CVJA Volume 23, Issue 5 by Clinics Cardive Publishing

JUNE 2012 VOL 23 NO 5

AFRICA www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Global target on non-communicable diseases • Obesity and blood pressure level of adolescents in Abeokuta • Prevalence, awareness, treatment and control of hypertension • Cardiovascular risk in black Africans • Robotically controlled ablation for atrial fibrillation • Cardiovascular disease in sub-Saharan Africa • Effusive constrictive pericarditis • Heart failure guidelines • The role of aspirin in cardiovascular disease

Cardiovascular Journal of Africa . Vol 23, No 5, June 2012

Printed by Durbanville Commercial Printers Tel: 021 946 4074

PUBLISHED ONLINE:

• The dangerous fifth chamber • Rocking mitral annuloplasty ring

Today’s Prevention. Tomorrow’s Protection.

Reduce your risk of stroke and heart attack with Bayer Aspirin Cardio® 100 Why take Bayer Aspirin Cardio® 100? Aspirin, an antiplatelet agent, which slows the clotting process, is widely used among patients with cardiovascular disease, which includes heart attacks, stroke and peripheral vascular disease. 1, 2, 5, 6 During a heart attack, blood clots form in an already-narrowed artery and block the flow of oxygen-rich blood to the heart muscle or to parts of the brain, in the case of a stroke. 7 Studies have shown that aspirin reduced the number of strokes by 20 % and heart attacks by 30 %. It has been determined that for every 67 patients treated to protect against heart attacks and stroke, one life could be saved with low-dose aspirin therapy. 6 Doctors use different guidelines to decide who should take daily aspirin. Consult your Doctor or Pharmacist.

What are the Risk Factors for Coronary Heart Disease and Stroke? 3, 4 Major Risk Factors Include:

• • • • • •

Cigarette smoking Hypertension (high blood pressure) High cholesterol Diabetes mellitus

Protect their passion for living.

Advancing age Atrial Fibrilation

Other Risk Factors Include:

• • • •

Obesity Physical Inactivity Family History of premature coronary heart disease Blood clotting abnormalities

Information brought to you by Bayer, the innovators of Aspirin. References: 1. Cox D, Maree O, Dooley M, Conroy R, Byrne M, Fitsgerald DJ. Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers. 2006;2153-2158. 2. Healthwise Website. WebMD Reference from Healthwise. Last Updated: December 09,2010 3. Grundy S, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka, Housten-Millar N, Kris-Etherton P, Krumholz HM, LaRosa J, Ockene IS, Pearson TA, Reed J, Washington R, Smith SC. Primary Prevention of Coronary Heart Disease: Guidance from Framingham. A statement for healthcare professionals from the AHA task force on risk reduction. 2011;1876-1887 4. Chock AWY, O’Brien KK, Stading JA, Shea JL. Stroke risks and primary stroke prevention. 2011. The Journal of Modern Pharmacy. August 20-26 5. Package Insert for Bayer Aspirin Cardio 100 6. Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. 2002;162:2197-2202. 7. WebMD. Heart Disease Health Centre: Low-Dose Aspirin Therapy – Topic Overview

S0 Bayer® Aspirin Cardio 100. Each tablet contains 100 mg of acetylsalicylic acid (ASA). Reg. No. 31/8/0413. For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority (MCC). Bayer (Pty) Ltd, Reg.No.1968/011192/07. 27 Wrench Road, Isando, 1609. Tel (011) 921-5911. L.ZA.GM.04.2012.0409 10000141HC

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

AFRICA

VOL 23, NO 5. JUNE 2012

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial

241

New global target on non-communicable diseases: a call to action for the global cardiovascular disease community J Ralston

245

Feeding the emergence of advanced heart disease in Soweto: a nutritional survey of black African patients with heart failure S Pretorius • K Sliwa • V Ruf • K Walker • S Stewart

Cardiovascular Topics

252 Treatment of subaortic stenosis in hearts with single-ventricle physiology B Saritas • E Ozker • C Vuran • Ç Gunaydin • C Ayabakan • R Turkoz 255

Early diastolic functional abnormalities in normotensive offspring of Nigerian hypertensives AM Adeoye • AA Adebiyi • OO Oladapo • OS Ogah • A Aje • DB Ojji • AK Adebayo • KC Ochulor • EO Enakpene • AO Falase

260 Obesity and blood pressure level of adolescents in Abeokuta, Nigeria IO Senbanjo • KA Oshikoya 265

Prevalence, awareness, treatment and control of hypertension among adults 50 years and older in Dakar, Senegal E Macia • P Duboz • L Gueye

270

Control of cardiovascular risk in black Africans with type 2 diabetes in Senegal (Contrôle du risque cardio-vasculaire chez les diabétiques de type 2 noirs africains au Sénégal) NV Yaméogo • A Mbaye • M Ndour • LJ Kagambega • H Diomande • R Hakim • A Thiam • A Diallo • SN Diop • D Diagne • B Diack • A Kane

274 Robotically controlled ablation for atrial fibrillation: the first real-world experience in Africa with the Hansen robotic system F Lorgat • E Pudney • H van Deventer • S Chitsaz INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors

SUBJECT Editors

Editor-in-Chief (South Africa) PROF AJ BRINK

Nuclear Medicine and Imaging DR MM SATHEKGE

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 Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Electrophysiology and Pacing dr a okreglicki Epidemiology and Preventionist dr ap kengne

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

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

PROF PETER SCHWARTZ Italy (Dysrhythmias)

DR J LAWRENSON Paediatric Heart Disease

Publishing Consultant

PROF H DU T THERON Invasive Cardiology

PROF ERNST VON SCHWARZ USA (Interventional Cardiology) Mike Gibbs

Letters to the Editor

273 The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives PMO Owira 285

Comment on: A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa Z-H Gao • R-Y Yuan

VOL 23, NO 5. JUNE 2012

CONTENTS

Review Article

281 The prevalence and outcome of effusive constrictive pericarditis: a systematic review of the literature M Ntsekhe • CS Wiysonge • PJ Commerford • BM Mayosi

Conference Report

286

Novo Nordisk incretin leadership summit, Cape Town P Wagenaar • G Hardy • J Aalbers

295

New ESC heart failure guidelines with South African expert comment J Aalbers

299

EINSTEIN-PE study results, with South African expert comment J Aalbers

Drug Trends

300 The role of aspirin in cardiovascular disease prevention P Wagenaar

PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) Case Reports

e1 Severe haemoptysis due to subclavian arteritis A Lioulias • P Misthos • P Drosos • N Karagiannidis • D Pavlopoulos • M Mitselou e3 The dangerous fifth chamber: congenital left atrial appendage aneurysm KM Tigen • CEM Dogan • A Guler • S Hatipoglu • M Yanartas • C Kirma e5

Corrected transposition of the great arteries with previously unreported cardiac anomalies A Kaya • IH Tanboga • M Kurt • T Işik • M Ozgokce • S Topçu • E Aksakal

e8 Rocking mitral annuloplasty ring P Panduranga • MK Mukhaini

HEALTHCARE

e11 Repair of a right coronary artery arising from the pulmonary artery A Guler • MA Sahin • C Gunay • A Jahollari • H Tatar managing editor

julia aalbers Tel: 021 976 4378 Fax: 086 610 3395 e-mail: julia@clinicscardive.com

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Editorial Assistant & Circulation ELSABÉ BURMEISTER Tel: 021 976 8129 e-mail: elsabe@clinicscardive.com

development editor

GLENDA HARDY Cell: 071 8196 425 e-mail: glenda@clinicscardive.com

Production Co-ordinator

WENDY WEGENER Tel: 021 976-4378 e-mail: wendy@clinicscardive.com

GAUTENG CONTRIBUTOR

PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za

CONTENT MANAGER

Copyright: Clinics Cardive Publishing (Pty) Ltd. Layout: Martingraphix Printer: Durbanville Commercial Printers ONLINE SERVICES: Design Connection All submissions to CVJA are to be made online via www.cvja.co.za

Michael Meadon (Design Connection) Tel: 021 975 3785 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

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

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.

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Electronic abstracts available on Pubmed Audited circulation Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact julia@clinicscardive.com Subscriptions for 10 issues: South Africa: R650 (excl VAT) Overseas: R1306 Online subscription: R200 The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

“THE CURRENT AHA DIETARY GUIDELINES RECOMMEND COMBINED EPA & DHA IN A DOSE OF APPROXIMATELY 1000 mg/DAY IN PATIENTS WITH CHD“ Lavie et al, Omega - 3 Polyunsaturated Fatty Acids and Vol. 54,No. 7 2009, August 11, 2009 585– 594

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Life. It’s what you put in. Help your patients love themselves a little more.

CRESTOR® 5 mg is suitable for select patients who need less aggressive lipid lowering1 CRESTOR® is the more effective statin at lowering LDL-C and raising HDL-C2 CRESTOR® 10 mg will get most patients to LDL-C goal1,3 CRESTOR® is well-tolerated and has a favourable benefit-risk profile4,5 S4 CRESTOR® 5 (Tablet) Each CRESTOR® 5 tablet contains 5 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 10 (Tablet) Each CRESTOR® 10 tablet contains 10 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 20 (Tablet) Each CRESTOR® 20 tablet contains 20 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 40 (Tablet) Each CRESTOR® 40 tablet contains 40 mg of rosuvastatin as rosuvastatin calcium. PHARMACOLOGICAL CLASSIFICATION: A. 7.5 Serum-cholesterol reducers INDICATIONS: Primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate. Indicated in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments. CRESTOR® 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of CRESTOR® or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated. REGISTRATION NUMBERS: CRESTOR® 5: 41/7.5/0298, CRESTOR® 10: 36/7.5/0349, CRESTOR® 20: 36/7.5/0350, CRESTOR® 40: 36/7.5/0351. DETAILS OF THE REGISTERED LICENCE HOLDER: AstraZeneca Pharmaceuticals (Pty) Ltd Reg No. 1992/005854/07. No. 5 Leeuwkop Road, Sunninghill, 2157, South Africa. Tel: 011 797 6000. Fax: 011 797 6001. www.astrazeneca.co.za. For full details relating to any information mentioned above please refer to the package insert of CRESTOR® 5 mg, 10 mg, 20 mg and 40 mg. CRESTOR® is a registered trademark of AstraZeneca group of companies. Licensed from Shionogi & Co Ltd, Osaka, Japan. EPI Date: 12/03/2008. Expiry Date: May 2014. References: 1. CRESTOR® package insert 2. Jones P, Davidson MH, Stein EA, et al. Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR* Trial). Am J Cardiol 2003;92:152-160. 3. Schuster H, Barter PJ, Stender S, et al. Effects of switching statins on achievement of lipid goals. Measuring Effective Reduction in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J 2004;147:705-712. 4. Rosenson RS. Statins: can the new generation make an impresssion? Expert Opin Emerg Drugs 2004;9(2):269-279. 5. Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosuvaststin. Am J Cardiol 2004;94:882-888. 17880

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Editorial New global target on non-communicable diseases: a call to action for the global cardiovascular disease community JOHANNA RALSTON For many years, cardiovascular disease (CVD) was regarded as a lifestyle disease primarily affecting ageing, affluent populations. This is reflected in the virtual absence of global policies concerned with CVD control in poor and rich countries alike. However, CVD and other non-communicable diseases (NCDs), including cancer, chronic respiratory disease and diabetes, account for nearly two-thirds (63%) of global deaths, with the majority of deaths from NCDs (80%) occurring in low- and middle-income countries (LMICs).1 This represents a public health emergency requiring an urgent worldwide response. Now with the World Health Organisation’s (WHO) adoption of a global target to prevent premature NCD mortality, the time has finally arrived for the global CVD community to join forces in reducing CVD suffering and death in all countries and among all populations. The World Heart Federation and its members and colleagues in the CVD community have been fighting the burden of diseases for years, while also advocating for governments to act. In the run up to the first-ever United Nations High-Level meeting on NCDs, which took place on 19 September 2011, the World Heart Federation worked with its 200 member organisations globally to lobby for CVD and the other NCDs to be recognised as a priority on the global health and development agendas. World leaders finally heeded our calls to action and they unanimously adopted a political declaration2 agreeing to address the prevention and control of NCDs worldwide, with an emphasis on developing countries. The declaration highlights NCDs as a major challenge for development in the 21st century, emphasising that NCDs undermine social and economic development, and threaten the achievement of global development and povertyeradication goals. Just eight months later, governments agreed to take responsibility for responding to the challenge of NCDs. At the 65th World Health Assembly, all 194 member states agreed to adopt the first ever global NCD target: a 25% reduction in premature mortality from NCDs by 2025.3 The adoption of this bold global target is the result of commitment, hard work and a major lobbying effort from CVD activists. Most important to note, the overall mortality target and additional targets to be adopted later this year place CVD prevention and control at the heart of the NCD agenda, with risk management, low-cost treatment and care of CVD central to achieving the mortality and risk-factor targets. Many members of the African CVD community are to be congratulated for their efforts to make these achievements

possible. In particular, Bongani Mayosi, chair of the World Heart Federation Rheumatic Heart Disease Working Group and, professor and head of the Department of Medicine at the University of Cape Town, participated in a civil society interactive hearing on NCDs at the United Nations in June 2011, to inform preparations for the UN meeting in September. At that High-Level meeting, Dr Kingsley Akinroye, then-president of the African Heart Network and board member of the World Heart Federation, spoke from the floor of the UN General Assembly about the importance of strengthening national policies and capacity to address the control of NCDs. But we cannot rest now. The target represents a rallying cry for further action by the CVD community. It automatically elevates CVD on the global health policy agenda, providing an ‘opportunity springboard’ from which we can accelerate action to reduce the global CVD burden. Because CVD is responsible for a higher proportion of NCD deaths than cancer, chronic respiratory diseases and diabetes combined (48 vs 36.5%),1 world leaders will look to us and our efforts to help reduce the CVD burden – and so our challenge is great. The next 13 years are crucial, and in order to mount a comprehensive response for achieving the target, the CVD community must forge innovative partnerships with policy makers, the private sector and healthcare professionals to create strategies that prevent CVD at local, regional and national levels. We need to look beyond the health sector and consider the many factors that influence heart health (including healthy eating, physical activity and tobacco consumption). We need to serve as the catalyst for renewed, global efforts to encourage heart-healthy behaviours. A concerted, global response is vital – we won’t curtail this global epidemic by continuing the same fragmented responses we have followed in the past. Everyone has a crucial role to play, and we must lead the charge and propel them to act. To achieve the target, policy makers urgently need to take action to help modify behavioural risk factors. Many CVD prevention strategies exist, however governments must do more to ensure that these are fully implemented and well articulated in NCD plans, which the UN political declaration requires governments to complete by the end of 2013. As an example, one of the success stories in the fight against CVD is the WHO’s Framework Convention on Tobacco Control (FCTC), a treaty addressing issues around tobacco consumption, including restricting sales and advertising. National smoke-free legislation has been passed in Ghana,

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Mauritius, Niger, Kenya, Zambia and South Africa.4 However, according to the latest (2010) global progress report on implementation of the FCTC, only 50% of parties in the African region reported implementing a comprehensive ban on tobacco advertising, promotion and sponsorship.5 Our job therefore is to advocate for the full implementation of the FCTC, and at the same time push for more public-health campaigns to educate people on the links between tobacco consumption, CVD and premature death. Collaboration with the private sector is also imperative. Let us consider access to healthy food as an example. The factors that influence an individual’s ability to eat healthily are many, and are often beyond the control of that individual. In Africa, where many countries are increasingly experiencing a dual burden of obesity and malnutrition, strategies are required not just to affect an individual’s consumption of food but to modify food production processes. We can spearhead strategies to reformulate food products, to distribute healthy food options to those communities most in need, to promote and foster incentives for fruit and vegetable consumption, and to educate consumers to drive healthy food choices among those who have options available to them. We may face resistance from some corporate leaders, policy makers and even donors, so advocacy to stress the need for action is required alongside the development of new and creative partnerships that meet both health and corporate objectives wherever possible. We must also campaign for companion strategies for policies to change food production in the long term. We must work with healthcare providers to implement strategies that improve access to care and treatment. Consider blood pressure: in high-income countries, widespread screening, diagnosis and treatment have led to an impressive decrease in mean blood pressure,1,6 and correspondingly a drop in mortality from stroke and coronary heart disease is to be expected. Yet in Africa, more than one in three people (36.8%) are estimated to have raised blood pressure, and the prevalence is increasing.1,6 Improving the availability of screening in primary care and treatment of high blood pressure with affordable essential drugs, including aspirin and statins, will prove vital to reducing premature CVD mortality in developing countries. More research is also needed to understand the burden of hypertension in the region in order to tailor approaches to addressing it. The distribution of penicillin to prevent rheumatic heart disease is a similar strategy that would cost little but have great impact. It is essential that we tackle these global inequalities in order to meet the target. Although we applaud the progress made at the World Health Assembly, the above examples show the complexity of CVD management. The global target is a landmark achievement that obliges action to deliver change for people with or at risk of NCDs and especially CVD. However, in isolation it is not enough

AFRICA

– further targets are needed to shape a more complete framework and better guide collaborative, global action against CVD and its risk factors. We must keep the pressure on our governments to ensure the best possible outcomes for the millions of people suffering from CVDs and to avoid the 17.3 million deaths that occur each year. Specific targets are being considered for adoption around reducing the consumption of tobacco, salt/sodium, trans fats, and harmful levels of alcohol; reducing physical inactivity, elevated blood pressure, cholesterol and obesity; and ensuring access to affordable, quality-assured essential medicines, including multidrug therapy for people who have been identified at high risk of CVD. The window of opportunity to change the face of CVD forever is now and throughout the year, since the final targets will be agreed by member states in October 2012. We call on the CVD community to champion the additional targets, and push world leaders to agree on these promptly. Together we can avert deaths from CVD using proven interventions, and save lives around the world. For further information about the work of the World Heart Federation, please visit www.worldheart.org or follow on twitter: @worldheartfed.

JOHANNA RALSTON, johanna.ralston@worldheart.org

Chief Executive Officer, World Heart Federation, Geneva, Switzerland

References 1.

World Health Organization. World Health Statistics 2012. [online] Geneva: World Health Organization. Available at: <http://who.int/gho/ publications/world_health_statistics/EN_WHS2012_Full.pdf> The United Nations General Assembly. Political declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases [online]. New York: United Nations. Available at: <http://www.world-heart-federation.org/fileadmin/user_upload/documents/members-only/Global_Health_Agenda/ UN_Health_Summit_on_NCDs/UN_HLM_NCDs_PD_english.pdf> World Health Organization. 65th World Health Assembly closes with new global health measures. Press release, 26 May 2012. Available at: <http://www.who.int/mediacentre/news/releases/2012/wha65_closes_20120526/en/index.html#> Global Smokefree Partnership. Global map of smokefree laws 2011 [online]. Global Smokefree Partnership. Available at: <http://www. globalsmokefreepartnership.org/index.php?section=artigo&id=32> WHO Framework Convention on Tobacco Control. 2010 Global Progress Report on Implementation of the WHO Framework Convention on Tobacco Control [online]. Geneva: World Health Organization. Available at: <http://www.who.int/fctc/reporting/ progress_report_final.pdf> World Health Organization. World Health statistics – A snapshot of global health [online]. Geneva: World Health Organization. Available at: http://www.who.int/gho/publications/world_health_statistics/EN_ WHS2012_Brochure.pdf

EVERY DAY IN SOUTH AFRICA

44** PATIENTS WILL HAVE AN AF* RELATED STROKE1, 2, 3

22** OF THEM WILL DIE

WITHIN A YEAR (50 %)4

90 % OF STROKE PATIENTS WITH KNOWN AF WERE NOT THERAPEUTICALLY ANTICOAGULATED4

THINGS ARE ABOUT TO CHANGE IN ANTICOAGULATION THERAPY

*AF – Atrial Fibrillation ** Best Estimate REFERENCES: 1. Stats South-Africa. Stats-Online. P0302 - Mid-year population estimates. Updated 20 July 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03022010.pdf 2. Connor M. Stroke Management in South Africa – Who is responsible? S Afr Psychiatry Rev 2005; 8: 125-126. 3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a populationbased study. Stroke 2005; 36:1115-9. 4. Gladstone DJ, Bui E,Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40;235-240.

Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348 2400 • Fax: +27 (011) 787 3766 • Company Reg. No. 1966/008618/07. BI Ref No. 254/2010 (Nov 10)

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Cardiovascular Topics Feeding the emergence of advanced heart disease in Soweto: a nutritional survey of black African patients with heart failure SANDRA PRETORIUS, KAREN SLIWA, VERENA RUF, KAREN WALKER, SIMON STEWART

Summary Aim: To describe dietary habits and potential nutritional deficiencies in black African patients diagnosed with heart failure (HF). Methods and Results: Dietary intake in 50 consecutively consenting HF patients (mean age: 47 ± 18 years, 54% female) attending a major hospital in Soweto, South Africa were surveyed using validated quantitative food frequency questionnaires. Food intakes, translated into nutrient data were compared with recommended values. In women, food choices likely to negatively impact on heart health included added sugar [consumed by 75%: median daily intake (interquartile range) 16 g (10–20)], sweet drinks [54%: 310 ml (85–400)] and salted snacks [61%: 15 g (2–17)]. Corresponding figures for men were added sugar [74%: 15 g (10–15)], sweet drinks [65%: 439 ml (71–670)] and salted snacks [74%: 15 g (4–22)]. The womens’ intake of calcium, vitamin C and vitamin E was only 66, 37 and 40% of the age-specific requirement, respectively. For men, equivalent figures were 66, 87 and 67%. Mean sodium intake was 2 372 g/day for men and 1 972 g/day for women, 470 and 294% respectively, of recommended consumption levels. Conclusions: The nutritional status of black African patients with HF could be improved by recommending healthier food choices and by reducing the intake of sweet drinks and excess salt. Keywords: heart failure, Africa, food preferences, malnutrition, salt Submitted 17/9/10, accepted 21/5/11 Cardiovasc J Afr 2012; 23: 245–251

www.cvja.co.za

DOI: 10.5830/CVJA-2011-021

Soweto Cardiovascular Research Unit, Department of Cardiology, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa Sandra Pretorius, RD (SA), sandra.pretorius@nashuaisp.co.za Karen Sliwa, MD, PhD, FESC Verena Ruf, MD

Baker IDI Heart and Diabetes Institute and Monash University, Melbourne, Australia Karen Walker, PhD, MND (APD)

Monash University, Melbourne, Australia

Simon Stewart, PhD, FCSANZ, NFESC, FAHA

Heart failure (HF) has become a major public health problem in that, unlike other cardiovascular diseases, the number of people discharged from hospital with a diagnosis of HF is increasing.1 In developed countries, HF can be observed in 2 to 3% of the population and asymptomatic ventricular dysfunction is evident in about 4% of the population.2 This will increase with age, and in the 70- to 80-year age group, HF can be observed in between 10 and 20% of people.2,3 The epidemic of cardiovascular disease (CVD) has probably stabilised in developed countries, but developing countries are increasingly suffering from the emerging burden of CVD.4 As populations in South Africa and sub-Saharan Africa undergo economic development, the disease profile shifts and CVD becomes a growing cause of death and disability.5 Previously considered a rarity in Africa and predominantly caused by infectious disease or idiopathic dilated cardiomyopathy,6 the syndrome of heart failure (HF) has emerged as a challenging public health problem in sub-Saharan Africa.7 The Heart of Soweto (HOS) study8 has documented a much higher-than-expected burden of modifiable risk factors9 and advanced forms of heart disease10 linked to epidemiological transition in one of Africa’s largest urban concentrations of black Africans. Data from the HOS study showed that during the period from 2006 to 2008, of the 5 328 de novo cases captured with heart disease, 2 505 (47%) of these cases presented with chronic heart failure.11,12 Ominously, in addition to the ‘traditional’ causes of HF in Africa, such as idiopathic dilated cardiomyopathy, rheumatic fever, HIV-related cardiomyopathy, peripartum cardiomyopathy and hypertensive heart failure, ‘lifestyle’ factors, including hypertension, obesity, dyslipidaemia and type 2 diabetes mellitis (particularly in women), appear to have expanded the pathways to, and burden of, HF in this community.8 Although the natural history of HF in Africa is still different from that of high-income countries, it results in the same high level of preventable morbidity and premature mortality.13,14 In those countries already in the midst of an epidemic of HF, multidisciplinary management programmes targeting the common factors leading to clinical instability have been successfully developed.15-17 Certain positive measures have been implemented in low- and middle-income countries for disease prevention, including WHO initiatives.5 However, inadequate funding hinders efforts to establish adequate multidisciplinary management programmes targeting the common factors leading to heart disease in South Africa.5 Moreover, the role of dieticians

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has been largely confined to patients with lipid disorders, obesity, diabetes and/renal failure.18 If, however, nutritional education and promotion of good nutrition could be better understood and recognised to be inclusive of behavioural change, then it will be viewed as a necessary component within contemporary cardiac rehabilitation and self-management programmes.18 One cornerstone of HF management particularly relevant to urban Africans affected by HF is dietary modification. For example, sodium restriction (2â&#x20AC;&#x201C;3 g/day) is standard therapy in the management of symptomatic chronic HF, and black individuals are particularly responsive to this strategy.19,20 However, lack of adherence and poor self-care behaviours persist, with dietary indiscretions contributing to a substantial portion (up to 20%) of hospital readmissions.21 Specific dietary interventions play an important role in improving health outcomes.21,22 Three major studies addressing food choices and dietary patterns in adult black South Africans were identified from the literature. However, given the historical rarity of the syndrome, there are very little data to describe the dietary habits of specifically urban African patients with HF. The Dikgale study23 examined food choices, nutrient intake and weight status of black adults. The Transition, Health and Urbanisation study (THUSA)24 examined the food choices, health status and the effect of urbanisation on a black population. The Black Risk Factor study (BRISK)25 examined the risk factors for developing CVD in urban black Africans. Data from these studies show that rural black adults have a very low consumption of fat and a high consumption of carbohydrates, typical of the traditional rural African diet.23,25 Urbanisation is associated with markedly increased intake of fat, sugar, meat and beverages.23-25 Although a decrease in the consumption of maize porridge with urbanisation was found, it is still consumed in high amounts by these black population groups.23 As the traditional diet is abandoned in favour of a Western diet, food choices shift away from complex carbohydrates and higher fibre to foods high in fat, bringing an increased risk for chronic diseases of lifestyle.26 According to Stewart et al., data on the population of Soweto have shown a low prevalence for CVD and the underlying risk factors.8 This situation however may be changing, as urbanisation and the nutritional transition in South Africa is accompanied by an increase in the CVD risk factors in black Africans.27 The overall study aim was therefore to provide a detailed description of the dietary habits and potential nutritional deficiencies in a subgroup of urban black African patients diagnosed with HF, living in Soweto, South Africa, and managed via the Cardiology Unit of the Chris Hani Baragwanath Hospital. It focused on the impact of varied dietary patterns, the poor socio-economic status of many patients and probable lack of awareness of the contribution of poor nutrition to cardiovascular disease. Ultimately, these data will be used to identify key targets for more culturally sensitive support and to argue for a greater role for dieticians in the management of an increasing number of urban black South Africans affected by HF.12

Methods As part of the previously described Heart of Soweto study,8 detailed demographic and clinical data are captured from all individuals with heart disease presenting to the Chris

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Hani Baragwanath Hospital, Soweto, via a prospective clinical registry. In 2006, this included 1 960 patients presenting with a primary or secondary diagnosis of HF (an average of 162 patients per month). All were diagnosed by echocardiography and specialist cardiological review. This was a prospectively planned study of 50 consecutively consenting black Africans (28 females, 22 males), referred to the Heart Failure Clinic in 2006/7 with a documented diagnosis of HF. The study was approved by the Human Research Ethics Committee (Medical), University of the Witwatersrand, Johannesburg, M050550. All participants provided written informed consent. The study fully conformed to the principles outlined in the Declaration of Helsinki.

Dietary instrument, data and nutrient analyses and recommendations In addition to the detailed clinical and demographic data collected as part of the Heart of Soweto Clinical Registry, an intervieweradministered quantitative food frequency questionnaire (QFFQ) was collected at a point in time when patients had received either limited, or no instructions for a low-sodium, low-fat therapeutic diet for HF.28,29 A quantitative food frequency questionnaire is a validated questionnaire to determine food choices and consumption. The previously validated QFFQ used in this study was developed by a researcher at Northwest University. This QFFQ has previously been used to evaluate the food choices of the African population living in the North West Province, South Africa, as part of the THUSA study.30,31 The quantitative QFFQ has been validated via statistical methods in an African population.30 It includes 139 types of food and records how often a given type of food is consumed as: time/s per day, per week, per month. It also records preparation methods. Quantities of food eaten were determined in relation to pictures of standardised portions of the most commonly consumed foods (e.g. maize meal porridge, rice, meat, etc.). The researcher also used standardised cups, teaspoons etc. to estimate portion sizes. The patients were also asked to name foods eaten that were not included in the questionnaire and to point out questions that were unclear or difficult to understand. The QFFQ was administered through interview by the researcher, SP, who is a registered dietician in the Heart Failure Outpatient Clinic, Chris Hani Baragwanath Hospital, and trained in administering the QFFQ. Food data were translated into nutrient data using the Medical Research Council (MRC) Food Finder 3, 2007, which is based on South African food composition tables. Total dietary starch was calculated from the total amount of carbohydrates minus the sum of total dietary fibre plus added sugars. To assess the consumption of high-sodium foods, data were aggregated to provide percentages of high-sodium foods consumed both daily and weekly. Collated dietary patterns and nutritional intake data were compared to the South African Food-Based Dietary Guidelines. Importantly, one guideline advises that unrefined or minimally processed starchy foods, such as maize, wheat, sorghum, oats, rice in the form of porridges, breads, pastas, samp, breakfast cereals and other products should be the main food around which the rest of the meal is planned.32 Promotion of carbohydraterich foods contributes to optimal nutrient intake, particularly

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in low-income groups. Largely unrefined carbohydrate-rich foods are excellent sources of dietary fibre and provide several important vitamins and minerals.33 It is also recommended that in a healthy, balanced diet, protective against chronic diseases of lifestyle, at least 55% of the total energy (%E) should be provided by a variety of carbohydrate-rich foods, with around 30%E provided by fat and 15%E by protein. To provide at least 55%E in an 8 500 kJ diet, at least 275 g carbohydrate should be consumed daily.32

Demographic and clinical data At the time the QFFQ was administered, body mass was measured with an electronic digital scale, measuring up to 200 kg in graduations of 0.1 kg (Seca 767), and body height was taken with a telescopic measuring rod (Seca 220) attached to the scale, to the nearest 1 mm. Data on the clinical [including left ventricular ejection fraction, New York Heart Association (NYHA) functional class and concurrent diagnoses] and sociodemographic profile (including age, gender and educational status) were collected prospectively.

Statistical analyses Data were analysed using SPSS for Windows version 14.0.1 (SPSS Inc, Chicago, Illinois). Normally and non-normally distributed continuous data are given as the mean (standard deviation: SD) and median (interquartile range: IQR), respectively. Categorical data are presented as counts and percentages. Proportional data were compared via the Chi-squared test while all nutrient data were compared via the Mann Whitney U-test according to gender, and actual versus recommended dietary intake. Significance has been accepted as p < 0.05 (two-tailed).

Results The demographic and clinical profile of the study cohort is shown in Table 1. Reflective of the overall Heart of Soweto study cohort, there were more women (56%) than men. Women were slightly, but not significantly younger than the men and the TABLE 1. DEMOGRAPHIC AND CLINICAL PROFILE OF THE STUDY COHORT Men Socio-demographic profile n = 22 (%) 51 ± 12 Mean age (years)1 No education 1 (4.5) 1–5 years’ education 5 (23) 6–10 years’ education 15 (68) Post-matriculation qualifications 1 (4.5) Risk profile 25.2 ± 4.8 Body mass index (kg/m2)1 Hypertension 14 (65) Diabetes 2 (10) Heart failure profile NYHA class II 11 (50) NYHA class III 4 (19) NYHA class IV 0 (0) 37.3 ± 9.1% Left ventricular ejection fraction1 1 Data are given as mean ± SD or as number (%).

Women n = 28 (%) 47 ± 18 4 (14) 7 (25) 16 (57) 1 (3.6) 26.5 ± 6.4 18 (65) 2 (7.6) 12 (43) 9 (32) 1 (3.6) 36.4 ± 13.4%

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entire HF cohort was typically two decades younger than that seen in high-income countries. Hypertension and obesity were highly prevalent in both genders. Concurrent diabetes was also common, particularly in men. The majority of patients had left ventricular systolic dysfunction (LVEF < 45%) and symptoms of exercise intolerance and dyspnoea indicative of NYHA functional class II or III. The daily food consumption of the cohort as measured by the QFFQ according to gender is shown in Table 2. Significantly, more women (79%) than men (65%) reported eating brown or wholemeal bread, 75% of women and 48% of men consumed sweets and chocolates, processed meat were eaten by 89% of women and 78% of men, and packet soup was consumed by TABLE 2. DAILY FOOD CONSUMPTION OF HF PATIENTS ACCORDING TO THE QUANTITATIVE FOOD FREQUENCY QUESTIONNAIRE Men (n = 22) Women (n = 28) Median Median Propor- daily intake Propor- daily intake tion (interquartile tion (interquartile (%) range) (%) range) 91 516 (200–750) 93 424 (140–688) 52 78 (25–64) 57 111 (55–136) 26 88 (55–107) 32 80 (50–100) 78 76 (28–91) 86* 59 (28–89) 22 88 (50–60) 29 73 (38–98) 65 102 (43–120) 79*** 87 (60–113)

Foods/food groups Maize meal (g) Mabella (g)1 Oats (g) Potatoes (g) White bread (g) Brown/wholegrain bread (g) Cereals: refined (g) 13 13 (13–15) 14 7 (4–10) Cereals: 22 29 (25–30) 21 17 (9–15) wholegrain (g) 30 208 (43–321) 39 64 (16–71) Mageu (ml)2 Added sugar (g) 74 15 (10–15) 75 16 (10–20) Sweets and 48 19 (7–30) 75*** 11 (3–12) chocolates (g) Cakes and biscuits (g) 48 45(15–25) 57 7(5–10)* Cold drinks 65 439 (71–670) 54* 310 (85–400) (sweetened) (ml) Meat, chicken, fish, 100 150 (105–190) 100 127 (83–168) eggs (g) Milk and milk 87 262 (129–370) 93* 113 (58-145)* products (ml) Legumes (g) 43 18 (10–24) 43 18 (9–28) Fruit (fresh) (g) 100 174 (150–160) 100 147 (40–160) Vegetables (fresh) (g) 100 76 (40–103) 100 78 (50–91) Margarine on 83 15 (7–20) 75 16 (10–20) bread (g) Salt added to cooked 91 2 (2–2) 75*** 2 (2–2) food (g) Salted snacks (g) 74 15 (4–22) 61** 15 (2–17) Take-away foods (g) 48 23 (10–15) 32*** 16 (10–25) Sauces and 57 7 (2–10) 64 4 (2–5) condiments Stock cubes 4 1 (1–1) 18*** 1 (1–2) Packet soup 43 3 (1–5) 57** 2 (1–2) Processed meat 78 35 (8–54) 89** 26 (8–35) 1 Unrefined porridge made from sorghum; 2 Dried and broken corn kernels; 3 A carbohydrate-rich drink made from fermented mealie (maize) meal and malt. Significant difference between men and women, *p < 0.05, **p < 0.01, ***p < 0.001.

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TABLE 3. ENERGY AND DAILY NUTRIENT INTAKE OF HF PATIENTS BASED ON A QUANTITATIVE FOOD FREQUENCY QUESTIONNAIRE Daily intake [median (interquartile range)] Nutrient Men (n = 22) Women (n = 28) Energy (kJ) 9 145 (6 857–12 879) 7 472 (5 568–9 478) Protein (g) 74.0 (101–62) 58.8 (51–66)* % plant-derived 42.8 43.5 % total energy 13.8 13.4 Total carbohydrate (g) 272 (223–404) 245 (170–336) % total energy 47.6 52.5 Starch (g) 17.8 (13–27) 11.0 (8–17) Dietary fibre (g) 20.6 (14–25) 16.2 (13–23) Added sugars (g) 40.2 (23–76) 33.1 (19–69) Total fat (g) 65.7 (5–91) 47.4 (39–81) % total energy 26.6 23.5 Saturated fat (g) 19.9 (16–29) 15.1 (12–20)* % total energy 8.1 7.5 Monounsaturated fat (g) 22.9 (17–31) 17.0 (14–26) % total energy 9.3 8.4 Polyunsaturated fat (g) 15.7 (11–22) 12.7 (9–25) % total energy 6.3 6.3 Total trans fat (g) 0.94 (0.62–1.8) 0.46 (0.28–0.67)** Cholesterol (mg) 308 (177–403) 214 (160–307) Significant difference between men and women, *p < 0.05, **p = 0.001.

57% of women and 43% of men. Women, but few men also reported eating stock cubes, 18% and 4% respectively, possibly since the women were more aware that they were added during food preparation. Conversely, more men than women reported the consumption of takeaway foods, 48 and 32%, respectively. Salted snacks were eaten by 74% of men and 61% of women, while more men than women reported adding salt to cooked food, 91% and 75% respectively. Despite differences in the proportions of men and women selecting certain foods, the median daily intake of foods eaten was broadly similar for men and women. Specific differences included a higher median intake for men of milk and milk products, and for cakes and biscuits (both p < 0.05). Median daily nutrient intake in this HF population group is shown in Table 3. Although men consumed a significantly greater quantity of protein (p < 0.05), protein as a percentage of energy was similar (around 13%E) for both men and women. Both men and women consumed high amounts of carbohydrate (47–52%E). Although added sugar intake was low (< 10%E), fibre intake was moderately low, suggesting that many carbohydrate foods eaten came from refined sources, rather than from wholegrain cereals, as recommended. Both women and men consumed < 30%E from fat. Consumption of saturated fat and trans fat was significantly lower in women than men (p < 0.05, p = 0.001, respectively). Four men (18%) consumed alcohol, with one reporting consumption equivalent to 27 g per day. Only one woman (3.5%) drank alcohol. Table 4 indicates mean daily micronutrient intake for men and women. In men, the mean intake of calcium and magnesium and of vitamins C, D, E and folate was inadequate. Mean intakes of these nutrients were also inadequate in women although mean intakes of vitamin D and magnesium were only marginally low. The mean intake of iron in women was only 50% of the level recommended, while mean intakes of riboflavin, vitamin B6, pantothenate and niacin were also moderately low.

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TABLE 4. MICRONUTRIENT INTAKE OF HF PATIENTS IN RELATION TO RECOMMENDED DIETARY INTAKES Daily Difference Daily Difference Micronutrient intake from DRI intake from DRI deficiency men (%) women (%) Vitamin D (mcg) 4.5 –0.5 (90) 4.7 –0.3 (6) Vitamin C (mg) 78 –12 (87) 47 –28 (37) Magnesium (mg) 361 –59 (86) 292 –29 (9) Vitamin E (mcg) 10 –5 (67) 9 –6 (40) Calcium (mg) 655 –345 (66) 411 –789 (66) Folate (mcg) 227 –173 (57) 187 –213 (53) Iron (mg) 9 –9 (50) Riboflavin (mg) 1.0 –0.1 (9) 1.2 –0.1 (8) Vitamin B6 (mg) Pantothenate (mg) 4.6 –0.4 (8) Niacin (mg) 13.4 –0.6 (4) Potassium (mg) 1938 –0.62 (4) Adequate intake Sodium (mg) 2.372 +1 872 (470) 1 972 +1 472 (294) Potassium (mg) 2512 +0.512 (150) 6.3 +3.9 (260) 6.1 +3.7 (254) Vitamin B12 (mcg) Pantothenate (mg) 6.5 +1.5 (130) Biotin (mcg) 39 +9.0 (130) 34 +4 (13) Iron (mg) 11 +3 (125) Riboflavin (mg) 1.5 +0.2 (115) Niacin (mg) 18 +2.0 (113) 1.4 +0.1 (108) Vitamin B6 (mg) Thiamine (mg) 1.3 +0.1 (108) 1.1 0 (0) Vitamin A (RE) (mcg) 949 +49 (105) 970 +270 (39)

Fig. 1 indicates that often over half of this patient group had inadequate micronutrient consumption, while all the women and the majority of men consumed excessive amounts of sodium. Sodium intake was 470% above recommended intake levels in men and 294% above recommended intake levels in women. As seen in Fig. 2, most sodium came from bread and processed foods. In the body, the ratio of sodium (in extracellular fluid) to potassium (in intracellular fluid) is about 2:3. As seen in Table 4, the intake of potassium in relation to sodium was too low, due to the increased consumption of processed food and the inadequate intake of fruits, vegetables and unrefined cereals. The likely cost of consuming a healthy diet in Soweto was calculated based on food prices relative to minimum income support available in May 2008. Current food intake required an expenditure of approximately 40% of the current disability grant, which in 2008 was R940 per month. A recommended food intake, where maize meal porridge is supplemented with mabella (coarse), legumes, carrots, spinach, apples, oranges and fullcream milk would require an expenditure of only 30% of this benefit and therefore represents an attractive option both from a financial and health status perspective.

Discussion The most significant finding is the inadequate nutrient intake and excessive salt consumption in this high-risk HF patient cohort. Processed and convenience foods contributed to the high intake of salt as well as saturated and trans fatty acids. Low consumption of fruit and vegetables contributed to the low micronutrient and dietary fibre intake. Overall, the pattern

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100

125%

90%

Percent

67%

60 37%

108%

113%

470% 294%

87%

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66% 66%

57%

53%

40%

50%

Vit D

Vit C

Vit E

Folate

Iron

Vit B6

Niacin

Sodium

Women

Men

Fig. 1. Proportion of men and women consuming more than the recommended daily intake of sodium or with less than the daily recommended intake of selected micronutrients. Significant difference between men and women, *p < 0.01, **p < 0.001.

of dietary consumption observed is likely to have been a major contributor to the pattern of sub-optimal health outcomes (i.e. premature mortality and recurrent morbid events) found in these patients from Soweto with HF.8 High salt intake, particularly in men, was a major problem in this black urban patient group. This, related to a high consumption of bread, processed and take-away foods and the use of high-salt stock cubes and sauces, consistent with North American findings where salt in bread and pre-prepared and cereal foods contributed to around one-quarter of total salt intake.33 Possible barriers to adherence to a healthy, low-salt diet in this black population were: lack of knowledge regarding high-salt foods and healthy affordable alternatives, perceptions that meals prepared without added salt were tasteless and boring, and lack of support for dietary change from family members.34 Although a salt restriction (2–3 g/day) is standard therapy for HF,35 black Sowetans with HF commonly consumed 5–7 g per day.36 This indicates the need for higher levels of dietetic education to achieve sodium-restricted diets. At Chris Hani Baragwanath Hospital, 10 registered dieticians currently provide a nutritional service to 2 500 patients; clearly an inadequate ratio of 1:250, instead of the more acceptable ratio of 1:50.37 In contrast to the rural areas of South Africa where more ‘traditional’ food patterns still apply, in the urban areas undergoing very rapid epidemiological transition, poor quality ‘Westernised’ diets are common.26,38 The South African Dietary Guideline (SADG) addresses these nutritional issues, although compliance with recommendations is not readily achieved by

disadvantaged urban populations.38 The SADG for example recommend servings of ‘meat, fish, chicken or eggs’ should be eaten daily as nutrient-rich sources of high-quality protein. As selection of fatty meats and full-fat dairy foods can increase cardiovascular disease risk, Scholtz and colleagues39 suggest a safe daily intake would comprise: 400–500 ml milk, two to three servings of fish and four eggs, and no more than 560 g of meat per week. In this group of CHF patients, median intake is less than half this amount, presumably as these foods are not affordable. Nevertheless, the proportion of dietary protein was within accepted levels (13%E), although the majority came from plant rather than animal sources, with implications for micronutrient intake. Calcium intake, particularly in women was inadequate. Some more affordable sources of plant protein, notably legumes, rich in many nutrients, were not selected in quantity, suggesting lack of familiarity with preparing meals using these foods. The total fat intake seen in this HF cohort was within recommended levels (< 30%E) but saturated fat intake was excessive, particularly in men, and was related to choice of poor-quality fatty meat, high-fat dairy foods, cakes and biscuits, and take-away foods. This is consistent with the trend for higher total fat and saturated fat consumption seen with urbanisation throughout South Africa.40 This patient group continued to eat more traditional carbohydrate foods such as maize porridge, oats and mabella, but also consumed highly refined carbohydrate foods such as cakes, biscuits, cold drinks, sweets, chocolates and added sugar, liable to increase triglycerides and to promote

100

Men Women

Percent

80 60 40 20 0

Salt added Processed to cooked meat food

Margarine

Sauces & Take-away condiments foods

Packet soup

Bread

Salted snacks

Stock cubes

Breakfast cereal

Fig. 2. Percentage of men and women consuming the 10 foods contributing most to mean sodium intake in HF patients.

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insulin resistance and obesity.33 Fruit and vegetables provide alternative sources of carbohydrates and contain many cardioprotective nutrients,41 including potassium (lowers blood pressure), folate (reduces plasma homocysteine), vitamin C and many polyphenolic compounds (with antioxidant activities), and soluble fibre (lowers cholesterol). Green leafy vegetables are also high in magnesium (associated with a lower CVD risk). The SADG therefore recommend an intake of five to eight portions (400– 600 g) of fruit and vegetables daily.41 Black urban Sowetans with HF however, consumed only around one piece of fruit and one vegetable serving per day. Poor affordability and availability probably accounted for this low intake.41,42 The 1999 South African National Food Consumption Survey indicated that where household income was less than R12 000 per annum, few foods were found in the house (maize, salt, white sugar, tea, fat/oils, white rice and white bread were most common) and micronutrient intakes were frequently low.42 This study has several limitations. Firstly, it was a preliminary investigation, performed in a fairly homogeneous group of HF patients. The study was unable to explore the effects of gender roles (women in Soweto still buy and prepare most of the food), effects of differences in average household income, and seasonal variance or the availability of food. These factors limit the extrapolation of these data to other patient populations. It would be of interest in further studies to explore the effects of the media on exposure to Western processed foods, as well as barriers to knowledge on the selection and preparation of healthier foods. However, data presented here were meticulously collected using validated tools.

References

Conclusion

12.

This study found that urbanised black Sowetans with HF have high salt intakes and a nutrient-poor diet, placing them at high risk for deteriorating cardiac function and a premature death. Many poor households remain food insecure, which limits their ability to improve their food choices and their overall management, with potentially life-saving consequences. Nutritional education should therefore focus on foods that are varied, available, affordable, culturally acceptable and popular, as well as consistent with the low-salt, low-fat, high-fibre guidelines.43 Home cooking should also be encouraged. By not adding salt to cooking and not eating processed foods high in salt, salt intake can be reduced,35,36 while dietary compliance can be improved by encouraging use of herbs and spices and by providing recipes for appealing low-salt foods. Patient education on reading food labels and recognising high-salt foods should also be expanded. Recommendations for future research include, therefore, sustainable, practical self-management programmes for black patients with HF living in developing urban areas, where their socio-economic circumstances often remain poor. When combined with other aspects of culturally specific multidisciplinary care, the positive impact of such programmes is likely to be profound. The Heart of Soweto registry is supported by unconditional research grants from Adcock-Ingram, the Medtronic Foundation and Servier. SP is supported by the University of the Witwatersrand and is the recipient of an NIH/Wits Non-Communicable Diseases Leadership Training award.

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hospital re-admission in older patients with heart failure: a systematic review and meta-analysis of published reports. Eur Heart J 2004; 25: 1570–1595. Arcand JA, Brazel S, Joliffe C, Choleva M, Berkoff F, Allard P, et al. Education by a dietitian in patients with heart failure results in improved adherence with a sodium-restricted diet: a randomized trial. Am Heart J 2005; 150: 716. Steyn NP. Nutrition and chronic diseases of lifestyle in South Africa. In: Chronic Diseases of Lifestyle in South Africa: 1995–2005. Cape Town: South African Medical Research Council, 2006: 33–47. Vorster HH, Kruger A, Venter CS, Margetts BM, MacIntyre UE. Cardiovascular disease risk factors and socio-economic position of Africans in transition: the THUSA study. Cardiovasc J Afr 2007; 18(5): 282–289. Nel JH, Steyn NP. Report on South African food consumption studies undertaken amongst different population groups (1983–2000): Average intakes of foods most commonly consumed. Pretoria: Department of Health, 2002. Bourne LT, Steyn K. Rural/urban nutrition-related differentials among adult population groups in South Africa, with special emphasis on the black population. S Afr J Clin Nutr 2000; 13(1): S23–S28. Vorster HH, Kruger. Poverty, malnutrition, underdevelopment and cardiovascular disease: a South African perspective. Cardiovasc J Afr 2007; 18(5): 321–324. Cleland J, Dargie H, Drexler H, Follath F, Komajda K, Smiseth OA, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 1115–1140. MacIntyre UE, Venter CS, Vorster HH. A culture-sensitive quantitative food frequency questionnaire used in an African population: 1. Development and reproducibility. Pub Hlth Nutr 2001; 4: 53–62. MacIntyre UE, Venter CS , Vorster HH. A culture-sensitive quantitative food frequency questionnaire used in an African population: 2. Relative validation by 7-day weighted records and biomarkers. Publ Hlth Nutr 2001; 4: 63–71.

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31. Katzenellenbogen JM, Joubert G, Abdool Karim SS. Epidemiology, A Manual for South Africa, 6th edn. Cape Town: Oxford University Press, 2004. 32. Vorster HH, Nell TA. Make starchy foods the basis of most meals. S. Afr J Clin Nutr 2001; 14(Suppl): S17–S24. 33. Slavin JL, Jacobs D, Marquart L, Wiemer K. The role of whole grains in disease prevention. J Am Diet Assoc 2001; 101: 780–785. 34. Colonna P, Sorino M, D’Agostino C, Bovenzi F, De Luca L, Arrigo F, et al. Nonpharmacological care of heart failure: counseling, dietary restriction, rehabilitation, treatment of sleep apnea, and ultrafiltration. Am J Cardiol 2003; 91(Suppl): 41F–50F. 35. Selektor Y, Weber KT. The salt-avid state of congestive heart failure revisited. Am J Med Sci 2008; 335: 209–218. 36. Charlton KE, Jooste PL. Eat salt sparingly – sprinkle, don’t shake! S Afr J Clin Nutr 2001: 14(Suppl): S55–S64. 37. Compher C, Colaizzo T. Staffing patterns in hospital clinical dietetics and nutrition support: a survey conducted by the Dietitians in Nutrition Support dietetic practice group. J Am Diet Assoc 1992; 92(7): 807–812. 38. Vorster HH, Love P, Browne C. Development of food-based dietary guidelines for South Africa – the process. S Afr J Clin Nutr 2001; 14(Suppl): S3–S6. 39. Scholtz SC, Vorster HH jr, Matshego L, Vorster HH. Foods from animals can be eaten every day – not a conundrum! S Afr J Clin Nutr 2001; 14(Suppl): S39–S47. 40. Wolmarans P, Oosthuizen W. Eat fats sparingly – implications for health and disease. S Afr J Clin Nutr 2001; 14(Suppl): S48–S55. 41. Love P, Sayed N. Eat plenty of vegetables and fruits everyday. S Afr J Clin Nutr 2001; 14(Suppl): S24–S32. 42. Maunder EMW, Matji J, Hlatshwayo-Molea T. Enjoy a variety of foods – difficult but necessary in developing countries. S Afr J Clin Nutr 2001; 14(Suppl): S7–S11. 43. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, et al. American Heart Association Nutrition Committee. Diet and Lifestyle Recommendations, revision 2006: A Scientific Statement from the American Heart Association Nutrition Committee. Circulation 2006; 114: 82–96.

Cardiovascular congress diary Date

Conference

Venue

Contact details to register

8–9 June

CCC 2012 – Cardiovascular Complications Conference

Frankfurt, Germany

www.complications2012.org

22–24 June

PAIN SA Congress

CSIR International Convention Centre, Pretoria

www.painsa.co.za

27 June

ICI 2012 – Imaging in Cardiovascular Interventions

Frankfurt, Germany

www.ici-congress.org

28–30 June

CSI 2012 – Catheter Interventions in Congenital & Structural Heart Disease Frankfurt, Germany

www.csi-congress.org

9–12 July

18th World Congress of the International Society for the Study of Hypertension in Pregnancy

Geneva, Switzerland

www.isshp2012.com

13–15 July

ASEAN Federation of Cardiology Congress (AFCC)

Singapore

www.afcc2012.com

19–22 Jul y

13th Annual SA Heart Congress

Sun City, South Africa

www.saheart.org

2012 ESC, European Society of Cardiology Congress

Munich, Germany

www.escardio.org

Trend 2012 Asia–Pacific

Hong Kong

www.csi-trend.org

5 October

New Horizons in Echocardiography

Sandton, South Africa

baraecho@gmail.com

10–13 October

8th World Stroke Congress

Brasilia, Brazil

www.2.kenes.com/stroke/pages/home.aspx

20 October

The Many Faces of AF symposium

Cape Town, South Africa

franciska@cassa.co.za

20–22 October

Acute Cardiac Care

Istanbul, Turkey

www.escardio.org

24 October

The Many Faces of AF symposium

Durban, South Africa

franciska@cassa.co.za

27 October

The Many Faces of AF symposium

Johannesburg, South Africa

franciska@cassa.co.za

3–7 November

American Heart Association Scientific Sessions

Los Angeles, US

www.americanheart.org

16–17 November

LAA 2012

Frankfurt, Germany

www.csi-laa.org

The 16th Annual EUROECHO and other imaging modalities

Athens, Greece

www.euroecho.org

JUNE 2012

JULY 2012

AUGUST 2012 25–29 August SEPTEMBER 2012 29 September OCTOBER 2012

NOVEMBER 2012

DECEMBER 2012 5–8 December

To advertise your conference/meeting, e-mail details and half page pdf advert to wendy@clinicscardive.com

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Treatment of subaortic stenosis in hearts with singleventricle physiology BULENT SARITAS, EMRE OZKER, CAN VURAN, ÇAĞRI GUNAYDIN, CANAN AYABAKAN, RIZA TURKOZ

Abstract Background: We evaluated the patients who had had a Damus-Kaye-Stansel (DKS) operation for single-ventricular physiology with the aorta originating from a hypoplastic ventricle and the pulmonary artery from the systemic ventricle. Methods: Seven patients who were operated on between May 2007 and November 2010 were evaluated retrospectively. The patients had been diagnosed with a transposed doubleinlet left ventricle and triscuspid atresia, and had been waiting for a Fontan operation. Systemic outflow stenosis was defined echocardiographically as those with a gradient greater than 20 mmHg, and angiographically those with greater than 5 mmHg in the subaortic region. Results: The mean age and weight of the patients was 15 ± 9.7 months and 8 ± 3.3 kg, respectively. The mean gradient between the systemic ventricle and the aorta was 35 ± 25 mmHg. This gradient decreased to 14.3 ± 4 mmHg postoperatively. The early hospital mortality was 14% (one patient). The mean extubation time and mean time in the intensive care unit (ICU) were 13 ± 7.3 hours and 2.2 ± 0.5 days, respectively. The mean follow-up time was 11 ± 2 months. No mortality and semi-lunar valve insufficiency were observed after discharge. Conclusions: One of the major problems that occur while waiting for a Fontan operation is systemic ventricular hypertrophy and deterioration in the compliance of the ventricle due to systemic ventricular outflow stenosis. When the disadvantages of outflow resection are encountered, a DKS proves to be a good alternative. Keywords: pulmonary artery band, univentricular heart, Fontan procedure, subaortic stenosis Submitted 11/4/110, accepted 31/5/11 Cardiovasc J Afr 2012; 23: 252–254

www.cvja.co.za

DOI: 10.5830/CVJA-2011-023

In patients with a double-inlet left ventricle (DILV) or tricuspid atresia (TA) where the aorta originates from the hypoplastic

Department of Cardiovascular Surgery, Baskent University Hospital, Istanbul, Turkey BULENT SARITAS, MD, bsaritas@hotmail.com EMRE OZKER, MD CAN VURAN, MD ÇAĞRI GUNAYDIN, MD RIZA TURKOZ, MD

Department of Paediatric Cardiology, Baskent University Hospital, Istanbul, Turkey CANAN AYABAKAN, MD

ventricle, the interventricular connection that is present at birth may narrow in time.1 There is increased pulmonary blood flow in DILV and TA patients with accompanying aortic arch pathology. In order to prevent pulmonary vascular disease, pulmonary artery banding is often preferred as a palliative procedure. However, ventricular hypertrophy caused by the pulmonary band may lead to narrowing of the interventricular connection.2-4 A restrictive ventricular septal defect (VSD) restricts flow from the systemic ventricle to the aorta, hence leading to progression of subaortic stenosis. Enlarging the interventricular connection either by resection or by performing a Damus-Kaye-Stansel operation are the two most applied techniques.5 We present cases of DILV or TA patients who were found to have subaortic stenosis in their clinical follow up and underwent DKS operations.

Methods Seven patients underwent DKS operations between May 2007 and November 2010. These patients had DILV and TA without any chance of bi-ventricular repair and had developed subaortic stenosis while they were waiting for Fontan operations. For the purpose of this study, we defined systemic outflow obstruction as a resting peak instantaneous gradient greater than 20 mmHg on echocardiography or a resting peak-to-peak gradient greater than 5 mmHg with cardiac catheterisation. Systemic outflow obstruction was considered clinically significant if the patient had findings of left ventricular hypertrophy. Three patients had concomitant bi-directional cava-pulmonary connection (BCPC) operations and one patient had a central shunt operation at the time of the DKS operation. All patients were evaluated in terms of postoperative surgical morbidity and mortality, the degree of subaortic stenosis, ventricle function and rate of re-operation, and semi-lunar valve insufficiency.

Surgical procedures Pulmonary artery banding: three patients with excessive pulmonary blood flow related to a hypoplastic aorta and the pulmonary artery originating from a non-hypoplastic ventricle underwent a pulmonary artery banding operation through an antero-lateral thoracotomy. One patient also had a Blalock-Hanlon atrial septectomy in addition to pulmonary artery banding, through a median sternotomy. The pulmonary band is tightened until the pressure distal to the band decreases to half of the systemic pressure. Among these four patients on whom palliative pulmonary band operations were performed, one patient died in the early postoperative period. The other three patients were followed up. The mean age and weight of these four patients was 22 ± 12 days and 3.1 ± 1.9 kg, respectively. Bi-directional cava-pulmonary connection: three patients with balanced pulmonary blood flow underwent BCPC operation. The operations were performed under cardiopulmonary bypass.

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012

The main pulmonary arteries were tied up in all patients. The mean age and weight of the patients was 6 ± 2.1 months and 8 ± 3.4 kg, respectively. Damus-Kaye-Stansel procedure: the decision to do a DKS operation was taken for seven patients who had subaortic stenosis in the follow-up period. An 11-day-old patient with pulmonary stenosis and restrictive interventricular connection underwent a DKS and central shunt operation. The procedure was performed under cardiopulmonary bypass and cardiac arrest by the same surgical team. Cardiopulmonary bypass was achieved with aortic and bi-caval cannulation. In patients in whom BCPC operations were planned, the innominate veins were cannulated. In these patients BCPC operations were performed without the use of aortic cross clamping. Cardiac arrest was maintained with antegrade intermittent normothermic blood cardioplegia using the miniplegia technique. After removing the pulmonary band, which was placed in the initial operation, the pulmonary artery and the aorta were transected. The distal pulmonary artery orifice was closed either with a patch or primarily, according to the orifice diameter. Then the adjacent walls of the pulmonary artery and aorta were joined. The two facing sinuses of both great vessels were sewn together. In order to prevent a mismatch between the diameter of the new artery and the distal aorta, the anterior side of the distal aorta was incised 3 to 4 mm. The new artery was sewn to the distal aorta.

Results The demographic data are shown in Table 1. The early hospital mortality was 14% (one patient). After the DKS operation, the pulmonary blood flow was maintained with a BCPC operation in six patients, and with a central shunt in one patient. The 11-day-old patient with transposed TA who underwent DKS and central shunt procedures was taken to ICU with a left ventricular assist device. The patient could not be weaned from high doses of inotropic support and died on the fifth postoperative day due to septicaemia and low cardiac output. The rest of the patients had an uneventful postoperative course. The mean extubation time and stay in ICU were 13 ± 7.3 hours and 2.2 ± 0.5 days, respectively. The mean duration between the first palliative operation and the DKS operation was 6 ± 1.8 months. There was no statistical difference between patients who had pulmonary banding and patients who had BCPC operations, in terms of timing of the DKS procedure.

TABLE 1. PRE-OPERATIVE AND PERI-OPERATIVE FINDINGS OF THE PATIENTS Age (month) 15 ± 9.7 Weight (kg) 8 ± 3.3 1.88 ± 1.18 IVC area index (cm2/m2) Systemic ventricular pressure (mmHg) 132 ± 43 Aortic pressure (mmHg) 91 ± 14 Gradient (mmHg) 35 ± 25 CPB time (min) 113 ± 28 ACC (min) 39 ± 14 IVC: interventricular connection, CPB: cardio-pulmonary bypass, ACC: aortic cross clamp.

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When the pulmonary arteries which had been tied up in order to create pulmonary atresia in the initial BCPC operation were transected during the DKS operation, no malformation was observed in the pulmonary valve. However, there was a thrombus on the pulmonary valve in two patients. When the thrombi were removed, the valve structures were found to be normal. All six patients were discharged home on the sixth postoperative day in a good condition. The mean duration of follow up was 11 ± 1.2 months. There was no mortality in the interim. In routine follow-up echocardiographical measurements, the mean gradient in the systemic ventricular outflow tract was 14.3 ± 4 mmHg. No semilunar valve insufficiency was observed in the follow up. None of the patients was re-hospitalised and none of those awaiting a Fontan operation needed re-operation.

Discussion Double-inlet left ventricle and tricuspid atresia with transposed great arteries (TA-TGA) are two forms of a single left ventricle at risk of developing systemic outflow obstruction and poor outcomes.2 In these patients, the only way that blood can be delivered to the aorta is through the VSD. Even when the VSD is non-restrictive at birth, it may narrow over time and hence subaortic obstruction becomes apparent.1 On the other hand, in patients with distal aortic arch anomalies, pulmonary vascular disease may develop due to the excessive pulmonary flow.2,3 In these patients, in order to reduce pulmonary blood flow, palliative treatment strategies have been established and pulmonary artery banding is the most common method used. However, since banding induces ventricular hypertrophy, the VSD becomes restrictive and subaortic stenosis develops.4 The restrictive VSD limits the flow of blood from the systemic ventricle to the aorta and reduces cardiac output. In addition, ventricular hypertrophy leads to the decrease in the compliance of the systemic ventricle. In patients awaiting a Fontan operation, the ventricle with impaired compliance is unable to maintain the Fontan circulation.5 Franklin and colleagues reported 11% survival rate at 10 years in patients with excessive pulmonary blood flow and systemic outflow obstruction. They also reported 79% survival rate at 10 years in patients with pulmonary stenosis without subaortic stenosis.6 Therefore, subaortic stenosis should be corrected surgically as early as possible. In order to achieve this goal, the most commonly used methods are BVF resection and a DKS operation. Direct BVF resection was found to have a high incidence of atrio-ventricular block and high mortality rates.7 Lan and colleagues reported 15 complete heart blocks in 44 subaortic resection patients and found that pacemaker requirement and the presence of tachyarrhythmia were important risk factors for mortality.2 Postoperative semi-lunar valve insufficiency is the most important disadvantage of the DKS operation. Matitiau and colleagues reported a 10% rate of postoperative semi-lunar valve insufficiency. In our echocardiographical evaluations, we did not detect any semi-lunar valve insufficiency and measured mild gradients between the systemic ventricle and aorta. However our mean duration of follow up was not long enough. There has been no consensus on the optimal timing of

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surgery to relieve the systemic outflow obstruction in transposed DILV and TA patients who have developed subaortic stenosis after pulmonary banding. However, Fiore and colleagues recommended performing the operation between the third and sixth month in order to prevent ventricular hypertrophy and related development of compensatory diastolic dysfunction.1 In our study group, this interval was approximately six months. This period is appropriate to perform DKS and concomitant BCPC operations, and there is then no need for a second operation to perform a BCPC. Furthermore, in cases where pulmonary blood flow is supplied by systemic-to-pulmonary artery shunt, low diastolic blood pressure and overload may worsen ventricular function.

References 1.

Conclusion In univentricular hearts with narrow interventricular connection, subaortic stenosis increases over time. Relieving the stenosis in the interventricular connection before the dominant ventricle’s function deteriorates is important to do ahead of the Fontan operation. This stenosis can be corrected safely with a DKS operation.

Fiore AC, Rodefeld M, ViJay P, et al. Subaortic obstruction in univentricular heart: results using the double barrel Damus-Kaye Stansel operation. Eur J Cardiothorac Surg 2009; 35(1): 141–148. Lan YT, Chang RK, Laks H. Outcome of patients with double-inlet left ventricle or tricuspit atresia with transposed great arteries. J Am Coll Cardiol 2004; 43(1): 113–119. Ilbawi MN, Deleon SY, Wilson WR, et al. Advantages of early relief of subaortic stenosis in single ventricle equivalents. Ann Thorac Surg 1991; 52: 842–849. Freedom RM, Benson LN, Smallhorn JF, Williams WG, Trusler GA, Rowe RD. Subaortic stenosis, the univentricular heart and banding of the pulmonary artery: an analysis of the courses of 43 patients with univentricular heart palliated by pulmonary artery banding. Circulation 1986; 73: 758–764. Pass RH, Solowiejczyk DE, Quaegebeur JM, et al. Bulboventricular foramen resection: hemodynamic and electrophysiologic results. Ann Thorac Surg 2001; 71: 1251–1254. Franclin RC, Spiegelhalter DJ, Anderson RH, et al. Double-inlet ventricle presenting in infancy. I. Survival without definitive repair. J Thorac Cardiovasc Surg 1991; 101: 767–776. Matitiau A, Geva T, Colan SD, et al. Bulboventricular foramen size in infants with double inlet left ventricle or tricuspit atresia with transposed great arteries: influence on initial palliative operation and rate of growth. J Am Coll Cardiol 1992; 19(1): 142–148.

DAKAR

Contact : BP : 6003 Dakar Tél : (221) 33 821 55 21 (221) 33 889 38 00 Poste : 3900 Fax : (221) 33 822 47 46 Mail: cardiodantec@orange.sn

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www.pascar.co.za www.sosecar.org

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Early diastolic functional abnormalities in normotensive offspring of Nigerian hypertensives AM ADEOYE, AA ADEBIYI, OO OLADAPO, OS OGAH, A AJE, DB OJJI, AK ADEBAYO, KC OCHULOR, EO ENAKPENE, AO FALASE

Abstract

Keywords: diastolic function, offspring, hypertension, Nigerian

Background: Some studies have suggested that diastolic dysfunction precedes the clinical manifestation of hypertension. Whether changes in cardiac structure and function predate the clinical manifestation of hypertension later in life is now being investigated. The aim of this study was to assess the differences in cardiac structure and function between the offspring of hypertensive and normotensive parents. Methods: Eighty normotensive offspring of hypertensive parents (OHyp) (41 females and 39 males) and 62 normotensive offspring of normotensive parents (ONorm) (31 males and 31 females) were recruited for echocardiography. Results: The mean age was 25.0 (5.31) and 24.3 (3.60) years in the OHyp and ONorm participants, respectively (p = 0.369). Other baseline parameters were comparable between the two groups. Septal wall thickness in systole was higher in the OHyp than the ONorm subjects [1.3 (0.35) vs 1.1 (0.25), p = 0.0173]. Indexed left ventricular mass [28.1 (7.33) vs 27.5 (7.23), p = 0.631] and relative wall thickness [(0.3 (0.10) vs 0.3 (0.90), p = 0.280] were similar in the two groups. The offspring of hypertensives had lower deceleration time [149.9 (38.89) vs 169.0 (50.08) ms, p = 0.012], prolonged duration of pulmonary A reverse flow [113.5 (70.69) vs 81.7 (38.31) ms, p = 0.024], increased myocardial isovolumic relaxation time [173.4 (47.98) vs 156.1 (46.74) ms, p = 0.033] and a lower myocardial Em [0.2 (0.05) vs 0.3 (1.38), p = 0.037] and myocardial Em/Am ratio [1.6 (0.01) vs 2.1 (0.01), p = 0.019] than the offspring of normotensives. Conclusion: This study showed that offspring of OHyp subjects had early diastolic functional abnormalities when compared with offspring of ONorm participants. Longitudinal studies are needed to determine the implications of this finding in this African population.

Submitted 17/8/09, accepted 6/6/11

Department of Medicine, University College Hospital, Ibadan, Nigeria

AM ADEOYE, MBBS, FWACP, adeoyemoshood@yahoo.com AA ADEBIYI, MBBS, FWACP OO OLADAPO, MBBS, MSc, FWACP OS OGAH, MBBS, MSc, FWACP A AJE, MBBS, FMCP DB OJJI, MBBS, FWACP AK ADEBAYO, MBBS, FMCP, FWACP KC OCHULOR, MBBS, FMCP EO ENAKPENE, MBBS, MSc, FMCP, FWACP AO FALASE, MBBS, MD, FMCP, FWACP, FRCP

Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria

AM ADEOYE, MBBS, FWACP AA ADEBIYI, MBBS, FWACP OO OLADAPO, MBBS, MSc, FWACP AO FALASE, MBBS, MD, FMCP, FWACP, FRCP

Cardiovasc J Afr 2012; 23: 255â&#x20AC;&#x201C;259

www.cvja.co.za

DOI: 10.5830/CVJA-2011-030

Worldwide, hypertension is an independent risk factor for cardiovascular morbidity and mortality.1 Hypertension is the most common non-communicable disease in Nigeria, a typical example of a developing country. Despite innovations in the drug-related management of hypertension, control remains poor.2 Less than a third of individuals with a usual blood pressure exceeding 140/90 mmHg are adequately treated.3 For this reason, global approaches now tend to focus on lifestyle changes and studies directed at the aetiopathogenesis of hypertension. The aim is to find markers for the early detection of hypertension so as to initiate preventive as well as control measures as widely as possible. Studies on offspring of hypertensive patients have shown the significant roles of heredity, salt intake, increased peripheral vascular resistance, insulin resistance and increased left ventricular (LV) mass in the pathogenesis of hypertension.4-6 Increased LV mass and diastolic dysfunction can be either a consequence of hypertension or precede the clinical manifestation of hypertension.7-10 Diastolic dysfunction has been demonstrated in borderline hypertensive and normotensive offspring of hypertensive patients in the absence of increased LV mass.10-16 Since most of these studies have been carried out in Europe and America, little is known about LV filling patterns in the offspring of hypertensive Nigerians, in a country with increasing prevalence of hypertension, as are most other African countries. This study therefore aimed to determine LV diastolic filling patterns in normotensive offspring of hypertensive Nigerians in comparison with normotensive control subjects without a family history of hypertension.

Methods The study was carried out at the cardiology unit of the Department of Medicine of the University College Hospital, Ibadan, Nigeria. Eighty normotensive offspring aged 18 to 40 years with hypertensive parents attending the cardiac clinic of the Hospital were recruited over a six-month period. Subjects were offspring of consecutive hypertensive parents seen at the medical outpatient department. Comparable control subjects were recruited among the children of normotensive hospital staff and relatives of patients on treatment for conditions other than hypertension or other chronic medical conditions. Ethical approval was obtained from the institutional ethics review board and informed consent was obtained from each participant. Blood pressure was measured with a mercury sphygmomanometer (Accosson) according to standard

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guidelines.17 Systolic and diastolic blood pressure was measured at Korotokoff sound phases 1 and V, respectively. Subjects with blood pressure higher than 140/90 mm/Hg and body mass index (BMI) above 25 kg/m2 were excluded from the study. Other exclusion criteria were existing heart disease and diabetes mellitus. Echocardiographic examination was performed with the subjects in partial left lateral decubitus position using an Aloka SSD1700 machine (Aloka Co. Ltd, Tokyo, Japan) with a 3.5-MHz transducer. Two-dimensional guided M-mode measurements were obtained as recommended by the American Society of Echocardiography.18 Left ventricular (LV), septal, posterior wall thickness and cavity dimensions were measured using leadingedge methodology at both end-diastole and end-systole. Left ventricular mass (LVM) was calculated using the formula of Devereux and Reichek.19 This has been shown to yield LVM closely related to autopsy measurements (r = 0.90),20 and had good inter-observer reproducibility (p = 0.93) in one study.21 LVM was indexed by the allometric power of height (LVM/ Ht2.7).22 Left ventricular hypertrophy was considered present if the left ventricular mass index (LVMI) was ≥ 46 g/m2.7. Relative wall thickness (RWT) was calculated as 2RWTd/LVIDd (left ventricular internal diameter).7 Increased wall thickness was present when RWT > 0.45.23 Ejection fraction was calculated using the formula of Teichholz.24 Doppler echocardiography was used for transmitral flow velocities, obtained with the Doppler sample volume placed just beyond the tip of the mitral valve leaflets. The parameters measured were early diastolic peak flow velocity (E), early diastolic flow time (EDFT), late diastolic peak flow velocity (A), late diastolic flow time (ADFT), the deceleration time of early mitral velocity, and the ratio of E to A (E/A). Isovolumic relaxation time (IVRT) was measured with the pulse-wave Doppler beam intersecting the LV outflow and inflow tracts. EDFT was measured from the onset of diastolic flow to the intersection of a line extrapolated to the baseline, and ADFT was measured from the onset of late diastolic flow to the end of diastolic flow.25 Pulmonary venous flow recordings were obtained from a four-chamber view directed at the right upper pulmonary vein. The sample volume was placed 1–2 cm into the pulmonary vein and the following measurement were recorded: peak S-wave velocity (peak systolic pulmonary venous inflow velocity during ventricular systole), peak D-wave velocity (peak diastolic pulmonary venous inflow velocity during early phase of diastole), peak AR-wave velocity (peak reversed systolic wave during atrial contraction), and duration of the reverse atrial contraction-induced diastolic flow.26 Myocardial Doppler velocities were measured in the apical four-chamber view with the Doppler beam well aligned to the septum and the pulsed Doppler sample volume placed 1 cm apically from the mitral annulus in the interventricular septal myocardium. The following measurements were made: myocardial isovolumic contraction time, myocardial peak systolic velocity (Sm), myocardial contraction time, myocardial isovolumetric relaxation time, myocardial early diastolic relaxation velocity (Em), and myocardial late relaxation velocity (Am). Other measurements were the duration of the diastolic period and the durations of Em and Am. Measurements from three cardiac cycles were taken and averaged.

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The calculation of the sample size for this study was based on a difference of 0.2 in the mitral E/A ratio between the controls and the subjects, with a 90% power to detect the difference at a significance level of 0.05 in a two-tailed test. The estimated sample size was 63 subjects per group. [This was based on data from a previous study where LVM (± SD) in hypertensive and normotensive offspring was 125 (29) and 109 (25) g, respectively.]27

Statistical analysis All data generated were entered into a standard proforma. SPSS software, version 10.0 (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Continuous variables were expressed as mean (standard deviation). Differences in continuous variables between the groups were assessed with a t-test for independent groups. Where data were not normal, the Mann-Whitney test was used to compare the two groups. Data were adjusted for covariates using analysis of covariance. A two-tailed p-value < 0.05 was considered significant.

Results Table 1 shows the baseline characteristics of the participants (subjects and controls). Systolic and diastolic pressure, mean arterial pressure, age, height and body mass index were comparable in the two groups. The cardiac structure and systolic functional data are listed in Table 2. Apart from the left atrial diameter and septal wall thickness at systole that was greater in the offspring of hypertensive subjects, relative LV wall thickness, LVM, LVMI, aortic root diameter, left atrial diameter, LV internal diameters and LV ejection fraction were similar in both groups. Table 3 shows the echocardiographic diastolic functional indices in both groups. The duration of the E wave and pulmonary A reversal flow was significantly higher in the offspring of hypertensive subjects than in the controls. The deceleration time of the E wave (DT) was lower in offspring of hypertensive subjects. Table 4 shows the measured tissue Doppler parameters. Offspring of hypertensive subjects had a higher myocardial isovolumetric relaxation time as well as a lower myocardial E TABLE 1: BASELINE CHARACTERISTICS OF THE SUBJECTS Offspring of hypertensive parents (n = 80)

Offspring of normotensive parents (n = 62)

Age (years)

25.0 (5.31)

24.3 (3.60)

0.369

Weight (kg)

64.2 (10.87)

63.2 (9.93)

0.565 0.856

Characteristics

p-value

Height (cm)

1.7 (0.10)

Body mass index (kg/m2)

22.9 (3.07)

22.6 (2.51)

0.499

1.7 (0.18)

1.7 (0.17)

0.659

Body surface area (m ) Waist circumference (cm)

79.8 (9.12)

77.6 (7.21)

0.177

Hip circumference (cm)

97.2 (8.78)

94.6 (8.85)

0.121

Waist–hip ratio Systolic blood pressure (mmHg)

0.8 (0.05)

0.8 (0.07)

0.838

115.0 (12.88)

111.7 (10.08)

0.122

Diastolic blood pressure (mmHg)

72.8 (8.57)

70.5 (8.76)

0.131

Pulse pressure (mmHg)

42.2 (11.35)

41.2 (10.19)

0.789

Mean arterial pressure (mmHg)

86.9 (8.70)

84.3 (7.87)

0.067

Heart rate

76.6 (12.90)

76.8 (12.30)

0.909

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TABLE 2. MEASURED ECHOCARDIOGRAPHIC CHARACTERISTICS

TABLE 3. ECHOCARDIOGRAPHIC DOPPLER INDICES OF LV DIASTOLIC FUNCTION IN SUBJECTS AND CONTROLS

Offspring of hypertensive parents (n = 80)

Offspring of normotensive parents (n = 62)

p-value

Adjusted p-value

Aortic root diameter

2.5 (0.29)

2.5 (0.27)

0.880

0.655

Transmitral E wave (m/s)

0.938

0.809

Left atrial diameter

3.1 (0.43)

3.0 (0.45)

0.197

0.042*

Duration of E wave (ms)

207.3 (45.35) 228.7 (50.40)

0.009*

0.020

IVSTd

0.9 (0.19)

0.642

0.989

149.9 (38.89) 169.0 (50.08)

0.012*

0.025

IVSTs

1.3 (0.35)

1.1 (0.25)

0.017*

0.038*

Deceleration time of E wave (ms)

PWTd

0.7 (0.18)

0.7 (0.17)

0.248

0.658

A-wave velocity (m/s)

0.123

0.100

Isovolumetric relaxation time (IVRT)

0.378

0.148

Variable (cm)

PWTs

1.1 (0.25)

1.2 (0.24)

0.100

0.108

LVIDd

4.4 (0.47)

4.3 (0.47)

0.811

0.151

LVIDs

2.8 (0.46)

2.8 (0.38)

0.919

0.844

Fractional shortening (%)

35.0 (7.60)

35.0 (5.90)

0.585

0.180

Ejection fraction (%)

64.0 (9.80)

63.0 (7.80)

0.734

0.220

Ejection time (ms)

357.0 (46.20)

375.0 (45.80)

0.042*

0.043*

Absolute LVM (g)

112.6 (31.60)

110.7 (33.90)

0.736

0.212

28.1 (7.33)

27.5(7.23)

0.631

0.129

0.3 (0.09)

0.3 (0.08)

0.280

0.277

LVM/Ht (g/m2.7) RWT

LVM = left ventricular mass, BSA = body surface area, RWT = relative wall thickness, Ht = height. *Statistically significant. Data adjusted for age, systolic blood pressure, diastolic blood pressure, body surface area and body mass index.

velocity and E/A ratio. The diastolic period was also longer in the OHyp subjects compared to controls. Among the male gender, statistical differences were found in only some echocardiographic parameters. Hypertensive vs normotensive offspring: left atrial diameter [3.20 (0.42) vs 2.93 (0.44) cm, p = 0.012]; posterior wall thickness in systole [1.13 (0.26) vs 1.29 (0.21) cm, p = 0.008]; and deceleration time of the E wave [180.8 (60.2) vs 152.7 (44.6) ms, p = 0.034]. On the other hand, among the females, statistical differences were found in some of the physical and echocardiographic parameters. Hypertensive vs normotensive offspring: height [1.64 (0.08) vs 1.60 (0.05) m, p = 0.032]; body surface area [1.66 (0.17) vs 1.59 (0.13) m2, p = 0.040]; diastolic blood pressure [71.1 (8.3) vs 671.(7.5) mmHg, p = 0.040]; mean arterial blood pressure [84.5 (9.0) vs 80.6 (6.5) mmHg, p = 0.040]; duration of the medial annulus IVRT [178.0 (55.4) vs 151.2 (54.5) ms, p = 0.045]. TABLE 4. TISSUE DOPPLER INDEXES AT THE MEDIAL (SEPTAL) MITRAL VALVE ANNULUS

Variable (medial annulus)

Offspring of hypertensive parents (n = 80)

Offspring of normotensive parents (n = 62)

p-value

Adjusted p-value

Medial Sm (m/s)

0.1 (0.02)

0.1 (0.04)

0.970

0.940

Medial Em (m/s)

0.2 (0.05)

0.3 (1.38)

0.037*

0.348

Medial Am (m/sec)

0.1 (0.03)

0.844

0.882

Medial Em/Am

1.6 (0.01)

2.1 (0.01)

0.019*

0.028

Duration of Sm (ms)

210.9 (40.58)

201.6 (42.06)

0.186

0.187

Duration of Em (ms)

133.7 (28.87)

128.0 (26.05)

0.227

0.156

Duration of Am (ms)

85.4 (18.40)

85.1 (27.06)

0.954

0.860

0.424

0.390

Duration of diastolic period (ms)

420.6 (136.89) 401.8 (139.32)

Isovolumetric relaxation 156.1 (46.74) time (IVRT) (ms)

173.4 (47.98)

0.033*

0.031

Isovolumetric contraction time (IVCT) (ms)

113.5 (38.01)

0.731

0.740

115.9 (44.09)

Variable

Offspring of hypertensive parents (n = 80) 0.7 (0.17)

0.4 (0.13)

Offspring of normotensive parents (n = 62) p-value 0.7 (0.13)

0.4 (0.09)

121.0 (30.82) 113.8 (23.14)

Adjusted p-value

E/A ratio

1.9 (0.51)

2.1 (0.61)

0.062

0.122

Pulmonary S wave (m/s)

0.5 (0.18)

0.4 (0.17)

0.848

0.937

Pulmonary D wave (m/s)

0.3 (0.10)

0.740

0.655

S/D ratio

1.5 (.0.44)

1.5 (0.54)

0.820

0.965

Pulmonary A wave (m/s)

0.2 (0.09)

0.2 (0.06)

0.652

0.545

Duration A reverse wave (ms)

113.5 (70.69)

81.7 (49.31)

0.024*

0.067

*Statistically significant. Data adjusted for age, systolic blood pressure, diastolic blood pressure, body surface area and body mass index.

Discussion This study shows that normotensive offspring of hypertensive Nigerians had abnormal diastolic functional parameters compared with normotensive control subjects without a family history of hypertension. The changes in left ventricular filling dynamics and an increased left ventricular mass occurred early in the development of systemic hypertension. Increased left ventricular mass and diastolic dysfunction have been demonstrated in the early stages of hypertension, in the stage of prehypertension, and in hypertensive subjects without left ventricular hypertrophy. In this study, the offspring of hypertensive subjects showed features of early diastolic dysfunction even in the absence of increased left ventricular mass. This was demonstrated by significantly higher deceleration time of E, as well as a prolonged diastolic period, assessed by tissue Doppler. Impaired relaxation is conventionally associated with increased A velocity, and reduced E/A ratio. Our finding was similar to the work of Graettinger et al.16 who also demonstrated that the flow time and the time integral of the A wave were higher in the offspring of hypertensives, implying a shift towards late diastolic filing. Pulmonary vein flow parameters are useful non-invasive methods of assessment of LV diastolic function. The present study showed prolonged duration of the A reverse flow (Ar) in the offspring of hypertensives. Prolonged Ar duration is associated with impaired relaxation, as well as reduced preload.28 There were no demonstrable changes in the loading condition, hence the prolonged duration of Ar can only be explained by impaired relaxation. Transmitral inflow measurements may be affected by age, BMI, LV mass, and heart rate but all these variables were comparable in the two groups,29-31 and were corrected for. Tissue Doppler imaging is a non-invasive and easily reproducible method of assessment of left ventricular function. The parameters are less influenced by preload changes compared with transmitral and pulmonary vein flow measurements and also believed to be more sensitive than the convectional Doppler methods. Our septal myocardial tissue Doppler measurements showed reduced Em and Em/Am ratio and increased IVRT in the offspring of hypertensives. These findings are indicative of

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diastolic dysfunction and were similar to those of Aeschbacher et al.32 in their prospective study of the offspring of hypertensive subjects, particularly offspring who became hypertensive after five years of follow up. In an earlier study by the same group,33 on offspring of hypertensives, there was no evidence of diastolic dysfunction using conventional Doppler methods. At follow up, pulmonary vein flow and myocardial tissue imaging were added and despite comparable blood pressure and left ventricular masses, the diastolic dysfunction became more evident. Our study confirms that if sensitive methods of assessing diastolic function are employed, deterioration in diastolic function can be demonstrated in normotensive subjects with a parental history of hypertension. This further confirms the hypothesis that abnormalities of cardiac function may predate clinical hypertension in genetically predisposed individuals. Studies that did not demonstrate differences between diastolic function in the offspring of hypertensives and normotensives used only mitral inflow parameters, which are inadequate in assessing diastolic function, as the parameters are easily affected by loading conditions.13,14 Our study had the advantage of assessing diastolic function in offspring of hypertensives using conventional Doppler parameters as well as myocardial tissue Doppler imaging. Our data suggest that diastolic dysfunction was present in offspring of hypertensive subjects despite the fact that they had similar baseline characteristics and left ventricular dimensions to the control group. Although the effect of the insignificantly higher blood pressure and LVM on the findings of diastolic function cannot be totally ruled out, our findings are similar to those of Aeschbacher et al,33 who also corrected for these variables in the analysis. Gender differences noted in the analysis are not surprising. Other workers have reported gender differences in LV parameters, as well as parameters of LV diastolic function.33-36 In a study of 121 normotensive youths, Kapuku et al.36 noted that females had a higher relative wall thickness, lower E/A ratio and shorter IVRT than males. Before changes in LV mass or hypertension become apparent, various changes occur at the cellular level that cause alterations in the myocardial architecture and collagen structure. Metabolic and neuro-endocrine changes also occur. Some studies have demonstrated acceleration of these factors in the offspring of hypertensives. The study had some limitations. We did not obtain information on and correct for factors such as socio-economic status, level of physical activity, diet or biochemical parameters, and this may have affected the results.

Conclusion Diastolic dysfunction has been shown to affect the quality of life of patients with advanced cardiac disease. Assessment of diastolic function is of paramount importance in the management of this disease. Early identification of subjects with or at risk for hypertension and diastolic dysfunction may help to stratify risk, guide therapy and prevent target-organ damage in these patients. The consistent independent effects of increased body weight and particularly male gender37,38 on the development of increased left ventricular mass reaffirms the need for early intervention

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with the institution of lifestyle modification in these subjects. Lifestyle modifications have been shown to reduce blood pressure in hypertensive patients. These interventions may prevent or delay the development of hypertension in normotensive subjects in the long term. Longitudinal studies are needed to determine the prognosis of these changes in normotensive offspring of hypertensive parents. We acknowledge the contribution and assistance of the ECG/ECHO unit team of Ms Ogunrinde, Adegbola, Adubi, Babatunde and Akinwale of University College Hospital, Ibadan. We are also grateful to Drs Ajit Mullasari and Ezhilan of Madras Medical Mission, Chennai, India, who read the manuscript and offered useful suggestions.

References 1.

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11.

12.

13.

14.

15.

Ezzati M, van der Hoorn S, Lawes CM, Leach R, James WP, Lopez AD, et al. Rethinking the ‘diseases of affluence’ paradigm: global patterns of nutritional risks in relation to economic development. PLoS Med 2005; 2: e133. Whelton PK, He J, Muntner P. Prevalence, awareness, treatment and control of hypertension in North America, North Africa and Asia. J Hum Hypertens 2004; 18: 545–551. Wolf-Maier K, Cooper RS, Kramer H, Banegas JR, Giampaoli S, Joffres MR, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004; 43: 10–17. Allemann Y, Aeschbacher B, Zwyssig P, Ferrari P, Hopf M, Shaw S, et al. Left ventricular structure and determinants in normotensive offspring of essential hypertensive parents. J Hypertens 1992; 10: 1257–1264. Allemann Y, Horber FF, Colombo M, Ferrari P, Shaw S, Jaeger P, et al. Insulin sensitivity and body fat distribution in normotensive offspring of hypertensive parents. Lancet 1993; 341: 327–331. Allemann Y, Weidmann P. Cardiovascular, metabolic and hormonal dysregulations in normotensive offspring of essential hypertensive parents. J Hypertens 1995; 13: 163–173. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114: 345–352. Cuocolo A, Sax FL, Brush JE, Maron BJ, Bacharach SL, Bonow RO. Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990; 81: 978–986. Devereux RB, de Simone G, Koren MJ, Roman MJ, Laragh JH. Left ventricular mass as a predictor of development of hypertension. Am J Hypertens 1991; 4: 603S–607S. Fouad FM, Slominski JM, Tarazi RC. Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function. J Am Coll Cardiol 1984; 3: 1500–1506. Verdecchia P, Schillaci G, Guerrieri M, Boldrini F, Gatteschi C, Benemio G, et al. Prevalence and determinants of left ventricular diastolic filling abnormalities in an unselected hypertensive population. Eur Heart J 1990; 11: 679–691. Inouye I, Massie B, Loge D, Topic N, Silverstein D, Simpson P et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984; 53: 120–126. Glen SK, Elliott HL, Curzio JL, Lees KR, Reid JL. White-coat hypertension as a cause of cardiovascular dysfunction. Lancet 1996; 348: 654–657. Gottdiener JS, Brown J, Zoltick J, Fletcher RD. Left ventricular hypertrophy in men with normal blood pressure: relation to exaggerated blood pressure response to exercise. Ann Intern Med 1990; 112: 161–166. Ravogli A, Trazzi S, Villani A, Mutti E, Cuspidi C, Sampieri L, et al. Early 24-hour blood pressure elevation in normotensive subjects with parental hypertension. Hypertension 1990; 16: 491–497.

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16. Graettinger WF, Neutel JM, Smith DH, Weber MA. Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension. Am J Cardiol 1991; 68: 51–56. 17. American Society of Hypertension. Recommendations for routine blood pressure measurement by indirect cuff sphygmomanometer. Am J Hypertens Suppl 1992: 207–209. 18. Devereux RB, Lutas EM, Casale PN, Kligfield P, Eisenberg RR, Hammond IW, et al. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 1984; 4: 1222–1230. 19. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977; 55: 613–618. 20. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458. 21. Palmieri V, Dahlof B, DeQuattro V, Sharpe N, Bella JN, de Simone G, et al. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective randomized study evaluating regression of ventricular enlargement. J Am Coll Cardiol 1999; 34: 1625–1632. 22. De Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992; 20: 1251–260. 23. Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson SJ, Stokes J, 3rd, et al. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987; 75: 126–133. 24. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37: 7–11. 25. Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997; 30: 8–18. 26. Appleton CP, Jensen JL, Hatle LK, Oh JK. Doppler evaluation of left and right ventricular diastolic function: a technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997; 10: 271–292.

27. Aeschbacher BC, de Marchi SF, Meier B. Identification of impaired ventricular relaxation by changes of pulmonary vein A-wave duration during Valsava. J Am Coll Cardiol 1998; 31: 423. 28. Nishimura RA, Housmans PR, Hatle LK, Tajik AJ. Assessment of diastolic function of the heart: background and current applications of Doppler echocardiography. Part I. Physiologic and pathophysiologic features. Mayo Clin Proc 1989; 64: 71–81. 29. De Maria AN, Wisenbaugh TW, Smith MD. Doppler echographic evaluation of diastolic dysfunction. Circulation 1991; 84: I-288–I-295. 30. Thomas JD, Weyman AE. Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991; 84: 977–990. 31. Aeschbacher BC, Hutter D, Fuhrer J, Weidmann P, Delacretaz E, Allemann Y. Diastolic dysfunction precedes myocardial hypertrophy in the development of hypertension. Am J Hypertens 2001; 14: 106–113. 32. Aeschbacher BC, Allemann Y, Hopf M, Weidmann P. Normotensive offspring of hypertensive parents: no evidence of left ventricular diastolic dysfunction in a cross-sectional study. Blood Press 1998; 7: 5–9. 33. Bella JN, Palmieri V, Roman MJ, Paranicas MF, Welty TK, Lee ET, et al. Gender differences in left ventricular systolic function in American Indians (from the Strong Heart Study). Am J Cardiol 2006; 98(6): 834–837. 34. Hinderliter AL, Light KC, Willis PWT. Gender differences in left ventricular structure and function in young adults with normal or marginally elevated blood pressure. Am J Hypertens 1992; 5(1): 32–36. 35. Petersen SE, Hudsmith LE, Robson MD, Doll HA, Francis JM, Wiesmann F, et al. Sex-specific characteristics of cardiac function, geometry, and mass in young adult elite athletes. J Magn Reson Imaging 2006; 24(2): 297–303. 36. Kapuku GK, Davis HC, Shah N, McMillan AM, Harshfield GA. Gender differences in diastolic function among youth. Pediatr Cardiol 2008; 29(1): 102–107. 37. Saitoh M, Nishimura H, Tanaka T, Kondoh T. Gender-related differences in target organ damage in untreated patients with essential hypertension. Intern Med 2006; 45: 377–383. 38. Fox ER, Taylor J, Taylor H, Han H, Samdarshi T, Arnett D, et al. Left ventricular geometric patterns in the Jackson cohort of the Atherosclerotic Risk in Communities (ARIC) study: clinical correlates and influences on systolic and diastolic dysfunction. Am Heart J 2007; 153: 238–244.

Diabetes congress diary Date JUNE 2012 8–12 June

Conference

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Pennsylvania, USA

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JULY 2012 9–12 July 24–26 July 25–28 July

The 3rd International Congress on Abnormal Obesity (ICAO) CDE Centres for Diabetes and Endocrinology 1st African Diabetes Congress

Quebec City, Canada Johannesburg, South Africa Arusha, Tanzania

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OCTOBER 2012 1–5 October 48th EASD Annual Meeting 10–13 October ISPAD 2012 – 38th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes 20–22 October 8th Asian Pacific Society of Atherosclerosis and Vascular Disease DECEMBER 2012 4–6 December 1st American Diabetes Association Middle East Congress: Diabetes Prevention and Treatment

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Obesity and blood pressure levels of adolescents in Abeokuta, Nigeria IO SENBANJO, KA OSHIKOYA

Abstract Background: We determined the prevalence of general and central obesity and their relationship with blood pressure levels among adolescents in Abeokuta, Nigeria. Methods: We selected 423 adolescents from seven schools in Abeokuta, Nigeria, using a multistage random-sampling technique. Body mass index (BMI), waist circumference (WC) and blood pressures were measured. Results: Twenty-one (5%) children had general obesity and 109 (24.5%) had central obesity. Of those with general obesity, 20 (95.1%) children were centrally obese. With simple linear regression analysis, BMI and WC explained 10.7 and 8.4%, respectively of the variance in systolic blood pressure (SBP), and 3.6 and 2.7%, respectively of the variance in diastolic blood pressure (DBP). Following logistic regression analysis, BMI was the major factor determining SBP levels (OR 0.8, 95% CI: 0.65–0.99, p < 0.05). Conclusion: BMI remains an important anthropometric screening tool for high blood pressure in Nigerian adolescents. Keyword: overweight, obesity, central obesity, blood pressure, adolescents, Nigeria Submitted 30/1/11, accepted 11/7/11 Cardiovasc J Afr 2012; 23: 260–264

www.cvja.co.za

DOI: 10.5830/CVJA-2011-037

Obesity is a disease in which excess body fat has accumulated to such an extent that the person’s health may be adversely affected.1 The International Obesity Task Force (IOTF) has reported that one in 10 children are overweight, with at least 155 million schoolchildren worldwide being affected.2 About 30 to 45 million of the overweight children are classified as obese and account for 2–3% of the world’s children aged five to 17 years old.2 In the United Kingdom,3 Canada4 and the USA,5 obesity has risen to epidemic levels among children, with the prevalence having more than doubled in the last two to three decades. Under-nutrition is the major nutritional problem in developing countries. Unfortunately, overweight and obesity are now becoming significantly prevalent in developing countries as a result of an environment characterised by easily available, cheap, Department of Paediatrics and Child Health, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria IO SENBANJO, MB ChB, FWACP, senbanjo001@yahoo.com

Pharmacology Department, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria, and Academic Division of Child Health, Medical School, University of Nottingham, Derbyshire Children’s Hospital, Derby, UK KA OSHIKOYA, MBBS, MSc

energy-dense foods, combined with increasingly sedentary lifestyles such as prolonged time spent watching television, playing video games or using computers. This is found particularly in families from a higher socio-economic status in developing countries.6,7 In India, the prevalence of obesity among adolescent schoolchildren from affluent families was found to be 7.4%.8 In Nigeria, among the privileged Nigerian schoolchildren the prevalence of obesity was 18%.9 Several epidemiological studies support the relationship between accumulation of body fat and the occurrence of non-communicable diseases such as hypertension and diabetes mellitus.10,11 More importantly, the accumulation of fat in the central region of the body is a good, proven clinical correlate of increased risk of these chronic diseases.12 Traditionally in clinical practice, general obesity is measured using body mass index (BMI). For the estimation of central obesity, there are several anthropometric parameters proposed for its reasonable estimation and they include sub-scapular skin-fold thickness, waist circumference (WC), waist-to-hip circumference ratio, and waist-to-height ratio. Waist circumference measures both the subcutaneous and visceral fat and has been shown to have the most consistent and generally the strongest correlation with adverse lipid concentrations and increased blood pressure levels among children and adolescents.13 In developing countries, both children and adult populations are characterised by lean body mass, and a high prevalence of underweight, wasting and stunting. According to Bogin, there is preferential accumulation of fat in the central portion of the body relative to peripheral fat storage in nutritionally stressed populations, with its attendant consequences of hypertension, coronary heart disease and diabetes mellitus.14 Information on the pattern of obesity and its influence on blood pressure levels among children in Nigeria is limited. Therefore the aim of this study was to determine the prevalence of general and central obesity and their relationship with blood pressure levels among adolescents in Abeokuta, south-west Nigeria.

Methods This was part of a larger study on anthropometric measures and body composition of children and adolescents in Abeokuta, Nigeria.15 It was carried out in randomly selected primary and secondary (both public and private) schools in Abeokuta. It was a questionnaire-based, cross-sectional study. Abeokuta is located on longitude 7° 10″ N and latitude 3° 26″ E and is the capital of Ogun State in south-western Nigeria. It is about 100 km north of Lagos, with an estimated population of four million people. Abeokuta is predominantly a Yoruba city but urbanisation and industrialisation have brought in many other ethnic groups. Ethical clearance was obtained from the Federal Medical Centre Research/Ethics Committee. Approval of the study came

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from the Ogun State Ministry of Education. The teachers, pupils and parents were well informed on the scope and extent of the survey. Consent was obtained from the parents and pupils. At the time of the survey, there was a total of 322 schools in Abeokuta (the ratio of public to private primary schools was 1:1, while the ratio of public to private secondary schools was 3:1). Using the multistage randomsampling technique, seven schools comprising two private and one public primary school, and one private and three public secondary schools were selected by balloting. The basis for this selection was because the number of students in the public primary schools was higher than that in private primary schools, whereas in the secondary schools the numbers were about equal. From each of the selected schools, all grades were studied (primary, grades 1–6; junior and senior secondary, grades 7–12). On the day of the study, one section of each grade was selected by balloting. Ballot papers were served to all the children in the selected section. These ballot papers were blank except those that were marked with numbers 1 to 15. After all the students had picked a paper, they were asked to open them and those with numbers 1 to 15 were selected. Ninety pupils were selected from each of the seven schools. In all, 630 pupils were selected but only 570 (90.5%) pupils completed the study. The other 60 pupils were excluded based on refusal to participate and evidence of chronic diseases. Blood pressure was not measured in 147 children aged five to nine years due to non-availability of an appropriate cuff. Each student was interviewed to obtain information on the demographic and socio-economic characteristics of the child’s family. The families were assigned a socio-economic class using the modified method recommended by Oyedeji.16 Trained student nurses took all anthropometric measurements. Each measurement was taken by the same examiner to minimise measurement error. The children were weighed using an electronic scale calibrated in 100-g units (SECA/UNICEF, Australia). All children were weighed wearing only underwear and to the nearest 0.1 kg. The height was measured using a specifically made wooden stadiometer with a steel tape measure. This was done with the child standing erect without shoes and with the eyes looking horizontally and the feet together on a horizontal base. These measurements were done to the nearest 0.1 cm. BMI was calculated by dividing the weight (kg) by the square of the height (m). Waist circumference was measured midway between the iliac crest and the lowermost margin of the ribs with bare belly and at the end of normal expiration, according to the WHO guidelines.17 Standardisation checks on the weighing scale, height boards and tape measure were done periodically during the study period. For blood pressure measurements, the subjects were seated and rested for five minutes. An appropriately sized cuff, covering at least two-thirds of the upper right arm with the lower border not less than 2.5 cm from the cubital fossa, was applied after restrictive clothing had been removed. Thereafter blood pressure was measured twice using an automatic blood pressure monitor (HEM-712C; Omron, China) and the mean was recorded. BMI is widely used as an index of general obesity although the cut-off points vary between the 85th and 97th percentiles.18 In this study, obesity was defined as BMI at or above the 95th percentile of age- and gender-specific data. A child was regarded

as having central obesity if the WC was ≥ the 75th percentile for age- and gender-specific data, as proposed by Fernandez et al.19 Systolic (SBP) and diastolic blood pressures (DBP) were defined as high when they were ≥ the 90th percentile, according to the Task Force on High Blood Pressure in Children and Adolescents.20

Statistical analysis Data analysis was by descriptive and inferential statistics, using the SPSS for Windows software version 13. The means and standard deviations (SD) of the weight, height, BMI, WC, and SBP and DBP were calculated according to gender. Gender differences in anthropometric and blood pressure values were compared using the independent-samples t-test, while proportions and ratios were compared using the Pearson Chi-squared (χ2) test. Simple and multiple logistic regression analyses were carried out on BMI and WC using blood pressure as the dependent variable. A probability (p) value of less than 0.05 was accepted as statistically significant.

Results A total of 423 subjects with ages ranging from 10 to 19 years had complete data sets, which were analysed. The mean age was 13.2 ± 2.41 years and 233 (55.1%) were males. The social distribution shows that 166 (29.1%), 304 (53.3%) and 100 (17.5%) children belonged to the upper, middle and lower socioeconomic classes, respectively. Table 1 shows the means (± SD) of the various anthropometric measures according to gender. All the anthropometric measures increased with age in both genders. The mean weight, BMI and WC were significantly higher in the females (p < 0.05, p < 0.001, p < 0.001, respectively). The BMI of the study population ranged from 11.59 to 34.14 kg/m2 with a mean value of 17.1 kg/m2. Twenty-one (5%) children were obese, 16 (76.2%) of them females, which was statistically significant (p = 0.012). WC ranged from 50.5 to 97 cm and 109 (25.8%) children had a WC above the 75th percentile for the population age and gender. There was a significantly higher prevalence of central obesity among females than males (38.4 vs 15.5%, p = 0.000). Twenty (95.2%) of the

TABLE 1. ANTHROPOMETRIC AND BLOOD PRESSURE VALUES OF THE STUDY SUBJECTS ACCORDING TO GENDER Variable Age (years) Weight (kg) Height (cm) BMI (kg/m2) WC (cm) SBP (mmHg) DBP (mmHg) BMI > 2 SD WC > 75th percentile High SBP High DBP

Total Male Female (n = 423) (n = 233) (n = 190) p-value 13. 7 (2.4) 13.7 (2.4) 13.8 (2.4) 0.688 39.3 (11.2) 38.0 (11.5) 40.7 (10.7) 0.013 149.7 (13.6) 150.2 (14.8) 149.1(12.1) 0.418 17.1 (2.7) 16.4 (2.1) 18.0 (3.1) 0.000 63.8 (8.5) 61.5 (5.9) 66.7 (10.1) 0.000 106.9 (11.5) 105.9 (10.9) 108.2 (12.2) 0.05 60.6 (10.4) 59.0 (10.1) 62.7 (10.4) 0.000 21 (5.0) 6 (2.6) 15 (7.9) 0.012 109 (25.8) 36 (15.5) 73 (38.4) 0.000 11 (2.6) 14 (3.3)

4 (1.7) 7 (3.0)

7 (3.7) 7 (3.7)

0.206 0.697

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TABLE 2. RELATIONSHIP BETWEEN BODY MASS INDEX AND BLOOD PRESSURE

BMI percentile Males ≤ 90th > 90th Females ≤ 90th > 90th Total ≤ 90th > 90th *p < 0.05

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TABLE 3. RELATIONSHIP BETWEEN WAIST CIRCUMFERENCE AND BLOOD PRESSURE

Systolic blood pressure, n (%) Normal High

Diastolic blood pressure, n (%) Normal High

225 (99.1) 4 (66.7)

2 (0.9) 2 (33.3)*

220 (96.9) 6 (100)

7 (3.1) 0 (0.0)

168 (96) 15 (100)

7 (4.0) 0 (0.0)

169 (96.6) 183 (96.3)

6 (3.4) 7 (3.7)

393 (97.8) 19 (90.5)

9 (2.2) 2 (9.5)*

389 (96.8) 20 (95.2)

13 (3.2) 1 (4.8)

children who had a BMI above the 90th percentile had a WC above the 75th percentile (χ2 = 55.8, p < 0.001). Both SDP and DBP increased significantly with age (r = 0.341, p = 0.000; r = 0.193, p = 0.000, respectively). The mean DBP was significantly higher in females (62.7 vs 59.0 mmHg, p < 0.001). Eleven children (2.6%) had high SBP and another 14 (3.3%) had high DBP. There was no significant gender difference in the prevalence of high SBP and high DBP (p = 0.206, p = 0.697, respectively). The weight, height, BMI and WC had a positive and statistically significant correlation coefficient with SBP and DBP (r = 0.126–0.421, p < 0.05). The correlation coefficient of BMI with SBP was higher than that of WC with SBP (0.327 vs 0.29). Similarly, the correlation coefficient of BMI with DBP was higher than that of WC with DBP (0.189 vs 0.129). Table 2 show the relationship between general obesity and blood pressure. There was a significantly higher prevalence of high SBP among male children with general obesity (χ2 = 36.5, p < 0.001). Among the children with central obesity, a significantly higher prevalence of high SBP (χ2 = 22.3, p < 0.001) and high DBP (χ2 = 4.1, p < 0.042) was seen in only the males (Table 3). In a simple linear regression analysis, BMI and WC explained 10.7 and 8.4%, respectively of the variance in SBP, and 3.6 and 2.7%, respectively of the variance in DBP. Each increment in BMI increased SBP and DBP by 0.327 and 0.189 mmHg, respectively, while each increment in WC increased SBP and DBP by 0.29 and 0.164 mmHg, respectively. When the effects of BMI and WC on blood pressure were studied in a multiple logistic regression equation model (Table 4), BMI was significantly associated with high SBP (OR 0.8, 95% CI: 0.65–0.99, p < 0.05).

Discussion Similar to previous studies from Nigeria,21-23 the prevalence of overweight and obesity from this study (using BMI as the indicator) was low when compared with children in the UK,3 Canada4 and the USA.5 It was also lower than the prevalence recorded in many North African, Middle Eastern and Latin American countries24 and in South Africa,6 where the prevalence of overweight and obesity has been rapidly increasing. This finding supports the fact that overweight and obesity is still an emerging nutritional problem affecting children in Nigeria. The

WC percentile Males ≤ 75th > 75th Females ≤ 75th > 75th Total ≤ 75th > 75th *p < 0.05

Systolic blood pressure, n (%) Normal High

Diastolic blood pressure, n (%) Normal High

197 (100) 32 (88.9)

0 (0.0) 4 (11.1)*

193 (98) 33 (91.7)

4 (2.0) 3 (8.3)*

113 (96.6) 70 (95.9)

4 (3.4) 3 (4.1)

113 (96.6) 70 (95.9)

4 (3.4) 3 (4.1)

310 (98.7) 102 (93.6)

4 (1.3) 7 (6.4)*

306 (97.5) 103 (94.5)

8 (2.5) 6 (5.5)

few cases of overweight and obese children seen in this study were from families of a high socio-economic class, in contrast with what is seen in developed countries. In our earlier study on the same population,25 there was a high prevalence of under-nutrition, which was associated with a high prevalence of moderate to vigorous physical activity among these adolescents. This suggests that there is a negative balance between energy intake and the energy expended in doing exercise. However, even though the mean BMI in this study was as low as 17.1 kg/m2, as much as 25.8% of the children had centrally accumulated fat. This is similar to the findings in the Karimojong children of Uganda26 and middleaged Indians,27 and is a characteristic feature of populations with chronic malnutrition. This phenomenon, coupled with adaptation to western lifestyles, could explain the rise in prevalence of non-communicable diseases such as hypertension and diabetes mellitus in these populations. The prevalence of elevated blood pressure in this study is similar to the 3.7% obtained earlier by Bugaje et al.28 in Zaria, Nigeria and the 4% obtained by Balogun et al.29 in Ile-Ife, Nigeria. It is lower than the prevalence of 6.69% in India,30 9.5% in Ilorin,31 Nigeria, and 12–23% among adolescents in Quebec, Canada.32 The upsurge in the prevalence of overweight and obesity, which varies between populations depending on their lifestyle, socio-economic status and other environmental interactions, has been implicated in the differences in prevalence of high blood pressure at a national and international level. In this study, general obesity was a good predictor of high SBP in males, and WC was a good predictor of high SBP and DBP in males. Surprisingly, despite a higher prevalence of TABLE 4. MULTIPLE REGRESSIONS OF BODY MASS INDEX AND WAIST CIRCUMFERENCE AS RISK FACTORS FOR HIGH BLOOD PRESSURE* Beta coefficient Standard error Systolic blood pressure BMI –0.223 0.109 WC 0.029 0.047 Diastolic blood pressure BMI –0.177 0.118 WC 0.013 0.053 *Adjusted for age and gender.

p-value 0.042 0.530 0.136 0.316

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general and central fatness in females, such strong relationships were not seen. This was different from the findings in other studies where strong relationships existed between BMI, WC and BP, irrespective of gender.13,30,32 In keeping with the work of Dobbelsteyn et al.33 and Yan et 34 al. on Chinese children, BMI was a better indicator of blood pressure levels when compared with WC. Similarly, among Nigerian adults who were urban civil servants, central obesity as assessed by waist:hip ratio made little contribution to elevated blood pressure levels.35 However, in Valencia, Spain,36 the waistto-hip ratio of children significantly contributed to SBP levels, while the relationship between waist-to-hip ratio and DBP was of borderline significance when compared with weight, height and ponderal index. The BMI is a measure of total adiposity. It has the limitation of not been able to distinguish between muscle mass and fat mass and therefore it is difficult to determine which is the most significant contributor to blood pressure variability. According to Stallones et al.,37 weight was more important than fatness in predicting systolic blood pressure. However, the mechanism of the relationship between weight and blood pressure is not fully known. In a lean black population, there was a threshold above which weight was related to blood pressure.38 This was also observed in a study on urban schoolchildren in India where the prevalence of high SBP suddenly increased beyond a BMI value of 20 kg/m2 in boys and 21.5 kg/m2 in girls.39 This aspect of the assessment was not carried out in our own study. The limitations of this study include use of the BMI-for-age percentile of the study population to define overweight and obesity rather than the internationally recommended standards. These international standards are designed for developed countries where under-nutrition is not a problem. There is a need to develop a national BMI classification for paediatric populations in Nigeria and other African countries.

Conclusion Overweight and obesity is an emerging health problem among adolescents in Abeokuta, Nigeria. However, periodic studies coupled with preventive strategies may be necessary to prevent childhood overweight and obesity in Abeokuta from rising at the alarming rate that is presently experienced globally. Although WC was a more direct measurement of body fat, in this study, BMI was a better predictor of blood pressure levels. Future studies are necessary to validate each of these anthropometric measures against adverse serum lipid profiles and other cardiovascular and metabolic risk factors. We thank the Ogun State Ministry of Education for giving us approval to enter their schools, and the schools, school principals, teachers and students who participated in this study. We are grateful to the student nurses who helped with data collection. The Federal Medical Centre, Abeokuta, Nigeria, funded this work.

10.

11.

12.

13.

14. 15.

16. 17.

18. 19.

20.

21.

22.

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(accessed June 2009). Lobstein T, James WP, Cole TJ. Increasing levels of excess weight among chidren in England. Int J Obes Relat Metab Disord 2003; 27: 1136–1138. Canning PM, Courage ML, Frizzell LM. Prevalence of overweight and obesity in a provincial population of Canadian preschool children. J Am Med Coll 2004; 171: 240–242. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999-2000. J Am Med Assoc 2002; 288: 1728–1732. Armstrong MEG, Lambert MI, Sharwood KA, Lambert EV. Obesity and overweight in South African primary school children-the health of the nation study. S Afr Med J 2006; 96: 486–444. Popkin BM, Richards MK, Montiero CA. Stunting is associated with overweight in children of four nations that are undergoing the nutrition transition. J Nutr 1996; 126: 3009–3016. Kapil U, Singh P, Pathak P, Dwiedi N, Bhasin S. Prevalence of obesity among affluent adolescent school children in Delhi. Indian Pediatr 2001; 39: 49–52. Owa JA, Adejuyigbe O. Fat mass, fat mass percentage, body mass index, and mid upper arm circumference in a healthy population of Nigerian children. J Trop Pediat. 1997; 43: 13–19. Braunschweig CL, Gomez S, Liang H, Tomey K, Doerfler B, Wang Y, Beebe C, Lipton R. Obesity and risk factors for the metabolic syndrome among low-income urban, African American schoolchildren: the rule rather than the exception? Am J Clin Nutr 2005; 81: 970–975. Perichart-Perera O, Balas-Nakash M, Schiffman-Selechnik E, BarbatoDosal A, Vadillo-Ortega F. Obesity increases metabolic syndrome risk factors in school-aged children from an urban school in Mexico city. J Am Diet Assoc 2007; 107: 81–91. Daniels SR, Morrison JA, Sprecher DL, Khoury P, Kimball TR. Association of body fat distribution and cardiovascular risk factors in children and adolescents. Circulation 1999; 99: 541–545. Maffeis C, Pietrobelli A, Grezzani A, Provera S, Tato L. Waist circumference and cardiovascular risk factors in prepubertal children. Obes Res 2001; 9: 179–187. Bogin B. Patterns of Human Growth. 2nd edn. Cambridge: Cambridge University Press, 1999: 260–261. Senbanjo IO, Njokanma OF, Oshikoya KA. Waist circumference Values of Nigerian children and adolescents Ann Nutr Metab 2009; 54: 145–150. Oyedeji GA. Socioeconomic and cultural background of hospitalized children in Ilesa. Nig J Paediatr 1985; 12: 111–117. World Health Organization expert committee: Physical status, the use and interpretation of anthropometry. WHO technical report series No 894. Geneva: WHO, 1995: 424–438. Guillaume M. Defining obesity in childhood: Current practice. Am J Clin Nutr 1999; 70(Suppl): 126s–130s Fernandez JR, Redden DT, Pietrobelli A, Allisson DB. Waist circumference percentiles in nationally representative samples of African American, European-American, and Mexican-American children and adolescents. J Pediatr 2004; 145: 439–444. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114 (suppl 4th Report): 555–576. Ansa VO, Odigwe CO, Anah MU. Profile of body mass index and obesity in Nigerian children and adolescents. Niger J Med 2001; 10(2): 78–80. Ben-Bassey UP, Oduwole AO, Ogundipe OO. Prevalence of overweight and obesity in Eti-Osa LGA, Lagos, Nigeria. Obes Rev 2007; 8: 475–479. Akesode FA, Ajibode HA. Prevalence of obesity among Nigerian school children. Soc Sci Med 1983; 17: 107–111. De Onis M, Blossner M. Prevalence and trends of underweight among preschool children in developing countries. Am J Clin Nutr 2000; 72: 1032–1039. Senbanjo IO, Oshikoya KA. Physical activity and body mass index of school children and adolescents in Abeokuta, Southwest Nigeria. World

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J Pediatr 2010; 6: 217–222. 26. Gray S, Akol HA, Sundal M. Mixed-longitudinal growth of Karimojong girls and boys in Moroto District, Uganda. Am J Hum Biol 2009; 21: 65–76. 27. Ghosh A. Factor analysis of metabolic syndrome among the middle aged Bengalese Hindu men of Calcutta, India. Diabetes Metab Res Rev 2005; 21: 58–64. 28. Bugaje MA, Yakubu AM, Ogala WN. Prevalence of adolescent hypertension in Zaria. Nig J Paediatr 2005; 32: 77–82. 29. Balogun JA, Obajuluwa VA, Abereoje OK, Olaogun MO, Oyeyemi AY, Balogun MO, Adeodu OO. Anthropometric determinants of resting blood pressure and heart rate of Nigerian school children. Ann Trop Paediatr 1990; 10: 425–431. 30. Mohan B, Kumar N, Aslam N, et al. Prevalence of Sustained Hypertension and Obesity in Urban and Rural School Going Children in Ludhiana. Ind Heart J 2004; 56: 310–314. 31. Obika LF, Adedoyin MA, Olowoyeye JO. Pattern of paediatric blood pressure in rural, semi-urban and urban communities in Ilorin, Nigeria. Afr J Med Med Sci 1995; 24: 371–377. 32. Paradis G, Lambert M, O’ Loughlin J, et al. Blood pressure and adiposity in children and adolescents. Circulation 2004; 110: 1832–1838. 33. Dobbelsteyn CJ, Joffres MR, MacLean DR, Flowerdew G. A compara-

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tive evaluation of waist circumference, waist-to-hip ratio and body mass index as indicators of cardiovascular risk factors: the Canadian Heart Health Surveys. Int J Obes Relat Metab Disord 2001; 25: 652– 661. Yan W, Wang X, Yao H, Dai J, Zheng Y, Yang X, Yibulayin X, Cui J. Waist-to-height ratio and BMI predict different cardiovascular risk factors in Chinese children. Diabetes Care 2006; 29: 2761. Adams-Campbell LL, Wing R, Ukoli FA, Janney CA, Nwankwo MU. Obesity, body fat distribution, and blood pressure in Nigerian and African-American men and women. J Natl Med Assoc 1994; 86: 60–64. Lurbe E, Alvarez V, Youlian L, et al. The Impact of Obesity and Body Fat Distribution on Ambulatory Blood Pressure in Children and Adolescents. Am J Hypertens 1998; 11: 418–424. Stallones L, Mueller WH, Christensen BL. Blood pressure, fatness, and fat patterning among USA adolescents from two ethnic groups. Hypertension 1982; 4: 483–486. Bunker CH, Ukoli FA, Matthews KA, Kriska AM, Huston SL, Kuller LH. Weight threshold and blood pressure in a lean black population. Hypertension 1995; 26: 616–623. Rao S, Kanade A, Kelkar R. Blood pressure among overweight adolescents from urban school children in Pune, India. Eur J Clin Nutr 2007; 61: 633–641.

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Prevalence, awareness, treatment and control of hypertension among adults 50 years and older in Dakar, Senegal E Macia, P DUBOZ, L GUEYE

Abstract Background: Older adults are disproportionately affected by hypertension, which is an established risk factor for cardiovascular disease. Despite these facts, no study on the prevalence, awareness, treatment and control on arterial hypertension in Senegal has been conducted, specifically among elderly people. Methods: Five hundred people aged 50 years and older, living in the city of Dakar were interviewed. This sample was constructed using the combined quota method in order to strive for representativeness of the target population. Results: Prevalence of hypertension was 65.4% in our sample. Half of those suffering from high blood pressure were aware of their problem and among the latter, 70% said they were on treatment. However, of these, only 17% had controlled arterial blood pressure. The only factor associated with awareness, treatment and control of hypertension was the frequency of doctor visits. Conclusion: Improving follow-up health checks of older adults are necessary to limit the consequences of hypertension in Dakar. Keywords: hypertension, risk factors, older adults, Senegal Submitted 11/5/11, accepted 19/7/11 Cardiovasc J Afr 2012; 23: 265–269

www.cvja.co.za

DOI: 10.5830/CVJA-2011-039

Cardiovascular disease is an emerging problem in sub-Saharan Africa.1 In Senegal, mortality associated with such diseases is already over half that related to non-contagious diseases.2 Moreover, hypertension is a prime risk factor for cardiovascular disease due to both its widespread prevalence and low control rate among populations,3 making hypertension a major public health problem per se in sub-Saharan Africa. Urbanisation and the adoption of a Western lifestyle contribute greatly to the rising incidence of hypertension in sub-Saharan Africa.4 Recent studies conducted in the region have shown that hypertension was already as frequent in these cities as it is in developed countries.5-14 In Dakar, its prevalence among adults 20 years and older was 27.5% in 2009.15 These findings are particularly alarming due to the present low rates of detection, treatment and control of hypertension observed in sub-Saharan Africa.5 UMI 3189 Environnement, santé, sociétés, Université Cheikh Anta Diop/CNRS/Université de Bamako/CNRST, BurkinaFaso, Senegal E Macia, PhD, enguerranmacia@gmail.com P DUBOZ, PhD L GUEYE, PhD

Whether carried out in Western countries or in sub-Saharan Africa, all studies show that the prevalence of arterial hypertension rises drastically with age and that the elderly are the population segment the most at risk.7,16 In Dakar, again according to the previously cited study, nearly 70% of adults 50 years and older are believed to suffer from hypertension.15 Despite this evidence, and to our knowledge, no study pertaining to the awareness, treatment and control of arterial hypertension in sub-Saharan Africa has been specifically conducted among the elderly. Most research conducted in this geographic area considers older people as a non-specific and homogenous population category (the ‘50 years and older’ for example). Yet, studies carried out in both developed and developing countries demonstrate clear evolution in the prevalence, awareness, treatment and control of hypertension during the aging process.17-19 The aims of this study were therefore to (1) assess the prevalence, awareness, treatment and control of hypertension in the population aged 50 years and older living in the city of Dakar; (2) identify factors associated with hypertension, and also its awareness, treatment and control.

Methods This study was conducted from January to June 2009 on a sample of 500 individuals. The sample was constructed using the quota method (cross-section by age, gender and town of residence) in order to strive for representativeness of the population 50 years and older living in the city of Dakar. Data from the Agence Nationale de la Statistique et de la Démographie dating from the last census (2002) were used to this end. The quota variables used were gender (male/female), age (50–59, 60–69, 70 years and older) and town of residence. The towns were grouped into the four districts making up the city of Dakar: Plateau-Gorée (five towns), Grand Dakar (six towns), Parcelles Assainies (four towns) and Almadies (four towns). This method requires building up a sample that follows the proportions observed in the general population: for example, according to the last census, men aged 50–59 years living in the town of Medina (district of Plateau-Gorée) represented 2.4% of the population of 50 years and older living in the city of Dakar. The sample was constructed so as to reflect this proportion and included 12 men 50–59 years old living in this town. For each town, four investigators (PhD students in the departments of Medicine and Pharmacy) started out from different points each day to measure and interview individuals in Wolof or French in every third home. Investigators had a set number of individuals to interview (women and men 50–59 years, 60–69 years, and 70 years and over in each town) to meet the quotas. Only one person was selected as a respondent in each home. The objective of this bio-anthropological survey was to carry

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out a holistic study on aging in the city of Dakar. To do so, faceto-face guided interviews based on a questionnaire were used to collect the data required for the study. These interviews were followed by a physical examination that involved taking blood pressure and anthropometric measurements.

Study definitions and measurements Blood pressure was measured twice for each participant in the course of a single visit. The first measurement was taken mid-way through the interview, just after the questions related to individual health. The second measurement was taken at the end of the questionnaire, after about 15–20 minutes’ rest. These measurements were taken by medical and pharmacy students in Dakar, using an Omron® M3 Intellisense device validated by the International Protocol.20 The mean of the two measurements was used for the analyses. In accordance with the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, individuals with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/ or who reported the current use of antihypertensive medication were considered to be suffering from high blood pressure.21 Weight was measured using a digital scale (accuracy of 100 g) with subjects dressed in minimum clothing and barefoot. To measure height, the subject was asked to stand ‘at attention’, arms at the sides, heels together and without shoes. Following World Health Organisation recommendations, body mass index (BMI) was calculated by dividing weight (kg) by the square of the height (m2). Overweight was defined as 25 ≤ BMI < 30 kg/ m2; obesity corresponded to a BMI of ≥ 30 kg/m2.22 Given the large proportion of people who had not visited a doctor in the year preceding the interview (48%), the frequency of doctor visits was split into two groups, as in the study conducted by the hypertension study group in India and Bangladesh.17 Therefore, people who had not visited a doctor in the year preceding the interview were distinguished from those who had seen a doctor at least once during the year. Among the socio-demographic data collected during the interviews, four variables were taken into account for this study: age, gender, educational level and marital status. Three age groups were defined: 50–59, 60–69 and 70 years and over. Gender was coded as follows: 1 for women, 0 for men. Three levels of education were defined: none, one to eight years of

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Hypertensive 65.4% (95% CI: 61.5–69.3) ≈ 52 700 Dakarites aged 50 years and older*

Not aware 50.5%

Aware 49.5% (95% CI: 44.1–54.9) ≈ 26 100 Dakarites aged 50 years and older*

Not treated 29.4%

Treated 70.6% (95% CI: 63.8–77.4) among the aware 37.0% (95% CI: 31.8–42.2) among the hypertensive ≈ 19 500 Dakarites aged 50 years and older*

Not controlled 82.6%

Controlled 17.4% (95% CI: 10.4–24.4) among the treated 6.7% (95% CI: 4.0–9.4) among the hypertensive ≈ 3 500 Dakarites aged 50 years and older*

*The numbers of older Dakarites aware of their hypertension, treated and controlled were obtained by multiplying the prevalence figure by the population aged 50 years and older, according to the last census (2002).

Fig. 1. Prevalence, awareness, treatment and control of hypertension in the population of Dakar aged 50 years and older.

schooling, more than eight years of schooling. Marital status was coded as follows: married = 0, other = 1.

Statistical analysis To answer our research questions, we used Chi-square tests and logistic regressions. The software used for the statistical analysis was PASW Statistics 18.

TABLE 1. CHARACTERISTICS OF THE SAMPLE (n = 500) Variable Age (years)

Educational level

Marital status Doctor visits in previous year BMI (kg/m2)

Category 50–59 60–69 ≥ 70 None 1–8 years ≥ 9 years Married Not married 0 ≥1 < 25 ≥ 25

Total, n (%) 268 (53.6) 136 (27.2) 96 (19.2) 228 (45.6) 186 (37.2) 86 (17.2) 372 (74.4) 128 (25.6) 240 (48) 260 (52) 231 (46.2) 269 (53.8)

Men, n (%) 144 (54.7) 71 (27) 48 (18.3) 97 (36.9) 100 (38.0) 66 (25.1) 234 (89) 29 (11) 141 (53.6) 122 (46.4) 149 (56.7) 114 (43.3)

Women, n (%) 124 (52.3) 65 (27.4) 48 (20.3) 131 (55.3) 86 (36.3) 20 (8.4) 138 (58.2) 99 (41.8) 99 (41.8) 138 (58.2) 82 (34.6) 155 (65.4)

Analysis Chi2 (2 df) = 0.41; NS c2 (2 df) = 29.46; p < 0.001 c2 (1 df) = 61.87; p < 0.001 c2 (1 df) = 7.00; p < 0.01 c2 (1 df) = 24.40; p < 0.001

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TABLE 2. FACTORS ASSOCIATED WITH HYPERTENSION, AWARENESS, TREATMENT AND CONTROL Prevalence (n = 500) Variable

Categories

None

1.28

0.73–2.23

1.72

0.8–3.69

0.73

0.33–1.61

0.2

0.04–1.07

1.66

0.32–8.56

2.14

0.34–13.54

1–8 years

1.23

0.71–2.14

2.15*

1.01–4.6

1.36

0.63–2.94

0.49

0.09–2.56

1.31

0.24–7.06

0.98

0.15–6.29

Not married

0.81

0.51–1.28

1.48

0.8–2.75

1.13

0.61–2.1

0.54

0.22–1.32

0.94

0.32–2.77

0.9

0.25–3.27

≥ 25 kg/m2 1.86** 1.24–2.79

1.23

0.73–2.06

1.13

0.66–1.91

0.94

0.44–2.03

0.7

0.27–1.81

0.62

0.22–1.8

0.17** 0.05–0.6

0.32

0.07–1.43

*p < 0.05; **p < 0.01; ***p < 0.001.

0.37*** 0.23–0.6

0.24*** 0.14–0.41

0.32** 0.15–0.69

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The results for the sub-sample of individuals who were aware of their hypertension problem were quite different. In this logistic regression analysis, only the frequency of doctor visits was significantly associated with treatment of hypertension (Table 3). Among the hypertensives, on multivariate analysis, only the frequency of doctor visits was associated with control of hypertension (Table 3). Therefore, people having seen a doctor during the preceding year more often had controlled hypertension than those who had not seen a doctor the previous year. However, among treated individuals, no variable was associated with control of hypertension (Table 3).

Discussion The prevalence of hypertension in our population sample corresponded with that observed among older people in other sub-Saharan African cities5-14 or in other developing countries such as India and Bangladesh.17 In Dakar, two out of three people 50 years and older suffered from arterial hypertension, a disease that has now become a major public health concern in the Senegalese capital. In keeping with what has been observed among other populations, aging and problems of overweight and obesity were associated with hypertension.23,24 However, this was not the case with educational level. This observation seems to indicate that the Dakar population is currently in an advanced stage of epidemiological transition. This process is characterised by a transfer of risk factors for chronic illnesses from the bettereducated individuals in the early stages of the process to the less educated at the end of the transition.25 The rate of awareness of hypertension among the hypertensives, approximately 50%, corresponds with that observed among the elderly living in other developing countries.17 This rate is, however, much lower than that noted in the West, where over two-thirds of older hypertensives are aware of the problem.18,19 If the ‘rule of halves’26 remains valid here, it nevertheless conceals great disparities, especially between men and women. As with most developing populations, women were more often informed on their problem of hypertension than men.27 However, the reasons for this association remain poorly understood.17 In fact, it may appear surprising in Senegal, where male domination over women is taken for granted.28 The Demographics and Health Survey conducted in 2005 indicated for instance that scarcely 12% of married women made their own decisions about their personal healthcare spending, whereas for 67% of them, only their spouse made such decisions.29 However, in Senegal, it is primarily women who take care of the health of members of the household, accompanying their daughters, daughters-in-law and grandchildren to healthcare institutions. This might explain both their more frequent visits to these institutions and their greater monitoring of hypertension. Unlike the results noted for elderly German and American populations,18,19 awareness of hypertension rises with age among the elderly in Dakar. Therefore the probability of having been identified as hypertensive rises with age. More surprisingly, we have seen that people with a higher educational level were often less informed on their hypertension than those with an average educational level. This result runs contrary to all research conducted on the subject, which generally demonstrates

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the opposite.30 More research is required to understand this specificity, but it could be that education does not have the same implications for health management in Dakar as in developed countries. Nevertheless, it is not surprising to note that the factor most strongly associated with awareness of hypertension was the frequency of doctor visits. More than 70% of individuals aware of their hypertension reported taking treatment, which seems well above the rule of halves. This theoretically encouraging statistic should, however, be discussed in light of the results associated with control of hypertension. Fewer than 17% of the people who reported being treated actually had controlled hypertension, i.e. 6.7% of hypertensives. A study conducted in Ghana could help explain why the hypertension control rate was so low among the elderly in Dakar. According to this study, 93% of the people treated for hypertension did not comply with their medical prescriptions, usually due to the high cost of medication.31 The same observation seems to hold true in Dakar where the price of medication is disproportionate to average expenditure per person per day, i.e. 1 224 FCFA (≈ 2.7 dollars).32 However, another explanation could be advanced. According to Salem, treatment of chronic disease is generally misunderstood. In Dakar, when a disease is identified, it is believed it should be ejected as a foreign body.33 The notion of chronic illness goes against this conception, which could explain the low level of compliance with treatment. Since pharmacological treatment of hypertension is the consequence of its detection by healthcare personnel, factors associated with treatment among hypertensives were the same as those associated with awareness of this health problem, i.e. frequency of doctor visits, gender and age. Among these factors, only the frequency of doctor visits was significantly associated with the control of hypertension. Therefore it was the only factor investigated that was associated with awareness, treatment and control of hypertension in this study. This result highlights the absolute necessity of improving the follow-up health checks of older adults to minimise the consequences of hypertension in Dakar.

Strengths and limitations of the study This research was, to our knowledge, the first study conducted specifically on hypertension among the elderly in sub-Saharan Africa. In years to come, the elderly in developing countries will represent the majority of older people on the planet.34 Therefore it is necessary to understand the prevalence of hypertension among these populations, as well as the rates of awareness, treatment and control of the disease, in order to combat this burden more effectively and in a more appropriate manner. This study has several limitations. As in many studies, arterial blood pressure was measured twice during a single visit, which may have led to overestimation of the prevalence of hypertension. Furthermore, the treatment rate of hypertension was assessed solely by individual self-reporting. Verification of the actual presence of medication in the home might have limited the bias associated with these declarations.

Conclusion The results of this study have several public health implications. Firstly, two-thirds of the Dakar elderly suffer from hypertension,

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and this disease therefore constitutes a major public health concern in the Senegalese capital. Detection could be considerably improved given that only 50% of those suffering from high blood pressure were aware of this problem. Nearly three-quarters of the people informed on their condition reported being treated, which is an encouraging statistic in a developing country. However, compliance with these treatments appears particularly problematic, given that fewer than 20% of individuals treated had controlled hypertension. It is likely that the high cost of pharmacological treatment when compared to income was responsible for the low rate of compliance with these treatments. One of the factors studied was associated with awareness, treatment and control of hypertension: the frequency of doctor visits. This result highlights the absolute necessity to improve follow-up health checks of older adults to minimise the consequences of hypertension in Dakar. This research was supported by grants from the National Institute for Heath Prevention and Education (INPES) and the Department of Research (ACI ‘Constructions, normes et écarts’ No. 045398). The manuscript was translated from French by Cynthia Schoch.

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Sani MU. Cardiovascular diseases in sub-Saharan Africa: an emerging problem. Ethn Dis 2007; 17: 574–575. World Health Organisation. Death and DALY estimates for 2004 by cause for WHO Member States. http://www.who.int/entity/healthinfo/ statistics/bodgbddeathdalyestimates.xls. Accessed 2006. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: 217–223. Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005; 112: 3554–3561. Addo J, Smeeth L, Leon DA. Hypertension in sub-Saharan Africa: a systematic review. Hypertension 2007; 50:1012–1018. Agyemang C. Rural and urban differences in blood pressure and hypertension in Ghana, West Africa. Publ Hlth 2006; 120: 525–533. Amoah AG. Hypertension in Ghana: a cross-sectional community prevalence in greater Accra. Ethn Dis 2003; 13: 310–315. Bovet P, Ross AG, Gervasoni JP, et al. Distribution of blood pressure, body mass index and smoking in the urban population of Dar es Salaam, Tanzania, and associations with socioeconomic status. Int J Epidemiol 2002; 31: 240–247. Damasceno A, Azevedo A, Silva-Matos C, Prista A, Diogo D, Lunet N. Hypertension prevalence, awareness, treatment, and control in Mozambic: urban/rural gap during epidemiological transition. Hypertension 2009; 54: 77–83. Edwards R, Unwin N, Mugusi F, et al. Hypertension prevalence and care in an urban and rural area of Tanzania. J Hypertens 2000; 18: 145–152. Kadiri S, Walker O, Salako BL, Akinkugbe O. Blood pressure, hypertension and correlates in urbanised workers in Ibandan, Nigeria: a revisit. J Hum Hypertens 1999; 13: 23–27. Mbanya JC, Minkoulou EM, Salah JN, Balkau B. The prevalence of hypertension in urban and rural Cameroon. Int J Epidemiol 1998; 27: 181–185. Steyn K, Gaziano TA, Bradshaw D, Laubscher R, Fourie J. South African Demographic and Health Coordinating Team. Hypertension in South African adults: results from the Demographic and Health Survey 1998. J Hypertens 2001; 19: 1717–1725.

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14. Vorster HH. The emergence of cardiovascular disease during urbanisation of Africans. Publ Hlth Nutr 2002; 5: 239–243. 15. Duboz P, Macia E, Dia M, Gueye L. Prevalence and risk factors of hypertension in Dakar’s department. Dakar Médical (in press). 16. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness, treatment, and control of hypertension among United-States adults 1999-2004. Hypertension 2007; 49: 69–75. 17. Hypertension study group. Prevalence, awareness, treatment and control of hypertension among the elderly in Bangladesh and India: a multicentre study. Bull Wld Hlth Organ 2001; 79: 490–500. 18. McDonald M, Hertz RP, Unger AN, Lustik MB. Prevalence, awareness, and management of hypertension, dyslipidemia, diabetes among United States adults aged 65 and older. J Gerontol A Bio Sci Med Sci 2009; 64: 256–263. 19. Van Rossum CTM, van de Mheen H, Witteman JCM, Hofman A, Mackenbach JP, Grobbee DE. Prevalence, treatment, and control of hypertension by sociodemographic factors among the Dutch elderly. Hypertension 2000; 35: 814–821. 20. Asmar R, Khabouth J, Topouchian J, El Feghali R, Mattar J. Validation of three automatic devices for self-measurement of blood pressure according to the International Protocol: the Omron M3 Intellisense (HEM-7051-E), the Omron M2 Compact (HEM 7102-E), and the Omron R3-I Plus (HEM 6022-E). Blood Press Monit 2010; 15: 49–54. 21. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252. 22. World Health Organisation. Obesity: Preventing and Managing the Global Epidemic. Report of the WHO Consultation. WHO Technical Report Series 894. WHO: Geneva, 2000. 23. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. J Am Med Assoc 1999; 282: 1593–1594. 24. Mufunda J, Mebrathu G, Usman A, et al. The prevalence of hypertension and its relationship with obesity: results from a national blood pressure survey in Erytrea. J Hum Hypertens 2006; 20: 59–65. 25. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998; 97: 596–601. 26. Marques-Vidal P, Tuomilehto J. Hypertension, awareness and control in the community: is the “rule of halves” still valid? J Hum Hypertens 1997; 11: 213–220. 27. 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: 521–529. 28. Macia E, Duboz P, Gueye L. Les dimensions de la qualité de vie subjective à Dakar. Sciences Sociales et Santé 2010; 28: 75–84. 29. Ndiaye S, Ayad M. Enquête Démographique et de Santé au Sénégal (EDS-IV) 2005. Demographic and Health Surveys: Dakar, 2005. 30. Regidor E, Guttiérez-Fisac JL, Banegas JR, Dominguez V, RodriguezArtalejo F. Association of adult socioeconomic position with hypertension in older people. J Epidemiol Commun Hlth 2006; 60: 74–80. 31. Ohene Buabeng K, Matowe L, Plange-Rhule J. Unaffordable drug price: the major cause of non-compliance with hypertension medication in Ghana. J Pharm Pharm Sci 2004; 7: 350–352. 32. Agence Nationale de la Statistique et de la Démographie (ANSD). Enquête de suivi de la pauvreté au Sénégal – EPPS 2005-2006. http://www.ansd.sn/publications/rapports_enquetes_etudes/enquetes/ Rapport_ESPS.pdf. Accessed 2007. 33. Salem G. La Santé dans la Vville. Géographie d’un Petit Espace Dense: Pikine (Sénégal). Paris: Karthala; 1998. 34. United Nations. Rapport de la deuxième assemblée mondiale sur le vieillissement. Madrid, 8-12 avril 2002. http://daccess-dds-ny.un.org/ doc/UNDOC/GEN/N02/397/52/PDF/N0239752.pdf?OpenElement. Accessed 2002.

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Control of cardiovascular risk in black Africans with type 2 diabetes in Senegal

(Contrôle du risque cardio-vasculaire chez les diabétiques de type 2 noirs africains au Sénégal)

NV YAMÉOGO, A MBAYE , M NDOUR, LJ KAGAMBEGA, H DIOMANDE, R HAKIM, A THIAM, A DIALLO, SN DIOP, D DIAGNE, B DIACK, A KANE

Abstract Introduction: Morbidity and mortality from diabetes are compounded by associated cardiovascular risk factors. For this reason, taking care of these risk factors is a public health goal. In this study we evaluated the level of control of cardiovascular risk factors in black Africans with type 2 diabetes in Senegal. Methods: Between March 2007 and July 2008, we recruited type 2 diabetes patients from outpatient care in a specialised hospital in Senegal. Data were collected on a survey form designed for this purpose. An electrocardiogram and laboratory examinations were also performed. The level of control of diabetes and associated cardiovascular risk factors were assessed, as recommended by the American Diabetes Association (ADA). Results: A total of 318 type 2 diabetes subjects (237 women) were recruited. The average age was 58.2 ± 9.2 years (40–85). The mean duration of diabetes was 6.9 ± 5.9 years. The average glycaemic level was 1.4 ± 0.5 g/l and glycated haemoglobin was 7.6 ± 3.2%. The average length of patient follow up was 6.7 ± 6.1 years with a single annual consultation; 63.2% of the patients were on an insulin + biguanide combination, with good diabetes control (HbA1c < 7%) in 25% of cases. Antihypertensive drugs were prescribed in 28.1% of hypertensive patients. More than half (51.9%) of these hypertensive patients were treated with angiotensin converting enzyme inhibitors. Their blood pressure was well controlled (< 130/85 mmHg) in 5.4% of the hypertensive patients (10/185). The low-density lipoprotein (LDL) cholesterol goal was achieved in 18.5% of cases (5/27). Conclusion: This study shows that the prevalence of cardiovascular risk factors is higher among black Africans suffering from type 2 diabetes. The control of these factors was not optimal in our study.

Service de cardiologie de l’Hôpital Général de Grand Yoff, Dakar, Senegal

NV YAMÉOGO, MD, drnova@hotmail.fr A MBAYE, MD M NDOUR, MD LJ KAGAMBEGA, MD H DIOMANDE, MD R HAKIM, MD A THIAM, MD A DIALLO, MD SN DIOP, MD D DIAGNE, MD B DIACK, MD A KANE, MD

Keywords: diabetes, cardiovascular risk factors, control, diabète, facteurs de risque cardio-vasculaire, contrôle Submitted 16/6/10, accepted 4/8/11 Cardiovasc J Afr 2012; 23: 270–272

www.cvja.co.za

DOI: 10.5830/CVJA-2011-040

Résumé Introduction: La morbidité et la mortalité du diabète sont aggravées par l’association de facteurs de risque cardiovasculaire dont la prise en charge est un objectif de santé publique. Nous évaluons dans cette étude le niveau de contrôle des facteurs de risque cardio-vasculaire dans une population de diabétiques de type 2 noirs africains au Sénégal. Méthodologie: Nous avons recruté, entre mars 2007 et juillet 2008, des diabétiques de type 2 suivis en ambulatoire en milieu hospitalier spécialisé au Sénégal. Les données ont été recueillies sur une fiche d’enquête conçue à cet effet. Un électrocardiogramme et des examens biologiques ont été aussi réalisés. Le niveau de contrôle du diabète et des facteurs de risque cardio-vasculaire associés a été évalué selon les recommandations de l’American Diabetes Association (ADA). Résultats: Un total de 318 diabétiques de type 2 (237 femmes) ont été colligés. L’âge moyen était de 58.2 ± 9.2 ans (40–85). La durée moyenne d’évolution du diabète était de 6.9 ± 5.9 ans avec un taux moyen de glycémie de 1.4 ± 0.5 g/l et d’hémoglobine glyquée de 7.6 ± 3.2%. La durée moyenne du suivi des patients était de 6.7 ± 6.1 ans avec une seule consultation annuelle; 63.2% des patients étaient sous l’association biguanide + insuline avec un bon contrôle du diabète (HbA1c < 7%) dans 25% des cas. Les antihypertenseurs étaient prescrits chez 28.1% des hypertendus dont plus de la moitié (51.9%) sous inhibiteurs de l’enzyme de conversion de l’angiotensine avec un bon contrôle de la tension artérielle (< 130/85 mmHg) dans 5.4% des cas (10/185). L’objectif de LDL-cholestérol était atteint dans 18.5% des cas (5/27). Conclusion: Cette étude montre que la prévalence des facteurs de risque cardio-vasculaire est élevé chez les diabétiques de type 2 noirs africains. Le contrôle de ces facteurs n’était pas optimal dans notre étude. Le diabète sucré est une maladie grave dont la prévalence est en constante progression. Il constitue un important facteur de risque cardio-vasculaire, avec une morbi-mortalité aggravée par les facteurs de risque communément associés telles que l’obésité, la dyslipidémie et l’hypertension artérielle.1 Il mérite d’être évalué dans ce sens surtout après une longue durée d’évolution.2 Il requiert un suivi continu et rigoureux des patients afin d’éviter la survenue les complications.3 La prise en charge des

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facteurs de risque cardio-vasculaire chez le diabétique de type 2 constitue ainsi un objectif prioritaire.4-6 Les objectifs de cette prise en charge sont de réduire l’incidence des complications dégénératives et le risque de survenue d’événements cardiovasculaires, d’augmenter l’espérance de vie et d’améliorer la qualité de vie de ces patients. Notre étude avait pour but d’évaluer la prise en charge des facteurs de risque cardio-vasculaire et leur niveau de contrôle chez les diabétiques de type 2 au Sénégal.

Patients et méthode Nous avons mené une étude transversale, descriptive, multicentrique de Mars 2007 à Juillet 2008 dans trois des principaux centres hospitaliers de Dakar (Centre Hospitalier National Abass Ndao, Hôpital Général de Grand Yoff, CHU Aristide Le Dantec). Elle a porté sur les diabétiques de type 2 des deux sexes âgés d’au moins 40 ans. Tous les patients ont bénéficié d’un interrogatoire, d’un examen physique, d’un ECG et d’un bilan biologique comprenant la glycémie, l’hémoglobine glycosylée, la créatininémie, la microabuminurie, une protéinurie des 24 heures et un lipidogramme (cholestérol total, HDL-cholestérol, LDL-cholestérol, triglycérides). Les facteurs de risque cardio-vasculaire modifiables recherchés étaient l’hypertension artérielle (HTA), la sédentarité, le tabagisme actif ou sevré depuis moins de 3 ans, l’obésité, la dyslipidémie et la microalbuminurie. Les atteintes des organes cibles recherchées étaient les atteintes cardio-vasculaire, rénale et cérébrale. Nous avons analysé le traitement en cours et considéré les objectifs thérapeutiques de l’American Diabetes Association (ADA).7-9 Ces objectifs comprenaient une pression artérielle < 130/85 mmHg, un taux de LDL-cholestérol < 1 mg/ dl et une hémoglobine glyquée < 7%. Les données ont été recueillies à l’aide d’une fiche d’enquête, saisie sur micro-ordinateur et analysées à l’aide du logiciel SPSS version 17 for Windows.

Résultats L’échantillon était composé de 318 diabétiques de type 2 dont 237 femmes (74.5%) et 81 hommes (25.5%). L’âge moyen des patients était de 58.2 ± 9.2 ans (extrêmes : 40–85 ans). La durée moyenne d’évolution du diabète était de 6.9 ± 5.9 ans (extrêmes: 0.1–31 ans). La durée moyenne du suivi des patients était de 6.7 ± 6.1 ans (extrêmes : 0.1–28.5 ans) avec une seule consultation annuelle. La glycémie moyenne était de 1.4 ± 0.5 g/l (extrêmes : 0.7–4.9 g/l), celle de l’hémoglobine glycosylée était de 7.6 ± 3.2 TABLEAU 1. CARACTÉRISTIQUES GÉNÉRALES DES DIABÉTIQUES DE TYPE 2 (n = 318) Facteurs de risque Sédentarité (%) Hypertension artérielle (%) Tabac (%) Dyslipidémie (%) Microalbuminurie (%) Obésité (%) Consommation d’alcool (%)

Population globale 82.4 58.2 6.0 43.1 36.8 10.1 3.8

Femmes 87.19 58.2 3.8 36.3 30 12.6 0.8

Hommes 77.27 58.0 17.3 62.9 25.9 7.8 12.3

% (extrêmes: 4.5–10.9%) (tableau 1). Les facteurs de risque cardio-vasculaire de nos patients sont indiqués dans le tableau I. Ils étaient dominés par la sédentarité (82.4%), l’hypertension artérielle (58.2%), la dyslipidémie (43.1%) et la microalbuminurie (36.8%). Plus de la moitié des patients (63.2%) était sous l’association biguanide + insuline + mesures hygiéno-diététiques. Les différents traitements antidiabétiques utilisés figurent dans le tableau 2. Les antihypertenseurs étaient prescrits chez 28.1% des hypertendus. Les inhibiteurs de l’enzyme de conversion de l’angiotensine étaient les médicaments les plus utilisés (51.9%). Les médicaments utilisés pour le traitement de l’hypertension artérielle figurent dans le tableau 3. L’aspirine était prescrite dans 6,9 % des cas. Quant aux statines, ils étaient prescrits chez 8.5% des patients. Le diabète était contrôlé dans 14.8% des cas. Dans 75.2% des cas, l’hémoglobine glyquée était supérieure à 7%; elle était comprise entre 7 et 8% chez 38.4% des patients et supérieure à 8 chez 36.8% des diabétiques. Parmi les patients hypertendus, 28.1% avaient un traitement antihypertenseur. La tension artérielle était supérieure à 130/85 mmHg chez tous les hypertendus non traités et chez 80.8% des hypertendus traités (soit 42 patients). L’hypertension artérielle était ainsi contrôlée dans 5.4% des cas. Lorsque le seuil de 140/90 mmHg était considéré, elle était contrôlée dans 11.9% des cas. La dyslipidémie à LDL était observée dans 39.3 % des cas soit 125 patients. Parmi ces patients, 27 étaient sous statines. Une LDLémie normale était retrouvée chez 18.5 % d’entre eux. Dans la population globale, la LDLémie était inférieure à 1 g/l dans 62.3% des cas et inférieure à 1.3 g/l dans 67.9% des cas. L’indice de masse corporelle était normal (< 25 kg/m2) dans 57.7% des cas. La surcharge pondérale était retrouvée dans 32.2% des cas et l’obésité dans 10.1% des cas. La pratique d’une activité physique régulière n’était retrouvvée que chez 17.6% des diabétiques. Le tabagisme était observé dans 6.0% des cas dont 2.5% avaient arrêté la consommation mais depuis moins de 3 ans.

TABLEAU 2. UTILISATION DES TRAITEMENTS ANTIDIABETIQUES Traitement Régime seul Biguanide + insuline Biguanide Sulfamides Total

Effectif (n) 91 201 21 5 318

Pourcentage (%) 28.6 63.2 6.6 1.6 100

TABLEAU 3. UTILISATION DES MEDICAMENTS ANTIHYPERTENSEURS Médicaments antihypertenseurs Inhibiteurs de l’enzyme de conversion Antagonistes des récepteurs de l’angiotensine II Bêta bloquants Diurétiques Inhibiteurs calciques

Effectifs (n) 27 8 8 12 5

Fréquence (%) 51.9 15.4 15.4 23.1 9.6

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Discussion Moins de 15 % de nos patients étaient bien contrôlés sur la base de l’hémoglobine glyquée. Moins du tiers des patients étaient contrôlés dans l’étude de Mcfarlane.10 Dans l’étude française ESPOIR, la proportion des patients contrôlés était de 27%.11 Ces résultats illustrent toute la difficulté de contrôle du diabète. Très peu de patients étaient sous traitement antihypertenseur dans notre étude; seulement 28.1% d’entre eux. La valeur cible n’était obtenue que chez 5.4% des patients hypertendus. Dans l’étude ESPOIR,11 moins du tiers des patients étaient contrôlés sur le plan de la tension artérielle bien que la valeur cible fut 140/90 mmHg. La difficulté de contrôle de la pression artérielle serait liée aux comorbidités qui rendent difficile la prise en charge, mais aussi à l’inadéquation du traitement (peu sont traités).10 Ces observations confirment la nécessité d’utiliser souvent une polymédication antihypertensive pour atteindre la cible thérapeutique. Dans notre étude, seuls 13 patients étaient sous bithérapie antihypertensive et 6 sous trithérapie antihypertensive. L’hypercholestérolémie à LDL était de 39.3% dans notre étude. La proportion des patients qui avaient une LDLémie inférieure à 1 g/l était de 62.3%. Dans l’étude de Mcfarlane,10 35.5% des patients avaient un LDL cholestérol < 1 g/l. Dans l’étude ESPOIR, 66% des patients avaient une LDLémie < 1.3 g/l. Ce taux a été retrouvé dans 67.9% des cas dans notre étude. La prescription des statines n’était pas courante dans notre étude, et concernait seulement 8.5% des patients. L’utilisation des antiagrégants plaquettaires était très faible dans notre étude (6.9%). Or selon les recommandations12 la prescription d’antiagrégant plaquettaire est justifiée chez les diabétiques qui ont en plus un des éléments suivants : cardiopathie ischémique, artériopathie des membres inférieurs, hypertension artérielle ou hypercholestérolémie. Cette situation était présente chez 52.51% de nos patients.

Conclusion Ce travail montre une prévalence élevée des facteurs de risque cardio-vasculaire modifiables chez les diabétiques de type 2 noirs africains. Le contrôle du diabète et des facteurs de risque associés n’était cependant pas optimal dans notre étude. Cette étude montre par ailleurs que la prise en charge des facteurs de risque cardio-vasculaire est souvent inadéquate chez les

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diabétiques noirs africains. Les recommandations internationales méritent d’être suivies pour une meilleure prise en charge de nos patients.

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Letter to the Editor Dear Sir The letter by Mullier in response to our article titled ‘The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives’2 refers. The author states that amiodarone is not only a prodrug but also has inherent pharmacodynamic effects, just like its metabolite N-desethyamiodarone (N-DEA), which he correctly suggests could have even greater pharmacological effects than the parent compound. However, we need to emphasise that even though N-DEA has similar class III antiarrythmic effects, it has faster sodium channel blockade and lower class IV effects than amiodarone.3-8 The inhibition of pre-hepatic/hepatic CYP3A4 metabolism of amiodarone alters both plasma and cardiac substrate:metabolite ratios. It therefore reduces alterations of PR and QTC intervals,9 and hence diminishes the anti-arrythmic effects of amiodarone. Both amiodarone and N-DEA have long half-lives (50 and 60 days, respectively),10-12 and at normal therapeutic doses, the relative contribution of either to the anti-arrythmic and overall cardiac electrophysiological effects is not presently known, despite the aforementioned interaction with grapefruit juice. This, however, does not disqualify amiodarone as a prodrug. The interaction of grapefruit juice with amiodarone is more complicated than previously thought. Naringenin, the naringin (the predominant flavonoid in grapefruit juice) aglycone, has recently been reported to prolong QTC by inhibiting the rapid component of delayed rectifier K+ current (Ikr), leading to significant QT prolongation in healthy subjects and in patients with dilated or hypertensive cardiomyopathy,13 as well as in experimental conditions.14 It is therefore envisaged that the pro-arrythmic actions of naringin or grapefruit juice, just like all class III anti-arrythmic agents, may put patients with myocardial structural disorders at risk of provoking torsades des pointes. Even though cases of QT prolongation and torsades de pointes with amiodarone are rare, a case has been reported of a female patient who presented with marked QT prolongation associated with ventricular arrhythmias including torsades de pointes, requiring electrical cardioversion after amiodarone administration, after she had been drinking large quantities of among others grapefruit juice.15 Perhaps we should have included these references in our previous article to emphasise the fact that the interaction between grapefruit juice and amiodarone is more elaborate than previously thought. We thank the author for pointing out the typing errors in our references. 1

PMO Owira, BSc, Med Hons (UCT), MSc (Medicine) (UCT), PhD (Pharmacology) (UKZN), Owirap@ukzn.ac.za

References 1. 2. 3.

7. 8.

10.

11. 12.

13.

14.

15.

Mullier FO. The grapefruit: an old wine in a new glass. Cardiovasc J Afr 2011; 22(1): 37. Owira PMO, Ojewole JAO. The grapefruit: an old wine in a new glass. Cardiovasc J Afr 2010; 21: 280–285. Wellens HJ, Brugada P, Abdollah H, Dassen WR. A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation 1984; 69: 120–124. Morady F, DiCarlo LA Jr, Krol RB, et al. Acute and chronic effects of amiodarone on ventricular refractoriness intraventricular conduction and ventricular tachycardia induction. J Am Coll Cardiol 1986; 7: 148–157. Shenasa M, Denker S, Mahmud R, et al. Effect of amiodarone on conduction and refractoriness of the His-Purkinje system in the human heart. J Am Coll Cardiol 1984; 4: 105–110. Torres V, Tepper D, Flowers D, et al. QT prolongation and the antiarrhythmic efficacy of amiodarone. J Am Coll Cardiol 1986; 7: 142–147. Connolly SJ, Latini R, Kates RE. Pharmacodynamics of intravenous amiodarone in the dog. J Cardiovasc Pharmacol 1984; 6: 531–535. Ikeda T, Nadamanee K, Kannan R, Singh BN. Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations. Am Heart J 1984; 108: 890–898. Libersa CC, Brique SA, Mote KB, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol 2000; 49: 373–378. Harris L, Mckenna W, Rowland DE, et al. Plasma amiodarone and desethylamiodarone levels in chronic oral therapy. Circulation 1981; 64 (Suppl IV): 263. Holt DW, Tucker GT, Jackson PR, Storey GCA. Amiodarone pharmacokinetics. Am Heart J 1983; 106: 840–847. Marchiset D, Bruno R, Djiane P, et al. Amiodarone and desethylamiodarone elimination kinetics following withdrawal of long-term amiodarone maintenance therapy. Biopharm Drug Dispos 1985; 6: 209–515. Piccirillo G, Magri D, Matera S, et al. Effects of pink grapefruit juice on QT variability in patients with dilated or hypertensive cardiomyopathy and in healthy subjects. Translational Res 2008; 151: 267–272. Lin C, Ke X, Ranade V, Somberg J. The additive effects of active component of grapefruit juice (naringenin) and antiarrythmic drugs on HERG inhibition. Cardiology 2008; 110(3): 145–152. Agosti S, Casalino L, Bertero G. A dangerous fruit juice. Am J Emergency Med 2012; 30: 248.e5–248.e8.

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Robotically controlled ablation for atrial fibrillation: the first real-world experience in Africa with the Hansen robotic system FAIZEL LORGAT, EVAN PUDNEY, HELENA VAN DEVENTER, SAM CHITSAZ

Abstract Background: We report the first single-centre experience in Africa with the Sensei X robotic navigation system in an unselected subset of patients with atrial fibrillation (AF). Methods: Data were recorded prospectively of all consecutive patients who underwent robotically assisted catheter ablation therapy using the Sensei X robotic navigation system at the Christiaan Barnard Memorial Hospital, Cape Town, South Africa, from July 2009 to July 2010. Outcomes were defined at one and nine months. Results: A total of 95 patients were included: 63% had only AF and 37% had AF plus atrial flutter. AF was of the persistent type in 81% of patients. The mean procedure, fluoroscopy and ablation times were 220.6 ± 89.6 min, 31.0 ± 20.4 min, and 61.3 ± 28.1 min, respectively. Both fluoroscopy and procedure times were significantly longer for the first 19 patients compared with the remaining 76 patients (43.5 ± 22.7 vs 27.8 ± 18.5 min and 274.7 ± 90.2 vs 207.1 ± 84.7 min, respectively, p = 0.002). The procedural endpoint of the study was successfully achieved in all patients. After one attempt, 27% were discharged from hospital off anti-arrhythmic drugs (AADs). At a median of nine months’ follow up, 74% were AF-free off AADs, and 11% were AF-free on AADs, yielding a total freedom from AF of 84% without any redo procedures. Freedom from relapse after 1.12 procedures was 88%. Conclusion: The Sensei X™ robotic navigation system offers a safe and effective approach for the treatment of AF. There was a learning curve with regard to fluoroscopy and procedure time, after which point reduction in radiation exposure and operator strain, as well as improvement in procedure throughputs were even more pronounced. Keywords: atrial fibrillation, catheter ablation, atrial flutter, robotic navigation, computer-assisted ablation Submitted 28/11/11, accepted 24/2/12 Cardiovasc J Afr 2012; 23: 274–280

www.cvja.co.za

DOI: 10.5830/CVJA-2012-015

Department of Cardiology, Christiaan Barnard Memorial Hospital, Cape Town, South Africa

FAIZEL LORGAT, MB ChB, PhD, florgat@iafrica.com EVAN PUDNEY HELENA VAN DEVENTER

Cardiac Biomechanics Laboratory, University of California San Francisco, San Francisco, California, USA SAM CHITSAZ, MD

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance in the general population.1 As life expectancy and average age increase, it is estimated that the number of patients affected by AF will increase 2.5-fold over the next five decades.2 Uncontrolled AF may result in devastating complications such as haemodynamic impairment and increased risk of stroke, which in turn have a dramatic impact on quality of life, morbidity and mortality. Hence, it is imperative to advance treatment options available for patients suffering from this condition. Over the past decade, catheter ablation has been proven to be effective in treating various types of arrhythmias. According to the latest guidelines, catheter ablation is indicated in cases of symptomatic arrhythmias refractory to conventional antiarrhythmia therapies.3-6 Specifically, limited success of antiarrhythmia drugs in the treatment of AF has made this condition the dominant indication for catheter ablation in high-volume electrophysiology centres.1 So far, two catheter-based approaches have emerged as accepted strategies for AF treatment: (1) ostial segmental disconnection of all pulmonary veins from the adjacent atrial tissue, and (2) circumferential pulmonary vein ablation (CPVA).6 The circumferential approach was found to be significantly more effective than segmental ablation for paroxysmal AF. However, these two seemingly different strategies are converging towards a unified strategy (i.e. circumferential approach) and are reporting similar success rates.7 Regardless of strategy, however, the safety and efficacy of these strategies and others under investigation are highly operator dependent and require reproducible catheter movements and optimal catheter stability and contact during mapping and ablation energy delivery. In recent years, remote catheter navigation systems have been introduced to improve precision during catheter manipulation, reduce physical demands on the operator, minimise fluoroscopy time, and increase patients’ safety by avoiding serious complications.8 The Sensei X robotic navigation system (Hansen Medical, Mountain View, CA) and the Niobe magnetic navigation system (Stereotaxis, St Louis, MO) are two commercially available remote catheter navigation systems currently available on the market. Performance of the Sensei X system has been evaluated in American and European studies.9-12 Researchers investigated technical characteristics and outcomes of robotic AF ablation and found that the complications and recurrence rates with the robotic system were comparable to those of manual ablation,13 while the amount of radiation exposure was significantly lower with the robotic navigation.14 The learning curve in early cases resulted in longer procedure times at each centre, mostly due to lack of experience with the set-up, which gradually improved.15 In this article, we report the first real-world experience in Africa with the Sensei X robotic navigation system in an unselected subset of patients with predominantly persistent AF.

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Methods This was a prospective, single-centre, single-operator study performed at the Christiaan Barnard Memorial Hospital, Cape Town, South Africa. The data of all consecutive symptomatic patients with AF who underwent robotically assisted catheter ablation therapy using the Sensei X robotic navigation system (Hansen Medical, Mountain View, CA) from July 2009 (the time of acquisition of the robotic system) to July 2010 were recorded in an electronic database. The exclusion criteria were: (1) patients with cardiac dysrhythmia without documented AF, e.g. only atrial flutter (AFlut) or regular supraventricular tachycardia (SVT), (2) congestive heart failure with New York Heart Association class IV or ejection fraction of < 30%, (3) recent acute coronary syndrome within two weeks, (4) impaired mental status that may affect timely taking of anti-arrhythmia drugs, (5) severe cerebrovascular disease, and (6) patient’s decline to sign informed consent. Ninety-five patients were finally included. Institutional research board approval was waived for this study. AF types were defined based on the latest European Society of Cardiology (ESC) guidelines5 as follows: paroxysmal AF is a self-terminating episode that lasts up to seven days; persistent AF either lasts between seven days and one year, or requires termination by cardioversion with drugs or direct current; longstanding persistent AF lasts a year or more. Screening (fluoroscopy) time involved the total minutes the X-ray was applied by the operator to visualise the position of devices or set up the system in the patient, using single-plane pulsed fluoroscopy with a rate of seven frames per second, i.e. the time needed to place the diagnostic catheter in the coronary sinus, to perform a trans-septal puncture, to assist with the initial creation of a three-dimensional (3D) map, and occasionally thereafter to verify accuracy of 3D mapping. Ablation (radiofrequency) time was defined as the total minutes the operator used electrical current to ablate the rebel atrial foci. The procedure time was defined as the time between first venipuncture in the operating room and full recovery of the patient from anaesthesia. All high-risk patients (CHADS2 score ≥ 2 or patients with impaired left ventricular function) and all patients with longstanding persistent AF were anticoagulated on warfarin for four weeks until five to seven days prior to the procedure. Subcutaneous enoxaparin (1 mg/kg daily) was administered three to four days pre-procedure. Low-risk patients (CHADS2 score < 2) who had persistent AF by definition but who were in sinus rhythm prior to the procedure because of drugs or recent direct-current cardioversion were not always anticoagulated on warfarin. All patients were instructed not to ingest any solid foods within six hours prior to their procedure. Three-dimensional mapping was performed to facilitate robotically assisted catheter ablation. In all patients, 3D reconstruction of the corresponding atrial chamber anatomy was performed with either the EnSite NavX system (76 patients) or CARTO electro-anatomic mapping system (19 patients).

Procedure All procedures were performed under general anaesthesia using propofol and remifentanil. All patients received a bolus of dexamethasone as part of the anesthesia to reduce the incidence

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of postoperative nausea. The use of corticosteroids may also be effective for preventing post-ablation recurrence of atrial tachycardia.16 A temperature probe was routinely placed into the oesophagus for continuous intra-oesophageal monitoring during radiofrequency (RF) ablation. A multipolar catheter was placed into the coronary sinus via a 7F sheath in the right femoral vein. An ablation catheter, either a 3.5-mm ThermoCool® catheter (Biosense-Webster, Diamond Bar, CA, USA) or a Cool Path™ Duo RF ablation catheter (St Jude Medical, St Paul, MN, USA) was placed into the Artisan sheath (Hansen Medical, Mountain View, CA). The steerable sheath system (SSS) was inserted via a 14F sheath in the right femoral vein and advanced manually into the right atrium under fluoroscopic visualisation. Approximately 0.5 cm of the ablation catheter was exposed. After placement of the SSS in the inferior right atrium was confirmed, the position of the SSS was registered into the robotic catheter remote-control system. This registration involved the use of LAO 30 and RAO 30 fluoroscopic views of the heart (anterior–posterior and lateral) to allow localisation of the SSS in the 3D space. In all patients, one trans-septal puncture was performed under fluoroscopic guidance. In exceptional patients transoesophageal echocardiographic guidance was used to facilitate trans-septal puncture. The trans-septal puncture was performed manually. Through this trans-septal puncture, a long sheath was advanced into the left atrium, and a circular mapping catheter was introduced into the left atrium. The ablation catheter was robotically guided into the left atrium through the same transseptal puncture site (adjacent to the shaft of the circular mapping catheter). This catheter was used for ablation. Systemic anticoagulation was initiated after the first transseptal puncture with the use of intravenous unfractionated heparin with a target activated clotting time (ACT) of approximately 250 s. A 15–25 variable loop Biosense LASSO circular mapping catheter (Biosense-Webster, Diamond Bar, CA, USA) was used for mapping the pulmonary vein (PV) antrum. With this configuration, the final set up before initiation of ablation included the following: a robotically controlled steerable sheath housing the ablation catheter (this is performed by a physician at the console) and a manually controlled circular mapping catheter handled and moved by the same physician at the procedure tableside. When intra-oesophageal temperature rises were noted, power output was reduced to 20 W. At the end of the procedure, systemic anticoagulation was discontinued and occasionally partially reversed with intravenous protamine before removal of the vascular sheaths.

Ablation Ablation along the pulmonary vein antrum, which encompasses the posterior wall, septal aspect of the right-sided pulmonary veins, and the ridge between the left atrial appendage and left pulmonary veins, was performed with the Artisan robotic system until disappearance of local PV potential, with the endpoint of electrical isolation of all PV antra. Radiofrequency power was set at 30 W with a maximum temperature limit of 45°C with irrigation using a heparinised saline infusion (2 000 IU/l) at a rate of 17 ml/min via the Cool Flow pump (Biosense-Webster,

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Diamond Bar, California, USA). After PV isolation was conducted, the circular ablation catheter was withdrawn. If AF persisted after PV isolation, flecainide was administered intravenously up to a maximum of 150 mg unless contraindicated, in which case amiodarone up to a maximum dosage of 300 mg was infused. If this restored sinus rhythm then no further left atrial ablation was performed. If AF persisted, then mapping for complex fractionated atrial electrograms was performed. If complex fractionation was noted along the coronary sinus musculature, then ablation was performed along the endocardial aspect of the coronary sinus. If AF organised into a regular tachycardia at any stage during mapping and ablation, then a detailed activation map was constructed and the appropriate ablation was performed to terminate the flutter or focal atrial tachycardia. If AF persisted despite all of these efforts, a direct-current cardioversion was performed. Ablation along the posterior cavo-tricuspid isthmus was performed in 30 patients with the robotic system in conjunction with the 3.5-mm Navistar® ThermoCool® catheters or Cool Path Duo. Bidirectional block was confirmed with differential pacing techniques (proximal coronary sinus/postero-lateral right atrial pacing). All patients received enoxaparin (Clexane) 40 mg bd a few hours post procedure until discharge the next day (two doses on average).

Follow up The procedural endpoint of the study was whether isolation of all PV or SVC potential foci was successfully achieved, or conversion to manual catheter ablation was needed. Our primary endpoints were recurrence of symptomatic AF lasting more than one minute at nine months post procedure, major cardiac complications that needed intervention/surgery, and all-cause mortality. A two-month blanking period was defined in which episodes of AF occurring within that time period were not considered recurrence. Follow up was scheduled at one and six months. A resting ECG was performed in each follow-up visit. Outside of the scheduled follow ups, additional assessment or investigation was considered if symptoms warranted it. Patients previously on warfarin resumed oral anticoagulation therapy with warfarin the day after the procedure, and oral anticoagulation therapy was continued for at least one month for patients with paroxysmal AF. Patients with persistent and long-standing persistent AF received a recommendation to take warfarin for at least three months, after which warfarin was discontinued if sinus rhythm was maintained and the CHADS2 score was less than 2. Warfarin-naïve patients were commenced on aspirin 81 mg and Plavix 75 mg for one month only. All of these patients were advised to take aspirin indefinitely. Antiarrhythmic drugs were continued for a one- to three-month period. All patients received esomeprazole (Nexium) 40 mg daily for one month.

Statistical analysis Categorical and continuous variables are presented as frequency (percentage) and mean ± one standard deviation, respectively. Distribution of the continuous variables was assessed using the Kolmogorov-Smirnov test. To compare normally distributed

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continuous parameters, the independent samples Student’s t-test was performed, while the Mann-Whitney test was used to compare non-normally distributed variables. Categorical parameters were compared using the Fisher’s exact or χ2 test. Statistical Package for the Social Sciences (SPSS) v 15.0 was used for plotting the graphs and statistical analyses and tests. Differences were considered significant at p < 0.05.

Results A total of 100 procedures were performed in the defined period. Five robotic ablations were redo procedures on patients who had previously undergone robotic ablation in our centre. Ninety-five patients met all the selection criteria and were enrolled in the final analysis. Demographics and baseline clinical characteristics are summarised in Table 1. Fourteen patients (15%) were receiving more than one AAD pre-procedure. For eight patients (8%), manual ablation was tried previously at least once (i.e. the robotic procedure was a redo ablation). Sixty patients (63%) had only AF, and 35 patients (37%) had documented atrial flutter (AFlut) along with their AF. In the majority of patients (81%), AF was of the persistent type. In patients who had AF + AFlut, AFlut was mainly typical (78%). Different types of AF and AFlut in the study population are summarised in Table 2. The procedural endpoint was achieved in all 95 patients enrolled in the study. All ablation procedures were performed using the Sensei X robotic navigation system. Seven patients (7%) needed medical cardioversion during the ablation procedure, three (3%) needed electrical cardioversion, and nine patients (9%) needed both.

TABLE 1. BASELINE CHARACTERISTICS OF ALL ENROLLED PATIENTS (n = 95) Male, n (%) Age (years) AF duration (years) Ischaemic heart disease, n (%) Diabetes mellitus, n (%) Systemic hypertension, n (%) Hypercholesterolaemia, n (%) Structural heart disease, n (%) Pre-procedure anti-arrhythmic drugs, n (%) Sotalol Amiodarone Flecainide Dronedarone Propafenone Sotalol + Flecainide Beta-blockers Pre-procedure digitalis, n (%) Pre-procedure warfarin, n (%) Ejection fraction (%) Left atrial size (cm) Procedure time (min) Screening time (fluoroscopy time, min) Ablation time (min)

71 (75) 59.4 ± 9.9 5.3 ± 6.1 23 (24) 9 (9) 49 (52) 38 (40) 11 (12) 19 (20) 27 (28) 10 (11) 1 (1) 1 (1) 1 (1) 34 (36) 4 (4) 36 (38) 61.3 ± 8.2 4.3 ± 0.6 220.6 ± 89.6 31.0 ± 20.4 61.3 ± 28.1

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TABLE 2. TYPES OF DYSRHYTHMIA IN THE STUDY POPULATION n (%) 95 (100) 13 (14) 77 (81) 5 (5) 35 (37) 29 (31) 2 (2) 3 (3) 1 (1)

The mean procedure, fluoroscopy and ablation times were 220.6 ± 89.6 min, 31.0 ± 20.4 min, and 61.3 ± 28.1 min, respectively. Both fluoroscopy (screening) and procedure times were significantly longer for the first 19 patients compared with the remaining 76 patients (43.5 ± 22.7 vs 27.8 ± 18.5 min, p = 0.002 and 274.7 ± 90.2 vs 207.1 ± 84.7 mins, p = 0.002, respectively), whereas ablation time did not change significantly as the number of performed procedures increased (ANOVA p = 0.455) (Fig. 1). Fluoroscopy time showed a significant decrescendo trend for the first half of the patients, with an R2 of 0.25 and p = 0.006 (Fig. 2). There was no significant correlation for the second half of the procedures (p = 0.619).

95% CI screening time (min)

Dysrhythmia Atrial fibrillation paroxysmal persistent long-standing persistent Atrial flutter typical atypical left atrial peri-mitral

50 40 30 20 10 0

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90 80 70 60 50

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350

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First fifth vs rest of the patients 95% CI radiofrequency time (min)

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1st

2nd

3rd

4th

Subgroups of 19 patients

5th

150

First 19 patients

Rest

Subgroups of 19 patients

Fig. 1. Error bars representing screening time, radiofrequency time and procedure time for subgroups of 19 patients; CI, confidence interval.

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Screening time (min)

100 80 60

y = –0.7012x + 46.979 R 2 = 0.2488

40 20 0

Patient number

Fig. 2. Scatter plot showing a decrescendo trend in screening time for the first half of the study group.

Complications Eighty-six patients (91%) completed the postoperative in-hospital period and were discharged without any remarkable complication. There were four minor complications. One patient had a groin haematoma and one had meralgia paresthetica, both of which resolved spontaneously and were most likely related to the large 14F sheath used for Artisan™. One patient developed congestive heart failure 24 hours post procedure, which was related to the underlying structural heart disease and significant fluid infusion (at 17 ml/min) necessary at the time for cooling of the ablation catheter. Septicaemia was suspected in one case, which was probably co-incidental and was controlled with antibiotic therapy and supportive measures. There were two intermediate-level complications. One patient developed a groin arteriovenous fistula, which was related to the large 14F sheath and was repaired surgically. One patient had lateonset pericardial effusion (on postoperative day 10), which was

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most likely related to fluid overload and inflammatory response to ablation and was treated successfully with pericardiocentesis. There were three major complications. One patient had cardiac tamponade, treated immediately with pericardiocentesis. The patient was female and rather small in size. Another patient had left atrial perforation, which was repaired surgically. Similarly, the patient was female and rather small in size. This case was caused by ‘catheter snap’ during ablation on the upper aspect of the ridge between the appendage and left superior pulmonary vein (LSPV). Poor tissue quality/elasticity probably contributed to this complication, as the patient had rheumatoid arthritis and was on long-term methotrexate therapy. One patient had aspiration pneumonia and blurring in the right eye due to embolus; his vision recovered after two months. This complication occurred because the patient was morbidly obese (160 kg) and it was difficult to keep his ACT above 250 s; he seemed resistant to unfractionated heparin. No case of pulmonary vein stenosis, transient ischaemic attack or stroke was reported throughout the post-procedure follow up.

Follow up for relapse As of March 2011, patients were followed up for an average of 13.4 ± 3.6 months. A freedom from AF of 94.7% was achieved after an average of 1.15 attempts per patient. One patient refused to undergo more attempts after developing relapse, and four patients (4.2%) finally underwent AV node ablation with placement of a permanent pacemaker, one of which had developed late-onset relapse 13 months after robotically assisted ablation. Five patients (5.3%) underwent a redo ablation within the six-month follow up, seven patients (7.4%) had a redo procedure after six months, and one patient received two redo

95 patients 1st robotic ablation

78 free from relapse

69 off AAD

17 developed relapse

15 relapse within 6 months

9 on AAD

6 on previously ineffective AAD

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3 on new AAD

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1 AVN ablation (already had a PPM)

2 relapse after 6 months

2 without redo ablation

1 AVN ablation + PPM after 1st redo 1 without redo ablation

1 controlled after 2nd redo 2 AVN ablation + PPM after 1st redo

Fig. 3. Flow chart showing outcomes for the whole study group; AAD, antiarrhythmic drugs; AVN, atrioventricular node; PPM, permanent pacemaker.

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ablations at five and 10 months (Fig. 3). The nine-month follow-up period was completed for 100% of patients; no cardiac mortality was observed among the study population within the nine-month period. However, one patient died of prostate cancer seven months post ablation. After one attempt, 26 patients (27.4%) were discharged from hospital off any sort of AADs. At nine months’ follow up, 70 patients (73.7%) were free from arrhythmia off AADs, and 10 (10.5%) were AF-free on AADs, yielding a total freedom from AF of 84.2% without any redo procedures (Table 3). Considering those patients who relieved completely after a redo procedure within the nine months post ablation, freedom from relapse rose to 88.4%. Multivariate logistic regression analysis showed that longerstanding types of AF and ablation (radiofrequency) time are independent predictors of arrhythmia relapse within the ninemonth period post ablation therapy (Table 4).

Discussion This is the first report on mid-term efficacy of robotically navigated catheter ablation in an unselected subset of patients with predominantly persistent AF. Overall success rate without any redos reported in this study is comparable to the results obtained in the largest randomised, controlled trial (n = 390 total; 197 robotic arm) performed to date by Di Biase et al. (84.2 v 85%).11 In the subset of patients with persistent AF, the results of this study compare favourably to that reported by Di Biase et al. (82 vs 70.9%).11 These results bolster our confidence in the robotic system as an efficacious treatment modality for patients with persistent AF. The overall mid-term success rate of 88.4% after the 1.12 procedures per patient reported in this study is comparable to the results reported by Hlivak et al. (n = 69, success rate 86% after 1.2 procedures per patient).13 These studies consistently show that robotic ablation is also a clinically viable option for redo procedures in patients who do not respond to ablation on the first attempt. Recently, an updated worldwide survey on the methods, efficacy and safety of manual catheter ablation for AF showed that across all surveyed centres, median overall success rates were 84.0% (79.7–88.6%; n = 9 590), 74.8% (66.1–80.0%; n = 4 712) and 71.0 (67.4–76.3%; n = 1 853) for paroxysmal, persistent and long-standing AF, respectively. For the main subset of patients in this study (i.e. patients with persistent AF), we see that overall success rate with the robotic ablation compared favourably with that of manual ablation. Given that robotic ablation technology, techniques and catheters are still in their infancy, the efficacy of this treatment modality has the potential to reliably surpass its manual counterpart in the near future. TABLE 3. FIRST-ATTEMPT SUCCESS RATES IN RELATION TO THE TYPE OF AF AND ANTIARRHYTHMIC DRUGS (AADs)

Type of AF Paroxysmal Persistent Long-standing persistent

Success off AADs n (%) 12/12 (100) 57/58 (98) 0/0

Success on AADs n (%) 1/1 (100) 6/19 (32) 2/5 (40)

Overall success n (%) 13/13 (100) 63/77 (82) 2/5 (40)

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As shown by the multivariate analysis, longer-standing types of AF and ablation (radiofrequency) time are independent predictors of arrhythmia relapse within the nine-month period post ablation therapy (Table 3). As described in the methods section, some of the more complex cases required ablation along the endocardial aspect of the coronary sinus or in an attempt to terminate the flutter or focal atrial tachycardia in addition to the standard PV isolation. Therefore, longer ablation time in fact points to a more complex underlying arrhythmia circuitry, which is the most likely explanation for its correlation with higher frequency of relapse. Association of long-standing AF type with higher relapse rate may also be related to the same aetiology. In general, because the robotic navigation system significantly reduces physical operator strain, mitigates concerns over excessive radiation exposure during complex cases, and enables operators to perform complex ablation patterns regardless of catheter skills, operators are more likely to take on more complex and challenging AF cases. Hence, we expect to see longer ablation times as a surrogate for more complex cases associated with higher relapse rates in future studies. As shown in Fig. 1, mean procedure and fluoroscopy times were statistically reduced after the first fifth of the patients (n = 19). Furthermore, fluoroscopy time showed a linear decrescendo trend for the first half of the patients (n = 48), after which point it reached a plateau. This observation was in line with the results reported by Di Biase et al., who showed statistically significant reduction in fluoroscopy time after the first 50 cases.11 These observations confirm that there is a learning curve in using the robotic navigation system and that operators can anticipate further reduction in fluoroscopy time, and hence safer operation once they overcome this learning curve. Reduction in procedure time allows for shorter cases, less physical operator strain and higher laboratory throughput. Regarding major complications related to the robotic navigation system, specifically the incidence of cardiac tamponade and left atrial perforation, Hansen Medical’s new Lynx™ catheter, which is smaller in size (requires a 12F sheath) and more gentle (less rigid and lighter) than the Artisan™ catheter used in all the procedures reported herein, will probably reduce the risk of these complications, especially in small female patients with previous tissue quality/elasticity problems. Arteriovenous fistula, considered here as an intermediate-level complication, will likely occur less frequently with the new Lynx™ catheter that requires a 12F sheath as opposed to the 14F sheath size of Artisan™. Additionally, the next generation of ablation catheters such as Carto SF (Biosense-Webster, Diamond Bar, CA, USA), TABLE 4. MULTIVARIATE LOGISTIC REGRESSION ANALYSIS OF AF RELAPSE PREDICTORS AFTER ROBOTIC ABLATION Variable Age Concomitant flutter AF type Mapping system/ablation catheter Procedure time Radiofrequency time Screening time

Odds Ratio 0.9957 0.8580 12.8330 1.8701 0.9835 1.0508 1.0177

95% CI 0.9386–1.0562 0.2334–3.1539 1.4454–113.9412 0.4034–8.6688 0.9700–0.9973 1.0104–1.0929 0.9838–1.0527

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which require a lower infusion rate (8 ml/min) due to design changes, producing more efficient cooling, will reduce the likelihood of post-procedural pericardial effusion or congestive heart failure. Lastly, the smaller size of the new Lynx catheter will significantly reduce the risk of minor complications such as groin haematoma or meralgia paresthetica. It is important to note that despite our modified post-ablation anticoagulation regimen, which differs substantially from the international guidelines due to poor patient compliance with anticoagulation on warfarin and INR testing, no case of transient ischaemic attack or stroke was reported in the median ninemonth post-ablation period. Physicians who care for similar types of patients in areas where compliance is an issue may find our modifications to the standard post-ablation anticoagulation regimen helpful. The main limitations of this study are the fact that it lacked a matched control group with manual ablation and that there were relatively few subjects in the paroxysmal and long-standing persistent AF groups. Furthermore, some of the therapeutic modifications presented in this article, mainly the modified post-ablation anticoagulation regimen, were based on clinical experience and characteristics of our specific patient population and are not in conformity with international guidelines. Hence, we do not propose that our methods be adopted by other centres. As a real-world study, we were treating symptomatic patients, with the main clinical endpoint being relief of symptoms. We were not able to confirm the absence of asymptomatic recurrence of AF without ECG Holter monitoring. Nevertheless, we believe that the safety and mid-term efficacy results of this study may provide valuable insights for the daily practice of medicine.

Conclusion The Sensei™ robotic navigation system offers a safe and effective approach for the treatment of AF. Its efficacy in patients with persistent AF is encouraging. Its overall success rate is comparable to manual techniques and impressive for a treatment approach that is relatively in its infancy. There is a learning curve with regard to fluoroscopy and procedure times, after which point reduction in radiation exposure and operator strain, as well as improvement in procedure throughputs are even more pronounced. Lynx™ as well as the newer generation of ablation catheters compatible with the Sensei™ system offer operators the possibility of even safer procedures with lower risks for complications. We acknowledge the anaesthetists, Drs Dirk Lilienfeld, Adi Smit, Claire Zondagh and Rene Verbeek, who worked on the patients.

7. 8.

10.

11.

12.

13.

14.

References 1.

Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation). J Am Coll Cardiol 2006; 48: 854–906. Pappone C, Santinelli V. Atrial fibrillation ablation: State of the art. Am

15. 16.

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J Cardiol 2005; 96: 59L–64L. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) task force on catheter and surgical ablation of atrial fibrillation developed in partnership with the European Heart Rhythm Association (EHRA) and the European Cardiac Arrhythmia Society (ECAS); in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). Endorsed and approved by the governing bodies of the American College of Cardiology, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, and the Heart Rhythm Society. Europace 2007; 9: 335–379. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA, 3rd, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline). A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2011; 57: 223–242. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task force for the management of atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429. Willems S, Hoffmann B, Steven D, Drewitz I, Servatius H, Mullerleile K, et al. Catheter ablation for atrial fibrillation: Clinically established or still an experimental method? Herz 2008; 33: 402–411. Pappone C, Santinelli V. Towards a unified strategy for atrial fibrillation ablation? Eur Heart J 2005; 26: 1687–1688; author reply: 1688. Chun KR, Schmidt B, Kokturk B, Tilz R, Furnkranz A, Konstantinidou M, et al. Catheter ablation – new developments in robotics. Herz 2008; 33: 586–589. Saliba W, Reddy VY, Wazni O, Cummings JE, Burkhardt JD, Haissaguerre M, et al. Atrial fibrillation ablation using a robotic catheter remote control system: initial human experience and long-term follow-up results. J Am Coll Cardiol 2008; 51: 2407–2411. Wazni OM, Barrett C, Martin DO, Shaheen M, Tarakji K, Baranowski B, et al. Experience with the Hansen robotic system for atrial fibrillation ablation – lessons learned and techniques modified: Hansen in the real world. J Cardiovasc Electrophysiol 2009; 20: 1193–1196. Di Biase L, Wang Y, Horton R, Gallinghouse GJ, Mohanty P, Sanchez J, et al. Ablation of atrial fibrillation utilizing robotic catheter navigation in comparison to manual navigation and ablation: single-center experience. J Cardiovasc Electrophysiol 2009; 20: 1328–1335. Steven D, Servatius H, Rostock T, Hoffmann B, Drewitz I, Mullerleile K, et al. Reduced fluoroscopy during atrial fibrillation ablation: benefits of robotic guided navigation. J Cardiovasc Electrophysiol 2010; 21: 6–12. Hlivak P, Mlcochova H, Peichl P, Cihak R, Wichterle D, Kautzner J. Robotic navigation in catheter ablation for paroxysmal atrial fibrillation: Midterm efficacy and predictors of postablation arrhythmia recurrences. J Cardiovasc Electrophysiol 2011; 22(5): 534–540. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias – executive summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPEHeart Rhythm Society. J Am Coll Cardiol 2003; 42: 1493–1531. Malcolme-Lawes L, Kanagaratnam P. Robotic navigation and ablation. Minerva Cardioangiol 2010; 58: 691–699. Koyama T, Tada H, Sekiguchi Y, Arimoto T, Yamasaki H, Kuroki K, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56: 1463–1472.

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Review Article The prevalence and outcome of effusive constrictive pericarditis: a systematic review of the literature MPIKO NTSEKHE, CHARLES SHEY WIYSONGE, PATRICK J COMMERFORD, BONGANI M MAYOSI

Abstract There is sparse information on the epidemiology of effusive constrictive pericarditis (ECP). The objective of this article was to review and summarise the literature on the prevalence and outcome of ECP, and identify gaps for further research. The prevalence of ECP ranged from 2.4 to 14.8%, with a weighted average of 4.5% [95% confidence interval (CI) 2.2–7.5%]. Sixty-five per cent (95% CI: 43–82%) of patients required pericardiectomy regardless of the aetiology. The combined death rate across the studies was 22% (95% CI: 4–50%). The prevalence of ECP is low in nontuberculous pericarditis, while pericardiectomy rates are high and mortality is variable. In this review, of 10 patients identified with tuberculous ECP, only one presumed case had a definite diagnosis of ECP. Appropriate studies are needed to determine the epidemiology of ECP in tuberculous pericarditis, which is one of the leading causes of pericardial disease in the world. Keywords: effusive constrictive pericarditis, prevalence, pericardiectomy and death Submitted 14/6/11, accepted 22/11/11 Cardiovasc J Afr 2012; 23: 281–285

www.cvja.co.za

DOI: 10.5830/CVJA-2011-072

Effusive constrictive pericarditis (ECP) is a clinical haemodynamic syndrome in which constriction of the heart by the visceral pericardium occurs in the presence of a compressive pericardial effusion. ECP is believed to be a rare manifestation of pericardial disease1 that occurs as part of a continuum from effusive to constrictive pericarditis. The outcome of ECP with regard to the development of constrictive pericarditis, pericardiectomy rates and death is not well defined.2 In the only prospective study of ECP, the prevalence was 6.8% of patients undergoing pericardiocentesis and 1.2% of all patients Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa MPIKO NTSEKHE, MD, PhD, mpiko.ntsekhe@uct.ac.za PATRICK J COMMERFORD, MBChB BONGANI M MAYOSI, DPhil (Oxon)

Institute of Infectious Disease and Molecular Medicine, and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa CHARLES SHEY WIYSONGE, MD

referred with effusive pericarditis.3 In the same study, 46.7% of participants with the diagnosis underwent pericardiectomy within four months, and the overall mortality rate was 60% over the subsequent seven-year mean follow-up period.3 The influence of the aetiology of pericarditis on the prevalence and outcome of ECP is not known. For example, tuberculous pericarditis is associated with significant inflammation,4 chronicity,5 and a high rate of development of constrictive pericarditis in about 25% of cases.5-7 It is likely therefore that the prevalence of ECP in patients with tuberculous pericarditis may be much higher than seen in acute forms of pericardial disease, such as idiopathic or viral pericarditis, which have formed the basis of the previous studies of ECP.8 With regard to the natural history, in the study of SagristaSauleda, those with neoplastic disease had a high mortality and low pericardiectomy rate, whereas those with idiopathic disease had a low mortality rate but high pericardiectomy rate.3 The impact of the aetiology of pericarditis on these outcomes of ECP among patients whose life expectancy is not severely limited by malignant disease is not known. There are very few investigators who have used the ‘gold standard’ to establish the diagnosis of ECP, which is invasive measurement of intra-pericardial and intra-cardiac pressures before and after pericardiocentesis.2 Even though non-invasive tools, such as echocardiography and magnetic resonance imaging are gaining wider acceptance as methods for establishing the diagnosis,9 none has been compared to invasive haemodynamic diagnosis of ECP.9,10 It has been proposed that visceral pericardiectomy may be necessary for a good clinical result in cases with ECP because drainage of pericardial fluid alone leads to incomplete relief of cardiac compression.3 The timely recognition of ECP therefore enables the clinician to choose the most appropriate therapy. Information about the prevalence and outcome of ECP is particularly important in the developing world, where tuberculosis causes hundreds of thousands of cases of pericarditis every year.5 There are at present no recommendations on the diagnosis and management of ECP in tuberculous pericarditis. We have conducted a systematic review of the literature to determine the prevalence and outcome of ECP in patients with viral, tuberculous, uraemic, purulent and idiopathic pericarditis. The outcomes of interest were pericardiectomy and mortality rates at 12 months. Furthermore, we determined whether the prevalence and the outcome of ECP were related to the aetiology of the effusion. We limited the review to observational studies of pericarditis due to these non-neoplastic medical conditions that commonly progress to constrictive pericarditis.1

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Methods MEDLINE, EMBASE and Google Scholar were searched for English-language publications of observational studies of ECP that were conducted from inception of the respective database through to December 2009. Search terms included: acute pericarditis, pericardial effusion, ECP, pericardial tamponade, cardiac tamponade, tuberculous pericarditis, uraemic pericarditis, purulent pericarditis, idiopathic pericarditis, viral pericarditis and constrictive pericarditis. Limits included: the English language, human beings and the following MeSH terms (‘Case-Control Studies’[MeSH] OR ‘Cohort Studies’[MeSH] OR ‘Epidemiologic Studies’[MeSH] OR ‘Cross-Sectional Studies’[MeSH] OR ‘Retrospective Studies’[MeSH] OR ‘Prospective Studies’[MeSH]). In addition to searching the databases, we contacted researchers in the field, and searched the bibliographies of published reviews and studies on pericardial disease for relevant studies. The eligibility criteria for inclusion and exclusion from the study, which are based on the Loney criteria for critical appraisal of research articles on prevalence of disease, are shown in Table 1.11 To be included in the review, a study had to provide sufficient information to enable determination of the proportion of study participants diagnosed with ECP and at least six other eligibility criteria. Studies where malignancy was the predominant cause of pericarditis were excluded from this systematic review because patients with this diagnosis generally do not survive long enough to develop constrictive pericarditis.1,12 Studies of patients with pericardial effusion that resulted from aortic dissection, myocardial infarction, and trauma to the thorax were also excluded because pericardial sequelae are uncommon among long-term survivors of these conditions.1,13-15 After the relevant studies were selected, individual patient data were extracted and reviewed in order to exclude patients with malignancy-associated ECP. Where relevant data could not TABLE 1. ELIGIBILITY CRITERIA FOR STUDIES OF THE SYSTEMATIC REVIEW Inclusion criteria 1. The study design was observational (case control, cross sectional and cohort); cross sectional studies were accepted for the determination of prevalence. 2. A definition of the syndrome of effusive constrictive pericarditis was given. 3. The inclusion and exclusion criteria for the participants were clearly stated. 4. There was a clear description of the number of participants in the study. 5. The number or proportion of participants in the study with effusive constrictive pericarditis was clearly stated. 6. The method of diagnosis of effusive constrictive pericarditis was described and determined in an unbiased manner. 7. There was an adequate description of the study setting. 8. There was an adequate description of the study population. Exclusion criteria 1. The number or proportion of participants with effusive constrictive pericarditis was not available. 2. The aetiology of pericarditis was a malignancy, myocardial infarction, aortic dissection, or trauma to the thorax. 3. The diagnosis of effusive constrictive pericarditis was based on clinical assessment only.

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be extracted from the published manuscripts, we were able to obtain the information on individual participants from the study authors. We conducted a meta-analysis of the individual patient data using the StatsDirect software (www.statsdirect.com). For the meta-analysis, StatsDirect first transformed proportions into a quantity (the Freeman-Tukey variant of the arcsine square roottransformed proportion) suitable for the usual fixed and randomeffects summaries.16,17 The pooled prevalence was calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed-effects model16 and DerSimonian-Laird17 weights for the random-effects model. We used the Cochran Q test to assess statistical heterogeneity between studies and, in the absence of significant heterogeneity (p > 0.1), combined the data using a fixed-effects method. Otherwise, we used the random-effects method. In addition, we used Higgins I2 statistic to quantify inconsistency across the studies included in the meta-analysis. The test statistic describes the percentage of the variability in effect it estimates that is due to true heterogeneity rather than chance. The closer the I2 value is to 100%, the more likely it is that true heterogeneity exists, and therefore the less reliable the combined estimate becomes. MN conducted the electronic searches and selected the studies, all of which were reviewed by CW and BMM. The reporting of the systematic review is in keeping with standard recommendations for reporting systematic reviews of observational studies.18

Definitions Effusive constrictive pericarditis was classified as definite or probable, based on the methods used to establish the diagnosis.2,9 Studies where the diagnosis was based on clinical assessment alone were rejected. Patients were classified as having definite ECP if the diagnosis was based on intra-pericardial and intra-cardiac haemodynamics, determined before and after pericardiocentesis. This haemodynamic definition required that: (1) the pre-pericardiocentesis transmural filling pressure (i.e. the difference between the elevated intra-pericardial pressure and the right atrial pressure) was less than 2 mmHg; (2) the post-pericardiocentesis intra-pericardial pressure fell to near 0 mmHg; and (3) the post-pericardiocentesis right atrial pressure failed to fall by 50% or to a level below 10 mmHg.3 The diagnosis of ECP was considered probable if it was established on the basis of echocardiography or magnetic resonance imaging. There are no published prospectively derived consensus diagnostic criteria for ECP using these imaging modalities,9 but widely accepted criteria include evidence of the following criteria in a patient with a pericardial effusion: (1) pericardial thickening; (2) abnormal or paradoxical movement of the interventricular septum; (3) a plethoric dilated inferior vena cava with reduced narrowing during inspiration; and (4) marked respiratory variation of the mitral inflow Doppler pattern. Finally, the diagnosis of ECP was rejected if it was established without ancillary imaging or haemodynamic assessment, i.e. if the diagnosis was made on clinical assessment alone.

Results A flow chart for the selection process is provided in Fig. 1. Five

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studies were included in the systematic review.3,19-22 The five studies had a total of 642 patients, 26 of whom met diagnostic criteria for ECP; 58% (15/26) had probable ECP and 42% (11/26) definite ECP. Of the 26 patients, 50% (13/26) had idiopathic pericarditis, 38% (10/26) had tuberculous pericarditis, 8% (2/26) had post-radiation pericarditis and 4% (1/26) postpericardiotomy pericarditis.

Prevalence of effusive constrictive pericarditis The study design and strength of diagnosis of ECP varied across the five selected studies. Three of the five studies were prospective cohorts.3,19,21 One of the three prospective case series was a single-centre South African study, designed to determine the 30-day and one-year outcomes of consecutive patients with predominantly tuberculous pericarditis, who were each given a standardised therapeutic protocol, which included pericardiocentesis.19 The proportion of those with ECP was 2.6% based on clinical and echocardiographic criteria. The second prospective case series was a single-centre French study designed to determine the role of surgical pericardioscopy as a diagnostic tool among patients with large pericardial effusion of uncertain aetiology.21 The proportion of patients diagnosed with ECP was reported as 1.4%. All patients underwent pericardiocentesis, and echocardiography was used to assess pericardial physiology and content. The third prospective case series was a single-centre Spanish study, which aimed to determine the prevalence of ECP and the incidence of pericarditis-related outcomes over a median followup period of seven years.3 Consecutive participants presenting with a diagnosis of pericardial tamponade over 15 years underwent measurement of the pre- and post-pericardiocentesis intra-pericardial and right atrial pressures. The prevalence of ECP was 5.8% in those patients undergoing pericardiocentesis, 6.8% in those with clinical tamponade, and 0.93% in patients with any pericardial disease.3 The remaining two studies of patients with a probable diagnosis of ECP were designed to (1) determine the longterm outcome of patients with symptomatic effusion;22 and (2) 1 138 potentially relevant publications 1 089 articles eliminated after review of the titles and abstract 49 articles evaluated Three studies excluded because diagnosis of ECP established by clinical assessment only

No data on proportion of patients with ECP in 41 studies

Five articles selected for inclusion in review Fig. 1. Flow chart for selection process.

compare echocardiographic differences between tuberculous and idiopathic pericardial effusions.20 The prevalence of ECP in these two studies was 4.3 and 14.8%, respectively. Overall there was significant variability in the prevalence of ECP across the five studies (p = 0.04; I2 = 61%); therefore we used both the random-effect and fixed-effect meta-analysis models to combine the prevalence. Using the fixed-effect model, the pooled prevalence of ECP in the five studies was 4.0% (95% CI: 2.7–5.7%). This increased marginally to 4.5% (95% CI: 2.2–7.5%) using the random-effects model (Fig. 2).

Outcomes of patients with effusive constrictive pericarditis One-year mortality data was available for only nine participants with non-malignant disease from two studies.19,22 These mortality rates are provided in Table 2. Two of the nine patients were dead at 12 months; one from peri-operative complications, and the other with tuberculous ECP died while awaiting pericardiectomy. The combined death rate across the studies was 22%, with wide 95% confidence intervals (4–50%) due to the small numbers involved. Seven patients did not undergo pericardiectomy. These seven included: the patient with tuberculosis who died from heart failure while awaiting surgery, three participants, also with tuberculosis, who did not consent to the procedure, and three participants with idiopathic disease in whom a conservative ‘wait-and-see’ approach had been adopted. The six participants, who survived the early stages of their illness without surgery were alive and well at their last follow-up visit. Only three of the studies provided data on the pericardiectomy rates.3,19,22 Overall, the combined pericardiectomy rate was 65% (95% CI: 43–82%) and the between-study variability in pericardiectomy rates was marginally significant (p = 0.10; I2 = 56%). A breakdown of the pericardiectomy rates by aetiology revealed that 73% of participants with idiopathic ECP, 60% of those with tuberculous ECP, and 50% of those with ECP of other aetiologies underwent the pericardiectomy. The persistence of heart failure was the reason for surgery in 54% of cases, making it the most common indication, followed by prophylaxis against progression to fibrous constrictive pericarditis in 23%. Recurrence of pericardial effusion was an indication in 15%. In only 8% was the operation performed Reuter 2007

2.5% (0.9, 6.0)

Tsong 2003

4.3% (1.2, 10.8)

Sagrista-Sauleda 2004

5.5% (2.9, 10.1)

Nugue 1995

1.4% (0.2, 5.0)

George 2004

14.8% (4.2, 33.7)

Combined

4.5% (2.2, 7.5)

Prevalence (95% confidence interval)

Fig. 2. Forest plot for the prevalence of ECP (random effects).

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TABLE 2. 12-MONTH MORTALITY AND PERICARDIECTOMY RATES OF PARTICIPANTS WITH NON-NEOPLASTIC EFFUSIVE CONSTRICTIVE PERICARDITIS Absolute number of study participants with Study non-neoplastic ECP Sagrista-Sauleda 2004 11 Reuter 2007 5 Tsang 2003 4 Nugue 1996 2 George 2004 4 Total 26

Number of patients with ECP who underwent pericardiectomy within 12 months 7/11 (64%) 2/5 (40%) 4/4 (100%) Pericardiectomy data not available Pericardiectomy data not available 13/20 (65%)

because of progression to non-effusive fibrous constrictive pericarditis.

Discussion This systematic review highlights that there are very few prospective studies on the prevalence and outcome of ECP. The prevalence of this syndrome in the available studies ranged from 1.4 to 14%. Although there was little information to ascertain the mortality rate reliably, the pericardiectomy rate was clearly high (44–100%). There was a total of 10 participants who had effusive constrictive tuberculous pericarditis in this review, one of whom had a definite diagnosis of ECP. Commerford and Strang have suggested that ECP may be a common form of presentation of tuberculous pericarditis that frequently progresses to fibrous constrictive pericarditis.8 By contrast, the IMPI Africa Registry has suggested that using clinical criteria alone, ECP may be present in only 15% of cases of tuberculous pericarditis.23 The results of this comprehensive review show a low prevalence of ECP in patients with tuberculous pericarditis, which ranged from 3 to 14%. It is noteworthy that there are no studies that have systematically used an invasive haemodynamic method to establish the diagnosis of effusive constrictive disease in patients with tuberculous pericarditis. There is therefore a need for a definitive study of the prevalence of tuberculous ECP that is based on invasive haemodynamic methods. Although the pericardiectomy rate across the studies was high, the indications for surgical intervention were not uniform among the 13 participants who had the operation. A significant proportion of patients who were managed conservatively had complete resolution of their effusive constrictive disease. This suggests that there is room for a study to test a strategy of watchful waiting compared to prophylactic pericardiectomy in those without persistence of heart failure. Finally, the mortality rate for tuberculous pericarditis in the HIV era is as high as 40% in patients with AIDS, at the end of six months of treatment with anti-tuberculosis medication.24 Despite the absence of data on mortality in patients with non-neoplastic ECP, it is possible that because of its well-documented haemodynamic sequelae,2 the pericardial syndrome is associated with a higher mortality rate than those without the syndrome.

and the impact of the syndrome on mortality, a study of wellcharacterised participants with adequate follow up and clearly defined outcomes is required to inform the development of clinical guidelines on the diagnosis and management of effusive constrictive pericardial disease.

References 1.

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5. 6. 7.

10. 11.

12.

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Conclusion In light of the lack of clarity on the prevalence of ECP among patients with proven tuberculous pericarditis, the role of prophylactic pericardiectomy in cases of varying aetiology,

Number of patients with ECP dead at 12 months Mortality data at 12 months not available for all patients 2/5 (40%) 0/4 (0%) Mortality data not available Mortality data not available 2/9 (22%)

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Cameron J, Oesterle SN, Baldwin JC, Hancock EW. The etiologic spectrum of constrictive pericarditis. Am Heart J 1987; 113(2 Pt 1): 354–360. Hancock EW. A clearer view of effusive-constrictive pericarditis. New Engl J Med 2004; 350(5): 435–437. Sagrista-Sauleda J, Angel J, Sanchez A, Permanyer-Miralda G, SolerSoler J. Effusive-constrictive pericarditis. N Engl J Med 2004; 350(5): 469–475. Reuter H, Burgess LJ, Carstens ME, Doubell AF. Characterization of the immunological features of tuberculous pericardial effusions in HIV positive and HIV negative patients in contrast with non-tuberculous effusions. Tuberculosis (Edinb) 2006; 86(2): 125–133. Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis. Circulation 2005; 112(23): 3608–3616. Desai HN. Tuberculous pericarditis. A review of 100 cases. S Afr Med J 1979; 55(22): 877–880. Schrire V. Experience with pericarditis at Groote Schuur Hospital, Cape Town: an analysis of one hundred and sixty cases studied over a six-year period. S Afr Med J 1959; 33: 810–817. Commerford PJ, Strang JIG. Tuberculous pericarditis. In: Coovadia HM, Benatar SR, eds. A Century of Tuberculosis South African Perspectives. 1st edn. Capetown: Oxford University Press, 1991: 123–137. Zagol B, Minderman D, Munir A, D’Cruz I. Effusive constrictive pericarditis: 2D, 3D echocardiography and MRI imaging. Echocardiography 2007; 24(10): 1110–1114. Grizzard JD. Magnetic resonance imaging of pericardial disease and intracardiac thrombus. Heart Fail Clin 2009; 5(3): 401–419, vii. Loney PL, Chambers LW, Bennett KJ, Roberts JG, Stratford PW. Critical appraisal of the health research literature: prevalence or incidence of a health problem. Chronic Dis Can 1998; 19(4): 170–176. Colombo A, Olson HG, Egan J, Gardin JM. Etiology and prognostic implications of a large pericardial effusion in men. Clin Cardiol 1988; 11(6): 389–394. Ling LH, Oh JK, Schaff HV, Danielson GK, Mahoney DW, Seward JB, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation 1999; 100(13): 1380–1386. Correale E, Maggioni AP, Romano S, Ricciardiello V, Battista R, Salvarola G, et al. Comparison of frequency, diagnostic and prognostic significance of pericardial involvement in acute myocardial infarction treated with and without thrombolytics. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI). Am J Cardiol 1993; 71(16): 1377–1381. Correale E, Maggioni AP, Romano S, Ricciardiello V, Battista R, Santoro E. Pericardial involvement in acute myocardial infarction in

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the post-thrombolytic era: clinical meaning and value. Clin Cardiol 1997; 20(4): 327–331. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22(4): 719–748. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3): 177–188. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. J Am Med Assoc 2000; 283(15): 2008–2012. Reuter H, Burgess LJ, Louw VJ, Doubell AF. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J South Afr 2007; 18(1): 20–25. George S, Salama AL, Uthaman B, Cherian G. Echocardiography in differentiating tuberculous from chronic idiopathic pericardial effusion.

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Heart 2004; 90(11): 1338–1339. 21. Nugue O, Millaire A, Porte H, de Groote P, Guimier P, Wurtz A, et al. Pericardioscopy in the etiologic diagnosis of pericardial effusion in 141 consecutive patients. Circulation 1996; 94(7): 1635–1641. 22. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Outcomes of clinically significant idiopathic pericardial effusion requiring intervention. Am J Cardiol 2003; 91(6): 704–707. 23. Mayosi BM, Wiysonge CS, Ntsekhe M, Volmink JA, Gumedze F, Maartens G, et al. Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry. BMC Infect Dis 2006; 6: 2. 24. Mayosi BM, Wiysonge CS, Ntsekhe M, Gumedze F, Volmink JA, Maartens G, et al. Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa. S Afr Med J 2008; 98(1): 36–40.

Letter to the Editor Comment on: A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa Dear Sir

References

It was with interest that I read the article titled ‘A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa’ by André Pascal Kengne, et al., which was published recently in this journal. In this excellent article, the author introduced the association between cardiovascular diseases and related risk factors by performing a systematic review. However, we feel the article did not cover all aspects of the relationship between cardiovascular disease and related risk factors. Firstly, habits may be very different among different ethnic groups, which is obvious in China, consisting of 56 ethnicities. This would have affected the outcome of the study,1 and it would have been better if there had been further subgroup analysis.2 Secondly, socio-economic status3,4 may be different in different regions in sub-Saharan Africa. Many studies may have come from different levels of hospitals, such as community and central hospitals, which also means that the available medical interventions may have been different.5,6 Thirdly, it is evident that that the study did not include all cardiovascular risk factors.7-9 There was no classification of the selected risk factors.10 All of these factors may increase the differences between the studies and affect the results to a certain extent. There is undoubtedly a need for well-designed, prospective, cohort studies from sub-Saharan Africa to clarify these issues.

Zhen-Hua Gao Ru-Yu Yuan, tjyuanruyu@yahoo.cn Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China

Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups N Engl J Med 2008; 358(13): 1336–1345. 2. Mcclelland RL, Chung H, Detrano R, et al. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2006; 113(1): 30–37. 3. Braveman PA, Cubbin C, Egerter S, et al. Socioeconomic status in health research: one size does not fit all. J Am Med Assoc 2005; 294(22): 2879–2888. 4. Lawlor DA, Davey SG, Patel R, et al. Life-course socioeconomic position, area deprivation, and coronary heart disease: findings from the British Women’s Heart and Health Study. Am J Public Health 2005; 95(1): 91–97. 5. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Br Med J 2009; 338: 1665. 6. Vorster HH, Kruger A, Venter CS, et al. Cardiovascular disease risk factors and socio-economic position of Africans in transition: the THUSA study. Cardiovasc J Afr 2007; 18(5): 282–289. 7. Steyn K, Sliwa K, Hawken S, et al. Risk factors associated with myocardial infarction in Africa: the INTERHEART Africa study. Circulation 2005; 112(23): 3554–3561. 8. Kaptein KI, de Jonge P, van den Brink RH, et al. Course of depressive symptoms after myocardial infarction and cardiac prognosis: a latent class analysis. Psychosom Med 2006; 68(5): 662–668. 9. Zatu MC, van Rooyen JM, Schutte AE. Smoking and vascular dysfunction in Africans and Caucasians from South Africa. Cardiovasc J Afr 2011; 22(1): 18–24. 10. Erbel R, Mohlenkamp S, Moebus S, et al. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol 2010; 56(17): 1397–1406.

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Conference Report Novo Nordisk incretin leadership summit, Cape Town A faculty of top local and international opinion leaders were unanimous at the incretin leadership summit hosted by Novo Nordisk in Cape Town on 5 May 2012. The incretin-based therapies represent a major advance on what was previously available for the treatment and management of type 2 diabetes and are revolutionising the way the condition is viewed.

GLP-1 and the beta-cell Islet cell dysfunction: an underlying defect in the pathophysiology of type 2 diabetes Juris Meier, head: Division of Diabetology and GI Endocrinology, St Josef-Hospital, Ruhr-Universitat, Bochum, Germany

Over the past 10 to 15 years, there has been a shift away from the focus on insulin resistance as the major cause of type 2 diabetes, with increasing recognition of the role of beta-cell mass and function. ‘We now look at many polymorphisms, few of which are found in adipose tissue, bone or the liver. The majority of the genes associated with type 2 diabetes are in the pancreas, making it primarily a pancreatic disease’, said Prof Meier. On average, patients with type 2 diabetes have 65% less beta-cells than non-diabetics, a finding that has been replicated often and in many different populations, irrespective of whether the individuals in question were lean or obese. Prof Meier therefore feels that there is an important relationship between beta-cells and glycaemic control and that

a normal beta-cell mass is required for glucose homeostasis. Autopsy studies have shown that those with type 2 diabetes experience an increased rate of beta-cell apoptosis.1 ‘We have no clear answers yet as to why this is the case, but there are many factors associated with it. In chronic hyperglycaemia, the higher the glucose concentrations, the higher the rate of apoptosis, which means that hyperglycaemia per se accelerates the loss of beta-cells.’ ‘Islet amyloid deposits, which are seldom seen in non-diabetics, are also a likely cause of the apoptosis; they are the result of IAPP, a beta-cytotoxic factor secreted with insulin. Other factors implicated include high concentrations of free fatty acids, endoplasmatic reticulum stress and autoimmune factors.’ He suggested that there might also be treatment-related factors involved over and above these endogenous ones. ‘The consequences of all of this include loss of first-phase insulin secretion, 85% of which is lost in type 2 diabetes patients. Loss of insulin pulsatility leads to peripheral insulin resistance. The clinical implications thereof are deficits in alphaand beta-cell function in the postprandial context, along with disturbances in glucagon secretion. The normal glucoseinduced decline in glucagon is almost absent in type 2 diabetes, leading to postprandial hyperglycaemia.’ Prof Meier cited an animal study, which showed a link between the reduction in insulin secretion, increased glucagon secretion and beta-cell loss.2 ‘Reduction in beta-cell mass in pigs was associated with high fasting glucagon levels, an almost identical picture to that seen in humans.’ There is an inverse relationship between insulin and glucagon, with the former driving down the latter. ‘This inverse interaction is lost in type 2 diabetes, leading to a failure to suppress glucagon’, said Prof Meier. Both insulin resistance and impaired insulin secretion increase the risk of type

2 diabetes, and the major factor driving resistance is obesity. Obese individuals need more than three times as much insulin to maintain normoglycaemia as normal-weight individuals. Those with a body mass index (BMI) > 30 kg/m2 have a 15% greater risk of developing diabetes. ‘But if these are the causes of diabetes, then all obese individuals should develop the condition; yet 85% don’t. The differentiator is that those who don’t have a healthy pancreas develop diabetes, which leads to the conclusion that obesity, insulin resistance and impaired insulin secretion are important co-factors increasing diabetes risk, but are not themselves the underlying causes.’ Turning to the question of whether loss of beta-cell mass or function is the key issue, Prof Meier argued that both are important, as one goes along with the other. ‘If beta-cells are the key problem where insulin impairment in diabetes is concerned, we should be able to restore normal function by normalising betacell mass and function. We’ve shown this by transplanting a healthy pancreas into a previously diabetic patient. After two years, glucose values were normal, evidence that healthy beta-cell mass and function can overcome insulin resistance.’ Summarising, Prof Meier observed that deficits in beta-cell mass can lead to stress and impaired function, allied to disturbances in alpha-cell function and insulin action. Beta-cell mass and function are closely related. ‘Restoration of betacell mass can normalise hyperglycaemia’, he concluded.

Targeting beta cells: the rationale for GLP-1 use in type 2 diabetes Wolfgang E Schmidt, chair and professor of Internal Medicine and director of the Department of Medicine, St JosefHospital, Ruhr-Universitat, Bochum, Germany The UKPDS showed that type 2 diabetes is associated with a progressive decline in beta-cells and by the time they are

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diagnosed, most patients will already have lost 50% of their beta-cells. Prof Schmidt underscored that stopping that decline is a challenge, but that glucagon-like peptide 1 (GLP-1), an incretin whose role in diabetes is increasingly being recognised, could help to achieve some currently unmet treatment goals. The so-called ‘incretin effect’ is severely impaired in type 2 diabetes patients, which suggests that if the ‘something missing’ is reconstituted, the condition could be positively impacted on. ‘The progressive loss of beta-cells starts early in the disease process, during the pre-clinical phase’, he said. ‘Even those who have only impaired fasting glucose levels experience beta-cell loss, and this loss is the basis for the deterioration in glucose control seen in so many studies. Different drugs have differing effects on beta-cell apoptosis. Incretin therapy now gives us the opportunity to intervene by targeting an aspect of islet cell dysfunction that other drugs don’t, namely the alphacell dysfunction/hyperactivity that causes hyperglucagonaemia.’ GLP-1 and 2 were discovered in 1983 and the former’s role in stimulating insulin secretion was identified in 1985. ‘It’s a player in the pathophysiology of diabetes as well as a promising candidate for therapy’, observed Prof Schmidt. ‘It normalises glucose levels in poorly controlled type 2 diabetes without inducing hyperglucagonaemia. Betacells are resensitised to glucose, elevated glucagon levels are reduced, and because GLP-1 is glucose dependent, its effects taper off as glucose levels normalise, therefore also minimising the risk of hypoglycaemic episodes. Because higher doses of GLP-1 improve the insulin response in type 2 diabetes, elevating GLP-1 levels is the basis for the therapeutic concept behind the use of GLP-1 analogues. One such

analogue, liraglutide, has been shown to improve both phases of insulin secretion. Its restoration of beta-cell sensitivity is an immediate effect, and it also works in a chronic setting, improving metabolic control, with positive effects on glycaemia, weight loss, insulin secretion and insulin sensitivity. ‘Liraglutide improves two markers of beta-cell function, HOMA-B and the pro-insulin/insulin ratio’, said Prof Schmidt. ‘Animal and in vitro studies have shown that it promotes beta-cell survival, stimulating proliferation and inhibiting apoptosis and, as a consequence, increasing mass.’ He added the rider that while the evidence for proliferation is currently indirect, it is hoped that longrunning clinical studies will, in time, confirm this. Liraglutide’s induction of weight loss, as seen in the LEAD studies,3-8 is a key advantage of the treatment. More than 75% of patients on liraglutide lost weight, with one-quarter losing an average of 7.7 kg. ‘Data from LEAD also support its being used as early as possible to preserve beta-cell mass and function, with greatest effectiveness seen in those with early-stage type 2 diabetes who still had a relatively high beta-cell mass.’ In conclusion, Prof Schmidt reiterated that targeting islet cell dysfunction resulted in preservation of beta-cell function and mass, with restoration of insulin pulsatility, normalisation of excessive glucagon secretion and normalisation of excessive hepatic glucose output. ‘GLP1 therapy is a promising option to help achieve this.’

Incretin-based therapies in type 2 diabetes: the clinical evidence Are all incretin-based therapies created equal? Mahomed AK Omar, specialist physician/endocrinologist/diabetologist, Parklands Medical Centre, and honorary professor, Department of Diabetes and Endocrinology, University of KwaZuluNatal, Durban There are two types of incretin therapy, namely GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, each with differing modes of action and hence differing efficacy and safety profiles. Prof Omar began by pointing

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out that endogenous GLP-1 is degraded by DPP-4 and rendered inactive within two minutes. ‘This means we need to prolong the activity of GLP-1 to achieve metabolic effects. We can either inhibit DPP-4 to lengthen GLP-1’s action, or we can use a GLP-1 analogue that acts in the same way as GLP-1, but is not degraded by DPP-4.’ GLP-1 analogues are given subcutaneously. DPP-4 inhibitors are oral medications. Liraglutide is a once-daily GLP-1 analogue with a 97% amino acid sequence similarity to human GLP-1. Its half-life has been prolonged to 13 hours. By contrast, the other GLP-1 analogue, exenatide, has only a 53% sequence homology compared to native GLP-1. It too is resistant to DPP-4 and has a longer half-life, though not as long as liraglutide’s. It is also available in an extended-release delivery system, exenatide ER, which is administered once a week (not available in South Africa). Turning to pharmacodynamics, Prof Omar said that the concentration of active liraglutide is significantly higher than the GLP-1 concentration achievable with a DPP-4 inhibitor. This is significant in that small levels have only modest effects and higher levels are necessary to increase satiety and reduce weight. The clinical advantages of liraglutide have been demonstrated in head-tohead trials. The 1860 LIRA-DDP-4 trial compared liraglutide to the DPP-4 inhibitor, sitagliptin.9 There was a significant drop in HbA1c levels in the liraglutide group, but only a modest benefit in the sitagliptin-treated patients. Sixty per cent of those on liraglutide achieved their target HbA1c level of < 7%, compared with only a quarter of those taking sitagliptin.’ When it came to body weight, liraglutide produced a 3- to 3.6-kg loss, where the drop with sitagliptin was only 1 kg. When it came to side effects, both

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agents were associated with some minor episodes of hypoglycaemia, while there was also some transient nausea with liraglutide’, Prof Omar noted. Patient satisfaction rates were higher with liraglutide. After a year, some sitagliptin patients were switched to liraglutide; they experienced improvements in HbA1c level as well as additional weight loss. ‘It is impressive that patients rated treatment satisfaction higher with an injectable therapy that cased mild gastrointestinal (GI) symptoms than an oral therapy with fewer GI symptoms.’ In the DURATION-2 study, which compared exenatide once weekly to sitagliptin or pioglitazone, superior HbA1c levels were achieved with exenatide ER.10 Sixty per cent of patients reached target on exenatide ER compared with only 30% on sitagliptin. ‘As expected, weight loss was also better with exenatide’, observed Prof Omar. ‘Side-effect profiles were similar, with no major hypoglycaemic episodes and only a low frequency of minor hypoglycaemia.’ So if the GLP-1 analogues are superior to the DPP-4 inhibitors, how do they compare against each other? In LEAD-6, exenatide was compared to liraglutide, with HbA1c level as the primary endpoint.8 Liraglutide had a significantly greater effect in lowering HbA1c levels than exenatide. Those switched from the latter to the former at 26 weeks experienced further improvement. Weight loss was similar with both agents. Where side effects were concerned, there was transient nausea with liraglutide, but the rates of nausea were higher with exenatide and persisted for longer. ‘Antibody formation was also much greater with exenatide, because of its only having a 53% homology with human GLP-1, compared with liraglutide’s 97%’, said Prof Omar. ‘This is significant because these antibodies may blunt exenatide’s effectiveness.’ DURATION-1 compared exenatide twice daily to exenatide ER.11 The latter was associated with a significantly greater drop in HbA1c levels, with many more exenatide ER-treated patients attaining the target of < 7%. Those switched to the ER formulation after 52 weeks experienced further improvements in HbA1c levels, suggesting that exenatide ER is more efficacious than exenatide twice daily. Exenatide ER also had a superior sideeffect profile.

DURATION-6 compared exenatide ER to liraglutide.12 Liraglutide performed better, with 60% of patients reaching their HbA1c target level of < 7%, compared with 52%. Weight-loss results were also better with liraglutide. When it came to side effects, liraglutide was associated with higher rates of nausea and vomiting, while injection site reactions were more common with exenatide ER (published at present as an abstract only). ‘In conclusion, there is evidence that HbA1c lowering is better with GLP-1 analogues than with DPP-4 inhibitors, and that of the former, liraglutide is superior to both exenatide formulations’, said Prof Omar. GLP-1 analogues, liraglutide in particular, also performed better in respect of weight loss. Exenatide ER, however, was superior overall in terms of side effects. Patient satisfaction was higher with the injectable GLP-1 agents than with the oral DPP-4 inhibitors.

Incretin-based therapies: focus on clinical effectiveness Jeffrey Wing, chief physician, professor of Medicine and clinical head, Department of Medicine, Charlotte Maxeke Johannesburg Hospital

There are many challenges and contradictions to be overcome where diabetes is concerned, and we want to have our cake and eat it, with access to therapeutic options that are safe, effective, cheap and free of side effects. This was the view expressed by Dr Wing. The first challenge is the numbers. ‘There has been a 98% increase in the number of diabetics in Africa,13 and South Africa has a strikingly high prevalence. According to the NHLS database, glucose control is poor in patients treated in the public sector, and based on the Ampath/ Lancet databases, the private sector is not doing any better. Rising rates of obesity,

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especially in urban women, are a further clinical challenge, as one can’t address glucose control without also looking at obesity.’ Where contradictions are concerned, normalising HbA1c levels has not yielded the risk reductions expected. ‘It was thought that normalisation of HbA1c levels would lead to better cardiovascular outcomes, yet in the ACCORD trial, intensive glucose lowering led to increased mortality rates, possibly as a result of increased hypoglycaemia and highly significant weight gain’, said Dr Wing. So obesity needs to be addressed. Treatment should not aggravate weight gain, and weight loss would be a bonus. HbA1c levels need to be lowered to < 7%, and with no hypoglycaemia. Looking at current drug options, Dr Wing underscored that metformin is associated with cardiac protection. ‘So you would need a very good reason not to start with metformin. ‘As far as the thiazolidinediones (TZD) are concerned, rosiglitazone is bad, pioglitazone less so. The sulphonylureas do not yield cardioprotection and most do badly relative to metformin, with the exception of gliclazide. So there is a real need for new therapies that lower glucose levels without weight gain and hypoglycaemia, while providing the bonus of cardiovascular protection.’ Dr Wing pointed out that there were very consistent messages coming through with regard to the clinical effectiveness of incretin therapies. ‘Vildagliptin produces very little hypoglycaemia and is associated with little or no weight gain, except when combined with sulphonylureas. There are convincing data that exenatide lowers blood glucose, whether used as monotherapy or in combination with other agents. There is impressive weight loss and little or no hypoglycaemia, except when it is used together with sulphonylureas. ‘The LEAD studies send the same message about liraglutide. It produces impressive reductions in HbA1c levels in various combinations, with similarly impressive weight loss and little or no hypoglycaemia except, once again, when it is combined with sulphonylureas.’ Looking at the composite endpoints of HbA1c lowering, weight loss and minimising of hypoglycaemia, Dr Wing assigned the following grades to the various drugs available. Both the thiazolidinediones (TZD) and

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sulphonylureas failed to impress, with scores of 15 and 33%, respectively. Exenatide was awarded a 72% pass, while liraglutide achieved a 78% pass for achieving composite endpoints. ‘To date, no other class of agent has achieved this level and incretin therapies, whether oral or injectable, perform much better than what we have. High-dose liraglutide will be leading the way.’ He added that it seemed almost greedy to want more, but that liraglutide 1.8 mg also reduced a secondary risk factor, namely systolic blood pressure. ‘The era of the incretins has arrived, and the new guidelines will reflect this’, Dr Wing concluded. ‘Diabetes is a progressive condition and the incretins may well be able to modify the disease process before overt type 2 diabetes manifests, delaying beta-cell failure and providing long-term durability by preserving beta-cell function.’

Early use of incretin-based therapies in type 2 diabetes treatment: clinical benefits Adri Kok, specialist physician, Union Hospital, Gauteng. CEO of Faculty of Consulting Physicians of South Africa, chairperson of the Medical Advisory and Ethics Committee of Netcare, and a director of the South African Private Practitioners Forum

Type 2 diabetes (T2DM) has traditionally been managed algorithmically. Following a T2DM diagnosis, initial interventions are diet and lifestyle modifications. The natural disease progression of T2DM implies that glycaemic control will continue to deteriorate over time and once required, oral therapy (usually metformin first) is prescribed. The dose of metformin is gradually uptitrated as the disease worsens, and when the maximal dose no longer maintains glycaemic

control, a second oral agent may be added; with more than half of patients ultimately requiring insulin therapy. Dr Adri Kok, specialist physician at Union Hospital (Alberton), expressed her views that an algorithmic approach to the management of T2DM is ‘reactive’ and may lead to unacceptable delays in treatment intensification, leaving patients exposed to long periods of hyperglycaemia. Dr Kok expressed particular concern about those patients who are diagnosed late, as is often the case in South Africa. In patients with an HbA1c level > 9%, the recommendation is to implement the early use of insulin therapy combined with oral agents to control initial hyperglycaemia within two weeks. Thereafter, the insulin can be withdrawn and other therapies considered. Dr Kok emphasised that it is of particular importance that pathophysiology, over and above HbA1c levels, needs to be addressed. To provide better glycaemic control and improve treatment outcomes, Dr Kok recommends the implementation of a more pro-active approach than those suggested by historical guidelines. The most recent AACE/ACE guidelines include multiple options for first-line monotherapy, including incretin-based therapy. The incretins are among the many hormones responsible for glucose homeostasis. Incretins, including glucagonlike peptide-1 (GLP-1), are released by intestinal enteroendocrine cells in response to a meal. GLP-1 elicits glucose-dependent insulin secretion; suppresses glucagon secretion, appetite and food intake; slows gastric emptying and stimulates beta-cell proliferation in pre-clinical models. Circulating GLP-1 is short lived; 80% is degraded within two minutes by the enzyme dipeptidyl peptidase-4 (DPP-4). GLP-1 secretion is diminished in patients with T2DM; however its insulinotropic activity is maintained, resulting in the targeting of this hormone for diabetic therapy. Incretin agents include GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists produce effects similar to native GLP-1 and are resistant to degradation by DPP-4. DPP-4 inhibitors inactivate the enzyme responsible for GLP-1 degradation. Exenatide, a synthetic formulation on

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exendin-4, has similar effects to native GLP-1. Concerns surrounding conventional oral diabetic therapies include risk of hypoglycaemia; however, the glucosedependant action of incretin-based therapies provides good glycaemic control with a low risk of hypoglycaemia. The incretin agents are also associated with weight neutrality, or even weight loss, whereas most conventional therapies are associated with weight gain. Also promising are findings that incretin-based therapy may have beneficial effects on beta-cell function, potentially slowing progression of diabetic disease. Dr Kok commented on her practical clinical experience, which included a significant number of patients who were put on liraglutide therapy through compassionate-use approval from the South African Medicines Control Council (MCC) prior to recent regulatory approval of liraglutide in South Africa. In her experience, she had patients losing up to 38 kg of weight while achieving excellent glycaemic control. Dr Kok went on to more closely examine the indications for incretin-based therapy, specifically the GLP-1 receptor agonists. There is a body of evidence supporting the use of GLP-1s across the continuum of disease progression, both as monotherapy and in combination with a number of other agents. Dr Kok advises an early combination approach for early management of glucose levels that can then be maintained. She noted that as yet, it is not known for how long beta-cell failure will be delayed with early use of GLP-1s. ‘Such information should emerge with the GRADE study (Glycaemia Reduction Approaches in Diabetes), a cohort of 7 500 recently diagnosed type 2 diabetes patients. The metabolic effects of five different agents in combination with metformin are being compared; as well as the benefits of early combination therapy versus sequential therapy in drug-naïve patients’, Dr Kok said. Usage trials of exenatide and liraglutide were then presented. Monotherapy trials of exenatide at doses of 5 and 10 µg yielded good results. Compared to placebo, there was a distinct improvement in HbA1c levels, with the higher dose shown to be more effective in reaching target HbA1c levels of < 7.0%. An exenatide ER trial showed the

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best change in HbA1c level, with 49% of patients achieving HbA1c levels of < 6.5%, and 63% achieving HbA1c < 7.0%. In an exenatide monotherapy trial, an average weight loss of 3 kg was evident in patients. ‘However, a number of patients lost significantly more weight, with those on the higher dose (10 µg) losing the most weight’, Dr Kok stressed. Also of note was evidence of betacell protection, particularly as loss of beta-cell mass prior to diagnosis is estimated to be as much as 70%. In these trials, exenatide was used as monotherapy or in combination with metformin, sulfonylureas (SFUs) and thiazolidinediones (TZDs). Exenatide can be safely used with insulin.14 The LEAD-3 trial compared monotherapy with liraglutide (1.2 and 1.8 mg) against glimepiride (sulfonylurea) monotherapy. It was found that the 1.8-mg liraglutide dose proved most effective in HbA1c level change from baseline, with 42% achieving target of < 6.5% and 51% achieving target of < 7.0%, while 27.8% of glimepiride-treated patients reached an HbA1c level of < 7%. The use of liraglutide also showed a 2.8-kg weight benefit over glimepiride, as well as significant benefits in reducing hypoglycaemic events. A trial comparing liraglutide and metformin therapy to therapy with both agents and added insulin detemir showed that the greater the betacell mass (as assessed by baseline HbA1c level) at initiation of liraglutide, the better the treatment outcomes, most likely due to greater beta-cell protection. In summary, Dr Kok noted that liraglutide can be used as monotherapy or in combination with metformin, a sulphonylurea or a TZD. The concurrent use of liraglutide with insulin is still under investigation. Source Dr Adri Kok, Johannesburg. Early treatment prevents loss of glycaemic control and beta-cell function. Campbell, RK. Clarifying the role of incretinbased therapies in the treatment of type 2 diabetes mellitus. Clin Therapeut 2011; 33(5); 511–527.

Incretin-based therapies in clinical practice Dr Ajay Kumar, consultant physician and diabetologist. Director of the Diabetes Care and Research Centre in Patna, India. He also holds a position at the University of Newcastle, Australia and is a committee

member of the Indian Council of Medical Research. He is principal investigator on a number of international phase II, III and IV trials.

Key challenges to be addressed as T2DM progresses are a decline in beta-cell function and beta-cell mass, a deterioration in glycaemic control and an increase in cardiovascular disease. Data from the ACCORD, ADVANCE, UKPDS and VADT trials have indicated that delayed treatment of T2DM can increase the risk of cardiovascular mortality. Anti-diabetic agents themselves may contribute to the development of cardiovascular disease. As early as the 1970s, the UGDP study indicated adverse cardiovascular outcome with the use of early sulfonylureas (tolbutamide). Newer agents within the sulfonylurea family may have varying and reduced degrees of adverse cardiovascular outcome. The availability of incretin-based therapies addresses some of the concerns surrounding progression and treatment of T2DM. Dr Kumar summarised clinical trial data on the safety and efficacy of these therapies, showing successfully improved glycaemic control with a low risk of hypoglycaemia and the added benefit of being weight neutral (DPP-4 inhibitors) or resulting in weight loss (GLP-1 receptor agonists). Evidence of preservation of beta-cell function also emerged. ‘There is limited information on the cardiovascular actions of incretin-based therapy. Short-term studies in human subjects demonstrate modest, yet beneficial action on cardiac function in patients with ischaemic heart disease. These agents also decrease blood pressure and have been shown to reduce inflammation in pre-clinical studies’, Prof Kumar noted. The early advocation of incretin-based therapy in the AACE/ACE (American Association of Clnical Endocrinologists/

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American college of Endocrinology) algorithm underscores the need for those agents to be in our armamentarium – Prof Kumar, Patna, India Although impressed with the very promising results of clinical trials, Dr Kumar did emphasise that the true potential of any therapy cannot be fully determined until it has been extensively used in clinical practice, and that costs, particularly in developing economies such as India, are a limiting factor. Recent findings from the Association of British Clinical Diabetologists (ABCD) suggest that the GLP-1 receptor agonists exenatide and liraglutide have been widely used in clinical practice in the UK since 2008 and 2009, respectively.15 Improvements in glycaemic control and body weight in the clinical setting correlate with that observed in the trial setting. With experience from his own practice, Dr Kumar commented that incretin therapies were superior to insulin, sulfonylureas and thiazides for weight advantage and avoidance of hypoglycaemia. With an excellent safety and tolerability profile (nausea usually settles within a week), incretin therapy has high acceptability in patients. Furthermore, Dr Kumar finds incretin therapy suitable for use in the patient failing metformin; and has noted efficacy in combination with almost all other oral anti-diabetic agents (as well as insulin) at different stages of the natural history of disease progression. Cost as a limiting factor was the only disadvantage highlighted, with Dr Kumar postulating that he expects this to also be a disadvantage for use in South Africa. Source Ussher JR, Drucker DJ. Cardiovascular Biology of the Incretin System. Endocrine Rev 2012; 33: 187–215.

Incretins in combination with insulin The rationale for using incretin mimetics with insulin was discussed by Prof Mahomed Omar (South Africa) and Dr Ajay Kumar (India) with reference to relevant studies.

Adding incretins to insulintreated patients ‘At the outset, this approach should seek to mitigate the problems associated with

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increasing insulin dosages such as weight gain, hypoglycaemia and complications of high insulin dose therapy’, Prof Omar said. He addressed firstly, the addition of DPP-4 inbhibitors, vildagliptin and sitagliptin to type 2 diabetes patients who are poorly controlled on insulin.16,17 ‘The reductions in HbA1c levels were modest, about 0.59%, but were sustained over a year, when these agents were added to patients on insulin, with or without metformin. Experience with hypoglycaemia was mixed, with vildagliptin reducing hypoglycaemic events and sitagliptin increasing these events, perhaps due to the latter study design, which tried to improve overall glucose control. The weight reduction effect was neutral in both studies’, Prof Omar pointed out. Turning to the incretin mimetics, Prof Omar cited a proof-of-concept study where the addition of exenatide to patients on insulin glargine resulted in a greater decrease in HbA1c level (a reduction of 1.9%), a low hypoglycaemic event rate and weight loss of 1 to 2 kg in the exenatide arm.18 In a further study of exenatide, which was given to patients with diabetes of long duration (10 years) and an expected low level of residual beta-cell function, who were already on insulin, metformin and pioglitazone, exenatide (bd) resulted in improved glucose control accompanied by a very significant reduction in insulin (glargine) dose.19 ‘The adverse GI events with incretin mimetics were as expected but did improve over time’, Prof Omar noted.

A newer concept: patients already on liraglutide who are then given added insulin In a well-conducted study over a year,20 the addition of insulin detemir to a group of patients on metformin and liraglutide, who were not yet at target HbA1c level, was contrasted with the larger primary group, which had reached optimal control on these two agents (61% of the 988 patients), and to a control group within the poorer-controlled arm without insulin. The patients receiving insulin were told When adding liraglutide to insulin-treated patients, one can pragmatically reduce the insulin units by 20–25%, and then monitor – Dr Mahomed AK Omar

to self-titrate, and in this well-controlled therapy reached the recommended range of 35–40 U/day of insulin detemir. Importantly, the addition of insulin detemir resulted in a further drop of 0.5% in HbA1c level and patients did not gain weight. The rate of hypoglycaemia was very low at 0.23 in these insulin-treated patients. ‘If you contrast this to the TreatTo-Target study, where a rate of three to 3.5 episodes/patient year was seen, this strategy was very successful’, Prof Omar noted. ‘In conclusion, it is better to put patients onto a GLP-1 agonist before using insulin than using the reverse strategy’, Dr Ajay Kumar.

Incretins and pancreatitis Dr Adri Kok and Prof Juris Meier This session scrutinised the evidence related to the increased prevalence of acute pancreatitis in type 2 diabetes patients, acknowledging that these patients have a three-fold higher risk of developing pancreatitis (4.5 cases per 1 000 patient years). ‘We know that the exocrine pancreas is also affected in diabetic patients, with increased fibrosis occuring in both type 1 and type 2 diabetes’, Dr Adri Kok noted. Prof Meier presented the animal studies on incretins and the risk of pancreatitis, noting the difficulty of extrapolating these findings to humans. Following the published analysis of the Adverse Event Reports (AERS) as reported to the FDA,21 the EASD has recently published their expert comment on their website http://www. easd.org/easd/index.php/easd-statements. Their evaluation indicates that at this juncture the AERS evaluation cannot be considered as robust data on which to base clinical decisions. Dr Kok concluded that physicians should not over-interpret this matter, but should be cautious. In summary, Prof Ascott-Evans noted that there is no major signal of concern about either incretin mimetics or DDP-4 inhibitors and the causation of pancreatitis.

‘There is no value in doing HOMA tests prior to using these incretin-based therapies, as they have been shown to be effective across the diabetes spectrum – Prof Juris Meier

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There have been no studies as yet using incretin-based therapies in children/ adolescents under the age of 18 years and clinicians should wait for these studies before treating this category of patient – Prof Juris Meier

Practical advice Adding liraglutide therapy to a sulphonylurea (SU) plus metformin therapy, clinicians can halve the SU dose and then monitor glucose levels to decrease the risk of hypoglycaemia.

Hypoglycaemic events mark vulnerability Prof Brian Frier, honorary professor of diabetes at the University of Edinburgh, affiliated to the BHF Centre for Cardiovascular Science.

‘Hypoglycaemia is a marker of a patient’s vulnerability to a wide spectrum of cardiovascular, cerebrovascular and musculoskeletal events. It is not a transient event, as commonly perceived. There are longer-term effects on cardiac function, platelets, the inflammatory response and overall endothelial function’. Expressing this view, Prof Brian Frier, University of Edinburgh, drew on his clinical insights gained from a research career focused on the pathophysiology of hypoglycaemia. While hypoglycaemia is more common in type 1 diabetes patients, type 2 diabetes patients on insulin experience on average one severe event per month. ‘In the definitive UK Hypoglycaemia study,22 we were surprised to see in a real-world setting that hypoglycaemia in type 2 diabetes patients treated with sulphonylureas was higher than we thought, at a rate of 7% per year. Hypoglycaemic events also increased over time in type 2 diabetes patients on

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insulin but remained less frequent than in type 1 diabetes patients.’ This study used patients’ self-reporting and biochemical episodes of less than 2.2 mmol/l on continuous glucose monitoring to determine events over nine to 12 months in UK secondary care diabetes centres. Insights from continuous glucose monitoring has shown that the majority of hypoglycaemic events occur at night, and in the younger patient, do not appear to impair cognitive function, although, the next day, subjective well being is affected. ‘These nocturnal events may, however, contribute to the development of impaired awareness of hypoglycaemia’, Dr Frier noted. Age affects hypoglycaemic awareness, with younger patients being able to tolerate lower glucose levels without cognitive dysfunction, while older patients, over the age of 65 years have less time for corrective action and generally experience wider cognitive dysfunction, including visual disturbances, inco-ordination and impaired balance.23 ‘These symptoms could be perceived by the attending physician as a transient ischaemic attack or early dementia and not correlated to low glucose levels’, Prof Freir warned. Hypoglycaemia provokes profound haemodynamic changes through sympatho-adrenal activation, resulting in the profuse secretion of catecholamines.24 This can provoke ECG-abnormalities; prolongation of the QT interval, and abnormalities in AV conduction (due also to a fall in plasma potassium), which are associated with a risk of life-threatening cardiac arrhythmias. Hypoglycaemic events adversely affect quality of life and ‘having events, increases the fear of having further events’. Dr Frier said. The rate of hypoglycaemic events induced by incretin-based therapies is trivial, as these drugs promote glucose-dependent insulin secretion’, Prof Frier concluded. Peter Wagenaar, Glenda Hardy, Julia Aalbers

References 1.

Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52(1): 102–110. Meier JJ, Kjems LL, Veldhuis JJ, et al. Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet

insulin hypothesis. Diabetes 2006; 55(4): 1051–1056. 3. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exentatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374(9683): 39–47. 4. Garber A, Henry R, Ratner R, GarciaHernandez PA, Rodriguez-Pattzi H, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase II, doubleblind, parallel-treatment trial. Lancet 2009; 373(9662): 473–481. 5. Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabetes Med 2009; 26(3): 268–278. 6. Nauck MA, Frid A, Hermansen K, Shah NS, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32(1): 84–90. 7. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 2009; 52(10): 2046–2055. 8. Zinman B, Gerich J, Buse JB, Lewing A, Schwartz S, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32(7): 1224–1230. 9. Pratley R, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel group, open-label trial. Int J Clin Pract 2011; 65(4): 397–407. 10. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exentatide once-weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 9739: 431–439. 11. Buse JB, Drucker DJ, Taylor KL. Duration-1: exenatide once weekly products sustained glycaemic control and wigth loss over 52 weeks Diabetes Care 2010; 33(6): 1255–1261. 12. Buse JB, Nauck MA, Forst T, Sheu WHH, Hoogwerf BJ, et al. Efficacy and safe-

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

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ty of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study. Diabetologia 2011; 54(suppl 1): 538. EASD 2011 congress abstract: oral presentation. Hall V, Thomson RW, Henriksen O, Lohse N. Diabetes in sub-Saharan Africa 1999–2011: Epidemiology and public health implications. A systematic review. BMC Public Health 2011; 15(11): 564. Levin P, Wei W, Wang L, et al. Combination therapy with insulin glargine and exenatide: real world outcomes in patients with type 2 diabetes. Curr Med Res Opin 2012; 28(3): 439–446. Thong KY, Jose B, Sukumar N, Cull ML, et al. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit. Diabetes Obes Metab 2011; 13(8): 703–710. Vilsboll T, Rosenstock Y, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12(2): 167–177. Bain SC, De Vries JH, Rodbard HW. Adding insulin detemir (IDet) to liraglutide and metformin improves glycaemic control with sustained weight reduction and low hypoglycaemia rate: 52-week results. EASD 2011 congress abstract. Arnolds S, Dellweg S, Clair J, et al. Further improvement in post prandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care 2010; 33(7): 1509– 1515. Bus JB, Bergenstol RM, Glass LC, et al. Use of twice daily exenatide in Basal Insulin-treated patients with type 2 diabetes: a randomised controlled trial. Arch Intern Med 2011; 154(2): 103–112. Fonseca V, Baron M, Shao Q, Dejager S. Sustained efficacy and reduced hypoglycaemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes. Horm Metab Res 2008; 40(6): 427–430. Elashoff M, Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic and thyroid cancer with GLP-1based therapies. Gastroenterology 2011; 141(1): 150–156. UK Hypoglycaemia Study Group Diabetologia. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50(6): 1140–1147. McAulay V, Deary IJ, Frier BM. Symptoms of hypoglyacamia in people with diabetes. Diabet Med 2001; 18(9): 690-705. Frier BM, Schernthaner G, Heller SR. Hypoglycaemia and cardiovascular risks. Diabetes Care 2001; 34: 5132–137.

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Victoza® is the first and only human GLP-1 analogue with 97 % homology to natural GLP-1 Reductions in HbA1C1-3 Reductions in weight1-3 Reductions in systolic blood pressure1-3 Improvements in beta-cell function4

References: 1. Nauck M, et al; for the LEAD-2 Study Group. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination with Metformin, in Type 2 Diabetes. The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32(1):84-90. 2. Gallwitz B, et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64(2):267-276. 3. Garber A, et al; on behalf of the LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes, Obes Metab. 2011; 13: 348-356. 4. Chang AM, et al. The GLP-1 Derivative NN2211 Restores ß-cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose. Diabetes. 2003;52:1786-1791. Proprietary Name: Victoza®. Scheduling Status: S4 Composition: Liraglutide 6 mg/ml. Indications: As an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus. Registration Number: 43/21.13/0781. For full prescribing information refer to package insert approved by the medicines regulatory authority. Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 2nd Floor, Building A, 345 Rivonia Boulevard, Edenburg, Rivonia, Sandton 2128, South Africa. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/5281/January/2012/ver1

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NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. TEL: +27(0) 861 70 0 90 0. FA X: +27(0)11 525 3401. R e f e r e n c e s: 1. Vi l a i n e J P e t a l. J C a rd i ova s c P h a rm a c o l 2 0 0 3;42:68 8 - 696 . 2 . C a m m A e t a l. D ru g s R &D 20 03;4:83 - 89. 3. Borer J et al. Circulation 20 03;107:817- 823. 4. Swedberg K et al. Lancet 2010;376: 875 - 885.

Coralan ® improves outcomes in heart failure patients with a heart rate above 70bpm - SHIFT 4

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Drug Trends in Cardiology New ESC heart failure guidelines with South African expert comment The new ESC heart failure guidelines, an update of the 2008 version, was released at the ESC Heart Failure Congress in Belgrade this weekend. This is the first time the guidelines have been presented at the Heart Failure Congress as opposed to at the annual European Society of Cardiology (ESC) Congress. Major updates are in the provision of new algorithms for the diagnosis of patients with suspected heart failure, treatment for systolic heart failure patients with reduced ejection fraction (HF-REF), and the management of acute heart failure.1,2 The diagnostic algorithm recognises the increasing importance of cardiac MRI and includes mid-regional proBNP as a ‘rule-out’ blood test in patients with acute heart failure. The pharmacological therapy section of the guideline has been updated to specifically relate the treatment to clinical outcome effects and provides the level of evidence supporting a use of the particular agent (Table 1). The cornerstone use of ACE inhibitors has been acknowledged with a class I, level A recommendation as has the use of the ARBs (also class I, level A). ‘ARBs, as they become generically available, can also be regarded as a cornerstone therapy, particularly as drug adherence is such an important issue’, Dr Erik Klug (cardiologist, Johannesburg) noted at the recent Physicians Congress held in Cape Town. In these 2012 guidelines, there is a new indication for the mineralocorticoid/ aldosterone receptor antagonists (MRA),

eplerenone in patients with systolic heart failure (HF-REF) and mild symptoms. This broadens the indication for a MRA to essentially all HF-REF remaining symptomatic, despite adequate treatment with a beta-blocker and ACE inhibitor or ARB. A further innovation is the recommendation that ivabradine be added to an ACE inhibitor, betablocker (at maximum tolerated doses) and MRA to HF-REF patients in sinus rhythm with a persistently high heart beat above 70 beats/min (Table 2). The new guidelines devote substantial space to co-morbidities, given their importance in relation to symptoms and progress, and therapeutic decision making. In this way, the guidelines recognise that heart failure and left ventricular systolic dysfunction (LVSD) may alter therapies for co-morbidities and that co-morbidities may also influence the use of heart failure therapies. Co-morbidities such as chronic obstructive pulmonary disease (COPD), diabetes, hypertension, kidney dysfunction and cardiorenal syndrome are discussed and guidelines presented. Recent evidence has also pointed to the value of physicians managing patients with chronic heart failure and co-morbidities.3

Comment from Dr Martin Mpe Cardiologist in private practice, Pretoria and a member of the CVJA editorial board The update of the 2008 guidelines is intended to advance the treatment of

heart failure in the light of the new scientific evidence from recent clinical trials. The purpose is to improve the clinical outcomes from contemporary interventions with improvement in both morbidity and mortality. This comes at a price since stringent application of the recommendations has cost implications on the already financially strained healthcare systems all over the world. Local adaptations of these guidelines are mandatory and should be sensitive to local circumstances. For the majority of patients, the logical approach is to ensure access to the ‘maximum’ recommended pharmacological intervention as the minimum standard of care. Special investigations in the setting of heart failure have been re-emphasised, which leads to further increase in cost. The escalation of therapy depends on special investigations over and above the symptom response. The main changes, as presented by the chairperson of the Task Force for the review committee of the 2012 ESC heart failure guidelines committee, John JV McMurray, are the following: An expanded indication for mineralocorticoid (aldosterone) receptor antagonists (MRAs) The use of MRAs following the use of ACEI/ARB and beta-blockers in symptomatic patients implies a revisit on the wider use of eplerenone. Spironolactone has an unpleasant side effect of gynaecomastia in a significant number of users, which may be more

TABLE 1. PHARMACOLOGICAL TREATMENTS INDICATED IN POTENTIALLY ALL PATIENTS WITH SYMPTOMATIC (NYHA FUNCTIONAL CLASS II–IV) SYSTOLIC HEART FAILURE Recommendations An ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF ≤ 40% to reduce the risk of heart failure hospitalisation and the risk of premature death. A beta-blocker is recommended, in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated), for all patients with an EF ≤ 40% to reduce the risk of heart failure hospitalisation and the risk of premature death. An MRA is recommended for all patients with persisting symptoms (NYHA class II–IV) and an EF ≤ 35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a beta-blocker, to reduce the risk of heart failure hospitalisation and the risk of premature death.

Classa Levelb I A I

ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; EF = ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association. a Class of recommendation; bLevel of evidence.

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TABLE 2. OTHER TREATMENTS WITH LESS CERTAIN BENEFITS IN PATIENTS WITH SYMPTOMATIC (NYHA CLASS II–IV) SYSTOLIC HEART FAILURE Recommendations Classa Levelb ARB Recommended to reduce the risk of heart failure hospitalisation and the risk of premature death in patients with an EF ≤ 40% and I A unable to tolerate an ACE inhibitor because of cough (patients should also receive a beta-blocker and an MRA). I A Recommended to reduce the risk of heart failure hospitalisation in patients with an EF ≤ 40% and persisting symptoms (NYHA class II–IV), who are unable to tolerate an MRA, despite treatment with an ACE inhibitor and a beta-blocker.c Ivabradine Should be considered to reduce the risk of heart failure hospitalisation in patients in sinus rhythm with an EF ≤ 35%, a heart rate IIa B remaining ≥ 70 beats/min, and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of betablocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB).d C May be considered to reduce the risk of heart failure hospitalisation in patients in sinus rhythm with an EF ≤ 35% and a heart rate IIb ≥ 70 beats/min who are unable to tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB).d Digoxin May be considered to reduce the risk of heart failure hospitalisation in patients in sinus rhythm with an EF ≤ 45% who are unable IIb B to tolerate a beta-blocker (ivabradine is an alternative in patients with a heart rate ≥ 70 beats/min). Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). May be considered to reduce the risk of heart failure hospitalisation in patients with an EF ≤ 45% and persisting symptoms IIb B (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB). H-ISDN May be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of heart failure IIb B hospitalisation and risk of premature death in patients with an EF ≤ 45% and dilated LV (or EF ≤ 35%). Patients should also receive a beta-blocker and an MRA. May be considered to reduce the risk of heart failure hospitalisation and risk of premature death in patients in patients with an EF IIb B ≤ 45% and dilated LV (or EF ≤ 35%) and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB). PUFAs IIb B An n-3 PUFAe preparation may be considered to reduce the risk of death and the risk of cardiovascular hospitalisation in patients treated with an ACE inhibitor (or ARB), beta-blocker and an MRA (or ARB). ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; CHARM-Added = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity-Added; EF = ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; PUFA = polyunsaturated fatty acid. a Class of recommendation; bLevel of evidence; CIn the CHARM-Added trial, candesartan also reduced cardiovascular mortality; d European Medecines Agency has approved ivabradine for use in patients with a heart rate ≥ 70 beats/min; e Preparation studied in cited trial; the GISSI-HF trial had no EF limit.

in combination with the use of digoxin. I would imagine that there will be a significant increase in the use of eplerenone with the perceived benefit of a better side-effect profile.

indirect cost of death.

A new indication for the sinus node inhibitor ivabradine This agent will enjoy much wider use in a substantial number of patients, given the qualifying criteria for use. I would hope that the pricing will improve with increase in the number of prescriptions.

New information on the role of coronary revascularisation in systolic heart failure The changing epidemics in coronary artery disease risk factors, especially in the developing world, will mean an increase in invasive interventions in the heart failure population as well. Infrastructural and human resource development are also imperative for the standard of care to be adequate in the not-so-distant future.

An expanded indication for cardiac resynchronisation therapy (CRT) With the proper selection of patients, there is still a significant proportion of patients who qualify for CRT. The cost implication is a given, but in the long run, this is cost saving in comparison to the cost of repeated hospitalisations and

Recognition of the growing use of ventricular assist devices (VADs) This is idealistic and will still not be a widely available treatment avenue. This is of course of major importance where the indication for appropriate use is met. The cost implication as well as availability remain deterrents for most nations.

The emergence of transcatheter valve interventions This is a further reflection of the evolution in the practice of medicine and cardiology in particular. I find these exciting but the economic realities dampen one’s enthusiasm. There may be a balance in the future as these interventions become more widely used and readily available. Julia Aalbers 1.

2. 3.

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J. Doi 10.1093/eurheartj/ ehs104.. ESC Press Conference, Belgrade, 20 May 2012. Boom NK, Lee DS, Tu JV. Comparison of processes of care and clinical outcomes for patients newly hospitalised for heart failure attended by different physician specialists. Am Heart J 2012; 163: 252–259.

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Mor 1 millio e than worldw n patients with X ide treated are ® THR an lto 10 in d TKR .*

Leading the way in new ORAL anticoagulation

10654/FPFC/CVJA

More than 75 000 patients enrolled

Clinical Trial Programme Study Programme

Venous thromboembolism (VTE) prevention in total hip replacements.

Dosage

Rivaroxaban 10 mg OD

4,541

Main Outcome Measures Efficacy:

Composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality Safety:

Venous thromboembolism prevention in total hip replacements - extended prophylaxis.

Venous thromboembolism prevention in total knee replacements.

Venous thromoboembolism prevention in total knee replacements - compared to enoxaparin 30mg BD.

◆

Outcome Superior efficacy vs enoxaparin, comparable safety. Superior efficacy of long term (5 week) prophylaxis with rivaroxaban vs short term (2 week) prophylaxis with enoxaparin, comparable safety.

NEJM 2008

ANCET THE L008 2

Rivaroxaban 10 mg OD

2,509

Rivaroxaban 10 mg OD

2,531

Superior efficacy vs enoxaparin, comparable safety.

NEJM

Rivaroxaban 10 mg OD

3,148

Superior efficacy vs enoxaparin, comparable safety.

ANCET THE L009 2

Major bleeding

2008

Xarelto® 10 OD is approved for clinical use for VTE prevention in adult patients undergoing major orthopaedic surgery of the lower limbs. OD = once daily.

Study Programme

Prevention of venous thromboembolism in hospitalised medically ill patients.

Treatment of acute symptomatic deep vein thrombosis.

Treatment of acute pulmonary embolism with or without symptomatic DVT.

Continued treatment of deep vein thrombosis or pulmonary embolism.

Prevention of stroke and embolism in atrial fibrillation.

Anti-Xa therapy to lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in subjects with acute coronary syndrome.

Dosage

Rivaroxaban 10 mg OD

~8,000

Rivaroxaban 15 mg BID, first 3 weeks Continue with Rivaroxaban 20 mg OD

3,464

4,300

Rivaroxaban 20 mg OD

1,197

Rivaroxaban 20 mg OD or Rivaroxaban 15 mg OD 30-49 ml/min CrCl

14,269

Rivaroxaban 15 mg OD

1,280

Rivaroxaban 2.5 mg BID Rivaroxaban 5 mg BID

Main Outcome Measures Efficacy: Composite of VTE (DVT and/or PE) and VTE related death Safety: Major and clinically relevant non-major bleeding Efficacy: Symptomatic recurrent VTE Safety: Major and clinically relevant non-major bleeding

Efficacy: Symptomatic recurrent VTE Safety: Major bleeding Efficacy: Composite of stroke and non-CNS systemic embolism Safety: Composite of major and clinically relevant non-major bleeding Efficacy: Composite of CV death, MI and stroke

~16,000

Safety: Major bleeding events not associated with CABG surgery

Outcome

Study completed

TED PRESEN

ACC

2011

NEJM 2010

te presen To be

ACC

Study completed

2012

NEJM Study completed

2010

NEJM Study completed

2011

TE PRESEN

Study completed

ISTH

Study completed

NE JM

2011

OD = once daily BID = twice daily CrCl = creatinine clearance. Rivaroxaban 2.5 mg, Rivaroxaban 5 mg, Rivaroxaban 15 mg and Rivaroxaban 20 mg are in Clinical Development; and thus not recommended for clinical use in all Indications under investigation.

The most extensive Phase III Clinical Trial Programme of any new oral anticoagulant ** www.thrombosisadviser.com *THR - total hip replacement. TKR - total knee replacement. **http://clinicaltrial.gov RECORD1: Eriksson BI, et al. N Engl J Med. 2008; 358(26):2765-2775. RECORD2: Kakkar AK, et al. Lancet. 2008; 372(9632):29-37. RECORD3: Lassen MR, et al. N Engl J Med. 2008; 358(26):2776-2786. RECORD4: Turpie AGG, et al. Lancet. 2009; 373(9676):1673-1680. MAGELLAN: http://clinicaltrials.gov/ct2/show/NCT00571649. EINSTEIN DVT and EXT: Einstein Investigators. N Engl J Med. 2010. EINSTEIN PE: http://clinicaltrials.gov/ct2/show/NCT00439777. ROCKET AF: Patel, et al. N Engl J Med. 2011. J-ROCKET AF: http://clinicaltrials.gov/ct2/show/NCT00973323. ATLAS ACS TIMI 51: http://clinicaltrials.gov/ct2/show/NCT00809965. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC) S4 XARELTO® 10 (Film-coated tablets). Reg.No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041 DATE: February 2012 L.ZA.GM.02.2012.0377

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EINSTEIN-PE study results, with South African expert comment Rivaroxaban has been shown to be as effective as initial and long-term treatment with enoxaparin and warfarin for pulmonary embolism (PE), with a potentially improved risk profile benefit.1 The results of the Einstein-PE study were announced at the recent American College of Cardiology meeting in Chicago and simultaneously published in the March issue of New England Journal of Medicine 2012. Commenting on the study results, Dr Harry Buller, Academic Medical Centre, Amsterdam pointed out that in the overall EINSTEIN-DVT and EINSTEINPE programme of 10 000 patients, there was a very convincing 50% lower rate of major bleeding, particularly intracranial haemorrhage and retroperitoneal bleeds with rivaroxaban compared with the difficult-to-manage warfarin standard therapy. ‘One of the patient groups who particularly benefited with regard to major bleeding with rivaroxaban was those over 75 years of age’, Dr Buller noted. The EINSTEIN-PE study was been heralded as a landmark study in the field of pulmonary embolism and marks a turning point in its management. It is the largest-ever study of PE, recruiting 4 833 patients from 36 countries, including South Africa. Designed as a non-inferiority study, oral rivaroxaban was given as 15 mg bid for three weeks, followed by 20 mg daily. This was compared to the standard treatment of subcutaneous injections for five to 10 days with a low-molecular weight heparin (LMWH) and an oral vitamin K antagonist (warfarin) for the prevention of recurrent thromboembolism. ‘Rivaroxaban was given as monotherapy, which was a very brave step and it is the first study to really bite the bullet with regard to its challenge of conventional LMWH therapy’, Dr Buller said. Rivaroxaban, an oral factor Xa inhibitor, has already been shown in phase III trials to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis and stroke prevention in atrial fibrillation and is currently registered in South Africa for the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery of the lower limbs. The EINSTEIN-PE study recruited a broad spectrum of patients with PE with and without deep-vein thrombosis. Exclusions

included patients treated with LMWH, fondaparinux or unfractionated heparin for more than 48 hours or if they had already received more than a single dose of a vitamin K antagonist before randomisation. Also patients who had undergone thrombectomy or other surgical procedures were excluded. Patients with contra-indications to vitamin K were also excluded, as were patients with active bleeding or at high risk of bleeding, contra-indicating anti-coagulant therapy. Randomisation was stratified according to country and the attending physician’s intention-to-treat duration of three, six or 12 months. Importantly, standard therapy was well controlled and time in therapeutic range (TTR) of the target INR (2–3) was 62.7%. The TTR percentage did vary from 57.8% during the first month, to 72.7% during month 11. In the rivaroxaban group, adherence to therapy was above 80%. In the study, rivaroxaban demonstrated efficacy comparable to that of the current standard therapy in reducing the primary endpoint of recurrent symptomatic VTE, a composite of symptomatic deep-vein thrombosis and non-fatal or fatal pulmonary embolism (2.1 vs 1.8%, respectively; p = 0.003 for non-inferiority). Rivaroxaban also demonstrated similar safety results compared to current standard of care for the principal safety outcome measuring a composite of major and non-major clinically relevant bleeding events (10.3 vs 11.4%, respectively; p = 0.23). Importantly, rivaroxaban treatment resulted in a significant reduction in major bleeding events (1.1 vs 2.2%, respectively; p = 0.003) compared to the current standard therapy. Acute coronary events were low (0.6%) and were equally distributed between the two groups. 1.

relevant non-major bleeding was the same, overall major bleeding episodes did differ, with 26 (1.1%) occurring in the rivaroxaban group and 52 (2.2%) in the standard-therapy group. This difference had a standard deviation of 0.49 (95% confidence interval of 0.31–0.79) and was significant (p = 0.003). Within this latter group was included other non-fatal episodes in critical sites, and a large proportion of the differences within the group of major bleeds was made up of intra-cerebral bleeds, which occurred in one patient (< 0.1%) with rivaroxaban, and 10 (0.4%) with standard therapy. Will this study change therapy? The important considerations are firstly efficacy, and in this regard rivaroxaban is non-inferior to standard therapy. Second is safety, and certainly with regard to major bleeding episodes, it is superior, although the numbers are small. Third is the issue of cost. If it is priced too high, the cost efficacy may make this therapy non-justifiable and this may prove to be an obstacle. Fourthly, some patients do not like injecting themselves and may prefer to take a tablet that has been proven to be equally efficacious. Bayer is to be congratulated, however, on successfully completing an arduous study without any pre-knowledge as to what the outcome would be. This study adds significantly to our knowledge of these new drugs and offers different options for the treatment of pulmonary embolus in the future. Julia Aalbers

The Einstein investigators. N Engl J Med 2012: 366: 1287–1297.

Prof Guy Richards (University of the Witwatersrand) comments on the importance of the EINSTEIN-PE study for South African clinicians This is an interesting study, the first assessing utilisation of one of the new orally available anticoagulants to treat pulmonary embolism. The outcomes were similar with regard to prevention of recurrence but there were differences with regard to safety. Whereas overall major or clinically

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The role of aspirin in cardiovascular disease prevention Prof Gordon T McInnes, University of Glasgow, Scotland Acetylsalicylic acid (aspirin) may have been around for over 100 years, but this ‘cheap and cheerful’ agent continues to surprise with new indications for its use. Prof Gordon McInnes feels that this ‘old drug with new tricks’ has an important ongoing role to play in both the primary and secondary prevention of cardiovascular disease (CVD). He was speaking at a meeting hosted by Bayer Healthcare in Johannesburg in May. ‘Aspirin was developed in 1897 and is still going strong, with new indications for its use continuing to appear’, he said. ‘We think we’re civilised, but we’re doing a lot of things wrong and driving ourselves to an early grave’, he warned. As the developing world, including South Africa, adopts Westernised lifestyles, the tsunami of CVD previously seen in Europe and North America is sweeping through Asia and Africa, with 80% of cases now seen in low- and middleincome countries. CVD accounts for 30% of all deaths, 12 million worldwide per year. ‘It’s the number one killer on the planet. Over and above that, there are 20 million survivors of a stroke or myocardial infarction (MI) each year, which makes it important to look at preventing subsequent events. Aspirin has a role to play in both primary and secondary prevention.’ All forms of vascular disease have the same underlying process and central to this is the role of platelets – their adhesion, activation and aggregation. Antiplatelet treatments such as aspirin are therefore very important.

Secondary prevention In the secondary prevention of CVD, aspirin’s role is clear and straightforward. According to the Antithrombotic Trialists’ Collaboration study published in the Lancet in 2009,1 it reduces the risk of any vascular event by 19%, non-fatal MI by 31%, stroke by 19% and vascular mortality by 9%. ‘So there are benefits across the board!’ When it comes to acute coronary syndrome, aspirin’s benefits have been shown in 15 trials. It prevents 30 serious vascular events per 1 000 patients per week, with the low risk of only one major bleed per 1 000 patients per year. ‘There is some debate around how long it should be taken for, but much of the evidence

suggests that once you initiate, you should continue for life.’ While it can be and often is used in combination with other treatments, it remains the foundation of any antiplatelet approach. Turning to aspirin’s longer-term use post MI and in chronic stable angina, Prof McInnes noted that there was good evidence of benefit. ‘Twelve trials have shown that post MI, it prevents 36 serious vascular events per 100 patients per two years, while 55 trials have shown that in coronary heart disease (CHD) with no MI, there is a 37% reduction in serious vascular events. Seven trials have shown benefit in acute ischaemic stroke, with nine serious vascular events prevented per 1 000 patients per three weeks. The early introduction of aspirin is therefore recommended.’ ‘The evidence for more intensive therapy with additional agents is weak, but we’re still awaiting the results of ongoing trials in this regard. Twenty-one trials also support the use of maintenance aspirin in transient ischaemic attack and ischaemic stroke.’ Not all the news is good, though. Prof McInnes feels that there is, sadly, not much benefit in atrial fibrillation, with only one trial having shown positive results. ‘Aspirin’s days as a protective agent in this setting are gone, especially with the advent of the newer agents that are safer than warfarin.’ However, the news is good where peripheral vascular disease is concerned. Aspirin is associated with a 23% reduction in serious vascular events and, importantly, improved symptoms

Primary prevention In this context, the evidence is less clear cut than that for secondary prevention. ‘The most recent meta-analysis published by Berger et al.2 showed a 50% or higher risk of major bleeding with only modest risk reduction in MI, stroke, CV death and all death. There is also conflicting evidence around the use of aspirin for primary CVD prevention in diabetics. ‘However, the POPADAD3 and JPAD4 trials, which produced these conflicting findings, were underpowered and imprecise, so clinical benefit cannot be ruled out.’ Another reason for the conflicting evidence in primary prevention is the phenomenon of aspirin resistance. ‘A meta-analysis by Kraspoulos et al.,5

showed that 28% of the CVD subjects involved were resistant. This would dilute apparent benefits and may be responsible for the modest nature of the benefits seen in primary prevention.’ There are also gender differences in primary prevention in that aspirin appears to reduce ischaemic stroke but not MI in women. The picture may be reversed in men. Discontinuation of aspirin in patients with a history of ischaemic events is nonetheless associated with a major increased risk of non-fatal MI or CHD death within 30 days. ‘This is evidence for continuation and suggests that patients should never discontinue aspirin therapy without careful consultation with medical professionals’, Prof McInnes advised.

Other benefits There has been some good news in recent years, with high-quality data indicating that aspirin reduces the risk of large bowel cancer. A meta-analysis of 51 trials showed substantial reductions in cancer death, incident cancer and spread of cancer, suggesting that ‘an aspirin a day keeps cancer away’. ‘A decreased risk of type 2 diabetes may also be added to the list of clinical benefits of aspirin’, said Prof McInnes, ‘although these data are somewhat less compelling.’ So what does all this mean for primary prevention? Prof McInnes feels that it is important to do an in-depth risk assessment to guide decision making but that in patients over 50 years, there is indeed clear benefit that becomes even more apparent as age increases, especially when one factors in cancer. ‘The provision of aspirin in people at increased vascular risk provides the greatest benefit and has the lowest cost by far of any preventive measures, apart from smoking cessation’, he concluded. ‘After all these years, aspirin still hits the target.’ Peter Wagenaar 1. 2. 3. 4. 5.

Antithrombotic trialists’ (ATT) collaboration. Lancet 2009; 373: 1849–1860. Berger JS, et al. Am Heart J 2011; 162: 115–124. Belch J, et al. Br Med J 2008; 337: 1030– 1034. Ogawa H, et al. J Am Med Assoc 2008; 300: 2134–2141. Krasopoulos G, et al. Br Med J 2008; 336: 195–198.

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Case Report Severe haemoptysis due to subclavian arteritis A LIOULIAS, P MISTHOS, J KOKOTSAKIS, P DROSOS, N KARAGIANNIDIS, D PAVLOPOULOS, M MITSELOU

Abstract Severe haemoptysis due to infective subclavian arteritis has, to our knowledge, never been documented. We report a case of subclavian arterial vasculitis that eroded into the left lung apex, causing a large intraparenchymal mycotic pseudoaneurysm. The patient presented with high fever and blood expectoration. An emergent left lateral thoracotomy was performed. The inflamed segment of the subclavian artery was resected and continuity was restored with a reversed saphenous vein graft. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day. Keywords: haemoptysis, subclavian artery, arteritis, lung

A chest computed tomography (CT) scan revealed a solid intraparenchymal mass at the apex of the left lung. CT angiography showed a giant intrapulmonary haematoma due to a subclavian artery leak (Figs 1, 2). An emergency left lateral thoracotomy was performed. The apex of the lung was separated from the rest of the lung with a linear staple. The subclavian artery was controlled distal to its origin at the aortic arch. The lung apex was dissected extrapleuraly until the subclavian artery was seen. The subclavian artery was distally controlled just before its exit at the thoracic outlet above the first rib. Resection of the subclavian artery was technically demanding because several branches that originate distal to the vertebral artery were difficult to find and control.

Submitted 8/6/10, accepted 26/11/10 Cardiovasc J Afr 2012; 23: e1â&#x20AC;&#x201C;e2

www.cvja.co.za

DOI: 10.5830/CVJA-2010-096

Seven cases of haemoptysis as the presenting symptom of a subclavian aneurysm have been published.1-7 However, severe haemoptysis due to infective subclavian arteritis has, to our knowledge, never been documented. We report a case of subclavian arterial vasculitis that eroded into the left lung apex, causing a large intraparenchymal mycotic pseudo-aneurysm. The patient presented with high fever and blood expectoration.

Case report A 17-year-old male presented with high-grade fever, which he had had for the previous three weeks, retrosternal pain, and multiple episodes of severe haemoptysis during the preceding two days. He was a heroin addict and used the subclavian vessels as vascular access. He reported that one month previously, injection at that location was accompanied by severe pain at the area of the thoracic outlet. Thoracic Surgery Department, Sismanogleio General Hospital, Athens, Greece

Fig. 1. CT angiography on the transverse plane, showing a giant intrapulmonary haematoma (arrow) due to a subclavian artery leak.

A LIOULIAS, MD, PhD P MISTHOS, MD, PhD, panmisthos@yahoo.gr J KOKOTSAKIS, MD, PhD P DROSOS, MD D PAVLOPOULOS, MD

Third Department of Pneumonology, Sismanogleio General Hospital, Athens, Greece N KARAGIANNIDIS, MD, PhD

Department of Anaesthesia, Sismanogleio General Hospital, Athens, Greece M MITSELOU, MD

Fig. 2. CT angiography on the coronal plane, showing a giant intrapulmonary haematoma (arrow) due to a subclavian artery leak.

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Fig. 3. The surgical specimen showing the ruptured subclavian artery and left lung apex associated with a giant pulmonary haematoma.

Macroscopically the surgical specimen showed the ruptured subclavian artery running into the left lung apex and associated with a giant pulmonary haematoma (Fig 3). The continuity of the subclavian artery was restored with a reversed saphenous vein graft, which was harvested before the thoracotomy. The blood loss was estimated to be approximately 350 cm3. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day.

Discussion An infected artery may rupture in the absence of aneurysmal dilatation.7 The pathogenesis, however, remains unclear in many cases. The commonest site of endarterial infection is the abdominal aorta.8 Infection of the main intrathoracic arteries is rarely reported and may present as haemoptysis,3 or it may mimic a bronchogenic carcinoma.4 In our case, the infected site had been used as an injection site. The infection caused the vascular wall to erode into the left lung and the intrapulmonary artery to rupture. Early diagnosis is important because untreated mycotic subclavian arterial disease has a dismal outcome. Therefore a high index of suspicion must be maintained. Moreover, haemoptysis due to subclavian arteritis has not been documented before. Numerous organisms can cause infection in the arterial wall but the most frequent is Salmonella, which is found in 36% of cases. It has a predilection for larger, diseased blood vessels. Other organisms known to cause such infection are staphylococci, streptococci, Escherichia coli, Pseudomonas, Bacteroides, Haemophilus, Clostridia and Enterobacter klebsiella. Predisposing factors to infective endarteritis include pre-existing atherosclerosis, aneurysms, diabetes, immunosuppression or active vasculitis. An early diagnosis allows both prompt, appropriate antibiotic treatment and timely surgical intervention before invasive pathogens destroy the arterial wall. Early diagnosis may be aided by greater awareness and improved radiological techniques such as ultrasonography, computer-aided tomography and digital subtraction angiography. In particular, enhanced computed

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tomography may demonstrate changes in the size or appearance of the infected artery or show peri-arterial nodularity, air or pus in the arterial wall. Arteriography is not specific but may show atheromatous disease or a saccular or multiloculated aneurysm in an otherwise normal vessel, suggesting a local infection.6 The accepted management of bacterial arteritis is intravenous antibiotic therapy, excision and debridement of the artery and the mycotic false aneurysm if present, and where possible, extraanatomical vascular reconstruction along an uncontaminated path. Surgical treatment for patients with subclavian arteritis should be considered in cases of unremitting infection after adequate antibiotic treatment, or rupture, and to avoid embolus formation or thrombosis. In our case, emergency surgical management was indicated because the recurrent severe haemoptysis had to be controlled. A variety of techniques are used with different surgical approaches and arterial repair. Surgical approaches include supraclavicular incision, axillary incision, median sternotomy with a transverse incision along the second rib bed, and posterolateral thoracotomy, or a combination of all of these, depending on the location of the aneurysm.

Conclusion In our case, a left posterolateral thoracotomy was performed through the fourth intercostal space with the patient under anaesthesia, using double-lumen endotracheal intubation. It provided a good approach to perform the excision and reconstruction of the subclavian artery and to perform a concomitant left upper lobectomy. A reversed saphenous vein bypass graft was used to reduce the risk of secondary blood-borne infection, which is associated with using prosthetic materials.9

References 1.

6. 7.

8. 9.

Saliou C, Badia P, Duteille F, D’Attellis N, Ricco JB, Barbier J. Mycotic aneurysm of the left subclavian artery presented with hemoptysis in an immunosuppressed man: case report and review of literature. J Vasc Surg 1995; 21(4): 697–702. Iijima K, Kuribayashi R, Sakarada T, Sekine S, Aida H, Abe T. [A left subclavian arterial aneurysm ruptured into the left lung – a case report]. Nippon Kyobu Geka Gakkai Zasshi 1992; 40(3): 440–443. Takagi H, Mori Y, Umeda Y, Fukumoto Y, Yoshida K, Shimokawa K, Hirose H. Proximal left subclavian artery aneurysm presenting hemoptysis, hoarseness, and diplopia: repair through partial cardiopulmonary bypass and perfusion of the left common carotid artery. Ann Vasc Surg 2003; 17(4): 461–463. Boundy K, Bignold LP. Syphilitic aneurysm of the right subclavian artery presenting with hemoptysis. Aust NZ J Med 1987; 17(5): 533–535. Deulofeu Fontanillas F, Barbeta Sánchez E, Bernet Vidal M, Sentis Criville M, Pujol Farriols R. [Massive hemoptysis secondary to mycotic aortic aneurysm]. Ann Med Interna 1989; 6(7): 373–375. Wu MH, Lai WW, Lin MY, Chou NS. Massive hemoptysis caused by a ruptured subclavian artery aneurysm. Chest 1993; 104(2): 612–613. Mii S, Ienaga S, Motohiro A, Okadome K. An unusual symptom of subclavian artery aneurysm: hemoptysis. J Vasc Surg 1991; 14(2): 243–245. Oz MC, Brener BJ, Budas JA, et al. A ten-year experience with bacterial aortitis. J Vasc Surg 1989; 10: 439–449. Visrutaratna P, Charoenkwan P, Saeteng S. Mycotic aneurysm of the left subclavian artery: CT findings. Singapore Med J 2006; 47(1): 77–79.

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Case Report The dangerous fifth chamber: congenital left atrial appendage aneurysm KURSAT M Tigen, CEM Dogan, AHMET Guler, SUZAN Hatipoglu, MEHMET Yanartas, CEVAT Kirma

Abstract Aneurysms of the left atrial appendage are extremely rare. Enlargement of the left atrial appendage can be congenital or acquired. Dysplasia of the left atrial muscles leads to congenital left atrial appendage aneurysm and usually presents as atrial tachyarrhythmia or embolic events in the second or third decade of life. We report a case of an asymptomatic 12-year-old child with a congenital left atrial appendage aneurysm. Transthoracic and transoesophageal echocardiography demonstrated a large left atrial appendage aneurysm without thrombus or spontaneous echo-contrast. The patient was successfully treated with surgical resection of the aneurysm. Keywords: congenital, left atrial appendage aneurysm Submitted 7/2/11, accepted 6/9/11 Cardiovasc J Afr 2012; 23: e3–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2011-051

Case report A 12-year-old female without symptoms and previous history of disease was referred to our clinic because of a chest X-ray demonstrating a prominent convexity of the left upper heart border in the position of the left atrial appendage (LAA). The physical examination was normal and an electrocardiograph (ECG) showed normal sinus rhythm. Laboratory findings were within the normal range. Transthoracic echocardiography (TTE) revealed a huge LAA aneurysm resembling a fifth cardiac chamber and normal ventricular and valvular function (Fig. 1). For better determination of the aneurysm, transoesophageal echocardiography (TEE) was performed. This revealed a 6.2 × 4.4-cm LAA aneurysm with a left atrial connection. There was no spontaneous echo-contrast or thrombus in the LAA and left

atrium, and there was dynamic blood flow within the aneurysm (Fig. 2). Because of the potential risk of embolism, the patient was referred to surgery for resection of the aneurysm. Following a median sternotomy, surgical exploration confirmed the diagnosis of an LAA aneurysm (Fig. 3). The aneurysm was resected without extracorporeal circulation. The anatomical features of the resected LAA were consistent with the echocardiographic images. The patient’s postoperative course was uneventful.

Discussion Aneurysm of the LAA is a very rare condition and can be categorised into two groups; congenital or acquired. Acquired LAA aneurysms are associated with increased left atrial pressure as a result of rheumatic valve disease or mitral regurgitation. The cause of congenital aneurysms of the LAA is dysplasia of the pectineal muscles.1 Symptoms associated with aneurysms of the LAA are supraventricular tachyarrhythmia, such as atrial fibrillation or flutter and paroxysmal atrial tachycardia, embolic events, heart failure and angina pectoris. Atrial tachyarrhythmia, which is the most common cause for presentation, could be explained by irritation of the enlarged LAA or congenital defects of the conduction system. Embolic events such as cerebrovascular infarcts are related to stasis caused by the increase in LAA volume and subsequent thrombus formation. More rarely in

Department of Cardiology, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey KURSAT M TIGEN, MD CEM DOGAN, MD AHMET GULER, MD, ahmetguler01@yahoo.com.tr Suzan Hatipoglu, MD CEVAT KIRMA, MD

Department of Cardiovascular Surgery, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey MEHMET YANARTAS, MD

Fig. 1. Apical four-chamber view of TTE demonstrating a large LAA aneurysm resembling a fifth cardiac chamber. LA: left atrium, LV: left ventricle, LAA: left atrial appendage.

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Fig. 3. A: Intra-operative image of the large LAA aneurysm. B: Postoperative image of the resected material.

LAA aneurysms should be treated even if the patient is asymptomatic because they could be the source of arrhythmias and life-threatening thromboembolic complications. The surgical treatment of congenital aneurysm of the LAA is resection with or without extracorporeal circulation.

Conclusion A left atrial appendage aneurysm is a rare but potentially dangerous entity. Because of the risk of embolic complications, resection is advised when possible. Fig. 2. Modified transoesophageal four-chamber, twodimensional (A), and colour flow (B) views showing a huge LAA aneurysm with a broad left atrial connective neck. There was no spontaneous echo-contrast or thrombus in the LAA and left atrium, and there was dynamic blood flow within the aneurysm. LA: left atrium, LV: left ventricle, LAA: left atrial appendage.

the literature, there are also reports of patients presenting with positional hypotension and tachycardia.2 An echocardiographic image of an LAA aneurysm could be confused with cystic tumours of the mediastinum, pericardial cysts, herniation of the left atrium through a pericardial defect, anomalous pulmonary venous drainage, and secondary causes of LAA enlargement.3-5 TEE, computed tomography and cardiac magnetic resonance imaging provide detailed information on the structure and composition of the LAA aneurysm.

References 1.

Chowdhury UK, Seth S, Govindappa R, Jagia P, Malhotra P. Congenital left atrial appendage aneurysm: a case report and brief review of literature. Heart Lung Circ 2009; 18(6): 412‒416. Zhang PF, Zhang M, Zhang W, Yao GH, Wu SM, Zhang Y. Giant aneurysm of the left atrial appendage: detected by real-time 3-dimensional echocardiography. Tex Heart Inst J 2010; 37(1): 129‒130. Foale RA, Gibson TC, Guyer DE, Gillam L, King ME, Weyman AE. Congenital aneurysms of the left atrium: recognition by cross-ectional echocardiography. Circulation 1982; 66: 1065–1069. Comess KA, Labate DP, Winter JA, Hill AC, Miller DC. Congenital left atrial appendage aneurysm with intact pericardium: diagnosis by transesophageal echocardiography. Am Heart J 1990; 120: 992–996. Gold JP, Afifi HY, Ko W, Horner N, Hahn R. Congenital giant aneurysms of the left atrial appendage: diagnosis and management. J Card Surg 1996; 11: 147–150.

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Case Report Corrected transposition of the great arteries with previously unreported cardiac anomalies AHMET KAYA, IBRAHIM HALIL TANBOGA, MUSTAFA KURT, TURGAY IŞIK, MESUT OZGOKCE, SELIM TOPÇU, ENBIYA AKSAKAL

Abstract The corrected transposition of the great arteries is a rare congenital cardiac anomaly characterised by atrio-ventricular and ventriculo-arterial discordance and is related to the largest incidence of cardiological complications. We report on a 40-year-old woman with congenitally corrected transposition of the great arteries, situs inversus, atrial septal defect, pulmonary stenosis, right arcus aorta and coronary artery anomalies. Keywords: corrected transposition, congenital heart disease, cardiovascular imaging Submitted 16/4/11, accepted 6/9/11 Cardiovasc J Afr 2012; 23: e5–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2011-049

Congenital cardiac anomalies are present in between approximately 3.7 and eight of every 1 000 live-birth infants. The corrected transposition of the great arteries (CTGA), characterised by atrioventricular and ventriculo-arterial discordance and normal atrial situs, occurs in approximately 0.5 to 1.4% of all congenital cardiac diseases.1 Most patients have one or more associated cardiac anomalies, and the presence or absence of these anomalies significantly alters the natural history.2 Peri-membranous ventricular septal defect (VSD) and pulmonary stenosis (PS), which may result from an aneurysm of the interventricular septum, an associated fibrous tissue tag, or a discrete ring of tissue in the subvalvular area, are the most common associated defects.3 VSD occurs in 70% of patients and PS in 40%.2 Systemic ventricular dysfunction, tricuspid regurgitation, heart blocks and arrhythmias are life-

threatening late complications in this patient group.4 In the medical literature, there is no evidence of any patient with corrected transposition combined with atrial septal defect (ASD), pulmonary stenosis, situs inversus totalis, right arcus aorta and coronary artery anomalies. We report here, for the first time, a case of CTGA with all of these anomalies.

Case report A 40-year-old woman was admitted to the cardiology clinic with chest pain and worsening dyspnoea. She had no history of cardiac disorder or risk factors for coronary artery disease. Her blood pressure and pulse rate were normal at 125/80 mmHg and 60 beats/min, respectively. Auscultation revealed a grade III holosystolic murmur, which was best heard at the left sternal border. There was no diastolic murmur. The laboratory examinations (blood count, biochemistry) were within normal ranges, and electrocardiography (ECG) demonstrated regular sinus rhythm. Transthoracic echocardiography (TTE) showed atrioventricular and ventriculo-arterial discordance and also revealed that the aorta was on the right side, anteriorly located. The final diagnosis was congenitally corrected transposition of the great arteries. TTE further revealed a normal systemic (morphological right) ventricular ejection fraction of 60%, and a normal

Department of Cardiology, Erzurum Regional Education and Research Hospital Erzurum, Turkey

AHMET KAYA, MD, drkayaahmet@yahoo.com IBRAHIM HALIL TANBOGA, MD MUSTAFA KURT, MD TURGAY IŞIK, MD

Department of Radiology, Medical Faculty, Atatürk University Erzurum, Turkey MESUT OZGOKCE, MD

Department of Cardiology, Medical Faculty, Atatürk University Erzurum, Turkey SELIM TOPÇU, MD ENBIYA AKSAKAL, MD

Fig. 1. TEE showing a discrete ring. PV: pulmonary valve, Ao: aorta, PA: pulmonary artery.

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Fig. 4. Left and right heart catheterisation. Right ventriculography showing prominent trabeculations, which are characteristic of a morphological right ventricle. RV: right ventricle, Ao: aorta. Fig. 2. TEE showing inter-atrial septal defect with intracardiac shunting. ASD: atrial septal defect.

pulmonary (morphological left) ventricular ejection fraction of 55%. There was ventricular inversion with anatomical preservation of the atrial and venous drainages, and the right ventricle (RV) was dilated. Transoesophageal echocardiography (TEE) showed there was significant pulmonary obstruction associated with a discrete ring of tissue in the subvalvular area (Fig. 1) and that the transpulmonary gradient pressure was high (81 mmHg). Additionally, there was an inter-atrial septal defect associated with intra-cardiac left-to-right shunting (Fig. 2). Cardiac magnetic resonance imaging (MRI) was performed

Fig. 3. Cardiac magnetic resonance imaging showing CTGA, right arcus aorta and situs inversus. RV: right ventricle, LV: left ventricle, Ao: aorta, PA: pulmonary artery.

to further evaluate the cardiac morphology and coronary anatomy. The results of MRI corroborated the findings on echocardiography (Fig. 3). The patient underwent right and left heart catheterisation, which showed increased right-side pressures (130 mmHg). Systemic ventricular end-diastolic pressures were normal. Systemic ventriculography revealed a heavily trabeculated ventricular chamber with an outflow tract leading to the aortic valve, which is an indication of a morphological right ventricle (Fig. 4) and D-transposition. There was no angiographic evidence of significant systemic atrio-ventricular valvular regurgitation, but there was intracardiac shunting on the inter-atrial septum. Selective coronary angiography revealed the circumflex artery originating from the right coronary artery, and a normal course of the left anterior descending and right coronary arteries (Fig. 5).

Fig. 5. Circumflex artery originating from the right coronary artery. CX: circumflex artery, RCA: right coronary artery.

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The patient was referred for cardiovascular surgery but she refused and has been followed up medically.

Discussion This case presents a unique feature rarely described in the medical literature, namely, the combination of several congenital anomalies. CTGA may remain asymptomatic for several years in individuals without associated cardiopathies and may only be seen on ECG or X-ray due to the unusual position of the ventricles. Over time, systemic ventricular failure may develop due to pressure overload, causing fatigue and dyspnoea.1 In this anomaly, the right atrium enters the morphological left ventricle, which leads to the pulmonary artery, and the left atrium communicates with the morphological right ventricle, which leads to the aorta. Therefore, atrio-ventricular and ventriculo-arterial discordance exists, and although blood flows in the normal direction, it passes through the ‘wrong’ ventricular chamber. This ‘double discordance’ results in the term CTGA, which is, in essence, a misnomer.5 It is also called L-transposition because the morphological right ventricle is in the levoposition. The aorta is also usually, but not universally, anterior and to the left, and the great arteries may be side by side. Because the tricuspid valve always enters a morphological right ventricle, it too is on the left side in the systemic circulation and is more appropriately termed the systemic atrio-ventricular valve.2 In our case, the morphological right ventricle was in the dextroposition, the aorta was anterior and to the right, and the great arteries were side by side (in the D-transposition) (D-CTGA). Coronary artery anomalies in congenitally corrected transposition of the great arteries have seldom been reported in the medical literature due to the rarity of this disorder and the relatively small number of patients in each reported series.6 The coronary arteries usually course to their respective ventricles. Significant coronary artery abnormalities may affect the surgical

approach, with unexpected anatomy being associated with higher morbidity and mortality rates,7 so clinicians must be careful to identify these anomalies in a timely manner.

Conclusion A single case of CTGA combined with ASD, pulmonary stenosis and situs inversus has been reported before.8 Our report, however, demonstrates the combination of ASD, pulmonary stenosis, right arcus aorta and coronary artery anomalies in a case of CTGA involving situs inversus. We believe that this combination is extremely rare. To our knowledge, this is the first case of its kind reported in the medical literature.

References 1.

2. 3.

5. 6.

Roger PO, Panayotis A, Ronaldo V, et al. Corrected transposition of the great arteries: late clinical presentation, in the fifth decade of life. Arq Bras Cardiol 2008; 91: 4. Warnes CA. Transposition of the great arteries. Circulation 2006; 114: 2699–2709. Taçoy G, Kula S, Cemri M. An unusual appearance: a heart in the heart in a patient with congenitally corrected transposition of great arteries. Anadolu Kardiyol Derg 2009; 9: 5–9. Ikeda U, Furuze M, Suzuku O, et al. Long-term survival in aged patients with corrected transposition of the great arteries. Chest 1992; 101: 1382–1385. Warnes CA. Congenitally corrected transposition: the uncorrected misnomer. J Am Coll Cardiol 1996; 27: 1244–1245. Donald SC, Bruce MB, Margaret HL, et al. Congenitally corrected transposition of the great arteries: imaging with 16-MDCT. Am J Radiol 2007: 188. Ismat FA, Baldwin HS, Karl TR, et al. Coronary anatomy in congenitally corrected transposition of the great arteries. Int J Cardiol 2002; 86: 207–216. Sefidbar M, Ludin H, Burckhardt D. Corrected d-transposition in situs inversus with atrial septal defect and pulmonary stenosis. Z Kardiol; 1973; 62(4): 360–365.

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Case Report Rocking mitral annuloplasty ring PRASHANTH PANDURANGA, MOHAMMED K MUKHAINI

Abstract Dehiscence of a mitral annuloplasty ring is a rare occurrence. We present a young patient with long-standing gross dehiscence of a Duran annuloplasty ring secondary to suture dehiscence, occurring three years after mitral valve surgery. It was detected by transthoracic echocardiography. This case emphasises the importance of clinical and echocardiographic follow-up examinations after mitral valve surgery to detect any unexpected complications. Keywords: Duran annuloplasty ring, dehiscence, mitral regurgitation Submitted 16/7/10, accepted 12/9/11 Cardiovasc J Afr 2012; 23: e8–e10

www.cvja.co.za

DOI: 10.5830/CVJA-2011-055

Dehiscence of a mitral annuloplasty ring is rare. We describe a young patient with long-standing dehiscence of a Duran annuloplasty ring, which on transthoracic echocardiography was seen rocking.

inside the left atrium. There was severe A2 prolapse with no chordal rupture seen. His left ventricle measured 62 mm in diastole and 44 mm in systole, with an ejection fraction of 60%. The patient was repeatedly advised to have the mitral valve surgery redone but he declined. He was doing well without any symptoms or haemolysis at the two-year follow up.

Discussion Mitral valve annuloplasty with flexible rings is a safe and stable reconstructive procedure in which preservation of spatial motility and configuration of the annulus allows a more physiologically natural valve repair with improvement of ventricular function. In one study, five-year significant MR-free survival was 75.1 ± 4.6% for the group of patients with Carpentier rings and 82.4 ± 4.5% for the group with Duran rings, with no significant difference.1 In another study using Duran rings, freedom from re-operation at seven years was 98% for both ischaemic and degenerative MR.2 Post mitral valve repair, early recurrent MR is usually procedure related [incomplete initial repair, suture dehiscence

Case report A 21-year-old man with mitral valve prolapse and severe symptomatic mitral regurgitation (MR) had undergone minimally invasive mitral valve repair three years earlier. Through an upper-J mini-sternotomy into the fourth right intercostal space, under standard moderate hypothermic cardiopulmonary bypass, he had undergone anterior leaflet (A2 segment) chordal shortening, followed by the placement of a 31-mm Duran flexible mitral ring, using interrupted sutures. Post-operatively as well as at his first annual echocardiographic examination, he showed no MR. He was followed up in the cardiology clinic and was doing well, with no symptoms. On cardiac auscultation, however, there was the appearance of a pansystolic murmur, which had not been noted after the surgery. There was no history of endocarditis or trauma. Transthoracic and transoesophageal echocardiographic studies revealed a rocking Duran annuloplasty ring in the left atrium, with severe eccentric, posterolateral-directed MR (Figs 1, 2). The Duran ring had completely detached from the mitral annulus except at the lateral commissural area and was flail Department of Cardiology, Royal Hospital, Muscat, Sultanate of Oman

PRASHANTH PANDURANGA, MD, MRCP (UK), prashanthp_69@ yahoo.co.in MOHAMMED K MUKHAINI, MD, FRCPC, FACC

Fig. 1. Transthoracic echocardiography in the parasternal long-axis (A) and short-axis (B) views showing gross dehiscence of the Duran mitral annuloplasty ring (arrowheads). LA, left atrium; LV, left ventricle; MV, mitral valve.

Fig. 2. Transoesophageal echocardiography showing dehiscence of the Duran mitral annuloplasty ring along with the disrupted sutures (A). Colour Doppler (B) showing the severe eccentric mitral regurgitation jet. LA, left atrium; AML, anterior mitral leaflet.

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(ring or leaflet), residual cleft/prolapse or residual annular dilatation, systolic anterior motion of the mitral valve causing left ventricular outflow tract obstruction, rupture of previously shortened or transferred chordae, elongations or ruptures of chordae from previously shortened papillary muscles, flail or perforated leaflet]. Late failure however is usually valve related (progressive degenerative disease, valvular retractions, or endocarditis).3,4 In their study, Dumont et al.3 observed that suture dehiscence was the most common cause (42%) for procedure-related early failure of mitral valve repair, occurring at the sites of leaflet resection and at the annuloplasty ring. This early suture dehiscence can occur due to a fragile mitral annulus, superficial sutures, regurgitation due to leaflet problem causing undue stress on the rings, or increased tension on suture lines,3 and due to endocarditis5 or blunt chest trauma.6,7 This underscores the importance of the creation of a tension-free repair, especially in large posterior leaflet resection. A sliding repair to reduce tension on the suture lines is suggested.3 Clinically, dehiscence of the annuloplasty ring can result in significant MR, heart failure or haemolysis.8 Our patient had gross dehiscence of the Duran ring secondary to suture dehiscence, occurring very late after surgery (without a history of endocarditis or chest trauma), which is uncommon. Late dehiscence of an annuloplasty ring at one year has previously been reported.5 In our patient, ring dehiscence as well as its attachment to the lateral commissural area of the annulus was clearly demonstrated with transthoracic and transoesophageal echocardiography. Recently, three-dimensional transoesophageal echocardiography has been reported to provide detailed anatomical information in patients with mitral ring dehiscence.8 Kronzon et al.8 reported eight patients with ring dehiscence and they observed that dehiscence occurred mainly in a posterior or lateral location. There was only one anterior dehiscence. The reasons postulated for increased occurrence of posterior dehiscence of the ring are: the posterior annulus is in the far surgical field, thus limiting the view while suturing, performance of a more superficial suturing posteriorly by the surgeon to avoid the circumflex artery, or due to calcifications and fibrosis of the mitral annulus, which are more prevalent posteriorly, making it less amenable to suturing.8 In our patient it was a circumferential dehiscence, but it was in the lateral commissural location, which is uncommon. Recently, it has been observed that saddle-shaped mitral rings, compared to presently available flat rings, may reduce systolic strain in both the radial and circumferential directions, leading to reduction in loading on the suture lines and potentially improving repair durability and preventing dehiscence.9,10 In another study, complete rings increased the non-planarity angle of the mitral valve (making the native mitral annulus less saddle shaped), compared with partial rings. Neither of the two types of rings was found to restore the non-planarity angle to the normal range.11 In a meta-analysis, Chee et al.12 observed that flexible annuloplasty rings demonstrated comparable outcomes for patients with MR secondary to degenerative mitral valve disease, compared to semi-rigid/rigid annuloplasty rings. With regard to ischaemic MR, it was observed that there was continued global and regional left ventricular remodelling with subsequent

dilatation of the anterior and posterior mitral ring segments, together with asymmetrical ventricular dilatation, causing tethering and therefore MR.13 It was noted that annuloplasty using flexible rings may not completely remodel the native valve and, in particular, neglect the insertion area of the anterior mitral leaflet. Silberman et al.14 analysed long-term outcomes in 169 patients who had undergone mitral valve annuloplasty and coronary artery bypass grafting. Over a mean clinical follow up of almost 58 months, 34% in the patient group with flexible rings had residual MR to a moderate or greater degree, compared with 15% in the group with rigid rings. Therefore we feel that a rigid or semi-rigid ring would cause significant reduction in the antero-posterior diameter and thus reduce residual MR, compared to a using flexible ring. Another novel surgical procedure with promising results is the use of biodegradable annuloplasty rings, which remodel the shape, reinforce the repair, restore the function of the atrioventricular valves, and maintain the three-dimensional dynamic motion and geometry of the mitral valve annulus.15

Conclusion The exact cause for such late suture dehiscence in our patient is not known, but the above drawbacks of the flexible ring would have played a significant role.

References 1.

Chung CH, Kim JB, Choo SJ, et al. Long-term outcomes after mitral ring annuloplasty for degenerative mitral regurgitation: Duran ring versus Carpentier-Edwards ring. J Heart Valve Dis 2007; 16: 536–544. 2. Makhija Z, Desai J. Early and mid-term functional and survival benefits in ischemic versus degenerative mitral valve repair using Duran flexible ring: a single surgeon series. Interact CardioVasc Thorac Surg 2009; 9: 471–475. 3. Dumont E, Gillinov AM, Blackstone EH, et al. Reoperation after mitral valve repair for degenerative disease. Ann Thorac Surg 2007; 84: 444‒450. 4. Agricola E, Oppizzi M, Maisano F, et al. Detection of mechanisms of immediate failure by transesophageal echocardiography in quadrangular resection mitral valve repair technique for severe mitral regurgitation. Am J Cardiol 2003; 91: 175–179. 5. Alexioua C, Doukasa G, Swanevelderb J, Sosnowski A. Late dehiscence of a mitral annuloplasty band in an asymptomatic patient: the value of follow-up with echocardiography. Eur J Cardiothorac Surg 2004; 25: 642. 6. Ramakrishna H. Incidental TOE finding – Carpentier mitral annuloplasty ring dehiscence during heart transplantation. Ann Card Anaesth 2008; 11: 49–50. 7. Kolowca M, Domaradzki W, Biernat J, et al. Mitral annuloplasty ring dehiscence after blunt chest trauma. Kardiol Pol 2007; 65: 575–576. 8. Kronzon I, Sugeng L, Perk G, et al. Real-time 3-dimensional transesophageal echocardiography in the evaluation of post-operative mitral annuloplasty ring and prosthetic valve dehiscence. J Am Coll Cardiol 2009; 53: 1543–1547. 9. Jensen MO, Jensen H, Smerup M, et al. Saddle-shaped mitral valve annuloplasty rings experience lower forces compared with flat rings. Circulation 2008; 118: S250–255. 10. Padala M, Hutchison RA, Croft LR, et al. Saddle shape of the mitral annulus reduces systolic strains on the P2 segment of the posterior mitral leaflet. Ann Thorac Surg 2009; 88: 1499–1504. 11. Mahmood F, Subramaniam B, Gorman JH 3rd, et al. Three-dimensional echocardiographic assessment of changes in mitral valve geometry after valve repair. Ann Thorac Surg 2009; 88: 1838–1844.

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12. Chee T, Haston R, Togo A, Raja SG. Is a flexible mitral annuloplasty ring superior to a semi-rigid or rigid ring in terms of improvement in symptoms and survival? Interact Cardiovasc Thorac Surg 2008; 7: 477–484. 13. Magne J, Pibarot P, Dumesnil JG, Sénéchal M. Continued global left ventricular remodeling is not the sole mechanism responsible for the late recurrence of ischemic mitral regurgitation after restrictive annulo-

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plasty. J Am Soc Echocardiogr 2009; 22: 1256–1264. 14. Neirotti R, Cikirikcioglu M, Della Martina A, Le Goff P, Kalangos A. New technology: valve repair using biodegradable rings. Rev Bras Cir Cardiovasc 2008; 23: 556–561. 15. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. Ann Thorac Surg 2009; 87: 1721–1727.

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Case Report Repair of a right coronary artery arising from the pulmonary artery ADEM GULER, MEHMET ALI SAHIN, CELALETTIN GUNAY, ARTAN JAHOLLARI, HARUN TATAR

Abstract We present here the fourth patient in the literature, over the age of 50 years old, with an abnormal right coronary artery arising from the pulmonary artery, who was successfully treated with surgery. Pre-operative computerised tomography (CT) angiography revealed an abnormal right coronary artery arising from the pulmonary artery. The right coronary artery was surgically transposed from the pulmonary artery to the ascending aorta with the aid of cardiopulmonary bypass. The patient had an uneventful postoperative course and the corrected anatomy was documented by postoperative CT angiography. Keywords: anomalous right coronary artery, coronary malformation, ARCAPA Submitted 13/4/10, accepted 12/9/11 Cardiovasc J Afr 2012; 23: e11–e13

www.cvja.co.za

DOI:10.5830/CVJA-2011-054

Transthoracic echocardiography revealed advanced hypokinesia of the posterior, inferior and mid-basal septum, minimal mitral regurgitation and decreased left ventricular ejection fraction (45%). The left ventricle’s internal diameter in diastole (LVIDd) was 57 mm. Coronary angiography revealed markedly dilated and tortuous coronary arteries. The right coronary artery arose from the pulmonary trunk and had collateral filling from the left coronary system. Computerised tomography (CT) angiography was applied for anatomical imaging and ARCAPA was confirmed (Fig. 1). The ectopic ostium of the RCA was from the right anterior pulmonary cusp.

Surgical technique After a median sternotomy and pericardiotomy, cannulas for cardiopulmonary bypass (CPB) were placed into the right atrium and ascending aorta. The left anterior descending artery (LAD) was markedly dilated and tortuous. The aorta and pulmonary

Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a rare congenital coronary malformation.1 In contrast to the Bland–Garland–White syndrome (anomalous left coronary artery from the pulmonary artery, ALCAPA), most patients with ARCAPA remain asymptomatic.2,3 Although the course of the disease has been considered benign, case reports of sudden cardiac death do exist. Successful surgical repair basically depends on re-establishment of a bi-coronary system.4 We present here the fourth case in the literature of a patient over the age of 50 years who was treated successfully with surgery.

Case report A 51-year-old man had been admitted to hospital with a history of syncope and complaints of palpitations and dyspnoea on effort since childhood. No pathology was found on physical examination. There was no murmur on cardiac auscultation. The ECG revealed Q waves and negative T waves in the inferior leads. The chest X-ray was normal. Cardiac enzymes were within the normal range. Department of Cardiovascular Surgery, Gülhane Military Medical Academy, Etlik, Ankara, Turkey ADEM GULER, MD MEHMET ALI SAHIN, MD, mali_irem@yahoo.com CELALETTIN GUNAY, MD ARTAN JAHOLLARI, MD HARUN TATAR

Fig. 1. Pre-operative CT angiography (three-dimensional reconstruction) showing the abnormal right coronary artery arising from the pulmonary artery. RCA: right coronary artery, Ao: aorta, PA: pulmonary artery.

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trunk were separated from each other. After institution of CPB, an aortic cross clamp was applied and cold crystalloid cardioplegia was administered. The origin of the anomalous right coronary artery arising from the right anterior aspect of the main pulmonary trunk was dissected and transected from the pulmonary trunk. The defect on the pulmonary trunk was repaired with a primary closure. A hole was created with a 5-mm punch slightly to the left anterior aspect of the ascending aorta, and the right coronary artery was anastomosed there. A standard decannulation procedure was performed. After sternal and wound closure, the patient was transferred to the cardiac surgical intensive care unit, and the following day to the postoperative ward. After an uneventful postoperative course, the patient was discharged on the sixth postoperative day. During the follow up, the patient was asymptomatic. No change in cardiac enzymes was observed. The corrected anatomy was documented by postoperative CT angiography (Fig. 2). At 24 months after the procedure, the patient had a normal treadmill test and echocardiography revealed a hypokinetic inferior septum, increased left ventricle ejection fraction (54%), minimal mitral regurgitation and a LVIDd of 54 mm.

Discussion Anomalous origin of the coronary arteries from the pulmonary artery is a rare congenital cardiac anomaly. Its incidence is one in 30 000 to 300 000 live births.5-8 ALCAPA is the most common form of this type of anomaly, accounting for more than 90% of cases and 0.5% of all congenital cardiac anomalies.6 ARCAPA is very rare compared to ALCAPA.7, 9 The only predictable morphological finding is an increase in the size of the left main coronary artery and its branches, and an increase in the size of the RCA with thinning of its wall.7 As in our patient, the ectopic ostium of the RCA originates from the right anterior pulmonary cusp in the majority of cases. Right coronary artery dominance is usual. The flow pattern in the collateral circulation between the left coronary system and the RCA is similar to that of coronary atherosclerosis. The major source of collateral circulation to the RCA is septal branches of the LAD.10 In this anomaly, left and right ventricular functions are not corrupted and findings of impaired cardiac function do not occur.10 Generally there are no signs of myocardial ischaemia, while symptoms and clinical findings of congestive heart failure may be present only in rare paediatric cases.11 In an autopsy series of nine cases, congestive heart failure was found in a two-year-old child who died without any previous symptoms, in an 11-year-old patient who died from cardiac arrest, and in a 72-year-old male patient. There were no signs of cardiac pathology or impaired cardiac function reported in the remaining six patients.7 In 30 of these 58 patients, other than the autopsy cases, the anomaly was primarily diagnosed with angiography. At the time of diagnosis their ages varied between one day and 90 years old.12 The real incidence of this anomaly is probably higher than reported because a large number of patients are asymptomatic. This is opposite to what is seen in ALCAPA. Findings of mitral regurgitation and myocardial infarction, often seen in the early ages of ALCAPA, are not encountered in this anomaly.

Fig. 2. Postoperative CT angiography (three-dimensional reconstruction) showing the right coronary artery transposed to the ascending aorta. RCA: right coronary artery, Ao: aorta.

This anomaly shows different clinical signs when it becomes symptomatic. Dyspnoea develops in 17% of patients, while fatigue occurs in 13%, angina in 17%, mitral regurgitation in 9%, congestive heart failure in 30% and cardiac arrest in 17% of patients.3 Objective findings were not specific in most of the cases, except in those who had angiography. Ischaemia was present in 40% of patients. In adults, this anomaly is typically diagnosed due to a cardiac murmur or during angiography performed for other reasons.10 However, hidden ischaemia, revealed from a positive stress test and angina (mostly atypical angina) may develop in some patients.13 Although an ECG is helpful in the investigation of ALCAPA, it does not play a meaningful role in diagnosing right coronary artery anomaly. Generally there are no ischaemic changes and ventricular hypertrophy is usually absent or borderline. The heart silhouette in telecardiography may be slightly increased. Although diagnostic findings may be present on echocardiography, there has been no report in the literature of any case diagnosed with only this method. Besides 12 cases diagnosed at autopsy, three cases were diagnosed intra-operatively, 25 cases with angiography, while in five cases, angiography was performed after the echocardiographic findings suggested this anomaly. It is not enough to show that the right coronary artery does not originate from the aortic root, it is important to determine

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whether it originates from the pulmonary artery or not. A dilated left coronary artery and a wide right coronary artery observed on echocardiography should be the first cause of suspicion. A definite diagnosis is determined with angiography. Passing contrast through the left coronary artery that originates from the aorta and observing the passage of contrast through the collaterals to the right coronary artery and finally into the pulmonary artery is diagnostic.7 As can be seen in the literature, medical treatment was given to a few patients in whom clinical follow up was not done.14 Usually surgical treatment is suggested, even in asymptomatic patients. In the literature it is reported that 87% of patients diagnosed early had surgical treatment.3 Besides the lesstraumatic simple proximal ligation of the abnormal coronary artery, in order to remove pulmonary steal, separating the abnormal artery from the pulmonary artery and re-implanting it into the aorta is the appropriate surgical procedure. Surgical treatment is important for two reasons: first, providing two coronary systems with antegrade flow, re-implanting the aberrant artery into the aorta decreases the risk of sudden cardiac death, and second, it removes the risk of pulmonary steal phenomenon.15 In their comprehensive study, Radke et al.3 reported the postoperative follow up of nine patients who had surgical intervention: there had been regression in the left coronary artery dilatation after surgical correction. It was also reported that symptoms and ischaemia did not disappear in two patients with a dilated left coronary artery and slow peripheral flow.

Conclusion Although medical treatment is an option in an abnormal right coronary artery (different from ALCAPA where re-implantation into the aorta of the aberrant artery is obligatory), surgical correction of the anatomy is strongly supported by physiopathological findings.

References 1.

Williams IA, Gersony W, Hellenbrand WE. Anomalous right coronary artery arising from the pulmonary artery: A report of 7 cases and a

7. 8.

10.

11.

12.

13.

14.

15.

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reviex of the literature. Am Heart J 2006; 152: 1004.e9–17. Kreutzer C, Schlicter AJ, Roman MI, Kreutzer GO. Emergency ligation of anomalous left coronary artery arising from the pulmonary artery. Ann Thorac Surg 2000; 69: 1591–1592. Radke PW, Messmer BJ, Haaher PK, Klues HG. Anomalous origin of the right coronary artery: preoperative and postoperative hemodynamics. Ann Thorac Surg 1998; 66: 1444–1449. Bunton R, Jonas RA, Lang P, Rein AJ, Castenada AR. Anomalous origin of coronary artery from pulmonary artery: ligation versus astablishment of a two coronary artery system. J Thorac Cardiovasc Surg 1987; 93: 103–108. Vouhe PR, Baillot-Vernant F, Trinquet F, Sidi D, de Geeter B, Khoury W, et al. Anomalous left coronary artery from the pulmonary artery in infants: which operation? When? J Thorac Cardiovasc Surg 1987; 94(2): 192–199. Wolf DD, Vercruysse T, Suys B, Blom N, Matthys D, Ottenkamp J. Major coronary anomalies in childhood. Eur J Pediatr 2002; 161: 637–642. Roberts WC. Major anomalies of coronary arterial origin seen in adulthood. Am Heart J 1986; 111: 941–963. Wu QY, Xu ZH. Surgical treatment of anomalous origin of coronary artery from the pulmonary artery. Chin Med J (Engl) 2008; 121(8): 721–724. Canale LS, Monteiro AJ, Rangel I, Wetzel E, Pinto DF, Barbosa RC, et al. Surgical treatment of anomalous coronary artery arising from the pulmonary artery. Interact Cardiovasc Thorac Surg 2009; 8(1): 67–69. Angelini P, Villason S, Chan AV, Diez J. Normal and anomalous coronary arteries in human. In: Angelini P (ed). Coronary Artery Anomalies: A Comprehensive Approach. Philadelphia: Lippincott Williams and Wilkins, 1999: 49. Vairo U, Marino B, de Simone G, Marcelletti C. Early congestive heart failure due to origin of the right coronary artery from the pulmonary artery. Chest 1992; 102: 1610–1612. Gerlish LM, Ho SY, Milo S. Three anomalies of the coronary arteries co-existing in a case of pulmonary atresia with intact ventricular septum. Int J Cardiol 1990; 29: 93–95. Ladowski JS, Belvedere DA, Wuest LF. Anomalous origin of the right coronary artery from the pulmonary artery: an unusual cause of angina. Cardiovasc Surg 1995; 3: 81–83. Mahdyoon H, Brymer JF, Alam M, Khaja F. Anomalous right coronary artery from the pulmonary artery presenting with angina and aneurysmal left ventricular dilatation. Am Heart J 1989; 118: 182–184. Mintz GS, Iskandrian AS, Bemis CE, Mundth ED, Owens JS. Myocardial ischemia in anomalous origin of the right coronary artery from the pulmonary trunk. Proof of a coronary steal. Am J Cardiol 1983; 51: 610–612.

Today’s Prevention. Tomorrow’s Protection.

What are the Risk Factors for Coronary Heart Disease and Stroke? 3, 4 Major Risk Factors Include:

• • • • • •

Cigarette smoking Hypertension (high blood pressure) High cholesterol Diabetes mellitus

Protect their passion for living.

Advancing age Atrial Fibrilation

Other Risk Factors Include:

• • • •

Obesity Physical Inactivity Family History of premature coronary heart disease Blood clotting abnormalities

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• The dangerous fifth chamber • Rocking mitral annuloplasty ring