address cardiovascular risk factors: A review in paedi-

2017; 31: 591–595.

Nongxa L. Leadership challenges for research-intensive universities. In:

19. Monyeki MA, Koppes LL, Kemper HC, Monyeki KD, Toriola AL,

Reflections of South African University Leaders (1981 to 2014), African

Pienaar AE, Twisk JW. Body composition and physical fitness of under-

Minds and CHE, 2016: 143–158.

nourished South African rural primary school children. Eur J Clin Nutr

Dlamini C. Challenges of leading a historically disadvantaged institu-

2005; 59(7): 877–883.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Intracoronary or intravenous abciximab after aspiration thrombectomy in patients with STEMI undergoing primary percutaneous coronary intervention Ali Bedjaoui, Karima Allal, Mohamed Sofiane Lounes, Chams Eddine Belhadi, Abdelmoumen Mekarnia, Saber Sediki, Maamar Kara, Adel Azaza, Jean-Jacques Monsuez, Salim Benkhedda

Abstract Objectives: To test whether aspiration thrombectomy with intracoronary (IC) instead of intravenous (IV) administration of abciximab could reduce the no-reflow phenomenon in patients undergoing primary percutaneous intervention (PCI) for ST-elevation myocardial infarction (STEMI). Background: Despite recanalisation with PCI, failure to restore microvascular flow may affect the prognosis of patients with STEMI. A combination of aspiration thrombectomy with IC abciximab may improve distal perfusion. Methods: After aspiration thrombectomy during primary PCI for STEMI, 160 patients were randomly assigned to either an IV or IC abciximab bolus delivered through the aspiration catheter, both followed by a 12-hour IV abciximab infusion. Results: ST-segment resolution ≥ 70% was achieved in 36 of 78 patients with IC versus 30 of 82 patients with IV abciximab (46.1 vs 36.6%, p = 0.368), and partial resolution in 28 of 78 versus 31 of 82 patients (35.9 vs 37.8%, p = 0.368). Postprocedural myocardial blush grade (MBG) 3 was obtained in 62.8 vs 63.4% (p = 0.235) and MBG ≥ 2 in 89.7 vs 81.7% (p = 0.148) of patients given IC and IV abciximab, respectively. There were three deaths in each group (3.8%). Major adverse cardiac events occurred in six of 78 patients given the IC and seven of 82 patients given the IV abciximab bolus (7.6 vs 8.5%, p = 0.410). One stroke occurred in each group, and two patients in the IC and nine in the IV group developed renal failure (2.5 vs 10.9 %, p = 0.414). Cardiology Oncology Research Collaborative Group (CORCG), Faculty of Medicine, Benyoucef Benkhedda University, Algiers, Algeria Ali Bedjaoui, MD Salim Benkhedda, MD, PhD

Department of Cardiology, Hôpital Central de l’Armée Ain Naadja, Algiers, Algeria Ali Bedjaoui, MD Karima Allal, MD Mohamed Sofiane Lounes, MD Chams Eddine Belhadi, MD Abdelmoumen Mekarnia, MD

Department of Cardiology, Mustapha University Hospital Centre, Algiers, Algeria Saber Sediki, MD Maamar Kara, MD Adel Azaza, MD Salim Benkhedda, MD, PhD

APHP Hôpital R Muret, Hôpitaux Universitaires de Paris, Seine Saint Denis, Paris, France Jean-Jacques Monsuez, MD, PhD, jean-jacques.monsuez@aphp.fr

Conclusion: IC versus IV abciximab did not enhance myocardial reperfusion in non-selected patients with STEMI undergoing primary PCI after aspiration thrombectomy had successfully been performed. Keywords: myocardial infarction, primary percutaneous intervention, aspiration thrombectomy, abciximab Submitted 25/5/18, accepted 31/10/18 Published online 20/11/18 Cardiovasc J Afr 2019; 30: 45–51

www.cvja.co.za

DOI: 10.5830/CVJA-2018-063

Rapid and sustained restoration of a thrombolysis in myocardial infarction (TIMI) 3 anterograde flow through the epicardial coronary artery, associated with a resolution of ST-segment elevation > 70% within 90 minutes are the primary goals of the current treatment of ST-segment elevation myocardial infarction (STEMI).1-3 Despite mechanical recanalisation of the occluded artery with primary percutaneous coronary intervention (PCI) and aggressive antithrombotic therapy directed at preventing thrombus growth and mitigating distal embolisation, these goals are not reached in many instances. A major limitation of primary PCI is the possibility of distal embolisation of thrombus and failure to restore flow at the microvascular level. ST-segment elevation persists in more than 40% of cases of patients in whom a TIMI 3 flow has been achieved by primary PCI, a drawback associated with subsequent impairment of left ventricular (LV) function and a worse prognosis.4-6 Over the past decade, several approaches have been directed to prevent or reverse the no-reflow phenomenon, including aspiration thrombectomy7-11 and intracoronary glycoprotein IIb/ IIIa inhibitor administration, such as abciximab.12-17 Abciximab, the Fab fragment of the chimeric human–murine monoclonal antibody 7E3, binds to the glycoprotein IIb/IIIa receptor of human platelets and inhibits platelet aggregation. However, randomised trials of both thrombus aspiration and intracoronary (IC) versus intravenous (IV) abciximab administration have shown inconsistent results of these adjunctive methods with regard to clinical outcomes as well as to surrogate reperfusion parameters. In addition, these two approaches have been compared to each other in the INFUSE-AMI study, in which intralesional abciximab was delivered through a dedicated infusion catheter consisting of a microporous balloon (ClearWay RX).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

IC abciximab delivery resulted in a modest but statistically significant reduction in infarct size compared with aspiration thrombectomy. However, in this trial, there was no control group of patients receiving IV abciximab.18 Therefore, whether IC or IV abciximab delivery would be more effective after removal of IC thrombotic and atherosclerotic materials has not been tested. This study was intended to compare the effects of IC versus IV administration of abciximab in patients with STEMI undergoing primary PCI with aspiration thrombectomy. Intracoronary abciximab was administered through the distal part of the same catheter (Export catheter) after aspiration thrombectomy was completed.

Methods This was a two-centre, open-label, controlled, single-blind, randomised study. The study was performed at the Department of Cardiology of the Military Hospital (Hôpital Central de l’Armée) and at the Department of Cardiology A2 of the Mustapha Pacha University Hospital, in collaboration with the Cardiology Oncology Collaborative Research Group (COCRG). Patients were recruited in this prospective, randomised, blind study from 1 October 2013 to 31 October 2015. Inclusion criteria were a chest pain suggestive of acute myocardial infarction (AMI) evolving for ≥ 30 minutes and less than 12 hours, resistant to nitroglycerin administration, and ST-segment elevation recorded ≥ 1 mm from standard and ≥ 2 mm from precordial leads. Exclusion criteria were cardiogenic shock, high blood pressure, not controlled by treatment, after measuring twice (systolic BP ≥ 240 mmHg, diastolic BP ≥ 120 mmHg, or both), left bundle branch block, pregnancy, thrombocytopaenia, severe kidney or liver failure, major surgery lasting for less than one month, gastrointestinal haemorrhage in the past year, coagulation disorders, including coagulation factors and platelet disorders, ischaemic stroke lasting for less than one month, current staging or treatment of cancer, oral anticoagulant therapy, administration of a thrombolytic treatment during the seven days preceding the study, and allergy/hypersensitivity to aspirin, heparin or abciximab. During the study period, 160 patients were consecutively included. The study was approved by the ethics committee of the institution and patients gave informed consent at admission to the catheterisation laboratory. Patients were randomly assigned on a 1:1 basis to either an IV or IC abciximab bolus (ReoPro 10 mg/5 ml, Eli Lilly, Indianapolis, IN), delivered over one minute through the aspiration thrombectomy catheter at the site of coronary occlusion, after anterograde flow had recovered. Intracoronary or IV bolus administration was followed by a 12-hour IV infusion of abciximab at 0.125 µg/kg/min. Coronary angiography was performed after introduction of a 6F catheter though the femoral or radial artery. Two-orthogonal-axis coronary artery imaging was performed to assess baseline and post-procedural TIMI flow grade and myocardial blush grade (MBG). TIMI flow grade was defined according to the TIMI study group.19 In brief, TIMI 0 denotes no perfusion (no anterograde flow beyond the point of occlusion); TIMI 1: penetration without perfusion (faint anterograde coronary flow beyond the occlusion with incomplete filling of

AFRICA

the distal coronary bed); TIMI 2: partial perfusion (delayed or sluggish anterograde flow with complete filling of the distal territory); TIMI 3: complete perfusion (normal flow with complete filling of the distal territory).19 Myocardial blush grade 0 denotes no contrast density or persistent blush or staining in the territory supplied by the infarct artery; MBG 1: minimal contrast density; MBG 2: moderate contrast density but less than that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery; and MBG 3: normal contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery.20 Before PCI, patients were treated with aspirin (bolus of 250 mg), intravenous heparin (60-IU/kg bolus) and clopidogrel (loading dose of 600 mg). Adjunctive therapy included 1 mg IC nitroglycerin during the procedure. After completion of primary PCI, patients received 150 mg clopidogrel daily p.o. for one month, then 75 mg p.o. daily for one year, together with a statin, beta-blocker, angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, and 75 mg aspirin. Aspiration thrombectomy was performed using an Export catheter (Medtronic, Minneapolis, Minnesota). IC abciximab was administered through the distal part of the same catheter after aspiration thrombectomy was completed. Additional or post-balloon predilatation as well as stenting remained at the discretion of the interventional cardiologist. The primary efficacy endpoint was assessed by ST-segment resolution. ST-segment elevation was measured to the nearest 0.1 mV, 40 ms after the end of the QRS using the TP segment as baseline. According to previous reports,5-6 ST-segment resolution was defined as successful if ≥ 70% of the sum of ST-elevation present on the baseline ECG had resolved by 60 minutes after primary PCI (complete ST-segment resolution). Partial ST-segment resolution was defined if ≥ 50% but < 70% of the sum of ST-elevation present on the baseline ECG had resolved by 60 minutes after primary PCI.5,6,21,22 Secondary efficacy endpoints consisted of (1) major adverse cardiovascular events (MACE), including cardiovascular death, stent thrombosis, target-vessel revascularisation, and recurrent myocardial infarction at 30 days and six months; and (2) achievement of MBG 2 to 3 after completion of primary PCI. Recurrent AMI was defined as recurrent symptoms or ST-elevation or increase in troponin levels.23 Target vessel revascularisation was defined as any repeat revascularisation procedure on the infarct-related coronary artery. Safety endpoints consisted of major and minor bleeding during hospital stay. Major haemorrhage was defined as retroperitoneal or intracranial bleeding, bleeding resulting in a ≥ 15% absolute decrease in haematocrit or a decrease in haemoglobin level > 5 g/dl.20 Minor haemorrhage consisted of clinical or echo/CT scan-documented bleeding associated with a decrease in blood haemoglobin level > 3 g/dl and < 5 g/dl or a decrease in haematocrit > 9% and < 15%.24

Statistical analysis This study was powered for a ST-segment resolution rate of 56% at 60 minutes.7 Evaluating two groups of 72 patients would provide 90% power to demonstrate a relative 25% difference in ST-segment resolution rate between the IC and IV groups.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Assuming approximately 10% lost to follow up, 160 patients were randomised. All statistical analyses were performed using the SPSS statistical software (graduate pack for Windows, version 20). For categorical variables, the frequencies and percentages were calculated. Continuous variables are presented as means ± SD and were compared using the Student’s t-test or the Mann–Whitney U-test as appropriate. Categorical variables are presented as proportions and were compared with the χ² or Fisher’s exact test. A p-value < 0.05 was considered significant.

Results

Table 1. Baseline characteristics of patients All patients, n = 160

IV abciximab, n = 82

IC abciximab, n = 78

Age, years

59.7 ± 13.5

60.6 ± 12.2

58.8 ± 14.8

0.383

Men, n (%)

137 (85.6)

72 (87.8)

65 (83.3)

0.420 0.437

Variables

p-value

Patients

Cardiovascular risk factors Diabetes, n (%)

54 (33.8)

30 (36.6)

24 (30.8)

Hypertension, n (%)

72 (45)

44 (53.7)

28 (35.9)

0.024

Smokers, n (%)

67 (41 .9)

29 (35.4)

38 (48.7)

0.087

Dyslipidaemia, n (%)

30 (18.8)

16 (19.5)

14 (17.9)

Obesity, n (%)

23 (14.4)

18 (22.2)

5 (6.4)

0.005

0.8

Heredity, n (%)

9(5.6)

4 (4.9)

5 (6.4)

0.674

Past history

The study flow chart is described in Fig. 1. Baseline characteristics of patients are summarised in Table 1. Patients randomised to IC administration were younger (58.8 ± 14.8 vs 60.6 ± 12.2 years) and less frequently hypertensive (36 vs 53%). An increased waist circumference was less frequently observed (6.4 vs 22.2%, p < 0.05). There was no significant difference with regard to the patients’ past history between the groups, including prior coronary artery bypass graft (CABG), PCI, stroke and peripheral artery disease. Previous AMI was less frequent among patients with IC versus IV abciximab (5.1 vs 19.5%, p = 0.05). There was no significant difference between the two groups with regard to delay from symptom onset to balloon, heart rate, systolic and diastolic blood pressure, heart failure signs and left ventricular ejection fraction (LVEF) at admission. Pre-procedural features of the target vessel lesions and coronary angiography findings are summarised in Table 2. The infarct-related coronary artery was the left anterior descending

Patients admitted with STEMI <12 h, n = 172 Excluded for exclusion criteria, n = 12 Patients included 2013-09-01 to 2015-10-30, n = 160 Patients randomised to IV abciximab bolus, n = 82

Patients randomised to IC abciximab bolus, n = 78

Aspiration thrombectomy: 68 patients

Aspiration thrombectomy: 62 patients

ECG criteria: available for 82 patients

ECG criteria: available for 78 patients

Angiographic criteria: available for 82 patients

Angiographic criteria: available for 78 patients

Stroke, n (%)

6 (3.8)

5 (6.1)

1 (1.3)

0.109

Peripheral artery disease, n (%)

4 (2.5)

3 (3.7)

1 (1.3)

0.336

Previous MI, n (%)

20 (12.5)

16 (19.5)

4 (5.1)

0.006

Previous PCI, n (%)

10 (6.3)

8 (8.9)

2 (2.6)

0.06

Clinical findings Heart rate, bpm

86.2 ± 21.7

84.8 ± 21.8

87.7 ± 21.6

0.852

137.5 ± 24.9

136.8± 27.0

138.1 ± 22.6

0.321

149 (93.1)

75 (91.5)

74 (94.9)

0.585

2 (1.3)

5 (6.1)

9 (5.6)

2 (2 .4)

4 (5.1)

Mean systolic blood pressure, mmHg Killip class, n (%):

3 Delay from symptom onset to cathlab, min LVEF, %

334.8 ± 192.1 345.2 ± 204.3 323.8 ± 179.1 52.6 ± 10.1

52.7 ± 10.1

52.5 ± 10.3

0.481 0.902

LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention.

coronary artery (LAD) in 62% of patients with IC and 61% with IV administration (p = 0.470). Single-vessel disease was observed in 70.5 vs 57% in patients with IC vs IV administration (p = 0.127). There was no difference with regard to pre-PCI TIMI flow between the two groups. A TIMI flow of 0 (occlusion) was observed in 67% with IC compared to 72% of those with IV administration (p = 0.799). Procedural characteristics of the two groups are shown in Table 3. There was no difference between the two groups with regard to radial catheterisation, aspiration thrombectomy and stenting rates. Manual aspiration thrombectomy was systematically performed before angioplasty or stenting. No serious complications, such as flow-limiting dissection or air embolisation occurred after angiography. Direct

Table 2. Target-vessel characteristics

Variables

All patients, n = 160

IV abciximab, n = 82

IC abciximab, n = 78

p-value

Anterior MI, n (%)

104 (65)

53 (64.6)

51 (65.4)

0.921

56 (35)

29 (35.4)

27 (34.6)

Posterior/inferior MI, n (%) Single vessel, n (%)

MACE at 1 month: available for 79 patients

MACE at 1 month: available for 75 patients

102 (63.8)

47 (57.3)

55 (70.5)

2 vessels, n (%)

40 (25)

26 (31.7)

14 (17.9)

3 vessels, n (%)

18 (11.3)

9 (11)

9 (11.5)

0, n (%)

111 (69.4)

59 (72)

52 (66.7)

1, n (%)

11 (6.9)

6 (7.3)

5 (6.4)

2, n (%)

21 (13.1)

10 (12.2)

11 (14.1)

3, n (%)

17 (10.6)

7 (8.5)

10 (12.8)

0.127

TIMI flow: MACE at 6 months: available for 71 patients

MACE at 6 months: available for 70 patients

Fig. 1. Study flow chart. MACE: major cardiac events.

TIMI: thrombolysis in myocardial infarction.

0.799

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 3. Procedural characteristics All patients, n = 160

Variables

IV abciximab, n = 82

Table 5. Major cardiac events IC abciximab, n = 78

p-value

Radial access, n (%)

116 (72.5)

57 (69.5)

59 (75.6)

0.385

Aspiration thrombectomy, n (%)

130 (81.3)

68 (82.9)

62 (79.5)

0.577 0.182

Predilatation, n (%)

49 (30.6)

29 (35.4)

20 (25.6)

Direct stenting, n (%)

83 (51.9)

44 (53.7)

39 (50)

58 (36.3)

28 (34.1)

30 (38.5)

0.851

UFH 5 000 IU, n (%)

Delayed stenting, n (%)

135 (84.4)

75 (91.5)

60 (76.9)

0.011

UFH 2 500 IU, n (%)

25 (15.6)

7 (8.5)

18 (23.1)

Clopidogrel 300 mg, n (%)

13 (18.1)

6 (7.3)

7 (9)

Clopidogrel 600 mg, n (%)

147 (91.9)

76 (92.7)

71 (91)

0.701

Abciximab IV perfusion, n (%)

112 (70)

64 (78)

48 (61.5)

0.074

UFH: unfractioned heparin.

stenting (stenting after thrombus aspiration without balloon pre-dilatation) was performed in 51.9% of the patients with IC administration and in 53.7% of those treated with IV administration (p = 0.851). Angiographic outcome is presented in Table 4. Post-procedural TIMI flow grade was similar in both groups, with achievement of a TIMI 3 flow grade in 89.7% of patients with IC and in 89% of those with IV administration (p = 0.747). Post-procedural MBG 3 was obtained in 62.8% of patients with IC and in 63.4% of those with IV administration (p = 0.235). An MBG ≥ 2 was more frequently obtained with IC versus IV administration (89.7 vs 81.7%), but this did not reach statistical significance (p = 0.148). There was no difference between patients randomised to IC and IV abciximab with regard to ST-segment resolution rate. ST-segment resolution ≥ 70% was achieved in 36 of 78 patients with IC versus 30 of 82 patients with IV abciximab bolus (46.1 vs 36.6%, p = 0.368). Partial ST-segment resolution was achieved in 28 of 78 versus 31 of 82 patients (35.9 vs 37.8%, p = 0.368). No resolution was observed in 14 of 78 versus 21 of 82 patients (17.9 vs 25.6%, p = 0.368) with IC and IV abciximab bolus, respectively. In-hospital outcome: major cardiac events are listed in Table 5. Occurrence of death, recurrent myocardial infarction and target revascularisation rates within 30 days were similar in the two groups. There were three deaths in each group (mortality rate: 3.8%). MACE occurred in six of 78 patients given the IC, and seven of 82 patients given the IV abciximab bolus (7.6 vs 8.5%, p = 0.410). One stroke occurred in each group, and two Table 4. Angiographic outcomes Variables

All patients, IV abcixIC abcixn = 160 imab, n = 82 imab, n = 78 p-value

Post-procedural TIMI flow: 0, n (%)

3 (1.9)

1 (1.2)

2 (2.6)

2, n (%)

14 (8.8)

8 (9 .8)

6 (7.7)

3, n (%)

143 (89.4)

73 (89)

0.747

70 (89.7)

Post-procedural MBG: 0, n (%)

8 (5)

4 (4.9)

1, n (%)

15 (9.4)

11 (13.4)

4 (5.1) 4 (5.1)

2, n (%)

36 (22.5)

15 (18.3)

21 (26.9)

3, n (%)

49 (62.8)

101 (63.1)

52 (63.4)

MBG 0/1, n (%)

23 (14.4

15 (18.3)

8 (10.3)

MBG 2/3, n (%)

137 (85.6)

67 (81.7)

70 (89.7)

0.235

0.148

TIMI: thrombolysis in myocardial infarction; MBG: myocardial blush grade.

IV abciximab, n = 82

IC abciximab, n = 78

Heart failure, n (%)

4 (4.9)

3 (3.8)

Cardiac death, n (%)

2 (2.4)

3 (3.8)

Non-cardiac death, n (%)

1 (1.2)

0 (0)

Major cardiac events, n (%)

7 (8.5)

6 (7.6)

Events

p-value 0.414

patients in the IC and nine in the IV group developed renal failure (2.5 vs 10.9 %, p = 0.414). Major bleeding complications occurred in one patient in the IC group and none in the IV group. Minor bleeding complications occurred in seven of 78 patients given IC versus eight of 82 patients given the IV abciximab bolus (9.3 vs 9.9%, p = 0.578). Thrombocytopenia occurred in five of 78 patients with IC versus three of 82 patients with IV abciximab (6.4 vs 3.7%, p = 0.414). Short-term clinical outcome: after the one-month follow up, there was only one cardiac death in each group, one stent thrombosis in the IC group, and similar rates of MACE in both groups (2.66 vs 2.53%, p = 0.588). Also, there was no difference in mortality rate (one death in the IV group), stent thrombosis (one in the IC group) and MACE (5.9 vs 8.8%, p = 0.714) after six months of follow up.

Discussion This study was intended to assess the potential benefit of IC over IV abciximab administration after manual thrombus aspiration in patients undergoing primary PCI for STEMI. It showed that distal, intralesional IC administration of abciximab through the aspiration catheter following aspiration thrombectomy did not provide additional benefit over IV administration of the drug. Among 160 patients randomised to either IC or IV abciximab bolus, no significant difference between the two groups was observed. Baseline clinical characteristics of patients, symptom-to-balloon time, which impacts on MBG,25 coronary angiography findings, infarct-related coronary artery, target vessel and procedural characteristics were similar in the two groups. Reperfusion parameters including the primary outcome endpoint, ST-segment resolution, and the secondary endpoint, achievement of MBG grade ≥ 2, did not differ between the groups. Also, no difference was observed with regard to the rate of MACE and major bleeding. Over the past decade, several approaches have been used to prevent or reverse the no-reflow phenomenon. This included aspiration thrombectomy and intralesional administration of glycoprotein IIb/IIIa inhibitors via dedicated perfusion catheters to achieve higher concentration of the drug at the coronary vascular bed in order to improve myocardial reperfusion and to reduce infarct size. Initial results from the Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS) trial suggested that aspiration thrombectomy could be effective in improving revascularisation at the microvascular level.7 Also, a meta-analysis of randomised trials, including 3 996 patients, showed improved myocardial perfusion, as assessed by ST-segment resolution and MBG.8 However, aspiration thrombectomy was subsequently challenged by the results of two trials, Thrombus Aspiration in ST-elevation

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

Myocardial Infarction in Scandinavia (TASTE) and Trial of Routine Aspiration Thrombectomy with PCI versus PCI alone in Patients with STEMI (TOTAL), which both failed to show substantial clinical and perfusion benefit in patients despite successful aspiration of clotting material.9-11 Coronary thrombus material triggers thrombotic, inflammatory, vasoconstrictor and other pathways, and evacuating a portion of the thrombus and plaque material addresses only a part of the pathophysiological problem. Pharmacologically disrupting thrombus formation may be more effective. Abciximab, a potent inhibitor of platelet aggregation, disrupts fresh thrombus at high local drug concentrations, such as those delivered by IC administration, and also exhibits antiinflammatory effects by inhibiting smooth muscle cell migration and proliferation, thereby suppressing platelets, white blood cells and endothelial-mediated mechanisms.26 Adjunctive abciximab administration has been demonstrated to reduce the rate of mortality and re-infarction in patients with STEMI referred for invasive management.12 The standard abciximab regimen consists of an IV bolus followed by a 12-hour IV infusion. Intracoronary administration has been suggested to optimise myocardial perfusion beyond recanalisation, since antiglycoprotein IIb/IIIa concentration has been reported as much as 280-fold higher with local compared with IV delivery.12 Initial studies, in which abciximab bolus was delivered through the guiding catheter after wiring the infarct-related artery, were followed by the use of new application systems such as infusion catheters. These systems consist of a perfusion balloon that occludes anterograde blood flow while drugs are infused through a microporous surface, thereby allowing achievement of high drug concentrations and prolonged focal dwelling times at the site of coronary thrombus. Delivery of abciximab through such dedicated catheters (ClearWay Rx, Atrium Medical Hudson, New Hampshire) was associated with a significant reduction in thrombotic burden, improved microcirculatory flow, and lower rates of one-year adverse events, compared with conventional intracoronary drug administration through the guiding catheter in the small, randomised COCTAIL-II trial.13 Also, a meta-analysis of eight randomised trials to assess the clinical efficacy and safety of intracoronary versus IV abciximab in STEMI patients undergoing primary PCI showed that intracoronary administration was associated with significant benefits in myocardial perfusion, but not in clinical outcome at short-term follow up.14 Another meta-analysis of 14 randomised trials of IC versus IV glycoprotein IIb/IIIa inhibitors with a total of 3 740 patients undergoing primary PCI showed no statistically significant difference between the IC and the IV groups for the primary outcome of MACE. Subgroup analysis showed however that the IC group was superior to the IV group in short-term MACE rate, TIMI 3 flow, MBG 2 to 3 rates, improvement of LVEF, and ST-segment resolution, compared to the IV group, with a trend towards less stent thrombosis.15 Among diabetic patients, IC versus IV abciximab bolus was associated with a significantly reduced risk of death and stent thrombosis and increased myocardial salvage.16,17 In addition, in the INFUSE-AMI study, randomisation to intralesional abciximab through a ClearWay Rx catheter resulted in a modest but statistically significant reduction in infarct size compared with aspiration thrombectomy, but not with IV abciximab

administration. However, in this trial, there was no control group of patients receiving IV abciximab.18 Uncertainties regarding the use of IC abciximab are due, in part, to mixed results observed across studies. Indeed, although initial, small-sized investigations found an improvement in surrogate endpoints with IC abciximab, the AIDA STEMI trial, which was powered to assess clinical outcomes, failed to demonstrate a reduction in the primary endpoint of all-cause mortality, recurrent infarction, or new incidence of congestive heart failure among patients randomised to IC compared to IV abciximab bolus.27 In the study by Piccolo et al. in diabetic patients, aspiration thrombectomy was performed in fewer than 20% of patients, while IC abciximab resulted in significant improvement of the effectiveness of PCI, including an increased myocardial salvage index and a reduced risk of death (5.8 vs 11.2%, p = 0.043).17 The effectiveness of IC abciximab administration is also supported by the Intracoronary Abciximab Infusion and Aspiration Thrombectomy in Patients Undergoing Percutaneous Coronary Intervention for Anterior ST-segment Elevation Myocardial Infarction (INFUSE-AMI) trial, in which an IC bolus of the glycoprotein IIb/IIIa inhibitor abciximab was effective in reducing the infarct size, whereas thrombectomy by means of manual aspiration was not.18 In the INFUSE-AMI trial, which did not include an IV abciximab administration control group, the beneficial effects of intralesional abciximab and thrombus aspiration were not additional. Nonetheless, although debated, the question of potential benefits of IC abciximab has recently been re-opened.28-30 A recent meta-analysis of 14 trials of IC versus IV glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI also showed improved ST-segment resolution rates and superior angiographic results with IC glycoprotein IIb/IIIa inhibitors, evidenced by improved achievement of post-procedural TIMI 3 flow and MBG 2 to 3, compared with the IV group.15 Overall, these observations suggest that adjuvant therapy with aspiration thrombectomy or IC abciximab administration, even in combination, are not required in all patients undergoing PCI. They should rather be considered for selected patients only, including those at increased risk of microvascular obstruction, such as diabetics and patients with a large thrombotic burden or severe distal coronary embolisation.11,15,17,28-30 Trials to evaluate the effectiveness of such approaches in these selected patients remain to be undertaken.

Study limitation A major limitation pertains to the selection of patients. Patients with STEMI were included for primary PCI after a rather long delay from symptom onset to catheterisation laboratory of about 300 minutes. This was due to the specific area where the study was carried out, namely northern Africa. However, similar symptomto-door and symptom-to-balloon times have been reported in registries from Egypt,25 Tunisia31 and Morocco.32 Despite this delay, primary PCI was performed instead of thrombolysis in our study, as it was done in about 35% of patients included in northern African registries.25,31-33 We acknowledge that this delay is not optimal to assess the efficacy of an IC delivery of abciximab, an approach expected to improve distal perfusion after recanalisation of the occluded coronary artery. Therefore

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

we cannot exclude any beneficial effect resulting from a shorter delay before primary PCI.

11. Jolly SS, James S, Dzavik V, et al. Thrombus aspiration in ST-segment

Conclusion

12. Romagnoli E, Burzotta F, Trani C, et al. Angiographic evaluation of the

elevation myocardial infarction: an individual patient meta-analysis: Thrombectomy Trialists Collaboration. Circulation 2017; 135: 143–152

These data further compliment the overall INFUSE-AMI trial results. Because the patients who received IC and IV abciximab combined with aspiration thrombectomy had similar rates of ST-segment resolution and MBG, we concluded that IC instead of IV abciximab did not enhance myocardial reperfusion in non-selected patients with STEMI undergoing primary PCI, even after aspiration thrombectomy had successfully been performed.

effect of intracoronary abciximab administration in patients undergoing urgent PCI. Int J Cardiol 2005; 105: 250–255. 13. Prati F, Capodanno D, Pawmowski T, et al. Local delivery versus intracoronary infusion of abciximab in patients with acute coronary syndromes. J Am Coll Cardiol Cardiovasc Interv 2010; 3: 928–934. 14. De Luca G, Verdoia M, Suryapranata H. Benefits from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: a meta-analysis of 8 randomized trials. Atherosclerosis 2012; 222: 426–433.

Funding was provided by the Cardiology Oncology Research Collaborative

15. Elbadawi A, Elgendy IY, Megaly M, et al. Meta-analysis of randomized

Group (CORCG), Department of Cardiology, CHU Mustapha, Faculty of

trials of intracoronary versus intravenous glycoprotein IIb/IIIa inhibi-

Medicine, Benyoucef Benkhedda University, Algiers, Algeria. There was no

tors in patients with ST-elevation myocardial infarction undergoing

financial relationship with industry.

primary percutaneous coronary intervention. Am J Cardiol 2017; 120: 1055–1061.

References 1.

Windecker S, Kohl P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014; 35: 2541–619.

Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with

and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. J Am Med Assoc 2012;

Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI

ACC/AHA/SCAI guideline for percutaneous coronary intervention and

myocardial reperfusion in patients treated with primary angioplasty for

the 2013 ACCF/AHA guideline for the management of ST-elevation

acute myocardial infarction: myocardial blush grade. Circulation 1998; 97: 2302–2306.

Nijveldt R, Beck AM, Hirsch A, et al. Functional recovery after acute

21. Aitmokhtar O, Paganelli F, Benamara S, et al. Impact of platelet inhi-

myocardial infarction: comparison between angiography, electrocardi-

bition level on subsequent no-reflow in patients undergoing primary

ography, and cardiovascular magnetic resonance measures of microvas-

percutaneous coronary intervention for ST-segment elevation myocar-

Schröder R. Extent of early ST-segment elevation resolution: a strong

International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. J Am Coll Cardiol 1995; 26: 1657–1664.

dial infarction. Arch Cardiovasc Dis 2017; 110(11): 626–633. 22. Bouleti C, Mewton M, Germain S. The no-reflow phenomenon: state of the art. Arch Cardiovasc Dis 2015; 108: 661–674. 23. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012; 33: 2251–2267. 24. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction

Schröder R, Dissmann R, Brüggemann T, et al. Extent of early

(TIMI) trial phase I: hemorrhagic manifestations and changes in plasma

ST-segment elevation resolution: a simple but strong predictor of

fibrinogen and the fibrinolytic system in patients treated with recombi-

outcome in patients with acute myocardial infarction. J Am Coll Cardiol

nant tissue plasminogen activator and streptokinase. J Am Coll Cardiol

1994; 24: 384–391.

1988; 11: 1–11.

Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and re-infarc-

25. Faragh EM, Al-Daydamony MM. Symptom-to-balloon time and

tion after 1 year in the Thrombus Aspiration during Percutaneous

myocardial blush grade are predictors of left ventricular remodeling

Coronary Intervention in Acute Myocardial Infarction Study (TAPAS).

after successful primary percutaneous intervention. Cardiovasc J Afr

Lancet 2008; 371: 1915–1920.

trial, phase I findings. N Engl J Med 1985; 312: 932–936. 20. Van’t Hof AWJ, Liem A, Suryapranata H. Angiographic assessment of

sensitive measure to compare thrombolytic regimens. A substudy of the

3017: 1817–1826. 19. TIMI Study group. The Thrombolysis in Myocardial Infarction (TIMI)

patients with ST-elevation myocardial infarction: an update of the 2011

predictor of outcome in patients with acute myocardial infarction and a

primary percutaneous intervention. Vasc Pharmacol 2015; 73: 32–37.

of the European Society of Cardiology (ESC). Eur Heart J 2018; 39(2):

cular injury. J Am Coll Cardiol 2008; 52: 181–189.

patients with ST-segment elevation myocardial infarction undergoing

myocardial infarction in patients presenting with ST-segment elevation

myocardial infarction. J Am Coll Cardiol 2016; 67: 1235–1250.

coronary intervention. J Am Coll Cardiol 2016; 68: 727–738. 17. Piccolo R, Eitel I, Galasso G, et al. Intracoronary abciximab in diabetic

18. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abciximab

focused update on primary percutaneous coronary intervention for

nary abciximab in diabetic patients undergoing primary percutaneous

ST-segment elevation: The Task Force for the management of acute

119–177. 3.

16. Piccolo R, Eitel I, Galasso G, et al. One-year outcomes with intracoro-

Kumbhani DJ, Bavry AA, Desai MY, et al. Role of aspiration and

2017; 28: 186–190. 26. Dominguez- Rodriguez A, Avanzas P, et al. Intracoronary abciximab

mechanical thrombectomy in patients with acute myocardial infarction

and local anti-inflammatory effects. Int J Cardiol 2013; 168: 2872.

undergoing primary angioplasty. J Am Coll Cardiol 2013; 62: 1409–1419.

27. Thiele H, Wohrle J, Hambrecht R, et al. Intracoronary versus intra-

Lagerqvist B, Fröbert O, Olivecrona GK, et al. Outcomes 1 year after

venous bolus abciximab administration during primary percutaneous

thrombus aspiration for myocardial infarction. N Engl J Med 2014; 371:

intervention in patients with acute ST-elevation myocardial infarction: a

1111–1120.

randomized trial. Lancet 2012; 379: 923–931.

10. Jolly SS, Cairns JA, Yusuf S, et al. Outcomes after thrombus aspiration

28. De Rosa S, Caiazzo G, Torella D, et al. Intracoronary abciximab reduces

for ST elevation myocardial infarction: 1-year follow up of the prospec-

death and major adverse cardiovascular events in acute coronary

tive randomized TOTAL trial. Lancet 2016; 387: 127–135.

syndromes: a meta-analysis of clinical trials. Int J Cardiol 2013; 168:

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

1298–1305. 29. De Rosa S, Caiazzo G, Torella D, et al. What accounts for the higher clinical efficacy of intracoronary abciximab? Int J Cardiol 2013; 168: 4410. 30. Zimarino M, Radico F, Dalby K, et al. Intracoronary vs intravenous abciximab in interventional cardiology: a reopened question? Vasc Pharmacol 2015; 73: 8–10. 31. Addad F, Gouider J, Boughzela E, et al. Management of patients treated

for acute ST-elevation myocardial infarction in Tunisia. Ann Cardiol Angeiol 2015; 64: 439–445. 32. Akoukad H, El Khorb N, Sekkali N, et al. Acute myocardial infarction in Morocco: FES-AMI registry data. Ann Cardiol Angeiol 2015; 64: 434–438. 33. Delport R. Toward developing guidelines and systems of care to facilitate early reperfusion for ST-elevation myocardial infarction in Africa. Cardiovasc J Afr 2014; 25: 256–258.

Extreme exercise and middle-aged athletes’ hearts For the past decade or so, there’s been increasing concern that high-volume, high-intensity exercise could injure the heart. A large US study found that in middle-aged men, extreme exercise did not raise the risk for cardiovascular or all-cause mortality, even with elevated coronary calcium, a footprint of atherosclerosis. Exercise is often cited as the best preventive medicine, but how much is too much for the hearts of middle-aged athletes? Sports cardiologist Dr Benjamin Levine led a study to find the answer. Levine is a professor of internal medicine and director of the Institute for Exercise and Environmental Medicine, a collaboration between UT Southwestern Medical Centre and Texas Health Presbyterian Hospital Dallas. Coronary calcium scanning is an imaging test that helps physicians classify patients without cardiac symptoms as low, intermediate, or high risk for heart attack. It represents how much calcium (and therefore cholesterol deposits) has accumulated in the blood vessels that supply the heart. The scan can help physicians determine the need for medication, lifestyle modification and other risk-reducing measures. ‘The question has never been whether exercise is good for you, but whether extreme exercise is bad for you. For the past decade or so, there’s been increasing concern that high-volume, high-intensity exercise could injure the heart. We found that high volumes of exercise are safe, even when coronary calcium levels are high,’ Levine said. High-volume, high-intensity exercise was defined in this study as at least five to six hours per week at a pace of 10 minutes per mile. The average amount of high-intensity exercise in this group was eight hours per week. Coronary calcium is a footprint of atherosclerosis, a disease in which plaque builds up in the arteries and gives rise to heart attack and stroke. When coronary calcium is detected in the heart, the clogging process within the blood vessels has begun. The majority of high-intensity athletes had low levels of coronary calcium, although their odds of having higher levels were 11% greater than men who exercised less. Most importantly, the researchers found that higher calcium scores did not raise the high-intensity athletes’ risk for cardiovascular or all-cause mortality. Levine studied data from the Cooper Centre Longitudinal

Study. A total of 21 758 generally healthy men ages 40 to 80 years and without cardiovascular disease were followed for mortality between 1998 and 2013. The athletes, a majority of them in middle age, reported their physical activity levels and underwent coronary calcium scanning. Most were predominantly runners, but some were cyclists, swimmers or rowers. A subgroup of athletes trained in three of these sports. Women were not included in the study as their mortality rates are lower than for men. Despite the findings that extreme exercise does not raise heart disease risk, Levine advises against using the protective effect of exercise to excuse poor lifestyle habits. ‘You cannot overcome a lifetime of bad behaviours – smoking, high cholesterol, hypertension – just from doing high levels of physical activity, so don’t use that as a magical cure,’ said Levine, who holds the distinguished professorship in exercise sciences at UT Southwestern. He also recommends caution when starting a new training programme. ‘If you want to train for a marathon, you have to have a long-range plan to build up slowly before you achieve those volumes and intensity of exercise.’ ‘The known benefits of regular physical activity in the general population include decreased incidence of mortality, heart disease, diabetes and many other medical conditions, which reminds us how important it is participate in regular physical activity as recommended by the 2018 Physical Activity Guidelines,’ said Dr Laura DeFina, chief scientific officer of the Cooper Institute and co-author of the study. ‘The current study shows no increased risk of mortality in high-volume exercisers who have coronary artery calcium. Certainly, these high-volume exercisers should review their cardiovascular disease risk with their primary care doctor or cardiologists and the study results provide helpful clinical guidance.’ ‘The most important take-home message for the exercising public is that high volumes of exercise are safe. The benefits of exercise far outweigh the minor risk of having a little more coronary calcium,’ Levine said. Source: Medical Brief 2019

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

AFRICA

Cardiovascular risk factors among people living with HIV in rural Kenya: a clinic-based study Kenneth Juma, Roseanne Nyabera, Sylvia Mbugua, George Odinya, James Jowi, Mzee Ngunga, David Zakus, Gerald Yonga

Abstract Objectives: To determine the prevalence of cardiovascular risk factors and their association with antiretroviral therapy (ART) among HIV-infected adults in a rural sub-county hospital in Kenya. Methods: This was a descriptive survey of patient charts characterising cardiovascular risk among adult patients (> 18 years) at Ukwala sub-county hospital between June 2013 and January 2015. Post-stratification survey weights were applied to obtain prevalence levels. Adjusted odds ratios (AOR) for each variable related to cardiovascular risk factors were calculated using logistic regression models. Results: Overall, the prevalence of diabetes mellitus was 0.4%, 0.3% of patients had had a previous cardiovascular event (heart attack or stroke), 40.4% had pre-hypertension, while 10.4% had stage 1 and 2.9% stage 2 hypertension. Up to 14% of patients had elevated non-fasting total cholesterol levels. Factors associated with hypertension were male gender (AOR 1.59, p = 0.0001), being over 40 years of age (AOR 1.78, p = 0.0001) and having an increased waist circumference (OR 2.56, p = 0.0014). Raised total cholesterol was more likely in those on tenofovir disoproxil fumarate (TDF) (AOR 2.2, p = 0.0042), azidothymidine (AZT) (AOR 2.5, p = 0.0004) and stavudine (D4T)-containing regimens (AOR 3.13, p = 0.0002).

African Population and Health Research Center, Nairobi, Kenya; Clinical Epidemiology Unit, School of Medicine, Makerere University, Kampala, Uganda Kenneth Juma, MSc, MPH, kjuma@aphrc.org

Department of Medicine, Aga Khan University Hospital, Nairobi, Kenya Sylvia Mbugua, MB ChB George Odinya, BSc Mzee Ngunga MB ChB

Cardiac Programme Coordination Unit, the Mater Hospital, Nairobi, Kenya Roseanne Nyabera, BSN, MPH

Division of Clinical Public Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada David Zakus, MES, MSc, PhD

Department of Medicine, Maseno University, Kenya James Jowi

School of Medicine, University of Nairobi, Nairobi, Kenya Gerald Yonga, MB ChB, MBA

Conclusions: An elevated prevalence of undiagnosed cardiovascular risk factors such as hypertension and raised total cholesterol levels was found among people living with HIV. There was an association between raised total cholesterol and nucleoside reverse-transcriptase inhibitor (NRTI)-based ART regimens. Our findings provide further rationale for integrating routine cardiovascular risk-factor screening into HIV-care services.

Keywords: people living with HIV, cardiovascular risk factors, antiretroviral therapy, hypertension, diabetes, hypercholesterolaemia, sub-Saharan Africa Submitted 4/7/18, accepted 31/10/18 Published online 24/1/19 Cardiovasc J Afr 2019; 30: 52â&#x20AC;&#x201C;56

www.cvja.co.za

DOI: 10.5830/CVJA-2018-064

With the use and effectiveness of antiretroviral therapy (ART), people with HIV are living longer.1 Non-AIDS events, of which cardiovascular disease (CVD) mediated by inflammation and atherosclerosis predominate, are becoming more prevalent.2,3 A meta-analysis found that people living with HIV have a significantly higher risk for CVD when compared to HIV-negative persons.4 This may be due to traditional cardiovascular risk factors such as smoking and hypertension, which have been found to be increased in some HIV-positive cohorts,2,5 as well as ART,6 exposure to HIV itself or immune activation and a pro-inflammatory state induced by HIV,7 or a combination of these factors. Although there are accumulating data on cardiovascular risk factors in people living with HIV in developed countries,3 there are limited data from Africa. We report on the prevalence of risk factors for CVD among HIV-infected adults enrolled in HIV care and treatment at a sub-county hospital in Kenya, and describe the association with ART.

Methods This was a cross-sectional survey of patient charts characterising cardiovascular risk among adult patients (> 18 years) at Ukwala sub-county hospital between June 2013 and January 2015. Within this period, individuals with HIV attending Ukwala sub-county hospital for HIV care were screened for cardiovascular risk factors as part of a pilot project for integration of non-communicable disease care into HIV programmes supported by Grand Challenge Canada (GCC). Ethical approval for this study was obtained from the Maseno

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

University ethics review committee. Data used in this study were obtained from patient charts routinely collected at the clinic, and a written informed consent was provided before screening by each participant while attending the HIV clinic. Confidentiality, anonymity and privacy of all participants were guaranteed at all levels of this study by excluding all unique identifiers for the participants. Baseline assessment included demographic variables, risk factors for CVD and measurement of body mass index (BMI), blood pressure, non-fasting total cholesterol and random blood glucose levels. World Health Organisation (WHO) cardiovascular risk score was calculated for patients aged above 40 years8 and the information included in the patients’ medical record files. All people with HIV attending the Ukwala HIV clinic were included. Those who declined consent for the cardiovascular risk-factor screening and pregnant women were excluded. Patients fulfilling national eligibility criteria (CD4 count > 350 cells/mm3 at time of the study) were treated with standard ART according to national guidelines.9 Standard regimens at that time included tenofovir, lamivudine and efavirenz (TNF/3TC/ EFV) or zidovudine, lamivudine and efavirenz (AZT/3TC/EFV). Some were still receiving stavudine, lamivudine and efavirenz (D4T/3TC/EFV), which was being phased out at the time. A minority received a lopinavir/ritonavir (LPV/r)-containing regimen. Prior to commencing CVD screening within the HIV clinics at Ukwala sub-county hospital, healthcare providers (including nurses, laboratory technologists, clinicians and data clerks) in the health facility received a two-day training, followed by regular intensive theoretical and practical skills training and mentoring in measuring and interpreting cardiovascular risk factors. The facility was also provided with regularly calibrated point-of-care diagnostic equipment for cardiovascular risk assessment. Blood pressure (BP) was measured using a hospital-grade Omron M3® (Omron, Netherlands) digital automatic blood pressure machine. Hypertension diagnosis was based on standard guidelines, and included blood pressure measurements, medical history, physical examination, assessment of absolute cardiovascular risks (where deemed necessary by the examining physician) and laboratory investigations. A comprehensive assessment of BP involved multiple measurements taken on separate occasions, at least twice or three times, one or more weeks apart or sooner if the hypertension was severe. Hypertension was defined as per the seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)10 as follows: pre-hypertension: systolic 120–139 mmHg, diastolic 80–89 mmHg; stage 1 hypertension: systolic 140–159 mmHg, diastolic 90–99 mmHg; stage 2 hypertension: systolic ≥ 160 mmHg, diastolic ≥ 100 mmHg, and those currently on antihypertensive drugs. Total cholesterol and blood glucose levels were measured in the clinic using finger-prick blood by a Humansence® (Human, Wiesbaden, Germany) meter calibrated with a control strip on the first and after every 10th specimen. Raised total cholesterol level was defined according to US National Cholesterol Education Program ATP III guidelines.11 Data collection involved the extraction of data from the patients’ charts using a standardised data tool by trained data clerks. Charts for patients who attended the clinic from June 2013 to January 2015 were targeted. Those with missing details

on key variables such as cardiovascular risk-factor screening results and ART regimen were excluded from the data. Detailed abstraction was then conducted on the remaining patients’ charts using a data tool that was made up of four sections, including: (1) anthropometric measures (age, body mass index, waist circumference and blood pressure), (2) behavioural and biomedical cardiovascular risk factors (including smoking status, excessive use of alcohol and non-fasting total cholesterol level), (3) clinical information (such as on HIV infection and HIV treatment, ART regimen and duration), and (4) medical history. Data extracted were entered in a paper data tool then later transferred into an EpiData software version 3.1 for cleanup in readiness for analysis using SPSS software.

Statistical analysis Statistical analysis was performed using SPSS software version 22 (IBM SPSS Statistics, Armonk, NY: IBM Corp). Descriptive statistics involved calculating the median and interquartile range (IQR) for continuous data and proportions for categorical variables. Comparisons of median duration between groups were done using the Mann–Whitney test with a 5% level of significance. Associations were assessed using a logistic regression model, and crude and adjusted odds ratios are reported with their corresponding confidence intervals.

Results A total of 1 510 subjects was screened, of whom eight were excluded from analysis because of incomplete data (Fig. 1). Data collected included demographic variables, risk factors for CVD and determination of BMI, measurement of blood pressure, and non-fasting total cholesterol and random blood glucose levels. Cardiovascular risk score was calculated for those above 40 years using the WHO (Afri-E) risk-screening chart.8 Of the subjects screened, 69% (1 036) were women. The median age was 30 (IQR 31–48) years and median CD4 count was 430 (IQR 308–574) cells/mm3; 79% of subjects were on ART with a documented regimen. Current smokers were 1.9% (29),

n = 1 510 n=8 with incomplete initial CVD screening

n = 1 217 On ART at initial CVD screening n = 36 Missing information on ART regimen

n = 285 Pre-ART Had not yet started ART at initial CVD screening

n = 1 181 with complete information on ART regimen

Fig. 1. Data flow chart for cardiovascular risk screening.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 1. Prevalence of cardiovascular risk factors among people living with HIV Variables

Table 3. Unadjusted and adjusted odds ratios for hypertension

Frequency (n)

Overall %

Age ≥ 40 years

716

47.4

Male gender

471

31.2

Current smokers

1.9

Increased waist circumference*

5.9

Total cholesterol ≥ 5.2 mmol/l

207

13.7

Body mass index ≥ 25 kg/m2

182

12.1

2.1

Known diabetes at screening

0.5

Cardiovascular risk score ≥ 10%

0.5

Pre-hypertension

609

40.4

Hypertension stage 1

157

10.4

Hypertension stage 2

2.9

Random blood glucose ≥ 7.8 mmol/l

Unadjusted OR OR (95% CI)

p-value

OR (95% CI)

p-value

Male gender

1.65 (1.32–2.06)

0.0001

1.68 (1.32–2.14)

0.0001

Age ≥ 40 years

2.06 (1.67–2.53)

0.0001

1.78 (1.43–2.22)

0.0001

Current smokers

1.42 (0.67–3.02

0.3653

1.02 (0.47–2.24)

0.9574

Body mass index ≥ 30 kg/m2

3.14 (1.35–7.31)

0.0079

1.47 (0.55–3.94)

0.4421

Random blood glucose ≥ 7.8mmol/l

1.13 (0.54–2.34)

0.7459

1.09 (0.51–2.33)

0.8225

Increased waist circumference*

2.95 (1.79–4.87)

0.0001

2.49 (1.39–4.43)

0.0020

ART regimen No ART

Females ≥ 90 cm, males ≥ 100 cm.

whereas 0.4% (seven) had known diabetes and 0.3% (four) had had a previous cardiovascular event (heart attack or stroke). The median BMI was 21 (IQR 20–23) kg/m2 with 11% of subjects underweight, 12% overweight and 2% obese. Waist circumference was > 100 cm (102 cm) in 1% of men and > 90 cm (88 cm) in 7.5% of women (Table 1). The median duration on ART was 32.5 (17.4–50.6) months. Cardiovascular risk-factor distribution stratified by ART status is shown in Table 2. Of the 1 502 individuals screened, 40.4% (609/1502) had pre-hypertension, 10.4% (157/1502) were stage 1 and 2.9% (43/1502) were stage 2 hypertension. In multivariate analysis, hypertension was associated with being male [adjusted OR 1.59 (1.26–2.01), p = 0.0001], being 40 years or older [adjusted OR 1.78 (1.44–2.21), p = 0.0001], and having an increased waist circumference [adjusted OR 2.56 (1.44–4.55), p = 0.0014]. While the association between lower CD4 count and prevalence of hypertension was not certain, lower CD4 count was indicative of a lower prevalence of hypertension among those with low CD4 counts. There was no association between hypertension and current ART regimen (Table 3). The median duration on ART was not significantly different for those with or without hypertension (Mann–Whitney test, p = 0.6794).

Table 2. Cardiovascular risk factors stratified by ART status

Ref

TDF-based

1.18 (0.88–1.58)

0.2794

1.10 (0.81–1.49)

0.5506

AZT-based

1.40 (1.07–1.84)

0.0152

1.26 (0.95–1.68)

0.1090

D4T-based

1.42 (0.97–2.06)

0.068

1.22 (0.82–1.81)

0.3226

LPV-based

0.91 (0.41–2.03)

0.8212

0.97 (0.42–2.25)

0.9385

Missing

0.71 (0.53–0.94)

0.0165

0.72 (0.54–0.97)

0.0307

0–100

0.47 (0.23–0.92)

0.0287

0.49 (0.24–0.99)

0.0472

101–200

0.78 (0.47–1.29)

0.3369

0.67 (0.40–1.14)

0.1406

201–350

0.67 (0.50–0.91)

0.0112

0.59 (0.43–0.82)

0.0015

351–500

0.84 (0.62–1.12)

0.2315

0.77 (0.56–1.04)

0.0882

Ref

CD4 count (cells/mm3)

> 500

Females ≥ 90 cm, males ≥ 100 cm.

A total of 207 (14%) patients had an elevated non-fasting total cholesterol level (> 5.2 mmol/l). On multivariate analysis, being above 40 years of age [adjusted OR 1.95 (1.42–2.69), p = 0.001] and having an increased waist circumference [adjusted OR 2.06 (1.14–3.71), p = 0.0164] were associated with having a raised total cholesterol level. In addition, raised total cholesterol was more likely in those on TDF [adjusted OR 2.20 (1.28–3.78), p = 0.0042], AZT [adjusted OR 2.50 (1.50–4.18), p = 0.004]

Table 4. Unadjusted and adjusted odds ratios for elevated total cholesterol Unadjusted OR OR (95% CI)

p-value

OR (95% CI)

p-value

Male gender

0.85 (0.61–1.17)

0.3194

0.83 (0.59–1.17)

0.2806

Age ≥ 40 years

2.21 (1.63–3.00)

0.0001

1.95 (1.42–2.69)

0.0001

Smoker

0.22 (0.03–1.64)

0.1404

0.22 (0.03–1.67)

0.1434

BMI ≥ 30 kg/m2

2.15 (0.95–4.86)

0.0647

1.03 (0.39–2.74)

0.946

Random blood glucose ≥ 7.8 mmol/l

1.96 (0.83–4.62)

0.1252

1.99 (0.82–4.81)

0.1278

2.68 (1.64–4.36)

0.0001

2.06 (1.14–3.71)

0.0164

Pre-ART, n (%)

p-value

OR (95% CI)

Male gender

396 (32.5)

74 (26.0)

0.0312

1.38 (1.03–1.84)

Age ≥ 40 years

629 (51.7)

87 (30.5)

0.0001

2.43 (1.85–3.21)

24 (2.0)

5 (1.8)

0.8100

1.13 (0.43–2.98)

Increased waist circumference*

186 (15.3)

19 (6.7)

0.0001

2.53 (1.55–4.13)

ART regimen

31 (10.9)

0.4761

1.16 (0.77–1.75)

13 (4.6)

0.2786

1.39 (0.76–2.55)

Current smokers Total cholesterol ≥ 5.2 mmol/l

Body mass index ≥ 25 kg/m2 151 (12.4)

No ART

Elevated waist circumference*

76 (6.2)

Random blood glucose ≥ 7.8 mmol/l

25 (2.1)

5 (1.8)

0.7447

1.17 (0.45–3.10)

6 (0.5)

2 (0.7)

0.6630

0.70 (0.14–3.49)

Cardiovascular risk score ≥ 10%

Adjusted OR

Characteristic

ART, n (%)

CVD risk factors

Adjusted OR

Characteristic

Ref

TDF-based

2.47 (1.45–4.22)

0.0009

2.20 (1.28–3.78)

0.0042

AZT-based

2.84 (1.72–4.71)

0.0001

2.50 (1.50–4.18)

0.0004

D4T-based

3.86 (2.14–6.95)

0.0001

3.13 (1.72–5.71)

0.0002

LPV-based

1.98 (0.55–7.17)

0.2968

1.85 (0.50–6.80)

0.3536

0.74 (0.49–1.11)

0.147

0.87 (0.57–1.33)

0.5217 0.7964

CD4 count (cells/mm3) Missing

6 (0.5)

1 (0.4)

1.000

1.41 (0.17–11.70)

0–100

1.04 (0.42–2.60)

0.9306

1.13 (0.44–2.92)

Hypertension

666 (54.7)

140 (49.3)

0.0985

1.24 (0.96–1.61)

101–200

0.48 (0.20–1.16)

0.1029

0.46 (0.19–1.13)

0.0885

Pre-hypertension

494 (47.3)

113 (44.0)

0.3415

1.14 (0.96–1.61)

201–350

0.79 (0.51–1.22)

0.2884

0.79 (0.50–1.25)

0.3174

Hypertension stage 1

132 (19.3)

24 (14.3)

0.1303

1.44 (0.90–2.30)

351–500

0.93 (0.62–1.39)

0.7106

0.92 (0.60–1.41)

0.6951

Hypertension stage 2

40 (6.6)

3 (2.0)

0.0291*

3.48 (1.06–11.42)

> 500

Ref

Known diabetes

Females ≥ 90 cm, males ≥ 100 cm; Fischer’s exact two-sided test.

Females ≥ 90 cm, males ≥ 100 cm.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

and D4T-containing regimens [adjusted OR 3.13 (1.72–5.71), p = 0.002]. However, the median duration on ART was not significantly different for those with or without a raised total cholesterol level (Mann–Whitney test, p = 0.1261). There was no significant association between CD4 count and total cholesterol level (Table 4). Thirty-one (2.1%) subjects had a random blood glucose level of > 7.8 mmol/l. These patients were referred to the physician for fasting glucose determination and/or oral glucose tolerance tests. Eight (0.55%) of those above 40 years of age had more than 10% risk of developing a major adverse cardiovascular event in 10 years, according the WHO (Afri-E) risk score performed on these clients.

Discussion In this study, cardiovascular screening of people living with HIV revealed a significant prevalence of undiagnosed hypertension (13.3%) and raised total cholesterol levels (14%), two of the major cardiovascular risk factors. Possible aetiological factors for hypertension include traditional risk factors (such as age, gender, smoking and obesity), ART, or possibly HIV infection itself. Our analysis of risk factors indicated significant associations between the occurrence of hypertension and male gender, older age (> 40 years) and increased waist circumference. There was however no association between ART regimen and hypertension, suggesting that other factors may have been contributory. In a population survey targeting a peri-urban community in Nairobi, prevalence of hypertension was 22%,12 which is higher than seen in this study. One of the possible reasons for this disparity is that despite living with HIV, the age of this cohort was relatively young and with fewer smokers compared to those reported in the general population (2015 Kenya STEPS survey). Also, the prevalence of other known risk factors for hypertension such as overweight and obesity was at 14%, well lower than reported in the national STEPS survey (27%). In another retrospective review of data from an HIV-positive population in western Kenya, the prevalence of hypertension was 11.2% in men and 7.4% in women.13 The figures observed in this review compare well with those found in our study. Possible aetiological factors for high cholesterol levels include genetic factors, diet, ART or HIV infection itself. After adjusting for confounders, elevated cholesterol level was associated with three ART regimens (TDF, AZT and D4T) suggesting a potential causal relationship. However, since a full lipid profile was not performed, it remains unclear if this was due to a raised low-density lipoprotein cholesterol level. A study in Tanzania showed a high prevalence of dyslipidaemia (low high-density lipoprotein cholesterol and elevated triglyceride levels) in an ART-naïve cohort of HIV patients.5 There is therefore a need for further research to illustrate the role of ART therapy on the patterns of dyslipidaemia. The prevalence of smoking, obesity, glucose intolerance and diabetes were low in this population at 1.9, 12.1 and 2.6%, respectively, and only 0.6% had a WHO cardiovascular risk score > 10%. This is much lower compared to the peri-urban population study of Nairobi where 10% were smokers, 5% had diabetes, and more than 40% had central obesity.12 Our rural hospital setting may present a different HIV population where disease and lifestyle advice provided to the patients may have

altered risk factors, particularly smoking incidence. With increasing longevity of people living with HIV, the prevalence of hypertension, hyperlipidaemia and glucose intolerance is likely to increase. Therefore routine and systematic screening for cardiovascular risk factors among this population is crucial. The majority of cardiovascular risk factors, also seen in people with HIV, such as smoking, hypertension and obesity, are modifiable, therefore early identification and treatment of these conditions provides an opportunity to improve the quality of care and possibly survival rate in this population. Existing studies conducted in sub-Saharan Africa suggest there is little knowledge of the risk posed by CVD in this population.14 There is therefore a need to establish CVD care in HIV programmes to potentially mitigate adverse cardiovascular events in these patients.15 This study has several limitations, including collecting data from patient charts at one time point. Further studies are needed to establish how screening, referral and evidence-based interventions could reduce cardiovascular risk of people living with HIV in rural Kenya and beyond. Cardiovascular risk was determined after a median duration of 32 months of ART. A longer period of observation may be required to detect transition in cardiovascular risk. However the high prevalence of hypertension indicates that there was a considerable amount of undiagnosed incipient and actual hypertension in this population. Lastly, fasting lipid profiles were not performed where elevated non-fasting values were found, and inferences from an elevated total cholesterol level may not accurately reflect the prevalence of hypercholesterolaemia. However, recent guidelines advocate the use of non-fasting cholesterol tests.16 Our data are from 2013 to 2016, and the situation in terms of ART regimens and cardiovascular risk may have changed since then.

Conclusion CVD screening in a primary HIV-care clinic revealed a high prevalence of undiagnosed hypertension and raised total cholesterol levels, and suggests an association between raised total cholesterol level and nucleoside reverse-transcriptase inhibitor (NRTI)-based ART regimens in an HIV-infected African population. Our findings provide further rationale for integrating routine cardiovascular risk-factor screening into HIV-care services in resource-limited settings. Larger studies with more detailed investigations and longer follow up are recommended. This work was supported by Grand Challenges Canada and implemented in collaboration with ICAP Kenya, which implements HIV PEPFAR care in the Nyanza region in Kenya.

References 1.

Lewden C, Bouteloup V, de Wit SP, Sabin C, Mocroft A, Wasmuth JC, et al. All-cause mortality in treated HIV-infected adults with CD4 500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 2012; 41(2): 433–445.

Virginia AT, Hang L, Colleen H, Steven KG. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007;

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

92(7): 2506–2512. 3.

Glass TR, Ungsedhapand C, Wolbers M, Weber R, Vernazza PL, disease in HIV-infected patients over time: the Swiss HIV Cohort Study.

Expert Panel on Detection, Evaluation, and Treatment of High

HIV Med 2006; 7(6): 404–410.

Blood Cholesterol in Adults (Adult Treatment Panel III) final report.

Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular

Prevalence of hypertension and associated cardiovascular risk factors

Armstrong C, Liu E, Grinspoon S, Okuma J, Spiegelman D, Guerino

in an urban slum in Nairobi, Kenya: A population-based survey. BMC

2011; 57(2): 141–145. Bavinger C, Bendavid E, Niehaus K, Olshen RA, Olkin I, Sundaram V, et al. Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review. PLoS One 2013; 8(3): e59551. Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected 8.

Circulation 2002; 106(25): 3143. 12. Joshi MD, Ayah R, Njau EK, Wanjiru R, Kayima JK, Njeru EK, et al.

analysis. HIV Med 2012; 13(8): 453–468.

population in Dar es Salaam, Tanzania. J Acquired Immune Defic Syndr

2003; 289(19): 2560–2571. 11. Third Report of the National Cholesterol Education Program (NCEP)

C, et al. Dyslipidemia in an HIV-positive, antiretroviral treatment-naïve

Treatment of High Blood Pressure: JNC 7 report. J Am Med Assoc

Rickenbach M, et al. Prevalence of risk factors for cardiovascular

disease among people living with HIV: a systematic review and meta5.

AFRICA

Public Health 2014; 14: 1177. 13. Bloomfield GS, Hogan JW, Keter A, Sang E, Carter EJ, Velazquez EJ, et al. Hypertension and obesity as cardiovascular risk factors among HIV seropositive patients in western Kenya. PLoS One 2011; 6(7): e22288. 14. Temu TM, Kirui N, Wanjalla C, Ndungu AM, Kamano JH, Inui TS, et al. Cardiovascular health knowledge and preventive practices in people living with HIV in Kenya. BMC Infect Dis 2015; 15: 421. 15. Abrahams-Gessel S, Denman CA, Gaziano TA, Levitt NS, Puoane T.

individuals. PLoS One 2012; 7(9): e44454.

Challenges facing successful scaling up of effective screening for cardio-

Prevention of recurrent heart attacks and strokes in low and middle

vascular disease by community health workers in Mexico and South

income populations. Evidence-based recommendations for poli-

Africa: policy implications. Health Syst Policy Res 2015; 3(1): 26.

cy makers and health professionals. Geneva, 2003 World Health

16. Nordestgaard BRG, Langsted A, Mora S, Kolovou G, Baum Hr,

Organization. 2007.

Bruckert E, et al. Fasting is not routinely required for determination

Ministry of Health. National AIDS/STI Control Program (NASCOP).

of a lipid profile: clinical and laboratory implications including flag-

Guidelines for Antiretroviral Therapy in Kenya. 4th edn. Nairobi, Kenya:

ging at desirable concentration cut-points: a joint consensus statement

2011. Goverment of Kenya, 2011.

from the European Atherosclerosis Society and European Federation of

10. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and

Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016; 37(25): 1944–1958.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Long-segment patchplasty of diffuse left anterior descending artery disease on the beating heart Erhan Kaya, Omer Isik

Abstract Objective: The rate of patients with diffuse left anterior descending artery (LAD) disease being referred for surgery has increased as a result of advances in endovascular techniques. In surgery of diffuse or multisegment LAD disease, surgical procedures with or without endarterectomy can be performed. In this article, we report our results of longsegment onlay patchplasty of the LAD with a left internal thoracic artery (LITA) graft without endarterectomy, on the beating heart, in patients with multisegment LAD disease. Methods: We retrospectively analysed patients who underwent coronary artery bypass grafting surgery in our hospital between 1 January 2015 and 31 July 2017. We included LITA onlay patchplasty patients with multisegment LAD disease who had been operated on the beating heart. We excluded patients who underwent coronary endarterectomy and were operated on under cardiopulmonary bypass. Results: In this period, 54 patients with multisegment LAD disease were treated with LITA patchplasty on the beating heart. The mean length of the arteriotomy was 42.8 ± 13.3 mm (25–75 mm). There were two postoperative myocardial infarctions (3.7%) and three deaths (5.5%). In the remaining patients, there was no haemodynamic instability that needed long-term (> 24 hour) inotropic support. Patients were discharged from hospital on postoperative 9.3 ± 7.1 days with dual antiplatalet therapy. Conclusion: Bypass grafting of the LAD with long-segment LITA onlay patchplasty can safely be performed in patients with multisegment LAD disease, with acceptable early-term results. In this procedure, proximal and distal segments of the diseased LAD are revascularised with LITA grafts, which may improve long-term survival and quality of life. Keywords: coronary artery disease, endarterectomy, patchplasty Submitted 6/8/18, accepted 31/10/18 Published online 7/1/19 Cardiovasc J Afr 2019; 30: 57–60

Methods We retrospectively analysed patients who had undergone CABG surgery at the Private Pendik Regional Hospital between 1 January 2015 and 31 July 2017. We included patients with multisegment LAD disease treated with LITA onlay patchplasty on the beating heart. We excluded patients who underwent LAD endarterectomy or distal bypass with other grafts and were operated under cardiopulmonary bypass. Demographic and clinical information were collected from a review of the medical records. All procedures were performed under general anaesthesia with off-pump technique and a median sternotomy. During the operation, distal anastomosis of the right coronary artery (RCA) and circumflex artery was performed with the standard procedure. Arteriotomy of the LAD was started distal of the first proximal lesion and extended to the disease-free distal portion. Arteriotomy of the LITA was done according to arteriotomy of the LAD. Then the LITA–LAD anastomosis was performed to reconstruct the LAD with an onlay LITA graft (Fig. 1). The operation was completed after haemostatic control. Statistical evaluation was performed using Microsoft Excel software. Continuous variables are reported appropriately as mean (± SD) and categorical variables are reported as frequency.

www.cvja.co.za

DOI: 10.5830/CVJA-2018-062

Percutaneous intervention is currently preferred in segmental coronary artery lesions as a result of advances in angiographic techniques. Recently, the rate of patients undergoing surgery for diffuse or multisegment disease in the left anterior descending Department of Cardiovascular Surgery, Private Pendik Regional Hospital, Istanbul, Turkey Erhan Kaya, MD, drerhankaya@yahoo.com Omer Isik, MD

(LAD) artery has increased. In long-segment LAD lesions, incomplete revascularisation is the most important factor that affects long-term mortality and morbidity rates.1 In surgical tratment of diffuse/multisegment LAD disease, endarterectomy, long-segment patchplasty without endarterectomy, sequential jumping bypass and bypass grafting with two different grafts can be performed.2 In diffuse LAD lesions, plaque exclusion with the left internal thoracic artery (LITA) is a safe method and has similar results to conventional coronary artery bypass graft (CABG) surgery with no diffuse lesions.1 In this article, we present our LITA onlay patchplasty experience on the beating heart in multisegment LAD lesions.

Results In this period, 54 patients with multisegment LAD disease were treated with LITA onlay patchplasty. Patients’ characteristics and demographic findings are shown in Table 1. Of the patients, 59.3% with acute coronary syndrome underwent surgery. All patients were operated on the beating heart and there was no conversion to cardiopulmonary bypass. A mean of 2.9 ± 0.7 coronary artery bypasses were performed and the mean length of LAD arteriotomy was 42.8 ± 13.3 mm (25–75 mm). In the postoperative period, there were two myocardial infarctions (MI) (3.7%) and three deaths (5.5%). One patient was re-operated due to low cardiac output and postoperative MI. In the re-operation, the grafts were patent and there was no

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

Fig. 1. ( A) Long-segment arteriotomy of the LITA. (B) Onlay anastomosis of the LITA. (C) Bleeding control of the anastomosis. (D) View of the anastomosis at the end of the procedure.

pericardial tamponade. This patient died on the postoperative sixth day despite inotropic and intra-aortic balloon pump support. Two patients, who had undergone urgent operation with acute coronary syndrome, were lost due to complications of prolonged ventilation on the postoperative 25th and 54th day, respectively. In the remaining patients, there was no haemodynamic instability that needed long-term (> 24 hour) inotropic support. A total of 59.3% of patients with acute myocardial infarction (AMI) underwent surgery. The mean pre-operative ejection fraction (51.3 vs 50%), number of bypass grafts (2.7 vs 3) and length of endarterectomy (42 vs 44 mm) was similar between patients with and without AMI. There were two deaths among patients with AMI and one death in a patient without AMI. Patients were discharged from hospital after postoperative 9.3 ± 7.1 days with a dual antiplatelet regimen (Table 2).

Discussion Coronary artery patients who are referred for surgery have either multiple diseased arteries or diffuse disease. In patients

with diffuse/multisegment LAD lesions, bypass grafting of only the distal LAD results in insufficient perfusion of the proximal Table 1. Pre-operative demographical data of the patients Variables

Value

Age (mean ± SD)

60.5 ± 9.7

Male, n (%)

42 (77.8)

Smoking, n (%)

31 (57.4)

Hypertension, n (%)

28 (51.9)

Diabetes mellitus, n (%)

29 (53.7)

Alcohol assumption, n (%) Hyperlipidaemia, n (%) Chronic renal failure, n (%)

2 (3.7) 27 (50) 5 (9.3)

History of AMI, n (%)

32 (59.3)

Atrial fibrillation, n (%)

6 (11.1)

NYHA classification, n (%) Class 1

9 (16.7)

Class 2

44 (81.5)

Class 3 Pre-operative EF (%) (mean ± SD)

1 (1.8) 50.9 ± 6.6

AMI: acute myocardial infarction, EF: ejection fraction, NYHA: New York Heart Association classification, SD: standard deviation.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 2. Operative findings Variables

Value

No of coronary artery anastomoses, n (%) CABG × 1

2 (3.7)

CABG × 2

15 (27.8)

CABG × 3

25 (46.3)

CABG × 4

11 (20.4)

CABG × 5

1 (1.8)

Length of LAD arteriotomy (mm)

42.8 ± 13.3

Drainage (ml)

451 ± 255

Revision, n Erythrocyte replacement (units) IABP, n (%) Postoperative EF (%) Postoperative atrial fibrillation, n (%) Duration of hospitalisation (days)

0 0.5 ± 1 5 (9.3) 50.2 ± 6.1 6 (11.1) 9.3 ± 7.1

CPB: cardiopulmonary bypass, EF: ejection fraction, IABP: intraaortic balloon pump, LAD: left anterior descending artery.

side branches.3 Incomplete revascularisation is an important factor increasing peri-operative mortality and morbidity rates. Different surgical alternatives have been reported in diffuse LAD lesions in order to avoid this. Kato et al.3 reported that in patients treated with longsegment LITA patchplasty in diffuse coronary artery disease, patients with and without endarterectomy had similar operative and long-term outcomes. Similarly, patients who underwent LITA patchplasty without endarterectomy were reported to have similar results to patients treated with conventional CABG.2 In our patients with LITA onlay patchplasty without endarterectomy on the beating heart, peri-operative MI was found to be 3.7% and the mortality rate was 5%. Our results are acceptable for patients with diffuse LAD lesions. The most important advantage of endarterectomy is to increase perfusion of the myocardial tissue from the side branches.4 However, in patients undergoing endarterectomy, peri-operative MI and postoperative complications in the first 30 days (low cardiac output, MI, renal dysfunction) are seen most frequently.5 After endarterectomy, peri-operative MI and hospital mortality has been reported as 1.5–8% and 2–6.5%, respectively.6 For patients undergoing endarterectomy, the mortality rate increased 3.9-fold and peri-operative MI increased 2.9-fold in diffuse LAD lesions compared to isolated CABG.5 With increased surgical experience and equipment, even though operative mortality rates after endarterectomy were close to that of conventional surgery, the rate of postoperative MI was higher in patients undergoing endarterectomy.7 In a study where 99 patients who underwent patch angioplasty on the LAD artery and 71 patients who underwent endarterectomy were compared, early and long-term survival were found to be similar.8 In a meta-analysis in which 63 730 CABG patients were evaluated, the early-stage results of endarterectomy were reported to be poor, especially in diffuse LAD lesions and highrisk patients.5 Therefore in consecutive LAD lesions, bypass on two intact regions of the LAD may be preferred, or patchplasty without endartercetomy could be performed on diffuse LAD lesions. In our clinic, in consecutive LAD lesions, we extend the arteriotomy from the distal part of the first stenosis to the distal part of the second stenosis. Then we apply onlay LITA patchplasty to this area.

Due to the low risk of atherosclerosis, long-term patency rates after LITA patchplasty are higher.9 In the study of Myers et al.,10 where saphenous vein patchplasty and LITA onlay patchplasty were compared after LAD endarterectomy, although peri-operative MI and mortality rates were found to be similar (4%) in both groups, five- and 10-year survival rate was 87.1 and 49.4% in the group with patchplasty with the LITA, and it was 78.6 and 45.4% in the saphenous vein patchplasty group. In another study, peri-operative mortality and MI rates of LAD endarterectomy and LITA patchplasty were reported at 2.7 and 12.2%, respectively.4 In 128 patients who underwent a control angiography after LITA patchplasty, the five-year patency rate was found to be 91%.11 In our clinic, we routinely use the LITA during application of patchplasty to the LAD. Appropriate to the incision of the LAD artery, we perform onlay patchplasty by preparing the LITA graft without plaque exclusion. In diffuse LAD lesions, onlay patchplasty can be performed with the saphenous vein or LITA without excising the plaque. In the study by Fukui et al.1 with 252 patients, where they used a LITA patch without LAD endarterectomy in 73% of the patients, they performed the arteriotomy at an average of 4.3 cm and reported the operative mortality rate to be 1.6% and the peri-operative MI rate at 6.4%. In diffuse coronary artery disease, Kato et al.3 reported a 10-year survival rate of 74% after LAD reconstruction with the LITA, and a freedom from cardiac-related death at 92%. In this group, no difference was found in terms of survival rate between patients who did or did not undergo endarterectomy.3 In our patient group, postoperative MI rate was 3.7% and mortality was 5.5%. Although these are acceptable rates, there is a need for a larger study series. There is more collateral development in diffuse disease of the LAD and patients better tolerate off-pump CABG. Therefore off-pump CABG and endarterectomy can be safely used in diffuse LAD lesions. Open endarterectomy and LITA onlay patchplasty of diffuse LAD lesions on the beating heart improves postoperative results.12 Fukui et al.1 applied bypass on the beating heart in 80% of 252 patients who underwent LITA patchplasty with or without endartectomy. However, Nishigawa et al.13 reported a peri-operative MI rate of 9% in patients who underwent patchplasty with LITA after endarterectomy on the beating heart. This rate was higher than that of conventional surgery and our postoperative MI rates. Prabhu et al.14 successfully performed LITA patchplasty without endarterectomy on the beating heart in 104 patients, and control angiography of 16 patients revealed that the grafts were patent.14 In our patients, we performed the operation on the beating heart. All of the patients tolerated off-pump CABG surgery and no emergency conversion to cardiopulmonary bypass was needed in any patient. During the endarterectomy, where the endothelial layer is dissected, the subendothelial tissue increases the risk of earlystage thrombotic occlusion in the anastomotic line. Nishigawa et al.13 reported the thrombotic occlusion rate of a reconstructed LAD at 6.4% despite a dual anti-aggregant and anticoagulant combination in patients with LITA onlay patchplasty after endarterectomy. Prevention of endothelial damage prevents complications arising from intimal damage in the early postoperative period. When a simple bypass cannot be performed due to diffuse LAD

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

artery disease, there is no need for endarterectomy during the LITA onlay patchplasty.2 The risk of thrombosis is minimised since the endothelial layer is not damaged in LITA onlay patchplasty without performing endarterectomy. We routinely treat our patients with dual antiplatelet therapy with clopidogrel and acetylsalicylic acid and we have not encountered any complications originating from the anastomotic line. Our study has the limitations inherent in a retrospective study. The absence of a control group and postoperative coronary angiography are limitations. The number of patients was low because it was a single-centre study. In our department we perform priority surgery on the beating heart in all patients, even those with diffuse coronary lesions. Therefore we did not have sufficient patients operated on with cardiopulmonary bypass to create a control group. Randomised, controlled studies are needed to confirm the results of our study.

long segmental reconstruction of left anterior descending artery using left internal thoracic artery. Ann Thorac Surg 2012; 93: 1195–1200. 4.

Takanashi S, Fukui T, Miyamoto Y. Coronary endarterectomy in the left anterior descending artery. J Cardiol 2008; 52: 261–268.

Wang J, Gu C, Yu W, Gao M, Yu Y. Short- and long-term patient outcomes from combined coronary endarterectomy and coronary artery bypass grafting: a meta-analysis of 63,730 patients (PRISMA). Medicine (Baltimore) 2015; 94: e1781.

Papakonstantinou NA, Baikoussis NG, Apostolakis E. Coronary endarterectomy: new flavors from old recipes. J Cardiol 2014; 63: 397–401.

LaPar DJ, Anvari F, Irvine JN Jr, Kern JA, Swenson BR, Kron IL, et al. The impact of coronary artery endarterectomy on outcomes during coronary artery bypass grafting. J Card Surg 2011; 26: 247–253.

Bitan O, Pirundini PA, Leshem E, Consalvi C, McGurk S, King Q, et al. Coronary endarterectomy or patch angioplasty for diffuse left anterior descending artery disease. Thorac Cardiovasc Surg 2018; 66(6): 491–497.

Tasdemir O, Kiziltepe U, Karagoz HY, Yamak B, Korkmaz S, Bayazit K. Long-term results of reconstructions of the left anterior descending

Conclusion With consecutive LAD lesions, LITA onlay patchplasty can be performed after long-segment arteriotomy for increased perfusion of myocardial tissue. Application of this method without endarterectomy limits the risk of early-stage graft thrombosis as it reduces the risk of endothelial damage. Application of LITA onlay patchplasty without endarterectomy on the beating heart is a useful surgical approach that provides acceptable early results in patients with consecutive LAD disease.

AFRICA

coronary artery in diffuse atherosclerotic lesions. J Thorac Cardiovasc Surg 1996; 112: 745–754 10.

Myers PO, Tabata M, Shekar PS, Couper GS, Khalpey ZI, Aranki SF. Extensive endarterectomy and reconstruction of the left anterior descending artery: early and late outcomes. J Thorac Cardiovasc Surg 2012; 143: 1336–1340.

11.

Ogus TN, Basaran M, Selimoglu O, Yildirim T, Ogus H, Ozcan H, et al. Long-term results of the left anterior descending coronary artery reconstruction with left internal thoracic artery. Ann Thorac Surg 2007; 83: 496–501.

References 1.

12.

coronary endarterectomy? Interact Cardiovasc Thorac Surg 2014; 19:

Fukui T, Takanashi S, Hosoda Y. Long segmental reconstruction of

295–301.

diffusely diseased left anterior descending coronary artery with left internal thoracic artery with or without endarterectomy. Ann Thorac

13.

Surg 2005; 80: 2098–2105. 2.

Nishigawa K, Fukui T, Yamazaki M, Takanashi S. Ten-year experience of coronary endarterectomy for the diffusely diseased left anterior descending artery. Ann Thorac Surg 2017; 103: 710–716.

Haberal I, Gurer O, Ozsoy D, Erturk E. Coronary flow reserve in patients with left anterior descending artery-left internal mammary

Soylu E, Harling L, Ashrafian H, Athanasiou T. Should we consider off-pump coronary artery bypass grafting in patients undergoing

14.

Prabhu AD, Thazhkuni IE, Rajendran S, Thamaran RA, Vellachamy

artery long patch plasty anastomosis: a prospective study. J Cardiothorac

KA, Vettath MP. Mammary artery patch reconstruction of left anterior

Surg 2015; 10: 51.

descending coronary artery. Asian Cardiovasc Thorac Ann 2008; 16:

Kato Y, Shibata T, Takanashi S, Fukui T, Ito A, Shimizu Y. Results of

313–317.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Review Article A diagnostic algorithm for pulmonary hypertension due to left heart disease in resource-limited settings: can busy clinicians adopt a simple, practical approach? Anastase Dzudie, Andre Pascal Kengne, Kim Lamont, Bonaventure Suiru Dzekem, Leopold Ndemnge Aminde, Martin Hongieh Abanda, Friedrich Thienemann, Karen Sliwa

Abstract Pulmonary hypertension (PH) has progressively moved from an orphan disease to a signiﬁcant global health problem with a major disease burden in limited-resource countries, where over 97% of patients live. The aetiologies of PH differ between highand low-income nations, but PH due to left heart disease is credited to be the most frequent contemporary form. Although a straightforward diagnosis of PH requires the use of right heart catheterisation (RHC), access to equipment for RHC is a deterrent. Furthermore, the risk associated with RHC limits its uptake to a selection of specialised centres. Moreover, the rigour and clinical reasoning for diagnosis in clinical medicine is rapidly changing and revealing that PH can complicate a diverse range of medical conditions needing other explorations. In this article, we provide for the busy clinician, a simplified diagnostic algorithm for PH that is relevant for making a correct early diagnosis and limiting the impact of PH. Keywords: pulmonary hypertension, diagnostic algorithm, left heart disease

Submitted 8/4/17, accepted 21/7/18 Published online 30/11/18 Cardiovasc J Afr 2019; 30: 61–67

www.cvja.co.za

DOI: 10.5830/CVJA-2018-042

Pulmonary hypertension (PH) is an elevation of the pressure in the arteries of the lungs, resulting from a variable combination of increased pulmonary vascular resistance, pulmonary blood ﬂow and pulmonary venous pressure.1 This definition applies irrespective of the underlying aetiology of PH, which includes a range of medical conditions such as chronic infectious diseases, and lung and left heart diseases. Pulmonary arterial hypertension (PAH), a specific type of PH, exclusively affects the pulmonary arterial circulation, resulting in increased pulmonary vascular resistance, and ultimately in right heart failure (HF) and reduced life expectancy. Over the last century, significant progress in the diagnosis and management of PH has moved this condition from an orphan disease to a multidisciplinary and now acknowledged major global health problem. In 2010, it was estimated that PH affects more than 25 million individuals worldwide.2,3 The ultimate diagnosis is still based on right heart catheterisation (RHC).

Department of Internal Medicine and Department of Physiology, Faculty of Medicine, University of Yaoundé, Yaoundé, Cameroon; and Soweto Cardiovascular Research Unit, University of the Witwatersrand, Johannesburg, South Africa

Non-communicable Diseases Unit, South African Medical Research Council, Cape Town, South Africa

Anastase Dzudie, MD, PhD, FESC

Leopold Ndemnge Aminde, MD

Clinical Research Education Networking and Consultancy, and Cardiology Unit, Douala General Hospital, Douala, Cameroon Anastase Dzudie, MD, PhD, FESC, aitdzudie@yahoo.com Bonaventure Suiru Dzekem, MD, dbos001@yahoo.com Leopold Ndemnge Aminde, MD Martin Hongieh Abanda, MD

NIH Millennium Fogarty Chronic Disease Leadership Program, Stanford, USA Anastase Dzudie, MD, PhD, FESC Kim Lamont, PhD

Andre Pascal Kengne, MD, PhD

Faculty of Medicine and Biomedical Sciences, School of Public Health, University of Queensland, Brisbane, Australia Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa; and Department of Internal Medicine, University Hospital of Zurich, Switzerland Friedrich Thienemann, MD

Hatter Institute for Cardiovascular Research in Africa, South African Medical Research Council Cape Heart Centre, IDM, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Karen Sliwa, MD, PhD, FESC

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Aetiologies of PH differ between high- and low-income nations, but left heart disease (LHD) has progressively been credited to be the most common cause of PH in contemporary clinical settings.4,5 Despite these improvements in understanding PH aetiologies, the condition is still diagnosed at an advanced stage in a significant proportion of patients, due to poor medical awareness and the paucity of symptoms in the early stages of the disease.6 This has negative impacts on subsequent quality of life and survival.7 The American College of Cardiology/American Heart Association8 and the European Society of Cardiology/European Respiratory Society7 guidelines have each provided a regularly updated diagnostic algorithm, based on prevalent aetiologies of PH as well as availability of several diagnostic tests, and especially, RHC in high-income countries. This algorithm may not apply or may be difficult to implement in low-income countries where human and financial resources more than just science often influence the diagnostic approach. In sub-Saharan Africa (SSA), given the additional high and increasing prevalence of chronic and endemic risk factors of PH, which are almost specific to the region, such as chronic infectious diseases (HIV, tuberculosis and schistosomiasis), hypertensive heart disease, peripartum cardiomyopathies and rheumatic heart disease,9 a clear diagnostic approach to PH due to LHD (PHLHD) is of particular importance. Furthermore, the high cost, low availability and scarcity of expertise for RHC limit its utility in this part of the world and justify the interest in a more pragmatic algorithm. Based on the experience and evidence from the Pan-African Pulmonary Hypertension Cohort (PAPUCO) study, we previously developed an algorithm,10 and herein suggest a fourstep diagnostic approach for PHLHD in low-resources settings. These steps include (1) clinical evaluation to detect predisposing conditions for PHLHD, (2) assessment with chest X-ray (CXR) and electrocardiogram (ECG) to uncover the presence of PHLHD, (3) conﬁrmation of the presence of PHLHD using Doppler echocardiography (echo), and (4) exploration of differential aetiologies of PHLHD and classiﬁcation of the type of PH.

Step 1: clinical evaluation and detection of a predisposing condition Data from the PAPUCO study11 showed that PH should be suspected in any African patient with otherwise unexplained shortness of breath, fatigue, palpitations, cough, dizziness and/ or signs of right ventricular dysfunction and right heart failure. Two-thirds of patients are likely to present in World Health Organisation functional class (WHO FC) III or IV and one-third may not walk further than 300 metres on a six-minute walk test. Clinical examination may reveal a systolic murmur (57%) or a loud P2 (41%). These clinical observations are largely similar for men and women. In the presence of these symptoms, clinicians should actively inquire about predisposing conditions, which in the SSA context, include hypertension (42%), previous or concurrent tuberculosis (22 and 5%, respectively), indoor cooking/heating without a chimney (32%) and HIV infection (22% overall). In the PAPUCO study, there were no significant differences in the risk-factor profiles of men and women besides exposure to indoor cooking/heating without a chimney (more women),

AFRICA

history of smoking (more men) and alcohol abuse (more men). Also, although being a traditional risk factor for PH, the endemicity of schistosomiasis was only related to one case. In some predisposing groups, such as sickle cell disease, PH signs and symptoms may often be subtle and may not be apparent for months as they are generally non-specific. When the clinical evaluation is not suggestive of PH, the clinician should search for other causes of symptoms (e.g. tuberculosis, chronic pulmonary disease, LHD, malignancy). On the other hand, as shown in Fig. 1, when step 1 is suggestive of PH, the patient should systematically undergo step 2, non-invasive investigations, which should include a CXR and ECG.

Step 2: the role of chest X-ray and electrocardiogram Chest X-ray In SSA where pulmonary tuberculosis and HIV-associated chronic lung diseases are common (e.g. recurrent pneumonia, pneumocystis pneumonia), CXR allows moderate to severe lung diseases to be reasonably excluded but also, abnormalities on CXR are frequent in PHLHD and after completion of TB treatment. In the PAPUCO registry, 59% of patients presented with cardiomegaly and 22% had prominent pulmonary arteries (Fig. 2A). Other findings supportive of underlying cardiac disease include left atrial enlargement, mild to moderate pleural effusion and cephalisation. In other circumstances, the presence of central pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss) of the peripheral blood vessels, is very suggestive of PH. Right atrial and right ventricular (RV) enlargement may be seen in more advanced cases.

Electrocardiogram The diagnostic utility of ECG in patients with PH was investigated in a sub-study of the PAPUCO registry.11 Our findings demonstrated that a normal ECG is very rare among patients with PH. Sinus tachycardia and left ventricular strain pattern were observed in around one-fifth of cases (Fig. 2B), but PH-specific abnormalities such as p-pulmonale (14%) and evidence of right ventricular hypertrophy (19%) were documented in less than one-quarter of cases. The sensitivity of ECG criteria for right heart strain ranged between 6.2 and 47.7%, while specificity ranged between 79.3 and 100%. Negative predictive value ranged between 81.5 and 88.9%, and positive predictive value between 25 and 100%. Positive predictive value was lowest (25%) for right bundle branch block and QRS right-axis deviation (≥ 100°) and highest (100%) for QRS axis ≥ +100°, combined with R/S ratio ≥ 1 or R in V1 > 7 mm. In short, signs involving PH on ECG were highly indicative of disease, but a normal ECG would not exclude disease. Because ECG patterns focusing on the R and S amplitude in V1 and right-axis deviation had good specificity and negative predictive value, their presence should trigger further investigation with Doppler echo (Fig. 1).

Step 3: the key role of Doppler echocardiography A transthoracic Doppler echo examination is the next and most appropriate course of study. Doppler echo provides several

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

A Symptoms, signs and medical history suggestive of PH

Step 1: clinical examination

Clinical examination supportive of PH

YES

Step 2: chest X-ray and ECG

Chest X-ray and ECG supportive of PH

Search for other causes, e.g. TB, PCP, COPD, LHD, malignancy

YES

Step 3: Doppler echo

Doppler echo supportive of PH

YES

Step 4: consider common causes of PH in Africa Probably less common Group 1 Pulmonary arterial hypertension (PAH): e.g. HIV-PAH, schistosomiasis, drugs/toxins

Step 4: HIV testing, urine screen, abdominal US, drug screen

Group 2 PH due to left heart disease: e.g. mitral stenosis due to RHD, hypertensive heart failure, valvular disease, coronary artery disease

Group 3 PH due to lung disease: e.g. COPD, post-TB bronchiectasis, interstitial lung disease

Group 4 CTEPH

Step 4: liverfunction test, HRCT

Step 4: CTPA, V/Q scan

Group 5 Multifactorial e.g. endomyocardial fibrosis, sickle cell disease

Fig. 1. D iagnostic algorithm to diagnose pulmonary hypertension due to left heart disease in low-resource settings, as evidenced from the PAPUCO study. PH, pulmonary hypertension; TB, tuberculosis; PCP, pneumocystis pneumonia; COPD, chronic obstructive pulmonary disease; LHD, left heart disease; Doppler echo, Doppler echocardiography; US, ultrasound; LFT, liverfunction tests; HRCT, high-resolution computerised tomography; CTEPH, chronic thromboembolic pulmonary hypertension; CTPA, CT pulmonary angiography; V/Q, ventilation/perfusion lung scan.

Fig. 2. Chest X-ray and electrocardiogram in pulmonary hypertension in sub-Saharan Africa. (A) Posteroanterior chest X-ray in a 51-year-old HIV-positive patient on antiretroviral therapy and with a past history of diabetes and one episode of TB, who presented with dyspnoea. CXR showing no signs of chronic lung disease, but combined heart enlargement and hilar pulmonary artery prominence. (B) ECG of a different patient showing sinus tachycardia, right atrial enlargement, right ventricular hypertrophy and strain, and right-axis deviation of the QRS complex. Courtesy of the PAPUCO investigators group.

variables that correlate with right heart haemodynamics, including an estimate of right ventricular systolic pressure (RVSP), and can simultaneously uncover functional and morphological cardiac sequelae of PH, and assist in the identiﬁcation of possible cardiac causes of PH. The Doppler echo estimation of RVSP (Fig. 3A) is based on the peak velocity of the jet of tricuspid regurgitation (TR). TR velocity can be obtained by either a duplex imaging from the right ventricular inflow view, parasternal short-axis view at the basal level, para-apical four-chamber view, apical four-chamber view, or even the subcostal view. The TR maximal instantaneous gradient (TR MIG) is frequently automatically calculated and displayed on the screen (Fig. 3A) when the maximal TR velocity is measured. Otherwise it is easily calculated using the simpliﬁed Bernoulli equation:12 TR MIG = 4 (TR velocity)²

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

AFRICA

B Insp diameter = 2.20 cm Exp diameter = 1.88 cm IVC collapsing index = 14.5%

TR Vmax = 3.75 m/s TR MIG = 56 mmHg

Insp

Exp

D IVSd = 0.85 cm LVEDd = 7.63 cm PWd = 0.85 cm IVSs = 1.2 cm LVESd = 5.97 cm PWs = 1.1 cm EF = 43%

TAPSE = 0.79 cm

F E = 1.16 m/s DT = 122msec A = 0.36 m/s E/A = 3.24

LA area = 26.1 cm

Fig. 3. E chocardiographic evaluation in patients with pulmonary hypertension in sub-Saharan Africa. Measurement of pulmonary pressure is based on identification of the tricuspid regurgitant (TR) jet and using continuous-wave Doppler to obtain the maximum instantaneous right ventricular–right atrial gradient, as indicated by the solid yellow line (A). The yellow dotted line indicates measurement of over-gained (shaggy) signals with significant overestimation in the gradient. TR Vmax indicates TR maximal velocity, TR MIG, TR maximal instantaneous gradient. (B) Right atrial pressure is estimated from the inferior vena cava (IVC) calibre and respiratory collapsibility. ins, inspiration, exp, expiration. (C) shows measurements of the ejection fraction using the Teicholz formula; IV(D/S) indicates interventricular septum (diastole/systole), LVED(S)d: left ventricular end-diastolic (systolic) diameter, PWd(s): posterior wall in diastole (systole). (D) indicates the measurement of the tricuspid annular plane systolic excursion (TAPSE) in a patient with right heart failure. (E) A visual assessment of right cardiac cavities in apical four-chamber view showing dilated heart cavities. (F) indicates a restrictive mitral Doppler pattern in the same patient. Modified from thesis ‘Predicting pulmonary hypertension and outcomes in patients with left heart disease’. http://hdl. handle.net/11427/16533.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

Table 1. Estimation of right atrial pressure from inferior vena cava calibre and respiratory collapsibility. Adapted from Beigel et al.12 Estimated RAP (mmHg)

IVC diameter (cm)

IVC collapse with inspiration (sniff)

< 2.1

> 50%

< 2.1

< 50%

≥ 2.1

> 50%

≥ 2.1

< 50%

RAP, right atrial pressure; IVC, inferior vena cava.

Table 2. Possible causes of pulmonary hypertension identified by echocardiography with relevance to sub-Saharan Africa13 Predisposing conditions for pulmonary hypertension • Valvular disease [mitral (aortic) stenosis/regurgitation, prosthetic valve dysfunction] • Left ventricular systolic dysfunction (including hypertensive heart failure, dilated cardiomyopathy, peripartum cardiomyopathy, myocardial infarction) • Left ventricular diastolic function (including ischaemic heart disease, hypertensive heart disease, hypertrophic cardiomyopathy, Fabry’s disease, infiltrative cardiomyopathies) • Other obstructive lesions (coarctation, supravalvular aortic stenosis, subaortic membrane, cor triatriatum)

Bernoulli’s equation then allows for the estimation of the RVSP,12 taking into account right atrial pressure (RAP): RVSP = TR MIG + RAP. RAP is estimated from the inferior vena cava (IVC) calibre and respiratory collapsibility (Table 1, Fig. 3B). In the absence of pulmonary stenosis and acute right HF, the estimated RVSP is assumed to equal the pulmonary artery systolic pressure. To avoid errors in the measurement of RVSP, it is mandatory to observe some conditions, including accurate measurement of the IVC, avoiding measuring over-gained (shaggy) signals (Fig. 3A). If the heart rhythm is irregular, it is recommended that three to five consecutive cycles be measured and the mean of these cycles be recorded. In patients with PH, Doppler echo also contributes to the evaluation of the RV systolic function through measurement of the tricuspid annular plane systolic excursion movement (TAPSE). TAPSE represents the distance of systolic excursion of the RV annular plane towards the apex. As shown in Fig. 3D, it is obtained using an M-mode cursor passed through the tricuspid lateral annulus in the four-chamber view and measuring the amount of longitudinal displacement of the annulus at peak systole. In the PAPUCO registry,11 Doppler echo findings showed that left ventricular (LV) function was moderately impaired overall (median LV ejection fraction 46%) (Fig. 3C). As expected, RVSP was markedly elevated (median value 58 mmHg), with concurrent moderate to severe right atrial (58%) and right ventricular (55%) hypertrophy a common feature. Only one-third of cases (n = 69; 33%) showed no evidence of right atrial or ventricular enlargement. Overall, 78 patients (37%) presented with a diagnosis of right HF based on TAPSE movement < 15 mm (Fig. 3D) plus one or more clinical signs of HF. The LHD aetiology13 of PH is suggested by (1) presence of heart disease as suggested by a dilation in the cavities (Fig. 3E), presence of heart valve disease or abnormal contractility, and (2) arguments suggestive of an elevation of left ventricular filling pressure, such as left atrial dilation (Fig. 3E) or a mitral Doppler restrictive pattern (Fig. 3F). In the subgroup of patients with PHLHD,13 aetiologies were predominantly hypertensive HF with reduced or preserved ejection fraction, dilated and peripartum cardiomyopathy and rheumatic valvular heart disease. Left atrium size and TAPSE were predictors of RVSP in these patients, and RVSP predicted short-term hospitalisations but not mortality. We therefore recommend that an estimated RVSP greater than 35 mmHg in SSA should warrant further evaluation for PH in patients with suggestive PH in step 1 and/or 2 (Fig. 1). Finally, Doppler echo can clearly help identify possible aetiologies of PH, and particularly PHLHD (Table 2), anticipating the contribution of other tests.

• Congenital disease with shunt [atrial (ventricular) septal defect, coronary fistula, patent ductus arteriosus, anomalous pulmonary venous return] • Pulmonary embolus (thrombus in inferior vena cava, right-sided cardiac chamber, or pulmonary artery; tricuspid or pulmonic valve vegetation) • Pulmonary vein thrombosis/stenosis Findings that suggest specific disease entity • Left-sided valve changes (systemic lupus erythematous, anorexigen use) • Intra-pulmonary shunts (hereditary haemorrhagic telangiectasia) • Pericardial effusion (idiopathic pulmonary arterial hypertension, systemic lupus erythematous, systemic sclerosis)

Step 4: other investigations A careful selection of other tests can contribute to establishing a diagnosis of PH in patients residing in low-income countries such as SSA. The utilisation of these other investigations will depend on both the results of the above initial tests and the clinical context. Given the high burden of HIV/AIDS in the region as well as its contribution in the PAPUCO registry (22%), it is reasonable to screen all patients with PH for HIV. Other tests, such as abdominal ultrasound, liver-function test, high-resolution computerised tomography (CT), CT pulmonary angiography, ventilation/perfusion lung scan, and electrophoresis of haemoglobin will be guided by the clinical context. It is only after these steps have been completed and once a deﬁnitive diagnosis of PH has been reached and potential underlying co-morbidities or causes identified, that classification within an appropriate aetiological group must be considered (Fig. 4). We acknowledge classification difficulties in SSA and other low-income countries, especially in the absence of RHC and Group 3 PH due to lung disease and/or hypoxia. e.g. COPD or tuberculosis

Group 1 Pulmonary arterial hypertension. e.g. HIV-associated PH Group 4 Chronic thromboembolic PH. e.g. chronic pulmonary embolism Group 2 PH due to left heart disease. e.g. mitral stenosis due to rheumatic heart disease Group 5 PH with unclear or multifactorial mechanism. e.g. endomyocardial fibrosis

Fig. 4. World Health Organisation classification of pulmonary hypertension with relevant examples for sub-Saharan Africa.1

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

other imaging studies. It noticeable that in some patients, several mechanisms may be involved in the pathogenesis of PH in Africa. For example, the interaction between sickle cell disease-related haemolysis and HIV, chronic lung disease due to tuberculosis, schistosomiasis, and viral hepatitis could yield very complex multifactorial and unclear PH.

AFRICA

patients in low-resource settings, especially those with various types of PHLHD, for which indications of RHC should be restricted to avoid unnecessary risk. We acknowledge the Wits/NIH Non-Communicable Diseases Leadership Program, funded through the Fogarty International Centre of the NIH Millennium Promise Awards: Non-Communicable Chronic Diseases Research

Limitations of the suggested algorithm

Training Program (NCoD) (D43), grant number:1D43TW008330-01A1.

It is important to acknowledge that a major limitation of our approach lies in the validity of RVSP for diagnosis of PH using Doppler echo. There is absolutely no doubt that RHC is the standard to accurately diagnose PH and determine its severity as well as its impact on right ventricular function. However, RHC is an invasive procedure, and it is expensive and not available in most low-resource settings where the majority of patients with PH are resident, particularly in SSA. There is abundant literature on the validity of Doppler echo RVSP estimates in patients with left heart disease using RHC values as the gold standard. Lanzarini et al.14 reported a concordance correlation coefficient of 0.88 between RHC and RVSP, with ± 20 mmHg and 95% limits of agreement. In their study of Doppler echo evaluation of haemodynamics in patients with decompensated systolic HF, Nagueh et al.15 reported that Doppler echo identified patients with invasive systolic pulmonary artery pressure > 35 mmHg with 94% sensitivity and 90% specificity. In an analysis of data from the ESCAPE trial, McClanahan and Guglin16 suggested that the accuracy of Doppler echo RVSP estimates in systolic HF might be inaccurate in the presence of right ventricular systolic dysfunction. However, at least two reasons could have explained this lack of accuracy: first, patients included in the ESCAPE trial16 were in acute HF and not haemodynamically stable; and second, echocardiography in ESCAPE was not protocol driven, and the time differential between RHC and RVSP evaluation using Doppler echo was widely variable. In view of the above and provided that patients are haemodynamically stable and a rigorous Doppler echo technique is used by experienced observers, it is acceptable and pragmatic to detect PH using Doppler echo estimates of RVSP, although we recommend a confirmation with RHC before any specific therapeutic action is required. Finally, our recommendations are based on a single study. Ideally, such a practice algorithm, which is intended to provide clinicians with recommendations, should be based on systematic review of the available evidence, and an assessment of the benefits and harms of care options, with the intention of optimising patient care and outcomes. However, expert opinion remains a major part of all such practice guidelines,17,18 particularly when high-quality evidence is lacking, as is the case in SSA.

Research Institute, Bayer Healthcare and the Maurice Hatter Foundation.

The study and publication were partly funded by the Pulmonary Vascular

References 1.

JE, et al. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult – a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2012; 31(9): 913–933. 2.

For the busy clinician, it is important to recognise the increasing burden of PHLHD in low-resource settings and be able to make an early diagnosis. Adopting a four-step diagnostic algorithm is recommended and the steps include: (1) a clinical evaluation, (2) CXR and ECG assessment, (3) Doppler echo, and (4) exploration of differential aetiologies before classiﬁcation of the type of PH. This strategy will help manage the majority of

Elliott CG, Barst RJ, Seeger W, Porres-Aguilar M, Brown LM, Zamanian RT, et al. Worldwide physician education and training in pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 2010; 137(6 Suppl): 85S–94S.

Bossone E, Butera G, Bodini BD, Rubenfire M. The interpretation of the electrocardiogram in patients with pulmonary hypertension: the need for clinical correlation. Ital Heart J 2003; 4(12): 850–854.

Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: Part 1: epidemiology, pathophysiology, and definitions. Circ Heart Fail 2013; 6(2): 344–354.

Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation 2012; 126(8): 975–990.

Van Wolferen SA, Grunberg K, Vonk Noordegraaf A. Diagnosis and management of pulmonary hypertension over the past 100 years. Respir Med 2007; 101(3): 389–398.

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30(20): 2493–2537.

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53(17): 1573–1619.

Conclusion

Fang JC, DeMarco T, Givertz MM, Borlaug BA, Lewis GD, Rame

Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012; 172(18): 1386–1394.

10. Thienemann F, Dzudie A, Mocumbi AO, Blauwet L, Sani MU, Karaye KM, et al. Rationale and design of the Pan-African Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary registry on pulmonary hypertension in Africa. Br Med J Open 2014; 4(10): e005950. 11. Thienemann F, Dzudie A, Mocumbi AO, Blauwet L, Sani MU, Karaye KM, et al. The causes, treatment, and outcome of pulmonary hyperten-

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

sion in Africa: Insights from the Pan-African Pulmonary Hypertension Cohort (PAPUCO) Registry. Int J Cardiol 2016; 221: 205–211. 12. Beigel R, Cercek B, Luo H, Siegel RJ. Noninvasive evaluation of right atrial pressure. J Am Soc Echocardiogr 2013; 26(9): 1033–1042.

heart failure. J Card Fail 2011; 17(12): 1023–1027. 17. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of

13. Dzudie TAI. Predicting pulmonary hypertension and outcomes in

Cardiology Foundation Task Force on Expert Consensus Documents

patients with left heart disease [Internet]. [cited 2016 May 17]. Available

and the American Heart Association: developed in collaboration with

from: https://open.uct.ac.za/handle/11427/16533.

the American College of Chest Physicians, American Thoracic Society,

14. Lanzarini L, Fontana A, Lucca E, Campana C, Klersy C. Non-invasive estimation of both systolic and diastolic pulmonary artery pressure

Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119(16): 2250–2294.

from Doppler analysis of tricuspid regurgitant velocity spectrum in

18. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al.

patients with chronic heart failure. Am Heart J 2002; 144(6): 1087–1094.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary

15. Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, et

hypertension: The Joint Task Force for the Diagnosis and Treatment

al. Echocardiographic evaluation of hemodynamics in patients with

of Pulmonary Hypertension of the European Society of Cardiology

decompensated systolic heart failure. Circ Cardiovasc Imag 2011; 4(3):

(ESC) and the European Respiratory Society (ERS): Endorsed by:

220–227.

Association for European Paediatric and Congenital Cardiology

16. McClanahan A, Guglin M. Right ventricular dysfunction compromises accuracy of echocardiographic diagnosis of pulmonary hypertension in

(AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46(4): 903–975.

Many take other drugs that lower effectiveness of blood pressure medications People who take pills to lower their blood pressure often take other drugs that reduce the pills’ effectiveness, a large study suggests. Reuters Health reports that researchers studied data on 521 028 adults prescribed blood pressure pills for the first time and 131 764 people taking at least four different pills to lower their blood pressure. Roughly 18% were also taking drugs that make blood pressure pills less effective, the study found. These included medicines like non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen or hormones. ‘In some cases, use of these blood pressure-interfering medications may be justified and the potential side effect of elevations in blood pressure may be acceptable to patients,’ said study leader Andrew Hwang of the High Point University Fred Wilson School of Pharmacy in North Carolina. ‘But in other cases… there may be significant opportunities to switch to alternative treatments or reassess the need for continuing the interfering treatment,’ Hwang said. ‘If these drugs can be discontinued, it’s possible we can reduce the prescribing cascade – that is, reduce the need for using additional medication to treat a side effect of another medication.’ Patients may not realise the risks, the report says the findings suggest. Among people recently prescribed blood pressure medications for the first time, 58% later refilled prescriptions for drugs known to increase blood pressure, the study found. Among people prescribed four or more blood pressure drugs, 65% refilled drugs known to increase blood pressure after stepping up their blood pressure treatment regimen. Patients who need blood pressure medicine should ask their doctor if any of the other medications they’re taking might interfere, said Dr Gunnar Gislason, a professor of cardiology at Copenhagen University Hospital Herlev and Gentofte, and director of research at the Danish Heart Foundation. ‘And if blood pressure drugs are not working, it’s important to consider not just other drugs that might

influence blood pressure but also herbal medications that often are considered harmless,’ Gislason, who wasn’t involved in the study, said. The way different drugs can increase blood pressure varies, Hwang is quoted in the report as saying. ‘Some drugs, such as NSAIDs and hormones, elevate blood pressure, mainly by causing the body to retain excess fluid,’ Hwang noted. ‘This effect counteracts the mechanism of some blood pressure medications like diuretics (water pills), which cause the body to get rid of fluid.’ ‘Other drugs can cause blood pressure elevation by constricting the blood vessels, increasing heart rate, or by a combination of mechanisms,’ Hwang added. ‘There are also some drugs, such as acetaminophen, that we know increase blood pressure, but we don’t know how.’ The report says the study wasn’t designed to prove whether or how certain prescription drugs might interfere with the effectiveness of blood pressure medicines or increase blood pressure. Another limitation is that it focused only on patients who were taking prescribed medicines that can interfere with blood pressure drugs, and many painkillers such as acetaminophen and naproxen are available over the counter without a prescription in the US, the study authors note. ‘Although this study cannot tell us the reasons why the prescription rate of blood pressure-interfering medication is so frequent, it may explain why in (the) US population, blood pressure control is still very poor,’ said Dr Liffert Vogt of Amsterdam University Medical Centre. ‘Poorly controlled blood pressure (is) a major cause of heart disease and stroke,’ Vogt, who wasn’t involved in the study, said by e-mail. ‘For that reason, prescribing drugs that contribute to poor blood pressure control should be carefully considered.’ Source: Medical Brief 2018

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

Why you should publish with CVJA • Increased international exposure (indexed in PubMed, Medline, PubMed Central, Scopus, Embase and Thompson Reuters/ISI)

• Quick return on submissions • Changing patterns of heart disease in Africa get more exposure than in other journals

• Acceptance of diabetes studies as vascular studies in CVJA • African studies are given preference • Well-illustrated interventional studies are needed for CME in Africa (full website support capability)

• Instructions for authors on www.cvja.co.za • A PowerPoint presentation for new authors: 'How to write a scientific paper'

• Submit your manuscript online at www.cvja.co.za

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

Case Report Delayed left ventricular pseudo-aneurysm after postinfarction repair of ventricular septal defect Yun-Seok Song, Sang-Hoon Seol, Seunghwan Kim, Dong-Kie Kim, Ki-Hun Kim, Doo-Il Kim, Hee-Jae Jun

Abstract Left ventricular pseudo-aneurysm is a rare complication that usually occurs after myocardial infarction or cardiac surgery. Sometimes it is related to cardiac rupture. We report on surgical management for a left ventricular pseudo-aneurysm that developed four years after surgery for ventricular septal defect in a patient with acute myocardial infarction.

Division of Cardiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea Yun-Seok Song, MD Sang-Hoon Seol, MD, shseol@paik.ac.kr Seunghwan Kim, MD Dong-Kie Kim, MD Ki-Hun Kim, MD Doo-Il Kim, MD

Division of Thoracic Surgery, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea Hee-Jae Jun, MD

Keywords: pseudo-aneurysm, ventricular septal defect, myocardial infarction Submitted 20/12/17, accepted 1/10/18 Published online 6/11/18 Cardiovasc J Afr 2019; 30: e1â&#x20AC;&#x201C;e3

www.cvja.co.za

DOI: 10.5830/CVJA-2018-049

Left ventricular (LV) pseudo-aneurysm or false aneurysm is a free-wall rupture contained by pericardial adhesion or the epicardial wall. Although the most common cause is myocardial infarction (MI), it can occur after heart surgery, trauma or infection.1,2 We report on a case of a 77-year-old woman with LV pseudo-aneurysm after post-infarction repair of a ventricular septal defect (VSD).

Case report A 77-year-old woman with a history of post-infarction repair of VSD was noted on regular check-up echocardiography to have an extra-cardiac mass. She had no symptoms. Four years earlier, she had presented with acute anterior wall MI with VSD and

Fig. 1. T ransthoracic echocardiography in the apical two-chamber view reveals a large extra-cardiac echo-free space adjacent to the LV apex (A), with colour Doppler image between the two (B). LV, left ventricle.

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

AFRICA

Fig. 2. E chocardiography with contrast microbubble demonstrates the left ventricle communicating with the pseudo-aneurysm through a small defect. LV, left ventricle.

underwent successful patch closure. The electrocardiogram revealed sinus bradycardia with marked T-wave inversion. A chest X-ray showed cardiomegaly. Echocardiography revealed thinning of the wall of the interventricular septum from the mid left ventricle to the apex, with an approximately 1.2-cm-sized free-wall defect at the LV apex, and shunt flow to the aneurysmal sac on colour Doppler (Fig. 1). Contrast echocardiography demonstrated the left ventricle with the contrast microbubble flowing into the aneurysmal area (Fig. 2). Coronary artery computerised tomography (CT) showed a huge LV pseudo-aneurysm of 7.5-cm maximum transverse diameter (Fig. 3). Coronary angiography of the left ventricle also

Fig. 4. Left ventriculography with contrast agent shows the left ventricle connecting to the false aneurysm via a narrow neck. LV, left ventricle.

identified LV apex rupture with a false aneurysm (Fig. 4). The patient underwent successful surgery with patch closure using Dacron and bovine pericardium. The operative finding showed an approximately 1-cm-sized defect at the LV apex with a pseudo-aneurysm, which may have occurred due to dehiscence of the previous surgical approach site (Fig. 5). The patient was discharged without any complications. She remained asymptomatic after six months of follow up.

Fig. 3. C oronary computerised tomography shows the left ventricular pseudo-aneurysm with a broad base and narrow orifice (A), and patch dehiscence (arrow) in three-dimensional reconstruction (B). LV, left ventricle.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

the left ventricle.9 There are no guidelines for the management of pseudoaneurysm due to its rarity. However, early diagnosis and prompt surgical repair is the treatment of choice because of a high risk of spontaneous rupture, leading to a poor prognosis.10 The pseudo-aneurysm in this case was identified four years after post-infarction VSD patch closure. The patient was asymptomatic and it was detected incidentally through regular follow-up echocardiography. The delayed pseudo-aneurysm may have occurred due to dehiscence of the patch in the friable myocardium, leading to mechanical rupture of the repaired pericardium.

Fig. 5. I ntra-operative photograph (surgeon’s view) reveals the 1-cm-diameter perforation. The arrow indicates the perforation, which was the point of communication with the pseudo-aneurysm.

Discussion LV pseudo-aneurysm is the result of myocardial rupture contained by adherent pericardium or scar tissue, unlike a true aneurysm, which involves the full thickness of the thin cardiac wall.1 The aetiology of pseudo-aneurysm is various, the most common cause being transmural MI.2 LV pseudo-aneurysm may also be found after cardiac surgery, previous chest trauma, infection or inflammation.1,3-5 In a study of 290 patients with cardiac pseudo-aneurysm, clinical presentation was characterised by congestive heart failure (36%), chest pain (30%) and dyspnoea (25%). However, over 10% of the aneurysms were asymptomatic and diagnosed incidentally using various imaging tools.2 Electrocardiogram and chest X-ray are not sensitive or specific enough to diagnose LV pseudo-aneurysm. Multiple diagnostic imaging modalities are useful in the differential diagnosis. Echocardiography is usually the first imaging modality to diagnose pseudo-aneurysm because of its wide availability, non-invasiveness and rapid diagnosis. Pseudo-aneurysm typically comprises a ratio of < 0.5 between the width of the neck and the maximal diameter of the aneurysmal sac.6 The presence of colour Doppler flow extending from the left ventricle to the aneurysmal space through the narrow neck is another important finding in LV pseudoaneurysm.7 Recently, contrast echocardiography with to-and-fro flow using a contrast microbubble was used to identify pseudoaneurysm. Cardiac CT is another useful non-invasive method to detect three-dimensional structure, such as location, anatomy of the aneurysm, myocardium, coronary arteries and bypass grafts.8 Recently, a LV coronary angiogram also identified a LV pseudo-aneurysm with a narrow neck that communicated with

Conclusion Because of the rarity of the condition, there are no long-term data on delayed complications after post-infarction VSD closure. However, from this case, we highlight the importance of longterm follow up using multiple imaging modalities.

References 1.

Hulten EA, Blankstein R. Pseudoaneurysms of the heart. Circulation 2012; 125: 1920–1925.

Frances C, Romero A, Grady D. Left ventricular pseudoaneurysm. J Am Coll Cardiol 1998; 32: 557–561.

Waller BF, Taliercio CP, Clark M, et al. Rupture of the left ventricular free wall following mitral valve replacement for mitral stenosis: a cause of complete (fatal) or contained (false aneurysm) cardiac rupture. Clin Cardiol 1991; 14: 341–345.

Ridley PD, Tew P, Patel NC, et al. Left ventricular false aneurysm after previous repair of acquired ventricular septal defect. Eur J Cardiothorac Surg 1996; 10: 68–70.

Ghatak A, Farrer M. Pseudoaneurysm of the left ventricle after repairing a ventricular septal defect complicating acute myocardial infarction. Heart 2007; 93: 782.

Gatewood RP, Jr, Nanda NC. Differentiation of left ventricular pseudoaneurysm from true aneurysm with two dimensional echocardiography. Am J Cardiol 1980; 46:8 69–878.

Sutherland GR, Smyllie JH, Roelandt JR. Advantages of colour flow imaging in the diagnosis of left ventricular pseudoaneurysm. Br Heart J 1989; 61: 59–64.

Niimura H, Mito T, Matsunaga A, et al. Left ventricular pseudoaneurysm following acute myocardial infarction. Intern Med 2006; 45: 1221–1223.

Yeo TC, Malouf JF, Oh JK, et al. Clinical profile and outcome in 52 patients with cardiac pseudoaneurysm. Ann Intern Med 1998; 128: 299–305.

10. Eren E, Bozbuga N, Toker ME, et al. Surgical treatment of postinfarction left ventricular pseudoaneurysm: a two-decade experience. Tex Heart Inst J 2007; 34: 47–51.

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 30, No 1, January/February 2019

AFRICA

Case Report Pulmonary thromboendarterectomy in a combined thrombophilia patient Hakan Akbayrak, Hayrettin Tekumit

Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially correctable cause of secondary pulmonary hypertension. Surgical treatment remains the primary treatment for patients with CTEPH. Pulmonary thromboendarterectomy (PEA) with deep hypothermic circulatory arrest is the standard and recommended surgical technique for the treatment of these patients. The prevalence of CTEPH after an acute pulmonary thromboembolism (PTE) has been found in various studies to be between 0.6 and 8.8%. Mortality rates in elective PEA cases with CTEPH are reported to be between 1.9 and 4.5%. We report on a 50-year-old female patient with combined inherited thrombophilia, including protein C and protein S deficiencies, who was diagnosed with CTEPH and was successfully treated with pulmonary thromboendarterectomy.

Keywords: protein C, protein S, pulmonary embolism, thromboendarterectomy Submitted 26/2/18, accepted 22/10/18 Published online 22/11/18 Cardiovasc J Afr 2019; 30: e4â&#x20AC;&#x201C;e6

www.cvja.co.za

DOI: 10.5830/CVJA-2018-052

Chronic thromboembolic pulmonary hypertension (CTEPH) is the end result of untreated or recurrent pulmonary thromboembolism (PTE). The incidence of CTEPH is about 5% in patients who survive after acute PTE and up to 30% after recurrent PTE.1 After acute PTE, the incidence of cumulative symptomatic CTEPH in the first six months was 1%, compared with 3.1% per year and 3.8% over two years.2 The prevalence of CTEPH was shown to be between 0.6 and 8.8% in studies evaluating the prevalence of CTEPH after an acute PTE.3

Department of Cardiovascular Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey Hakan Akbayrak, MD, hakanakbayrak@gmail.com

Department of Cardiovascular Surgery, Faculty of Medicine, Bezmialem University, Istanbul, Turkey Hayrettin Tekumit, MD

CTEPH is currently largely under-diagnosed and must be sought in all patients presenting with exertional dyspnoea, reduction in effort capacity, fatigue, or clinical symptoms of right-sided heart failure. It can be seen with or without a prior history of deep venous thrombosis (DVT) and/or PTE. The patients with permanent symptoms of dyspnoea, fatigue, limitation of exercise, vertigo or chest pain following an acute PTE, as well as patients in whom pulmonary hypertension is reported as an acute event, could potentially benefit from further investigations to rule out CTEPH.1 Echocardiography, ventilation/perfusion (V/Q) scan, computerised tomography (CT), pulmonary angiography and cardiac catheterisation are standard diagnostic procedures.3 The severity of the pulmonary hypertension determines the prognosis of CTEPH. If the mean pulmonary artery pressure (PAP) is greater than 30 mmHg, the five-year survival is approximately 30%. If the mean PAP is greater than 50 mmHg, the five-year life expectancy is estimated at 10%.1 V/Q scan is the preferred and recommended screening test for patients with CTEPH. Pulmonary angiography remains the gold standard for confirmation of chronic thromboembolic disease and evaluation of operability.2 It is recommended that all patients with CTEPH should be evaluated with right heart catheterisation and pulmonary angiography to assess their prognosis.4 Surgical techniques have improved over the last 20 years but the standard surgical technique for PEA has not changed in the last five years. These procedures are currently safely performed in clinics with experienced surgeons.5,6 The progressive increase in pulmonary vascular resistance affects the clinical course of CTEPH. If left untreated, it could result in progressive pulmonary hypertension, right ventricular dysfunction and death.4 The standard treatment options for CTEPH patients are surgical treatment and/or balloon pulmonary angioplasty procedure (BPAP). BPAP can be performed on inoperable patients or as complementary treatment to surgery.5 The protein C system, which contains protein C, protein S and thrombomodulin, is a natural profibrinolytic system. Protein C and protein S are vitamin K-dependent plasma proteins that play a role in the negative feedback system in blood clotting. Thrombomodulin, which is a surface protein of endothelial cells, is also a part of the protein C system. Poor fibrinolytic activity is seen in protein C-deficient patients.7-9 Patients between 15 and 40 years who develop venous thrombotic complications, with a high incidence of DVT and PTE, usually have protein C and protein S deficiencies. Protein C- and protein S-deficient patients are treated medically with

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

heparin, warfarin, fresh frozen plasma, and protein C and protein S extract.7 We present a case of a surgically treated CTEPH patient with protein C and protein S deficiencies.

Case report A 50-year-old female had been admitted to another university hospital with exertional dyspnoea, palpitation and reduction in effort capacity. She had been treated with medical therapy only in that medical centre. Warfarin therapy had been started and continued after discharge. When she applied to our hospital, her effort capacity was remarkably decreased, in New York Heart Association (NYHA) functional class IV. She also had leg swelling and sometimes haemoptysis. The patient was treated medically (bronchodilator therapy, glycocorticosteroid, furosemide, nitroglycerin, sildenafil) for severe dyspnoea and pulmonary hypertension in our cardiology and chest disease clinics. Because of the development of her symptoms, she was referred to our clinic. Her weight was 65 kg and height was 165 cm. Blood pressure and pulse rate were in the normal range. The second heart sound was increased and widely split on chest auscultation. The lung sounds were normal. The liver was detected 5 cm below the right costal margin. There was mild bilateral leg oedema. The patient did not have any other risk factors such as smoking history, hormone use and family history. We did not find any thromboembolic focus for the pulmonary embolism in our patient. A biochemical study revealed that the patient’s protein C activity was 34.9% (normal range: 70–150%) and protein S activity was 22.7% (normal range: 65–160%). Her partial oxygen pressure was 45 mmHg in room air on arterial blood gas analysis. The cardiothoracic ratio was 55% on chest X-ray. Her left ventricular ejection fraction was 60% and systolic PAP was 110 mmHg on echocardiography. V/Q scan showed total occlusion of the right pulmonary artery (Fig. 1). Cardiac catheterisation showed that the systolic PAP was 110 mmHg and diastolic PAP was 9 mmHg (mean PAP 56 mmHg), right ventricular pressure was 110/0 mmHg (mean 25 mmHg), and pulmonary capillary wedge pressure was 10 mmHg. The pulmonary angiogram showed total right pulmonary artery occlusion. The patient was haemodynamically stable but urgent surgery was planned because of low partial oxygen pressure and

severe clinical symptoms. After a median sternotomy, cardiopulmonary bypass (CPB) was established by cannulation of the aorta and two-stage caval cannulation. The patient was cooled to 18°C, the aorta was cross-clamped and cardiac arrest was established using antegrade blood cardioplegia and local cold application. The pulmonary arteries were explored by moving the aorta to the right side. PEA was performed through right and left pulmonary incisions under total circulatory arrest (TCA) (Fig. 2). Firstly, we performed PEA on the right pulmonary artery and its branches within 20 minutes. There after we performed a left pulmonary artery incision for PEA in 12 minutes, but there were no thromboembolic material in the left pulmonary artery. The TCA time was 32 minutes and aortic cross-clamp time was 81 minutes. Ultrafiltration was performed on the patient and about 2 500 cm3 was filtered from the patient during CPB. Alprostadil infusion and nitric oxide inhalation were administered after surgery. Alprostadil infusion was administered at a dose of 50 ng/kg/min for two days after the operation. Nitric oxide inhalation therapy was maintained until the patient was extubated at postoperative 18 hours. A low-molecular-weight

Fig. 1. P re-operative total perfusion defect in the right lung on V/Q scan.

Fig. 3. There were no perfusion defects in the lungs on V/Q scan after the operation.

Fig. 2. The pulmonary thromboendarterectomy material that was removed from the right pulmonary artery.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 1, January/February 2019

heparin was initiated at full dose within six hours of the end of the operation and continued up to the postoperative third day. When the patient was extubated on the first day postoperatively, oral sildenafil and warfarin were started. A 3-l/min nasal oxygen tube was applied after the extubation. She was transferred to a general ward from the intensive care unit on the third day postoperatively. Postoperative echocardiography, V/Q scan and computerised tomographic angiography (CTA) showed marked improvement in our patient. There were no perfusion defects in the lungs on the V/Q scan after the operation (Fig. 3). She was discharged uneventfully on the postoperative 10th day. The patient was controlled at three, six, 12 and 24 months after the operation. She was evaluated according to NYHA functional class on echocardiography. She was in NYHA class I at the second-year check-up after the operation. The systolic PAP was 25 mmHg in the first year postoperatively. We designed the prothrombin time/international normalised ratio to range from two to three to control the warfarin effect postoperatively.

lifelong administration of warfarin is important to prevent recurrent attacks. In our patient, we did not use an inferior vena cava filter because she did not have acute or sub-acute DVT.

Conclusion Patients diagnosed with CTEPH should have the diagnosis confirmed and the best therapeutic option determined according to the haemodynamic and morphological data provided by an invasive pulmonary angiogram and/or CTA. PEA for patients with CTEPH may be associated with acceptable peri-operative morbidity and mortality rates, and improved haemodynamic indices and survival rate. This article was presented at the 16th National Congress of Vascular and Endovascular Surgery on 26–29 October 2013 in Istanbul, Turkey.

References 1.

De Perrot M, McRae K, Shargall Y, Pletsch L, Tan K, Slinger P, et al. Pulmonary endarterectomy for chronic thromboembolic pulmo-

Discussion PTE is normally eliminated by active fibrinolytic systems. Complete dissolution of a thromboembolism has been shown in four to eight days after a thromboembolic event in one study using pulmonary scanning. This study showed 0.5 to 4% of patients developed CTEPH, while 22% of patients continued to have signs of the disease.6 PEA is potentially the most successful procedure for patients with CTEPH. These procedures are currently performed with low mortality rates in clinics with experienced surgeons.5,6 If chronic thromboembolic disease leads to CTEPH, it aggravates and leads to right ventricular failure due to a decline in vascular compliance across the pulmonary arterial circulation and increased vascular resistance.10 Thromboembolic disease also leads to redistribution of blood flow within the pulmonary vasculature, resulting in the development of overflow and post-obstructive vasculopathy in the small pulmonary vessels, similar to that seen in pulmonary arterial hypertension.11 The progressive increase in pulmonary vascular resistance affects the clinical course of CTEPH. If CTEPH is left untreated, it could result in progressive pulmonary hypertension, right ventricular dysfunction and death.4 Protein S acts as a co-factor to activated protein C to form the protein C–protein S complex. Thrombin generation via the inhibition of factor Va and factor VIIIa by binding to Ca2+ and phospholipids is prevented by the protein C–protein S complex.9 Our patient had protein C and protein S deficiencies. A mortality rate of 5 to 9% seemed to be an acceptable risk for surgical treatment of her disease.7 Surgical treatment was planned for our patient because of a poor prognosis on medical treatment. Control and prevention of recurrent PTE is very important. Pre-operative implantation of an inferior vena cava filter and

AFRICA

nary hypertension: the Toronto experience. Can J Cardiol 2011; 27(6): 692–697. 2.

Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350(22): 2257–2264.

Guérin L, Couturaud F, Parent F, Revel MP, Gillaizeau F, Planquette B, et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014; 112(3): 598–605.

McNeil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Heart 2007; 93(9): 1152–1158.

Kim NH, Delcroix M, Jenkins DP, Channick R, Dartevelle P, Jansa P, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D92–99.

Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014; 130(6): 508–518.

Isoda S, Kimura T, Nishimura K, Yamanaka N, Nakamura S, Ando M, et al. A case report of pulmonary thromboendarterectomy for chronic thromboembolism in a patient with protein C deficiency. Ann Thorac Cardiovasc Surg 2014; 20(Suppl): 885–889.

Briffa NP, Wilson I, Clarke DB. Surgical treatment of pulmonary hypertension in protein C deficiency. Br Heart J 1991; 66: 460–462.

Mayo D, Zavada MC, Southerland CC Jr. The vascular adverse events of protein S deficiency: a case report. Ther Adv Cardiovasc Dis 2011; 5: 209–212.

10. Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999; 160: 523–528. 11. Reichenberger F, Voswinckel R, Enke B, Rutsch M, El Fechtali E, Schmehl T, et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J 2007; 30: 922–927.

Africa STEMI Live! 2019 9

April 25 - 27, 2019 The Radisson Blu Hotel, Nairobi, Kenya

Kindly refer to the website www.africastemi.com for submission guidelines Stand a chance to win a complimentary registration to Africa STEMI Live! 2019.

IMPORTANT INFORMATION

WHEN ALL THE PARTS FIT...

PERFECTLY. EFFICACY

All abstracts must be submitted via the Cardiovascular journal of Africa submission portal http://cvja.co.za/abstract-submissions/ Case submission deadline - 11.59pm March 1st 2019 (SA time)

SAFETY 2

PROVEN OUTCOMES 3

For additional information Heart & Life Medical Conferences Tel: +254 721 575 483 Address: P.O. Box 34172, Oval Building, Nairobi Kenya. Email: heartandlifeconferences@gmail.com

JANUARY/FEBRUARY 2019 VOL 30 NO 1

Need endurance when treating CVS disease?

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Surrogate measures of sympathetic activity: SABPA • Cardiovascular risk factors with HIV in rural Kenya

Cardiovascular Journal of Africa . Vol 30, No 1, January/February 2019

Perindopril has proven outcomes in: • Coronary Artery Disease1 • Acute Myocardial Infarction2 • Stroke3 • End-stage Renal Failure4

• Diagnostic algorithm for pulmonary hypertension

Published online: • Pulmonary thromboendarterectomy in a thrombophilia patient