CVJA Volume 27 Issue 6 by Clinics Cardive Publishing

NOVEMBER/DECEMBER 2016 VOL 27 NO 6 A Lupin Group Company

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Effect of colchicine on tuberculous pericarditis • Hypertension in semi-urban south-western Nigeria • Uncontrolled hypertension in primary healthcare in DRC • Body weight and body fat distribution in black SA women • FTY720 after myocardial ischaemia/reperfusion • SABPA study: cortisol:BDNF and silent ischaemia in black males

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Amloc 5 mg. Each tablet contains amlodipine maleate equivalent to 5 mg amlodipine. Reg. No.: RSA S3 38/7.1/0183. NAM NS2 06/7.1/0011. BOT S2 BOT 0801198. Amloc 10 mg. Each tablet contains amlodipine maleate equivalent to 10 mg amlodipine. Reg. No.: RSA S3 38/7.1/0147. NAM NS2 06/7.1/0012. BOT S2 BOT 0801199. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 25 November 2011. 1) IMS, MAT unit sales, December 2015. 2) Dahlof B, Sever PS, Poulter NR, et al. for the Ascot investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906. 3) Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: A randomised controlled trial. JAMA 2004;292:2217-2226. 4) Department of health website: http//www.doh.gov.za - Accessed 10/03/2016. ACD271/04/2016.

Cardiovascular Journal of Africa . Vol 27, No 6, November/December 2016

WHEN ALL THE PARTS FIT...

• European Society of Cardiology congress update • SASCI/SCTSSA guidelines on TAVI in South Africa

PUBLISHED ONLINE: • Circumflex artery-to-right atrial fistula in a 10-month-old child

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Pharma Dynamics Clopidogrel 75 mg. Each film coated tablet contains clopidogrel hydrogen sulphate equivalent to clopidogrel 75 mg. Reg. No.: RSA S3 42/8.2/0128. NAM NS2 10/7.1/0377. For full prescribing information, refer to the package insert approved by the Medicines Control Council, October 2008. 1) Vs originator clopidogrel. Department of Health website http://www.doh.gov.za – Accessed 09/04/2015. 2) Poponina TM, et al. Current approaches to the prevention of thrombotic complications in patients with acute coronary syndrome without ST-segment elevation. Topical issues of heart and vascular diseases. 2009;4:4-9. (English translation) 3) Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Vascular Medicine 1998;3:257-260. 4) COMMIT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet 2005;366(9497):1607-1621. 5) Sabatine MS, et al. Addition of Clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. New England Journal of Medicine 2005;352:117989. 6) The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine 2001;345:494-502. PDCLC203/06/2015

For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). S4 XARELTO® 10 (Film-coated tablets). Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. S4 XARELTO® 15 and XARELTO® 20 (Film-coated tablets). Reg. No.: XARELTO® 15: 46/8.2/0111; XARELTO® 20: 46/8.2/0112. Each film-coated tablet contains rivaroxaban 15 mg (XARELTO® 15) or 20 mg (XARELTO® 20). PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM.01.2016.1265 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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

Vol 27, No 6, NOVEMBER/DECEMBER 2016

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

From the desk 335 Measuring publication impact, and publishing and funding models Paul Brink

EditoriaL 336 The importance of perseverance, pilot studies and the search for effective adjuvant therapies in the management of tuberculous pericarditis A Mutyaba • M Ntsekhe

Cardiovascular Topics 338 Should patients undergo ascending aortic replacement with concomitant cardiac surgery? M Yalcin • KD Tayfur • M Urkmez 345 Procedural and one-year clinical outcomes of bioresorbable vascular scaffolds for the treatment of chronic total occlusions: a single-centre experience E Özel • A Taştan • A Öztürk • EE Özcan • B Kilicaslan • Ö Özdogan 350 A prospective investigation into the effect of colchicine on tuberculous pericarditis JJ Liebenberg • CJ Dold • LR Olivier 356 Epidemiology and patterns of hypertension in semi-urban communities, south-western Nigeria MA Olamoyegun • SO Iwuala • SO Asaolu • R Oluyombo 361 Uncontrolled hypertension among patients managed in primary healthcare facilities in Kinshasa, Democratic Republic of the Congo TM Kika • FB Lepira • PK Kayembe • JR Makulo • EK Sumaili • EV Kintoki • JR M’Buyamba-Kabangu 367 Determinants of change in body weight and body fat distribution over 5.5 years in a sample of free-living black South African women S Chantler • K Dickie • LK Micklesfield • JH Goedecke 375 The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/reperfusion D van Vuuren • E Marais • S Genade • A Lochner

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

Editors

SUBJECT Editors

Editorial Board

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

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

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

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

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

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

387

Cortisol:brain-derived neurotrophic factor ratio associated with silent ischaemia in a black male cohort: the SABPA study CE Schutte • L Malan • JD Scheepers • W Oosthuizen • M Cockeran • NT Malan

Congress Report

Vol 27, No 6, NOVEMBER/DECEMBER 2016

CONTENTS

392 European Society of Cardiology congress update AJ Dalby

Consensus Guidelines 399 SASCI/SCTSSA joint consensus statement and guidelines on trans-catheter aortic valve implantation (TAVI) in South Africa J Scherman • H Weich

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

e1 A circumflex coronary artery-to-right atrial fistula in a 10-month-old child E Şişli • MF Ayık • M Akyüz • M Dereli • Y Atay

The management and staff of Clinics Cardive Publishing (publishers of the Cardiovascular Journal of Africa and the South African Journal of Diabetes & Vascular Disease) take this opportunity to thank you for your loyal support during 2016, and we look forward to being of service during 2017. Wishing you and your family happy holidays and a new year filled with prosperity and success.

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The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month.

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335

From the Desk Measuring publication impact, and publishing and funding models The impact factor, or, more correctly, the journal impact factor [JIF; Thompsons Reuters (ISI)] has featured in previous reports of the Cardiovascular Journal of Africa (CVJA).1-3 As expected, it has been steadily rising and is now at 1.022 (2015). This is not to be scoffed at. Of the 14 listed medical journals in Africa, it is third to the South African Medical Journal (SAMJ; JIF = 1.5). Similarly, in another major database, Scopus, it ranks at number 184 out of 333 journals of cardiovascular medicine globally. Within Africa it is the only cardiovascular journal indexed by Thompson Reuters and also by Scopus. These statistics are based on citations to articles that appear in journals, and formulae that relate the number of citations to published articles in a journal over a given time period,4 and are part of the more extensive ways of evaluating scientific output under the umbrella term bibliometrics. Historically, authors tied their status to that of the journals in which they published, and the higher the JIF, the higher the status of an author. However, similar exercises can also be performed for an article impact and individual impact (H factor). This is very nicely set out in the article by Agarwal et al., where using the first author as an example, the gamut of journal, article and individual-level citation-based statistics are calculated and discussed.4 However, although the journal is progressing well, there are significant challenges, and as a medico-scientific publication, the CVJA receives many more submissions than it accepts for publication. These are turbulent times in the publishing world and one is reminded of the words in Bob Dylan’s song (1964), “The times they are a-changin’, … you better start swimmin’ or you’ll sink like a stone, for the times they are a-changin’.” Globally, the reading of printed versions of newspapers and scholarly articles has declined, particularly of the latter, in favour of the internet. However, advertisements in printed journals are a very important source of income. Furthermore, concomitant with these changes in printdistribution has been the Open Access (OA) movement, which believes that the products of science should be freely available to all and easily attainable since publishing on the internet, superficially at least, is cheap. However, even if articles are not printed on paper, there are many processes involved in publishing. Some of these include the handling of submissions, refereeing of submitted articles (traditionally free of charge by fellow scientists), editing, proof reading, loading onto a website and management of the website. Therefore personnel and outsourcing functions become necessary.5 This has led to public-funded research reports, with universities and some private organisations requiring scientific content to be freely available on publication on the internet. This removes subscription incentives. In addition, being accepted into PubMed Central (PMC) also requires content to be made freely available. PMC, as pointed out in a previous article, may effectively steal traffic.3 Targeting articles of interest and finding them on PMC does not even bring the searcher to the website of the journal. So, this becomes a disincentive to both subscription to journals and to buying single articles.3 Print has rapidly been making way for a digitised form of presentation and the CVJA has kept pace with this trend.6 The journal has also followed suit with OA, it has been accepted by PMC, and its content is freely available in other ways.2,3 To make up for the loss of income from reducing printing, for a fee, articles are published online ahead of publication. Many authors are making use of this option, but it does not adequately cover the loss of income.

This is an appropriate time to consider the role of countrybased or territorial journals; in this case the CVJA, which is the official journal for the Pan-Africa Society of Cardiology. Important functions of a medico-scientific journal are to publish quality, peerreviewed, original scientific articles and good review articles. Credible reviews are very important as we are competing with predatory journals that solicit articles with a promise of quick (mostly superficial) reviews and acceptance of almost all submissions.7 Other important functions for societies are the publishing of abstracts from congresses, and providing a platform for exchange of letters, debates, dissemination of policy, guidelines, community news, and news on appliances and pharmaceutical developments. How then should medico-scientific journals be funded in this changed environment? Most OA journals now require an articleprocessing charge (APC).8 This is the so-called ‘author-pay’ model. Even journals that remained propriety-based with paid-for content, such as the New England Journal of Medicine (NEJM) and Circulation, will make content available on an OA basis if a research sponsor requires it. Consequently, we now see three types of journals in terms of availability of content, namely, pure OA, hybrid (commercial content-for-sale with some OA articles) and pure content-for-sale journals. With regard to viewing the content, we see it as pure internet, hybrid internet and paper-based content and, nowadays, the almost extinct pure paper-based distribution of content. APCs average at about US$2 000 while hybrid journals such as Circulation and NEJM average at about US$3 000 per article if it has to be OA.8 The CVJA currently requires a submission fee to cover at least the submission costs. This fixed fee is because every submission on the Editorial Manager system costs money, whether the article is accepted or not. Most OA journals just request an APC on acceptance of a manuscript for publishing. CVJA will have to follow this trend, in line with other journals, or the route of maintaining the submission fee, and add on an APC. Paul Brink Department of Medicine, University of Stellenbosch, South Africa

References 1. Brink AJ. Impact factor: use and abuse. Cardiovasc J Sth Afr 2004; 15(1): 5–7. 2. Brink AJ. New impact factor and PubMed Central service from the Cardiovascular Journal of Africa. Cardiovasc J Afr 2012; 23(7): 364. 3. Brink PA. Article visibility: journal impact factor and availability of full text in PubMed Central and open access. Cardiovasc J Afr 2013; 24(8): 295–296. 4. Agarwal A, Durairajanayagam D, Tatagari S, Esteves SC, Harlev A, Henkel R, et al. Bibliometrics: tracking research impact by selecting the appropriate metrics. Asian J Androl 2016; 18(2): 296–309. 5. Bjork B-C, Shen C, Laakso M. A longitudinal study of independent scholar-published open access journals. Peer J 2016; 4: e1990. 6. Brink AJ. CVJSA e-journal publication. Cardiovasc J Sth Afr 2003; 14(2): 57–58. 7. Vinny PW, Vishnu VY, Lal V. Trends in scientific publishing: Dark clouds loom large. J Neurol Sci 2016; 363: 119–120. 8. Solomon F, Bjork B-C. Article processing charges for open access publication – the situation for research intensive universities in the USA and Canada. Peer J 2016; 4: e2264.

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Editorial The importance of perseverance, pilot studies and the search for effective adjuvant therapies in the management of tuberculous pericarditis Arthur Mutyaba, Mpiko Ntsekhe

Tuberculous pericarditis remains one of the most feared manifestations of extra-pulmonary tuberculosis (TB). The relatively high morbidity and mortality rates associated with the condition arise via two distinct mechanisms. The first is related to the combined impact of the virulence of Mycobacterium tuberculosis (MTb) itself and TB-induced dysregulated immune responses in both HIV-positive and -negative individuals, resulting in disseminated infection, multi-organ involvement, and prolonged acute infection.1 The second mechanism is related to compressive pericardial disease (cardiac tamponade, effusive constrictive pericarditis and constrictive pericarditis), which can cause significant compromise of cardiovascular function. Prior to the advent of modern four-drug anti-tuberculous regimens, tuberculosis-related mortality was almost universal in patients with pericarditis. With the use of modern combination anti-tuberculous therapy, which is able to achieve pericardial sterilisation, prevent dissemination and cure tuberculous infection, the mortality rate had fallen to below 10% by the 1980s. Given that anti-tuberculous therapy is now widely available and used almost empirically, the residual morbidity and mortality rate is driven predominantly by the second dreaded mechanism discussed above. Heart failure, haemodynamic collapse and death from reaccumulation of compressive effusion, constrictive pericarditis and effusive constrictive pericarditis occur in up to 30% of cases.2,3 Factors such as the size of effusion at presentation, whether or not patients underwent pericardiocentesis at onset, the degree of immunocompromise from HIV, and use of adjuvant therapies such as corticosteroids have all been shown, albeit inconsistently, to influence this composite complication rate in various studies.3–6 To date, corticosteroids remain the most studied adjuvant therapy to reduce the rates of post-tuberculous constriction and other compressive pericardial syndromes. In the largest of these studies, the IMPI trial, a six-week tapered course

Division of Cardiology, University of Cape Town Medical School, Cape Town, South Africa Arthur Mutyaba, MB ChB, MMed, FCP (SA) Mpiko Ntsekhe, BA, MD, PhD, FCP (SA), Cert Cardio (SA), FACC, mpiko.ntsekhe@uct.ac.za

of prednisolone added to four-drug anti-tuberculous therapy reduced the incidence of pericardial constriction in both HIV-positive and -negative patients, compared to placebo, by approximately 50%.3 There has been much discussion and debate about the role of corticosteroids in this condition since the completion of the IMPI trial, particularly given the finding that HIV-infected patients had an increased risk of malignancy with the use of prednisolone. With this background in mind, the study by Liebenberg et al., published in this issue of the journal (page 350), is a welcome attempt by colleagues who work in an environment where they are still confronted with the scourge of tuberculous pericarditis, to test whether an adjuvant medical intervention other than steroids may be effective. Drawing from the effectiveness of colchicine in preventing recurrences of acute idiopathic pericarditis, as demonstrated in the COPE trial,7 they sought to test whether the same agent added to standard anti-tuberculous therapy would significantly reduce the occurrence of pericardial constriction in patients with definite or probable tuberculous pericarditis, compared to placebo. Thirty-three HIV-positive patients with definite or probable tuberculous pericarditis were randomly assigned to receive 1 mg per day of colchicine over six weeks (versus placebo) in addition to standard four-drug anti-tuberculous therapy for six months and oral steroids over eight weeks. Anti-retroviral therapy was available to all participants. Pericardial constriction was assessed by echocardiography after a follow-up period of 16 weeks in 21 participants. Five participants developed echocardiographic features of constriction with no demonstrable difference between the intervention and placebo arms of the study (relative risk 1.07, 95% CI: 0.46–2.46, p = 0.88). While the focus of the authors’ conclusions and discussion centres around the absence of a significant efficacy outcome with colchicine, rather than despair about yet another negative study in TB pericarditis, it is important to keep in mind what this study actually tested and teaches us. The first lesson is about the importance of perseverance for clinician researchers. Just because steroids have been shown not to work, Liebenberg and colleagues have not folded their arms and given up trying to find an effective intervention to help their patients with this condition. Their perseverance and that of others reminds us that there are in fact various other medical interventions that have the potential to be efficacious adjunctive therapies in tuberculous pericarditis but are as yet untested in large-scale clinical trials. The use of

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

intra-pericardial fibrinolytic therapy to facilitate pericardial drainage is one such technique,8,9 which has been touted as potentially effective at reducing constriction by breaking up fibrous adhesions, and will be tested in the soon-to-be-launched second investigation into the management of pericarditis trial (IMPI-2). Angiotensin convertase enzyme inhibitors are capable of activating anti-fibrotic cytokines within the pericardium and may also hold promise.10,11 Finally, we should also applaud the on-going attempts to better understand the pathobiology of tuberculous pericarditis and its complications through highquality basic science research that will hopefully identify new targets for adjuvant therapies.12-14 Secondly, it is also important to emphasise that, strictly speaking, this study by Liebenberg et al. is by no means a negative study. Small pilot or vanguard studies such as this are not designed to provide definitive answers on efficacy; in fact, if they do, it’s likely that there is a type II or similar error. The main objectives of such studies, even if unstated, are actually to make sure that important design, method and safety issues necessary to successfully conduct an appropriately sized study are in place. Important questions that often need addressing include: is the recruitment rate achieved in the pilot study adequate to reach calculated sample sizes in a reasonable time frame if a definitive study is conducted; is the investigational drug free of harmful side effects and safe enough in this unique condition to be tested on hundreds or thousands of patients; is the infrastructure and set up required to not lose any patients during follow up adequate; are the tools such as those for data collection and storage adequate; and finally, are the resources available and allocated for conducting a full study appropriate to ensure success? To this end the authors have gone some way in providing at least some of the required answers. On the face of it, a large, simple, randomised trial that is feasible and safe, and that would require multiple collaborating sites and mitigation strategies to prevent loss to follow up and completion within acceptable time frames is possible. In conclusion, the authors should be congratulated for continuing to fight the good fight and demonstrating that we in the developing world must never lose sight of the principle that where there are unresolved clinical conditions unique to our environment, if we who face the problem do not try to find the solutions, no one else will do it for us. They have reminded us that it is imperative for us to continue to believe that there is no reason why with hard work, dedication and application, we cannot find appropriate solutions to improve the lot of our patients. We hope their demonstrated perseverance remains, and look forward to the news of a full-scale, large, randomised, controlled trial with them at the helm.

337

References 1.

Pasipanodya JG, Mubanga M, Ntsekhe M, et al. Tuberculous pericarditis is multibacillary and bacterial burden drives high mortality. EBioMedicine 2015; 2(11): 1634–1639.

Mayosi BM, Wiysonge CS, Ntsekhe M, et al. Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa. S Afr Med J 2008; 98(1): 36–40.

Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014; 371(12): 1121–1130.

Ntsekhe M, Wiysonge CS, Gumedze F, et al. HIV infection is associated with a lower incidence of constriction in presumed tuberculous pericarditis: a prospective observational study. PLoS One 2008; 3(6): e2253.

Strang JI, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987; 2(8573): 1418–1422.

Strang JI, Kakaza HH, Gibson DG, et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988; 2(8614): 759–764.

Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112(13): 2012–2016.

Augustin P, Desmard M, Mordant P, et al. Clinical review: intrapericardial fibrinolysis in management of purulent pericarditis. Crit Care 2011; 15(2): 220.

Kakia A, Wiysonge CS, Ochodo EA, Awotedu AA, Ristic AD, Mayosi BM. The efficacy and safety of complete pericardial drainage by means of intrapericardial fibrinolysis for the prevention of complications of pericardial effusion: a systematic review protocol. Br Med J Open 2016; 6(1): e007842.

10. Ntsekhe M, Matthews K, Wolske J, et al. Scientific letter: Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: implications for pathogenesis and prevention of pericardial constriction. Heart 2012; 98: 1326-1328. 11. Mnguni AT, Engel ME, Borkum MS, Mayosi BM. The effects of angiotensin converting enzyme inhibitors (ACE-I) on human N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels: A systematic review and meta-analysis. PLoS One 2015; 10(12): e0143338. 12. Zumla A, Maeurer M, Moll G, Mayosi BM. Host-directed therapies for tuberculous pericarditis. Int J Infect Dis 2015; 32: 30–31. 13. Manjunatha UH, Mahadevan S, Visweswariah SS, Nagaraja V. Monoclonal antibodies to mycobacterial DNA gyrase A inhibit DNA supercoiling activity. Eur J Biochem 2001; 268(7): 2038–2046. 14. Glatman-Freedman A, Martin JM, Riska PF, Bloom BR, Casadevall A. Monoclonal antibodies to surface antigens of Mycobacterium tuberculosis and their use in a modified enzyme-linked immunosorbent spot assay for detection of mycobacteria. J Clin Microbiol 1996; 34(11): 2795–2802.

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Cardiovascular Topics Should patients undergo ascending aortic replacement with concomitant cardiac surgery? Mihriban Yalcin, Kaptan Derya Tayfur, Melih Urkmez

Abstract Aim: To determine whether concomitant surgery is a predictor of mortality in patients undergoing surgery for ascending aortic aneursym. Methods: Ninety-nine patients who underwent ascending aortic aneursym surgery between January 2010 and January 2015 were included in this study. Nineteen patients underwent ascending aortic replacement (RAA) only, 36 underwent aortic valve replacement (AVR) and RAA, 25 underwent coronary artery bypass grafting (CABG) and RAA, 11 underwent the Bentall procedure, and eight underwent AVR, CABG and RAA. Results: Depending on the concomitant surgery performed with RAA, the mortality risk increased 2.25-fold for AVR, 4.5-fold for CABG, 10.8-fold for AVR + CABG and four-fold for the Bentall procedure, compared with RAA alone. Conclusion: Concomitant cardiac surgery increased the mortality risk in patients undergoing RAA, but the difference was not statisticaly significant. Based on these study results, patients undergoing cardiac surgery, with a pre-operative ascending aortic diameter of over 45 mm, should undergo concomitant RAA.

Keywords: ascending aortic aneurysm, ascending aortic replacement, concomitant cardiac surgery, mortality

Methods

Submitted 27/12/15, accepted 8/3/16 Published online 12/4/16 Cardiovasc J Afr 2016; 27: 338–344

www.cvja.co.za

DOI: 10.5830/CVJA-2016-026

Ascending aortic dilatation is the most common cardiac condition requiring surgery. Dilatation causes aneursym, dissection and rupture, and aortic valve insufficiency.1 The aorta is aneurysmatic when there is a 50% increase in its normal diameter. Underlying physiological circumstances, body surface

Cardiovascular Surgery Department, Ordu State Hospital, Ordu, Turkey Mihriban Yalcin, MD, mihribandemir33@hotmail.com Kaptan Derya Tayfur, MD Melih Urkmez, MD

area and the patient’s age are the main determinants of the size of the ascending aorta.2 Valvular or coronary cardiac diseases frequently occur with ascending aortic aneurysm. Indications for surgery depend on the underlying pathology or when dissection or rupture occur. Although there is weak evidence, the current ACC/ AHA guidelines recommend concomitant replacement of a significantly enlarged ascending aorta at the time of cardiac surgery.3 Many other factors, including patient age, co-morbidities, type of valve prosthesis and surgeon-specific results must be considered when determining whether or not to replace the aorta.4 If the aortic valve leaflets, the annulus and the sinuses of Valsalva are intact, the aneurysm is replaced with a simple supracoronary Dacron tube graft. If the aortic valve is diseased but the aortic sinuses and annulus are normal, then a Wheat procedure [aortic valve replacement (AVR) and a separate ascending aortic replacement (RAA)] are performed. In cases with root dilation, a modified Bentall procedure (replacement of a vascular tube graft with a biological or mechanical aortic valve prosthesis and re-insertion of the graft into the coronary ostia) is the gold standard. This retrospective study aimed to establish the effect of concomitant cardiac surgeries on mortality rates in patients undergoing ascending aorta surgery.

Between January 2010 and January 2015, 99 patients underwent surgery for RAA at the Ordu State Hospital. We retrospectively reviewed the medical records of these patients. Those who underwent either mitral valve replacement (MVR) or any other cardiac surgery, or patients with aortic dissection were excluded. Information about age, gender, ejection fraction (EF), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and peripheral arterial disease (PAD) was collected. The diameter of the ascending aorta, aortic cross-clamp time, cardiopulmonary bypass time, total circulatory arrest time, the type of cardiac surgery that was performed, use of intra-aortic balloon pump (IABP) support, and whether or not positive inotropic support was required were also evaluated. Mechanical ventilation time, total drainage amount, duration of intensive care and hospital stay, and death were evaluated (Tables 1, 2). There were 39 female and 60 male patients. The mean size of the ascending aorta in our patients was 52.28 ± 5.78 mm in females and 52.30 ± 5.36 mm in males. The mean age was 65.23 ± 8.49 years for females and 65.05 ± 9.27 years for males.

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The decision to replace the ascending aorta was based on the aortic diameter. Patients with an ascending aortic diameter of more than 45 mm mostly underwent concomitant RAA. In our study, 80 of 99 patients underwent multiple operations. Nineteen patients underwent RAA only, 36 underwent AVR and RAA, 25 underwent coronary artery bypass grafting (CABG) and RAA, 11 underwent a Bentall procedure, and eight patients underwent AVR, CABG and RAA. AVR + RAA was performed in patients who had aortic valve stenosis or aortic valve regurgitance and a dilated ascending aorta with normal aortic sinuses. CABG + RAA was performed in patients who had coronary artery disease (CAD; coronary artery stenosis ≥ 70%). The Bentall procedure was performed in patients who had aortic root aneurysm. If the ascending aorta was dilated and the aortic root was normal, we replaced the aortic valve and the supracoronary ascending aorta. If the non-coronary sinus of valsalva was dilated, we replaced only the non-coronary sinus by tailoring the supracoronary graft to extend down to the aortic annulus, but the left and right sinuses and the coronary arteries were left intact. For patients with an aortic root abnormality and a dilated ascending aorta, the Bentall procedure is appropriate. All surgeries were performed via a median sternotomy incision. Cardiopulmonary bypass (CPB) was established via right axillary cannulation and a single venous cannula, and antegrade and retrograde blood cardioplegia was performed. All ascending replacements were performed under deep hypothermic circulatory arrest with a nasopharyngeal temperature of 18 ± 1°C. Antegrade cerebral perfusion was used in all patients. Replacement of the ascending aorta was performed using a woven Dacron prosthetic graft (AlboGraft LeMaitre Vascular). If concomitant surgical procedures were required, distal coronary anastomosis and concomitant surgical procedures were performed before the replacement of the ascending aorta. The proximal anastomosis was performed during aortic crossclamping and the distal anostomosis was performed under deeep hypothermic circulatory arrest. After appropriate blood pressure and cardiovascular stability were ensured, CPB was ended. Patients were taken to the intensive care unit (ICU) during the postoperative period.

mean ± standard deviation for the numerical variables (e.g. age, diameter of ascending aorta) or as the number and percentage of cases for categorical variables (e.g. mortality, COPD, DM). Univariate logistic regression analysis was performed to assess the main factors associated with mortality. Variables in univariate analysis that were associated with mortality [p < 0.20 in the likelihood ratio test (−2LL)] were selected for multivariate logistic regression analyses. All identified individual variables were analysed using a manual backward elimination procedure, starting with a full multivariate logistic regression model. Variables were kept in the model if the −2LL ratio test of the model with and without the variable was significant (p < 0.05). The odds ratios (OR) are presented with 95% confidence intervals (95% CI). The final individual model was tested using the Hosmer–Lemeshow test for goodness-of-fit.

Results In the patients who died, age, ascending aortic diameter, crossclamp time, CPB time, total circulatory arrest time and ICU stay were longer, bleeding was greater and EF was lower than the patients who survived (Table 1). The extubation time was 17.2 ± 6.13 hours and patients were discharged after 7.30 ± 2.41 days. Patients who died had COPD (20%), PAD (20%) and DM (24%), and required inotrope use (24.6%) and IABP support (60%) ( Table 2). Table 3 shows descriptive statistics for patients who underwent RAA alone and additional surgery. Patients who underwent AVR + CABG were older (71.3 ± 12.74 years) than those in the other groups. The ascending aortic diameter was larger in patients who underwent RAA alone (56.2 ± 4.03 mm) compared to the other groups. CPB time and extubation time in patients who underwent the Bentall procedure (229.5 ± 82.79 minutes, 15.6 ± 11.36 hours, respectively) were longer and there was more bleeding (716.7 ± 557.9 ml) compared to the other patients. Table 4 shows that mortality was 5.3% in patients who underwent RAA alone, 11.1% in patients who underwent AVR, Table 2. Frequencies and percentages [n (%)] of the examined variables for mortality

Statistical analysis Statistical analysis was performed using SPSS 17.0 for Windows software (SPSS Inc, Chicago, IL, USA). Data are presented as the

Table 1. Descriptive statistics (mean ± standard deviation) of the examined variables for mortality Mortality Variables

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Variables

Mortality No

Yes

76 (85.4)

13 (14.6)

Yes

8 (80.0)

2 (20.0)

80 (85.1)

14 (14.9)

Yes

4 (80.0)

1 (20.0)

COPD

PAD

Yes

Age (year)

64.3 ± 8.46

70.6 ± 9.98

65 (87.8)

9 (12.2)

Aortic diameter (mm)

52.4 ± 5.31

51.8 ± 6.79

Yes

19 (76.0)

6 (24.0)

EF (%)

55.8 ± 9.75

47.6 ± 11.62

Inotrope use

99.3 ± 41.16

139.1 ± 61.26

41 (97.6)

1 (2.4)

CPB time (min)

165.3 ± 59.83

193.8 ± 65.32

Yes

43 (75.4)

14 (24.6)

TCA time (min)

25.6 ± 7.34

29.2 ± 7.05

ICU stay (days)

2.65 ± 1.31

10.0 ± 14.03

80 (89.9)

9 (10.1)

725.0 ± 381.09

Yes

4 (40.0)

6 (60.0)

Cross-clamping time (min)

Bleeding (ml)

501.8 ± 344.57

CBP: cardiopulmonary bypass, EF: ejection fraction, ICU: intensive care unit , TCA: total circulatuar arrest.

IABP

COPD: chronic obstructive pulmonary disease, DM: diabetes mellitus, PAD: peripheral arterial disease, IABP: intra-aortic balloon pump.

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20% in patients who underwent CABG, 37.5% in patients who underwent AVR + CABG, and 18.2% in patients who underwent the Bentall procedure. The most frequently observed co-morbidities were DM (48%) in patients who underwent CABG, COPD (12.5%) in patients who underwent AVR + CABG, and PAD (25%) in patients who underwent AVR + CABG. All patients (100%) who underwent the Bentall procedure required inotrope, while 25% of patients who underwent AVR + CABG required IABP support. Univariate logistic regression analysis showed that the mortality risk was increased 2.321-fold in patients ≥ 70 years of age and 1.36-fold in men. The mortality risk was increased 2.25-fold in patients requiring RAA + AVR, 4.5-fold in patients requiring RAA + CABG, 10.8-fold in patients requiring RAA + AVR + CABG, and four-fold in patients requiring the Bentall procedure. Patients with COPD were at 1.462 times higher risk of mortality, those with PAD were at 1.429 times higher risk and those with DM were at 2.281 times higher risk. Patients requiring inotropic drugs were at 13.329 times higher risk and those requiring IABP were at 13.333 times higher risk of mortality (Table 5). Multivariate logistic regression analysis final model results showed that the mortality risk was 9.779-fold higher in patients who required inotropic drugs and 9.029-fold higher in patients who required IABP compared to those who did not (Table 6). Five variables were included in the initial multivariate logistic regression model and three variables (gender, COPD, PAD) were excluded, based on the likelihood ratio test (p < 0.20). In the final model, the following were identified as being associated with mortality: inotrope (OR, 9.779) and IABP (OR, 9.029) (Table 6). The final model fit was tested using the Hosmer–Lemeshow test. The H–L statistic had a significance of 0.889, which means that it was not statistically significant and therefore our model was a good fit.

Diameter, connective tissue disease (e.g. Marfan or Loeys– Dietz syndrome), pregnancy, bicuspid aortic valve (BAV), familial history of thoracic aortic aneurysm and dissection, hypertension, gender, and aortic growth are factors that may influence the need for surgery.5 Size of the aneurysm is considered the most important independent factor in the decision for a patient to undergo surgery. The required indications for RAA are acute dissection, rupture and intramural haematoma.6 Elective indications are generally prophylactic in nature, and they aim to prevent progression of aortic insufficiency and aortic rupture or dissection. Aortic aneurysms are usually asymptomatic, with slow growth and they may develop distal thromboembolism, rapid expansion and rupture, with catastrophic complications. The law of Laplace predicts that, as the aneurysm size increases, wall tension also rises.7 Dissections have a high early mortality rate of up to 1–2% per hour. In patients with atherosclerotic aneurysms of the ascending aorta, rupture is the most common cause of death.8 Joyce et al. (1964) found that approximately 50% of patients with thoracic

Discussion Ascending aortic aneurysms start from the aortic valve and extend to the innominate artery, and they generally require openheart surgery. Increasing age, hypertension, smoking, genetics, atherosclerosis and connective tissue disorders are aetiological factors that are associated with ascending aortic aneurysms.5 Medical therapy or various surgical interventions may reduce the risk factors.

Table 4. Frequencies and percentages [n (%)] of the examined variables for additional operations Additional operations No

AVR

CABG

AVR + CABG

Bentall

18 (94.7)

32 (88.9)

20 (80.0)

5 (62.5)

9 (81.8)

Yes

1 (5.3)

4 (11.1)

5 (20.0)

3 (37.5)

2 (18.2)

17 (89.5)

35 (94.6)

22 (88.0)

7 (87.5)

9 (90.0)

Yes

2 (10.5)

2 (5.4)

3 (12.0)

1 (12.5)

2 (10.0)

16 (84.2)

37 (100.0)

25 (100.0)

6 (75.0)

11 (100.0)

Yes

3 (15.8)

0 (0.0)

2 (25.0)

0 (0.00)

17 (89.5)

33 (89.2)

13 (52.0)

6 (75.0)

6 (54.5)

Yes

2 (10.5)

4 (10.8)

12 (48.0)

2 (25.0)

5 (45.5)

10 (52.6)

22 (61.1)

9 (36.0)

1 (12.5)

0 (0.0)

Yes

9 (47.4)

14 (38.9)

16 (64.0)

7 (87.5)

11 (100.0)

19 (100.0)

34 (94.4)

21 (84.0)

6 (75.0)

9 (81.8)

Yes

0 (0.00)

2 (5.6)

4 (16.0)

2 (25.0)

2 (18.2)

Variables Mortality

COPD

PAD

Inotrope use

IABP

COPD: chronic obstructive pulmonary disease, DM: diabetes mellitus, PAD: peripheral arterial disease, IABP: intra-aortic balloon pump.

Table 3. Descriptive statistics (mean ± standard deviation) of the examined variables for additional operations Additional operations Variables

AVR

CABG

Age (year)

64.5 ± 8.68

64.3 ± 8.17

67.7 ± 5.65

Aortic diameter (mm)

56.2 ± 4.03

51.5 ± 5.59

Cross-clamping time (min)

80.9 ± 48.46

97.2 ± 34

TCA time (min)

26.6 ± 4.88

EF (%)

58.6 ± 8.42

AVR+CABG 71.3 ± 12.74

49.6 ± 3.57

52.3 ± 7.85

54.3 ± 5.48

104.0 ± 29.43

167.8 ± 63.04

130.7 ± 53.87

24.6 ± 8.10

29.4 ± 8.70

22.6 ± 3.50

25.5 ± 5.07

55.4 ± 11.78

54.0 ± 9.81

50.4 ± 11.96

144.0 ± 54.52

164.5 ± 44.28

159.6 ± 59.21

Extubation time (hour)

17.4 ± 4.41

15.2 ± 5.12

16.9 ± 9.21

11.4 ± 10.47

ICU stay (day)

2.11 ± 0.46

4.06 ± 7.10

5.08 ± 8.04

2.5 ± 2.07

Bleeding (ml)

373.7 ± 175.1

533.8 ± 355.7

541.3 ± 259.7

6.89 ± 1.79

6.08 ± 2.98

6.04 ± 3.48

CPB time (min)

Discharge from hospital

Bentall 58.7 ± 11.36

CBP: cardiopulmonary bypass, EF: ejection fraction, ICU: intensive care unit, TCA: total circulatory arrest.

202.3 ± 61.6

700.0 ± 539.3 4.57 ± 4.5

52.1 ± 4.88 229.5 ± 82.79 15.6 ± 11.36 3.36 ± 2.80 716.7 ± 557.9 8 ± 4.82

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Table 5. Potential risk factors associated with mortality in the univariate logistic regression equation Variable

Total no

Prevalence (%)

Constant

95% CI for exp (B) B

Wald

Sig

Exp (B)

Lower

–1.72

0.280

37.774

< 0.001

0.179

Upper

0.842

0.572

2.162

0.141

2.321

0.756

7.127

0.307

0.591

0.271

0.603

1.360

0.427

4.332

Age (years) < 70

11.6

≥ 70

23.3

12.8

16.7

Gender Female Male Additional operations No

5.3

4.815

0.307

AVR

11.1

0.811

1.156

0.492

0.483

2.250

0.233

21.694

CABG

20.0

1.504

1.143

1.733

0.188

4.500

0.479

42.248

AVR+CABG

37.5

2.380

1.261

3.564

0.059

10.800

0.913

127.754

Bentall

18.2

1.386

1.291

1.153

0.283

4.000

0.319

50.229

0.379

0.846

0.201

0.654

1.462

0.279

7.667

0.357

1.155

0.095

0.757

1.429

0.149

13.741

0.824

0.588

1.966

0.161

2.281

0.720

7.221

2.591

1.058

6.001

0.014

13.349

1.679

106.145

2.590

0.735

12.419

< 0.001

13.333

3.157

56.312

COPD No

14.6

Yes

20.0

14.9

Yes

20.0

PAD

DM No

12.2

Yes

24.0

Inotrope use No

2.4

Yes

24.6

IABP No

10.1

Yes

60.0

AVR: aortic valve replacement, CABG: coronary arterial bypass grafting, COPD: chronic obstructive pulmonary disease, DM: diabetes mellitus, PAD: peripheral arterial disease, IABP: intra-aortic balloon pump.

aortic aneurysms died within five years of the diagnosis.9 Aortic surgeries are complex and have high morbidity and mortality rates. The risks of surgery include paraplegia, stroke, bleeding and death; however rupture, dissection and death may also occur when the aneurysm is left unoperated. If no intervention is done at the time of cardiac surgery, the aneurysm may develop and rupture, and will need a second

open-heart procedure, with additional technical challenges and complications. An initial concomitant surgery may increase the operative risks but protects patients from long-term aneurysmatic complications. Replacement of ascending aortic aneurysms often requires significant additional surgery, such as CABG and AVR. Severe aortic valve disease is occasionally associated with dilation of the

Table 6. Potential risk factors associated with mortality in the multivariate logistic regression equation 95% CI for exp (B) Variables

Wald

Sig

Exp (B)

Lower

Upper

STEP 1a (beginning model) Constant

1.587

10.844

0.001

0.005

1.146

0.732

2.452

0.117

3.144

0.750

13.190

AVR

0.945

1.246

0.575

0.448

2.573

0.224

29.606

CABG

0.540

1.272

0.180

0.671

1.716

0.142

20.752

AVR+CABG

1.013

1.434

0.499

0.480

2.755

0.166

45.761

Bentall

0.088

1.426

0.004

0.951

1.092

0.067

17.856

DM (yes)

0.573

0.767

0.559

0.455

1.774

0.395

7.971

Inotrope use (yes)

2.510

1.134

4.899

0.027

12.308

1.333

113.645

IABP (yes)

2.173

0.881

6.091

0.014

8.789

1.564

49.379

0.021

Age (≥ 70 years)

–5.23

Additional operations

STEP 4 (final model) 1.028

14.154

< 0.001

Inotrope use (yes)

2.280

1.078

4.471

0.034

9.779

1.181

80.947

IABP (yes)

2.200

0.770

8.177

0.004

9.029

1.998

40.797

Constant

–3.87

Variable(s) entered on step 1: age, additional operations, DM, inotrope use, ABP. AVR: aortic valve replacement, CABG: coronary arterial bypass grefting COPD: chronic obstructive pulmonary disease, DM: diabetes mellitus, PAD: peripheral arterial disease, IABP: intra-aortic balloon pump. a

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ascending aorta. One possible cause of dilation is haemodynamic flow disturbance in the aorta beyond the stenotic valve. The second possibility is a genetic predisposition to aortic dilation. We performed AVR and RAA in 36 patients and Bentall in 11 patients. In recent years, ascending aortic surgery has been performed in an increasingly elderly population, with a 15–40% incidence of co-existing CAD. Therefore pre-operative coronary angiography is routinely performed in elective patients, and concomitant CABG has begun to be performed more frequently, with an incidence of between 11 and 25% in some larger aortic surgery studies.10-12 We performed CABG and RAA in 25 patients, and eight underwent both CABG and AVR with RAA. In our study it was shown that the aneurysm was discovered in patients who underwent coronary angiography for symptoms of ischaemia. Ueda et al. identified incomplete coronary revascularisation as a risk factor for cardiovascular events.13 Atherosclerosis and inflammation are important factors in the development of valve stenosis and CAD.14,15 CAD is also a common finding in patients undergoing endovascular or surgical repair of descending, thoraco-abdominal or abdominal aortic aneurysms.16,17 In older patients undergoing planned aortic reconstruction, pre-operative coronary angiography should be performed and appropriate revascularisation must be performed.18 We suggest that surgery of the ascending aorta with concomitant CABG may increase the mortality rate. A study in the UK showed that the overall mortality rate was 3.2% for isolated aortic valve procedures and 6.8% for aortic valve procedures with concomitant CABG.10 However, Ueda et al. reported that complete revascularisation of major coronary arteries with significant stenosis is essential to reduce postoperative cardiac events.13 In a report by Houel and colleagues from France, the type of surgery had no effect on long-term survival, but AVR + RAA was associated with more aortic wall complications (aortic root dilation and false aneurysms) than the Bentall procedure. However, AVR + RAA was performed in patients with Marfan syndrome and others with aortic root aneurysm.19 Yun and colleagues compared 255 patients who underwent AVR + RAA, and 135 patients who underwent the Bentall procedure between 1965 and 1995.20 In the AVR + RAA group, the surgical mortality rate was 15.3%. Survival at 10 years was 51 ± 3% and at 15 years it was 36 ± 3%. Urbanski and colleagues reported a similar operative risk and late mortality and morbidity among 100 patients who underwent AVR + RAA or a modified Bentall procedure using Carbomedics mechanical valves.21 Sioris and associates reported no differences in peri-operative mortality rate or freedom from re-operation in 133 patients after 10 years between AVR associated with RAA and a modified Bentall procedure.22 Rizzoli and colleagues, in their study of 809 patients undergoing AVR, including 110 RAA patients, reported a 30-day mortality rate of 5.5%.23 Garrido-Olivares et al. reported on combined AVR and supracoronary RAA in 89 patients with an operative mortality rate of 2.3%.24 Simple AVR does not prevent the enlargement of the ascending aorta. Patients who have dilated ascending aortas at the time of AVR are at high risk of developing postoperative ascending aortic complications.25 This is not because of the primary surgery but due to intrinsic changes in the aortic wall. The time interval between initial AVR and late ascending aortic

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events ranged from two to 18 years. In a study by Tsutsumi et al., 50% of patients who developed late ascending aortic events during the follow-up period died.26 Replacement of the ascending aorta does not significantly increase the mortality risk. Moreover, AVR cannot reduce the risk of fatal aortic complications. Some authors reported that in patients with bicuspid aortic valve after AVR only, the aorta continues to enlarge and aorta-related complications increase.27,28 It was shown that concomitant RAA during AVR did not increase the rate of morbidity and mortality in the short-term, despite an increase in aortic cross-clamp and total cardiopulmonary bypass times.29 Our findings are compatible with these studies. The goal should be to avoid the catastrophic consequences of acute aortic dissection or rupture. The decision for surgical treatment is primarily based on comparative estimation of the natural prognosis of the disease versus the prognosis with treatment.30 The spontaneous prognosis is related to aortic diameter, mechanical properties of the vascular wall, and blood pressure. Aortic diameter has been best studied and is considered the primary prognostic parameter.30 The prognosis after treatment depends on complications of surgery and its mortality risk. In our study the mortality rate was increased insignificiantly. Type I aortic dissection occurs in 0.6% of patients late after AVR.31 Thirteen per cent of patients with acute type I aortic dissections had a history of previous AVR.32 In contrast to previous AVR, a history of CABG alone is not an independent risk factor for type I aortic dissection.33 However, diameter is not specific enough to affect the risk of dissection, and the law of Laplace must be taken into account; the incidence of dissection and rupture increases with increasing size of the ascending aortic aneurysm.34 The primary aim of prophylactic replacement is to prevent this catastrophic complication. Our decision to replace the ascending aorta was based on the size of the aortic diameter. Patients with ascending aortic diameter more than 45 mm underwent concomitant ascending aorta replacement. In their study, Davies at al. reported that relative aortic size is more important than absolute aortic size in predicting complications. A new measurement, the aortic size index, which takes into account both aortic diameter and body surface area, was used for calculating the risk of negative events. According to them, increasing aortic size index was a significant predictor of increasing rates of rupture.35 Lentini at al. reported their initial experience for ascending aortic surgery with or without valve or root surgery via a ministernotomy approach. Surgery of the aortic root and ascending aorta has traditionally been performed via a conventional median full sternotomy. The development of minimally invasive surgical techniques reduces surgical trauma, length of mechanical ventilation and ICU stay, improves post-operative outcomes and also has cosmetic benefits.36 Especially in high-risk patients, a mini-sternotomy approach can improve recovery of respiratory function and allow earlier extubation, reducing ICU and hospital stay in complex aortic surgery. There are a few examples of this procedure: Tabata et al.37 and Perrotta et al.38 reported on a Bentall procedure with mini-sternotomy, using this approach on both elective and emergency patients, and in redo surgery. Svensson et al. reported 36 patients operated for ascending aorta replacement,

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of whom 18 had aortic arch repair through mini-sternotomy.39 The minimal incision does not allow for easy manipulation of the aortic arch while using selective antegrade cerebral perfusion. The need for CABG was the exclusion criterion in our study. There are several ways of dealing with an enlarged aorta. One is by remodelling the aorta, using a supracoronary graft, or with a valved conduit. Some surgeons40 suggest a conservative approach and would rather remodel the aorta but we believe that the risk of recurrent dilatation of the aorta remains, so a more radical approach of supracoronary graft replacement is the main choice in our clinic. We use hypothermic circulatory arrest and antegrade cerebral perfusion generally, as we have more experience with this approach. We do not have experience of the minimal approach. Some authors have argued against the strategy of routinely replacing the enlarged ascending aorta, based on their observations that significant increase in the ascending aorta after simple AVR is infrequent.41 We have not experienced this. The results of our study suggested that concomitant RAA did not significantly increase the mortality rate despite an increase in the aortic cross-clamp and total cardiopulmonary bypass times. If type A aortic dissection is life threating but elective surgery carries a low surgical risk, we prefer to perform surgery earlier. According to the Society of Thoracic Surgeons, the operative risk associated with replacement of the proximal aorta under elective circumstances is 3.4%.42 In our study, the mortality rate was 5.3% in patients who underwent RAA alone, 11.1% in those who underwent AVR, 20% in those who underwent CABG, 37.5% in patients who underwent AVR + CABG, and 18.2% in those who underwent the Bentall procedure. We found no statistically significant differences between mortality rates. Therefore, this study supports the strategy of concomitantly replacing the ascending aorta at the time of cardiac surgery to prevent possible aortic rupture, dissection or death.

As we have become more successful in performing the surgery, a higher proportion of patients undergoing open-heart surgery and requiring RAA will be operated on. A multicentre study is necessary to develop the best strategy for treatment of these patients. We acknowledge medical writing assistance provided by American Manuscript Editors (www.americanmanuscripteditors.com) for the final draft of the manuscript. We thank to Prof Arisan Ergin for sharing his surgical experiences with us.

References 1.

This was a retrospective, single-centre, observational study and it had a small patient population. These results were also obtained in a small-volume centre (< 40 aortic operations per year), therefore the results cannot be generalised. In addition, we examined data from surgeries that were performed by different surgical groups, which limits standardisation. This study reflects clinical experiences in a small area and cannot be generalised for all hospitals. Prospective studies are required to define optimal prophylactic surgical techniques.

Lima B, Hughes GC, Lemaire A, Jaggers J, Glower DD, Wolfe WG. Short-term and intermediate-term outcomes of aortic root replacement with St. Jude mechanical conduits and aortic allografts. Ann Thorac Surg 2006; 82: 579–585.

Roman MJ, Devereux RB, Kramer Fox R, O’Loughlin J. Two-dimensional echocardiographic aortic root dimensions in normal childrens and adults. Am J Cardiol 1989; 64: 507–512.

Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, et al. ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/ SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010; 121: e266–e369.

Borger MA,Preston M, Ivanov J, Fedak PW, Davierwala P, Armstrong S, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004; 128: 677–683.

Study limitations

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Lavall D, Schafers H, Bohm M, Laufs U. Aneurysms of the ascending aorta. Deutsches Arzteblatt Internat 2012; 109(13): 227–233.

Ergin MA, McCullough J, Galla JD, Lansman SL, Griepp RB. Radical replacement of the aortic root in acute type A dissection: indications and outcome. Eur J Cardiothorac Surg 1996; 10: 840–845.

Sales Mda C, Frota Filho JD, Aguzzoli C, Souza LD, Rösler ÁM, Lucio EA, et al. Aortic Center: specialized care improves outcomes and decreases mortality. Rev Bras Cir Cardiovasc 2014; 29: 494–504.

Pressler V, McNamara JJ. Thoracic aortic aneurysm. J Thorac Cardiovasc Surg 1980; 79: 489–498.

Joyce JW, Fairbaine JF, Kincaid OW, Juergens JL. Aneurysms of the thoracic aorta: a clinical study with special reference to prognosis. Circulation 1964; 29: 176–181.

Conclusions It is common to deal with an associated ascending aortic aneurysm during concomitant surgery. In this retrospective study, we investigated whether concomitant surgery was a predictor for mortality after proximal aortic replacement. We found that the procedure for simultaneous correction of the ascending aorta and concomitant cardiac surgery (CABG, AVR, Bentall procedure) could be performed safely and with good results. Our study supports replacement of the ascending aorta during AVR or CABG if the aortic dimension is larger than 45 mm, to prevent aortic dissection or rupture after the procedure.

10. Keogh BE, Kinsman R. UKCSR: miscellaneous operations for acquired heart disease financial year 2003. In: Keogh BE, eds. Fifth National Adult Cardiac Surgical Database Report 2003. Oxfordshire: Dendrite Clinical Systems, 2004: 46. 11. Miller JS, Lemaire SA, Coselli JS. Evaluating aortic dissection: when is coronary angiography indicated? Heart 2000; 83: 615–616. 12. Penn MS, Smedira N, Lytle B, Brener SJ. Does coronary angiography before emergency aortic surgery affect in-hospital mortality? J Am Coll Cardiol 2000; 35(4): 889–894. 13. Ueda T, Shimizu H, Shin H, Kashima I, Tsutsumi K, Iino Y, et al. Detection and management of concomitant coronary artery disease in patients undergoing thoracic aortic surgery. Jpn J Thorac Cardiovasc

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Surg 2001; 49: 424–430. 14. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–1695. 15. Ngo DT, Sverdlov AL, Horowitz JD. Prevention of aortic valve stenosis: a realistic therapeutic target? Pharmacol Ther 2012; 135: 78–93.

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ing aorta repair. J Thorac Cardiovasc Surg 2011; 142: 622–629. 29. Lim JY, Jung SH, Kim JB, Kim DK, Chung CH, Song H, et al. Concomitant replacement of the dilated ascending aorta during aortic valve replacement; does it increase the perioperative morbidity and mortality risks? J Card Surg 2013; 28(3): 285–290.

16. Kieffer E, Chiche L, Baron JF, Godet G, Koskas F, Bahnini A.

30. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G,

Coronary and carotid artery disease in patients with degenerative aneu-

Baumgartner H, et al. Guidelines on the management of valvular heart

rysm of the descending thoracic or thoracoabdominal aorta: prevalence

disease (version 2012): The Joint Task Force on the Management of

and impact on operative mortality. Ann Vasc Surg 2002; 16: 679–684.

Valvular Heart Disease of the European Society of Cardiology (ESC)

17. Marin ML, Hollier LH, Ellozy SH, Spielvogel D, Mitty H, Griepp R, et al. Endovascular stent graft repair of abdominal and thoracic aortic aneurysms: a 10-year experience with 817 patients. Ann Surg 2003; 238: 586–593. 18. Narayan P, Rogers CA, Caputo M, Angelini GD, Bryan AJ. Influence of concomitant coronary artery bypass graft on outcome of surgery of the ascending aorta/arch. Heart 2007; 93: 232–237.

and the European Asso ciation for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012; 33: 2451–2496. 31. Prenger K, Pieters F, Cheriex E. Aortic dissection after aortic valve replacement: incidence and consequences for strategy. J Card Surg 1994; 9: 495–499. 32. Crawford ES, Svensson LG, Coselli JS, Safi HJ, Hess KR. Aortic dissection and dissecting aortic aneurysms. Ann Surg 1988; 208: 254–272.

19. Houel R, Soustelle C, Kirsch M, Hillion ML, Renaut C, Louisance DY.

33. Orszulak TA, Pluth JR, Schaff HV, Piehler JM, Smith HC, McGoon

Long-term results of the Bentall operation versus separate replacement

DC. Results of surgical treatment of ascending aortic dissections occur-

of the ascending aorta and aortic valve. J Heart Valve Dis 2002; 11:

ing late after cardiac operation. J Thorac Cardiovasc Surg 1982; 83:

485–491.

538–545.

20. Yun KL, Miller DC, Fann JI, Mitchell RS, Robbins RC, Moore KA,

34. Davies RR, Goldstein LJ, Coady MA, Tittle SL, Rizzo JA, Kopf GS,

et al. Composite valve graft versus separate aortic valve and ascending

et al. Yearly rupture or dissection rates for thoracic aortic aneurysms:

replacement. Is there a role for the separate procedure? Circulation 1997; 96(Suppl 2): 368–375. 21. Urbanski PP, Wagner M, Zacher M, Hacker RW. Aortic root replacement versus aortic valve replacement: a case-match study. Ann Thorac Surg 2001; 72: 28–32.

simple prediction based on size. Ann Thorac Surg 2002; 73: 17–28. 35. Davies, R. Gallo A,Coady MA, Tellides G, Botta DM, Burke B, et al. Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006; 81: 169–177. 36. Lentini S, Specchia L, Nicolardi S, Mangia F, Rasovic O, Di Eusanio G,

22. Sioris T, David TE, Ivanov J, Armstrong S, Feindel CM. Clinical

et al. Surgery of the ascending aorta with or without combined proce-

outcomes after separate and composite replacement of the aortic valve

dures through an upper ministernotomy: outcomes of a series of more

and ascending aorta. J Thorac Cardiovasc Surg 2004; 128: 260–265.

than 100 patients. Ann Thorac Cardiovas 2015; 22(1): 44–48.

23. Rizzoli G, Mirone S, Ius P, Polesel E, Bottio T, Salvador L, et al.

37. Tabata M, Khalpey Z, Aranki SF, Couper GS, Cohn LH, Shekar PS.

Fifteen-year results with the Hancock II valve: a multicenter experience.

Minimal access surgery of ascending and proximal arch of the aorta: a

J Thorac Cardiovasc Surg 2006; 132: 602–609.

9-year experience. Ann Thorac Surg 2007; 84: 67–72.

24. Garrido-Olivares L, Maganti M, Armstrong S, David T. Aortic valve

38. Perrotta S, Lentini S, Rinaldi M, D’armini AM, Tancredi F, Raffa G, et

replacement with Hancock II bioprothesis with and without replace-

al. Treatment of ascending aorta disease with Bentall–De Bono opera-

ment of the ascending aorta. Ann Thorac Surg 2011; 92: 541–547.

tion using a mini-invasive approach. J Cardiovasc Med (Hagerstown)

25. Tsutsumi K, Inoue Y, Hashizume K, Kimura N, Takahashi R. Risk factor analysis for acute type A aortic dissection after aortic valve replacement. Gen Thorac Cardiovasc Surg 2010; 58: 601–605.

2008; 9: 1016–1022. 39. Svensson LG, Nadolny EM, Kimmel WA. Minimal access aortic surgery including re-operations. Eur J Cardiothorac Surg 2001; 19: 30–33.

26. Tsutsumi K, Hashizume K, Inoue Y. Natural history of the ascending

40. Carrel T, Von Segesser L, Jenni R, Gallino A, Egloff L, Bauer E, et al.

aorta after aortic valve replacement: risk factor analysis for late aortic

Dealing with dilated ascending aorta during aortic valve replacement:

complications after aortic valve replacement. Gen Thorac Cardiovasc

Advantages of a conservative surgical approach. Eur J Cardiothorac

Surg 2015; Dec 24. [Epub ahead of print].

Surg 1991; 5: 137–143.

27. Yasuda H, Nakatani S, Stugaard M, Tsujita-Kuroda Y, Bando K,

41. Andrus BW, O’Rourke DJ, Dacey LJ, Palac RT. Stability of ascending

Kobayashi J, et al. Failure to prevent progressive dilation of ascending

aortic dilatation following aortic valve replace ment. Circulation 2003;

aorta by aortic valve replacement in patients with bicuspid aortic valve:

108(Suppl 1): I295–I299.

Comparison with tricuspid aortic valve. Circulation 2003; 108: 291–294.

42. Williams JB, Peterson ED, Zhao Y, O’Brien SM, Andersen ND, Miller

28. Svensson LG, Kim KH, Blackstone EH, Rajeswaran J, Gillinov AM,

DC, et al. Contemporary results for proximal aortic replacement in

Mihaljevic T, et al. Bicuspid aortic valve surgery with proactive ascend-

North America. J Am Coll Cardiol 2012; 60: 1156–1162.

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Procedural and one-year clinical outcomes of bioresorbable vascular scaffolds for the treatment of chronic total occlusions: a single-centre experience Erdem Özel, Ahmet Taştan, Ali Öztürk, Emin Evren Özcan, Baris Kilicaslan, Öner Özdogan

Abstract Introduction: The bioresorbable vascular scaffold system (BVS) is the latest fully absorbable vascular therapy system that is used to treat coronary artery disease. The BVS has been used in different coronary lesion subsets, such as acute thrombotic lesions, bifurcation lesions, ostial lesions and lesions originating from bypass grafts. However, data about the use of BVS in chronic total occlusions (CTO) are limited. We report our BVS experience for the treatment of CTOs in terms of procedural features and one-year clinical follow-up results. Methods: An analysis was made of 41 consecutive patients with CTO lesions who were referred to our clinic between January 2013 and December 2014. A total of 52 BVS were implanted. An analysis was made of patient characteristics, procedural features [target vessel, BVS diameter, BVS length, post-dilatation rate, type of post-dilatation balloon, procedure time, fluoroscopy time, contrast volume, postprocedure reference vessel diameter (RVD), post-procedure minimal lesion diameter (MLD), type of CTO technique and rate of microcatheter use] and one-year clinical follow-up results [death, myocardial infarction, angina, coronary artery bypass graft (CABG), target-lesion revascularisation (TLR) and target-vessel revascularisation (TVR)]. Descriptive and frequency statistics were used for statistical analysis. Results: The mean age of the patient group was 61.9 ± 9.7 years, 85.4% were male, and 51.2 % had diabetes. Prior myocardial infarction incidence was 65.9%, 56.1% of the patients had percutaneous coronary intervention and 17.1% had a previous history of CABG. The procedure was performed via the radial route in 24.3% of the patients. The target vessel was the right coronary artery in 48.7% of the patients. Post-dilatation was performed on the implanted BVS in 97.5% of the patients, mainly by non-compliant balloon; 87.8% of the BVS were implanted by the antegrade CTO technique. Mean procedure time was 92 ± 35.6 minutes. Mean contrast volume was 146.6 ± 26.7 ml.

Cardiology Department, Tepecik Training and Research Hospital, İzmir, Turkey Erdem Özel, MD, erdem.ozel@hotmail.com Baris Kilicaslan,MD Öner Özdogan, MD

Cardiology Department, Sifa University, İzmir, Turkey Ahmet Taştan, MD Ali Öztürk, MD

Cardiology Department, Dokuz Eylul University, İzmir, Turkey Emin Evren Özcan, MD

At one year, there were no deaths. One patient had lesionrelated myocardial infarction and needed revascularisation because of early cessation of dual anti-platelet therapy. Eleven patients had angina and five of them needed target-vessel revascularisation. Conclusions: BVS implantation appeared to be effective and safe in CTO lesions but randomised studies with a larger number of patients and with longer follow-up times are needed. Keywords: bioresorbable vascular scaffold, chronic total occlusion, percutaneous coronary intervention Submitted 11/1/16, accepted 13/3/16 Published online 12/4/16 Cardiovasc J Afr 2016; 27: 345–349

www.cvja.co.za

DOI: 10.5830/CVJA-2016-033

Chronic total occlusion (CTO) is described as complete coronary vessel occlusion with a duration of three months or longer.1 Among patients diagnosed with coronary disease on angiography, the incidence of CTO lesions was between 20 and 30%.2 Successful CTO recanalisation provides better symptom control and survival outcome in the long term over failed revascularisation.3-5 According to recent guidelines, percutaneous recanalisation of CTOs should be considered in patients with expected ischaemia reduction in a corresponding myocardial territory and/or angina relief with a class 2a indication.6 Clinical outcomes of drugeluting stents (DES) are superior to bare-metal stents (BMS) in percutaneous revascularisation of CTOs.7,8 The bioresorbable vascular scaffold (BVS) (Absorb, Abbott Vascular, Santa Clara, CA, USA) is the latest fully absorbable vascular therapy system that is used to treat coronary artery disease. BVS has been tested in many randomised trials and provides some advantages over metallic stents because of its complete bioresorption process.9-11 BVS can facilitate the return of vessel vasomotor functions, reduce device thrombosis rates in the long term, make future surgical revascularisations more feasible and facilitate non-invasive imaging of the coronary arteries, since no metallic cage remains after two years.12,13 BVS has been used in different coronary lesion subsets, such as acute thrombotic lesions, bifurcation lesions, ostial lesions and lesions originating from bypass grafts. However, data on the use of BVS in chronic total occlusions (CTO) are limited. We report our BVS experience for the treatment of CTOs in terms of procedural features and one-year clinical follow-up results.

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Methods Forty-one consecutive patients who underwent CTO revascularisation with one or two BVSs between January 2013 and December 2014 were analysed in the present study. A total of 52 BVSs were implanted. All patients were over 18 years old and had a diagnosis of stable angina pectoris. Lesions with a reference vessel diameter (RVD) of between 2.5 and 4 mm were included. Patients who had suffered from a myocardial infarction (MI) within one month of the procedure and patients who had left main coronary artery (LMCA) lesions or bifurcation lesions consisting of a side branch of over 2.5 mm were excluded. An informed consent for the procedure was obtained from each patient. All CTO lesions were recanalised with dedicated CTO guide wires. After a mandatory pre-dilatation with an appropriate balloon, one or two BVS were implanted in the lesion. We did not use a strategy of hybrid stenting and no metallic stent was implanted in the lesions. Post-dilatation was performed with a compliant or non-compliant balloon after BVS implantation at the physician’s discretion if it was necessary. Procedural features [target vessel, Japanese CTO score (J-CTO score), BVS diameter, BVS length, post-dilatation rate, type of post-dilatation balloon, procedure time, fluoroscopy time, contrast volume, post-procedure reference vessel diameter (RVD), post-procedure minimal lesion diameter (MLD), CTO technique and rate of microcatheter use] were analysed. Quantitative coronary angiography (QCA) measurements were used to assess RVD and MLD. One-, three- and six-month, and one-year follow-up visits were made after each intervention. During routine visits, cardiovascular stress tests (treadmill exercise test or myocardial perfusion imaging test) were performed to diagnose the ischaemic situation associated with the intervention. Re-intervention and revascularisation were performed as needed. Rates of death, myocardial infarction (MI), angina, coronary artery bypass graft (CABG), target lesion revascularisation (TLR) and target-vessel revascularisation (TVR) were analysed.

descending (LAD) artery and seven had lesions on the circumflex (CX) artery. Six patients had easy lesion complexity, 23 had intermediate complexity, eight had difficult, and four had very difficult complexity, according to the J-CTO score. Procedural success rate was 100%. Case examples are shown in Fig. 1. All patients were treated with acetylsalicylic acid after the intervention. Additionally, 35 patients were treated with clopidogrel, three with ticagrelor and three with prasugrel. The rate of statin use was 97.5% among our patient group and betablocker use was 85.3%. Mean BVS diameter and BVS length were 2.8 ± 0.29 and 25.6 ± 4.2 mm, respectively. Our post-dilatation rate was 97.5%, mainly by non-compliant balloon (NCB) (92.6%). Postprocedure RVD was 2.8 ± 0.25 mm and post-procedure MLD was 2.5 ± 0.25 mm. We performed CTO procedures mainly by the antegrade approach (87.8%). We used a microcatheter in 13 patients (31.7%). Six patients had side branch occlusion and four had side branch narrowing. All of these patients were treated successfully by provisional stenting and final kissing balloon dilatation. Our procedure time was 92 ± 35.6 min, fluoro time was 20.2 ± 4.8 min and the mean value of contrast volume was 146.6 ± 26.7 ml (Table 2). At the end of one year, no death was observed. One patient had lesion-related MI and needed revascularisation because of early cessation of dual anti-platelet therapy. Eleven patients had angina and five of them needed TVR. Our TLR rate was 2.4% and TVR rate was 12.2% (Table 3). Table 1. Patient characteristics and therapy at discharge Patient characteristics

Measurement data were described as mean and standard deviation. Descriptive and frequency statistics were used for statistical analysis. The level of statistical significance accepted was 0.05. Data were analysed with the use of SPSS 17.0 software (SPSS, IBM, Chicago, USA).

Results Baseline patient characteristics and therapy at discharge are shown in Table 1. Thirty patients were treated by single BVS, and 11 patients were treated with two BVSs. Mean age was 61.9 ± 9.7 years, and 85.4% of the patients were male. Among our patient group, 51.2% had diabetes mellitus, 80.5% had hypertension and 46.3% had hyperlipidaemia. Renal function was within normal limits in all patients, 65.9% had prior MI, 56.1% had prior percutaneous coronary intervention (PCI) and 17.1% had prior CABG surgery; 24.3% of the procedures were performed by the radial route. Nearly half of the BVSs were implanted in the right coronary artery (RCA). Fourteen patients had lesions on the left anterior

n = 41 patients (%)

Age (years)

61.9 ± 9.7

Male gender

35 (85.4)

Diabetes

21 (51.2)

Hypertension

33 (80.5)

Hyperlipidaemia

19 (46.3)

Smoking

14 (34.1)

Chronic renal failure

Statistical analysis

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–

Prior MI

27 (65.9)

Prior PCI

23 (56.1)

Prior CABG Radial intervention

7 (17.1) 10 (24.3)

Lesion complexity (J-CTO score) Easy (J -CTO score of 0) Intermediate (J-CTO score of 1)

6 (14.6) 23 (56)

Difficult ( J-CTO score of 2)

8 (19.5)

Very difficult (J-CTO score of ≥ 3)

4 (9.7)

Target vessel LAD CX RCA Procedural success

14 (34.1) 7 (17) 20 (48.7) 41 (100)

Therapy at discharge ASA

41 (100)

Clopidogrel

35 (85.3)

Prasugrel Ticagrelor

3 (7.3) 3 (7.3)

Statin

40 (97.5)

Beta-blocker

35 (85.3)

CABG: coronary artery bypass graft, CX: circumflex artery, J-CTO: Japanese CTO, LAD: left anterior descending artery, MI: myocardial infarction, PCI: percutaneous coronary intervention, RCA: right coronary artery.

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Fig. 1. C oronary angiography showing recanalisation of chronic total occlusions. (A) Chronic total occlusion of the LAD from the proximal portion. (B) Successfull recanalisation of the LAD with two BVSs (3.5 × 28 mm and 3.0 × 28 mm) via antegrade approach. (C) Chronic total occlusion of the LAD from the mid portion. (D) Successfull recanalisation of LAD with two BVSs (3.5 × 18 mm and 3.0 × 28 mm ) via antegrade approach. (E) Chronic total occlusion of the RCA from the mid portion. (F) Successfull recanalisation of the RCA with one BVS (3.0 × 18 mm) via antegrade approach with the aid of a microcatheter.

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Table 2. Procedural characteristics n = 41 patients n = 52 BVS (%)

Procedure

2.8 ± 0.29

BVS diameter, mm

25.6 ± 4.2

BVS length, mm Post-dilatation

40 (97.5)

Post-dilatation with NCB

38 (92.6)

RVD post-procedure, mm

2.8 ± 0.25

MLD post-procedure, mm

2.5 ± 0.25

Side-branch occlusion

6 (11.5)

Side-branch narrowing

4 (7.6)

CTO technique Antegrade

36 (87.8)

Retrograde

5 (12.1)

Microcathater use

13 (31.7) 92 ± 35.6

Procedure time, min

20.2 ± 4.8

Fluoro time, min

146.6 ± 26.7

Contrast volume, ml

BVS: bioresorbable vascular scaffold, CTO: chronic total occlusion, MLD: minimal lumen diameter, NCB: non-compliant balloon, RVD: reference vessel diameter.

Discussion Our study shows that BVS implantation in CTO lesions appeared to be effective and safe in terms of acute procedural and shortterm clinical follow-up results. Theoretically, complete resorption of BVS, which is used for treating complex and calcific lesions, such as CTOs, seems to be advantageous. Lack of a metallic cage in these lesions can decrease the risk of restenosis, especially in the long term. Restoration of the vessel’s vasomotor functions may be easier with BVS implantation than with metallic stents. Since patients with complex lesions such as CTOs have a greater risk for future CABG surgery, resorption of BVS in the treated segment may facilitate the performance of future graft anastomosis. However, in practice, the real effectiveness and safety of the use of BVS in CTO lesions are unclear and longterm clinical results are lacking. A few records and case reports have been published in the literature which analyse the role of BVS implantation in CTO lesions.14-17 The baseline characteristics of our patients were similar to those in previous BVS studies including patients with CTO lesions.14-16 In addition the cardiovascular risk profile of our patients was high and parallel with real-life records that investigate the effect of regular PCI procedures in CTO lesions. Our mean BVS length was shorter than in previous studies.14,15 Most of our CTO lesions were within the treatable length of one BVS. Only 11 patients were treated with double BVS and no patients were treated with more than two BVSs. Although we had similar TLR rates and short-term clinical results with the

Table 3. Clinical outcomes One-year outcome Death Myocardial infarction Angina Coronary artery bypass graft

n = 41 patients (%) – 1 (2.4) 11 (26.8) –

Target-lesion revascularisation

1 (2.4)

Target-vessel revascularisation

5 (12.2)

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BVS CTO studies, which included longer CTO lesions treated with a larger number of BVSs, studies with longer follow up beyond the resorption period of BVSs are needed in order to clearly determine the effect of scaffolds. It is known that longer CTOs treated with a larger number of metallic stents have a greater risk of restenosis and worse clinical outcomes during follow up.18,19 Currently, we do not know whether complete resorption of the implanted scaffolds eliminates the risk of restenosis in long CTO segments in the long term. Although BVS has thick struts (150 µm), a low crossing profile and less distensibility, our procedural success rate was 100% in our patient group. The main reasons for procedural success are effective dilatation after wiring the lesions, exact scaffold sizing with the aid of quantitative coronary angiography (QCA) measurements, and a high rate of post-dilatation. Lesion preparation before BVS implantation is a crucial factor, especially for CTO lesions. Since a non-compliant balloon (NCB) reduces the procedure time compared with the compliant balloon,20 and is advised by many experienced centres,21,22 we preferred NCB for effective dilatation after pre-dilatation with lower-profile balloons. Also, a cutting balloon and rotablator can be used if needed. We performed post-dilatation in almost every lesion, mainly with a non-compliant balloon. We did not use balloons that had a size of more than 0.5 mm larger than the implanted BVS diameter. Post-dilatation with an inappropriate size of balloon can lead to fracture of the BVS in heavily calcific CTO lesions. We did not experience BVS fracture in our patient group. Despite our high procedural success rate, implanting BVS in CTO lesions should be reserved for less complex CTO lesions, since experience is still limited. The J-CTO score, which characterises lesion complexity, could be a useful tool for decision making on indication. According to previous studies, CTO lesions that have a score of more than three (very difficult category) are associated with an unsuccessful procedure.14,23 The majority of our lesions were within the intermediate category according to the J-CTO score (56%). More complex lesions with a higher J-CTO score could affect procedural success and clinical outcomes. During CTO procedures, jailing of the major side branches could be a problem, affecting the success of the procedure.14,15 Complete resorption of the BVS at the site of the bifurcation could lessen the effect of jailing and help return the side branch to normal vasomotor function. In our study, six side branch occlusions and four side branch narrowings were observed because of scaffold jailing. All of these lesions were treated with a provisional strategy with final kissing balloon dilatation. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are very valuable tools for evaluating the apposition of BVS during implantation.12 Not using IVUS or OCT is a limitation of our study but we had used QCA measurements for exact sizing of the BVS. Since our study was non-randomised and lacked a control group, one should be cautious when interpreting the clinical data. A randomised study with a larger number of patients would be more valuable for evaluating the clinical outcomes. Our clinical follow-up results are too limited to evaluate the real clinical effectiveness of the use of BVS in CTO lesions. One year is a short follow-up period and cannot answer the question as

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to whether complete resorption of the BVS over two years will affect the clinical outcomes. However, short-term clinical results are promising.

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385: 43–54. 10. Ellis SG, Kereiakes DJ, Metzger DC, et al. Everolimus-eluting bioresorbable scaffolds for coronary artery disease. N Engl J Med 2015, Oct 12. [Epub ahead of print].

Conclusion BVS implantation appears to be effective and safe in CTO lesions, according to our results, but randomised studies with a larger number of patients and a longer follow up are needed.

11. Kimura T, Kozuma K, Tanabe K, et al. A randomized trial evaluating everolimus-eluting Absorb bioresorbable scaffolds vs. everolimus-eluting metallic stents in patients with coronary artery disease: ABSORB Japan. Eur Heart J 2015, Sep 1. pii: ehv435. [Epub ahead of print]. 12. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimuseluting coronary stent system (ABSORB): 2-year outcomes and results

References 1.

from multiple imaging methods. Lancet 2009; 373(9667): 897–910. 13. Dudek D, Onuma Y, Ormiston JA, et al. Four-year clinical follow-up

Di Mario C, Werner GS, Sianos G, et al. European perspective in the

of the ABSORB everolimus-eluting bioresorbable vascular scaffold

recanalisation of chronic total occlusions (CTO): consensus document

in patients with de novo coronary artery disease: the ABSORB trial. EuroIntervention 2012; 7: 1060–1061.

from the EuroCTO Club. EuroIntervention 2007; 3(1): 30–43.   2.

Fefer P, Knudtson ML, Cheema AN, et al. The Canadian Multicenter

14. Wiebe J, Liebetrau C, Dörr O, et al. Feasibility of everolimus-eluting

Chronic Total Occlusions Registry. Current perspectives on coronary

bioresorbable vascular scaffolds in patients with chronic total occlusion. Int J Cardiol 2015; 179: 90–94.

chronic total occlusions. J Am Coll Cardiol Mar 2012; 59(11): 991–997. 3.

Claessen BE, Dangas GD, Godino C, et al. Long-term clinical outcomes

15. Goktekin O, Yamac AH, Latib A, et al. Evaluation of the safety of

of percutaneous coronary intervention for chronic total occlusions in

everolimus-eluting bioresorbable vascular scaffold (BVS) implantation

patients with vs. without diabetes mellitus. Am J Cardiol 2011; 108(7):

in patients with chronic total coronary occlusions: acute procedural and short-term clinical results. J Invasive Cardiol 2015; 27: 461–466.

924–931.   4.

Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of chronic

16. Ojeda S, Pan M, Romero M, et al. Outcomes and computed tomography

total occlusions: a systematic review and meta-analysis. Am Heart J

scan follow-up of bioresorbable vascular scaffold for the percutaneous

2010; 160(1): 179–187.

treatment of chronic total coronary artery occlusion. Am J Cardiol 2015; 115: 1487–1493.

Grantham JA, Jones PG, Cannon L, Spertus JA. Quantifying the early health status benefits of successful chronic total occlusion reca-

17. Rama-Merchan JC, Mattesini A, Dall’Ara G, Mario CD. Chronic total

nalization: Results from the Flow-Cardia’s Approach to Chronic Total

occlusion successfully treated with a bioresorbable everolimus-eluting vascular scaffold. Postepy Kardiol Interwencyjnej 2014; 10: 128–129.

Occlusion Recanalization (FACTOR) Trial. Circ Cardiovasc Qual Outcomes 2010; 3(3): 284–290. 6.

18. Galassi AR, Brilakis ES, Boukhris M, et al. Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an

Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines

overview. Eur Heart J 2015, Aug 7. pii: ehv391. [Epub ahead of print].

on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and

19. Ito T, Tsuchikane E, Nasu K, et al. Impact of lesion morphology on

the European Association for Cardio-Thoracic Surgery (EACTS).

angiographic and clinical outcomes in patients with chronic total occlu-

Developed with the special contribution of the European Association

sion after recanalization with drug-eluting stents: a multislice computed

of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35(37): 2541–2619. 7.

tomography study. Eur Radiol 2015; 25: 3084–3092. 20. Özel E, Taştan A, Öztürk A, Özcan EE, Uyar S, Şenarslan Ö. What is

Colmenarez HJ, Escaned J, Fernandez C, et al. Efficacy and safety of

better for predilatation in bioresorbable vascular scaffold implantation:

drug-eluting stents in chronic total coronary occlusion recanalization:

a non-compliant or a compliant balloon? Anatol J Cardiol 2015, Jun 18.

a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55(17): 1854–1866. 8.

doi:10.5152/Anatol J Cardiol.2015.6184. [Epub ahead of print]. 21. Caiazzo G, Kilic ID, Fabris E, et al. Absorb bioresorbable vascular scaffold: What have we learned after 5 years of clinical experience? Int J

Patel MR, Marso SP, Dai D, et al. Comparative effectiveness of drug-

Cardiol 2015; 201: 129–136.

eluting vs. bare-metal stents in elderly patients undergoing revascularization of chronic total coronary occlusions: results from the National

22. Tamburino C, Latib A, van Geuns RJ, et al. Contemporary practice and

Cardiovascular Data Registry, 2005–2008. J Am Coll Cardiol Cardiovasc

technical aspects in coronary intervention with bioresorbable scaffolds: a European perspective. EuroIntervention 2015; 11: 45–52.

Interv 2012; 5(10): 1054–1061. 9.

Serruys PW, Chevalier B, Dudek D, et al. A bioresorbable everolimus-

23.

Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire

eluting scaffold versus a metallic everolimus-eluting stent for ischae-

crossing through chronic total occlusion of native coronary lesions

mic heart disease caused by de-novo native coronary artery lesions

within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan)

(ABSORB II): an interim 1-year analysis of clinical and procedural

score as a difficulty grading and time assessment tool. J Am Coll Cardiol

secondary outcomes from a randomised controlled trial. Lancet 2015;

Cardiovasc Interv 2011; 4: 213–221.

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A prospective investigation into the effect of colchicine on tuberculous pericarditis Jurgens Jacobus Liebenberg, Catherine Jane Dold, Lourens Rasmus Olivier Abstract Introduction: Tuberculous (TB) pericarditis carries significant mortality and morbidity rates, not only during the primary infection, but also as part of the granulomatous scar-forming fibrocalcific constrictive pericarditis so commonly associated with this disease. Numerous therapies have previously been investigated as adjuvant strategies in the prevention of pericardial constriction. Colchicine is well described in the treatment of various aetiologies of pericarditis. The aim of this research was to investigate the merit for the use of colchicine in the management of tuberculous pericarditis, specifically to prevent constrictive pericarditis. Methods: This pilot study was designed as a prospective, double-blinded, randomised, control cohort study and was conducted at a secondary level hospital in the Northern Cape of South Africa between August 2013 and December 2015. Patients with a probable or definite diagnosis of TB pericarditis were included (n = 33). Study participants with pericardial effusions amenable to pericardiocentesis underwent aspiration until dryness. All patients were treated with standard TB treatment and corticosteroids in accordance with the South African Tuberculosis Treatment Guidelines. Patients were randomised to an intervention and control group using a webbased computer system that ensured assignment concealment. The intervention group received colchicine 1.0 mg per day for six weeks and the control group received a placebo for the same period. Patients were followed up with serial echocardiography for 16 weeks. The primary outcome assessed was the development of pericardial constriction. Upon completion of the research period, the blinding was unveiled and data were presented for statistical analysis. Results: TB pericarditis was found exclusively in HIV-positive individuals. The incidence of pericardial constriction in our cohort was 23.8%. No demonstrable benefit with the use of colchicine was found in terms of prevention of pericardial constriction (p = 0.88, relative risk 1.07, 95% CI: 0.46–2.46). Interestingly, pericardiocentesis appeared to decrease the incidence of pericardial constriction. Conclusion: Based on this research, the use of colchicine in TB pericarditis cannot be advised. Adjuvant therapy in the prevention of pericardial constriction is still being investigated and routine pericardiocentesis may prove to be beneficial in this regard.

Worcester Hospital, Worcester, South Africa Jurgens Jacobus Liebenberg, MB ChB, liebjurg@gmail.com

Hanover Park Day Hospital, Cape Town, South Africa Catherine Jane Dold, MB ChB

Medi-Clinic Hospital, Durbanville, South Africa Lourens Rasmus Olivier, MMed (Int), DTMH (Wits)

Keywords: pericarditis, colchicine, tuberculosis, constrictive pericarditis Submitted 6/10/15, accepted 16/3/16 Cardiovasc J Afr 2016; 27: 350–355

www.cvja.co.za

DOI: 10.5830/CVJA-2016-035

South Africa, a land of stark contrasts, contains a diverse natural beauty that can easily be compared with some of the world’s most majestic outdoor scenes. One of the new seven wonders of the natural world, Table Mountain, parades its splendour to the capital of South Africa, Cape Town. Unfortunately, South Africa is also considered by many to be one of the tuberculosis (TB) capitals of the world. The incidence of TB in South Africa is estimated to have increased by over 400% in the past 15 years. This is confounded by a staggering co-infection rate of approximately 73% with the human immunodeficiency virus (HIV).1 One of the most dreaded complications of TB pericarditis is pericardial scar formation. Due to scarring, the pericardium becomes calcified and contracts over the cardiac chambers, thereby encasing the heart in a fibrocalcific skin that impedes diastolic filling.2 Constrictive pericarditis (CP) is the natural consequence of about 17 to 40% of cases of TB pericardial infection.3 The definitive treatment of CP is surgical removal of the pericardium, a procedure with a significant peri-operative mortality rate of approximately 15%.4 South Africa is on the forefront of research on TB heart disease and has recently published the large, multi-centre IMPI trial.5 One of the goals of the IMPI trial was to assess the impact of corticosteroids in the management of TB pericarditis. The major findings of the study included (1) corticosteroids had no impact on mortality rates in patients with TB pericarditis, (2) corticosteroids decreased the incidence of pericardial constriction by 46%, and (3) HIV-positive patients who received corticosteroids had a significantly increased risk of developing HIV-associated malignancies. In established TB, early and effective treatment with shortcourse anti-TB therapy is the mainstay of management. Various strategies have been investigated as adjuncts to anti-TB drugs in the prevention of pericardial constriction. The ongoing discussions and numerous investigations into a wide array of agents as possible ‘magic bullets’ in the prevention of pericardial constriction (post-TB infection) illustrates both the interest in the field, and also the lack of a satisfying solution to this problem. The following strategies have previously been evaluated: Mycobacterium indicus pranii immunotherapy,5 corticosteroids,5 pericardiocentesis,6 open surgical drainage (pericardial window),7 thalidomide,8 instilling intrapericardial fibrinolytic therapies,9-11 and a wide array of non-steroidal anti-inflammatory medication. Not one of these therapies has, to date, been internationally

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recognised as an acceptable standard of therapy, and the choice of adjuvant treatment varies significantly among experts in the field. Colchicine is an inhibitor of microtubule polymerisation. It acts by binding to tubulin and is registered for the acute treatment of gout crystal arthropathies. The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described as treatment for arthritis in the Ebers Papyrus in 1500 BC.12 In modern medicine, colchicine has however played a wider role in the treatment of pericarditis of various aetiologies, both acute and chronic. This has been investigated in a prospective, randomised trial named COPE (Colchicine for Acute Pericarditis),13 and the major findings concluded that colchicine significantly reduced the recurrence rates and symptom persistence due to pericarditis. To date however, the use of colchicine has, to the best of our knowledge, never been systematically assessed in the context of pericardial TB. The purpose of this research was to assess the merit for the use of colchicine in the context of TB pericarditis.

Patients presenting to Kimberley Hospital with pericardial effusion (Aug 2013–Dec 2014) (n = 72) Assessment for inclusion and exclusion criteria

Study participants (n = 33) Baseline Investigation Pericardiocentesis if deemed safe Standard therapy Double-blinded randomisation

Colchicine (n = 19)

Methods This research was conducted in the Northern Cape province of South Africa at a secondary-level hospital in Kimberley between August 2013 and April 2015. The research was approved by the ethics committee of the University of the Free State and the study was registered with the National Health Research Committee. The research was conducted in accordance with the Declaration of Helsinki. This pilot study was designed as a prospective, doubleblind, randomised, control cohort. All patients presenting to the Kimberley Hospital complex (KHC) with pericardial effusions were assessed for inclusion and exclusion criteria. In the absence of contra-indications, patients underwent therapeutic pericardiocentesis if the procedure was deemed safe and possible. Standard therapy was initiated in accordance with the South African National Tuberculosis Management Guidelines:14 weight-adjusted anti-TB drugs (Rifafour®) and oral corticosteroids. (prednisone: 1.5 mg/kg per day for four weeks; 1.0 mg/kg per day for two weeks; 0.5 mg/kg per day for one week; 0.25 mg/kg per day for one week). HIV co-infected patients not previously on treatment were initiated on fixeddose combination (FDC) antiretroviral treatment six weeks after initiation of TB treatment (FDC: Tenofovir Disoproxil Fumarate 300 mg, Emtricitabine 200 mg and Efavirenz 600 mg). Patients were randomly assigned to the intervention group with the use of a web-based randomisation system that ensured assignment concealment. The intervention group received colchicine (dose 1.0 mg per day) for a total of six weeks, whereas the control group received a placebo for the same period (Fig. 1). Patients subsequently underwent serial echocardiographic examinations on an out-patient basis and adherence checks, including pill counts, were done at follow-up visits. The primary outcome assessed was the development of pericardial constriction and this diagnosis was made echocardiographically at four months post initial presentation. Upon completion of the follow-up period of all patients, the blinding was unveiled and data were presented for statistical analysis. Two groups of patients were included: (1) definite TB pericarditis: the presence of TB bacilli was observed on microscopic examination of pericardial fluid; cultures of

351

Placebo (n = 14)

Follow-up echocardiography. Primary outcome: pericardial constriction.

Statistical analysis

Fig. 1. Flow diagram illustrating study methodology.

pericardial fluid were positive for Rifampicin-sensitive Mycobacterium tuberculosis (MTB); pericardial fluid was positive for MTB on direct polymerase chain reaction (PCR) (Gene Xpert); and (2) probable TB pericarditis: proof of TB was found elsewhere (positive cultures for MTB on sputum or cerebrospinal fluid); pericardial fluid with adenine deaminase (ADA) level > 40 U/l; a total diagnostic index score > 6 on using the Tygerberg clinical prediction score (Table 1).15 The exclusion criteria were: patients with renal or hepatic impairment (creatinine clearance rate < 85 ml/min or transaminases > 1.5 upper limit of normal); and pregnant patients or patients intending to become pregnant within four months. The gold-standard diagnostic test for the diagnosis of CP is the demonstration of increased interventricular interdependence during cardiac catheterisation. Doppler echocardiography and other novel echocardiographic techniques have provided us with reliable non-invasive alternatives to the diagnosis of CP.

Table 1. The Tygerberg clinical prediction score for the diagnosis of TB pericarditis. A total diagnostic score > 6 yields a sensitivity of 82% and a specificity of 76% for the diagnosis of TB pericarditis Admission variable

Diagnostic index

Weight loss

Night sweats

Fever

Serum globulin > 40 g/l

Leukocyte count < 10 × 109

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Fig. 2. A . Tissue Doppler of the medial aspect of the mitral valve annulus demonstrating early diastolic tissue velocity of 0.14 m/s. B. Tissue Doppler of the lateral aspect of the mitral valve annulus showing early diastolic tissue velocity of 0.12 m/s. The lower tissue velocity on the lateral aspect is the opposite of the normal phenomenon (annulus reversus).

In this study, the diagnosis of CP was made by means of echocardiography by adhering to the principles in the article by Dal-Bianco et al. on the echocardiographic diagnosis of CP.16 Initial echocardiographic assessment ensured that no features of constriction were present at the time of enrolment in the study. Follow-up echocardiograms were performed four months after the initiation of therapy. The echocardiograms were performed and co-reviewed by two experienced echocardiographers (who had both attended a dedicated workshop at a tertiary-level academic hospital aimed at the echocardiographic diagnosis of CP). A GE Vivid E6® ultrasound machine was used to perform a systematic examination according to the basic minimum standards as stipulated by the British Society of Echocardiography.17 Numerous other echocardiographic parameters were assessed, including the presence of a septal shudder, respiratophasic septal shift, left atrial enlargement and echocardiographic features of pericardial thickening (Figs 2–4).

Fig. 3. P ulse-wave Doppler at the level of the mitral valve leaflet tips demonstrating a respiratophasic variation in the early diastolic transmitral inflow velocities in excess of 25%.

Statistical analysis Statistical analysis was performed by the Department of Biostatistics of the University of the Free State, Bloemfontein, South Africa. The SAS Version 8.3 was used. Groups were compared regarding outcomes using frequency tables with appropriate hypothesis testing (chi-squared of Fisher’s exact test) and 95% confidence intervals for differences in percentages. The standard deviation value p < 0.05 was considered significant.

Results Thirty-three patients met the initial inclusion criteria. Three patients passed away while in hospital and an additional three passed away during the follow-up period. In-patient deaths were due to neutropenic sepsis, cerebrovascular incident and nosocomial pneumonia, respectively. In all out-patient deaths, the cause was undetermined. Five patients were lost to follow up and one patient was removed from the study due to presumed drug side effects. A total of 21 patients completed the follow-up period (Fig. 5).

Fig. 4. Dilated and distended inferior vena cava. No respiratory variation was observed.

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The study population had a female preponderance (66% females) and the mean age of the studied patients was 31 years. Disseminated pericardial tuberculosis was found to be a disease exclusive to the immune-compromised in this cohort; all 21 patients were HIV positive. The median CD4+ count was 162 and 346 cells/mm3 in the colchicine and placebo groups, respectively. Of the 21 eligible participants, 12 had been assigned to the treatment group and the remaining nine were in the placebo group. The diagnosis of definite pericardial tuberculosis was made in 23.8% of the patients, while the remaining 76.2% were diagnosed on the basis of suggestive clinical and biochemical features (see inclusion criteria). Of the studied patients, 47.6% underwent pericardiocentesis, whereas the remaining 52.4% could not undergo safe pericardiocentesis. The average volume of fluid drained via single pericardial aspiration was 622 ml. The macroscopic appearance of the fluid varied from serosanguineous to haemorrhagic, reflecting the different pathological stages of development. Mycobacterium tuberculosis was proven on pericardial aspirates in 50% of cases, either by positive culture (30%) or by direct PCR technique (Gene Xpert) (20%) (Table 2). Pericardial constriction is the natural sequela of approximately 17 to 40% of TB pericardial infections.3 In our cohort, the incidence of pericardial constriction (demonstrated by echocardiography) four months after the initial diagnosis was 23.8%. Of the five patients who developed pericardial constriction, two were in the control group and the remaining

72 patients screened August 2013 – April 2015 39 not eligible 33

19 colchicine group

14 placebo group

In-patient deaths

Deaths during follow-up period

Lost to follow-up

1 drug induced liver injury

Total: 12 patients completing follow up (colchicine)

Total: 9 patients completing follow up (placebo)

Fig. 5. S creening, randomisation, follow up and analysis of the study patients.

Table 2. Pericardial fluid biochemistry Biochemical parameter

Average

Protein (g/l)

62.7

ADA (U/l)

96.6

LDH (U/l)

4494

7.3

Glucose (mmol/l)

2.8

Table 3. Two-by-two table demonstrating the primary study outcome Colchicine

Placebo

Constriction

No constriction

Total

three were in the group treated with colchicine. Of those who did not develop pericardial constriction, nine were in the colchicine group and seven were in the placebo group. The data from Table 3 yields a p-value of 0.88. The relative risk for developing constriction in the colchicine group compared to the intervention group was 1.07 (95% CI: 0.46–2.46). There was therefore no statistically demonstrable correlation between the use of colchicine and pericardial constriction in this study cohort. The side effects among the patients using colchicine were usually minor; 56% of the initial 19 patients who were in the colchicine group reported self-limiting diarrhoea during their hospital stay. Serious side effects were observed in one patient who developed hepatitis during his course of treatment. The patient was removed from the study and daily liver function testing showed a rapid recovery. Although the study was neither empowered nor designed to evaluate the effect of pericardiocentesis on the subsequent development of pericardial constriction, a very apparent and interesting finding was observed. We found that, with the exception of one patient, all those who developed pericardial constriction were in the group that did not undergo pericardiocentesis. Conversely, in the group that underwent pericardiocentesis, only one participant developed pericardial constriction. Pericardiocentesis therefore seemed to be very effective in the prevention of pericardial constriction and in this cohort only one patient (10%) who underwent pericardiocentesis developed constriction. These findings are observational and disregard the initial group allocations.

Discussion The proverbial ‘eureka moment’ in the management of TB pericarditis seems to be elusive. Numerous interventions have been postulated and investigated in an attempt to prevent the devastating post-inflammatory changes in the pericardium following TB pericarditis. In this pilot study, the merit of adding colchicine to the current management guidelines was investigated in a systematic manner. As all the participants of this study were HIV positive, the findings can only be applied to this subgroup of patients with TB pericarditis. There was a notable difference in the median CD4+ lymphocyte count between the treatment and placebo groups, but when assessed as an independent variable, no correlation could be demonstrated between degree of immunocompetency, as measured by CD4+ count, and the risk for development of constriction.

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This pilot study could not demonstrate any benefit derived from the addition of colchicine to the routine management of HIV-positive patients with TB pericarditis. The power of this pilot trial was insufficient to detect small differences in outcome; however, it appears that colchicine use has no correlation with the prevention or formation of post-TB CP. This pilot trial could not assess the beneficial effects of colchicine in the HIV-negative patient with TB pericarditis. After considering the findings of this pilot research, the costs of the drug, the polypharmacy these patients are exposed to, drug–drug interactions and side effects (albeit mild), this study would advise against the use of colchicine in the management of HIV-positive patients with TB pericarditis. The implementation of a pericardiocentesis until dryness (with or without extended drainage) was up to this point never studied in a controlled or comparative manner. Research conducted by Reuter et al.6 in 2007 found the first evidence to suggest the benefit of a pericardiocentesis until dryness with extended drainage. In their research, 162 patients with TB pericarditis underwent pericardiocentesis, and over a followup period of six years, only two patients (1.23%) developed fibrous pericardial constriction. The research concluded that echocardiographic-guided pericardiocentesis with extended drainage is a safe and effective management option, and when combined with short-course anti-tuberculous therapy, it almost completely prevents the development of CP. A few leading centres are employing a routine ‘pericardiocentesis until dryness’ approach based on this literature, whereas most do not. The interesting observation made in our pilot study was that the findings made by Reuters et al. in 2007 were reproducible on a much smaller scale. Pericardial constriction, although having a low incidence, was almost exclusively seen in the group that did not undergo pericardiocentesis (observational – disregard original group allocation). As suggested by some expert opinion and as supported by the data published by Reuters et al. and observational findings of our pilot trial, the practice of routine pericardiocentesis until dryness in the absence of contraindications appears to be the preferred management option and this might well be the long-awaited ‘eureka moment’, in an attempt to halt the development of pericardial constriction.

months. There may however be patients who will only develop constriction after four months. Research to address this aspect may be valuable. Corticosteroids were used as part of the standard therapy in all patients. However, subsequent to the initiation of the research, the IMPI trial brought to light their findings that corticosteroids should not be used in TB pericarditis in HIV-infected patients. The South African National TB guidelines published in 2014 still advised the use of corticosteroids in all patients and the findings of the IMPI trial had not yet been incorporated into current South African National Tuberculosis Management Guidelines.15

Conclusion Based on current research, the use of colchicine in addition to standard antituberculous therapy cannot be advised in the context of TB pericarditis in the HIV-positive population. The jury is still out on which adjuvant strategies may prove to be beneficial in the prevention of CP, especially in the HIV-coinfected subgroup. Based on observations from this research and some other studies, routine pericardiocentesis until dryness with extended drainage may prove to be the long-awaited solution to the common dilemma of post-TB CP. Our special thanks go to Ms Kassandra Barnard, Dr Danie Steenkamp and Dr Pieter van Der Bijl for technical assistance and quality control with the echocardiographic assessment of study participants. Our sincere gratitude goes to Mr Shaun Zeelie for supplying and monitoring the treatment of the participants.

References 1.

Global Health Education. TB Facts. tbfacts.org (Accessed 18 August 2015).

Maosi B, Burgess L, Doubell A. Heart disease in Africa – tuberculous

pericarditis.

Circulation

2005;

112:

doi:

10.1161/

CIRCULATIOHAHA.105.543066 (assessed 21 August 2015). 3.

Syed F, Mayosi B. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis 2007; 50(3): 218–236.

Mauyaba AK, Balkaran S, Cloete R, et al. Constrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Cape Town, South Africa: causes and perioperative outcomes in the HIV era (1990–

Limitations of the study The diagnosis of pericardial constriction was made with echocardiography, whereas the gold standard for diagnosing CP is invasive haemodynamic studies. Work done by Oh et al.18 and Boonyaratevej et al.19 demonstrated that one of the most characteristic findings of CP, a respiratory variation in early transmittal inflow velocity, is neither perfect in its sensitivity nor specificity for the diagnosis. In patients with markedly elevated left atrial pressures, the respiratory variation in the inflow velocities may be less than 25%. Furthermore, in patients with chronic obstructive pulmonary disease and severe right ventricular dysfunction, the variation may be elevated in the absence of CP. This research emphasises the importance of using a variety of recognised echocardiographic diagnostic tools to confirm a non-invasive diagnosis of CP. The duration of follow up was only four months. Some comparative research had follow-up periods of up to six years. Most patients who develop CP, do so in a period of three to four

2012). J Thorac Cardiovasc Surg 2014; 148(6): 3058–3065. 5.

Mayosi B, Ntsekhe M, Bosch J, Pogue J, Gumedze F, Badri M, et al. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014; 371(12): 1121–1130.

Reuter H, Burgess L, Louw V, Doubell A. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J Afr 2007; 18(1): 20–25.

Strang J, Kakaza H, Gibson D, Allen B, Mitchison D, Evans D, et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in the treatment of tuberculous pericardial effusion in Transkei. Lancet 1988; 2: 759–764.

Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995; 1: 384–397.

Mann-Segal DD, Shanahan EA, Jones B, Ramasamy D. Purulent pericarditis: rediscovery of an old remedy. J Thorac Cardiovasc Surg 1996; 111: 487–488.

10. Ekim H, Dermirbag R. Intrapericardial streptokinase for purulent peri-

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

355

lous pericarditis. Q J Med 2006; 99(12): 827–839.

carditis. Surg Today 2004; 34: 569–572. 11. Juneja R, Kothari SS, Saxena A, et al. Intrapericardial streptokinase in purulent pericarditis. Arch Dis Child 1999; 80: 275–277.

16. Dal-Bianco JP, Sengupta PP, Mookadam F, Chandrasekaran K, Tajik AJ, Khandheria BK. Role of echocardiography in the diagnosis of

12. Graham W, Roberts JB. Intravenous colchicine in the treatment of gouty arthritis. Ann Rheum Dis 1953; 12(1): 16–19.

constricitve pericarditis. J Am Soc Echocardiogr 2009; 22(1): 24–33. 17. BSE: A standard transthoracic echo. 2015. [online] Available at: http://

13. Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, et

www.bsecho.org/tte-minimum-dataset/ [Accessed 23 August 2015].

al. Colchicine in addition to conventional therapy for acute pericarditis –

18. Oh JK, Tajik JT, Christopher PA, Hatle LK, Nishimura RA, Seward

results of the Colchicine for Acute Pericarditis (COPE) trial. Circulation

JB. Preload reduction to unmask the characteristic Doppler features of constrictive pericarditis. Circulation 1997; 95: 796–799.

2005; 112: 2012–2016. 14. Guidelines: National Tuberculosis Management Guidelines. Health-e.

19. Boonyaratavej S, Oh JK, Tajik AJ, Appleton CP, Seward JB. Comparison

2015 [online] Available at: http://www.health-e.org.za/2014/06/10/guide-

of mitral inflow and superior vena cava Doppler velocities in chronic

lines-national-tuberculosis-manangement-guidelines/. [Accessed 23

obstructive pulmonary disease and constrictive pericarditis. J Am

August 2015].

Cardiol 1989; 63: 483–488.

15. Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tubercu-

Conﬁdence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 References: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). S4 XARELTO ® 10 (Film-coated tablets). Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. S4 XARELTO ® 15 and XARELTO ® 20 (Film-coated tablets). Reg. No.: XARELTO ® 15: 46/8.2/0111; XARELTO ® 20: 46/8.2/0112. Each film coated tablet contains rivaroxaban 15 mg (XARELTO ® 15) or 20 mg (XARELTO ® 20). PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM.01.2016.1265 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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Epidemiology and patterns of hypertension in semi-urban communities, south-western Nigeria MA Olamoyegun, R Oluyombo, SO Iwuala, SO Asaolu

Abstract Objective: To determine the prevalence and subtypes of hypertension among semi-urban residents in south-western Nigeria. Methods: All adults aged 18 years or older in 10 semi-urban communities were recruited for the study. The blood pressure (BP) reading taken with a validated electronic BP monitor after at least 10 minutes of rest was used in the analysis. Hypertension was defined as BP ≥ 140/90 mmHg. Results: Seven hundred and fifty subjects with a mean age of 61.7 ± 18.2 years participated in the study. The prevalence of hypertension was 55.5%. Stage 2 hypertension was the most common, present among 225 (54.1%) of the participants with hypertension, and 191 (45.9%) had stage 1 hypertension. Of those with hypertension, systolic–diastolic hypertension (SDH) was present among 198/416 (47.6%), while isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) were present among 181/416 (43.6%) and 37/416 (8.9%), respectively. The prevalence of hypertension increased significantly with age. Conclusion: The prevalence of hypertension was high in these semi-urban communities. Hence, increased awareness and integrating hypertension care into primary healthcare and other community health services in these areas may prove beneficial in ameliorating its adverse effects. Keywords: epidemiology, hypertension, pattern, semi-urban Submitted 4/6/15, accepted 22/3/16 Published online 11/5/16 Cardiovasc J Afr 2016; 27: 356–360

www.cvja.co.za

DOI: 10.5830/CVJA-2016-037

Ladoke Akintola University of Technology (LAUTECH), LAUTECH Teaching Hospital, Ogbomoso, Nigeria MA Olamoyegun, MB BS, FWACP, FACE, dryemi@yahoo.com, maolamoyegun@lautech.edu.ng

Department of Medicine, Endocrinology, Diabetes and Metabolism Unit, Lagos University Teaching Hospital, Idi Araba, Lagos, Nigeria SO Iwuala, MB BS, FWACP, FACE

Department of Internal Medicine, LAUTECH Teaching Hospital, Ogbomoso, Nigeria SO Asaolu, BSc

Department of Medicine, Federal Teaching Hospital, Ido Ekiti, Nigeria R Oluyombo, MB BS, FMCP

Hypertension is regarded as a major public health problem1 and is also an important threat to the health of adults in sub-Saharan Africa.2 Emerging evidence identifies hypertension as a major cause of morbidity and mortality globally, including sub-Saharan Africa.2-4 Hypertension is now recognised as one of the most important causes of cardiovascular diseases, accounting for almost 40% of the diseases on the African continent, including Nigeria.5,6 According to a World Health Organisation report, hypertension is the third cause of deaths, accounting for one in eight deaths worldwide.7 The overall worldwide burden of hypertension in the year 2000 was 26.4% of the adult world population, 34.3% in developed and 65.8% in developing countries.8 Also, about 62% of cardiovascular diseases (CVDs) and 49% of ischaemic heart disease (IHD) are attributable to suboptimal blood pressure (systolic blood pressure > 115 mmHg).9 Indeed, it has been projected that up to three quarters of the world’s hypertensive population will be in economically developing countries by the year 2025.10 Nigeria, due to its population size and the projected increase in the prevalence of hypertension, will face a huge economic health burden from hypertension. The prevalence of hypertension has been variously studied in Nigeria, however, most studies were done among urban and rural dwellers. In a review of hypertension prevalence in Nigeria by Akinlua et al.11 using a blood pressure cut-off value of 140/90 mmHg, the crude prevalence of hypertension ranged from 6.2 to 48.9% and 10.0 to 47.3% for males and females, respectively. Comparing urban versus rural differences in crude prevalence, estimates showed an overall prevalence ranging from 17.5 to 51.6% in urban areas and 4.6 to 43.0% in rural areas. There have been few studies done to determine the prevalence of hypertension among dwellers in semi-urban areas, which have mixtures of urban and rural areas. Our study therefore aimed to assess the prevalence and subtypes of hypertension among the population in semi-urban communities in south-western Nigeria. The findings in this study will further add to the available data on the increasing prevalence of hypertension in Nigeria, thereby stimulating increased effort by health policy makers to control the emerging health burden. This study could also demonstrate the need for prevention and control of hypertension in daily medical practice.

Methods This study was conducted in Ekiti State, located in the southwestern zone of Nigeria. The state is divided into three senatorial zones (Ekiti south, north and west). The study area, Ekiti north senatorial zone, is made up of five local government areas (Ido/ Osi, Ikole, Moba, Ilejemeje and Oye). A total of 10 communities (all semi-urban) were randomly selected within the senatorial district (two communities per local government area).

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A semi-urban community is one with a population of between 500 and 5 000, with basic amenities such as secondary and primary schools, electricity and a few primary healthcare (PHC) centres, with few private clinics.12 In a semi-urban community, most inhabitants are individuals with low socio-economic status, mainly artisans, traders and low-income workers who live in over-crowded areas with poor sanitary conditions. There is an adaption to a Western lifestyle in semi-urban communities compared to a rural community. This was a cross-sectional, community-based study in which 750 participants were recruited. At the community level, screening of residents who volunteered to participate was undertaken by trained interviewers until approximately equal numbers of participants were selected from each of the selected sites. A person not normally resident in the community was not included in the analysis (even if screened). Community approval and entry was facilitated after interacting with the heads of these communities, religious leaders and other community leaders and also by meeting with the health workers of PHCs available in these communities. The purpose of such meetings was to explain the aims of the study and obtain communal consent. The study was approved by the institutional ethics committee of the Federal Medical Centre, Ido-Ekiti. A questionnaire, which was researcher-developed and interviewer-administered, was used to obtain data from the participants. The questionnaire contained two parts, the first being demographic information including age, gender, occupation, monthly income and family history of hypertension. The second part involved measurement of height, weight, waist and hip circumferences, and blood pressure. Height was measured without shoes or headgear, using a wooden platform stadiometer ruled to the nearest 0.5 cm, while weight was measured to the nearest 0.5 kg using a weighing scale (Hanson HX5000 electronic bathroom scale). Body mass index (BMI) was calculated as weight (kg) divided by the square of the height in metres (m2). Waist circumference (WC) was measured to the nearest 0.1 cm, at the midpoint between the costal margin and iliac crest, at the end of normal expiration, using a non-stretchable measuring tape. Hip circumference (HC) was measured at the level of the greater trochanters (widest diameter of hips) to the nearest 0.1 cm with a measuring tape, while the subject was standing with the arms by the side and feet together.13,14 The waistto-hip ratio (WHR) was calculated from WC:HC Blood pressure was measured on the left arm in a seated position with the subjects in a relaxed state, using a validated electronic blood pressure monitor (Omron MX2 Basic, Omron Healthcare Co, Ltd, UK). A standard aneroid sphygmomanometer with an adult cuff size (Medicare instrument, NUXI, Ltd, China) was used to confirm the reading by electronic monitor. Blood pressure was classified according to the seventh Joint National Committee and Treatment of High Blood Pressure (JNC7)15 criteria into normal, prehypertension, stage 1 hypertension and stage 2 hypertension. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg and/or concomitant use of antihypertensive medications.16

357

variables are expressed as means ± standard deviation (SD) while categorical variables are presented as frequencies and percentages. Comparison for statistical significance was done with the Student’s t-test for continuous variables that were normally distributed, or Chi-square analysis for categorical variables. All tests were two-tailed with p < 0.05 taken as statistical significance.

Results A total of 856 participants were encountered for the study but only 750 participants had complete data for analysis, which represented a response rate of 87.6%. The majority were females (529, 70.5%). The mean age of the participants was 61.7 ± 18.2 years. Farmers and petty traders dominated the occupation of the participants (520, 68.4%). With regard to educational level, the majority (77.6%) had either no formal education or

Table 1. Sociodemographic and clinical characteristics of the study population Variable

All (n = 750)

Male (n = 218)

Female (n = 542)

p-value

Age (years) < 20

5 (0.7)

3 (60.0)

2 (40.0)

20–40

112 (14.9)

41 (36.9)

70 (63.1)

41–60

212 (28.3)

53 (25.6)

154 (74.4)

> 60

421 (56.1)

120 (29.1)

293 (70.9)

61.7 ± 18.2

60.0 ± 20.0

62.4 ± 17.3

Mean age ± SD

0.072

0.090

Marital status Single

45 (6.0)

31 (68.9)

14 (31.1)

Married

434 (57.9)

177 (40.8)

257 (59.2)

Widow/widower

268 (35.7)

11 (4.1)

257 (95.9)

3 (0.4)

2 (66.7)

1 (33.3)

Unemployed

85 (11.3)

14 (16.5)

71 (83.5)

Petty trader

309 (41.2)

9 (2.9)

300 (97.1)

Farmer

Divorced

< 0.001

Occupation

211 (28.1)

111 (52.6)

100 (47.4)

Unskilled labourer

52 (6.9)

35 (67.3)

17 (32.7)

Clerk/typist

1 (0.1)

1 (100.0)

0 (0.0)

Professional

40 (5.3)

16 (40.0)

24 (60.0)

Other

52 (6.9)

35 (67.3)

17 (32.7)

None

413 (55.1)

89 (21.5)

324 (78.5)

Primary

169 (22.5)

54 (32.0)

115 (68.0)

Secondary

107 (14.3)

52 (48.6)

55 (51.4)

61 (8.1)

26 (42.6)

35 (57.4)

< 20 000

626 (83.5)

159 (25.4)

467 (74.6)

20 000–40 000

89 (11.9)

40 (44.9)

49 (55.1)

41 000–60 000

26 (3.5)

16 (61.5)

10 (38.5)

61 000–00 000

6 (0.8)

5 (83.3)

1 (16.7)

> 100 000

3 (0.4)

1 (33.3)

2 (66.7)

< 25

525 (70.0)

172 (77.8)

353 (66.7)

25–29.9

161 (21.5)

44 (19.9)

117 (22.1)

< 0.001

Educational level

Tertiary

< 0.001

Income (Naira) < 0.001

BMI (kg/m2)

≥ 30 Mean BMI (kg/m2) Mean WC (cm)

< 0.001

64 (8.5)

5 (2.3)

59 (11.2)

23.4 (5.5)

22.6 (5.5)

23.7 (5.5)

0.015

85.7 (11.9)

83.3 (9.6)

86.7 (12.7)

< 0.001

Statistical analysis

Mean WHR

0.93 (0.36)

0.93 (0.06)

0.93 (0.43)

0.919

Mean SBP (mmHg)

142.4 (28.6)

142.3 (28.7)

142.4 (28.5)

0.976

The Statistical Package for Social Sciences software version 17 (SPSS Inc, Chicago, IL) was used for data analysis. Continuous

Mean DBP (mmHg)

81.6 (14.2)

81.1 (15.0)

81.8 (13.8)

0.534

Fisher’s exact, values are mean (SD) or n (%).

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Normal (15.1%) Stage 2 (30.0%) Systolic–diastolic hypertension (47.6%)

Prehypertension (29.1%)

Stage 1 (25.5%)

Fig. 1. Prevalence of hypertension according to JNC7.

primary school as the highest educational level attained. Only six (0.8%) persons were current smokers. The sociodemographic characteristics of the subjects are shown in Table 1. Mean BMI, WC, WHR, SBP and DBP of the study participants were 23.4 ± 5.5 kg/m2, 85.7 ± 11.9 cm, 0.93 ± 0.36, 142.4 ± 28.6 mmHg and 81.6 ± 14.2 mmHg, respectively. Out of the 750 participants, 116 (15.5%) had normal blood pressure, 218 (29.0%) had prehypertension and 416 (55.5%) had hypertension. Of the study participants, 195 (26.0%) had been diagnosed with hypertension previously, 81 (10.9%) were on antihypertensive medication, and 24 (3.2%) had a positive family history of hypertension. Twenty (2.6%) said they were taking herbal remedies for hypertension. The proportion of those on antihypertensive medication who had good blood pressure control of ≤ 140/90 mmHg was 22.0%. Of the participants with hypertension, isolated systolic hypertension (ISH) was present among 181/416 (43.6%) while isolated diastolic hypertension (IDH) and systolic–diastolic hypertension (SDH) were present among 37 (8.9%) and 198 (47.6%), respectively (Fig. 1). Stage 2 hypertension was the most common, being present among 225 (54.1%) of the participants with hypertension. Of those with hypertension 191 (45.9%) had stage 1 hypertension (Fig. 2). Table 3 shows the gender and sociodemographic relationships of the hypertension subtypes. ISH (67.4%) and IDH (59.5%) were more prevalent among females compared to males. Also, participants with ISH were significantly older than those with IDH (p = 0.014). After adjusting for confounding variables, factors associated with hypertension among the study participants were age group, educational level and body mass index (BMI) (Table 2).

Discussion This study assessed the prevalence and pattern of hypertension in its different subtypes in semi-urban communities in south-

Isolated systolic hypertension (43.6%)

Isolated diastolic hypertension (8.9%)

Fig. 2. Prevalence of hypertension according to subtypes.

western Nigeria. The majority of the participants were females, as is common in most cross-sectional studies. Married petty traders made up the majority of the population, which was not unusual, as most people living in semi-urban areas participate in business and petty trading. Slightly more than half

Table 2. Predictors of hypertension among the study participants No hypertension (n = 334)

Hypertension (n = 416)

p-value

Male

96 (28.7)

125 (30.0)

0.697

Female

238 (71.3)

291 (70.0)

Variable Gender

Age (years) < 20

4 (1.2)

1 (0.2)

82 (24.6)

30 (7.2)

41–60

98 (29.3)

114 (27.4)

> 60

150 (44.9)

271 (65.1)

20–40

< 0.001

Marital status Single

25 (7.5)

20 (4.8)

309 (92.5)

396 (95.2)

None

152 (45.5)

261 (62.7)

Primary

84 (25.1)

85 (20.4)

Secondary

62 (18.6)

45 (10.8)

Tertiary

36 (10.8)

25 (6.0)

< 20 000

272 (81.4)

354 (85.1)

20 000–40 000

43 (12.9)

46 (11.1)

41 000–60 000

15 (4.5)

11 (2.6)

61 000–100 000

2 (0.6)

4 (1.0)

> 100 000

2 (0.6)

1 (0.2)

< 25

172 (77.8)

353 (66.7)

25–29.9

44 (19.9)

117 (22.1)

5 (2.3)

59 (11.2)

Married/widow/widower/divorced

0.084

Educational level < 0.001

Average family income (Naira) 0.472

BMI (kg/m2)

≥ 30

< 0.001

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Table 3. Comparison of sociodemographic and clinical characteristics according to hypertension subtypes Variable

Both (n = 198)

IDH (n = 37)

ISH (n = 181)

p-value

Age (years)

68.2 (13.7)

61.4 (18.4)

64.4 (17.6)

0.014 0.117

Gender Male, n (%)

51 (25.8)

15 (40.5)

59 (32.6)

Female, n (%)

147 (74.2)

22 (59.5)

122 (67.4)

Educational level None

133 (67.2)

18 (48.6)

110 (60.8)

Primary

38 (19.2)

10 (27.0)

37 (20.4)

Secondary

17 (8.6)

4 (10.8)

24 (13.3)

Tertiary

10 (5.1)

5 (13.5)

10 (5.5)

0.199

Income (Naira) < 20 000

174 (87.9)

29 (78.4)

151 (83.4)

20 000–40 000

18 (9.1)

7 (18.9)

21 (11.6)

0.512

41 000–60 000

4 (2.0)

1 (2.7)

6 (3.3)

61 000–100 000

1 (0.5)

0 (0.0)

3 (1.7)

> 100 000

1 (0.5)

0 (0.0)

Mean BMI (kg/m2)

23.4 (5.3)

24.1 (5.1)

23.7 (7.3)

0.823

Mean WC (cm)

87.3 (11.2)

88.9 (10.5)

86.5 (12.7)

0.483

Mean WHR

0.94 (0.15)

0.95 (0.05)

0.92 (0.07)

0.109

Mean SBP (mmHg)

169.8 (25.3)

125.5 (9.1)

158.3 (17.2)

< 0.001

Mean DBP (mmHg)

98.9 (9.9)

92.4 (4.4)

78.6 (7.8)

< 0.001

359

that only 26% of individuals with hypertension had been diagnosed previously, 10.9% were on antihypertensive treatment, while 22% were controlled (BP ≤ 140/90 mmHg). This finding demonstrates a high proportion of undiagnosed, untreated and poorly controlled hypertension in Nigeria, a problem that has been reported by others. For instance, good hypertension control could only be achieved in 24.2% of the patients seen in a Port Harcourt hospital.30 Ekwunife et al.31 also found only 23.7 and 17.5% of males and females, respectively, with hypertension were on antihypertensive treatment, while 5.0% of males and 17.5% of females with hypertension were controlled. In the present study, participants with IDH were significantly younger than those with ISH. This is in keeping with a similar study done by Adeoye et al.,32 who found subjects with IDH to be significantly younger among the hypertensive patients in Ibadan. The strength of this study is in its relatively moderate sample size that was spread across many communities. It however has some limitations. Many of the participants were illiterate with no recorded biodata, so the age given may not be accurate. Also, participation in this study was voluntary, which might have influenced the results.

Conclusion of the population had no formal education, limiting their access to quality information about healthy lifestyles. Although the government is putting efforts into increasing awareness in these rural and semi-urban settlements,17,18 health education is still largely inadequate. Estimates from our study showed that 55.5% of the adults had hypertension, with SDH being the commonest subtype. This prevalence was much higher than the 29.7% reported by Adedoyin et al.19 in south-western Nigeria, and the 46.4% reported by Ejim et al.20 in south-eastern Nigeria. This higher prevalence may have been related to participants being older in our study compared to these other studies (61.6 vs 41.5 years and 61.6 vs 59.8 years, respectively). Many studies have recorded a high prevalence of hypertension among elderly participants. For example, Peltzer et al.21 in a study among the elderly in 2008 recorded a high prevalence of hypertension (77.3%, mean age 65 years). Other studies reported higher prevalence rates of hypertension among older adult population surveys in Tanzania in 2010 (69.9%, mean age 76 years), Tunisia in 2003 (69.3%, mean age 69 years) and Senegal in 2009 (65.4%, mean age 69.5 years).22-24 Similar to Banegas et al.25 and Onwubere et al.,26 a larger percentage of participants in our study had ISH compared to IDH. ISH was also more common in those above 60 years of age, compared to IDH. Age is known to significantly influence the prevalence and pattern of elevated blood pressure, therefore SBP tends to increase with advancing age as a result of loss of arterial compliance, while DBP tends to plateau or decrease after 50 years of age. The decrease in compliance results in higher SBP. An increase in peripheral resistance is also known to result in elevated DBP, whereas loss of elasticity in the large vessels causes a reduction with increasing age. Therefore the net effect of these opposing factors may results in a normal or near-normal DBP,27,28 depending on the predominant factor. The prevalence of ISH obtained in this study is much higher than in a study by Tesfaye et al.29 Our study showed

The estimate of prevalence of hypertension obtained in this study was higher than in most other studies in Nigeria, which is contrary to the existing trend of low prevalence found many years ago in semi-urban communities. The predominant patterns of hypertension observed were both SDH and ISH. The prevalence of hypertension was found to increase with age, therefore age was a significant predictor of hypertension among these subjects. Hypertension, because of its high prevalence, deserves to be the health priority of policy makers. Therefore policy makers and other stakeholders in the health sector need to urgently institute community-based strategies towards creating awareness of hypertension, encouraging health-seeking behavioural habits, and educating people on the main risk factors such as unhealthy diet, high salt intake and sedentary lifestyles. It is important that the findings of this study prompt appropriate response at state and national levels, towards improved detection, control and management of hypertension in Nigeria.

References 1.

Murray CJ, Lopez AD. Mortality by cause for eight regions of the world. Global burden of disease. Lancet 1997; 349: 1269–1276.

Cappuccio FP, Cook DG, Atkinson RW, Stuzzullo P. Prevalence, detection, and management of cardiovascular risk factors in different ethnic groups in South London. Health 1997; 78: 555–563.

Cooper R, Rotimi C, Ataman S, McGee D, Osotimehin B, Kadiri S, et al. The prevalence of hypertension in seven populations of West African origin. Am J Public Health 1997; 87(2): 160–168.

Olatunbuson ST, Kaufman JS, Cooper RS, Bella AF. Hypertension in a black population: Prevalence and biosocial determinants of high blood pressure in a group of urban Nigerians. J Hum Hypertens 2000; 14: 249–257.

Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005; 112(23): 3562–3568.

Esayas K, Yadani M, Sahilu A. Prevalence of hypertension and its risk

360

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

factors in southwest ethiopia: a hospital-based cross-sectional survey.

al. Prevalence of Cardiovascular Risk Factors in the Middle-Aged and

Integrated Blood Pres Contr 2013; 6: 111–117.

Elderly Population of a Nigerian Rural Community. J Trop Med 2011;

Psaltopoulou P, Orfanos P, Naska A, Lenas D, Trichopoulos D,

2011: 308687. doi:10.1155/2011/308687.

Trochopoulos A. Prevalence, awareness, treatment and control of hyper-

21. Peltzer K, Phaswana-Mafuya N. Hypertension and associated factors in

tension in a general population sample of 26913 adults in the Greek

older adults in South Africa. Cardiovasc J Afr 2013; 24(3): 66–71. doi:

EPIC study. Int J Epidemiol Assoc 2004; 33(6): 1345–1352. 8.

AFRICA

Hajjar I, Kfotchen JM, Kotchen TA. Hypertension: trends in preva-

10.5830/cvja-2013-002. 22. Dewhurst MJ, Dewhurst F, Gray WK, Chaote P, Orega GP, et al. The

lence, incidence, and control. A Rev Public Health 2006; 27: 465–490.

high prevalence of hypertension in rural-dwelling Tanzanian older

Tesfaye F, Nawi NG, Minh HV, Byass P, Berhane Y, Bonita R, et al.

adults and the disparity between detection, treatment and control: A

Association between body mass index and blood pressure across three

rule of sixths? J Hum Hypertens 2013; 27(6): 374–380. doi: 10.1038/

populations in Africa and Asia. J Hum Hypertens 2007; 21: 28–37.

jhh.2012.59.

10. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK.

23. Laouani Kechrid C, Hmouda H, Ben Naceur MH, Ghannem H, Toumi

Global burden of hypertension: analysis of worldwide data. Lancet

S, et al. [High blood presure for people aged more than 60 years in the

2005; 365: 217–23.

district of Sousse]. Tunisie Medicale 2004 82: 1001–1005.

11. Akinlua JT, Meakin R, Umar AM, Freemantle N. Current prevalence

24. Macia E, Duboz P, Gueye L. Prevalence, awareness, treatment and

pattern of hypertension in Nigeria: A systematic review. PLoS ONE

control of hypertension among adults 50 years and older in Dakar,

10(10): e0140021. doi.1371/journal.pone.0140021.

Senegal. Cardiovasc J Afr 2012; 23: 265–269. doi: 10.5830/cvja-2011-039.

12. Akande TM, Sekoni OO. A survey of birth and death registration in

25. Banegas JR, Cruz de la JJ, Rodríguez-Artalejo F, Graciani A, Guallar-

a semi-urban settlement in Middle-Belt Nigeria. Eur J Sci Res 2005;

Castillón P, Herruz R. Systolic vs diastolic blood pressure: community

8(2): 56–61.

burden and impact on blood pressure staging. J Hum Hypertens 2002;

13. Bowring AL, Peters A, Freak-Poll R, Lim MSC, Gouillou M, Hellard

16(3): 163–167.

M. Measuring the accuracy of self-reported height and weight in a

26. Onwubere BJC, Ejim EC, Okafor CI, Emehel A, Mbah AU, Onyia U,

community-based sample of young people. BMC Med Res Methodol

et al. Pattern of blood pressure indices among the residents of a rural

2012; 12: 175.

community in South East Nigeria. Int J Hypertens 2011; 2011: 621074.

14. Himes JH. Challenges of accurately measuring and using BMI and

doi:10.4061/2011/621074.

other indicators of obesity in children. Pediatrics 2009; 124(1): S3–S22.

27. Messerli FH, Sundgaard Riise K, Ventura HO. Essential hypertension in

15. Chobanian AV, Bakris JL, Black HR, Cushman WC, Green LA, Izzo

the elderly: haemodynamics, intravascular volume, plasma renin activity,

JL. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc 2003; 289: 2560. 16. Giles TD, Materson BJ, Cohn JN, Kostis JB. Definition and classification of hypertension: an update. J Clin Hypertens (Greenwich) 2009; 11: 611–614. 17. Babalola YT, Babalola AD, Okhale FO. Awareness and Accessibility

and circulating catecholamine levels. Lancet 1983; 2(8357): 983–985. 28. Grassi G, Seravalle G, Bertinieri G, et al. Sympathetic and reflex alterations in systo-diastolic and systolic hypertension of the elderly. J Hypertens 2000; 18(5): 587–593. 29. Tesfaye F, Byass P, Wall S. Population based prevalence of high blood pressure among adults in Addis Ababa: uncovering a silent epidemic. BMC Cardiovasc Disorders 2009; 9: 39.

of Environmental Information in Nigeria: Evidence from Delta State.

30. Ordinioha B. The prevalence of hypertension and its modifiable risk

Library Philosophy and Practice 2010. Paper 460. http://digitalcommons.

factors among lecturers of a medical school in Port Harcourt, south-

unl.edu/libphilprac/460. ISSN 1522 – 0222.

south Nigeria: Implications for control effort. Niger J Clin Pract 2013;

18. Abdulraheem IS, Olapipo AR, Amodu MO. Primary health care services in Nigeria: Critical issues and strategies for enhancing the use by the rural communities. J Public Health Epidemiol 2012: 4(1); 5–13. 19. Adedoyin RA, Mbada CE, Ismaila SA, Awotidebe OT, Oyeyemi AL,

16: 1–4. 31. Ekwunife O, Udeogaranya P, Nwatu I. Prevalence, awareness, treatment and control of hypertension in a Nigerian population. Health 2010: 731–735. doi:10.4236/health.2010.2711.

Ativie RN. Prevalence of cardiovascular risk factors in a low-income

32. Adeoye AM, Adebiyi A, Tayo BO, Salako BL, Ogunniyi A, Cooper

semi-urban community in the north-east Nigeria. TAF Prev Med Bull

RS. Hypertension Subtypes among Hypertensive Patients in

2012; 11(4): 463–470.

Ibadan. Int J Hypertens 2014; 2014: 295916. Article ID: 295916.

20. Ejim EC, Okafor CI, Emehel A, Mbah AU, Onyia U, Egwuonwu T, et

doi:10.1155/2014/295916

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Uncontrolled hypertension among patients managed in primary healthcare facilities in Kinshasa, Democratic Republic of the Congo TM Kika, FB Lepira, PK Kayembe, JR Makulo, EK Sumaili, EV Kintoki, JR M’Buyamba-Kabangu

Abstract Background: Uncontrolled hypertension remains an important issue in daily clinical practice worldwide. Although the majority of patients are treated in primary care, most of the data on blood pressure control originate from populationbased studies or secondary healthcare. Objective: The aim of this study was to evaluate the frequency of uncontrolled hypertension and associated risk factors among hypertensive patients followed at primary care facilities in Kinshasa, the capital city of Democratic Republic of the Congo. Methods: A sample of 298 hypertensive patients seen at primary healthcare facilities, 90 men and 208 women, aged ≥ 18 years, were consecutively included in this cross-sectional study. The majority (66%) was receiving monotherapy, and diuretics (43%) were the most used drugs. According to 2007 European Society of Hypertension/European Society of Cardiology hypertension guidelines, uncontrolled hypertension was defined as blood pressure ≥ 140/90 or ≥ 130/80 mmHg (diabetes or chronic kidney disease). Logistic regression analysis was used to identify the determinants of uncontrolled hypertension. Results: Uncontrolled hypertension was observed in 231 patients (77.5%), 72 men and 159 women. Uncontrolled systolic blood pressure (SBP) was more frequent than uncontrolled diastolic blood pressure (DBP) and increased significantly with advancing age (p = 0.002). The proportion of uncontrolled SBP and DBP was significantly higher in patients with renal failure (p = 0.01) and those with high (p = 0.03) to very high (p = 0.02) absolute cardiovascular risk. The metabolic syndrome (OR 2.40; 95% CI 1.01–5.74; p = 0.04) emerged as the main risk factor associated with uncontrolled hypertension. Conclusion: Uncontrolled hypertension was common in this case series and was associated with factors related to lifestyle and diet, which interact with blood pressure control.

Division of Cardiology, University of Kinshasa Hospital, Kinshasa, Democratic Republic of the Congo TM Kika, MD EV Kintoki, MD JR M’Buyamba-Kabangu, MD

Division of Nephrology and Hypertension, Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo FB Lepira, MD, PhD, lepslepira@yahoo.fr JR Makulo, MD EK Sumaili, MD

Department of Internal Medicine, University of Kinshasa, Kinshasa, Democratic Republic of the Congo PK Kayembe, MD

Keywords: uncontrolled hypertension, risk factors, primary care, black Africans Submitted 9/8/14, accepted 22/3/16 Cardiovasc J Afr 2016; 27: 361–366

www.cvja.co.za

DOI: 10.5830/CVJA-2016-036

Hypertension is the most prevalent treatable cause of cardiovascular (CVD) and chronic kidney disease (CKD).1 Controlling hypertension leads to significant reduction in the prevalence and incidence of target-organ damage (TOD) and mortality from CVD.1 Despite the availability of effective antihypertensive treatments and guideline recommendations on the management of high blood pressure, hypertension remains one of the most poorly controlled risk factors in patients with and without CVD.1 This highlights the need to consider lifestyle and diet as well as tolerance and adherence to treatment with several antihypertensive drugs.1 Controlling hypertension often requires the use of several antihypertensive agents, especially in elderly patients or those with stroke or diabetes.1 Patients with hypertension and one or more co-morbidities increasingly form a significant part of the primary care practitioner’s case load.2 Insufficient blood pressure control remains an important issue in daily clinical practice worldwide.3 However, most of the international data on blood pressurecontrol studies originate from national surveys, populationbased studies or secondary healthcare, despite the fact that the majority of patients are treated in a primary care (PC) setting.3 Therefore, data on hypertension treatment and control from PC are awaited. In Democratic Republic of the Congo (DRC), despite the ever-growing prevalence of hypertension, data on uncontrolled hypertension are scarce and rely upon few population-based studies.4-6 Therefore, the objective of this study was to evaluate the frequency of uncontrolled hypertension and associated risk factors among hypertensive patients followed at primary care facilities in Kinshasa, the capital city, with an estimated population of 10 million.

Methods From 30 April to 24 August 2012, all consecutively appearing patients with known hypertension and regularly followed at healthcare centres of the Roman Catholic Church Network (BDOM) were asked to participate in this cross-sectional study. Inclusion criteria were: age ≥ 18 years, being on antihypertensive treatment for at least three months, and giving a written informed consent to participate in the study.

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Data were obtained using a standard questionnaire, which collected information on age, gender, education level, duration of hypertension, the number and class of drugs taken for hypertension or other conditions, compliance with antihypertensive drugs, family history of hypertension (FH-HT), diabetes (FH-DM) or cardiovascular disease (CVD), smoking and alcohol use, and physical activity. A physical examination was performed on each patient to measure height, weight, waist circumference (WC), blood pressure and pulse rate. Height and weight were measured with reference to recommended procedures. Body mass index (BMI) was calculated as weight (kg)/height2 (m). Overweight and obesity were defined as BMI > 25 and > 30 kg/m².7 Waist circumference (WC) was taken to the nearest 1 cm, using a tape measure. Central obesity was defined as WC > 94 cm in men and > 80 cm in women.8 Seated blood pressure (BP) was measured using an electronic device, OMRON M3 Intellisense (OMRON Health, Vietnam), on the left arm at the level of the heart after five minutes’ rest. BP was measured three times and the mean of the last two readings was used for analysis. Pulse pressure (PP) was calculated as systolic (SBP) minus diastolic blood pressure (DBP). Mean arterial pressure (MAP) was DBP + PP divided by 3. While on their usual diet, a venous blood sample was taken from an antecubital vein for the determination of levels of serum uric acid, cholesterol and its sub-fractions, and triglycerides using enzymatic methods (Biomérieux France). Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula.9 For estimated glomerular filtration rate (eGFR) determinations, the abbreviated equation from the MDRD study was used.10 We calibrated the creatinine results measured using the Jaffe method against a traceable isotope dilution mass spectrometry (IDMS) enzymatic method (creatinine +, Roche enzymatic diagnostics) as described elsewhere.11 Recalibrated serum creatinine values were thereafter computed for each participant and the new MDRD study equation was used for estimation of eGFR as 175 × [serum creatinine level (mg/ dl)] – 1.154 × [age (years)] – 0.203. For women and for blacks (all patients in our study), the product of this equation was multiplied by a correction factor of 0.742 and 1.21, respectively. All analyses were performed at the National Laboratory of the National AIDS Control Program. Capillary blood glucose was determined using Accu-chek Compact plus glucometer (Roche Diagnostica, Manheim, Germany) with the glucose oxidase method. Reactive Dipstick Condor Teco (Condor Teco Medical Technology Co, China) was used to determine semi-quantitative proteinuria. A resting electrocardiogram (ECG) was performed for each patient and the Sokolow index was calculated. The 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines12 were used to evaluate global cardiovascular (CV) risk in the study population. Subjects were classified as having: controlled SBP and DBP if current antihypertensive treatment was accompanied by clinic SBP < 140 mmHg and clinic DBP < 90 mmHg; uncontrolled SBP only if SBP was ≥ 140 mmHg and DBP < 90 mmHg; uncontrolled DBP only if DBP was ≥ 90 mmHg and SBP < 140 mmHg; uncontrolled SBP and DBP if SBP and DBP were ≥ 140 mmHg and ≥ 90 mmHg, respectively.12

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The metabolic syndrome was defined according to International Diabetes Federation criteria.8 Diabetes was defined as blood glucose level ≥ 126 mg/dl (6.99 mmol/l) or current use of antidiabetic drugs.13 Excessive alcohol intake was defined by regular intake of two or more glasses per day of beer or equivalent for at least one year, knowing that one glass of beer contains 10 g of alcohol.14 Smoking was defined as regular consumption of at least one cigarette per day for more than five years or having stopped smoking for less than five years.15 Physical activity in leisure time was categorised as active for subjects who exercised for at least four hours per week, and inactive or sedentary for all the others.16 Compliance with therapy was defined as self-reported regular intake of antihypertensive drugs. ECG-determined left ventricular hypertrophy (ECG-LVH) was defined as a Sokolow index > 35 cm.17 According to K/DOQI guidelines,18 chronic kidney disease (CKD) and renal failure (RF) were defined as eGFR < 90 and < 60 ml/min/1.73 m², respectively. According to the 2007 ESH/ESC guidelines,12 moderate, high and very high absolute CV risk were defined as 10–20, 20–30 and ≥ 30% probability of a CV event in the next 10 years, respectively. Proteinuria was defined as dipstick proteinuria ≥ 1+.19 The study was conducted in accordance with the principles of the 18th World Assembly (Helsinki, 1964). The study protocol was submitted to the ethics committee of Kinshasa School of Public Health of the University of Kinshasa and received clearance under the number ESP/CE/024/2012.

Statistical analysis Data are expressed as mean ± standard deviation (SD) or relative frequency (%). Chi-squared and Student’s t-tests were used to compare categorical and continuous variables, respectively. Skewed continuous variables were compared using the non-parametric Mann–Whitney test. Stepwise logistic regression analysis was used to identify correlates of uncontrolled hypertension; odds ratio (OR) and confidence interval (CI) were obtained for each independent variable. To remain in the model a factor had to reach a p-value ≤ 0.05. All statistical analyses were performed with SPSS version 20 for Windows at the Division of Epidemiology and Biostatistics of Kinshasa School of Public Health, University of Kinshasa.

Results A total of 298 hypertensive patients, 208 women and 90 men, were recruited in this study. Clinical characteristics of the study population as a whole are given in Table 1. Their mean age was 64 ± 10 years; they had on average a BMI of 26 ± 5 kg/m², a WC of 90 ± 11 cm, a SBP of 151 ± 24 mmHg and a DBP of 87 ± 14 mmHg. A family history of hypertension or diabetes was present in 50 and 31% of patients, respectively. In 67% of patients, the duration of hypertension was less than 10 years. The majority of patients (66%) were receiving monotherapy, most with diuretics (43%) (Table 2). Of the 34% of patients on combined therapy, a notable proportion (17%) was receiving a fixed combination of an angiotensin converting enzyme and a thiazide diuretic. With regard to non-antihypertensive drugs, 29, 9 and 6% of

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Table 1. Clinical characteristics of the study population as a whole and by blood pressure control status

Variable

Whole group (n = 298)

Controlled HT (n = 67)

Uncontrolled HT (n = 231)

64 ± 10

Age, years Gender, % Males

Females

DHT, %

0.548 0.179

< 1 year

1–4 years

5–9 years

≥ 10 years

FH-HT, %

0.851

FH-DM, %

0.166

BMI, kg/m²

26 ± 5

25 ± 5

0.238

WC, cm

90 ± 11

0.953

SBP, mmHg

151 ± 24

122 ± 10

160 ± 20

0.001

DBP, mmHg

87 ± 14

75 ± 7

91 ± 13

0.001

MBP, mmHg

109 ± 16

91 ± 7

114 ± 13

0.001

PP, mmHg

64 ± 19

47 ± 9

69 ± 18

0.001

Pulse rate, bpm

76 ± 13

77 ± 12

77 ± 13

0.493 0.171

AntiHT regimen, % 1 drug

≥ 2 drugs

Non-drug compliance, %

0.050

Data are expressed as mean ± standard deviation (SD) or relative frequency (%). DHT, duration of hypertension; FH-HT, family history of hypertension; FH-DM, family history of diabetes mellitus; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; bpm, beats per minute; AntiHT, antihypertensive.

patients were on antidiabetic, non-steroidal anti-inflammatory and antiplatelet drugs, respectively. A sizeable proportion of treated patients (42%) self-reported non-compliance with antihypertensive therapy. Uncontrolled hypertension was observed in 231 patients (77.5%), 72 men and 159 women, of whom 43, 24 and 5% had uncontrolled SBP and DBP, isolated uncontrolled SBP and isolated uncontrolled DBP, respectively (Table 1). The frequency of uncontrolled SBP and DBP was significantly higher in patients with reduced eGFR (62.5 vs 43.2%; p = 0.01) in comparison with those with relatively normal renal function

(n = 298)

Non-antihypertensive drugs

Lipid-lowering drugs, %

Diuretic, %

Uric acid-lowering drugs, %

CCB, %

Antiplatelet drugs, %

ACEI, %

NSAIDs, %

Monotherapy, %

CAA, %

Diuretic + ACEI, %

Diuretic + CCB, %

ACEI + CCB, %

Others, %

Antidiabetic drugs,

0.3 0

Data are expressed as relative frequency (in percent). CCB, calcium channel blocker; ACEI, angiotensin converting enzyme inhibitor; CAA, central-acting agents; NSAID, non-steroidal anti-inflammatory drugs.

(Fig. 1). Uncontrolled SBP increased significantly (p = 0.002) with advancing age (Fig. 2). Compared to patients with controlled hypertension (Table 3), those with uncontrolled BP had significantly higher levels of blood glucose (119 ± 14 vs 104 ± 27 mg/dl; p = 0.011); there were also higher numbers of subjects with diabetes (42 vs 22%; p = 0.003), lower high-density lipoprotein cholesterol levels (HDL-C) (24 vs 13%; p = 0.034), and moderate (45 vs 18%; p = 0.006) and high to very high (38 vs 13%; p = 0.02) global CV risk (Table 4). In patients with uncontrolled hypertension, a higher proportion was not compliant with the antihypertensive therapy; but the difference did not reach the level of statistical significance (Table 1). In multivariate analysis, the metabolic syndrome (MetS) and non-compliance with antihypertensive therapy emerged as the main risk factors for uncontrolled hypertension (Table 5). Compared to patients without the MetS, those bearing this metabolic abnormality had a 2.4-fold greater risk (OR 2.4; 95% CI 1.008–5.735; p = 0.04) of having uncontrolled hypertension. Patients not compliant with antihypertensive therapy had a 2.14fold greater risk (OR 2.14; 95% CI 0.986–4.236; p = 0.05) of uncontrolled hypertension in comparison with those compliant with therapy; but the difference was not statistically significant.

Discussion

62.5

43.2

40 Syst HT, %

30 20 10 0

Combined therapy, %

(n = 298)

The main findings of this cross-sectional study were as follows: first, uncontrolled hypertension with mainly uncontrolled SBP was frequent in these case series; second, the frequency of uncontrolled hypertension and that of uncontrolled SBP

60 Syst-Diast HT, %

Table 2. Antihypertensive and non-antihypertensive drugs in the study population Antihypertensive drugs

p-value

363

< 60

≥ 60 eGFR (ml/min/1.73 m2)

Fig. 1. F requency of uncontrolled systolic and diastolic hypertension (Syst-Diast HT) by renal function status (n = 231).

32.1 27.8

30 20

11.3

10 0

< 60

60–69 Age (years)

≥ 70

Fig. 2. Frequency of uncontrolled systolic hypertension (Syst HT) by age category (n = 231).

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Table 3. Biological characteristics of the study population as a whole and by blood pressure control status

Variable Blood glucose, mg/dl

237

(mmol/l) Lipids

Whole group (n = 298)

Controlled HT (n = 67)

Uncontrolled HT (n = 231)

p-value 0.011

115 ± 53

104 ± 27

119 ± 59

6.38 ± 2.94

5.77 ± 1.50

6.60 ± 3.27

TC, mg/dl

220 ± 58

225 ± 60

219 ± 57

0.548

(mmol/l)

5.7 ± 1.5

5.83 ± 1.55

5.67 ± 1.48

0.462

LDL-C, mg/dl

135 ± 55

139 ± 57

134 ± 55

0.537

3.50 ± 1.42

3.60 ± 1.48

3.47 ± 1.42

HDL-C, mg/dl (mmol/l) TG, mg/dl (mmol/l) Creatinine, mg/dl

255

63 ± 18

62 ± 19

63 ± 18

1.63 ± 0.47

1.61 ± 0.49

1.63 ± 0.47

111 ± 51

118 ± 62

109 ± 47

1.25 ± 0.58

1.33 ± 0.70

1.23 ± 0.53

1.04 ± 0.56

0.95 ± 0.27

1.07 ± 0.62

0.530 0.261 0.133

91.94 ± 9.50 83.98 ± 23.87 94.59 ± 54.81

(μmol/l) eGFR, ml/min/0.73 m²

255

82 ± 31

86 ± 28

81 ± 32

0.319

Uric acid, mg/dl

259

6.38 ± 2.50

6.60 ± 2.40

6.30 ± 2.50

0.488

Data are expressed as mean ± standard deviation (SD) or relative frequency (%). TC, total cholesterol ; LDL-C, low-density lipoprotein cholesterol; HDL-C, highdensity lipoprotein cholesterol; TG, triglycerides; eGFR, estimated glomerular filtration rate.

increased with reduced eGFR and advancing age, respectively; third, the MetS emerged as the main risk factor for uncontrolled hypertension. In this study, 77.5% of patients had uncontrolled hypertension. This observation agrees with previous reports highlighting the fact that in most countries, less than 30% of patients achieve BP goals,20 and therapy with a single antihypertensive agent fails to achieve BP goals in up to 75% of patients.21 The frequency of uncontrolled hypertension observed in the present study was somewhat higher than that reported in Table 4. Cardiovascular risk factors among the study population as a whole and by blood pressure control status UnconWhole Controlled trolled group HT HT (n = 298) (n = 67) (n = 231)

p-value

Variable

OR (95% CI)

Constant

–1.901

0.924

–

0.877

0.444

2.40 (1.008–5.735)

0.04

MetS+ vs MetS– Non-compliance vs compliance

B, regression coefficient; SE, standard error; OR, odds ratio; MetS, metabolic syndrome.

259

(mmol/l)

Table 5. Multivariate independent determinants associated with uncontrolled hypertension

Variable

Age, %

298

p-value 0.989

Smoking, %

298

0.348

Alcohol, %

298

0.462

Overweight, %

298

0.228

Obesity, %

298

0.228

Central obesity, %

298

1.000

Diabetes, %

298

0.003

Hypercholesterolaemia, %

259

0.229

Low HDL-C, %

259

0.034

Hypertriglyceridaemia, %

259

0.700

Hyperuricaemia, %

259

0.210

Dipstick proteinuria, %

227

0.396

Renal failure, %

255

0.103

ECG-LVH, %

164

0.843

MetS, %

298

0.105

Global CV risk, %

298

Low

0.0001

Moderate

0.0006

High/very high

0.03

Data are expressed as mean ± standard deviation (SD) or relative frequency (%). HDL-C, high-density lipoprotein cholesterol; ECG-LVH, electrocardiographically determined left ventricular hypertrophy; MetS, metabolic syndrome; CV, cardiovascular risk.

primary care settings by Rayner et al. (60.2%)22 and Dennison et al. (64% in the public sector and 49% in the private sector)23 in South Africa and by Onwemu et al. (29.4%)24 in Nigeria. It was also higher than that observed at tertiary care level by Yaméogo et al. (54.2%)25 in Burkina Faso, by Kramoh et al. (56.3%) in Ivory Coast,26 and by Ayodele et al. (68.6%)27 and Sani et al. (67%)28 in Nigeria. Our clinically generated frequency of uncontrolled hypertension was quite similar to the 76.4% reported by Dzudie et al.29 in Cameroon but lower than the 97, 94 and 86.4% previously reported by M’Buyamba-Kabangu et al., Sumaili et al. and Katchunga et al. in the general population of Kinshasa and south-eastern part of Democratic Republic of Congo, respectively.4-6 Higher frequencies of uncontrolled hypertension ranging from 82.2 to 97.4% were also reported by Hendricks et al. from Namibia to Kenya in a community-based crosssectional study.30 Apart from differences in methodology applied and population characteristics studied, the higher frequency of uncontrolled hypertension in sub-Saharan Africa appears to be multifactorial and is determined by patients, care providers and healthcare systems.31 Among the factors related to patients, non-compliance with diet and antihypertensive therapy has been reported to be an important determinant of uncontrolled BP.32 Non-compliance with antihypertensive therapy emerged in our study as the second risk factor associated with uncontrolled hypertension but the difference was not statistically significant. In many studies, non-compliance with antihypertensive therapy was responsible for two-thirds of the cases of uncontrolled hypertension.33,34 Krousel-Woods et al.33 found that non-compliance was associated with a nearly two-fold greater risk (OR 1.68; 95% CI 1.01–2.88) of uncontrolled BP. Yaméogo et al.25 in Burkina Faso found that non-compliance with both diet and antihypertensive therapy was associated with an eightfold (OR 8.40; 95% CI 1.11–4.17; p = 0.04) and nearly three-fold greater risk of uncontrolled hypertension, respectively. With regard to the care provider, clinical therapeutic inertia has been reported to be a major contributor to uncontrolled hypertension.35 Although patients with a high to very high CV risk level need more than two antihypertensive drugs to reach the BP goal,8 the majority of patients in our study were still on monotherapy, indicating clinical therapeutic inertia. The association of high to very high residual global CV risk has been reported by Yaméogo et al.25 in Burkina Faso and Kramoh et al.26 in Ivory Coast, using the Framingham CV risk score and 2007 ESH/ESC guidelines, respectively. In addition, Bohen et al.,35 using a cohort of hypertensive diabetics, found that non-intensification of therapy is frequent in this category of patients and is responsible for uncontrolled BP and glycaemia. Uncontrolled SBP is more frequent and its frequency increases with advancing age, especially after 60 years. A

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greater frequency of uncontrolled SBP has been reported by Yaméogo et al. in Burkina Faso and Ayodele et al. in Nigeria.25,27 Significant reduction in systemic arterial elasticity is common with advancing age. This decrease in elasticity results in higher systolic pressures, as large vessels become less able to reduce the pressure generated by the left ventricle by means of distension. On the other hand, while increases in peripheral resistance will cause elevation in diastolic pressure, the loss of large vessel elasticity does the opposite. Therefore, with increasing age, the counteracting forces may keep the diastolic pressure normal, while in the background, there is increasing systolic pressure.20,25,26 In our study, the frequency of uncontrolled SBP and DBP increased with reduced eGFR. Schmitt et al.36 reported in a study of 7 227 chronic kidney disease (CKD) patients receiving at least one antihypertensive drug, that only 35% of them had controlled blood pressure. They suggested non-compliance with therapy as the main determinant of uncontrolled hypertension in these CKD patients. Indeed, 33% of patients with CKD were not compliant with therapy and the frequency of non-compliance increased with decreased eGFR.36 In univariate analysis, diabetes and low HDL-C levels were significantly associated with uncontrolled hypertension, whereas in multivariate analysis, the MetS and self-reported non-compliance emerged as the main predictors of risk for uncontrolled hypertension; however, the differences observed in non-compliance did not reach the level of statistical significance. Poor adherence to therapeutic plans and non-compliance with antihypertensive therapy have been reported to be perhaps the most important factors responsible for poor BP control.37 In most cases, poverty has been adduced to be responsible for non-compliance, especially in sub-Saharan Africa.37 Health education and patient counselling, along with availability of free drugs could help improve adherence to antihypertensive drug therapy.37 Previous reports have associated the MetS with an increased risk of uncontrolled hypertension.38,39 Central obesity via secreted adipocytokines, mainly adiponectin and leptin, appears to be the link between the MetS and uncontrolled hypertension.38 Adiponectin, besides its effects on insulin sensitivity, may act directly on the vasculature; indeed, hypo-adiponectinaemia was found to be associated with impaired endothelium-dependent dilation in humans.38 Furthermore, leptin has also been reported to increase sympathetic tone and therefore the renin– angiotensin system, with subsequent increase in vascular tone and remodelling.38 Several potential limitations of the study need to be underscored. The cross-sectional design of the study did not allow us to establish clear evidence of a causal relationship between the variables of interest. The study sample size was not large enough to be empowered to detect additional associations. The frequency of uncontrolled hypertension could have been overestimated by the lack of inclusion of home blood pressure monitoring while defining BP control.40 The non-quantitative evaluation of compliance with antihypertensive therapy may have caused underestimation of this important determinant of BP control; the same could be true for socio-economic status and compliance with diet, especially salt intake. The use of a clinically based sample may limit generalisation of the conclusions of this study to the entire hypertensive population because of bias in referral of patients to the source of care.

365

Conclusion Uncontrolled hypertension was frequent in the present case series and was associated with factors related to lifestyle and diet, which interact with blood pressure control. The authors gratefully thank Dr Jeremie Muwonga for the facilities provided for analysis of biological samples at the National Laboratory of the National AIDS Control Program. We are indebted to Prof Dr Mashinda for his pertinent advice and to all the staff of BDOM network, particularly Dr François Minzemba and Dr Josée Nkoy Belila for their commitment during the conduct of the study. We thank all the participants who, by their consent, made the present study possible.

References 1.

Cordero A, Bertomeu-Martinez V, Mazon P, Facila L, BertomeuGonzalez V, Cosin J, et al. Factors associated with uncontrolled hypertension in patients with and without cardiovascular disease. Rev Esp Cardiol 2011; 64(7): 587–593.

Schmieder RE, Lehmann MV, Schmidt S. Optimizing blood pressure in hypertension: The need to use ABPM. Blood Press 2012 Oct 4 [Epub ahead of print].

Chmiel C, Wang M, Senn O, Del Prete V, Zoller M, Rosemann T, Steurer-Stey C. Uncontrolled arterial hypertension in primary care – patient characteristics and associated factors. Swiss Med Wkly 2012; 142: w13693.

M’Buyamba-Kabangu JR, Fagard R, Staessen J, Lijnen P, Amery A. Correlates of blood pressure in rural and urban Zaire. J Hypertens 1987; 5(3): 371–375.

Katchunga

PB,

M’Buyamba-Kayamba

JR,

Masumbuko

BE,

Lemogoum D, Kashongwe ZM, Degaute JP, et al. Arterial hypertension among Congolese adults of South Kivu: results from VITARAA study. Presse Med 2011; 40(6): e315–323. 6.

Krzesinski JM, Sumaili KE, Cohen E. How to tackle the avalanche of chronic kidney disease in sub-Saharan Africa: the situation in the Democratic Republic of Congo as an example. Nephrol Dial Transplant 2007; 22(2): 332–335. Epub 2006 Oct 11.

WHO. The problem of overweight and obesity: preventing and managing the global epidemic. Report Series 894; Geneva, WHO, 2000: 537.

Alberti KG, Zimmet P, Shaw. Metabolic syndrome – a new world-wide definition. A Consensus Statement from the International Diabetes Federation. J Diabetes Med 2006; 5(5): 469–480. doi: 10.1111/j.14645491.2006.01858.x.

Friedewald WT, Levi RI, Fredrickson DS. Estimation of the concentration of LDL-cholesterol without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–508.

10. Levey AS, Cohen J, Greene T, Stevens LA, Zhang YL, Hendricksen S, et al. Using standardized serum creatinine values in the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145: 247–254. 11. Sumaili KE, Krzesinski JM, Zinga CV, Cohen EP, Delanaye P, Munyanga SM, Nseka NM. Prevalence of chronic kidney disease in Kinshasa: results of a pilot study from the Democratic Republic of the Congo. Nephrol Dial Tranplant 2009; 24(1): 117–122. 12. Guidelines Committee 2007 European Society of Hypertension – European Society of Cardiology Guidelines for the management of arterial Hypertension. J Hypertens 2007; 25: 1105–1187. 13. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26(Suppl 1): S5–20.13 14. World Health Organization (2002). The World Health Report 2002.

366

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

Reducing risks, promoting healthy life. Geneva; World Health Organization.

AFRICA

sure control among treated hypertensives in a tertiary health institution. Niger J Med 2008; 17(3): 270–274.

15. Orth SR, Stockman A, Conradt C, Ritz E, Ferro M, Kreusser W, et al.

29. Dzudie A, Kengne AP, Muna WF, Ba H, Menanga A, Kouam KC, et

Smoking as a risk factor for end-stage renal failure in men with primary

al. Prevalence, awareness, treatment and control of hypertension in a

renal disease. Kidney Int 1998; 54: 926–931.

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

16. Physical activity. Guidelines for Americans. Office of Disease Prevention & Health Promotion, US Department of Health and Human Services, October 2008 (www.health.gov/paguidelines). 17. Surawicz B. Electrocardiographic diagnosis of chamber enlargement. J Am Coll Cardiol 1986; 8: 711–724. 18. K/DOQI clinical practical guidelines for chronic kidney disease (CKD): Evaluation, classification and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002; 39(2Suppl): S22–26. 19. Longo AL, Lepira FB, Sumaili EK, Makulo JR, Mukumbi H, Bukabau

study. Br Med J Open 2012; 24: 2(4), pii: e001217. Doi: 10.136/bmjopen-2012-001217. 30. Hendriks ME, Wit FW, Roos MT, Brewster LM, Akande TM, de Beer IH, et al. Hypertension in sub-Saharan Africa: cross-sectional surveys in four rural and urban communities. PLoS One 2012; 7(3): e32638. doi: 10.1371/journal.pone.0032638. Epub 2012 Mar 12. 31. Hyman DJ, Pavlik VN. Barriers to blood pressure control. In: Hypertension Primer, the Essentials of High Blood Pressure. 4th edn. Wolters Kluwer/Lippincott Williams and Wilkins, 2008: 418–420.

JB, et al. Prevalence of low estimated glomerular filtration rate, protein-

32. Redon J, Erdine S, Böhm M, Ferri C, Kolloch R, Kreutz R, et

uria, and associated risk factors among HIV-infected black patients

al. Physician attitudes to blood pressure control: findings from the

using Cockroft-Gault and modification of diet in renal disease study

supporting hypertension awareness and research Europe-Wide Survey. J

equations. J Acquir Immune Defic Syndr 2012;59(1): 59–64. doi: 10.1097/ QAI.0b013e31823587b0. 20. Benetos A, Salvi P, Lacolley P. Blood pressure regulation during the aging process: the end of the “hypertension era”? J Hypertens 2011; 29(4): 646–652.

Hypertens 2011; 29: 1633–1640. 33. Saradon-Eck A, Egrot M, Blance MA, Faure M. Anthropological approach of adherence factors for antihypertensive drugs. Health Policy 2010; 5(4): e157–175. 34. Krousel-Wood M, Joyce C, Holt E, Muntner P, Webber LS, Morisky

21. Cowart JB, Taylor AA. Should two-drug initial therapy for hyperten-

DE, et al. Predictors of decline in medication adherence: results from the

sion be recommended for all patients? Curr Hypertens Rep 2012; 14(4):

cohort study of medication adherence among older adults. Hypertension

324–332. doi: 10.1007/s11906-012-0280-9. Review.

2011; 58(5): 804–810.

22. Rayner B, Schoeman HS. A cross-sectional study of blood pressure

35. Bohen SD, Samuels TA, Yeh C, Marinopoulos SS, Mc Guire M, Abuid

control in hypertensive patients in general practice (the I-TARGET

M, et al. Failure to intensify antihypertensive treatment by primary care

study). Cardiovasc J Afr 2009; 20(4): 224–227.

providers: a color study in adults with diabetes mellitus and hyperten-

23. Dennison CR, Peer N, Lombard CJ, Kepe L, Levitt NS, Steyn K, Hill

sion. J Gen Intern Med 2008; 23(5): 543–560.

MN. Cardiovascular risk and comorbid conditions among black South

36. Schimtt KE, Edie CF, Laflam P, Simbartl LA, Thaker CV. Adherence

Africans with hypertension in public and private primary care settings:

to antihypertensive agents and blood pressure control in chronic kidney

the HiHi study. Ethn Dis 2007; 17(3): 477–483.

disease. Am J Nephrol 2010; 32(6): 541–548.

24. Omuemu VO, Okojie HO, Omuemu CE. Awareness of high blood

37. Adedapo AD, Sikuade O, Adeleke S, Okechukwu R. Drug utilization

pressure status, treatment and control in rural community in Edo State.

and blood pressure control in a population where antihypertensive

Niger J Clin Pract 2007; 10(3): 208–212.

are given free: effect of policy change. Afr J Med Med Sci 2012; 41(4):

25. Yaméogo NV, Kagambèga LJ, Millogo RCG, Kologo KJ, Yaméogo AA,

349–356.

Mandi GD, et al. Factors associated with poor blood pressure control

38. Zidek W, Naditch-Brûlé L, Perlini S, Farsang C, Kjeldsen SE. Blood

in hypertensive black patients: cross-sectional study of 456 patients from

pressure and components of the metabolic syndrome: the Good Survey.

Burkina Faso. Ann Cardiol Angéiol 2013; 62(1): 38–42.

Cardiovasc Diabetol 2009; 8: 51.

26. Kramoh EK, N’goran YN, Aké-Traboulsi E, Anzouan-Kacou JB,

39. Cortez-Dias N, Martins SR, Belo A, Fiuza M. Association of metabolic

Konin CK, Coulibaly I, et al. Hypertension management in an outpa-

risk factors with uncontrolled hypertension: comparison of the several

tient clinic at the Institute of Cardiology of Abidjan (Ivory Coast). Arch

definitions of metabolic syndrome. J Hypertens 2013, Jun 27. [Epub

Cardiovasc Dis 2011; 104(11): 558–564. doi: 10.1016/j.acvd.2011.08.002. Epub 2011 Oct 28.

ahead of print]. 40. Maseko MJ, Woodiwiss AJ, Majane OH, Molebatsi N, Norton GR.

27. Ayodele OE, Alebiosu CO, Salako BL. Differential control of systolic

Marked underestimation of blood pressure control with conventional

and diastolic blood pressure in blacks with essential hypertension. J Natl

vs ambulatory measurements in an urban, developing community of

Med Assoc 2004; 96(3): 310–314.

African ancestry. Am J Hypertens 2011; 24(7): 789–795.

28. Sani MU, Mijinyawa MS, Adamu B, Abdu A, Borodo MM. Blood pres-

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Determinants of change in body weight and body fat distribution over 5.5 years in a sample of free-living black South African women Sarah Chantler, Kasha Dickie, Lisa K Micklesfield, Julia H Goedecke

Abstract Objective: To identify socio-demographic and lifestyle determinants of weight gain in a sample of premenopasual black South African (SA) women. Methods: Changes in body composition (dual-energy X-ray absorptiometry, computerised tomography), socio-economic status (SES) and behavioural/lifestyle factors were measured in 64 black SA women at baseline (27 ± 8 years) and after 5.5 years. Results: A lower body mass index (BMI) and nulliparity, together with access to sanitation, were significant determinants of weight gain and change in body fat distribution over 5.5 years. In addition, younger women increased their body weight more than their older counterparts, but this association was not independent of other determinants. Conclusion: Further research is required to examine the effect of changing SES, as well as the full impact of childbearing on weight gain over time in younger women with lower BMIs. This information will suggest areas for possible intervention to prevent long-term weight gain in these women. Keywords: body fat distribution, weight gain, black women, South Africa Submitted 10/12/15, accepted 22/3/16 Published online 25/5/16 Cardiovasc J Afr 2016; 27: 367–374

www.cvja.co.za

DOI: 10.5830/CVJA-2016-038

Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, South Africa Sarah Chantler, MSc Kasha Dickie, MSc Lisa K Micklesfield, PhD Julia H Goedecke, PhD

Non-Communicable Disease Research Unit, South African Medical Research Council, Cape Town, South Africa Julia H Goedecke, PhD, julia.goedecke@mrc.ac.za

MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa Lisa K Micklesfield, PhD

Obesity and its co-morbidities continue to increase worldwide, with women from low- and middle-income countries (LMICs) being most affected.1 Within South Africa, the prevalence of overweight/obesity has increased from 56.2 to 64.8% in the most recent South African National Health and Nutrition Examination survey (SANHANES),1,2 confirming the problem within South Africa. Our study in a cohort of black South African (SA) women reported a 9% increase in body weight over a 5.5-year period.3 The weight gain was attributed predominantly to an increase in fat mass, which was greatest in central compared to peripheral depots. The relative redistribution of body fat was associated with increases in fasting plasma glucose and triglyceride concentrations, with reduced insulin sensitivity and a compensatory increased insulin secretion at follow up.3 Other longitudinal studies measuring changes in body composition over time reported weight gain that ranged from 0.5–0.9 kg/year.4-7 However, these studies were undertaken in high-income countries (HICs). These data are valuable since to the authors’ knowledge, there are no known longitudinal studies from populations living in LMICs. Determinants of weight gain in these studies include non-modifiable factors such as age, gender and race, and modifiable factors such as baseline body mass index (BMI),5 dietary intake,4,7-9 physical activity,10 socio-economic status (SES)11,12 and parity.13-15 Associations between these factors are often complex in nature, and it is difficult to draw conclusions regarding the relative contribution of these factors to increasing body weight in different populations. Furthermore, many of these studies failed to assess the impact of these determinants on changes in body composition or body fat distribution. Due to the risk of cardiometabolic disease associated with increasing total and central fat mass,16-18 and the possible protective benefits associated with peripheral fat mass,19 a greater understanding of the determinants of body composition changes are important to inform future intervention studies. In addition, within LMICs, other factors such as urbanisation and the ‘transition’ from a traditional to a more westernised lifestyle have been associated with obesity and other non-communicable diseases.20 The relationship between SES and obesity in LMICs differs from that in HICs, with studies in LMICs reporting a positive association between SES and BMI, with the inverse association being reported in HICs.21 To our knowledge no longitudinal studies have assessed the impact of change in SES on body composition and body fat distribution. Therefore, the aim of this study was to assess lifestyle factors and SES variables at baseline and the changes in these factors over a 5.5-year follow-up period, and how these are associated with changes in body weight and whole-body fat distribution in a sample of peri-urban free-living black SA women.

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Methods Participants included a sample of 64 women from the original convenience sample of 240 apparently healthy premenopausal black SA women who were tested in 2005/06,22 and were followed up approximately 5.5 years later, as previously described.3 The original cohort of women were recruited at baseline from church groups, community centres, universities and through the local press, and were included in the study if they were (1) 18–45 years old; (2) had no known diseases and were not taking medication for type 2 diabetes (T2D), hypertension, HIV/AIDS, or any other metabolic diseases; (3) were not pregnant, lactating or postmenopausal (self-reported); and (4) were of SA ancestry (self-reported). At follow up, the original cohort of 240 women were contacted and invited to participate in the longitudinal follow-up study in 2010/11. Testing procedures at baseline included body composition measures, questionnaires on SES and reproductive health, and an assessment of baseline physical activity and dietary intake. The dietary and physical activity assessment was not included at follow up. At follow-up testing, voluntary HIV screening was included. Participants were excluded on the basis of a confirmed positive HIV test (Sanitests Home Test Kits, SA). For ethical reasons, those who declined HIV screening were not excluded from the study. The study was approved by the Human 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 subjects, and written informed consent was obtained. Body composition was assessed using basic anthropometry (weight, height and circumference), dual-energy X-ray absorptiometry (DXA) and computerised tomography (CT) scans. DXA was used to measure whole-body composition (Discovery-W®, software version 12.7.3.7; Hologic, Bedford, MA). In vivo precision (CV) was 0.7 and 1.67% for fat-free softtissue mass and fat mass, respectively. Percentage fat mass for the whole body was obtained and fat mass for the various regions of interest, including the trunk, limbs, android and gynoid regions, were derived using DXA cut-off lines positioned at anatomical markers, as previously described.23 CT was used to measure abdominal visceral adipose tissue (VAT) and superficial adipose tissue (SAT) areas (Toshiba X-press Helical Scanner®; Toshiba Medical Systems, Tokyo, Japan) in 43 women at baseline and follow up. A Xhosa-speaking field worker administered the sociodemographic questionnaire at baseline and follow up. The questionnaire included measures of SES such as housing density, asset index, educational level, current employment and household sanitation. Housing density was defined as the number of persons in the household divided by the number of rooms. Asset index was based on 14 appliances/items, reflecting the individual and household wealth and resources. These included electricity in the home, ownership of a television, radio, motor vehicle, fridge, stove/oven, washing machine, telephone, video machine, microwave, computer, cellular telephone and paid television channels (MNET or DSTV). Level of education was described as those who had completed grade 12 (secondary school) or lower. Participants were categorised as employed (including students) or unemployed. Sanitation was described as access to running water or a flush toilet inside or outside the house.

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Behavioural factors included self-reported indicators of current smoking status (smoker or non-smoker), alcohol consumption (non-drinker or drinker of any alcohol), and hormonal contraceptive use (none, oral or injectable). Parity was defined as those who had children at baseline or follow up, and those who had children during the follow-up period. Physical activity was assessed at baseline using the global physical activity questionnaire (GPAQ).24 As walking was the most frequent activity, walking for travel was used as a proxy for physical activity. Dietary intake was determined using a quantitative food frequency questionnaire,25 which has been validated in black SA women.26 A higher diet quality index – international (DQI-I) score represents a higher quality of dietary intake.

Statistical analysis Parametric data are presented as means and standard deviations and non-parametric data are presented as medians and interquartile ranges (IQR) and compared using paried t-tests and the Mann–Whitney U-test. Socio-demographic or categorical data are presented as percentages and were compared over the follow-up period using McNemar chi-squared tests. For univariate analysis, Spearman’s rank correlations were used to assess non-parametric associations between continuous variables (housing density, asset index) and the changes in body composition, while ANOVA was used to explore the effects of categorical variables (parity, access to sanitation, smoking, alcohol and walking for travel) on changes in body composition. To analyse the effect of baseline age and BMI on changes in body composition, median age and accepted BMI classifications were used to create groups, and a two-way analysis of covariance (ANCOVA), adjusting for age, was performed. Based on the significant univariate associations with changes in body weight and body composition (baseline age and BMI, access to sanitation, parity, level of education and employment status, and changes in these SES and lifestyle variables), multiple stepwise linear regression was used to determine the independent contribution of these variables to changes in weight gain and body fat distribution over the 5.5-year follow-up period. Statistical significance was set at p < 0.05. Data were analysed using STATISTICA version 10 (Statsoft Inc. Tulsa, OK) and STATA 12.1 (StataCorp, College Station TX).

Results Subject characteristics, including body composition, SES and lifestyle variables at baseline and follow up are presented in Table 1. Mean percentage weight gain over the follow-up period was 8.8%, with an average increase of 1.2 kg/year. There was a significant increase in fat mass (16.4 ± 26.9%, p < 0.001), but no significant increase in fat-free soft-tissue mass (p = 0.234). The increase in fat mass was largely attributed to an increase in central fat mass, characterised by increases in trunk (as a percentage of total fat mass) and android fat mass, as well as both VAT and SAT areas. Conversely, there was a decrease in peripheral fat mass (gynoid and leg fat mass as a percentage of total fat mass). The measures of SES of the participants increased over the follow-up period, as characterised by increases in asset index

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Table 1. Socio-economic and lifestyle variables at baseline and after 5.5 years of follow up Indicator

Baseline 27 ± 7.5

Age (years)

Follow up

p-value

32 ± 7.6

–

Body composition Height (m)

1.6 ± 0.1

–

Weight (kg)

86.9 ± 19.6

92.8 ± 18.9

< 0.001 < 0.001

BMI (kg/m2)

33.8 ± 7.5

36.4 ± 7.7

Fat-free soft-tissue mass (kg)

45.6 ± 6.8

46.2 ± 6.3

Fat mass (kg)

36.3 ± 10.3

40.9 ± 10.6

< 0.001

Body fat (%)

42.3 ± 7.8

44.9 ± 6.4

< 0.001

Trunk fat mass (% total FM)

43.6 ± 5.8

46.2 ± 5.3

< 0.001

Leg fat mass (% total FM)

42.6 ± 6.3

40.1 ± 6.1

< 0.001

7.7 ± 1.6

8.4 ± 1.6

< 0.001

Gynoid fat mass (% total FM)

19.3 ± 2.7

18.5 ± 2.4

< 0.001

VAT (cm3)

59 (37–93)

75 (49–110)

0.038

SAT (cm3)

508 (324–611)

499 (352–604)

0.013

Obtained grade 12 (%)

32.8

42.1

0.134

Employed/students (%)

32.8

45.3

0.042

Android fat mass (% total FM)

0.234

Socio-demographic variables Education and employment

Reproductive health Hormonal contraceptive use (%)

46.8*#

34.3

0.201

Parity (≥ 1 child) (%)

57.8*

85.9

0.001

Housing density (people/room)

1.33 ± 0.9

1.38 ± 1.19

Running water inside house (%)

26.5

37.5

Housing

Flush toilet inside house (%)

26.5

0.630 < 0.001

40.6

0.001

42.1 ± 19.4

55.8 ± 17.3

< 0.001

Current smoker (%)

12.5#

15.6

< 0.001

Consume alcohol (%)

37.5

48.4

0.291

Asset index (%14) Lifestyle variables

Data are represented as either mean ± standard deviations or medians (interquartile range), Continuous data were compared using Wilcoxon rank test or dependent t-test, frequencies were compared using McNemar chi-squared test, significance p < 0.05. *Significant difference in age between groups at baseline # Significant difference in BMI between groups at baseline. FM, fat mass; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue.

(p < 0.001), access to flush toilets and running water inside the house (p < 0.001), and an increase in the number of participants who were employed (p < 0.05). At baseline, 58% of the women had at least one child, and this increased to 86% at follow up (p = 0.001). During the follow-up period, 24 (38%) women had one child, and three women (5%) had two children. Hormonal contraceptive use did not change significantly over time. The proportion of women who smoked increased over the follow-up A

% Δ Weight

r = –0.35 p = 0.04

–20

period, but the proportion of women who consumed alcohol did not change significantly. At baseline, the median moderate- to vigorous-intensity physical activity of the women was 60 min/day, with 70% of women using walking as a mode of travel. At baseline, the majority of dietary energy (kcal) was derived from carbohydrates (52.2%), followed by fat (34.8%) and protein (12.4%). The median total DQI-I score was 54 (IQR: 47–60), with a median (IQR) variety score of 17 (15–20), adequacy score of 25 (20–32), moderation score of 6 (3–12) and balance score of 3 (2–4). None of the baseline physical activity or dietary factors contributed significantly to weight change during the follow-up period so were not included in any further statistical analyses. Although there was no association between age and BMI at baseline, both were inversly associated with change in body weight (Fig. 1A, B). To further investigate the effect of baseline age on changes in body composition, participants were divided into two categories, those above and those below the median age of 25 years (Fig. 2). The younger participants (< 25 years) gained significantly more body weight, total fat mass, appendicular fat mass, and trunk fat mass than the older participants (≥ 25 years) (p < 0.05), with a three-fold greater increase in fat mass in the younger compared to the older group (6.3 ± 6.9 vs 2.1 ± 6.5 kg, p = 0.016). The increase in fat mass in the younger versus the older group occurred mainly in the central (trunk) region (3.9 ± 3.7 vs 1.2 ± 3.4 kg, p = 0.005) rather than the appendicular region (2.4 ± 3.4 vs 0.8 ± 3.2 kg, p = 0.066). To further explore the effect of baseline BMI on changes in body composition, the participants were separated into three BMI categories, non-obese (NO: BMI < 30 kg/m2, n = 17), obese class 1 (OBc1: BMI: 30–34.9 kg/m2, n = 17) and obese class 2 (OBc2: BMI ≥ 35 kg/m2, n = 35). The annual average weight gain was 1.8 ± 0.9, 1.2 ± 2.1 and 0.9 ± 1.9 kg in the NO, OBc1 and OBc2 groups, respectively. Absolute and percentage changes in body composition over the 5.5-year follow-up period in the three BMI groups are presented in Table 2. There was no significant difference in age between the BMI groups (NO: 24.7 ± 1.8 vs OBc1: 28.7 ± 1.8 vs OBc2: 27.2 ± 1.3 years, p = 0.283). While the absolute changes (kg) in the various body composition variables were not significantly different between the groups, the percentage changes in body composition (relative to baseline) were significantly greater in the NO group compared to the other two groups. In addition, when expressed as a percentage of total fat mass, there were significant group × time interaction effects for the changes in B

25 30 35 40 Baseline age (years)

369

r = –0.39 p = 0.001

–20

30 40 Baseline BMI (kg/m2)

Fig. 1. R elationship between baseline age, baseline BMI and relative change in body weight (%).

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Table 2. Changes in body composition over the 5.5-year follow-up period by baseline BMI groups

60 *

%Δ

ApFM < 25 years

Weight (kg)

TFM SAT ≥ 25 years

VAT

Fig. 2. P ercentage changes in body composition variables in younger (< 25 years) and older age groups (≥ 25 years). Data are means ± standard error. W, weight; FM, fat mass; ApFM, appendicular fat mass; TFM, trunk fat mass; SAT, superficial adipose tissue; VAT, visceral adipose tissue; *p < 0.01.

body fat distribution, such that there was a significant increase in central fat mass (trunk and android as a percentage of fat mass) and decrease in peripheral fat mass (appendicular and gynoid as a percentage of fat mass) in the NO group, but not the two obese groups (Fig. 3). As baseline BMI was a strong determinant of weight gain over the follow-up period, differences in baseline SES and lifestyle variables were also examined between BMI groups (NO, OBc1 and OBc2). There were no differences in baseline SES, reproductive health, moderate- to vigorous-intensity physical

SAT (cm2)

VAT (cm2)

B *

4 2

OBc1 Baseline BMI

OBc2

Absolute change (kg)

% change

p-value for % change

61.2 ± 9.2

71.7 ± 9.6

10.4 ± 5.4

17.6 ± 9.7#

0.009

OBc1

85.9 ± 6.4

91.6 ± 12.2

5.6 ±12.1

6.8 ± 14.2

OBc2

100.4 ± 14.5

105.1 ± 15.2

4.7 ±10.5

5.2 ± 10.8

19.6 ± 5.8

26.3 ± 5.8

6.7 ± 4.1

39.6 ± 31.8#

OBc1

37.5 ± 5.5

40.7 ± 9.4

2.5 ± 8.5

7.6 ± 23.8

OBc2

46.7 ± 10.2

50.0 ± 11.5

3.6 ± 7.2

8.0 ± 16.4

7.6 ± 2.7

11.6 ± 2.9

4.0 ± 2.1

63.2 ± 51.9#

OBc1

16.5 ± 3.6

18.7 ± 5.3

1.8 ± 4.7

13.7 ± 32.9

OBc2

21.6 ± 4.9

23.7 ± 5.5

2.2 ± 3.9

11.0 ± 20.1

OBc1 Baseline BMI

OBc2

11.1 ± 3.4

13.8 ± 3.2

2.6 ± 2.1

27.9 ± 26.1#

OBc1

20.2 ± 3.2

21.2 ± 5.4

0.8 ± 4.0

3.3 ± 20.6

OBc2

24.1 ± 6.2

25.4 ± 7.0

1.4 ± 3.6

5.8 ± 15.3

227.1 ± 100.5

300.4 ± 78.3

90.5 ± 68.4

58.9 ± 62.6#

OBc1

487.7 ± 107.7 495.7 ± 107.7

15.6 ± 99.3

2.3 ± 27.2

OBc2

637.1 ± 118.9 651.6 ± 131.4

18.8 ± 84.1

2.2 ± 13.5

31.9 ± 12.5

54.9 ± 29.4

24.8 ± 23.1

94.1 ± 101.1#

OBc1

77.3 ± 44.3

81.4 ± 38.2

2.9 ± 38.9

15.4± 67.8

OBc2

73.4 ± 36.0

99.9 ± 38.6

1.5 ± 23.5

7.7± 30.5

< 0.001

0.003

0.033

0.003

0 –2 –4 –6 –8

Follow up (kg)

Data are represented as means ± standard deviations. Groups are divided into BMI at baseline as NO: < 30 kg/m2 (n = 17), OBc1: 30–34.9 kg/m2 (n = 17) and OBc2: ≥ 35 kg/m2 (n = 30). # Change in NO group significantly greater than both OB groups, Kruskal–Wallis used for the relative change in SAT and VAT. BMI, body mass index; TFM, trunk fat mass; ApFM, appendicular fat mass; SAT, subcutaneous adipose tissue, VAT, visceral adipose tissue.

3 Δ Android FM (%FM)

ApFM (kg)

TFM (kg)

Δ Appendicular FM (%FM)

Δ Trunk FM (%FM)

Fat mass (kg)

Δ Gynoid FM (%FM)

Baseline (kg)

Param- BMI eters (kg/m2)

* *

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OBc1 Baseline BMI

OBc2

OBc1 Baseline BMI

OBc2

0 –1 –2 –3

Fig. 3. C hanges in body fat distribution, expressed as a percentage of total fat mass (kg), in three baseline BMI groups. Data are represented as means ± standard deviation, FM; fat mass. Three BMI groups defined at baseline: NO: < 30 kg/m2, OBc1: 30–34.9 kg/m2 and OBc2: ≥ 35 kg/m2. *Change in NO group significantly different to both other BMI groups, p < 0.01 via Tukey post-hoc analysis.

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activity, walking for travel, absolute dietary intake or DQI-I between BMI groups (data not shown). Those who smoked at baseline had a significantly higher BMI than those who did not smoke. Baseline housing density and asset index were not associated with change in body weight, body composition or body fat distribution. By contrast, other SES variables at baseline and the changes in these variables were associated with changes in body weight or changes in body composition over the follow-up period (Table 3). Baseline and changes in access to sanitation and employment had siginficant effects on weight gain over the 5.5 years, while education and contraceptive use did not. Nulliparty had significant associations with changes in body weight as well as changes in body fat distribution. Parity was associated with redistribution of fat mass, with larger decreases in appendicular fat mass (percentage of total fat mass) (–3.1 ± 2.9 vs –1.5 ± 2.7%, p = 0.040) and gynoid fat mass (percentage of total fat mass) (–1.1 ± 1.0 vs –0.5 ± 1.2%, p = 0.088), and larger increases in trunk fat mass (percentage of total fat mass) (3.69 ± 3.5 vs 1.9 ± 3.1%, p = 0.044) and trunk:leg ratio (0.19 ± 0.2 vs 0.08 ± 0.1%, p = 0.004) in the nulliparous women compared to the women with children at baseline. Furthermore, those women who were still nulliparous at follow up (n = 9) increased their body weight significantly more over the 5.5-year follow-up period than their childbearing counterparts (p = 0.001). There was a trend for those who had children over the 5.5-year period to increase their body weight less than those who already had children, but it was not significant after adjusting for baseline age and BMI. Those who increased their education level (n = 11) had a greater increase in relative trunk fat mass (percentage of fat mass) compared to those who did not (n = 53) (p = 0.035). Dietary intake and physical activity at baseline, and baseline and follow-up smoking and alcohol intake were not associated with changes in body composition (data not shown). Multiple regression analysis was used to explore the independent determinants of the changes in body weight and body fat distribution over the 5.5-year follow-up period (Table 4), based on the significant univariate analyses described above.

Based on the regression model, increasing body weight over time was associated with a lower baseline BMI, being nulliparous at baseline, not having children during the follow-up period, lack of household sanitation at baseline and improved sanitation at follow up. This model explained 51% of the variance in the change in body weight (p < 0.001). The model that explained the greatest variance in the change in relative trunk fat mass (percentage of fat mass), change in trunk:leg ratio and change in relative gynoid fat mass (percentage of fat mass) (model B) included only baseline BMI and being nulliparous at baseline.

Discussion The main findings of this study were that lower BMI and nulliparity, together with sanitation as a proxy for SES, were significant determinants of weight gain and change in body fat distribution over a 5.5-year period in a sample of free-living periurban black SA women. In addition, younger women increased their body weight more than their older counterparts, but this association was not independent of baseline BMI. The finding that there was an inverse relationship between baseline BMI and weight gain is similar to other studies in HICs. Few researchers have highlighted the effect of baseline BMI as a predictor of future weight gain. Brown et al.5 showed that a baseline BMI of 25–30 kg/m2, in conjunction with a high energy intake, was a significant determinant of weight gain over five years in middle-aged Australian women. Another study in the USA reported greater weight gain in those who were both younger and who had a lower baseline BMI.4 In addition, this study showed that a lower baseline BMI was associated with a greater redistribution of fat from the periphery to the central depots over time. The women with a lower BMI may have a higher capacity for increasing body weight and increased centralisation of fat mass over time. This highlights a group that is at increased risk and should be targeted for future interventions aimed at preventing an increase in body weight and centralisation of fat mass over time, due to the associated negative cardiometabolic outcomes.18 Table 4. Multivariate models for changes in body composition over the 5.5-year period

Table 3. Change in body weight and trunk fat mass in response to differences in SES/behaviour/lifestyle variables Change in body weight (kg)

SEE

p-value

Baseline BMI

–0.24

0.13

0.016

Presence of running water and a flush toilet

–0.28

2.66

0.023

Improvement in sanitation (toilet and water)

0.30

2.41

0.005

SES/behaviour/lifestyle variable

Access to inside running water at baseline?

1.7 ± 11.2 45 8.8 ± 8.8

0.012

Access to inside flush toilet at baseline?

2.3 ± 12.1 45 8.5 ± 8.8

0.032

Employed at baseline?

20 10.2 ± 10.9 41 5.1 ± 8.7

0.050

Grade 12 at baseline?

7.2 ± 8.8

40 6.5 ± 10.3

0.803

2.07

0.000

8.0 ± 8.9

31 5.5 ± 10.6

0.982

Child/children at baseline

–0.42

Hormonal contraceptive use at baseline?

2.12

0.025

25 10.7 ± 9.5

36 3.8 ± 8.9

0.005

Children over follow-up period

–0.25

Nulliparous at baseline? Nulliparous at follow up?

9 16.6 ± 7.2

52 5.4 ± 9.3

0.001

R2 = 0.51, p < 0.001 VIF: 1.25.

Improvement in sanitation over time?

14 15.1 ± 7.5

44 4.8 ± 9.4

< 0.001

Loss of employment over time?

8 11.7 ± 6.4

53 5.8 ± 11.6

Yes

Change in body weight (kg) β

Variable

p-value

0.043

Change in trunk fat mass (% TFM) n

Yes

Improvement in level of education over time?

2.2 ± 3.3

Nulliparous at baseline

3.7 ± 3.5

53 4.6 ± 3.1 36 1.9 ± 3.1

Change in body fat distribution Variable

Δ Trunk:leg Δ Trunk FM (% FM) Δ Gynoid FM (% FM) (R2 = 0.43) (p < 0.001)(R2 = 0.35) (p < 0.001)(R2 = 0.20 (p = 0.001)

VIF

1.02 β

p-value

1.02

SEE p-value

1.02 β

SEE p-value

0.035

Baseline BMI

–0.61 0.04 < 0.001 –0.47 0.00 < 0.001 0.40 0.02

0.001

–0.34 0.69

0.001 –0.42 0.03 < 0.001 0.22 0.27

0.022

0.044

Child/children at baseline

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A younger age at baseline was also found to be associated with increased weight gain and centralisation of fat mass over the 5.5-year follow-up period, however this was not independent of baseline BMI. Women under 25 years of age increased their weight by an average of 1.2 kg/year, compared to 0.3 kg/year in those who were older than 25 years. These marked age-related differences in weight gain have been reported previously, with increases in body weight being more pronounced in the younger compared to the older age groups over the same time period.4,6 These studies reported increases in body weight of 0.93, 0.73, 0.61 and 0.17 kg/year in participants from 21–35, 35–45, 39 and 59 years of age, respectively.4-6 The CARDIA study, which included black women of a similar age to our study, showed that women between the ages of 18 and 20 years at baseline increased their weight by an average of 1.2 kg/year, compared to 0.9 kg/year over 10 years in those who were 27–30 years at baseline.28 Although several studies have shown an association between a younger age and body weight gain, none have measured changes in body composition or body fat distribution over time. This study also showed a greater increase in trunk fat mass, and abdominal VAT and SAT areas in the younger age group, reflecting an increased centralisation of fat mass. However, when entered into the multiple regression analysis, baseline age was no longer significant in predicting weight gain and centralisation of body fat over the follow-up period. In the regression model, it was also shown that having a child over the follow-up period was associated with less weight gain over the 5.5-year follow-up period. This finding is in contrast to previous research that has reported that child bearing is weightpromoting.29 Rosenberg et al.14 have shown in a group of black women that the first child was associated with a 0.4 kg/m2 larger increase in BMI compared to those who had a second/additional child. In other studies from the USA, a higher energy intake30 and lower SES31 increased the risk of poor postpartum weight loss, while a study from Brazil found that high prepregnancy weight and higher gestational weight gain32 both increased obesity risk. Although the women in this study were of a very low SES (Table 1), weight gain was found to be lower in women who gave birth during the study period compared to those who did not have children. It has been shown that with exclusive breastfeeding, postpartum weight loss may be improved,33 and even though exclusive breastfeeding rates in SA are considered low (1.4% of infants at six months), breastfeeding as part of mixed feeding is still popular33 and may contribute to lower weight gain postpartum in these women. Furthermore, recent data from SANHANES-1 reported that one in three women (32.4%) experience hunger in the urban informal (peri-urban) environment.2 Unfortunately, since this study did not assess breastfeeding rates or household food insecurity, it is difficult to draw further conclusions as to the effect of these factors on postpartum weight loss. Nonetheless, given the poor SES of the study population, it is likely that more children introduced into the house may promote greater food insecurity, facilitating higher postpartum weight loss. Notably, those who did not have children at baseline were significantly younger than those who already had children, illustrating the possible co-linearity between parity and age. The younger women, who were also nulliparous, were also significantly less active, further confounding the effect of parity on weight gain.

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Longitudinal studies to determine risk of future weight gain in high-income populations often use more static variables of education, employment or income as proxies for SES. To our knowledge, there are no longitudinal studies examining the impact of changes in SES, on body weight or obesity risk, which may be an important factor to consider in this highly mobile population. Although, in this study there was a significant improvement in SES indicators over the follow-up period, specifically sanitation, household assets, level of education and rate of employment, it is still worth noting that less than 50% of the women had completed secondary level education, were formally employed, or came from households with running water and a toilet inside. In spite of the improvements in SES within this population, the traditional markers of SES, including level of education and employment, and the changes in these markers over time, were not independently associated with changes in body weight or body fat distribution. However, women who had access to sanitation at baseline, representing a higher SES, had smaller weight gains over time. Conversely, those who improved their sanitation (and hence SES) over the study period had larger gains in body weight. This may suggest that with improving SES, women may increase their body weight, whereas if SES is stable, body weight might remain more stable. In high-income populations, it has been shown that SES is inversely associated with obesity, with a stronger relationship in women than men.12 Conversely, in LMICs, studies have shown a positive association between SES and BMI,34,35 while others have shown an increasing prevalence of obesity in the lower SES groups.36 Therefore, sanitation rather than the traditional measures of SES may better reflect the poor SES in this study. Although this study did not find any associations with change in body weight and baseline dietary intake, DQI-I or physical activity, other large longitudinal studies have shown that different dietary patterns or physical activity levels have been associated with weight gain over time.8,37,38 The most recent data from SANHANES-1 and other studies also highlight poorer dietary diversity in the urban informal (peri-urban) environment compared to the urban formal areas,2 which may illustrate the interaction between SES and dietary quality. Therefore, even though diet was not found to directly influence the body composition changes in this study, dietary intake is likely to be influenced by the SES of the women. Furthermore, although the food frequency questionnaire used in this study has been validated in black SA women, the lack of association with changes in body composition may be due to limitations with reporting of dietary intake and change over time. Considering the body of evidence from other studies showing the impact of change in dietary intake on increases in body weight, this would be a priority to assess further. Lastly, this study was unable to assess household food security. Due to its interaction with both SES and dietary quality, this would be vital to include in future research. Although most women met the physical activity guidelines (≥ 30 min moderate- to vigorous-intensity physical activity per day, American College of Sports Medicine), baseline physical activity was not associated with weight gain. Most of the physical activity was reported to be for transport, which is of low intensity and may not confer any reasonable effect on energy balance.39 As with dietary intake, the use of subjective measures of physical

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activity (GPAQ) may be limiting due to the misinterpretation of light- and moderate-intensity activity, leading to falsely elevated levels of reported daily physical activity.40 While the change in parity independently influenced weight gain, the use of hormonal contraceptives was not associated with a change in body weight or body fat distribution in this study. Previous studies have found significant increases in body weight and central fat mass with the use of hormonal contraceptives,41 but due to the lack of data regarding length of usage, it is difficult to correctly estimate the effect of the hormonal contraceptive in these women. In addition, SES and access to healthcare may influence the choice, as well as the consistency of contraceptive use in this group and dilute the possible impact on weight change. A limitation of the study was that measurements were only taken at two time points, which may limit our interpretation of subtle changes within the time period. Therefore, acute or shortterm changes could not be measured. Even though the sample size was limited, the longitudinal nature of this study contributes to knowledge regarding the determinants of weight gain and their impact over time in a population at high risk of obesity and metabolic disease. Since only baseline dietary intake and physical activity were measured, this would be vital to follow up in future research studies.

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Boggs DA, Palmer JR, Spiegelman D, Stampfer MJ, Adams-Campbell LL, Rosenberg L. Dietary patterns and 14-y weight gain in African American women. Am J Clin Nutr 2011; 94(1): 86–94.

Brown WJ, Williams L, Ford JH, Ball K, Dobson AJ. Identifying the energy gap: magnitude and determinants of 5-year weight gain in midage women. Obes Res 2005; 13(8): 1431–1441.

Ebrahimi-Mameghani M, Scott JA, Der G, Lean MEJ, Burns CM. Changes in weight and waist circumference over 9 years in a Scottish population. Eur J Clin Nutr 2007; 62(10): 1208–1214.

Zamora D, Gordon-Larsen P, Jacobs DR, Popkin BM. Diet quality and weight gain among black and white young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985 obesity 2005). Am J Clin Nutr 2010; 92(4): 784–793.

Schulze MB, Fung TT, Manson JE, Willett WC, Hu FB. Dietary patterns and changes in body weight in women. Obesity 2006; 14(8): 1444–1453.

Rosell M, Appleby P, Spencer E, Key T. Weight gain over 5 years in 21 966 meat-eating, fish-eating, vegetarian, and vegan men and women in EPIC-Oxford. Int J Obes Relat Metab Disord 2006; 30(9): 1389–1396.

10. Hankinson AL, Daviglus ML, Bouchard C, Carnethon M, Lewis CE, Schreiner PJ, et al. Maintaining a high physical activity level over 20 years and weight gain. J Am Med Assoc 2010; 304(23): 2603. 11. Monteiro CA, Moura EC, Conde WL, Popkin BM. Socioeconomic status and obesity in adult populations of developing countries: a

Conclusion This study showed that lower BMI and nulliparity in the younger women were significant determinants of weight gain and centralisation of body fat over 5.5 years. In addition, although higher SES at baseline was associated with a smaller change in body weight, improvements in SES over the follow-up period were associated with greater weight gain. Many health programmes are targeted at women of reproductive age (e.g. family planning clinics). Accordingly, the introduction of weight-management interventions in these clinics is recommended to prevent and manage weight gain in these vulnerable young women, as well as future generations due to the intergenerational transfer of risk. Research to understand the relationship between alternative measures of SES, including sanitation and housing, and weight gain are required to guide future policy recommendations.

review. Bull World Health Org 2004; 82(12): 940–946. 12. Coogan PF, Cozier YC, Krishnan S, Wise LA, Adams-Campbell LL, Rosenberg L, et al. Neighborhood socioeconomic status in relation to 10-year weight gain in the Black Women’s Health Study. Obesity 2012; 18(10): 2064–2065. 13. Kac G, Benício MHDA, Velásquez-Meléndez G, Valente JG, Struchiner CJ. Gestational weight gain and prepregnancy weight influence postpartum weight retention in a cohort of Brazilian women. J Nutr 2004; 134(3): 661–666. 14. Rosenberg L, Palmer JR, Wise LA, Horton NJ, Kumanyika SK, Adams-Campbell LL. A prospective study of the effect of childbearing on weight gain in African-American women. Obes Res 2003; 11(12): 1526–1535. 15. Luoto R, Mannisto S, Raitanen J. Ten-year change in the association between obesity and parity: results from the National FINRISK Population Study. Gend Med 2011; 8(6): 399–406. 16. Wagenknecht LE, Magriples U, Langefeld CD, Kershaw TS, Scherzinger

We thank the research volunteers for their participation in this study,

AL, et al. Insulin sensitivity, insulin secretion, and abdominal fat: the

Nandipha Sinyanya for her fieldwork, Hendriena Victor for her technical

Insulin Resistance Atherosclerosis Study (IRAS) family study. Am

assistance, Linda Bewerunge for performing the DXA scans and Mark

Diabetes Assoc 2003; 52(10): 2490–2496.

Punyanitya for analysing the CT scans. This study was funded by the

17. Liu J, Fox CS, Hickson DA, May WD, Hairston KG, Carr JJ, et al.

Sugar Association of South Africa, the South African Medical Research

Impact of abdominal visceral and subcutaneous adipose tissue on

Council, the International Atomic Energy Agency and the National Research

cardiometabolic risk factors: the Jackson Heart Study. J Clin Endocrinol

Foundation of South Africa.

Metab 2010; 95(12): 5419–5426. 18. Lovejoy JC, Smith SR, Rood JC. Comparison of regional fat distribu-

References 1.

Popkin BM, Slining MM. New dynamics in global obesity facing lowand middle-income countries. Obes Rev 2013; 14: 11–20.

tion and health risk factors in middle-aged white and African American women: the Healthy Transitions study. Obes Res 2001; 9(1): 10–16. 19. Snijder MB, Dekker JM, Visser M, Yudkin JS, Stehouwer C, Bouter LM, et al. Larger thigh and hip circumferences are associated with better

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

glucose tolerance: the Hoorn Study. Obes Res 2003; 11(1): 104–111.

et al. The South African National Health and Nutrition Examination

20. Vorster HH, Venter CS, Wissing MP, Margetts BM. The nutrition and

Survey: SANHANES-1. HSRC Press, 2013 Aug 15: 1–4.

health transition in the North West Province of South Africa: a review

Chantler S, Dickie K, Micklesfield LK, Goedecke JH. Longitudinal

of the THUSA (Transition and Health during Urbanisation of South

changes in body fat and its distribution in relation to cardiometabolic risk in black South African women. Metab Syndr Relat Disord 2015; 13(9): 381–388.

Africans) study. Public Health Nutr 2007; 8(5): 480–490. 21. Dinsa GD, Goryakin Y, Fumagalli E, Suhrcke M. Obesity and socioeconomic status in developing countries: a systematic review. Obes Rev

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2012; 13(11): 1067–1079.

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31. Parker JD, Abrams B. Differences in postpartum weight retention

22. Jennings CL, Lambert EV, Collins M, Joffe Y, Levitt NS, Goedecke JH. Determinants of Insulin-resistant phenotypes in normal-weight and obese black African women. Obesity. 2012; 16(7): 1602–1609.

between black and white mothers. Obstet Gynecol 1993; 81(5, Pt 1): 768–774. 32. Kac G, Abrams B, Benício MHDA, Velásquez-Meléndez G, Valente

23. Goedecke JH, Micklesfield LK, Levitt NS, Lambert EV, West S,

JG, et al. Gestational weight gain and prepregnancy weight influence

Maartens G, et al. Effect of different antiretroviral drug regimens on

postpartum weight retention in a cohort of brazilian women. J Nutr

body fat distribution of HIV-infected South African women. AIDS Res Human Retrovirus 2013; 29(3): 557–563.

2004; 134(3): 661–666. 33. Department of Health. South African Demographic and Health Survey

24. Bull FC, Maslin TS, Armstrong T. Global physical activity questionnaire (GPAQ): nine country reliability and validity study. J Phys Act

(SADHS) 2008, Oct 9: 1–569. 34. Fernald LCH. Socio-economic status and body mass index in lowincome Mexican adults. Soc Sci Med 2007; 64(10): 2030–2042.

Health 2009; 6(6): 790–804. 25. Steyn NP, Senekal M. A guide for the use of the dietary assessment and education kit (DEAK). Medical Research Council, Cape Town, 2004. 26. De Villiers A, Lambert EV, Senekal M. Relative validity of a quanti-

35. Subramanian S, Dinsa GD, Perkins JM, Goryakin Y, Ozaltin E, Fumagalli E, et al. Obesity and socioeconomic status in developing countries: a systematic review. Obes Rev 2012; 13(11): 1067–1079.

fied food frequency questionnaire in black South African women. BSc

36. Jennings CL, Gordon-Larsen P, Lambert EV, Collins M, Joffe Y, et al.

(Med) (Hon) in Nutrition and Dietetics. University of Cape Town, Cape

Determinants of insulin-resistant phenotypes in normal-weight and obese black African women. Obesity 2008; 16(7): 1602–1609.

Town, 2006. 27. Kim S, Haines PS, Siega-Riz AM, Popkin BM. The diet quality index

37. Quatromoni PA, Pencina M, Cobain MR, Jacques PF, D’Agostino

– international (DQI-I) provides an effective tool for cross-national

RB. Dietary quality predicts adult weight gain: findings from the

comparison of diet quality as illustrated by China and the United States. J Nutr 2003; 133(11): 3476–384.

Framingham Offspring Study. Obesity 2006; 14(8): 1383–1391. 38. Gordon-Larsen P, Hou N, Sidney S, Sternfeld B, Lewis CE, Jacobs

28. Lewis CE, Jacobs DR, McCreath H, Kiefe CI, Schreiner PJ, Smith DE, et al. Weight gain continues in the 1990s: 10-year trends in

DR, et al. Fifteen-year longitudinal trends in walking patterns and their impact on weight change. Am J Clin Nutr 2008; 89(1): 19–26.

weight and overweight from the CARDIA study: Coronary Artery

39. Luke A, Cooper RS. Physical activity does not influence obesity risk:

Risk Development In young Adults. Am J Epidemiol 2000; 151(12):

time to clarify the public health message. Int J Epidemiol 2014; 42(6): 1831–1836.

1172–1181. 29. Gore SA, Brown DM, West DS. The role of postpartum weight reten-

40. Nicaise V, Marshall S, Ainsworth BE. Domain-specific physical activ-

tion in obesity among women: a review of the evidence. Ann Behav Med

ity and self-report bias among low-income Latinas living in San Diego County. J Phys Act Health 2011; 8(7): 881–890.

2003; 26(2): 149–159.

41. Berenson AB, Rahman M. Changes in weight, total fat, percent body

relationship between diet, activity and other factors, and post partum

fat, and central-to-peripheral fat ratio associated with injectable and oral

weight change by race. Obstet Gynecol 1995; 86: 834–838.

contraceptive use. Am J Obst Gynecol 2009; 200(3): 329.e1–329.

2017

30. Boardley DL, Sargent RG, Coker AL, Hussey JR, Sharpe PA. The

A course by and for the African Cardiovascular Community

Save the date! SA

Hear t

23–25 March 2017 Century City Conference Centre Cape Town, South Africa

Europa Organisation Africa info@eoafrica.co.za | Tel +27 (0)11 325 0020 www.africapcr.com | www.eoafrica.co.za

Your Daily Practice Companion

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The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/ reperfusion Derick van Vuuren, Erna Marais, Sonia Genade, Amanda Lochner

Abstract Aim: The aim of this study was to evaluate the effects of the sphingosine analogue, FTY720 (Fingolimod), on the outcomes of myocardial ischaemia/reperfusion (I/R) injury. Methods: Two concentrations of FTY720 (1 or 2.5 µM) were administered either prior to (PreFTY), or following (PostFTY) 20 minutes’ global (GI) or 35 minutes’ regional ischaemia (RI) in the isolated, perfused, working rat heart. Functional recovery during reperfusion was assessed following both models of ischaemia, while infarct size (IFS) was determined following RI. Results: FTY720 at 1 µM exerted no effect on functional recovery, while 2.5 µM significantly impaired aortic output (AO) recovery when administered prior to GI (% recovery: control: 33.88 ± 6.12% vs PreFTY: 0%, n = 6–10; p < 0.001), as well as before and after RI (% recovery: control: 27.86 ± 13.22% vs PreFTY: 0.62%; p < 0.05; and PostFTY: 2.08%; p = 0.0585, n = 6). FTY720 at 1 µM administered during reperfusion reduced IFS [% of area at risk (AAR): control: 39.89 ± 3.93% vs PostFTY: 26.56 ± 4.32%, n = 6–8; p < 0.05), while 2.5 µM FTY720 reduced IFS irrespective of the time of administration (% of AAR: control: 39.89 ± 3.93% vs PreFTY: 29.97 ± 1.03%; and PostFTY: 30.45 ± 2.16%, n = 6; p < 0.05). Conclusion: FTY720 exerted divergent outcomes on function and tissue survival depending on the concentration administered, as well as the timing of administration. Keywords: functional recovery, FTY720, ischaemia/reperfusion injury, infarct size, myocardial, working heart perfusion Submitted 28/10/15, accepted 30/3/16 Cardiovasc J Afr 2016; 27: 375–386

www.cvja.co.za

DOI: 10.5830/CVJA-2016-039

In 2008 the WHO reported that non-communicable diseases (NCDs), including cardiovascular disease, are the leading causes of death globally.1 South Africa, as well as the broader African region, is no exception, with recent research indicating the prevalence of NCDs and cardiovascular disease.2-5 Ischaemic heart disease has been identified as a major contributor to

Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa Derick van Vuuren, PhD, dvvuuren@sun.ac.za Erna Marais, PhD Sonia Genade, BSc Amanda Lochner, PhD

global morbidity and mortality rates6 in a trend set to continue, irrespective of affluence.7,8 The current clinical approach to myocardial ischaemia is to limit the duration of ischaemia by re-establishing perfusion of the affected tissue as fast as possible.9,10 The first description of ischaemic preconditioning11 however also exposed the innate ability of the heart to increase its resistance to ischaemia/reperfusion (I/R) injury. The fact that interventions can also be applied in conjunction with reperfusion to enhance the beneficial effects of reperfusion proves that (1) a degree of damage is imparted by reperfusion per se, a phenomenon that is known as reperfusion injury;12,13 and (2) the modulation of intracellular events inside the cardiomyocyte can protect the heart over and above the beneficial effect of rapid reperfusion.13 This is known as cardioprotection. Research has revealed several well-defined intracellular signalling pathways associated with cardioprotection, including the reperfusion injury salvage kinase (RISK)14 and survivor activating factor enhancement (SAFE)15 pathways. These, and others, have been extensively reviewed elsewhere.16,17 Two molecules that have been implicated in the mediation of cardioprotection is the sphingolipid, sphingosine and its phosphorylated metabolite, sphingosine-1-phosphate (S1P).18,19 It has been shown that sphingosine and S1P can elicit cardioprotection through the activation of several of the known cardioprotective pathways.20-24 FTY720 (also known as Fingolimod), a derivative of a metabolite of a fungal species that has long been associated with medicinal effects in Chinese folk medicine,25 is a structural analogue of sphingosine. As such, it is metabolised in a similar fashion to sphingosine in that; it easily traverses the cell membrane to be phosphorylated intracellularly by sphingosine kinase 2 (SK2). The phosphorylated FTY720 (P-FTY720) then exits the cell to bind to a sphingosine-1-phosphate (S1P) receptor. Five receptors have been identified, of which four can interact with P-FTY720: S1P1, 3, 4 and 5.26,27 Since S1P and sphingosine have been associated with a reduction in the myocardial damage caused by I/R,20-14 several researchers have turned their attention to the potential benefits of FTY720 within this setting, with mixed success. Especially three endpoints have been addressed by the current body of research: rhythmicity, cell death/survival and functional ability following I/R. FTY720 appears to exert an effect on rhythmicity, however, the results obtained are controversial. Egom and co-workers28 reported that FTY270 reduced the occurrence of rhythmic disturbances post-I/R in an ex vivo rat heart, as well as in a sino-atrial node preparation. These beneficial effects were however absent in an in vivo rat model, where FTY720 administered during reperfusion proved detrimental due to an increased occurrence of tachycardia and ventricular fibrillation.29 Similarly, the effects of FTY720 on cell death are controversial; some researchers have reported that it decreases infarct size

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(IFS)30 and increases cell viability,31 while others have found no effect on IFS and cell survival.29,32 There seems to be more consensus regarding function following I/R. FTY720 given at the onset of reperfusion increases functional ability.30,32 The effect of acute pre-ischaemic administration of FTY720 to the heart has not yet been described. Clinical interest in FTY720 has however not centred on its postulated cardioprotective effects, but rather on its immunosuppressant effects, which led to the approval of a commercial form of the drug for use as an oral treatment for multiple sclerosis (MS).33,34 One of the proposed explanations for the mechanism by which FTY720 suppresses the autoimmune response associated with MS is by binding to S1P1 in the lymphoid tissue. This initiates a paradoxical reduction in the effects linked to S1P1 activation, including the egress of lymphoid cells from the lymph nodes. This ‘functional antagonism’, as Brinkmann26 puts it, can be explained by the down-regulation of S1P1 receptors due to sustained activation by P-FTY720. The end-effect is the specific suppression of lymphocyte release from the lymph tissue.25-27 In addition to its immuno-modulatory effects, FTY720 has also received attention as a possible tumour suppressor.35 Studies have shown that FTY720 induces cell death in cancerous cells, while not eliciting any toxic effects in other tissues.35-37 One of the proposed mechanisms by which FTY720 induces cell death in these cells entails the FTY720-mediated activation of the serine/ threonine protein phosphatase, protein phosphatase 2A (PP2A), which, when activated, favours the de-phosphorylation and inactivation of pro-survival proteins such as protein kinase B (PKB/Akt), extracellular signal-regulated kinase p42/p44 (ERK p42/p44), Bad and others.36-39 FTY720 is therefore a drug with both existing and potential clinical applications in divergent fields: MS, cancer and cardioprotection following I/R, although the precise nature of its influence in the latter context is still controversial. Consequently it is important to clarify its effects on the heart since, on one hand, FTY720 could present as a clinically feasible drug for the treatment of myocardial I/R injury, while on the other hand, it also has clinical potential in other scenarios, making it important A

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to better illuminate the ‘off-target’ effects of this drug on organs such as the heart. The controversies associated with FTY720 administration in the context of myocardial I/R injury highlight questions regarding the effects of different doses of the drug, administered at different time points relative to sustained ischaemia, on different endpoints associated with I/R injury. The aim of this study was therefore to investigate and describe the effects of FTY720 administration at two different concentrations (1 and 2.5 µM) prior to ischaemia or at the onset of reperfusion in two different models of ischaemia (20 minutes’ global ischaemia and 35 minutes’ regional ischaemia) on different endpoints (functional recovery and IFS) in the isolated, working rat heart model. In view of the immunomodulatory effects of FTY720, the isolated heart preparation allows for the study of direct cardiac effects independent of systemic, in this case specifically, immune interactions and effects.40 Regional ischaemia (RI) of the isolated heart is an accepted model of ischaemia of only a portion of the left ventricle, thereby simulating myocardial infarction. Global ischaemia (GI) on the other hand is of scientific interest, as it is well characterised and commonly used in basic research studies requiring relatively large amounts of homogenous tissue where biochemical analysis of tissue is required, or in instances where functional recovery is the primary endpoint of interest, for example in studies investigating stunning.40,41

Methods Male Wistar rats were allowed free access to food and water prior to experimentation. Rats weighing between 250 and 350 g were anaesthetised by intraperitoneal injection of 60 mg pentobarbital per rat. All experimental protocols were approved by the Animal Ethics committee of the University of Stellenbosch (Faculty of Medicine and Health Sciences) and were executed in accordance with the revised South African National Standard for the care and use of laboratory animals for scientific purposes (SABS, SANS 10386, 2008). For all experimentation, the isolated, working rat heart preparation was used as described previously.42 Following the B

Retrograde

Work

Control

PreFTY

PostFTY

Retrograde Ischaemia Retrograde 20 15 FTY 20

Work

Retrograde Work Retrograde Ischaemia Retrograde Work Retrograde

20 GI

Control

35 RI

20 GI

PreFTY

15 FTY

35 RI

PostFTY

35 RI

20 GI

15 FTY

15 FTY 0 15 30 50 70 90 105 * * Time duration (minutes)

0 15 30 45 80 100 120 * * Time duration (minutes)

140 #

Fig. 1. Isolated working rat heart perfusion protocols used to investigate the effects of different concentrations of FTY720, administered at different time points relative to sustained ischaemia, in different models of ischaemia and their respective endpoints. FTY720 (1 μM or 2.5 μM) was administered for a period of 15 minutes either immediately prior to sustained ischaemia (PreFTY), or directly at the onset of reperfusion (PostFTY). Two models of ischaemia were used: (A) 20 minutes’ global ischaemia (GI), followed by a total of 35 minutes’ reperfusion; and (B) 35 minutes’ regional ischaemia (RI), followed by 60 minutes’ reperfusion. In the RI model, the reperfusion administration of FTY720 already commenced during the final five minutes of RI. Functional recovery was measured in both groups at the end of the last episode of work during reperfusion. Infarct size (IFS) was the primary endpoint for this model of ischaemia. *Determination of functional ability both pre- and post ischaemia. #Determination of infact size.

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establishment of sufficient sedation, the heart was rapidly removed and mounted by cannulation of the aorta, where after it was exposed to a perfusion protocol containing periods of both retrograde, as well as work-mode perfusion, as shown in Fig. 1. Cardiac temperature was monitored throughout using a thermal probe inserted into the coronary sinus and maintained at a temperature of 36.5°C. Functional performance of the hearts was determined by the timed measurement of coronary flow (CF) during retrograde perfusion, as well as aortic output (AO) and CF during work mode. A pressure transducer (Viggo Spectromed) inserted into the aortic cannula was used to determine heart rate, as well as intra-aortic pressure. Aortic pressure and cardiac output (CO = AO + CF) were used to determine left ventricular work performance, as described by Kannengieser et al.43 Following a suitable period of stabilisation, the hearts were exposed to either 20 minutes of GI, or 35 minutes of RI as described in the next section. FTY720 was obtained from Cayman Chemical (product number 10006292; Cayman Chemical, MI, USA). After dissolving it in dimethyl sulfoxide (DMSO), it was administered to the isolated hearts at a concentration of either 1 or 2.5 µM. The DMSO never exceeded a final concentration of 0.03% (vol/ vol), i.e. 0.004 M. This concentration was lower than those reported to be associated with toxicity44 or changes in cardiac function.45 Both concentrations of FTY720 were administered to the isolated rat heart for a period of 15 minutes directly prior to (PreFTY) sustained ischaemia or at the onset of reperfusion (PostFTY) (Fig. 1). Global ischaemia (GI) entailed the complete cessation of perfusion of the heart for a period of 20 minutes, at a temperature of 36.5°C. Function during reperfusion was expressed relative to pre-ischaemic values and served as an endpoint for the damage caused by ischaemia. RI was initiated by occluding the left anterior descending coronary artery using a silk suture to ensnare the proximal section of the artery and closing it with two interlocking pieces of plastic tubing, thereby rendering the tissue distal to the occlusion ischaemic [the area at risk (AAR)], while the remainder of the heart still received adequate perfusion [the viable area (VA)]. Following 35 minutes of RI, at a maintained temperature of 36.5°C, the AAR was reperfused by opening the suture. Following RI, FTY720 administration was initiated five minutes before the end of ischaemia and progressed for the first 10 minutes of reperfusion. Both the extent of infarct development as well as functional recovery were used to assess the effects of this ischaemic stress. Hearts were reperfused for a period of 35 minutes following 20 minutes’ GI, and for 60 minutes following 35 minutes’ RI. Although many researchers in the field prefer longer periods of reperfusion following RI, previous work in our laboratory has shown that shorter periods of reperfusion did not influence the relative degree of IFS development between groups.46,47 Post-ischaemic function was assessed at 35 minutes’ reperfusion following 20 minutes’ GI, and 40 minutes’ reperfusion following RI. Infarct size was determined as previously described.48,49 Briefly, following the application of RI and a suitable period of reperfusion, the suture surrounding the left coronary artery was re-occluded and the heart was infused with 0.5% Evans blue dye, administered through the aortic cannula. This then delineated

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the VA (which received adequate perfusion throughout the protocol) from the AAR (the portion of the heart that was exposed to ischaemia, including infarcted tissue).50,51 The heart was then promptly removed from the perfusion apparatus and frozen at –20°C for later analysis. After no more than five days, the frozen ventricles were cut into slices of approximately 2 mm in thickness and stained with 1% w/v triphenyltetrazolium chloride (TTC) in a phosphate buffer (pH 7.4) at room temperature. Triphenyltetrazolium chloride (TTC) stains viable tissue a brick-red colour through its reaction with active dehydrogenases.51,52 After 15 minutes, the heart slices were fixed in a 10% v/v formaldehyde solution. The final result was slices of heart tissue stained blue (VA), red (viable tissue in the AAR) and white (infarcted tissue in the AAR) (Fig. 2). The surface areas of these zones were quantified using the UTHSCSA ImageTool program (developed at the University of Texas Health Science Center at San Antonio, Texas, which is available from the internet at http://ddsdx.uthscsa.edu/dig/ itdesc.html) and the data for all the individual slices were added together for each heart. For comparison of the data, IFS is expressed relative to the AAR, while the degree of occlusion is indicated by the AAR relative to the total area (AAR + VA). For an overview of the determination of IFS in pre-clinical experimental models see Csonka et al.51

A Blue tissue never exposed to ischaemia

White infarcted tissue Red viable tissue in the area at risk

B Heart slices traced

Quantification of surface areas using the UTHSCSA ImageTool program

Graphed data calculated as follows: Percentage IFS = [IFS (white)/AAR (white+red)] × 100 Percentage AAR = [AAR (white+red)/total area] × 100

Fig. 2 Graphic scheme illustrating the determination of infarct size (IFS) using Evans blue dye and triphenyltetrazolium chloride (TTC) staining. A, B. Evans dye is retrogradely injected through the aorta of the heart to distinguish between tissue that has received adequate perfusion (perfusing blue) and tissue exposed to ischaemia. This ischaemic area is also called the area at risk (AAR). It contains both infarcted tissue (white) and viable tissue, which stains red in a reaction with TTC. These three zones are then traced on an overlaying transparency (C), which is then scanned and the different areas determined using planimetry software. D. The data that is finally used for statistical comparison is the infarct size expressed as a percentage of the AAR, as well as the AAR expressed relative to the total surface area. This latter parameter is an indication of the degree of coronary occlusion.

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Table 1. Functional parameters of isolated, perfused rat hearts recorded at baseline (i.e. prior to both the administration of FTY720, as well as exposure to sustained ischaemia) and at the end of work-mode reperfusion (following sustained ischaemia). Reperfusion function was compared to baseline function using a paired t-test Coronary flow† (ml/min) Group

Aortic output (ml/min)

Post-ischaemic

Baseline

Cardiac output (ml/min)

Post-ischaemic

Baseline

Total work (mW)

Post-ischaemic

Baseline

Heart rate (beats/min)

Systolic pressure (mmHg)

Post-ischaemic

Baseline

Post-ischaemic

Baseline

Post-ischaemic

5.92 ± 1.22#

317.4 ± 19.8

263.4 ± 13.5

90.25 ± 3.75

78.88 ± 3.84@ 5–10 82.25 ± 3.39

20 minutes’ global ischaemia Control

8.45 ± 0.75

7.50 ± 0.80

44.20 ± 3.41 16.00 ±3.75* 60.55 ± 4.10 28.35 ± 4.29* 13.17 ± 1.22

1 µM FTY720 PreFTY

9.13 ± 1.13

6.31 ± 0.43@

47.13 ± 4.11 13.50 ± 3.62* 63.81 ± 4.78 24.25 ± 4.83* 14.41 ± 0.56

5.94 ± 1.09$

278.6 ± 18.4

255.0 ± 15.9

96.25 ± 4.05

PostFTY

6.70 ± 0.47

12.20 ± 0.93* 51.50 ± 1.78 14.00 ± 3.66* 66.39 ± 2.45 23.72 ± 5.45* 14.02 ± 0.74

4.96 ± 1.24*

267.0 ± 10.2

189.0 ± 37.1

94.89 ± 3.01 72.11 ± 14.01 9–10

5–8

2.5 µM FTY720 13.98 ± 0.41

0.40 ± 0.40*

266.8 ± 23.5

24.3 ± 24.3#

101.7 ± 4.78 16.00 ± 16.00# 4–6

58.93 ± 4.81 24.00 ± 4.73* 11.54 ± 1.09

4.60 ± 0.92*

282.1 ± 15.2

259.4 ± 9.6

88.71 ± 5.47

77.14 ± 3.23@ 6–7

48.33 ± 3.56 14.33 ± 6.82# 62.83 ± 4.34 29.83 ± 7.09# 13.46 ± 1.13

5.60 ± 1.49#

292.7 ± 10.3

277.5 ± 8.0@

96.00 ± 1.88

81.33 ± 2.72#

216.5 ± 38.8

96.50 ± 1.50

76.33 ± 5.40#

PreFTY

6.50 ± 0.52

6.58 ± 0.37

41.00 ± 5.21

0.0 ± 0.0$

PostFTY

5.50 ± 0.49

9.57 ± 0.98#

44.29 ± 2.88

8.21 ± 1.83$

55.25 ± 6.48

5.92 ± 0.45$

35 minutes’ regional ischaemia Control

9.00 ± 0.52

9.27 ± 0.46

1 µM FTY720 8.92 ± 0.45

9.50 ± 1.71

55.50 ± 1.63

9.50 ± 3.38*

69.08 ± 3.98 19.75 ± 4.52$ 15.46 ± 0.63

3.98 ± 0.55*

274.7 ± 9.9

PostFTY 10.00 ± 0.82

12.07 ± 1.14

44.00 ± 4.30

2.57 ± 1.49$

58.14 ± 5.49 14.16 ± 3.59# 11.67 ± 1.13

2.31 ± 0.74$

285.6 ± 15.5 205.1 ± 40.8@ 90.29 ± 1.11 59.29 ± 12.03@

PreFTY

2.5 µM FTY720 PreFTY

10.25 ± 0.54

9.42 ± 0.27

47.00 ± 3.53

0.33 ± 0.33*

63.17 ± 4.39 12.08 ± 4.09$ 13.02 ± 0.98

1.82 ± 0.67$

279.7 ± 17.4

146.3 ± 47.3

92.67 ± 1.20 45.50 ± 15.74@

PostFTY

9.67 ± 0.76

10.67 ± 0.76

52.33 ± 3.20

1.00 ± 1.00*

69.42 ± 3.94

14.62 ± 0.87

1.55 ± 0.58$

269.8 ± 13.2

156.0 ± 50.2

94.83 ± 1.08 48.33 ± 15.66@

9.42 ± 3.25$

As measured during retrograde perfusion; *p < 0.0001 versus baseline; $p < 0.001; #p < 0.01 versus baseline; @p < 0.05 versus baseline.

†

Statistical analysis Animals were randomly assigned to different experimental groups on the day of experimentation. Where functional recovery was assessed as the primary endpoint (i.e. after 20 minutes’ GI) data were collected from a minimum of four to a maximum of 10 rats per group. Infarct size was compared between groups containing a minimum of six rats per group. All statistical analyses were done using Graphpad Prism (version 6.01). For all comparisons (unless otherwise specified) a one-way analysis of variance (ANOVA) was performed, followed by Dunnett’s test to compare all relevant experimental groups to control alone. A p-value of less than 0.05 was considered statistically significant.

Results The effect of FTY720 in a model of 20 minutes’ GI Isolated, working rat hearts exposed to 20 minutes’ GI were treated with either 1 or 2.5 µM FTY720, either prior to sustained ischaemia or immediately at the onset of reperfusion (Fig. 1). All functional data recorded in this study are shown in Table 1. Baseline functional measurements of the hearts, prior to both FTY720 administration and ischaemia, are shown in Table 2.

Table 2. Baseline functional ability of isolated rat hearts prior to exposure to both 20 minutes’ global ischaemia (GI), as well as treatment with FTY720 (1 or 2.5 µM) either before sustained ischaemia or during initial reperfusion Group

Aortic output (ml/min)

Cardiac output (ml/min)

Total work (mW)

Number

Control

44.20 ± 3.41

60.55 ± 4.10

13.17 ± 1.22

5–10

1 µM FTY720 PreFTY

47.13 ± 4.11

63.81 ± 4.78

14.41 ± 0.56

5–8

PostFTY

51.50 ± 1.78

66.39 ± 2.45

14.02 ± 0.74

9–10

2.5 µM FTY720 PreFTY

41.00 ± 5.21

55.25 ± 6.48

13.98 ± 0.41

4–6

PostFTY

44.29 ± 2.88

58.93 ± 4.81

11.54 ± 1.09

6–7

C 60

30 20 10 0

Control

PreFTY

PostFTY

Functional recovery

50 Functional recovery

Functional recovery

There were no significant differences in the basal capacity of any of the groups compared to the control. Administration of FTY720 at a dose of 1 µM had no effect on functional recovery (Fig. 3), irrespective of whether it was administered before ischaemia or during early reperfusion. Similar to the effects associated with 1 µM, reperfusion administration of 2.5 µM FTY720 did not exert any significant effects on post-ischaemic function (Fig. 4).

40 30 20 10 0

Control

PreFTY

PostFTY

40 30 20 10 0

Control

PreFTY

PostFTY

Fig. 3 T he effect of FTY720 (1 μM) administered either immediately before sustained ischaemia (PreFTY), or for the first 15 minutes of reperfusion (PostFTY), on functional recovery in isolated hearts exposed to 20 minutes’ GI, followed by 35 minutes’ reperfusion. Functional recovery was assessed as post-ischaemic (A) aortic output (AO); (B) cardiac output (CO); and (C) total work expressed as a percentage of pre-ischaemic values, n = 5–10.

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40 30 20 10 0

C 60

p < 0.001

Control

PreFTY

40 30 20 10 0

PostFTY

Control

p < 0.001

Functional recovery

379

PreFTY

50 40 30 20 10 0

PostFTY

Control

PreFTY

PostFTY

Fig. 4 T he effect of FTY720 (2.5 μM) administered as either pre-treatment (PreFTY) or immediately following ischaemia (PostFTY) on functional recovery. Pre-ischaemic administration of FTY720 was associated with a profound suppression of functional recovery in terms of (A) aortic output, (B) cardiac output, and (C) total work, n = 4–10.

Surprisingly, at a dose of 2.5 µM, FTY720 administered as a pre-treatment potently suppressed all functional recovery (Fig. 4), as evident by the fact that of the six hearts pre-treated with FTY720, only one recovered sufficiently to generate recordable total work data (aortic output: control: 33.88 ± 6.12% vs PreFTY: 0%, n = 6–10; p < 0.001; cardiac output: control: 45.94 ± 5.57% vs PreFTY: 12.20 ± 2.68%, n = 6–10; p < 0.001; and total work: control: 45.67 ± 8.98% vs PreFTY: 2.79%, n = 4–5; p < 0.01). In view of this severe suppression of post-ischaemic function, we also analysed heart rate (percentage recovery: control: 85.00 ± 6.11% vs PreFTY: 10.53%, n = 6–8; p < 0.001) as well as systolic pressure (percentage recovery: control: 88.13 ± 4.45% vs PreFTY: 15.10%, n = 6–8; p < 0.001). We found both to be significantly reduced in the FTY720 pre-treatment group. During the perfusion experiments we noticed that FTY720 A

elicited a profound increase in coronary flow (CF) (Figs 5, 6). Expression of CF at the end of pre-ischaemic drug administration relative to retrograde perfusion stabilisation values (Fig. 5) shows that both doses increased CF when administered prior to ischaemia [control: 0.95 ± 0.05 arbitrary units (AU) vs PreFTY (1 µM): 2.25 ± 0.27 AU and PreFTY (2.5 µM): 2.56 ± 0.27 AU, n = 5–8; p < 0.01]. Expression of reperfusion CF relative to pre-ischaemic stabilisation CF reveals a similar trend when FTY720 was administered at the onset of reperfusion [Fig. 6; control: 1.21 ± 0.11 AU vs PostFTY (1 µM): 2.59 ± 0.18 AU and PostFTY (2.5 µM): 2.19 ± 0.15 AU, n = 4–9; p < 0.01]. Surprisingly, the vasodilatory effect of FTY720 pre-treatment (Fig. 5) was replaced by a reduction in CF during the first 15 minutes of reperfusion relative to the control [CF expressed relative to retrograde stabilisation: control: 1.94 ± 0.17 AU vs

B Coronary flow at the end of 15-minute drug administration relative to stabilisation 3.0 @

Coronary perfusion at the end of retrograde reperfusion relative to stabilisation 1.50

2.0 1.5 1.0 0.5

Retrograde Control

PreFTY

stabilisation

1 μM FTY

Control

2.5 μM FTY

1.25

2.0 @ 1.5

1.0 0.5 0.0

Coronary flow ratio

Average coronary flow over the first 15 minutes of reperfusion relative to stabilisation 2.5

2.5

0.0

1.00 0.75 0.50 0.25

Control

1 μM FTY

2.5 μM FTY

0.00

Control

1 μM FTY

2.5 μM FTY

Work

Retrograde

Ischaemia

Retrograde

Work

20 GI

15 FTY

Fig. 5 T he effect of pre-treatment with FTY720 on coronary flow (CF) in a model of global ischaemia. Coronary flow was collected during retrograde perfusion at the end of stabilisation, the end of drug administration and every two minutes for the first 15 minutes of reperfusion, as well as at the end of retrograde reperfusion. For comparison purposes, the CF of each time point was expressed relative to the stabilisation values of that group. FTY720 increased CF during administration of the drug, but reduced CF during initial reperfusion.@p < 0.05 vs control, n = 3–11.

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B Coronary flow at the end of 15-minute drug administration relative to stabilisation 3.0 @ @ Coronary flow ratio

Coronary flow ratio

2.5

Coronary perfusion at the end of 20 minutes’ retrograde reperfusion relative to stabilisation 2.5

2.0 1.5 1.0 0.5 1 μM FTY

Control

Retrograde Control

PreFTY

stabilisation

0.0

1 μM FTY

2.5 μM FTY

1.5 1.0 0.5 0.0

2.5 μM FTY

2.0

Work

Retrograde

Ischaemia

20 GI

Control

Retrograde

Work

20 15 FTY

15 20

Fig. 6 T he effect of the reperfusion administration of FTY720 on coronary flow (CF). FTY720 was associated with an increase in CF, which was still evident five minutes after the cessation of drug administration.@p < 0.01 vs control, n = 4–11.

PreFTY (1 µM): 1.60 ± 0.08 AU and PreFTY (2.5 µM): 1.14 ± 0.07 AU, n = 3–5; p < 0.05]. This effect was however transient, with CF in the drug-treated groups returning to control levels after 20 minutes of retrograde perfusion (Fig. 5C).

the functional ability of the hearts after the index ischaemia can also be measured alongside the primary endpoint of IFS. Table 1 contains the functional values recorded at reperfusion. Similar to our GI experiments, 1 µM of FTY720 failed to elicit any effect on functional recovery following 35 minutes of RI (Fig. 7).

The effect of FTY720 in a model of 35 minutes’ RI Although functional recovery is a useful endpoint, IFS is considered by many workers to be the gold standard for evaluating the effects of an intervention on I/R injury. We therefore also investigated the effects of FTY720 administration on IFS following 35 minutes of RI (Fig. 1). Although IFS was the primary endpoint for these experiments, functional recovery was also recorded. Pre-ischaemic functional patency of the hearts used for these experiments is shown in Table 3. None of the experimental groups differed from the control group prior to the administration of FTY720 and the onset of regional ischaemia. One of the advantages of a model of regional ischaemia is that A

Group

Aortic output (ml/min)

Cardiac output (ml/min)

Total work (mW)

Number

Control

48.33 ± 3.56

62.83 ± 4.34

13.46 ± 1.13

1 µM FTY720 PreFTY

55.50 ± 1.63

69.08 ± 3.98

15.46 ± 0.63

PostFTY

44.00 ± 4.30

58.14 ± 5.49

11.67 ± 1.13

2.5 µM FTY720 PreFTY

47.00 ± 3.53

63.17 ± 4.39

13.02 ± 0.98

PostFTY

52.33 ± 3.20

69.42 ± 3.94

14.62 ± 0.87

30 20 10

Control

PreFTY

PostFTY

60 Functional recovery (%)

C 60

Functional recovery (%)

50 Functional recovery (%)

Table 3. Baseline functional ability of isolated rat hearts prior to exposure to both 35 minutes’ regional ischaemia (RI), as well as treatment with FTY720 (1 or 2.5 µM) either before sustained ischaemia or during initial reperfusion

50 40 30 20 10 0

Control

PreFTY

PostFTY

50 40 30 20 10 0

Control

PreFTY

PostFTY

Fig. 7 T he effects of 1 μM FTY720, administered either before (PreFTY) ischaemia or at the onset of reperfusion (PostFTY), on functional recovery following 35 minutes of regional ischaemia (RI) in terms of (A) aortic output, (B) cardiac output, and (C) total work, n = 6–8.

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40 30 20 10 @ Control

PreFTY

PostFTY

60 Functional recovery (%)

Functional recovery (%)

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50 40 30 @

20 10 0

Control

PreFTY

PostFTY

50 40 30 @

10 0

Control

PreFTY

PostFTY

Fig. 8 T he effect of 2.5 μM FTY720 on functional recovery following 35 minutes’ regional ischaemia (RI) in terms of (A) aortic output, (B) cardiac output, and (C) total work. @p < 0.05 vs control, n = 6.

As was the case in the 20-minute GI model, FTY720 elicited a much more evident effect when administered at 2.5 µM (Fig. 8), showing a profound effect on functional recovery during reperfusion. Pre-treatment was associated with a reduction in aortic output (only one heart recovered sufficiently to generate AO: control: 27.86 ± 13.22% vs PreFTY: 0.62%, n = 6; p < 0.05) and work recovery (control: 40.74 ± 9.98% vs PreFTY: 15.07 ± 5.69%, n = 6; p < 0.05), while reperfusion administration significantly reduced cardiac output (control: 46.56 ± 10.25% vs PostFTY: 15.02 ± 5.38%, n = 6; p < 0.05) and work recovery (control: 40.74 ± 9.98% vs PostFTY: 11.84 ± 4.59%, n = 6; p < 0.05). Although reperfusion treatment did not statistically reduce aortic output recovery, it is noteworthy that of the six hearts included in the group, only one recovered sufficiently to actually

p = 0.0663

Area at risk (% of total area)

70 60 50 40

30 20 10 0

Control

60 50 40

20 10 0

Control

60 50 40 30 20 10 0

PreFTY PostFTY 1 μm FTY720

PreFTY PostFTY 2.5 μm FTY720

Area at risk (% of total area)

Infarct size (% of area at risk)

generate an aortic output. These profound inhibitory effects of reperfusion-administered FTY720 on post-ischaemic CO and work are especially intriguing in the light of the increase in CF shown to be associated with FTY720 administration (Fig. 6). These combined observations suggest a direct effect of FTY720 on contractility per se. Since 2.5 µM FTY720 elicited such a strong detrimental effect on functional recovery, we also analysed two additional functional parameters: heart rate and systolic pressure. Unexpectedly, FTY720 treatment was not associated with a significant reduction in heart rate recovery (control: 95.00 ± 1.85% vs PreFTY: 56.92 ± 18.69% and PostFTY: 60.73 ± 19.46%, n = 6; p = NS) or systolic pressure recovery (control: 84.79 ± 2.69% vs PreFTY: 48.89 ± 17.03% and PostFTY: 50.96 ± 16.58%, n = 6; p = NS).

Control

PreFTY PostFTY 1 μm FTY720

Control

PreFTY PostFTY 2.5 μm FTY720

50 40 30 20 10 0

Fig. 9 E ffect of FTY720 on infarct size in hearts exposed to 35 minutes of regional ischaemia. At a dose of 1 μM (A), FTY720 reduced infarct size when administered at the onset of reperfusion, while pre-ischaemic treatment seemed to aggravate the ischaemic injury. At a higher dose of 2.5 μM, FTY720 however reduced infarct size (C) irrespective whether it was administered prior to ischaemia or during early reperfusion. Area at risk, an indication of the ischaemic intervention experimentally induced did not differ between any of the groups ((B) and (D)). @p < 0.05 vs control, n = 6–8.

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Surprisingly, FTY720 exerted a considerably different effect on infarct size (Fig. 9), in contrast to the effects seen on functional recovery after regional ischaemia. Administration of 1 µM FTY720 as a pre-treatment showed a very strong tendency to increase IFS (control: 39.89 ± 3.93% vs PreFTY: 51.73 ± 2.36%, n = 6; p = 0.066), while administration during reperfusion limited the development of infarction (control: 39.89 ± 3.93% vs PostFTY: 23.96 ± 3.99%, n = 6–7; p < 0.05). In contrast to this dependence on the time point of administration relative to sustained ischaemia, 2.5 µM FTY720 consistently reduced IFS (control: 39.89 ± 3.93% vs PreFTY: 29.97 ± 1.03% and PostFTY720: 30.45 ± 2.16%, n = 6; p < 0.05). The area at risk, relative to the total area, did not differ among any of the groups. We are therefore left with these two disparate observations: on one hand, 1 µM FTY720 had no effect on post-ischaemic functional recovery and 2.5 µM reduced functional recovery, while on the other hand FTY720 caused a significant reduction in IFS, with the exception of the increase observed when 1 µM FTY720 was administered prior to ischaemia.

Discussion Recently there has been great interest in the sphingosine analogue, FTY720, mostly because of its immunomodulatory functions, but also because of its potential to stimulate similar pathways to sphingosine-1-phosphate. In this context, several researchers have investigated its potential to confer protection against myocardial ischaemia/reperfusion injury, however, with divergent results. In this study we investigated the effects of two different concentrations of FTY720, administered prior to ischaemia or during initial reperfusion in two models of ischaemia with function and infarct size as endpoints. We found that 1 µM FTY720 exerted no effect on functional recovery regardless of the time of administration, although pre-treatment augmented infarction, while reperfusion treatment reduced IFS. Increasing the dose to 2.5 µM proved severely detrimental to functional recovery, although it was associated with an unexpected reduction in IFS. FTY720 is a sphingosine analogue, therefore it can elicit similar effects to sphingosine and it can also be phosphorylated by intracellular SK2 to generate a phosphorylated form (P-FTY720) similar to S1P, which can exit the cell of origin and then bind on any one of the S1P receptors (except receptor 2).53 This leads to a conundrum when administering and experimenting with FTY720, which has also been reported by others,30,37 namely, are the effects observed due to FTY720 simulating sphingosine or P-FTY720 mimicking S1P? Although we were unable to distinguish between these two forms of the drug in our experimental setup, there is an observation and an argument, which both point to a possible significant involvement of P-FTY720. First, a significant increase in coronary flow was observed during the administration of FTY720 at both dosages tested. This vasodilatory effect has been linked to the activation of S1P receptor 1 and/or 3 in the endothelium, which then recruits a PI3-kinase pathway, as well as a Ca2+-mediated mechanism to activate endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO), which ultimately facilitates vascular relaxation.54-56 Although

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the IC50 values for P-FTY720 binding to both S1P1 and S1P3 are extremely low (0.21 ± 0.17 nM for S1P1 and 5.0 ± 2.7 nM for S1P353), the observed vasodilation in our experimental hearts nonetheless implies the presence of P-FTY720 in the system. This possibility is further confirmed by the fact that the enzyme responsible for phosphorylating FTY270, SK2, is the predominant sphingosine kinase in the heart57,58 and is also activated by FTY720.57 It is therefore probable that the relatively high dose of FTY720 employed in this study would further stimulate FTY720 phosphorylation. In this regard, Tölle and colleagues55 found that SK2 in human umbilical vein endothelial cells (HUVECs) and whole aortae converted FTY720 to P-FTY720 at a notable rate: 70% of 1 µM FTY720 was phosphorylated after two minutes, and 90% after 10 minutes. Taken together, it is highly likely that a large portion of the FTY720 administered in our study had been phosphorylated. The S1P receptors are all G-coupled protein receptors, which, when activated, can induce the activation of several pathways associated with cardioprotection, such as protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3-kinase) and protein kinase B (PKB/Akt).20-24,59 It is therefore no surprise that several researchers have investigated the ability of S1P to limit infarct size.21-24 Even unphosphorylated sphingosine has been associated with cardioprotection if administered concentrations are low enough (~0.4 µM22). These observations have led to the question whether FTY720 can also be used to confer protection. In 2009, Hofmann and colleagues addressed this in an ex vivo rat heart preparation and found that although FTY720 increased post-ischaemic function, it failed to limit IFS,32 a result repeated in an in vivo model of ischaemia.29 In 2011, however, Egom et al.31 illustrated the ability of FTY720 to increase cell viability in isolated neonatal rat cardiomyocytes exposed to either simulated ischaemia or hypoxia. These observations were subsequently confirmed by Vessey and co-workers,30 who reported that 600 nM FTY720, administered as a post-conditioning intervention, exerted an infarct-sparing effect in an isolated mouse heart model exposed to global ischaemia. Wang and colleagues60 administered FTY720 for a period of one or three weeks in a mouse model and found that this relatively chronic treatment regime also reduced IFS. Therefore our results agree with the latter set of findings that FTY720 is able to reduce infarct size. These results can probably be explained by the expected activation of S1P receptor-mediated pro-survival pathways and/or suppressed inflammation in the heart, as has been shown by others (although we did not assess the mechanism of protection). The surprising exception was pre-treatment with 1 µM, which, at best, did not influence IFS, while not having an effect on postischaemic functional recovery. To our knowledge, this is the first study to have experimented with the acute administration of FTY720 prior to ischaemia, although both Hofmann et al.29 and Wang et al.60 administered the drug to their respective animal models for a substantial period of time (from one day once off to three weeks’ chronic treatment) prior to ischaemia. We did not investigate the mechanism by which FTY720 pre-treatment influences injury. We however propose that it can be explained, at least in part, by the concurrent activation of protein phosphatase 2A (PP2A). The concentration of FTY720 used in the present

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study was notably higher than those used by others. Egom et al.28 used as little as 25 nM, Hofmann et al.32 used 500 nM, while Vessey et al.30 used 600 nM. Our dose was based on work done on FTY720 as an activator of PP2A in the setting of cancer and cancerous cell lines. In 2003, Matsuoka and colleagues38 reported that 8 µM FTY720 could suppress the phosphorylation of PKB/Akt, Bad and p70S6 kinase in T-cell leukaemia cells through the activation of PP2A. Others have also reported on the ability of FTY720 to activate PP2A in the range of 2.5 to 10 µM.36,37,39 Recently it was reported that FTY720 established this activation by binding to SET (Suvar3-9, enhancer of zeste, trithorax), an endogenous inhibitor of PP2A, thereby mediating the dissociation of SET from PP2A.37,39 This mechanism is however dependent on FTY720 not being phosphorylated, since P-FTY720 has the potential to phosphorylate SET through a Jak2-mediated pathway, thereby enhancing its PP2A inhibitory function.37 Others have however also shown that FTY720 can activate PP2A through the activation of a Pak1-mediated signalling pathway.61-63 It is therefore possible that the increase in infarct size that we observed in the 1-µM pre-treatment group was due to the activation of PP2A, which theoretically could suppress the phosphorylation-mediated pro-survival pathways, also co-activated by FTY720, which we have observed (unpublished data) and others have reported.21,2230-32,63 In contrast to this, in the 2.5-µM pre-treatment group, pro-survival activation probably dominated over PP2A activation, thereby inducing protection. As will be discussed in the following paragraphs, 2.5 µM FTY720 also induced a profound reduction in post-ischaemic functional ability, thereby reducing energy demand and also potentially contributing to a reduction in IFS. Contrary to the infarct-sparing effects associated with FTY720 treatment in our study, we found that 1 µM exerted no effect on functional recovery, while 2.5 µM significantly suppressed post-ischaemic function in both the GI, as well as RI models. This is in contrast to Hofmann et al.32 and Vessey et al.,30 who both showed that FTY720 maintained functional ability after ischaemia at doses of 500 nM, 600 nM and 1 µM. It seems as if FTY720 has a dose-dependent effect, with an increase in FTY720 concentration being detrimental to postischaemic function. This was a surprising finding since, in the context of cancer research, it has been reported that relatively high doses of FTY720, administered chronically to mouse models, did not exert any toxic effects.36,37 Neither of these studies however investigated isolated heart performance or resistance to ischaemic stress. The concentrations of FTY720 used in our study were also not as high as those of sphingosine, which have been shown by others to be detrimental: Suzuki and colleagues64 reported that 10 or 20 µM sphingosine induced apoptosis in several cell lines, while Karliner18 specified 5 µM of sphingosine as cardiotoxic. With regard to the phosphorylated form, Theilmeier and co-workers59 reported that a dose as high as 10 µM of S1P protected neonatal rat cardiomyocytes from apoptosis in a model of glucose and growth factor withdrawal. It is therefore unlikely that the FTY720 concentrations that we used were toxic. A possible explanation for our seemingly controversial results may be found in the perfusion model used, as well as the effects of S1P receptor stimulation on heart function per se.

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Our experimental model differed from those used by others. Hofmann32 showed cardioprotection in retrogradely perfused rat hearts and human myocardial muscle strip preparations, while Vessey et al.30 used an isolated retrogradely perfused mouse heart model, with FTY720 administered as a postconditioning intervention (four cycles of five seconds’ ischaemia and reperfusion at the onset of reperfusion). We however utilised an isolated working rat heart preparation, which has an additional energy demand65 and free radical exposure66 associated with it. This more challenging setting than normal retrograde perfusion might explain the inability of FTY720 to protect functional capacity in our model, and even contribute to its loss. Although not investigated by us, it has been reported by others that S1P receptor activation has the potential to suppress both heart rate, as well as contractility, largely through effects on intracellular calcium ion (Ca2+) dynamics. We propose that these mechanisms, at least in part, explain the observed detrimental effects of FTY720 on post-ischaemic function as follows. Heart tissue expresses S1P receptors 1, 2 and 3.67 Of these, it is only 1 and 3 that can be activated by P-FTY720.53 It has been reported that activation of these receptors in the heart, especially receptor 3, induces a reduction in heart rate68-70 through the activation of the inwardly rectifying atrial potassium ion channel (IKACh), thereby allowing an increased inward flux of potassium ions into the cell and hyperpolarising the sarcolemma.70,71 Activation of the S1P receptor 1 also exerts a negative inotropic effect, through a reduction in the availability of intracellular Ca2+ from the sarcoplasmic reticulum (SR) for the initiation of contraction. Two mechanisms have been shown to be involved in this inotropic effect: (1) similarly to the reduction in heart rate, activation of IKACh leads to the hyperpolarisation of the sarcolemma, leading to a subsequent reduction in action potential duration, which in turn implies a reduced influx of Ca2+ into the cardiomyocytes, thereby reducing the stimulus for the Ca2+-induced release of Ca2+ from the SR; (2) linking with the previous mechanism, S1P has been shown to reduce Ca2+ flux through the L-type Ca2+ channel, thereby also diminishing the potency of Ca2+-induced Ca2+ release. This reduction in flow through the L-type Ca2+ channel could be due to a Gi-mediated reduction in cyclic AMP levels, associated with the stimulation of the S1P receptors.67,72,73 Ironically, these same mechanisms that reduce intracellular Ca2+ levels might also limit Ca2+ overload during reperfusion, thereby contributing to the infarct-limiting effects of FTY720. In view of the effect of S1P activation on heart rate (as discussed above), the divergent results that have been generated regarding the effect of FTY720 on rhythmicity,28,29 and the relevance of arrhythmia in the pathology of myocardial I/R injury, it is a limitation of this study that we did not include the incidence of arrhythmia in early reperfusion as an additional endpoint. We speculate that the FTY720-mediated reduction in intracellular Ca2+ levels associated with a general reduction in functional ability, in combination with the dual stressor of I/R and work-mode perfusion could explain the severely detrimental effects of FTY720 on post-ischaemic functional recovery. It would therefore be interesting to assess the effects of acute FTY720 administration at these doses in hearts either not exposed to ischaemia and reperfusion, and/or not exposed to work-mode perfusion.

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We are therefore confronted with two sets of disparate observations: FTY720 administration limited IFS, yet simultaneously suppressed functional recovery. Such a dissociation between changes in IFS and changes in functional recovery, as observed here, have been reported by us 44,74,75 and others.76-78 Although it is unexpected, it is therefore not without precedent or possible explanation through combination of the diverse effects of FTY720 on the heart. FTY720, both unphosphorylated and phosphorylated, activates several cardioprotective pathways, possibly including components such as protein kinase A (PKA), protein kinase G (PKG), protein kinase C (PKC), PKB/Akt, ERK p42/p44 and Pak1.21,22,30-32,63 The robust activation of these pathways culminated in protection of the heart tissue against injury and cell death, thereby explaining the reduction in IFS associated with the administration of 1 µM FTY720 at the onset of reperfusion, as well as 2.5 µM both prior to ischaemia and at the onset of reperfusion. The effect of the pre-ischaemic administration of FTY720 on IFS may be due to the contribution of PP2A activation, which at this dose and during ischaemia and the onset of reperfusion, opposes cardioprotective signalling by de-phosphorylating some of the proteins involved in the mediation of protection. Theoretically, possible targets for PP2A under these conditions include PKC, PKA, PKB/Akt and ERK p42/p44.79 Work done in our laboratory has also implicated PP2A as a negative regulator of PKB/Akt at the onset of reperfusion (unpublished data). These results highlight the importance of the time point of intervention in determining the outcome of I/R. Simultaneously however, FTY720, especially at the higher dose of 2.5 µM, exerted a potent effect on heart rate and contractility of the heart by contributing to an increase in membrane potential and reducing the availability of Ca2+ at the myofibrils of the cardiomyocytes. The result of this is a major and profound reduction in cardiac function during reperfusion. The prescribed dose of FTY720 for recurring MS is 0.5 mg once daily. This translates into a blood concentration of less than 0.5 ng/ml after 96 hours in renal transplant recipients,80,81 which is less than 1.45 nM. Even though FTY720 in these small concentration ranges exerted a very small and transient effect on heart rate in patients,80,82 it is still much lower than the concentrations we used. Our study therefore does not address concerns with regard to the current FTY720 treatment regime. Our results are however of potential importance in the context of anticancer therapy, where the administration of relatively high doses of FTY720 becomes relevant, as well as the potential use of FTY720 to limit the development of myocardial I/R injury.62

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in the context of its effects on kinase/phosphatase signalling and Ca2+ handling. This work was financially supported by the Harry Crossley Foundation, the Medical Research Council of South Africa, and the National Research Foundation of South Africa.

References 1.

World Health Organisation. Global status report on noncommunicable diseases 2010: description of global burden of NCDs, their risk factors and determinants, 2011 (ISBN: 978 924 156422 9).

Sliwa K, Wilkinson D, Hansen C, Ntyintyane L, Tibazarwa K, Becker A, Stewart S. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study. Lancet 2008; 371: 915–922 (PMID: 18342686).

Onen CL. Epidemiology of ischaemic heart disease in sub-Saharan Africa. Cardiovasc J Afr 2013; 24: 34–42 (PMID: 23612951).

Statistics South Africa. Mortality and causes of death in South Africa, 2013: Findings from death notification. Pretoria: Statistics South Africa; 2014.

Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A, et al. The global burden of ischemic heart disease in 1990 and 2010: The global burden of disease 2010 study. Circulation 2014; 129: 1493–1501 (PMID: 24573351).

Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–2128 (PMID: 23245604).

Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997; 349: 1498–1504 (PMID: 9167458).

Mathers CD, Loncar D. Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLoS Med 2006; 3: 2011–2030 (PMID: 17132052).

Ting HH, Yang EH, Rihal CS. Narrative review: Reperfusion strategies for ST-segment elevation myocardial infarction. Ann Intern Med 2006; 145: 610–617 (PMID: 17043342).

10. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol 2007; 50: 917–929 (PMID: 17765117). 11. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–1136 (PMID: 3769170). 12. Vinten-Johansen J, Zhao Z-Q, Zatta AJ, Kin H, Halkos ME, Kerendi F. Postconditioning: A new link in nature’s armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol 2005; 100(4): 295–310

Conclusion We have shown that the effects of acute FTY720 treatment are dependent on both the timing of the intervention, as well as the dose at which it is administered. Although FTY720 has the ability to limit IFS, acute pre-ischaemic administration was much less beneficial than reperfusion administration. Increasing the concentration of FTY720, although still reducing IFS development, exerted a profoundly negative effect on postischaemic heart function. More work is needed to describe the mechanism by which acute FTY720 administration at these concentrations exerts its effects on cardiac function, especially

(PMID: 15793629). 13. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121–1135 (PMID: 17855673). 14. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia–reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK) pathway. Cardiovasc Res 2004; 61: 448–460 (PMID: 14962476). 15. Lecour S. Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol 2009; 47: 32–40 (PMID: 19344728). 16. Yang X, Cohen MV, Downey JM. Mechanism of protection by early

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

385

ischemic preconditioning. Cardiovasc Drug Ther 2010; 24: 225–234

products. In: US Food and Drug Administration. http://www.access-

(PMID: 20505987).

data.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.

17. Huesch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015; 116: 674–699 (PMID: 25677517). 18. Karliner JS. Sphingosine kinase and sphinosine 1-phosphate in cardioprotection. J Cardiovasc Pharmacol 2009; 53: 189–197 (PMID: 19247197). 19. Knapp M. Cardioprotective role of sphingosine-1-phosphate. J Physiol Pharmacol 2011; 62: 601–607 (PMID: 22314562).

DrugDetails. Accessed 30 January 2014. 34. Novartis. Novartis receives European Commission approval for Gilenya®, the first oral multiple sclerosis treatment for use in the EU. In: Novartis Media Releases. 2011. http://www.novartis.com/newsroom/ media-releases/en/2011/1498377.shtml. Accessed 29 January 2014. 35. Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol 2013; 14: e229–e238 (PMID: 23639323). 36. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW,

20. Jin Z-Q, Zhou H-Z, Zhu P, Honbo N, Mochly-Rosen D, Messing

et al. FTY720, a new alternative for treating blast crisis chronic myelog-

RO, et al. Cardioprotection mediated by sphingosine-1-phosphate and

enous leukemia and Philadelphia chromosome–positive acute lympho-

ganglioside GM-1 in wild-type and PKCε knockout mouse hearts. Am J

cytic leukemia. J Clin Invest 2007; 117: 2408–2421 (PMID: 17717597).

Physiol Heart Circ Physiol 2002; 282: H1970–H1977 (PMID: 12003800).

37. Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G,

21. Vessey DA, Li L, Kelley M, Karliner JS. Combined sphingosine,

et al. Antagonistic activities of the immunomodulator and PP2A-

S1P and ischemic postconditioning rescue the heart after protracted

activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hema-

ischemia. Biochem Biophys Res Commun 2008; 375: 425–429 (PMID: 18706887). 22. Vessey DA, Kelley M, Li L, Huang Y. Sphingosine protects aging hearts from ischemia/reperfusion injury: superiority to sphingosine 1-phosphate and ischemic pre- and post-conditioning. Oxid Med Cell Longev 2009; 2: 146–151 (PMID: 20592769). 23. Somers SJ, Frias M, Lacerda L, Opie LH, Lecour S. Interplay between

tologic malignancies. Blood 2013; 122: 1923–1934 (PMID: 23926298). 38. Matsuoka Y, Nagahara Y, Ikekita M, Shinomiya T. A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. Br J Pharmacol 2003; 138: 1303–1312 (PMID: 12711631). 39. Saddoughi SA, Gencer S, Peterson YK, Ward KE, Mukhopadhyay A, Oaks J, et al. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-

SAFE and RISK pathways in sphingosine-1-phosphate-induced cardio-

dependent necroptosis. EMBO Mol Med 2013; 5: 105–121 (PMID:

protection. Cardiovasc Drugs Ther 2012; 26: 227–237 (PMID: 22392184).

23180565).

24. Kelly-Laubscher RF, King JC, Hacking D, Somers S, Hastie S, Stewart T, et al. Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3. Cardiovasc J Afr 2014; 25: 118–123 (PMID: 25000441). 25. Chun J, Brinkmann V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of Fingolimod (FTY720, Gilenya). Discov Med 2011; 12: 213–228 (PMID: 21955849). 26. Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009; 158: 1173–1182 (PMID: 19814729). 27. Hla T, Brinkmann V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology 2011; 76: S3–S8 (PMID: 21339489). 28. Egom EEA, Ke Y, Musa H, Mohamed TMA, Wang T, Cartwright E, et

40. Sutherland FJ, Hearse DJ. The isolated blood and perfusion fluid perfused heart. Pharmacol Res 2000; 41: 613–627 (PMID: 10816330). 41. Skrzypiec-Spring M, Grotthus B, Szeląg A, Schulz R. Isolated heart perfusion according to Langendorff—Still viable in the new millennium. J Pharmacol Toxicol Methods 2007; 55: 113–126 (PMID: 16844390). 42. Lochner A, Genade S, Tromp E, Podzuweit T, Moolman JA. Ischemic preconditioning and the β-adrenergic signal transduction pathway. Circulation 1999; 100: 958–966 (PMID: 10468527). 43. Kannengieser GJ, Opie LH, van der Werff. Impaired cardiac work and oxygen uptake after reperfusion of regionally ischaemic myocardium. J Mol Cell Cardiol 1979; 11: 197–207. (PMID: 423263). 44. Shlafer M, Karow AM. Pharmacological effects of dimethyl sulfoxide on the mammalian myocardium. Ann N Y Acad Sci 1975; 27: 110–121 (PMID: 236711).

al. FTY720 prevents ischemia/reperfusion injury-associated arrhythmias

45. Bell JR, Eaton P, Shattock MJ. Role of p38-mitogen-activated protein

in an ex vivo rat heart model via activation of Pak1/Akt signaling. J

kinase in ischaemic preconditioning in rat heart. Clin Exp Pharmacol

Molec Cell Cardiol 2010; 48: 406–414 (PMID: 19852968).

Physiol 2008; 35: 126–134. (PMID: 17892505).

29. Hofmann U, Hu K, Walter F, Burkard N, Ertl G, Bauersachs J, et al.

46. Marais E, Genade S, Salie R, Huisamen B, Maritz S, Moolman JA,

Pharmacological pre- and post-conditioning with the sphingosine-

Lochner A. The temporal relationship between p38 MAPK and HSP27

1-phosphate receptor modulator FTY720 after myocardial ischaemia–

activation in ischaemic and pharmacological preconditioning. Basic Res

reperfusion. Br J Pharmacol 2010; 160: 1243–1251 (PMID: 20590616).

Cardiol 2005; 100: 35–47 (PMID: 15526116).

30. Vessey DA, Li L, Imhof I, Honbo N, Karliner JS. FTY720 postcondi-

47. Fan W-J, Genade S, Genis A, Huisamen B, Lochner A. Dexamethasone-

tions isolated perfused heart by a mechanism independent of sphingo-

induced cardioprotection: a role for the phosphatase MKP-1? Life Sci

sine kinase 2 and different from S1P or ischemic postconditioning. Med Sci Monit Basic Res 2013; 19: 126–132 (PMID: 23567658). 31. Egom EEA, Mohamed TMA, Mamas MA, Shi Y, Liu W, Chirico D, et al. Activation of Pak1/Akt/eNOS signaling following sphingosine-

2009; 84: 838–846. (PMID: 19361533). 48. Lochner A, Genade S, Moolman JA. Ischemic preconditioning: Infarct size is a more reliable endpoint than functional recovery. Basic Res Cardiol 2003; 98: 337–346 (PMID: 12955407).

1-phosphate release as part of a mechanism protecting cardiomyocytes

49. Salie R, Moolman JA, Lochner A. The role of β-adrenergic receptors in

against ischemic cell injury. Am J Physiol Heart Circ Physiol 2011; 301:

the cardioprotective effects of beta-preconditioning (βPC). Cardiovasc

H1487–H1495 (PMID: 21705677). 32. Hofmann U, Burkard N, Vogt C, Thoma A, Frantz S, Ertl G, et al. Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia–reperfusion. Cardiovasc Res 2009; 83: 285–293 (PMID: 19416991). 33. US Food and Drug Administration. Drugs@FDA: FDA approved drug

Drugs Ther 2011; 25: 31–46 (PMID: 21225332). 50. Ytrehus K. The ischemic heart – experimental models. Pharmacol Res 2000; 42: 193–203 (PMID: 10945923). 51. Csonka C, Kupai K, Kocsis GF, Novák G, Fekete V, Bencsik P, et al. Measurement of myocardial infarct size in preclinical studies. J Pharmacol Toxicol Meth 2010; 61: 163–170 (PMID: 20188845).

386

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

52. Pitts KR, Stiko A, Buetow B, Lott F, Guo P, Virca D, Toombs CF.

AFRICA

Heart Circ Physiol 2008; 294: H736–H749 (PMID: 18024550).

Washout of heme-containing proteins dramatically improves tetrazoli-

68. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, et

um-based infarct staining. J Pharmacol Toxicol Meth 2007; 55: 201–208

al. Immune cell regulation and cardiovascular effects of sphingosine

(PMID: 16931060).

1-phosphate receptor agonists in rodents are mediated via distinct

53. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346–349 (PMID: 11923495).

receptor subtypes. J Pharmacol Exp Ther 2004; 309: 758–768 (PMID: 14747617). 69. Sanna MG, Liao J, Jo E, Alfonso C, Ahn M-Y, Peterson MS, et al.

54. Dantas APV, Igarashi J, Michel T. Sphingosine 1-phosphate and control

Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3,

of vascular tone. Am J Physiol Heart Circ Physiol 2003; 284: H2045–

respectively, regulate lymphocyte recirculation and heart rate. J Biol

H2052 (PMID: 12742827).

Chem 2004; 279: 13839–13848 (PMID: 14732717).

55. Tölle M, Levkau B, Keul P, Brinkmann V, Giebing G, Schönfelder G,

70. Koyrakh L, Roman MI, Brinkmann V, Wickman K. The heart rate

et al. Immunomodulator FTY720 induces eNOS-dependent arterial

decrease caused by acute FTY720 administration is mediated by the

vasodilatation via the lysophospholipid receptor S1P3. Circ Res 2005;

G protein-gated potassium channel IKACh. Am J Transplant 2005; 5:

96: 913–920 (PMID: 15802614). 56. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc Res 2009; 82: 212–220 (PMID: 19233865). 57. Vessey DA, Kelley M, Zhang J, Li L, Tao R, Karliner JS.

529–536 (PMID: 15707407). 71. Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007; 115: 84–105 (PMID: 17561264).

Dimethylsphingosine and FTY720 inhibit the SK1 form but activate the

72. Ochi R, Momose Y, Oyama K, Giles WR. Sphingosine-1-phosphate

SK2 form of sphingosine kinase from rat heart. J Biochem Mol Toxicol

effects on guinea pig atrial myocytes: alterations in action potentials and

2007; 21: 273–279 (PMID: 17912702). 58. Strub GM, Maceyka M, Hait NC, Milstien S, Spiegel S. Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 2010; 688: 141–155 (PMID: 20919652). 59. Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I, et al. High-density lipoproteins and their constituent, sphingosine-

K+ currents. Cardiovasc Res 2006; 70: 88–96 (PMID: 16545787). 73. Means CK, Brown JH. Sphingosine-1-phosphate receptor signalling in the heart. Cardiovasc Res 2009; 82: 193–200 (PMID: 19282351). 74. Van Vuuren D, Genis A, Genade S, Lochner A. Postconditioning the isolated working rat heart. Cardiovasc Drugs Ther 2008; 22: 391–397 (PMID: 18563544).

1-phosphate, directly protect the heart against ischemia/reperfusion

75. Huisamen B, Dietrich D, Bezuidenhout N, Lopes J, Flepisi B, Blackhurst

injury in vivo via the S1P3 lysophospholipid receptor. Circulation 2006;

D, Lochner A. Early cardiovascular changes occurring in diet-induced,

114: 1403–1409 (PMID: 16982942).

obese insulin-resistant rats. Mol Cell Biochem 2012; 368: 37–45 (PMID:

60. Wang G, Kim RY, Imhof I, Honbo N, Luk FS, Li K, et al. The

22638648).

immunosuppressant FTY720 prolongs survival in a mouse model of

76. Cohen MV, Yang X-M, Downey JM. Smaller infarct after precondition-

diet-induced coronary atherosclerosis and myocardial infarction. J

ing does not predict extent of early functional improvement of reper-

Cardiovasc Pharmacol 2014; 63: 132–143 (PMID: 24508946).

fused heart. Am J Physiol Heart Circ Physiol 1999; 277: H1754–H1761

61. Ke Y, Lei M, Solaro RJ. Regulation of cardiac excitation and contraction by p21 activated kinase-1. Prog Biophys Mol Biol 2008; 98: 238–250 (PMID: 19351515). 62. Ke Y, Sheehan KA, Egom EEA, Lei M, Solaro RJ. Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase. Am J Physiol Heart Circ Physiol 2010; 298: H1283–H1289 (PMID: 20154261). 63. Ke Y, Lei M, Wang X, Solaro RJ. Novel roles of PAK1 in the heart. Cell Logistics 2012; 2: 89–94 (PMID: 23162741).

(PMID: 10564128). 77. Ford WR, Clanachan AS, Hiley CR, Jugdutt BI. Angiotensin II reduces infarct size and has no effect on post-ischaemic contractile dysfunction in isolated rat hearts. Br J Pharmacol 2001; 134: 38–45 (PMID: 11522595). 78. Uematsu M, Okada M. Differences in prolonged ischemia length using ischemic preconditioning in the rabbit heart: tolerable limitation time for surgically induced myocardial ischemia during normothermic cardiac operation. J Cardiovasc Surg 2001; 42: 323–331 (PMID: 11398027).

64. Suzuki E, Handa K, Toledo MS, Hakomori S. Sphingosine-dependent

79. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein

apoptosis: a unified concept based on multiple mechanisms operating in

kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;

concert. Proc Natl Acad Sci 2004; 101: 14788–14793 (PMID: 15466700).

24: 186–191 (PMID: 10322434).

65. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing

80. Budde K, Schmouder RL, Brunkhorst R, Nashan B, Lücker PW, Mayer

substrates in the isolated working rat heart. Biochem J 1980; 186:

T, et al. First human trial of FTY720, a novel immunomodulator, in

701-711 (PMID: 6994712).

stable renal transplant patients. J Am Soc Nephrol 2002; 13: 1073–1083

66. Damerau W, Ibel J, Thürich T, Assadnazari H, Zimmer G. Generation of free radicals in Langendorff and working hearts during normoxia, hypoxia, and reoxygenation. Basic Res Cardiol 1993; 88: 141–149 (PMID: 8389121).

(PMID: 11912269). 81. David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of Fingolimod. Clin Pharmacokinet 2012; 51: 15–28 (PMID: 22149256). 82. Gold R, Comi G, Palace J, Siever A, Gottschalk R, Bijarnia M, et al.

67. Landeen LK, Dederko DA, Kondo CS, Hu BS, Aroonsakool N, Haga

Assessment of cardiac safety during fingolimod treatment initiation in a

JH, Giles WR. Mechanisms of the negative inotropic effects of sphin-

real-world relapsing multiple sclerosis population: a phase 3b, open-label

gosine-1-phosphate on adult mouse ventricular myocytes. Am J Physiol

study. J Neurol 2014; 261: 267–276 (PMID: 24221641).

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Cortisol:brain-derived neurotrophic factor ratio associated with silent ischaemia in a black male cohort: the SABPA study Christiaan E Schutte, Leoné Malan, Jacobus D Scheepers, Woudri Oosthuizen, Marike Cockeran, Nicolaas T Malan

Abstract Aim: Emotional distress has been associated with cardiovascular disease (CVD) in Africans. Cortisol and brain-derived neurotrophic factor (BDNF), as markers of emotional distress, increase cardiometabolic risk. We therefore aimed to investigate associations between cardiometabolic risk markers and the cortisol-to-BDNF ratio (cortisol:BDNF). Methods: A cross-sectional study included a bi-ethnic gender cohort (n = 406) aged 44.7 ± 9.52 years. Ambulatory blood pressure (ABPM), ECG, fasting serum cortisol and BDNF levels and cardiometabolic risk markers were obtained. Results: Africans had increased incidence of hyperglycaemia and 24-hour silent ischaemic events, and elevated 24-hour blood pressure (BP) and cortisol:BDNF ratios compared to Caucasians. Forward stepwise linear regression analysis underscored a similar trend with associations between hyperglycaemia, 24-hour BP [Adj R2 0.21–0.29; β 0.23 (0.1–0.4); p = 0.01], silent ischaemia [Adj R2 0.22; β 0.40 (0.2–0.6); p < 0.01] and cortisol:BDNF levels in Africans, mostly in the men. Conclusion: Attenuated cortisol levels in this group may be indicative of emotional distress and if chronic, drive the cortisol:BDNF ratio to desensitise BDNF. Desensitised cortisol:BDNF may sustain cardiometabolic risk and induce neurodegeneration in African men via silent ischaemia. Compensatory increases in blood pressure to increase perfusion and maintain homeostasis may increase coronary artery disease risk. Keywords: cortisol, brain-derived neurotrophic factor (BDNF), cardiometabolic disease Submitted 20/3/15, accepted 29/5/16 Cardiovasc J Afr 2016; 27: 387–391

www.cvja.co.za

DOI: 10.5830/CVJA-2016-065

Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, South Africa Christiaan E Schutte, MSc Leoné Malan, RN, PhD, Leone.Malan@nwu.ac.za Jacobus D Scheepers, MSc Woudri Oosthuizen, MSc Nicolaas T Malan, DSc

Statistical Consultation Services, North-West University, Potchefstroom Campus, South Africa Marike Cockeran, MSc

Cardiovascular disease (CVD) is a major concern throughout the world.1 There are various factors that contribute to the risk of CVD, such as alcohol abuse, obesity and urbanisation.2 A significant contributing risk factor for CVD, stroke and ischaemic heart disease is high blood pressure.3 Indeed, the South African National Health and Nutrition Examination Survey (SANHANES) found that systolic hypertensive rates ranged from 19.0 to 29.4% and diastolic hypertensive rates ranged from 8.3 to 19.4%. The prevalence of hypertension and psychological distress is escalating in South Africa, especially in urban communities.3-5 Prolonged exposure to a taxing emotionally stressful environment, such as an urban lifestyle, disrupts homeostasis, which can lead to chronic stress.6,7 A major pathway for regulating the stress response, the hypothalamic–pituitary–adrenal (HPA) axis, secretes corticotropin-releasing factor (CRF). CRF induces the release of adrenocorticotropic hormone (ACTH), where it stimulates the synthesis and secretion of glucocorticoids, with cortisol as the end product.6 Furthermore it has been observed that augmented HPA-axis responses towards challenges in normotensive individuals enhance the risk of developing hypertension.8 Dysregulation of the HPA axis may also be a result of unmitigated increases in cortisol where prolonged elevations ultimately result in the down-regulation of CRF, ACTH and subsequently cortisol.9 Mineralocorticoid-based hypertension is associated with an excess of extracellular fluid as a result of increased sodium and water retention.7 Resultant elevations in blood pressure will emerge with increased total peripheral resistance responses, which may burden the heart. This may contribute to silent ischaemic events because of a decrease in coronary blood supply.3 Brain-derived neurotrophic factor (BDNF), a protein complex and part of the neurotrophin family, is synthesised and secreted by the central nervous system and plays a major role in brain plasticity and survival of the developing neurons.10 The neurotrophic hypothesis of depression states that during times of stress, BDNF is down-regulated, especially in the limbic areas, influencing emotional responses.7 It is suggested that the downregulation is caused by corticosterone.11 The down-regulation may reduce neuroplasticity and ultimately lead to neurodegeneration. As the reduction by itself may not be enough to lead to destruction of hippocampal neurons, it may lead to an increased vulnerability to neuronal damage, especially during times of emotional distress.11,12 This suggests that attenuated levels of BDNF act in tandem with lower levels of cortisol in individuals when psychological distress is suspected. BDNF circulates systemically and supports the notion

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that BDNF may play an important role in cardiometabolic morbidity.10,13 Therefore, we aimed to investigate associations between cardiometabolic risk markers (glycated haemoglobin, blood pressure and silent ischaemic events), cortisol and cortisol:BDNF ratio in a bi-ethnic cohort.

Methods This sub-study is part of the Sympathetic Activity and ambulatory Blood Pressure in Africans (SABPA) study carried out in 2008– 2009 and described elsewehere.14 The population consisted of 409 teachers from the Dr Kenneth Kaunda Education District, South Africa. Selection ensured a socio-economically similar population despite differences in cultural characteristics. Exclusion criteria included tympanum temperature above 37.5°C, the use of anti-depressants, α- and β-blockers, and blood donors or individuals vaccinated within a period of three months prior to data collection. Additionally we excluded cortisone users (n = 3), and the final sample comprised 406 individuals. Participants were fully informed with regard to the study procedure and signed an informed consent form. The study was approved by the Ethics Review Board of the North-West University (NWU-00036-07-S6). During the 48-hour clinical data-collection process, ambulatory blood pressure (ABPM), electrocardiogram (Cardiotens CE120®, Meditech, Budapest, Hungary) and accelerometer measures were obtained (Actical®, Mini Mitter, Montreal, Quebec). The BP apparatus was fitted before 09:00, with an appropriately sized cuff on the non-dominant side of the participant. The participants were asked to record abnormalities such as nausea, feeling stressed or having a headache on a 24-hour diary card. The apparatus was pre-programmed to measure blood pressure every 30 minutes (08:00–22:00) and hourly (22:00–06:00). The ABPM and ECG data were analysed using the CardioVisions 1.19 Personal Edition software (Meditech). An average 24-hour systolic blood pressure (SBP) of ≥ 130 mmHg and/or diastolic blood pressure (DBP) of ≥ 80 mmHg were used as the criteria to define hypertension.16 Silent ischaemia was assessed by two-channel ECG recordings (Cardiotens CE120®) for 20 seconds at five-minute intervals. An ischaemic event was defined according to the following criteria: horizontal or descending ST-segment depression of 1 mm, duration of ST-segment episode lasting for one minute, and a one-minute interval from the preceding episode.15 At 16:30, participants were transported to the North-West University’s Metabolic Unit Research Facility where they were introduced to the experimental procedures. They completed psychosocial questionnaires under supervision of a registered clinical psychologist. They received a standardised dinner and were advised to go to bed at 22:00 and to fast overnight. At 05:45 they were woken, and the devices were removed after the last ambulatory recording at 06:00. Anthropometric measurements and fasting blood samples followed. The participant’s daily physical activity was monitored over 24 hours, considering resting metabolic rate, with the Actical® activity monitor (Mini Mitter Co, Inc, Bend, OR; Montreal, Quebec, Canada). Gamma-glutamyl transferase (γ-GT) and cotinine levels were used to assess alcohol intake and smoking habits.

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Anthropometric measurements were done in triplicate by level two-accredited anthropometrists using calibrated instruments (Precision health scale, A & D Company, Tokyo, Japan; Invicta Stadiometer IP 1465, Invicta, London UK). Body mass and height of the participants were measured while remaining in underwear, for accuracy. Body surface area (BSA) (in m2) was calculated according to the Mosteller formula. The mean of three measurements was used to ensure accuracy. Inter- and intra-observer variability was found to be less than 10%. Fasting blood samples were obtained from the ante-brachial vein branches with a winged infusion set using standardised protocol, and were stored at –80°C until batch assay. Sequential multiple analysers analysed serum gamma-glutamyl transferase, high-sensitivity C-reactive protein (hsCRP) (low-grade inflammation was defined when hsCRP was > 3 mg/l), cotinine and HbA1c levels (glycated haemoglobin) (Konelab 20i, Thermo Scientific, Vantaa, Finland; Unicel DXC 800- Beckman and Coulter®, Germany and the Integra 400, Roche, Switzerland respectively). Quantikine colorimetric-sandwich immunoassays from R & D Systems (catalogue number: DBD00) were used to determine serum BDNF levels with an intra-assay and inter-assay precision of 3.8–6.2% and 7.6–11.3%, respectively. Serum cortisol samples were obtained before 09:00, avoiding the cortisol awakening responses (CAR),17 and analysed with ECLIA on Elecsys 2010, Roche. The cortisol:BDNF ratio was calculated by converting cortisol to the same SI unit as BDNF (from nmol/ml to pg/ml) to obtain cortisol:BDNF.

Statistical analysis Data analysis was done using Statsoft (Statistica V.12). The Shapiro–Wilks test ascertained normality of data, and skewed data were log normalised (log physical activity, log cotinine levels, log γ-GT). Multiple comparisons were not done and a priori hypotheses for all tests were performed. Baseline characteristics of the bi-ethnic population were compared via independent t-tests. Chi-squared (χ2) tests computed proportions and prevalence. The raw data are presented as mean ± standard deviation in the descriptive table (Table 1) to ensure clarity of clinical observations. General linear models determined interactions on the main effects (ethnic × gender) for all cardiometabolic variables independent of a priori confounders (age, body surface area, log physical activity, log cotinine and log γ-GT). There after ANCOVAs, using least-square means, compared bi-ethnic gender groups while adjusting for a priori confounders. Pearson and partial correlation analyses determined unadjusted and adjusted associations between HbA1c level, 24-hour BP, silent ischaemia and cortisol level, as well as cortsol:BDNF, independent of a priori covariates. Forward stepwise linear regression analyses determined associations in several models between dependent variables: HbA1c level, blood pressure, ischaemia and the independent variables: cortisol, cortisol:BDNF and a priori covariates in the separate ethnic gender groups. Sensitivity analyses: forward stepwise linear regression analyses were repeated after excluding HIV-positive status teachers, and hypertension and diabetes medication users. Significant values were noted as p ≤ 0.05.

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In Table 2, ANCOVA analyses, considering a priori covariates, showed that the cortisol level was lower in African men, while BDNF was lower in African women compared to their Caucasian counterparts. The African gender groups showed increased hyperglycaemia, low-grade inflammation, 24-hour BP values and heart rate compared to their Caucasian counterparts. Pearson correlations showed inverse associations between silent ischaemia and cortisol:BDNF (r = 0.34; p = 0.001) in the African male cohort but not in any of the other ethnic gender groups (data not shown). When considering a priori covariates (Tables 3, 4), forward stepwise linear regressions confirmed similar trends with a stronger association between silent ischaemia [Adj R2 0.22; β 0.40 (0.2–0.6); p < 0.01] and cortisol:BDNF ratio in African men, but not in any of the other ethnic gender groups. Cortisol level was positively associated with HbA1c level, and 24-hour BP with a tendency for silent ischaemia (p = 0.07) in the African men only. No change in the outcome was demonstrated after adjustment for HIV-positive status, hypertension and diabetes medication use.

Table 1. Characteristics of a South African bi-ethnic gender cohort Africans (n = 197)

Variables

Caucasians (n = 209)

p-values

Confounders Age (years)

44.4 ± 8.2

45.0 ± 10.9

0.49

Body mass index (kg/m2)

30.1 ± 7.0

27.6 ± 5.9

< 0.001

2.0 ± 0.3

< 0.001

1.9 ± 0.2

Body surface area (m2)

2670 ± 794.4

Physical activity (kcal/day)

3112 ± 1596.5 < 0.001

Cotinine (ng/ml)

27.5 ± 61.3

22.71 ± 77.5

0.5

γ-Glutamyl transferase (U/l)

66.3 ± 83.0

26.91 ± 33.9

< 0.001

Potential cardiometabolic risk markers Cortisol (nmol/l)

358.03 ± 151.63

384.11 ± 159.9

0.093

BDNF (pg/ml)

1411.6 ± 652.3

1687.3 ± 888.1

< 0.001

126.6 ± 114.4

102.7 ± 71.6

0.012

8.55 ± 10.56

3.1 ± 3.88

< 0.001 < 0.001

Cortisol:BDNF ratio C-reactive protein (mg/l) Cholesterol (mmol/l)

4.6 ± 1.16

5.5 ± 1.28

HbA1c (%)

6.1 ± 1.2

5.5 ± 0.42

< 0.001

24-h SBP (mmHg)

133 ± 16

124 ± 12

< 0.001 < 0.001

24-h DBP (mmHg)

83 ± 11

77 ± 8

12-lead ECG HR (bpm)

68 ± 13

66 ± 11

0.045

Silent ischaemic events

6.0 ± 15.56

2.5 ± 5.94

0.003

Hypertension, n (%)

43 (26.54)

18 (9.33)

< 0.001

69 (35.03)

27 (12.92)

< 0.001

2 (1.23)

9 (4.67)

0.05

Discussion

Medications Hypertensive treatment, n (%) Statins, n (%) Diabetes medication, n (%) CRP > 3 mg/l, n (%)

10 (5.08)

2 (0.96)

0.01

106 (65.35)

39 (20.97)

< 0.001

HIV status, n (%)

19 (9.5)

389

Our objectives were to investigate associations between cortisol, the cortisol:BDNF ratio and cardiometabolic risk markers, Table 3. Independent associations between cardiometabolic risk markers, cortisol as well as cortisol:BDNF in a South African cohort

< 0.001

Values presented as arithmetic mean ± SD. BDNF, brain-derived neurotrophic factor; HbA1c, glycated haemoglobin; 24-h hypertension (SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg); HR, heart rate; CRP, C-reactive protein; physical activity, 24-h total energy expenditure, considering resting metabolic rate; n, prevalence (%).

South African cohort (n = 406) HbA1c β (95% CI)

β (95% CI)

0.16

Adjusted R2 Cortisol

Silent ischaemia p-value

p-value

0.10 0.03

0.1 (0.0–0.2)

< 0.01

0.26 (0.2–0.4)

< 0.01

–0.13 (–0.2–0.0)

< 0.01

Results

Ethnicity

–0.34 (–0.4– –0.2)

Gender

–0.09 (–0.2–0.0)

In Table 1, the black African group portrayed a more vulnerable cardiometabolic profile than the Caucasians. They consumed more alcohol, had higher BP and mean pre-diabetes (HbA1c) levels, lower BDNF levels (p < 0.001), larger cortisol:BDNF ratios (p = 0.012) and a higher mean 24-hour hypertensive state. Caucasians were more physically active compared to the Africans. Both ethnic groups’ cortisol levels were within the normal range of 138–635 nmol/l but the Africans’ cortisol levels showed a tendency towards lower levels (p = 0.093) than their Caucasian counterparts.

Age

0.15 (0.1–0.2)

< 0.01

0.11 (0.0–0.2)

Body surface area

0.17 (0.1–0.3)

< 0.01

–

Adjusted R2

0.15

0.08

– 0.02

0.10

Cortisol:BDNF

–

0.26 (0.2–0.4)

< 0.01

Ethnicity

–

–0.13 (–0.2–0.0)

< 0.01

Age

–

0.11 (0.0–0.2)

0.02

HbA1c, glycated haemoglobin. Additional covariates included: log physical activity, log cotinine levels, log gamma glutamyl transferase. Where ethnicity (1 = African, 2 = Caucasian); gender (1 = men, 2 = women).

Table 2. Comparing differences in cardiometabolic risk markers in ethnic male and female groups Risk markers

African men (n = 99)

Caucasian men (n = 101)

African women (n = 98)

Caucasian women (n = 108)

Unadjusted cardiometabolic risk markers γ-Glutamyl transferase (U/l)

84.83 (70.1–99.5)

34.83 (20.2–49.4)**

46.9 (35.9–57.9)

19.9 (9.6–30.2)**

Cholesterol (mmol/l)

4.64 (4.4–4.9)

5.63 (5.4–5.9)**

4.4 (4.1–4.7)

5.57 (5.3–5.8)**

C-reactive protein,(mg/l)

5.93 (4.6–7.2)

1.71 (0.4–3.0)**

11.14 (9.4–12.8)

HbA1c (%)

6.29 (6.1–6.5)

5.60 (5.4–5.8)**

5.85 (5.7–6.1)

4.41 (2.8–6)** 5.40 (5.2–5.6)**

Adjusted cardiometabolic risk markers 24-h SBP (mmHg)

140 (137–142)

125 (123–128)**

128 (126–131)

121 (119–123)**

24-h DBP (mmHg)

89 (87–91)

78 (77–80)**

79 (77–80)

74 (72.7–76)**

24-h heart rate (bpm)

79 (77–82)

72 (70–74)**

80 (78–82)

76 (73.7–77)**

Silent ischaemic events, score

10.3 (6.9–13.6)

Cortisol (nmol/l) BDNF (pg/ml) Cortisol:BDNF ratio

1.1 (0.02–4.4)**

2.8 (1.7–4.0)

364.38 (334.59–394.2)

410.41 (380.86–440.0)*

343.95 (308.5–379.4)

1250.41 (1095.8–1405.1)

1426.28 (1272.9–1579.7)

1599.62 (1429–1770.3)

139.67 (115.3–164.1)

96.16 (82.9–109.4)

142.8 (118.2–167.4)

3 (1.9–4.0) 368.87 (335.7–402.1) 1925.77 (1765.3–2086.3)** 80.43 (67.9–92.9)

Values depicted as mean (± 95% confidence interval) and proportions as n (%). Adjustments were made for age, body surface area, log physical activity, log cotinine and log γ-GT. HbA1c, glycated haemoglobin; BDNF, brain-derived neurotrophic factor; DBP, diastolic blood pressure; SBP, systolic blood pressure. *p ≤ 0.05; **p ≤ 0.01.

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Table 4. Independent associations between cardiometabolic risk markers, cortisol as well as cortisol:brain derived neurotrophic factor (BDNF) in an African male cohort HbA1c β (95% CI) Adjusted R2

0.16

Cortisol

0.21 (0.0–0.4)

24-h SBP p-value

β (95% CI)

24-h DBP p-value

0.29

Silent ischaemia p-value

0.21

β (95% CI)

0.23 (0.1–0.4)

0.01

0.23 (0.1–0.4)

0.01

0.18 (0.0–0.4)

–

0.14 (0.0–0.3)

0.10

0.22 (0.0–0.4)

0.02

–

Age

–

0.30 (0.1–0.5)

< 0.01

0.20 (0.0–0.4)

0.04

0.33 (0.1–0.5)

Log physical activity

–

0.30 (0.1–0.5)

0.02

0.28 (0.0–0.5)

0.08

–

Body surface area

–

0.18 (–0.1–0.4)

0.14

0.15 (–0.1–0.4)

0.26

–

< 0.10

Adjusted R

Log cGGT

0.20 (0.0–0.4)

0.03

–

p-value

0.12

GGT

Cortisol:BDNF

0.04

β (95% CI)

0.26

0.15

0.07 < 0.01

0.22 0.40 (0.2–0.6)

< 0.01

–

0.36 (0.2–0.5)

< 0.01 0.09

Age

0.32 (0.1–0.5)

< 0.01

Log physical activity

0.29 (0.0–0.5)

0.02

–

0.16 (0.0–0.4)

Body surface area

0.21 (0.0–0.5)

0.09

–

HbA1c, glycated haemoglobin; SBP, systolic blood pressure; DBP, diastolic blood pressure; log cGGT, log gamma-glutamyl transferase. Additional covariates included log cotinine levels.

specifically HbA1c level, ambulatory BP and silent ischaemia in a bi-ethnic gender cohort. Overall, African men showed a poorer cardiometabolic profile accompanied by lower cortisol levels when compared to their Caucasian counterparts. Attenuated cortisol levels therefore seem to act as the driving force in the cortisol:BDNF ratio and may ultimately down-regulate BDNF. The novel ratio of cortisol:BDNF may sustain cardiometabolic risk and induce neurodegeneration. Cardiometabolic morbidity further increased in the African men as their reduced coronary perfusion, as evidenced in the number of 24-hour silent ischaemic events, would increase BP as a compensatory mechanism to maintain homeostasis. Despite the fact that a pre-diabetic state was demonstrated in the African gender cohort, it was not directly associated with cortisol:BDNF ratio. In another SABPA sub-study, chronic hyperglycaemia was shown to facilitate endothelial dysfunction and susceptibility to stroke risk in the African male cohort.17 Indeed, Hamer et al.18 also demonstrated associations between glucose homeostasis as assessed by HbA1c concentration and coronary artery calcification. A hyperglycaemic state therefore predisposes to cardiometabolic morbidity in the presence of emotional distress markers such as cortisol:BDNF. A profile of blunted cortisol and norepinephrine metabolite responses were associated with structural wall remodelling in a depressed SABPA African male cohort.12 The attenuated cortisol levels of the current African sub-group may therefore support the notion of increased chronic distress.19,20 Attenuated BDNF levels in Africans might also induce decreased neuroplasticity, vulnerability to depression and cardiovascular risk.6 In this study, cortisol:BDNF ratio was associated with silent ischaemia, suggesting possible downregulation of BDNF, and implicating a central neural regulatory role.10 In animal studies, high concentrations of BDNF in hypothalamic nuclei and neurons secreting CRF support the role of BDNF in the stress response.6 During chronic stress, a maladaptive cortisol response is elicited due to structural changes in the HPA axis.21-23 A state of psychological distress in Africans may therefore be present.12,19,20 Indeed, we have confirmed that chronic depression in the SABPA African teachers’ cohort was associated with microvascular dysregulation and perfusion deficits.21 If this

state is further supported by high levels of alcohol abuse, the central depressant effect of alcohol may disturb central cardiometabolic homeostasis.21 Chronic psychological stress induces sympathetic hyperactivity,17 higher circulating levels of catecholamine and cortisol, and ultimately down-regulation will occur.12,22-24 Therefore, the lower cortisol level may act as the driving force behind a possible down-regulated BDNF. The cortisol:BDNF ratio in African men suggests a susceptibility to increased cardiometabolic risk. Indeed, cortisol:BDNF is associated with silent ischaemia in African men and impairs central autoregulation, explaining the compensatory increases in blood pressure to maintain homeostasis.3,14,19 During chronic stress, sympathetic hyperactivity and increased norepinephrine and cortisol levels will elicit vasoconstrictive responses and reduce perfusion in the coronary circulation.12,23 Furthermore, susceptibility to emotional distress as well as HPA-axis disturbance is enhanced when using defensive coping mechanisms.14 Defensive coping facilitated autonomic dysfunction or sympathetic hyperactivity in the current African male cohort.14 This underpins the importance of a central regulatory control system where higher emotional demands impact on cardiometabolic health. Cortisol can further induce or exacerbate down-regulation of BDNF during chronic stress conditions.6,10 Lower levels of BDNF have been associated with depression,6 and recently cardiometabolic risk.10 Down-regulation and the aftermath of low BDNF levels impair neuroplasticity and homeostasis.11,13,23,24 With BDNF down-regulation, dysregulation of the HPA axis may also occur, as both BDNF and cortisol critically impact on the stress response.24 This suggests that central neural control dysregulation enforces a disturbed cortisol:BDNF ratio, augmenting silent ischaemia and overburdening the heart. This is the first time this ratio has been reported, and further research is needed to support the findings and significance. Susceptibility to emotional distress may be an underlying factor in the observed differences in the bi-ethnic gender cohort. We suggest that attenuated cortisol levels may act as the driving force to downregulate BDNF, increasing cardiometabolic risk and reducing coronary perfusion during psychological distress. One limitation of the study is that a very specific population was studied and results may vary across populations, depending

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on similar lifestyle and behavioural factors. Another limitation is the cross-sectional nature of the study where causality cannot be inferred. ECG assessment of silent ischaemia showed a sensitivity of 68% and a specificity of 77%,25 therefore further studies are needed to support silent ischaemic events, such as troponin T determinations, in order to confirm reduced blood supply to the heart. We recommend prospective analyses to underpin downregulation of the cortisol:BDNF pathway, as well as the use of a validated depression score to substantiate chronic emotional distress and its relationship with cortisol:BDNF ratio.

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Circulation 2004; 110(1): 74–78. 9.

Jeanneteau F, Chao MV. Are BDNF and glucocorticoid activities calibrated? Neuroscience 2013; 239: 173–195.

10. Smith AJ, Malan L, Uys AS, et al. Attenuated brain-derived neurotrophic factor and hypertrophic remodelling: the SABPA study. J Hum Hypertens 2015; 29: 33–39. 11. Issa G, Wilson C, Terry Jr AV, et al. An inverse relationship between cortisol and BDNF levels in schizophrenia: Data from human postmortem and animal studies. Neurobiol Dis 2010; 39(3): 327–333. 12. Mashele N, Malan L, van Rooyen JM, et al. Blunted neuroendocrine responses linking depressive symptoms and ECG-left ventricular hyper-

Conclusion Central neural dysregulation may mediate cortisol levels as the driving force in the cortisol:BDNF ratio, as it seemingly disturbs BDNF levels during chronic stress. A possible down-regulation may lead to neurodegeneration and add to cardiometabolic risk in Africans. The combined impact of cortisol and BDNF levels associated with silent ischaemia may increase future coronary artery disease risk via compensatory increases in blood pressure.

trophy in black Africans: the SABPA study. Cardiovasc Endocrin 2014; 3(2): 59-65. 13. Golden E, Emiliano A, Maudsley S, et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: Data from the Baltimore Longitudinal Study of Aging. PLOS ONE 2010; DOI: 10.1371/journal.pone.0010099. 14. Malan L, Hamer M, Frasure-Smith N, et al. Cohort profile: Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) Prospective Cohort Study. Int J Epidem 2015; 44(6):1814–1822. 15. Uen S, Fimmers R, Weisser B, Balta O, Nickenig G, Mengden T.

The research was funded by the Metabolic Syndrome Institute, France; South

ST-segment depression in hypertensive patients: A comparison of exer-

African Medical Research Council; National Research Foundation (NRF),

cise test versus Holter ECG. Vasc Health Risk Man 2008; 4: 107301080.

North-West University; North-West Department of Education; and ROCHE

16. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for

Diagnostics, South Africa.

the management of arterial hypertension: The task force for the manage-

The funding organisations played no role in the design and conduct of

ment of arterial hypertension of the European Society of Hypertension

the study; collection, management, analysis and interpretation of the data;

(ESH) and of the European Society of Cardiology (ESC). Eur Heart J

and preparation, review or approval of the manuscript. The authors declare no conflict of interest in the content of this article. Opinions and conclusions are those of the authors.

2013; 34(28): 2159–2219. 17. O’Donnell K, Badrick E, Kumari M, et al. Psychological coping styles and cortisol over the day in healthy older adults. Psychoneuroendocrinology 2008; 33(5): 601–611.

References 1.

Shisana O, Labadarios D, Rehle T, SANHANES-1 Team. South African National Health and Nutrition Examination Survey (SANHANES-1).

higher blood pressure and early sub-clinical structural vascular disease via alterations in heart rate variability: The SABPA study. Atherosclerosis

of peripheral vascular disease, abdominal aortic aneurysm, and heart

silent ischaemia and ECG left-ventricular hypertrophy: the SABPA

failure: Pooling of sixteen cohort studies. Atherosclerosis 2014; 236(2): 21. Malan L, Hamer M, von Känel R, et al. Chronic depression symptoms

risk factors explain differences in sub-clinical vascular disease between

and salivary NOx are associated with retinal vascular dysregulation: the

2011; 215(1): 237–242. Malan L, Schutte AE, Malan NT, et al. Coping mechanisms, perception of health and cardiovascular dysfunction in Africans. Int J Psychophys 2006; 61(2): 158–166. Harvey BH, Hamer, M, Louw R, et al. Metabolic and glutathione redox markers associated with brain-derived neurotrophic factor in depressed African men and women: Evidence for counterregulation? 7.

SABPA study. Nitric Oxide Biol Chem 2016; 55–56: 10–17. 22. Seldenrijk A, Hamer M, Lahiri A, et al. Psychological distress, cortisol stress response and subclinical coronary calcification. Psychoneuroendocrinology 2012; 37(1): 48–55. 23. McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur JPharmacol 2008; 583(2–3): 174–85. 24. Wirtz PH, von Känel R, Emini L, et al. Evidence for altered hypo-

Neuropsychobiol 2013; 67(1): 33–40.

thalamus–pituitary–adrenal axis functioning in systemic hypertension:

Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best

Blunted cortisol response to awakening and lower negative feedback

Practice Res Clin Endocrin Met 2006; 20(3): 337–353. 8.

385–388.

Hamer M, Malan L, Schutte AE, et al. Conventional and behavioral black and Caucasian South Africans: The SABPA study. Atherosclerosis

2013; 227(2): 391–397. 20. Batty GD, Russ TC, Stamatakis E, et al. Psychological distress and risk

Malan L, Hamer M, Schlaich MP, et al. Facilitated defensive coping, study. J Hypertens 2012; 30(3): 543–550.

men and women. Eur Heart J 2010; 31: 424–429. 19. Malan L, Hamer M, Schlaich MP, et al. Defensive coping facilitates

Malan L, Malan NT, Wissing MP, et al. Coping with urbanization: 323–328.

mental stress are associated with coronary artery calcification in healthy

Cape Town: Health Sciences Research Council Press, 2013: 1–423. A cardiometabolic risk? The THUSA study. Biol Psych 2008; 79(3): 3.

18. Hamer M, O’Donnell K, Lahiri A, et al. Salivary cortisol responses to

Matthews KA, Katholi CR, McCreath H, et al. Blood pressure reactivity to psychological stress predicts hypertension in the CARDIA study.

sensitivity. Psychoneuroendocrinology 2007; 32(5): 430–436. 25. Stern S. State of the art in stress testing and ischemia monitoring. Cardiac Electrophysiol Rev 2002; 6(3): 204–208.

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Congress Report European Society of Cardiology congress update, Rome, 27–31 August 2016 The annual European Society of Cardiology (ESC) meeting was held at the Nuova Fiera di Roma with over 32 000 delegates from 126 countries in attendance. The meeting commenced with an outstanding address on the heart and art by a British cardiac surgeon, who demonstrated the amazing discoveries in cardiac anatomy and function made by Leonardo da Vinci over 500 years ago, and the awarding of the ESC gold medal to Dr Bernard Gersh of the Mayo Clinic, whose foundational training in cardiology took place at Groote Schuur Hospital. Four new ESC guidelines addressing atrial fibrillation (AF), heart failure, cardiovascular (CV) disease prevention and dyslipidaemia, as well as a position paper on cardiooncology, were released during the meeting. The full texts of these documents are available to all at https://www.escardio.org/ Guidelines/Clinical-Practice-Guidelines. The meeting planners placed particular emphasis on the ‘heart team’ approach and included a large number of ‘heart hub’ presentations. The latter were delivered ‘in the round’ and provided a more informal, more easily accessible presentation format, which improved interaction between presenters and the audience. The following are my impressions of the presentations I attended over the five days of the meeting.

Dyslipidaemia The 2016 dyslipidaemia guideline has been harmonised with the CV disease prevention guideline, which appeared simultaneously. The ESC has maintained the SCORE risk factor charts as well as a chart estimating relative risk in younger people. The risk categories have likewise been maintained. However, whereas the presence of significant plaque on carotid ultrasound classifies the patient as very high risk, increased carotid intima–media thickness does not. Treatment targets have been maintained. Very high-risk patients have a low-density lipoprotein cholesterol (LDL-C) target of < 1.8 mmol/l, high-risk subjects < 2.6 mmol/l and moderate- to low-risk individuals < 3.0 mmol/l. In patients with diabetes an HbA1c < 7% is recommended in addition. In very high- and high-risk patients, treatment should achieve a > 50% reduction in LDL-C. High-density lipoprotein cholesterol (HDL-C), apoB/apoA1 and non-HDL-C/HDL-C ratios are not recommended as treatment targets. Statins remain first-line treatment, given up to the highest recommended dose or highest tolerable dose to achieve the treatment goal. Statin treatment should be given for the same indications and using the same targets in women and the elderly. A small Japanese study from the Heart Institute of Japan involving 1 734 patients with dyslipidaemia followed for 3.9 years after acute coronary syndrome (ACS) found no benefit from

the addition of ezetimibe to pitivastatin vs pitivastatin alone. LDL-C was 1.7 mmol/l in the combination group vs 2.2 mmol/l in the statin-only group. Patients with heterozygous familial hypercholesterolaemia (FH) respond inadequately to statin therapy and frequently require plasma apheresis to lower their LDL-C. Apheresis is both expensive and inconvenient for the patient. A study evaluating the PCSK9 inhibitor, alirocumab, demonstrated a 75% reduction in the need for apheresis.1 Unfortunately many patients were not taking statins during the study, so the effect of the combination of PCSK9 inhibition, statin therapy and apheresis could not be determined (Table 1).

Hypertension A session on hypertension dealt with the problems of masked and white-coat hypertension (WCH). Masked hypertension is defined as a normal office blood pressure, but elevated home blood pressure or 24-hour ambulatory blood pressure readings. Home monitoring (generally recorded at rest) and ambulatory blood pressure (recorded over 24 hours) measure different aspects of the blood pressure profile. Masked-hypertension patients are, by definition, untreated. Masked uncontrolled hypertension (MUCH) is seen in treated hypertensives. The blood pressure typically fluctuates and elevations may occur either during waking hours or at night (typically in obstructive sleep apnoea). Masked hypertension is present in 10–20% of the population and doubles the risk of a CV event. There is currently no guidance from clinical trials as to the correct treatment of masked hypertension. The MASTERS trial commenced recently to explore what the correct treatment should be. At present the recommendation is to establish strict risk factor control and, though ‘logically’ incorrect, not to institute antihypertensive therapy.

Table 1. ESC CP guidelines 2016: dyslipidaemia Treatment targets 2011 ESC dyslipidaemia guidelines Recommendation

2016 ESC dyslipidaemia guidelines

Class Level Recommendation

Class Level

Very-high CV risk: LDL-C goal < 70 mg/dl (1.8 mmol/l) and/or 50% reduction when target cannot be reached

Very-high CV risk: LDL-C goal < 70 mg/dl (1.8 mmol/l) and/or 50% reduction if baseline is 70–135 mg/dl (1.8–3.5 mmol/l)

High CV risk: LDL-C goal < 100 mg/l (2.5 mmol/l)

IIa

High CV risk: LDL-C goal < 100 mg/l (2.6 mmol/l) or 50% reduction if baseline is 100–200 mg/dl (2.6–5.1 mmol/l)

Moderate CV risk: LDL-C goal < 115 mg/l (3.0 mmol/l)

IIa

Moderate CV risk: LDL-C goal < 115 mg/l (3.0 mmol/l)

IIa

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WCH affects 30–40% of the hypertensive population. Patients with WCH have a metabolic profile similar to that of hypertensive patients. Their baseline blood pressure is marginally higher than that of the normotensive population. The WCH group has a higher incidence of increased pulse pressure and left ventricular hypertrophy and a higher 10-year risk of developing established hypertension and diabetes. The prognosis of WCH is intermediate between normotensive and hypertensive patients with a higher incidence of CV events. There are no therapeutic strategies proven to be effective in WCH. McManus and Sheppard evaluated the application of multiple serial office blood pressure readings to reasonably predict out-of-hospital blood pressure levels. Their data from the PROOF blood pressure study support the value of obtaining ambulatory blood pressure recordings in patients with an office blood pressure of 130/80 to 144/89 mmHg, therefore requiring ambulatory blood pressure recordings in 58% of patients.2 They have published an algorithm for calculating home blood pressure (https://sentry.phc.ox.ac.uk/proof-bp) (Fig. 1). Kario from Japan pointed out that central aortic pressure is a further component to be considered in blood pressure control.

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It is best controlled with an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) and not with beta-blockade. Diurnal variation in blood pressure and aortic stiffness are other aspects receiving attention. He commented that when combined with an ARB (olmesartan), hydrochlorothiazide is superior to calcium channel blockade for the control of nocturnal hypertension. A lunchtime symposium was devoted to the underuse of mineralocorticoid antagonists (MRAs), namely spironolactone and eplerenone, in both hypertension and heart failure. Both have proven benefits in improving blood pressure control in resistant hypertension3 and patient survival in heart failure. Hypertension is controlled best at a serum potassium level of around 4.5 mmol/l, but concerns about the development of hyperkalaemia result in avoiding appropriate prescription or under-dosing of MRAs. The survival benefit for heart failure patients is not eliminated in those who develop hyperkalaemia. However, the detection of a high potassium level most often leads to the discontinuation of the whole spectrum of renin–angiotensin– aldosterone system (RAAS) inhibitors and a consequent loss of efficacy. Hyperkalaemia may be controlled in the short term

General population Clinic BP 120/70 – 250/130 mmHg

Blood pressure measurement strategy

Ambulatory BP monitoring

PROOF-BP algorithm

Calculate adjusted clinic BP

Adjusted clinic BP from 130/80 – 144/89 mmHg

Clinic blood pressure screening

Clinic BP >140/90 mmHg

Clinic BP <140/90 mmHg

Adjusted clinic BP <130/80 mmHg

Initial management decision

Repeat clinic measurment

Measure again in 5 years

Sustained clinic BP >140/90 mmHg

Subsequent clinic BP <140/90 mmHg

Send for amulatory BP monitoring

Measure again in 5 years

Ambulatory BP >135/85 mmHg

Ambulatory BP <135/85 mmHg

Ambulatory BP >135/85 mmHg

Ambulatory BP <135/85 mmHg

Offer treatment

Measure again in 5 years

Offer treatment

Measure again in 5 years

Additional blood pressure monitoring or management

Final management decision

Adjusted clinic BP >130/80 mmHg

Offer treatment

Send for ambulatory BP monitoring

Fig 1. Algorithm for using the Predicting Out-of-Office Blood Pressure in clinic tool (PROOF-BP) prediction model to triage patients for out-of-office blood pressure monitoring. Existing strategies are based on the hypertension diagnostic pathway specified by the US Preventive Services Task Force and the National Institute for Health and Care Excellence. BP indicates blood pressure. Source: Hypertension 2016; 67(5): 941–950.

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by calcium carbonate, alkalinisation, beta-stimulants, insulin and potassium, and Na+ polystyrene sulphonate (Kayexalate). Patiromer4 and Na+ zirconium cyclosilicate5 are two agents currently in development that control hyperkalaemia in the long term and may enable the uninterrupted continuation of therapeutic doses of RAAS inhibitors. The CLARIFY study analysed data from 22 672 patients with stable coronary artery disease (CAD) and treated hypertension. It found an increase in cardiovascular events in those with systolic blood pressure > 140 mmHg and diastolic blood pressure > 80 mmHg. However systolic blood pressure < 120 mmHg and diastolic blood pressure < 70 mmHg were also associated with an increase in cardiovascular events, except for stroke. This finding supports the presence of a J-shaped curve in relation to outcomes and the blood pressure achieved on treatment.6

Prevention The 2016 guidelines on the prevention of CV disease target smoking, diet, physical activity, body weight, blood pressure, serum lipids and diabetes. Management should be individualised after assessment of personal risk using the SCORE tables. No additional predictive accuracy derives from the measurement of biomarkers. In apparently healthy individuals, risk assessment should be carried out from the age of 40 years in men and 50 years in women or when they are post-menopausal. Risk assessment may be repeated at five-year intervals in those with no identifiable risk factors and more often in those with risk close to threshold. Broadly speaking, management targets are avoidance of any exposure to smoking, a diet low in saturated fat, activity for at least 150 minutes each week, a body mass index (BMI) of 20–25 kg/m2, blood pressure < 140/90 mmHg, LDL-C according to the guideline on dyslipidaemia (i.e. < 3.0 mmol/l in low- to moderate-risk individuals) and, in patients with diabetes, an HbA1c level < 7%. Aside from the general recommendations, the guidelines contain specific recommendations for the management of patients with hypertension, CAD, chronic heart failure, cerebrovascular disease and peripheral vascular disease. A ‘naturally randomised’ study evaluated outcomes dependent on whether the study population’s LDL-C and blood pressure lay above or below the median, therefore evaluating lifelong exposure to these recognised risk factors. The differences between the lower and higher groups were LDL-C 0.31 mmol/l and blood pressure 5 mmHg. Outcomes were better in those with a lower LDL-C or blood pressure with a multiplicative effect observed when both were below the median. Population data have been collected in Finland since 1972. At the outset, the regions in the east of the country had the world’s highest incidence of CAD. A programme to encourage behavioural change was launched, including, smoking cessation and a reduction in dairy product intake. Since then there has been a continuous decline in CV disease of 4.4% per annum, thus achieving a cumulative reduction of 80% since the start of the project. Two-thirds of the decline is ascribed to risk factor management and one-third to medication and intervention.7 The Europe-wide survey EURO-ASPIRE IV demonstrates persistent overweight and obesity in the population. Eightyeight per cent of respondents were found to be overweight with two-thirds exhibiting central obesity. Women were more frequently affected than men.

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A study from the Netherlands examined medication compliance in 59 000 patients after either ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI). It showed that only 34% of patients took all five of the recommended therapies. STEMI patients were more likely to adhere (43%) than those with NSTEMI (28%). The latter group was more likely not to be taking statins and antiplatelet therapy. A Korean study showed that medication adherence can be improved by simplifying the timing of daily administration. The PALM registry found that underdosing of secondary preventative therapies was prevalent and that untreated and underdosed patients exhibited a higher LDL-C value. The OPTICARE study involved an educational and interventional programme in patients after ACS, comparing standard care versus a face-to-face physical training programme combined with counselling, versus a programme of telephone contact. More than 80% of patients completed the programme. A high percentage received optimal medical therapy (OMT). The study found no benefit to patients from more intensive management. Depression and anxiety are frequent concomitants in patients with CAD (25%) or stroke (33%). Its occurrence is more frequent with advancing age, elevated blood pressure and alcohol use. In the study reported at the meeting, effective secondary preventative treatment did not influence the rate of depression or anxiety. Very few patients had received treatment for their depression/anxiety. Bisphosphonates may reduce arterial calcification and so influence the progression of atherosclerotic disease. A retrospective analysis showed that the cardiovascular mortality rate was reduced by 19% and all-cause mortality by 10%. An international randomised study in 2 717 patients with prior CAD or stroke, who had obstructive sleep apnoea, showed that the use of continuous positive airway pressure (CPAP) over four years failed to improve cardiovascular outcomes. Quality of life was improved. The apparatus was used on average only for around 3.5 hours each night. Fewer stroke events were noted in those who used CPAP for more than four hours per night.8

Coronary artery disease Several reports were predicated on concerns about the high incidence of normal coronary angiograms in patients investigated for suspected stable CAD. Most quoted an incidence of 60–70% without obstructive disease. The CONSERVE trial over 12 months used coronary computed tomography angiography (CCTA) first, to assess whether invasive angiography was required. This approach reduced the assessed need for invasive angiography by 78%, revascularisation from 17 to 10% and the cost by 50%. In the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial (CE-MARC 2), the NICE guidelines were compared to cardiac magnetic resonance (CMR) and to myocardial perfusion imaging. This reduced the ‘unnecessary’ angiography rates to 28, 7 and 7%, respectively. In both studies, the MACE rates were not impacted on by avoidance of angiography.9 The PACIFIC study carried out a head-to-head comparison of CCTA, myocardial perfusion single-photon emission computed tomography (SPECT), positron emission tomography (PET) and hybrid imaging in the diagnosis of ischaemic heart

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disease. The finding was that PET scanning was superior to both CCTA and SPECT. Plasma apheresis was used in patients with uncontrolled angina receiving maximally tolerated medical therapy. Apheresis improved myocardial perfusion and increased exercise tolerance, as assessed by the six-minute walk test. The 15-year follow up of the FRISC-II study was reported; it had compared an early invasive strategy in NSTEMI to an initial non-invasive strategy.10 Patients who participated are now 80 years old on average. The overall mortality rate has been 40%. Sixty per cent of patients initially treated without intervention have subsequently undergone revascularisation. The frequency of unplanned revascularisation followed a parallel trajectory in the two groups after three to four years. CV death or MI was ‘postponed’ by three to four years in the intervention group, which also experienced a substantial reduction in the frequency of rehospitalisation. These benefits were seen in those patients who were troponin positive at the time of enrollment. By contrast, the 10-year follow up of the ICTUS study again found no benefit from early intervention, with the incidence of MI driven by peri-procedural events. A Japanese trial, which had compared ad hoc to deferred PCI in patients with stable CAD, reported its five-year outcomes. There were no differences in incidence of death or MI. Deferred cases fared better when heart failure was present, but the deferred group also had a higher incidence of stroke. Widimsky presented a small trial (1 230 patients) from the Czech Republic that looked at one-month outcomes in STEMI patients who received either prasugrel or ticagrelor (PRAGUE-18 study). No differences were discernible at seven and 30 days. Due to financial constraints, many patients had to switch to clopidogrel after discharge, frustrating the assessment of effect at a later time point.11 NORSTENT included 9 013 patients receiving their first coronary stent [either bare-metal (BMS) or newer drug-eluting stents (DES)] between 2008 and 2011.12 Seventy-one per cent of cases were treated for ACS. Eighty-four per cent of procedures were performed by the radial route. Forty per cent of patients had multi-vessel disease. An average of 1.7 stents was implanted per patient. Dual antiplatelet therapy (DAPT) was given for nine months in both groups. Median follow up was for five years. There were no differences in outcome between the two types of stent. Repeat revascularisation was 3.3% less with DES. Stent thrombosis occurred in 0.8% with DES and 1.2% in BMS patients. Quality of life was no different between the two groups. In the LEADERS FREE trial, patients over 75 years of age at high risk of bleeding received either a BioFreedom® polymerfree drug-coated stent or Gazelle® BMS and DAPT for only one month. Their average age was 81 years, 63% had multi-vessel disease and one-third had atrial fibrillation (AF). Sixty per cent of procedures were performed via the radial artery. At one year the event rate was 14 versus 11% in favour of the BioFreedom® stent, the difference being driven by the incidence of MI. There was a 49% reduction in target-vessel revascularisation and no increase in rate of bleeding.13 A 10-year follow up of the SIRTAX trial showed an increase in non-CV mortality rate between five and 10 years and a constant rate of MI, but a fall-off in the incidence of target lesion revascularisation and stent thrombosis with no difference between

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paclitaxel- and sirolimus-eluting stents. The use of DAPT, aspirin and statin treatment was observed to be declining.14 A five-year follow up of the trial comparing Biolimus® (biodegradable polymer) to sirolimus-eluting stents showed some crossover of benefit in favour of Biolimus® with regard to rates of death, MI, stent thrombosis and target-vessel revascularisation.15 A two-year follow up of the ABSORB® stent (bio-absorbable vascular scaffold) study found four instances of very late stent thrombosis. Optical coherence tomography showed that undersizing of the stent and discontinuities in stent structure might have been the cause.16 The DOCTORS study compared optical coherence tomographyguided to angiography-guided intervention in localised single-vessel disease. Fractional flow reserve (FFR) results were moderately improved when using optical coherence tomography. The BBK II trial compared TAP stenting with Culotte stenting in bifurcation lesions, demonstrating that the Culotte technique yielded better results in the side branch. Commentators cautioned against use of the Culotte technique by those who are not experts.17 Jang, from Harvard Medical School, reported on an optical coherence tomography-guided study in Chinese patients with ACS, which identified plaque erosion as the underlying cause in 30%. These patients were treated with aspirin and ticagrelor without stenting. He showed that thrombus volume was diminished at one month.18 A sub-study of the DAPT trial evaluated whether OMT (using ACE-I/ARB, beta-blockade, statin, thienopyridine and aspirin when indicated by guidelines) influenced the outcome of prolonging DAPT. The benefit of DAPT was shown to be consistent, whether or not patients were receiving OMT.19 The ITALIC trial two-year result showed no difference between six months and 24 months of DAPT (predominantly using clopidogrel). However, there was a trend towards increased events in patients with prior MI who received only six months of DAPT. A study of an ‘as-treated’ subgroup of the FREEDOM trial compared coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) in patients with diabetes and multi-vessel CAD, both with and without chronic kidney disease. CABG was associated with a lower incidence of death and MI but with an increase in the risk of stroke.20 The STITCH trial evaluated the benefit of CABG in patients with left ventricular systolic dysfunction (LVSD). CABG benefited patients in all age groups. CV mortality was the most frequent cause of death at all ages. Non-cardiac causes of death were more frequent in the elderly. BASKET-SAVAGE compared BMS to DES in saphenous vein graft stenting with the option of using a filter wire and/ or GPIIb/IIIa inhibitors. DES were associated with an 80% reduction in MACE (12 vs 30%) driven by non-fatal MI and target-vessel revascularisation. There was no difference in mortality rate. The contribution of the filter wire and GPIIb/IIIa inhibition used in 67% of cases could not be determined.

Heart failure The 2016 heart failure guideline discusses means to prevent or delay the onset of symptomatic heart failure. Predominant among these are treatment of hypertension, statins for those with

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CAD or at high risk thereof, smoking cessation, avoidance of excess alcohol intake, an ACE-I for patients with asymptomatic LVSD, and beta-blockade for those with LVSD after MI. Heart failure is defined as appropriate symptoms, possibly accompanied by physical signs of congestion, with evidence of structural heart disease on echocardiography. The guideline includes a new category of heart failure with mid-range ejection fraction (HFmrEF) of 40–49% in the range between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Treatment of HFmrEF is yet to be clearly defined. ProBNP is more important in ruling out heart failure than in proving the diagnosis. Novel additions to the guidelines are the use in appropriately selected patients of an angiotensin receptor neprilysin inhibitor (ARNI) (sacubitril-valsartan) to replace ACE-I, cardiac resynchronisation therapy (CRT), and ivabradine should they remain symptomatic on ACE-I/ARB, beta-blockade and MRA treatment. HFpEF and HFmrEF should be treated symptomatically, using diuretics to relieve congestive symptoms. The guideline discusses at length various co-morbidities and their management in the setting of heart failure. A ‘hotline’ session was devoted to device interventions in heart failure. The DANISH study evaluated the use of implantable cardioverter defibrillators (ICDs) in non-ischaemic heart failure in patients with NYHA class II to III symptoms and an ejection fraction < 35% (Fig. 2).21 The study did not achieve its primary endpoint of reducing mortality rates. There was a reduction in incidence of sudden death and a reduction in total mortality rate in the subgroup under 60 years of age. Two other studies, REM-HF and MORE-CARE, reported on remote monitoring for worsening heart failure. Both failed to show any improvement in outcome. Another two studies on cell therapy in heart failure could not demonstrate any benefit.

Cardio-oncology This is an emerging area of concern for cardiologists and oncologists alike, given the increasing numbers of patients who 1.0

Cumulative event rate

0.8

120 died in the ICD group and 131 in the control group Hazard ratio = 0.87 (0.68 – 1.12) p = 0.28

0.6

0.4 Controls

0.2

ICD 0.0

540 540

517 526

438 451

344 358

248 272

169 186

88 107

12 17

Years Controls 560 556 ICD

Fig 2. Primary outcome – all-cause mortality

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may now survive for years after cancer treatment. The heart and blood vessels may be affected in a variety of ways by either chemotherapy or radiation. Myocardial dysfunction and heart failure, CAD, valvular heart disease, pericardial involvement, arrhythmias, hypertension, pulmonary thromboembolism, stroke, peripheral vascular disease or pulmonary hypertension may occur, not only acutely but also after a delay of months or years. The patient’s presentation is influenced by the agent used, the dose and duration of treatment, age, kidney function and pre-existing CV disease. Myocardial toxicity is of particular concern and its early detection, as evidenced by deteriorating LVSD on echocardiography in comparison to baseline values and/or by elevation in hs-troponin T, is important. Baseline echocardiography with follow up at the completion of treatment and then at three and six months is recommended. ACE-I or ARB, beta-blocker and MRA therapies are cardioprotective as well as effective in managing overt heart failure. Not all patients recover normal left ventricular function after the cessation of treatment. In those who do, it may be possible to discontinue the cardioprotective treatment.22

Atrial fibrillation Apart from death and stroke, the ESC 2016 guideline includes recognition of hospitalisations, left ventricular dysfunction and heart failure, cognitive decline and vascular dementia, and impaired quality of life as consequences of AF. An algorithm is provided for the detection of AF in patients with an implanted device presenting after detection of a high atrial rate episode lasting longer than five to six seconds or a rate > 180 beats/min. For the assessment of stroke risk and the need for anticoagulation, the CHADS-VaSC score remains unchanged but the stroke risk has been reclassified for women. Anticoagulation is indicated in men with a score of 2 or more; for women it’s a score of 3 or more. Anticoagulation is not mandated but may be considered in men and women with respective scores of 1 or 2. Bleeding risk scores should be considered to determine the presence of modifiable risk factors for major bleeding in patients taking anticoagulant therapy. A non-vitamin K antagonist (VKA)/novel oral anticoagulant is preferred to warfarin. Occlusion of the left atrial appendage may be considered in patients who have a long-term contra-indication to anticoagulation. The guideline provides recommendations for the initiation of anticoagulation after transient ischaemic attack or stroke and the re-initiation of anticoagulation after intracranial bleeding. The integrated management of AF includes symptom control, maintenance of haemodynamic stability and the preservation of LV function, stroke prevention and the management of CV risk factors. Recommendations for ventricular rate control include consideration of digoxin as a second-line therapy. ENSURE-AF23 examined the use of the factor Xa inhibitor (edoxaban) versus enoxaparin/warfarin-VKA in electrical cardioversion of non-valvular AF in 2 199 patients with and without transoesophageal echocardiography (TEE). The average CHADS-VaSC score was 2.6. The procedure was undertaken with a delay of two and 23 days, respectively, depending on whether or not patients had undergone TEE. There was a very low event rate following cardioversion with a 50–60% reduction in events with edoxaban and no increase in bleeding.

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Connolly reported on the ongoing trial of the antidote, andexanet alfa, in patients treated with a factor Xa inhibitor presenting with critical bleeding. Haemostasis was achieved in 79% of patients. However, thrombotic events have been observed after reversal. The 30-day mortality rate was 15%.24

Arrhythmias The channelopathies include long-QT syndrome (QT interval > 480 ms or > 460 ms in association with syncope and in the absence of factors prolonging the QT interval), short-QT syndrome (QT interval < 340 ms or < 360 ms in the presence of additional features), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, early repolarisation syndrome, progressive conduction system disease and idiopathic ventricular fibrillation. Although genetic testing is helpful in a variety of these conditions, it cannot rule out the presence of a particular condition. However once a genetic marker has been identified in a patient, there is a class I indication for testing family members. ‘Overlap’ syndromes may occur. Depending on the specific diagnosis, the management armamentarium includes lifestyle changes, reduction in the risk of exposure to triggers (e.g. exercise, sudden fright) betablockade (possibly nadolol to be preferred), late sodium channel blockers (e.g. flecainide, propafenone), quinidine, ablation of an ectopic focus and consideration of an ICD or pacemaker. Fever and alcohol exposure should be avoided in Brugada syndrome. Priori presented her basic science research on gene therapy in mice using adeno-associated virus (AAV) infection to either add an active gene or silence a mutant. Problems may be posed by the high incidence of antibodies to this virus.25

Valvular heart disease In a session on mitral valve repair, Obadia illustrated several surgical approaches to the mitral valve. Alifieri discussed the problems associated with mitral valve repair. He emphasised the importance of recognising that ‘everything is closer than you think’: the commissure between the left and non-coronary aortic valve leaflets, the circumflex coronary artery, the artery to the atrioventricular node, the atrioventricular node itself and the coronary sinus all lie in close proximity to the mitral annulus and risk being injured during repair. It is challenging to remove calcification from the mitral annulus. As a result, mitral leaks in the region of the posterior annulus are seen more frequently in the elderly. Mitraclip®, discussed by Latib, may be complicated by inadequate grasping of the leaflet or leaflet perforation. Occasionally systolic anterior motion of the mitral anterior leaflet may result in intermittent mitral regurgitation during exercise only; this may require provocation with isoprenaline to demonstrate its presence. It is important to recognise that in patients with aortic regurgitation, only 50% have primary aortic valve disease; the primary pathology is in the aorta in the other half. Sinotubular dilatation, aortic dissection and occasionally aortic dissection flap prolapse may be at fault. Three-dimensional echocardiography is to be preferred over two-dimensional to quantify the degree of aortic regurgitation. A left ventricular end-systolic diameter > 50 mm or left ventricular end-diastolic diameter > 70 mm predicts the need for surgery. However, earlier referral for surgery is

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recommended in symptomatic patients and those with LVSD. TEE is strongly recommended prior to referral for surgery as well as intra-operatively. The feasibility of aortic valve repair depends upon the pliability of the leaflets and their freedom from calcification. Repair of a bicuspid aortic valve is less successful, especially when decalcification and cusp repair with a pericardial patch is required. There are many smaller studies reporting successful aortic root repair with freedom from re-operation and absence of residual regurgitation.

Venous thromboembolism Computed tomographic pulmonary angiography (CTPA) is frequently used in suspected acute pulmonary embolism (PE). The majority of these costly investigations yield a negative result. The YEARS project devised a simplified algorithm for diagnosing acute PE. The first step is to obtain a D-dimer test and score 1 point for each of the following: clinical assessment for signs of deep venous thrombosis (DVT), haemoptysis and whether PE is the most likely diagnosis. If the YEARS score is 1 or more or if the D-dimer value is > 1 000 ng/ml, order CTPA. If not, PE can be ruled out and CTPA is unnecessary. This method has been shown to be safe and will reduce the frequency of CTPA by 14% overall and to a greater degree in younger patients. In DVT-PE the outcome is not influenced by whether treatment is initiated with rivaroxaban or with enoxaparin with later bridging to rivaroxaban. Following treatment for venous thromboembolism (VTE), it is problematic to decide whether anticoagulant therapy may be safely withdrawn owing to the potential for recurrent events. Rodger presented a validation of the ‘men continue and HERDOO2 rule’ which identifies those at low risk of recurrence in whom anticoagulation can be withdrawn. The rule states that all males and certain females scoring 2 or more using the HERDOO rule must continue anticoagulation long term after unprovoked or minor provoked VTE. The HERDOO factors are HER: hyperpigmentation, oedema or redness in either leg, D: level of D:dimer assessed through blood testing, O: obesity defined as BMI ≥ 30 km/m2, and O: older than 65 years of age. Anthony J Dalby, FCP (SA), FACC, FESC Previously published by deNovo Medica, Cape Town, October 2016 http://www.denovomedica.com/cpd-online/modules/european-society-ofcardiology-congress-update-2016/

References 1.

Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016; Aug 29 (Epub ahead of print).

Sheppard JP, Stevens R, McManus RJ, et al. Predicting out-of-office blood pressure in the clinic (PROOF BP). Hypertension 2016; 67(5): 941–950.

Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, doubleblind, crossover trial. Lancet 2015; 386(10008): 2059–2068.

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Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS Inhibitors. N Engl J Med 2015; 372: 211–221.

Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium

patients. Heart 2016; Aug 10 (Epub ahead of print).

hyperkalemia: The HARMONIZE randomized clinical trial. J Am Med

and serial optical coherence tomographic follow-up after implementa-

Assoc 2014; 312(21): 2223–2233.

tion of an everolimus-eluting bioresorbable scaffold and an everolimus-

Vidal-Petiot E, Ford I, Greenlaw N, et al. Cardiovascular event rates and

eluting metallic stent: insight from the randomised ABSORB Japan trial. EuroIntervention 2016; Jul 6: 12(7) (Epub ahead of print). 17. Ferenc M, Gick M, Comberg T, et al. Culotte stenting vs TAP stenting

Aug 26 (Epub ahead of print).

for treatment of de-novo coronary bifurcation lesions with the need for

Jousilahti P, Laatikainen T, Peltonen M, et al. Primary prevention and

side-branch stenting: the Bifurcations Bad Krozingen (BBK) II angio-

risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population

graphic trial. Eur Heart J 2016; Aug 30 (Epub ahead of print). 18. Jia H, Dal J, Hon J, et al. Effective anti-thrombotic therapy without

based observational study. Br Med J 2016; 352: i721.

stenting: intravascular optical coherence tomography-based manage-

McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardio-

ment in plaque erosion (the EROSION study). Eur Heart J 2016; Aug

vascular events in obstructive sleep apnea. N Engl J Med 2016; Aug 28 (Epub ahead of print). 9.

a biodegradable polymer-coated biolimus-eluting stent in unselected 16. Onuma YY, Solomi Y, Shiomi H, et al. Two-year clinical, angiographic

patients with stable CAD: an international cohort study. Lancet 2016;

Heart J 2016; Aug 30 (Epub ahead of print). 15. Danzi GB, Piccolo R, Chevalier B. Five-year clinical performance of

cyclosilicate on potassium lowering for 28 days among outpatients with

mortality according to achieved systolic and diastolic blood pressure in

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Ripley P, Brown M, Everett C, et al. Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease

30 (Epub ahead of print). 19. Resor CD, Nathan A, Kereiakes DF, et al. Impact of optimal medical therapy in the dual antiplatelet therapy study. Circulation 2016; Aug 30 (Epub ahead of print).

2 (CE-MARC 2): A prospective, multicenter, randomized trial of diag-

20. Baber U, Farkouh ME, Arbel Y, et al. Comparative efficacy of coronary

nostic strategies in suspected coronary heart disease. Am Heart J 2015;

artery bypass surgery vs percutaneous coronary intervention in patients

169(1): 17–24.e1

with diabetes and multivessel coronary artery disease with or without

10. Wallentin L, Lindhagen L, Arnstrom E, et al. Early invasive versus

chronic kidney disease. Eur Heart J 2016; Aug 29 (Epub ahead of print).

non-invasive treatment in patients with non-ST elevation acute coronary

21. Kober L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in

syndrome (FRISC-II): a 15-year follow-up of a prospective randomised

patients with nonischemic systolic heart failure. N Engl J Med 2016; Aug

multicentre study. Lancet 2016; Aug 25 (Epub ahead of print).

27 (Epub ahead of print).

11. Motovska Z, Hlinomaz O, Maklik R, et al. Prasugrel versus ticagrelor

22. Zamorano JL, Lancellotti P, Rodriguez Munoz D, et al. 2016 ESC posi-

in patients with acute myocardial infarction treated with primary percu-

tion paper on cancer treatments and cardiovascular toxicity developed

taneous coronary intervention: Multicentre randomized PRAGUE 18

under the auspices of the ESC Committee for Practice Guidelines:

study. Circulation 2016; Aug 30 (Epub ahead of print).

The Task Force for cancer treatments and cardiovascular toxicity of

12. Bonaak M, Annsverk J, Wiseth R, et al. Drug-eluting or bare metal stents for coronary artery disease (NORSTENT). N Engl J Med 2016; Aug 19 (Epub ahead of print).

the European Society of Cardiology (ESC). Eur Heart J 2016; Aug 26 (Epub ahead of print). 23. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxapa-

13. Stefanini GG, Behan M, Valgimigli M. Will LEADERS-FREE

rin-warfarin in patients undergoing cardioversion of atrial fibrillation

change my practice? A randomised double-blind comparison of the

(ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet 2016;

BioFreedom® drug-coated stent versus Gazelle® bare metal stent in patients at high bleeding risk using a short (1 month) course of dual antiplatelet therapy. EuroIntervention 2016; 12(6): 798–800. 14. Yamaji K, Raber L, Zanchin T. Ten-year clinical outcomes of firstgeneration drug-eluting stents: the sirolimus-eluting vs paclitaxel-eluting stents for coronary revascularization (ZIRTAX) VERY LATE trial. Eur

Aug 26 (Epub ahead of print). 24. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; Aug 30 (Epub ahead of print). 25. Bongianino R, Priori SG. Gene therapy to treat cardiac arrhythmias. Nat Rev Cardiol 2015; 12(9): 531–546.

Events 23rd Annual Conference of The Egyptian Society of Cardiothoracic Surgery 23rd annual conference of The Egyptian Society of Cardiothoracic Surgery in collaboration with National Heart Institute of Egypt, from 4–7 April 2017 at Mena House Hotel, Cairo, Egypt. Workshops: RV-PA conduit implantation, electrophysiology anatomy for ablation surgery, aortic repair, simulation for wire-based techniques, basic anatomy of the heart for junior staff, TEE for surgeons and anaesthetics, endoscopic vein harvesting, coronary anastomoses (hands on).

Main topics: minimal invasive surgery, aortic root surgery, TEVAR, surgery for heart failure, cardiovascular perfusion, RV-PA connections, AV valve repair in infants, staging modalities in lung cancer, woman in cardiac surgery, personal skill development for surgeons. Kindly submit abstracts before the deadline 31 December 2016. Please check the link for abstract form: www.escts2017.com

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Consensus Guidelines SASCI/SCTSSA joint consensus statement and guidelines on transcatheter aortic valve implantation (TAVI) in South Africa Jacques Scherman, Hellmuth Weich

The South African Heart Association (SA Heart) together with two of its special-interest groups, the South African Society of Cardiovascular Intervention (SASCI) and the Society of Cardiothoracic Surgeons in South Africa (SCTSSA), represent the scientific, educational and professional interests of South African cardiac specialists, with a combined membership of over 200 members. These two interest groups exclusively represent practicing cardiologists and cardiothoracic surgeons in South Africa. SASCI and SCTSSA are dedicated to maintaining the highest standards of specialist practice and the highest quality of patient care. As a result, SASCI and SCTSSA seek to serve as a knowledge resource for patients and funders in matters related to new technology used in the cardiac interventional and surgical disciplines. The introduction of new technology is a constant in modern medicine. While authorities in the United States of America (USA) and European Union, such as the Food and Drug Administration (FDA) and Conformité Européene (CE), provide regulatory clearance on safety and effectiveness, practicing medical practitioners require scientific evidence on net health outcomes before offering new procedures to their patients. In addition, to meet clinical expectations of practicing specialists, new technology must stay consistent with fundamental medical and surgical principles. Transcatheter aortic valve implantation (TAVI) is considered a feasible technique, which may be used as an alternative to standard surgical aortic valve replacement in selected cases. The procedure is performed on the beating heart without the need for a sternotomy or cardiopulmonary bypass. There are currently two devices available in South Africa that are CE-marked and approved by the FDA. The procedure may be performed via the transfemoral, transsubclavian and transapical approaches or via a mini-sternotomy (transaortic approach). Previously published in SA Heart 2016; 13(4): 298–300.

DOI: 10.5830/CVJA-2016-092

Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, South Africa Jacques Scherman, MB ChB, DipOccMed, MMed, FCCardio (SA), jacques.scherman@uct.ac.za

Division of Cardiology, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa Hellmuth Weich, MB ChB, MRCP (UK), MMed (Int), Cert Cardiology (CMSA), hweich@sun.ac.za

SA Heart and the respective boards of the SASCI and SCTSSA by consensus hereby adopt the TAVI procedure for aortic stenosis in line with the principles of evidence-based medicine after considering the most recent published evidence and the various multinational society position statements and guidelines concerning TAVI. This consensus guideline considers all the literature reviewed, including the 2014 American Heart Association/American College of Cardiology guideline for the management of patients with valvular heart disease, the 2012 European Society of Cardiology/ European Association for Cardiothoracic Surgery guidelines on the management of valvular heart disease, and the updated standardised endpoint definitions for TAVI [as per the Valve Academic Research Consortium-2 (VARC-2) consensus document].1-3

Consensus guidelines on transcatheter aortic valve implantation (TAVI) Members of the SA Heart Association, SASCI and SCTSSA with experience in the technique and knowledge of the TAVI literature have agreed to the following consensus statement:

Requirements and structure of the multidisciplinary heart team • The performance of TAVI, ab initio, should be restricted to a limited number of high-volume centres, which have both cardiology and cardiac surgery departments on site, with expertise in structural heart disease intervention and high-risk valvular surgery. Interventional cardiologists should be experienced in catheter-based valvular interventions and peripheral access using large devices. Cardiac surgeons should be experienced in valve surgery and the management of complex cases. It is recommended that all TAVI teams aim to perform more than 10 implants per year. • TAVI should currently be reserved for patients who, after evaluation by a multidisciplinary heart team (MDT) are found to have a risk/benefit ratio favouring TAVI rather than open-heart surgery. The heart team should at least include a cardiologist, cardiac surgeon and imaging specialist. Its composition is however dynamic and can also include a cardiac anaesthetist, geriatrician and neurologist as well as other members as the MDT sees fit. • Patients should be screened into a TAVI programme by a MDT (as defined above) and not by an individual specialist.

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• Formal training of the implanting team should include: –– didactic theoretical training –– simulator training where available –– a visit to an experienced centre to observe TAVI cases –– support for the initial cases at any site by a proctor until the proctor has certified the centre to be independent.

Patient selection/mandatory prerequisites • Proof of severe symptomatic aortic valve stenosis. • Patient evaluation by a MDT.

Indications for TAVI • TAVI is recommended in patients who are, according to the MDT heart team, considered to be unsuitable for conventional surgery because of severe co-morbidities. These include: –– Possible procedure-specific impediment, for example: ›› porcelain aorta or severely atherosclerotic aorta ›› hostile chest ›› patent coronary artery bypass grafts crossing the midline and/or adherent to the posterior table of the sterum OR –– Frailty. In the absence of validated frailty scores, this remains the opinion of an experienced physician. We recommend that it is the opinion of at least two physicians of which one should be a cardiac surgeon experienced in aortic valve replacement surgery OR –– Major organ compromise of two or more organ systems. Examples include: ›› cardiac: severe left or right ventricular dysfunction, severe pulmonary hypertension ›› pulmonary dysfunction (FEV1 or DLCO2 < 50% predicted) ›› central nervous system dysfunction (dementia, Alzheimer’s disease, Parkinson’s disease) ›› gastro-intestinal dysfunction (Chron’s disease, ulcerative colitis) ›› liver cirrhosis, variceal bleeding. • TAVI is recommended in patients who are, according to the MDT, considered to be at high risk for conventional surgery. In line with other guidelines, the evaluation of surgical risk should rely on the clinical judgement of an MDT rather than quantitative risk scores as these have not been well validated in this population. These risk scores may be used in addition, with cut-off values of an STS (Society of Thoracic Surgeons) risk score > 4 or a log EuroSCORE > 20 recommended. It must be emphasised that risk scores should not be used in isolation to determine whether a patient qualifies to undergo a TAVI procedure. Growing evidence supports the efficacy of TAVI in ‘intermediate-risk group’ patients.4 The final recommendation therefore remains with the MDT.

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• Clinical improvement in quality of life after TAVI limited by co-morbidities. This may be especially relevant if the indication for TAVI is major organ compromise, as outlined above. • Anatomical factors –– inadequate annulus size –– active endocarditis –– inadequate access site. • Significant other valve lesions or coronary artery disease that requires additional valve or coronary artery bypass surgery. • Relative contra-indications –– left ventricular ejection fraction (LVEF) < 20% –– haemodynamic instability.

Establishing a TAVI programme • The centre should be sufficiently equipped to perform transcatheter procedures safely.1-3 • Minimum infrastructure requirements include: –– The ability to set up an MDT (as outlined above). –– Immediate availability of transthoracic and transoesophageal echocardiography. –– Availability of a dedicated cardiac catheterisation laboratory or hybrid theatre [a theatre with mobile fluoroscopy (‘C’-arm) screening facilities is generally not appropriate for TAVI procedures]. –– Computed tomography (CT) scanning facilities. –– Immediate availability of perfusion services in case emergency cardiopulmonary bypass (extracorporeal circulation) becomes necessary. –– On-site availability of a surgical recovery area and intensive care with staff experienced in looking after patients following surgical aortic valve replacement. –– Facilities for immediate renal support if necessary. –– Immediate access to vascular surgery and interventional radiology to deal with peripheral vascular complications. • The above requirements will mean that this procedure should only be performed in a unit currently carrying out surgical aortic valve replacement.

References 1.

Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin III JP, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014 7; 148(1): e1–e132.

Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33(19): 2451–2496.

Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document (VARC-2). Eur J Cardiothorac Surg 2012; 42(5): S45–S60.

Contra-indications • Absence of an MDT heart team and no cardiac surgery on site. • Patients whose life expectancy is less than one year.

Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al. Transcatheter or surgical aortic-valve replacement in intermediaterisk patients. N Engl J Med 2016; 374(17): 1609–1620.

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Case Report A circumflex coronary artery-to-right atrial fistula in a 10-month-old child Emrah Şişli, Mehmet Fatih Ayık, Muhammet Akyüz, Münevver Dereli, Yüksel Atay

Abstract A coronary fistula (CF) is a rare congenital cardiac anomaly in which there is a connection between the coronary artery and a cardiac chamber or a great vessel. In the paediatric population, a CF is usually asymptomatic. While the circumflex coronary artery (Cx) is the least common source of a CF, the right heart chambers are the most common location of drainage. Herein, we present a symptomatic 10-month-old boy with an atrial septal defect (ASD) in whom we incidentally detected a CF, which stemmed from the Cx and drained to the right atrium. Because the patient was symptomatic and his small size was not appropriate for percutaneous closure of the ASD, surgical closure of the ASD and CF was performed. Keywords: heart defects, congenital, atrial septal defect, vascular fistula, cardiac surgical procedures

Section of Paediatric Cardiovascular Surgery, Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Izmir, Turkey Emrah Şişli, MD, dresisli@gmail.com Mehmet Fatih Ayık, MD Muhammet Akyüz, MD Münevver Dereli, MD Yüksel Atay, MD

Submitted 25/7/15, accepted 3/4/16 Cardiovasc J Afr 2016; 27: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2016-044

A coronary fistula (CF) is a rare congenital cardiac anomaly in which there is a connection between one or more coronary arteries and a cardiac chamber or great vessel.1-3 Herein, we present a paediatric case with a CF between the circumflex coronary artery (Cx) and the right atrium (RA).

Case report In the follow up of a 10-month-old boy (weight 8 kg and height 70 cm) with a prenatal diagnosis of atrial septal defect (ASD), apart from the fixed splitting of the second heart sound, a prominent increase in the severity of the mid-systolic murmur at the pulmonary auscultation area was incidentally detected. On echocardiography, a new continuous jet flow into the RA indicative of a CF was detected. His history showed he had had recurrent upper respiratory infection and failure to thrive so that both the weight and height of the patient were within the third and 10th percentiles. There was no evidence of myocardial ischaemia on electrocardiography. On echocardiography, the ASD (5 mm) was secundum type. The opening of the jet was sited adjacent to the superior cavo-atrial B

Fig. 1. P re-operative subcostal (A) and modified parasternal short-axis (B) echocardiographic views demonstrating the jet flow and trajectory of the coronary fistula.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016

Fig. 2. T hree-dimensional reconstructed computed tomographic view demonstrating the trajectory of the coronary fistula. Note the dilated left main and circumflex coronary arteries. AO: aorta, LMCA: left main coronary artery, PA: pulmonary artery, SVC: superior vena cava.

junction (Fig. 1A). Posterior to the aorta, turbulent flow of the CF originating from the left coronary system was detected (Fig. 1B). The Qp/Qs was 1.7. In contrast-enhanced computed tomography, the left main and circumflex coronary arteries were dilated (6 and 4.5 mm, respectively). The CF originated from the proximal Cx and coursed posterior to the aorta before draining into the RA (Fig. 2). Because of the small size of the patient, percutaneous closure of both the ASD and CF was not appropriate therefore surgical closure was planned. After a median sternotomy and pericardiotomy, the CF was located adjacent to the posterior part of the superior cavo-atrial junction. Under cardiopulmonary bypass (CPB), the aorta was cross-clamped and cardiac electromechanical quiescence was established. Through a right atriotomy, the secundum ASD was primarily closed.

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It was detected under cardioplegic wash-out that the opening of the CF was located inferior to the cavo-atrial junction and it had multiple openings, which were connected with a loose membrane (Fig. 3). Following the primary closure of the openings from within the RA, the connection was checked with a second cardioplegic wash-out. Because of the loose membranous connection between the openings and to ensure that the fistulous connection was separated, the fistula was ligated outwardly, close to the opening of the RA. After weaning from CPB, no electrocardiographic changes indicative of myocardial ischaemia occurred. The postoperative course was uneventful. In postoperative echocardiography, the atrial septum was intact and no turbulent flow in the right atrium was detected. Aspirin was given for three months. At the six-month follow-up visit, he was found to have gained weight (12 kg). Additionally, no turbulent flow within the atrium or posterior to the aorta was detected in echocardiographic evaluation.

Discussion As the use of selective coronary angiography became widespread, recognition of a CF has been improving since the 1950s.1 Sercelik et al. found the incidence of congenital CFs in the Turkish population was 0.08%.4 Among 286 cases with CF, the source of the CF was the right coronary artery in 56% and the left coronary system in 36% of cases. In the literature, while the Cx was the least common source of a CF, the right heart chambers were the most common location of drainage.1-7 Although spontaneous closure has been demonstrated, either surgical or interventional closure of the CF was recommended during childhood, even though they were asymptomatic, because of the risks that can occur during adulthood, including myocardial ischaemia, endocarditis and the complications of long-standing left-to-right shunt.2,5,7 Contrary to our case, nine of 10 CFs were asymptomatic in an evaluation of CFs in paediatric cases, and surgical ligation under CPB support without application of an aortic crossclamp was performed in four cases.5 According to Sakakibara et al.,3 our CF was type A in which ligation of the CF distal to the origin without CPB was recommended. Because the patient was symptomatic and due to the associated ASD, of which percutaneous closure was not feasible, we implemented ASD closure under CPB, suture closure of the atrial opening of the fistula from within the RA, and ligation of the CF outwardly, close to the connection with the RA.

Conclusion In our opinion, based on the clinical presentation and coexistent cardiac pathology, the choice of therapeutic management strategy should be individualised. Because of the possibility of the development of complications in the future, we successfully operated on a symptomatic paediatric case in whom the CF was incidentally diagnosed in association with an ASD.

Fig 3. S urgeon’s view revealing the multiple openings of the coronary fistula. ASD: atrial septal defect.

References 1.

Lowe JE, Oldham HN, Jr., Sabiston DC, Jr. Surgical management of congenital coronary artery fistulas. Ann Surg 1981; 194: 373–380.

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Liberthson RR, Sagar K, Berkoben JP, Weintraub RM, Levine FH.

ric patients. Turk Gogus Kalp Dama 2015; 23: 217–221.

of the literature and delineation of management. Circulation 1979; 59: 3.

Kamiya H, Yasuda T, Nagamine H, Sakakibara N, Nishida S, Kawasuji

Sakakibara S, Yokoyama M, Takao A, Nogi M, Gomi H. Coronary

M, et al. Surgical treatment of congenital coronary artery fistulas: 27

arteriovenous fistula. Nine operated cases. Am Heart J 1966; 72:

years’ experience and a review of the literature. J Card Surg 2002; 17: 173–177.

307–314. 4.

Doksöz Ö, Küçük M, Güven B, Genç B, Özdemir R, Meşe T, et al. Congenital coronary arteriovenous fistulas: an evaluation of 10 pediat-

Congenital coronary arteriovenous fistula. Report of 13 patients, review 849–854.

Sercelik A, Mavi A, Ayalp R, Pestamalci T, Gumusburun E, Batiraliev

Yim D, Yong MS, d’Udekem Y, Brizard CP, Konstantinov IE. Early

T. Congenital coronary artery fistulas in Turkish patients undergoing

surgical repair of the coronary artery fistulae in children: 30 years of

diagnostic cardiac angiography. Int J Clin Pract 2003; 57: 280–283.

experience. Ann Thorac Surg 2015; 100: 188–194.

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Pharma Dynamics Clopidogrel 75 mg. Each film coated tablet contains clopidogrel hydrogen sulphate equivalent to clopidogrel 75 mg. Reg. No.: RSA S3 42/8.2/0128. NAM NS2 10/7.1/0377. For full prescribing information, refer to the package insert approved by the Medicines Control Council, October 2008. 1) Vs originator clopidogrel. Department of Health website http://www.doh.gov.za – Accessed 09/04/2015. 2) Poponina TM, et al. Current approaches to the prevention of thrombotic complications in patients with acute coronary syndrome without ST-segment elevation. Topical issues of heart and vascular diseases. 2009;4:4-9. (English translation) 3) Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Vascular Medicine 1998;3:257-260. 4) COMMIT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet 2005;366(9497):1607-1621. 5) Sabatine MS, et al. Addition of Clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. New England Journal of Medicine 2005;352:117989. 6) The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine 2001;345:494-502. PDCLC203/06/2015

NOVEMBER/DECEMBER 2016 VOL 27 NO 6 A Lupin Group Company

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CardioVascular Journal of Africa (official journal for PASCAR)

PERFECTLY. EFFICACY

SAFETY 2 PROVEN OUTCOMES 3 AFFORDABILITY 4

Cardiovascular Journal of Africa . Vol 27, No 6, November/December 2016

WHEN ALL THE PARTS FIT...

• European Society of Cardiology congress update • SASCI/SCTSSA guidelines on TAVI in South Africa

PUBLISHED ONLINE: • Circumflex artery-to-right atrial fistula in a 10-month-old child