CVJA Volume 25 Issue 4 by Clinics Cardive Publishing

JULY/AUGUST 2014 VOL 25 NO 4

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Cognitive decline: role of the RAAS • Sudden cardiac death in Africa • Ambulatory blood pressure profiles in HIV-positive patients • Evaluation of African patients at risk of venous thrombosis • Infliximab in patients with rheumatoid arthritis • The Pan-African SCD study • Clinical applications of cardiovascular MRI

Cardiovascular Journal of Africa . Vol 25, No 4, July/August 2014

Printed by Tandym Printers

• Adverse effects of the ‘Noakes’ diet

PUBLISHED ONLINE: • Ross procedure used in Aspergillus endocarditis with bicuspid aortic valve

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References: 1. Jones PH et al. Comparison of the efficacy and safety of rosuvasorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial).Am J Cardiol 2003;92:152–160 2. IMS Data, July 2014 3. The Generics Dictionary, May/June 2014 4. Department of Health website http://www.doh.gov.za – referenced August 2014 S4 VUSOR 5: Reg. No: 45/7.5/0310. S4 VUSOR 10: 45/7.5/0311. S4 VUSOR 20: 45/7.5/0312. S4 VUSOR 40: 45/7.5/0313. Each tablet contains 5 mg, 10 mg, 20 mg or 40 mg of rosuvastatin respectively as rosuvastatin calcium. For full prescribing information see package insert. DETAILS OF THE REGISTERED LICENCE HOLDER: Watson Pharma No. 1 (Pty) Ltd, 1st Floor Block C, Sandton Close 1, Cnr 5th Street & Norwich Close, Sandown. MARKETED BY: Cipla Medpro (Pty) Ltd. Reg. No. 1995/004182/07,Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA. Tel (021) 943 4200, Fax (021) 914 4699. E-mail: medicalpa@ciplamedpro.co.za Website: www.cipla.co.za Customer Care: 080 222 6662

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

Vol 25, No 4, JULY/AUGUST 2014

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

147

From the Editor’s Desk

149

Cognitive decline: mechanisms and proposed role of the renin–angiotensin–aldosterone system LH Opie

P Commerford

Editorials

151 Sudden cardiac death in Africa A Chin

Cardiovascular Topics 153 Ambulatory blood pressure profiles in a subset of HIV-positive patients pre and post antiretroviral therapy M Borkum • N Wearne • A Alfred • JA Dave • NS Levitt • B Rayner 159 Epidemiological African day for evaluation of patients at risk of venous thrombosis in acute hospital care settings S Kingue • L Bakilo • JZ Minkande • I Fifen • YP Gureja • HJC Razafimahandry • N Okubadejo • R Mvuala • DA Oke • A Manga • T Rajaonera • C Nwadinigwe • E Pay Pay • N Rabearivony 165 Decline in mean platelet volume in patients with patent foramen ovale undergoing percutaneous closure B Düzel • NK Eren • R Berilgen • U Kocabaş • M Gönençer • C Nazli • O Ergene 168 Infliximab, an anti-TNF-alpha agent, improves left atrial abnormalities in patients with rheumatoid arthritis: preliminary results Ç Süha • VM Gökhan • K Göksal • Y Ekrem • D Mehmet • ÖM Akif 176

Rationale and design of the Pan-African Sudden Cardiac Death survey: the Pan-African SCD study A Bonny • M Ngantcha • SN Amougou • A Kane • S Marrakch • E Okello • G Taty • A Gehani • M Diakite • MA Talle • PD Lambiase • M Houenassi • A Chin • H Otieno • G Temu • I Koffi Owusu • KM.Karaye • AAM Awad • BG Winkel • SG Priori • on behalf of the Pan-African Society of Cardiology (PASCAR) Task Force on Sudden Cardiac Death

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 Renal Hypertension dr brian rayner

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease

Surgical dr f aziz

DR OB FAMILONI Clinical Cardiology

Adult Surgery dr j rossouw

DR V GRIGOROV Invasive Cardiology & Heart Failure

Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

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)

Review Article 185

Current clinical applications of cardiovascular magnetic resonance imaging L Scholtz • A Sarkin • Z Lockhat

In Memoriam

Vol 25, No 4, JULY/AUGUST 2014

CONTENTS

191 Donald Nixon Ross

Letter to the Editor 192 Adverse effects of the ‘Noakes’ diet on dyslipidaemia C Schamroth

Industry News 192

Cipla Medpro wins R280-million State therapeutic drugs tender

194

Clearing hurdles in anticoagulation therapy P Wagenaar

Drug Trend in Cardiology

195 Dedicated programme for paediatric cardiologists at SA Heart Congress 2014

Advertorial 196 Stroke prevention in non-valvular atrial fibrillation with rivaroxaban

PUBLISHED ONLINE (Available on www.cvja.co.za, Pubmed and in Pubmed Central) Case ReportS

e1 Ross procedure in a child with Aspergillus endocarditis and bicuspid aortic valve FA Mitropoulos • MA Kanakis • C Contrafouris • C Laskari • S Rammos • C Apostolidis • P Azariadis • AC Chatzis e4

Closure of ruptured aneurysm of the sinus of Valsalva using a native aortic valve leaflet P Buczkowski • M Walczak • S Stefaniak • M Puślecki • I Katyńska • M Jemielity

e7 A penetrating nail-prick injury of the lateral plantar artery leading to pseudo-aneurysm formation and rupture E Şişli • Aİ Hasde • M Mavi • S Dursun e10 Anaesthetic management of a newborn with trisomy 18 undergoing closure of patent ductus arteriosus and pulmonary artery banding O Arun • B Oc • M Oc • A Duman

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From the Editor’s Desk I am delighted to have been appointed Editor-in-Chief of the Cardiovascular Journal of Africa and believe it appropriate in this first issue in which I am involved to pay tribute to my predecessors, to acknowledge my previous error and express my hope that I can continue the traditions of the Journal. When the late Professor Andries Brink approached me as a newly appointed head of Cardiology at the University of Cape Town and Groote Schuur Hospital in the late 1980s with his innovative proposal for a uniquely South African cardiology journal, I was not enthusiastic. I responded with youthful arrogance and ignorance that ‘there were more than enough journals and we did not need another one’. How wrong that was! Professor Andries Brink forged ahead, despite widespread scepticism, founded the Cardiovascular Journal of South Africa and under his guidance and rigorous scholarship it became established and recognised as a repository for publications of quality, initially mainly from South Africa, but with increasing numbers from other countries. When Professor Andries Brink passed away, his son Professor Paul Brink single-handedly continued to edit and direct the Journal. I consider that the highpoint of its 25-year growth trajectory was the acceptance of the Journal as the official journal of the Pan-African Society of Cardiology (PASCAR) and its change of name to the current one of the Cardiovascular Journal of Africa. In 2014 it is difficult for those who did not personally experience the events of the decades prior to 1994 to understand or appreciate exactly how important the changes and developments post 1994 have been. In the 1980s, academic, clinical and scientific contact between South African cardiologists and our colleagues in most of the rest of Africa was negligible. South Africans faced academic boycotts from countries both within and without Africa. Travel to African countries for South Africans was extraordinarily difficult and it was equally difficult, if not more so, for colleagues from other African countries to visit South Africa. How wonderful to have experienced how things have changed for the better! Today there is vigorous interchange and interaction, with collegial participation at continental meetings, exchanges of trainees, and a generous willingness to share expertise throughout the continent. Very importantly, multicentre co-operative research into the diseases of Africa has been instituted, and hopefully in the near future, new insights facilitating the management of patients with diseases that are common in Africa will become available. Other multicentre epidemiological investigations and registries on the impact of conditions not previously investigated in depth in Africa, such as coronary artery disease and atrial fibrillation, have been remarkably successful. The Journal has been involved directly or indirectly in much of this. The two Professors Brink, Andries and Paul, deserve recognition for their major contributions to clinical medicine, cardiology and cardiovascular science, but very importantly also, for their role in helping to develop and grow a continental publishing initiative that is enhancing patient care, medical

training, and cardiovascular research in Africa. In this editorial I have tried to highlight some items of particular interest to me in the current issue. This is not comprehensive and inevitably driven by personal preference. Many states in Africa lack reliable information on health and illness issues, which would allow planners to allocate scarce resources to areas of need, and healthcare practitioners to examine and improve outputs. There are new and very helpful efforts to correct this problem. In this issue Bonny and colleagues (page 176) provide an overview of sudden cardiac death in Africa and an ambitious proposal to collect reliable information. Chin (page 151) provides an editorial comment summarising the problem and potential solutions. The outcome of the project will be eagerly awaited. In a similar vein, Brun and colleagues (page 159) examine a large number of patients at risk of venous thromboembolism and demonstrate under-use of recommended prophylactic anticoagulation. These two initiatives are both multicentre studies involving sites from many different African countries and it is heartening to see such co-operation, which can only bode well for the future. In a prospective cohort study, Borkum and co-workers (page 153) examined ambulatory blood pressure and renal function in asymptomatic HIV-positive patients. The prevalence of chronic kidney disease was lower than anticipated and HIV infection was associated with an ambulatory non-dipping status, which suggests an underlying dysregulation of the cardiovascular system. In the short term, anti-retroviral therapy did not seem to improve loss of circadian rhythm. A non-dipping pattern is an established entity with clinical implications, and is associated with higher cardiovascular morbidity and mortality rates. The high prevalence of non-dippers in the HIV-infected group in this study supports data from other countries. How this non-dipping pattern will impact on long-term mortality and morbidity in HIV-positive patients remains to be established. With the increasing and widespread use of new imaging modalities, we are learning more about cardiac function and involvement in systemic diseases. An article from Turkey (page 168) describes echocardiographic abnormalities in patients with rheumatoid arthritis and the influence of treatment on those abnormalities. Interestingly for me, the old-fashioned but evergreen ECG also reflected some of the changes. Cardiac imaging is further highlighted in a review of cardiac magnetic resonance imaging by Scholtz and others (page 185). This reports the clinical utility of this exciting modality. The letter from Schamroth (page 192) regarding the adverse effects of the Noakes diet on lipids is of considerable interest and concern, given several such anecdotal verbal reports from colleagues around South Africa. PATRICK COMMERFORD, MB ChB, FCP (SA), FACC, editor@clinicscardive.com Professor Emeritus, Senior Scholar, Cardiac Clinic, Department of Medicine, University of Cape Town

IT TAKES THE RIGHT COMBINATION TO ACHIEVE SUCCESS.1,2

Introducing the only RAASi/CCB combination with proven all-cause mortality benefits.2,3

Reference: 1. South African Hypertension Guideline 2011. YK Seedat, BL Rayner. S Afr Med J 2012;102:57-84 2. 2013 ESH/ESC Guidelines for the managment of arterial hypertension. Mancia G, Fagard R et al. Euro Heart J. Doi:10.1093/eurheart/eht151 3. Mourad JJ, Jeaune SL et al. Current Medical Research and Opinion. 2010;9:2263-2276 S3 Coveram速 5 mg /5 mg tablets: Perindopril arginine 5 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0933 S3 Coveram速 5 mg/10 mg tablets: Perindopril arginine 5 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0934 S3 Coveram速 10 mg/5 mg tablets: Perindopril arginine 10 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0935 S3 Coveram速 10 mg/10 mg tablets: Perindopril arginine 10 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0936 For full prescribing information, refer to the package insert approved by the medicines regulatory authority, Dec 2013. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27 (0)861 700 900. Fax: +27 (0)11 525 3401.

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Editorials Cognitive decline: mechanisms and proposed role of the renin–angiotensin–aldosterone system Lionel H Opie Normal cognitive functioning Cognition is derived from the Latin ‘cognitio’, meaning the process of acquiring knowledge, with related meanings such as study, recognition, social connectivity and discovery. The most crucial components of cognition are the ability to learn and remember new information,1 and to function adequately in daily intellectual and interactive aspects of life. Maintenance of normal functional cognitive activity is vitally important in everyday activities. Conversely, cognitive decline, as normally occurs during the ageing process, is a handicap. Such decline varies from moderately inconvenient benign forgetfulness to the devastating losses associated with Alzheimer’s disease and brain ischaemia.2

Cognitive function as part of optimal health Stroke, often associated with untreated hypertension, is common in Africa. In the USA, the move is towards stroke prevention, by paying attention to the blood pressure as one of life’s simple seven (LS7) health metrics (blood pressure, cholesterol, glucose, body mass index, smoking, physical activity and diet).3 Healthy levels of these components are in the higher ranges of the following scale: inadequate (0–4), average (5–9), or optimum (10–14) cardiovascular health. In a large USA population (22 914, 42% black) over 4.9 years of follow up, better cardiovascular health on the basis of the LS7 score was associated with lower risk of stroke. Therefore, not surprisingly, higher LS7 scores were associated with lower incidence of cognitive impairment.4 As expected, cognitive function may be related to blood pressure (BP) control. Starting with a population of Japanese subjects with mean age 63 years and without cognitive decline, follow up after nearly eight years showed about one in 10 had undergone cognitive decline that was associated with an increase in systolic BP (odds ratio 1.48; p = 0.03).5 Also of interest was the link between increases in home systolic BP and the significant association with cognitive decline (odds ratio, 1.48; p = 0.03).5 The benefit of BP reduction was endorsed by links between systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg and faster decline of cognitive function over two years of follow up in 1 385 persons.6 Thus far there has been no formal trial on the effects of BP control on cognitive function but one large trial is planned.7

Role of the renin–angiotensin–aldosterone system (Fig. 1) The brain has an essential evolutionary role in self-protection, centered on the concept that harmful stimuli must evoke

protective mechanisms. As the renin–angiotensin–aldosterone system (RAAS) has a pivotal role in cognitive impairment,8 logically, the use of centrally acting angiotensin converting enzyme (ACE) inhibitors should and does slow the rate of decline.9 These agents act on the RAAS in the hippocampus. Although statins also benefit mild cognitive impairment,10 they do not act centrally on the brain but on the blood–brain barrier.11

Inhibition of the RAAS to limit cognitive decline Inhibition of the RAAS ranks among the best established and most used cardiovascular therapies by providing protection against hypertensive damage and heart failure, and the microvascular complications of diabetes. RAAS inhibitors have contributed to the longer life expectancy now found in higherincome populations throughout the world. However, longevity propels aging persons closer to the inevitable cognitive decline that is of variable gravity. Perhaps unexpectedly, it is here that the RAAS inhibitors may have a special role, especially in the many elderly persons with hypertension. The two centrally active ACE inhibitors, captopril Angio 1 ACE converting enzyme Angio 2

Effect on AT 2 receptor ACEi centrally acting

AT 1 receptor

Ox stress Inflammation Blood-brain-barrier damage Brain blood flow less

Ox stress less Inflammation countered Blood-brain-barrier better Brain blood flow increased

Cognitive function Redrawn & revised from Int J HPT, Dec 2012

Fig. 1. The proposed opposite effects on cognitive function of stimulation of the angiotensin 1 (AT1) and AT2 receptors. The ARBs have a similar functional effect on the centrally acting ACE inhibitors in enhancing cognitive function (see text).

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and perindopril can delay cognitive decline.12 Likewise, the brain-penetrating angiotensin receptor blockers (ARBs) counter cognitive decline, as in the case of telmisartan.11,12 The cellular mechanisms whereby the RAAS inhibitors act on the brain are still under study but experimentally include stress relief,13,14 and an anti-inflammatory benefit.15,16

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home blood pressure is associated with cognitive decline: the Ohasama study. Hypertension 2014; 63: 1333–1338. 6.

Goldstein FC, Levey AI, Steenland NK. High blood pressure and cognitive decline in mild cognitive impairment. J Am Geriatr Soc 2013; 61: 67–73. doi: 10.1111/jgs.12067.

Zanchetti A, Liu L, Mancia G, et al. Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence. J Hypertens 2014, Jun 27.

Conclusion Cognitive function is one of the most important functions of the activity of the healthy mind and brain.14 On present data, it is reasonable to give a centrally acting ACE inhibitor or an ARB to a person with developing cognitive decline. The possible risk is that of a modest rise in blood pressure, which could be treated by lifestyle modification and/or drug therapy as needed. Solid data from large, long-term, appropriately designed trials are required.

[Epub ahead of print]. 8.

Yagi S, Akaike M, Ise T, Ueda Y, Iwase T, Sata M. Renin–angiotensin– aldosterone system has a pivotal role in cognitive impairment. Hypertens Res 2013; 36: 753–758. doi: 10.1038/hr.2013.5.

Gao Y, O’Caoimh R, Healy L, Kerins DM, et al. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. Br Med J Open 2013; 3. pii: e002881. doi: 10.1136/bmjopen-2013-002881.

10. Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impair-

Lionel H Opie, MD, FRCP, Lionel.opie@uct.ac.za Hatter Institute for Cardiovascular Research in Africa, Groote Schuur Hospital and University of Cape Town Medical School, Cape Town, South Africa

ment. J Am Geriatr Soc 2013; 61: 1449–1455. doi: 10.1111/jgs.12414. 11. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–2221. doi: 10.1016/S0140-6736(13)62242-4.

References

12. Opie LH, Gersh BG (eds). In: Drugs for the Heart, 8th edn. Philadelphia:

13. Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment

Opie LH, Dalby AJ. Cardiovascular prevention: lifestyle and statins – competitors or companions? S Afr Med J 2014; 104: 168–173.

Geerlings MI, Jonker C, Bouter LM, Adèr HJ, Schmand B. Association

10.1016/j.pharep.2013.11.00. 14. Wincewicz D, Braszko JJ. Angiotensin II AT1 receptor blockade by

people with normal baseline cognition. Am J Psychiatry 1999; 156:

telmisartan reduces impairment of spatial maze performance induced

531–537.

by both acute and chronic stress. J Renin Angiotensin Aldosterone Syst

Kulshreshtha A, Vaccarino V, Judd SE, et al. Life’s Simple 7 and risk

2014, Mar 12 [Epub ahead of print]. 15. Opie LH. Living Longer, Living Better; Exploring the Heart–Mind

stroke study. Stroke 2013; 44: 1909–1914.

Relationship. Oxford: Oxford University Press, 2011, Ch 7: 137–169.

Thacker EL, Gillett SR, Wadley VG, et al. The American Heart

Online: http://www.amazon.co.uk/Living-Longer-Better-Heart-Mind-

Association life’s simple 7 and incident cognitive impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) 5.

caused by chronic stress in rats. Pharmacol Rep 2014; 66: 436–441. doi:

between memory complaints and incident Alzheimer’s disease in elderly

of incident stroke: the reasons for geographic and racial differences in 4.

Elsevier, 2013: 570.

Connection/dp/0198525672. 16. Saavedra JM. Angiotensin II AT(1) receptor blockers ameliorate inflam-

study. J Am Heart Assoc 2014; 3:e000635.

matory stress: a beneficial effect for the treatment of brain disorders.

Matsumoto A, Satoh M, Kikuya M, et al. Day-to-day variability in

Cell Mol Neurobiol 2012; 32: 667–681. doi: 10.1007/s10571-011.

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Sudden cardiac death in Africa Ashley Chin Africa is facing a huge health burden of both communicable and non-communicable diseases. Cardiovascular disease is becoming an important cause of mortality in Africa.1 Unfortunately, statistics on the incidence of cardiovascular disease in Africa are not readily available and in many sub-Saharan African countries there is no information or only poor-quality data. Sudden cardiac death (SCD) is an unexpected natural death due to cardiovascular disease that occurs within one hour of the onset of symptoms.2 The epidemiology of SCD in Africa is unknown. In the United States, SCD results in approximately 300 000 deaths per year.2 Ischaemic heart disease is responsible for 80% of cases, followed by non-ischaemic myopathic diseases, such as hypertrophic and dilated cardiomyopathy, which account for 10 to 15% of cases. Approximately 5% of cases of SCD can be attributed to primary electrical disorders such as congenital long QT syndrome and Brugada syndrome. In this article of the Journal, Bonny et al. and the Pan-African Society of Cardiology task force on Sudden Cardiac Death present the rationale and design of the Pan-African SCD study (page 176). This will be a multicentre, community-based, prospective cohort registry that will report on cases of SCD from all African regions. The well-designed, epidemiological study will be the first and largest of its kind from Africa. This registry will be community-based and led by senior physicians, working together with a multidisciplinary team. Genetic testing and autopsy data will be obtained to confirm clinical diagnoses as far as possible. This study is important for several reasons. The Pan-African SCD study may highlight important differences in the incidence and relative causes of SCD in Africa. In contrast to the developed world, cardiovascular disease in Africa is still predominantly non-ischaemic.1,3 The THESUSHF registry has confirmed that the major causes of acute heart failure in Africa are non-ischaemic. Hypertensive heart disease, cardiomyopathy (peripartum cardiomyopathy, idiopathic dilated cardiomyopathy and endomyocardial fibrosis), pericardial disease and rheumatic valvular heart disease account for the majority of cases. Left ventricular hypertrophy, whether confirmed by ECG or echocardiogram, is a strong independent predictor of cardiovascular death and SCD.2 An autopsy study from Nigeria found that hypertensive heart disease was the most common cause of SCD in that region.4 Therefore the Pan-African SCD study may provide insight into the burden of SCD due to neglected diseases that are endemic to Africa, such as rheumatic valvular heart disease and tuberculous myo/pericardial disease. Tuberculosis is a major cause of mortality in Africa and reports suggest that tuberculous myocarditis may cause SCD.1,5 While SCD due to degenerative aortic stenosis and mitral regurgitation is well appreciated, less is known about SCD in patients with underlying rheumatic aortic and mitral valve disease. These pre-transitional diseases are now uncommon in the developed world and have been neglected in major society guidelines of implantable cardioverter defibrillators (ICDs) in the prevention and treatment of SCD.6 This study has important implications for other developing countries, such as India and

China, where these diseases are still prevalent. This study will also highlight the magnitude of well-recognised causes of SCD in Africa. Countries in Africa find themselves at different stages of the epidemiological transition. Many countries, such as South Africa, have reported a rising incidence of ischaemic heart disease.7 According to the Global Burden of Disease in 2010, ischaemic heart disease was responsible for more deaths in Africa than either rheumatic heart disease or hypertensive heart disease.1 With the introduction of antiretroviral therapy (ART), patients with HIV/AIDS are living longer, and with the increasing atherogenic complications of ART, sub-Saharan Africa is facing an impending epidemic of cardiovascular and metabolic disease.8 The Pan-African SCD study will provide contemporary data on the burden of SCD secondary to ventricular arrhythmias related to ischaemic heart disease. There is little doubt that the primary inherited arrhythmia syndromes [congenital long QT syndrome, arrhythmogenic right ventricular dysplasia (ARVD), Brugada syndrome, early repolarisation (ER) syndrome] exist in Africa. These diseases are frequently under-recognised and are missed diagnoses. Nevertheless, there have been several large cohorts reported from Africa, which report a similar presentation to other populations around the world. In a large series of 50 ARVD patients from South Africa, the study found a similar clinical presentation and an annual mortality rate comparable to other large registries in North America and Europe.9 Brugada syndrome has also been described in 23 patients from Tunisia, who share a similar clinical profile to their Asiatic and Western counterparts.10 In another series of 44 congenital long QT 1 syndrome patients in South Africa, a strong founder effect was found, with a single mutation responsible for 52% of cases.11 An important study finding will be whether the ER pattern is associated with SCD in young black Africans. While a report from Cameroon reported that the ER pattern may occur in up to 20% of patients who present with cardiovascular symptoms, a recent study found that the ER pattern in the precordial leads was not associated with increased mortality in black African-Americans.12,13 If an association of the ER pattern and SCD indeed exists, it will have major clinical implications because of the high prevalence rate of this ECG pattern in black Africans. The study will face significant challenges in terms of diagnosis and management. First, one can expect that a significant proportion of patients who survive SCD will be managed by general physicians or cardiologists, who may have limited experience in the diagnosis and management of these complex patients. Second, special investigations such as echocardiography, cardiac catheterisation, magnetic resonance imaging, electrophysiological testing and Holter monitoring may be unavailable in many African centres. Certain diseases, such as ARVD, which require multiple investigations to make a diagnosis, may prove difficult to diagnose in the absence of clinical expertise and special investigations.

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Third, from a therapeutic standpoint, treatment options will be limited in many countries for financial reasons. Will ICDs be available for secondary prevention and are there enough skilled doctors to implant them? Hospitals and healthcare systems will face huge financial challenges in funding these high-cost devices, even in the secondary-prevention setting. A paucity of cardiologists and electrophysiologists exists in sub-Saharan and west Africa with very few or no centres able to implant pacemakers and ICDs. Even in north African countries, where the situation is slightly better, ICD centres are few.14 This study has the potential to create a legacy on the management of SCD in Africa. Regional centres participating in this study have the potential to become centres of expertise in the management of SCD. Information gained from this study may help governments develop healthcare policies, including the placement of defibrillators in public places, such as schools, sports venues and health facilities, to improve out-of-hospital resuscitation attempts; and providing adequate funding for highcost devices. Recognising the paucity of expertise may facilitate training of future African physicians and cardiologists. Determining the magnitude and nature of the problem of SCD in Africa, which is the main goal of this study, is the first major step.

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Intern Med 2012; 172(18): 1386–1394. 4.

Akinwusi PO, Komolafe AO, Olayemi OO, et al. Pattern of sudden death at Ladoke Akintola University of Technology Teaching Hospital, Osogbo, South West Nigeria. Vasc Health Risk Manag 2013; 9: 333–339.

Liu A, Hu Y, Coates A. Sudden cardiac death and tuberculosis – how much do we know? Tuberculosis (Edinb) 2012; 92(4): 307–313.

Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013; 61(3): e6–75.

Mayosi BM, Lawn JE, van Niekerk A, et al. Health in South Africa: changes and challenges since 2009. Lancet 2012; 380(9858): 2029–2043.

Commerford P, Ntsekhe M. Ischaemic heart disease in Africa. How common is it? Will it become more common? Heart 2008; 94(7): 824–825.

Watkins DA, Hendricks N, Shaboodien G, et al. Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa. Heart Rhythm 2009; 6(11 Suppl): S10–17.

10. Ouali S, Boughzela E, Haggui A, et al. Clinical and electrophysiological profile of Brugada syndrome in the Tunisian population. Pacing Clin Electrophysiol 2011; 34(1): 47–53.

Ashley Chin, MB ChB, FCP (SA), Ashley.chin@uct.ac.za Cardiac Clinic, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa

11. Hedley PL, Durrheim GA, Hendricks F, et al. Long QT syndrome in South Africa: the results of comprehensive genetic screening. Cardiovasc J Afr 2013; 24(6): 231–237. 12. Bonny A, Noah DN, Amougou SN, Saka C. Prevalence and significance of early repolarisation in a black African population: data of

References 1.

246 individuals with cardiovascular morbidity. Cardiovasc J Afr 2013;

Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality

13. Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and

atic analysis for the Global Burden of Disease Study 2010. Lancet 2012;

outcomes associated with the natural history of early repolarization in

380(9859): 2095–2128.

a young, biracial cohort followed to middle age: The Coronary Artery

Zipes DP, Wellens HJ. Sudden cardiac death. Circulation 1998; 98(21):

Risk Development In young Adults (CARDIA) study. Circ Arrhythm Electrophysiol 2014; 7(3): 392–399.

2334–2351. 3.

24(7): 280–285.

from 235 causes of death for 20 age groups in 1990 and 2010: a system-

Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch

14. Arribas F, Auricchio A, Wolpert C, et al. The EHRA White Book. Europace 2012; 14(Suppl 3): iii1–55.

Cardiovascular congress diary 2014 DATE SEPTEMBER 10–14 OCTOBER 16–19 22–24 NOVEMBER 15

CONFERENCE

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CONTACT DETAILS TO REGISTER

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ICC, Cape Town, SA

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15th Annual SA Heart Congress 2014 4th World Congress of Regional Anaesthesia and Pain Therapy

ICC, Durban, SA

www.saheart.org

AHA scientific session CME

ICC, Cape Town, SA Illiniois, Chicago, USA

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

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Cardiovascular Topics Ambulatory blood pressure profiles in a subset of HIV-positive patients pre and post antiretroviral therapy Megan Borkum, Nicola Wearne, Athlet Alfred, Joel A Dave, Naomi S Levitt, Brian Rayner

Abstract Objectives: Human immunodeficiency virus (HIV) and antiretroviral therapy (ART) are associated with renal disease and increased cardiovascular risk. The relationship between HIV and ambulatory blood pressure (ABP) non-dipping status, a risk factor for cardiovascular events and targetorgan damage, has never been assessed in South Africa. Study objectives were to establish the prevalence of chronic kidney disease, and assess the ABP profile in asymptomatic HIV-positive clinic out-patients. Methods: This was a prospective cohort study. Office blood pressure (BP), urinary microalbumin–creatinine ratio, urine dipsticks, serum creatinine and estimated glomerular filtration rate (eGFR) were measured at baseline and six months after ART initiation. A subset of HIV-positive subjects and an HIV-negative control group underwent 24-hour ABP monitoring. Results: No patient had an eGFR < 60 ml/min, three patients (4.7%) had microalbuminuria and one had macroalbuminuria. Mean office systolic BP was 111 ± 14 mmHg at baseline and increased by 5 mmHg to 116 ± 14 mmHg (p = 0.05) at six months. This increase was not confirmed by ABP monitoring. In the HIV-positive and -negative patients, the prevalences of non-dipping were 80 and 52.9%, respectively (p = 0.05, odds ratio = 3.56, 95% CI: 0.96–13.13). No relationship between dipping status and ART usage was found. Conclusion: The prevalence of chronic kidney disease (CKD) was lower than anticipated. HIV infection was associated with an ambulatory non-dipping status, which suggests an underlying dysregulation of the cardiovascular system. In the short term, ART does not seem to improve loss of circadian rhythm.

Department of Medicine, University of Cape Town, Cape Town, South Africa Megan Borkum, MD, mborkum@gmail.com Athlet Alfred, MD

Department of Nephrology and Hypertension, University of Cape Town, Cape Town, South Africa Nicola Wearne, MD Brian Rayner, MD

Division of Diabetic Medicine and Endocrinology, University of Cape Town, Cape Town, South Africa Joel A Dave, MD Naomi S Levitt, MD

Keywords: human immunodeficiency virus, antiretroviral therapy, microalbuminuria, chronic kidney disease, ambulatory blood pressure, non-dipping Submitted 6/10/13, accepted 3/5/14 Cardiovasc J Afr 2014; 25: 153–157

www.cvja.co.za

DOI: 10.5830/CVJA-2014-029

South Africa has 5.6 million people living with HIV/AIDS and has the largest antiretroviral therapy (ART) programme globally, with more than two million people accessing ART.1 Although ART has significantly decreased the mortality rate from HIV infection, these individuals are now living longer and are at risk of developing metabolic (dyslipidaemia, lipodystrophy, dysglycaemia), cardiovascular and renal complications from ART and chronic exposure to HIV infection.2-7 Chronic HIV and ART are associated with increased risk of developing hypertension.8 In studies of HIV-positive patients in high-income countries, hypertension prevalence ranges from 13 to 34%.9,10 However, data from low- and middle-income countries remain sparse. Nocturnal blood pressure (BP) is superior to daytime or office BP as a predictor of cardiovascular disease.11 Non-dipping is defined as an abnormal diurnal rhythm manifested by a blunted nocturnal decline in systolic BP (SBP).11 It is associated with more severe hypertensive target-organ damage (left ventricular hypertrophy, microalbuminuria and cerebrovascular disease) and is also a predictor of increased cardiovascular risk, both in hypertensive and normotensive populations.11 Studies from high-income countries have shown an increased prevalence of non-dipping with HIV infection.9,12 However, the participants in these studies were largely white, middle-aged males. Since the majority of subjects with HIV infection in sub-Saharan Africa are young black females, it is not known whether the same relationship between dipping status and HIV infection would be found. In addition, there are data showing that black HIV-negative individuals have less nocturnal dipping compared to their white counterparts.5,13,14 Therefore, the aims of this study were to document the prevalence of chronic kidney disease (CKD) and hypertension at baseline (ART naïve) in a healthy HIV-positive cohort, and to assess changes in these parameters after six months on ART. The characteristics of ambulatory blood pressure (ABP) in a subset of patients were to be recorded and compared to a control group of HIV-negative patients.

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Methods A longitudinal, prospective cohort study was conducted. It was approved by the Research Ethics Committee of the Faculty of Health Sciences of the University of Cape Town. Before participating in the study, procedures and risks were explained to the patients, who gave written informed consent to take part in the study. This study formed part of an as yet unpublished larger longitudinal study, investigating the metabolic complications of ART in an HIV-positive population, at an HIV clinic in a community health centre in Cape Town, South Africa. All patients recruited for the parent study over a six-month period were enrolled into this study (Fig. 1). The following measurements were done at baseline and repeated at six months: urine dipstick (AccuBioTech Co. Ltd, Beijing, China), office BP, serum creatinine (umol/l), spot urine microalbumin–creatinine ratio (mg/mmol), and estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2). Three office BP readings were performed on the right arm with the patient in a seated position using a mercury barometer in accordance with the South African hypertension guidelines.15 A urinary albumin–creatinine ratio between 3 and 30 mg/ mmol was identified as microalbuminuria and a level greater than this as macroalbuminuria.16 eGFR was estimated using the four-variable Modification of Diet in Renal Disease (MDRD)

Initially included (n = 64) A cross-section of asymptomatic HIV-positive patients

ABP substudy (n = 30) Enrolled patients willing to participate

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equation, which accounts for the gender, age, creatinine level and race of a patient.17 Clinical guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) work group were used to categorise CKD.18 After the baseline measurements, all patients were started on ART (Table 1). The treatment regimen used depended on the date of enrolment into the study. Initially patients were prescribed stavudine (D4T), lamivudine (3TC) and efavirenz (EFV) according to the previous national guidelines, but later tenofovir (TDF) replaced D4T.19,20 All enrolled patients were invited to participate in the ABP substudy. Consenting individuals underwent ABP monitoring prior to and after the initiation of ART. A control group of confirmed serologically HIV-negative patients formed the control group of another study from our institution investigating HIV-associated dementia.21 They were originally recruited by trained fieldworkers from a community primary healthcare clinic in Cape Town. Seventeen individuals from a list of 32 contacted telephonically were available to participate. They were equally matched for age, body mass index (BMI) and socio-economic background. Patients were excluded if they had underlying hypertension, diabetes mellitus, ischaemic heart disease, concurrent illness or any condition affecting BP (i.e. pregnancy or renal disease). ABP monitoring was set up by a trained nurse on a weekday, with an oscillometric device (SpaceLabs Medical Inc, WA, USA). BP and heart rate were recorded every 20 minutes during the day (06:00 to 22:00) and every 30 minutes at night (22:00 to 06:00). Hypertension was defined as a SBP ≥ 140 mmHg or diastolic BP (DBP) ≥ 90 mmHg, in accordance with the South African hypertension guidelines 2011.15 Non-dipping was defined as a nocturnal reduction of SBP ≤ 10%.22

Statistical analyses Six months (n = 53) Excluded = 11 Reasons for exclusion: • Defaulted on ART (n = 8) • Pregnancy (n = 3)

Six months (n = 28) Excluded = 2 Reasons for exclusion: • Pregnancy (n = 2)

Fig. 1. Flow of study.

Statistical analyses were performed using STATA statistical software, version 11.0 (STATA Corporation, College Station, Texas, USA). Mean ± standard deviation was used for normally distributed data and median plus interquartile ranges for skewed data. Continuous and categorical variables were compared using chi-square, Student’s t-test or Pearson’s χ2 as appropriate. All p-values were considered significant at p ≤ 0.05.

Table 1. Patient characteristics and demographics

Age (years) mean ± SD Men (%) Women (%) BMI (kg/m2) mean ± SD Men Women CD4 (cells/mm3) median (IQR) ART regimen (%) Current Earlier Other

Baseline (n = 64)

Six months (n = 53) 33 ± 7 23 77 25.7 ± 5.2 23.1 ± 4.8 26.9 ± 5.6 359 (231–411)

ABPM group at baseline (n = 30) 32 ± 8 37 63 24.6 ± 5.2 22.9 ± 5.0 25.4 ± 4.9 242 (165–330)

ABPM group at six months (n = 28) 32 ± 8 36 64 24.8 ± 5.4 22.7 ± 5.3 25.8 ± 5.4 361 (240–406)

33 ± 7 23 77 24.8 ± 5.4 22.5 ± 4.6 25.5 ± 5.4 239 (169–322) – – –

67 29 4

– – –

72 26 2

Controls (n = 17) 31 ± 9 40 60 24.0 ± 4.8 22.8 ± 5.1 25.2 ± 4.8 N/A – – –

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 4, July/August 2014

Results Sixty-four patients were entered into the study, with baseline characteristics as shown in Table 1. All were black South Africans, mean age 33 ± 7 years, and 77% were female. Eleven patients were excluded on follow up [defaulted on treatment (n = 8), pregnant (n = 3)]. Mean BMI was 24.8 ± 5.4 kg/m2 and increased to 25.7 ± 5.2 kg/m2 after six months on ART (p = 0.39). At baseline, median CD4 count was 239 (169–322) cells/mm3, and after six months of ART the CD4 count increased to 359 (231–411) cells/mm3. All patients had suppressed viral loads. Thirty patients agreed to participate in the ABP substudy. Two were excluded at six months due to pregnancy. There were no significant differences between those who underwent ABP monitoring and those who did not, according to age, gender, ethnicity, BMI, CD4 count, ART status or office BP. Baseline demographics were similar in the HIV-negative control group except there were more males in this group compared with the HIV-positive cohort. However, there was still a greater percentage of females than males in the control group (Table 1). At baseline, 13 patients (20%) had an eGFR of 60–89 ml/ min/1.73 m2 (GFR category G2). No patient had an eGFR < 60 ml/min/1.73 m2 (Table 2). Microalbuminuria was present in three of the 64 patients (4.7%) and only one patient (1.6%) had macroalbuminuria. At the end of six months, microalbuminuria persisted in the three patients and developed in two new cases. In the patient who had initially had macroalbuminuria, it resolved on follow-up sampling. No patient had a change in eGFR over the study period. Mean office SBP increased significantly from 111 ± 14 mmHg at baseline to 116 ± 14 mmHg (p = 0.05) at six months, but this was not confirmed by the ABP substudy (Table 2). The mean day and night ABP values for each group are shown in Table 3. The mean nocturnal SBP was higher at 110 ± 6 mmHg in the Table 2. BP and renal parameters at baseline and six months

MDRD eGFR (ml/min/1.73 m2) ≥ 90, n (%) 60–89, n (%) < 60, n (%) Microalbuminuria (mg) Office systolic BP (mmHg) Office diastolic BP (mmHg)

Baseline (n = 64) 109 ± 23 51 (80) 13 (20) 0 (0) 0.9 ± 5.0 111 ± 14 72 ± 9

Six months (n = 53) p-value 0.66 107 ± 22 51 (80) – 13 (20) – 0 (0) – 0.67 0.8 ± 2.8 0.05 116 ± 14 0.69 75 ± 10

Table 3. Mean day and night BP and dipping status in 30 patients with HIV and in 17 control subjects HIV positive

Mean BP (mmHg) Daytime SBP Daytime DBP Night-time SBP Night-time DBP Non-dipper, n (%) Dipper, n (%) Total

Baseline

Six months

HIV negative

114 ± 10 75 ± 12 110 ± 6 65 ± 8 24 (80) 6 (20) 30

116 ± 12 72 ± 11 111 ± 4 67 ± 11 23 (82) 5 (18) 28

114 ± 14 73 ± 16 99 ± 6 60 ± 9 9 (52.9) 8 (47.1) 17

Baseline BP vs controls (p-value) 1.00 0.63 < 0.0001 0.05 – 0.05 –

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HIV-positive group at baseline compared to 99 ± 6 mmHg in the control group (p < 0.0001). There were no significant differences in age, gender, ethnicity, BMI, CD4 count, ART status or office BP between those patients who did and those who did not undego ABP monitoring. The prevalence of non-dipping in HIV-positive patients (Table 3) did not differ at baseline or after six months on ART. Twentyfour of 30 subjects (80%) were non-dippers at baseline and 23 of 28 subjects (82%) (odds ratio = 1.15, p = 0.84, 95% CI: 0.31–4.29) were non-dippers at six months (Fig. 2). In the HIV-negative control group, nine of 17 (52.9%) were non-dippers; therefore non-dipping was 3.6 times more likely in HIV-positive patients at baseline than in controls (p = 0.05, 95% CI: 0.96–13.13).

Discussion This is the first study from Africa, to our knowledge, to have used ABP monitoring to characterise differences in nocturnal blood pressure dipping status between HIV-positive and HIV-negative patients. The study found that: (1) there was a low prevalence of CKD and microalbuminuria in the healthy HIV-positive patients; (2) there was a greater prevalence of non-dipping of nocturnal blood pressure in HIV-positive patients than HIV-negative controls. Studies from a high-income country found the estimated prevalence of CKD in HIV-infected subjects to be 11 to 15.5%.23,24 Our study found a lower prevalence of microalbuminuria in HIV-positive patients. In contrast, a study from Johannesburg reported a prevalence of microalbuminuria of 18.5% in their cohort of HIV-positive patients.25 A possible explanation for this difference is that their patients were significantly more immunosuppressed (CD4 < 200 cells/mm3), with a mean CD4 count of 130 cells/mm3. They also had a high prevalence of co-morbid disease, whereas the patients in our study were all healthy, with a mean CD4 count of 239–339 cells/mm3. Microalbuminuria is an important finding in HIV as it may reflect early kidney disease. In a study from KwaZulu-Natal, six of 25 (24%) patients with an eGFR > 60 ml/min/1.73 m2 had persistent microalbuminuria and HIV-associated nephropathy (HIVAN) detected on renal biopsy.26 This is an isolated study. Nocturnal (10 pm to 6 am) dip in blood pressure

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–10

–20

–30 Systolic Diastolic Baseline

Systolic Diastolic 6 months

Fig. 2. Dipping status for systolic and diastolic BP at baseline (n = 30) and at six months (n = 28).

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It is important to note that renal biopsies are not routinely performed in patients with microalbuminuria and normal renal function. In a large biopsy series from Cape Town, HIVAN presented with nephrotic range proteinuria and impaired renal function.7 Patients not receiving ART had a poor prognosis.27,28 Microalbuminuria is non-specific and is a marker of inflammation and cardiovascular risk independent of renal function.29 In our small study, no patient had a clinically relevant reduction in eGFR (< 60 ml/min/1.73 m2), and only one patient had overt macroalbuminuria, which resolved on treatment with ART. This suggests that the approximate prevalence of CKD in an otherwise-healthy HIV population is about 1.6%, considerably lower than previously reported.23,30 Importantly, a high CD4 count and normal creatinine level does not exclude renal disease in HIV.6,7,26 Patients demonstrating proteinuria, who would not normally be eligible for ART due to an elevated CD4 count, benefit from timely initiation of ART, which can greatly improve survival rates, with stabilisation of eGFR.7,30 Therefore screening of patients enrolling into an ART programme, with urine dipsticks or spot urine sampling for proteinuria should be standard practice and could have an impact on the prevalence of HIVAN. This is particularly important in South Africa where, due to the problem of limited access to renal replacement, there is a need for early identification and management of renal disease. In this study, no cases of hypertension were identified, and there was a small but significant increase in office SBP after six months on ART. However in a subset of patients, ABP monitoring did not confirm these findings. ABP monitoring is the most reliable method of assessing BP and suggests that the effect of ART on BP may be minimal. In the ABP substudy there was no difference in mean daytime SBP and DBP between patients and controls. However the mean night-time SBP was significantly higher in the HIV group, as was the proportion of non-dippers compared to the control group with similar demographics (BMI, age, gender, socioeconomic status). A non-dipping pattern is an established entity, with important clinical implications, and is associated with a higher cardiovascular morbidity and mortality rate.31 The high prevalence of non-dippers in the HIV-infected group in this study supports data from Italy and Norway.9,12 The potential mechanisms underlying the non-dipping phenomenon in HIV-positive patients are uncertain. It does suggest an underlying dysregulation of the cardiovascular system. Chronic infection and arterial inflammation contribute to endothelial dysfunction, which may be further exacerbated by ART.2,3 In addition, HIV-related endocrinopathies (i.e. hyperaldosteronism and hypercortisolism) and autonomic dysfunction may play a role.32,33 However, the lack of improvement in dipping status after six months of ART with suppressed viral loads suggests that other mechanisms may also be involved. Our study has several limitations. Firstly, the sample size for the ABP substudy was small and the nocturnal dipping status between HIV-positive and HIV-negative controls was marginal. Secondly, the short length of follow up (six months) may have been a limitation as the effects of ART on BP and nocturnal dipping may take longer to manifest. Thirdly, a single spot sample was used for establishing microalbuminuria. Also, ABP measurements were conducted during a presumed

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typical weekday and we could not objectively observe daytime activity and duration of night-time bed rest, which has been shown to affect diurnal BP patterns. Lastly, the HIV-negative ABP-monitoring control group was recruited from another study. The focus of HIV care in our country remains viral suppression and management of opportunistic infections. Our findings correlate with established evidence linking HIV to increased cardiovascular risk. Young black females are traditionally at low risk for cardiovascular disease. However a non-dipping status in the context of HIV infection could confer a greater risk in this group. If there are approximately 5.6 million HIV-positive people in South Africa, potentially 4.48 million (80%) are non-dippers. Therefore, as HIV-infected patients are living longer, investigating and addressing the cardiac and metabolic complications related to HIV is becoming more important. The authors acknowledge all the patients in this study and the staff at the Groote Schuur Hospital hypertension clinic for their participation. The Faculty of Health Sciences, University of Cape Town research fund provided the funding.

References 1.

UNAIDS 2012. World AIDS Day report.

Fourie CMT, van Rooyen JM, Schutte AE. HIV infection and cardiovascular risk in black South Africans [Editorial]. Cardiovasc J Afr 2011; 22(3): 117–118.

Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med 2005; 118(2): 23S–28S.

Durand M, Sheehy O, Baril JG, et al. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec’s public health insurance database. J Acquir Immune Defic Syndr 2011; 57(3): 245–253.

Dave JA, Lambert EV, Badri M, et al. Effect of nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy on dysglycemia and insulin sensitivity in South African HIV-infected patients. J Acquir Immune Defic Syndr 2011; 57(4): 284–289.

Arendse C, Okpechi I, Swanepoel C. Acute dialysis in HIV-positive patients in Cape Town, South Africa. Nephrology 2011; 16: 39–44.

Wearne N, Swanepoel C, Boulle A, et al. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant 2012; 27(11): 4109–4118.

Gazzaruso C, Bruno R, Garzaniti A, et al. Hypertension among HIV patients: prevalence and relationship to insulin resistance and metabolic syndrome. J Hypertension 2003; 21(7): 1377–1382.

Vittorio G, De Socio L. Negative influence of HIV infection on day– night blood pressure variability. J Acquir Immune Defic Syndr 2010; 55: 356–360.

10. Jerico C, Knobel H, Montero M, et al. Hypertension in HIV-infected patients: prevalence and related factors. Am J Hypertens 2005; 18: 1396–1401. 11. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality. The Dublin outcome study. Hypertension 2005; 46: 156–161. 12. Baekken M, Os I, Stenehjem A, et al. Association between HIV infection and attenuated diurnal blood pressure rhythm in untreated hypertensive individuals. HIV Med 2009; 10: 44–52. 13. Morar N, Seedat YK, Naidoo DP, Desai DK. Ambulatory blood pres-

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sure and risk factors for coronary heart disease in black and Indian medical students. J Cardiovasc Risk 1998; 5(5–6): 313–318. 14. Flack JM, Sica DM, Bakris G. Management of High Blood Pressure in Blacks consensus statement. Hypertension 2010; 56: 780–800. 15. Seedat YK, Rayner BI. South African hypertension guidelines 2011. S Afr Med J 2011; 102(1): 57–88. 16. De Jong PE, Curhan GC. Screening, monitoring, and treatment of albuminuria: public health perspectives. J Am Soc Nephrol 2006; 17(8): 2120–2126.

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infection. AIDS 2007; 21(8): 1003–1009. 25. Fabian J, Naicker S, Venter W, et al. Urinary screening abnormalities in antiretroviral naïve HIV infected outpatients and implications for management. Ethnicity Dis 2009; 19: 80–85. 26. Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV- seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int 2006; 69: 2243–2250. 27. Wyatt CM, Klotman PE. HIV-1 and HIV-associated nephropathy 25 years later. Clin J Am Soc Nephrol 2007; 2: S20–24.

17. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate

28. Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and

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course of the spectrum of renal diseases associated with HIV infection.

tion. Modification of diet in renal disease study group. Ann Intern Med 1999; 130(6): 461–470.

Kidney Int 2004; 66: 1145–1152. 29. Klausen K, Borch-Johnsen K, Fieldt-Rasmussen B, et al. Very low levels

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group. KDIGO 2012 clinical practice guideline for the evaluation and

heart disease and death independantly of renal function, hypertension

management of chronic kidney disease. Kidney Inter 2013; S3: 1–150. 19. National Department of Health. National antiretroviral treatment guideline. South Africa 2004. 20. National Department of Health. Clinical guidelines for the management of HIV and AIDS in adults and adolescents. South Africa 2010. 21. Joska JA, Westgarth-Taylor J, Myer L, et al. Characterization of HIVassociated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa. AIDS Behav 2011; 15(6): 1197–203.

and diabetes. Circulation 2004; 110(1): 32–33. 30. Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV associated nephropathy. A Rev Med 2012; 63: 147–59. 31. Mancia G, Bombelli M, Facchetti R, et al. Long term prognostic value of blood pressure variability in the general population. Results of the Pressioni Arteriose Montiorate E Loro Associazioni Study. Hypertension 2007; 49: 1265–1270. 32. Clement DL, De Buyzere ML. Office versus ambulatory pressure study

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ings in patients with treated hypertension. N Engl J Med 2003; 348:

56–61. 23. Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease in HIV infection: an urban epidemic. AIDS 2007; 21(15): 2101–2103. 24. Szczech LA, Grunfeld C, Scherzer R, et al. Microalbuminuria in HIV

2407–2415. 33. Birkenhager AM, van den Meiracker AH. Causes and consequences of a non-dipping blood pressure profile. Netherlands J Med 2007; 65(4): 127–131.

Cardiac death risk in diabetic haemodialysis patients increased due to thyroid problems A prospective study found that diabetic haemodialysis patients’ subclinical hyperthyroidism and euthyroid sick syndrome might increase the risk of sudden cardiac-related deaths. Dr Christiane Drechsler, of University Hospital Würzburg in Würzburg, Germany, and colleagues conducted a study that included 1 000 patients undergoing haemodialysis for diabetes. Of those patients, 78.1% had euthyroidism, 13.7% had subclinical hyperthyroidism, 1.6% had subclinical hypothyroidism and 5.4% had euthyroid sick syndrome. Patients with euthyroidism were compared with those who had subclinical hyperthyroidism and euthyroid sick syndrome, with regard to which group showed an increased short-term (within a 12-month period) risk of sudden cardiac death. It showed that patients who had euthyroidism had a 2.0-times increased short-term risk of sudden cardiac death, and those who had

subclinical hyperthyroidism and euthyroid sick syndrome had a 2.7-fold increase. The results showed that euthyroid sick syndrome was associated with a three-fold increased risk of short-term mortality, but in the long term (two to four years) it showed no increased risk. The study revealed that subclinical hypothyroidism was not associated with cardiovascular events or all-cause mortality, which revealed thyroid disorders had no influence on the risks of myocardial infarction and stroke.

This study led researchers to conclude, ‘Regularly assessing a patient’s thyroid status may help estimate the cardiac risk of dialysis patients.’ Source:

http://www.renalandurologynews.com/thyroid-problems-up-

cardiac-death-risk-in-diabetic-hd-patients/article/348571/

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Epidemiological African day for evaluation of patients at risk of venous thrombosis in acute hospital care settings Samuel Kingue, Limbole Bakilo, Jacqueline Ze Minkande, Inoussa Fifen, Yash Pal Gureja, Henri Jean Claude Razafimahandry, Njideka Okubadejo, Richard Mvuala, DA Oke, Alexandre Manga, Tovohery Rajaonera, Cajetan Nwadinigwe, Emmanuel Pay Pay, Nirina Rabearivony

Abstract Introduction: This study aimed to identify patients at risk for venous thromboembolism (VTE) among all patients hospitalised, and to determine the proportion of at-risk hospital patients who received effective types of VTE prophylaxis in sub-Saharan Africa (SSA). Methods: A multinational, observational, cross-sectional survey was carried out on 1 583 at-risk patients throughout five SSA countries. Results: The prevalence of VTE risk was 50.4% overall, 62.3% in medical and 43.8% in surgical patients. The proportion of at-risk patients receiving prophylaxis was 51.5% overall, 36.2% in medical and 64% in surgical patients. Low-molecular weight heparin was the most frequently used prophylactic method in 40.2% overall, 23.1% in medical and 49.9% in surgical patients. Discussion: This study showed a high prevalence of VTE risk among hospitalised patients and that less than half of all at-risk patients received an American College of Clinical Pharmacy-recommended method of prophylaxis. Conclusion: Recommended VTE prophylaxis is underused in SSA.

Submitted 18/1/13, accepted 9/5/14 Cardiovasc J Afr 2014; 25: 159–164

www.cvja.co.za

DOI: 10.5830/CVJA-2014-025

Acute venous thromboembolism (VTE) is a complication in patients hospitalised for a wide variety of acute medical and surgical conditions.1,2 In developed countries, VTE is the most common preventable cause of death among hospitalised patients. Over the last 30 years, extensive research has demonstrated a high risk of VTE in patients who undergo major surgery or experience severe trauma. Patients hospitalised for acute medical illness have approximately the same level of VTE risk as patients who undergo major general surgery.3-5 The benefits of VTE prophylaxis are similar for both medical and moderate-risk surgical patients.6,7 VTE prophylaxis is substantially underused. There is great variation in the use of prophylaxis between countries. Even when prophylaxis is used, it may be used sub-optimally.8-10 Although some surveys and studies suggest that physicians have begun to recognise VTE as a serious health problem and use prophylaxis for at least some high-risk patients, a number of recent studies demonstrate that VTE prophylaxis remains underutilised.11-20

Keywords: thromboprophylaxis, venous thromboembolism, ENDORSE-Africa

Department of Cardiology, General Hospital, Yaoundé, Cameroon

Department of Neurology, Lagos University Teaching Hospital, Lagos, Nigeria

Samuel Kingue, MD

Njideka Okubadejo, MD

Department of Internal Medicine, Clinic Ngaliema, Kinshasa, DRC

Department of Cardiology, Lagos University Teaching Hospital, Lagos, Nigeria

Limbole Bakilo, MD Richard Mvuala, MD

DA Oke, MD

Department of Anaesthesiology and Reanimation, Hospital Gynéco obstetrique et Pédiatrique, Yaoundé, Cameroon Jacqueline Ze Minkande, MD

SANOFI, North-East Africa, Lagos, Nigeria Inoussa Fifen, MD, fifen.inoussa@sanofi.com

Orthopaedic Department, Princess Marina Hospital, Gaborone, Botswana Yash Pal Gureja, MD

Orthopaedist, Antananarivo, Madagascar Henri Jean Claude Razafimahandry, MD

Orthopaedic Department, Hopital du Caisse nationale de prévoyance Sociale, Yaoundé Cameroon Alexandre Manga, MD

Department of Anaesthesiology and Reanimation, Mother and Child Hospital, Antananarivo, Madagascar Tovohery Rajaonera, MD

National Orthopaedic Hospital, Enugu, Nigeria Nwadinigwe Cajetan, MD

Orthopaedic Department, Clinic Ngaliema, Kinshasa, DRC Emmanuel Pay Pay, MD

Department of Cardiology, Mother and Child Hospital, Antananarivo, Madagascar Nirina Rabearivony, MD

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Study rationale and objectives A previous study, ENDORSE, was conducted in 32 countries worldwide, except in sub-Saharan Africa. The results of this study confirmed the high prevalence of patients at risk for VTE; about 52%, among medical and surgical hospital patients. Despite the high prevalence of VTE risk factors, only 58.5% of surgical patients and 39.5% of medical patients received thromboprophylaxis.21 ENDORSE-Africa aimed to collect specific African data on thromboprophylaxis and to structure the doctors’ and other healthcare stakeholders’ awareness on the challenges of VTE prophylaxis. The primary objectives of this survey were (1) to identify patients at risk for VTE among all patients hospitalised in representative hospitals throughout some African countries, and (2) to determine the proportion of at-risk hospital patients who receive effective types of VTE prophylaxis. The secondary objectives were: (1) to define the overall rate of appropriate prophylaxis in medical versus surgical populations, (2) to define the global rate of patients at risk by type of acute illness (medical and/or surgical), (3) to describe the factors driving the prophylaxis decisions; (4) to carry out all preceding analyses in each country.

Methods The study was a multinational, observational, cross-sectional survey on prevalence of VTE risk in hospital patients. The survey aimed at collecting information on the prevalence of VTE risk in hospital patients in selected sub-Saharan African countries. No intervention or modification of standard care was carried out. Subjects were evaluated during a single audit visit. However, the information regarding VTE risk, prophylaxis and bleeding risk were recorded retrospectively to reflect the conditions present on admission or that developed within the first 14 days following hospital admission, regardless of the overall length of stay of a given patient. The focus on the first 14 days following hospital admission reflected the evidence base for the survey, that is, randomised clinical trials of VTE prophylaxis in a wide variety of at-risk hospitalised patients. In published trials, patients at risk were identified and VTE prophylaxis was begun at or soon after hospital admission. This survey therefore focused on the first 14 days following hospital admission for an acute medical illness or major surgery. No follow-up data were collected. In the medical group, patients 40 years of age or older who were admitted for treatment of a serious medical illness and/ or were admitted for a major traumatic event that required no major operation (including closed head injury) were included in the study. In the surgical group, to be included in the surgical arm of the study, patients had to be 18 years or older and to have undergone a major surgical operation requiring general or epidural anesthesia lasting at least 45 minutes. Patients were excluded from the study on one criterion; exclusion by type of illness. Patients admitted to or cared for in a hospital ward, floor or care unit dedicated to psychiatric, paediatric, palliative care, maternity, ear, nose and throat, burns, dermatological/ophthalmological, alcohol/drug treatment were excluded from the survey. Patients in bed on the day of this survey in eligible wards (clinical units) were reviewed individually for eligibility to participate in this survey.

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This survey was conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all subsequent amendments and guidelines for good epidemiology practice. In addition, each participating country obtained all necessary regulatory and ethics approvals in accordance with local regulations.

Data collection The survey was conducted in hospitals in one or two big cities of each participating country. The participating hospitals were selected from a complete list of all hospitals in each city. Hospitals dedicated exclusively to psychiatric care, care of children, rehabilitation/hospice care, or scheduled for only major operations were excluded. Hospitals with more than 50 beds that admit patients for treatment of acute medical illnesses or exacerbation of chronic disease, and schedule routine major surgical procedures were included in this survey. Data were collected using the following tools and methods. A hospital information questionnaire was completed by the lead investigator at each participating hospital. This was used to collect the following information on each participating hospital: hospital address, type of hospital (general/speciality), number of hospital beds, number of ICU beds, services available at the hospital (e.g. orthopedic surgery, ICU, emergency room), name and contact information of the ENDORSE investigator at the hospital, types of VTE prophylaxis that are available for use (formulary coverage), annual number of patient discharges, hospital-wide standards for VTE prophylaxis, types of patient wards (care units) that were not eligible for inclusion in ENDORSE, and total number of patients in units not eligible for this audit. A ward questionnaire was completed by the investigator or his/her co-workers on the day of the ENDORSE audit, at each participating hospital. The ward information questionnaire was used to collect the following information on each participating hospital ward: total number of patient beds in the ward, ward standards for VTE prophylaxis, number of beds occupied on the day of the ENDORSE audit, and for ward patients who were not eligible for enrollment in ENDORSE, the reason for ineligibility. A two-page patient case report form (CRF), was completed for each patient who was hospitalised in a qualified ward and who was otherwise eligible for enrollment. For eligible patients whose medical charts were available, the following information was collected and entered in the CRF: demographic information (age, gender), weight and height, type of major surgical procedure performed or major medical illness present on admission or during the first 14 days of hospitalisation, day of admission (as day 1 up to day 14) on which the surgical procedure/major medical illness was recorded in the chart (diagnosed), additional risk factors for VTE present during the first 14 days of hospitalisation, risk factors for bleeding present during the first 14 days of hospitalisation, day of hospitalisation on which the VTE risk factor/bleeding risk factor was first noted in the chart (first to 14th), type of VTE prophylaxis used and the day of hospitalisation on which it was initiated /terminated, presence/absence of the therapeutic anticoagulation, and the day of hospitalisation on which it was initiated/terminated. The two-page case report form was collected and sent to data management for analysis.

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Evaluation criteria The main evaluation criteria were the proportion of patients at risk of VTE among patients hospitalised in medicine and surgery, and the proportion of these patients at risk who received proper thromboprophylaxis during the first 14 days of admission. The secondary criteria were the proportion of at-risk patients by type (medical versus surgical), the proportion of at-risk patients properly prophylaxed by type (medical versus surgical), and the factors determining the decision of the type of prophylaxis given.

Statistical analysis The primary objective of ENDORSE was to assess the prevalence of VTE risk in hospitalised patients. In order to assess the true prevalence of VTE risk at 50%, confidence interval of 95% with a precision of ± 3%, a minimum of 1 068 patients were needed. Based on the assumption of 10% missing data, a minimum of 1 186 patients should be included. The study aimed at including 1 200 patients, with the following split by country: Madagascar: 400; Nigeria: 400; Cameroon: 400; Democratic Republic of Congo: 300; Namibia: 100 patients. Population characteristics (including demographics, medical history, nature, duration and severity of the disease, co-morbidities, current treatment or no treatment) were summarised into numbers of non-missing data, mean, standard deviation, minimum, maximum, median, 95% confidence interval (CI) of the mean for quantitative variables, and number and percentage with 95% CI of the population for categorical data. The prevalence of VTE risk defined as risk factors meeting the minimum criteria established by the American College of Chest Physicians (version 2004) and any other valid guidelines available at the time of data collection were provided for both the medical and surgical population, with 95% confidence interval by country. Analysis was carried out based on populations Table 1. Characteristics and reasons for admission of assessable surgical patients

Reason for hospitalisation Age, mean ± SD Gender, M (%) F (%) Hip replacement Knee replacement Hip fracture Curative arthroscopy Other orthopaedic trauma Colon/small bowel surgery Rectosigmoid surgery Gastric surgery Hepatobiliary surgery Urological surgery Vascular surgery Thoracic surgery Gynaecological surgery Other surgery Admitted with major trauma but surgery not done

Met VTE risk criteria (n = 445) (%) 45.15 ± 16.59 153 (34.4) 292 (65.6) 49 (11.0) 7 (1.6) 19 (4.3) – 2 (0.5) 47 (10.6) 2 (0.5) 10 (2.3) 1 (0.2) 31 (7.0) 1 (0.2) 1 (0.2) 169 (38.0) 16 (3.6)

Did not meet VTE risk criteria (n = 571) (%) 48.95 ± 17.24 368 (64.4) 203 (35.6) 2 (0.4) 2 (0.4) 1 (0.2) 1 (0.2) 219 (34.8) 2 (0.4) 2 (0.4) – 5 (0.9) 1 (0.2) 7 (1.2) 4 (0.7) 1 (0.2) 107 (18.6)

–

where level of data was satisfactory. The distribution of patients by range of VTE risk factors and the distribution of patients by type of VTE prophylaxis were provided. The prevalence of prophylaxis for VTE is provided by country and globally.

Results Between June 2009 and December 2010, eligible patients were enrolled from 14 hospitals across five sub-Saharan African countries (Madagascar, Democratic Republic of Congo, Cameroon, Botswana and Nigeria). A total of 1 623 patients were surveyed; 567 were medical patients, 1 016 were surgical patients and 27 were unclassified due to incomplete information. Twelve subjects violated the protocol while one subject was below the required age for inclusion. Therefore, the overall number of subjects assessed was 1 583. Reasons for hospital admission and general characteristics of the patients are shown in Tables 1, 2 and 3. The median age of the surgical patients was 45 (IQR 33–59) years, median body mass index (BMI) was 24.2 (IQR 20.9–28.9) kg/m2, and 290 (51.2%) were female. The median age of the medical patients was 60 (IQR 51–72) years, median BMI was 23.5 (IQR 20.5–26.7) kg/m2, and 521 (51.3%) were male. Due to missing values, the BMI could only be calculated for 374 surgical and 196 medical patients. The median length of hospital stay up to the survey date was five days in the overall study population. Of the 1 583 enrolled patients, 798 (50.4%) were deemed to be at risk for VTE; 445 (43.8%) of the 1 016 surgical patients were at risk, as were 353 (62.3%) of the 567 medical patients. There were 88 surgical patients who were at medical risk for VTE. Cardiovascular diseases, endocrine/metabolic diseases and active malignancy were the commonest conditions and/or reasons for admission among surgical patients at risk of VTE, while cardiovascular diseases, endocrine/metabolic diseases, and infections (including pulmonary) were the commonest among medical patients. Of the surgical patients, 454 (44.5%) were admitted with major trauma, while only three (0.5%) of the medical patients had major trauma on admission. Among the surgical patients admitted with

Table 2. Assessable surgical patients presenting with more than one surgery

Reason for hospitalisation Age, mean ± SD Gender, M (%) F (%) Urological and other surgery Hip fracture and other surgery Thoracic and other surgery Other orthopaedic trauma and other surgery Gastric and hepatobiliary surgery Gynaecological and colon/small bowel surgery Hip and knee replacement surgery Colon/small bowel and thoracic surgery Hip replacement and hip fracture

Met VTE risk Did not meet criteria VTE risk criteria (n = 445) (%) (n = 571) (%) 45.15 ± 16.59 48.95 ± 17.24 153 (34.4) 368 (64.4) 292 (65.6) 203 (35.6) 1 (0.2) 1 (0.2) – 1 (0.2) 1 (0.2) – –

2 (0.4)

1 (0.2)

–

1 (0.2)

–

1 (0.2)

–

1 (0.2)

–

1 (0.2)

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Table 3. Characteristics and reasons for admission of assessable medical patients

Reason for hospitalisation Age, mean ± SD Gender, M (%) F (%) Acute heart failure Ischaemic stroke Haemorrhagic stroke Other cardiovascular disease Haematological diseases Malignancy (active) Acute non-infectious respiratory disease Pulmonary infection Infection (non-respiratory) Haematological or inflammatory Neurological disease Renal disease Endocrine/metabolic disease Gastrointestinal/hepatobiliary disease Other medical conditions

Met VTE risk criteria (n = 353) (%) 63.0 ± 12.8 103 (48.1) 111 (51.9) 179 (50.7) 113 (32.0) 32 (9.1) 277 (78.5) 50 (14.2) 42 (11.9)

Did not meet VTE risk criteria (n = 214) (%) 59.0 ± 12.2 174 (49.3) 179 (50.7) – – – 143 (66.8) 38 (17.7) –

42 (11.9)

–

136 (38.5) 49 (13.9) 18 (5.1) 21 (5.9) 59 (16.7) 100 (28.3)

– 86 (40.2) 23 (10.7) 38 (17.7) 67 (31.3) 101 (47.2)

46 (13.0)

42 (19.6)

37 (10.5)

47 (22.0)

a major trauma, 46 (4.5%) had hip fractures, 27 (2.7%) had head injuries while the rest had mixed types of trauma or other forms of trauma. Orthotrauma and gynaecological conditions were the commonest causes/reasons for post-admission operations among the surgical patients with 219 (21.6%) and 169 (16.6%) undergoing the respective operations. Forty patients (5.7%) had operations due to cancer. Sixty-two (6.1%) surgical patients had operations performed prior to admission, while 437 (43%) had operations performed within the first two days of admission. A total of 271 (38.5%) of the surgical patients had emergency surgery performed. Risk factors for VTE that were present before admission are shown in Table 3. Of the 798 patients at risk of VTE prior to admission, 471 (59.0 %) were female; the median age was 54.07 (IQR 39–66) years. In the surgical population, the most common risk factors for VTE prior to hospitalisation were obesity, pregnancy, longterm immobility and chronic pulmonary disease, whereas chronic heart failure, obesity and chronic pulmonary disease were the commonest in the medical population (Table 4). VTE risk factors in patients during hospitalisation are shown in Table 4. Some patients (surgical and medical) presented with more than one VTE risk factor, and these are shown in Table 5. The most common post-admission risk factors to VTE for both surgical and medical patients were immobilisation with bathroom privileges, complete immobilisation, and admission to intensive care unit (Table 6). Table 7 shows the contra-indications to pharmacological VTE prophylaxis. Receiving an NSAID on admission and bleeding on admission were the most common contra-indications to pharmacological prophylaxis in surgical patients. In medical patients, significant renal impairment and receiving an NSAID (including aspirin) on admission were the most common contraindications (Table 7). Of the population at risk for VTE, 112

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Table 4. Risk factors for thromboembolism among patients on admission Number (%) of patients Risk factor Previous VTE Chronic pulmonary disease (CPD) Obesity Thrombophilia Long-term immobility Contraceptive Varicose veins or venous insufficiency (VVI) Pregnancy Chronic heart failure Post-menopausal hormone replacement therapy None

Surgical Medical (n = 1016) (n = 567) 3 (0.3) 2 (0.4) 21 (2.0) 45 (8.0)

All patients (n = 1583) 5 (0.3) 66 (4.2)

104 (10.2) – 44 (4.3) 10 (1.0) 17 (1.7)

59 (10.4) 2 (0.4) 41 (7.2) – 7 (1.2)

163 (10.3) 2 (0.1) 85 (5.4) 10 (0.6) 24 (1.5)

81 (8.0) 13 (1.3) –

1 (0.2) 95 (16.8) 1 (0.2)

82 (5.2) 108 (6.8) 1 (0.1)

764 (75.2)

354 (62.4)

1118 (70.6)

(25.2%) surgical patients and 115 (32.6%) medical patients were considered to have a high bleeding risk, sufficient to present a contra-indication to anticoagulant prophylaxis. Of patients deemed to be at risk for VTE, 411 (51.5%) received ACCP-recommended types of prophylaxis, of whom 283 (64%) were surgical patients and 128 (36.2%) were medical patients. Anticoagulants were the most frequently used form of VTE prophylaxis in the at-risk population; low-molecular weight heparin was the most commonly prescribed anticoagulant (Table 8). Mechanical prophylaxis (foot pump and graduated compression stockings) were used more frequently in surgical patients than in medical patients. Table 5. Patients presenting with more than one risk factor Number (%) of patients All Surgical Medical patients (n = 1016) (n = 567) (n = 1583) 5 (0.5) 1 (0.2) 6 (0.4) – 1 (0.2) 1 (0.1)

Risk factor CPD + obesity Previous VTE + obesity + VVI + CHF CPD + long-term immobility 1 (0.1) – 1 (0.1) CPD + pregnancy 1 (0.1) – 1 (0.1) Obesity + long-term immobility 2 (0.2) 3 (0.5) 5 (0.3) Obesity + VVI + CHF 1 (0.1) – 1 (0.1) Obesity + VVI 4 (0.4) 1 (0.2) 5 (0.3) Obesity + pregnancy 23 (2.3) – 23 (1.4) Long-term immobility + VVI 3 (0.3) 1 (0.2) 4 (0.2) CPD + obesity + CHF – 1 (0.1) 1 (0.1) CPD + long-term immobility – 2 (0.3) 2 (0.1) + CHF CPD + VVI + CHF – 1 (0.1) 1 (0.1) CPD + CHF – 10 (1.8) 10 (0.6) Obesity + CHF – 5 (0.9) 5 (0.3) Thrombophilia + long-term – 1 (0.1) 1 (0.1) immobility + CHF Long-term immobility + CHF – 5 (0.9) 5 (0.3) VVI + CHF – 1 (0.2) 1 (0.1) CPD: chronic pulmonary disease, CHF: chronic heart failure, VVI: varicose veins or venous insufficiency.

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Table 6. Risk factors for thromboembolism among patients during hospitalisation

Table 8. ACCP-recommended prophylaxis to VTE received

Number (%) of patients

571 (56.3) 132 (23.3) 703 (44.4) 20 (1.9) 9 (1.6) 29 (1.8) – – –

The proportion of patients at risk for VTE and the use of ACCP-recommended prophylaxis by country are shown in Fig. 1. The proportion of hospital patients at risk for VTE ranged among countries from 23 to 66%, and the proportion of at-risk patients receiving ACCP-recommended prophylaxis ranged from 22 to 80%. The proportion of surgical patients at risk for VTE ranged among countries from 22 to 73%, and for medical patients the range was from 26 to 90%. The use of recommended VTE prophylaxis in surgical patients varied from 25 to 100% between countries, and for medical patients between 1 and 46% (Fig. 1).

Discussion The data gathered show a high prevalence of VTE risk among hospitalised patients in sub-Saharan Africa. More than half of all hospitalised patients were at risk for VTE, and medical patients were at higher risk than surgical patients. The data further show that less than half of all at-risk patients received an ACCP-recommended method of prophylaxis. Data from this survey showed that the proportion of hospital patients at risk for VTE ranged from 23 to 66% and the proportion of at-risk patients receiving ACCP-recommended prophylaxis ranged from 22 to 80%. The proportion of surgical patients at risk for VTE ranged from 22 to 73%, and for medical patients the range was from 26 to 90%. The use of recommended VTE prophylaxis in surgical patients varied from 25 to 100%, and for medical patients between 1 and 46%.

Table 7. Contra-indications to anticoagulant prophylaxis Number (%) of patients All Surgical Medical patients Risk factor (n = 1016) (n = 567) (n = 1583) Significant renal impairment 19 (1.9) 88 (15.5) 107 (6.8) Active gastro-duodenal ulcer 8 (0.8) 8 (1.4) 16 (1.0) Intracranial haemorrhage 12 (1.2) 14 (2.5) 26 (1.6) Aspirin on admission 21 (2.1) 57 (10.0) 78 (4.9) Low platelet count 6 (0.6) 21 (3.7) 27 (1.7) Known bleeding disorder 1 (0.1) 4 (0.7) 5 (0.3) Hepatic impairment 7 (0.7) 17 (3.0) 24 (1.5) NSAID on admission (excluding 191 (18.8) 31(5.5) 222 (14.0) aspirin) Bleeding at hospital admission 63 (6.2) 14 (2.5) 77 (4.9)

Type of prophylaxis Low-molecular weight heparin Unfractionated heparin Vitamin K antagonist Fondaparinux Other anticoagulants Foot pump Graduated compression stockings Intermittent pneumatic compression

–

Although there is little information on VTE prevalence and the rate of usage of VTE prophylaxis in Africa,22 data from this survey support data from previous studies that have shown a similar trend. Studies conducted elsewhere have reported overall VTE prophylaxis rates ranging from 13 to 64%. The data showed marked differences between countries in the frequency of use of ACCP-recommended types of prophylaxis, which could be due to many factors, including physician awareness, availability of guidelines, education factors, reimbursement, and national healthcare resources. The use of recommended VTE prophylaxis was particularly poor in medical patients, with prophylaxis received by only 35.1% of medical patients deemed to be at risk. This finding is consistent with other studies that have shown low use of prophylaxis in at-risk medical patients.12,19 In surgical patients, prophylaxis rates were generally higher. The increased use of prophylaxis in the surgical setting compared with the medical setting could result from several factors. First, the benefits of prophylaxis in the surgical setting have been

180 160 Number of patients

Risk factor Admitted to ICU/UCU Central venous catheter Mechanical ventilation Immobile with bathroom privileges Complete immobilisation Cancer therapy Heparin-induced thrombocytopenia

All Surgical Medical patients (n = 1016) (n = 567) (n = 1583) 195 (19.2) 31 (5.5) 226 (14.5) 26 (2.6) 11 (2.0) 37 (2.5) 106 (10.5) – 106 (6.7) 400 (39.5) 280 (49.3) 680 (43.1)

Number (%) of patients All Surgical Medical patients (n = 1016) (n = 567) (n = 1583) 506 (49.9) 132 (23.1) 638 (40.2) 5 (0.5) 11 (2.0) 16 (1.2) 7 (0.7) 4 (0.8) 11 (0.8 – – – 2 (0.2) – 2 (0.1) 12 (1.2) – 12 (2.0) 54 (5.3) – 54 (3.4)

140 120 100 80 60 40 20 0 Botswana

Cameroon

DR Congo Madagascar

Nigeria

Country At risk for VTE – surgical

Received prophylaxis – surgical

At risk for VTE – medical

Received prophylaxis – surgical

Fig. 1. Percentage at-risk patients versus patients that received ACCP-recommended VTE prophylaxis by country.

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accepted for many years,16 while trials in medical patients have been more recent and physician awareness of VTE risk is lower in this population.1 Second, assessment of VTE risk in surgical patients is simpler than in medical patients, the principal criterion being the type of surgery rather than a range of illnesses and risk factors as presented in medical patients.

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Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl): 338S–400S. 7.

Nicolaides AN, Breddin HK, Fareed J, Goldhaber S, Haas S, Hull R, et al; Cardiovascular Disease Educational and Research Trust and the International Union of Angiology. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1–37.

Conclusion While venous thromboembolism is a well-recognised condition in clinical practice in the developed world, with event rates of at least two to three million per year, little attention is paid to this threat in the developing world where the burden of infectious diseases and limited access to healthcare have not recognised VTE as a significant cause of morbidity and mortality. VTE is a major public health issue. It is an easily preventable disease with a substantial risk of morbidity and mortality in patients hospitalised for acute medical and surgical illnesses. Data from this survey show that in sub-Saharan African, as elsewhere in the world, a large proportion of hospitalised patients are at risk for VTE, and that recommended VTE prophylaxis is underused. Data from this survey are important in providing an overview of the magnitude of VTE prevalence in Africa and the gaps that exist in the prophylaxis of VTE in at-risk patients in hospital settings.

Ageno W, Squizzato A, Ambrosini F, Dentali F, Marchesi C, Mera V, et al. Thrombosis prophylaxis in medical patients: a retrospective review of clinical practice patterns. Haematologica 2002; 87: 746–750.

Ahmad HA, Geissler A, MacLellan DG. Deep venous thrombosis prophylaxis: are guidelines being followed? Austr NZ J Surg 2002; 72: 331–334.

10. Bergmann J-F, Mouly S. Thromboprophylaxis in medical patients: focus on France. Semin Thromb Hemost 2002; 28(Suppl 3): 51–55. 11. Goldhaber SZ, Tapson VF; DVT FREE steering committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 2004; 93: 259–262. 12. Mismetti P, Laporte-Simitsidis S, Tardy B, Cucherat M, Buchmuller A, Juillard-Delsart D, Decousus H. Prevention of venous thromboembolism in internal medicine with unfractionated heparin or low-molecularweight heparins: a meta-analysis of randomized clinical trials. Thromb Haemost 2000; 83: 14–19. 13. Alikhan R, Cohen AT. A safety analysis of thromboprophylaxis in acute medical illness. Thromb Haemost 2003; 89: 590–591. 14. Arnold DM, Kahn SR, Shrier I. Missed opportunities for prevention of

This study was sponsored by Sanofi.

venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines. Chest 2001; 120: 1964–1971.

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registry. Semin Thromb Hemost 2002; 28(Suppl 3): 47–50. 18. Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov B,

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Goldhaber SZ; PREVENT Medical Thromboprophylaxis study group.

Surg Edinb 2001; 46: 329–333. 17. Caiafa JS, de Bastos M, Moura LK, Raymundo S; Brazilian registry of

Heit JA, O’Fallon WM, Petterson TM, Lohse CM, Silverstein MD, thrombosis and pulmonary embolism: a population-based study. Arch

1398–1402. 16. Burns PJ, Wilsom RG, Cunningham C. Venous thromboembolism

933–938.

in a South Australian teaching hospital. Ann Pharmacother 2003; 37:

NA, Jovanovic B, et al. A population-based perspective of the hospital nary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 2.

15. Learhinan ER, Alderman CP. Venous thromboembolism prophylaxis

Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP

sectional study. Lancet 2008; 371: 387–394. 22. Duncan A. The case for venous thromboembolism prophylaxis in Africa. East Afr Med J 2009: 86(12 Suppl): S108–109.

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Decline in mean platelet volume in patients with patent foramen ovale undergoing percutaneous closure Barış Düzel, Nihan Kahya Eren, Rida Berilgen, Uğur Kocabaş, Mustafa Gönençer, Cem Nazli, Oktay Ergene

Abstract Introduction: The presence of patent foramen ovale (PFO) is considered a possible cause for cryptogenic stroke. The mechanism underlying the ischaemic neurological events in the presence of PFO has not been firmly established. The purpose of this study was to compare: (1) the mean platelet volume levels in PFO patients with and without a cryptogenic stroke, and (2) pre- and post-procedural mean platelet volumes (MPV) in patients undergoing percutaneous PFO closure. Methods: Sixteen PFO patients undergoing percutaneous closure to prevent recurrent ischaemic events and 15 asymptomatic patients with PFO were enrolled in the study. Mean platelet volume was compared between patients with and without a history of stroke. We also compared pre- and postprocedural MPV levels in patients undergoing percutaneous PFO closure. Results: Mean platelet volume, which is a marker for platelet activity, was similar in PFO patients with and without stroke (9.34 ± 1.64 vs 9.1 ± 1.34 fl; p = 0.526). Interestingly, MPV decreased significantly after percutaneous closure compared to pre-procedural levels (9.34 ± 1.64 vs 8.3 ± 1.12 fl; p = 0.001). Conclusion: Our findings suggest interatrial communication through a PFO may be related to increased MPV and increased platelet activity. Keywords: patent foramen ovale, ischaemic stroke, platelets, transcatheter closure

(TTE) with contrast injection and showed that patients with stroke of unknown cause had PFOs more frequently than the controls.2 Since then, many studies have confirmed this association. In 2000, a meta-analysis summarised the evidence that PFO was more likely to be found in stroke patients than in stroke-free individuals.3 In about 50 to 60% of patients younger than 55 years, the cause of acute ischaemic stroke remains undefined.4 In this group, interatrial septal abnormalities are found in 55 to 60% of cases, which is higher than in the normal population. In another meta-analysis, Mattle et al. reported a higher prevelance of PFO in patients with cryptogenic stroke than in patients with a stroke of known causes.1 The postulated possible mechanisms underlying the stroke in the presence of PFO are: paradoxycal embolism, thrombus formation within the conduit of the PFO, or susceptibility of patients with PFO to atrial arrhythmias with possible intra-atrial thrombus formation.4-8 Although paradoxycal embolism, which is associated with deep-vein thrombosis (DVT), is the favoured hypothesis, DVT in patients with PFO is usually undetectable.9 Therefore, increased platelet activity as well as disorders in the coagulation cascade may contribute to the association between PFO and stroke. Mean platelet volume (MPV) is a measure of platelet size and is a potential marker of platelet reactivity. It has been shown that larger platelets are metabolically and enzymatically more active and have greater prothombotic potential.10,11 The aim of this study was (1) to compare MPVs of PFO patients with and without a history of cryptogenic stroke, and (2) to determine the effect of percutaneous PFO closure on MPV.

Submitted 22/7/13, accepted 9/5/14 Cardiovasc J Afr 2014; 25: 165–167

www.cvja.co.za

DOI: 10.5830/CVJA-2014-027

Patent foramen ovale (PFO) is a haemodynamically insignificant communication that is present in 24% of the general population.1 In 1988 Lechat et al. performed transthoracic echocardiography

Mersin State Hospital, Mersin, Turkey Bariş Düzel, MD

Izmir Katip Çelebi University, Cardiology Clinic, Atatürk Research and Education Hospital, Turkey Nihan Kahya Eren, MD, nkahya77@yaho.com Uğur Kocabaş, MD Mustafa Gönençer, MD Cem Nazli, MD Oktay Ergene, MD

Mardin Kiziltepe State Hospital, Mardin, Turkey Rida Berilgen, MD

Methods Between January 2008 and June 2012, 16 consecutive patients who had suffered cryptogenic stroke and underwent percutaneous PFO closure to prevent recurrent cerebral ischaemic events, and 15 consecutive patients with a diagnosis of PFO but without a history of stroke were recruited into the study. The diagnosis of PFO was established if any microbubble was seen in the left-sided cardiac chambers within three cardiac cycles from the maximum right atrial opacification after contrast injection during transoesophageal echocardiography (TEE). Demographic data and history of conventional risk factors such as smoking habits, hypertension, diabetes mellitus, hyperlipidaemia, history of vascular disease (stroke, coronary artery disease, peripheral artery disease) and medications were recorded for every patient. Non-fasting blood samples were taken from each patient to assess mean platelet volume and standard blood tests. In patients who underwent percutaneous PFO closure, mean platelet volume was measured before percutaneous PFO closure and at the six-month follow up after the intervention. In patients with PFO without a history of stroke, MPV was measured once at the time of enrollment.

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Percutaneous PFO closure was performed under fluoroscopic and TEE guidance and under general anaesthesia. Procedural success was defined as successful implantation of the occluder at the closure site with no procedural complications. Dual antiplatelet therapy including 75 mg clopidogrel for three months and 100 mg aspirin lifelong was recommended after the closure procedure. Patients in the intervention group were followed up at one, three, six and 12 months after the procedure and closure rates and residual shunt were evaluated at the six-month follow up by contrast transthroracic echocardiography.

Statistical analysis Continuous variables are presented as mean ± standard deviation and categorical variables are presented as percentages. Group differences for continuous variables were examined by the Mann– Whitney U-test. For categorical variables, comparisons between groups were made with the χ2 or Fisher exact test, as appropriate. Pre- and post-procedural MPV levels in the intervention group were compared with the Wilcoxon signed-rank test.

Results A total of 31 patients were enrolled in the study. Baseline demographic and clinical characteristics of all patients are presented in Table 1. The patients in the intervention group were significantly older than those without a history of stroke (48.25 ± 12.1 vs 37.4 ± 15.32 years; p = 0.028). The other baseline characteristics were similar between the two groups. The mean age of the patients in the intervention group at the time of their first ischaemic attack was 45.38 ± 12.01 years. Procedural success rate was 100% in the intervention group. Cardio Fix, BioSTAR, Amplatzer and Cardioseal/Starflex devices were implanted in eight, six, one and one patients, respectively. Residual shunt was detected in three (19%) patients at the six-month follow up. None of the patients suffered a recurrent ischaemic attack after the intervention during a mean follow-up period of 26.5 ± 1.3 months. Forty-four per cent of the patients undergoing PFO closure were receiving aspirin (100 mg/day), and the remainder (56%) were taking oral anticoagulant therapy before the procedure.

After PFO closure, all patients were prescribed dual antiplatelet therapy with asetylsalicilic asid (100 mg/day) and clopidogrel (75 mg/day). The patients with PFO and cryptogenic stroke had similar mean platelet volumes to the patients with PFO but without stroke (9.34 ± 1.64 fl vs. 9.1 ± 1.34 fl; p = 0.526). On the other hand, we observed a significant decline in MPV after transcatheter PFO closure in patients with stroke compared with their pre-procedural levels (9.34 ± 1.64 fl vs 8.3 ± 1.12 fl; p = 0.001). Pre- and post-procedural changes in MPV in patients undergoing percutaneous closure is represented in Fig. 1. There was no difference in platelet count in patients with and without stroke. There were also no significant differences in preand post-closure platelet count levels in the intervention group (Table 1).

Discussion We presumed that platelet activity may be increased in PFO patients with stroke compared to those without stroke, but we did not find a difference between these two groups. Interestingly, we observed that MPV levels decreased after percutaneous PFO closure in patients with previous stroke compared with their pre-procedural levels. Mean platelet volume is a measure of platelet size, and is a determinant of platelet activity. Larger platelets are metabolically and enzymatically more active than smaller platelets, containing more prothrombotic material such as thromboxane A2 and serotonin, and expressing greater numbers of adhesion molecules such as Glp IIb/IIIa receptor and P-selectin.11-14 They also show greater aggregation in response to ADP.10 Previous studies have shown that MPV was increased in myocardial infarction and ischaemic stroke, both of which are atherothrombotic events where platelets play a pivotal role. The association of PFO with cryptogenic stroke has been established previously,1,4 but the pathogenic link between PFO and stroke is still unclear in most cases. One of the postulated mechanisms underlying the stroke in the presence of PFO is paradoxycal embolism with an occult DVT. Although some studies have shown increased frequency of prothrombotic mutations, which may be a predisposing factor for the

Table 1. Demographic and clinical characteristics of the patients

16 14 12 MPV (fl)

PFO patients PFO patients with stroke without stroke p-value Number 16 15 Male (%) 44 13 0.113 Age (years) 0.028 48.2 ± 12.1 37.4 ± 15.3 Current smoker (%) 44 47 0.870 Hypertension (%) 19 7 0.600 Diabetes mellitus (%) 25 0 0.101 Hyperlipidaemia (%) 6 0 1.00 Coronary artery disease (%) 0 0 1.00 Antiplatelet use at 44 0 baseline (%) Oral anticoagulan therapy 56 0 at baseline (%) MPV at baseline (fl) 0.526 9.34 ± 1.64 9.10 ± 1.34 Platelet count at baseline 288562 ± 80180 267400 ± 56368 0.527

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10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Pre-procedural MPV

Post-procedural MPV

Fig. 1. Pre- and post-procedural mean platelet volume (MPV) in PFO patients undergoing percuteneous closure.

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development of DVT in patients with PFO, other studies found no difference between PFO patients and controls.15-18 Accordingly, the majority of strokes associated with PFO cannot be explained by paradoxycal embolism. We hypothesised that increased platelet activity may be a factor in the pathogenesis of cryptogenic stroke in patients with PFO, and found that PFO patients with and without stroke had similar MPV, which was decreased after percutaneous closure. Increased platelet activity in patients with right-to-left shunt may be a precipitating factor in thrombus formation in the conduit of PFO, which is one of the proposed pathogenic links between PFO and stroke. The absence of recurrent neurological events during the mean follow-up period of 26.5 ± 1.3 months in the intervention group may also suggest that decreased MPV and platelet activity may have a possible protective role for recurrent ischaemic events after the closure procedure. However, why patients with right-to-left shunt have increased platelet activity is a dilemma. Forty-four per cent of patients in the intervention group were receiving aspirin before the procedure, after which dual antiplatelet therapy was prescribed to all patients for three months. Finally, aspirin monotherapy was recommended lifelong. Although there are limited data regarding the effect of antiplatelet agents on MPV, aspirin does not seem to significantly affect platelet volume.19,20 Likewise, large platelets exhibit increased reactivity even after dual antiplatelet therapy in patients with stable coronary artery disease.21 These data support the hypothesis that post-procedural decline in MPV cannot be solely attributed to a higher rate of usage of antiplatelet therapy after the intervention. This study is limited by its small sample size. The lack of significant difference in MPV between patients with and without stroke may be a type 2 error due to insufficient sample size. Mean platelet volume may be greater in patients with cryptogenic stroke and PFO compared with asymptomatic patients with PFO. This should be clarified in further randomised studies with larger patient populations. Additionally, the observed post-procedural decline in MPV may be related to factors such as different rates of pre- and post-procedural antiplatelet and anticoagulant therapy usage as well as the PFO closure device itself. Therefore, performing other laboratory tests in addition to platelet count and MPV to estimate platelet activity would have strenghtened our results. On the other hand, this is the first study to our knowledge that demonstrates a decrease in platelet activity in patients with PFO undergoing percutaneous closure. Our findings warrant further studies to investigate the platelet activity in PFO patients as a risk factor for cryptogenic stroke and its possible association with percutaneous closure.

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References 1.

Mattle HP, Meier B, Nedeltchev K. Prevention of stroke inpatients with patent foramen ovale. Int J Stroke 2010; 5: 92–102.

Lechat P, Mas JL, Lascaut G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318: 1148–1152.

Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a metaanalysis of case-control studies. Neurology 2000; 55: 1172–1179.

Amarenco P. Patent foramen ovale and the risk of stroke: smoking gun guilty by association? Heart 2005; 91: 441–443.

Nellessen U, Daniel WG, Matheis G, et al. Impending paradoxical embolism from atrial thrombus: correct diagnosis by transesophageal echocardiography and prevention by surgery. J Am Coll Cardiol 1985; 5: 1002–1004.

Schreiter SW, Phillips JH. Thromboembolus traversing a patent foramen ovale: resolution with anticoagulation. J Am Soc Echocardiogr 1994; 7: 659–662.

Hust MH, Staiger M, Braun B. Migration of paradoxic embolus through a patent foramen ovale diagnosed by echocardiography: successful thrombolysis. Am Heart J 1995; 129: 620–622.

Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31: 398–403.

Lethen H, Flaschskampf FA, Schneider R, et al. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol 1997; 80: 1066–1069.

10. Karpatkin S. Heterogeneity of human platelets. II. Functional evidence suggestive of young and old platelets. J Clin Invest 1969; 48: 1083–1087. 11. Kamath S, Blann AD, Lip GY. Platelet activation: assessment and quantification. Eur Heart J 2001; 22: 1561–1571. 12. Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinol 1996; 7: 157–161. 13. Thompson CB, Jakubowski JA, Quinn PG, et al. Platelet size as a determinant of platelet function. J Lab Clin Med 1983; 101: 205–213. 14. Giles H, Smith RE, Martin JF. Platelet glycoprotein IIb–IIIa and size are increased in acutemyocardial infarction. Eur J Clin Invest 1994; 24: 69–72. 15. Botto N, Spadoni I, Giusti S, et al. Prothrombotic mutations as risk factors for cryptogenic ischemic cerebrovascular events in young subjects with patent foramen ovale. Stroke 2007; 38: 2070–2073. 16. Pezzini A, Del Zotto E, Magoni M, et al. Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 2003; 34: 28–33. 17. Belvis R, Santamaria A, Marti-Fabregas J, et al. Patent foramen ovale and prothrombotic markers in young stroke patients. Blood Coagul Fibrinol 2007; 18: 537–542. 18. Florez JC, Ay H,Van Cott EM, Buonanno FS. Patent foramen ovale and hypercoagulability as combined risk factors for stroke. J Stroke Cerebrovasc Dis 2003; 12: 114–118. 19. Erhart S, Beer JH, Reinhart WH. Influence of aspirin on platelet count and volume in humans. Acta Haematol 1999; 101: 140–144.

Conclusion Our findings suggest interatrial communication through a PFO may be related to increased MPV and increased platelet activity.

20. Vizioli L, Muscari S, Muscari A. The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases. Int J Clin Pract 2009; 63: 1509–1515. 21. Guthikonda S, Alviar CL, Vaduganathan M, et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual

The authors gratefully thank M Erdinc Arikan for his assistance in language

antiplatelet therapy with aspirin and clopidogrel in patients with stable

editing.

coronary artery disease. J Am Coll Cardiol 2008; 52: 743–749.

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Infliximab, an anti-TNF-alpha agent, improves left atrial abnormalities in patients with rheumatoid arthritis: preliminary results Çetin Süha, Vural Mustafa Gökhan, Keskin Göksal, Yeter Ekrem, Doğan Mehmet, Öztürk Mehmet Akif

Abstract Background: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality. In the current prospective study, we addressed the impact of RA on left atrial (LA) function and electrical remodelling. Further, we tried to demonstrate the effects of infliximab, an anti-TNFalpha agent, on echocardiographical LA abnormality in RA patients with preserved left ventricular (LV) ejection fraction. Methods: We compared 38 female RA patients without clinical evidence of heart disease and 30 female controls without RA and clinical evidence of heart disease. Further, we compared RA patients receiving infliximab and increasing doses of prednisolone over a three-month period. At baseline and post treatment, this study assessed (1) LA and LV parameters using conventional and speckle tracking echocardiography (STE), and (2) electrocardiographic P-wave changes. Results: The values of C-reactive protein (CRP), isovolumic relaxation time (IVRT), A wave, and deceleration time (DT) were significantly higher in RA patients compared to the control group (p < 0.05), whereas E/E′ and E/A values were found to be lower (p < 0.05) in RA patients. E/E′ values were lower in prednisolone- compared to infliximab-treated patients (p < 0.05). After three months of infliximab and prednisolone treatment, CRP and disease activity score (DAS 28) values decreased in both groups (p < 0.05), and Duke activity status index (DASI) increased (p < 0.05). Maximal left atrial volume index (LAVImax), pre-contraction left atrial volume index (LAVIpreA) and maximum P wave (Pmax) of the RA patients were higher compared to the control group (p < 0.05), whereas LA global strain was found to be lower (p < 0.05). There was no difference in Pmax values between groups before and after the treatment period. E/E′, LAVImax and LAVIpreA values of infliximab-treated patients decreased and LA global strain increased after three months of therapy compared to

Department of Cardiology, 29 Mayis Hospital, Ankara, Turkey Çetin Süha, MD, ceramos3@gmail.com

Department of Cardiology, Dişkapi Research and Education Hospital, Ankara, Turkey Vural Mustafa Gökhan, MD Yeter Ekrem, MD Doğan Mehmet, MD

Department of Internal Medicine, Dişkapi Research and Education Hospital, Ankara, Turkey Keskin Göksal, MD

Department of Rheumatology, School of Medicine, Gazi University, Ankara, Turkey Öztürk Mehmet Akif, MD

baseline (p < 0.05). At baseline in both treatment groups, E/E′ and LA global late diastolic strain rate were lower in prednisolone- compared to infliximab-treated patients (p < 0.05). Conclusion: There was echocardiographic LA abnormality in these RA patients. In this patient group there was also a meaningful increase in maximum P wave assessed by electrocardiography. Infliximab therapy for a period of three months improved LA abnormality. Keywords: electrocardiography, infliximab, left atrium, rheumatoid arthritis, speckle tracking echocardiography Submitted 14/1/14, accepted 13/6/14 Cardiovasc J Afr 2014; 25: 168–175

www.cvja.co.za

DOI: 10.5830/CVJA-2014-036

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting about 1% of the population.1 It is also characterised by an excess risk of cardiovascular disease and mortality, probably via chronic systemic inflammation.2 TNF-alpha represents the major inflammatory cytokine in RA patients.3 Apart from being the major promoter and regulator of the inflammatory cascade resulting in joint damage, it may mediate cardiac injury through a variety of biological mechanisms.4 Treatment of RA with anti-TNF-alpha agents such as infliximab has been shown to be effective in reducing signs and symptoms of the disease and in preventing joint damage,5-7 but their impact on cardiovascular disease, especially in RA patients with preserved LV function (EF ≥ 50) remains controversial. In this prospective study we tried to elucidate (1) whether myocardial abnormality as assessed by echocardiography is present in RA patients compared to normal controls, (2) the electrocardiographic P-wave changes in RA patients, and (3) the impact of infliximab treatment on left ventricular (LV) and left atrial (LA) echocardiographic parameters in comparison to treatment with corticosteroids. We used conventional and speckle tracking echocardiography (STE), a novel method for the evaluation of myocardial abnormality.

Methods Thirty-eight female patients (age 52.1 ± 11.1 years) with RA diagnosed by revised American Rheumatism Association criteria, who had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) and corticosteroids were recruited from the RA out-patient section of the Rheumatology Unit, Ministry of Health, Dişkapi Yildirim Beyazit Research and Education Hospital, Ankara, Turkey, between January 2011

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and January 2012.8 The control group consisted of 30 female patients without RA (age 50.7 ± 3.4 years). Patients of the RA group were on methotrexate 15 mg once per week and prednisolone 5–7.5 mg once daily. The patients had occasionally been treated with non-steroidal anti-inflammatory drugs within the previous six months. The disease activity score (DAS 28), which utilises C-reactive protein (CRP) level, and the visual analogue score of wellbeing plus the number of tender and swollen joints, was used in order to evaluate the activity of RA.9 We used the Duke activity status index (DASI), a brief self-administered questionnaire designed to estimate the patient’s exercise capacity in metabolic equivalents (METs).10 Out of 38 RA patients, 20 subjects (age 53.4 ± 13.5 years) additionally received infliximab treatment (initially 3 mg/kg; the same dose two and six weeks after the first infusion, and thereafter the same dose every eight weeks) for three months. The remaining 18 patients in the RA group were treated with prednisolone in increasing doses in accordance with standard clinical practice. Patients were examined in the out-patient clinic monthly to assess clinical status and compliance with therapy. None of the patients had had ischaemic or arrhythmic events during the previous year. The RA patients’ biochemical parameters, and echocardiographic LA and LV function were measured at baseline and after three months of infliximab and prednisolone therapy. Electrocardiographic P waves were evaluated. The control subjects had a single baseline measurement of the examined parameters. The study protocol was approved by the local ethics committee.

Conventional echocardiography All echocardiographic examinations were performed by a single experienced observer blinded to clinical and laboratory data. Transthoracic echocardiography studies were performed using a commercially available ultrasound system with a 2.5–3.5 MHz transducer (ie33, Phillips Medical System, Bothell, Washington, USA). Patients lay at rest in the left lateral decubitus position, and apical four-chamber and parasternal views of the LA and LV were obtained at end-expiratory apnoea. Three cardiac cycles were stored from each view in ciné-loop format for subsequent off-line analysis by an investigator blinded to the patients’ data. Speckle tracking analysis was performed off-line by commercially available software QLAB 6.0 (Phillips Medical System, Bothell, Washington, USA). We measured the following parameters from crosssectional echocardiographic images of the cardiac chambers. (1) End-diastolic interventricular septum thickness (IVS), end-diastolic posterior wall thickness (PW) of the LV, (2) end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction of the LV using the modified Simpson’s method,11 and (3) maximal (LAVImax), pre-contraction (LAVIpreA) and minimal (LAVImin) LA volumes were measured just before mitral valve opening, at the beginning of the P wave, and at mitral valve closure. All LA volumes were determined using the modified Simpson’s method. LA volume indices were calculated by dividing the LA volumes by the body surface area.12 Pulsed-wave Doppler of transmitral LV inflow was performed in the apical four-chamber view, with the sample volume placed at the level of the mitral valve tips, and Doppler variables

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were analysed during three consecutive beats. The following measurements of LV diastolic function were determined: peak early (E) and late (A) diastolic mitral flow velocity and their ratio E/A, early diastolic mitral annular velocity (E’), late diastolic mitral annular velocity (A′), deceleration time of the E wave, and LV isovolumic relaxation time (IVRT).13 The E/E′ ratio was used as an index of LV filling pressures.

Speckle tracking echocardiography The methods of image acquisition and post-processing of strain and strain rate measurements with speckle tracking have been described previously.14 All images were obtained at a frame rate of 50 to 80 frames per second. Briefly, the observer traced the endocardial and epicardial borders of the LA on an end-systolic frame and the software automatically tracked the border on the subsequent frames. Adequate tracking can then be verified in real-time and corrected by adjusting the region of interest or manually correcting the border to ensure optimal tracking. The aortic valve closure measured by Doppler has been identified as end-systole. The software is able to represent abnormality in time–strain graphs where it is possible to identify the different phases of the cardiac cycle.

Electrocardiography After a 20-minute resting period in the supine position, all subjects underwent a 12-lead ECG recording at a paper speed of 50 mm/s and 2 mV/cm. The P-wave duration was measured manually in all simultaneously recorded 12 leads of the surface ECG by one of the investigators blinded to the study hypothesis. In each lead the mean values for the three complexes were calculated. For greater accuracy, the measurements were performed with callipers and a magnifying lens, as described by previous investigators.15,16 The onset of the P wave was defined as the point of first visible upward departure from baseline for positive waveforms, and as the point of first downward departure from baseline for negative waveforms. The return to baseline was considered to be the end of the P wave. Pmax measured in any of the 12 leads of the surface ECG was used as the longest atrial conduction time. The difference between Pmax and minimum P wave (Pmin) was calculated and defined as P-wave dispersion (Pd = Pmax – Pmin).17

Laboratory assays CRP was measured using routine methods. IgM rheumatoid factor (RF) was measured by means of immunonephelometry using the quantitave N Latex RF system (Dade Behring, Marburg, Germany) with RF titers of > 15 IU/ml being considered positive. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and creatinine were determined using an auto-analyser under fasting conditions on the same day as the other evaluations.

Statistical analysis Propensity scores, a methodology that can be used to compare the effectiveness of different treatments and to examine whether patients included in the two treatment groups were

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adequately balanced for atherosclerosis, between infliximab- and prednisolone-treated patients, were compared using a two-tailed t-test. Categorical data were compared by contingency tables, and between each treatment group and normal controls by the χ2 test or Fisher exact test when five patients or fewer were included in each cell. Continuous variables were tested for normality using the Kolmogorov–Smirnov test. Normally distributed variables are given as mean and standard deviation (SD). Spearman correlation analysis was used to determine bivariate correlations. Because biomarkers had a non-normal distribution, data are expressed as median (interquartile range) and were analysed after transformation into ranks. Analysis of variance (ANOVA) for repeated measurements was applied to compare the effects of infliximab versus prednisolone, with measurements at baseline and three months post treatment used as a within-subject factor, and type of treatment as between-subject factor. The F- and p-values of interaction between time measurement of the examined markers and type of treatment were calculated. Post hoc comparisons were performed within Bonferroni’s correction. Comparisons between controls and each treatment group at baseline or three months were performed using the unpaired t-test (normally distributed variables) and Mann–Whitney test (non-normally distributed variables). Statistical significance was considered as p < 0.05. All statistical analysis was performed using SPSS for Windows (release 15.0, SPSS Inc, Chicago, Illinois).

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Results The demographic, clinical, biochemical and conventional echocardiographic parameters are given in Tables 1 and 2. All RA patients were seropositive. The mean DAS was 6.4 ± 0.7 and the disease duration was 85.7 ± 66.8 months. Age, cardiac medication, cardiovascular risk factors, systolic and diastolic blood pressure, heart rate, and cholesterol, fasting glucose and creatinine levels were similar between the control group and the RA patients and also in the infliximab- and prednisolone-treated patients. Therefore our patients had similar characteristics regarding risk factors for atherosclerosis. Control group patients had normal electrocardiograms, transthoracic echocardiography and treadmill tests. Baseline CRP, DAS 28 and RF values showed significant differences. None of the subjects was excluded from the study because of adverse effects or discontinuation of therapy. On transthoracic echocardiography there was no pericardial effusion or significant valvular heart disease. Parameters showing diastolic function such as LV diastolic filling pressure (E/E′), A-wave values, deceleration time (DT) and isovolumic relaxation time (IVRT) were significantly higher in the RA patients. E/A ratio showed a significant reduction (p < 0.05). E/E′ was found to be decreased in prednisolone- compared to infliximab-treated patients (p < 0.05). Significant improvement in RA parameters, as assessed by CRP, DAS 28 and DASI were achieved in both treatment groups (p < 0.05) (Table 3).

Table 1. Clinical and biochemical characteristics of the study population

Controls (n = 30) – – – 50.7 ± 3.4 30.5 ± 3.7 7 (23) 10 (33) 8 (26) 8 (26) 2 (6)

RA patients (n = 38) 6.4 ± 0.7 85.7 ± 66.8 226.8 (25.2–66.1) 52.1 ± 11.1 30.5 ± 5.5 5 (13) 17 (44) 5 (13) 8 (21) 8 (21)

Infliximab-treated patients (n = 20) 6.4 ± 0.5 98.4 ± 77.4 194.4 (25.2–321.8) 53.4 ± 13.5 31.0 ± 5.9 2 (10) 9 (45) 2 (10) 3 (15) 4 (20)

Prednisolone-treated patients (n = 18) 6.1 ± 0.8 71.6 ± 51.1 165.8 (30.5–366.1) 50.7 ± 7.6 29.9 ± 5.2 3 (16) 8 (44) 3 (16) 5 (27) 4 (22)

p-value* – – – 0.52 0.91 0.21 0.24 0.13 0.39 0.09

p-value# 0.06 0.21 0.57 0.44 0.70 0.47 0.63 0.32 0.56 0.24

DAS-28 Disease duration (months) RF (mg/dl) Age (years) Body mass index (kg/m2) Obesity (%) Hypertension (%) Current smoking (%) Dyslipidaemia (%) Diabetes mellitus (%) Medication RAAS blocker (%) 5 (16) 11 (28) 6 (30) 5 (27) 0.18 0.48 5 (16) 4 (10) 1 (5) 3 (16) 0.34 0.43 β-blocker (%) CaCh blocker (%) 4 (13) 4 (10) 3 (15) 1 (5) 0.5 0.62 Statin (%) 7 (23) 4 (10) 2 (10) 2 (11) 0.13 0.36 SBP (mmHg) 0.33 0.24 121.6 ± 9.8 124.7 ± 13.9 122.1 ± 14.4 127.4 ± 13.2 DBP (mmHg) 0.92 0.12 79.0 ± 6.6 78.7 ± 8.9 75.5 ± 9.1 82.2 ± 7.5 HR (beats/min) 0.45 0.5 70.6 ± 6.3 74.4 ± 10.5 74.9 ± 12.2 71.1±7.7 Total cholesterol (mg/dl) 0.4 0.74 171.1 ± 29.7 163.0 ± 24.6 170.3 ± 20.2 166.5 ± 10.8 HDL cholesterol (mg/dl) 0.36 0.53 39.1 ± 8.1 41.3 ± 11.3 40.4 ± 12.9 43.7 ± 9.5 LDL cholesterol (mg/dl) 0.44 0.76 112.4 ± 16.4 117.2 ± 26.6 115.6 ± 25.4 119.0 ± 22.9 Glucose (mg/dl) 0.77 0.47 96.7 ± 10.7 98.4 ± 15.9 102.3 ± 13.1 98.6 ± 10.0 Creatinine (mg/dl) 0.62 0.82 0.8 ± 0.1 0.8 ± 0.2 0.8 ± 0.1 0.8 ± 0.1 CRP (mg/dl) 1.2 (0.6–4.3) 20.4 (8.0–34.9) 20.4 (10.5–34.9) 17.6 (8.0–33.5) 0.16 < 0.01 Values are expressed as mean ± SD. Values for CRP and RF are median and interquartile range. *For comparisons between RA patients and control group. # For comparisons between infliximab- and prednisolone-treated patients. DAS-28 = disease activity score, RF = rheumatoid factor, RAAS = renin–angiotensin–aldosteron system, CaCh = calcium channel, SBP = systolic blood pressure, DBP = diastolic blood pressure, HR = heart rate, CRP = C-reactive protein.

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Table 2. Conventional echocardiographic characteristics of the study population

Controls (n = 30) 80.1 ± 10.1 29.3 ± 5.6 64.6 ± 4.1 9.5 ± 0.6 8.5 ± 0.6 38.7 ± 4.8 7.6 ± 2.9 9.0 ± 3.1 7.8 ± 2.0 86.8 ± 5.5 78.1 ± 12.5 49.5 ± 9.3 1.4 ± 0.2 179.8 ± 25.5

RA patients (n = 38) 83.2 ± 6.1 28.8 ± 6.2 64.2 ± 3.0 9.7 ± 0.5 8.5 ± 0.4 39.8 ± 4.0 7.3 ± 3.2 8.6 ± 2.1 9.0 ± 2.6 93.7 ± 10.4 76.9 ± 7.7 69.3 ± 10.6 1.14 ± 0.25 199.3 ± 32.6

Infliximab-treated patients (n = 20) 85.7 ± 6.6 28.3 ± 4.2 63.8 ± 4.0 9.7 ± 1.7 8.6 ± 0.6 39.4 ± 3.3 7.2 ± 1.8 7.9 ± 2.5 9.4 ± 3.9 96.7 ± 10.8 76.1 ± 7.4 67.5 ± 9.9 1.1 ± 0.2 199.1 ± 35.3

Prednisolone-treated patients (n = 18) 83.9 ± 4.7 29.2 ± 5.3 64.1 ± 3.3 9.5 ± 2.5 8.5 ± 0.8 40.4 ± 4.6 7.4 ± 2.5 8.3 ± 1.9 8.5 ± 2.5 90.3 ± 10.1 77.9 ± 8.2 71.3 ± 11.2 1.1 ± 0.2 198.6 ± 30.3

p-value*

p-value#

LV EDV (ml) 0.74 0.2 LV ESV (ml) 0.49 0.51 LV EF (%) 0.35 0.7 IVS (mm) 0.39 0.06 PW (mm) 0.91 0.82 LAV (ml) 0.29 0.43 0.16 0.1 S′ (cm/s) 0.18 0.09 E′ (cm/s) E/ E′ < 0.05 < 0.05 IVRT (ms) 0.56 < 0.01 E (cm/s) 0.13 0.48 0.28 A (cm/s) < 0.001 E/A 0.66 < 0.001 DT (ms) 0.86 < 0.001 Values are expressed as mean ± SD. *For comparisons between RA patients and control group. # For comparisons between infliximab- and prednisolone-treated patients. LV = left ventricle, EDV = end-diastolic volume, ESV = end-systolic volume, EF = ejection fraction, IVS = interventricular septum, PW = posterior wall, LAV = left atrial volume, IVRT = isovolumic relaxation time, DT = deceleration time.

Table 4 shows LA echocardiographic and ECG parameters between RA patients and controls: LAVImax and LAVIpreA revealed a significant increase in comparison with the control group (p < 0.05). As assessed by two-dimensional (2D) STE, the global left atrial strain showed a significant impairment in the RA patients (p < 0.05). Electrocardiographically we evaluated the P-wave durations, Pmax, Pmin, and Pd. In the RA patients, Pmax was significantly higher compared to the control group (p < 0.05). There were no differences in Pmax values between the groups before and after the treatment period. Tables 5 and 6 illustrate the effects of infliximab therapy on LA and LV echocardiographic and electrocardiographic parameters versus the prednisolone-treated patients. Baseline conventional and 2D STE parameters were similar between the two treatments groups. Only E/E′ ratio and LA global late diastolic strain rate showed some significant differences (p < 0.05). There was a significant improvement in E/E′, LAVImax, LAVIpreA and LA global strain values in the infliximab-treated patients (p < 0.05).

Discussion In this prospective, preliminary study, we showed echocardiographic LA abnormalities in RA patients in comparison to the control group. Furthermore, there was an Table 3. Effects of infliximab treatment on RA parameters versus prednisolone-treated patients Infliximab-treated RA patients (n = 20) Baseline 3-month p-value

Prednisolone-treated RA patients (n = 18) Baseline 3-month p-value

CRP 19.9 ± 6.4 4.7 ± 1.2 < 0.05 17.5 ± 7.5 5.6 ± 2.2 < 0.05 (mg/dl) DAS-28 6.4 ± 1.0 5.4 ± 1.1 < 0.05 7.1 ± 0.7 6.2 ± 1.0 < 0.05 DASI 3.9 ± 0.8 6.8 ± 0.5 < 0.05 3.6 ± 1.0 6.1 ± 0.9 < 0.05 Values are expressed as mean ± SD. CRP = C-reactive protein, DAS-28 = disease activity score 28, DASI = Duke activity status index.

improvement in LA abnormalities in the RA patients who were treated with infliximab in comparison to the prednisolonetreated group. There is substantial evidence that RA is associated with increased cardiovascular morbidity and mortality.18 Cardiovascular manifestations of RA include atherosclerosis, myocardial infarction, heart failure and cerebrovascular disease.19 It is becoming increasingly apparent that inflammation mediators are strongly linked to this excess risk of cardiovascular disease and mortality.20 The impairment of coronary microcirculation may compromise myocardial perfusion and cause LV systolic and diastolic dysfunction.21,22 Additionally, interstitial fibrosis caused by cytokine-induced fibroblast activity, and collagen deposition in the heart muscle are present in RA.23 Previous studies24,25 also

Table 4. Comparisons of left atrial echocardiographic and electrocardiographic parameters between rheumatoid arthritis patients and the control group Controls (n = 30) 19.7 ± 3.9 15.1 ± 3.3 10.9 ± 3.2 83.3 ± 9.5 41.3 ± 5.7 42.0 ± 8.0 34.1 ± 10.1 1.8 ± 0.3

RA patients (n = 38) 23.4 ± 3.3 17.1 ± 3.4 10.9 ± 2.6 88.6 ± 9.0 43.1 ± 7.3 45.5 ± 6.4 28.3 ± 13.4 1.7 ± 0.3

p-value LAVImax (ml/m2) < 0.001 LAVIpreA (ml/m2) < 0.01 0.915 LAVImin (ml/m2) Pmax (ms) < 0.05 0.255 Pmin (msec) P dispersion (msec) 0.056 LA global strain (%) < 0.05 LA global systolic strain rate (/s) 0.053 LA global early diastolic strain 0.434 –1.2 ± 0.2 –1.2 ± 0.3 rate (/s) LA global late diastolic strain 0.492 –1.0 ± 0.3 –1.1 ± 0.2 rate (/s) Values are expressed as mean ± SD. LA = left atrium, LAVI = left atrial volume index, P = electrocardiographic P wave.

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Table 5. Effects of infliximab therapy on conventional echocardiographic parameters versus prednisolone-treated patients Infliximab-treated RA patients (n = 20) Prednisolone-treated RA patients (n = 18) Baseline 3-month p-value Baseline 3-month p-value p-value# LV EDV (ml) 0.411 0.868 0.2 81.7 ± 6.6 79.7 ± 6.9 83.9 ± 4.7 85.4 ± 9.8 LV ESV (ml) 0.14 0.557 0.5 28.3 ± 4.2 27.2 ± 3.6 29.2 ± 5.3 27.9 ± 2.6 LV EF (ml) 0.096 0.35 0.71 63.8 ± 4.0 64.6 ± 2.8 64.1 ± 3.3 64.9 ± 2.8 IVS (mm) 0.267 0.316 0.06 9.7 ± 1.7 9.5 ± 3.9 9.5 ± 2.5 9.4 ± 4.6 PW (mm) 0.056 0.381 0.82 8.6 ± 0.6 8.3 ± 0.4 8.5 ± 0.8 8.7 ± 0.4 0.258 0.369 0.1 S′ (cm/sec) 7.2 ± 1.8 6.8 ± 0.8 7.4 ± 2.5 7.6 ± 0.6 0.181 0.6 0.09 E′ (cm/sec) 7.9 ± 2.5 9.0 ± 1.3 8.3 ± 1.9 7.8 ± 2.4 0.379 E/E′ 9.4 ± 3.9 8.0 ± 1.4 < 0.01 8.5 ± 2.5 8.8 ± 2.4 < 0.05 E (cm/s) 0.979 0.493 0.476 76.1 ± 7.4 76.0 ± 11.8 77.9 ± 8.2 79.5 ± 11.7 A (cm/s) 0.221 0.407 0.284 67.5 ± 9.9 66.0 ± 7.7 71.3 ± 11.2 70.2 ± 9.8 E/A 0.758 0.184 0.656 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.3 0.609 DT (ms) 0.055 0.858 199.1 ± 35.3 203.0 ± 34.1 198.6 ± 30.3 211.5 ± 22.4 IVRT (ms) 0.626 0.99 0.056 96.7 ± 10.8 95.3 ± 16.9 90.3 ± 10.1 90.3 ± 16.8 Values are expressed as mean ± SD. # For comparisons between infliximab- and prednisolone-treated patients at baseline. LV = left ventricle, EDV = end-diastolic volume, ESV = end-systolic volume, EF = ejection fraction, IVS = interventricular septum, PW = posterior wall, DT = deceleration time, IVRT = isovolumic relaxation time.

described reduced myocardial deformation markers assessed by STE in addition to abnormal tissue Doppler imaging (TDI) parameters in RA patients compared to controls. As a further finding, there was a significant increase in Pmax in the ECG of RA patients compared to the control group. The increase in atrial strain, as well as dilatation and fibrosis bring about a heterogenous and different conduction in the atrial myocardium.26-28 Such pathophysiological changes can trigger atrial re-entry, thus playing an important role in the development of atrial fibrillation.26 One of the most important cytokines implicated in the progression of chronic heart failure is TNF-alpha.20 Although treatment with anti-TNF-alpha agents represents a major advance in the treatment of rheumatic disease, its impact on cardiovascular risk, especially in RA patients with preserved LV function (EF ≥ 50), remains controversial. In a study by Santos et al. there was a decrease in cardiac output and stroke volume in RA patients without clinical and echocardiographical evidence of previous cardiac dysfunction.29 On the other hand, Listing et al. showed that therapy with anti-

TNF-alpha agents is more likely to be beneficial than harmful with regard to the risk of heart failure.30 In the present study, we showed an improvement in LA global strain and volume index parameters in patients who were treated with infliximab, a monoclonal antibody against TNF-alpha. We used conventional echocardiography and STE. STE is an imaging technique, in which ultrasound speckles within the image are tracked, and strain is derived from the displacement of speckles relative to each other.31 This new modality enables accurate and reliable measurements of both global and regional myocardial strain and strain rates without the confounding effects of angle dependency (Fig. 1).32 To the best of our knowledge, this is the first study evaluating the effects of infliximab on LA function in RA patients. There are only limited data on the pathophysiological mechanisms in this regard. In our study, significant improvement in LA global strain and volume indices after infliximab treatment was clearly demonstrated. In addition, there was also a remarkable improvement in parameters of LV diastolic dysfunction as

Table 6. Effects of infliximab therapy on left atrial echocardiographic and electrocardiographic parameters versus prednisolone-treated patients Infliximab-treated RA patients (n = 20) Baseline 3-month p-value 23.1 ± 2.9 21.9 ± 2.3 < 0.05 16.8 ± 2.7 15.8 ± 2.1 < 0.01 0.082 11.4 ± 2.2 11.0 ± 2.1 0.072 86.0 ± 8.8 82.0 ± 10.5 0.505 42.5 ± 7.8 41.0 ± 12.5 0.056 43.5 ± 7.4 41.0 ± 7.1 25.4 ± 10.6 30.4 ± 2.6 < 0.05 0.073 1.6 ± 0.3 1.7 ± 0.2 0.098 –1.1 ± 0.3 –1.2 ± 0.3 0.567 –1.2 ± 0.2 –1.2 ± 0.2

LAVImax (ml/m2) LAVIpreA (ml/m2) LAVImin (ml/m2) Pmax (ms) Pmin (ms) P dispersion (ms) LA global strain (%) LA global systolic strain rate (ms) LA global early diastolic strain rate (/s) LA global late diastolic strain rate (/s) Values are expressed as mean ± SD. # For comparisons between infliximab- and prednisolone-treated patients at baseline. LA = left atrium, LAVI = left atrial volume index.

Prednisolone-treated RA patients (n = 18) Baseline 3-month p-value 0.453 23.7 ± 3.7 23.3 ± 2.1 0.892 17.5 ± 3.0 17.6 ± 3.1 0.368 10.4 ± 2.9 10.1 ± 1.5 0.09 91.6 ± 8.5 87.7 ± 10.6 0.749 43.8 ± 6.9 42.7 ± 14.4 0.172 47.7± 4.2 45.0 ± 7.8 0.21 31.5 ± 14.7 36.3 ± 6.9 0.536 1.7 ± 0.3 1.7 ± 0.4 0.751 –1.2 ± 0.3 –1.2 ± 0.2 0.367 –1.0 ± 0.2 –1.1 ± 0.2

p-value# 0.435 0.369 0.066 0.052 0.568 < 0.05 0.181 0.59 0.596 < 0.01

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shown by ‘better’ E/E′ values following infliximab treatment. E/E′ value, which is used as an index of LV filling pressures, correlates strongly with LV diastolic dysfunction.33-35 There are two possible explanations for these findings. First, we may speculate that LV diastolic dysfunction in patients with RA may be a result of inflammation-induced endothelial

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dysfunction, a common finding in this patient group.21,22 AntiTNF-alpha agents may restore endothelial function in these patients, which in turn reduces LV diastolic dysfunction and leads to ‘relief’ of LA.36,37 Second, as assessed with magnetic resonance imaging, LA strain has been related to LA structural remodelling and fibrosis of the atrial wall.38 By reducing inflammation

Fig. 1. C omposite figures showing measurement of peak atrial longitudinal strain (A) and strain rate (B) using speckle tracking echocardiography. AVO = aortic valve opening, AVC = aortic valve closure, MVO = mitral valve opening, MVC = mitral valve closure, BA = basal anterior, BI = basal inferior, MA = mid-anterior, MI = mid-inferior, ApA = apical anterior, ApI = apical inferior.

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mediators with anti-TNF-alpha agents, the fibroblast activity and collagen deposition in the LA myocardium may be diminished, which consequently could lead to improvement in LA function. There are some limitations to this study. The first was the rather small number of RA patients in each subgroup, which limited the power of comparison. Further studies with larger numbers are needed to assess the effects of infliximab on stain and strain rate parameters of LA. The second limitation was the duration of treatment, which was only three months. The impact of the medication on cardiac function could have been much more impressive with a longer period of treatment.

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Califf RM, et al. A brief self administered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 1989; 64: 651–654. 11. Shiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommitee on Quantition of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367. 12. Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol 2003; 41: 1036–1043.

Conclusion In this study, we demonstrated significant echocardiographical LA abnormalities in RA patients compared with the control group, in the presence of preserved LV systolic function. The early detection of myocardial abnormalities by conventional echocardiography and STE may be useful for better clinical assessment and treatment of cardiovascular disease. Furthermore, we showed a meaningful increase in Pmax in the ECG of RA patients, which may contribute to the development of supraventricular arrhythmias. It was also found that patients with RA and preserved ejection fraction had significant improvement in LA function with anti-TNF-alpha treatment compared to patients treated with prednisolone.

13. Gilman G, Nelson TA, Hansen WH, Khandheria BK, Ommen SR. Diastolic function: a sonographers approach to the essential echocardiographic measurements of left ventricular diastolic function. J Am Soc Echocardiogr 2007; 20(2): 199–209. 14. Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Bienenbaum M, et al. Two dimensional strain- a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiog 2004; 17(10): 1021–1029. 15. Dilaveris PE, Gialafos EJ, Sideris SK, Theopistou AM, Andikopoulos GK, Kyrakidis M, et al. Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J 1998; 135: 733–738. 16. Weber UK, Osswald S, Huber M, Buser P, Skarvan K, Stulz P, et al. Selective versus non-selective antiarrhythmic approach for prevention of atrial fibrillation after coronary surgery: is there a need for pre-operative

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Low-density-lipoprotein cholesterol does not predict cardiac risk in diabetes Low-density-lipoprotein cholesterol (LDL-C) level wasn’t a good predictor of cardiovascular disease in type 1 diabetes, but the total cholesterol-to-high-density lipoprotein cholesterol (HDLC) ratio appeared more reliable, an observational study has shown. Dr Christel Hero, of Sahlgrenska University Hospital in Gothenburg, Sweden, and colleagues reported that LDL-C had modest associations with the development of cardiovascular disease but no consistent dose response above the 100-mg/dl threshold for statin treatment in this population (American Diabetes Association 2014; Abstract 301-OR). In type 1 diabetes patients already on statins, LDL-C levels didn’t have any significant link to subsequent cardiovascular disease in the Swedish National Diabetes Registry data. The total cholesterol-to-HDL-C ratio had similarly modest links to cardiovascular disease in patients on or off lipid medications, but with a consistent rise in risk across categories. Hero added, ‘The ratio of total cholesterol to HDL-C is a more reliable marker for risk when considering primary prevention.’ Dr Fernando Ovalle, director of the Comprehensive Diabetes Centre of the University of Alabama in Birmingham, commented, ‘The findings emphasised how much remains unknown about cardiovascular disease in type 1 diabetes. We made a lot of assumptions and jumped to a lot of conclusions

that the markers of cardiovascular disease and treatments for prevention of cardiovascular diseases will be the same in type 1 diabetes as in type 2, and that just may not be the case. This could potentially change how we see the use of statins and the assessment of cardiovascular risk in general.’ Dr Elizabeth Seaquist, president for medicine and science and a moderator at the session, cautioned, ‘Don’t toss out LDL-C in clinical practice just yet.’ Dr Seaquist continued by saying that LDL-C may not be as strong a predictor for cardiovascular disease as in type 2 diabetes, as has been suspected from prior studies, but further research is needed to determine what to use in the clinic. ‘These patients are still at great risk for cardiovascular events, and we need to make certain that we’re doing the right things to prevent that’, she said. ‘It will help us if we were to do a trial to determine the benefits of lipid-lowering in type 1 patients.’ This study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal. Source: http://www.diabetesincontrol.com/articles/53-/16480-ada-ldl-doesntpredict-heart-risk-in-diabetes

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Rationale and design of the Pan-African Sudden Cardiac Death survey: the Pan-African SCD study Aimé Bonny, Marcus Ngantcha, Sylvie Ndongo Amougou, Adama Kane, Sonia Marrakchi, Emmy Okello, Georges Taty, Abdulrrazzak Gehani, Mamadou Diakite, Mohammed A Talle, Pier D Lambiase, Martin Houenassi, Ashley Chin, Harun Otieno, Gloria Temu, Isaac Koffi Owusu, Kamilu M Karaye, Abdalla AM Awad, Bo Gregers Winkel, Silvia G Priori; on behalf of the Pan-African Society of Cardiology (PASCAR) Task Force on Sudden Cardiac Death

Abstract Background: The estimated rate of sudden cardiac death (SCD) in Western countries ranges from 300 000 to 400 000 annually, which represents 0.36 to 1.28 per 1 000 inhabitants in Europe and the United States. The burden of SCD in Africa is unknown. Our aim is to assess the epidemiology of SCD in Africa. Methods: The Pan-Africa SCD study is a prospective, multicentre, community-based registry monitoring all cases of cardiac arrest occurring in victims over 15 years old. We will

use the definition of SCD as ‘witnessed natural death occurring within one hour of the onset of symptoms’ or ‘unwitnessed natural death within 24 hours of the onset of symptoms’. After appro val from institutional boards, we will record demographic, clinical, electrocardiographic and biological variables of SCD victims (including survivors of cardiac arrest) in several African cities. All deaths occurring in residents of districts of interest will be checked for past medical history, circumstances of death, and autopsy report (if possible). We will also analyse the employment of resuscita-

Teaching Hospital Laquintinie, University of Douala, Douala, Cameroon

Institute of Cardiovascular Sciences, University College London, UK

Aimé Bonny, MD, aimebonny@yahoo.fr

Pier D Lambiase, MD

Service de Cardiologie, Centre Hospitalier Victor Provo, Roubaix, France

Service de Cardiologie, Centre Hospitalier Universitaire Abomey Calavi de Cotonou, Benin

Aimé Bonny, MD

Martin Houenassi, MD

Biostatistics, Statprest, Paris, France

Department of Cardiology, UCT Private Academic Hospital, Cape Town, South Africa

Marcus Ngantcha, MD

Service de Réanimation Médicale, Centre Hospitalier, Universitaire de Yaoundé, Cameroon Sylvie Ndongo Amougou, MD

Service de Cardiologie, Centre Hospitalier le Dantec, Dakar, Senegal Adama Kane, MD

Service de Cardiologie, Hopital Abderrrahmen Mami Ariana, Tunis, Tunisia Sonia Marrakchi, MD

Department of Internal Medicine, Mulago Hospital, Makerere University, Kampala, Uganda Emmy Okello, MD

Service de Médecine Interne, Centre Hospitalier Général de Port-Gentil, Gabon Georges Taty, MD

Ashley Chin, MD

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

Department of Cardiology, Kilimanjaro Christian Medical Centre, Tanzania Gloria Temu, MD

Department of Cardiology, University Teaching Hospital of Accra, Ghana Isaac Koffi Owusu, MD

Department of Cardiology, Aminu Kano Teaching Hospital, Kano, Nigeria Kamilu M Karaye, MD

Department of Cardiology, University Hospital of Khartoum, Sudan

Heart Hospital, HMC, Tripoli, Libya

Abdalla AM Awad, MD

Abdulrrazzak Gehani, MD

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark

Service de Cardiologie, Hôpital Général de Bamako, Mali Mamadou Diakite, MD

Department of Internal Medicine, University of Maiduguri Teaching Hospital, Nigeria Mohammed A Talle, MD

Bo Gregers Winkel, MD

Department of Molecular Genetics, Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy Silvia G Priori, MD

Department of Molecular Medicine, University of Pavia, Italy Silvia G Priori, MD

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tion attempts during the time frame of sudden cardiac arrest (SCA) in various patient populations throughout African countries. Conclusion: This study will provide comprehensive, contemporary data on the epidemiology of SCD in Africa and will help in the development of strategies to prevent and manage cardiac arrest in this region of the world. Keywords: sudden cardiac death, epidemiology, ethnicity, Africa Submitted 25/3/14, accepted 13/6/14 Cardiovasc J Afr 2014; 25: 176–184

www.cvja.co.za

DOI: 10.5830/CVJA-2014-035

For many years there has been a debate about the definition and nature of ‘sudden death’ or out-of-hospital cardiac arrest.1-8 Issues pertaining to this debate have been the temporal definition of ‘sudden’, whether death was unexpected, whether death was witnessed, and the aetiology of the event. The time frame used to describe the duration of the terminal event initially was 24 hours. The current definition of sudden cardiac death (SCD) describes death within one hour of the onset of symptoms,2 since this period seems to describe most accurately patients with arrhythmic sudden cardiac death.9

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A very difficult issue is the classiﬁcation of unwitnessed deaths. Most authors have erred in favour of classifying such events as SCDs, even though it is often impossible to determine when the patient was last seen alive or the duration of symptoms prior to death. Hence, SCD can be deﬁned as follows: ‘Natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms’. Pre-existing heart disease may have been known to be present, but the time and mode of death are unexpected.1 The incidence of SCD occurring out of hospital varies with age, gender and presence or absence of cardiovascular disease. Incidence rates of SCD between 0.36 and 1.28 per 1 000 inhabitants per year have been reported in Europe and the United states.10-13 In these studies, only witnessed victims seen or resuscitated by the emergency medical services are included; these data therefore underestimate the incidence of SCD in the general population. Sudden cardiac death is responsible for about 300 000 to 400 000 deaths per year in Europe and the United States, respectively.14 Several diseases linked with sudden cardiac arrest (SCA) have been reported.15,16 Autopsy studies in unselected subjects suggest that about two-thirds of such deaths are cardiac in origin, with coronary artery disease and its complications accounting for the overwhelming majority of deaths in the industrialised world.17,18 Indeed, coronary artery disease (CAD) is the leading cause of sudden death worldwide.3

Table 1. Reported cases of syncope or sudden cardiac death in black Africans living in Africa

Main disease BrS

Authors Bonny A, et al. Ouali S, et al.

Title Brugada syndrome in pure black Africans

Type of Country publication Ivory Coast, Article Benin, RD of Congo Tunisia Article

Journal and year Journal of Cardiovascular Electrophysiology 2008

Size (patients) 6

Clinical and electrophysiological profile Pacing and Clinical 24 of Brugada syndrome in the Tunisian Electrophysiology 2011 population 2 HCM Hiam I, Mort subite du sportif au Sénégal: étude Senegal Abstract PASCAR conference, 5 et al. rétrospective sur 8 ans Dakar 15–20 May, 2013 3 IHD Rotimi O, Sudden unexpected death from cardiac Nigeria Article International Journal of 50 et al. causes in Nigerians: a review of 50 Cardiology 1998 autopsied cases 4 Paediatric sample Arthur JT, Sudden deaths: cardiac and non-cardiac Ghana Article West Africa J 1995 16 et al. in children in Accra 5 CAD and RHD Schneider Causes of sudden death in Addis Ababa, Ethiopia Article Ethiop Med J 2001 63 J, et al. Ethiopia 7 Unknown Houenassi Aspect epidémiologiques de la mort Benin Abstract PASCAR conference, 23 M, et al. subite dans la ville de Parakou Dakar 15–20 May, 2013 8 Multiple causes Talle MA, SCD in sub-Saharan Africa: A 12-month Nigeria Abstract PASCAR conference, 17 (CAD, DCM, et al. review in University of Maiduguri Dakar 15–20 May, 2013 LQTS, RHD) Teaching Hospital, Nigeria 9 Multiple causes Thiam I, La mort subite cardio-vasculaire au Senegal Abstract PASCAR conference, 235 (DCM, CAD, RHD) et al. Sénégal- Etude rétrospective sur 7 ans Dakar 15–20 May, 2013 10 LQTS Leye M, QT long congenital syncopal évocateur Senegal Abstract PASCAR conference, 1 et al. de Syndrome de Jervell Lange Nielsen Dakar 15–20 May, 2013 11 NCCM Kamotho A rare presentation of non-compaction Kenya Abstract PASCAR conference, 1 C, et al. cardiomyopathy in Kenya Dakar 15–20 May, 2013 12 ARVD/C Kouakam Syncope in a black African with arrhyth- Cameroon Unpublished Unpublished data 1 C mogenic right ventricular dysplasia data 13 Hypertensive CMP Akinwusi Pattern of sudden death at Ladoke Akin- Nigeria Article Vascular Health Risk Approx (mainly) PO, et al. tola University of Technology Teaching Management 2013 16 Hospital, Osogbo, south-west Nigeria BrS: Brugada syndrome, HCM: hypertrophic cardiomyopathy, CAD: coronary artery disease, PASCAR: Pan-African Society of Cardiology, LQTS: long QT syndrome, RHD: rheumatic heart disease, DCM: dilated cardiomyopathy, ARVD/C: arrhythmogenic right ventricular dysplasia/ cardiomyopathy, CMP: cardiomyopathy.

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In Europe, cardiovascular diseases (CVD) account for around 40% of all deaths under the age of 75 years. SCA is responsible for more than 60% of adult deaths from ischaemic heart disease (IHD).2 Conversely, in young populations under 40 years, inherited ‘arrhythmogenic’ cardiac disorders are the main cause.8 The initial recorded rhythm in patients presenting with a sudden cardiovascular collapse is ventricular ﬁbrillation (VF) in 75 to 80%, whereas bradyarrhythmias and asystole are thought to contribute to a minority of SCDs.4,16

Rationale The high prevalence and incidence of SCD in Western countries have led to the recognition that SCD is a major public health problem and the increased deployment of automatic external defibrillators in public places. Recent reports by the World Health Organisation (WHO) indicated that non-communicable diseases (NCDs) are becoming a significant cause of morbidity and mortality in African countries.19-26 About 50% of this burden is attributable to CVD.27 Projections from the Global Burden of Disease project suggest that from 1990 to 2020, the burden of CVD faced by African countries will double and a large proportion of the victims of CVD will be middle-aged people.28 National public health policies regarding detection, prevention and treatment of NCDs are inconsistent, mainly due to lack of epidemiological data. Regarding the magnitude of the problem, the ministers of health and heads of delegations of the WHO African region convened at a regional consultation on the prevention and control of NCDs in Brazzaville and acknowledged the everincreasing dual burden of communicable and non-communicable diseases in the region, and the associated disabilities and premature deaths.29 Almost all leading causes of SCD have been described in Africa (Table 1). Indeed some reports of SCD in sub-Saharan Africa have been published;30-37 and several studies report conflicting data regarding the prevalence of CHD in sub-Saharan Africa.38-40 SCA from acute myocardial infarction is a rapidly growing

Fig. 1. E CG of a patient from Nigeria who died suddenly in ICU within one hour of onset of chest pain, revealing anterior myocardial infarction. ECG: electrocardiogram, ICU: intensive care unit.

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cause of morbidity and mortality among black Africans (Fig. 1). However, studies specifically targeted to provide robust data regarding the epidemiology of SCD in Africa are warranted. Missed diagnosis rather than misdiagnosis is a characteristic of unexpected cardiac death in Africa.31 The occurrence of an unexpected death in a young, otherwise healthy individual is a devastating event for the family and society. It is now clear that a genetic predisposition may exist and therefore a targeted diagnostic work-up is required in subjects resuscitated from cardiac arrest who show a structurally intact heart. Since these approaches are often not available within the medical system in sub-Saharan Africa and as the population is not aware of the role of the heart in death, juvenile cases are still often attributed in several instances to witchcraft, which prevents the investigation of the medical causes (Fig. 2).36, 41 The second major concern regarding SCD in Africa is the lack of qualified personnel to accurately diagnose and manage CVD, as well as the absence of basic diagnostic tools in many health facilities.42 Given these weaknesses, policies for prevention and control of CVD are incomplete without addressing the problem of SCD. Moreover, there is an opportunity to address these challenges through primary prevention of SCD, secondary prevention through the introduction of widespread cardiopulmonary resuscitation (CPR) education efforts, and lastly, tertiary prevention through treatment of reversible causes, as well as the dissemination of implantable automatic cardiac defibrillators. Understanding the epidemiology of SCD allows the introduction of a comprehensive strategy and implementation of appropriate actions in the WHO global agenda for the fight against NCDs. The Pan-African Sudden Cardiac Death (Pan-African SCD) study is a collaborative study that aims to collect comprehensive

Fig. 2. I n a 45-year-old patient from Ivory Coast, syncope while eating was managed in ICU. ECGs show spontaneous coved-type BrS patterns in the right precordial leads (M, N). Further, the patient experienced arrhythmic storms treated by quinidine hydrochloride in the setting of implantation of an ICD. Stored electrograms show several episodes of VF (O). The patient was managed in France, his older brother died suddenly in Ivory Coast at age 45 years and the death was attributed to witchcraft. ICU: intensive care unit, ECG: electrocardiogram, BrS: Brugada syndrome, VF= ventricular fibrillation.

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data on the prevalence and incidence of sudden cardiac death in Africa, disease and patient characteristics, mechanisms of cardiac arrest, as well as the survival rate in the setting of underutilised CPR programmes.

Methods This is a multicentre, community-based, prospective cohort registry monitoring all cases of SCA. Several countries from all African regions will take part in this Pan-African registry. The specific objectives of the registry are as follows: • to estimate incidence of SCD in Africa • to estimate the prevalence of SCD among all causes of death • to determine factors associated with SCA in African victims • to study the characteristics and outcomes of SCA in Africa • to evaluate the extent of the use of cardio-pulmonary resuscitation efforts. To be eligible, subject must be a resident of the administrative area (district) included in the study registry, and the district must have an updated population census. Inclusion criteria are victims of cardiac arrest, either SCD or aborted SCA. Exclusion criteria are age ≤ 15 years, and refusal of consent (by the family).

Data collection In each country and each city of interest, we will conduct a pilot survey in some districts aiming to determine the number of SCDs as well as to evaluate the adherence of the team of each district to effectively collect data during the run-in period of three months. The choice of these districts will be based on eliminating areas of < 30 000 inhabitants in the first step, and random sampling among the remaining districts in the second. We will calculate the approximate mean incidence rate of SCD from all studied districts, taking into account the accuracy of data collection in each area. After the exclusion of districts with inaccurate data collection, we will randomly select a few districts to constitute a sampling of 150 000 to 200 000 inhabitants in each country. All administrative staff and community healthcare committees of selected districts will be a key component of the research team, helping to identify every case of death in the monitored area. • Every case of death will be reported by the non-medical district staff in a specific questionnaire form (Appendix 1). • A nurse will collect circumstances of death to rule out the cause of death, either natural or not. • A post-graduate medical student will collect socio-demographic and clinical data of every natural death victim. • A senior physician will study every case of suspected sudden death, using all medical files available, as well as information from the surroundings. Final diagnosis will be obtained by at least two physicians. In the case of disagreement between the experts, a third opinion will be sought. Data will be recorded in an electronic case report form (e-CRF, Appendix 2). • For victims with ascertained diagnosis of SCD, informed consent will be given to families for autopsy and eventually for genetic analysis. • Biological sampling will be performed as much as is feasible including: (1) blood sample for genetic test (DNA analysis) of surviving individuals < 40 years in the absence of clinical diagnosis of cardiac disease, or in first-degree relatives of

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individuals who died suddenly at a young age (< 40 years) and in whom autopsy was either not performed or failed to identify the cause of death, and (2) autopsy for macroscopic and cytological evaluation of victims. During the time frame of the survey, all residents of districts of interest will be monitored with regard to occurrence of death. The non-medical staff will identify and report each case of death to the medical staff. In addition to the deaths noted by the district administrator’s staff and collaborators, we will pay attention to all notices of deaths in local newspapers, radio, interrogation of health area residents and death certificates from local medical centres. We will propose ECG screening and a long-term follow up for all first-degree relatives of victims under 40 years old. The Pan-African SCD investigators will be members of the PASCAR task force on SCD, which will be governed by the PASCAR governing council to whom annual progress reports will be provided. During bi-annual meetings, each research team will discuss all cases of suspected SCD. Research teams for each district will be composed of medical and non-medical staff. Both will collect data of the victims. The role of each member of the research team will as follows: • The district administrator and other collaborators (civil society volunteers living in the neighbourhood constituting areas of interest) will provide information about all deaths among residents in the area where the survey is conducted. • One qualified nurse will organise collection of in-hospital deaths. He or she will be expected to work in collaboration with the chief of the mortuary to record out-of-hospital deaths, and with medical students who are voluntarily involved in the project. All cases of SCD will be recorded in the study data book. Either the nurse or the chief of the mortuary will call the student when a suspicion of SCD needs to be investigated within a short period of time, when family members may provide valuable information. • One post-graduate fellow focusing on the topic ‘SCD epidemiology in Africa’ for his/her thesis will participate in the project. Apart from impromptu visits that will be dictated by certain cases, the student will be expected to visit the mortuary and the chief of the district bimonthly to evaluate the records of all victims and determine causes of death. He or she will be required to review the progress of the work with the supervising physician on a monthly basis, during which the work will be appraised. • The physician will be the leading coordinator in all districts of the city where the survey is going on. Together with other members of the research team, he will analyse all deaths and resolve uncertainties in suspected cases of SCD. Approval from the national ethics committee and local institutions will be obtained before starting the survey in each country. Before sampling, informed consent will be obtained from the victim (for survivors of SCA) or his/her legal representative and family members (for SCD) prior to inclusion in this study. Confidentiality will be ensured in accordance with the Helsinki Declaration.

Statistical analysis Given the rate of incidence of SCD in the Maastricht study,43 the need for about 70 SCAs to reach statistical significance, and the average sample of 150 000 residents per district randomly

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chosen, the number of SCAs found during the run-in period will determine the duration of monitoring in every district (and country). Characteristics of persons experiencing SCA will be presented as frequencies or mean values with standard deviations. Differences between men and women will be tested by chi-square tests for categorical variables and t-tests for continuous variables. Age- and gender-specific incidence rates of ascertained SCA will be calculated. The counts of SCA will be used as the numerators, and the denominators will be the population of all districts included in the survey, as determined by the last census. The rates will be adjusted directly to the age distribution of the total population of each country. Standard errors and 95% confidence intervals (CI) around the point estimates will be calculated, assuming a Poisson distribution. A Poisson regression model will be used to examine the temporal trends in the incidence of SCA, with categorical year variables and adjustment for age. Results will be summarised by presenting the relative risk (RR) of SCA for men and women in each year group. Logistic regression models will be used to examine the association between occurrence of SCA and socio-demographic and clinical factors. In the model, year will be modelled categorically, and a non-linear effect of age will be assessed by testing the quadratic term. Comparison of time trends across age groups will be accomplished by including interaction terms between year groups and age. A value of p = 0.05 will be selected for the threshold of statistical significance, except when an interaction will be tested for, when p = 0.10 will be used. All analyses will be replicated in 1 000 random samples to ensure that results are robust.

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ECG testing, stress echocardiography, radionuclide imaging, coronary CT scan and coronary angiography underestimate the ischaemic heart disease burden, which is the leading cause of SCD in developed Western countries.7,8,14 Also, the underutilisation of genetic screening, diagnostic drug challenges and electrophysiological studies in the regions where the study will be conducted are likely to limit the identification of some complex diagnoses, such as those of inherited arrhythmogenic disorders, which are among the commonest causes of SCD in young people under 35 years old.44-46 Hence, our results will address a global view of SCD burden rather than show the real burden of each aetiology.

Perspectives Expected results of this survey are aimed at understanding whether or not SCA is a public health problem in Africa. As preliminary reports tend to indicate, and in the light of what is being done in Western and Asian countries,47,48 this maiden survey in the field of SCD in Africa will present the platform for advocating preventive public health policies in the fight against SCA, and also primary cardiovascular prevention in general.

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Discussion The Pan-African SCD study is the first attempt to comprehensively characterise the SCD burden in Africa. We will collect detailed clinical data as well as information from an electrocardiogram (if available). Other diagnostic evaluations of SCD will also be used where possible. We will, therefore, have a contemporary dataset on the incidence, aetiology, patient characteristics and outcomes of cardiac arrest in African countries. Almost all causes of SCD have already been reported in blacks living in Africa. However, these data are limited to case or series reports. The PASCAR study will therefore provide a comprehensive data on the epidemiology of SCD in this part of the world. In line with its international outlook, the Pan-African SCD study aims to provide an avenue for examining regional similarities and differences in clinical features, management and outcomes of SCA.

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1–35 years. Eur Heart J 2011; 32: 983–990.

Age

Date of death

Place of death

Dwelling place

Suggested cause of death/ circumstances of death

Identity and contact of family member

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Each staff representative of the district will fill in the questionnaire. Afterwards, a nurse will select files of victims from natural causes of death, and eventually the post-graduate fellow will contact family member of the victim for further investigations.

Gender

��

INVESTIGATOR:

Identity of the victim

��

MONTH/YEAR:

DISTRICT/COUNTRY: ��

Appendix 1. Identification questionnaire

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Pan-African SCD task force survey Country*:

State:

Ethnicity*:

Completed by*: Identity*:

Date*: Sex*: ❏ M ❏ F

Date of birth*:

Age*:

EPIDEMIOLOGY OF SCD AND INITIAL CLINICAL PRESENTATION – Criteria for Eligibility • Natural death due to cardiac causes, heralded by abrupt loss of conciousness within 1 hour of the onset of acute symptoms • Pre-existing heart disease may have been known to be present, but the time and mode of death are unexpected

❏ In-hospital SCD

❏ Out-of-hospital SCD ❍

❏ Unwitnessed SCD

Resuscitation attempts

Home

❍

Work

❍

Public place

❍

Others, precise: ______________________

Colleagues

❍

Others, precise: ______________________

❏ Witnessed SCD ❍

Family

❍

Friends

❍

Yes

❏ Defibrillation

❏ VT

❏ VF

❏ Bradycardia/asystole/pulseless electrical activity ❏ Others __________________________________________

Documented ECG

❍

Yes

Activity at the time of SCD

❍

Sleeping

❍

Resting

❍

Others, precise: __________________________________________

Hour of occurrence

❍

Night time

Time interval between cardiac arrest and first CPR (if available)

__________ (min)

Post-resuscitation syndrome

❍

Cardiac death

❍

Day time

❏ Survive

❍

Neurological death

❍

Physical activity

❍

Sport activity

❍

❏ Hour (if available) ❍

Yes

❍

Motor and/or cognitive deficits

PREVIOUS HISTORY OF STRUCTURAL CARDIAC DISEASE ❍

Previous cardiac evaluation

❍

Yes, precise ______________________

LV ejection fraction:

❏ Ambulatory

❍

Yes

❍

❏ In-hospital

❍

Yes

❍

NYHA classification:

MEDICAL HISTORY ❍

CARDIOLOGIC

Yes

❏ HF

❏ Congenital

❏ Family history of

❏ RAA

❏ Coronary artery

❏ Idiopathic dilated

❏ Hypertrophic

❏ Other

❏ Pacemaker or ICD

❏ Hypertension

❏ Cerebro-vascular

❏ Other, precise _____________________________________

❏ Smoking

❏ Other addiction

cardiomyopathy

❍

NEUROLOGICAL

❏ Cor pulmonary ❍

OTHERS

TROPICAL DISEASES

Yes

cardiomyopathy

❍

cardiomyopathy

diseases

❏ Epilepsy ❍

SCD

disease

❏ Diabetes

❏ Alcoholism

❏ HIV/AIDS

❏ Other, precise ______________________________________________________________

❍

Yes, precise _____________________________________

❍

❏ Depression/anxiety disorders

❏ Other, precise _____________________________________

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MEDICAL HISTORY ❏ Beta-blockers

❏ ACE inhibitors/ ARB-II

❏ Anti-arrhythmic drugs

❏ Antialdosterone

❏ Digoxine

Current treatment

❏ Antihistaminic drugs/Antibiotics (erythromycin,pentamidine..)

__________________________________

❏ Traditional

❏ Diuretics

❏ Prolonged-QT

❍

Antiepileptic drugs

❍

Psychotropic drugs

❏ Other, precise ___________________________________________

CLINICAL EVALUATION AND DIAGNOSTIC TESTS ❍

Not available

❍

Normal

❍

Abnormal, precise

Physical examination

ECG

❍

Available

❍

Not Available

Blood biochemistry

❍

Normal

❍

Abnormal, precise

❏ TTE Non-invasive screening test

❏ Holter ECG

Genetic screening test

Normal

❏ Stress test

❍

Measured

❍

Visual

❍

Abnormal, precise

❏ SA-ECG

Value of BMI

❏ Cardiac MRI

❍

Normal

❍

Normal

❍

Normal

❍

Normal

❍

Normal

❍

Abnormal, precise

❍

Abnormal, precise

❍

Abnormal, precise

❍

Abnormal, precise

❍

Abnormal, precise

❏ Coronarograpy Invasive screening test

❍

❏ BMI

❏ Electrophysio-logical study

❏ Autopsy

❍

Normal

❍

Normal

❍

Normal

❍

Abnormal, precise

❍

Abnormal, precise

❍

Abnormal, precise

❍

Normal

❍

Abnormal, precise

DIAGNOSTIC HYPOTHESIS: CLINICAL/ECG/BIOLOGY/NON- AND/OR INVASIVE SCREENING TESTS Diagnostic

Heart disease

❍

Certain

❍

Probable (clinical suggestive but not sure)

❍

Unknown

❏ Acute MI

❏ Dilated CM

❏ Hypertrophic CM

❏ Other inherited CM ___________________

❏ Congenital

❏ CAD

❏ AV block

❏ Toxic/latrogenic/Proarrhythmic (precise)

coronary Anomalies

❏ Tropical disease (precise)

__________________________________

❏ Others, precise ________________________________________________________

❏ Absence of structural heart disease-idiopathic VF (in this case, expert ECG reviewing) Date of death:

❍

Cardiac

❍

Non-cardiac

❍

Unknown

Aetiology*:

All information of interest for establishing causes of death will be recorded in the e-CRF. These data include socio-demographic (identity, age, gender, nationality, employment status, monthly incomes), past medical history focusing on cardiovascular conditions, the aetiology of death and associated medical conditions. In-hospital/out-of-hospital, unwitnessed/witnessed deaths, activity of the time of SCD, time of occurrence (day/night) and postresuscitation outcome will be noted. Medical history reports heart diseases (as HF, MI, CM, CAD, RHD), neurological, tropical, infectious and other. Clinical evaluation and diagnostic tests refer to physical examination, 12-lead ECG, blood biochemistry, non-invasive cardiac tests (TTE, Holter ECG, stress imaging, signal-averaged ECG, cardiac MRI), invasive tests (coronarography, electrophysiological study, autopsy) and genetic screening. e-CRF: electronic case report form; SCD: sudden cardiac death; HF: heart failure; MI: myocardial infarction; CM: cardiomyopathy; CAD: congenital heart disease; RHD: rheumatic heart disease; ECG: electrocardiogram; TTE: transthoracic echocardiography; MRI: magnetic resonance imaging.

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Review Article Current clinical applications of cardiovascular magnetic resonance imaging L Scholtz, A Sarkin, Z Lockhat

Abstract Cardiovascular magnetic resonance (CMR) imaging is unsurpassed in the evaluation of myocardial anatomy, function and mass. Myocardial perfusion pre- and post-stress, as well as late enhancement is increasingly used in the work-up for ischaemic heart disease, especially in establishing the presence of myocardial viability. Late enhancement patterns can contribute substantially to the diagnosis of myocarditis and various cardiomyopathies as well as infiltrative diseases and tumours. With their high incidence of cardiovascular disease, patients on the African continent could potentially benefit enormously from the proper utilisation of this exciting, continually evolving and versatile technique, via thorough didactic and clinical training as well as interdisciplinary co-operation. Keywords: cardiovascular, cardiomyopathy, imaging, Africa, non-invasive Submitted 9/10/13, accepted 25/4/14 Cardiovasc J Afr 2014; 25: 185–190

www.cvja.co.za

DOI: 10.5830/CVJA-2014-021

Owing to initial obstacles, mainly related to cardiac motion and ECG triggering, cardiovascular magnetic resonance (CMR) established itself within the cardiac imaging armamentarium long after its first diagnostic application in other disciplines. Faster and more effective sequences were subsequently developed to ‘freeze’ heart motion. Vector ECG and other solutions have also minimised the initial problems during ECG triggering that were due to the magneto-hydrodynamic effect of pulsatile blood in the aorta.

The quality of CMR imaging has consequently improved dramatically since the first MR images of the human heart were described more than 20 years ago, and it is still advancing apace. CMR now represents one of the most versatile, non-invasive imaging modalities available, offering high spatial resolution and image contrast along with tissue characterisation and haemodynamic assessment, without applying ionising radiation, and with complete multiplanar coverage of the heart. Good communication between the referring physician and the CMR specialist is paramount to streamline the type and order of sequences required for each particular scenario. Although new sequences are constantly being developed, the basic principles of CMR remain unaltered, as follows.

Basic principles of CMR Scout imaging Each examination starts with a series of scout views performed on each patient to establish the short- and long-axis views of the heart. These act as localisers in planning the rest of the study. The pulse sequences used for scouting are based on steady-state free-precession (SSFP). Typically, 27 scout images are acquired to define the thoracic contents, including nine parallel images in each of the axial, coronal and sagittal planes.

Anatomical and morphological imaging To assess anatomy and morphology, static images are required. Black-blood imaging is usually preferred because it allows clear distinguishing of the inner portion of the vessel or myocardium from blood. Half-Fourier single-shot fast-spin echo (HASTE) is a special variant of the fast-spin echo sequences, and ideal for delineation of anatomy. Anatomical and morphological information is particularly important in the diagnosis of congenital abnormalities and cardiac tumours.

Functional imaging Department of Radiology, Steve Biko Hospital, Pretoria, South Africa Leonie Scholtz, MB ChB, MMed (Rad) (Diag), (Pret), leonie@ scholtzrad.co.za Z Lockhat, FFRAD (D) (SA)

Department of Cardiology, Steve Biko Hospital, Pretoria, South Africa Andrew Sarkin, MB BCH, FCP (Wits)

Dynamic ciné CMR white blood imaging is used for global and regional left ventricular (LV) and right ventricular (RV) wall motion assessment as well as ventricular volume, ejection fraction and mass measurements. It is now widely regarded as the gold standard.1 The SSFP sequence is fast and ideal for white blood ciné imaging owing to its high signal-to-noise ratio and excellent ability to visualise the endocardial border. Functional analysis is especially important in the work-up of ischaemic heart disease as well as the non-ischaemic cardiomyopathies.

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Myocardial perfusion imaging During perfusion scanning, a movie of the wash-in of gadoliniumbased contrast through the myocardium is obtained (so called ‘first-pass perfusion’). The gradient echo (GRE) pulse sequence is most commonly used nowadays to visualise perfusion of the myocardium at rest or during adenosine stress testing. Perfusion defects appear as dark regions surrounded by bright contrastenhanced, normally perfused myocardium. CMR perfusion is playing an increasingly important diagnostic role in ischaemic heart disease.

Oedema imaging Myocardial oedema is associated with prolonged magnetic resonance relaxation time on T2-weighted pulse sequences. Static dark blood images of the myocardium can be obtained, confirming the presence or absence of oedema, which manifests as bright areas among the normal darker myocardium.

Late gadolinium enhancement (LGE) CMR imaging LGE images are acquired with an inversion recovery-prepared GRE or SSFP imaging pulse sequences, with images acquired 10–15 minutes following gadolinium (Gd) chelate contrast administration. Gd circulates in the extracellular space and is excluded by intact myocardial cell membranes. They accumulate in areas of abnormal myocardium, resulting in T1 shortening manifesting as higher signal intensity on T1-weighted images. Gd migrates through damaged myocitic membranes into the cells (for example, in the case of myocardial infarction) or accumulates in the enlarged interstitial space (in the case of scar tissue). The goal of LGE imaging is to create images with high contrast between the hyper-enhanced, damaged, fibrotic or non-viable tissue and the normal myocardium. LGE patterns play an important role in viability assessment during acute or chronic myocardial infarction as well as in the setting of non-ischaemic cardiomyopathies and cardiac tumours.

Flow/velocity imaging Velocity-encoded (VENC) CMR imaging of blood flow is usually performed to measure velocity in the arteries, veins and across valves or shunts. With VENC CMR, a ciné series of greyscale images reflecting flow during the cardiac cycle is acquired. The grey level is proportional to the velocity of blood into or out of the measured plane. VENC CMR allows quantification of valvular stenosis or regurgitation and is used in the assessment of valvular pathology.

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differentiate between acute and chronic myocardial infarction.3 CMR is consequently also useful in patients with acute chest pain of unclear aetiology with suspected acute coronary syndrome (Fig. 1).4,5 More importantly, high signal intensity on T2-weighted CMR, in the absence of LGE in the same area, reflects reversible ischaemic injury.2 There is excellent correlation between the area at risk (AAR) measured by T2-weighted imaging and the angiographic APPROACH score, which is an anatomically and prognostically validated measure of the extent of myocardial jeopardy.6,7

LGE imaging LGE plays an important diagnostic and prognostic role in patients with ischaemic heart disease.8-10 In patients with chronic myocardial infarction scheduled for implantable cardioverterdefibrillator (ICD) implantation, transmural involvement as defined by LGE CMR identifies a subgroup with increased risk for life-threatening arrhythmias and cardiac death.11 According to a recent study by Desjardins et al.,12 ventricular tachycardia (VT) circuits are mainly located in the centre of the LGE CMR-defined infarcts. Total infarct size can be ascertained by LGE CMR and is a strong predictor of future events in patients with coronary artery disease.13 The absence of contrast enhancement during the first two minutes after contrast injection in the centre of an area of infarction that may persist on the LGE images points to microvascular obstruction, which is associated with a worse prognosis and outcome.14-16

Stress perfusion imaging Adenosine perfusion CMR has a high diagnostic accuracy in detecting coronary artery stenosis in patients with suspected coronary artery disease (CAD).17,18 A combined perfusion and infarction CMR examination with a visual interpretation algorithm can accurately diagnose CAD in the clinical setting.19 In a recent large, multicentre, multivendor study, the sensitivity of perfusion CMR in detecting CAD was superior to singlephoton emission computed tomography (SPECT), while its specificity was inferior to SPECT.20 Adenosine perfusion CMR provides excellent risk stratification and intermediate-term prognostic value in patients

Role of CMR in cardiovascular pathology CMR plays an increasingly important role in cardiovascular pathology, as follows.

Ischaemic heart disease Myocardial infarction and T2-weighted imaging In the event of an acute myocardial infarct, myocardial oedema can be seen on T2 sequences as early as 30 minutes after the onset of ischaemia.2 T2-weighted CMR imaging can help to

Fig. 1. CMR methods for the assessment of ACS. Short-axis views of different patients illustrate the different imaging techniques used (rows 1 and 2), their morphological correlates (row 3), and main clinical application (row 4).

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with stable CAD.21 The presence of a reversible perfusion deficit is associated with a tripled risk for death or non-fatal myocardial infarction.22 The presence of abnormal CMR characteristics, including a reversible perfusion deficit, is a strong predictor of myocardial events during follow up.23

Viability assessment Several different methods of assessing myocardial viability are available in the diagnostic armamentarium. Viability tests have become a crucial tool in evaluating whether patients with congestive cardiac failure related to CAD might benefit from revascularisation therapy.24-26 Allman et al.27 demonstrated a strong association between viable myocardium on non-invasive testing and increased survival after revascularisation, with a reduction in annual mortality of 79.6% compared with medical therapy. Three CMR methods exist for the evaluation of viability: • resting LV wall end-diastolic wall thickness (> 5 mm regarded as viable)28 • low-dose dobutamine (LDD) stress assessment of contractile reserve29 • LGE of non-viable scar tissue.30 According to a recent meta-analysis, LGE CMR provides the highest sensitivity and negative predictive value among the three methods. LDD CMR, however, has the highest specificity and PPV.31 If LGE CMR is compared with PET-FDG, restdistribution thallium-201 SPECT and technetium-99m sestamibi-SPECT, and dobutamine stress echocardiography, it also performs better for predicting functional improvement after revascularisation of hibernating myocardium. LGE CMR also has a higher sensitivity, NPV and PPV than the other available techniques.25,32 Cardiovascular MRI provides a unique tool to assess multiple interrelated clinical markers of viability in a single test.29 The comprehensive assessment of ventricular mass, volume, function and perfusion as well as the ability to establish the presence and extent of non-viable tissue and AAR during a single CMR scan is unparalleled in the diagnostic work-flow of ischaemic heart disease.

oedema on T2-weighted CMR has also been observed in patients with HCM.36 The presence of LGE has been shown to be a marker for adverse outcomes in several other non-ischaemic cardiomyopathies.37,38 LGE CMR can help to differentiate between ischaemic and non-ischaemic dilative cardiomyopathy.39 According to the revised Task Force criteria for arrhythmogenic right ventricular dysplasia published in Circulation in 2010, MRI findings now fall under the major and minor criteria.40 Albeit non-specific, CMR findings in ARVD include fatty infiltration of the RV wall, dilatation of the RV, regional or global RV dyskinesis and patchy areas of LGE in the RV wall mainly. CMR shows a characteristic pattern of global sub-endocardiallate enhancement as well as abnormal myocardial and blood-pool kinetics in patients with cardiac amyloidosis.41 CMR is a useful diagnostic tool in cardiac involvement owing to sarcoidosis, which is responsible for the majority of deaths resulting from sarcoidosis.42,43

Myocarditis Endomyocardial biopsy (EMB) is considered to be the gold standard for the diagnosis of myocarditis. Recently, CMR has emerged as a promising non-invasive alternative. Three CMR techniques are applied in myocarditis:

Hyperenhancement patterns Non-ischaemic

Ischaemic A. Subendocardial Infarct

A. Mid-wall HE

• Idiopathic Dilated • Hypertrophic Cardiomyopathy Cardiomyopathy • Myocarditis

B. Transmural Infarct

• Right ventricular pressure overload (e.g. congenital heart disease, pulmonary HTN)

• Sarcoidosis • Myocarditis • Anderson-Fabry • Chagas Disease

B. Epicardial HE

Cardiomyopathies CMR is fast becoming an invaluable tool in the assessment of cardiomyopathies. Regional and global myocardial function can be assessed, and its unique capability to visualise the apex and lateral wall supersedes all other imaging modalities. It is also unique in being able to perform tissue characterisation and to suppress fat, which, combined with LGE, assists in differentiating between various forms of cardiomyopathy (Fig. 2). Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young people. The majority of HCM patients with sudden cardiac death have few or no clinical symptoms.33 CMR is a powerful tool in the diagnosis and risk stratification of HCM; it is widely accepted as the gold standard for assessment of myocardial function as well as left ventricular mass, which has been shown to be a sensitive predictor of adverse outcomes in HCM.34 According to a recent meta-analysis, the presence of LGE can predict a higher risk for sudden cardiac death (SCD) and heart failure in patients with HCM, thereby identifying patients who would benefit from ICD placement.35 The presence of

• Sarcoidosis, Myocarditis, Anderson-Fabry, Chagas Disease

C. Global Endocardial HE

• Amyloidosis, Systemic Slcerosis, Post cardiac transplatation

Fig. 2. Hyper-enhancement patterns that one may encounter in clinical practice. If hyper-enhancement is present, the endocardium should be involved in patients with ischaemic disease. Isolated mid-wall or epicardial hyper-enhancement strongly suggests a ‘non-ischaemic’ aetiology. (Reprinted with permission from Shah et al. Clinical Magnetic Resonance Imaging, 3rd edn. New York: Elsevier Press; 2005.)

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• LGE sequences for detection of myocardial necrosis/fibrosis • T2-weighted images for assessment of myocardial oedema44 • T1-weighted sequences before and after contrast injection for the detection of myocardial hyperaemia. The Lake Louise criteria for CMR diagnosis of myocarditis state that CMR findings are consistent with myocarditis if two out of three of the above criteria are found to be positive.45 Although the CMR findings in myocarditis are not specific, they can act as a useful tool for the assessment of myocardial inflammation in patients with suspected acute myocarditis.46

Pericardial disease CMR is emerging as a most useful tool in the assessment of the pericardium. CMR, owing to its excellent resolution, can comprehensively assess pericardial anatomy. Through evaluation of regional myocardial deformation, ventricular interaction and venous return, CMR can also assess the physiological consequences of pericardial constriction. Owing to its combined anatomical and functional capabilities, CMR is a unique tool that enables one to distinguish between restrictive cardiomyopathy and constrictive pericarditis.

Congenital heart disease Echocardiography is the primary diagnostic tool for the assessment of congenital heart disease but CMR can provide valuable information to confirm uncertain diagnoses. The large field of view allows assessment of the anatomical relationships between cardiac and vascular structures.

Valvular heart disease Although echocardiography remains the initial tool for assessing cardiac valves, CMR can provide similar information in patients with sub-optimal or unsatisfactory echocardiographic examination.47 Valve anatomy and motion as well as the presence of vegetations, thrombi or tumours can be visualised. Velocity measurements can be performed and pressure gradients calculated accurately with good reproducibility. The concomitant excellent determination of ventricular function and volume makes CMR a good alternative when echocardiography is sub-optimal.

Cardiac masses The goal of CMR for assessing cardiac and paracardiac masses includes confirming or excluding a mass suspected by X-ray or echocardiography, assessing its location, mobility and relationship to surrounding tissues, and imaging the degree of vascularity; and distinguishing solid lesions from fluid and determining tissue characteristics as well as the specific nature of a mass. Owing to its excellent resolution, tissue characterisation and multiplanar approach, the extent of intra- or pericardial mass lesions can be clearly visualised. The additional administration of gadolinium contrast agents can assess vascularity and help to differentiate tumour from thrombus.

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and examination time in coronary artery imaging with CMR. Hamden et al.48 recently compared 3.0-T MRI with 64-slice CT angiography of the coronary arteries and concluded that, although both modalities could similarly identify significant coronary stenosis in patients with suspected or known CAD, CT angiography showed a favourable trend towards higher diagnostic performance. CMR is a most useful alternative modality to CT for the detection of anomalous coronary vessels, especially when ionised contrast administration is contra-indicated.49

The future Imaging speed is likely to continue to increase and larger and larger imaging volumes will become accessible at any given spatial and temporal resolution. The ability to accurately assess total scar burden via T1 mapping could provide a more objective method of non-invasively quantifying diffuse myocardial fibrosis, as recent studies have validated this method in various myocardial diseases.50,51 Quantitative analysis of perfusion studies will become easier and more applicable in the clinical setting. Myocardial tagging, enabling the CMR specialist to quantify diastolic wall motion will probably move from the research environment into clinical practice. Although coronary artery imaging via CMR is still in its infancy, the imaging of carotid plaque composition looks promising, especially in evaluating the response to lipid-lowering drugs.52 Plaque characterisation with 3.0-T MRCA will probably play an important role in the diagnosis and risk stratification of CAD in the future.

Conclusion CMR is a unique, versatile, rapidly evolving, non-invasive diagnostic tool offering complete coverage of the heart, and is independent of chest wall anatomy. Owing to its excellent resolution, interstudy reproducibility, user independence and absence of radiation exposure, it is bound to play an increasingly important role in cardiac imaging. CMR is regarded as the gold standard for evaluating ventricular function, because of its reproducibility and validated assessment of ventricular size, function and mass of both the left and right ventricles. CMR plays an increasingly important role in the work-up of ischaemic heart disease as well as the non-ischaemic cardiomyopathies. Owing to the versatility and multitude of possible sequences, it is necessary to assemble lists of sequences into protocols that are specifically tailored to diagnostic questions or scenarios, in order to decrease scan time, and streamline and simplify the technique.

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photon emission computed tomography for the detection of coronary

by cardiovascular magnetic resonance heralds an adverse prognosis in

artery disease: a comparative multicenter, multivendor trial. Eur Heart J 2013; 34(10): 775–781. 21. Buckert D, Dewes P, Walcher T, Rottbauer W, Bernhardt P. Intermediate-

nonischemic cardiomyopathy. J Am Coll Cardiol 2008; 51: 2414–2421. 39. McCrohon JA, Moon JC, Prasad SK, et al. Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using

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gadolinium-enhanced cardiovascular magnetic resonance. Circulation 2003; 108: 54–59. 40. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force criteria. Circulation 2010; 121: 1533–1541.

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46. Lurz P, Eitel I, Adam J, et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. J Am Coll Cardiol Img 2012; 5: 513–524. 47. Cawley PJ, Maki JH, Otto CM. Cardiovascular magnetic resonance imaging for valvular heart disease. Circulation 2009; 119: 468–478.

41. Maceira AM, Prasad SK, Hawkins PN, Roughton M, Pennell DJ.

48. Hamdan A, Asbach P, Wellnhofer E, et al. A prospective study for

Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation

comparison of MR and CT imaging for detection of coronary artery

2005; 111: 186–193.

stenosis. J Am Coll Cardiol Img 2011; 4(1): 50–61.

42. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Evaluation of the

49. Dirksen MS, Bax JJ, Blom NA, et al. Malignant right coronary

accuracy of gadolinium-enhanced cardiovascular magnetic resonance

artery anomaly detected by magnetic resonance coronary angiography.

in the diagnosis of cardiac sarcoidosis. J Am CollCardiol 2005; 45: 1683–1690. 43. Patel MR, Cawley PJ, Heitner JF, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009; 120: 1969–1977.

Circulation 2002; 106: 1881–1882. 50. Iles L, Pfluger H, Phrommintikul A, et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast enhanced T1 mapping. J Am Coll Cardiol 2008; 52: 1574–1580.

44. Abdel-Aty H, Boyé P, Zagrosek A, et al. Diagnostic performance of

51. Flett AS, Hayward MP, Ashworth MT, et al. Equilibrium contrast

cardiovascular magnetic resonance in patients with suspected acute

cardiovascular magnetic resonance for the measurement of diffuse

myocarditis: comparison of different approaches. J Am Coll Cardiol

myocardial fibrosis: preliminary validation in humans. Circulation 2010;

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45. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular

52. Zhao XQ, Dong L, Hatsukami T, et al. MR imaging of carotid plaque

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composition during lipid-lowering therapy. J Am Coll Cardiol Img 2011;

Cardiol 2009; 53: 1475–1487.

4: 977–986.

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In Memoriam Mr Donald Nixon Ross 4 October 1922 to 7 July 2014 (91 years) We are deeply saddened by the loss of our great teacher Donald Ross, a truly global mentor in cardiac surgery, a friend, a respectful colleague, an admirer, and custodian of our profession, who passed away on July 7, 2014. On behalf of the community of cardiac surgeons I would like to share our sincere condolences and deepest sympathy during this time of grief with Barbara Ross and the family. Donald Ross was born of Scottish parents on October 4, 1922 in Kimberley, Republic of South Africa, and was a fellow student of Christiaan Barnard at the University of Cape Town. After completion of his medical school training, he came to the United Kingdom in 1947 to pursue his cardiothoracic surgical career. He was appointed as the senior registrar in the Department of Thoracic Surgery at the University Hospital, Bristol in 1952 and at the Guy’s Hospital, London in 1954. He took the position of consultant cardiothoracic surgeon at the Guy’s Hospital in 1958 and at the National Heart Hospital in 1963, and subsequently became a senior surgeon in 1967. He was appointed as the Director of the Department of Surgery, Institute of Cardiology, London, in 1970 and retired in 1997 from there.1 Many surgeons came to London to learn the artistry of Donald Ross’s pioneering reconstructive surgery of the aortic root using the aortic homograft and the pulmonary autograft (the eponymous ‘Ross procedure’) as well as that of the right ventricular outflow tract during his times at the National Heart Hospital, the Harley Street Clinic, and the Italian Hospital.2-5 I first met him in 1975 during my paediatric cardiac surgery training at the Hospital for Sick Children, Great Ormond Street. Later it was a great privilege and honour to

be invited by the European Association for Cardio-Thoracic Surgery (EACTS) to comment on the article of this great surgeon titled ‘The pulmonary autograft – a permanent aortic valve’ during the 5th annual meeting in London in September 1991.6 Donald Ross epitomised biological aortic root surgery following the credo that since God created the aortic root as non-thrombogenic and non-obstructive anatomical units, the relationship between its morphology and function should be maintained to allow an unimpeded physiological blood flow. He has reigned as a caretaker of ‘reconstructive surgery of the left and right ventricular outflow tracts’ and served it admirably in his unpretentious, dignified but very effective way. Donald Ross also paved the way for heart transplantation in Britain. He performed the first operation of this kind in Britain on May 3, 1968 at the National Heart Hospital, closely following the world’s first heart transplantation by Christiaan Barnard in Cape Town on December 3, 1967.7 For many colleagues who experienced his utterly honest and forthright ways during his reign as a global champion in cardiac surgery and as a teacher, he has made an indelible mark and won an undying respect. He set a shining example of the kind of unconditional passion required to see a cardiac surgery profession through good times and bad. Donald Ross was a gentle spirit who loved passionately and who gave unselfishly of his time and himself. Though he has departed from this earth, his soul is still alive in our minds and hearts to guide the present and the coming generation and cardiac surgery as a whole. May his soul rest in peace.

Mr Donald Nixon Ross, DSc, FRCS

References 1.

Donald Ross (surgeon). Available at: http:// en.wikipedia.org/wiki/Donald_Ross_ (surgeon)#Education. Accessed July 12, 2014

Duran CG, Gunning AJ. A method for placing a total homologous aortic valve in the subcoronary position. Lancet 1962; 2(7254): 488–489

Ross DN. Homograft replacement of the aortic valve. Lancet 1962; 2 (7254): 487

Ross DN, Radley-Smith R, Somerville J. Pulmonary autograft replacement for severe aortic valve disease. Br Heart J 1969; 31(6): 797–798

Somerville J, Ross D. Long-term results of complete correction with homograft reconstruction in pulmonary outflow tract atresia. Br Heart J 1972; 34(1): 29–36

Ross D, Jackson M, Davies J. The pulmonary autograft – a permanent aortic valve. Eur J Cardiothorac Surg 1992; 6(3): 113–116, discussion 117

BBC. 1968: Surgeons conduct UK’s first heart transplant. Available at: http://news. bbc.co.uk/onthisday/hi/dates/stories/may/3/ newsid_ 4294000/4294423.stm. Accessed July 12, 2014

Charles Yankah, cyankah@web.de Charite Medical University Berlin and German Heart Institute Berlin, Berlin, Germany Previously published in Thorac Cardiovasc Surg 2014. Permission granted by Thieme Publishers NY, 333 Seventh Ave, NY 10001, USA.

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Letter to the Editor Adverse effects of the ‘Noakes’ diet on dyslipidaemia Dear Sir There has been much hype and controversy over the so-called ‘Noakes’ diet. This diet advocates a low-cardohydrate, highfat and high-protein intake. As previously reported in the Journal, Noakes has expressed the view that this diet coupled with exercise could have a favourable impact on lipid levels and potentially avoid the need for drug therapy.1 In that same report, it was noted that this has not been subjected to scientific validation. More recently the ability of the Noakes diet to give better weight-control results than a ‘balanced diet’ has been questioned.2 I have recently seen a patient who had been diagnosed with dyslipidaemia several years ago and was receiving rosuvastatin 5 mg daily. A lipogram taken in April 2012 (on therapy) showed a total cholesterol (TC) level of 5.1 mmol/l and low-density lipoprotein cholesterol (LDL-C) of 2.9 mmol/l, respectively. After two months on the Noakes diet, she had the lipogram repeated. This now showed a TC of 12.9 mmol/l and LDL-C of 9.6 mmol/l, respectively. This was in the absence of diabetes

mellitus and hypothyroidism. While one case does not make a scientific study, it should nevertheless alert practitioners involved in treating patients with dyslipidaemia and attempting to lower cardiovascular risk, that subjects on the Noakes diet should be cautioned as to the potential risks and have their lipid profiles closely monitored. C Schamroth, MBBCh (Wits), FCP (SA), MMed (Wits) Milpark Hospital, Johannesburg

References 1.

Dalby AJ, Albers JL. Congress report: Cardiology and Diabetes at the Limits. Cardiovasc J Afr 2013; 24: 147–148.

Naude CE, Schoonees A, Senekal M, et al. Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis. PLOS One 2014; DOI 10.1371/ journal.pone.0100652).

Industry News Cipla Medpro wins R280-million State therapeutic drugs tender Cipla Medpro, the third largest pharmaceutical company in South Africa, today announced that it has been awarded a R280 million share of the South African Government’s national solid-dose tender to supply therapeutic drugs. The contract is effective from 1 August 2014 and will run for a period of two years. According to Cipla Medpro, the majority of products to be supplied will be in the mental health, cardiovascular and women’s health categories. Paul Miller, CEO of Cipla Medpro, says that the company has for many years been providing the private market with high-quality products, and is now committed to supporting Government by providing all South Africans with

high-quality and affordable medicine. ‘With our country’s evolving healthcare environment, Government has clearly identified a growing need for therapeutic drugs in the mental health, cardiovascular and women’s health arenas, and we remain committed to supporting them in these much-needed therapeutic drug categories.’ Miller points to Health Minister, Dr Aaron Motsoaledi’s recent Health Budget speech, which highlighted the need to tackle mental health and women’s health challenges in South Africa. ‘With this contract, Cipla will now be assisting Government with its National Development Plan goals which include, among others, reducing the burden of non-communicable diseases such as

mental health among everyday South Africans, as well as reducing maternal deaths and improving women’s health by tackling diseases such as hypertension.’ This latest Government tender win is the third in the space of less than two years for the growing pharmaceutical company, and follows Cipla Medpro winning a R345 million national respiratory tender (June 2014) and an antiretroviral tender valued at approximately R1.448 billion (November 2012). ‘We are extremely proud to have won this tender which is not only testament to our high-quality product portfolio, but is also in line with Cipla’s ethos of advancing healthcare for all South Africans’, concludes Miller.

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Drug Trends in Cardiology Clearing hurdles in anticoagulation therapy Prof Sylvia Haas, emeritus professor of Medicine, Technical University Munich, Germany The hurdles that need to be cleared when initiating therapy with the novel anticoagulants (NOACs) are the following, says Prof Sylvia Haas: • ‘The different dosing regimens, depending on whether these agents are being used for venous thromboembolism (VTE) treatment or stroke prevention. • The practical usage of them. • The management of bleeding associated with their use.’ She was speaking at a meeting held in Johannesburg in late July as a guest of Bayer Healthcare. What makes the NOACs different from earlier anticoagulant therapies? They are administered orally (unlike the heparins), have a wide therapeutic window (unlike warfarin), fast onset/offset of action, carry a low risk of food/drug interactions and have a predictable mode of action. In addition, they require no monitoring and are administered in a fixed dose. ‘That we no longer need to bridge patients is a major advantage’, she said.

The NOACs’ many indications and different dosing regimens can be both an advantage and a source of confusion. Prof Haas feels that the former aspect far outweighs the latter. ‘We just need to know what is right for each patient, taking into account the pharmacology of the agent and the pathophysiology of the underlying disease.’ She cautioned that it’s also important to bear in mind the differences between arterial clots (associated with acute coronary syndromes) and venous clots [associated with VTE (deep-vein thrombosis and pulmonary embolism) and atrial fibrillation]. The former are characterised by high shear rates, the latter by low shear rates. Conventional VTE therapy entails overlapping parenteral anticoagulation [with low-molecular weight heparin (LMWH) or fondaparinux] with warfarin in the initial phase of treatment, before warfarin alone is used for long-term maintenance after an INR value of at least 2.0 has been reached.

The development of NOACs for VTE treatment raises the question of whether a NOAC should replace both of the conventional agents or just warfarin.

Prof Haas mentioned that history has shown pitfalls with the former option and therefore some manufacturers developed their compounds only to replace warfarin, i.e. the treatment with two anticoagulants (dual-drug approach) remains in place. However, rivaroxaban has been successfully developed to replace both the initial therapeutic doses of parenteral anticoagulation and warfarin for secondary prevention and long-term anticoagulation. The phase II dose-finding ODIXa-DVT study,1 which evaluated rivaroxaban versus enoxaparin and warfarin for the treatment of proximal deep-vein thrombosis, found rivaroxaban to be comparable to standard anticoagulation therapy in respect of efficacy (thrombus regression) and safety (the incidence of major bleeding up to two days after last administration of the study drug). A second phase II study2 also showed different doses of rivaroxaban to be at least as good as standard care, paving the way for the phase III EINSTEIN-DVT and EINSTEIN-PE studies, which used the so-called single-drug approach consisting of intensified anticoagulation with 15 mg rivaroxaban twice a day for three weeks, followed by 20 mg once daily for long-term anticoagulation.

In these phase III studies the efficacy curves ran in parallel for rivaroxaban versus enoxaparin and warfarin, showing non-inferiority. However, major bleeding was significantly lower in those receiving rivaroxaban versus those receiving standard care. While the NOACs undoubtedly add value, it is important to be aware of other medications a patient may be taking. Rivaroxaban, for example, is not recommended with HIV protease inhibitors (e.g. ritonavir) a third-line treatment in HIV-positive patients or azole antimycotics. All NOACs should also be used with caution in patients taking other drugs that affect haemostasis, such as NSAIDs, aspirin or platelet-aggregation inhibitors. Standard atrial fibrillation doses should not

be used in patients receiving dual antiplatelet therapy, for example, after coronary stenting. Converting patients from warfarin to a NOAC needs careful consideration: ‘Stop the warfarin, continue measuring the INR and introduce the new agent when the INR value is approaching the lower end of the recommended range of 2.0’, said Prof Haas. Switching from LMWH to a NOAC (and vice versa) is easy, i.e. introduce the NOAC or LMWH, respectively, when the next dose of the last anticoagulant would have been given. The EINSTEIN studies showed that rivaroxaban’s safety and efficacy parameters are maintained, even in ‘fragile’ patients [older than 75 years, with reduced creatinine clearance (< 50 ml/min) and/or body weight ≤ 50 kg). It also holds true in cancer patients. In patients about to undergo surgery, in general the NOAC should be stopped at least 48 hours prior to the procedure in patients at high risk of bleeding and at least 24 hours prior in patients with lower bleeding risk, however, more time might be needed with dabigatran should a patient’s renal clearance be poor. It should be reintroduced once haemostasis has been achieved, at least eight hours after surgery.3 The procedure for reversing severe bleeding is currently the same as for warfarin. ‘The race for specific antidotes is, however, gaining momentum’, observed Prof Haas. ‘Three types of antidote are currently in development but they remain a work in progress.’ Concluding, she underscored that the NOACs are effective and safe, and more convenient to use than vitamin K antagonists. All carry a bleeding risk, however, so responsible use is critical. This entails a careful assessment of benefits versus risks, as well as knowledge of the chosen drug’s pharmacology, switching procedures and bleeding management.

P Wagenaar 1. Agnelli G, et al. Circulation 2007; 116: 180–187. 2. Buller HR, et al. Blood 2008; 112: 2242–2247. 3. Heidbuchel H, et al. Eur Heart J 2013; 34: 2094–2106.

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Dedicated programme for paediatric cardiologists at SA Heart Congress 2014 The 2014 SA Heart Congress has a dedicated and comprehensive programme for paediatric cardiologists that will be taking place daily at the International Conference Centre in Durban from Friday 17 to Sunday 19 October. There will be a pre-congress workshop on peri-operative and peri-interventional transoesophageal echocardiograhy (TOE) on Thursday 16 October from 12:00 to 17:00. This will cover basic views, evaluation of congenital heart disease and ASD closures, as well as evaluation of the mitral valve. The AGM for the Paediatric Cardiac Society of South Africa (PCSSA) will be held immediately after the workshop from 17:00 to 18:00. Key topics designated for the paediatric cardiology track on Friday, 17 October include:

• providing a service with limited resources (Dr Krishna Kumar, India) • the status quo of paediatric cardiac services in South Africa (Dr Liesl Zühlke) • making difficult decisions with limited resources. Paediatric cardiologists will join the general plenary sessions on Friday afternoon for the session on valvular/ structural heart disease. On Saturday 18 October, various aspects of congenital heart disease will be discussed in the morning by speakers who include Drs Krishna Kumar and Tim Jones (UK). The afternoon session will focus on single-ventricle physiology and will cover the evaluation and monitoring of patients over their lifetime, surgical techniques, and the anaesthetising

and imaging of Fontan patients for non-cardiac procedures. The morning of Sunday 19 October has been dedicated to an interactive session covering some of the more challenging percutaneous interventions in congenital heart disease. This workshop will include: • percutaneous closure of peri-membranous VSDs • ballooning and stenting of branch pulmonary arteries • percutaneous closure of PDAs safely in infants below 5 kg • PDA stenting. For full programme details, and to register for the SA Heart Congress and pre-congress workshops, visit www.saheart.org/congress2014. For queries, contact Europa Organisation Africa on (011) 325-0020, or email info@eoa.co.za

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Advertorial Stroke prevention in non-valvular atrial fibrillation with rivaroxaban The new oral anticoagulants are the way of the future when it comes to stroke prevention in atrial fibrillation (AF). The ROCKET-AF trial1 showed that not only was rivaroxaban non-inferior to warfarin for preventing stroke and systemic embolism, but safer too. One of the authors of that study, Prof Keith Fox, Duke of Edinburgh, Professor of Cardiology of the University of Edinburgh and Professor of Cardiology for the British Heart Foundation, underscores that it has a similar adverseevent profile, but causes less intracranial and fatal bleeding. He was speaking in Johannesburg at the South African launch of the drug, Bayer Healthcare’s Xarelto®. ‘The UK’s National Institute of Clinical Excellence (NICE) guidelines support not only the efficacy of new agents, such as rivaroxaban, but also their cost-effectiveness, given that warfarinassociated complications come at a much higher cost’, he said. Non-valvular AF is defined as the absence of valvular disease in the cause of the AF, as well as the absence of haemodynamically significant mitral disease.

It is a common condition, accounting for one-third of all hospitalisations for cardiac rhythm disturbances. Prevalence rates are high (4.5 million in Europe, 5.1 million in the USA). Individuals over the age of 55 years have a one-in-four chance of developing AF (24% of men and 22% of women), which can have serious lifethreatening consequences, such as heart failure, stroke and death. ‘It’s a serious condition and its prevalence is increasing; it is expected to more than double by 2050. It’s therefore important to identify patients with unsuspected AF, introduce adequate anticoagulation and ensure adherence. There is suboptimal use of warfarin, given its many drawbacks. These include bleeding risk, drug–drug and drug–food interactions. Many patients either stop using it or have difficulty maintaining therapeutic range. And contrary to widely held beliefs, aspirin is not a safer alternative. It causes as much bleeding as warfarin and is less effective.’ This is where newer agents such as rivaroxaban can improve treatment outcomes. ‘It’s at least as effective as

warfarin and better in respect of safety, even in elderly patients over the age of 75’, said Prof Fox. ‘It works as secondary prevention and carries a lower risk of causing haemorrhagic stroke. Its net clinical benefit favours patients both younger and older than 75 years. So yes, we need newer agents such as rivaroxaban with their entirely consistent benefits.’ He underscored too that ROCKETAF showed that clinicians need to be more aggressive when transitioning patients to open-label therapy as there was a clear significant difference in off-treatment events. ‘Doctors are also sometimes overly cautious about anticoagulating high-risk patients for fear of causing bleeding, and the new oral anticoagulants now allow us to treat these patients more safely than was possible with warfarin’, he concluded. 1.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.

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Case Report Ross procedure in a child with Aspergillus endocarditis and bicuspid aortic valve Fotios A Mitropoulos, Meletios A Kanakis, Constantinos Contrafouris, Cleo Laskari, Spyridon Rammos, Christos Apostolidis, Prodromos Azariadis, Andrew C Chatzis Case report

Abstract The case is presented of a previously healthy infant with a known asymptomatic bicuspid aortic valve who developed fungal endocarditis. The patient underwent aortic root replacement with a pulmonary autograft (Ross procedure). Cultured operative material revealed Aspergillus infection. The patient had an excellent recovery and remained well one year later. Submitted 7/4/13, accepted 28/4/14 Cardiovasc J Afr 2014; 25: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2014-031

Department of Paediatric and Congenital Cardiac Surgery, Onassis Cardiac Surgery Centre, Athens, Greece Fotios A Mitropoulos, MD Meletios Kanakis MD, MD, meletis_kanakis@yahoo.gr Constantinos Contrafouris, Cleo Laskari, MD Spyridon Rammos, MD Christos Apostolidis, MD Prodromos Azariadis, MD Andrew C Chatzis, MD

A previously healthy 20-month-old girl with a known asymptomatic bicuspid aortic valve presented to a children’s hospital with a three-day history of low-grade fever, anorexia, weight loss and irritability. In spite of the absence of positive blood cultures, the provisional diagnosis of endocarditis was made based on clinical history, the presence of a new cardiac murmur, elevated white blood cell (WBC) count and C-reactive protein (CRP) level, as well as echocardiographic evidence of aortic and mitral regurgitation in conjunction with suspicious vegetations on the aforementioned valves. The patient was put on broad-spectrum antibiotics and transferred to our hospital for further management five days post her initial admission. On arrival, the patient was comfortable and apyrexial. Blood pressure measured 110/40 mmHg and heart rate 135 beats/min. There were no endocarditis stigmata. On auscultation, a reduced second sound was noted, along with a 3/6 ejection systolic and 1/6 diastolic murmur, best heard at the aortic position. Laboratory investigations showed WBC 16 000 cells/ml, haemoglobin 8.7 g/dl and CRP 23 mg/l. Echocardiography revealed mild aortic stenosis (PG 15 mmHg), severe aortic (3+/4+) and less severe (2+/4+) mitral regurgitation, and left atrial (LA) and ventricular (LV) enlargement with preserved LV function. Vegetations were noted on both valves (Fig. 1). Brain, chest and abdominal CT scans were negative for septic emboli. Repeat blood cultures turned out negative. Since the haemodynamic burden was well tolerated, the patient continued B

Fig. 1. P arasternal long-axis view with the aortic valve open (A) and closed (B). The arrows point to a large, grape-like vegetation covering both cusps of the bicuspid aortic valve, particularly the fused right and non-coronary cusp.

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Fig. 2. P ostoperative parastenal long-axis view with the neo-aortic valve open (A) and closed (B). A thin, well-functioning neo-aortic valve is depicted.

on the same antibiotic regimen targeted to a completion of a six-week course before any surgical action would be taken. By the end of the fourth week of conservative treatment, the patient unexpectedly went into cardiac arrest and immediate cardiac resuscitation was instituted. Cardiac function was restored an hour later and the patient was transferred to the intensive care unit (ICU). Due to her critical condition, after initial haemodynamic stabilisation with appropriate inotropic support, the patient was able to undergo surgery three days later. At operation, the aortic valve appeared severely damaged with two of the cusps (left, non-coronary) bearing vegetations and perforations. Two small vegetations were also found and removed from the anterior leaflet of the mitral valve. The aortic valve was replaced with a pulmonary autograft (Ross procedure) while the right ventricular outflow tract (RVOT) was reconstructed with a 14-mm bovine jugular vein conduit (Contegra®, Medtronic Inc, Minneapolis MN, USA). The patient made an uneventful recovery. Cultures of valve and vegetations were positive for Aspergillus. After a further four weeks of appropriate intravenous antibiotic and antifungal treatment, the patient was discharged home in excellent clinical condition with negative blood cultures. One year later, both the neo-aortic and the implanted xenograft in the pulmonary position were found to perform well, without stenosis or regurgitation (Fig. 2). The patient remained in an excellent clinical condition and continued to receive oral antifungal prophylaxis.

Discussion Despite the increase in number of documented reports of fungal endocarditis in children, bacterial endocarditis remains more common. Aspergillus is a rare cause of endocarditis, usually affecting immunosuppressed children younger than a year of age, and premature neonates.1 Mortality rate is high and the commonly negative blood cultures render diagnosis elusive, the latter not infrequently established on post mortem.2 While searching for the ideal prosthesis for replacement of the aortic valve in children, the pulmonary autograft transfer, first described by DN Ross, has emerged as an attractive

option.3 Advantages include lack of immunological degenerative changes, freedom from anticoagulation, excellent haemodynamic performance, and potential for growth.4-8 The need for simultaneous RVOT reconstruction has been met by the extensive use of aortic and pulmonary cryopreserved homografts.9,10 Alternatively, the Contegra® valved conduit is also well suited for RVOT reconstruction without the use of additional foreign material, remaining well functioning without calcification during early and medium follow up.11,12 Although technically demanding, the Ross procedure has been recommended as the procedure of choice for aortic valve replacement in children, with excellent operative, shortand medium-term results.4,13-15 Nonetheless, concern has been expressed about the long-term durability of the neo-aortic valve as the need for re-operation increases with time due to late dilation and valve insufficiency.6,7 Although aortic homograft root replacement has been described as a reliable option for acute aortic valve endocarditis in children, the Ross procedure has been successfully performed with minimal mortality and recurrence rate.16,17

Conclusion Aspergillus endocarditis may occur even in immunologically healthy young children in the setting of structural cardiac pathology. The Ross procedure proves to be a reliable option for surgical treatment of acute aortic endocarditis and can be performed whenever indicated owing to commercially available bioprosthetic valved conduits.

References 1.

Millar BC, Jugo J, Moore JE. Fungal endocarditis in neonates and children. Pediatr Cardiol 2005; 26: 517–536.

Challa S, Prayaga AK, Vemu L, Sadasivan J, Jagarlapudi MKM, Digumarti R, Prabhala. Fungal endocarditis: an autopsy study. Asian Cardiovasc Thorac Ann 2004; 12: 95–98.

Gonzalez-Lavin L, Geens M, Ross DN. Pulmonary valve autograft for aortic valve replacement. J Thorac Cardiovasc Surg 1970; 60: 322–330.

Raja SG, Pozzi M. Ross operation in children and young adults: the

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Alder Hey case series. BMC Cardiovasc Dis 2004; B: 3–9.

Segesser LK. Bovine valved xenograft in pulmonary position: medium-

Doss M, Wood JP, Martens S, et al. Do pulmonary autografts provide

term follow-up with excellent hemodynamics and freedom from calcifi-

better outcomes than mechanical valves? A prospective randomized trial. Ann Thorac Surg 2005; 80: 2194–2198. 6.

Sarris GE. New xenograft valved conduit (Contegra®) for right ventricu-

long term clinical and echocardiographic follow-up. Ann Thorac Surg

lar outflow tract reconstruction. Heart Surg Forum 2003; 6: 396–398.

Mitropoulos FA, Kanakis MA, Apostolopoulou SC, Rammos S,

in children: 10-year experience. Ann Thorac Surg 1998; 65: 496–502. 14. Kouchoukos NT, Davila-Roman VG, Spray TL, Murphy SF, Perillo JB.

ment in a young adult with congenital aortic stenosis. Heart Surg Forum

Replacement of the aortic root with a pulmonary autograft in children

Concha M, Aranda PJ, Casares J, et al. The Ross procedure. J Card Surg 2004; 19: 401–409.

13. Elkins RC, Knott-Craig CJ, Ward KE, Lane MM. The Ross operation

Anagnostopoulos CE. The Ross–Konno procedure as reoperative treat2012; 15: 182–184. 8.

cation. Ann Thorac Surg 2004; 78: 1382–1388. 12. Chatzis AC, Giannopoulos NM, Bobos D, Kirvassilis GB, Rammos S,

Kouchoukos NT, Masetti P, Nickerson NJ, et al. The Ross procedure: 2004; 78: 773–781.

Forbess JM, Shah AS, louis JD, et al. Cryopreserved homografts in the pulmonary position: determitants of durability. Ann Thorac Surg 2001; 71: 54–60.

10. Bando K, Danielson GK, Schaff HV, et al. Outcome of pulmonary and aortic Homografts for right ventricular outflow reconstruction. J Thorac Cardiovasc Surg 1995; 109: 509–518. 11. Corno AF, Qanadli SD, Sekarski N, Artemisia S, Hurni M, Tozzi P, von

and young adults with aortic valve disease. N Engl J Med 1994; 330: 1–6. 15. Hraska V, Krajci M, Haun Ch, et al. Ross and Ross-Konno procedure in children and adolescents: mid-term results. Eur J Cardiothorac Surg 2004; 25: 742–747. 16. Chaturvedi R, de Leval M, Sullivan ID. Urgent homograft aortic root replacement for aortic root abscess in infants and children. Heart 1999; 81: 62–66. 17. Birk E, Sharoni E, Dagan O, Gelber O, Georghiou GP, Vidne BA, Erez E. The Ross procedure as the surgical treatment of active aortic valve endocarditis. J Heart Valve Dis 2004; 13: 73–77.

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Case Report Closure of ruptured aneurysm of the sinus of Valsalva using a native aortic valve leaflet Piotr Buczkowski, Maciej Walczak, Sebastian Stefaniak, Mateusz Puślecki, Izabela Katyńska, Marek Jemielity Case report

Abstract We present a case of the native valve used to complete closure of a ruptured aneurysm of the sinus of Valsalva. Aneurysm of the sinus of Valsalva is rare and a non-coronary artery is affected in only 20% of cases. To close the rupture, we decided to use a non-coronary leaflet in a young patient with moderate aortic stenosis and fibrosis of the leaflets. In our opinion, use of a native non-coronary valve leaflet should be considered when making intra-operative decisions for repair of non-coronary aneurysm of the sinus of Valsalva. Keywords: sinus of Valsalva, aortic valve replacement, ruptured aneurysm Submitted 10/2/14, accepted 22/4/14 Cardiovasc J Afr 2014; 25: e4–e6

www.cvja.co.za

DOI: 10.5830/CVJA-2014-020

Aneurysm of the sinus of Valsalva is rare, the majority occurring in males. It occurs when a congenital heart disease is combined with the absence of normal elastic tissue and media in this region. Nearly 70% of aneurysms of the sinus of Valsalva are located in the right coronary sinus, 20% are non-coronary, and the rest are in the left coronary artery.1,2 Aneurysm of the sinus of Valsalva as a congenital disease is very rare and is diagnosed in the third and fourth decades of life, usually after rupture. Patients qualify for urgent cardiac surgery. Depending on the location and penetration to other cavities of the heart, we see a wide range of symptoms and haemodynamic changes. There is no consensus on whether to operate or not for non-ruptured aneurysms of the sinus of Valsalva.3

A 50-year-old male with no past medical history was admitted to our hospital for acute chest pain after salt water aspiration while swimming. Initially he was hospitalised in the medical observation unit because of jaundice. Blood tests showed abnormalities, as presented in Table 1. Ultrasonography of the abdomen revealed a large amount of free fluid in the abdominal cavity, with liver enlargement. Chronic hepatitis was diagnosed as liver failure. Pharmacological treatment was administered and a cardiologist was involved in the treatment. Transthoracic echocardiography (TTE) revealed a ruptured aneurysm of the non-coronary sinus of Valsalva with penetration to the right atrium. Qp:Qs was 2.1:1. The patient was transported to the cardiology clinic, where treatment was continued for the next four days. After rapid deterioration, his clinical state was unstable and he had right ventricular dysfunction with cardiogenic shock (systolic blood pressure: 70 mmHg) and a EuroSCORE II of 53.41%, the patient was moved to the cardiac surgery unit for an emergency operation. Using cardiopulmonary bypass (CPB) with superior and anterior vein cannulation, the procedure was performed at 32°C hypothermia, with cardiac protection in the form of cold 4°C cardioplegic solution (St Thomas Hospital). After aortotomy, the non-coronary aneurysm rupture of the sinus of Valsalva was revealed, with a typical narrow band leading to the right atrium (Fig. 1A, B). The band from the right atrium was closed using Prolen 5-0. Because of the pre-operative diagnosis of moderate aortic stenosis [peak-to-peak gradient (PPGmax): 35 mmHg, aortic valve area: 1.5 cm2], calcification and fibrosis of the right and left coronary leaflets, and the relatively young age of the patient, a decision was made to implant a mechanical prosthesis. Table 1. Blood examination showing abnormal parameters.

Department of Cardiac Surgery and Transplantology, University of Medical Sciences Poznan, Poland Piotr Buczkowski, PhD Maciej Walczak, MD Sebastian Stefaniak, MD, Seb.kos@wp.pl Mateusz Puślecki, PhD Izabela Katyńska, MD Marek Jemielity, MD

Parameter Mean value Normal values Bilirubin (mg/dl) 5.16 < 1.1 ALT (U/l) 2 706 5–40 AST (U/l) 1 940 5–40 Alkaline phosphatase (U/l) 86.1 20–70 GGT (U/l) 125.4 15–90 INR 2.15 0.8–1.2 ALT = alanine transaminase, AST = aspartate transaminase, GGT = gamma-glutamyl transferase.

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1 2 1

1 2

Fig. 1. ( A) Rupture of the non-coronary aneurysm of the sinus of Valsalva was revealed with the typical narrow band leading to the right atrium. (B) 1, aorta, 2, rupture of the aneurysm of the non-coronary sinus of Valsalva. (C) The left leaflet was used to close the narrow band of aneurysm from inside the aorta. 1, non-coronary leaflet of the aortic valve. 2, rupture of the aneurysm of the non-coronary sinus of Valsalva.

After visual inspection of the aortic valve, the surgeon decided to use the non-coronary leaflet. The left leaflet was used to close the narrow band of the aneurysm from inside the aorta (Figs 1C, 2A, B). A Prolen 6-0 suture on the edge of the leaflet was used to sew closed the aortic non-coronary sinus of Valsalva. An ON-X mechanical prosthesis was implanted using a typical technique with 18 sutures with pledget. The right atriotomy and aortotomy was closed. Intra-operative transoesophageal echocardiography (TEE) performed after cardiopulmonary bypass confirmed the positive result, with no leakage between the sinus of the aorta and the right atrium. In the postoperative period, the patient was re-operated twice because of high fluid drainage. After A

re-operation he was haemodynamically stable and was extubated on the third day postoperatively. Every day, TTE was done to confirm the outcome and the repair of the right ventricle. On the fourth day postoperatively, there was rapid clinical deterioration, with rapid increase in serum C-reactive protein and procalcitonin levels, which led to multi-organ failure. The patient died on the fifth day postoperatively. TTE examination did not reveal any fistula between the aorta and the right atrium.

Discussion We present a case of the native valve being used to complete closure of the ruptured aneurysm of the sinus of Valsalva B

1 2

3 Fig. 2. P lacement of the sutures in closing the non-coronary sinus of Valsalva with a native leaflet. (A). The left leaflet was used to close the narrow band of the aneurysm from inside the aorta. 1, non-coronary leaflet of the aortic valve. 2, rupture of the aneurysm of the non-coronary sinus of Valsalva. 3, sutures with pledget. (B) 1, non-coronary leaflet of the aortic valve sewn to the aorta. 2, closed aneurysm of the non-coronary sinus of Valsalva.

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(RAoSV). Despite the fact that this congenital disease is usually seen in the third to fourth decades of the life,1 we found pathology of the native valve in this 50-year-old patient, with an indication for its replacement. We believe in this situation the use of a native valve was acceptable. The use of a native valve leaflet is reasonable when it needs no alteration, and there is dysfunction of the valve needing replacement. Use of a native leaflet can only be performed for repair of an aneurysm of the non-coronary sinus of Valsalva. This case shows how important a quick decision is for surgical or transcatheter treatment. Four days of delay led to right ventricular dysfunction with cardiogenic shock, and symptoms of multi-organ failure, which were probably involved in the fatal patient outcome. Our patient was operated on as an emergency with a diagnosis of moderate aortic valve stenosis. When the patient’s clinical state is stable, other less-invasive techniques of RAoSV treatment, such as transcatheter closure, should be involved. The first report of transcatheter closure of a ruptured aneurysm of the sinus of Valsalva with the use of Rashkind umbrella was published in 1994 by Cullen.4 Today we find many interesting case presentations of RAoSV closure with a new generation of devices; the Amplatzer septal occluders or Amplatzer duct occluders.5,6 Patients undergoing transcatheter device closure are spared the morbidity related to a sternotomy and the use of cardiopulmonary bypass. As it is an effective and safe treatment modality for isolated RAoSV, it is usually reported in case reports or short early and mid-term results in small groups of usually less than 10 patients. Transcatheter device closure can be lifesaving if it can be done within a short space of time in heart-failure patients in a poor general condition and with co-morbidities. In hospitals with no teams experienced in transcatheter closure techniques, or in haemodynamically unstable patients, cardiac surgery is still the gold standard in treating patients with RAoSV.7 In our case, double re-operation due to fluid drainage, and with the INR

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above 2.5 (after the use of Octaplex and fresh frozen plasma) could have led to the final septic state.

Conclusion In surgery on patients with ruptured aneurysm of the non-coronary sinus of Valsalva and with aortic valve disease, the use of native valve leaflets should be considered. Rupture of the sinus of Valsalva with significant left-to-right shunt should be an indication for urgent surgery or transcatheter closure.

References 1.

Skalski J, Religa Z. Tętniaki Zatoki Aortalnej Kardiochirurgia dziecieca. Polish Handbook. Katowice, Poland: Wydawnictwo Naukowe ‘Śląsk’, 2003: 410–418.

Takach TJ, Reul GJ, Duncan JM, Cooley DA, Livesay JJ, Ott DA, Frazier OH. Sinus of Valsalva aneurysm or fistula: management and outcome. Ann Thorac Surg, 1999; 68: 1573–1577.

Vural KM, Sener E, Taşdemir O, Bayazit K. Approach to sinus of Valsalva aneurysms: a review of 53 cases. Eur J Cardiothorac Surg 2001; 20(1): 71–76.

Cullen S, Somerville J, Redington A. Transcatheter closure of a ruptured aneurysm of the sinus of Valsalva. Br Heart J 1994; 71: 479–480.

Cullen S, Vogel M, Deanfield JE, Redington AN. Rupture of aneurysm of the right sinus of Valsalva into the right ventricular outflow tract: treatment with Amplatzer atrial septal occluder. Circulation 2002; 105: 1–2.

Kerkar PG, Lanjewar CP, Mishra N, Nyayadhish P, Mammen I. Transcatheter closure of ruptured sinus of Valsalva aneurysm using the Amplatzer duct occluder: immediate results and mid-term follow-up. Eur Heart J 2010; 31: 2881–2887.

Balduccia A, Gesuetea V, Fabia M, Picchioa FM, Gargiulob G. An unusual case of sinus of Valsalva aneurysm in a GUCH patient: an unusual side of the aorto-cardiac fistula. Cardiol Res 2011; 2(4): 193–195.

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Case Report A penetrating nail-prick injury of the lateral plantar artery leading to pseudo-aneurysm formation and rupture Emrah Şişli, Ali İhsan Hasde, Mustafa Mavi, Suat Dursun

Submitted 7/5/13, accepted 13/5/14

Abstract Pseudo-aneurysm in the plantar region is so rare that there are only sporadic case reports in the literature. The aetiology is usually either iatrogenic or stepping on a piece of glass. In comparison to the medial plantar artery, the lateral plantar artery is the most common arterial structure injured in the plantar region due to its more superficial course and it being less protected by the surrounding structures. With variable presentation and different time intervals from injury to diagnosis, the mechanism and penetration depth of the injury is thought to have a major impact on the formation of a pseudo-aneurysm. The aims of this article were to present a case of a lateral plantar artery injury after stepping on a construction nail, leading to pseudo-aneurysm formation and rupture, and to review the literature with regard to the clinical characteristics of these rare and overlooked cases.

Keywords: leg injuries, vascular injuries, pseudo-aneurysm, rupture, symptom evaluation

Department of Cardiovascular Surgery, Acıbadem Bakırköy Hospital, Istanbul, Turkey Emrah Şişli, MD, dresisli@gmail.com

Clinics of Cardiovascular Surgery, Antakya State Hospital, Hatay, Turkey Ali İhsan Hasde, MD Mustafa Mavi, MD

Department of Radiology, Antakya State Hospital, Hatay, Turkey Suat Dursun, MD

Cardiovasc J Afr 2014; 25: e7–e9

www.cvja.co.za

DOI: 10.5830/CVJA-2014-028

The incidence of plantar pseudo-aneurysm is so rare that there are only sporadic case reports in the literature1-5 (Table 1). The aims of this article were to present a case of lateral plantar artery injury after stepping on a construction nail, leading to pseudo-aneurysm formation and rupture, and review of the literature with regard to the clinical characteristics of these rare and overlooked cases.

Case report A 58-year-old female was referred to our emergency department because of bleeding from the sole of her foot. On physical examination, pulsatile bleeding from the enlarged lesion through the eroded skin on the plantar surface of the left foot was noted (Fig. 1A). The bleeding was controlled with manual compression along with a tourniquet applied to the calf, and the patient was urgently transferred to the operating room. She had stepped on a rusty construction nail three weeks earlier. Because there was no apparent bleeding, she had not made much of her injury. On the third day, the patient had attended a tertiary-level healthcare facility due to pain and swelling. There the wound was dressed and treated medically. The patient had not kept her follow-up appointment. She noted ‘I have been feeling my heartbeat in my sole for the last five days’. In the operating room, the lesion was hastily evaluated with a portable duplex ultrasound (Sonosite, MicroMaxx, Washington, USA) using a linear phased array, 6–13 MHz bandwidth transducer. In two dimensions, the lesion, with a diameter of 3.1

Table 1. The demographic and clinical characteristics of the cases in the reviewed articles Age Extensive Time interval No of (years)/ bleeding at the from injury to Authors cases gender Injury mechanism time of injury diagnosis 1 8/F Stepped on glass Yes 3 weeks Economou et al. (1993)2 2 5/F Stepped on glass Yes 8 weeks Thornton et al. (2003)5 11/F Stepped on glass Yes 3 weeks 1 18/M Iatrogenic No 10 days Ptaszek et al. (2006)4 1 68/M Iatrogenic No 11 days Bazea et al. (2009)1 1 26/M Stepped on glass Yes 6 weeks Murakami et al. (2010)3 F: female, LPA: lateral plantar artery, M: male, MPA: medial plantar artery. *Indicates small branches of the distal MPA.

Presentation Haemorrhage Pulsatile mass Pulsatile mass Pulsatile mass Incidental Pain

Plantar Aneurysmal artery sac dimention Procedure of injured (cm) choice LPA 2 Ligation, excision LPA 2×2 Ligation LPA 8×4 Ligation LPA 2 Ligation MPA* 2 × 1.5 Embolisation LPA 3.3 × 3 × 2 Embolisation

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Fig. 1. V iew of the pseudo-aneurysm on the left sole (A). Ultrasonographic evaluation revealed a pulsatile aneurysmal sac with turbulent flow (B).

× 2.5 cm, was originating from the lateral plantar artery (LPA). Colour duplex examination revealed turbulent flow within the sac (Fig. 1B). Under spinal anaesthesia, the aneurysmal sac was freed from the surrounding tissues with blunt dissection until the plantar fascia was exposed. To gain access to the plantar vasculature, the plantar fascia was vertically incised and the flexor digitorum muscle was retracted medially. After removal of the aneurysmal sac, the injury of the LPA was detected and ligated proximally and distally (Fig. 2). Following the release of the tourniquet, no haemorrhage at the surgical site was observed. Capillary filling of the toes was normal. The hospitalisation period was uneventful and the patient was discharged on postoperative day three.

Discussion While significant bleeding at the time of injury was stated in cases where the mechanism of injury was a cut from glass,2,3,5 all cases with iatrogenic aetiology did not reveal significant bleeding.1,4 In comparison with stepping on a piece of glass, the mechanism of injury in stepping on a construction nail, as in our case, is quite different, in that the disruption of the tissues is less than with glass laceration. Additionally, the penetration depth of the nail cannot be predicted so significant bleeding would not be obvious. In our case, pain was persistent from the time of injury to rupture. While pain is a non-specific symptom, persistence of it was reported by Murakami et al.3 In our opinion, persistence of pain should indicate pseudo-aneurysm or abscess formation. At that point, a simple physical examination looking for pulsatility is essential. While it may be impossible to evaluate all plantar injury cases with duplex ultrasonography, it can provide salient data and accurate evaluation. The time interval from injury to diagnosis ranges from 10 days to eight weeks.1-5 In our opinion, this time gap depends on the symptomatology of the case and/or the paucity of follow up. A pulsatile mass, which was stated to be the presenting symptom in three cases,4,5 is the cornerstone of diagnosis of pseudoaneurysm. In our case rupture occurred in the third week after injury, as in another case.2 Thornton et al. stated that continuous

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Fig. 2. Intra-operative view of the case. (A) The aneurysmal sac was reached under the plantar fascia. (B) The flexor digitorum muscle was retracted medially (#). After excision of the aneurysmal sac, the injury of the LPA was detected. Ligation of the LPA proximally and distally of the injury was performed. Note the arrow indicates lateral plantar nerve.

and intermittent trauma of the plantar region can lead to expansion and rupture of the pseudo-aneurysm.5 In addition to this, ambulation, resulting in compression of the plantar region, could lead to different time intervals for formation of the pseudo-aneurysm and for it to become symptomatic or physically evident. This also makes it difficult to decide how long the follow up of these cases should be. The anatomy of the plantar vasculature was studied in cadaveric dissections and, when compared with the medial plantar artery (MPA), the course of the LPA is more superficial, and the MPA is protected by the musculature. As a consequence, the LPA is more vulnerable to injury.5 Other than being more superficial than the MPA, the LPA coincides with the footprint, which is the weight-bearing plantar region and the first to touch the ground during ambulation. Therefore the LPA is more vulnerable to injury.

Conclusion In cases of plantar injury, significant bleeding at the time of injury depends on the mechanism of injury. Prompt surgical exploration in cases of bleeding and in cases with injury extending beyond the plantar fascia appears to be beneficial. Deciding on the duration of follow up in cases without evident bleeding is a challenge and duplex ultrasonographic evaluation in selected cases may be beneficial. Moreover, a prospective study including larger volumes of cases with plantar injury is needed with regard to symptomatology, influencing factors that contribute to pseudo-aneurysm formation, and differences in time interval for the pseudo-aneurysm to become symptomatic. I thank my colleagues for supporting me in writing this article. This article was presented as a poster presentation (HPP-239) at the 9th International Congress of Update in Cardiology and Cardiovascular Surgery which was held between 21 and 24 March 2013 in Antalya, Turkey.

References 1.

Baeza L, Farrell ED, Salgado CJ. Medial plantar artery pseudoaneurysm following percutaneous pinning for Lisfranc fracture-dislocation. J Am Podiatr Med Assoc 2009; 99(1): 58–60.

Economou P, Paton R, Galasko CS. Traumatic pseudoaneurysm of the

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lateral plantar artery in a child. J Pediatr Surg 1993; 28(4): 626. 3.

pseudoaneurysm after calcaneal osteotomy: a case report. Foot Ankle Int 2006; 27(2): 141–143.

Murakami AM, Chang A, Foo LF. Traumatic lateral plantar artery pseudoaneurysm and the use of time-resolved MR angiography.

Thornton BP, Minion DJ, Quick R, Vasconez HC, Endean ED.

Musculoskelet J Hospital Special Surg 2010; 6(2): 214–218.

Pseudoaneurysm of the lateral plantar artery after foot laceration. J

Ptaszek AJ, Aminian A, Schneider JR, Milos S. Lateral plantar artery

Vasc Surg 2003; 37(3): 672–675.

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Case Report Anesthetic management of a newborn with trisomy 18 undergoing closure of patent ductus arteriosus and pulmonary artery banding Oguzha Arun, Bahar Oc, Mehmet Oc, Ates Duman

Abstract Background: Peri-operative management of infants with trisomy 18 syndrome is challenging due to various congenital cardiac and facial anomalies. Case report: We report the anaesthetic management of a 13-day-old neonate with 1 540 g body weight, undergoing closure of patent ductus arteriosus and pulmonary artery banding. Anaesthesia was induced with sevoflurane, fentanyl and rocuronium. Despite dysmorphic facial features, ventilation and endotracheal intubation were achieved uneventfully. Anaesthesia was maintained with sevoflurane and fentanyl and was uneventful. The patient was transferred to the neonatal ICU intubated and with ventilatory support. The baby was extubated on the second day postoperatively. Conclusion: Our knowledge of the proper anaesthetic technique for children undergoing palliative or corrective surgery is limited. Further case reports will increase our experience in peri-operative management of children with trisomy 18. Keywords: Edwards syndrome, trisomy 18, newborn, anaesthesia Submitted 28/6/13, accepted 6/5/14 Cardiovasc J Afr 2014; 25: e10–e12

www.cvja.co.za

DOI: 10.5830/CVJA-2014-024

Trisomy 18 syndrome, first described by Edwards in 1960, is characterised by an autosomal chromosomal disorder with multiple congenital anomalies.1 The syndrome consists of major and minor anomalies, prenatal and postnatal growth deficiency, and an increased risk of neonatal and infant mortality. It is the second most common autosomal trisomy syndrome after trisomy 21, and the live-birth prevalence of trisomy 18 is estimated at between 1/3 600 and 1/10 000. The overall prevalence is higher Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey Oguzhan Arun, MD, oguzarun@selcuk.edu.tr Bahar Oc, MD Ates Duman, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey Mehmet Oc, MD

(1/2 500–1/2 600) due to the high frequency of foetal loss and pregnancy termination after prenatal diagnosis.2 Structural heart defects occur in over 90% of infants with the syndrome, and the most common cardiac lesions are atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and polyvalvular disease.3 There is some controversy regarding offering cardiac surgery to patients with trisomy 18 because of the elevated risk of mortality during surgery and in the first month of life, and the presence of significant developmental disability in surviving children. If scheduled for surgery, the peri-operative management of these children is challenging. We report on the anaesthetic management of a newborn with Edwards syndrome undergoing closure of patent ductus arteriosus and pulmonary artery banding.

Case report The patient was a 13-day-old girl born at 36 weeks and 4 days of gestation with 1 540 g body weight. She had three healthy sisters and there was not any consanguinity between her parents. Foetal growth retardation, single umbilical artery, and polyhydramnios were detected with ultrasonography during the second and third trimester follow ups. After a successful caesarean section, the first-, fifth-, and tenth-minute APGAR scores were 5, 7 and 10, respectively. At birth she had dysmorphic facial features including microcephaly, malformed ears, micrognathia, redundant skin at the neck, and hypotonia (Figs 1, 2). Karyotype analysis revealed trisomy 18. Structural heart defects such as atrial and ventricular septal defects and patent ductus arteriosus; bilateral hydronephrosis and hydro-ureter in the right kidney, and mega cisterna magna variation in the central nervous system were also present. She was transferred to the neonatal intensive care unit (NICU) and given daily digitalis and antibiotic therapy. Despite two doses of intravenous indomethacin treatment, the patient’s pulmonary pressure increased and her general condition gradually worsened. Echocardiography revealed a left atrium/aorta ratio (LA/Ao) of 1.4, PDA diameter of 3–4 mm, systolic pulmonary arterial pressure of 55 mmHg and enlargement of the left ventricle. Cardiovascular surgeons, paediatric cardiologists and the patient’s parents were invited for consultation. Closure of the PDA and pulmonary banding were expected to reduce pulmonary blood flow and pulmonary artery pressure. The parents were informed that closure of the PDA and pulmonary

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Fig. 1. Dysmorphic face of the baby.

artery banding would be a palliative intervention and the probable survival outcome was not expected to change. The family insisted on the surgical procedure, and according to the local medical laws, the patient was scheduled for surgery. The baby was accepted for anaesthesia as class ASA IV. The parents were informed about the risks and a written consent was obtained. Initial laboratory investigations showed abnormalities such as aspartate aminotransferase (AST) 86 μg/l, indirect bilirubin 7.7 mg/dl, potassium 6.0 meq/l, albumin 2.4 g/dl, and platelet 55 000 per mcl. Pre-operative laboratory investigation was normal. No premedication was given, and the baby was transferred to the operating room with oxygen supply in the transport incubator. After the application of standard non-invasive monitoring, including ECG, SpO2 and NIBP, due to the problem of existing vascular access, general anaesthesia was induced with sevoflurane 8% in 50:50% oxygen in air. We refrained from using a high concentration of oxygen due to the risk of retinopathy of prematurity. Peripheral venous access was achieved with a 24-G iv catheter at the dorsum of the left hand. In order to facilitate endotracheal intubation, 2 mcg/kg of fentanyl and 0.5 mg/kg of rocuronium bromide were given intravenously. After two minutes of ventilation with 100% O2 via a face mask, a laryngoscopy was performed using a size 0 Miller blade. Laryngoscopy revealed grade II Cormach-Lahane, and intubation was achieved easily with a 3.0 mm uncuffed endotracheal tube. Central venous and arterial accesses were achieved via the right femoral route with 4-F double-lumen 5-cm and 22-G singlelumen 5-cm catheters, respectively. Anaesthesia was maintained using controlled ventilation with sevoflurane 1.5–2% in 50:50% oxygen in air; 1 mcg/kg of fentanyl and 0.2 mg/kg of rocuronium were added as needed. Pre-banding invasive blood pressure, which was 66/34 (45) mmHg, increased to 84/48 (60) mmHg following PDA ligation and banding. Also SpO2 decreased from 99 to 95% after banding (FiO2 = 0.5). The operation lasted for 35 minutes without any surgical and/ or anaesthetic problems. After pulmonary banding, 5 mcg/kg/

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Fig. 2. Malformed ear of the baby.

min dopamine infusion was started for haemodynamic support. After an uneventful closure of the PDA and pulmonary artery banding, the baby was transferred to the NICU intubated with mechanical ventilation support. The baby was extubated on the second day postoperatively. She died in the NICU 10 weeks later after an episode of resistant bradycardia despite proper resuscitation.

Discussion The clinical pattern of trisomy 18 is characterised by growth deficiency that starts in the prenatal period; specific craniofacial features such as dolichocephaly, short palpebral fissures, micrognathia, external anomalies of the ears, and redundant skin at the back of the neck; and marked psychomotor and cognitive developmental delay. The presence of major systemic malformations is common, and any organ and system can be affected. Prenatal and early postnatal infant mortality rates are high when compared to the general population.4 The postnatal median survival of children with trisomy 18 is three to 4.5 days; approximately 50% of babies with trisomy 18 live longer than one week and only five to 10% of children survive beyond the first year. One of the major causes of death is cardiac failure due to congenital heart defect-related problems.5 The severity of the cardiac and extra-cardiac lesions is an important factor for the timing and extent of cardiac surgery. Kaneko et al. hypothesised that trisomy 18 patients who underwent intra-cardiac repair had more complicated cardiac lesions and, therefore, mortality rates were increased.6 We believe similarly that postponement or abandonment of the cardiac operation can have a negative impact on survival because of longer exposure to excessive pulmonary blood flow and heart failure. Therefore palliative cardiac surgery may be sufficient to relieve symptoms, prevent heart-related death, and improve life expectancy when performed at an early stage. Due to the limited data regarding anaesthesia techniques in patients with trisomy 18, it is impossible to suggest a

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definite anaesthesia protocol. Anaesthetic goals in paediatric patients with congenital heart disease include preservation of haemodynamic stability with minimal depression of contractility, avoiding arrhythmias, and the maintenance of homeostasis between systemic and pulmonary circulations. One of the routes used for induction in cardiac paediatric patients is via inhalational agents. Although induction with volatile anaesthetics in cardiac paediatric patients can have potentially deleterious effects due to compromised haemodynamic stability, of these agents, sevoflurane appears to have less cardiac depressant effects than other halogenated agents.7 Courreges et al. reported that the anaesthetic management for a Cohen procedure in a girl with Edwards syndrome,8 and longer duration of induction (8 min) with sevoflurane was linked to a change in the ventilation/perfusion ratio caused by the cardiac disease. In our patient, due to the problem of existing vascular access, we chose sevoflurane and performed an uneventful and regular duration of induction. Although pancuronium may be preferred for neuromuscular blockade of patients undergoing cardiac surgeries, it has a slow onset and prolonged duration of action, and is eliminated mainly by renal excretion. Instead we preferred rocuronium, a non-depolarising NMB agent structurally related to pancuronium, based on its rapid onset, intermediate duration of action, and non-histamine release property with a metabolism rate of less than 1%, taken up by the liver and excreted into bile.9 We also preferred fentanyl because it improves the protein metabolism of premature neonates enduring the stress of a PDA and is considered to be the first drug choice in children with pulmonary hypertension.10 In the early postoperative course of congenital cardiac surgery, more than 20% of patients exhibit low cardiac output syndrome (LCOS), characterised by poor systemic perfusion and high vasoactive drug requirements.11 We transferred our patient with a 5-µg/kg/min dopamine infusion to the neonatal ICU.

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of the proper anaesthetic technique for children undergoing palliative or corrective surgery is limited. Further case reports will increase our experience in peri-operative management of children with trisomy 18.

References 1.

Edwards JH, Harnden DG, Cameron AH, Crosse VM, Wolff OH. A new trisomic syndrome. Lancet 1960; 1: 787–789.

Embleton ND, Wyllie JP, Wright MJ, Burn J, Hunter S. Natural history of trisomy 18. Arch Dis Child 1996; 75: 38–41.

Kaneko Y, Kobayashi J, Achiwa I, Yoda H, Tsuchiya K, Nakajima Y, et al. Cardiac surgery in patients with trisomy 18. Pediatr Cardiol 2009; 30(6): 729–734.

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Conclusion Neonates with trisomy 18 are an uncommon subgroup of cardiac surgery patients with a short life expectancy. Our knowledge

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