CVJA Volume 29 Issue 6 by Clinics Cardive Publishing

JULY/AUGUST 2018 VOL 29 NO 4

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CardioVascular Journal of Africa (official journal for PASCAR)

• Advances in percutaneous closure of patent ductus arteriosus • The African context of the Cape Town Declaration • Pulmonary hypertension in rural sub-Saharan Africa • Hypertension in newly diagnosed diabetics in Uganda • Management of acute coronary syndrome in Kenya • Left ventricular twist before and after haemodialysis

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

• Tribute to Professor Bongani Mawethu Mayosi Cardiovascular Journal of Africa . Vol 29, No 4, July/August 2018

the endurance ACE-inhibitor

• The challenge in diagnosing coarctation of the aorta

Published online: • Carcinoid syndrome and carcinoid heart disease

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Vol 29, No 4, JULY/AUGUST 2018

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EDITORIALS 203

The changing face of percutaneous closure of the patent ductus arteriosus: advances over the last few years A Greyling

204

The African context of the Cape Town Declaration P Zilla • L Zühlke • K Sliwa • P Commerford

Obituary 206 Bongani Mayosi, a hero remembered M Ntsekhe • P Commerford • P Brink • S Yusuf

CARDIOVASCULAR TOPICS 208

Pulmonary hypertension as seen in a rural area in sub-Saharan Africa: high prevalence, late clinical presentation and a high short-term mortality rate during follow up A Dzudie • BS Dzekem • CT Tchoumi • LN Aminde • AO Mocumbi • M Abanda • F Thienemann • AP Kengne • K Sliwa

213

Does the use of N-butyl-2 cyanoacrylate in the treatment of lower extremity superficial varicose veins cause acute systemic inflammation and allergic reaction? Ö Korkmaz • S Göksel • M Gül • H Başçil • Y Yildir • Ö Berkan

218

Hypertension among newly diagnosed diabetic patients at Mulago National Referral Hospital in Uganda: a cross sectional study M Muddu • E Mutebi • I Ssinabulya • S Kizito • CK Mondo

225

Presentation, management and outcomes of acute coronary syndrome: a registry study from Kenyatta National Hospital in Nairobi, Kenya E Bahiru • T Temu • B Gitura • C Farquhar • MD Huffman • F Bukachi

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

Editors

SUBJECT Editors

Editorial Board

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

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

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

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

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

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 29, No 4, JULY/AUGUST 2018

231

Left ventricular twist before and after haemodialysis: an analysis using speckletracking echocardiography A Yip • S Naicker • F Peters • E Libhaber • N Maharaj • M Mashabane • MR Essop

237

Management of stable angina pectoris in private healthcare settings in South Africa P Tlhakudi • LJ Mathibe

241

Short-term results of flanged Bentall de Bono and valve-sparing David V procedures for the treatment of aortic root aneurysms S Ergün • M Dedemoğlu • MB Rabuş • B Özbek • MM Özgür • MA Tuncer • M Balkanay • MK Kırali

246

Transcatheter closure of the patent ductus arteriosus at a public sector hospital in Soweto, South Africa: a review of patient outcomes over 15 years PE Adams • MF Chersich • A Cilliers

252

The challenge in diagnosing coarctation of the aorta JIE Hoffman

245

Tribute to Professor Bongani Mawethu Mayosi OS Ogah

260

Multivessel disease in STEMI patients: a perspective from limited-resource settings AAA Suliman • N Naseer • B Gersh

262

Feasibility of south–south collaboration in Africa: the Uganda–Mozambique perspective J Namuyonga • PS Lwabi • J Omagino • M Yacoub • AO Mocumbi

256

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World P Zilla • RM Bolman • MH Yacoub • F Beyersdorf • K Sliwa • L Zühlke • RSD Higgins • B Mayosi • A Carpentier • D Williams

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

Cases in a series of carcinoid syndrome and carcinoid heart disease MR Matshela

REVIEW ARTICLE

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Editorial The changing face of percutaneous closure of the patent ductus arteriosus: advances over the last few years Adele Greyling Patent ductus arteriosus (PDA) closure is recommended for patients with moderate-to-large PDAs with significant left-toright shunting, left-sided volume overload, reversible pulmonary arterial hypertension (PAH) or a previous episode of endocarditis.1 In patients with either a small or silent PDA, the decision to close may be less clear. However, closure is still recommended in small, audible PDAs and in selected small, silent PDAs, if so preferred by the clinician and the family, due to the theoretically increased risk for the development of endocarditis.1 Since the first transcatheter PDA closure over 50 years ago, it has become the procedure of choice in infants over 5 kg as it is less invasive and more cost effective than surgery and does not leave a surgical scar.2 The Amplatzer duct occluders, ADO I and ADO II, are widely used and have been shown to be safe and effective to close moderate-to-large PDAs.3 They are probably best suited to Krichenko type A or E PDAs. Similar in design to the ADO I, but with flaring on the pulmonary side of the device, the Occlutech PDA occluder has been proven to be safe and effective, even in the low- to middle-income setting.4 With these devices, use is limited in smaller infants due to the size of the delivery system and the large aortic retention disc, which could lead to vascular complications, iatrogenic pulmonary artery stenosis or coarctation of the aorta. In the ADO II AS device, the occlusive material has been removed, making the device smaller and more flexible. Combined with a lower-profile 4F delivery system, it can be delivered from the aortic or pulmonary side. This makes it particularly well suited for the closure of small- to moderate-sized elongated PDAs (Krichenko type C and D PDAs) in small children. In centres with experienced operators, the outcomes are similar to surgical closure and it is more cost effective.5 In smaller PDAs, Cook coils can be used, and although the cost is significantly less, they are associated with increased procedure times and radiation doses, higher risk of migration, residual leak and the need for a redo procedure.5 A recent study suggested that a ‘foetal type PDA’, type F, be added to the Krichenko classification and that the Amplatzer vascular plug II (AVP-II) was the most effective device for closure.6 They report that PDAs in pre-term infants are similar

to those seen during foetal life; typically wide in relation to the descending aortic diameter, and long and tortuous without significant stenosis. Type F PDAs are morphologically most similar to type C PDAs; but they are longer and wider, with a tortuous segment closest to the PA end. The shape resembles a ‘hockey stick’ with an initial mild cranial angulation, followed by a caudal turn at the PA end. They are significantly larger, with the minimal luminal ductal diameter:descending aortic diameter ratio of 0.67 ± 0.12 and device diameter:descending aortic diameter ratio of 1.04 ± 0.18, higher than in any other PDA type. The biggest change in practice in recent years has been the move to percutaneous closure in smaller and pre-term infants with relatively larger PDAs, even in infants with a weight of less than 2 kg. In centres with experienced operators, outcomes comparable to surgical ligation can be achieved at a lower cost. In this issue of the journal, Adams and co-workers discuss the development of transcatheter closure of PDAs over a 15-year period at Chris Hani Baragwanath Hospital in Johannesburg (page 246). They found the procedure to be safe and effective in this setting.

References 1.

Doyle T, Kavanaugh-McHugh A, Soslow J, Hill K. Management of patent ductus arteriosus in term infants, children, and adults. UpToDate 2018. http://www.uptodate.com (Accessed 1 July 2018.)

Rodríguez Ogando A, Planelles Asensio I, de la Blanca ARS, Ballesteros Tejerizo F, Sánchez Luna M, Gil Jaurena JM, et al. Surgical ligation versus percutaneous closure of patent ductus arteriosus in very lowweight preterm infants: which are the real benefits of the percutaneous approach? Pediatr Cardiol 2018; 39: 398–410.

Bass JL, Wilson N. Transcatheter occlusion of the patent ductus arteriosus in infants: Experimental testing of a new Amplatzer device. Catheter Cardiovasc Interven 2014; 83(2): 250–255.

Pepeta L, Greyling A, Nxele MF, Makrexeni ZM. Patent ductus arteriosus closure using Occlutech® Duct Occluder, experience in Port Elizabeth, South Africa. Ann Pediatr Card 2017; 10: 131–136.

Pamukcu O, Tuncay A, Narin N, Baykan A, Korkmaz L, Argun M, et al. Patent ductus arteriosus closure in preterms less than 2 kg: surgery versus transcatheter. Int J Cardiol 250; 2018: 110–115.

Division of Paediatric Cardiology, Department of Paediatrics, Dora Nginza Hospital, Port Elizabeth, South Africa Adele Greyling, MD, Adelegreyling1@gmail.com

Philip R, Waller BR, Agrawal V, Wright D, Arevalo A, Zurakowski D, et al. Morphologic characterization of the patent ductus arteriosus in the premature infant and the choice of transcatheter occlusion device. Catheter Cardiovasc Interven 2016; 87: 310–317.

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The African context of the Cape Town Declaration Peter Zilla, Liesl Zühlke, Karen Sliwa, Patrick Commerford This issue of the Cardiovascular Journal of Africa publishes the Cape Town Declaration (page 256) simultaneously with eight other journals worldwide.1 It is a call to arms within the cardiac surgical community. A decade after the late Professor Bongani Mayosi led the Pan-African Cardiology of Africa (PASCAR) call and alerted the world to the huge public health crisis of rheumatic heart disease (RHD) in the Drakensberg Declaration,2 the cardiac surgery community has also recognised the magnitude of the problem, aggravated by the lack of cardiac surgery in the most affected regions of the world. When representatives of all major cardiothoracic societies, industry, civic organisations as well as surgeons from all over the world convened to celebrate the 50th anniversary of the first heart transplant in Cape Town, an entire day was dedicated to a south–north dialogue, focusing on the unmet needs of cardiac surgery in low-income countries. Nowhere is this unmet need more glaring than on the African continent. In most countries, as far as children are concerned, this lack of life-saving therapy in the absence of a curative alternative has been only sporadically relieved by fly-in missions from high-income countries, bringing teams of specialists and consumables to remote places to operate on a handful of children, before departing. For RHD, however, it is adolescents and young adults who represent the majority of patients in need of cardiac surgery among the more than six billion people living outside high-income countries. Although their numbers approximate those of patients with HIV3 (World Health Organisation Global Health Observatory data 2017), to date, this startling comparison has been largely ignored globally. There has been little RHD activism similar to the one that drove the worldwide HIV campaigns, until recently. Of all the efforts to create awareness for the neglected millions of patients with RHD, the tireless work of Bongani Mayosi stands out.1-4,6-9 His focus on cardiovascular diseases of the poor in Africa led to South Africa becoming an epicentre of research on RHD, with other internationally renowned scientists following in his Chris Barnard Division of Cardiothoracic Surgery, Groote Schuur and Red Cross Children’s Hospital, University of Cape Town, Cape Town, South Africa Peter Zilla, MD, PhD, FCS, peter.zilla@uct.ac.za

Division of Paediatric Cardiology, Department of Paediatrics, Red Cross Children’s Hospital; Division of Cardiology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa Liesl Zühlke, MB ChB, FCPaeds, Cert Card, MPH, PhD

Hatter Institute for Cardiovascular Research in Africa, Department of Cardiology and Internal Medicine, University of Cape Town Karen Sliwa, MD, PhD

Division of Cardiology, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; Editor-in-Chief (CVJA) Patrick Commerford, MB ChB, FCP (SA)

footsteps.1,3-5,7-9 Therefore, it seems fitting that all the international cardiac surgical societies came to Cape Town to not only celebrate a medical event that happened here 50 years ago and that was unparalleled in its impact, but to finally unite the cardiac surgical community behind the plight of those living with and affected by RHD. Furthermore, in May 2018, the World Health Assembly resolution against RHD was finally adopted, following the African Union communique spearheaded by Mayosi in 2016.7 We stand at a powerful new juncture in the fight against rheumatic heart disease, led by those living in RHD-endemic countries. As a first concrete result of this gathering of leaders from all over the world, which led to the Cape Town Declaration, an analysis of the cardiac surgical capacity of 16 different countries will soon be published.8 More importantly, this analysis for the first time provides a needs assessment in affected regions. Although echocardiographic screening studies had provided better insight into the burden of asymptomatic RHD, hardly any data existed on the proportion of patients actually needing cardiac surgery. Furthermore, cohort studies from tertiary institutions had already started to highlight one inconvenient truth for health politicians: although the incidence of rheumatic fever has significantly dropped, the drastic cuts to financing cardiac surgery in the public domain of countries such as South Africa are not justified, since both the incidence of RHD among adults and the need for surgery remain high.9 Yet, while the indigent population of South Africa and the Maghreb has at least some limited access to heart valve surgery, the majority of Africans south of the Sahara has none. What makes the plight of Africa so particularly sobering in this regard is that the cardiac surgery dilemma is not only a reflection of economic prowess. In our comparison of 16 different countries being home to four billion people, there was only a weak correlation between the per capita GDP and the provision of cardiac surgery. With a near-identical per capita GDP, Iran and South Africa spend nearly identical per capita amounts on health, yet Iran performs 525 cardiac operations per million, as opposed to 142 in South Africa. Likewise, Nigeria’s per capita GDP is almost a third higher than that of India, but India delivers 154 cardiac operations per million, as opposed to 0.5 in Nigeria.8 Similarly, the Gini index, as an expression of societal inequality, does not always correlate with access to cardiac surgery: Algeria, with a Gini index of 28 and South Africa with 63, provide similar levels of cardiac surgery (127/million versus 142/million operations). Yet, an access ratio between affluent private patients and indigent patients of 12 in South Africa but only 1.2 in Algeria does correlate with the extremely divergent Gini indices between these two countries.8 In that regard, South Africa is at the extreme end: those 17% of the population who have access to private medical care receive 595 cardiac operations per million, while the 83% of the population who depend on public medical care receive only 50 operations per million per year. Alternatively expressed, one private hospital cares for 300 000 cardiac surgical patients who have medical insurance (with 7.1 cardiac surgeons/million), as opposed to 6.1 million patients per centre who depend on the public sector (with 0.7 cardiac surgeons/

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million).8 In an even more blunt comparison, South Africa’s almost 50 private cardiac centres serving a population of 10 million medical aid patients are in stark contrast to an indigent population of a billion people living in sub-Saharan Africa, with access to half this number of hospitals offering heart valve surgery. Changing this appalling state of affairs will take huge efforts on many levels. Pressure on governments will need to be coordinated to have any effect. Activist groups such as RHD Action will need to be broadly supported. International awareness needs to increase dramatically and the readiness of the medical device industry to become a partner and adjust their price policy to indigent patients and not only to the African private sector will be paramount. Advice from health economists needs to be sought to provide cost-effective, evidencebased interventions and present a high-level business model to international agencies such as the World Heart Federation and World Health Organisation. Once these prerequisites are in place, training specialists in a country that has exposure to RHD, rather than in North America or Europe, will be crucial, with the goal firmly focused on local capacity building. Critically important will be political will and funding to drive a unified and integrated RHD agenda. These key demands have been formulated in the Cape Town Declaration. Much depends now on the support it gets to implement them. One thing is undisputed: the time to act is now!

References

The authors acknowledge the immense contribution of Professor Bongani

205

Zilla P, Bolman RM, Yacoub M, Beyersdorf F, Sliwa K, Zühlke L, et al. The Cape Town Declaration on access to cardiac surgery in the developing world. Ann Thorac Surg 2018 (in press).

Mayosi B, Robertson K, Volmink J, Adebo W, Akinyore K, Amoah A, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006; 96: 246.

Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S. Incidence and characteristics of newly diagnosed rheumatic heart disease in urban African adults: insights from the heart of Soweto study. Eur Heart J 2010; 31(6): 719–727.

Zuhlke L, Karthikeyan G, Engel ME, et al. Clinical outcomes in 3343 children and adults with rheumatic heart disease from 14 low- and middle-income countries: two-year follow-up of the global Rheumatic Heart Disease Registry (the REMEDY study). Circulation 2016; 134(19): 1456–1466.

Sliwa K, Zilla P. Rheumatic heart disease: the tip of the iceberg. Circulation 2012; 125(25): 3060–3062.

Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med 2017; 377(8): 713–722.

Watkins D, Zuhlke L, Engel M, Daniels R, Francis V, Shaboodien G, et al. Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communique. Cardiovasc J Afr 2016; 27: 1–5.

Zilla P, Yacoub M, Zühlke L, Beyersdorf F, Sliwa K, Khubulava G, et al. Global unmet needs in cardiac surgery. Global Heart 2018 (in press). Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart

Mayosi in the field of rheumatic heart disease and his passion and drive for

S. Incidence and characteristics of newly diagnosed rheumatic heart

capacity building and action. He had agreed to write this editorial shortly before

disease in urban African adults: insights from the heart of Soweto study.

his passing and we dedicate the ongoing work against RHD to his memory.

Eur Heart J 2010; 31(6): 719–727.

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Obituary Bongani Mayosi, a hero remembered Mpiko Ntsekhe, Patrick Commerford, Paul Brink, Salim Yusuf Shortly after joining the internal medicine rotation at Groote Schuur Hospital, Bongani Mayosi admitted a patient with suspected tuberculous pericarditis to one of the medical wards. Little did he anticipate the reaction of the attending consultant the next day on the post-intake ward round when he let her know that he had added high-dose corticosteroids to the patient’s antituberculosis therapy. Stumped by the simple request to provide evidence for his decision and shocked by the absence of definitive answers when he looked it up, he made a mental note to one day be the person who would provide the answers. Twenty years later, Professor Mayosi had not only published the largest clinical trial of interventions for tuberculous pericarditis in the New England Journal of Medicine, but he was widely acknowledged as the world’s foremost authority on the subject. Mayosi was born and brought up in the Eastern Cape Province of South Africa (Transkei) where his father, the regional district surgeon and his mother, a nurse, inspired his lifetime commitment to patient care, and nurtured his belief that he could be whatever he wanted to be and achieve anything. He often reflected on his early years in rural Transkei where everyone he looked up to, admired and wanted to grow up to be like, looked like him and believed in him. He was grateful to that environment, which he believed had spared him the crippling consequences of self-doubt that is one of the main legacies of apartheid South Africa. He graduated from St John’s College in Mthatha at the age of 15 years, with six distinctions, and then went on to graduate cum laude and at the top of his medical school class from the

Department of Cardiology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Mpiko Ntsekhe, MD, PhD

Department of Cardiology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Patrick Commerford, MB ChB, FCP (SA)

Department of Internal Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg, South Africa Paul Brink, MB ChB, PhD

Department of Medicine, and Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Hamilton, Ontario, Canada Salim Yusuf, MD, DPhil, MRCP

This article may be reproduced in other medical and scientific journals provided the original source is acknowledged: Cardiovascular J Afr 2018; 20(4): 205–206.

Professor Bongani Mayosi

then University of Natal. When asked to explain the source of his subsequent passion for research, he pointed to, as crucial, the extra year he had taken from his medical degree programme (MB ChB) to study the intricacies of the navicular bone. His MB ChB was followed in quick succession by fellowship of the College of Physicians and formal cardiology training, both at the University of Cape Town (UCT). In 2001 he returned to Cape Town from Oxford University with a DPhil and the dream of creating a cadre of people and building a programme of clinical research that would be capable of eradicating the unacceptably high burden of neglected diseases of poverty afflicting sub-Saharan Africa. Shortly after that he was appointed and served as professor and head of the Department of Medicine at Groote Schuur Hospital and UCT until 2015. Whether it was his warm smile, infectious enthusiasm, engaging intellect or irresistible charm, few people who met him were not immediately smitten. Mayosi was endowed with unique combinations of academic brilliance and vision, ambition and humility, and the ability to persuade people around him to believe that they could achieve the near impossible. Among his many mentees and colleagues, he became famous for a number of inspiring ‘Bongani-isms.’ One such -ism, which came to encapsulate so much of who he was and what was important to him, was the idea that we should all strive to ‘lift others as we rise.’ Whether it was individuals or institutions, he believed

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that there is little point in having lonely islands of success. And importantly, he would argue, Africa’s long-term ability to address the great health-related and other challenges of the day was crucially dependent on making sure we have as many high achievers and people with the requisite skills and ability as possible. In his role as a global leader in medicine, he managed to strike up and lead critical collaborations with international partners, which allowed him a large number of important scholarly contributions on cardiovascular disease and health at local and international levels. Working with Salim Yusuf of the Population Health Research Institute (PHRI) at McMaster University in Canada, research funding was raised and expertise was developed that allowed for the creation of the Pan-African Investigation of the Management of Pericarditis (IMPI), a multicentre research consortium that conducted many important studies and a trial on tuberculous pericarditis. Again it was his relationship with partners at the PHRI that led to the establishment of the Global Rheumatic Heart Disease Registry, or REMEDY, which evolved into the first large, multicountry registry and cohort study of 3 000 people with rheumatic heart disease (RHD) across much of the African continent, the Middle East and east Asia. The INVICTUS trial of 4 500 people evaluated antithrombotics in a global registry and cohort study of 20 000 patients in 30 countries, and a Wellcome Trust-funded study worked on the genetics of RHD. Finally, working with Peter Schwartz, Hugh Watkins and other collaborators from Europe and the United Kingdom, a programme of research on heart muscle disease and novel genes in Africans was established. Through these pioneering programmes, optimal methods for the diagnosis and treatment of tuberculous pericarditis were defined, rheumatic heart disease was put on the global agenda of the World Heart Federation and World Health Organisation, and it led to the discovery of novel genes, which allowed for better understanding of the biological mechanisms of heart disease and fibrosis. Mayosi’s research output was enormous and included many articles, book chapters and books with multiple citations. His contributions to capacity development and skills output were equally impressive and included numerous individuals who he personally supervised and mentored as academics, clinician scientists and leaders, and even more people whom he inspired, influenced and created opportunities to do the same. Among his many achievements, he was particularly proud, over the 20 years of service to the organisation, of helping to resurrect the Pan-African Society of Cardiology into a vibrant, active society, and helping to give the organisation a sense of gravitas and purpose, making it fit and able to help tackle Africa’s cardiovascular health priorities. For his tremendous contribution to society, Mayosi was honoured with numerous awards and prizes during his outstanding career. Among those that he prized most were South Africa’s highest honour, the Order of Mapungubwe in Silver, for excellent contributions to medical science in 2009, the National Science and Technology Foundation – BHP Billiton award 2012 (to an individual for outstanding contribution to science, engineering, technology and innovation through management and related activities over the previous five to 10 years or less), and the National Research Foundation award for transforming the science cohort of South Africa (the award is focused on

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transforming the science cohort to be more representative of South African demographics). Importantly, this recognition came as he actively advanced and supported the careers of students and colleagues, irrespective of ethnicity, race, religion or social class. His unique ability to be both ‘colour blind’ and proudly promote transformation and the all-inclusive African-ness was enormously important to a wounded country and it’s institutions of higher learning. In 2016 Mayosi received the Honorary Fellowship of Wolfson College, University of Oxford (to individuals whom they particularly value and admire for their outstanding distinction in their field, and for the intellectual contribution they have made in the world to areas in which the College has a strong interest). In 2017 he became one of the few Africans inducted to the National Academy of Medicine in the USA. Bongani remained grounded and humble until the very end. It is fair to say he was respected and revered, and will be remembered as much for who he was as a human being and his qualities of ‘ubuntu’ (humanity towards others) as for what he achieved. He was a peoples’ person who could fit in comfortably almost anywhere with anyone. He developed warm, strong bonds and interpersonal relationships with people at all levels. He was kind and compassionate and cared deeply about the welfare and well-being of others. When asked how it was that he was able to give so much to others, he famously responded by reminding people that ‘the gift of the giving is in the giving’. He was a devoted, loving family man who met his wife and life partner Professor Nonhlanhla Khumalo on a bus during orientation at medical school when he was 16 years old, and knew immediately that he had found his life partner. Their lifelong bond was palpable and obvious to all who met them. Adorning the walls of his office at work were numerous short, handwritten messages from his three daughters Nosipho, Vuyi and Gugu, who he loved much and were not only incredibly special to him but were his pride and joy. Bongani was appointed as dean of the Faculty of Medicine at the University of Cape Town in 2016. This appointment coincided with the start of country- and university-wide, student-led unrest and protests, and one of the most difficult periods ever experienced in the higher education landscape. By his own admission, being at the symbolic centre of the tense turmoil that ensued and the target of often intense criticism from all stakeholders was incredibly difficult, given his own value system, beliefs and way of being. Importantly it also took him away from his first love of teaching, training and research, and the grand plans for the Faculty of Health Sciences, country and continent, which he had been developing over the preceding 12 to 15 months, in preparation for becoming dean. No one will ever know or understand how much the events of 2016–2018 contributed to his painful battle with clinical depression, which he eventually succumbed to through suicide on 27 July of this year, but there is little doubt that the turbulent times and environment clearly had a significant impact on him. Bongani will be sorely missed by all who knew him and knew of him. Among the many legacies he leaves behind are the numerous people, programmes and partnerships, which he inspired and infused with a collective sense of purpose to work towards his dreams of a healthier, wealthier and wiser Africa, capable of defining its own priorities, solving its own problems and being the master of its own destiny.

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Cardiovascular Topics Pulmonary hypertension as seen in a rural area in sub-Saharan Africa: high prevalence, late clinical presentation and a high short-term mortality rate during follow up Anastase Dzudie, Bonaventure Suiru Dzekem, Cabral Tantchou Tchoumi, Leopold Ndemnge Aminde, Ana O Mocumbi, Martin Abanda, Friedrich Thienemann, Andre Pascal Kengne, Karen Sliwa

Abstract Introduction: The epidemiology of pulmonary hypertension (PH) in low- to middle-income countries is poorly characterised. We assessed the prevalence, baseline characteristics and mortality rate in patients with echocardiographically diagnosed PH at a rural cardiac centre in Cameroon. Methods: We conducted a prospective cohort study in a subsample of 150 participants, aged 18 years and older, diagnosed with PH [defined as right ventricular systolic pressure (RVSP) ≥ 35 mmHg in the absence of pulmonary stenosis and right heart failure]. PH was classified as mild (RVSP: 35–50 mmHg), moderate (RVSP: 51–60 mmHg) and severe (RVSP: > 60 mmHg). Results: Of 2 194 patients screened via echocardiograms, 343 (crude prevalence 15.6%) had PH. The sub-sample of 150 patients followed up (54.7% women, mean age of 62.7 ± 18.7 years) had a mean RVSP of 68.6 mmHg. They included 7.3% mild, 29.3% moderate and 63.4% severe PH cases. Co-morbidities included log smoke (80.7%), hypertension

(52.0%), family history of cardiovascular disease (50.0%), diabetes (31.3%), alcohol abuse (21.3%) and HIV infection (8.7%). Main clinical features were dyspnoea (78.7%), fatigue (76.7%), palpitations (57.3%), cough (56.7%), jugular venous distension (68%) and peripheral oedema (66.7%). Overall, 70% presented in World Health Organisation functional class III/IV. PH due to left heart disease (PHLHD) was the commonest (64.7%), and rheumatic valvular disease accounted for 36.1%. The six-month mortality rate was 28%. Conclusion: PH, dominated by PHLHD, was common among adults attending this rural centre and was associated with a high mortality rate. Related co-morbidities and late clinical presentation reflect the poor socio-economic context. Improved awareness of PH among physicians could promote early diagnosis and management.

Keywords: pulmonary hypertension, prevalence, mortality, Shisong, Cameroon

Departments of Internal Medicine and Physiology, Faculty of Medicine, University of Yaoundé, Yaoundé, Cameroon

Shisong Cardiac Centre, Kumbo, Cameroon

Anastase Dzudie, MD, PhD, FESC Bonaventure Suiru Dzekem, MD, dbos001@yahoo.com Martin Abanda, MD

Instituto Nacional de Saúde, and Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique

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

Non-communicable Diseases Unit, South African Medical Research Council, Cape Town, South Africa

Anastase Dzudie, MD, PhD, FESC Bonaventure Suiru Dzekem, MD Leopold Ndemnge Aminde, MD Martin Abanda, MD

Andre Pascal Kengne, MD, PhD

Soweto Cardiovascular Research Group, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

Friedrich Thienemann, MD

Anastase Dzudie, MD, PhD, FESC

NIH Millennium Fogarty Chronic Disease Leadership Programme Anastase Dzudie, MD, PhD, FESC Karen Sliwa, MD, PhD, FESC

Cabral Tantchou Tchoumi, MD, PhD

Ana O Mocumbi, MD, PhD, FESC

Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Karen Sliwa, MD, PhD, FESC

School of Public Health, Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, Australia Leopold Ndemnge Aminde, MD

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Submitted 15/10/16, accepted 14/1/18 Published online 8/12/17 Cardiovasc J Afr 2018; 29: 208–212

www.cvja.co.za

DOI: 10.5830/CVJA-2018-007

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure (mPAP) at or above 25 mmHg at rest.1,2 It is currently classified by the World Health Organisation (WHO) into five subtypes, which include pulmonary arterial hypertension (PAH), PH due to left heart disease (PHLHD), PH due to lung disease or hypoxia (PHLDH), chronic thromboembolic PH (CTEPH) and PH due to unclear or multifactorial mechanisms (PHUM).3,4 The prevalence of pulmonary vascular disease in the developing world is unknown, but estimates suggest that about 25 million individuals may be affected.5 Little information exists on the epidemiology of PH in sub-Saharan Africa, however there is some evidence that based on the high prevalence of risk factors such as rheumatic heart disease, schistosomiasis and HIV infection in this area of the world, the prevalence and mortality rate of PH may be higher than in Western countries.6,7 In South Africa, PH has been identified as one of the commonest causes of death, accounting for 31% of total cardiovascular deaths,8 while only 8% of cardiovascular deaths in the United Kingdom were attributed to PH in 2012.9 Furthermore, studies from the United States have shown that the prevalence of PH among African Americans is higher than in Caucasians.10 These differences in the epidemiology of PH in different regions of the world are determined by genetic, geographic, environmental and socio-economic factors. Left heart disease has been widely suggested to be the most common cause of PH. In developing countries, chronic infectious diseases, hypertensive heart diseases, cardiomyopathy and rheumatic heart disease are the main contributors.6 This study aimed at determining the prevalence, baseline clinical characteristics and mortality rate during six months of follow up of patients with PH diagnosed via echocardiography at the rural Shisong Cardiac Centre (SCC) in Cameroon.

Methods This was a prospective cohort study in a sub-sample of 150 participants aged 18 years and older who were diagnosed with PH via echocardiography. It was conducted at the Shisong Cardiac Centre from September 2013 to December 2014. This study also forms part of the Pan-African Pulmonary Hypertension Cohort study (PAPUCO). Shisong is a rural village in the Kumbo sub-division of the north-west region of Cameroon. Shisong, on the outskirts of Kumbo town, is about 400 km north of Douala, the economic capital of Cameroon, and 450 km north-west of Yaoundé, the political capital of Cameroon.11 The Shisong Cardiac Centre (SCC) is a well-equipped centre for the diagnosis and management of a variety of cardio-surgical conditions including PH. On average 185 echocardiographic examinations are done per month. In this study, the target population was restricted to patients living in rural or sub-urban areas, aged 18 years and above, who underwent echocardiographic examination at the centre between September 2013 and December 2014.

The PAPUCO study design and procedures have been described in detail elsewhere.12 In brief, PH was diagnosed using echocardiography in patients with a right ventricular systolic pressure (RVSP) ≥ 35 mmHg in the absence of acute right heart failure (HF) and pulmonary stenosis. The datacollection form, adapted from the PAPUCO study, was used to obtain patients’ information and clinical characteristics, including socio-demographic factors and past medical history [age, gender, body mass index (BMI), HIV status, family history of cardiovascular disease, systemic hypertension, dyslipidaemia, smoking and alcohol consumption], clinical presentation (dyspnoea, cough, fatigue, pedal oedema, palpitations and World Health Organisation functional classification). At six months post-baseline, patients and/or their next-of-kin were contacted by phone to determine their vital status. For all fatal outcomes, the probable cause of death was assessed through a verbal autopsy.

Statistical analysis Data were analysed using SPSS® (Statistical Package for Social Sciences for Windows) version 20. Qualitative variables are summarised as frequencies and percentages. Continuous variables are represented as means and standard deviations, or median (25th to 75th percentiles). Patients were categorised in three groups depending on PH severity; mild if RVSP was 36–50 mmHg, moderate if RVSP was 51– 60 mmHg and severe if RVSP was > 60 mmHg. We used χ² to compare proportions and Student’s t-test or Kruskal–Wallis test to compare mean differences for continuous variables. Statistical significance was accepted at a p-value of 0.05.

Results Out of a total of 2 194 patients who underwent cardiac echography at baseline, 343 had PH (prevalence rate 15.6%). Mean age was 61.9 ± 18.0 years and female gender (189, 55.1%) was predominant. As shown in Fig. 1, the peak prevalence of PH was noticed between 60 and 69 years (91/343, 26.5%). Characteristics of the sub-sample followed up (n = 150) were similar to those of the overall PH group. The mean baseline age was 62.7 years [standard deviation (SD) =18.7]. Mean age did not 30

n = 343

26.5

25 21.0 Percentages

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20 15

12.0

10 5.8

12.2

13.1

6.4

5 0

2.9

18–29 30–39 40–49 50–59 60–69 70–79 80–89 Age group of patients with PH (years)

≥90

Fig. 1. Age distribution of patients with pulmonary hypertension in the Shisong Cardiac Centre.

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n = 150

90 80

80.7

70 60

52.0 50.0 49.3

50 40

31.3

9.3

8.7

8.0

Cur smoker

16.7

CLD

21.3

HIV

5.3

3.3

CLiD

Ex-smoker

Dyslipidaemia

Alc abuse

Diabetes

MVR

FHCVD

HTN

0 Ind smoke

vary significantly by severity of PH (p = 0.25). Most participants (44.7%) had primary education, 32% had secondary education while 15.3% had never been to school. Variations by severity of PH were not significant (p = 0.69). The 150 followed-up participants included 11 (7.3%) with mild PH, 44 (29.3%) with moderate PH and 95 (63.4%) with severe PH. The proportion of women was 54.7% overall, and 5, 20 and 57%, respectively among the mild, moderate and severe PH groups (p = 0.09). The distribution of risk factors for PH and co-morbidities are depicted in Fig. 2. Exposure to cooking fumes (80.7%), systemic hypertension (52.0%), family history of cardiovascular disease (50.0%), mitral valve regurgitation (49.3%), diabetes (31.3%) and alcohol abuse (21.3%) were the most common factors and co-morbidities identified in our study participants. Dyspnoea (78.7%), fatigue (76.7%), palpitation (57.3%) and non-productive cough (56.7%) were the main symptoms reported by patients on initial presentation. Syncope (6.7%) and cyanosis (6.0%) were rarely reported by our patients. Most patients who participated in this study had distended jugular veins (68.0%) and peripheral oedema (66.7%). Table 1 summarises variations in clinical signs and symptoms with PH severity. Chest pain varied significantly with PH severity (p = 0.03) Fig. 3 shows variations of the World Health Organisation functional class (WHO FC) according to PH severity. More than half (53%) of the patients presented in WHO FC III, 28% presented in class II, while 17 and 2% presented in class IV and I, respectively. Therefore a greater proportion of patients presented with marked functional limitation. The main cause of PH was left heart disease (group 2), accounting for 64.7% of all cases, as shown in Fig. 4. In addition, 15.3% was due to unclear or multifactorial aetiology (group 5),

Percentage of patients with PH

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Risk factors/co-morbidities Ind Smoke = exposure to smoke from burning firewood, HTN = hypertension, FHCVD = family history of cardiovascular disease, MVR = mitral valve regurgitation, Alc abuse = alcohol abuse, CLD = chronic lung disease, Cur smoker = current smoker, CLiD = chronic liver disease, PE = pulmonary embolism.

Fig. 2. Risk factors and co-morbidities among 150 patients with pulmonary hypertension followed up at the Shisong Cardiac Centre.

10% due to pulmonary arterial hypertension (group 1), 8% due to lung disease or hypoxia (group 3), and only 2% due to chronic thromboembolic mechanisms (group 4). Out of 97 participants with PHLHD, 50.5% had left ventricular systolic dysfunction (heart failure with reduced ejection fraction, HFrEF: EF ≤ 50%),

Table 1. Clinical and echocardiographic findings of adult patients with PH Mild PH (n = 11)

Moderate PH (n = 44)

Severe PH (n = 95)

p-value

118 (78.7)

9 (7.6)

32 (27.1)

77 (65.3)

0.32

9 (6.0)

1 (11.1)

2 (22.2)

6 (66.7)

0.58

Non-productive cough, n (%)

85 (56.7)

10 (11.8)

22 (25.9)

53 (62.3)

0.14

Fatigue, n (%)

115 (76.7)

8 (7.0)

30 (26.0)

77 (67.0)

0.10

Syncope, n (%)

10 (6.7)

3 (30.0)

7 (70.0)

0.33

Palpitations, n (%)

86 (57.3)

8 (9.3)

28 (32.6)

50 (58.1)

0.06

Chest pain, n (%)

49 (32.7)

6 (12.2)

17 (34.7)

26 (53.1)

0.03

Distended jugular veins, n (%)

102 (68.0)

8 (7.8)

26 (25.5)

68 (66.7)

0.22

Peripheral oedema, n (%)

100 (66.7)

9 (9.0)

25 (25.0)

66 (66.0)

0.43

NYHA I and II, n (%)

45 (30.0)

3 (6.0)

19 (42.2)

23 (51.1)

0.13

NYHA III and IV, n (%)

105 (70.0)

8 (7.6)

25 (23.8)

72 (68.6)

0.13

Parameters

All (n = 150)

Clinical features at presentation Difficulty breathing (dyspnoea), n (%) Cyanosis, n (%)

Vital signs BMI (kg/m2)

26.3 (18–46.8)

23.9 (21.2–26)

26.2 (18.6–42.4)

27.1 (18–46.8)

0.03

Systolic BP (mmHg)

126 (65–250)

133 (102–190)

123 (95–235)

127 (65–250)

0.26

Diastolic BP (mmHg)

79 (45–154)

73 (58–106)

78 (60–154)

80 (45–130)

0.73

Heart rate (beats/min)

88 (52–150)

96 (80–119)

88 (52–120)

86 (56–150)

0.43

Respiratory rate (breaths/min)

23 (13–40)

22 (19–28)

22 (13–35)

23 (15–40)

0.20

O2 saturation (%)

93 (55–100)

90 (82–98)

94.5 (67–99)

91.5 (55–100)

0.37

Echographic parameters LVEDD (mm)

53 (16–72)

36 (18–56)

50 (38–70)

55 (16–72)

0.0001

LVESD (mm)

42 (13–60)

35 (13–43)

42 (22–60)

42 (18–97)

0.003

Ejection fraction (%)

48 (20–91)

66 (32–91)

46 (32–72)

46 (20–88)

0.06

Fractional shortening (%)

23 (6–95)

49 (28–61)

29 (18–33)

21 (6–95)

0.09

TAPSE (mm)

10 (7–25)

11 (8–20)

10 (8–17)

10 (7–25)

0.70

Data are number (%) or median (IQR). BMI = body mass index, O2 = oxygen, LVEDD = left ventricular end-diastolic diameter, LVESD = left ventricular end-systolic diameter, TAPSE = tricuspid annular plane systolic excursion.

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45 38.7

Percentage

35 30 25 20 14.7

15 10 5 0

11.3

1.3 0.6

WHO FC I

2.7

WHO FC II WHO FC III WHO FC

Mild PH

Moderate PH

9.3 2.7

4.7

WHO FC IV Severe PH

Fig. 3. D istribution of patients across WHO functional classes and PH severity.

36.1% had valvular heart disease and 13.4% had left ventricular diastolic dysfunction (HFpEF: EF > 50%). The duration of follow up of the 150 participants ranged from five to 180 days. After a median follow up of 90.5 days, 42 deaths (cumulative mortality rate of 28%) were recorded. Equivalent figures were five deaths (cumulative incidence 45.5%) in mild PH, nine deaths (cumulative incidence 20.5%) in moderate PH and 28 deaths (cumulative incidence 29.5%) in severe PH (p = 0.28).

Discussion Our study aimed at determining the prevalence, clinical profile and mortality rate from PH in a rural setting in sub-Saharan Africa. We noted a high prevalence of PH, late presentation to healthcare facilities in an advanced state of heart failure, and consequently a high mortality rate at six months of follow up. These findings could be attributed to the poor socio-economic status, hyper-endemicity of risk factors for PH, and limited availability of PH-specific drug therapies. In the PAPUCO study,7 which was a multinational study on the epidemiology of PH in Africa with recruitment centres mostly in urban areas, similar findings were noted. Therefore it can be said that PH still presents a challenge on the African continent overall and not only in the rural setting. Our observed prevalence of 15.6% is higher than the average of 10% prevalence observed in Australia in 2012 and

15.3%

10% Group 1 (PAH)

Group 2 (PHLHD)

Group 3 (PHLDH) Group 4 (CTEPH) 64.7%

Group 5 (PHUM)

n = 150

Fig. 4. P atient distribution according to the updated clinical classification of PH.

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in other European countries.13 This is somewhat to be expected considering the high burden of risk factors such as rheumatic heart disease, schistosomiasis, tuberculosis, sickle cell disease and HIV infection in sub-Saharan Africa, in addition to other risk factors shared with high-income countries. In addition, the SCC is located in a rural area that is difficult to access. Therefore, patients are usually reluctant to visit the centre until they are in advanced disease states or when referred by cardiologists. A recent expert review on the global perspective of the epidemiology of PH also supports our findings.6 Among the several co-morbidities assessed in our study population, exposure to cooking fumes was the most common, especially in women. This most likely results from the common practice in Africa and Cameroon, particularly in the rural setting, where women cook using open fires, unlike in high-income countries. Systemic arterial hypertension was also common and in line with studies from Africa,7 USA14,15 and Germany.16 Hypertension is very common in sub-Saharan Africa where it affects about 30% of the adult population, and mostly goes undetected, undertreated and inadequately controlled.17 It is the principal cause of HF in sub-Saharan Africa. In the Pan-African THESUS-HF registry of HF for instance, it was estimated that up to 50% of HF cases were due to uncontrolled hypertension.18This high prevalence of uncontrolled hypertension would most likely also account for the high proportion of PHLHD in our study population. With the growing epidemic of HF, LHD is now globally recognised as the main cause of PH.6,7,13 PHLHD was dominated by patients with left ventricular systolic dysfunction, while PH due to rheumatic valvular heart disease is still common in our setting. The clinical presentation was dominated by exertion dyspnoea, fatigue, cough and palpitations, which are common and non-specific symptoms in most patients with cardiovascular and/or respiratory conditions. Study participants were slightly overweight with a mean BMI higher than observed in a study in Nigeria,19 but lower than reported in the USA.15 Most of our participants presented with moderate to severe functional limitation, with 70% of them presenting in WHO FC or New York Heart Association (NYHA) class III and IV. These findings are similar to those in the PAPUCO study,7 and to those of Baptista and colleagues in Portugal in 2013,20 who observed that 71% of their patients presented in WHO FC III and IV, as well as those of Fikret and colleagues in Germany.16 This global observation of late presentation to medical attention could be explained by the fact that most symptoms and signs of PH are non-specific and therefore cases are usually misdiagnosed in primary care until the later stages when patients seek specialist care. Furthermore, in Africa, poor access to healthcare, limited availability of diagnostic tools for PH, and the general reluctance of patients in rural settings to seek medical attention until the later stages of illness could explain at least in part the late presentation. About a third of our patients died within the first six months of being diagnosed with PH. This mortality rate is three times higher than that observed in the USA15 and the UK.9 The high mortality rate in our setting is most likely accounted for to some extent by the unavailability of disease-specific drug therapies. The fact that patients present at an advanced stage of the disease, and their inability to comply with follow-up visits reflects to some extent their limited financial coping capacity, resulting in death in the absence of adequate care.

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Limitations Our study has some limitations. Some cases of PH could have been missed because indications for cardiac echocardiography are usually symptom driven. This would lead to over-diagnosis of patients with severe disease, and accordingly, poor outcomes. Therefore whether our finding reflects those of a typical population with PH in this setting is unknown. Diagnosis of PH in our study was done by echocardiography, which is more a screening tool for PH, while right heart catheterisation (RHC), which is the gold standard for diagnosing PH, was not used. Therefore, cases of mild PH could have been missed in our study. Furthermore the operator-dependent nature of echocardiography could lead to over- or under-diagnosis. Despite the fact that echocardiography is only a screening tool, it is paramount in the diagnosis of PH as it is non-invasive, more available and less expensive compared to RHC. Moreover, in expert hands, it yields reliable and reproducible results. Indeed, studies carried out to evaluate the diagnostic accuracy of echocardiography compared to RHC have demonstrated a sensitivity of 83% and a specificity of 72%.21

AFRICA

Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54(1 Suppl): S43–54. 5.

Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008; 118(17): 1758–1766.

Mocumbi AO, Thienemann F, Sliwa K. A global perspective on the epidemiology of pulmonary hypertension. Can J Cardiol 2015; 31(4): 375–381.

Thienemann F, Dzudie A, Mocumbi AO, Blauwet L, Sani MU, Karaye KM, et al. The causes, treatment, and outcome of pulmonary hypertension in Africa: Insights from the Pan African Pulmonary Hypertension Cohort (PAPUCO) Registry. Int J Cardiol 2016; 221: 205–211.

Steenekamp JH, Simson IW, Theron W. Cardiovascular causes of death at Tshepong Hospital in 1 year, 1989–1990. A necropsy study. South Afr Med J 1992; 81(3): 142–146.

Health and Social Care Information Centre. National Audit of Pulmonary Hypertension 2013, Report for the audit period 2012. UK;

2013.nih.gov/pubmed/1734552http://www.ncbi.nlm.nih.gov/

pubmed/1734552. 10. Todd NW, Lavania S, Park MH, Iacono AT, Franks TJ, Galvin JR, et al. Variable prevalence of pulmonary hypertension in patients with advanced interstitial pneumonia. J Heart Lung Transplant 2010; 29(2):

Conclusion Our findings suggest that PH is very common among patients attending our rural cardiac centre, with PHLHD being the most frequent type, and the short- to medium-term mortality rate being excessively high. Patients tend to present in advanced stages of disease and usually with several co-morbidities, most of which are cardiovascular conditions. Healthcare practitioners in this setting should be made more aware of this devastating condition, in order to prompt timely referral to specialised centres for proper evaluation and care of patients with suspected PH.

188–194. 11. http://shisonghospital.org/wordpress/cardiac-centre/location/. Accessed on 20 June 2014. 12. Thienemann F, Dzudie A, Mocumbi AO, Blauwet L, Sani MU, Karaye KM, et al. Rationale and design of the Pan African Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary registry on pulmonary hypertension in Africa. Br Med J Open 2014; 4(10): e005950. 13. Strange G, Playford D, Stewart S, Deague JA, Nelson H, Kent A, et al. Pulmonary hypertension: prevalence and mortality in the Armadale echocardiography cohort. Heart Br Card Soc 2012; 98(24): 1805–1811. 14. Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based

We are grateful to Sister Jethro Nkengelefack and her staff at the Shisong Cardiac Centre, and all cardiologists who referred their patients to this cardi-

registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 2007; 30(6): 1103–1110.

ac centre. The study was partly funded by the Pulmonary Vascular Research

15. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost

Institute, Bayer Healthcare, and the Maurice Hatter Foundation and the

AE, et al. Pulmonary arterial hypertension: baseline characteristics from

Non-communicable Disease Research and Leadership Programme of the National Institute of Health, University of the Witwatersrand, Johannesburg,

the REVEAL Registry. Chest 2010; 137(2): 376–387. 16. Er F, Ederer S, Nia AM, Caglayan E, Dahlem KM, Semmo N, et al.

South Africa.

Accuracy of Doppler-echocardiographic mean pulmonary artery pres-

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a self-selected sub-Saharan African urban population: a cross-sectional

hypertension: the Joint Task Force for the Diagnosis and Treatment

18. Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et

(ESC) and the European Respiratory Society (ERS): endorsed by:

al. The causes, treatment, and outcome of acute heart failure in 1006

(AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46(4): 903–975. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D42–50. 3.

Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hyper-

study. Br Med J Open 2012; 2(4): e001217.

of Pulmonary Hypertension of the European Society of Cardiology Association for European Paediatric and Congenital Cardiology

17. Dzudie A, Kengne AP, Muna WFT, Ba H, Menanga A, Kouam CK,

Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al.

Africans from 9 countries. Arch Intern Med 2012; 172(18): 1386–1394. 19. Karaye KM, Saidu H, Bala MS, Yahaya IA. Prevalence, clinical characteristics and outcome of pulmonary hypertension among admitted heart failure patients. Ann Afr Med 2013; 12(4): 197–204. 20. Pulmonary Hypertension in Portugal: First Data from a Nationwide Registry [Internet]. [cited 2016 Jul 27]. Available from: http://www. hindawi.com/journals/bmri/2013/489574/ 21. Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocar-

tension. J Am Coll Cardiol 2013; 62(25 Suppl): D34–41.

diography for pulmonary hypertension: a systematic review and meta-

Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M,

analysis. Heart Br Card Soc 2011; 97(8): 612–622.

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Does the use of N-butyl-2 cyanoacrylate in the treatment of lower extremity superficial varicose veins cause acute systemic inflammation and allergic reactions? Özge Korkmaz, Sabahattin Göksel, Müslim Gül, Hasan Başçil, Yavuz Yildir, Öcal Berkan

Abstract Introduction: In this study we used N-butyl-2 cyanoacrylate (NBCA), including dimethyl sulfoxide (DMSO), via the endovenous route, for mechanochemical ablation in the treatment of superficial venous insufficiency, in an attempt to establish whether an early systemic inflammatory response and an allergic reaction occurred in the patients. Methods: A total of 102 patients were treated with endovenous medical ablation in two centres between October 2015 and February 2016. This study was a two-centre, retrospective, non-randomised investigational study. Ablation treatment with endovenous NBCA was used in patients with C3 to C4b grade superficial venous insufficiency, according to the CEAP (clinical, aetiology, anatomy and pathophysiology) clinical classification, with sapheno-femoral junctional insufficiency and a reflux of 0.5 seconds and longer on duplex ultrasonography. Pre-operative whole blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and blood chemistry were studied in all patients on admission to the clinic, and repeated in the second hour post-intervention. Results: All patients were treated successfully. Pre-operative white blood cell count (WBC) was 6.82 ± 1.67 × 109 cells/μl, and post intervention it was 6.57 ± 1.49 × 109 cells/μl; the difference was not statistically significant (p = 0.68). The neutrophil count before the intervention was 4.09 ± 1.33 × 109 cells/μl, while afterwards, it was 4.09 ± 1.33 × 109 cells/μl, with no statistically significant difference (p = 0.833). Pre-intervention eosinophil count was 0.64 ± 1.51 × 109 cells/μl, while it was 0.76 ± 1.65 × 109 cells/μl after the intervention, and the difference was statistically significant. Pre-intervention ESR and CRP values were 18.92 ± 9.77 mm/h and 1.71 ± 1.54 mg/dl, respectively. Postoperative ESR and CRP values were 19.78 ± 15.90 mm/h and 1.73 ± 1.59 mg/dl, respectively, but the differences were not statistically significant. When the parameters were analysed by gender, the differences between pre- and postoperative WBC and eosinophil count, ESR and CRP in

Department of Cardiovascular Surgery, Cumhuriyet University School of Medicine, Sivas, Turkey Özge Korkmaz, MD, ozgekorkmaz73@hotmail.com Sabahattin Göksel, MD Öcal Berkan

Sivas Numune State Hospital, Sivas, Turkey Müslim Gül, MD Hasan Başçil

Department of Medical Biology, Cumhuriyet University, Sivas, Turkey Yavuz Yildir

women were not statistically significant. On the other hand, although the change in WBC count and CRP value were not statistically significant in males, the differences in eosinophil count and ESR were statistically significant. Conclusion: Cyanoacrylate has been used in the endovenous medical ablation of varicose veins and superficial venous insufficiency over the last few years without the use of thermal energy and tumescent anaesthesia, which represents the greatest advantage of this method. In addition, since it causes no systemic allergic or acute inflammatory reaction, it appears to be safe to use. Keywords: N-butyl-2 cyanoacrylate, lower-extremity superficial varicous vein, acute systemic inflammation, allergic reaction Submitted 8/11/16, accepted 14/2/18 Cardiovasc J Afr 2018; 29: 213–217

www.cvja.co.za

DOI: 10.5830/CVJA-2018-012

Lower extremity venous insufficiency and the secondary development of varicose veins are important health problems that are frequently encountered in society. They impair the quality of life of individuals, and in certain conditions cause severe complications. The prevalence of venous insufficiency has been reported to be between 20 and 40% in many studies.1,2 Surgery has been the preferred method of treatment for this disease for more than 100 years. However, due to postoperative complications and frequent recurrence, alternative methods of treatment have been sought. Newly developed endovascular techniques have gradually replaced open surgery during the last two decades. Haematoma, paresthesia, wound site scars, deformities, and a high rate of recurrence are among the complications of surgery.3,4 Minimally invasive endovenous thermo-ablation techniques (radiofrequency and laser), applied in the last decade in the treatment of superficial venous insufficiency and varicose veins, have decreased postoperative complications, shortened the healing process and improved quality of life.5 However, the necessity of tumescent anaesthesia during these techniques, and complications in the postoperative period, such as pain, ecchymosis and paresthesia caused by perforation of the vein wall, have limited the use of these techniques.6,7 The introduction of cyanoacrylate (CA) in medical applications dates back to the 1960s. Surgeons used CA in order to stop bleeding and close wounds during the Vietnam War.8 Also, endoscopic CA injection to stop gastric variceal bleeding has been safely and widely used.9 Recently, it has been used in the closure of type I and II endoleaks developing during the repair

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of abdominal aortic aneurysms, varicoceles, pelvic congestion syndromes and arteriovenous malformations.10 N-butyl-2 cyanoacrylate (NBCA) has been used via the endovenous route in the treatment of venous insufficiency and varicose veins, with the aim of biochemical ablation.11 NBCA rapidly hardens in a polymerisation reaction following intravenous injection and occludes the vein. In addition, it causes a local inflammatory reaction in the vein wall and surrounding tissues.10,12 However, there are no studies in the literature evaluating whether NBCA causes systemic inflammation following contact with the blood circulation. We attempted to establish whether NBCA caused a simultaneous systemic inflammatory response in the early period while causing a local inflammatory reaction in the vein wall and surrounding tissues in patients who were administered NBCA, including dimethyl sulfoxide (DMSO), for the treatment of superficial venous insufficiency. We retrospectively evaluated preand post-interventional blood samples in order to determine this.

Methods This study was a two-centre, retrospective, non-randomised investigational study. Ablation treatment with endovenous NBCA was applied to patients with C3 to C4b grade venous insufficiency, according to the CEAP (clinical, aetiology, anatomy and pathophysiology) clinical classification, with saphenofemoral junctional insufficiency and a reflux of 0.5 seconds and longer on duplex ultrasonography, between October 2015 and February 2016. This treatment was abandoned in patients with a greater saphenous vein diameter of > 15 mm and < 5 mm. The treatment is contra-indicated in patients who have a past history of deep venous thrombosis, have femoral vein insufficiency, congenital vasculopathy, thrombophilia, the presence of severe systemic disease, and in pregnant and lactating patients. This procedure was not used in any patient who had any of these conditions. Detailed demographic data of the patients who were treated using endovenous NBCA ablation therapy were collected. Whole blood count, sedimentation rate, C-reactive protein (CRP) and blood chemistry were studied in all patients on admission to the clinic. These examinations were repeated in the second hour post-intervention. Patients who were taken into the operating room to undergo endovascular medical ablation were monitored by the anaesthesiology team. Subsequently, both legs were re-evaluated with Doppler ultrasonography. The integrity of the iliac vein and inferior vena cava in the abdominal region was confirmed in order not to overlook some rare conditions, such as possible inferior vena cava agenesis. Patients were placed in the supine position and the leg and inguinal region were cleaned and draped in order to perform the intervention under sterile conditions. With the aid of Doppler ultrasonography, an appropriate segment of the greater saphenous vein was selected for catheterisation, and a 5F introducer sheath was placed following local anaesthesia. The placement of the catheter was confirmed by ultrasonography. A 0.035-inch J guidewire was advanced into the sheath. Ultrasonography was used to determine whether the guidewire had reached the sapheno-femoral junction and a 4F carrier catheter was advanced into it. The catheter was confirmed to

be at the sapheno-femoral junction and then withdrawn 3 mm, and a 3-ml syringe and piston system, which provides NBCA injection, was positioned. The location of the catheter was checked again by ultrasonography and it was confirmed not to be in the sapheno-femoral junction. The junction was then compressed by the ultrasonography probe and obstructed The piston of the syringe administered 0.3 ml of NBCA during each pulse into the saphenous vein and compression was performed simultaneously. Intravenous administration of NCBA, which provided medical ablation, was continued while the catheter was withdrawn rapidly at a rate of 2 cm/s. At the end of the procedure, compression was continued for five to 10 seconds and the procedure was terminated after the saphenofemoral junction was demonstrated by ultrasonography to be open and the rest of the greater saphenous vein was occluded. A compression sock was placed on the leg that underwent the procedure and medium pressure was applied. The patient was taken to the ward for follow up and repeat testing of the whole blood count, blood chemistry, CRP and sedimentation rate. Patients with no complications in the eighth hour postoperatively were discharged with a follow-up plan of visits on the 10th day, and one, three, six and 12 months postoperatively.

Statistical analysis The results were evaluated using SPSS version 17. Changes in the patients’ values were calculated using the paired-samples t-test. The α-value was accepted as 0.05. The change in values by gender was calculated using the independent-samples t-test (p < α was accepted as significant).

Results A total of 102 patients were treated with endovenous medical ablation at two centres between October 2015 and February 2016. The mean age of the patients was 51.16 ± 1.17 years (range: 25–74); 72 (70.6%) were female and 30 (29.4%) were male. The mean diameter of the saphenous vein was 7.72 ± 2.02 mm (range: 6–14). Among the general risk factors, a positive family history was present in 31 cases (30.3%), use of tobacco products in 17 (16.7%), hypertension in six (5.9%), abnormal lipid profile in 19 (18.7%), obesity in 24 (23.5%) and diabetes mellitus in five cases (4.9%) (Table 1). Table 1. Demographics of the patients Demographic data

Number (%)

Age (years)

51.16 ± 1.17

Gender (female/male)

72 (70.6)/30 (29.4)

Presence of family history

31 (30.3)

Use of tobacco products

17 (16.7)

Hypertension

6 (5.9)

Abnormal lipid profile

19 (18.7)

Obesity (BMI ≥ 30 kg/m2)

24 (23.5)

Diabetes mellitus

5 (4.9)

CEAP classification C3

42 (41.2)

C4a

37 (36.3)

C4b Vein diameter (mm)

23 (22.5) 7.72 ± 2.02

BMI: body mass index; CEAP: clinical, aetiology, anatomy and pathophysiology.

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Table 2. Pre- and postoperative changes in whole blood and serological parameters of patients

Table 3. Pre- and postoperative changes in whole blood and serological parameters by gender

Pre-operative value

Postoperative value

Amount of change

WBC (× 103 cells/μl)

6.82 ± 1.67

6.57 ± 1.49

0.24 ± 1.33

1.846

0.068

Neutrophils (× 103 cells/μl)

4.09 ± 1.33

–0.00 ± 0.02

0.211

0.833

Eosinophils (× 103 cells/μl)

0.64 ± 1.51

0.76 ± 1.65

–0.11 ± 0.46

–2.624

0.010*

Basophils (× 103 cells/μl)

0.14 ± 0.43

0.06 ± 0.13

0.08 ± 0.42

1.966

0.052

Haemoglobin (g/dl)

13.79 ± 1.47

13.84 ± 1.61

–0.05 ± 0.80

–0.503

0.617

Haematocrit (%)

42.00 ± 3.82

Parameter

Platelets (× 103 cells/μl) Sedimentation (mm/h)

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t-value p-value

Parameter

Pre-operative value

Postoperative value

t-value

p-value

WBC (× 103 cells/μl) Female

6.87 ± 1.55

6.65 ± 1.53

1.375

0.173

Male

6.68 ± 1.96

6.37 ± 1.41

1.262

0.217

Female

3.99 ± 1.30

–0.985

0.328

Male

4.35 ± 1.39

4.34 ± 1.38

1.116

0.273

Neutrophils (× 103 cells/μl)

Eosinophils (× 103 cells/μl)

42.54 ± 7.11

–0.53 ± 5.78

238.01 ± 64.33 225.40 ± 78.97 12.61 ± 75.39 18.92 ± 9.77

–0.656

0.515

1.285

0.204

19.78 ± 15.90 –0.86 ± 12.29 –0.709

0.480

CRP (mg/dl)

1.71 ± 1.54

1.73 ± 1.59

–0.21 ± 0.59

–0.634

0.714

Rheumatoid factor (IU/ml)

6.89 ± 5.52

6.65 ± 4.92

0.23 ± 3.80

0.634

0.527

WBC: white blood cells; CRP: C-reactive protein. *p < 0.05 statistically significant.

When the distribution of CEAP classification was analysed, 42 (41.2%) patients were found to be C3 grade, 37 (36.3%) were C4a, and 23 (22.5%) were C4b. All patients were treated successfully. Pre-operative white blood cell count (WBC) was 6.82 ± 1.67× 109 cells/μl, while after the intervention it was 6.57 ± 1.49 × 109 cells/μl; the difference was not statistically significant (p = 0.68). The neutrophil count before the intervention was 4.09 ± 1.33 × 109 cells/μl, and post intervention it was 4.09 ± 1.33× 109 cells/μl, with no statistically significant difference (p = 0.833). The eosinophil count was 0.64 ± 1.51 × 109 cells/μl prior to the procedure, and after the procedure it was 0.76 ± 1.65 × 109 cells/ μl. The difference was statistically significant, demonstrating a negative correlation (p = 0.01) (Table 2). Pre-intervention sedimentation rate and CRP values were 18.92 ± 9.77 mm/h and 1.71 ± 1.54 mg/dl, respectively, and postoperative values were 19.78 ± 15.90 mm/h and 1.73 ± 1.59 mg/dl, respectively. The differences were not statistically significant (psedim = 0.480, pCRP = 0.714). The change in values preand post intervention are presented in detail in Table 2. The change in values by gender are summarised in Table 3. Differences in pre- and postoperative WBC and eosinophil count, sedimentation rate and CRP were not statistically significant in women. On the other hand, although the change in WBC count and CRP value was not statistically significantly different in males, the difference in the eosinophil count was statistically significant, with a negative correlation (p = 0.002). The difference in sedimentation rate was also statistically significant and demonstrated a positive correlation (p = 0.005) (Table 3). In other words, postoperative sedimentation rate decreased in men and the change was 2.66 ± 4.76 mm/h, which was statistically significantly different (p < 0.05) (Table 3). When the difference in the rheumatoid factor was evaluated pre- and postintervention, no statistically significant changes were found in either gender (p < 0.05) (Table 3).

Discussion The field of use of cyanoacrylate (CA) in medical treatment has gradually increased since its discovery.13,14 It has been used

Female

0.51 ± 1.03

0.51 ± 0.98

0.000

Male

0.96 ± 2.28

1.37 ± 2.57

–3.479

1.000

Female

0.06 ± 0.16

0.04 ± 0.07

1.199

0.235

Male

0.33 ± 0.74

0.09 ± 0.22

1.740

0.093

0.002*

Basophils (× 103 cells/μl)

Haemoglobin (g/dl) Female

13.17 ± 0.93

13.05 ± 0.89

1.000

0.324

Male

15.26 ± 1.51

15.76 ± 1.32

–2.584

0.022*

Haematocrit (%) Female

40.64 ± 2.77

39.78 ± 2.76

1.837

0.075

Male

45.29 ± 4.08

49.16 ± 9.74

–1.650

0.121

Thrombocytes (103 cells/μl) Female

260.80 ± 61.55 239.31 ± 88.02

1.551

0.129

Male

186.11 ± 33.16 193.72 ± 38.98 –2.061

0.055

Sedimentation rate (mm/h) Female

22.08 ± 9.42

Male

11.33 ± 5.54

24.41 ± 16.79 –1.407 8.66 ± 3.07

3.065

Female

1.24 ± 1.25

1.30 ± 1.26

–1.540

0.128

Male

2.84 ± 1.62

2.75 ± 1.85

0.526

0.603

0.164 0.005*

CRP (mg/dl)

Rheumatoid factor (IU/ml) Female

6.80 ± 5.83

6.41 ± 5.63

0.853

0.396

Male

7.11 ± 4.79

7.24 ± 2.50

–0.205

0.839

WBC: white blood cells; CRP: C-reactive protein.

in ophthalmological operations, cosmetic procedures, dental applications and acute bleeding, with the aim of stopping the bleeding and attaching the tissues. Also, endoscopic injection of CA has been widely and safely used in order to cease gastric variceal bleeding.9 Recently it has been administered via the endovenous route for the treatment of varicose veins and superficial venous insufficiency without the need for tumescent anaesthesia11 or thermal energy, with increasing evidence proving that it could be an appropriate agent for the treatment of peripheral varicose veins.10,15 The mechanism of effect of NBCA is simple; it stimulates polymerisation when it comes into contact with blood and plasma, hence causing an obstruction of the vein in which it is administered. This occurs in three steps: the initiation phase lasts approximately 10 seconds and the tensile force increases rapidly; the second phase lasts for approximately one minute and creates a steady tensile force; the last phase is completion of the polymerisation and a strong tensile force is obtained.16 Almeida et al. closed the truncal vein of pigs using CA and after a follow-up period of 60 days, found no thrombus obstructing the lumen of the vein on sonography or histology. Instead he observed a chronic foreign body reaction against NBCA.15 When the tissues were examined, they observed an inflammatory reaction and the formation of giant cell foreign bodies, followed by the development of intraluminal fibrosis.15 Endovenous NBCA application has been well tolerated in

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patients. The results of our administration are similar. Inflammation is activated when an organism is triggered by stimulants. An acute inflammatory reaction is characterised by neutrophil predominance in the region of the event.17 Neutrophil and leukocyte counts in the blood are increased during acute inflammation. No statistically significant changes were detected between pre- and postoperative counts of either WBC or neutrophils in our study. Acute inflammation in the endovenous administration of NBCA was therefore most likely localised in the vein wall and surrounding tissues. There are reports in the literature demonstrating that NBCA causes a local inflammation,10,12 but there are no studies that have evaluated the systemic response. The acute-phase response includes endocrinological, neurological and immunological events.18 Proteins, whose levels increase or decrease during this period, are called acute-phase proteins or acute-phase reactants.19 Change in the levels of acute-phase proteins demonstrate the presence and severity of inflammation.20 Cytokines are released as a response to stress by inflammatory cells such as neutrophils and macrophages. Interleukine-6, interleukine-1 and tumour necrosis factor-α induce CRP secretion from the hepatocytes.21 CRP has a pro- and antiinflammatory effect. Its pro-inflammatory effects result in the activation of the complement system and the induction of tissue factor and inflammatory cytokines from the monocytes, but its most important role is its anti-inflammatory effect.22 Erythrocyte sedimentation rate (ESR) is a frequently used test for the evaluation of acute-phase response.23 ESR increases from the start of the inflammation and resolution may take up to a month.24 In our study, no statistically significant change was seen in the CRP level and sedimentation rate between the preand post-procedure states of endovenous NBCA use. Changes in sedimentation rate from the pre- to the postoperative values by gender were statistically significant in the male patients (p < 0.05); however they were within the normal range, and postoperatively showed a decreasing trend. CRP levels were similar between the pre- and post-procedural states by gender and in the overall group of patients. Since there was no change demonstrated in the CRP level and sedimentation rate, and in the neutrophil and WBC counts, it can be concluded that NBCA did not cause an acute systemic inflammatory response. Sensitivity has been detected in patients when NBCA was used to repair skin wounds, and also in individuals who were occupationally exposed to CA.25 In a study by Quinn et al., eosinophilic inflammation was detected at a rate of approximately 2% following NBCA use in the closure of intracranial arteriovenous malformations. The authors reported that no history of sensitivity against or exposure to CA was previously detected in those patients.25 When our patients was evaluated, no statistically significant changes in the pre- and postoperative eosinophil and basophil counts were found. From these results, we concluded that NBCA caused no allergic reaction in this patient group.

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allergic or acute inflammatory reaction, it appears safe to use. However, we suggest that evaluations should be performed in a larger group of patients to confirm the results.

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Perrin MR, Guex JJ, Ruckley CV, dePalma RF, Royle JP, Eklof B, et al. Recurrent varies after surgery (REVAS), a consensus document. REVAS group. Cardiovasc Surg 2000; 8: 233–245.

Van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapies of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009; 49: 230–239.

Witte ME, Reijnen MM, de Vries JP, Zeebregts CJ. Mechanochemical endovenous occlusion of varicose veins using the ClariVein® device. Surg Technol Int 2015; 26: 210–225.

Rassmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical sripping for great saphenous varicose veins. Br J Surg 2011; 98: 1079–1087.

Ameida JI, Kaufmann J, Gockeritz O, Chopra P, Evans MT, Hoheim DF, et al. Radiofrequency Endovenous Closure FAST Versus laser ablation for the treatment of great saphenous vein Reflux: a multicenter, single-blinded, randomized study (RECOVERY study). J Vasc Interv Radiol 2009; 20: 752–759.

Coover HW. Discovery of superglue shows power of pursuing the unexplained. Research Technology Management. 1 September 2000. See http://www.allbusiness. com/medicine-health/medical-treatmentsprocedures/ 10616945-1.html (last checked 14 May 2010).

Akahoshi T, Hashizume M, Shimabukuro R, et al. Long-term results of endoscopic histoacryl injection sclerotherapy for gastric variceal bleeding: a 10-year experience. Surgery 2002; 131: 176–781.

10. Min RJ, Almeida JI, McLean DJ, Madsen M, Raabe R. Novel vein closure procedure using a proprietary cyanoacrylate adhesive: 30-day swine model results. Phlebology 2012; 27: 398–403. 11. Bootun R, Lane TR, Davies AH. The advent of non-thermal, nontumescent techniques for treatment of varicouse veins. Phebology 2016; 31(1): 5–14. 12. Levrier O, Mekkaoui C, Rolland PH, Murphy K, Cabrol P, Moulin G, et al. Efficacy and low vascular toxicity of embolization with radical versus anionic polimerizaytion of N-butly-2-cyanoacriylate (NBCA) :an experimental study in the swine. J Neuroradiol 2003; 30: 95–102. 13. Chan YC, Ting AC, Yiu WK, Cheng SW. Cyanoacrylate superglue to treat varicose veins: truly office based and minimally invasive? Eur J Vasc Endovasc Surg 2013; 45: 176–177. 14. Pollack JS, White RI. The use of cyanoacrylate adhesive in peripheral embolization. J Vasc Interv Radiol 2001; 12: 908–913. 15. Almeida JI, Min RJ, Raabe R, McLean DJ, Madsen M. Cyanoacrylate adhesive for the closure of truncal veins: 60-day swine model results. Vasc Endovascular Surg 2011; 45: 631–635.

Conclusion The greatest advantage of the endovenous medical ablation method using NBCA is that tumescent anaesthesia and thermal energy are not necessary. In addition, since it causes no systemic

16. Kailasnath P, Chaloupka JC. Quantitative assessment of polymerization-binding mechanics of cyanoacrylates: model development and validation. Am J Nueroradiol 2002; 23: 772–778. 17. Anderson JM, Rodriguez A, Chang DT. Foreing body reaction to biomaterials. Semin Immunol 2008; 20: 86–100.

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18. Saez-Lorens X, Lagrutta F. The acute phase reaction during bacterial infection and its clinical impact in children. Pediatr Infect Dis J 1993; 12: 83–87. 19. Batırel A, Gencer S, Ozer S. Enfeksiyon göstergesi olarak akut faz reaktanları: C-reaktif protein (CRP) ve serum amiloid A (SAA). Kartal Eğitim ve Araştırma Hastanesi Tıp Dergisi 2003; 14: 220–224. 20. Kılıçarslan A, Uysal A, Roach EC. Acute phase reactants. Acta Medica 2013; 2: 2–7. 21. Volanakis JE. Human C-reactive protein: expression, structure, and

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22. Vanderschueren S, Deeren D, Knockaert DC, et al. Extremely elevated C-reactive protein. Eur J Intern Med 2006; 17: 430. 23. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. S Afr Med J 1998; 91: 220–225. 24. Sox HC Jr, Liang MH. The erythrocyte sedimentation rate: guidelines for rational use. Ann Intern Med 1986; 104: 515–523. 25. Aalto-Korte K, Alanko K, Kuuliala O, Jolanki R. Occupatinal methacrylate and acrylate allergy from glues. Contact Dermatitis 2008; 58: 340–346.

function. Mol Immunol 2001; 38: 189.

Significant financial stress associated with 13-fold higher odds of having a heart attack Significant financial stress is associated with a 13-fold higher odds of having a heart attack, according to research presented at the 18th Annual Congress of the South African Heart Association. ‘The role of psychosocial factors in causing disease is a neglected area of study in South Africa, perhaps because there are so many other pressing health challenges such as tuberculosis and HIV,’ said lead author Dr Denishan Govender, associate lecturer, University of the Witwatersrand, Johannesburg. ‘The INTERHEART study showed that psychosocial factors are independently associated with acute myocardial infarction (heart attack) in Africa but as far as we are aware there are no other published local data,’ said last author Professor Pravin Manga, professor of cardiology, University of the Witwatersrand. This study included 106 patients with acute myocardial infarction who presented to a large public hospital in Johannesburg. A control group of 106 patients without cardiac disease was matched for age, gender and race. All participants completed a questionnaire about depression, anxiety, stress, work stress and financial stress in the previous month. The Likert scale was used to grade the experience of each condition. Regarding financial stress, patients were graded with no financial stress if they were coping financially; mild financial stress if they were coping financially but needed added support; moderate financial stress if they had an income but were in financial distress; and significant financial stress if they had no income and at times struggled to meet basic needs. Levels of psychosocial conditions were compared between groups and used to calculate associations with having a heart attack. Self-reported stress levels were common, with 96% of heart attack patients reporting any level of stress, and 40% reporting severe stress levels. There was a three-fold increased risk of myocardial infarction if a patient had experienced any level of depression (from mild to extremely severe) in the previous month compared to those with no depression.

Both work stress and financial stress were associated with a higher risk of acute myocardial infarction. The odds of myocardial infarction was 5.6 times higher in patients with moderate or severe work stress compared to those with minimal or no stress. Patients with significant financial stress had a 13-fold higher odds of having a myocardial infarction. Dr Govender said: ‘Our study suggests that psychosocial aspects are important risk factors for acute myocardial infarction. Often patients are counselled about stress after a heart attack but there needs to be more emphasis prior to an event. Few doctors ask about stress, depression or anxiety during a general physical and this should become routine practice, like asking about smoking. Just as we provide advice on how to quit smoking, patients need information on how to fight stress.’ Professor Manga said: ‘There is growing recognition that many developing countries are experiencing an increasing prevalence of chronic diseases of lifestyle such as myocardial infarction, and South Africa is no exception. Our study shows that psychosocial aspects are an area of cardiovascular prevention that deserves more attention.’ Dr David Jankelow, chairman of the SA Heart 2017 congress, commented: ‘We know that the depressed cardiac patient is at greater risk. We as clinicians need to identify them much earlier, so that they can be referred for appropriate intervention. Cardiac rehabilitation together with counselling and reassurance will play an important role as well.’ Professor Fausto Pinto, ESC immediate past president and course director of the ESC programme in South Africa, said: ‘Psychosocial factors including stress at work, depression and anxiety contribute to the risk of developing cardiovascular disease and having a worse prognosis. European prevention guidelines say that psychosocial risk-factor assessment should be considered in people with, or at high risk of, cardiovascular disease to identify possible barriers to lifestyle change or adherence to medication.’ Source: European Society of Cardiology Press Office

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Hypertension among newly diagnosed diabetic patients at Mulago National Referral Hospital in Uganda: a cross sectional study Martin Muddu, Edrisa Mutebi, Isaac Ssinabulya, Samuel Kizito, Charles Kiiza Mondo

Abstract Background: The prevalence of hypertension in patients with diabetes is approximately two-fold higher than in age-matched subjects without the disease and, conversely, individuals with hypertension are at increased risk of developing diabetes compared with normotensive persons. Up to 75% of cases of cardiovascular disease (CVD) in patients with diabetes are attributed to hypertension. Diabetics who have hypertension are more likely to develop complications and die, and appropriate blood pressure control in these individuals reduces the risk. This study sought to determine the prevalence and factors associated with hypertension among newly diagnosed adult diabetic patients in a national referral hospital in Uganda. Methods: In this cross-sectional study, conducted between June 2014 and January 2015, we recruited 201 newly diagnosed adult diabetic patients. Information on patients’ socio-demographics was obtained using a pre-tested questionnaire, while biophysical profile, blood pressure measurement, biochemical testing and echocardiographic findings were obtained by the research team for all the participants. Bivariate and multivariate logistic regression analyses were used to investigate the association of several factors with hypertension. Results: Of the 201 patients recruited, 102 were male (50.8%) and the mean age was 46 ± 15 years. The majority of patients (159) had type 2 diabetes mellitus (DM) (79.1%) with a mean HbA1c level of 13.9 ± 5.3%. The prevalence of hypertension was 61.9% (95% CI: 54.8–68.6%). Knowledge of hypertension status was at 56 (27.7%) patients, 24 (44.4%) hypertensives were on treatment, and 19 (33.9%) were using ACE inhibitors/angiotensin receptor blockers. The independent factors associated with hypertension were being employed (OR 0.37, 95% CI: 0.16–0.90, p = 0.029) and being overweight or obese (OR 11.6, 95% CI: 4.29–31.2, p < 0.0001). Conclusion: The prevalence of hypertension was high in this population of newly diagnosed diabetics, few patients had knowledge of their hypertension status and few were on appropriate treatment. Both modifiable and non-modifiable risk factors were associated with hypertension in this group. Therefore routine assessment, treatment and control of hypertension among diabetics is necessary to prevent cardiovascular complications and death. There is also a need to address the modifiable risk factors. Department of Medicine, College of Health Sciences, Makerere University, Mulago Hospital Complex, Mulago, Uganda Martin Muddu, MB ChB, MMed, muddu.martin@gmail.com Edrisa Mutebi, MB ChB, MSc, MMed Isaac Ssinabulya,MB ChB, MMed Charles Kiiza Mondo, MB ChB, MMed, PhD

Clinical Epidemiology Unit, College of Health Sciences, Makerere University, Mulago, Uganda Samuel Kizito, MB ChB, MSc

Keywords: hypertension, newly diagnosed, diabetes, Uganda Submitted 21/5/16, accepted 5/3/18 Published online 20/4/18 Cardiovasc J Afr 2018; 29: 218–224

www.cvja.co.za

DOI: 10.5830/CVJA-2018-015

The burden of non-communicable diseases (NCDs) is increasing rapidly in sub-Saharan Africa.1 It is anticipated that NCDs may account for 46% of deaths in sub-Saharan Africa by 2030, compared to 28% in 2008.1 Hypertension and diabetes mellitus (DM) are of particular concern; however, precise epidemiological data are rare.1-4 One of the commonest NCDs experienced during this early stage of the epidemiological transition is hypertension. It is predicted that more than 125 million adults in sub-Saharan Africa alone will have hypertension by 2025,5,6 and in Uganda, hypertension is the most reported NCD.7-10 Increasing urbanisation and associated lifestyle changes as well as improvements in life expectancy have contributed to a surge in NCDs, including hypertension.1,5 Likewise, the prevalence of DM is on a rise in sub-Saharan Africa and will more than double by 2025.11 The prevalence of hypertension in patients with diabetes is approximately two-fold higher than in age-matched subjects without the disease,12-14 and conversely, individuals with hypertension are at increased risk of developing diabetes compared with normotensive persons. Furthermore, up to 75% of cases of cardiovascular disease (CVD) in patients with diabetes can be attributed to hypertension.15 CVD, especially stroke, accounts for up to 80% of all deaths in the diabetic population and three-quarters of these deaths occur in sub-Saharan Africa.16,17 The high burden of hypertension in diabetics has led to an increase in the risk and prevalence of cardiac abnormalities in diabetes.18 Also, life expectancy in sub-Saharan Africa has risen in the past 50 years. Many more people living with diabetes are therefore exposed to the risk of hypertension for long periods for the complications to develop and for them to experience the clinical syndromes of CVD.19 Diabetics who have hypertension are more likely to develop complications and die, and appropriate blood pressure control in these individuals reduces the risk. The lower the systolic blood pressure, the lower the risk of complications.12 There is an additional risk reduction with angiotensin converting enzyme inhibitors (ACE inhibitors) and β -blockers over and above that associated with lowering of blood pressure.12 In patients with type 2 DM, hypertension is associated with left ventricular hypertrophy (LVH),20,21 which is an independent

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predictor of cardiovascular events in hypertensive patients with diabetes.22 Hypertension is also a major risk factor for myocardial infarction and stroke,12,23,24 and indeed hypertension is the leading risk factor for mortality worldwide.5,25-28 Additionally, hypertension is a major causal factor of end-stage kidney failure, blindness and non-traumatic amputation in people with diabetes, where attributable risks are 50, 35 and 35%, respectively.16 Unfortunately the majority of people with hypertension in sub-Saharan Africa do not know they have it, and most are not on treatment. This reflects the low level of knowledge of the dangers of untreated hypertension in this population.10 In sub-Saharan Africa there is still a lack of awareness about the growing problem of NCDs, which, unfortunately, is often coupled with the absence of a clear policy framework for prevention and management.7 Given the long-term decreased productivity associated with hypertension among diabetics, identifying and treating a large proportion of patients has the potential to generate tremendous social and economic benefits in this region.5,29-31 In this study we sought to determine the prevalence and factors associated with hypertension among newly diagnosed adult diabetic patients in a national referral hospital in Uganda. These findings are not only necessary, but also contribute to the diagnosis and management of DM and hypertension in sub-Saharan Africa.

Methods This study was carried out in the diabetes out-patient clinic, the medical endocrine ward and the medical emergency ward of Mulago National Referral Hospital. It is the only national referral hospital for Uganda and is the teaching hospital for Makerere University, with a bed capacity of 1 500. Mulago Hospital receives referrals from all parts of the country including from neighbouring countries such as Southern Sudan, the Democratic Republic of Congo and Rwanda. The study population is representative of the Ugandan diabetic population. This was a cross-sectional study among 201 newly diagnosed diabetic patients at Mulago Hospital in Uganda, conducted between June 2014 and January 2015. All newly diagnosed diabetic patients aged 18 years and above attending the diabetes clinic or admitted to the medical wards of Mulago Hospital during the study period, who met the inclusion criteria and provided informed consent, were recruited consecutively. We excluded patients with urinary tract infection in order to avoid confounding in microalbuminuria, and those who were unable to provide the necessary information. Fig. 1 illustrates the patient recruitment flow. Institutional consent was sought from the Department of Medicine, Makerere University, Mulago National Referral Hospital and the School of Medicine research and ethics committee of Makerere University College of Health Sciences. All study participants provided written informed consent for involvement in the study. Enrolment was totally free and voluntary, and participants were free to withdraw at any time without any consequences. The patients’ records/information was anonymised and de-identified prior to analysis. We took a focused history and performed a specific physical examination to determine biophysical measurements. Information gathered was entered into a pre-tested questionnaire. We assessed

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the following factors: patients’ demographic data, history of hypertension, age, physical exercise at work and leisure, marital status, date of diagnosis of DM, drug history, occupation, education level and last normal menstrual period. Body mass was measured to the nearest kilogram using a Secco weighing scale, height was measured in metres using a non-stretchable tape, and these were used to compute body mass index (BMI). Waist and hip circumferences were measured and waist-to-hip ratios were determined for all patients. Glycated haemoglobin (HbA1c) was measured by automated high-performance liquid chromatography. Other investigations included urinalysis and microalbuminuria using albumin-tocreatinine ratio. Echocardiography parameters were acquired using a commercially available machine, Phillips HD11XE (Eindhoven, the Netherlands), with two-dimensional, M-mode and Doppler capabilities. It was used according to the American Society of Echocardiography guidelines.32 Blood pressure was measured using a mercury sphygmomanometer, according to the American Heart Association guidelines for the auscultatory method of blood pressure assessment.33 The degree of precision of blood pressure measurement in this study was ± 2 mmHg.33 Hypertension was defined as present if subjects were on anti-hypertensive medication, had a history of hypertension and/or evidence of hypertension (blood pressure ≥ 140/90 mmHg).

Statistical analysis Data were double entered in a database developed with Epidata version 3.1, validated, and inconsistences were cleared. The data were then exported to Stata 13 for analysis. Continuous data were summarised using measures of central tendency while categorical data were summarised as frequencies and percentages and presented in tables. Prevalence was presented as percentages

Screened 263 newly diagnosed diabetic patients in MOPD, Ward 3B Emergency and Ward 4B Endocrine Excluded 46: 20: age below 18 years 5: declined to participate 21: too sick to give information Completed history, examination and questionnaire for 218 patients. Performed urinalysis for microscopy and ACR. HbA1c was determined. Excluded 16 with urinary tract infection Enrolled 201 patients. Cardiac echo was done for LVH, wall motion, diastolic and systolic function by the principle investigator first and then reviewed by a cardiologist MOPD: Mulago out-patient department, ACR: albumin-to-creatinine ratio, HbA1c: glycated haemoglobin, LVH: left ventricular hypertrophy.

Fig. 1. Patient flow chart.

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with their confidence intervals. Comparisons were made using the Student’s t-test for continuous data and chi-squared or Fisher’s exact test for categorical data. The outcome was dichotomised as patients having hypertension or not, then logistic regression was used to determine the association between the predictors and hypertension. This was presented as odds ratio (OR) and their 95% confidence interval (CI). Only factors with a p-value < 0.2 at bivariate analysis were considered for multivariate analysis. Multivariate logistic regression was performed and interaction was assessed for with the Chunk test. Confounding was assessed for using a 10% difference between the crude and adjusted models. Significance was at p ≤ 0.05.

Results

Table 1. Social demographics of 201 newly diagnosed diabetic patients at Mulago National Referral Hospital who participated in the study Total (n)

Total (%)

Hypertensive n (%)

Normotensive n (%)

< 40 years

28.9

21 (36.2)

37 (63.8)

> 40 years

143

71.1

105 (73.4)

38 (26.6)

102

50.8

54 (52.9)

48 (47.1)

49.3

72 (72.7)

27 (27.3)

Employed

38.0

41 (53.9)

35 (46.1)

Unemployed

124

62.0

85 (68.6)

39 (31.4)

Yes

5.4

3 (50.0)

105

94.6

74 (70.5)

31 (29.5)

Age

Gender Male Female

Table 2. Characteristics of 201 newly diagnosed diabetic patients at Mulago National Referral Hospital who participated in the study Characteristic

Total (n)

Total (%)

Hypertensive n (%)

Normotensive n (%)

Physical activity at work Sedentary

12.4

16 (69.6)

7 (30.4)

Mild

25.3

33 (64.7)

18 (35.3)

Moderate

40.6

54 (66.7)

27 (33.3)

22 (50.0)

Strenuous Does not work

21.8

1 (50.0)

Sedentary

142

71.0

96 (67.6)

46 (32.4)

Moderate

29.0

29 (50.0)

Type 1

20.9

11 (26.2)

31 (73.8)

Type 2

159

79.1

115 (72.3)

44 (27.7)

Absent

44.9

50 (62.5)

30 (37.5)

Present

55.1

58 (61.1)

37 (38.3)

Underweight

19.4

10 (25.6)

29 (74.4)

Normal weight

37.3

40 (53.3)

35 (46.7)

Over weight

1.5

1 (33.3)

2 (66.7)

Obesity

41.8

75 (89.3)

9 (10.7)

Normal

141

69.8

81 (57.9)

59 (42.1)

Abnormal

30.2

45 (73.8)

16 (26.2)

Physical activity at leisure

DM type

Microalbumin in urine

This study recruited 201 newly diagnosed diabetic patients between June 2014 and January 2015. Of these, 102 (50.8%) were males. The mean age of the participants was 46 ± 15 years (Table 1). Patients with type 1 and type 2 DM had mean ages of 25.6 (18–42) and 51.9 (26–90) years, respectively. The majority of patients had type 2 DM (n = 159, 79.1%) and the rest had type 1 DM (n = 42, 20.9%) (Table 2). The mean HbA1c was 13.9 ± 5.3%. Mean duration of diabetes was two months. The majority of patients (124, 62.0%) were unemployed. Blood pressure assessment was performed on all 201 participants and the results are shown in Table 3. Prevalence of hypertension was 61.9% (95% CI: 54.8–68.6%). Systolic hypertension was present in 104 (51.5%) participants (95% CI: 45.3–59.2%) while diastolic hypertension was present in 92 (45.5%) (95% CI: 39.3–53.2%). Among those who were hypertensive, only 56 (27.7%) knew that they were hypertensive, and among these, only 24 (44.4%) were on treatment for hypertension. The use of either ACE inhibitors or angiotensin receptor blockers (ARBs) among those who knew their hypertension status was only 19 (33.9%) subjects.

Characteristics

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Employment

Pregnancy

Education

BMI

Waist:hip ratio

HbA1c (%) < 7%

8.4

11 (73.3)

4 (26.7)

> 7%

164

91.6

101 (61.9)

62 (38.0)

> 50%

158

78.2

102 (64.6)

56 (35.4)

< 50%

21.8

24 (55.8)

19 (44.2)

Present

19.3

89 (77.4)

26 (26.5)

Absent

163

80.7

37 (43.0)

49 (56.9)

Normal

45.1

44 (48.9)

46 (51.1)

Impaired

111

54.9

82 (73.9)

29 (26.1)

193

96.5

120 (62.2)

73 (37.8)

3.5

5 (71.4)

2 (28.6)

Ejection fraction (%)

LVH

Diastolic function

Wall motion Normal Abnormal

For participants who knew their hypertension status, the majority 44 (77.2) had been hypertensive for less than five years. The number who had been hypertensive for durations between five and 10 years and more than 10 years were eight (4.3%) and five (8.8%), respectively. In bivariate analysis, the factors associated with hypertension included: female gender, age above 40 years, participants who Table 3. Prevalence, knowledge and treatment of hypertension among 201 newly diagnosed diabetic patients at Mulago Hospital Parameters

Number

Prevalence (%)

95% CI

Hypertension

125

61.9

54.8–68.6

None

8.5

10 (58.8)

7 (41.2)

Systolic BP > 140 mmHg

104

51.5

45.3–59.2

Primary

38.8

50 (64.1)

28 (35.9)

Diastolic BP > 90 mmHg

45.5

39.3–53.2

Secondary

37.3

45 (60.0)

30 (40.0)

Knowledge of hypertension

27.7

22.1–34.6

Tertiary

15.4

21 (67.7)

10 (32.3)

HTN newly diagnosed

34.2

27.6–39.8

ACEI/ARB use in known HTN

33.9

26.7–39.2

Marital status Never married

14.4

7 (24.1)

22 (75.9)

Known HTN on drugs

44.4

38.9–52.4

Currently married

119

59.2

83 (69.8)

36 (30.3)

Known HTN not on drugs

55.6

47.2–62.1

No longer married

26.4

36 (67.9)

17 (32.1)

HTN: hypertension, ACEI: ace inhibitor, ARB: angiotensin receptor blocker.

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were employed, participants who were never married and those who were currently married, overweight and obesity, increase in waist:hip ratio, LVH and diastolic dysfunction (Table 4). After adjusting for the patients’ gender, age, employment, marital status, BMI, waist:hip ratio, LVH and diastolic dysfunction, the only significant factors associated with hypertension were being employed (OR 0.37, 95% CI: 0.16–0.90, p = 0.029), and overweight and obesity (OR 11.6, 95% CI: 4.29–31.2, p < 0.0001).

Discussion The prevalence of hypertension among newly diagnosed diabetics was high in this group, with more than six patients out of 10 having hypertension. This is in keeping with earlier studies, which found that the prevalence of hypertension in patients with diabetes was approximately two-fold higher than in age-matched subjects without the disease,12-14 and conversely, individuals with hypertension were at increased risk of developing diabetes compared with normotensive persons.15 In Uganda, the prevalence of hypertension among non-diabetics ranges between 20 and 35%, with a higher prevalence in the urban areas.10,34-37 This is consistent with evidence from other parts of sub-Saharan Africa that indicated

the prevalence of hypertension was between 20 and 50%.7,35,37-40 Therefore, the prevalence we found of 62% in diabetic subjects is approximately twice the current prevalence of hypertension in non-diabetic patients in Uganda. Unfortunately only one-quarter of all those who are hypertensive know their status, and this is evident from other studies in the region, which found that the majority of patients with hypertension in sub-Saharan Africa did not know they were hypertensive and very few were on treatment, yet hypertension is the leading cause of stroke in Africa. In another cross-sectional study in Uganda, awareness of hypertension was low, at less than 30%.7 This low awareness could be explained by the fact that only 27.8% of the population ever has their blood pressure measured in Uganda. Awareness of hypertension largely depends on the capacity of the health system to provide diagnostic services for hypertension to the general population.40 Unfortunately, the healthcare system in Uganda is largely constrained by communicable diseases and NCDs have not received the attention they deserve.7 In order to increase awareness, there is a need to screen all adults at an appropriate opportunity when they come into contact with the health system. This could even be done through outreaches and community programmes.7,41,42

Table 4. Logistic regression for factors associated with hypertension among 201 newly diagnosed diabetic patients at Mulago Hospital Hypertension Factors

Absent, n (%)

Present, n (%)

Crude OR (95% CI)

p-value

Adjusted OR (95%)

p-value

Gender Male

48 (47.1)

54 (52.9)

Female

27 (27.3)

72 (72.7)

2.37 (1.32–4.27)

0.004

Age < 40 years

37 (63.8)

21 (36.2)

> 40 years

38 (26.6)

105 (73.4)

4.87 (2.54–9.34)

1 < 0.0001

2.49 (0.62–9.95)

0.039

0.37 (0.16–0.90)

0.197

Employment Unemployed

39 (31.5)

85 (68.6)

Employed

35 (46.1)

41 (53.9)

0.54 (0.30–0.97)

1 0.029

Marital status No longer married

17 (32.1)

36 (67.9)

Never married

22 (75.9)

7 (24.1)

7.25 (2.84–18.5)

< 0.0001

2.86 (0.69–11.9)

1 0.149

Currently married

36 (30.3)

83 (69.8)

6.66 (2.38–18.6)

< 0.0001

1.37 (0.28–6.63)

0.703

HbA1c Normal

4 (26.7)

11 (73.3)

Abnormal

62 (38.0)

101 (61.9)

0.59 (0.18-1.94)

0.387

Microalbuminuria Normal

30 (37.5)

50 (62.5)

Abnormal

37 (38.3)

58 (61.1)

0.94 (0.51-1.74)

Normal weight

66 (56.4)

51 (43.6)

Overweight, obesity

9 (10.7)

75 (89.3)

10.8 (4.9–23.6)

0.844

BMI 1 < 0.0001

11.6 (4.29–31.2)

0.034

1.03 (0.39–2.73)

< 0.0001

Waist:hip ratio Normal

59 (42.1)

81 (57.9)

Abnormal

16 (26.2)

45 (73.8)

2.05 (1.06–3.97)

> 50%

56 (35.4)

102 (64.6)

< 50%

19 (44.2)

24 (55.8)

0.69 (0.35–1.38)

1 0.949

Ejection fraction 0.295

LVH Absent

49 (56.9)

37 (43.0)

Present

26 (26.5)

89 (77.4)

4.53 (2.46–8.35)

1 < 0.0001

1.97 (0.88–4.38)

< 0.0001

0.94 (0.40–2.18)

0.098

Diastolic function Normal

46 (51.1)

44 (48.9)

Impaired

29 (26.1)

82 (73.9)

2.96 (1.64–5.34)

HbA1c: glycated haemoglobin, BMI: body mass index, LVH: left ventricular hypertrophy.

1 0.885

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Furthermore, among those who knew they had hypertension, less than half were on treatment. This is similar to what earlier studies found, and this carries a great risk for the complications of diabetes, especially CVDs such as stroke, LVH, myocardial infarction, as reported by the United Kingdom Prospective Diabetes Study (UKPDS). In one cross-sectional study among people with hypertension in Uganda, less than 10% were controlled. In another retrospective study conducted in an urban diabetes clinic in Kampala, optimal blood pressure control, defined as â&#x2030;¤ 140/80 mmHg, was noted in 56% of the patients.43 This corroborates the notion that blood pressure control among adult diabetic patients in Uganda is sub-optimal. This calls for the development and implementation of local guidelines to improve diabetes care and minimise complications due to hypertension.43 Possible reasons for this very low level of control may be that the majority of people with hypertension are not aware they have the condition, and even among those who are aware, less than half are receiving treatment. However, even among those receiving treatment, only one in three achieve blood pressure control. A worrying global trend is that low levels for the control of hypertension are widespread in both low- and high-income countries.7,40,44,45 There is an additional risk reduction with ACE inhibitors and Î˛ -blockers over and above that associated with lowering of blood pressure among diabetics.12 However, the use of ACE inhibitors/ ARBs among those who knew their status was in only one-third of all participants, yet we know that ACE inhibitors reduce the risk for nephropathy and other complications of diabetes, such as LVH. For this reason, the JNC 7 and JNC 8 recommend that every diabetic who has hypertension must be started on ACE inhibitors/ARBs among other treatment options.46 In patients with type 2 DM, hypertension is associated with LVH.20,21 According to the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, LVH is an independent predictor of cardiovascular events in hypertensive patients with diabetes.22 Hypertension is also a major risk factor for myocardial infarction and stroke,12,23,24 and indeed it is the leading risk factor for mortality worldwide.5,25-27 Therefore prevention and control of hypertension are critical in reducing morbidity and mortality attributable to cardiovascular diseases among diabetics. According to the UKPDS, the incidence of clinical complications among diabetics is significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mmHg decrease in updated mean systolic blood pressure is associated with risk reductions of 12% for any complication related to diabetes, 15% for deaths related to diabetes, 11% for myocardial infarction and 13% for microvascular complications. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mmHg.12 An upcoming comprehensive review of global publications on NCD costs from low- and middle-income countries confirms that primary prevention of CVD, stroke and diabetes is far less expensive and has lower unit costs than treatment interventions for these conditions. One way to achieve this is to control hypertension.34 The following factors were associated with hypertension among the newly diagnosed diabetics in the bivariate model: age above 40 years, female gender, unemployment, lack of

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physical exercise, overweight and obesity, increased waist:hip ratios, LVH and diastolic dysfunction. However after adjusting for possible confounders, only unemployment, gender and increasing BMI were independently associated with hypertension in this model. Among these factors, unemployment and BMI are modifiable, while gender is the non-modifiable factor associated with hypertension. Attaining and maintaining a healthy weight improves blood pressure and diabetes management, and reduces cholesterol levels. The Trials of Hypertension Prevention (TOHP) study showed that a decrease of 4.4 kg can lead to a blood pressure reduction of 4/3 mmHg.16 In a study to determine the prevalence and factors associated with hypertension among residents of the rural district of Rukungiri, Uganda, some of the factors found to be associated with hypertension included: being overweight or obese, female gender and older age.37 However all these factors, apart from obesity and being overweight, had no significance in our study in the multivariate model. The reason could be that Wamala et al.37 in the earlier study had a bigger sample size compared to ours and enrolled community members, while our population was for newly diagnosed diabetics. Similar findings have been reported by Wamala and co-workers37 and Musinguzi et al.7 in other cross-sectional studies. These observations suggest that demographic transition, urbanisation and increasing life expectancy are major determinants of prevalence of hypertension among diabetics.7,47-49 In a population-based, cross-sectional survey, Baziel et al.1 found further evidence to show that increasing BMI and a waist circumference above the normal range were associated with hypertension. In the same study, sociodemographic factors associated with hypertension included increasing age, male gender, overweight and obesity. With the substantial burden of hypertension in Uganda coupled with low awareness and limited treatment of hypertension, especially among diabetics, enhanced communitybased education and prevention efforts tailored to addressing modifiable factors are needed.5 In our study, participants who were employed were 63% less likely to have hypertension compared to their unemployed counterparts. One possible explanation would be the lack of physical exercise among the unemployed participants, whereas those who are working often do manual labour in most parts of sub-Saharan Africa. As observed elsewhere, the prevalence of hypertension increases with increasing age, and the increase is more marked among women than men.33,50 We found age above 40 years to be associated with hypertension in the bivariate model, however this level of significance was lost in the multivariate model. With increasing life expectancy, the risk of hypertension becomes very important in sub-Saharan Africa, a region undergoing an epidemiological transition. In addition patients who had LVH and/diastolic dysfunction were more likely to have hypertension compared to their counterparts without these heart problems. However this was no longer significant at multivariate level. One of the possible explanations could be that hypertension among diabetics caused LVH and diastolic dysfunction, as cited in the ABCD trial and other studies.22 Therefore treating hypertension would be one way to prevent these complications because 75% of all CVD in diabetics can be attributed to hypertension.

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Microalbuminuria was not associated with hypertension in this study, despite the fact that it is one of the major CVD risk factors. Okpere et al., in a cross-sectional study among young people in the community, found contradictory evidence,51 but the population they studied was not diabetic. Type 2 DM and hypertension share several common risk factors, such as physical inactivity and unhealthy diet. Overweight and obesity are potentially amenable to behavioural modification. The benefits of prevention and care extend beyond cardiovascular disease to related conditions of public health importance. They are the focus of efforts to ensure greater prioritisation of NCDs on the global research agenda as well as of development agencies and in the health and development policies of low-income countries.

sion in sub-Saharan Africa by sex, age and habitat: an estimate from population studies. J Hypertens 2011; 29: 1243–1252. 3.

In the diagnosis of hypertension, we did not perform ambulatory blood pressure monitoring, which is the gold standard, according to guidelines for the diagnosis of hypertension.29 This was due to lack of capacity. A non-diabetic control group would have provided better comparison, however in this study we assessed the prevalence and associated factors of hypertension but not its risk factors among diabetics. The recruitment time between June 2014 and January 2015 was relatively short due to limitations in logistics. This could have obscured seasonal differences.

Bloomfield GS, Barasa FA, Doll JA, Velazquez EJ. Heart failure in subSaharan Africa. Curr Cardiol Rev 2013; 9: 157–173.

Moran AE, Tzong KY, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, et al. Variations in ischemic heart disease burden by age, country, and income: the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob Heart 2014; 9: 91–99.

Kotwani P, Kwarisiima D, Clark TD, Kabami J, et al. Epidemiology and awareness of hypertension in a rural Ugandan community: a crosssectional study. BMC Public Health 2013; 13: 1151.

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.

Limitations

223

Musinguzi G, Nuwaha F. Prevalence, awareness and control of hypertension in Uganda. PloS One 2013; 8(4): 62236.

Maher D, Waswa L, Baisley K, Karabarinde A, Unwin N. Epidemiology of hypertension in low-income countries: a cross-sectional populationbased survey in rural Uganda. J Hypertens 2011; 29: 1061–1068.

Maher D, Waswa L, Baisley K, Karabarinde A, Unwin N, et al. Distribution of hyperglycaemia and related cardiovascular disease risk factors in low-income countries: a cross-sectional population-based survey in rural Uganda. Int J Epidemiol 2011; 40: 160–171.

10. Mondo CK, Otim MA, Akol G, Musoke R, Orem J. The prevalence and distribution of non-communicable diseases and their risk factors in Kasese district, Uganda. Cardiovasc J Afr 2013; 24(3): 31–36 11. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of

Conclusion The prevalence of hypertension was high in this population of newly diagnosed diabetics, who had little knowledge of hypertension, and very few patients were on appropriate treatment. Both modifiable and non-modifiable risk factors were associated with hypertension in this group. Therefore, routine assessment, treatment and control of hypertension among diabetics is necessary to prevent CVD complications and death. Pharmacotherapy should be combined with lifestyle changes to address the modifiable risk factors.

diabetes: estimates for 2000 and projections for 2030. Diabetes Care 2004; 27: 1047–1053. 12. Adler AI, Stratton IM, HAW Neil, Yudkin JS. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Br Med J 2000; 321: 412–419. 13. Cutler JA. High blood pressure and endorgan damage. J Hypertens 1996; 14(Suppl): 36. 14. Tuomilehto J, Rastenyte D, Birkenhäger WH, Thijs L, Antikainen R, Bulpitt CJ, et al. Effect of calcium channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999; 320: 67784. 15. Sowers J. Recommendations for special populations: diabetes mellitus

Research reported in this manuscript was supported by the Fogarty

and the metabolic syndrome. Am J Hypertens 2003; 16(11 pt 2): 41S–45S.

International Center of the National Institutes of Health under award

16. Makowsky M, Ally PH, Prebtani A, Gelfer M, Manohar A, Jones C.

number R24TW008861. Dr Mudda was also supported by the Fogarty

Management of hypertension in people with diabetes mellitus: translat-

International Center and the National Heart, Lung, and Blood Institute

ing the 2012 Canadian Hypertension Education Program recommenda-

(NHLBI) at the National Institutes of Health under the Global Health Equity

tions into practice. Can J Diabetes 2012; 36: 345–353.

Scholars Consortium at Yale University (D43TW010540). The content is

17. Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, et al. Insulin

solely the responsibility of the authors and does not necessarily represent

resistance and glycemic abnormalities are associated with deterioration

the official views of the National Institutes of Health. The authors are grate-

of left ventricular diastolic function: a cross-sectional study. Cardiovasc

ful to the following persons for their invaluable support: Professors Nelson

Diabetol 2010; 9: 63.

Sewankambo and Moses R Kamya, the staff of Ward 4B Endocrine, Diabetic

18. Cooper R, Rotimi C, Ataman S, McGee D, et al. The prevalence of

Clinic, and the echocardiography and clinical laboratory of Mulago Hospital.

hypertension in seven populations of west African origin. Am J Public Health 1997; 87: 160–168.

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of diabetes mellitus in sub-Saharan Africa. Circulation 2005; 112: 3592–3601.

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20. Baba MM, Balogun MO, Akintomide AO, Adebayo RA, Talle MA, et

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24. Collins R, Peto R, MacMahon S, Herbert P, Fiebach N, Eberlein K, et al. Blood pressure, stroke, and coronary heart disease. Lancet 1990; 335: 827–838. 25. Lawes CM, van der Hoorn S, Rodgers A. Global burden of bloodpressure related disease, 2001. Lancet 2008; 371: 1513–1518. 26. Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases: overcoming impediments to prevention and control. J Am Med Assoc 2004; 291: 2616–2622. 27. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attrib-

Hypertension 2009; 54: 77–83. 39. Agyemang C, Bruijnzeels MA, Owusu-Dabo E. Factors associated with hypertension awareness, treatment, and control in Ghana, West Africa. J Hum Hypertens 2005; 20: 67–71. 40. Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens 2009; 27: 963–975. 41. Tumwesigye E, Wana G, Kasasa S, Muganzi E, Nuwaha F. High uptake of home-based, district-wide, HIV counseling and testing in Uganda. AIDS Patient Care STDS 2010; 24: 735–741.

utable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010:

42. Menzies N, Abang B, Wanyeze R, Nuwaha F, Mugisha B, et al. The

a systematic analysis for the Global Burden of Disease Study 2010.

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Uganda. AIDS Patient Care STDS 2009; 23: 395–401.

28. Daskalopoulou SS, Rabi DM, Prebtani A, et al. The 2015 Canadian

43. Kibirige D, Atuhe D, Sebunya R, Mwebaze R. Suboptimal glycaemic

Hypertension Education Program recommendations for blood pressure

and blood pressure control and screening for diabetic complications

measurement, diagnosis, assessment of risk, prevention, and treatment

in adult ambulatory diabetic patients in Uganda: a retrospective study

of hypertension. Can J Cardiol 2015; 31: 549–568. 29. Mensah GA. Epidemiology of stroke and high blood pressure in Africa. Heart 2008; 94: 697–705. 30. Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005; 112: 3562–3568. 31. Addo J, Smeeth L, Leon DA. Hypertension in sub-Saharan Africa: a systematic review Hypertension 2007; 50: 1012–1018. 32. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantiﬁcation: A report from

from a developing country. J Diabetes Metab Dis 2014; 13: 40. 44. Psaltopoulou T, Orfanos P, Naska A, Lenas D, Trichopoulos D, et al. Prevalence, awareness, treatment and control of hypertension in a general population sample of 26 913 adults in the Greek EPIC study. Int J Epidemiol 2004; 33: 1345–1352. 45. Dzudie A, Kengne AP, Muna WF, Ba H, Menanga A, et al. Prevalence, awareness, treatment and control of hypertension in a self-selected subSaharan Africa urban population: a cross-sectional study. Br Med J Open 2012; 2: 2012–001217.

the American Society of Echocardiography’s Guidelines and Standards

46. Reisin E, Harris RC, Rahman M. Commentary on the 2014 BP guide-

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in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440–1463. 33. Drawz PE, Abdalla M, Rahman M. Blood pressure measurement: clinic,

(JNC 8). J Am Soc Nephrol 2014: ASN. 2014040371. 47. Walker R, Whiting D, Unwin N, Mugusi F, Swai M, et al. Stroke incidence in rural and urban Tanzania: a prospective, community-based study. Lancet Neurol 2010; 9: 786–792.

home, ambulatory, and beyond. Am J Kidney Dis 2012; 60(3): 449–462.

48. Walker RW, McLarty DG, Kitange HM, Whiting D, Masuki G, et

34. Schwartz JI, Guwatudde D, Nugent R, Kiiza KM. Looking at non-

al. Stroke mortality in urban and rural Tanzania. Lancet 2000; 355:

communicable diseases in Uganda through a local lens: an analysis using locally derived data. Glob Health 2014; 10: 77. 35. Mayega RW, Makumbi F, Rutebemberwa E, Peterson S, Ostenson CG, Tomson G, et al. Modifiable socio-behavioural factors associated with overweight and hypertension among persons aged 35 to 60 years in eastern Uganda. PLoS One 2012; 7: e47632. 36. Mayega RW, Guwatudde D, Makumbi FE, Nakwagala FN, Peterson

1684–1687. 49. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global Burden of Disease and Risk Factors. New York: The World Bank and Oxford University Press, 2006. 50. Wild S, Roglic G, Green A, Sicree R. King. Global prevalence of diabetes: estimates for 2000 and projections for 2030. Diabetes Care 2004; 20: 1047–1053.

S, Tomson G, et al. Comparison of fasting plasma glucose and haemo-

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glucose regulation in a rural low income setting. Diabetes Res Clin Pract

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Presentation, management and outcomes of acute coronary syndrome: a registry study from Kenyatta National Hospital in Nairobi, Kenya Ehete Bahiru, Tecla Temu, Bernard Gitura, Carey Farquhar, Mark D Huffman, Frederick Bukachi

Abstract Background: Acute coronary syndrome (ACS) is understudied in sub-Saharan Africa despite its increasing disease burden. We sought to create an ACS registry at Kenyatta National Hospital to evaluate the presentation, management and outcomes of ACS patients. Methods: From November 2016 to April 2017, we conducted a retrospective review of ACS cases managed at Kenyatta National Hospital between 2013 and 2016, with a primary discharge diagnosis of ACS, based on International Classification of Diseases (ICD) 10 coding (I20-I24). We compared the presentation, management and outcomes by ACS subtype using analysis of variance testing. We created multivariable logistic regression models using the Global Registry of Acute Coronary Events (GRACE) risk score to evaluate the association between clinical variables, including guideline-directed medical therapy and in-hospital outcomes. Results: Among 196 ACS admissions, the majority (65%) was male, and the median age was 58 years. Most (57%) ACSadmissions were for ST-segment-elevation myocardial infarction (STEMI). In-hospital dual antiplatelet (> 85%), beta-blockade (72%) and anticoagulant (72%) therapy was common. A minority (33%) of patients with STEMI was eligible for reperfusion therapy but only 5% received reperfusion. In-hospital mortality rate was 17%, and highest among individuals presenting with STEMI (21%). After multivariable

Northern Pacific Global Health Research Fellowship Training Consortium, University of Washington, Seattle, WA, and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA Ehete Bahiru, MD, ebahiru@mednet.ucla.edu

Department of Preventive Medicine, Northwestern University, Chicago, IL, USA Mark D Huffman, MD, MPH

Department of Global Health, University of Washington, Seattle, WA, USA Tecla Temu, MD, PhD

Kenyatta National Hospital, Division of Cardiology, Department of Medicine, Nairobi, Kenya Bernard Gitura, MB ChB, MMed, FACC

Departments of Global Health, Epidemiology and Medicine, University of Washington, Seattle, WA, USA Carey Farquhar, MD, MPH

Department of Medical Physiology, University of Nairobi, Nairobi, Kenya Frederick Bukachi, MB ChB, MMed, PhD

adjustment, higher serum creatinine level was associated with higher odds of in-hospital death (OR = 1.84, 95% CI: 1.21– 2.78), and STEMI and Killip class > 1 were associated with in-hospital composite of death, re-infarction, stroke, major bleeding or cardiac arrest (STEMI: OR = 8.70, 95% CI: 2.52–29.93; Killip > 1: OR = 10.7, 95% CI: 3.34–34.6). Conclusions: We describe the largest ACS registry at Kenyatta National Hospital to date and identify potential areas for improved ACS care related to diagnostics and management to optimise in-hospital outcomes. Keywords: acute coronary syndrome, sub-Saharan Africa, global health Submitted 29/5/17, accepted 11/3/18 Published online 24/5/18 Cardiovasc J Afr 2018; 29: 225–230

www.cvja.co.za

DOI: 10.5830/CVJA-2018-017

Sub-Saharan Africa is increasingly facing a dual disease burden of infectious and non-communicable chronic diseases (NCDs), including ischaemic heart disease, which is the leading cause of deaths globally.1 The prevalence of ischaemic heart disease is steadily rising in sub-Saharan Africa due to the increasing prevalence of risk factors, including diabetes, obesity, smoking, physical inactivity, hypertension and dyslipidaemia in the context of urbanisation and globalisation.1 The prevalence and mortality rates of ischaemic heart disease in sub-Saharan Africa are predicted to rise by 70% in African men and 74% in African women by 2030.2 While the increasing burden of ischaemic heart disease in sub-Saharan Africa is recognised, few studies have evaluated the presentation, management and outcomes of acute manifestations of ischaemic heart disease, such as acute coronary syndrome (ACS). Accurate and timely assessment of ACS disease burden and current management trends in sub-Saharan Africa can help national and regional healthcare systems build capacity to respond appropriately to the rising epidemic of ischaemic heart disease in the region.3 Internationally, ACS registries have been valuable in studying the presentation, management and outcomes of patients for quality-improvement purposes.3 Data from large ACS registries in sub-Saharan Africa are limited, particularly public hospitals in Kenya. Societies such as the Pan-African Society of Cardiology (PASCAR) have recognised the need for improved understanding of ACS in the region and are advocating for initiatives including large-scale ACS registries.4 To improve current understanding of ACS management in Kenya, we sought to create an ACS registry at Kenyatta

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National Hospital, a major public referral centre, to evaluate the presentation, management and outcomes of patients with ACS.

two-sided p-value < 0.05. We used Stata version 14.0 (StataCorp, LLC. College Station, TX).5

Methods

Results

From November 2016 to April 2017 we conducted a retrospective chart review of ACS cases managed at Kenyatta National Hospital from 2013 to 2016. We used the existing electronic disease code database to identify ACS cases, using primary discharge codes (I20-I24) from the World Health Organisation International Classification of Diseases (ICD-10) system.5 The diagnosis of ACS subtype was made by the primary treating physician at the time of the index hospitalisation, based on the Third Universal Definition of Myocardial Infarction.6 We excluded cases that had a primary diagnosis of ACS, but upon further review of the medical admission, most likely had myocardial infarction secondary to a non-ACS aetiology (i.e. a non-type 1 myocardial infarction). In cases that the ACS subtype was not directly specified in the medical record, the primary data extractor (EB) reviewed each clinical presentation, biomarkers and ECG findings and determined the ACS subtype based on the Third Universal Definition of Myocardial Infarction.6 We included adults over 18 years with a diagnosis of ACS admitted and managed between 2013 and 2016. We abstracted demographics, presentation, self-reported medical history, diagnostics, treatment data and in-hospital clinical events. We used combined paper and electronic data-capture systems to abstract data from the medical record, which was performed by one author (EB). We defined guideline-directed in-hospital medical therapy as receiving a combination of aspirin, a second antiplatelet (e.g. clopidogrel, ticagrelor or prasugrel), beta-blocker within 24 hours of presentation and anticoagulation at any point during the hospitalisation. We defined guideline-directed discharge medical therapy as receiving a combination of aspirin, second antiplatelet drug, beta-blocker and statin. We assessed in-hospital outcomes, including in-hospital death and in-hospital major adverse cardiovascular events (MACE), defined as the composite of in-hospital death, re-infarction, stroke, heart failure, major bleeding or cardiac arrest. We acquired ethics approval to conduct this research from the Kenyatta National Hospital and University of Nairobi ethics research committee (KNH-UON ERC), Northwestern University institutional review board, and University of Washington institutional review board. Informed consent was waived based on the retrospective nature of the study for the collection of anonymised data.

Fig. 1 demonstrates the flow of participants in this study. We identified a total of 330 admissions that met our study criteria. We could only retrieve partial admission data from 2013 due to a hospital-wide electronic database loss that occurred between 2011 and 2013, which led to the exclusion of 51 cases. A further 81 cases were excluded because of incorrect diagnosis (20) or ACS not being the primary discharge diagnosis (61). We therefore included 196 cases in our final analysis. Table 1 summarises patients’ baseline characteristics by ACS subtype. The majority (57%) of the cases were ST-elevation myocardial infarction (STEMI) followed by non-ST-elevation myocardial infarction (NSTEMI, 26%) and unstable angina (UA, 12%). Cases without an ECG but with positive biomarkers and clinical presentation consistent with ACS represented 5% of cases. Most participants (64%) were men, and the median age (IQR) was 58 (48–68) years. More than one-third (38%) of all admissions were transferred from an outside hospital. Hypertension (63%) was the most common co-morbidity, followed by diabetes (41%). Smoking rates were low across all groups (9%); however, 27% had undocumented smoking status, which likely led to underestimation of the overall smoking prevalence. The proportion of patients who presented in heart failure with Killip class > 1 was highest among STEMI cases (44%). Table 2 shows a summary of the in-hospital management of ACS patients. We stratified the data into four groups: key investigations, in-hospital acute medical therapy focusing on administration of guideline-directed medications within the first 24 hours of admission, in-hospital reperfusion therapy, and discharge medical therapy. Overall, 82% of all cases received an ECG within 24 hours of presentation, with higher rates among patients who were transferred versus non-transfer patients (88 vs 71%, p < 0.001). The proportion of patients that received an ECG within 24 hours of admission each year between 2013 and 2016 was 82,

Statistical analysis We present continuous data as means (standard deviation) or median (range or interquartile range) when skewed, and categorical data as proportions. Comparisons by ACS subtype were made via analysis of variance for continuous variables and chi-squared testing for categorical variables. We created multivariable logistic regression models using the Global Registry of Acute Coronary Events (GRACE) risk score to evaluate the association between clinical variables, including guidelinedirected medical therapy and in-hospital death or major adverse cardiovascular events.4 We defined statistical significance using a

330 cases identified through electronic database search with WHO ICD-10 code I20-I24

51 charts not available due to hospital-wide electronic database loss

Retrieved charts for 277 cases

81 cases excluded: 20 wrong diagnoses 61 ACS not the primary diagnosis

196 cases included in final analysis 2016: 68 cases 2015: 50 cases 2014: 50 cases 2013: 28 cases

Fig. 1. Study flow chart of ACS cases admitted to Kenyatta National Hospital between 2013 and 2016.

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Table 1. Basic characteristics of patients admitted with ACS at Kenyatta National Hospital between 2013 and 2016 by ACS subtype All n = 196

STEMI n = 112

NSTEMI n = 50

UA n = 24

Biomarker (+) only n = 10

196

112 (57)

50 (26)

24 (12)

10 (5)

Age, years (median, IQR)

57.5 (48, 68)

60 (53, 69)

56.5 (44, 68)

51.5 (48, 67)

62.5 (45, 65)

Male, n (%)

127 (65)

81 (65)

31 (24)

9 (8)

6 (5)

0.01

Transferred, n (%)

74 (38)

56 (50)

11 (22)

5 (21)

2 (20)

< 0.001 0.34

Variables Type of ACS

p-value 0.18

History of hypertension, n (%)

124 (63)

67 (60)

34 (680

18 (75)

5 (50)

History of diabetes, n (%)

80 (41)

53 (47)

16 (32)

9 (38)

2 (20)

0.14

History of stroke, n (%)

1 (0.5)

1 (0.9)

0.86

History of end-stage renal disease, n (%)

4 (2)

2 (4)

2 (8)

0.03

History of smoking, n (%)

17 (9)

13 (12)

3 (6)

1 (4)

0.07

Heart rate, bpm (median, IQR)

84 (72–101)

84 (72–103)

86 (100–73)

90 (95–76)

79 (66–101)

0.79

Systolic blood pressure, mmHg (median, IQR)

137 (116–156)

136 (114–155)

143 (116–156)

138 (103–156)

150 (132–172)

0.41

73 (39)

50 (44)

17(34)

5 (21)

5 (50)

0.07

Killip class > 1, n (%)

STEMI: ST-elevation myocardial infarction, NSTEMI: non-ST-elevation myocardial infarction, UA: unstable angina, bpm: beats per minute.

80, 80 and 72%, respectively (p = 0.69). Cardiac biomarkers were measured in 86% of cases, and approximately half (52%) received echocardiography during their hospitalisation. A total of 10 cases were primarily diagnosed by symptoms and positive biomarkers without an ECG, with six of these cases managed in 2016, three in 2015, one in 2014 and none in 2013.

During the acute management phase, dual antiplatelet use was 87%. The rates of beta-blocker use (72%) within the first 24 hours of admission and anticoagulant use (72%; 80% enoxaparin) during hospitalisation were also relatively high. After excluding transfer patients, the rate of guideline-directed in-hospital medical therapy, defined as receiving aspirin, a second

Table 2. In-hospital and discharge diagnostics, medical and reperfusion therapy, and rates of guideline-directed in-hospital and discharge medical therapy of ACS patients admitted to Kenyatta National Hospital between 2013 and 2016 All n = 196

STEMI n = 112

NSTEMI n = 50

UA n = 24

ECG < 24 h, n (%)

152 (78)

95 (85)

37 (74)

20 (83)

–

Non-transferred

87 (71)

43 (77)

29 (74)

15 (79)

–

Variables

Biomarker (+) only n = 10

p-value

Key investigations

Transferred

5 (100)

–

9 (90)

< 0.001

65 (84)

52 (93)

8 (73)

Cardiac enzyme (+) in 24 h, n (%)

134 (68)

75 (67)

49 (98)

Echocardiography, n (%)

101(52)

61 (54)

28 (56)

10 (42)

2 (20)

0.13

LVEF < 40%, n (%)

33 (33)

25 (41)

6 (21)

2 (20)

0 (0)

< 0.001

Aspirin, n (%)

185 (94)

104 (93)

50 (100)

22 (92)

–

0.21

Second antiplatelet, n (%)

172 (88)

99 (88)

46 (92)

20 (83)

–

0.20

Beta-blocker, n (%)

137 (72)

79 (75)

32 (65)

18 (75)

–

0.68

Anticoagulation

140 (72)

85 (76)

38 (76)

15 (65)

–

< 0.001

58 (56)

34 (60)

22 (56)

10 (53)

2 (25)

< 0.001

In-hospital medical therapy

Guideline-directed in-hospital medical therapy*, n (%) In-hospital reperfusion therapy Eligible for reperfusion, n (%)

–

37 (33)

–

Thrombolysis, n (%)

–

2 (5)

–

17 (9)

12 (11)

4 (8)

1 (10)

0 (0)

Diagnostic catheterisation, n (%)

–

PCI, n (%)

2 (12)

0 (0)

1 (25)

1 (100)

–

CABG, n (%)

0 (0)

Aspirin, n (%)

152 (96)

86 (99)

41 (91)

19 (86)

6 (100)

0.62

Second antiplatelet, n (%)

131 (82)

79 (91)

34 (76)

13 (59)

5 (83)

0.07

Beta-blocker, n (%)

115 (72)

67 (77)

25 (56)

17 (77)

6 (100)

0.04

Statin, n (%)

137 (86)

78 (90)

34 (76)

18 (82)

4 (67)

0.31

ACEI/ARB for LVEF < 40%, n (%)

19 (63)

13 (59)

5 (83)

1 (50)

–

0.41

Guideline directed discharge medical therapy**, n (%)

89 (56)

34 (64)

22 (47)

10 (41)

Medications on discharge

3 (60)

ACS: acute coronary syndrome, STEMI: ST-elevation myocardial infarction, NSTEMI: non-ST-elevation myocardial infarction, UA: unstable angina, Biomarker (+) only: these are cases that presented with symptoms of ACS and had a positive biomarker test, however did not get an ECG during their hospitalisation, LVEF: left ventricular ejection fraction, PCI: percutaneous coronary intervention, CABG: coronary artery bypass graft, ACEI: ACE inhibitor, ARB: angiotensin receptor blocker. *Guideline-directed in-hospital medical therapy includes patients who received aspirin, a second antiplatelet and a beta-blocker within 24 hours of presentation and an anticoagulant at any point during hospitalisation. **Guideline-directed discharge medical therapy includes patients who received aspirin, a second antiplatelet, a beta-blocker and a statin at discharge.

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antiplatelet, beta-blocker within 24 hours of admission and an anticoagulant at some point during the hospitalisation was 56%. A minority of overall (17 cases, 9%) and STEMI cases (12 cases, 11%) underwent in-hospital diagnostic cardiac catheterisation with only 12% undergoing percutaneous coronary intervention (one NSTEMI, one unstable angina). Using the 2013 American College of Cardiology/American Heart Association guidelines for the management of STEMI,7 we identified 37 (33%) STEMI cases eligible for reperfusion, half of whom were transfers. Two eligible STEMI cases (5%) received thrombolytic therapy and both were transferred from outside hospitals. We assessed discharge medical therapy, focusing on guidelinedirected prescription of medications upon discharge and excluding patients who left against medical advice (n = 4). Discharge aspirin use was 96%, and second antiplatelet agent discharge use was 82%; combined dual antiplatelet use was 81%. Beta-blocker discharge use was 70%, and statin discharge use was 86%. The rate of guideline-directed discharge medical therapy defined as receiving aspirin, a second antiplatelet and beta-blocker therapy was also 56%. Among individuals with an ejection fraction less than 40% (n = 33), 63% received an ACE inhibitor or angiotensin receptor blocker (ARB). Among patients with ejection fraction less than 40%, the rate of guideline-directed medical therapy with simultaneous dual Table 3. In-hospital mortality and major adverse cardiovascular events and association between in-hospital guideline-directed therapy and in-hospital outcomes of ACS patients admitted and managed at Kenyatta National Hospital between 2013 and 2016 In-hospital mortality 33 (17)

78 (40)

STEMI, n (%)

23 (21)

61 (54)

NSTEMI, n (%)

5 (10)

11 (22)

UA, n (%)

2 (8)

3 (13)

BM (+) only

3 (30)

*Guideline-directed in-hospital medical therapy, n (%)

8 (12)

27 (40)

Non-guideline-directed in-hospital medical therapy, n (%)

8 (15)

14 (26)

0.76 (0.27–2.20)

antiplatelet, beta-blocker, statin and ACE inhibitor or ARB use was 48%. The overall in-hospital mortality rate was 17%, with a gradient in mortality rate by ACS subtype (STEMI 21%, NSTEMI 10%, UA 9%, biomarker positive only 30%, p = 0.16) (Table 3). The rate of MACE, defined as death, re-infarction, stroke, cardiogenic shock, major bleeding or cardiac arrest was 40%, with a similar gradient by ACS subtype (STEMI 54%, NSTEMI 20%, UA 7%, biomarker positive only 30%, p < 0.001) (Table 3). Table 4 summarises variables assessed as potential predictors of in-hospital mortality before and after adjustment using the GRACE risk score. After multivariable adjustment, higher serum creatinine level was associated with higher odds of in-hospital death (OR = 1.84, 95% CI: 1.21–2.78), and Killip class > 1 was associated with in-hospital composite of death, re-infarction, stroke, major bleeding or cardiac arrest (STEMI: OR = 4.71, 95% CI: 2.46–9.02; Killip > 1: OR = 10.7, 95% CI: 3.34–34.6). We also evaluated the association between receiving guidelinedirected in-hospital medical therapy and in-hospital MACE level using logistic regression and adjusting for covariates in the GRACE risk score. We did not demonstrate an association between in-hospital death and combined in-hospital death and MACE before and after multivariable adjustment (OR = 0.77, 95% CI: 0.27–2.20; OR = 1.88, 95% CI: 0.86–4.10, respectively), but these results were imprecise and were likely driven by the small sample size and number of events.

In-hospital MACE

All, n (%)

Guideline-directed vs non-guideline-directed, OR (95% CI)

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Discussion

1.88 (0.86–4.10)

ACS: acute coronary syndrome, STEMI: ST-elevation myocardial infarction, NSTEMI: non-ST-elevation myocardial infarction, UA: unstable angina, BM (+): biomarker positive only: these are cases that presented with symptoms of ACS and had a positive biomarker test, however did not get an ECG during their hospitalisation, MACE: major adverse cardiovascular events. *Guideline-directed in-hospital medical therapy includes patients who received aspirin, a second antiplatelet and a beta-blocker within 24 hours of presentation and an anticoagulant at any point during hospitalisation.

Through this retrospective chart review we report the presentation, management and outcomes of ACS patients managed at Kenyatta National Hospital between 2013 and 2016. Most patients were men in their late 50s presenting with STEMI. Approximately one out of every five patients did not receive an ECG within the first 24 hours, and one out of every 20 patients did not receive an ECG at all. While more than one out of every two patients received echocardiography, the gap in ECG care represents an opportunity for diagnostic improvement. Rates of in-hospital medical therapy were relatively high but reperfusion rates among eligible individuals were low. Increasing timely, appropriate reperfusion therapy for eligible STEMI patients may be an important area of focus because of the high mortality rate demonstrated among these patients.

Table 4. Predictors of in-hospital death and major adverse cardiovascular events (MACE) including death, re-infarction, stroke, heart failure, cardiogenic shock, major bleeding and cardiac arrest of ACS patients admitted to Kenyatta National Hospital between 2013 and 2016 Unadjusted OR (95% CI)

Adjusted (for age, gender and GRACE risk score variables) OR (95% CI)

In-hospital death, n = 33

In-hospital MACE, n = 78

In-hospital death, n = 33

Age (per year)

1.03 (1.0–1.06)*

1.00 (1.01–1.05)*

1.04 (0.98–1.11)

1.01 (0.98–1.06)

Heart rate (per bpm)

0.98 (0.97–1.00)

1.00 (0.99–1.02)

1.02 (0.99–1.11)

1.01 (098–1.04)

Variables

In-hospital MACE, n = 78

SBP (per mmHg)

0.99 (0.98–1.00)

0.96 (0.93–0.98)

0.98 (0.96–0.99)

Serum Cr (per mg/dl)

1.35 (1.12–1.66)*

1.13 (0.94–1.34)

1.84 (1.21–2.78)*

1.04 (0.84–1.31)

Killip class 1 vs > 1

5.80 (2.5–13.7)*

11.45 (0.80–22.4)*

1.8 (0.42–8.14)

Positive cardiac enzyme

2.60 (0.58–11.8)

2.23 (0.89–5.63)

0.91 (0.94–8.80)

1.42 (0.35–5.73)

ST-segment deviation

2.11 (0.85–5.22)

5.35 (2.60–10.99)*

3.12 (0.57–16.87)

1.72 (0.12–24.40)

STEMI vs UA (ref)

2.84 (062–2.98)

8.37 (2.36–29.70)*

0.77(0.02–38.56)

1.71 (0.21–13.80)

*p-value < 0.05; GRACE risk score variables: age, gender, SBP, HR, positive cardiac enzyme, ST-segment change, creatinine, cardiac arrest. SBP: systolic blood pressure, HR: heart rate, Cr: creatinine, STEMI: ST-segment myocardial infarction.

10.7 (3.34–34.6)*

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The median age of presentation found in this study is similar to other studies from sub-Saharan Africa, which demonstrate that ACS cases in sub-Saharan Africa tend to present at a younger age, typically in their 50s, compared to high-income countries, which have a median age in the mid-to-late 60s.4 A 2010 retrospective study by Ogeng’o et al. at Kenyatta National Hospital of 120 ACS cases admitted between 2000 and 2009 reported the mode of diagnosis, demographics, risk factors and in-hospital heart failure and mortality rates.8 The mean age in this study was 56.8 years with a similar 2:1 male-to-female ratio. Our study also demonstrates a doubling in rates of hypertension and diabetes (63 and 41%, respectively) compared to the 35 and 21% rates reported in the Ogeng’o study, while smoking rate was similarly low (9 and 13%, respectively).8 The 2010 Ogeng’o study did not specify ACS subtypes and overall rates of in-hospital diagnostics such as ECG, echocardiography and coronary angiography, and therefore we were unable to make comparisons in those areas. However, total mortality rate demonstrated in our study was notably higher (17%) compared with the previous report of 5%.8 The 2004 INTERHEART study, a multi-continental case–control study, which incorporated nine countries from sub-Saharan Africa, including Kenya, demonstrated that acute myocardial infarction risk factors among the sub-Saharan African cohort were similar to that of the overall study population. However, a history of hypertension was associated with increased myocardial infarction risk among the black African group compared to the general study population.9 The high frequency of STEMI (57%) presentation demonstrated in this study is also similar to other studies from sub-Saharan Africa, including a 2012 prospective study of 111 ACS admissions from the Aga Khan University Hospital, a private institution in Nairobi (56%, n = 111).10 The Acute Coronary Events – a Multinational Survey of Current Management Strategies (ACCESS) registry is another largescale multi-national study that included 642 patients from South Africa. This study had 41% STEMI, 32% NSTEMI and 27% unstable angina cases. Rates of in-hospital medical therapy such as aspirin and beta-blocker use demonstrated in this study are comparable to the ACCESS-South Africa cohort findings; however, there are important differences in reperfusion rates. The Aga Khan University study demonstrated a 68% reperfusion rate [either percutaneous coronary intervention (PCI) or thrombolysis], while the ACCESS registry reported 96% in-hospital reperfusion rate with thrombolysis and/or PCI.11 Caution must be applied when comparing these reperfusion rates to our study, given the likely significant patient- and hospital-level socio-economic variation across these studies. Future directions of study include evaluating initiatives for quality improvement related to diagnostics (e.g. ECG evaluation of all patients with chest pain) and management (e.g. reperfusion of eligible patients). One integral component includes an ongoing, prospective ACS registry to assess time trends in presentation, management and outcomes and devise future quality-improvement initiatives. Internationally, results of large-scale registries such as GRACE-ACS4 have contributed significantly to better understanding of ACS presentation, management and outcomes and have led to the design of other ACS registries

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globally, including in low-middle-income countries such as the Kerala ACS registry,13 China Acute Myocardial Infarction (CAMI) registry14 and the Registry for Acute Coronary Syndrome Events in Nigeria (RACE-Nigeria) from a sub-Saharan African country.2 Cardiology societies in sub-Saharan Africa including the Kenyan Cardiac Society (KCS) and the Pan-African Society of Cardiology (PASCAR) have recognised the need for data on ACS and are advocating for initiatives to build local and regional ACS registries to have improved understanding of disease presentation, management and outcomes in the region. ACS registries in both high- and low-middle-income countries have also led to subsequent quality-improvement initiatives. These include ACS quality-improvement randomised, control trials, such as the Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes (BRIDGE-ACS),15 the Clinical Pathways for Acute Coronary Syndromes, phases 2 and 3 (CPACS-2 and -3)16 in China, and the Acute Coronary Syndrome Quality Improvement in Kerala (ACS QUIK) study in India.17 These multi-institutional randomised, control trials have investigated the impact of quality-improvement tools such as clinical pathways, audits and performance feedback on both processes of care and outcomes, with the goal of improving ACS management. Such future efforts within sub-Saharan Africa could be instrumental in identifying unique solutions tailored to the needs and capacity of the region to improve ACS care. Through this research process, we have engaged with key stakeholders at Kenyatta National Hospital within the division of cardiology and department of research to assess the existing research infrastructure and capacity, to improve processes and outcome measures of patients with ACS.

Strengths and limitations This study, the largest study at Kenyatta National Hospital to date, has assessed the presentation, management and outcomes of ACS patients managed at the hospital. The main study limitation is based upon the retrospective design of the study. Like most hospitals in the region, Kenyatta National Hospital uses paper charts for medical records, and we were not able to locate 51 charts that met our study criteria. Additionally, there was loss of electronic disease code database at Kenyatta National Hospital in 2013, which resulted in only 40 admissions being identified from 2013. However, it is unlikely that these omissions would have influenced the overall findings from this study. One author (EB) made assessments to include and exclude cases and completed the data extraction, which adds another potential limitation to data quality.

Conclusions This is the largest study at Kenyatta National Hospital to evaluate the presentation, management and outcomes of ACS patients managed at a public referral hospital that provides care to a diverse pool of patients in Kenya. The findings present opportunities for future quality-improvement initiatives, especially in the areas of initial diagnostic capabilities and reperfusion therapy. A prospective ACS registry and linked quality-improvement programme would be valuable to improve quality and safety of ACS patients and as a model for other cardiovascular conditions.

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MDH receives grant support from the World Heart Federation to serve as

Ettinger SM, et al. 2013 ACC/AHA guildeline for management of

its senior programme advisor for the Emerging Leaders programme, which

ST-elevation myocardial infarction. J Am Coll Cardiol 2013; 61(4):

is supported by unrestricted educational grants from Boehringer Ingelheim

e78–e140.

and Novartis, with previous support from AstraZeneca and Bupa. Funding

10. Ogeng’o JA, Olabu BO, Ong’era D, Sinkeet SR. Pattern of acute

was provided by the Fogarty International Center TW R25TW009345. MDH

myocardial infarction in an African country. Acta Cardiol 2010; 65(6):

also receives support from the American Heart Association, Verily and AstraZeneca that is unrelated to this article.

613–618. 11. Schamroth C. Management of acute coronary syndrome in South Africa: insights from the ACCESS (Acute Coronary Events – a

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

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

Onen CL. Epidemiology of ischaemic heart disease in sub-Saharan

Joseph J, et al. Presentation, management, and outcomes of 25 748 acute

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

coronary syndrome admissions in Kerala, India: results from the Kerala

Africa: the need for data. PloS One 2014; 9(5): e96688.

The China Acute Myocardial Infarction (CAMI) Registry: A national

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long-term registry–research–education integrated platform for exploring

outcomes of patients hospitalized with acute coronary syndromes in the

acute myocardial infarction in China. Am Heart J 2016; 175: 193–201.

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ICD-10 Version (2016). International Statistical Classification of

AA, Zazula AD, et al. Effect of a multifaceted intervention on use of

Diseases and Related Health Problems, 10th revision. Retrieved from

evidence-based therapies in patients with acute coronary syndromes in

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Brazil: the BRIDGE-ACS randomized trial. J Am Med Assoc 2012;

Thygesen K, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint

307(19): 2041–2049.

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16. Li M, Huang Y, Du X, Li S, Ji J, Patel A, et al. Impact of Prior Use of

Myocardial Infarction, Third universal definition of myocardial infarc-

Four Preventive Medications on Outcomes in Patients Hospitalized for

tion. Circulation 2012; 126: 2020–2035.

Acute Coronary Syndrome – Results from CPACS-2 Study. PloS One

Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, et al. Predictors of hospital mortality in the global registry of acute

ACS Registry. Eur Heart J 2013; 34(2): 121–129. 14. Xu H, Li W, Yang J, Wiviott SD, Sabatine MS, Peterson ED, et al.

Steg PG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD,

Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 5.

2012; 23(6): 318–321. 13. Mohanan PP, Mathew R, Harikrishnan S, Krishnan MN, Zachariah G,

Africa. Cardiovasc J Afr 2013; 24(2): 34–42. AT, Bloomfield GS, et al. Acute myocardial infarction in sub-Saharan 4.

Cardiovasc J Afr 2012; 23(7): 365–370.

Mensah GA. Descriptive epidemiology of cardiovascular risk factors 240–250.

Multinational Survey of Current Management Strategies) registry.

2016; 11(9): e0163068. 17. Huffman MD, Mohanan PP, Devarajan R, Baldridge AS, Kondal D,

coronary events. Arch Internal Med 2003; 163(19): 2345–2353.

Zhao L, et al. Acute coronary syndrome quality improvement in Kerala

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O’Gara PT KG, Ascheim DD, Casey DE, Chung MK, De lemos JA,

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Left ventricular twist before and after haemodialysis: an analysis using speckle-tracking echocardiography Anthony Yip, Saraladevi Naicker, Ferande Peters, Elena Libhaber, Nirvathi Maharaj, Mduduzi Mashabane, Mohammed Rafique Essop

Abstract Background: The most commonly used parameter of cardiac function in the chronic kidney disease (CKD) patient is ejection fraction (EF), using transthoracic echocardiography (TTE). EF is a highly load-dependent measurement, which varies considerably in CKD patients undergoing haemodialysis. The aim of this pilot study was to evaluate a novel measure of myocardial function, left ventricular twist, which is defined as the ‘wringing action of the heart’, using speckletracking echocardiography in CKD patients before and after haemodialysis. Methods: Twenty-six patients were recruited from the Chris Hani Baragwanath Hospital haemodialysis unit. TTE was performed according to a detailed standardised protocol before and after a single haemodialysis session. Echocardiography was also performed on 26 age- and gendermatched healthy subjects. Results: The mean age of the control versus CKD group was 44 ± 11.4 and 43.4 ± 12.2 years, respectively; 46% were male. Apical rotation was diminished in CKD patients comparedto controls (4.83 ± 2.3 vs 6.31 ± 1.6 °; p = 0.01) despite no difference in EF (61.7 ± 6.2 vs 58.8 ± 13; p = 0.68). There were no differences in the components of twist: apical rotation, basal rotation and net twist before and after dialysis, despite an increase in EF (58.8 ± 13.7 vs 61.2 ± 13.6; p = 0.02) following dialysis.

Division of Cardiology, Chris Hani Baragwanath Hospital, Johannesburg, South Africa Anthony Yip, MB BCh, MSc, FCP (SA), MRCP (UK), Cert Cardiology (SA) Ferande Peters, MB BCh, FCP, FACC, FESC Elena Libhaber, PhD Nirvathi Maharaj, MB BCh, FCP, PhD Mohammed Rafique Essop, MB BCh, FCP, FRCP, FACC

Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital, South Africa Saraladevi Naicker, MB BCh PhD, FRCP

Division of Nephrology, Chris Hani Baragwanath Hospital, Johannesburg, South Africa Mduduzi Mashabane, MB BCh, FCP

Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Anthony Yip, MB BCh, MSc, FCP (SA), MRCP (UK), Cert Cardiology (SA), dranthonyyip@gmail.com Saraladevi Naicker, MB BCh, PhD, FRCP Ferande Peters, MB BCh, FCP, FACC, FESC Elena Libhaber, PhD Nirvathi Maharaj, MB BCh, FCP, PhD Mduduzi Mashabane, MB BCh, FCP Mohammed Rafique Essop, MB BCh, FCP, FRCP, FACC

Conclusion: Unlike EF, the components of twist are relatively independent of changes in haemodynamic load seen during dialysis. The decrease in apical rotation may represent an early marker of cardiac pathology in the late-stage CKD patient. Keywords: left ventricular twist, speckle-tracking echocardiography, chronic kidney disease, dialysis Submitted 5/12/17, accepted 11/3/18 Published online 20/4/18 Cardiovasc J Afr 2018; 29: 231–236

www.cvja.co.za

DOI: 10.5830/CVJA-2018-019

Cardiovascular pathology accounts for half of the deaths in chronic kidney disease (CKD) patients.1,2 Causes of increased mortality rates include sudden death from arrhythmias, heart failure and ischaemic heart disease.1,3-6 Transthoracic echocardiography (TTE) is the most commonly used imaging modality to assess cardiac function in patients with CKD. However, the most widely used echocardiographic measurement is ejection fraction (EF), which is load dependent and varies considerably with the volume shifts experienced during haemodialysis.7 Cardio-renal specialists have explored other measures to evaluate cardiac function in CKD, using myocardial deformation or strain, which more accurately describes ventricular movement during systolic and diastolic function. It consists of longitudinal, radial and circumferential strain, and ventricular twist.8 Tissue Doppler imaging was previously used to measure strain but required correct alignment of the Doppler signal to the angle of the myocardial fibres.8 In recent years, speckle-tracking echocardiography (STE) has emerged as a potentially more accurate technique to measure myocardial deformation.9 STE is an echocardiographic modality based on the accurate tracking of groups of pixels called ‘speckles’ throughout the cardiac cycle.9 Using this technique, parameters reflecting myocardial deformation, such as global longitudinal strain, radial and circumferential strain, and left ventricular twist can be assessed. The initial studies conducted in chronic kidney disease patients using speckle tracking to evaluate myocardial function demonstrated a reduction in longitudinal strain but not in circumferential or radial strain and did not evaluate left ventricular twist.10-12 Left ventricular (LV) twist is described as a ‘wringing’ action of the heart. It represents a clockwise rotation of the base and a counter-clockwise rotation of the apex during systole.13Using STE, LV twist14 has been validated against

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magnetic resonance imaging (MRI)15 and evaluated in conditions such as hypertension,16 ischaemic heart disease17 and a variety of cardiomyopathies.18 In CKD, LV twist has been shown to increase as calculated glomerular filtration rate (GFR) decreased.19-21 A major limitation of the above studies on LV twist is that the impact of varying loading conditions in patients undergoing haemodialysis was not evaluated. The aim of this pilot study was to examine LV twist in African patients with stage 5 CKD before and after a single haemodialysis session.

Methods This prospective, longitudinal, single-centre study was conducted at the Chris Hani Baragwanath Hospital Renal Unit in Johannesburg, South Africa. Volunteers were screened from November 2010 until February 2011. Inclusion criteria were: ages between 20 and 65 years and documented CKD on intermittent haemodialysis three times weekly. Exclusion criteria were: pre-existing cardiac disease, known coronary artery disease, valvular heart disease, arrhythmias, and poor echocardiography windows that precluded speckle tracking. Of the 71 patients receiving intermittent haemodialysis in this unit, 26 meeting the entry criteria were recruited among volunteers (Fig. 1). Similarly, 26 age- and gender-matched individuals were recruited from healthy volunteers with no known underlying medical conditions among unrelated staff members at Chris Hani Baragwanath Hospital and local churches around the Soweto, Johannesburg area.22 Ethics approval for this study was obtained from the University of the Witwatersrand human research ethics committee. Written informed consent was obtained from all patients, and the study protocol (approval number M10510) conformed to the 1975 Declaration of Helsinki. Patients with CKD with end-stage kidney failure (ESKF) were on three-times-a-week intermittent haemodialysis (HD). Haemodialysis was performed for an average of four hours with mean ultrafiltration volume of 2.2 ± 0.9 litres, using bicarbonate dialysate. Fresenius FX dialysers were used, with most patients dialysed on the FX 80 dialysers, although the range of dialysers used were FX 60, FX 80 and FX 100, according to the patient’s weight. The recombinant erythropoietin, epoetin-beta, was used to maintain haemoglobin levels at a target of 11 to 12 g/dl, in keeping with KDIGO guidelines at the time. An average of 12 000 units was given subcutaneously per patient per week. Eighty-eight per cent of patients receiving haemodialysis were on an ACE inhibitor or angiotensin receptor blocker, with the most frequently used agents being perindopril and telmisartan. All 52 participants underwent complete transthoracic echocardiographic evaluation. CKD patients were evaluated before and within an hour of a single haemodialysis session. According to a standardised protocol used by our institution,22-25 a comprehensive echocardiographic examination was performed in the lateral decubitus position using a commercially available system (iE33 xMATRIX, Philips Healthcare, Andover, MA, USA) equipped with an S5-1 transducer (frequency transmitted 1.7 MHz, frequency received 3.4 MHz). Measurements obtained were averaged from three heartbeats. All data were transferred to an Xcelera workstation (Phillips Healthcare) for offline analysis.

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Chamber size measurements and function were performed according to the American Society of Echocardiography (ASE) chamber quantification guidelines of 2006.26,27 EF was calculated using LV volumes with the modified biplane Simpson’s rule, in keeping with guidelines.26 Diastolic function was evaluated and analysed in accordance with the ASE 2009 guidelines.28 Left ventricular end-diastolic volume (LVEDV) was taken as representative markers of preload. Pulse pressure over stroke volume (PP/SV) was used as a surrogate of arterial stiffness,29,30 which takes into account the contributions of systemic vascular resistance (SVR) and ventricular compliance to afterload.31 PP/SV has previously been validated as a measure of arterial stiffness and afterload in trials such as the LIFE study.32 Mean arterial pressure (MAP) was used as an indirect marker for afterload as it is a major contributor to SVR. Speckle-tracking basal images were obtained in the parasternal short axis at the level of the mitral valve, showing the tips of leaflets with the most circular image possible. Apical images were acquired by moving the transducer one or two spaces caudally, using a method described by van Dalen.33 Images were acquired at a frame rate of 50–80 frames/s during sinus rhythm with less than 10% variability in heart rate for optimal speckle tracking.18 These images were reviewed and analysed by a cardiologist experienced in STE, using QLAB Advanced Quantification software (Version 8.0, Philips Healthcare).9,34 Tracking points were placed within the myocardium to avoid the pericardium. In keeping with ASE/European Association of Echocardiography (EAE) consensus,35 counter-clockwise rotation was assigned a positive value and clockwise rotation a negative value as viewed from the apex (Figs 2, 3).

Chris Hani Baragwanath Hospital haemodialysis unit 71 patients attending morning, afternoon or evening shift 30 patients refused consent due to difficulties with transport 41 patients with informed consent and preliminary screening and echocardiography performed before and after dialysis 8 patients excluded with pre-existing cardiac disease such as valvular heart disease or did not meet entry criteria 33 patients’ echocardiography performed with speckle tracking analysis performed 7 patients had more than two segments that did not track adequately using speckletracking 26 haemodialysis with pre- and post-dialysis echocardiography images and speckle-tracking imaging included for final analysis with age- and gendermatched controls

Fig. 1. Flow chart of patient recruitment.

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Fig. 2. Short-axis view through the apex.

Peak apical rotation was measured during the ejection systolic phase. Basal rotation was measured at a time isochronous to peak apical systolic rotation, in keeping with a standard protocol used by our institution, which has previously been published.22,24,25 Net instantaneous twist was calculated as peak apical rotation minus the isochronous basal rotation. Measurements were independently made by two cardiologists trained in STE. The combined mean inter-observer variability for measurements of apical, basal and net twist of renal patients pre-dialysis was 3.67% (range 2–37%) and post-dialysis 3.7% (range 2.5–31%). The mean intra-observer variability pre-dialysis was 2.76% (range 2–10%) and post-dialysis 3.72% (range 2.5–26%).

Statistical analysis Data were analysed using the Statistica version 11 (Statsoft; Tulsa, Oklahoma, USA) program. Results are expressed as means with standard deviations or medians for non-normal distribution or frequencies, and percentages for categorical variables. To assess differences between the control groups versus pre-dialysis patients, and control versus post-dialysis patients, the Mann– Whitney test for non-normally distributed variables was used. Pre-dialysis and post-dialysis comparisons were performed with the Wilcoxon matched paired test. Significance was assumed at two-sided values of p < 0.05. Fisher’s exact test was used to compare categorical data. The Schapiro–Wilk test was used to assess normality. Univariate linear regression analysis was used to identify independent factors associated with twist pre-dialysis and post-dialysis, and change in twist.

Results Clinical characteristics of control participants and CKD patients are summarised in Table 1. The mean ages of control versus CKD patients were 44.0 ± 11.4 versus 43.4 ± 12.2 years (p = 0.81), with a 46% male incidence in both groups. The most common aetiology of the CKD patients was hypertension (81%). Weight (mean 66.2 ± 8.5 vs 65.2 ± 12.9 kg; p = 0.44), body mass index (BMI) and body surface area (BSA) were similar between

Fig. 3. Basal rotation in the short-axis view.

the groups (Table 1). By contrast, with the CKD patients, the pre-dialysis systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were significantly higher compared to levels observed in the control group (Table 1). On echocardiography, patients on haemodialysis had significantly higher pre-dialysis LV diastolic volumes, LV end-systolic volumes, LV end-systolic diameter (LVESD) and stroke volume compared to the controls, whereas there was no difference in EF and PP/SV (Table 2). In addition, patients on haemodialysis had significantly thicker LV walls and greater LV mass compared to controls. LV hypertrophy (LVH) was present in 88% of renal patients (23 of 26 patients). In those Table 1. Clinical characteristics of patients and controls Control (n = 26)

Pre-dialysis (n = 26)

Post-dialysis (n = 26)

44.0 ± 11.4

43.4 ± 12.2

–

12 (46)

–

Height (cm)

163.6 ± 8.9

164.0 ± 9.6

–

Weight (kg)

66.2 ± 8.5

65.2 ± 12.9

63.0 ± 12.6† 2.2 ± 1.0

Characteristics Mean age (years) Male gender, n (%)

Change in weight (kg)

–

Haemoglobin (g/dl)

–

9.9 ± 2.3

Heart rate (beats/min)

70.3 ± 11.9

81.8 ± 11.9*

89.7 ± 18.3

Body mass index (kg/m2)

24.7 ± 2.5

24.2 ± 4.0

–

Body surface area (m2)

1.7 ± 0.1

1.7 ± 0.2

–

Diabetes mellitus, n (%)

2 (8)*

–

Hypertension, n (%)

22 (81)*

–

Systolic blood pressure (mmHg)

122.7 ± 5.1

151.8 ± 17.6*

145.0 ± 24.5

Diastolic blood pressure (mmHg)

75.5± 10.2

90.1 ± 14.1*

88.4 ± 16.5

Mean arterial pressure (mmHg)

91.2 ± 7.4

110.6 ± 13.7*

107.4 ± 18.0

Pulse pressure (mmHg)

47.2 ± 10.3

61.7 ± 14.4*

56.6 ± 16.3

Volume ultra-filtrated (l)

–

2.2 ± 0.9

Years on dialysis

–

6.7 ± 3.4

–

Corrected calcium (mmol/l)

–

2.3 ± 0.3

–

Corrected calcium (g/dl)

–

9.2 ± 1.3

–

Phosphate (mmol/l)

–

1.3 ± 0.5

–

Phosphate (g/dl)

–

4.1 ± 1.7

–

Calcium × phosphate product (g2/dl2)

–

37.6 ± 15.5

–

Parathyroid hormone level (pg/ml)

–

66 ± 68

–

*p-value < 0.05 vs control group, †p-value < 0.05 vs pre-dialysis group.

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Table 2. Echocardiographic characteristics

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the use of an ACE inhibitor or ARB versus net twist (regression coefficient of 0.34; p = 0.09). A significant association was demonstrated between the differences in systolic and diastolic blood pressure versus basal twist post-dialysis (p = 0.02 and p = 0.006, respectively), and the difference in diastolic blood pressure and apical twist post-dialysis (p = 0.04).

Control (n = 26)

Pre-dialysis (n = 26)

Post-dialysis (n = 26)

LV end-diastolic volume (ml)

71.0 ± 9.8

97.9 ± 39.2*

83.5 ± 23.9†

LV end-systolic volume (ml)

30.6 ± 7.6

41.1 ± 23.7

35.2 ± 20.3†

Stroke volume (ml)

40.5 ± 10.2

57.4 ± 28.3*

49.3 ±16.5

LV end-diastolic diameter (mm)

44.9 ± 0.3

45.8 ± 0.7

45.3 ± 0.6

LV end-systolic diameter (mm)

28.8 ± 0.4

32 .0 ± 0.6*

29.7 ± 0.6

Interventricular septal diameter (mm)

10.0 ± 0.2

14.1 ± 0.3*

14.0 ± 0.3

Discussion

Posterior wall thickness (mm)

9 .0 ± 0.1

13.5 ± 0.3*

13.2 ± 0.3

Relative wall thickness (mm)

0.4 ± 0.04

0.6 ± 0.1*

0.6 ± 0.1 61.2 ± 13.6†

The major findings of this study are (1) apical rotation appears to be reduced in patients on chronic haemodialysis with net twist remaining unchanged; and (2) LV twist is less susceptible to haemodynamic fluctuations associated with dialysis than EF. The use of EF as a measure of systolic function in CKD is suboptimal because of the variable load changes and the effects of uraemic metabolites during dialysis. According to the ‘Starling effect’, LV function is determined by load, with increasing preload resulting in improved LV function, and vice versa. Similarly, systolic function is inversely related to afterload. However, it is not only load changes that play a role in systolic function in CKD patients on dialysis. An additional possibility is that the removal of negatively inotropic uraemic toxins during haemodialysis improves cardiac function.7,11,36 In clinical practice, trying to predict the relative interplay of load changes and uraemia on EF is extremely complex.7 In this study, CKD patients had similar EF to the control participants at baseline, which is not surprising since systolic dysfunction is seen in only 15% of CKD patients.37 During dialysis, there was a significant reduction in preload (LVEDV, LVESV, LAVI and E/Ea ratios), but no significant change in afterload (MAP and PP/SV ratios).31 Therefore, it would be reasonable to postulate that the EF should have been reduced, according to Starling. Since EF increased after dialysis, the removal of uraemic metabolites during haemodialysis may have been responsible for the improvement.7 Considering these changes, one might suppose that if apical, basal and net twist were subject to load changes, any or all of these parameters would decrease with reduced preload. These measures of rotation did not change with dialysis. This lack of significant change after dialysis implies that the components of myocardial rotation: apical rotation, basal rotation and net LV twist are relatively load independent, but whether they are also relatively immune to the acute metabolic changes of uraemia requires further study. The key to understanding LV twist and its contribution to cardiac systolic function is in understanding the arrangement of myocardial fibres in a ‘left-handed’ helix sub-endocardially with clockwise rotation, and a ‘right-handed’ helix sub-epicardially with counter-clockwise rotation (Fig. 4). In normal cardiac physiology, apical rotation provides the greater contribution to net twist because of the larger radius of rotation of its sub-epicardial predominant fibres compared to the sub-endocardial predominant base. For example, conditions that are known to affect mainly the sub-endocardial layer of the myocardium, such as hypertensive LVH,38 aortic stenosis,39 hypertrophic cardiomyopathy,39 amyloidosis40 and early myocardial ischaemia41 have been shown to cause apical hyper-rotation through the relatively unopposed sub-epicardial muscle fibres. This may be a compensatory function to preserve systolic function, with many of these conditions showing increase in net LV twist despite a

Characteristics

Ejection fraction (%)

61.7 ± 6.2

58.8 ± 13.7

LV mass index (g/m2)

84.5 ± 18.9

156.1 ± 61.9* 152.7 ± 62

Left atrial volume index(ml)

25.8 ± 5.6

33.4 ± 15.2 *

27.8 ± 15.6†

Mitral E/A (ratio)

1.2 ± 0.4

1.1 ± 0.4

1.1 ± 0.7

E/E′ (ratio)

9.8 ± 2.4

15.2 ± 5.2*

13.0 ± 5.8†

Pulse pressure/stroke volume (mmHg/ml)

1.3 ± 0.8

1.4 ± 0.9

1.3 ± 0.8

*p-value < 0.05 vs control group, †p-value < 0.05 vs pre-dialysis group‡

patients with hypertrophy, 96% (22 patients) were concentric in pattern and 4% had eccentric hypertrophy (one patient). As expected, patients had diastolic dysfunction with significantly greater indices of elevated filling pressure [E/E′ and left atrial (LA) volume index] pre-dialysis compared to the normal control group. During dialysis, CKD patients were ultra-filtrated a mean of 2.2 ± 0.9 litres, with a mean change in weight of 2.2 ± 1.0 kg. As a result, there was a significant difference in pre- and postdialysis weights (Table 1). No statistically significant differences between systolic, diastolic, mean arterial pressure and heart rate were found. There was a significant decrease in LVEDV, LVESV, E/E′ and LA volume index (LAVI) after dialysis whereas a significant increment in EF was noted compared to pre-dialysis values (Table 2). However, the stroke volume and PP/SV did not change. At baseline, there was no difference in net speckle-tracking twist and basal rotation between controls compared to CKD patients prior to their dialysis session. However, there was a significant decrease in apical rotation between the control and pre-dialysis group (6.3 ± 1.6 vs 4.8 ± 2.3°; p = 0.01). There was no statistically significant difference when comparing net twist, basal rotation or apical rotation in CKD patients before and after dialysis (Table 3). In the univariate linear regression analysis of twist, the presence of hypertension, diabetes, the use of ACE inhibitor or angiotensin receptor blocker (ARB), and change in weight before and after dialysis were compared against the difference in apical, basal and net twist before and after dialysis. These variables showed a trend towards statistical significance with an independent association between hypertension and the difference in apical twist (regression coefficient of 0.34; p = 0.088), and in Table 3. Speckle-tracking characteristics Control (n = 26)

Characteristics

6.3 ± 1.6

Apical rotation (°) Basal rotation (°)

–3.3 ± 1

Net twist (°) *p-value < 0.05 vs control group.

9.6 ± 1.9

Pre-dialysis (n = 26) 4.8 ± 2.3*

Post-dialysis (n = 26) 5.5 ± 3.6

–3.4 ± 1.9

–3.3 ± 1.9

8.2 ± 3.1

8.8 ± 4.1

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an early marker of loss of rotational compensation, which preserves EF in the CKD patient This study was supported by unrestricted research grants by Medtronic Ltd, Servier Ltd and Novartis AG.

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reduction in global longitudinal strain.22 This compensatory increase in twist present in the CKD patient was documented in a study by Panoulas et al.19 This study demonstrated that twist increases while longitudinal strain decreases in CKD patients with preserved EF. This is postulated to represent an adaptive mechanism to preserve EF in the face of declining longitudinal myocardial function. The increase in twist was inversely related to worsening GFR in patients with preserved EF.19 By contrast, our study, which only included very late-stage CKD patients, showed significant decrease in the apical myocardial rotation with no difference in net twist found in haemodialysis patients compared to controls. This is despite there being no difference in baseline EF between the dialysis patients and controls, implying that diminution of apical rotation and a normal LV twist as opposed to an expected increase in twist may be an early indicator of further myocardial dysfunction and loss of compensatory mechanisms aimed to preserve EF (Fig. 4). The limitations of this study are that it was a pilot study using a single vendor (Philips Healthcare). The small sample size was due to the size of the haemodialysis patient population at our institution. This did not allow adequate numbers to perform multiple linear regression analysis. The homogenous nature of our study population may not translate to other patient cohorts. It would be useful in larger studies to determine how twist is affected in CKD patients with and without hypertension. Multicentre studies with longitudinal follow up may confirm the findings of this study.

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10. Yan P, Li H, Hao C, Shi H, Gu Y, Huang G, et al. 2D-speckle tracking echocardiography contributes to early identification of impaired left ventricular myocardial function in patients with chronic kidney disease. Nephron Clin Pract 2011; 118(3): c232–240. 11. Choi JO, Shin DH, Cho SW, Song YB, Kim JH, Kim YG, et al. Effect of preload on left ventricular longitudinal strain by 2D speckle tracking. Echocardiography 2008; 25(8): 873–879. 12. Murata T, Dohi K, Onishi K, Sugiura E, Fujimoto N, Ichikawa K, et al. Role of haemodialytic therapy on left ventricular mechanical dyssynchrony in patients with end-stage renal disease quantified by speckle-tracking strain imaging. Nephrol Dial Transplant 2011; 26(5): 1655–1661. 13. Nakatani S. Left ventricular rotation and twist: why should we learn? J Cardiovasc Ultrasound 2011; 19(1): 1–6. 14. Hansen DE, Daughters GT, 2nd, Alderman EL, Ingels NB, Jr., Miller DC. Torsional deformation of the left ventricular midwall in human hearts with intramyocardial markers: regional heterogeneity and sensitivity to the inotropic effects of abrupt rate changes. Circ Res 1988;

Conclusion

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tion in hypertension. J Am Coll Cardiol Cardiovasc Imaging 2012; 5(3): 273–281. 17. Lam W, Leano R, Haluska B, Marwick TH. Effects of myocardial ischaemia on left ventricular untwist and filling pressure. Heart 2011; 97(9): 757–761. 18. Sengupta PP, Tajik AJ, Chandrasekaran K, Khandheria BK. Twist mechanics of the left ventricle: principles and application. J Am Coll Cardiol Cardiovasc Imaging 2008; 1(3): 366–376. 19. Panoulas VF, Sulemane S, Konstantinou K, Bratsas A, Elliott SJ, Dawson D, et al. Early detection of subclinical left ventricular myocardial dysfunction in patients with chronic kidney disease. Eur Heart J Cardiovasc Imaging 2015; 16(5): 539–548. 20. Sulemane S, Panoulas VF, Konstantinou K, Bratsas A, Tam FW, Brown

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24(3): 277–313. 36. Mendes L, Ribeiras R, Adragao T, Lima S, Horta E, Reis C, et al. Load-

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ran Africa: a clinical and echocardiographic perspective. Circ Cardiovasc Imaging 2012; 5(2): 187–193. 26. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from

2008; 27(9): 1011–1125. 37. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, et al. Clinical and echocardiographic disease in patients starting endstage renal disease therapy. Kidney Int 1995; 47(1): 186–192.

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Management of stable angina pectoris in private healthcare settings in South Africa Pride Tlhakudi, Lehlohonolo John Mathibe

Abstract Aim: Angina pectoris continues to affect multitudes of people around the world. In this study the management of stable angina pectoris in private healthcare settings in South Africa (SA) was investigated. In particular, we reviewed the frequency of medical versus surgical interventions when used as first-line therapy. Methods: This was a retrospective inferential study carried out using records of patients in private healthcare settings. All cases that were authorised for reimbursement by medical aid schemes for revascularisation between 2009 and 2014 were retrieved and a database was created. Data were analysed using Microsoft® Excel and GraphPad Prism® version 5. The differences (where applicable) were considered statistically significant if the p-value was ≤ 0.05. Results: Nine hundred and twenty-two patients, consisting of 585 males (average age 64.7 years; SD 12.9) and 337 females (average age 65.5 years; SD 14.3), met the inclusion criteria. One hundred and seventy-eighty or 54%, 156 (43%) and 86 (63%) patients with hypertension, hyperlipidaemia and diabetes, respectively, were treated with surgery only. For these patients, percutaneous coronary interventions (PCIs) were significantly (p < 0.0001) preferred first-line interventions over optimal medical therapy (OMT). Four hundred and thirty-six or 47% of all patients studied were managed with surgery only, while only 25% (227) were managed with OMT. It took 60 months (five years) for patients who were treated with OMT before their first surgical intervention(s) to require the second revascularisation. About 71% of patients who received medical therapy were placed on only one drug, the so called sub-optimal medical therapy (SOMT). Conclusion: The management of stable angina pectoris in private healthcare settings in SA is skewed towards surgical interventions as opposed to OMT. This is contrary to what consistent scientific evidence and international treatment guidelines suggest. Keywords: revascularisation, angina pectoris, optimal medical therapy (OMT), medical aid scheme, South Africa, private healthcare Submitted 6/1/16, accepted 15/3/18 Published online 10/2/18 Cardiovasc J Afr 2018; 29: 237–240

www.cvja.co.za

DOI: 10.5830/CVJA-2018-020

Division of Pharmacology (Therapeutics), University of KwaZulu-Natal, Durban, South Africa Pride Tlhakudi, MPharm Lehlohonolo John Mathibe, MSc, PhD, mathibel@ukzn.ac.za

The World Health Organisation (WHO) estimates indicate that in 2010, ischaemic heart diseases were responsible for 7.3 million deaths worldwide, and that 58 million disability-adjusted life years (DALYs) were lost as per the global burden of this disease.1 Furthermore, the American Heart Association has reported that about 15.4 million people in the United States of America in 2010 had ischaemic heart diseases.2 In South Africa (SA), ischaemic heart disease is one of the 10 leading causes of death.3 This is in line with global trends.4 However, there is very little epidemiological data about the burden caused by stable angina and the economic implications of the way it is managed in SA (both in the public and private healthcare settings). Angina pectoris is one of the symptoms of various ischaemic heart diseases that affect the coronary arteries. It is mainly due to atherosclerosis, coronary embolism and/or calcific aortic stenosis.5,6 Angina is characterised by thoracic pain that occurs as a result of deficiency in blood delivery to the myocardium. Depending on the nature, duration and its responsiveness to medical therapy, angina pectoris may be regarded as stable or unstable.7 With the former, the symptoms, which are associated with the extent of physical exertion, are generally responsive to medical therapy. However, in patients with unstable angina, a thoracic pain, which occurs even at rest, is not amenable to medical therapy.8 Management of angina pectoris includes non-pharmacological measures, such as lifestyle modifications. For the relief of symptoms, a step-wise management approach or an optimal medical therapy (OMT) is recommended.9 For OMT, eligible patients are treated with a triple-drug regimen, which consists of aspirin, beta-blockers, nitrates, calcium channel blockers, potassium channel activators and/or vasodilators, such as nicorandil, sodium channel blockers, such as ranolazine, or 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, such as simvastatin.10-12 Revascularisation and other surgical procedures play a life-saving role for the majority of patients with angina.13-15 Commonly used surgical techniques include percutaneous coronary interventions (PCIs), bare-metal stents (BMS), coronary artery bypass grafting (CABG) and drug-eluting stents (DES). Myocardial infarction causes death in many untreated and asymptomatic angina patients.5 Treatment of unstable angina, an emergency condition, is undisputed.16 However, management of stable angina remains the elephant in the room.17 In several developed countries, about 85% of revascularisations were performed on stable coronary patients who could have been well controlled on OMT.18 This continues to happen despite overwhelming evidence from studies such as the Clinical Outcomes Utilizing Revascularisation and Aggressive drug Evaluation Trial (COURAGE trial) pointing to the contrary.19 Unfortunately, in developing countries such as SA, there is insufficient evidence on how stable angina is managed, especially in private healthcare settings.

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The main aim of this study was to investigate management patterns of stable angina pectoris in private healthcare settings in SA. In particular, we sought to: investigate how frequent medical versus surgical interventions were used as first-line therapy in patients with stable angina pectoris; assess the rationale of choice of surgical interventions over medical interventions; and assess the need for subsequent surgical interventions, if surgical therapy was preferred over medical interventions.

Methods This was a retrospective inferential study conducted using a database of reimbursement by a medical scheme in the private healthcare sector. An inferential data analysis aims to deduce whether the observed pattern(s) will hold in another population(s) as opposed to individuals.20 All patients diagnosed with ischaemic heart disease (IHD) or angina and authorised for reimbursement between 2009 and 2014 were included for analysis. To determine the duration between the first and second interventions, the month and year in which the second intervention was done was subtracted from the month and year in which the first intervention was carried out. In those instances where the month was not indicated or only the year was indicated, it was assumed that the intervention was done in January. The protocol was given full ethics approval by the Research Ethics Committee, University of KwaZulu-Natal (Ref BE 398/14).

Statistical analysis Variables were characterised using 95% confidence intervals (CIs). Means with standard deviations for continuous variables were used to analyse proportions/ratios for the categorical data. Binary logistic regression was used to identify independent associations between the first intervention (revascularisation) versus the second intervention, and between OMT versus revascularisation. Associations were considered statistically significant if p ≤ 0.05. The GraphPad Prism version 5.0 with the freeware package R version 2.13.1 was used for statistical manipulations and analyses. The outliers were included, unless otherwise stated.

Results A total of 922 patient files were included in the analysis in this study. There were 585 (63%) males and 337 (37%) Table 1. The relationship between various co-morbidities and gender in patients with stable angina pectoris Males n (%)

Females n (%)

Both n (%)

Hypertension (H)

74 (8.03)

52 (5.64)

126 (13.67)

Hyperlipidaemia (HL)

44 (4.77)

21 (2.28)

65 (7.05)

Diabetes (D)

48 (5.21)

24 (2.6)

72 (7.81)

H + HL + D

30 (3.25)

13 (1.41)

43 (4.66)

136 (14.75)

66 (7.16)

202 (21.91)

31 (3.36)

16 (1.74)

47 (5.1)

Co-morbidities

H + HL H+D HL + D

17 (1.84)

5 (0.54)

22 (2.39)

Other*

205 (22.23)

140 (15.18)

345 (37.42)

Total

585 (63.44)

337 (36.55)

922 (100)

*Other co-morbidities were asthma, chronic obstructive pulmonary disease, hypotension and heart failure.

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females, with average ages of 64.7 (SD ± 12.9) and 64.7 (SD ± 14.3) years, respectively. Angina-related co-morbidities included hypertension, hyperlipidaemia and diabetes, present in 45, 36 and 20% of patients, respectively. These co-morbidities, when they existed separately, were spread evenly between males and females. However, as shown in Table 1, co-existing incidences of hypertension and hyperlipidaemias were significantly (p < 0.05) twice as high in males as females. The incidence of other conditions in males compared to females was not statistically significantly different. One hundred and seventy-eighty or 54%, 156 (43%) and 86 (63%) patients with hypertension, hyperlipidaemia and diabetes, respectively, were treated with surgery only. For these patients, PCIs were significantly (p < 0.0001) the preferred first-line interventions over OMT. A combination of OMT and surgery as a preferred intervention accounted for only 8% of all patients studied. As a result, a total of 436 (47%) of all patients studied were managed with surgery only, while only 25% (227) were managed with OMT, as shown in Table 2. About 71% of patients who received medical therapy were placed on only one drug, the so-called sub-optimal medical therapy (SOMT). In some cases, reasons or motivation for not using OMT as the first-line intervention were provided. For example OMT was considered inappropriate/contra-indicated in 3.5, 5.2, 5.2, 3.8, 1.5 and 0.8% of patients with asthma, chronic obstructive pulmonary disease, hypotension, heart failure, poor lung function and uncontrolled diabetes, respectively. The use of a beta-blocker was stopped in 1.2% of patients due to intolerance, asthma, wheezing, poor lung function and depression. Largevessel occlusion, heart failure, peripheral vessel disease and single-vessel disease were stated as motivating factors for revascularisation. Unfortunately and without explanation, 20% (183) of patients, although diagnosed with stable angina pectoris, did not receive any treatment. Fifty-six per cent (or 520 of all patients studied, that is 333 males and 187 females) were treated with one type or another of revascularisation with or without medicine. Subsequently, 139 (42%) males and 94 (50%) females who were treated with revascularisation needed a second surgical intervention. However, the differences in the need for the second surgical intervention between males and females were marginally significantly different (p = 0.06). Thereafter, about 18% (25) of males and 21% (20) of females who received the second surgical

Table 2. Use of OMT versus surgical interventions in patients with stable angina pectoris with different co-morbidities OMT n (%)

OMT plus PCIs n (%)

PCIs only n (%)

Hypertension (H)

16 (1.74)

13 (1.41)

52 (5.64)

Hyperlipidaemia (HL)

90 (0.98)

4 (0.43)

41 (4.45)

Diabetes (D)

7 (0.76)

5 (0.54)

33 (3.58)

H + HL + D

7 (0.76)

6 (0.65)

22 (2.39)

H + HL

68 (7.38)

23 (2.49)

83 (9)

H+D

9 (0.98)

7 (0.76)

21 (2.28)

Co-morbidities

HL + D

5 (0.54)

3 (0.33)

10 (1.08)

Other*

25 (2.71)

15 (1.63)

174 (18.87)

Total**

227 (24.6)

76 (8.2)

436 (47.3)

*Other co-morbidities were asthma, chronic obstructive pulmonary disease, hypotension and heart failure. **20% (183) of patients, although diagnosed with stable angina pectoris, did not receive any treatment.

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invention needed a third revascularisation to be carried out. A total of 16 patients (eight males and eight females) needed more than three surgical interventions. As depicted in Fig. 1, it took 60 months (five years) for patients who were treated with OMT before their first surgical intervention to require the second revascularisation. Those who received SOMT and those who did not receive medication at all before their first surgery took 48 and 26 months, respectively, to require the second revascularisation. The differences (i.e. 34 months) between those who were on OMT and those who did not receive any medical therapy before their first surgical intervention were statistically significant (p < 0.001). Similarly, the differences (22 months) between those who were on SOMT and those who did not receive any medical therapy before their first surgical intervention were statistically significant (p < 0.05). The specific type of the first surgical intervention had a significant (p < 0.05) impact on how long it took for the second revascularisation to be needed. For example, it took 138 months (about 11.5 years), 46 months (nearly four years) and 18 months for patients who received CABG, BMS and DES, respectively, to require the second revascularisation.

Discussion The main findings of this study indicate that OMT is pivotal in the management of stable angina pectoris. This is in support of several recent studies that have shown that there were no differences between PCIs and OMT with regard to the all major outcomes in patients with stable angina pectoris.21 What is more exciting and novel about our findings, in addition to corroborating other recent findings such as those reported by Iqbal et al., is that OMT reduces the need for subsequent PCIs when used before or together with an appropriate surgical intervention(s).22 More importantly, this study has shown that OMT lengthens the period between surgical interventions. However, the average age (65 years) of patients in this study might have played a role in these findings. Recently, Won and colleagues reported that PCIs were more beneficial than OMT in patients with stable angina pectoris, aged 75 to 85 years old.23 It was regrettable, as shown by the findings of our study,

Period (in months)

* p < 0.05

that 75% of patient aged 65 years old (on average), who might have benefited immensely, were not treated with OMT as the initial management approach. Furthermore, the use of OMT in this study was significantly less than the 44% reported in the COURAGE study.19 However it was much better than the 17% reported from the New York State Registry.21 Therefore, it means that the vast majority of medical practitioners in private healthcare settings in South Africa still prefer surgical interventions as the initial management approach for stable angina pectoris, although there is strong evidence to the contrary. The barriers to effective implementation of clinical guidelines and their uptake into routine clinical practice are well documented worldwide.24,25 For example, Grol and Grimshaw reported that absence of facilities, lack of feasibility, old routines, heavy work-load, as well as no immediate risk of consequences for non-compliance were the main barriers for poor implementation of evidence.26 The latter offers a possible explanation for the lack of implementation of the findings of the COURAGE trial19 in private healthcare settings in South Africa, as reported in this study. In these settings, there are generally no immediate consequences for medical practitioners not adhering to clinical guidelines. This happens because other than the strict requirements set by medical aid schemes in South Africa, mostly each medical practitioner relies on his/her own expert judgement. More importantly, ‘professional pride and payer profit’ have a big impact on ‘perspectives on optimal care and the best method for improving health care’.27 Therefore, it is also possible that OMT was less favoured in private healthcare settings because of its minimal financial benefits for medical practitioners, compared to surgery. As a result, the majority of cardiologists in private healthcare settings, as was recently reported by Mohee and Wheatcroft, continue to underestimate the benefits of OMT in patients with stable angina pectoris.28 There are some limitations to this study. As it often the case with other retrospective studies, there were missing data from the files of patients studied. Most notably, we could not assess the impact OMT on survival because of missing mortality data. However, there is a low prevalence of mortality due to stable angina pectoris.29,30 Therefore it is unlikely that lack of data on survival rates in the population studied had a significant impact on the findings of this study.

Conclusion

Compelling evidence suggests that OMT should be the initial management approach in patients with stable angina. Therefore a reasonable approach is to optimise OMT and reserve coronary revascularisation for mainly older patients who are sub-optimally controlled on medical therapy, or for patients who are at high risk of major adverse cardiac events.

239

OMT

SOMT

No medication

Fig. 1. P eriod (in months) it took for groups of patients with stable angina to require second surgical intervention. OMT: optimal medical therapy; SOMT: sub-optimal medical therapy.

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Anaesth Analges 2014; 119(5): 1053–1063. 30. Ilashchuk T, Glubochenko O, Senyuk B, Bachuk-Ponich N, Lukashevich I. Influence of beta-blockers and ivabradine on long-term prognosis of patients with stable angina. Georgian Med News 2017; 267: 57–61.

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Short-term results of flanged Bentall de Bono and valvesparing David V procedures for the treatment of aortic root aneurysms Servet Ergün, Mehmet Dedemoğlu, Murat Bülent RabuŞ, Baburhan Özbek, Mustafa Mert Özgür, Mehmet Altuğ Tuncer, Mehmet Balkanay, Mehmet Kaan Kırali

Abstract Aim: Even though the Bentall de Bono procedure is widely used for the treatment of aortic root aneurysms, the procedure is under scrutiny nowadays because of complications due to mechanical prosthetic valves and the need for life-long anticoagulation. Due to these complications, aortic valvesparing operations are being researched. In this study we compared the short-term morbidity and mortality rates of both Bentall de Bono and valve-sparing David V procedures. Methods: We retrospectively evaluated data from 70 patients who had undergone surgery for aortic root aneurysm between April 2009 and June 2013. We had performed the Bentall de Bono procedure on 46 patients and the David V procedure on 24 patients. Mortality rates, cardpulmonary bypass (CPB) and aortic cross-clamp durations, postoperative arrhythmias, and prolonged intensive care unit (ICU) and hospital stays were compared in this study. Results: There was no statistical difference for mortality rate (p = 0.57), while the CPB time and cross-clamp duration were shorter in the Bentall group. When we compared the length of ICU and hospital stay, we observed that the David group stayed longer in ICU (p = 0.003) but the duration of hospital stay was shorter (p = 0.007). Conclusion: Despite Bentall de Bono being the most commonly used procedure, the short-, mid- and long-term results of both procedures were similar. Spared native aortic valve and lack of anticoagulation usage are notable advantages of the David V procedure.

Cardiovascular Surgery Department, Kars Harakani Hospital, Kars, Turkey Servet Ergün, MD, drservetergun@hotmail.com Department of Pediatric Heart Surgery, Dr Siyami Ersek Training and Research Hospital, Istanbul, Turkey Mehmet Dedemoğlu, MD

Department of Cardiovascular Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey Murat Bülent Rabuş, MD Baburhan Özbek, MD Mustafa Mert Özgür, MD Mehmet Altuğ Tuncer, MD Mehmet Kaan Kırali, MD

Department of Cardiovascular Surgery, Izmir Katip Çelebi University, Atatürk Training and Research Hospital, Izmir, Turkey Mehmet Balkanay, MD

Keywords: valve-sparing aortic root surgery, flanged Benthall, David V Submitted 24/6/16, accepted 15/3/18 Published online 26/6/18 Cardiovasc J Afr 2018; 29: 241–245

www.cvja.co.za

DOI: 10.5830/CVJA-2018-021

Several surgical procedures are used to repair ascending aortic aneurysms. Factors such as feasibility, percentage of complications, and surgical morbidity and mortality rates are critically important in choosing the best operation strategy. Valve-sparing procedures have some advantages, such as not needing to use anticoagulation therapy and there are no complications related to mechanical valves. Procedures using a mechanical composite valved graft also have advantages, such as long-term valve durability.1-5 There are many discussions about which procedure is better. The first aortic root replacement with a composite valve graft was performed by Bentall and de Bono in 1968.6 In this procedure, the ascending aorta and aortic valve was resected. Firstly a mechanical prosthetic valve was sutured to a tubular graft and then the valved graft was sutured to the aortic annulus with continuous prolene sutures. A flanged Bentall procedure was reported by Yakut in 2000.7 In this procedure about 5 mm of the proximal end of the graft is everted outward. The mechanical valve is fixed to the graft with continuous polyprolene sutures from the stent of the valve to the graft. Then the everted part of the graft is returned to its original position and the conduit is implanted onto the aortic annulus from the flanged part with continuous polyprolene sutures. The rest is the same as with the classical Bentall de Bono procedure. Classical valve-sparing root replacement was reported by David and Feindel in 1992. They defined their procedure as first resecting the aortic root completely while sparing the valve, preparing the coronary ostia in a button shape, then suturing a dacron graft to the aortic root, and finally suturing the buttons to the dacron graft.8 When we assessed the complications related to long-term risk of anticoagulation, we observed the superiority of using homografts, pulmonary otografts, valve-sparing procedures or bioprosthetic valved composite grafts instead of composite grafts with mechanical valves.4-8 In this study, we evaluated the initial results of the flanged Bentall procedure versus the David V procedure in terms of surgical morbidity and mortality rates, and complications related to the procedures.

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Methods We operated on 70 patients (flanged Bentall de Bono: 46, David V: 24) for aortic root aneurysm in our hospital between April 2009 and June 2013. Data were evaluated retrospectively. Patients were divided into two groups according to the procedure. Patients who had the flanged Bentall de Bono procedure were in group 1, and those who had the David V procedure were in group 2. All patients were intubated under general anaesthesia and they were on mechanical ventilation during the operation. A right jugular central venous catheter was inserted routinely. A standard median sternotomy was performed and cardiopulmonary bypass was instituted. The venous line was inserted through the right atrial appendage generally, but selective bicaval venous cannulation was performed in some cases. Myocardial protection was achieved by cardioplegia, specifically by intermittent antegrade or simultaneous antegrade and retrograde (66.5%) administration of hypothermic blood cardioplegia, according to the decision of the surgeon. A venting cannula was inserted through the right superior pulmonary vein. In group 1 we performed a modified version of the Bentall procedure, called a flanged Bentall. In this procedure, the ascending aorta is resected and the coronary ostia are prepared as buttons. Then the aortic root and valve is resected. A mechanical aortic valve is sutured to the composite graft, leaving a part of the proximal side everted outwards (flange). This is done with continuous polyprolene sutures from the stent of the valve to the graft. The conduit is sutured to the aortic annulus with polyprolene sutures from the flanged part. After this, the coronary buttons are sutured to the graft. The distal part of the graft is then sutured to the distal aorta with teflon felt. In group 2, a routine transverse aortotomy was done about 2 cm above the coronary ostia. If it was clear that there was no structural pathology on the aortic valve, the ascending aorta was resected, keeping 5 mm of aortic tissue on the aortic annulus. Thereafter the standard David V procedure was performed.

Statistical analysis Statistical analyses were performed using SPSS version 15.0 software. Compliance with the normal distribution of variables was evaluated with visual (histogram and probability graphics) and analytical methods (Kolmogorov–Simirnov/Shapiro–Wilk tests). Descriptive analysis was done using frequency tables for categorical variables and means and standard deviations for normally distributed variables. We used the median and 25th and 75th quartiles for analysis of variables without a normal distribution. To compare the groups, we performed an independent samples t-test for variables with normal distribution, and the Mann–Whitney U-test for those without a normal distribution. We also performed Pearson’s chi-squared test (χ2) for categorical variables; p < 0.05 was considered as significant.

Results The mean age of the patients was 52.01 ± 16.82 years, and 52 (74.3%) were male and 18 (25.7%) were female. There were statistically significant differences between the groups in terms of age and having coronary artery disease (p = 0.04 and p < 0.001, respectively). Demographic features of the groups are summarised in Table 1.

Table 1. Demographic data of the two groups Group 1 (n = 46)

Group 2 (n = 24)

p-value

50.04 ± 18.05

58.70 ± 12.67

0.04

35 (76)

17 (70.8)

0.63

COPD, n (%)

16 (34.7)

10 (41.6)

0.57

Smoking, n (%)

14 (30.4)

12 (50)

0.10

Hypertension, n (%)

26 (56.5)

18 (75)

0.12

Diabetes mellitus, n (%)

15 (32.6)

6 (25)

0.51

2 (4.3)

9 (37.5)

< 0.001 0.54

Demographics Age Male gender, n (%)

Coronary artery disease, n (%) Peripheral vascular disease, n (%)

2 (4.3)

0 (0)

NYHA class 1, n (%)

8 (17.3)

4 (16.6)

NYHA class 2, n (%)

12 (26.08)

7 (29.1)

NYHA class 3, n (%)

14 (30.4)

7 (29.1)

NYHA class 4, n (%)

12 (26.08)

6 (25)

< 0.06

COPD: chronic obstructive pulmonary diesase, NYHA: New York Heart Association.

When we compared the pre-operative echocardiographic findings, there was a statistically significant difference in the aortic annulus diameter between the groups (p = 0.03). Mean aortic annulus diameter was 3.30 ± 1.32 cm in group 1 and 2.76 ± 0.41 cm in group 2. Mean ascending aorta diameter was 5.49 ± 1.18 cm in group 1 and 5.73 ± 0.99 cm in group 2 (p = 0.39). There was no significant difference in terms of degree of aortic insufficiency between the groups (p > 0.05) (Table 2). When we compared surgical data (Table 3), average cardiopulmonary bypass time was 69.55 min shorter in group 1 (p = 0.001, 95% CI: 108.19–30.90 min). Average arterial crossclamp time was 80.75 min shorter in group 1 (p < 0.001, CI: 101.55–59.95 min). With regard to postoperative complications, postoperative arrhythmias were seen in four (8.6 %) and one (4.2%) patient in groups 1 and 2, respectively (p = 0.004). There was no statistically significant difference between the groups in terms of respiratory complications, bleeding requiring re-exploration, and intraaortic balloon pump (IABP) usage. No stroke was observed in either group. We lost one patient in each group and there was no statistically significant difference between the groups in terms of mortality rate. ICU stay was shorter in group 1. Average ICU stay was 1.85 ± 1.02 days in group 1 and 3.70 ± 3.07 days in group 2 (p = 0.003).

Table 2. Pre-operative echocardiographic findings Pre-operative echo findings

Group 1 (n = 46)

Group 2(n = 24)

p-value

Ascending aorta diameter

5.49 ± 1.18

5.73 ± 0.99

0.39

Aortic annulus diameter

3.30 ± 1.32

2.76 ± 0.41

0.03

Sinus of Valsalva diameter

5.16 ± 1.17

5.08 ± 0.69

0.79

EF (%)

60.85 ± 7.4

57.50 ± 10.57

0.42

LVESD (cm)

3.74 ± 1.04

5.45 ± 7.8

0.17

LVEDD (cm)

5.43 ± 1.06

7.98 ± 11.59

0.16

IVS (cm)

1.25 ± 0.19

1.11 ± 0.12

0.50

AI, n (%)

31 (67.3)

19 (79.1)

0.30

1, n (%)

7 (15.2)

0 (0)

2, n (%)

11 (23.9)

10 (41.6)

3, n (%)

4 (8.6)

4 (16.6)

9 (19.5)

5 (20.8)

AI degree

0.13

Echo: echocardiography, EF: ejection fraction, LVESD: left ventricular endsystolic diameter, LVEDD: left ventricular end-diastolic diameter, IVS: interventricular septum, AI: aortic insufficiency, cm: centimetre.

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Table 3. Surgical data between groups Group 1 (n = 46)

Group 2 (n = 24)

TPT (min)

134.84 ± 86.93

204.39 ± 44.7

0.001

ACC (min)

83.11 ± 41.64

163.86 ± 38.06

< 0.001

TCA (min), n (%)

0 (0)

4 (16)

Hypothermia (°C)

28.21 ± 1.57

28.1 ± 2.73

Surgical data

Axillary, n (%) Brachiocephalic, n (%) Femoral, n (%)

0.004 0.86

Table 5. Pre-operative and postoperative parameters related to aortic insufficiency in the David V group Pre-operative AI (median/min–max)

Postoperative AI (median/min–max)

p-value

2.5 ( 2–4)

0 (0–2)

< 0.001

AI: aortic insufficiency.

< 0.001

Cannulation side Aortic, n (%)

p-value

44 (95.6)

6 (25)

1 (2.2)

17 (70.8)

0 (0)

1 (4.2)

1 (2.2)

0 (0)

TPT: total perfusion time, ACC: arterial cross-clamping time, TCA: total circulatory arrest.

Duration of hospital stay was longer in group 1 (average 14.64 ± 3.52 days, p = 0.007) (Table 4). On postoperative echocardiography, we observed that degree of aortic insufficiency was significantly decreased in patients who had undergone the David V procedure (p < 0.001). No moderate or severe aortic insufficiency was detected (Table 5). When we compared factors related to mortality rate, age, hemi-arch replacement as an additional procedure, ascending aortic diameter and hypothermia were important parameters. We observed that advanced age (p = 0.04), wide ascending aortic diameter (p = 0.04), hypothermia (p = 0.001) and hemiarch intervention (p = 0.01) increased mortality rates (Table 6). Age (p = 0.01), ascending aortic diameter (p = 0.02), degree of hypothermia (p < 0.001) and hemi-arch replacement (p = 0.001) were factors that negatively affected ICU stay (Table 6). We performed mitral reconstruction in four (5.7%) patients, mitral valve replacement in three (4.3%), atrial septal defect repair in two (2.9%), radiofrequency ablation in one (1.4%), hemi-arch replacement in five (7.1%) and coronary artery bypass grafting (CABG) in eight (11.4%) patients as an additional procedure, out of a total of 70 patients. In addition to these findings, aortic cross-clamp and cardiopulmonary bypass time were significantly longer in patients who underwent CABG as an additional procedure (p < 0.001, p = 0.007, respectively).

Discussion The Bentall de Bono procedure is seen as the gold-standard surgical choice for the treatment of standard aortic root aneurysms but because of complications (mortality, morbidity) related to the use of anticoagulants when mechanical valves are used, valve-sparing procedures have come into prominence. When we look at initial and mid-term results of valve-sparing procedures, there is no doubt that these techniques can be confidently used for aortic root aneurysms.1,2,4

An important study on this subject was done by Gaudino et al.4 in 890 patients, where 289 mechanical valve composite grafts, 421 biological valve composite grafts and 180 valve-sparing procedures were evaluated. The surgical mortality rate was 0.2% (none for the valve-sparing procedures). They observed that length of hospital stay was related to age, emergency operation, renal function, re-operation, New York Heart Association class, ejection fraction, and additional procedures. At five years, follow-up survival was 89.4%. Renal function, previous myocardial infarction, redo operations and additional procedures were related to long-term survival. They observed no significant difference regarding early and longterm mortality rates between the groups. At five years, the need for follow-up re-operation was 0% for the mechanical valve composite grafts, 2.4% for biological valve composite grafts and 7.3% for valve-sparing procedures.4 We noticed that valve durability was of importance in the mechanical valve graft group in that study. In our study, older age (p = 0.04), wide ascending aortic diameter (p = 0.004), less degree of hypothermia (p = 0.001) and additional hemi-arch replacement (p = 0.001) were the parameters that increased early period mortality rates. Additionally, advanced age (p = 0.01), wide ascending aortic diameter (p = 0.02), degree of hypothermia (p < 0.001) and additional hemiarch replacement (p = 0.001) also increased length of ICU stay. In a recent study, Lamana et al.9 analysed 324 patients, of whom 263 had undergone mechanical composite valve graft surgery and 61 valve-sparing root surgery. They observed that there were no statistically significant differences in short-term mortality rates (p = 0.71), but the long-term mortality rate was lower in the valve-sparing group (p = 0.001). In the same study, they noticed that bleeding (requiring re-exploration) was lower in the valve-sparing group and they associated the higher mortality rate in the composite valve graft group with early and late-term complications related to bleeding. Additionally, there were significant differences between the groups in terms of thromboembolic events in that study.9 Coselli et al.10 studied early and mid-term results of 83 patients (82 re-implantations, one Florida sleeve procedure). Table 6. Parameters related to mortality and ICU stay Correlation coefficient

p-value

Age

0.23

0.04

Diameter of ascending aorta

0.35

0.004

(–) 0.39

0.001

Parameters Parameters related to mortaliy

Table 4. Postoperative complications and length of hospital stay of the two groups Postoperative complications

Group 1 (n = 46)

Group 2 (n = 24)

p-value

Bleeding revision, n (%)

0 (0)

1 (4.2)

0.34

Hypothermia

Respiratory, n (%)

2 (4.3)

1 (4.2)

0.73

Hemi-arch replacement

IABP usage, n (%)

1 (2.2)

0 (0)

0.65

Arrhythmias, n (%)

4 (8.6)

1 (4.2)

0.004

Mortality, n (%)

1 (2.2)

1 (4.2)

0.57

ICU stay (days)

1.85 ± 1.02

3.70 ± 3.07

0.003

Hypothermia

Hospital stay (days)

14.64 ± 3.52

12.20 ± 8.08

0.007

IABP: intra-aortic balloon pump, ICU: intensive care unit.

0.28

0.01

Age

0.31

0.01

Diameter of ascending aorta

0.29

Parameters related to ICU stay

Hemi-arch replacement ICU: intensive care unit.

0.02

(–) 0.54

< 0.001

0.42

0.001

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They observed one surgical mortality, one stroke (because of acute aortic dissection) and intra-operative valve replacement was performed on one patient. They concluded that valvesparing procedures had satisfying early period results.10 Arabkhani et al.11 studied 4 777 patients and 1 659 articles in a meta-analysis. They compared valve-sparing procedures (72% re-implantation, 27% remodelling, 1% other procedures) and indicated that early period mortality rate was 2%, and there were no statistically significant differences between the procedures in terms of survival and re-operation. They concluded that valvesparing procedures were an alternative to mechanical valve grafts in terms of survival rate.11 Patel et al.12 studied 140 patients (56 Bentall de Bono, 84 valve-sparing procedures). They implied that thromboembolic events were higher in the Bentall group. Additonally eight-year survival rate was higher in the valve-sparing group.12 David et al.5 studied 296 patients who underwent re-implantation procedures. They observed four surgical deaths and 18 late-term deaths. Five-year survival rate was 95.1 ± 3.5%, 10-year survival was 93.1 ± 4.4% and 15-year survival was 76.5 ± 18%. They performed mechanical composite valve grafts on three patients because of severe aortic insufficiency.5 Kallenbach et al.13 and Svensson et al.14 showed similar results in their studies. Parallel to these findings, in our study, there was no statistically significant difference between the Bentall de Bono and David V procedures in terms of morbidity and mortality rates (p = 0.57). Karendi et al.15 compared the David procedure (37 patients) with the Bentall de Bono procedure (73 patients) in highrisk patients (type A aortic dissections, re-operations). They indicated that there was no statistically significant difference between the procedures related to pre-operative and operative data, except for cross-clamp time.15 Similar to this, in our study, CPB time and cross-clamp time were significantly longer in the David V group but there was no statistically significant difference in other surgical data between the groups. In our study there was no statistically significant difference between the groups in terms of in-hospital mortality rate, bleeding (requiring re-exploration), thromboembolic events, respiratory complications and IABP usage. Incidence of cardiac arrhythmias was higher in the Bentall group (p = 0.004). There were no operative deaths in either group. We lost one patient in each group because of pneumonia in the early period. Skripochnik et al.16 studied 70 patients (25 valve-sparing, 45 Bentall procedure) and observed no difference between the groups regarding peri-operative mortality rates. In addition, there was no significant difference between the groups in terms of length of hospital and ICU stay.16 In our study, ICU stay was longer (p =0.003), but hospital stay was shorter in the David V group (p = 0.007). We believe that long hospital stay for the Bentall group was associated with warfarin use and dose adjustments, because we routinely follow patients at in-patient clinics until appropriate INR values are achieved. In addition, we found that age (p = 0.01), diameter of ascending aorta (p = 0.002), hypothermia (p < 0.001) and hemiarch replacement (p = 0.001) had an impact on length of ICU stay. We believe that longer ICU stay for the David V group was associated with longer cross-clamp time, longer total perfusion time (p = 0.001) and higher average age (p = 0.04).

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Conclusion Although the Bentall de Bono procedure is seen as the goldstandard surgical approach for aortic root aneurysms, there are some complications related to this procedure. Because the native aortic valve is not protected in the dilated aortic root, physiological superiority of the native valve is lost. In addition, warfarin use and dose adjustment prolongs hospitay stay. Many studies have revealed that early, mid- and long-term results of the Bentall and David V procedures are similar. Since there was no difference between the two procedures in our study in terms of morbidity and mortality rates, the biggest advantage of the David V procedure is that it protects the native valve. In addition, the David V procedure is safer because there are no complications related to the use of mechanical valves and anticoagulants in the postoperative period. Therefore we propose use of the David V procedure primarily for patients with dilated aortic root and/or dilated ascending aorta with normal aortic valves.

References 1.

David TE, Maganti M, Armstrong S. Aortic root aneurysm: principles of repair and long-term follow-up. J Thorac Cardiovasc Surg 2010; 140: 14–19.

Silva VF, Real DS, Branco JN, Catani R, Kim HC, Buffolo E, et al. Bentall and De Bono surgery for correction of valve and ascending aortic disease: long-term results. Rev Bras Cir Cardiovasc 2008; 23: 256–261.

David TE, Feindel CM, Webb GD, Colman JM, Armstrong S, Maganti MD. Aortic valve preservation in patients with aortic root aneurysm: results of the reimplantation technique. Ann Thorac Surg 2007; 83: 732–735.

Gaudino M, Lau C, Munjal M, Avgerinos D, Girardi LN. Contemporary outcomes of surgery for aortc root aneurysms: A propensity-matched comprasion of valve-sparing and composite valve graft replacement. J Thorac Cardiovasc Surg 2015; 150: 1120–1129.

David TE, Maganti M, Armstrong S. Aortic root aneurysm: principles of repair and long-term follow-up. J Thorac Cardiovasc Surg 2010; 140: 14–19.

Bentall H, de Bono A. A technique for complete replacement of the ascending aorta. Thorax l968; 23: 338–338.

Yakut C. A new modified Bentall procedure: the flanged technique. Ann Thorac Surg 2001; 71: 2050–2052.

David TE, Feindel CM. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta. J Thorac Cardiovasc Surg 1992; 103: 617–621.

Lamana F de A, Dias RR, Duncan JA, Faria LB, Malbouisson LM, Borges L de F, et al. Surgery of the aortic root: should we go for the valve-sparing root reconstruction or the composite graft valve replacement is still the first choice of treatment for these patients? Rev Bras Cir Cardiovasc 2015; 30: 343–352.

10. Coselli JS, Hughes MS, Green SY, Price MD, Zarda S, de la Cruz KI, et al. Valve-sparing aortic root replacement: Early and midterm outcomes in 83 patients. Ann Thorac Surg 2014; 97: 1267–1274. 11. Arabkhani B, Mookhoek A, Di Centa I, Lansac E, Bekkers JA, De Lind van Wijngaarden R, et al. Reported outcame after valve-sparing aortic root replacement for aortic root aneurysm: A systematic review and meta-analysis. Ann Thorac Surg 2015; 100: 1126–1131. 12. Patel ND, Weiss ES, Alejo DE, Nwakanma LU, Williams JA, Dietz HC, et al. Aortic root operations for Marfan syndrome: A comparison

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of the Bentall and valve-sparing procedures. Ann Thorac Surg 2008; 85: 2003–2011. 13. Kallenbach K, Baraki H, Khaladj N, Kamiya H, Hagl C, Haverich A, et al. Aortic valve-sparing operation in Marfan syndrome: what do we know after a decade? Ann Thorac Surg 2007; 83: 764–768. 14. Svensson LG, Cooper M, Batizy LH, Nowicki ER. Simplified David reimplantation with reduction of annular size and creation of artificial

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15. Kerendi F, Guyton RA, Vega JD, Kligo PD, Chen EP. Early results of valve-sparing aortic root replacement in high-risk clinical scenarios. Ann Thorac Surg 2010; 89: 471–478. 16. Skripochnik E, Michler ER, Hentschel V, Neragi-Miandoab S. Repair of aortic root in patients with aneurysm or dissection: comparing the outcomes of valve-sparing root replacement with those from the Bentall procedure. Rev Bras Cir Cardiovasc 2013; 28: 435–441.

sinuses. Ann Thorac Surg 2010; 89: 1443–1447.

Letter to the Editor Tribute to Professor Bongani Mawethu Mayosi A friend, a brother, a mentor, a leader, a champion, a warrior and a true son of Africa Since Friday 28 July 2018 when I got the news of the sudden death of Prof Bongani M Mayosi, I have been in ‘psychological shock’ and this will remain with me for a long time to come. Bongani had called me a day or two earlier (while I was in Mombasa, Kenya, attending the annual conference of the Kenya Cardiac Society) to get an update on the INVICTUS trial in Nigeria. I had promised to call him back from Nigeria on Monday 30 July. It is therefore very hard for me to accept that a brother, a friend, a mentor, a warrior, a champion, a leader and a true son of Africa has suddenly left this side of eternity. This is devastating. My first personal contact with Bongani was at the PASCAR renaissance meeting (4–9 February 2007) in Kenya (although he had earlier contacted some of us indirectly via e-mail through Prof Mpiko Ntsekhe/Dr Akinyemi Aje on 3 January 2007 to join the IMPI trial). At the PASCAR meeting, Bongani spoke with great passion and emotion and a very rare eloquence on the need for collaboration to tackle endemic diseases on the continent (especially ‘cardiovascular diseases of the poor’, such as rheumatic heart disease, tuberculous pericarditis and endemic cardiomyopathies). Since then, Bongani has remained a source of leadership and inspiration, not only to me but also to my other colleagues from Nigeria, such as Prof Mahmoud Sani and Dr Dike Ojji. On 17 October 2007, I sent the proposal/protocol of the Nigerian Heart Failure Registry to him. Bongani replied and made vey useful comments but suggested we join the Continental HF registry (THESUS-HF). Division of Cardiology, Department of Medicine, University College Hospital Ibadan, Ibadan, Oyo State, Nigeria

Then started the era (contemporary) of very fruitful and rewarding collaboration in cardiovascular disease research through the instrumentality and able leadership of Prof Bongani Mayosi, Prof Karen Sliwa (who I first met at the WHO/ WELLCOME Trust workshop on secondary prevention of CVDs in LMIC in London, 6–8 June 2007) and Prof Albertino Damasceno (who I first met at the ISH hypertension teaching seminar in Maputo, Mozambique, 21–22 September 2006). These include the IMPI trial, REMEDY, RELY_AF registry, PAPUCO, BAHEF trial, CREOLE and INVICTUS trials. For Bongani to leave us at a moment like this is very saddening and frustrating. We shall miss his useful advice. We shall miss his encouraging words and leadership. ‘O death, where is thy sting? O grave, where is thy victory?’ Our consolation is that you fought a good fight and ran your race well while you were on this side of eternity. The story of the African Union and United Nations Resolution on Rheumatic Heart Disease will not be complete without the name Bongani M Mayosi. My deepest condolences go to his immediate family and all his associates worldwide. God willing, we shall keep the candle of collaboration he ignited burning. ‘Fading away like the stars of the morning, Losing their light in the glorious sun – Thus would we pass from the earth and its toiling, Only remembered by what we have done. Only remembered, only remembered, Only remembered by what we have done.’ (Horatius Bonar)

Dr OS Ogah, MB BS, MSc, PhD, FWACP, FACP, FESC

Adieu Bongani Mayosi

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Transcatheter closure of the patent ductus arteriosus at a public sector hospital in Soweto, South Africa: a review of patient outcomes over 15 years Paul Ernest Adams, Matthew Francis Chersich, Antoinette Cilliers

Abstract Background: Methods of closing patent ductus arteriosus (PDA) have evolved over time. We review this development in our setting. Methods: This was a retrospective analysis of children who had transcatheter PDA closure at Chris Hani Baragwanath Hospital between 1993 and 2008. Results: Over 15 years, 1 254 PDAs were diagnosed, of which 293 required intervention; 139 patients had transcatheter closure, the median age was 1.8 years (interquartile range = 1–4.5 years) and 66% were female (92/139). Mean PDA diameter was 3.2 mm (standard deviation = 1.6 mm), with an average 2:1 shunt. Transcatheter closure was performed using COOK® Flipper coils (n = 93) or Amplatzer™ devices (n = 46). Early occlusion rates for coils were 52% (39/75) and late occlusion occurred in 91% (68/75) of patients. For Amplatzer devices, early occlusion rates were 94% (33/35) and late occlusion was 100%. Amplatzer™ devices, available since 2003, were overwhelmingly used in the later years. Conclusion: Transcatheter PDA closure was safe and effective in this setting, with outcomes similar to reports elsewhere. Keywords: patent ductus arteriosus (PDA), intervention, percutaneous, transcatheter Submitted 15/2/18, accepted 4/4/18 Published online x/x/18 Cardiovasc J Afr 2018; 29: 246–251

www.cvja.co.za

DOI: 10.5830/CVJA-2018-028

The patent ductus arteriosus (PDA) is a common congenital heart lesion, with isolated PDAs accounting for six to 11% of all congenital heart defects.1 Surgical closure of the PDA was the standard management of PDAs for many years,2 with the first report of surgical ligation by Gross and Hubbard in 1939.3 In the

Division of Paediatric Cardiology, Department of Paediatrics, Chris Hani Baragwanath Academic Hospital, Soweto, and School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa Paul Ernest Adams, FCPaed (SA), pauleadams@gmail.com Antoinette Cilliers, FCPaed (SA)

Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Matthew Francis Chersich, PHD, mcherisch@wrhi.ac.za

last few decades only, has this been challenged by transcatheter options, which are now the preferred alternatives.4,5 With the development of new devices, the majority of PDAs can be effectively and safely closed without surgery. This prevents not only complications of the PDA itself, but also the morbidity associated with surgery in general.1 The spectrum of PDAs amenable to transcatheter closure continues to increase. With advances in closure technologies, only very small infants with large, symptomatic PDAs, and PDAs with unfavourable anatomy or failed device closure are now candidates for surgical closure.5,6 The first transcatheter options for closure of the PDA were described by Porstmann and co-workers in 1967.7 Since then, the number of available devices has expanded rapidly, most especially in recent years. They range from close copies of the Amplatzer™ design to devices with different shapes and release mechanisms (for example, Ceraflex and Occlutec). The Amplatzer™ devices were first implanted in 19968 and have since been shown to be safe, effective and relatively easy to use.5,9-11 The Amplatzer™ range has increased steadily over time, offering devices with different shapes and even a range to close very small PDAs.12 In many settings, the detachable COOK® PDA coils were widely used in small PDAs (< 2.5 mm).4,5,8,13 The Amplatzer™ devices, conversely, became increasingly popular for moderate to large PDAs (> 2.5 mm).4,5 In this study, we review outcomes of transcatheter closure of PDAs at a large tertiary-level facility in South Africa over a 15-year period, which included the introduction of the Amplatzer™ range of devices. We also document differences between PDAs closed with coils or Amplatzer™ devices, and the shifts in closure methods that occurred over time.

Methods A retrospective analysis was conducted of patient records and the Paediatric Cardiology database (Microsoft Access 2003) at the Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. All children who had transcatheter or surgical PDA closure at the facility between January 1993 and July 2008 were included in this analysis. A brief update on more recent figures is also provided (January 2009 – August 2017). After explaining the procedure to the parent or legal guardian, informed consent was obtained. The child was sedated and femoral arterial and venous access was obtained. During the period under study, two groups of transcatheter devices were available, COOK® coils and Amplatzer™ devices. Specifically, the coils used were the detachable MReye® Flipper® PDA coils, and the Amplatzer™ devices encompassed the Amplatzer™ duct occluders (ADO) and the Amplatzer™ vascular plugs (AVP).

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Transcatheter PDA closure was undertaken following standardised procedures, described in full elsewhere.8 In brief, a descending aortogram in the lateral position was performed at the start of each catheterisation in order to measure the dimensions of the PDA. This was done to prevent any interference with the PDA that may have caused constriction and inaccurate measurements. A full diagnostic catheterisation was performed in all patients prior to attempted PDA occlusion; the shunt and pulmonary vascular resistance were calculated. The narrowest point and ampulla were routinely measured and these factors were used to select an appropriate device. With experience, and particularly for Amplatzer™ devices, additional measurements were added. These included the length of duct and diameter of the aorta just proximal to the duct (in smaller children), due to concerns about possible aortic obstruction. Selection of the size of Amplatzer™ device was based on the manufacturer’s recommendation of at least 2 mm greater than the narrowest point,14 but other factors were also considered in device selection, including PDA shape, ampulla size and the size of the aorta. For sizing of the coils, the narrowest point was also taken into account and a coil with a diameter twice the narrowest measurement was chosen. Coils also have a variable number of loops, the number of which depends on the space available in the ampulla of the particular PDA.15 Amplatzer™ devices were routinely delivered from the pulmonary side, except in a patient who had an interrupted inferior vena cava, where an Amplatzer™ duct occluder 2 was placed from the aortic side. The majority of coils were delivered from the aortic side; however, if multiple coils were placed in a duct, they were sometimes placed from the pulmonary side, or even using a combination of aortic and pulmonary routes. Following device placement and prior to release, we performed a number of checks to assess whether the device was correctly placed. A repeat descending aortogram was performed. Pressure gradients in the aorta across the newly closed PDA were measured to ensure there was no significant obstruction to flow in the descending aorta. Once it was ascertained that the device was correctly positioned, it was released. A repeat angiogram was done and a gradient was measured between the ascending and descending aorta to assess any change in position during release that may result in a coarctation. Following the procedure, the patients were observed in the ward until a follow-up echocardiography was done and, provided there were no complications, discharged 24 to 48 hours later. Patient characteristics consisted of age, gender and anthropometric variables. Clinical details, haemodynamic data, and anatomical details, such as PDA shape and dimensions at echocardiogram and at angiography were used to describe the PDA and resultant haemodynamics. To assess the time taken to close the PDA, the fluoroscopy time for each procedure was captured, where possible. The shape of each PDA was assessed angiographically by reviewing each angiogram and classifying them according to the Krichenko classification (A1-3, B1-3,C13,D,E ).16 Failure of transcatheter procedure was defined as any patient requiring a second procedure to effect closure. Early complete occlusion was defined based on an echocardiogram done within 48 hours of the procedure.

Statistical analysis Data with a normal distribution were described using means and standard deviations, or medians and interquartile ranges for non-normal data. The χ2 test was used to compare categorical variables, such as patient characteristics and outcomes between those treated with a coil or an Amplatzer™ device. Continuous data were compared using a Student’s t-test (normally distributed data) or Wilcoxon rank sum test (non-normal data).

Results Over the 15-year study period, 1 254 PDAs were diagnosed, of which 293 required an intervention to effect closure (23%). Surgical ligation was performed on 167 children and 139 underwent transcatheter closure. No differences were detected in the demographics of patients who had their PDA closed with an Amplatzer™ device and those who had coiling of their PDA (Table 1). Two-thirds of the study patients were female and the median age was 1.8 years. The anthropometric indices between those who had an Amplatzer™ device or coils to close their PDA were similar. The majority of patients who had a PDA closure weighed more than 6 kg. Amplatzer™ devices were occasionally used in children under 6 kg, even though the product guidelines recommend use only in children above this weight.14 As shown in Table 2, the average PDA size at its narrowest point was 3.2 mm [standard deviation (SD) = 1.6 mm]. There was a difference in the mean size of coiled PDAs (2.6 mm) compared to those closed with the Amplatzer™ device (4.0 mm). The majority of PDAs under 2.5 mm were closed with coils and the PDAs larger than 2.5 mm were more likely to be closed with the Amplatzer™ device (p = 0.005). Krichenko type A PDAs (conical shaped) dominated, accounting for 73% of cases, with type E (long, tubular with narrowed pulmonary end) the next most frequent at 18%. Type B (short window like) was rare (2% of all patients). As presented in Table 2, the haemodynamic measurements of the PDAs showed a significant mean left-to-right shunt with a Qp:Qs of 2:1 (SD = 1.2). The mean pulmonary vascular resistance was 2.1 Woods units (SD = 1.8), with a pulmonaryto-systemic pressure ratio of 0.39 (SD = 0.2). Chest X-rays documented cardiomegaly in 85% of the patients, with plethoric lung fields noted on 66% of the X-rays. Several differences were noted in comparisons between haemodynamic features of PDAs Table 1. Characteristics of patients who had transcatheter procedures, by closure device Total patients (n = 139)

Coils (n = 101)

Amplatzer™ devices (n = 49)

p-value

1.8 (1–4.5)

1.8 (1.0–4.4)

2.1 (1.1–4.5)

0.47

Female

66.2 (92/139)

68.3 (69/101)

63.3 (31/49)

Male

33.8 (47/139)

31.7 (32/101)

36.7 (18/49)

12.8 (7)

13.1 (8.1)

12.9 (9.6)

< 6 kg, % (n/N)

5.4 (7/130)

5.3 (5/95)

4.4 (2/45)

0.87

≥ 6 kg, % (n/N)

94.6 (123/130)

94.7 (90/95

95.6 (43/45)

0.84

87.4 (22.9)

87.0 (23)

89.2 (24.3)

0.62

Variable Age, median years (IQR) Gender, % (n/N)

Weight, mean kg (SD)

Height, mean cm (SD)

0.54

N varied due to missing data. The total sum of coils and Amplatzer devices exceeded the number of patients as more than one device was used in some patients. IQR: inter-quartile range. SD: standard deviation.

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Table 2. Characteristics of patent ductus arteriosus and haemodynamic measurements in patients, by closure device

Variable

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Total patients (n = 139)

Coils (n = 101)

Amplatzer™ devices (n = 49)

3.2 (1.6)

2.6 (1.1)

4.0 (1.9)

p-value < 0.001

100

92.9

Narrowest point, mean (SD) Size, % (n/N)

0.005

< 2.5 mm

37.5 (42/112)

47.8 (33/69)

21.7 (10/46)

≥ 2.5 mm

62.5 (70/112)

52.2 (36/69)

78.3 (36/46)

PDA shape A, % (n/N)

72.8 (91/125)

74.1 (63/85)

72.9 (35/48)

B, % (n/N)

1.6 (2/125)

2.4 (2/85)

2.1 (1/48)

C, % (n/N)

5.6 (7/125)

3.5 (3/85)

8.3 (4/48)

D, % (n/N)

2.4 (3/125)

2.4 (2/85)

2.1 (1/48)

E, % (n/N)

17.6 (22/125)

17.7 (15/85)

14.6 (7/48)

Cardiomegaly, % (n/N)

85.4 (111/130)

80.2 (73/91)

93.6 (44/47)

0.04

Plethora, % (n/N)

66.2 (86/130)

56.0 (51/91)

83.0 (39/47)

0.002

46.6 (9.6)

44.9 (10)

48.8 (8.5)

0.03

Percentage closed

PDA size 60

p < 0.001

52.0

0.82

20.0

18.7 4.8

Chest X-ray

<1 week

2.4

6.7 0.0

1 week – 6 months – 1–2 years 6 months 1 year Amplatzer (n = 42)

2.7

0.0

> 2 years

Coil (n = 75)

Haemodynamics Pulse pressure, mean mmHg (SD) LA:AO*, mean (SD)

1.6 (0.4)

1.7 (0.4)

0.5

Shunt, (Qp:Qs) mean (SD)

2.0 (1.2)

1.8 (0.8)

2.5 (1.6)

< 0.001

Pulmonary resistance (Woods units), mean (SD)

2.1 (1.8)

2 (1.9)

2.2 (1.6)

0.5

Pulmonary pressure: systemic pressure ratio mean (SD)

0.39 (0.2)

0.4 (0.1)

0.5 (0.2)

< 0.001

23.1 (15.3–31.6)

21.3 (14.7–29.8)

23.5 (16.8–32.4)

0.55

Fluoroscopy time Median minutes, (IQR)

N varied due to missing data. The total sum of coils and Amplatzer devices exceeded the number of patients as more than one device was used in some patients. SD: standard deviation; IQR: interquartile range.

closed with coils and with Amplatzer™ devices. Overall, the PDAs where Amplatzer™ devices were used were bigger, with larger shunts and higher pulmonary:systemic pressure ratios. In about a third of patients, the fluoroscopy time for the procedure had not been recorded. The median fluoroscopy time for those with these data was 23.1 minutes, being similar with coils and Amplazer placement. The shortest procedure took 8.3 minutes and the longest two hours 27 minutes. Altogether, 150 transcatheter procedures were performed on the 139 patients. More than 80% of patients required only one procedure to effect closure (114), 16% required further intervention (22) and no data on outcomes were available for 2% of cases (three). Twelve of the 22 patients who required further intervention had a second catheterisation, eight of which were successful and the other four had a residual PDA that was haemodynamically insignificant and it was decided to observe them. A total of eight patients required surgical closure (six with coils and two with Amplazer devices). Two of the 22 were lost to follow up and no further data were available. Of the cases where complete PDA closure was documented on echocardiography (117), closure had occurred within one week in over 90% of the Amplatzer™ device cases, but in only half of the procedures using coils (p < 0.001; Fig. 1). Overall, of the whole cohort, no patients had a significant residual PDA in the long run.

Fig. 1. Time to complete closure. Only PDAs in which closure was confirmed on echocardiography were included (p < 0.001 for the comparison between time to closure with Amplazer and coils).

A total of 101 COOK® coils were placed in 92 patients who underwent transcatheter PDA closure with a coil (Fig. 2). In the majority of patients, a single coil was used (74), however in larger PDAs (before the Amplatzer™ devices were available) more than one coil was occasionally required. In the 18 patients who required more than one coil at their initial procedure, 13 had two coils, four had three and one had four coils. Overall, in 78% of patients with a known outcome, the PDA was successfully closed with one or more coils (66/85). Surgical closure was required in six patients where a coil was initially attempted. Five patients had a small residual PDA that did not require surgical closure, one PDA was noted to have closed spontaneously at follow up, and seven patients were lost to follow up.

Coils (n = 92)

Single coil (n = 74)

Deployed (n = 69) Closed: 51 Repeat cath: 8 (2 unknown result, 6 closed) Residual flow: 4 Lost to follow up: 6

Unsuccessful (n = 5) Surgery: 2 Lost to follow up: 1 Closed spontaneously: 1 Tiny residual PDA: 1

Multiple coils (n = 18)

Deployed (n = 12) Closed: 12

Unsuccessful (n = 6) Surgical closure: 4 Repeat cath: 1 Lost to follow up: 1

Fig. 2. Flow chart describing the patients who had PDA closure with coiling.

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25 20 15 10 5

2008

2007

2006

2005

2004

2003

2001

2002

1999

2000

1998

1997

1996

1995

1994

1993

0 1992

A total of 49 Amplatzer™ devices were used in 46 patients. Three devices were used during the study period: Amplatzer™ duct occluder 1 (37 patients), Amplatzer™ vascular plug (eight patients), and one patient had an Amplatzer™ duct occluder 2 placed, a device that became available only towards the end of the study period. Closure occurred in 93% of cases where an Amplatzer™ device was used (43/46). In two instances, surgical closure was required and in one patient a tiny residual PDA was present that did not require closure. Two patients with Amplatzer™ devices required another catheterisation. In the first, an AVP was placed and there was a tiny residual shunt. We attempted to place a coil inside the AVP, which was unsuccessful, but as the residual PDA was very small and insignificant, no further intervention was undertaken. In the other patient, there was a gradient in the ADO pre-release, so the device was removed and the procedure was abandoned. It was later successfully closed with a smaller device. Once Amplatzer™ devices became available at the facility, they rapidly became the preferred device, with the drop in number of coils used mirroring the increase in use of Amplatzer™ devices. The number of patients who had a repeat procedure decreased steadily over the 15 years, except for a brief period where repeat procedures increased around the time the Amplatzer™ device was introduced (Fig. 3). Lastly, the number of patients having their PDA surgically ligated decreased several-fold over the 15-year period (Fig. 4). The age of the child at surgical closure of the PDA also reduced over time, from one year 10 months (1993–1997), to nine months (1998–2002) and then seven months (2003–2008). Minor complications were noted in 20% of patients (29/145) (Table 3). A total of eight devices embolised (seven coils and one Amplatzer device). None of these resulted in any permanent problems. No differences were detected in the occurrence of either minor or major complications related to the PDA shape. Three major complications occurred (2%), all of which resolved. In the first instance, a significant left pulmonary artery obstruction was noted post PDA occlusion. The patient was sent for surgery, the PDA was ligated and the device was removed. The second patient developed complete heart block during the procedure when the balloon on an Arrow–Berman™ catheter burst. Atropine was administered, supraventricular

Number of PDAs

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Fig. 4. Number of PDAs surgically ligated per year over the study period.

tachycardia followed, which did not respond to adenosine, but following DC cardioversion, sinus rhythm resumed. The PDA was then successfully closed. The third patient had unusual PDA anatomy with a Kommerell diverticulum. The PDA was closed successfully, but on a cardiothoracic angiogram done after the closure, a vascular ring was noted.

Recent experience with transcatheter closure From January 2008 to August 2017, a total of 162 procedures were performed at the facility for transcatheter occlusion of PDA. These were predominately done with Amplatzer devices (101 ADO1, 10 ADO2, 14 AVP2 and 6 ADO additional sizes). An additional 22 cases were done with the Occlutech (Occ Duct Occluder devices) and only two with coils. In four cases, the device was removed and replaced during the transcatheter procedure. In total, there were 10 procedures where a device failed. In eight of these cases, the device was removed and the patient then had a surgical procedure, and in the remaining two cases, the device embolised. One was removed in the catheter Table 3. Details of minor complications Minor complications

Number

Details

General 12

LV dysfunction

6 resolved, 2 lost to follow up

Diminished leg perfusion

Resolved with heparin infusion

Arrhythmia

SVT – reverted to sinus easily 1 – adenosine 2 – stimulation of RA with catheter

Haemolysis

Lost to follow up

Number of patients

10 8

Embolisation Coils

6 4

Amplatzer

Removed percutaneously

Coil

Mild gradient, observed, left in situ

Amplatzer

Removed, smaller device used

Coil

Coil removed

Amplatzer

Mild gradient noted, not significant. Devices left in situ

Obstruction and site

2 0

7 5 coils (4 patients) left in situ – no (6 patients) long-term problems 2 coils removed by snares

Aorta (n = 2) 1994–1996

1997–1999 2000–2002 2003–2005 2005–2008

Fig. 3. N umber of patients requiring a repeat procedure to close the PDA. This graph includes patients who initially had surgery and then went for transcatheter closure.

Pulmonary arteries (n = 6)

Total

29/145 (20%)

SVT: supraventricular tachycardia.

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laboratory, while the other was referred for surgery where the PDA was ligated and the embolised device was removed.

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100 90 80

This study shows that transcatheter occlusion of PDAs is safe and effective in our setting. In particular, the introduction of the Amplatzer™ devices raised the safety and effectiveness of closure and a wider spectrum of PDAs can now be closed at the facility. The need for surgical intervention has declined markedly. Reducing the number of these cases by using percutaneous closure of PDAs decreases the time patients with other congenital heart diseases spend waiting for surgery. The data presented for the period 2008– 2017 showed the predominance of Amplatzer devices continued and that few complications occurred with these procedures. The predominance of females in our study is notable and consistent with what is commonly found in isolated PDAs.17 Interestingly, in contrast with Krichenko’s description of PDA shapes, where type B was the second commonest,1 this shape was the least common in our population. The findings of our study add to reports from other settings. In 2006, Galal et al. summarised evidence on PDA occlusion from 1995 to 2004, covering 21 articles, which included almost 2 800 patients.6 Our early closure rates are lower than those reported in that review, although definitions of early closure differ between our study and the review (Fig. 5). Late closure rates in our population, however, approximate their reported range. Late occlusion is perhaps the most important outcome measure, as it is a key determinant of whether further procedures are required and of the patient’s risk of endocarditis.18 The rate of device embolisation during our study period was acceptable, falling between the highest and lowest rates reported in the review. In 2004, Pass published a multicentre review of closure of PDAs with the Amplatzer™ duct occluder, covering 484 patients from 25 centres.19 Our results are very similar to those of the review, with early closure rates around 90% in the review and in our study. Total closure rates of 97% in our study were almost identical to the 98% in that review. The characteristics of our population and that of the Pass review are similar (e.g. age and weight), as are the PDA sizes and shunt ratios. While the above studies were done mostly in high-income countries, use of these devices has also been assessed in other middle-income countries.4,5 A study in Bloemfontein confirmed the effectiveness of coils in 36 patients in a southern African environment.14 Notably, our fluoroscopy time was considerably longer than all the results reported by Galal et al.6 There are multiple reasons likely account for this finding. Firstly, we perform a full diagnostic catheterisation prior to closing the PDA, while in other settings a briefer catheterisation may have been done, focused on only closing the duct. Secondly, the introduction of a new device (Amplatzer) necessitated a considerable learning curve for the catheterisation team, prolonging the procedure for the initial patients. The slight increase in number of patients requiring a repeat procedure to close a PDA around the time that the Amplatzer devices were introduced was also likely due to the learning curve. Finally, our facility is a nationally accredited paediatric cardiac training centre, with a high turnover of trainees who each need to perform several procedures in order to become

70 PDA closures

Discussion

60 50 40 30 20 10 0

Fluoroscopy time (mins) CHBH

Early Late Embolisation occlusion (%) occlusion (%) (%) Galal et al. – lowest

Galal et al. – highest

Fig. 5. Comparison of PDA closure with coils between our results and the review reported by Galal et al.6 (lowest refers to lowest values in studies reviewed, and highest refers to highest values in studies reviewed).

proficient, and to complete their sub-speciality. As a result, these procedures most often involve close supervision and teaching of trainees with little or no experience. The long fluoroscopy time is an important finding, and results in increased radiation exposure to both patients and staff. Clearly, attention needs to be paid to strategies to reduce radiation exposure in our setting.

Study limitations Types of procedures and outcomes of current care may differ from that of our study, given that our data collection ended in 2008 and new devices have been introduced since then. Nevertheless, these data describe the important transitions in our unit from one type of device, coils, to the Amplatzer range, and from surgery to transcatheter closure. Furthermore, this study is limited in that it is a retrospective record review. While efforts were made to capture all available data, some information was missing. Similarly, most patients who underwent surgery prior to the era of device closure did not undergo cardiac catheterisation so the data relating to PDA size and shape were not available for these patients, limiting our ability to compare these and other patients.

Conclusions Transcatheter closure of PDAs in the catheterisation laboratory at Chris Hani Baragwanath Academic Hospital is both safe and effective. The treatment outcomes are similar to those in highincome countries, which have considerably more resources for treating their patient populations. The introduction of a new device, although associated with a learning curve, broadened the range of PDAs that could be closed and improved closure rates. Efforts are needed to address the factors influencing fluoroscopy times. As more devices become available, the range of PDAs that could be closed will likely further increase.

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References 1.

Rao PS. Percutaneous closure of patent ductus arteriosus: state of the art. J Invasive Cardiol 2007; 19(7): 299–302.

scatheter patent ductus arteriosus closure using Amplatzer duct occlud-

Gross RE, Hubbard JP. Landmark article, Feb 25, 1939: Surgical Robert E Gross and John P Hubbard. J Am Med Assoc 1984; 251(9): 1201–1202. Moore JW, Levi DS, Moore SD, Schneider DJ, Berdjis F. Interventional treatment of patent ductus arteriosus in 2004. Catheterization and cardiovascular interventions: J Soc Cardiac Angiogr Intervent 2005; 64(1): 91–101. Atiq M, Aslam N, Kazmi KA. Transcatheter closure of small-to-large patent ductus arteriosus with different devices: queries and challenges. J

Cardiovasc Intervent 2014; 83(2): 250–255. 13. Brown S, Bruwer A, Al-Zaghal A, Claassens A. Effectiveness of single detachable COOK coils in closure of the patent ductus arteriosus. Cardiovasc J Sth Afr 2004; 15(2): 76–80. 14. AGA Medical Corporation. Amplatzer Duct Occluder. Instructions for Use: 7. 15. Grech V, DeGiovanni JV. Flipper coil closure of patent ductus arteriosus. Images Paediat Cardiol 2007; 9(2): 1–15. 16. Krichenko A, Benson LN, Burrows P, Moes CA, McLaughlin P, Freedom RM. Angiographic classification of the isolated, persistently patent ductus arteriosus and implications for percutaneous catheter occlusion. Am J Cardiol 1989; 63(12): 877–880.

Porstmann W, Wierny L, Warnke H. Closure of persistent ductus

17. Tripathi A, Black GB, Park YM, Jerrell JM. Prevalence and manage-

arteriosus without thoracotomy. German Med Monthly 1967; 12(6):

ment of patent ductus arteriosus in a pediatric medicaid cohort. Clinical Cardiol 2013; 36(9): 502–506.

Masura J, Walsh KP, Thanopoulous B, Chan C, Bass J, Goussous Y, et

18. Saint-Andre C, Iriart X, Ntsinjana H, Thambo JB. Residual shunt after

al. Catheter closure of moderate- to large-sized patent ductus arteriosus

ductus arteriosus occluder implantation complicated by late endocardi-

using the new Amplatzer duct occluder: immediate and short-term results. J Am Coll Cardiol 1998; 31(4): 878–882. 9.

sus in infants: Experimental testing of a new Amplatzer device. Catheter

Galal MO, Hussain A, Arfi AM. Do we still need the surgeon to close

259–261. 8.

ers. Am Heart J 2006; 151(3): 755, e7–e10. 12. Bass JL, Wilson N. Transcatheter occlusion of the patent ductus arterio-

Invasive Cardiol 2007; 19(7): 295–298. the persistently patent arterial duct? Cardiol Young 2006; 16(6): 522–536. 7.

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ductus arteriosus division at Children’s Memorial Hospital of Chicago.

ligation of a patent ductus arteriosus. Report of first successful case.

safety of the Amplatzer ductal occluder in young children and infants. 11. Masura J, Tittel P, Gavora P, Podnar T. Long-term outcome of tran-

9–10.

10. Al-Ata J, Arfi AM, Hussain A, Kouatli AA, Jalal MO. The efficacy and

Mavroudis C, Backer CL, Gevitz M. Forty-six years of patient Standards for comparison. Ann Surg 1994; 220(3): 402–409; discussion

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tis. Circulation 2012; 125(6): 840–842. 19. Pass RH, Hijazi Z, Hsu DT, Lewis V, Hellenbrand WE. Multicenter

Bilkis AA, Alwi M, Hasri S, Haifa AL, Geetha K, Rehman MA, et al.

USA Amplatzer patent ductus arteriosus occlusion device trial: initial

The Amplatzer duct occluder: experience in 209 patients. J Am Coll

and one-year results. J Am Coll Cardiol 2004; 44(3): 513–519.

Cardiol 2001; 37(1): 258–261.

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Review Article The challenge in diagnosing coarctation of the aorta Julien IE Hoffman

Abstract Critical coarctation of the aorta in neonates is a common cause of shock and death. It may be the most difficult of all forms of critical congenital heart disease to diagnose because the obstruction from the coarctation does not appear until several days after birth (and after discharge from the hospital), and because there are no characteristic murmurs. Some of these patients may be detected by neonatal screening by pulse oximetry, but only a minority is so diagnosed. Older patients are usually asymptomatic but, although clinical diagnosis is easy, they are frequently undiagnosed.

This is important, because unlike most other smooth muscle, ductus smooth muscle tends to contract when exposed to high oxygen concentrations. The arch is often hypoplastic and when present, an associated intracardiac shunt should be suspected. Most commonly this is an isolated ventricular septal defect, but almost any form of complex congenital heart disease can be associated. About 50 to 70% of the patients have a bicuspid aortic valve. The left subclavian artery is often hypoplastic, and in approximately 5% of these patients arises distal to the shelf.

Developmental physiology Keywords: patent ductus arteriosus, left ventricular failure, pulse oximetry, balloon dilatation, stent Submitted 14/7/17, accepted 19/11/17 Published online 11/12/17 Cardiovasc J Afr 2018; 29: 252–255

www.cvja.co.za

DOI: 10.5830/CVJA-2017-053

Coarctation of the aorta is a congenital lesion that occurs in 2.5 to four per 10 000 live births.1,2 With a total world population of 7.5 × 109 and an annual crude birth rate of about 1.365 × 106, each year about 340 000 to 550 000 children are born with coarctation of the aorta. The anomaly is usually sporadic and is more frequent in males. Most coarctations fall into one of two groups: critical coarctation of the aorta that causes symptoms within two months of birth and if untreated causes death, and asymptomatic coarctation of the aorta that presents later, usually with hypertension in the upper limbs. Critical coarctation of the aorta accounts for about 60% of all coarctations.

In the foetus, the patency of the ductus arteriosus depends on a balance between constrictors and dilators. Constriction is due mainly to an increased sensitivity of ductus smooth muscle to calcium3 but also to endothelin. By contrast, the ductus smooth muscle is relaxed by vasodilator prostaglandins (mainly PGE2) that are produced in the ductus wall and also circulate from the placenta.4 The PGE2 increases intracellular concentrations of cAMP, which decreases calcium sensitivity. Nitric oxide and

LCA IA

Hypoplastic arch

LSA

Ductus sling PDA

Pathological anatomy Anatomically a coarctation of the aorta is a shelf of tissue extending from the postero-lateral aortic wall towards the ductus arteriosus (Fig. 1). The shelf is near the patent ductus arteriosus, sometimes above or below it, and is better termed juxtaductal. A sling of ductus muscle passes around the shelf, and more ductus muscle extends into the aortic wall above and below the shelf.

Department of Pediatrics, University of California, San Francisco, CA, USA Julien IE Hoffman, MD, jiehoffman@gmail.com

Asc aorta

Fig. 1. Basic anatomy of coarctation of the aorta. Asc: ascending; IA: innominate artery; LCA: left carotid artery; LSA: left subclavian artery; PA: main pulmonary artery; PDA: patent ductus arteriosus.

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carbon monoxide may play minor roles. In addition to these chemical factors, the high pressure in the ductus lumen helps to keep it open. After birth, the lowered pulmonary vascular resistance lowers pressure in the ductus lumen, and PGE2 decreases both from loss of placental prostaglandins and a reduced number of PGE2 receptors in the ductus wall. The increase in arterial oxygen content has several actions that favour constriction of the ductus. A membrane-bound cytochrome 450 acts as a transducer to produce vasoconstrictors.5 Oxygen inhibits potassium channels, produces membrane depolarisation, increases smooth muscle calcium, and induces the formation of endothelin-1; all these changes stimulate vasoconstriction, although the role of endothelin-1 is not clear.

Pathophysiology At birth, the ductus is wide open so that despite the shelf, blood can flow freely from ascending to descending aorta (Fig. 2A). The ductus closes first at its pulmonary arterial end, but the wide ductus ampulla provides space for unobstructed flow (Fig. 2B). This region then narrows further as the ductus ampulla shrinks and the ductus sling contracts, drawing the lateral wall towards the closing ampulla (Fig. 2C).6,7 As a rule of thumb, an artery must be narrowed by more than 50% before any obstruction occurs, but once this degree of narrowing occurs, it takes very little additional narrowing to produce severe obstruction, which can occur very rapidly. (This functional narrowing can be reversed by infusing PGE1.7,8) The sudden severe obstruction overloads the left ventricle, causing left ventricular failure, pulmonary hypertension, right ventricular failure and systemic congestion. Pulmonary oedema is often seen. If the foramen ovale is patent there will be a left-to-right atrial shunt that can be large, and if it occurs there may be no or less pulmonary oedema, because left atrial pressure is lower. A

PDA

PDA Coa

Coa

Fig. 2. A : At birth, the ductus (PDA) is wide open, so that despite the coarctation shelf (Coa), flow is not obstructed. Dashed line with arrow shows unimpeded flow. B: Ductus closes at its connection to the main pulmonary artery, but its ampulla still provides a detour for flow. Dashed line with arrow shows unimpeded flow. C: Narrowing of the ductus ampulla leads to severe flow obstruction. Heavy dashed line shows obstructed flow. AA: ascending aorta; DA: descending aorta.

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The patient often goes into shock. If the narrowing of the aorta occurs very slowly, the left ventricle has time to adapt to the increased pressure load and develop a collateral circulation and shock and congestive heart failure do not occur. These patients are usually asymptomatic and are diagnosed at older ages.

Diagnosis: critical coarctation of the aorta in neonates Coarctation of the aorta is a treacherous disease that is often undiagnosed. When neonates present with shock, the most common cause is sepsis, followed closely by left heart obstruction (aortic stenosis, coarctation of the aorta), which must always be excluded. These cardiac lesions usually have insignificant and non-diagnostic murmurs. The electrocardiograms show right ventricular hypertrophy, not left ventricular hypertrophy as expected from a left heart obstructive lesion. A chest radiogram will show a dilated heart and either pulmonary oedema or a leftto-right shunt. The liver is usually enlarged. Recent studies done in Scandinavia found that at least 50% of these neonates were discharged without a diagnosis,9 and that most were still undiagnosed at five days after birth.10 In California, Chang et al.11 found that 27% of patients with coarctation of the aorta died undiagnosed at a median age of 17 days. Ward et al.12 observed that infants with symptomatic coarctation of the aorta presented between five and 14 days after birth. Coarctation can be detected by foetal echocardiography if performed by an expert, but even then is often not detected.9 This is therefore not a diagnostic method for general use. In older patients the main physical signs are hypertension in the arms and weak, delayed femoral arterial pulses. These signs however, are either not detected or are unreliable in neonates because in most of the infants there is no obstruction to flow immediately after birth, and hypertension or weak femoral pulses may take several days to appear. Feeling femoral pulses may be difficult, especially in plump babies, and by the time decreased femoral pulses are obvious, the obstruction is fairly severe. Taking four-limb blood pressures in normal neonates is not routine, and even if performed, the pressures may not be accurate. If blood pressures are taken, use the right rather than the left arm. When pulse oximetry screening for critical congenital heart disease in neonates was introduced, several patients with coarctation of the aorta were detected because they had a rightto-left shunt through the patent ductus arteriosus. Unfortunately, this occurs in only a minority of coarctations, perhaps related to the anatomy of the region, so that pulse oximetry cannot be relied upon for the diagnosis.9,13 At present, there is no easy way to make this diagnosis in a timely fashion. The best way is to have all neonates seen between three and seven days after birth by a physician or nurse who can check the femoral pulses. If these are found to be decreased then immediate transfer to a hospital for treatment should be done. Waiting is not an option because the likely course is rapid deterioration. If the patient is already symptomatic, an infusion of prostaglandin PGE1 at 0.05 to 0.15 mcg/kg/min will help to relax the ductus muscle and reduce the obstruction, relieve the symptoms, allow the left ventricle to recover, and make definitive treatment safer.

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Diagnosis: coarctation of the aorta in older patients Although the diagnosis of coarctation of the aorta in older patients is easy, the diagnosis is often missed or delayed. In fact, even in older children, coarctation of the aorta is missed in about 85% of coarctation patients referred to a hospital for murmurs or hypertension.12,14-16 In these patients, the left ventricle has adapted to the pressure load with hypertrophy, and lower body perfusion is achieved by hypertension in the upper aorta. Most are asymptomatic until later in life, although a few may have pain on walking (intermittent claudication). If left untreated, 50% die under 30 years of age and few survive beyond 50 years of age. Death is due to congestive heart failure, dissection and rupture of the aorta, ruptured berry aneurysm in the cerebral circulation, or infective endocarditis. The clinical diagnosis is based on finding signs of left ventricular hypertrophy, hypertension in the upper body, weak and delayed femoral arterial pulses, and upper body collateral circulation. • Left ventricular hypertrophy is appreciated by a forceful, heaving apical thrust in systole. • Blood pressure should be taken with an appropriate-sized cuff in both arms because the left subclavian artery is often hypoplastic or distal to the coarctation, and in more than 1% of people, the right subclavian artery is aberrant and could originate below the coarctation. In these people the pressure will be higher in the left than the right arm. • If the arm pressure is high, then feel the femoral pulses. In coarctation of the aorta they are weaker than the radial pulses, and when felt simultaneously with the radial pulse, the femoral pulse is delayed. Confirmation is obtained by obtaining a leg blood pressure with an appropriate-sized cuff. • Collateral arteries are perceptible in over 50% of these patients, and are prominent over the edges of the scapulae. • An ejection-type systolic murmur may be heard at the base, and between the spine and the left scapula. • Confirmation of the diagnosis can be obtained by a chest radiogram that will show the aortic indentation at the coarctation site (three sign) and rib notching of the lower ribs due to enlarged intercostal arteries. Echocardiography is indicated if additional cardiac lesions are suspected.

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An alternative is to dilate the coarctation with a balloon and then insert a stent to prevent the dilated region from narrowing due to elastic recoil. Usually infants are treated surgically because they are too small for introducing the stent on a catheter, whereas balloon dilatation and stenting are usually used in adults and for treating re-coarctation. All procedures carry a small risk of aneurysm formation.

Prognosis In general, the results are good, although coarctation patients had a greater and earlier incidence of cardiovascular disease than the normal population.19,20 In addition, although blood pressure decreases after removal of the obstruction, a high proportion of these patients develop persistent hypertension.19,21-23

Conclusions The timely diagnosis of critical coarctation of the aorta in neonates is difficult, and data from Scandinavia, Europe and the USA show how poorly this is done. Delayed diagnosis also occurs in older patients, despite the ease of diagnosis. These problems are likely to be worse in Africa with a widely dispersed largely rural population and a shortage of medical resources. Furthermore, with the high average birth rate in Africa, the present population of 1.2 billion is expected to double by 2050, thereby increasing the number of children born with congenital heart disease in general and coarctation of the aorta in particular. Nevertheless, attempts should be made to diagnose and treat coarctation of the aorta at any age, especially because diagnosis needs only good physical examination. Treatment of coarctation of the aorta is cheaper, easier, and results are better than for most other forms of critical congenital heart disease, and most patients do well after the obstruction is removed.

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Treatment There are two main treatment choices: surgery or balloon dilatation with stenting.17,18 A variety of surgical procedures has been used, but most common are mobilising the aorta, excising the region around the coarctation and reconnecting the two ends, or mobilising the aorta, excising the region around the coarctation and connecting the descending aorta to the underside of the aortic arch. The latter is the preferred technique in infants with a hypoplastic arch because it allows reconstruction of the aortic arch. The operative mortality rate is very low. There is a small incidence of paraplegia with surgery unless precautions are taken to prevent spinal cord ischaemia. With current surgical methods there is a 3–5% chance of re-coarctation. Surgery in older adults has a higher mortality rate because of an abnormal aortic wall and the development of huge, thin-walled intercostal aneurysms.

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Crichton CA, Smith GC, Smith GL. Alpha-toxin-permeabilised rabbit fetal ductus arteriosus is more sensitive to Ca2+ than aorta or main pulmonary artery. Cardiovasc Res 1997; 33: 223–229.

Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate 2006; 89: 330–335.

Coceani F, Wright J, Breen C. Ductus arteriosus: involvement of a sarcolemmal cytochrome P-450 in O2 constriction? Can J Physiol Pharmacol 1989; 67: 1448–1450.

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Carroll SJ, Ferris A, Chen J, Liberman L. Efficacy of prostaglandin E1 in relieving obstruction in coarctation of a persistent fifth aortic arch

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Lannering K, Bartos M, Mellander M. Late diagnosis of coarctation despite prenatal ultrasound and postnatalp oximetry. Pediatrics 2015; 136: e406–412.

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10. Mellander M, Sunnegardh J. Failure to diagnose critical heart malformations in newborns before discharge – an increasing problem? Acta Paediatr 2006; 95: 407–413.

condition or life long disease process? Heart 2005; 91: 1495–1502. 19. Maron BJ, Humphries JO, Rowe RD, Mellits ED. Prognosis of surgically corrected coarctation of the aorta. A 20-year postoperative appraisal.

11. Chang RK, Gurvitz M, Rodriguez S. Missed diagnosis of critical

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RC. Delayed detection of coarctation in infancy: implications for timing of newborn follow-up. Pediatrics 1990; 86: 972–976.

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13. Riede FT, Schneider P. Most wanted, least found: coarctation.

RM. Results after repair of coarctation of the aorta beyond infancy: a

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10 to 28 year follow-up with particular reference to late systemic hyper-

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tension. Am J Cardiol 1983; 51: 1481–1488. 22. Presbitero P, Demarie D, Villani M, Perinetto EA, Riva G, Orzan F, et

14. Strafford MA, Griffiths SP, Gersony WM. Coarctation of the aorta: a study in delayed detection. Pediatrics 1982; 69: 159–163.

al. Long term results (15-30 years) of surgical repair of aortic coarctation. Br Heart J 1987; 57: 462–467.

15. Thoele DG, Muster AJ, Paul MH. Recognition of coarctation of the

23. O’Sullivan JJ, Derrick G, Darnell R. Prevalence of hypertension in

aorta. A continuing challenge for the primary care physician. Am J Dis

children after early repair of coarctation of the aorta: a cohort study

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using casual and 24 hour blood pressure measurement. Heart 2002; 88:

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Report The Cape Town Declaration on Access to Cardiac Surgery in the Developing World Peter Zilla, R Morton Bolman, Magdi H Yacoub, Friedhelm Beyersdorf, Karen Sliwa, Liesl Zühlke, Robert SD Higgins, Bongani Mayosi, Alain Carpentier, David Williams

Mission: to urge all relevant entities within the international cardiac surgery, industry and government sectors to commit to develop and implement an effective strategy to address the scourge of rheumatic heart disease in the developing world through increased access to life-saving cardiac surgery. Cardiovasc J Afr 2018; 29: 256–259

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DOI: 10.5830/CVJA-2018-046

Christiaan Barnard Division of Cardiothoracic Surgery, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Peter Zilla, MD, PhD, peter.zilla@uct.ac.za

Division of Cardiothoracic Surgery, University of Vermont, Burlington, Vermont, USA R Morton Bolman, MD

Chain of Hope, Chelsea, London, United Kingdom Magdi H Yacoub, MD

Department of Cardiovascular Surgery, UniversitätsHerzzentrum Freiburg–Bad Krotzingen, Freiburg, Germany Friedhelm Beyersdorf, MD

Hatter Institute of Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Karen Sliwa, MD, PhD

Division of Paediatric Cardiology, Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa Liesl Zühlke, MB ChB, PhD

Department of Surgery, Johns Hopkins Medicine, Baltimore, Maryland, USA Robert SD Higgins, MD

Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Bongani Mayosi, MD

Hôpital Européen Georges Pompidou, Paris, France Alain Carpentier, MD

Wake Forest Institute of Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA David Williams, PhD

Twelve years after cardiologists and cardiac surgeons from all over the world issued the Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa, calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and rheumatic heart disease, and to periodically review progress made and challenges that remain,1 RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world’s population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide.2 Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open-heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality. Elimination of RHD and relief from its debilitating consequences can only occur through interdisciplinary effort, as outlined in the Cairo Accord.3 Previous initiatives have focused on primary and secondary prevention of RHD.4 Their declarations have been recognised by the heads of state of African Union countries and by the World Health Organisation. This recognition has been important in developing recommendations by the World Health Organisation executive board to the 2018 World Health Assembly to enlist global commitment to RHD. Progress in the prevention of RHD has been slow during the past 15 years,5 and therefore surgery will likely remain an integral part of RHD treatment for several generations. Lack of access to cardiac surgery services and the cost of valve replacement render this disease fatal for millions of patients. In endemic regions of low-income countries, the need for cardiac surgery is estimated at 300 operations per one million population (Global Unmet Needs in Cardiac Surgery, unpublished work by Zilla and colleagues), yet, the nearly one billion people living in sub-Saharan Africa between the Maghreb and South Africa have access to only 22 cardiac centres.6 Although there is one cardiac centre per 120 000 people in the United States, there is only one centre per 33 million in Africa. Furthermore, RHD is not restricted to sub-Saharan Africa. India, Pakistan, China and Indonesia together account for 72% of the mortality rate of RHD cases worldwide.2

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We strongly endorse the position that building local capacity is the best solution for this serious public health problem. Many lives have been saved by humanitarian ‘fly-in’ missions, but these efforts are neither sustainable nor cost effective. The non-governmental organisations associated with these programmes are shifting focus towards building long-term partnerships with host countries to develop autonomous local services with government buy-in.7 A massive investment in new cardiac centres in these regions is unrealistic; globally, an additional few thousand cardiac centres would be required to address the unmet needs (Global Unmet Needs in Cardiac Surgery, unpublished work by Zilla and colleagues). It is not sufficient for governments and non-governmental organisations to support the training of cardiologists and cardiac surgeons from these regions at high-income country facilities, because they will not be trained in most of the pathologies awaiting them in their own countries and will be unfamiliar with resource-constrained circumstances. There is an urgent need for a concerted effort by all stakeholders to address the plight of the poor in these regions, who need cardiac surgery. As signatories and endorsing organisations of the Cape Town Declaration, we propose a comprehensive solution with two principal aims. Aim 1: To establish an international working group (coalition) of individuals from cardiac surgery societies and representatives from industry, cardiology and government to evaluate and endorse the development of cardiac care in low- to middle-income countries. It is proposed that the international coalition will have two representatives from each of the major cardiac surgery societies (the Society of Thoracic Surgeons, American Association for Thoracic Surgery, European Association for Cardio-Thoracic Surgery, the Asian Society for Cardiovascular and Thoracic Surgery), and ideally, two additional committed members. There will be at least one representative from industry and at least one appointee to represent cardiology/the World Heart Federation. The responsibilities of the coalition will include establishing criteria for centres for clinical care and training as well as selecting and endorsing the centres. The coalition will derive metrics of quality and performance for the endorsed centres of training and clinical care and will encourage standardisation of care to the extent possible. The coalition will advocate mutually agreed policies and prescriptions to relevant governmental bodies. In addition, the coalition will engage with industry and private sources of philanthropy for financial assistance with large-scale initiatives. Aim 2: To advocate for the training of cardiac surgeons and other key specialised caregivers at identified and endorsed centres in lowto middle-income countries. The case has been made above for critical providers obtaining training in settings and conditions and dealing with the cardiac pathologies that they will be encountering in their practice in their countries of origin. It is preferred that centres endorsed by this coalition be based on an alliance of four stakeholders: a programme initiator (e.g. a government, a university, or a non-governmental organisation), an audited training centre in a low- to middle-income country, a committed partner institution in a high-income country, and a

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consortium of industry that would sign on as benefactors to the specific programme. Because regional centres in low- to middleincome countries typically operate within a resource-scarce environment, resulting in lower case numbers than needed for the training of outside residents, a facilitated capacity increase to help achieve higher case numbers would benefit all participants. Summary: It is imperative that action be taken urgently. A nucleus of one to three centres should be identified and endorsed, with co-ordination by global stakeholders, as quickly as possible. The implementation of this initiative will only be made possible by the endorsement of all the relevant cardiothoracic societies and agencies subscribing to clearly defined targets and timelines, and committing appropriate resources. The time to act is now.

Signatories For Cardiothoracic Societies (in alphabetical order) Joseph Bavaria [past-president, the Society of Thoracic Surgeons (STS), USA] Friedhelm Beyersdorf (editor in chief, European Journal of Cardio-Thoracic Surgery, Germany) R Morton Bolman, III [representative, American Association for Thoracic Surgery (AATS), USA] Kumud Dhital [representative, Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS), Australia] Robert SD Higgins [president elect, the Society of Thoracic Surgeons (STS), USA] James Kirklin [representative, American Association for Thoracic Surgery (AATS), USA] Robert Kleinloog [president, Society of Cardiothoracic Surgeons of South Africa (SCTSSA), South Africa] Bongani Mayosi [past president, Pan-African Society of Cardiology (PASCAR), South Africa] Juan Mejia (representative, Brazilian Society of Cardiovascular Surgery, Brazil) Jose Pomar [past president, European Association for CardioThoracic Surgery (EACTS), Spain] Karen Sliwa [president elect, World Heart Federation (WHF), South Africa] Shinichi Takamoto [president, Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), Japan] Wei Wang (representative, Chinese Society for Thoracic and Cardiovascular Surgery, China) David Wood [president, World Heart Federation (WHF), United Kingdom] Charles Yankah (president, Pan-African Society for Cardiothoracic Surgery (PASCaTS), Ghana/Germany] Liesl Zühlke (president, South African Heart Association, South Africa)

Humanitarian and government organisations (in alphabetical order) Alain Carpentier (Alain Carpentier Foundation, France) Sylvain Chauvaud (La Chaîne de l’Espoir, France) Afksendiyos Kalangos (President: Kalangos Foundation, Greece) Richard Kamwi (Past Minister of Health, Namibia) René Prêtre (Le Petit Coeur, Switzerland) Nicole Sekarski (Le Petit Coeur, Switzerland) Magdi Yacoub (President, Chain of Hope, United Kingdom/Egypt)

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Industry and health economy representatives (in alphabetical order) Iraj Abedian (Pan-African Capital Holdings, South Africa) Francois Bonnici (director, Bertha Centre for Social Innovation and Entrepreneurship, South Africa) Lenias Hwenda (chief executive officer, Medicines for Africa, Zimbabwe/Switzerland) Sidhant Jena (chief executive officer, Jana Care, USA) Samukeliso Dube (chief medical officer, Royal Philips, Netherlands) Jacques Kpodonu (author, Global Health Innovations, USA/ Ghana) Salah Malek (president, Middle East and Africa, Getinge, United Arab Emirates) Markus Stirner-Schilling (VP Marketing and Academy, Europe, Middle East and Africa, Getinge, Germany) Patrice Matchaba (global head corporate responsibility, Novartis, Switzerland) Lee Chuen Neng (Biomedical Institute for Global Health Research and Technology, Singapore) Michael P Phalen (executive president, MedSurg Boston Scientific, USA) Tim Ring (chairman and chief executive officer, CR Bard Inc, USA) Kathryn Gleason (co-founder, TeamFund Inc) Devi Prassad Shetty (NH Group, India) Alistair Simpson (general manager cardiac surgery, LivaNova, United Kingdom) Raenette Taljaard [Economic Research of South Africa (ERSA), South Africa] Helmut Straubinger (ex-chief executive officer, Jena Valve; chief executive officer, Tricares, Germany) Barry Wilson (former president, Medtronic International)

For major journals and publications (in alphabetical order) Friedhelm Beyersdorf (editor in chief, European Journal of Cardio-Thoracic Surgery, Germany) Sampath Kumar (editor in chief, Asian Cardiovascular and Thoracic Annals, India) Dan Ncayiyana (past editor in chief, South African Medical Journal, South Africa) JP van Niekerk (past editor in chief, South African Medical Journal, South Africa) G Alexander Patterson (editor in chief, The Annals of Thoracic Surgery, USA) Marko Turina [past editor in chief, European Journal of CardioThoracic Surgery; past editor in chief, Cardiothoracic Surgery Network (CTSNet) and Multimedia Manual of CardioThoracic Surgery, Switzerland] David Williams (past editor in chief, Biomaterials, USA)

Other signatory delegates to the Cape Town Dialogue (in alphabetical order) Elena Aikawa (USA) Masanori Aikawa (USA) Henning Rud Andersen (Denmark) Manuel Antunes (Portugal) Eduardo Becerra (Chile) Solomon Benatar (South Africa/Canada)

Richard Bianco (USA) Bojan Biocina (Croatia) Carlijn Bouten (Netherlands) Abdelmalek Bouzid (Algeria) Luke Brewster (USA) Johan Brink (South Africa) Taweesak Chotivatanapong (Thailand) Patrick Commerford (South Africa) David Cooper (USA) John Curci (USA) Manfred Deutsch (Austria) Richard Daly (USA) Frederick C de Beer (USA) Norberto de Vega (Spain) Howard Eisen (USA) Max Emmert (Switzerland) Giuseppe Faggian (Italy) Volkmar Falk (Germany) Ted Feldman (USA) Giovanni Ferrari (USA) Teddy Fischlein (Germany) Robert Frater (USA) Glen Gaudette (USA) Gino Gerosa (Italy) Bernard Gersh (USA) Allan Glanville (Australia) Craig Goergen (USA) Claudia Goettsch (Germany) Mervyn Gotsman (Israel) Martin Grabenwoeger (Austria) Andrea Griesmacher (Austria) Christian Hagl (Germany) Ulf Hedin (Sweden) Simon Hoerstrup (Switzerland) Saeid Hosseini (Iran) Joshua Hutcheson (USA) Willie Koen (South Africa) Gennadiy Khubulava (Russia) Robin Kleinloog (South Africa) Walter Klepetko (Austria) Michael Knaut (Germany) Theodoros Kofidis (Singapore) Guenther Laufer (Austria) Nicolas lâ&#x20AC;&#x2122;Heureux (France) Georg Lutter (Germany) Simon Maltais (USA) Simon Matskeplishvili (Russia) Jo Meinhart (Austria) Ana Olga Mocumbi (Mozambique) Elmi Muller (South Africa) Mathias Mueller (Austria) Paul Mohacsi (Switzerland) Ivan Netuka (Czech Republic) Mpiko Ntsekhe (South Africa) Minoru Ono (Japan) Otmar Pachinger (Austria) Timothy Pennel (South Africa) Olga Plattner (Austria) Bruno Podesser (Austria) Darshan Reddy (South Africa)

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Bruno Reichart (Germany) Hermann Reichenspurner (Germany) Hector Sanchez (Argentina) Jacques Scherman (South Africa) Stephan Schueller (United Kingdom) Jim Schurman (USA) Rainald Seitelberger (Austria) Toshi Shinoka (USA) Agneta Simionescu (USA) Dan Simionescu (USA) Francis Smit (South Africa) Ulrich Steinseifer (Germany) Cynthia St Hilaire (USA) Justiaan Swanevelder (South Africa) Hendrik Treede (Germany) Nir Uriel (USA) Devagourou Velayodamu (India) David Vorp (USA) Susan Vosloo (South Africa) Beath Walpoth (Switzerland) Georg Wieselthaler (USA) Mike Wolf (USA) Andreas Zuckermann (Austria)

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2018 by the STS, AATS, Clinics Cardive Publishing (Pty) Ltd, EACTS, National

Centre of Cardiovascular Disease, Polish Society of Cardiothoracic Surgeons, SAGE Publications Ltd, SA Heart and SAMJ. Published by Elsevier Inc.

References 1.

Mayosi B, Robertson K, Volmink J, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006; 96: 246.

Watkins DA, Johnson CO, Colquhoun SM, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med 2017; 377: 713–722.

Yacoub M, Mayosi B, El Guindy A, Carpentier A, Yusuf S. Eliminating acute rheumatic fever and rheumatic heart disease. Lancet 2017; 390: 212–213.

Watkins D, Zühlke L, Engel M, et al. Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué. Cardiovasc J Afr 2016; 23: 184–187.

Zühlke LJ, Karthikeyan G. Primary prevention for rheumatic fever. Glob Heart 2013; 8: 221–226.

Yankah C, Fynn-Thompson F, Antunes M, et al. Cardiac surgery capacity in sub-Saharan Africa: quo vadis? Thorac Cardiovasc Surg 2014; 62: 393–401.

Swain J, Sinnott C, Breakey S, et al. Ten-year clinical experience of

This article is co-published in the Annals of Thoracic Surgery, Asian Cardiovascular

humanitarian cardiothoracic surgery in Rwanda: building a platform for

and Thoracic Annals, Cardiovascular Journal of Africa, Chinese Circulation

ultimate sustainability in a resource-limited setting. J Thorac Cardiovasc

Journal, European Journal of Cardio-Thoracic Surgery, the Journal of Thoracic

Surg 2018; 155: 2541–2550.

and Cardiovascular Surgery, Polish Journal of Thoracic and Cardiovascular Surgery, South Africa Heart Journal, and South African Medical Journal.

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Letters to the Editor Multivessel disease in STEMI patients: a perspective from limited-resource settings Ahmed Ali Ahmed Suliman, Nauman Naseer, Bernard Gersh

Keywords: debate, Africa STEMI Live, multivessel disease, STEMI, limited-resource setting, infarct-related artery, noninfarct-related artery, complete revascularisation Cardiovasc J Afr 2018; 29: 260–261

www.cvja.co.za

DOI: 10.5830/CVJA-2018-034

During the Africa STEMI Live meeting held in Nairobi from 26 to 28 of April 2018, the Great Debate session was on how to approach non-infarct-related (N-IRA) disease in patients who present with STEMI and multivessel disease (MVD) in a limitedresource setting. Dr Nauman Naseer, professor of cardiology at Akhtar Saeed Medical College and chief of cardiology at Bahria International Hospital, was the protagonist for complete revascularisation of

University of Khartoum, Khartoum, Sudan Ahmed Ali Ahmed Suliman, MB BS, FACP, FESC, sulima01@ hotmail.com

Department of Cardiology, Akhtar Saeed Medical College, Lahore, Pakistan Nauman Naseer, MD, FACC, FSCAI, FACP

Department of Medicine, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA Bernard Gersh, MB ChB, DPhil

significant N-IRA disease and Dr Ahmed Suliman, associate professor of cardiology at the University of Khartoum and cardiologist at the National Cardiothoracic Centre in Khartoum, Sudan, argued for infarct artery (IRA)-only revascularisation. The session was moderated by Dr Bernard Gersh, professor of medicine and consultant in the Department of Cardiovascular Diseases at the Mayo Clinic, College of Medicine, USA. Both debaters agreed that the main focus is to achieve successful revascularisation of the IRA and the restoration of TIMI 3 flow but cited the evidence demonstrating that concomitant multivessel disease is frequently encountered in ST-elevation myocardial infarction (STEMI) patients and is associated with poorer outcomes than those who present with IRA disease only. Prof Naseer explained the four possible strategies to deal with N-IRA significant disease: intervention within the setting of primary percutaneous intervention; a staged procedure during the index admission and before discharge; a staged procedure after discharge; or treating the N-IRA disease as per stable angina pectoris guidelines. Prof Naseer supported full revascularisation preferably during the same hospital admission, an approach endorsed by the ESC guidelines (class IIa indication).1 His main arguments were: • Several randomised trials demonstrated the superiority of complete revascularisation of N-IRA versus IRA only. The largest four trials were PRAMI,2 CvLPRIT,3 DANAMI-3 PriMULTI4 and COMPARE-ACUTE5 trial (Table 1). Benefit was driven primarily by the need for repeat revascularisation with only a trend towards a reduction in hard end-points.

Table 1. Summary of outcomes of major trials comparing complete revascularisation versus IRA-only Study PRAMI

CvLRIT

DANAMI-3 PriMULTI

COMPARE-ACUTE

Primary outcome

HR ( 95% CI)

p-value

Secondary outcomes

HR ( 95% CI)

CV death, non-fatal MI and refractory angina

0.35 (0.21–0.58)

< 0.001

CV death

0.34 (0.11–1.08)

Non-fatal MI

0.32 (0.13–0.75)

0.009

Repeat revascularisation

0.30 ( 0.17–0.56)

< 0.001

Death, non-fatal MI, heart failure, repeat revascularisation

Death, non-fatal MI and repeat revascularisation Death, non-fatal MI, repeat revascularisation, CVA

0.45 (0.24–0.48)

0.56 (0.38–0.83)

0.35 (0.22–0.55)

0.009

0.004

< 0.001

HR = hazard ratio; CI = confidence interval; CV = cardiovascular; MI = myocardial infarction.

p-value 0.07

Death

0.32 (0.06–1.60)

0.14

Non-fatal MI

0.48 (0.09–2.62)

0.39

Heart failure

0.43 (0.13–1.39)

0.14

Repeat revascularisation

0.55 (0.22–1.39)

0.2

Death

1.4 (0.63–3·0)

0.43

Non-fatal MI

0.94 (0.47–1.9)

0.87

Repeat revascularisation

0.31 (0.18–0.53)

< 0.001 0.7

Death

0.8 (0.25–2.56)

Non-fatal MI

0.5 (0.22–1.13)

0.1

Repeat Revascularisation

0.32 (0.20–0.54)

< 0.001

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• FFR/iFR (fractional flow reserve/instantaneous free-wave ratio) helps to identify haemodynamically significant disease in non-culprit vessels. • Many patients in the developing world live far away from cities and the need for urgent repeat revascularisation may translate into a mortality difference due to treatment delay. • Saving costs initially via the IRA-only approach could incur higher costs at a later stage and this is particularly relevant in the African setting since most patients are liable for ‘out-of pocket’ expenses.

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Dr Suliman concluded by advocating a strategy of culpritartery only and non-invasive ischaemia-testing for limited-resource settings. At the end of the debate, the audience was almost evenly split when polled regarding the two approaches. Results of ongoing trials are eagerly awaited to shed more light on the subject

References 1.

Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute

The counter argument that the initial strategy should be primary percutaneous coronary intervention (PPCI) of the IRA-only was made by Dr Suliman who presented the evidence cited below: • All studies did not demonstrate a mortality benefit and event rates were primarily driven by the need for repeat revascularisation. • All studies cited above performed complete revascularisation on the IRA-only without any attempt to risk-stratify the haemodynamic significance of the lesions in the non-IRA vessels using non-invasive testing. The Prague 13 trial, which excluded patients with angina more than a month before STEMI, was equivocal. • Patients with left main stem or proximal significant disease in the N-IRA should undergo full revascularisation with PCI or coronary artery bypass grafting (CABG). • FFR is not available in most cardiac catheterisation laboratories on the African continent. • On average, one to two extra stents were used in patients undergoing complete revascularisation and extra contrast was used, adding a significant financial burden. Such valuable resources can be shifted to perform more primary angioplasty procedures for STEMI patients.

myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39(2): 119–177. 2.

Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventative angioplasty in myocardial infarction. N Engl J Med 2013; 369(12): 1115–1123.

Gershlick, AH, Khan, JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015; 65(10): 963–972.

Engstrøm T, Kelbæk H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3— PRIMULTI): an open-label, randomised controlled trial. Lancet 2015; 386(9994): 665–671.

Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserveguided multivessel angioplasty in myocardial infarction. N Engl J Med 2017; 376(13): 1234–1244.

Hlinomaz O, Groch L, Poloková K, et al. Multivessel coronary disease diagnosed at the time of primary PCI for STEMI: complete revascularization versus conservative strategy. PRAGUE-13 trial. Kardiol Rev Int Med 2015; 17: 214–220.

South Africa–Cuba medical training programme: flawed but successful After more than 20 years, the contentious South Africa– Cuba medical training programme is being downscaled. Business Day’s Tamar Kahn assessed the situation as the largest-ever cohort of 720 students prepares to return to embark on local clinical training. More than 20 years ago, Desmond Kegakilwe left Tlakgameng village in rural North West to study medicine in Cuba. According to a Business Day report, back then there were few local doctors serving in his community and little hope for young people from underprivileged backgrounds who aspired to a medical career. Today he is the acting clinical manager at Ganyesa District Hospital near Vryburg, and five of the eight doctors employed at the rural facility are Cuban-trained South Africans. ‘Obviously it was not an easy route, but rural areas now have permanent South African doctors who can speak the language of their patients. Some of us would never have had the opportunity to study medicine in South Africa,’ Kegakilwe says.

The report says South Africa began sending aspirant doctors to train in Cuba in 1997 under a deal that also saw Cuba send its doctors to work in South Africa’s rural areas. The South Africans joined students from all over the world taking advantage of the many medical schools created under Fidel Castro’s watch to provide personnel for his country’s free universal healthcare system. South Africa recruited bright young people from underprivileged backgrounds and sent them to Cuba on bursaries that required them to work for an equal number of years in the state sector after they had qualified. But, the report says, the programme was contentious from the beginning, as the ANC-led government maintained close political ties to Castro, in recognition of his support for the organisation when it was in exile during apartheid.

continued on page 264…

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Feasibility of south–south collaboration in Africa: the Uganda–Mozambique perspective Judith Namuyonga, Peter Solomon Lwabi, John Omagino, Magdi Yacoub, Ana Olga Mocumbi

Keywords: cardiovascular research, south–south partnerships, Uganda–Mozambique Cardiovasc J Afr 2018; 29: 262–263

www.cvja.co.za

DOI: 10.5830/CVJA-2018-030

Existing collaborations in health have been common between developed countries (north) and low-income countries (south). Not only have such partnerships developed capacity in African institutions, they have also enhanced skills transfer and increased research.1 Uganda and Mozambique are low-income countries (LICs) located in the eastern part of the African continent that have much in common. The health budgets of both countries are less than 15%, as documented in the Abuja Declaration by African heads of state and the World Health Organisation.2 High infant and maternal mortality rates occur in these nations, as well as chronic diseases of poverty such as rheumatic heart disease (RHD) and endomyocardial fibrosis (EMF), among others.3,4 We report here on an experience of collaboration between two institutions from these LICs using small budgets for mentorship in research and speciality training, with a focus on poverty-related cardiovascular diseases.

Existing partnerships The Uganda Heart Institute (UHI) is the only centre in Uganda mandated by an act of parliament to offer cardiovascular services, including diagnosis, open-heart surgery and training of doctors, nurses and other health professionals. The Institute has had some collaboration with foreign teams from the USA and UK.5 On the other hand, Mozambique has a heart institute that functions as a private not-for-profit organisation, and a national referral public hospital, both offering comprehensive cardiovascular services, including catheterisation laboratories and open-heart surgery, supported by collaborations with universities Uganda Heart Institute Ltd, Kampala, Uganda Judith Namuyonga, MB ChB, MMed, F paed cardiology, jnamuyonga@gmail.com Peter Solomon Lwabi, MB ChB, MMed, FCard John Omagino, MB ChB, MMed, F Cardiac Surgery

Imperial College of London, UK; Aswan Heart Centre, Cairo, Egypt Magdi Yacoub, MB ChB, MMed, F Cardiac Surgery, PHD

Mozambique Institute of Health Education and Research (MIHER); Instituto Nacional de Saúde; Universidade Eduardo Mondlane, Maputo, Mozambique Ana Olga Mocumbi, MB BCh, FRCS, PhD

and hospitals from the UK, Switzerland, Portugal, France, USA and Spain.1 Mozambique has also prioritised research into neglected cardiovascular diseases through its National Health Institute and the Eduardo Mondlane University.

Rationale One of the most neglected cardiovascular diseases, EMF, is prevalent in certain areas of Mozambique and Uganda, where it is an important cause of heart failure. This restrictive cardiomyopathy usually affects underprivileged young people living in remote rural areas. Whereas Uganda pioneered EMF-related research in the 40s,6 the most recent studies have emerged in Mozambique, in a rural coastal district of Inharrime, near Maputo.4 EMF was first described in Uganda by Davies in 1948,6,7 who reported biventricular involvement in over 50% of the autopsies and a 14% prevalence. In the 1970s, Somers and colleagues demonstrated a familial component of EMF.8 More recently, Mocumbi et al. used portable cardiac ultrasound to assess EMF prevalence in the general population in Inharrime, which was found at 18.9%.3 Diagnostic criteria are currently based on echocardiography,4 which increases sensitivity and is becoming increasingly accessible in the affected countries. The aetiology of EMF has been linked to genetic and environmental factors,4,9 but the exact cause of the disease remains unknown. Clinical features depend on the severity of the disease10 and how affected the ventricles are, and characteristically include prominent ascites disproportionate to little or no lower-limb oedema. Death usually results from heart failure, thromboembolism and arrhythmias.11 Among individuals with advanced disease, surgery has shown substantial benefits,12 but remains challenging and palliative, as it improves symptoms only, carrying high morbidity and mortality rates.13 Therefore, visiting teams to endemic areas are not keen to operate on such cases.

Mozambique–Uganda collaboration: feasibility study on 10-year follow up of EMF While cases of EMF in Uganda seem to have reduced over the years, the reverse is true in Mozambique. A comprehensive programme has been started by Mozambique to understand the epidemiology, clinical characterisation and natural history of the disease, and to explore new therapeutic options. Teams of the UHI and NPHI (National Public Health Institute) decided to exchange knowledge by starting a collaborative project with both training and research arms. A paediatric cardiologist (Judith Namuyonga) from the UHI Paediatric Cardiology Department, mentored by Peter Lwabi, had a placement arranged in Mozambique’s NPHI, under the mentorship of the local principal investigator and paediatric

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cardiologist (AO Mocumbi), to participate in the feasibility study with a 10-year follow up. The presence of this Ugandan colleague was particularly important to strengthen the capacity of the Mozambican team to perform cardiac ultrasound in the field, a crucial part of the follow-up study that can only be performed by the 16 existing cardiologists in Mozambique. This exchange occurred between 5 and 16 September 2017 in Maputo city and in the rural district of Inharrime, located 400 km from Maputo. The study was co-funded by the NPHI and UHI, as well as the Aswan Heart Centre and Chain of Hope, where EMF surgery will potentially be done for selected patients, owing to the presence of Prof Magdi Yacoub, who has in-depth experience on the surgical approach to the disease and mentored Mocumbi in her post-graduate studies.12,14 This personnel link has now been used to promote exchange of researchers between Mozambique, Uganda and Egypt, through projects focusing on the epidemiology and management of EMF. Research mentorship consisted of skills transfer in grant application processes, including acquisition of unique Data Universal Number System (DUNS) number, data management, budgeting and use of electronic platforms for data entry. The use of research administration number (eRA Commons D) was also introduced to Namuyonga. The mentor (Mocumbi) and the mentee/fellow (Namuyonga) travelled from Maputo to Inharrime where the team held several preparatory meetings with the village local leaders and did house-to-house visits. Portuguese is the national language and was the most frequently used medium of communication, which was a limitation to Namuyonga during the family visits. Therefore she was in charge of performing cardiac ultrasound while Mocumbi consulted participants, collected clinical history and took verbal autopsy, whenever applicable. Using GPS, we were able to find all houses previously visited, and have obtained consent from all heads of households. In this early study phase, we visited 25 locations from four administrative areas, where we performed 31 cardiac ultrasounds. Extreme poverty was noted in this geographic area, coupled with the dry tropical weather. Few gardens of cassava were seen, most people could only afford a single meal a day, and there was low access to clean water.

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and the initiation of other projects on cardiovascular risk factors in young populations. As African trainees do not easily get hands-on training in affluent/well-developed nations, this kind of collaboration could be one of the avenues to overcome this problem in certain areas of clinical and research training. South-to-south research collaboration projects may be a platform to foster these partnerships and promote efficient use of resources in underserved areas.

References 1.

Mocumbi AO. African experiences of humanitarian cardiovascular medicine: the Mozambican experience. Cardiovasc Diagn Ther 2012; 2(3): 246–251.

Valfrey MV, Umarji MB. Sector Budget Support in Practice: Health Sector in Mozambique, 2010.

Okello E, Longenecker C, Beaton A, Kamya MR, Lwabi P. Rheumatic heart disease in Uganda: predictors of morbidity and mortality one year after presentation. BMC Cardiovasc Disord 2017; 17: 20.

Mocumbi AO, Ferreira MB, Sidi D, Yacoub MH. A population study of endomyocardial fibrosis in a rural area of Mozambique. N Engl J Med 2008; 359: 43–49.

Aliku TO, Lubega S, Namuyonga J, Mwambu T, Oketcho M, Omagino JO, et al. Pediatric cardiovascular care in Uganda: Current status, challenges, and opportunities for the future. Ann Pediatr Cardiol 2017; 10(1): 50–57.

Davies JNP. Endomyocardial fibrosis in Uganda. East Afr Med J 1948; 25: 10–16.

Davies JNP, Ball JD. The pathology of endomyocardial fibrosis. Br Heart J 1955; 17(3): 337–359.

Somers K. Proceedings of the 3rd Asian Pacific Congress on Cardiology. Int J Cardiol 1964; 1: 162.

Beaton A, Sable C, Brown J, Hoffman, Mungoma M, Mondo C, et al. Genetic susceptibility to endomyocardial fibrosis. Glob Cardiol Sci Pract 2014: 60.

10. Grimaldi A, Mocumbi AO, Freers J, Lachaud M, Mirabel M, Ferreira Bea. Tropical endomyocardial fibrosis: natural history, challenges, and perspectives. Circulation 2016; 133: 2503–2515. 11. Tharakan JA. Electrocardiogram in endomyocardial fibrosis. Ind Pacing Electrophysiol J 2011; 11(5): 129–1333.

Immediate outcomes

12. Bogere H, Tucciarone A. Experts in landmark heart surgery at Mulago.

This report demonstrates the feasibility of collaboration between LICs in sub-Saharan Africa, including clinical research mentorship, the conduction of high-quality, patient-orientated research, and community-based research. Immediate outcomes were the reinforcement of Mozambique’s capacity for performing field ultrasound, creation of a network of three African countries,

13. Moraes F, Lapa C, Hazin S, Tenorio E, Gomes C, Moraes CR. Surgery

The Observer 5 June 2012. for endomyocardial fibrosis revisited. Eur J Cardiothorac Surg 1999; 15(3): 309–312. 14. Mocumbi AO, Sidi D, Vouhe P, Yacuob M. An innovative technique for the relief of right ventricular trabecular cavity obliteration in endomyocardial fibrosis. J Thorac Cardiovasc Surg 2007; 134: 1070–1072.

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Critics questioned the wisdom of training doctors in a country with a vastly different burden of disease, along with a completely different approach to healthcare that emphasised prevention rather than cure. The government’s defence was that South Africa needed more doctors, and local medical schools did not have the capacity to immediately expand their student intake. The initiative was neither efficient nor cheap, the report says. Although the cost of living was lower in Cuba, the students took at least two years longer to qualify than their locally trained peers. They spent a year learning Spanish before they could begin their medical training and required more time to adjust to South African medical schools after their return. Although the students obtained a Cuban medical degree, they were required to pass South African final-year medical exams to graduate and register with the Health Professions Council of South Africa. Many students found the adjustment to life in Cuba daunting, and their return to South Africa as difficult. ‘The South African students were more fluent with the terminology, the equipment was different, and we were thinking in Spanish. ‘But the worst part was the lecturers: they didn’t provide support and (some) would tell us to our faces, “you are dumb … you will fail”,’ Kegakilwe is quoted in the report as saying. His cohort was ill-prepared for the trauma and infectious diseases affecting South African patients, particularly the horror of the HIV epidemic. ‘It was before the ARV (antiretroviral) roll-out and we were seeing patients with fullblown AIDS and its complications,’ he says. ‘But if you have the basics right, wherever you go, you can adapt,’ Kegakilwe says. The report says now Cuban-trained students appear to be getting a better reception from medical students who trained locally than they did in the past. ‘When we came back, they taught us how to tackle questions and get used to the systems here. We integrate well, and the students don’t look down on you. But some lecturers say that we haven’t learnt enough skills,’ says Cedrick Thete, a Cuban-trained medical student from Bushbuckridge in Mpumalanga, who is completing his studies at the University of the Witwatersrand. ‘Yet the system in Cuba is better: they taught us how to work without technology, deal with prevention and study a community to identify risk factors for disease.’ Initially the number of students sent to Cuba each year was fairly small but, in 2012, Health Minister Aaron Motsoaledi announced an almost 10-fold increase in the size of the training programme. At that stage, South Africa’s eight medical schools were producing a mere 1 200 graduates a year

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– a figure that remained flat for more than a decade despite the growing population and the soaring HIV epidemic. The plan then was to increase the number of students going to Cuba to about 500 a year. In the end, the report says, a far higher figure left for Cuba and about 720 Cuban-trained students are due to return to South Africa in July – the biggest cohort to enrol into the system at once. While they were studying, medical schools have steadily increased their enrolments and 1 800 doctors are expected to graduate this year, according to Martin Veller, chair of the South African Committee of Medical Deans. Medical schools and provincial health departments now have to gear up to integrate an unusually large number of students at undergraduate level and provide the clinical training platform they need to get vital hands-on experience. ‘We are wrestling with how to adapt the curriculum,’ says Lionel Green-Thompson, assistant dean for teaching and learning in the Faculty of Health Sciences at Wits University, who recently visited Cuba with deputy health minister Joe Phaahla to assess the programme. ‘Their skill set is very similar to South African-trained students, but this needs to be supplemented with additional competencies to deal with the different burden of disease in South Africa, which includes a high level of trauma not seen in Cuba. The capacity of these students for primary healthcare is greater and we don’t want to erode that ethos,’ he is quoted in the report as saying. Wits is expecting to take about 150 students for their final round of training. Discussions are under way with the Treasury to ensure that provinces have the requisite budgets to provide for the increased number of internship and community service posts that will be required after the Cuban-trained students and the enlarged cohort of locally qualified doctors graduate, says the health department’s chief director for human resources, Gavin Steel. Internships have historically been conducted at large hospitals. However, they may in the future also take place at smaller facilities, while community service for Cuban-trained doctors is likely to take place in a primary healthcare setting, Steel says. Motsoaledi said recently that the Cuban doctor-training programme was so big it was a headache for both countries, and the National Health Council had decided it should be temporarily scaled back but Steel says in the report that it is likely that there will always be a place for Cuban medical training but the numbers are likely to diminish significantly as local training capacity grows. ‘The programme had two targets: increase the number of medical graduates and provide opportunities for kids from disadvantaged backgrounds. If you look at it from that perspective it has been a success,’ he says. Source: Medical Brief 2018

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Case Report Cases in a series of carcinoid syndrome and carcinoid heart disease Mamotabo R Matshela

Abstract Although carcinoid syndrome is regarded as a rare entity, carcinoid patients with evidence of cardiac involvement show a markedly reduced survival time. Patients with advanced signs of right-sided heart failure represent a subgroup at particularly high risk. Echocardiography remains the gold standard to diagnose or confirm structural cardiac involvement in patients with underlying carcinoid disease. This is the notion that propelled us to report on cases of carcinoid syndrome with cardiac involvement. We also review carcinoid syndrome and carcinoid heart disease, and challenges regarding the diagnosis and management of carcinoid heart disease. Keywords: carcinoid syndrome, carcinoid heart disease, 5-hydroxyindoleacetic acid Submitted 20/9/17, accepted 24/6/18 Cardiovasc J Afr 2018; 29: e1–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2018-040

Carcinoid heart disease (CHD) has previously been reported as a rare form of valvular heart disease, mostly associated with metastatic carcinoid tumour. Most systemic manifestations of carcinoid tumours are related to the release of vasoactive University of KwaZulu-Natal, Durban, South Africa; Mediclinic Heart Hospital, Pretoria, South Africa; London School of Economics and Political Science, London, UK Mamotabo R Matshela, MB ChB, PhD, FESC, matshela.mamotabo@mayo.edu, mamotabomatsh@gmail.com

substances from the tumour, including serotonin and other circulating humoral substances. Although CHD is presumed to be rare, we use this opportunity to report on a collection of interesting patients with CHD, who presented differently and posed challenges in their short- and long-term management.

Case report Seven patients with carcinoid and cardiac involvement are summarised in Table 1. However, two of these patients with classical echocardiographic images were extensively reviewed and are reported on below. Patient 1: The first patient was a 78-year-old African male who first presented to his local hospital with constitutional symptoms and abdominal distension, which progressed over a four-month period. He was later referred to us for further management. This was his first-ever consultation and admission to any medical facility. There was no past surgical or medical history of note and no history of illicit drug use. However he was an occasional drinker and a smoker with a three-pack year history. He had no family history of note. Physical examination revealed skin hyperpigmentation, lower abdominal mass and features of severe tricuspid regurgitation with right heart failure. The rest of his clinical examination was unremarkable. Carcinoid syndrome with CHD was suspected during routine transthoracic echocardiographic assessment, and his images are shown in Fig. 1. His biochemical laboratory results revealed a markedly elevated serum 5-hydroxyindoleacetic acid (HIAA), which was more than 10 times the upper limit of normal. An octreotide scan was positive for the primary lesion localised around the periprostatic area. Additional blood results revealed normal renal and hepatic function. His full blood count revealed features in

Table 1. Summary of patients with confirmed carcinoid syndrome and carcinoid heart disease Parameters

Patient 1

Patient 2

Patient 3

Patients 4

Patient 5

Patient 6

Age, years

Male

Female

Male

female

< 200

Gender Urinary 5-HIAA, µmol/24 h Echo features

Octreotide scan Hepatic lesions on CT Management Follow up

406–548

465–269

< 300

< 200

Restrictive TV leaflet motion, torrential TR

Restrictive TV and PV leaflets motion

Moderately restrictive TV leaflet motion

Mildly restrictive TV leaflet motion

Moderately restrictive TV leaflet motion

Patient 7

Mildly restrictive Mildly restrictive TV leaflet motion TV leaflet motion

Multiple

One

None

Multiple

None

Declined surgery

TVR

Medical management

Died

Improved

Died

Improved

5-HIAA, 5-hydroxyindole acetic acid; TV, tricuspid valve; TR: tricuspid regurgitation, TVR, tricuspid valve replacement; PV, pulmonary valve.

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Fig. 1. P atient 1. (A) Apical four-chamber view showing tricuspid leaflets that are thickened and retracted (arrows). The right ventricle and atrium are dilated. (B) Colour Doppler with free flow through the tricuspid valve during systole in a parasternal short-axis view at the level of the aortic valve (arrow).

keeping with anaemia of chronic diseases. The prostate-specific antigen level was mildly elevated. Chest radiography revealed a mildly increased cardiothoracic ratio and hyperinflated lungs. Unfortunately, the patient refused further hospital management, including surgery, and died a year later. Patient 2: The second patient was a 32-year-old male of Indian descent who presented with a two-month history of abdominal pain, weight loss and diarrhoea. He had no significant past medical, surgical, family or occupational history. A

His clinical examination revealed features of right heart failure with severe tricuspid and moderate pulmonary valve regurgitation. The rest of his examination was unremarkable. Chest radiography revealed a mildly increased cardiothoracic ratio and an electrocardiogram revealed sinus rhythm. Blood results revealed mild pre-renal dysfunction, anaemia of chronic disease, normal liver function test and normal comprehensive metabolic panel. Further biochemical results revealed an elevated 5-HIAA level and prior to referral, his private practitioner had C

Fig. 2. P atient 2. (A) Apical four-chamber view: note the thickened, immobile and retracted tricuspid leaflets and minimally thickened mitral valve leaflets (arrows), and the dilated right atrium and ventricle. (B) Torrential tricuspid regurgitation (note the arrow). (C) Marked failure of coaptation (indicated by arrows) of the tricuspid valve leaflets.

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Fig. 3. P atient 2. Computed tomography scan. Notice a large echogenic mass on the right lobe of the liver, and further multiple echogenic masses on both lobes (arrows).

already commenced medical therapy, which included octreotide. Two weeks later the patient was referred for a specialistâ&#x20AC;&#x2122;s opinion and further management. His echocardiographic and computed tomographic images are presented in Figs 2 and 3, respectively. His symptoms improved dramatically on medical therapy and he was subsequently referred to the surgical team, where an elective tricuspid valve replacement (TVR) was successfully performed six months later. His intra-operative and postoperative periods were uneventful, and his symptoms continued to improve on subsequent follow-up visits.

Discussion Prevalence of carcinoid syndrome and CHD Reports have indicated that at least 50% of patients with clinical manifestations of carcinoid syndrome present with echocardiographic evidence of cardiac or cardiovascular involvement.1-5 At least a quarter of carcinoid patients with cardiac manifestations present with right-sided cardiac disease. Although CHD is undoubtedly regarded as a rare entity, it is an interesting and important cause of intrinsic tricuspid and pulmonary valve disease and is associated with significantly high morbidity and mortality rates. Tricuspid and pulmonary valve regurgitations usually occur as secondary phenomena due to dilatation of the valve annular ring, secondary to right ventricular failure or as a result of severe pulmonary hypertension. Previous reports have indicated that the incidence of carcinoid tumours occurs at a rate of 1.2 to 2.1 in 100 000 of the general population.6,7 In most instances, at the time of diagnosis, 20 to 30% of patients present with carcinoid syndrome and approximately 50% of these patients develop CHD, which typically causes abnormalities of the right side of the heart.5,8,9 In an estimated 20% of patients with carcinoid tumours, CHD is

the primary presentation of the metastatic carcinoid disease.5,8,9 Although it is usually believed that carcinoid tumours that have hepatic involvement are highly associated with pathological cardiovascular damage, particularly right-sided cardiac involvement related to the large amount of metabolic products reaching the heart, a small proportion of patients, around five to 10%, present with significant left-sided disease due to direct blood flow from the right to the left side of the heart, or in some cases related to the presence of a primary lung tumour. In addition, cardiac manifestations of carcinoid syndrome could also be related to the paraneoplastic effects of vasoactive substances released by malignant cells rather than any direct metastatic involvement of the heart. Most importantly, patients with progressive cardiac disease tend to have higher levels of these vasoactive substances compared to those without cardiac disease.

Cardiac and cardiovascular structural changes in CHD Typical pathological features of CHD are plaque-like deposits of fibrous tissue deposited on the endocardium of the valvular cusps and leaflets, atria and ventricles, sometimes involving the downstream aspects of the tricuspid and pulmonary valves, endocardium of the cardiac chambers, intima of the vanae cavae, pulmonary artery and coronary sinus (Figs 1, 2). Although the fibrous tissue may result in distortion of the valves, the morphology of the valve leaflets is classically not disrupted. However, the endocardial thickening may lead to valve retraction and fixation (Figs 1, 2). The tricuspid valve is most commonly involved, with typical tricuspid valvular regurgitation and rarely stenosis. The pulmonary valve is the second most commonly affected, presenting as mixed pulmonary valve disease. Pulmonary stenosis is more frequently noted, compared with tricuspid

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stenosis, due to the smaller orifice of the pulmonary valve and also due to plaque deposition on the pulmonary valve, within the pulmonary annulus and sinuses, results in narrowing of the pulmonary roof. In rare situations, primary ovarian carcinoid disease may lead to CHD without evidence of hepatic metastases because the ovarian vein drainage bypasses the portal circulation. This pathognomic mechanism was previously reported in four patients from the Mayo Clinic.10 The sub-valvar apparatus, including the tendinous chords and papillary muscles of the mitral valve, could also be affected in rare instances where the left side of the heart is involved. The mitral and/or aortic valves are frequently involved in patients with right-to-left shunt or primary bronchial carcinoma. Metastatic involvement of the myocardium is uncommon; however, it has been reported.11 The Mayo Clinic previously reported 132 carcinoid syndrome patients, where a total of 74 (56%) patients had echocardiographic evidence suggestive of CHD. A total of 62 (90%) of the 74 patients had moderate to severe tricuspid valve regurgitation and 36 (49%) developed thickened, retracted, immobile pulmonary leaflets.10 In the same report, pulmonary regurgitation and stenosis were demonstrated in 81 and 53% of the patients, respectively.10 Only five patients (7%) had left-sided CHD and four (5%) of these had a patent foramen ovale or lung carcinoma.10 Myocardial metastases were also reported in only three (4%) patients and 10 (14%) had small pericardial effusions.

Natural history and controversies of CHD Cardiac involvement in carcinoid syndrome heralds a decline in clinical outcome with poor survival rate without treatment. The previous three-year mortality rate data on CHD patients had indicated only a 31% survival rate, compared with approximately twice the survival rate for patients without cardiac involvement.5 Treatment of the cardiac aspects of carcinoid syndrome improves symptoms and increases longevity in carcinoid patients.4 Previously, a small study evaluated and reported on a total of 71 patients with carcinoid syndrome, who had serial echocardiograms performed a year apart, and retrospectively assessed factors that were associated with progression of cardiac disease.8,9 Although serotonin level was associated with progression of CHD, the risk of progressive heart disease was also higher in those patients who received chemotherapy than in those who did not, which is very controversial. 8-9 In addition, Denney et al.12 reported that patients with carcinoid syndrome in whom heart disease developed had higher levels of serotonin before and after treatment with somatostatin analogue, compared with patients without cardiac lesions. Their data also reported similar finding in patients with pre-existing heart disease not related to carcinoid syndrome. In addition, peaked levels of 5-HIAA were also a significant predictor of progressive CHD and were reported to be markedly increased in patients with severe symptomatic heart disease who were referred for cardiac surgery.8,12-16

Diagnosis of CHD Clinical presentations: usually a high index of clinical suspicion is needed to diagnose CHD. The time interval from the onset of carcinoid symptoms to the diagnosis of CHD is usually

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approximately two years, however it may take as long as five years.5 Patients with florid or classical carcinoid symptoms have a 50% chance of cardiac involvement.5 The physical examination will usually reveal features of regurgitant lesions and most commonly a pansystolic murmur of tricuspid regurgitation along the left sternal border. In some cases, there may be a concomitant murmur of pulmonary stenosis or regurgitation or both. A careful interpretation of the jugular venous pressure is crucial when assessing patients with suspected CHD. The classical large V wave may be the first finding on physical examination, suggestive of significant tricuspid regurgitation. Biochemical screening: clinical suspicion of carcinoid syndrome or CHD usually leads to further evaluation, including biochemical screening, with the measurement of urinary 5-HIAA excretion. The biochemical measurement of 24-hour urinary 5-HIAA excretion has shown a sensitivity and specificity of 75 and 100%, respectively, for the diagnosis of carcinoid syndrome.7 Measurement of blood serotonin levels of an alternative biochemical marker such as plasma chromogranin A may be helpful if the urinary test is inconclusive. Chest radiography: a chest radiograph and electrocardiogram have limited value in diagnosing CHD. A chest X-ray is usually normal in at least 50% of patients and in the remainder it may be non-specific. Other radiographic features in carcinoid patients with CHD include cardiac enlargement and pleural effusions or nodules. Electrocardiography:5,8,15 in most cases, electrocardiograms are normal in patients with carcinoid syndrome or CHD, however, in severely symptomatic patients, usually low QRS voltages or poor R-wave progression have been reported, and this usually occurs in patients with advanced cardiac disease. The non-specific abnormal findings in CHD patients may include STâ&#x20AC;&#x201C;T-wave abnormalities, sinus arrhythmias, P pulmonale or right bundle branch block.

Fig. 4. Continuous-wave Doppler demonstrating a daggershaped pattern in a patient with severe tricuspid regurgitation due to carcinoid heart disease, with early peak pressure and a rapid decline. In addition, the patient had marked failure of coaptation (FOC) resulting from severely thickened and retracted tricuspid valve leaflets due to underlying carcinoid disease (image courtesy of Fox and Khattar).5

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Transthoracic echocardiography (2D-TTE): this remains the gold standard during the initial diagnostic evaluation of any patients suspected of CHD. Classical 2D-TTE findings will include thickened and shortened tricuspid valve (TV) leaflets. Similar to our two cases, the TV leaflets may become severely retracted, with reduced leaflet mobility. In most instances, the septal and anterior TV leaflets are predominantly affected (Figs 1, 2). In advanced stages of TV disease, the leaflets may become fixed in the semi-open position (Figs 1, 2). Similar to the tricuspid valve, pulmonary valvular cusps usually appear thickened, with retraction and reduced leaflet mobility, and it may be difficult to visualise them during routine echocardiographic evaluation. Doppler echocardiographic assessment of the pulmonary valve may be helpful as there are challenges related to difficulties in demonstrating anatomical changes. The right atrium and ventricle may become increasingly dilated over time (Figs 1, 2). A dagger-shaped profile with an early peak velocity and a rapid decline, which indicates rapid pressure equalisation between the right atrium and ventricle, is a common finding during continuous-wave Doppler tracing in CHD patients presenting with severe tricuspid regurgitation (Fig. 4).

Management strategies for CHD The principal management strategies in CHD patients should strictly focus on primary treatment of right heart failure, therapy to reduce secretion of tumour product, and valve surgery. Medical management: medical treatment modalities for right heart failure in patients with CHD include standard heart-failure therapy. However these strategic approaches have not been proven effective in most patients with CHD. Somatostatin analogue, particularly octreotide, has a direct effect on reducing the vasoactive peptides and has demonstrated direct clinical benefit and biochemical improvement. Alternatively, lanreotide, which has the advantage of less frequent administration compared with octreotide, may be a good option. Reports have indicated that somatostatin analogue has demonstrated symptomatic relief and a decrease in measurable urinary 5-HIAA excretion and serum serotonin concentration.10 Newer treatment options include the leukocyte interferonalpha, which may be used in conjunction with somatostatin antagonist. However data on this treatment option are limited. Cardiac surgery: asymptomatic patients or those who exhibit minimal symptoms usually need closer follow up with regular transthoracic echocardiography and exercise testing to assess their functional status. Patients who develop severe cardiovascular symptoms related to CHD should be evaluated for valve-replacement surgery. For suitable candidates, valve surgery is the only definitive curative treatment modality for severe heart failure. Although reports have implicated balloon valvoplasty as an alternative and it has produced symptomatic improvement in some patients with stenotic valve lesions related to CHD, data on its application in CHD patients are limited.17 Indications for surgery: right heart-failure symptoms, severely impaired exercise capacity, progressive right ventricular enlargement or decline in right ventricular systolic function are some of the indications for surgical intervention in CHD patients. However, some patients with severe CHD may require cardiac valve surgery despite minimal cardiac symptoms.

Although tricuspid mechanical valve prostheses may be considered adequately durable and relatively unaffected by vasoactive substances, bioprosthetic valves may be preferable since anticoagulants can be avoided.17-39 Due to high bleeding tendencies in patients with hepatic metastases, bioprosthetic valves would be the best option for this group of patients. However, the life expectancy of bioprosthetic tricuspid valves is likely to be shorter than that of mechanical valves, particularly in CHD. Tricuspid valve repair could be an option and important area of future research, however currently, tricuspid valve repair does not seem feasible in CHD. Pulmonary valvectomy or valve replacement is preferred for those with pulmonary valve disease secondary to carcinoid disease. Although pulmonary valve replacement may reduce the risk of right heart dilatation postoperatively, larger studies with more convincing results are warranted. Successful surgical intervention has been associated with an improvement in survival rate and quality of life in those patients who were successfully treated surgically. Despite this premise, older patients (over the age of 60 years) remain a high surgical risk group, with an associated high death rate, which is even higher in those with significant co-morbidities. Peri-operative management: the surgical approach for CHD patients requires a highly skilled multidisciplinary team with broad experience, as anaesthesia can trigger carcinoid crisis and subsequent death in patients going for surgery.26,40-57 The most crucial pre-operative anaesthetic management should encompass optimum control of carcinoid symptoms, and intensified and close monitoring of intra-operative blockade of serotonin receptors. Drugs that may stimulate the release of vasoactive substances from tumour cells should be avoided.26,40-57 The most important drugs to be avoided during the peri-operative period include histamine-releasing neuromuscular relaxants and opioids, as they are associated with detrimental outcomes in CHD patients. The introduction of somatostatin analogues remains a key component to prevent peri-operative carcinoid crisis, and the administration of larger doses of somatostatin analogue is highly recommended in CHD patients.

Prognosis of CHD Previous studies have reported outcome differences between carcinoid syndrome patients with versus those without CHD, and demonstrated markedly shortened life expectancy in patients with underlying cardiac involvement.8,9 Patients with right heart failure and those with advanced signs of right-sided heart failure represent a subgroup of patients at high risk. Progression of CHD contributes to poor survival; as a result, early detection and regular follow up are mandatory in the management algorithm of patients with CHD.8,9 Levels of 5-HIAA should be closely monitored, as this is an independent predictor for the development or progression of CHD while on or even after medical management. Although, it was believed that optimal control of serotonin release may prevent or delay development of early cardiac lesions, reports have indicated that somatostatin analogues, chemotherapy and hepatic de-arterialisation may not sufficiently counteract the pathophysiological mechanisms involved in the causation and progression of valvular heart lesions.8,9 Surgical valve replacement reduces heart-failure symptoms

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and is associated with improvement in a patient’s functional state. However, a significantly high 30-day mortality rate, which is attributed to bleeding complications, intractable heart failure and other concomitant co-morbidities, has been a major drawback. According to the Duke carcinoid database, supported by other databases, older age, particularly over 60 years of age, is an important independent risk factor for high peri-operative complications and is also associated with high mortality rates.55-59

Conclusion

11. Davis G, Birbeck K, Roberts D, Naqvi N. Nonvalvular myocardial

Moller JE, Pellikka PA, Bernheim AM, Schaff HV, Rubin J, Connolly HM. Prognosis of carcinoid heart disease – Analysis of 200 cases over two decades. Circulation 2005; 112: 3320–3327.

Moller JE, Connolly HM, Rubin J, et al. Factors associated with the progression of carcinoid heart disease. N Engl J Med 2003; 348: 1005–1015.

10. Pellikka PA, Tajik AJ, Khandheria BK, Seward JB, Callahan JA, Pitot HC, Kvols LK. Carcinoid heart disease – Clinical and echocardiographic spectrum in 74 patients. Circulation 1993; 87: 1188–1196.

At least half of the patients with carcinoid syndrome present with structural heart disease, usually evidenced during routine transthoracic echocardiographic examination. Although carcinoid heart disease is undoubtedly regarded as a rare form of structural heart disease, a strong suspicion should be raised in patients with classical or florid carcinoid syndrome. Although echocardiography remains the gold standard for diagnostic and confirmatory purposes, biochemical screening and imaging for primary carcinoid tumour should form an integral part of the diagnostic algorithm. Valve replacement is associated with significant improvement in heart-failure symptoms and improves patients’ functional capacity. However, stringent peri-operative management is vital to avoid carcinoid crisis and impending death. Although there are no definite stringent criteria for the choice of an artificial valve, mechanical valve prostheses are considered durable as they are not affected by vasoactive substances. However bioprosthetic valves should be preferred to avoid long-term anticoagulation. Early detection and valve surgery should be considered to avoid the development of right heart failure, as advanced heart failure represents a high-risk subgroup. In patients with advanced heart failure and possible advanced myocardial dysfunction, transplantation could be an option.

involvement in metastatic carcinoid disease. Postgrad Med J 1996; 72: 751–752. 12. Denney WD, Kemp WE Jr, Anthony LB, Oates JA, Byrd BF III. Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease. J Am Coll Cardiol 1998; 32: 1017–1022. 13. Robiolio PA, Rigolin VH, Harrison JK, Lowe JE, Moore JO, Bashore TM, Feldman JM. Predictors of outcome of tricuspid-valve replacement in carcinoid heart disease. Am J Cardiol 1995; 75: 485–488. 14. Lundin L, Norheim I, Landelius J, Oberg K, Theodorsson-Norheim E. Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation 1988; 77: 264–269. 15. Westberg G, Wangberg H, Ahlman C, et al. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg 2001; 88: 865–882. 16. Joy T, Walsh GRN, Tokmakejian S, van Uum SH. Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over-the-counter 5-hydroxytryptophan intake. Can J Gastroenterol 2008; 22: 49–53. 17. Onate A, Alcibar J, Inguanzo R, Pena N, Gochi R. Balloon dilation of tricuspid and pulmonary valves in carcinoid heart disease. Tex Heart I J 1993; 20: 115–119. 18. Takahashi H, Okada K, Asano M, Matsumori M, Morimoto Y, Okita Y. Bioprosthetic pulmonary and tricuspid valve replacement in carcinoid

I thank the Servier Programme for Registrars in Cardiology for their enthu-

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siasm and dedication and the support they offered me for the abstract I

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