CVJA Volume 23, Issue 6

JULY 2012 VOL 23 NO 6

AFRICA www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Prevention of infective endocarditis • WHO STEPS-wise approach to cardiovascular risk factors • Acute coronary syndromes in sub-Saharan Africa • 12-lead ECG in peripartum cardiomyopathy • Plaque vulnerability in acute coronary syndrome • Oral health and rheumatic heart disease • Neuropathic pain management • Insulin glargine safety and efficacy

• Sustained idiopathic ventricular tachycardia Cardiovascular Journal of Africa . Vol 23, No 6, July 2012

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

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VOL 23, NO 6. JULY 2012

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorials

303

Prevention of infective endocarditis in developing countries B Maharaj • A Parrish

306

First annual congress of the Faculty of Consulting Physicians of South Africa, 18–20 May 2012 N Rapeport

309

Prevalence of cardiovascular risk factors in an urban area of Togo: a WHO STEPS-wise approach in Lome, Togo S Brgou • M Djibril • B Atta • F Damorou • M Pio • A Balagou

Cardiovascular Topics

313 Association between plasma homocysteine and myocardial SPECT abnormalities in patients referred for suspected myocardial ischaemia A Ankrah • J Buscombe • MM Sathekge 318 A prospective review of acute coronary syndromes in an urban hospital in sub-Saharan Africa J Shavadia • G Yonga • H Otieno 322 The 12-lead ECG in peripartum cardiomyopathy K Tibazarwa • G Lee • B Mayosi • M Carrington • S Stewart • K Sliwa 330 Assessment of serum leptin, pregnancy-associated plasma protein A and CRP levels as indicators of plaque vulnerability in patients with acute coronary syndrome M Lodh • B Goswami • A Parida • A Saxena 336 Oral health of patients with severe rheumatic heart disease B Maharaj • AC Vayej 340 An investigation of the frequency of bacteraemia following dental extraction, tooth brushing and chewing B Maharaj • Y Coovadia • AC Vayej

Letter to the Editor

312

Hermansky‒Pudlak/Chediak‒Higashi syndromes HD Solomons

347

Prof Andrzej Michael Okreglicki, 1960–2012 R Scott Millar

In Memoriam

INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors

SUBJECT Editors

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

Nuclear Medicine and Imaging DR MM SATHEKGE

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

Heart Failure Dr g visagie Paediatric dr s brown Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Electrophysiology and Pacing dr a okreglicki Epidemiology and Preventionist dr ap kengne

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

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

PROF PETER SCHWARTZ Italy (Dysrhythmias)

DR J LAWRENSON Paediatric Heart Disease

Publishing Consultant

PROF H DU T THERON Invasive Cardiology

PROF ERNST VON SCHWARZ USA (Interventional Cardiology) Mike Gibbs

CONTENTS VOL 23, NO 6. JULY 2012

Your Life and Your Heart

345

Focus on omega-3 PUFAs in heart failure J Aalbers

348

Hypertension, chronic kidney disease, atrial fibrillation and the newer anticoagulants: Prof Brian Rayner comments G Hardy

Conference Reports

Faculty of Consulting Physicians of South Africa 350 Saving brain with dabigatran J Aalbers • G Hardy 351

Managing neuropathic pain: first expert recommendation for South Africa places emphasis on stepwise pharmacological intervention J Aalbers

355 Rheumatoid arthritis management options for 2012 J Aalbers 356

Benefit versus risk in the use of non-selective NSAIDs and selective COX-2 inhibitors J Aalbers

Drug Trends

357 ORIGIN trial shows safety and efficacy of insulin glargine L Lombard • L Distiller • J Aalbers 360 SHIfT: ivabradine’s additional clinical benefits regardless of background beta-blocker dose J Aalbers

PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) e1

Cardiovascular Topics

p53 negatively regulates the osteogenic differentiation of vascular smooth muscle cells in mice with chronic kidney disease K Li • J Chen • Z Li • J Zhan • L Zhao • Y He

Case Reports

e10 Successful emergency double valve repair operation during acute aortic dissection type A T Adademir • A Tuncer • M Ozkokeli • A Sasmazel • H Erdem • R Zeybek e12 Dilated cardiomyopathy secondary to coarctation of the aorta was completely resolved after stent implantation Mt Ağaç • Z Acar • R Akdemir • L Korkmaz • A Kiriş • Ar Akyüz • H Erkan e14 A rare case of spontaneous rectus sheath haematoma in a patient with mechanical prosthetic aortic and mitral valves A Aykan • A Oguz • M Yildiz • M Özkan e16 Sustained idiopathic ventricular tachycardia originating from the posteroseptal tricuspid annulus T Celik • B Bugan • S Kose • UC Yuksel • A Iyisoy • HK Kabul • H Kursaklioglu • E Isik e19 LEOPARD syndrome PL Massoure • C Latremouille • G Lamblin • F Leca

managing editor

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

Production Editor

SHAUNA GERMISHUIZEN Tel: 021 785 7178 Fax: 086 628 1197 e-mail: shauna@clinicscardive.com

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

development editor

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

Production Co-ordinator

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

GAUTENG CONTRIBUTOR

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CONTENT MANAGER

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

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

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

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

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

303

Editorial Prevention of infective endocarditis in developing countries BREMINAND MAHARAJ, ANDREW PARRISH Infective endocarditis (IE) causes substantial morbidity and mortality despite modern antimicrobial chemotherapy and advances in the ability to diagnose and treat complications.1,2 Prevention of IE is, therefore, very important. Infective endocarditis usually develops following a bacteraemia in individuals with underlying structural cardiac defects. Bacteraemia may occur spontaneously, follow everyday procedures or complicate certain interventions, such as dental extraction.3,4 In developing countries, IE occurs most frequently in patients with rheumatic heart disease (RHD).1,2 The first step in the prevention of IE would be to reduce the pool of patients who are susceptible to this infection. This requires the effective implementation of programmes to prevent rheumatic fever and, therefore, RHD.5,6 Regrettably, this has not happened in developing countries.5 Furthermore, prophylaxis against IE has been neglected or seen as a separate issue.

The prevention of both IE and rheumatic fever recurrences should be viewed as part and parcel of the care of a patient with RHD in order to reduce unnecessary morbidity and mortality in patients with RHD in developing countries. RHD should be prioritised in developing countries and a greater emphasis needs to be placed on the simple and cost-effective measures that are currently available to combat RHD in the developing world.5-8 Many patients with RHD are unaware of the presence of their underlying heart disease and are, therefore, unable to request prophylaxis against IE.1,9,10 School-based screening programmes are beneficial in detecting undiagnosed RHD.1,7,9-12 It has been proposed that in developing countries, registered nurses be trained to detect children with cardiac abnormalities, refer them to doctors organising the screening programme for assessment, and thereafter maintain follow up of these patients.9 The nurses would be responsible for ensuring secondary prophylaxis against rheumatic fever and prophylaxis against IE. The doctor in such a nurse-orientated primary healthcare service would be responsible for the organisation, monitoring and continuity of such programmes.

Dodu and Bothig stated that in many countries, nurses are trained to recognise certain criteria such as heart murmurs for referral and have proved to be both reliable and efficient in identifying children who need medical examination.13 Schoolbased surveys could be made more effective if performed as part of a general-purpose health survey of school children. The ultimate aim should be to incorporate screening surveys into a routine school examination system conducted on a regular basis or to establish such services where they do not exist.

Such school-based surveys can only reach children who attend school. Children who do not attend school belong more

often to the poorer, crowded communities where the problem of rheumatic fever/rheumatic heart disease is of greater magnitude.

Ultimately, a strategy for the early detection of RHD in childhood that includes non-school goers will have to be developed.

Children identified with RHD or a history of rheumatic fever should be referred for secondary prophylaxis against rheumatic fever as well as prophylaxis against IE. In addition, adults with a history of rheumatic fever, RHD or cardiac valve surgery can be referred. One team could therefore be responsible for the prevention of both rheumatic fever/rheumatic heart disease and IE. Health education programmes should also be designed to motivate such patients and their families to accept secondary prophylaxis against rheumatic fever and prophylaxis against IE on a regular long-term basis and to enlist their co-operation for maintaining a high level of patient compliance.

Antibiotic prophylaxis against IE has been accepted in most countries for many years,14-17 even though no prospective studies have proven their effectiveness.16-20 Antimicrobial prophylaxis has been recommended prior to dental extraction in order to prevent post-extraction bacteraemia and the subsequent development of IE. In the study of amoxicillin, clindamycin or chlorhexidine administered prior to dental extraction, none of the treatments eliminated post-extraction bactraemia.17 The article by Durack, which evaluated some of the drugs used for prophylaxis prior to dental extraction, confirmed that antimicrobials do not prevent post-extraction bacteraemia.18 Recent guidelines have introduced major changes to recommendations for the use of prophylactic antibiotics.

The working party of the British Society for Antimicrobial Chemotherapy (BSAC) stated that despite the lack of evidence for prophylactic antibiotics to prevent IE associated with dental procedures, they considered that many clinicians would be reluctant to accept the radical but logical step of withholding antibiotic prophylaxis for dental procedures.21 They therefore compromised and recommended prophylaxis for only those patients in whom the risk of developing IE is high and, if infected, would carry a particularly high mortality rate.

The new American Heart Association (AHA) guidelines22,23 are similar to the BSAC guidelines for dental procedures, but differ in that they do not recommend prophylaxis before gastrointestinal or genitourinary procedures. Neither of these guidelines included RHD as one of the cardiac conditions for which prophylaxis is recommended. The National Institute for Clinical Excellence (NICE) does not recommend antibiotic prophylaxis for patients undergoing dental, gastrointestinal or genitourinary procedures.20 The National Essential Drug List Committee prepares and

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

revises standard treatment guidelines for the public sector in South Africa. The Adult Expert Review Group for the hospital level reviewed the literature, including the above guidelines, and acknowledged that clinicians would be concerned with both the exclusion of RHD from the list of cardiac conditions that required prophylaxis and with not giving an antibiotic prior to dental extraction. The Review Group recommended the use of antibiotics prior to certain dental procedures and included acquired valvular heart disease with stenosis or regurgitation as a cardiac condition that requires prophylaxis. Further debate culminating in a concensus position on antibiotic prophyaxis in developing countries is needed.

It should be noted, however, that antibiotic prophylaxis no longer occupies centre stage in the prevention of IE. The BSAC has endorsed the NICE guidelines.24 The emphasis for IE causation has shifted from procedure-related bacteraemia to cumulative bacteraemia, i.e. infective endocarditis is more likely to result from frequent exposure to random bacteraemias associated with daily activities such as tooth brushing than with a dental procedure.3,4,18,20-23 Poor oral hygiene may increase the risk of bacteraemia associated with these everyday procedures.22,25 A number of authors have stressed good oral health as a far more important preventative measure than chemoprophylaxis against IE.3,26-30 The BSAC stated that good oral hygiene is probably the most important factor in reducing the risk of IE in susceptible individuals, and access to high-quality dental care should be facilitated.21 The AHA has stated that the maintenance of optimal oral health and hygiene may reduce the incidence of bacteraemia from daily activities, and it is more important than prophylactic antibiotics for dental procedures to reduce the risk of IE.23 NICE has also placed emphasis on the importance of this aspect of prophylaxis.20 Improving oral hygiene and reducing or eliminating gingivitis would reduce the incidence of bacteraemia following tooth brushing and the need to extract teeth due to periodontal disease and caries.25 The accompanying study on the oral health status of patients with severe RHD who were awaiting cardiac surgery revealed that inadequate attention is being paid to the maintenance of good oral health in these patients (page 336). It is very likely that within the healthcare systems of developing countries, the oral health of patients with less-severe RHD who are not attending specialist cardiac facilities is also suboptimal. Also knowledge regarding the need and measures for prevention of IE among patients is insufficient.31-35 Care of the oral health of patients at risk of developing IE needs to be improved. Greater awareness of this problem among cardiologists, cardiothoracic surgeons, physicians, paediatricians, medical practitioners and dental surgeons is needed. The results of the study by Bobhate and Pinto indicate that the majority of oral lesions could have been prevented if patients had been informed of the vital importance of preventative dentistry.36 Therefore, advice on regular oral care and the maintenance of oral health must be given to all patients at risk of developing IE and their parents (in the case of children).36 Furthermore, patients and parents of children need to be given appropriate advice regarding antibiotic prophylaxis, including informing their dentist that they have heart disease that may require antibiotics, before dental procedures, particularly dental

AFRICA

extraction, can be done. Patients and parents of children with RHD also need advice on secondary prophylaxis of rheumatic fever.

At the time of diagnosis of a heart lesion that could predispose to IE, a full oral examination, including dental radiography, should be performed. Further examinations at frequent and regular intervals will ensure early diagnosis and treatment of oral lesions, and maintenance of good oral hygiene. It is advisable to issue patients with a warning card on which their cardiac condition, drug therapy, suggested prophylactic measures to be taken before dental manipulations, and name, address and telephone number of the attending doctor is recorded. A medical history should be obtained from every patient before institution of any dental treatment.

Co-operation between doctors and dental surgeons and their support staff, e.g. oral hygienists, would ensure that the oral health needs of every susceptible patient, including patient education, can be catered for more adequately. Supplies such as toothbrushes and toothpaste should be made available to these patients. Social support, including social grants, could assist patients in financial difficulty. The key to protection of susceptible patients is improved oral health education, effective preventative care, oral hygiene instruction and sensible treatment planning. An oral hygienist should form part of the team that cares for patients with RHD. A number of surveys have revealed that doctors and dentists are familiar with the concept of prophylaxis against IE, are aware of the published recommendations and believe them to be authoritative, yet prophylaxis is not used for many patients for whom it is indicated, and specific recommendations and regimens are not followed.37-40 The medical and dental curricula need to place appropriate emphasis on all aspects of prophylaxis, including patient education, maintenance of good oral health and antibiotic prophylaxis.

The prevention of IE has been neglected in the past and does not solely concern antibiotic prophylaxis.21 There should be a shift in emphasis away from antibiotic prophylaxis prior to dental procedure, towards a greater emphasis on improved access to dental care and oral heath in patients with predisposing cardiac conditions.22 The first step in the prevention of IE in developing countries would be to reduce the pool of patients who are susceptible to this infection through implementation of programmes to prevent rheumatic fever.

The second step would be the early identification of at-risk patients, and prompt referral to oral health specialists, e.g. oral hygienists, for comprehensive evaluation and treatment. The third step would be to educate these patients and the parents of children on the need for maintaining optimal oral health and about antibiotic prophylaxis for IE. The fourth step would be to integrate IE prophylaxis into rheumatic fever/rheumatic heart disease prevention programmes and provide more holistic care of patients with rheumatic heart disease.

Accordingly, a comprehensive prevention programme, which incorporates the secondary prevention of rheumatic fever and the prevention of IE, is urgently needed in developing countries.

Optimal oral healthcare, in conjunction with the judicious use of antibiotic prophylaxis for prevention of IE, should serve to reduce the significant morbidity and mortality associated with this infection. It is hoped that the care of patients at risk of developing infective endocarditis will thus be improved.

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

BREMINAND MAHARAJ, MB ChB, FCP (SA), MD, PhD, FRCP (London), maharajb4@ukzn.ac.za Department of Therapeutics and Medicines Management, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa ANDREW PARRISH, MB ChB, DA (SA), FCP (SA), MMed (Med), MMed Sci (Clin Epi) Department of Internal Medicine, Walter Sisulu University, Umtata, South Africa Submitted 14/12/11, accepted 16/1/12 DOI: 10.5830/CVJA-2012-004

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Carapetis JR. Rheumatic heart disease in Asia. Circulation 2008; 118: 2748–2753.

Guntheroth WG. How important are dental procedures as a cause of infective endocarditis? Am J Cardiol 1984; 54: 797–801.

Roberts GJ. Dentists are innocent! “Everyday” bacteraemia is the real culprit: A review and assessment of the evidence that dental surgical procedures are a principle cause of bacterial endocarditis in children.

Pediatr Cardiol 1999; 20: 317–325.

Carapetis JR, Mayosi BM, Kaplan EL. Controlling rheumatic heart disease in developing countries. Cardiovasc J South Afr 2006; 17: 164–165.

Carapetis JR. Rheumatic heart disease in developing countries. N Engl J Med 2007; 357: 439–441.

Saxena A, Ramakrishnan S, Roy A, et al. Prevalence and outcome of subclinical rheumatic heart disease in India: The RHEUMATIC (Rhematic Heart Echo Utilisation and Monitoring Actuarial Trends in Indian Children) study. Heart doi:10. 1136/heartjnl-2011-300792.

Brink AJ, Aalbers J. Strategies for heart disease in sub-Saharan Africa.

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Maharaj B, Dyer RB, Leary WP, et al. Screening for rheumatic heart disease amongst black schoolchildren in Inanda, South Africa. J Trop Pediatr 1987; 33: 60–61 McLaren MJ, Hawkins DM, Koornhof HJ, et al. Epidemiology of rheumatic heart disease in black schoolchildren of Soweto, Johannesburg.

Br Med J 1975; 3: 474–478.

Longo-Mbenza B, Bayekula M, Ngiyulu R et al. Survey of rheumatic heart disease in school children of Kinshasa town. Int J Cardiol 1998; 63: 287–294.

Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007; 357: 470–476.

Dodu SRA, Bothig S. Rheumatic fever and rheumatic heart disease in developing countries. World Health Forum 1989; 10: 203–212.

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Simmons NA. Recommendations for endocarditis prophylaxis. J Antimicrob Chemother 1993; 31: 437–438.

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Maharaj B, CoovadiaA Y, Vayej AC. A comparative study of amoxicillin, clindamycin and chlorhexidine in the prevention of post-extraction bacteraemia. Cardiovasc J Afr 2012; 23: in press. DOI: 10.5830/CVJA2012-049.

Durack DT. Prevention of infective endocarditis. N Engl J Med 1995; 332: 38–44.

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19. Oliver R, Roberts GJ, Hooper L, Worthington HV. Antibiotics for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Syst Rev 2008; 4: CD003813.

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21. Gould FK, Elliott TSJ, Foweraker J, et al. Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2006; 57: 1035–1042.

22. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–1754.

23. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 Guideline update on valvular heart disease: focused update on infective endocarditis. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines.

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24. Watkin RW, Roberts GJ, Elliott TSJ on behalf of the BSAC Working Party on Infective Endocarditis. New guidance from NICE regarding antibiotic prophylaxis for infective endocarditis – response by the BSAC working party. J Antimicrob Chemother 2008; 62: 1477–1478.

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26. Wahl MJ. Myths of dental-induced endocarditis. Arch Intern Med 1994; 154: 137–144.

27. Montazem A. Antibiotic prophylaxis in dentistry. Mt Sinai J Med 1998; 65: 388–392.

28. Bayliss R, Clarke C, Oakley C, et al. The teeth and infective endocarditis. Br Heart J 1983; 50: 506–512.

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30. Barco CT. Prevention of infective endocarditis: a review of the medical and dental literature. J Periodontol 1991; 62: 510–523.

31. Thom AR, Howe GL. The dental status of cardiac patients. Br Heart J 1972; 34: 1302–1307.

32. Holbrook WP, Willey RF, Shaw TR. Dental health in patients susceptible to infective endocarditis. Br Med J 1981; 283: 371–372.

33. Smith AJ, Adams D. The dental status and attitudes of patients at risk from infective endocarditis. Br Dent J 1993; 174: 59–64.

34. Rai K, Supriya S, Hegde AM. Oral health status of children with congenital heart disease and the awareness, attitude and knowledge of their parents. J Clin Pediatr Dent 2009; 33: 315–318.

35. Balmer R, Booras G, Parsons J. The oral health of children considered very high risk for infective endocarditis. Int J Paediatr Dent 2010; 20: 173–178.

36. Bobhate P, Pinto J. Summary of the new guidelines for the prevention of infective endocarditis: implications for the developing countries. Ann Pediatr Cardiol 2008; 1: 56–58.

37. Gutschik E. Prevention of endocarditis in Nordic countries. Eur Heart J 1995; 16(Suppl B): 117–121.

38. Van der Meer JTM, van Wijk W, Thompson J, et al. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother 1992; 29: 187–194.

39. Murenha E, Stein CM. Chemoprophylaxis of bacterial endocarditis – a survey of current practice in Zimbabwe. J Antimicrob Chemother 1990; 25: 291–296.

40. Danchin N. The prophylaxis of infective endocarditis: current practices in France. Eur Heart J 1995; 16(Suppl B): 122–125.

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Editorial First annual congress of the Faculty of Consulting Physicians of South Africa, 18–20 May 2012 NAOMI RAPEPORT The specialist physician has always played a pivotal role in the healthcare of South Africans. Following specialisation, either through the College of Medicine or a Master’s of Medicine obtained from a university, many of these doctors have branched out into the private sector and continue to play a vital role in the management of patients.

The total number of specialist physicians registered with the Health Professions Council of South Africa (HPCSA) in both the public and private sector is fewer than 600 and these doctors provide specialist healthcare for a population of over 40 million people. Over the past four decades there has been a major ‘brain drain’ of academic and private physicians to North America, Australia and New Zealand and this resultant shortage of specialists places an enormous burden on those who have remained in South Africa.

Due to the burgeoning epidemic of HIV and AIDS in our country, patients with AIDS-associated conditions have swamped medical admission wards, placing a huge load on clinicians. The increase in prevalence of non-communicable diseases such as diabetes mellitus and coronary artery disease in our previously disadvantage populations has also contributed to an increased work load as our population undergoes epidemiological transition from famine and pestilence to degenerative and man-made disease. South Africa now has the distinction of having one of the most obese populations in the world.

All private-practice doctors are required to be registered with the HPCSA as well as the Board of Healthcare Funders (BHF), who are responsible for issuing MP and private practice numbers, respectively. The latter is known as the practice code numbering system (PCNS). The HPCSA, a statutory body, established in terms of the Health Professions Act No. 56, is committed to serving and protecting the public. It regulates the health profession in aspects pertaining to registration, education and training, professional conduct and ethical behaviour, continuing professional development, and fostering compliance with healthcare standards. Neither of these organisations is involved in, or has the interests of the private practitioner at heart. This is the role of the various professional associations.

Previously, as far as consulting physicians were concerned, matters relating to cost coding for medical services, procedures and the introduction of new codes were the responsibility of the private practice committee of the South African Medical Association (SAMA) and in particular the Association of Physicians. Due to the political milieu of South Africa prior to the abolition of apartheid, the Medical Association did not represent the interest of most of our fellow colleagues and in particular, the Association of Physicians did not have any active

membership. It consisted of a lone physician who did all the coding work.

In 1997, a group of concerned specialist physicians in Johannesburg, under the leadership of Dr Naomi Rapeport, established the Faculty of Consulting Physicians of South Africa (FCPSA) to try and unite all specialist physicians in private practice into one professional group. No accurate data were available from the HPCSA, SAMA or BHF as to how many physicians were practicing in South Africa. Through networking with colleagues in all the different provinces, a nucleus of physicians was established. The work of coding, and interaction with SAMA, BHF and HPCSA was undertaken by the Faculty, who took over the role of the defunct Association of Physicians.

Countless hours were expended on the workings of the organisation. Annual academic meetings were held from 1998 to 2002 in the major centres, and regular updates were sent to members. Although there was a constant drive to encourage doctors to join the Faculty, it was a persistent uphill battle.

To date, many doctors in private practice have no idea what an essential role the organisation plays in terms of their daily practice management.

In 2004, Dr Adri Kok took over the leadership of the organisation from Dr Rapeport. The faculty has expanded to include dermatologists, rheumatologists, pulmonologists, neurologists and nephrologists in private practice, and consulting physicians in the public sector who do limited private practice.

Through tireless ongoing effort, Dr Kok has continued to head and run the organisation.

Due to major changes in the private practice arena, ranging from the introduction of prescribed minimum benefits (PMB), formation of the Council of Medical Schemes (CMS), the ruling of the Compensation Commissioner on the so-called collusion of doctors’ fees, and conflict between the Department of Health and SAMA regarding ownership of coding, the Faculty has continued to play a vital role. The organisation, together with many of the other medical and surgical disciplines, have left SAMA and now operate under the umbrella of the South African Private Practitioners Forum (SAPPF) and continue to represent the private practice specialist.

This umbrella group together with private hospital groupings was awarded costs in a court case against the Department of Health regarding ownership of coding in 2010. The case was to challenge the validity of the reference price list (RPL) in its present form. Despite numerous meetings with assigned colleagues of the Department of Health to resolve this issue, it ended in a stalemate.

The RPL is a list of fees for medical professionals based on

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service and procedure codes, as detailed in the SAMA Doctors’ Guide to Billing. The Department of Health tried to take over ownership of the RPL without having any experience of the workings of the coding system. They did not take into account issues such as the practice costs incurred by doctors (many practices have huge practice overheads), which was validated by a practice cost study submission undertaken by the professional groupings.

Medical schemes also choose their rates of reimbursement on a basis that they consider to be reasonable, based on the RPL. It directly affects the amount which privately insured patients will be able to recoup from their medical schemes for the cost of health services. New codes are introduced as clinical practice expands and changes.

The SAPPF with SAMA members have assessed approximately 600 codes for validation. The hope of the future is the compilation of a new South African procedure coding structure which will accurately describe consultations and procedures. Fees charged by service providers are governed by the Health Professions Act of 1974. However there is also the issue of the Competition Act of 1998, which enforces anti-competitive behaviour by the profession, and this states that doctors may not conduct unfair, collusive and undesirable business practices by all charging the same fees.

The organisation has been involved in designing updated algorithms for PMB conditions. This is the minimum set

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of healthcare benefits to which all patients contributing to medical schemes are entitled. Meetings with the CMS have been held and evidence-based medicine outcomes shown to motivate appropriate revisions of the PMB algorithms. As practicing clinicians, best practice is encouraged and doctors from the different groups have been involved in updating clinical guidelines. This includes the lipid and diabetes guidelines, to name a few. The organisation has been involved in reviewing the green paper of the National Health Insurance. It also has joined the International Society of Internal Medicine, which was originally established in 2004, and is one of three country members from Africa.

The first annual congress of the FCPSA was held in Cape Town recently. It was very well received by all attending colleagues and the calibre of lectures was excellent. Local speakers from the private sector and academic institutions, as well as international speakers covered a wide range of subjects pertinent to practicing physicians. A number of training medical registrars from different universities were sponsored to attend the meeting and they were surprised by the extremely high academic standard.

NAOMI RAPEPORT, MB BCh (Wits), FCP (SA), FACP, FACP (Hon), cscham@global.co.za Milpark Hospital, Johannesburg, South Africa

DAKAR

HEALTHCARE

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

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

HEALTHCARE

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Cardiovascular Topics Prevalence of cardiovascular risk factors in an urban area of Togo: a WHO STEPS-wise approach in Lome, Togo S BARAGOU, M DJIBRIL, B ATTA, F DAMOROU, M PIO, A BALOGOU

Abstract Objective: To determine the prevalence of hypertension and other cardiovascular risk factors in the general adult population of Lome.

Methods: A cross-sectional household survey was conducted in Lome from October 2009 to January 2010, which focused on hypertension and other cardiovascular risk factors in 2 000 subjects 18 years and older. The World Health Organisation’s STEPS-wise approach on non-communicable diseases was used. During the first session, blood pressure (BP) was measured on three successive occasions, one minute apart, and the mean was recorded. A second measurement session was done three weeks later in patients with BP ≥ 140/90 mmHg during the first session. Hypertension was defined as BP > 140/90 mmHg after the second session, or on antihypertensive treatment. The other risk factors were studied by clinical and blood analysis.

Results: We found 532 hypertensive patients out of a total of 2 000 subjects. The prevalence of hypertension was 26.6%.

The mean age of hypertensive patients was 45 ± 10 years, ranging from 18 to 98 years. The prevalence of other cardiovascular risk factors was: stress (43%), sedentary lifestyle (41%), hypercholesterolaemia (26%), obesity (25.2%), hypertriglyceridaemia (21%), smoking (9.3%), alcohol use (11%) and diabetes (7.3%).

Conclusions: The prevalence of hypertension and other cardiovascular risk factors in the population of Lome is high.

These findings should draw the attention of authorities to define a national policy to combat hypertension and other cardiovascular risk factors.

Keywords: hypertension, risk factors, epidemiology, Togo, subSaharan Africa Submitted 25/5/11, accepted 22/11/11 Cardiovasc J Afr 2012; 23: 309–312

www.cvja.co.za

DOI: 10.5830/CVJA-2011-071

The whole of sub-Saharan Africa and Togo in particular, have for some years seen an epidemiological transition, obligating Department of Cardiology, University of Lome, Lome, Togo S BARAGOU, MD, rbaragou@yahoo.fr M DJIBRIL, PhD B ATTA, MD F DAMOROU, MD M PIO PhD A BALOGOU, MD

people to face infectious transmissible diseases as well as non-transmissible ones, and particularly cardiovascular diseases.

This epidemiological transition is largely associated with urbanisation and the change in lifestyle.1-5

In Togo, the prevalence of hypertension in hospital cardiology departments is 52%,6 but it is unknown in the general population. Cardiovascular diseases are the second cause of death in Togo after malaria.6 Knowledge of epidemiological data on cardiovascular risk factors is fundamental in order to define a national policy and combat cardiovascular diseases. The purpose of this study was therefore to determine the prevalence of hypertension and other cardiovascular risk factors in the general population of the urban area of Togo.

Methods A cross-sectional, prospective, community-based study was conducted in the town of Lome, which is subdivided into five districts and has approximately 1 056 200 inhabitants.7 Lome, the capital of Togo, is cosmopolitan and largely commercial, with an inter-tropical climate and varied socio-economic layers.

It is located in southern Togo on the coast of the Atlantic Ocean.

The population of subjects aged 18 years and over was estimated at 497 098 at the time of the study.7 This work was conducted from 1 October 2009 to 31 January 2010 using the STEPS-wise WHO method on the monitoring of risk factors of non-communicable diseases.8 The General Director of Health and local administrative authorities in the town of Lome were informed of the period and the course of the investigation, and had issued their written authorisation. Fifteen investigators (10 medical assistants and five nurses), divided into five groups, were selected and trained. Supervision was provided by three physicians, including two cardiologists.

Calculation of sample size was done using the formula: n = ∑² × P × Q/I ² where ∑ = standard deviation = 4, P = estimated prevalence of hypertension in Togo (20%), Q = 1–P = 0,8; I = precision index = 0.05. The final sample size was 2 000 subjects.

The sampling technique was random; 30 clusters were selected and 1 000 households were surveyed (34 households per cluster). In each household, one individual was recruited by gender, for a total of 68 individuals per cluster. Only subjects aged 18 years and over were examined. The investigators were careful to explain the purpose, importance and conduct of the study to participants. Verbal consent from each selected individual was acquired.

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A preliminary investigation was done using the WHO questionnaire, adapted to the local situation.9 Each subject was first rested for 10 minutes and then questioned on the presence of diabetes, smoking and use of alcohol, sedentary or active lifestyle, stress and eating habits. Participants were also asked about the use of antihypertensive medication and those who were already on antihypertensive therapy were required to produce the drugs used.

Blood pressure (BP), weight and height were then measured, and the body mass index was calculated (kg/m2). BP was measured in both arms with a validated electronic BP monitor (Omron Inc), recommended for STEPS-wise surveys by the WHO.8 Three successive measurements were taken, one minute apart, and the mean was calculated. Any missing subjects were seen during a second visit.

A second measurement session was performed three weeks later in patients with BP ≥ 140/90 mmHg during the first session.

Hypertension was defined as BP > 140/90 mmHg after the second measurement session,10 or on antihypertensive treatment, no matter what the blood pressure values were.

The other cardiovascular risk factors studied were obesity, alcohol use, smoking, stress, sedentary lifestyle and biological factors (diabetes, hypercholesterolaemia, hypertriglyceridaemia).

Obesity was defined by a body mass index ≥ 30 kg/m2. Smoking was defined by a consumption of at least one cigarette daily, alcohol use by regular consumption of alcohol no matter the quantity, sedentary by lack of physical activity or less than 30 minutes of sport activity at least three times a week. Stress was evaluated with the rapid evaluation of Cunci11 and was defined as a score ≥ 30.

Blood analysis was done to determine glycaemia, total cholesterol and triglyceride levels. Some subjects refused blood sampling, and laboratory tests were therefore conducted only on those who accepted sampling, and no other selection criteria were used. In total, blood analyses were done for 1 012 (520 men and 492 women) of the 2 000 individuals involved in the study.

The blood samples were analysed at the University Hospital of Lome, and a maximum of two hours between sampling and arrival of the samples at the laboratory was allowed.

Diabetes was defined as fasting glycaemia > 7 mmol/l TABLE 1. CHARACTERISTICS OF THE STUDY POPULATION Age (years) 18–30 31–45 46–60 61–75 76–90 91–105 Overall

Male, n (%) 350 (38.9) 212 (23.6) 154 (17.1) 133 (14.8) 32 (3.5) 17 (1.9) 898 (100)

Female, n (%) 461 (42) 268 (24.3) 183 (16.6) 157 (14.2) 24 (2.2) 9 (0.8) 1102 (100)

Overall, n (%) 811 (40.5) 480 (24.1) 337 (16.8) 290 (14.5) 56 (2.8) 26 (1.3) 2000 (100)

TABLE 2. PREVALENCE OF HYPERTENSION (%)

BY GENDER AND AGE Age groups (years) Gender 18–30 31–45 46–60 61–75 76–90 91–105 Female 8 10.7 23 52.5 88.6 100 Male 9 17.3 28.4 51 75 88

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(1.26 g/l) after two measures two weeks apart or > 11 mmol/l (2 g/l) during the first measure. Total hypercholesterolaemia was defined as cholesterolaemia > 5.16 mmol/l (2 g/l), and hypertriglyceridaemia as > 1.71 mmol/l (1.5 g/l).

Statistical analysis Confidence intervals (95% CI) and the chi-square (χ2) test were used to compare the prevalence of hypertension and other risk factors, with a significance set at p < 0.05. Epi Info 6.04 was used to record and analyse the data. Quantitative variables were reported as mean ± standard deviation and qualitative variables as percentages.

Results The total number of subjects included in the study was 2 000 (898 men and 1 102 women), with an overall mean age of 39 ± 10 years (40 ± 12 years for men, 38 ± 11 years for women), ranging from 18 to 98 years (Table 1). Forty-eight per cent of subjects had no school education, 28.5% had a primary level of education, 18.2% had secondary-level education, and 5.3% were university educated. According to diet, all respondents admitted to consuming fatty and processed foods, but not much vegetables and fruits.

We identified 532 hypertensive individuals (243 men and 289 women). The prevalence of hypertension was 26.6% (25.7% in men and 27.6% in women, p = 0.09). Of the 532 hypertensive patients, 174 subjects (32.7%) were on antihypertensive treatment. Sixty-one per cent of hypertensive patients were classified as stage I, and 39% were classified as stage II, according to the JNCVII classification.10 The prevalence of hypertension increased with age (p < 0.001) (Table 2). The overall mean age of hypertensive individuals was 45 ± 10.4 years, with 45 ± 10.4 years for men and 46 ± 11.4 years for women. The mean systolic (SBP) and diastolic (DBP) blood pressure was 129.6 and 84.3 mmHg, respectively (Table 3).

Pre-hypertension, as defined by the JNCVII,10 was detected in 641 subjects (32%). The prevalence of other cardiovascular risk factors were stress (43%), sedentary lifestyle (41%), hypercholesterolaemia (26%), obesity (25.2%), hypertriglyceridaemia (21%), active smoking (9.3%), alcohol use (11%) and diabetes (7.3%) (Table 4).

Regarding professional groups, hypertension was observed among the unemployed (43%), civil servants (42.4%), housewives (54.2%), private-sector workers (23.8%), pensioners (56.2%)

TABLE 3. MEAN ARTERIAL BLOOD PRESSURE

BY AGE GROUP Age (years) Number SBP (mmHg) DBP (mmHg) 18–30 811 121.7 ± 3.1 78.6 ± 2.4 31–45 337 127.7 ± 3.4 84.2 ± 2.5 46–60 480 136.1 ± 3.7 90.1 ± 3.4 61–75 290 147.2 ± 4.6 92.3 ± 3.8 76–90 56 150 ± 4.4 94 ± 3.4 91–105 26 152 ± 5.7 100 ± 4.8 Overall 2000 129.6 ± 3.5 84.3 ± 3.4 SBP = systolic blood pressure; DBP = diastolic blood pressure; mean ± standard deviation

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TABLE 4. OTHER CARDIOVASCULAR RISK FACTORS, ACCORDING TO GENDER Male Female Overall n (%) n (%) n (%) Obesity* 150 (16.7) 354 (32.2) 504 (25.2) Smoking 182 (20.2) 40 (3) 186 (9.3) Sedentary lifestyle 192 (21.4) 628 (57) 820 (41) Stress 420 (46.7) 440 (39.9) 860 (43) Hypercholesterolaemia 114 (22) 149 (30.3) 263 (26) Hypertriglyceridaemia 114 (21.9) 98 (19.9) 212 (21) Alcohol use 165 (18.3) 55 (5) 220 (11) Diabetes 36 (6.9) 38 (7.7) 74 (7.3) *Android obesity: 18%; *gynoid obesity: 7.2% Sixty per cent of subjects had two or more risk factors.

and farmers (6.3%). Forty-three per cent of hypertensive subjects had no education, 27.5% had a primary level of education, 18% had a secondary level of education, and 7.2% were university educated.

Discussion This research was done using the STEPS-wise approach of the WHO with regard to risk factors for non-communicable diseases at the population level.8 The sample was representative. This standard method of the WHO served as the official barometer in our particular context by which we collected comparable data and conducted reproducible surveys.

The main objective was to assess the current prevalence of hypertension and other cardiovascular risk factors in Lome, in order to assess the impact of individual preventive strategies in certain populations. The prospect of an investigation on a larger scale could determine the national prevalence of hypertension.

The average level of SBP of our respondents, 128.6 mmHg, was comparable to that reported in Morocco,12 at 129.8 mmHg. However, it was below the upper limit of 145 mmHg observed in Ouagadougou.5 The mean DBP was 84.6 mmHg in our study.

The authors cited above5,12 found the respective values of 76 and 78 ± 12 mmHg in their studies.

SBP and the prevalence of hypertension increased with age, peaking at around 50 years.1-5 This was in agreement with what several other authors observed1-5,9 on the prevalence of hypertension in male participants. It should be noted that a slight female predominance of hypertension was inconsistently found in some African series: 21% of women versus 18.7% of men in rural Senegal,13 and 33% of women and 31% of men in Egypt.14 The overall prevalence of hypertension was 26.6% in Lome, explained partly by the new definition of hypertension used in this study, the urban area of residence of our respondents and their lifestyle, including their eating habits. Our result was lower than the overall prevalence of 32.9 and 33.6%, respectively, observed in urban areas at Ashanti in Ghana1 and in Morocco.12 However, the Eritrean investigation15 reported a prevalence of hypertension of 16.5%, reflecting the profile of these populations. These authors all used the current definition of hypertension.

Professional concerns, such as conditions of work and family life could explain the high prevalence of hypertension that we found among the unemployed, civil servants and housewives.

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In Zaire, Malu et al.16 reported a prevalence of hypertension of 35.5% among employees and 45.4% among housewives. At the autonomous port of Abidjan, 54.5% of hypertensive workers said they were stressed while they executed their duties.17 Educational level, according to Bertrand et al.18 was inversely associated with the occurrence of hypertension. In our respondents, 43% with no education were hypertensive, and 27.5% had a primary-level education. Literacy levels of hypertensive individuals, especially in Africa, represents a real challenge. It is imperative to lay particular emphasis on education and the change of lifestyle in pre-hypertensive subjects. It is also important to inform new patients with hypertension, even those who are asymptomatic, of the need for lifelong treatment.

Other cardiovascular risk factors were also present, namely stress, a sedentary lifestyle, dyslipidaemia, obesity and active smoking. These risk factors are modifiable, and a change of lifestyle is imperative. People need to change their eating habits by avoiding fatty foods and eating more vegetables and fruit.

These other risk factors, once detected, help prevent the occurrence of complications related to hypertension, and atherosclerosis. This could prevent the development from pre-hypertensive to hypertensive status. It should therefore be emphasised that the most important part of prevention, with little cost for state and communities, is based on the primary level.

This involves educating people about the practices of a healthy lifestyle.

Conclusion The prevalence of hypertension and other cardiovascular risk factors in the general population is currently high in Lome.

The situation is probably similar in other urban and suburban areas of Togo. These findings should draw the attention of the authorities to define a national policy to combat the development of hypertension and other cardiovascular risk factors. It is imperative to establish a national surveillance system for hypertension and other risk factors for atherosclerosis.

We thank the Ministry of Health of Togo for its administrative and material support, the Physicians’ Association ‘People-Togo’ for their material support, and the supervising physicians and investigators who helped obtain the data.

We also thank Joan Minguet and Sophie Domingues-Montanari at Koonec (www.koonec.com) for the excellent scientific translation.

References 1.

2.

3.

4.

5.

6.

Cappucio FP, Micah FB, Emmert L, et al. Prevalence, detection, management and control of hypertension Ashanti, West Africa.

Hypertension 2004; 43: 1017–1022.

Van der Sande MA. Cardiovascular disease in sub-Saharan Africa: a disaster waiting to happen. Neth J Med 2003; 61: 32–36.

Addo J, Amoah AG, Koram KA. The changing patterns of hypertension in Ghana: a study of four rural communities in the Ga District. Dis Ethnol 2006; 16: 894–899.

Addo J, Smeeth L, Leon DA. Hypertension in sub-Saharan Africa: a systematic review. Hypertension 2007; 50: 1012–1018 Niakara A, Fournet F, Gary J, Harang M, Nebie L, Salem G. Hypertension, urbanization, social and spatial disparities: a crosssectional population-based survey in West African urban environment (Ouagadougou, Burkina Faso) Transactions of the Royal Society of Tropical Med Hygiene 2007; 101: 1136–1142.

Baragou S, Yogui MY, Soussou B. Aspects épidémiologiques des pathologies cardiovasculaires en milieu hospitalier à Lomé. J Rech Sc Lomé (Togo) 2005; 7: 312–315

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Authors? Recensement Général de la Population et de l’Habitat (RGPH) 1984. Analyse des résultats définitifs. Lomé, 1992; 4: pages?.

Bonita R, De Courten M, Jamrozick K, et al. Surveillance of risk factors for non-communicable diseases: the WHO STEP-wise approach. Geneva: World Health Organization 2001.

Megnigbeto AC, Niakara A, Nebie LVA, et al. Validation of a method of blood pressure measurement for a study of hypertension in a black African population. Cahiers d’études recherches francophones/santé 2002; 12: 313–317.

Chobanian VA, Bakris LG, Black HR, Cushman WC, Green LA, Izzo JL, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. J Am Med Assoc 2003; 289: 2560–2725.

Cunci 1997??. Echelle brève d’évaluation du stress. Evaluation rapide du stress. http://www.champsy.org/index.htm. 21 Sept, 2009.

Tazi MA, Abir-Khalil S, Chouaki N, et al. Prevalence of the main cardiovascular risk factors in Morocco: result of a national survey, 2000. J Hypertens 2003; 21: 897–903.

Kane AM, Basa A, Diop AK, et al. Etude clinique des facteurs de risque

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15.

16.

17.

18.

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vasculaire chez l’adulte en milieu rural à Thiadiaye. Dakar médical 1997; 4: 77–82.

Ibrahim MM, et al. Hypertension prevalence, awareness treatment, and control in Egypt. Results from the Egyptian National Hypertension Program (BHP). NHP investigate team. Hypertension 1995; 25: 886–890.

Mufunda J, Mebrahtu G, Usman A, et al. The prevalence of hypertension and its relationship with obesity: results from a national blood pressure survey in Eritrea. J Human Hypertens 2005; 11: 4–10.

Malu K, Baka-Tubia M, Mongolo M. Quelques caractéristiques de l’hypertension, artérielle dans la région Sud-Est du Zaïre. Cardiologie Tropicale 1990; 16: 19–23.

Koffi NM, Sally SJ, Kouame P, Silue K, Diarra Nama AJ. Faciès de l’hypertension artérielle en milieu professionnel au port autonome d’Abidjan. Etude prospective à propos de 220 cas. Méd d’Afrique Noire 2001; 50: 40–46.

Bertrand E, Akinkugbe OO, Frances Y. Hypertension artérielle des populations originaires d’Afrique Noire. Editions Pradel, Paris?, 1995: pages?.

Letter to the Editor Hermansky–Pudlak/Chediak–Higashi syndromes The common denominator in both of these conditions is albinism. Hermansky–Pudlak syndrome affects the platelets and patients have a tendency to bleed.1 Chediak–Higashi syndrome affects the leukocytes, results in immune disorders and causes intracytoplasmic inclusions. These latter patients are prone to malignant lymphomas as the immune system is involved.

Hermansky–Pudlak symptoms occur due to defects in the melanosomes and the disease affects the lysosomal organelles in the cells, especially the platelet-dense granules. For this reason these patients have a haemorrhagic tendency.

Patients with Chediak–Higashi syndrome usually die at an early age. The disease also affects the lysosomal organelles.2 Chediak–Higashi syndrome is an autosomal recessive disorder, as is Hermansky–Pudlak syndrome.3 Subtypes of Hermansky–Pudlak disease exist. Chromosomes 3, 5 and 10 are involved. Hermansky–Pudlak is seen predominantly in Puerto Ricans but is also found in the Swiss Alps.

In Chediak–Higashi disease, eight known gene allele defects

are found, natural killer cells are deficient and the immune system is involved, predisposing patients to lymphomas. In both disorders hair, skin and eye colour are deficient, making albinism the common factor.3 It can therefore be concluded that both Hermansky–Pudlak and Chediak–Higashi syndromes affect the platelets and white cells, namely the haematological system.

Hilary Denis Solomons, MB BCh, MMed (Haem) Path (Wits) Johnnesburg, South Africa

References 1.

2.

3.

Fukai K, Oh J, Frenk E, et al. Linkage disequilibrium mapping of the gene for Hermansky–Pudlak syndrome to chromosome 10q23.3 Hum Mol Genet 1995; 4(9); 1665–1669.

Windhorst DB, Zelickson AS, Good RA. A human pigmentary dilution based on a heritable subcellular structural defect – the Chediak–Higashi syndrome. J Invest Dermatol 1968; 50(1); 9–18.

Oetting WS, et al. The clinical spectrum of albinism in humans. Mol Med Today 1996; 2(8); 330–335.

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Association between plasma homocysteine and myocardial SPECT abnormalities in patients referred for suspected myocardial ischaemia ALFRED ANKRAH, JOHN BUSCOMBE, MIKE MACHABA SATHEKGE

Abstract Background: Elevated plasma homocysteine level has emerged as a relatively newly recognised risk factor for coronary artery disease (CAD). However, reduction of plasma homocysteine levels in large prospective studies did not appear to reduce the risk for subsequent cardiac events. In this study, we investigated the association between plasma homocysteine levels and quantitative indices of myocardial perfusion SPECT imaging in patients referred for myocardial ischaemia.

Methods: Quantitative myocardial perfusion SPECT indices were obtained for 120 patients who were recruited for the study. All patients underwent a two-day rest–stress myocardial perfusion imaging. Plasma venous sampling was done on all patients after an overnight fast. Of the 120 participants (mean age 56 years, 53% males), 33% had elevated plasma homocysteine levels. The plasma homocysteine level was then compared to the results of imaging and other known risk factors.

Results: After adjustment for traditional risk factors of coronary artery disease, patients with elevated homocysteine levels had a significantly higher mean summed stress score (SSS) (11.3 vs 6.9, p = 0.02) than patients with a normal homocysteine level. This was true for both single- and multivessel disease. Also, patients with elevated homocysteine levels had a higher stress end-systolic volume (SESV) (137 vs 105 ml, p = 0.03) and lower post-stress left ventricular ejection fraction (SEF) (54 vs 64%, p = 0.02). The patients with elevated plasma homocysteine levels also had a significantly lower mean body mass index (BMI) (26.6 vs 30.6 kg/m2, p = 0.002). There was a significant relationship between the total number of known risk factors in a patient with CAD and the proportion of patients presenting with elevated plasma homocysteine levels (p = 0.03). Also, the extent of infarct, as measured by the summed rest score (SRS), was more closely correlated with an elevated homocysteine level than with the degree of ischaemia.

Conclusion: There was a correlation between plasma homocysteine level and the presence and extent of myocardial perfusion abnormalities in patients with established coronary artery disease, in particular those with multiple risk factors and multi-vessel infarction.

Department of Nuclear Medicine, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa ALFRED ANKRAH, MD JOHN BUSCOMBE, MB ChB, MD MIKE MACHABA SATHEKGE, MB ChB, MMed (Nucl Med), PhD, mike.sathekge@up.ac.za

Keywords: plasma homocysteine, coronary artery disease, myocardial SPECT indices, myocardial ischaemia Submitted 15/4/11, accepted 6/9/11 Cardiovasc J Afr 2012; 23: 313–317

www.cvja.co.za

DOI: 10.5830/CVJA-2011-048

In the past two decades, plasma homocysteine level has been extensively investigated and proposed as an independent cardiovascular disease risk factor.1 An elevated homocysteine level was first shown to be a risk factor for coronary artery disease (CAD) and later an independent risk factor for thromboembolism.2 Elevated homocysteine level has been linked in many studies to greater risk of adverse cardiovascular disease outcomes, which include myocardial infarction, stroke and cardiovascular mortality.3-7 However, clinical trials have not been able to demonstrate a reduction in clinical cardiovascular endpoints after therapeutic reduction of plasma homocysteine levels.8 This is in contrast to the outcome with other traditional risk factors of CAD, such as lowering plasma cholesterol levels. This is at variance with animal studies, which have shown that elevated homocysteine level is associated with increased cardiac dysfunction, and that lowering plasma homocysteine levels with folic acid may have a beneficial effect.9 The relationship between homocysteine level and myocardial dysfunction, and the potential therapeutic usefulness of lowering plasma homocysteine level is still being explored.

Myocardial perfusion SPECT is a validated imaging technique providing for both diagnosis and risk stratification of the possibility of future cardiac events.10 Validated automated algorithms provide semi-quantitative assessment of myocardial perfusion and left ventricular systolic function.11 In this study we aimed to assess the correlation between homocysteine level and myocardial SPECT abnormalities in 120 patients with suspected myocardial ischaemia.

Methods This prospective, open-label trial, approved by the ethics committee of the University of Pretoria, Faculty of Health Science, was designed to evaluate the association between homocysteine level and myocardial SPECT abnormalities. A total of 120 patients referred to our department with suspected myocardial ischaemia for myocardial perfusion imaging were recruited, after giving informed consent.

Information was obtained from each patient concerning any history of hypertension, diabetes mellitus, smoking and dyslipidaemia. Each patient’s weight and height were recorded. Exclusion criteria included pregnancy, use of vitamin supplementation (for more than five days a week in the previous three months), and renal insufficiency (defined as creatinine

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level > 20 mmol/l). Patients with an acute coronary syndrome of less than 48 hours and those unable to undertake a stress study because they were unfit were also excluded.

Measurement of homocysteine Prior to stressing, venous blood was obtained from the fasting patients and immediately sent to the laboratory where it was centrifuged and frozen. Total homocysteine level was determined by enzymatic assay and by Abbott florescence polarisation immunoassay. This method has been shown to correlate well with both gas chromatography–mass spectrometry and highperformance liquid chromatography (HPLC) methods.12 Elevated homocysteine level was defined as plasma level > 12 µmol/l. The homocysteine results were not known at the time of analysis of the myocardial perfusion scintigraphy.

Stress protocol All patients were imaged using the department’s standard two-day 99m Tc MIBI protocol. Patients were stressed physically on a bicycle ergometer or with pharmacological agents. Pharmacological stress was performed using an infusion of 0.14 mg/kg/min dipyridamole combined with four minutes of low-level exercise.

Dobutamine stress was used in patients who could not undergo exercise stress or dipyridamole pharmacological stress. At peak stress, 555 MBq 99mTc MIBI was administered, with a similar activity used for the resting imaging.

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Results Of the 120 patients enrolled in the study, 63 (53%) were male.

The mean and median age was 56 years (Table 1). Elevated plasma homocysteine levels (> 12 µmol/l) were present in 39 patients (33%). In addition, 38 (32%) patients had diabetes mellitus, 94 (78%) had a history of hypertension, 59 (49%) had dyslipidaemia and 20 (17%) had a significant history of smoking. The group studied was representative of the patient demographics of patients who are referred for suspected myocardial ischaemia at the Steve Biko Academic Hospital, Pretoria.

Using the criteria of gender and age to determine which patients were considered to be at higher risk for CAD, i.e. males older than 45 years and females older than 55 years, 88 (73%) patients were considered to be at higher risk for CAD. However, there was no effect of the patient’s age on normal or elevated homocysteine levels (Table 1).

The presence of any single individual risk factor did not have a good correlation with plasma homocysteine levels.

However the number of risk factors for CAD in an individual patient demonstrated a significant correlation with a raised homocysteine level (p = 0.038), such that when four risk factors were present, 61% of patients had an abnormal homocysteine level (Table 2).

Those patients with a raised homocystiene level had a significantly higher SSS and SESV compared to those with a normal homocytsiene level (Table 3). The SEF was also significantly lower in those patients with a raised homocysteine level.

Image acquisition and interpretation Tomographic images were acquired on a dual-headed gamma camera (Siemens ECAM, Erlangen, Germany). A low-energy, high-resolution collimator was used for acquisition with a 140-Kev photopeak and 15% window. A 180° non-circular (body contour) orbit was used.

Images were processed using E soft and 4 DM SPECT processing software (Siemens, Erlangen, Germany) for visual display and quantitative analysis. The summed stress score (SSS), summed rest score (SRS), stress end-systolic volume (SESV) and post-stress left ventricular ejection fraction (SEF) were obtained. The SSS and SRS were categorised into normal, mild, moderate and severe categories using the American College of Cardiology/American Society of Nuclear Cardiology (ACN/ ASNC) standard 17-segment model of the left ventricle, and their scoring model and criteria for classification of perfusion.13

Statistical analysis The data were collected into an excel worksheet and STATA 11 software (Microsoft, Redmond, USA) was used to find any univariate and multivariate correlation between the factors measured. Patients were also divided into two groups depending on whether homocysteine level was raised or not, and compared using a two-tailed paired Students t-test with a significance level of p < 0.05.

Non-parametric data between those with and without raised homocysteine levels were compared using a Chi-square test.

The plasma homocysteine level was also log transformed and correlated with the SSS and SRS and compared with different sub-groups derived from the collected data.

TABLE 1. DEMOGRAPHY AND RISK FACTORS FOR PATIENTS WITH A CORRELATION BETWEEN SUMMED STRESS SCORE (SSS) AND SUMMED REST SCORE (SRS) AND ELEVATED HOMOCYSTEINE LEVELS

Demography Male Female Age (years) 26–49 50–64 65–84 Racial origin Caucasian Coloured African

n 63 57

% 53 47

Correlation of log homocysteine levels and SSS SRS r p r p –0.028 ns 0.059 ns 0.029 ns –0.003 ns

30 60 30

25 50 25

0.004 0.279 –0.246

77 23 20

64 19 17

–0.02 0.308 –0.022

ns 0.03 ns

0.120 0.135 0.014

ns –0.022 ns 0.373 ns –0.082 Correlation of Patients with homocysteine levels and raised homocysteine SSS SRS n % r p r CAD risk factors Diabetes mellitus 38 32 0.055 ns 0.092 Hypertension 94 78 0.155 ns 0.119 Smoker 20 17 0.278 ns 0.073 Dyslipidaemia 59 50 0.120 ns 0.085 Age and gender 88 73 0.133 ns 0.097 Total 120 100 0.077 ns 0.096 CAD = coronary artery disease, r = correlation coefficient, p = significance, ns = not significant.

ns ns ns ns ns ns

p ns ns ns ns ns ns

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TABLE 2. NUMBER OF RISK FACTORS PER PATIENT SHOWING A SIGNIFICANT CORRELATION BETWEEN THE NUMBER OF RISK FACTORS PER PATIENT AND RAISED HOMOCYSTEINE LEVELS Number of risk Patients with the factors for CAD number of risk present in each factors in column 1 1 29 2 24 3 48 4 18 CAD = coronary artery disease, p = 0.028 (χ2).

Patients with raised homocysteine n % 5 14 8 33 17 35 11 61

When multivariate regression analysis was applied to all the variables, including risk factors for CAD and SPECT myocardial perfusion indices, only age emerged as a significant factor (Table 4). In addition, univariate analysis showed that patients with elevated homocysteine levels had a lower BMI (26.6 kg/m2) compared to those with normal homocysteine levels (30.6 kg/ m2) (p = 0.002).

When homocysteine levels were log transformed and the correlation was determined with the myocardial indices, no significant correlation was found for SSS, SRS, SESV and SEF over the whole population, and sub-group analysis found no correlation with various known risk factors (Table 4). We did note however, a significant correlation between homocysteine level and SSS in the patients between 50 and 64 years.

The extent of disease was important. A significant correlation was noted between the extent of disease measured by the number of involved coronary artery territories demonstrating infarct, as seen by the SRS evaluated from the myocardial perfusion scintigraphy, and the plasma homocysteine level, where the presence of disease in two or three coronary artery territories was significant (Table 5, Figs 1, 2). Such a correlation was not as strong when comparing the extent of ischaemia as seen by the SSS, with a raised homocysteine level, where there was only a significant correlation in single-vessel disease.

Discussion This study examined the relationship between plasma homocysteine levels and myocardial SPECT perfusion indices.

Previous investigators have reported a good correlation between scintigraphically detected ischaemia and plasma homocysteine levels in patients on haemodialysis.14 A further study demonstrated elevated homocysteine levels with reduced regional left ventricular ejection fraction in an asymptomatic group of young patients,1 while others found a high prevalence of patients with elevated homocysteine levels

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TABLE 4. MULTIVARIATE REGRESSION ANALYSIS FOR RISK FACTORS AND MYOCARDIAL PERFUSION INDICES AND PLASMA HOMOCYSTEINE LEVELS Factor Odds ratio SE Z p > [Z] Age 1.076 0.033 2.36 0.019 Diabetes mellitus 1.104 0.681 0.16 ns Hypertension 3.635 3.280 1.43 ns Dyslipidaemia 1.209 0.705 0.33 ns Smoker 3.525 2.771 1.52 ns SSS 1.002 0.036 0.05 ns SRS 1.140 0.085 1.75 ns SEF 0.969 0.029 –1.05 ns SESV 0.999 0.021 –0.06 ns SSS = summed stress score, SRS = summed rest score, SEF = post-stress left ventricular ejection fraction, SESV = stress end systolic volume, ns = not significant.

in patients with heart failure with preserved ejection fraction.15 This was similar to the figures we obtained where the presence of infarct seemed to have more influence on homocysteine levels than ischaemia.

Another study demonstrated the association of homocysteine with left ventricular dysfunction independent of the presence of CAD. The same study did not demonstrate a significant correlation with myocardial ischaemia.16 These results, together with the failure of homocysteine-lowering therapy to reduce cardiac events, show the relationship between raised homocysteine levels and myocardial damage remains poorly understood,17-19 although there is clearly a need to investigate this link.20,21 Myocardial SPECT imaging analysed with software such as 4D gives semi-quantitative indices for assessment of myocardial perfusion, in addition to its ability to assess left ventricular function22,23 and regional wall abnormalities.24 When we subdivided our study patients based on the number of affected coronary artery territories, we noted a significant positive but weak correlation between SSS and patients with dual- or triplevessel CAD, but a stronger link with the SRS, again suggesting infarct was more important than ischaemia. In addition to this finding, we also demonstrated a significant positive correlation between SRS and plasma homocysteine level in patients with single-vessel CAD. These findings suggest that higher homocysteine levels are associated with more severe and extensive infarct. This may help to explain why such patients with established, irreversible disease are unlikely to benefit from reduction in homocysteine levels alone. This is somewhat confirmed by the findings in our study that higher SESV and lower SEF were observed in

TABLE 3. MEAN MYOCARDIAL PERFUSION INDICES IN PATIENTS WITH ELEVATED AND NORMAL HOMOCYSTEINE LEVELS

TABLE 5. CORRELATION BETWEEN ELEVATED HOMOCYSTEINE AND THE SSS AND SRS IN PATIENTS WITH A GIVEN NUMBER OF DISEASED CORONARY ARTERY TERRITORIES, AS SEEN ON MPS

Index of Elevated Normal myocardial function homocysteine level homocysteine level p SSS 11.3 6.9 0.02 SRS 3.4 2.1 ns SEF (%) 54 64 0.02 SESV (ml) 137 105 0.03 SSS = summed stress score, SRS = summed rest score, SEF = post-stress left ventricular ejection fraction, SESV = stress end-systolic volume.

SSS SRS Number of abnormal coronary artery territories r p r p 0 –0.05 ns –0.1 ns 1 0.31 0.005 0.1 ns 2 –0.05 ns 0.18 0.049 3 0.15 ns 0.28 < 0.001 SSS = summed stress score, SRS = summed rest score, r = correlation co-efficient, p = significance level, ns = not significant.

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Fig. 1. Myocardial perfusion scintigraphy and ‘bullseye’ plots of a 48-year-old male with diabetes, hypertension, dyslipidaemia and significant smoking history. His plasma homocysteine level was normal (7 μmol/l). There was normal perfusion at stress and rest, and the left ventricular ejection fraction was normal (69%).

patients with elevated homocysteine levels compared to those with normal homocysteine levels. This again suggests that higher homocysteine levels are seen in patients with established and more extensive disease, often resulting in a dilated left ventricle and reduced left ventricular pump efficacy. This correlation between plasma homocysteine level and poorer left ventricular function has been noted in other studies.1 The lack of the statistical significance with multivariate regression analysis of other indices, except age, suggests that elevated plasma homocysteine level may well be an independent risk factor for the presence of CAD, as noted in earlier studies.25,26 We did however demonstrate a significant relationship between the number of risk factors for CAD present in a patient and the presence of elevated plasma homocysteine level.

Most of the patients involved in our study had relatively wellcontrolled diabetes, hypertension and dyslipidaemia. Despite good control in the study group for these risk factors, there was a higher percentage of patients with increased plasma homocysteine levels among those patients with higher numbers of risk factors for CAD (Table 2). This finding is consistent with several studies27,28 that show an association of diabetes, hypertension and smoking with plasma homocysteine levels.

This would suggest that despite the association of plasma homocysteine level with smoking, diabetes and hypertension, control of these risk factors does not necessarily result in reduced homocysteine levels. The treatment of underlying risk factors may therefore not provide any benefit to the added risk for CAD, due to the elevated plasma homocysteine levels. These facts may further explain the failure of homocysteine-lowering therapy to reduce cardiac events, as these treatments may be given too late and the raised homocysteine level is less a cause than a marker of established disease.

However, several mechanisms have been proposed for the adverse effects of homocysteine on the endothelium of blood vessels, including coronary arteries. These effects include: decreased bioavailability of nitric oxide, homocysteine-induced oxidative stress, and vascular smooth muscle proliferation,

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Fig. 2. Myocardial perfusion scintigraphy and ‘bullseye’ plots of a 49-year-old male with diabetes, hypertension and significant smoking history. His plasma homocysteine level was elevated (13 μmol/l). 99mTc MIBI imaging at stress and rest showed a significant persistent defect in the anterior wall, apex and inferior wall, with no concurrent ischaemia. The left ventricular ejection fraction was reduced (37%).

among others.27-30 Most of these mechanisms also underlie the mechanism by which other risk factors such as diabetes cause endothelial dysfunction.

It may also be postulated that homocysteine initiates the endothelial dysfunction that underlies the CAD, and that once initiated, it is self-propagating, again explaining the link between plasma homocysteine level and the degree of established heart disease, especially as seen with myocardial perfusion scintigraphy.29,31 This would confirm that lowering homocysteine levels at this late stage in the disease process would offer no benefit.

It has also recently been demonstrated using SPECT myocardial imaging that disease duration and type of therapy provide independent and incremental prognostic information for coronary artery disease in patients with diabetes.29,31 Patients with elevated homocysteine levels had significantly lower BMI with no significant correlation between homocysteine level and BMI. The lack of significant association was similar to the findings by some groups,32 although other groups found at least a weak correlation.33,34 The statistical significance (p > 0.038) for age in the multivariate regression analysis was also noted by previous investigators.31 This was probably due to the fact that modifiable risk factors for coronary artery disease, such as diabetes mellitus, hypertension and dyslipidaemia increase with age. Therefore, although age was a risk factor, it was not an independent risk factor for CAD. Finally, the prevalence of elevated homocysteine levels in our study population was similar to previous work done on the prevalence in angiographically proven patients with coronary artery disease in Pretoria, South Africa,35 showing there was no significant bias in the patient selection for this study.

A limitation to the study was the reliance on semi-automated analysis of the perfusion indices and LVEF without angiographic correlation. However the advantage of using such a method is the reduction in subjective influence by the operator.

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Conclusion There was a correlation between plasma homocysteine level and myocardial perfusion indices for patients with scintigraphically proven CAD but not in those patients without disease. We also confirmed that homocysteine level may be an independent risk factor for the presence of CAD, marking the extent of established disease and a higher number of known risk factors. These findings may help to explain why lowering high homocysteine levels is clinically ineffective.

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Zylberstein DE, Bengstsson C, Bjorkelund C, Landass S, Sundh V, Theille D, et al. Serum homocysteine in relation to mortality and morbidity from coronary artery disease: a 24-year follow up of the population study of the women in Gothenburg. Circulation 2004; 109: 601–606. de Bree , Vershuren VM, Blom HJ, Nadeau M, Trijbels FJ, Kromhout D. Coronary artery disease mortality, plasma homocysteine, and B vitamins: a prospective study. Atherosclerosis 2003; 166: 369–377.

Fallon UB, Ben-Shlomo Y, Elwood P, Ubbink JB, Smith DG. Homocysteine and coronary heart disease in the Caerpillay cohort: a 10-year follow up. Heart 2001; 85: 153–158.

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Rossi GP, Seccia TM, Pessina AC. Homocysteine, left ventricular dysfunction and coronary artery disease: is there a link? Clin Chem Lab Med 2007; 45: 1645–1651.

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Knollman D, Knebel I, Koch K-C, Gebhard M, Krohn T, Buell U, Schaeffer WM, et al. Comparison of SSS and SRS calculated from normal databases provided by QPS and 4D-MSPECT manufacturers and identical institutional normal. Eur J Nuc Med Mol Imaging 2008; 35; 311–318.

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17. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VD, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death: the vitamin Intervention for stroke prevention (VISP) randomized controlled trial. J Am Med Assoc 2004; 291: 565–575.

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Homocysteine lowering with folic acid and B vitamins in vascular disease. N Eng J Med 2006; 354: 1567–1577.

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20. Rosenberger D, Gargoum R, Tyagi N, Metreveli N, Sen U, Maldonado C, et al. Homocysteine enriched diet leads to prolonged QT interval and reduced left ventricular performance in telemetric monitored mice. Nutr Metab Cardivasc Dis 2011; 21: 492–498. DOI:10.1016/ jnumcd.2009.11.014.

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22. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, et al. Incremental value of prognostic testing in patients with known or suspected ischaemic heart disease: a basis for optimum utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1995; 26: 639–647.

23. Germano G, Kiat H, Kavanagh PB, Moriel M, Mazzanti M, Su HT, et al. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nuc Med 1995; 36: 2138–2147.

24. Germano G, Erel J, Lewin H, Kavangagh PB, Bermen DS. Automatic quantitation of regional myocardial wall motion and thickening from gated technetium-99m sestamibi myocardial single-photn emission computered tomography. J Nuc Med 1997; 30: 1360–1367.

25. Shai I, Stampfer MJ, Ma J, Manson JE, Hankinson SE, Cannuscio C, et al. Homocysteine as a risk factor for coronary artery disease and its association with inflammatory biomarkers, lipids and dietary factors.

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26. Soinio M, Marniemi J, Lakso M, Lehto S, Ronnemaa T. Elevated plasma homocysteine levels is an independent predictor of coronary artery events in patients with type 2 diabetes mellitus. Ann Intern Med 2004; 140: 94–100.

27. Sutten-Tyrrel K, Bostom A, Sehlub J, Zeigler-Johnson C. High homocysteine levels are independently related to Systolic hypertension in older adults. Circulation 1997; 96: 1745–1749.

28. Wijekoon EP, Brosnan ME, Brosnan JT. Homocysteine metabolism in diabetes. Biochem Soc Trans 2007; 35: 1175–1179.

29. Rodrigo T, Wallter P, Araya J, Orellana M, Rivera G. Homocysteine and essential hypertension. J Clin Pharmacol 2003; 43: 1299–1306.

30. Wald DS, Law M, Morris J. Serum homocysteine and the severity of coronary artery disease. Throm Res 2003; 111: 55–57.

31. Barmpouletos D, Starvens G, Ahlberg AW, Katten DM, O’Sullivan DM, Heller GV. Duration and type of therapy for diabetes: Impact on cardiac risk stratification with stress electrocardiographic-gated SPECT perfusion imaging. J Nuc Cardiol 2010; 17: 1041–1049.

32. Lin Y, Pao K, Yang W, Wu V, Chen Y, Lin Y, et al. Waist to hip ratio correlates with homocysteine levels in males with coronary artery disease. Clin Chem Lab Med 2008; 46: 125–130.

33. Jacques PF, Bostom AG, Wilson PWF, Rich S, Rosendurg IH, Selhub J. Determinants of total plasma homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73: 613–623.

34. Karatela Ra, Sainani GS. Plasma homocysteine, obese, overweight and normal weight hypertensives and non hypertensives. Indian Heart J. 2009; 61: 156–159.

35. Ubbink JB, Vermark WJ, Bennet JM, van Staden DA, Bissbort S. The prevalence of homocystenemia and hypercholesterolemia in angiographically defined coronary artery disease. J Mol Med 1991; 69: 527–534.

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A prospective review of acute coronary syndromes in an urban hospital in sub-Saharan Africa JAY SHAVADIA, GERALD YONGA, HARUN OTIENO

Abstract Objectives: To determine the epidemiology of acute coronary syndromes (ACS) in sub-Saharan Africa.

Methods: A prospective survey was carried out of all patients with a diagnosis of ACS who were admitted to the critical care unit of a tertiary teaching hospital over a 25-month period. Demographics, presentation, management and outcomes were subsequently recorded.

Results: A total of 111 (5.1% of all hospitalisations) patients were recruited, with 56% presenting with ST-elevation myocardial infarction (STEMI) and the rest non-ST-elevation myocardial infarction (NSTEMI) or unstable angina (UA). Chest pain was the most common presenting symptom, and up to one-third of all STEMI patients did not receive any form of reperfusion therapy, primarily due to late presentation. As in the developed world, diabetes, hypertension and cigarette smoking still account for the most common predisposing risk-factor profile, and the mortality associated with ACS is about six to 10% in our unit.

Conclusions: ACS, contrary to common belief, is increasingly more prevalent in sub-Saharan Africa, with similar risk profiles to that in the developed world. Late presentation to hospital is common and accounts for the increased mortality associated with this condition.

Keywords: acute coronary syndrome, clinical characteristics, sub-Saharan Africa Submitted 8/2/11, accepted 16/1/12 Cardiovasc J Afr 2012; 23: 318–321

www.cvja.co.za

DOI: 10.5830/CVJA-2012-002

Sub-Saharan Africa has traditionally been viewed as the home of communicable diseases, and coronary artery disease was thought to be an extremely rare occurrence. Evidence for this emerged about 50 years ago when Florentin et al.1 reported no myocardial infarctions in 182 consecutively performed autopsies among Ugandans. At about the same time, Shaper2 reported no coronary artery disease in 100 Samburu elders, based on a physical examination and electrocardiography. These were about the only tools available to make an ante-mortem diagnosis of ischaemic heart disease at the time.

Smaller studies from other parts of East and central Africa consistently reported a paucity of ischaemic heart disease with little evidence of the traditional risk factors of hypertension, hyperlipidaemia and obesity.3-6 No information regarding diabetes mellitus and smoking status has been reported in these groups.

Aga Khan University Hospital, Nairobi, Kenya

JAY SHAVADIA, MD, jay.shavadia@aku.edu GERALD YONGA, FACC, FESC HARUN OTIENO, FACC

The last few decades have witnessed considerable transition in epidemiology and with it came a change in the pattern of disease. Increasing urbanisation and changing lifestyle profiles have triggered an exponential rise in the frequency of the historically absent traditional coronary artery disease risk factors in black Africans.7-11 In addition to the unfinished agenda on communicable diseases, health planners in African countries are now being faced with a rising burden of non-communicable diseases.12 Cardiovascular disease, particularly coronary artery and cerebrovascular disease are on the rise, and will soon represent the bulk of the morbidity and mortality in this non-communicable medical disease bracket. We set out to define the demographics, presentation and outcomes of patients admitted with an acute coronary syndrome (ACS) at the Aga Khan University Hospital, Nairobi (AKUHN), a tertiary-care hospital running a cardiac catheterisation laboratory with a cardiac intervention programme in Nairobi, Kenya.

Methods A prospective survey was done of all consecutive patients with a diagnosis of ACS admitted to AKUHN between April 2008 and May 2010. All patients had their data regarding the study variables entered into the study questionnaire after giving informed consent. ACS was defined as patients admitted with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA).

STEMI was diagnosed if ST-segment elevation at the J point of ≥ 1 mm occurred in any location or a new left bundle branch block (LBBB) was found on the electrocardiogram (ECG) with biochemical evidence of myocyte necrosis.13 NSTEMI was diagnosed in patients with biochemical indication of myocyte necrosis without new ST-segment elevation or LBBB on ECG.13 Markers of myocyte necrosis utilised in our study included an elevated (exceeding the 99th percentile of a reference control group) serum troponin I and CK-MB level.13 Unstable angina was considered to be present in patients with ischaemic symptoms and no elevation in CK-MB or troponin levels, with or without ECG changes suggestive of ischaemia (e.g. ST-segment depression or new T-wave inversion).14 All patients with a confirmed diagnosis of ACS were prospectively recruited from either the intensive care or the high dependency units, where critically ill patients requiring continuous monitoring were admitted. Data were entered into a questionnaire within 24 hours of the patient’s hospitalisation. The questionnaire was subdivided into the following components: • Demographics: age (years), gender, height (cm) and weight (kg) were recorded and a body mass index (kg/m2) was subsequently computed.

• Clinical presentation: patients presenting with symptoms (chest pain, syncope, dyspnoea, cardiac arrest, other), systolic blood pressure (mmHg), heart rate (beats/minute), Killip class

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(I, II, III or IV) and time from symptom onset to hospital presentation (minutes).

• ECG and laboratory findings: predominant rhythm, ST-segment and T-wave changes were recorded according to the ECG site of myocardial involvement. Serum chemistries included biomarkers of myocyte necrosis (CK-MB, troponin I levels), fasting lipid profile including total cholesterol, highdensity lipoprotein, low-density lipoprotein, blood glucose (mmol/l) levels and calculated creatinine clearance (ml/min) at presentation using the Cockcroft-Gault formula.

• Risk factor assessment: a record of pre-existing type 2 diabetes mellitus, hypertension, cigarette smoking status, history of dyslipidaemia, family history of premature coronary artery disease, prior anginal episodes, myocardial infarction, percutaneous coronary interventions (PCI) or coronary artery bypass graft (CABG) operations and prior history of stroke/ cerebrovascular accident was obtained from the patients’ history and medical notes.

• Diagnosis and management: all patients were sub-grouped into two classes: STEMI and NSTEMI/UA, according to the ECG and serum biomarkers of myocyte necrosis. Management strategies were analysed in terms of reperfusion therapy and adjunctive therapies administered during hospitalisation.

–– acute reperfusion strategy and modality utilised (none, fibrinolysis, PCI) for the STEMI subgroup.

–– adjunctive therapy including the use of anti-thrombotic therapy, antiplatelet agents, beta-blockade, angiotensin receptor blockade and lipid-lowering agents.

All patients who underwent diagnostic coronary angiography alone or in addition to PCI had their angiographic findings and procedural details recorded.

• Outcomes: in-hospital outcomes were recorded according to the proportion of patients alive and complications (heart failure, major bleeding, post-myocardial infarction (MI) re-infarction and sudden death) at discharge.

TABLE 1. BASELINE CHARACTERISTICS OF PATIENTS PRESENTING WITH ACS STEMI NSTEMI/UA (n = 62) (n = 49) p Mean age (years) 63.3 ± 13.0 64.5 ± 15.2 NS Male gender (%) 80.6 69.4 NS 26.7 ± 3.9 27.3 ± 4.8 NS BMI (kg/m2) Chest pain as presenting symptom (%) 83.9 69.4 NS Mean time to presentation (hours after 12.9 ± 17.3 29.3 ± 52.8 0.02 symptom onset) Mean systolic BP at presentation 133 ± 35 139 ± 29 NS (mmHg) Mean heart rate at admission (bpm) 85 ± 22 82 ± 18 NS Killip class (%) I 88.7 89.8 II 11.3 4.1 III 0 6.1 IV 0 0 ECG rhythm at presentation (%) Sinus 91.9 93.9 Atrial fibrillation 3.2 4.1 Other 4.8 2.0 Random glucose at admission (mmol/l) 8.9 ± 5.0 6.9 ± 3.2 0.009 Creatinine clearance (ml/min) 68.3 ± 31.3 64.2 ± 31.3 NS bpm = beats per minute, NS = non-significant.

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Statistical analysis All patients were grouped into either STEMI or NSTEMI/UA and data were subsequently analysed using SPSS version 15.0.

All continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentages.

Statistical comparisons between subgroups were performed using the Chi-square test, the Fisher exact test for categorical variables, and the Student’s t-test for continuous variables, and regression analyses as appropriate, using SPSS.

Results A total of 2 156 mainly medical patients were admitted to the high dependency and intensive care units between April 2008 and May 2010, 111 (5.1%) of whom had a confirmed diagnosis of ACS. Fifty-six per cent (62) of the patients had a diagnosis of STEMI with the rest being NSTEMI/UA (44%). The baseline characteristics and risk-factor profiles of these groups are shown in Tables 1 and 2.

About 58% (36) of the STEMI patients and 72% (36) of the NSTEMI/UA patients had one or two of the risk factors described above, while 14% (nine) and 16% (eight) of the STEMI and NSTEMI/UA arms, respectively, had none of the above traditional risk factors at presentation. Over 85% (52) of the patients in the STEMI subgroup had a TIMI risk score between two and eight, while 69.4% (34) in the NSTEMI/UA subgroup had a score of two and three at admission. The site of myocardial involvement in patients with STEMI is shown in Fig. 1.

The current ACS management strategy for STEMI at AKUHN is prompt fibrinolysis within 30 minutes, and primary PCI whenever deemed logistically feasible within 90 minutes of arrival. Fifty-five per cent (34) of patients presenting with STEMI received fibrinolysis, with the majority receiving tenecteplase.

Thirteen per cent (eight) of the patients underwent primary PCI because they had an absolute contraindication to fibrinolysis.

Over 30% (20) of the patients did not receive any form of reperfusion, primarily due to late presentation at hospital.

TABLE 2. CARDIOVASCULAR RISK FACTOR PROFILE STEMI NSTEMI/UA (n = 62) (n = 49) p History of diabetes mellitus (%) 38.7 34.7 NS History of hypertension (%) 46.8 51.0 NS Current smoker (%) 24.2 22.4 NS Family history of CAD (%) 16.1 16.3 NS Dyslipidaemia (%) 9.7 20.4 NS Prior angina (%) 6.5 14.3 NS History of CABG (%) 1.6 0 NS Previous PCI (%) 3.2 2.0 NS Previous MI (%) 6.5 12.2 NS History of stroke (%) 0 4.1 NS Total cholesterol (mmol/l) 5.4 ± 1.4 5.5 ± 1.6 NS LDL-C (mmol/l) 3.3 ± 1.0 3.0 ± 1.2 NS HDL-C (mmol/l) 1.1 ± 0.5 0.9 ± 0.2 0.018 CAD = coronary artery disease, PCI = percutaneous coronary interventions, CABG = coronary artery bypass graft, MI = myocardial infarct, LDL-C = low-density lipoprotein cholesterol, HDL-C = high-density lipoprotein cholesterol.

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The mean door-to-needle time in our study was 47 ± 48 minutes while the mean door-to-balloon time was 84 ± 67 minutes. Patients with STEMI had an average hospital stay of 5.2 ± 3.9 days while patients with NSTEMI were in hospital for an average of 4.7 ± 2.8 days (p = 0.54).

Just under half (48%) of the STEMI subgroup, and 49% of the NSTEMI/UA subgroup underwent coronary angiography, with the following findings: in the STEMI group, the left anterior descending artery was the culprit vessel in 40% of the patients, and 33% had the right coronary and 7% the left circumflex arteries as the culprit arteries, respectively. Twenty per cent (six) of the patients who had coronary angiography in the STEMI subgroup had multi-vessel disease. These patients were maintained on optimal medical therapy, and none underwent multi-vessel PCI at the time of their STEMI presentation.

As anticipated, over half (56%) the patients in the NSTEMI/ UA subgroup had angiographically double- or triple-vessel disease. Of this subgroup, 29% (14) were deemed appropriate, and referred for surgical revascularisation, since this service was not being offered at our institution. Data on the surgical outcomes of these patients were not available, as a majority were referred to overseas centres for surgery. An additional 12% (six) underwent staged PCI. Data on the revascularisation strategy for the remainder of the NSTEMI/UA subgroup were unknown.

Ninety per cent (56) of the STEMI patients were alive at discharge, compared to 94% (46) of the NSTEMI/UA patients.

Of all the patients in the study, 10% (11) developed clinical heart failure, 1.8% (two) major bleeding (according to TIMI 7, 8 11B criteria)15 and 1.8% (two) had other complications. One of the patients in the major bleed subgroup had intracranial haemorrhage and was discharged with severe disability (modified Rankin scale 5). None of the study patients developed post MI re-infarction.

Discussion Contrary to earlier statistics that ACS is rare in sub-Saharan Africa, our study illustrates that nearly 5% of all the high SITE OF INFARCTION BY ECG

Anterior 41%

Anterolateral 10%

Inferior 37%

Septal 6%

Lateral 6%

Fig 1. Site of myocardial involvement in patients with STEMI.

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dependency and intensive care admissions in our hospital are due to an acute coronary event. This clearly illustrates the changing prevalence of ischaemic heart disease in eastern Africa in comparison with earlier data.

Over half of the patients admitted in our study had a diagnosis of STEMI. This contrasts to larger databases, such as the GRACE registry from North America and Europe, which reported 30% of their total number to be STEMI.16 This difference could primarily be due to the small numbers involved in our study.

The mean age of 63–64 years at presentation in our two study subgroups was comparable, however the mean age in our study was about a decade older compared to that in the INTERHEART Africa cases.11 There was an overwhelming male predominance in both subgroups in our study, similar to data from the INTERHEART Africa study.11 This could be due to the already established risk the male gender confers, or represents the healthseeking behaviour of the male gender in our country.

Diabetes mellitus, hypertension and current smoking, akin to data from other parts of the world, comprised the commoner risk factors for the development of CAD in our study. Data from INTERHEART Africa showed that the traditional cardiovascular risk factors (current/former tobacco smoking, diabetes, hypertension, obesity and dyslipidaemia) relating to ischaemic heart disease in the West also account for nearly 90% of the risk for an initial MI in Africans.11 Our data reaffirm the fact that the risk-factor profile for the development of an MI may be no different in a black African, and that the rise in ischaemic heart disease is probably due to the increasing prevalence of these traditional risk factors in sub-Saharan Africa.

Chest pain was the commonest presenting symptom. However, one in every five (20%) patients in our study presented with a symptom other than chest pain. These atypical presentations included epigastric pain, dyspnoea or syncope. It is this cohort of patients who are likely to be improperly triaged in the emergency room, only to present later as a medical catastrophe. Emphasis should therefore be laid on these atypical presentations in patients at risk for ACS presenting to the triage facilities of the emergency departments in this part of the continent.

It was surprising to note that patients with STEMI took over 13 hours, while NSTEMI more than twice as long to present to the emergency room from the onset of their symptoms. Since these patients had had on-going symptoms for over 12 hours, the reasons for late presentation will be important to evaluate in the future. This information may help improve patient education in the community on the symptoms of ACS, and hopefully improve outcomes in such patients in our setting by earlier administration of reperfusion therapy in the hospital.

Reperfusion strategies in STEMI have clearly been outlined in many international management guidelines.17 However, the unavailability of PCI facilities and trained personnel, as well as cost implications are the major causes of deviance from these guidelines in our set up. This is highlighted by the low rates of primary PCI and prolonged door-to-balloon times in our study, with the majority of the eligible patients receiving fibrinolysis.

An even more grim observation is the failure of one-third of all STEMI patients to receive any form of reperfusion due to late presentation to hospital.

The presumed reasons for this could be several, but include challenges at multiple tiers in the healthcare delivery system, including patient awareness of symptoms of myocardial

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ischaemia, the risks of delayed medical care for STEMI, lack of pre-hospital transportation systems and ECGs, and failure to diagnose STEMI on initial ECG by poorly exposed healthcare personnel. All these areas deserve future evaluation and study in order to reduce the time of presentation to hospital for ACS. In our study, the majority of patients received loading doses of aspirin, clopidogrel and enoxaparin as the anticoagulant of choice. The anticoagulant doses were calculated on approximate body weight; however, no record of dose adjustment on the estimated creatinine clearance rate was noted. Over half the patients in both arms of the study received ACE inhibitors or ARBs and over three-quarters received a beta-blocker. The adherence rates to guideline-based therapies for ACS were similar to centres in North America and Europe, reflecting similarities in practice for adjunctive therapies for ACS.18,19 GP IIb/IIIa inhibitors were more commonly utilised in the NSTEMI subgroup and this group had more coronary angiographies compared to the STEMI subgroup. As anticipated, patients with NSTEMI had more double- and triple-vessel disease. However, the lower rates of total revascularisation in this subgroup were due to associated patient comorbidities tilting the risk–benefit balance, cost of surgical revascularisation, and the lack of an effective surgical revascularisation team, hence treating physicians opting for a staged PCI procedure or medical treatment alone in these patients with multi-vessel coronary artery disease.

The average length of hospital stay in the study was five days, accounting to direct hospital costs of approximately Kenya Shillings 400 000 (US$ 6 000; 1 US$ = KSh 70). This includes the cost of admission to the critical care unit and ward stay, laboratory and radiological investigations, cardiac catheterisation and stenting, and drug therapy in hospital. Strategies to lower costs and make this superior reperfusion strategy more available will need to be addressed.

The in-hospital mortality rates were 9.7 and 6.0% in the STEMI and NSTEMI subgroups, respectively. These figures are much higher than those reported in the GRACE and NRMI registries. This reflects the delayed presentation time of our STEMI patients. One-year data for the UA/NSTEMI patients will need to be evaluated to see the long-term mortality trends.

The beginning of every good policy is generation of good local data. This article serves as an important first step in understanding the characteristics of patients with ACS in sub-Saharan Africa. AKUHN receives patients from all over the East African region and reflects practice in a modern sub-Saharan tertiary referral hospital. Improved public and patient education on the early recognition of myocardial ischaemia, development of an integrated pre-hospital emergency medical transportation system and reducing costs of reperfusion therapy may facilitate reduction of mortality associated with ACS. This observational study was limited by its small numbers and therefore was unable to be conclusive. We were also unable to make strong comparisons between the differences in

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presentation, management and outcomes of patients with STEMI compared to NSTEMI. We thank Dr Sitna for her valuable critique, and the Medical Records Department, Accident and Emergency and the Catheter Laboratory team.

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Florentin RA, Lee KT, Daoud AS, et al. Geographic pathology of atherosclerosis: a study of the age of onset of significant coronary arterio-sclerosis in adult Africans and New Yorkers. Exper Molec Path 1963; 2: 103.

Shaper A. Cardiovascular studies in the Samburu tribe of northern Kenya. Am Heart J 1962; 63: 437.

Shaper AG, Jones KW, Jones M, et al. Serum lipids in three nomadic tribes of northern Kenya. Am J Clin Nutr 1963; 13: 135.

Miller DC, Spencer SS, White. P. Survey of cardiovascular disease among Africans in the vicinity of the Albert Schweitzer Hospital in 1960. Am J Cardiol 1962; 10: 432.

Blahos J, Reisenauer I. Levels of serum uric acid and serum cholesterol in various population groups in Ethiopia. Am J Med Sci 1965; 250: 308.

Loginov A. Blood cholesterol and cholesterol-ester level in Ethiopians.

Kardiologiia 1962; 2: 145.

Jagoe K, Edwards R, Mugusi F, et al. Tobacco smoking in Tanzania, East Africa: population-based smoking prevalence using expired alveolar carbon monoxide as a validation tool. Tob Control 2002; 11: 210–214.

Otiento C. Type 2 diabetes – an emerging epidemic in Kenya. East Afr Med J 2007; 84(6): 249–250.

Addo J, Smeeth L, Leon D. Hypertension in sub-Saharan Africa: a systematic review. Hypertension 2007; 50(6): 1012–1018.

Seedat Y. Hypertension in developing nations in sub-Saharan Africa. J Hum Hypertens 2000; 14(10–11): 739–747.

Krisela S, Karen S, Steven H, et al. risk factors associated with myocardial infarction in Africa: The INTERHEART Africa study. Circulation 2005; 112: 3554–3561.

Jamison DT, Breman JG, Measham AR, et al. Disease Control Priorities in Developing Countries. New York: Oxford University Press, 2006.

Kristian T, Joseph SA, Harvey D. Universal definition of myocardial infarction. Circulation 2007; 116: 2634–2653.

Jeffrey LA, Cynthia DA, Elliott MA, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction. J Am Coll Cardiol 2007; 50: 1–157.

Steinhubl SR, Kastrati A, Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J 2007; 154: 3–11.

Steg PG, Goldberg RJ, Gore JM, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002; 90: 358–363.

Kushner FG, Hand M, Smith SC, et al. 2009 focused updates: ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 2009; 54(23): 2205–2241.

Dziewierz A, Siudak Z, Dykla D, et al. Management and mortality in patients with non-ST-segment elevation vs.ST-segment elevation myocardial infarction. Data from the Malopolska Registry of Acute Coronary Syndromes. Kardiol Pol 2009; 67: 115–120.

Gibson C. NRMI and current treatment patterns for ST-elevation myocardial infarction. Am Heart J 2004; 148: S29–33.

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The 12-lead ECG in peripartum cardiomyopathy KEMI TIBAZARWA, GERALDINE LEE, BONGANI MAYOSI, MELINDA CARRINGTON, SIMON STEWART, KAREN SLIWA

Abstract Background: The value of the 12-lead electrocardiogram (ECG) to provide prognostic information in the deadly and disabling syndrome peripartum cardiomyopathy (PPCM) is unknown.

Aims: To determine the prevalence of major and minor ECG abnormalities in PPCM patients at the time of diagnosis, and to establish whether there are ECG correlates of persistent left ventricular dysfunction and/or clinical stability at six months of follow up, where available.

Methods: Twelve-lead ECGs were performed at the point of diagnosis on 78 consecutive women presenting with PPCM to two tertiary centres in South Africa and 44 cases (56%) at the six-month follow up. Blinded Minnesota coding identified major ECG abnormalities and minor ECG changes.

Results: The cohort mainly comprised young women of black African ancestry (90%) [mean age 29 ± 7 years and median body mass index 24.3 (IQR: 22.7–27.5) kg/m2]. The majority of cases (n = 70; 90%) presented in sinus rhythm (mean heart rate 100 ± 21 beats/min). At baseline, at least one ECG abnormality/variant was detected in 96% of cases. Major ECG abnormalities and minor changes were detected in 49% (95% CI: 37–60%) and 62% (95% CI: 51–74%) of cases, respectively; the most common being T-wave changes (59%), p-wave abnormality (29%) and QRS-axis deviation (25%).

Of the 44 cases (56%) reviewed at six months, normalisation of the 12-lead ECG occurred in 25%; the most labile ECG features being heart rate (mean reduction of 27 beats/ min; p < 0.001) and abnormal QRS axis (36 vs 14%; p = 0.014). On an adjusted basis, major T-wave abnormalities on the baseline 12-lead ECG were associated with lower left ventricular ejection fraction (LVEF) at baseline (average of –9%, 95% CI: –1 to –16; p = 0.03) and at six months (–12%; 95% CI: –4 to –24; p = 0.006). Similarly, baseline ST-segment elevation was also associated with lower LVEF Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa KEMI TIBAZARWA, MD, MPH BONGANI MAYOSI, D Phil, FCP (SA) KAREN SLIWA, MD, PhD, sliwa-hahnlek@mdh-africa.org

Soweto Cardiovascular Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa KEMI TIBAZARWA, MD, MPH MELINDA CARRINGTON, PhD SIMON STEWART, PhD KAREN SLIWA, MD, PhD

Baker IDI Heart and Diabetes Institute, Melbourne, Australia GERALDINE LEE, MPhil MELINDA CARRINGTON, PhD SIMON STEWART, PhD

at six months (–25%; 95% CI: –0.7 to –50; p = 0.04).

Conclusions: In this unique study, we found that almost all women suffering from PPCM had an ‘abnormal’ 12-lead ECG. Pending more definitive studies, the ECG appears to be a useful adjunctive tool in both screening and prognostication in resource-poor settings.

Keywords: peripartum cardiomyopathy, ECG, baseline, follow up, comparative study, South Africa Submitted 5/5/11, accepted 17/1/12 Published online 15/2/12 Cardiovasc J Afr 2012; 23: 322–329

www.cvja.co.za

DOI: 10.5830/CVJA-2012-006

Peripartum cardiomyopathy (PPCM) is a form of heart failure (HF) with poorly understood aetiology, occurring between the last trimester of pregnancy and up to the first five to six months postpartum.1,2 Despite an early definition,3 later modified by Pearson and colleagues,4 there is no consensus regarding PPCM as a single entity among the leading cardiology societies.5 The European Society of Cardiology recently declared PPCM a distinct disease entity,1 although it may take time before wider awareness of PPCM facilitates more timely diagnosis and pro-active treatment. This is unfortunate given that PPCM causes left ventricular (LV) dysfunction, is more common in particular populations (e.g. African women6) and is associated with poor clinical outcomes and survival rates.7,8 Some studies suggest the incidence of PPCM is one in 3 000 live births. However, one African study found it to be one in 1 000 live births.9 There is also a very high risk of relapse in subsequent pregnancies,10,11 even following full recovery of LV function after the first pregnancy.6 Therefore, early and definitive diagnosis of PPCM is essential to limit the high risk of morbidity and mortality in both current and subsequent pregnancies.

Definitive diagnosis and subsequent management of PPCM requires a high index of suspicion. It also usually requires referral to a tertiary centre for echocardiographic studies and specialist cardiological management. Anecdotal evidence suggests that many women who initially present with signs and symptoms indicative of PPCM are diagnosed with ‘non-specific symptoms of the puerperal period’. The misdiagnosis of PPCM (often leading to clinical deterioration and in some instances death) represents a clear target for early intervention and prevention.

Until specific aetiologies are identified, PPCM remains a diagnosis of exclusion.

Women in their peripartum period suspected with PPCM require rigorous investigation; a costly and laborious process for the patient and healthcare provider. This is particularly difficult in a resource-poor environment. Although screening with (point-ofcare derived) brain natriuretic peptide (BNP) levels may offer a means of detecting elevated atrial pressures secondary to systolic dysfunction (particularly given the age of those affected6,12,13),

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for example, technical and cost issues remain that prohibit their use. In settings such as sub-Saharan Africa where resources are scarce but the incidence of PPCM is high, the advantages of finding alternative screening tools for this condition that truncate the need for more extensive investigations, while being simple and inexpensive to apply, are abundantly clear.2,14 Although there is a paucity of electrocardiographic data specifically relating to PPCM, an ‘abnormal’ 12-lead electrocardiogram (ECG) is common in individuals with HF syndrome, with common anomalies including supraventricular arrhythmias, bundle branch block, and sinus bradycardia.15 Given the above, we undertook a prospective, pilot study of the 12-lead ECG in a consecutive cohort of newly diagnosed women with PPCM in South Africa. Specifically, the primary aim of this study was to describe the baseline ECG characteristics in PPCM patients, noting the type and prevalence of major and minor ECG abnormalities. We also sought to analyse six-month follow-up ECGs (where available) of PPCM patients to determine potential ECG correlates of persistent LV dysfunction and/or clinical stability, where possible, as repeat ECGs are not part of the routine follow up of PPCM patients.

Methods Consecutive patients presenting with de novo PPCM to two tertiary centres in South Africa (Chris Hani Baragwanath Hospital, Johannesburg, and Groote Schuur Hospital, Cape Town) between January 2003 and August 2008 were studied.

Patients were referred from primary and secondary health facilities, as well as internally from other departments. Only patients aged ≥ 17 years who fulfilled the diagnostic criteria for PPCM4 were considered eligible for the study. For recruitment, previously described16 inclusion and exclusion criteria had to be met.

Ethical approval was obtained from each of the local ethical committees of the universities of Cape Town and the Witwatersrand, respectively, prior to the commencement of the study. This study complied with all the requirements of the Declaration of Helsinki. All patients were offered treatment and follow up as per the local standard of tertiary care.

A total of 78 women presenting with PPCM were studied.

Of these, 56% had follow-up ECG data and were included in the comparative study analyses. Of those patients who had not had six-month ECGs (n = 34), three patients died (3.9%).

Importantly, patients with repeat six-month ECG data did not differ significantly with respect to baseline heart rate, NYHA TABLE 1. MAJOR ABNORMALITIES AND MINOR 12-LEAD ECG VARIATIONS BASED ON MINNESOTA CODING Major ECG abnormality Minor ECG variations Q-wave abnormalities Borderline Q waves ST-segment depression Left- or right-axis deviation T-wave inversion High-amplitude R waves Borderline ST-segment depression 2o or 3o AV block Complete LBBB or RBBB T-wave flattening Frequent premature atrial or Low QRS voltage ventricular beats Atrial fibrillation or flutter AV = atrio-ventricular; LBBB = left bundle branch block; RBBB = right bundle branch block. (Adapted from de Bacquer et al., 1998).19

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functional class, and left ventricular ejection fraction (LVEF) from the remaining cohort.

All patients with the provisional diagnosis of PPCM underwent a thorough medical interview and examination, and were investigated to confirm the diagnosis at baseline. All patients had a 12-lead ECG and echocardiography. Additional investigations were performed on a case-by-case basis. Data were captured on standardised case report forms.

A 12-lead resting ECG was performed by a trained technician and analysed by a reviewer blinded to all clinical data (GL), using the Minnesota code classification system.17 The code allows systematic classification of Q and QS patterns, axis deviation, R waves, ST depression and elevation, T-wave changes, along with conduction abnormalities in both atria and ventricles.17,18 The abnormalities detected by the Minnesota code were pooled into major abnormalities and minor variations from the ‘normal’ 12-lead ECG using the classification system previously applied by de Bacquer and colleagues19 (Table 1). Separate analyses for ST-segment depression, arrhythmia or atrio-ventricular (AV) block, bundle branch block and left-axis deviation were also performed.

Standard methods for two-dimensional Doppler transthoracic echocardiography were applied as per the American Society of Echocardiography guidelines.20 LV systolic dysfunction was defined by echocardiographic documentation of left ventricular ejection fraction (LVEF) ≤ 45%. All studies were saved onto hard-drive facilities, and a random sample of these was reviewed by a cardiologist blinded to the clinical details of these patients, to confirm the accuracy of parameters describing cardiac structure and function.

Statistical analyses All data analyses were performed with STATA-8.21 For numerical variables, we report on the mean [standard deviation (SD)] TABLE 2. BASELINE CLINICAL AND DEMOGRAPHIC PROFILE Socio-demographic profile Mean age (years) 29 ± 7* Proportion black African (%) 90 Obstetric profile Median parity 2 (IQR 1–3)** Median postpartum period at presentation 18 (IQR 6–30)** (days) Clinical presentation Proportion with New York Heart Associa64 tion functional class III or IV (%) 24.3 (IQR 22.7–27.5)** Median body mass index (kg/m2) Mean pulse rate 99 ± 19* Blood pressure (mmHg) Mean systolic 116 ± 20* Mean diastolic 76 ± 14* 2D Doppler echocardiography Median intra-ventricular septal thickness 0.9 (IQR 0.8–1.1)** in diastole (cm) 5.8 ± 0.7* Mean left ventricular end-diastolic diam30.5 ± 9* eter (cm) Mean ejection fraction (%) *Standard deviation (± SD); **interquartile range (IQR).

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for normally distributed variables, and median [inter-quartile range (IQR)] for non-parametric variables. Comparison between baseline and follow-up ECGs was done using paired t-tests for normally distributed numerical variables, Mann-Whitney/ Wilcoxon signed rank tests for non-parametric paired numerical variables, and chi-squared tests for categorical variables and proportions. Multivariate analysis was conducted using linear and logistic regression for numerical and categorical outcome variables, respectively.

Results Table 2 summarises the clinical and demographic profiles of the 78 women with de novo PPCM, 10 of whom experienced a firstever detected episode of mildly raised blood pressure at some stage during the index pregnancy. The case report and Fig. 1 describe such a typical case.

Interestingly, no patients under the age of 17 years presented to either study unit and 90% of patients included were young women of African ancestry. Of the 10% that were of non-black African ethnicity, almost all were of mixed ancestry, with only one Caucasian patient. The majority of respondents were normotensive and experienced onset of symptoms in the postpartum period (median 18 days, IQR 6–30 days). However, 8% of respondents reported the onset of symptoms prepartum, of which only two were hypertensive (one mild and the other with moderate hypertension, defined as per standard protocol).22-24 Table 3 summarises baseline ECG abnormalities/variations from normal (n = 78). The majority of cases (90%) were in sinus

Case report: the ECG in PPCM

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rhythm, although mean heart rate was markedly elevated, with 45% of cases in sinus tachycardia (defined as those ≥ 100 beats/ min, given that our patients’ maximum heart rate was 134 beats/ min). Only three patients (4%) had completely normal ECGs; excluding those with an elevated heart rate, this increased to nine patients (12%). Overall, 49% (95% CI: 37–60) of cases had a major Minnesota ECG abnormality detected, while 62% (95% CI: 51–74) had a minor ECG variant. A combined total of 63 (81%; 95% CI: 70–89%) cases had one or both forms of abnormality detected on their 12-lead ECG. Of the major abnormalities, major T-wave anomalies (38%), followed by abnormal QRS axis (26%) were the most common (Fig. 2). T-wave anomalies were also the most common of all documented ECG abnormalities overall (59%), followed by atrial abnormalities (29%).

Univariate analysis showed no association between LV systolic function and baseline ECG readings. However, on adjustment for age, functional class, echocardiographic LV dimensions, and all the other ECG parameters listed in Table 3, major T-wave abnormalities correlated negatively with left ventricular systolic dysfunction. The presence of major T-wave changes was associated with a clinically relevant 9% (95% CI: 1–16; p = 0.03%) reduction in LVEF compared to those without T-wave changes.

At six months, a number of clinical parameters had improved in surviving cases subjected to study follow up (n = 44) (Table 4).

Overall, 55% had no residual evidence of LV systolic dysfunction (p < 0.001), although 10% still reported functional impairment (NYHA class II or more). Overall, 25% of this sub-set of cases had a normal 12-lead ECG at six months.

Our patient presented to hospital one week after giving birth through spontaneous vaginal delivery, reporting a fiveweek history of shortness of breath equivalent to New York Heart Association functional class II, two-pillow orthopnoea associated with cough, bilateral leg swelling, and mild dizziness. On further interrogation, there was a positive family history of sudden ‘unexplained’ death of her grandmother. Our patient denied any consumption of alcohol or tobacco products.

Clinical examination revealed central and peripheral signs of fluid overload. The pulse rate was 92 beats per minute, this being weak, with occasional irregularities suggestive of ventricular extrasystoles. Her blood pressure was 97/72 mmHg, her apex beat displaced laterally, and the abdominal examination proved there to be tender hepatomegaly.

Positive findings on cardiac auscultation included a loud, split, second heart sound, and systolic murmur best heard over the mitral and tricuspid areas. Chest auscultation revealed bilateral basal crepitations.

Chest X-ray demonstrated four-chamber cardiomegaly and pulmonary congestion, while her ECG abnormalities included right-axis deviation, with poor R-wave progression and diffuse T-wave inversion (Fig. 1a). Echocardiography showed dilated cardiac chambers, markedly reduced systolic ventricular function (EF 35%), moderate to severe functional mitral regurgitation, trace tricuspid regurgitation, and a small clear pericardial effusion. Tissue Doppler imaging revealed no further evidence of diastolic dysfunction.

Further tests permitted the exclusion of other common causes of dilated cardiomyopathy, as well as important differential diagnoses. The working diagnosis remained that of peripartum cardiomyopathy.

The patient was started on carvedilol, enalapril, spirinolactone and furosemide. Given the high risk for thromboembolic phenomena presented with the ejection fraction of 35% and below, she was started on warfarin. Despite being seen several times in between, six weeks later she continued to manifest the subtle arrhythmia of moderate-frequency ventricular extrasystoles, with suboptimal heart rate control; hence digoxin was introduced.

Following regular follow-up visits, after six months she reported that she was well, without any heart-failure symptoms.

Her blood pressure had normalised to 113/64 mmHg and heart rate to 58 beats/min, while the pulse rhythm remained irregular as if with ventricular extrasystoles (now at low frequency). The mitral regurgitation murmur had diminished to grade 1. On ECG, the axis had now normalised, and although there remained diffusely inverted T-waves, their depths had improved, and this inversion normalised in limb lead I. The patient now qualified for left ventricular hypertrophy by voltage criteria using this same lead I (Fig. 1b). Echocardiography showed persistent but improved LV dilatation, minimal functional tricuspid and mitral regurgitation, with improvement of LV systolic function to an EF of 49%.

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a.

b.

Fig. 1. A typical ECG in PPCM at baseline (a) and after six months (b).

According to univariate analyses, no difference between ‘clinically stable/responded to treatment’ (i.e. recovered LV function) versus non-responders (persistent LV dysfunction)

were found in respect of any ECG parameter. However, on an adjusted basis, major T-wave changes and major ST-segment depression found on the baseline 12-lead ECG subsequently

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TABLE 3. 12-LEAD ECG AT BASELINE IN 78 PPCM PATIENTS ECG characteristic Mean heart rate (beats/min) ± SD Proportion in sinus rhythm Proportion with sinus tachycardia Proportion with arrhythmias • premature ventricular complex • supraventricular tachycardia • sinus arrhythmias Axis QRS axis • abnormal • left axis • right axis • indeterminate Conduction PR interval > 220 ms Proportion with bundle branch block (BBB) • left BBB • right BBB Proportion with prolonged QTc (> 470 ms) Repolarisation Proportion with T-wave abnormalities • major • minor Proportion with ST-segment changes • major ST-segment changes • minor ST-segment changes • ST-segment elevation Hypertrophy Proportion with left ventricular hypertrophy [Defined by Minnesota codes III1 and (IV1-3 or V1-3)] Atria Proportion with atrial abnormalities • left atrium • right atrium • bi-atrial *This sum exceeds that of individual BBB as some patients manifested incomplete BBB (either left or right). **This sum exceeds that of individual sub-categories as some patients manifested features of each sub-category.

Rate and rhythm

Proportion of PPCM patients, % (n = 78)

correlated with persistently impaired systolic function at six months. Specifically, the presence of major T-wave changes at baseline was associated with a markedly lower LVEF at six months (–12%, 95% CI: –4 to –21; p = 0.006) compared to those without T-wave changes at baseline. In addition, ST-segment elevation at baseline was associated with an even greater 50 45 40 35 30 25 20 15 10 5 0

Major T-wave inversion

Bundle branch block

Premature ventricular complex

Major Q-wave changes

Major STdepression

Fig. 2. Prevalence of Minnesota major criteria at baseline in 78 PPCM patients.

No. (%) (n = 78) 100 ± 21 70 (90%; 95% CI: 81–95) 35 (45%; 95% CI: 34–57) 3 (4%; 95% CI: 0.8–11) 1 (1%; 95% CI: 0.03–7) 4 (5%; 95% CI: 1–13) 20 (26%; 95% CI: 16–37) 9 (12%; 95% CI: 5–21) 8 (10%; 95% CI: 5–19) 3 (4%; 95% CI: 0.8–11) 1 (1%; 95% CI: 0.04–7) 9 (12%; 95% CI: 5–21)* 4 (5%; 95% CI: 1–13) 1 (1%; 95% CI: 0.03–7) 4 (5%; 95% CI 1–13) 46 (59%; 95% CI: 47–70)** 30 (38%; 95% CI: 28–50) 24 (31%; 95% CI: 21–42) 1 (1%; 95% CI: 0.03–7) 3 (4%; 95% CI: 0.8–11) 1 (1%; 95% CI: 0.03–7) 7 (9%; 95% CI: 4–18) 23 (29%; 95% CI: 20–41)** 8 (10%; 95% CI: 5–19) 11 (14%; 95% CI: 7–24) 4 (5%; 95% CI: 1–13)

reduction in LVEF at six months (–25%, 95% CI: –0.7 to –50; p = 0.044) compared to those without this ECG pattern at baseline.

Discussion To the best of our knowledge, this is the first study to systematically describe the 12-lead ECG in de novo cases of PPCM. Our main aim was to examine the potential utility of the 12-lead ECG (a relatively inexpensive and easy-to-apply diagnostic tool) in detecting underlying LV dysfunction in confirmed cases of de novo PPCM in African women. This would require a high underlying level of ECG abnormalities in such a cohort in order to discriminate against (presumably) more normal 12-lead ECGs in African women experiencing healthier pregnancies.

Of the 78 cases studied, 49% demonstrated major ECG abnormalities, usually associated with significant underlying cardiac pathology, while 62% demonstrated one or more forms of minor variation/abnormality, potentially indicative of the same. We also attempted to examine whether the 12-lead ECG is a useful tool for discriminating between those cases who respond to treatment (by the resolution of initially observed ECG abnormalities) and those who had persistent LV dysfunction.

In this respect, we found that the presence of two major abnormalities (T-wave inversion and ST-segment depression) and a third Minnesota code criterion not listed as one of the major or minor criteria (ST-segment elevation) found on the baseline

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TABLE 4. COMPARING BASELINE AND SIX-MONTH ECG CHARACTERISTICS IN 44 PPCM PATIENTS WITH FOLLOW-UP DATA Baseline % of population 104 ± 18 84 (95% CI: 70–93) 48 (95% CI: 32–63)

6-month follow up % of population 77 ± 14 66 (95% CI: 50–80) 7 (95% CI: 1–19)

Mean heart rate (beats/min) ± SD Proportion in sinus rhythm Proportion with sinus tachycardia Proportion with arrhythmias • premature ventricular complex 2 (95% CI: 0.06–12) 2 (95% CI: 0.06–12) • sinus arrhythmias 7 (95% CI: 1–19) 27(95% CI: 15–43) Axis Proportion with QRS axis being: • abnormal 36 (95% CI: 22–52) 14(95% CI: 5–27) • left axis 18 (95% CI: 8–33) 7 (95% CI: 1–19) • right axis 11 (95% CI: 4–25) 5 (95% CI: 0.6–15) • indeterminate 7 (95% CI: 1–19 ) 2 (95% CI: 0.06–12) Conduction Proportion with bundle branch block (BBB) 20 (95% CI: 10–35)* 18 (95% CI: 8–33) • left BBB 9 (95% CI: 3–22) 9 (95% CI: 3–22) • right BBB 2 (95% CI: 0.06–12) 2 (95% CI: 0.06–12) Repolarisation Proportion with T-wave abnormalities 45 (95% CI: 30–61)** 27(95% CI: 15–43) • major 30 (95% CI: 17–45) 34 (95% CI: 20–50) • minor 16 (95% CI: 7–30) 9 (95% CI: 3–22) Proportion with ST-segment changes • major ST changes 0 0 • minor ST changes 2 (95% CI: 0.06–12) 0 • ST-segment elevation 2 (95% CI: 0.06–12) 0 7 (95% CI: 1–19 ) 7 (95% CI: 1–19 ) Hypertrophy Proportion with left ventricular hypertrophy [Defined by Minnesota Codes III1 and (IV1-3 or V1-3)] Atria Proportion with atrial abnormalities 20 (95% CI: 10–35)** 9 (95% CI: 3–22) • left atrium 5 (95% CI: 0.6–15) 2 (95% CI: 0.06–12) • right atrium 9 (95% CI: 3–22) 7 (95% CI: 1–19) • bi-atrial 7 (95% CI: 1–19 ) 0 *This sum exceeds that of individual BBB as some patients manifested incomplete BBB (either left or right). **This sum exceeds that of individual sub-categories as some patients manifested features of each sub-category.

Rate and rhythm

12-lead ECG correlated with persistently poor LV systolic function at six months. T-wave inversion also correlated with LV systolic function at baseline.

Typically, LV systolic functional recovery in PPCM is a slow and drawn-out process that enters the second year of treatment.2 On this basis, while LVEF in those patients subjected to six-month follow up improved overall, just under half still had defined impaired LV dysfunction, and this represents a major therapeutic target for treatment. Therefore, long-term follow up using the ECG in PPCM might well show ECG reversal to normality as late as 18 months after first diagnosis, as our long-term echocardiographic data suggest.8 Moreover, we have identified potentially useful markers (i.e. major T-wave inversion and/or ST-segment depression on the 12-lead ECG) as simple but important prognostic markers that might trigger more intensive/ aggressive treatment and follow up in PPCM cases.

Our findings and the overall utility of the 12-lead ECG in this clinical setting require careful interpretation when fundamental investigations such as echocardiography remain inaccessible to most hospitals and patients in sub-Saharan Africa. Serum levels of NT-proBNP are known to strongly predict the degree of heart failure,12 yet this test is still not available in most referral hospitals in Africa where PPCM is prevalent. Surprisingly, because of vast differences in sensitivity and specificity in detecting HF, it has been suggested that the overall cost-effectiveness of measuring serum NT-proBNP becomes comparable to that of screening for HF using the 12-lead ECG alone,25,26 due mainly to the relatively low specificity of the 12-lead ECG.26

p-value < 0.001 0.049 < 0.001 1.0 0.011 0.014 0.107 0.237 0.306 0.787 1.0 1.0 0.123 0.647 0.334 – 0.315 0.315 1.0 0.133 0.557 0.694 0.078

The scarcity of the serum NT-proBNP test in our setting almost mandates using something as inexpensive and easy as the 12-lead ECG to screen for PPCM, even if its sensitivity and specificity prove to be imperfect. These data will be particularly useful if (after comparing ECG patterns in healthy African women, derived from the Heart of Soweto cohort27) the 12-lead ECG has the potential to be applied as a ‘rule-out’ test (i.e. high specificity to identify all truly negative for PPCM cases).

Unfortunately, the ability to combine 12-lead ECG with typical symptoms of HF (to increase its accuracy in detecting PPCM) is confounded by their parallel presence in the late stages of pregnancy (but not typically post-partum).

As indicated, our data suggest that baseline major T-wave abnormalities were associated with poorer LV systolic function at baseline, and, alongside baseline ST-segment depression, they were also associated with persistent LV systolic dysfunction in the short to medium term (i.e. six months). In Western countries, major ST-segment depression and T-wave abnormalities are often regarded as indications of myocardial ischaemia, bearing consistent prognostic significance for cardiovascular disease mortality across prospective studies, especially for men.28 We remain wary of the fact that gender differences in ECG findings often show women to have a higher prevalence of ST-segment depression or T-wave changes, such as to question the true significance of any association between ST-segment depression and T-wave abnormalities with coronary heart disease (CHD) mortality in women.28 However, we are greatly reassured by the number of large, population-based studies that show major

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ST-depression to be the most predictive ECG characteristic of cardiovascular disease (CVD) and CHD mortality, lending an average two-fold risk of CVD and CHD mortality, and, as with our study, predicting these outcomes from their mere presence at baseline.19 Studies reporting on the ECG in prognostication of PPCM remain scarce, with two from Nigeria suggesting it to be a weak predictor of recovery and long-term prognosis in PPCM.29,30 However these studies did not use echocardiography to confirm the diagnosis of PPCM,30 and had a greater proportion of patients with hypertension than those without.29,30 Given recent insight that patients with the PPCM phenotype who present with hypertension appear to follow a different natural history to those without,2 any comparisons between data from PPCM patients with hypertension with those without hypertension should be interpreted with great caution.

Systematic reports of ECG abnormalities associated with idiopathic dilated cardiomyopathy (IDCM), which bears some resemblance to PPCM, are few. One such study of IDCM reported that the ECG was found to be normal in up to 25% of affected relatives of IDCM patients (who by definition suffer from familial DCM), although these were not all newly diagnosed IDCM cases.31 Hence, as in our study, an overwhelming majority had abnormal ECGs. It remains fair to say that the shortage of studies systematically reporting on the prevalence of ECG anomalies in PPCM may account for most for our inability to corroborate our findings with other available evidence, yet no reports contradict our findings. Overall, therefore, our data can only suggest that the 12-lead ECG in PPCM may be sensitive to underlying LV dysfunction and/or that it can serve as a marker of more extensive cardiac insult early in the disease process.

Lastly, we note that the 1% prevalence of first-degree heart block, usually not considered to bear any significant risk to adverse CVD outcome, except for its association with lamin A/C mutation in familial DCM, may in our PPCM cohort merely reflect the 1–2% prevalence in normal young adults.32 However, after recent reports implicating this so-called benign form of heart block in the general population with increased risk of atrial fibrillation and adverse CVD outcome 20 years down the line,32 and suggestions that post-exercise measurements of PR intervals may be more prognostic within five-year follow-up periods than resting ECG PR intervals,32 it would be useful to revise the prognostic implications of first-degree heart block post exercise in patients with underlying myocardial disease and congestive cardiac failure as in PPCM. Furthermore, evaluation of this conduction disorder may be of particular importance in PPCM, in view of several reports of first-degree AV block being among one of the earliest signs of lamin A/C mutation, which in turn commonly leads to a phenotype of apparently unexplained DCM.33 It is worth considering that the prognostic implications behind each of the criteria for major and minor ECG abnormalities/variants derived from the Minnesota code appear more applicable in the screening of high-risk persons only,34 as in this clinical context.

This pilot study has a number of limitations that require comment. Firstly, the Minnesota code may not be sufficiently validated for the detection of heart disease in pregnant women.

Moreover, the ‘normal’ 12-lead ECG in African women is yet to be definitively described. Whether the combined presence

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(81% of cases) of major abnormalities and minor variations is sufficient to support further investigation of the 12-lead ECG as a screening tool (particularly when there are few data to describe the ‘normal’ 12-lead ECG in pregnant and non-pregnant African women), is open to debate.

In determining the sensitivity of ECG changes over time, relative to underlying LV dysfunction, we had valid data for only 56% of the cohort. Although our PPCM patients who did not have follow-up ECGs did not differ in clinical and echocardiographic outcome from those with follow-up data, the possibility that the former group may have been clinically worse off than those with six-month data cannot be excluded, given that greater proportions of the former manifested minor T-wave anomalies, and that their left ventricular diameters and BMI at baseline appeared greater than those who had six-month ECGs. However, in light of the lower prevalence of QRS-axis deviation and bundle branch block among the former group, interpretation of the similarity of patients with and without follow up with regard to ECG characteristics becomes speculative.

Further data are required to better characterise the 12-lead ECG as a marker of LV dysfunction in this specific clinical (and ethnic) context, before any firm recommendations can be made in respect of obtaining a 12-lead ECG at the conclusion of each pregnancy in sub-Saharan Africa.

Conclusions Despite a number of limitations, this still represents a unique study that will prove to be invaluable in determining the future role of the 12-lead ECG as an inexpensive and simple ‘rule-out’ screening tool for PPCM, and perhaps an important tool for increasing the intensity of subsequent treatment and management.

Overall, we found the majority (96%) of PPCM patients presented with ‘abnormal’ 12-lead ECGs, which improved significantly to 75% after the first six months of treatment. Over 80% of patients displayed either major abnormalities or minor variations using the Minnesota code. Of these, sinus tachycardia and QRS-axis deviation were most likely to be attenuated after six months.

Even though these ECG abnormalities were mostly non-specific and similar to those of other dilated cardiomyopathies, our study further suggests the ECG to be useful in simple monitoring of clinical progress during treatment and prognostication.

Specifically, the baseline presence of major T-wave and ST-segment abnormalities in the context of PPCM patients may place these patients at similar risk of adverse outcomes to those with myocardial ischaemia. More definitive studies are required to determine if this simple and relatively inexpensive tool will prove to be of particular clinical use in the setting of PPCM. Any progress in this regard will be welcome, given the persistently poor health outcomes associated with PPCM in resource-poor settings.

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Sliwa K, Tibazarwa K, Hilfiker-Kleiner D. Management of peripartum cardiomyopathy. Curr Heart Fail Rep 2008; 5: 238–244 [PMID: 19032920].

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Sliwa K, Forster O, Tibazarwa K, et al. Long-term outcome of peripartum cardiomyopathy in a population with high seropositivity for Human Immunodeficiency Virus. Int J Cardiol 2011; 147(2): 202–208. Epub 2009 Sep 13 [PMID: 19751951].

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Cardarelli R, Lumicao TG Jr. B-type natriuretic peptide: a review of its diagnostic, prognostic, and therapeutic monitoring value in heart failure for primary care physicians. J Am Board Fam Pract. 2003; 16(4): 327–333 [PMID: 12949034].

Martin-Du Pan RC, Ricou F. [Use of brain natriuretic peptide (BNP) in the diagnosis and treatment of heart failure]. Rev Med Suisse Romande.

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Stewart S, Sliwa K. Preventing CVD in resource-poor areas: perspectives from the ‘real-world’. Nat Rev Cardiol 2009; 6(7): 489–492 [PMID: 19554008].

McMurray J. Clinical Practice. Systolic Heart Failure. N Engl J Med 2010; 362: 228–238 [PMID: 20089973].

Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proofof-concept pilot study. Circulation 2010; 121(13): 1465–1473 [PMID 20308616].

Prineas R, Crow R, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings. Littleton, MA: John Wright-PSG, Inc, 1982.

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20. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58(6): 1072–1083 [PMID: 709763].

21. StataCorp 2003: STATA Statistical Software: Release 8.0 College Station, TX: Stata Corporation.

22. Seedat YK, Croasdale MA, Milne FJ, et al. South African Hypertension Guideline. S Afr Med J 2006; 96: 337–362 [PMID: 16670808].

23. Helewa ME, Burrows RF, Smith J, et al. Report of the Canadian Hypertension Society Conference: 1. Definitions, evaluation, and classification of hypertensive disorders in pregnancy. Can Med Assoc J 1997; 157: 715–725 [PMID 9307560].

24. Brink A, Akande W, Moodley J, et al. Hypertension in pregnancy – round table discussion: Part 2. Cardiovasc J South Afr 2002: 13(2); 68–72 [PMID: 12166357].

25. Lee G, Carrington M, Sliwa K, Stewart S. Are ECG abnormalities common in black Africans with heart failure? Results from the Heart of Soweto Study. South Afr Heart J 2008: 5(1); 4–11.

26. Galasko GI, Barnes SC, Collinson P, et al. What is the most costeffective strategy to screen for left ventricular systolic dysfunction: natriuretic peptides, the electrocardiogram, hand-held echocardiography, traditional echocardiography, or their combination? Eur Heart J 2006; 27(2): 193–200 [PMID: 16040618].

27. Sliwa K, Wilkinson D, Hansen C, et al. A broad spectrum of heart disease and risk factors in a black urban population in South Africa: Results from The Heart of Soweto Study Clinical Registry. Lancet 2008; 371: 915–922 [PMID: 18342686].

28. Wu CC, Yeh WT, Crow RS, et al. Comparison of electrocardiographic findings and associated risk factors between Taiwan Chinese and US White adults. Int J Cardiol 2008; 128: 224–231 [PMID: 17655945].

29. Boomsma LJ. Peripartum caridiomyopathy in a rural Nigerian hospital.

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30. Fillmore SJ, Parry EH. The evolution of peripartal heart failure in Zaria, Nigeria. Circulation 1977: 56; 1058–1061 [PMID: 923045].

31. Gimeno JR, Lacunza J, Garcia-Alberola A, et al. Penetrance and Risk Profile in Inherited Cardiac Diseases Studied in a Dedicated Screening Clinic. Am J Cardiol 2009; 104:406–410 [PMID: 19616675].

32. Nieminen T, Verrier RL, Leino J, et al. Atrioventricular conduction and cardiovascular mortality: Assessment of recovery PR interval is superior to pre-exercise measurement. Heart Rhythm 2010; 7: 796–801 [PMID: 20188862].

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Assessment of serum leptin, pregnancy-associated plasma protein A and CRP levels as indicators of plaque vulnerability in patients with acute coronary syndrome MOUSHUMI LODH, BINITA GOSWAMI, ASHOK PARIDA, SURAJEET PATRA, ALPANA SAXENA

Abstract Introduction: A multifactorial aetiology of coronary artery disease (CAD) has been established in the recent past.

Extensive research is now underway to understand the mechanisms responsible for plaque vulnerability. The identification of a novel biomarker that will help in the assessment of plaque status is urgently needed for the purpose of patient stratification and prognostication. The aim of the present study was to evaluate leptin, pregnancy-associated plasma protein A (PAPP-A) and C-reactive protein (CRP) levels in patients with acute coronary syndrome and to assess their diagnostic efficacy in the identification of vulnerable plaques.

Methods: The study group comprised 105 patients who had chest pain along with ECG changes (ST elevation, ST depression, T inversion) and raised cardiac enzyme levels. Sixty-two patients with chest pain and ECG changes but with normal cardiac enzyme profiles were included in the control group.

Lipid profiles, and leptin, PAPP-A and CRP levels were assessed in these two groups. Receiver operating characteristics (ROC) curves were plotted to determine the utility of the parameters under study as markers of plaque vulnerability.

Results: Significantly higher levels of serum lipoprotein (a), leptin, PAPP-A and high-sensitivity CRP (hs-CRP) were observed in the cases than in the controls. A positive correlation was observed between CRP and PAPP-A levels as well as CRP and leptin concentrations. ROC curve analysis revealed similar efficacies of CRP and PAPP-A levels in their ability to detect unstable plaques with areas under the curve of 0.762 and 0.732, respectively. Multivariate analysis established the superiority of hs-CRP as a predictor of plaque instability.

Conclusions: Our study highlights the utility of both CRP and PAPP-A levels as determinants of plaque instability. Our

Department of Biochemistry, The Mission Hospital, Durgapur, West Bengal, India MOUSHUMI LODH, MD

Department of Biochemistry, GB Pant Hospital, New Delhi, India BINITA GOSWAMI, MBBS, MD, DNB, binita.dr@gmail.com

Department of Cardiology, The Mission Hospital, Durgapur, West Bengal, India ASHOK PARIDA, MD

Department of Biochemistry, Lady Hardinge Medical College and associated hospitals, New Delhi, India SURAJEET PATRA, MD

Department of Biochemistry, Maulana Azad Medical College and associated hospitals, New Delhi, India ALPANA SAXENA, MD

findings necessitate population-based follow-up studies to establish the superiority of either of the two biomarkers in the field of preventive cardiology.

Keywords: leptin, hs-CRP, PAPP-A, metalloproteinase, plaque rupture Submitted 7/2/11, accepted 8/2/12 Cardiovasc J Afr 2012; 23: 330â&#x20AC;&#x201C;335

www.cvja.co.za

DOI: 10.5830/CVJA-2012-008

Acute coronary syndrome (ACS) accounts for 20% of all medical emergency admissions and has the highest risk for adverse effects and deaths.1 ACS encompasses patients who present with unstable ischaemic heart disease (ST elevation myocardial infarction, non-ST-elevation myocardial infarction).

The rupture of coronary atherosclerotic plaque and subsequent thrombus formation are major events underlying ACS. Apart from traditional risk factors, several novel risk factors have been found to be associated with acute coronary syndromes.2 Atherosclerosis results due to the complex interplay between environmental, genetic and individual risk factors. Physical inactivity, along with the intake of calorie-dense food account for the energy imbalance that is widely prevalent in developing and developed countries. The metabolic perturbations due to this energy imbalance along with smouldering inflammatory processes and other as yet poorly understood mechanisms initiate and aggravate the atherosclerotic process.3,4 The scientific community is engrossed in extensive research in order to discover biomarkers that will help stratify patients who are more prone to develop the complications consequent to atherosclerosis. The inability of lipid levels to provide an insight into the ongoing atherosclerotic process and impending complications has further necessitated the identification of novel markers that assess the dynamics of atherosclerosis.

Adipocytokines (leptin), pregnancy-associated plasma protein A (PAPP-A) and high-sensitivity C-reactive protein (hs-CRP) are the newer emerging biomarkers for assessing plaque stability.5 Adipose tissue is now identified as an active endocrine organ and not merely a storage site for fat. The mediators released by adipose tissue are known as adipocytokines or adipokines.6 Leptin is one such adipokine implicated in a number of physiological processes.7 Other important adipokines are adiponectin and resistin. It has been demonstrated that alterations in the plasma levels of these adipokines as well as disturbances in the signalling pathways disrupt the delicate adipokine biology and subsequently give rise to many disorders.6 Recent studies have indicated that hyperleptinaemia may serve as a cardiovascular risk factor.8-10 PAPP-A is a glycoprotein produced by the placental synctiotrophoblastic cells and was initially discovered in the sera

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of pregnant women.11 However, many non-placental sites of PAPP-A production have also been identified. It is a member of the metzincin metalloproteinase superfamily. Metalloproteinases may contribute to the fragility of the lipid-rich atherosclerotic plaque and eventually to its rupture by degrading the extracellular matrix.12 Recent studies by Bayes-Genis et al. reveal that it may be a potential determinant of plaque instability by degrading the extracellular matrix of the fibrous cap of the atherosclerotic plaque.13 C-reactive protein, determined by high-sensitivity techniques, is the most widely studied marker of inflammation in the field of atherosclerosis. Its role has been identified in the initiation, progression and final outcome of the atherosclerotic process. It is an acute-phase reactant and is an important player in the inflammatory process observed to be active in atherosclerosis. Studies have revealed that it is not an innocent bystander and indicator of the inflammatory process; rather it is actively involved in the pathogenic mechanisms underlying atherosclerosis.14,15 Lipoprotein (a) is a cardiovascular risk factor highly prevalent in subjects with Asian Indian origin. It has both thrombogenic and atherogenic properties. This is due to its homology to plasminogen and its low-density lipoprotein (LDL)-like properties. Hence it is known as a dual pathogen. It may play an important role in the susceptibility of atherosclerotic plaques to instability.3 The present study aimed to evaluate these novel risk factors and to look for interrelationships between them in the setting of acute coronary syndrome.

Methods The study was jointly conducted by the Departments of Biochemistry and Medicine, Maulana Azad Medical College and associated hospitals, New Delhi, India. The study involved screening of 379 patients with symptoms of ‘chest pain’, presenting to the medical emergency department during the period between April and October 2010. These patients were then further evaluated by electrocardiography. One hundred and sixty-seven patients demonstrated ECG abnormalities such as ST elevation, ST depression and T inversion. They were enrolled as the study population.

Cardiac enzymes such as troponins and CK-MB levels were evaluated in these patients. One hundred and five patients had raised serum cardiac enzyme concentrations and hence depicted the onset of acute coronary syndrome. These patients were TABLE 1. DEMOGRAPHIC DETAILS AND RISK FACTOR PROFILE OF THE STUDY POPULATION Cases Controls Characteristics (n = 105) (n = 62) p-value Age (years) 56.9 ± 11.1 48.8 ± 10.9 NS Male/female 86/19 45/17 – 28.5 ± 5.7 25.2 ± 5.3 – BMI (kg/m2) Waist circumference (cm) 101.46 ± 10.2 88.9 ± 15.9 < 0.01 Smoking (%) 50 (48%) 9 (13%) < 0.01 Hypertension (%) or antihyperten55 (52%) 31 (50%) NS sive drugs taken Diabetes (%) or hypoglycaemic 46 (44%) 4 (8%) < 0.001 drugs Hypolipidaemic drugs 42 (40%) 15 (25%) < 0.01

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classified as cases and they were further evaluated by coronary angiography.

Angiography was conducted by cardiologists using standard techniques. The angiograms were done by two different cardiologists who did not have any information regarding patient identity and aetiology, to avoid any subjective bias. Those who had normal cardiac enzyme concentrations were enrolled as controls.

The inclusion criteria were: • AMI patients diagnosed by typical rise and gradual fall of biochemical markers (troponins, CK-MB) of myocardial necrosis with at least one of the following: –– ischaemic symptoms –– development of pathological Q waves on the ECG reading –– ECG changes indicative of ischaemia (ST elevation or depression) –– coronary artery intervention (e.g. coronary angioplasty) • Unstable angina: chest discomfort at rest with either ST depression of at least 0.1 mV or T-wave inversion in two or more contiguous ECG leads, CK-MB levels normal and angiographically confirmed coronary artery disease (CAD).

The exclusion criteria that were considered during the selection of the study population were: • advanced kidney failure indicated by high serum urea and creatinine • overt heart failure as diagnosed by echocardiography • history of major surgery/trauma within the previous month • suspected systemic inflammatory diseases • pregnancy • chronic stable angina (effort induced) diagnosed as chest pain of at least six months’ duration, accompanied by severe CAD on angiography (70% stenosis in any major artery).

A fasting blood sample (8–10 ml) was drawn prior to angiography and the serum was extracted and stored at –70°C until further testing. Fasting serum leptin, hs-CRP and PAPP-A levels were estimated with ELISA kits provided by DRG International, Germany.

Statistical analysis The data were expressed as mean ± standard deviation. Student’s t-test was used to compare the values between the cases and controls. Spearman’s correlation analysis was used to find the association between the various parameters of our study.

A p-value < 0.05 was accepted as statistically significant.

Multivariate regression analysis was carried out to assess the role of the different biomarkers in unstable CAD. All statistical analyses were performed with the program Statistical Package for the Social Science 12.0 (SPSS Inc, Chicago, Illinois).

Results The demographic and risk-factor profiles of the study population are shown in Table 1. One hundred and five patients fulfilled the inclusion criteria for enrolment as cases (acute myocardial infarction) while 62 were classified as controls (angina pectoris).

The mean age of the cases was higher than the controls (56.9 ± 11.1 vs 48.8 ± 10.9 years, respectively). Females comprised 18% of the cases and 23% of the controls.

The body mass index and waist circumferences were higher in the cases compared to the controls. The prevalence of

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Controls 150.1 ± 43. 9 125.2 ± 49.6 100.5 ± 27.3 38.8 ± 7.6 16.7 ± 13.5 8.06 ± 5.8 10.4 ± 5.8 2.93 ± 2.49

p-value 0.063 0.353 0.067 < 0.001 < 0.001 0.01 < 0.001 < 0.001

The burden of atherosclerotic disease is a major public health problem in developed as well as developing countries and is primarily attributed to physical inactivity, calorie-rich food and a host of environmental and individualistic factors.16 The present study was undertaken to determine the efficacy of the novel biomarkers, adipocytokines (leptin), inflammatory mediator (hs-CRP) and a metalloproteinase (PAPP-A), for the identification of unstable plaques.

In order to achieve the goal of our study, the patients presenting to the hospital with acute coronary syndrome were classified as cases or controls depending on the angiographic findings. Those patients with normal coronary arteries comprised the control group and those with documented lesions in their coronary arteries were included in the patient group. The novelty of our study lies in the comparison of four markers of cardiovascular risk: dyslipidaemia [lp(a)], insulin reistance (leptin), inflammation (hs-CRP) and matrix remodelling (PAPP-A), as

p-value 0.001

Leptin

0.705

0.015

PAPP-A

Hs-CRP

0.901

0.849

0.002

< 0.001

Cut offs chosen from ROC curves 15.9 mg/dl Sensitivity 72% Specificity 70% 6.9 ng/ml Sensitivity 66% Specificity 60% 11.75 mIU/l Sensitivity 68% Specificity 60% 3.1 mg/l Sensitivity 77% Specificity 73%

60 40 20 0

60 40 20 0

0

80 60 40 20 0

100-Specificity

80

20 40 60 80 100

100-Specificity

ROC (LPa)

100

20 40 60 80 100

ROC (PAPPA)

100 Sensitivity

AUC 0.778

80

0

TABLE 3. RECEIVER OPERATING CHARACTERISTICS OF THE PARAMETERS UNDER STUDY Characteristics Lipoprotein (a)

ROC (LEPTIN)

100

Sensitivity

Cases 167.7 ± 32.2 136.9 ± 61.7 112.7 ± 29.8 30.6 ± 6.8 34.8 ± 30.1 11.97 ± 8.5 16.84 ± 8.93 5.46 ± 2.8

Discussion

0

20 40 60 80 100

100-Specificity ROC (CRP)

100 Sensitivity

TABLE 2. BIOCHEMICAL PROFILE OF THE STUDY POPULATION Characteristics Total cholesterol (mg/dl) Triglycerides (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Lipoprotein (a) (mg/dl) Leptin (ng/ml) PAPP-A (mIU/l) Hs-CRP (mg/l)

and 60% specificity. An attempt to increase the sensitivity was accompanied by a corresponding reduction in specificity and vice versa. Our study therefore proves the superiority of hs-CRP as a marker of plaque rupture. However, PAPP-A also proved to be a sensitive marker. Fig. 1 illustrates the ROC curves of the different parameters in the study.

A positive correlation was observed between hs-CRP with PAPP-A levels (r = 0.658, p < 0.01) and leptin (r = 0.612, p < 0.01). However, no such correlations were observed between leptin, PAPP-A and lipid levels. This finding highlights the interaction between hs-CRP and PAPP-A in initiating plaque rupture. Multivariate regression analysis proved the superiority of CRP over all the other parameters, with the order of significance being CRP > CK-MB > HDL > total cholesterol/ HDL ratio > LDL/HDL ratio > fasting plasma glucose > lp(a) > total cholesterol > LDL > insulin > triglycerides > PAPP-A > leptin (Table 4).

Sensitivity

smoking and diabetes mellitus was significantly higher in the cases than the the controls. Subjects with none of the above risk factors comprised 16% of the cases and 28% of the controls, respectively.

The biochemical profile of the study population is given in Table 2. Total cholesterol, triglyceride and LDL cholesterol levels were higher in the patients compared to the controls (167.7 ± 32.2 vs 150.1 ± 43. 9 mg/dl; 136.9 ± 61.7 vs 125.2 ± 49.6 mg/ dl; 112.7 ± 29.8 vs 100.5 ± 27.3 mg/dl, respectively). However the differences were not statistically significant.

High-density lipoprotein (HDL) levels were significantly lower in the cases than the controls (30.6 ± 6.8 vs 38.8 ± 7.6 mg/dl; p < 0.001). Lipoprotein (a) [lp(a)] levels demonstrated a non-Gaussian distribution pattern with significantly higher levels (34.8 ± 30.mg/dl) in the cases compared to 16.7 ± 13.5 mg/dl in the controls (p < 0.001). Significantly higher levels of serum leptin, PAPP-A and hs-CRP were observed in the cases compared to the controls (11.97 ± 8.5 vs 8.06 ± 5.8 ng/ml; 16.84 ± 8.93 vs 10.4 ± 5.8 mIU/l and 5.46 ± 2.8 vs 2.93 ± 2.49 mg/l, respectively).

In order to evaluate the performance of serum lp(a), leptin, PAPP-A and hs-CRP levels as indicators of plaque rupture, the receiver operating characteristics (ROC) curves were plotted.

Table 3 illustrates the findings elaborated by the ROC curves.

The area under the curve for hs-CRP was highest at 0.762, followed closely by PAPP-A at 0.732. Cut-off points of these parameters were determined from the curves, which could help in prospective stratification of patients predisposed to unstable atherosclerotic sequelae.

According to this, a cut off of 3.1 mg/l for hs-CRP has a sensitivity of 77% and specificity of 73%. Similarly, a watershed value of 11.75 mIU/l for PAPP-A exhibited 68% sensitivity

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80 60 40 20 0

0

20 40 60 80 100

100-Specificity

Fig. 1. ROC curves of the different parameters under study.

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TABLE 4. MULTIVARIATE REGRESSION ANALYSIS OF THE VARIOUS PARAMETERS IN THE STUDY Fasting plasma glucose Fasting insulin Leptin Ck-mb Papp-a Crp Lipoprotein (a)

0.194 0.026 0.000 0.383 0.001 0.396 0.111

Triglycerides Cholesterol Ldl Hdl Ldl/hdl Cholesterol/hdl

0.010 0.051 0.041 0.241 0.202 0.230

possible predictors of plaque instability. This holistic view of plaque instability was the cardinal point of our study.

Our study revealed that serum leptin levels were significantly higher in the patient group than in the controls. Hyperleptinaemia has been implicated in the aetiopathogenesis of atherosclerosis in a number of studies.17-20 The various underlying mechanisms responsible for its pro-atherogenecity are being revealed with a multitude of in vitro and in vivo studies. These include influences on cytokine signalling mechanisms,21 stimulation of pro-inflammatory cytokine production,22 stimulation of smooth muscle cell proliferation,23 up regulation of phagocytotic mechanisms,17 platelet aggregation and thrombosis,24,25 and the promotion of endothelial dysfunction.26 Serum leptin is also responsible for the stimulation of mitochondrial superoxide production27 and calcification of smooth muscle cells.21 It has been observed that leptin levels correlate with insulin resistance, obesity and cardiovascular risk factors. In fact, it has been hypothesised that the disturbances in adipocytokine balance and signalling pathways in obesity eventually culminate in atherosclerotic disease.23,28 Our findings are in accordance with studies carried out by many researchers. Serum leptin levels could predict adverse cardiovascular events, even after adjustment for the traditional risk factors, in the WOSCOPS trial.18 Cincone et al. reported a positive correlation between serum leptin levels and intima– media thickness in healthy individuals.29 Karaduman et al. evaluated the levels of hs-CRP and leptin in atherosclerotic plaques and found leptin levels to be significantly higher in diabetics than non-diabetics.17 Iribarren et al. reported a positive correlation between serum leptin levels and coronary artery calcium scores in healthy women.30 Reilly et al. concluded from their study that plasma leptin levels may represent a marker for adiposity, insulin resistance and vascular dysfunction, leading eventually to atherosclerosis.31 However, the Quebec Heart study as well as a study carried out by van den Beld did not find any correlation between leptin levels and cardiovascular events.32 C-reactive protein level has been established as a determinant of the inflammatory process in atherosclerosis. In fact, hs-CRP levels have been correlated with disease initiation, progression and prognosis.33 CRP carries out a multipronged attack on the endothelium with pro-inflammatory, stimulatory and pro-oxidant actions leading to endothelial dysfunction and other events that predispose to atherosclerosis. The mechanisms are explained in our previous article.34 The present study also highlights the significance of hs-CRP levels in determining CAD. The ability of statins to decrease CRP levels has garnered interest in the recent years. The PROVE IT TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction

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22) study highlighted that the CRP levels after statin therapy were as efficient in predicting CAD as LDL levels.35 The recent JUPITER study also highlighted the pro-atherosclerotic role of CRP and its response to statin therapy.36 Pravastatin therapy led to maximal benefit in patients with highest CRP values regardless of their LDL concentrations, according to the Cholesterol And Recurrent Events (CARE) trial.37 Similar findings were reported by the AFCAPS/ TexCAPS24 and Physicians Health study.38,39 Our study also highlights the importance of hs-CRP in the prediction of unstable plaques. However, caution is warranted in the interpretation of the utility of hs-CRP due to its non-specificity. Being an acutephase reactant, its significance must be analysed by excluding all other causes of its elevation.

Anand et al. concluded from their study that CRP was independently associated with CAD in Asian Indians after adjustment for Framingham risk factors and anthropometric measurements.40 The INTERHEART study demonstrated that increased apolipoprotein B/apolipoprotein AI, smoking, abdominal obesity, psychosocial stress, diabetes mellitus and hypertension accounted for 90% of the CAD risk in Asian Indians.413 PAPP-A is an emergent biomarker signifying plaque instability.

The role of PAPP-A as a biomarker for unstable atherosclerotic plaques was initially suggested by Bayes-Genis et al., who measured PAPP-A levels in the cells and the extracellular matrix of unstable plaques in eight patients who had sudden death due to cardiac causes.13 PAPP-A is a member of the metzincin metalloproteinase superfamily and is also produced by non-placental tissue such as fibroblasts, vascular endothelial cells and vascular smooth muscle cells. The circulating form of the protein comprises a heterotetrameric complex formed of two subunits of 200 and 250 kDa, bound by eosinophil major basic protein.42 PAPP-A is secreted by activated macrophages that take part in the atherosclerotic process.

Studies have revealed that PAPP-A contributes to plaque instability by promoting degradation of the extracellular matrix of the fibrous cap.43 PAPP-A acts as an insulin-like growth factor (IGF) binding protein 4 protease. PAPP-A degrades IGF-binding protein 4 protease and thus increases the availability of free IGF-I.44 IGF-I induces macrophage activation, chemotaxis, LDL cholesterol uptake by macrophages, and the release of pro-inflammatory cytokines by these cells.45,46 IGF-I is also implicated in the proliferation and migration of smooth muscle cells and the consequent vascular response to injury.45,47 These events lead to the initiation of plaque destabilisation.

We observed significantly higher levels of PAPP-A in the patients compared to the control group. It also emerged as a good indicator of plaque vulnerability, just behind hs-CRP, with an area under curve of 0.732. Our findings corroborate the results of previous studies that have been carried out.48,49 Lund et al. concluded that PAPP-A was a good predictor of both ischaemic cardiac events and the need for revascularisation in patients with ACS.50 Cosin-Sales et al. concluded from their study on patients with ACS that those with complex coronary lesions had significantly higher PAPP-A levels than patients who were free of such lesions.13 Heeschen et al. evaluated PAPP-A levels in 547 patients with angiographically proven ACS. They found that elevated PAPP-A levels indicated an increased risk

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of plaque rupture, myocardial infarction, revascularisation and cardiovascular death in both troponin T-positive or -negative patients.51 Studies in patients with stable angina have proved the superiority of PAPP-A over troponin T and hs-CRP levels.52 Elevated PAPP-A levels in asymptomatic hyperlipidaemic patients were associated with increased echogenicity of carotid atherosclerotic plaques.53 Experimental as well as epidemiological data substantiated the role of PAPP-A in the detection of unstable CAD in patients with normal troponin levels.54,55 This could help in the prompt identification and timely intervention in high-risk populations.

We also observed a statistically significant correlation between PAPP-A and CRP levels in patients with ACS. It has been reported that pro-inflammatory cytokines such as TNF-α stimulate PAPP-A synthesis by macrophages. The accumulation of activated macrophages at the site of unstable plaques leads to the release of PAPP-A by these cells.56 The correlation between these two mediators suggests the complex interplay between various pathways that eventually converge to promote plaque instability. Such an association between CRP and PAPP-A levels was also reported by Heeschen et al.51 and Jin-Lai et al.57 A similar correlation was observed between CRP and leptin levels. Obesity is associated with an inflammatory response characterised by high levels of pro-inflammatory cytokines.58 Receptors for leptin and cytokines are structurally related. Leptin can also directly induce the production IL-6, which is the most potent stimulator of CRP synthesis.59 Hence a positive correlation was observed between leptin and CRP levels. Obesity therefore leads to a higher risk of CAD due to the synergism between hyperleptinaemia and the on-going low-grade inflammatory process.

Conclusions Coronary artery disease is the root cause of mortalities due to non-infectious aetiology. The initiation of florid plaque rupture and the consequent complications lead to various life-threatening sequelae of atherosclerotic disease. Hence, identification of plaque vulnerability at the incipient stages may help in effective and timely management.

Currently, detection of plaque status involves invasive procedures such as coronary angiography and intravascular ultrasound, which have their own shortcomings due to their invasive nature and patient non-compliance, as well as financial constraints. Therefore the identification of a simple blood test that may aid in this endeavour is the need of the hour.

We observed hs-CRP and PAPP-A levels to be effective indicators of plaque rupture. Interpretation of CRP data requires consideration of confounding factors such as inflammation.

PAPP-A levels are not affected by infections or any underlying inflammation. Therefore assessment of PAPP-A levels may be a very attractive alternative for detecting unstable plaque activity and hence useful in stratification and prognostication of subjects.

The ability of PAPP-A to detect plaque function even when the other markers of myocardial injury such as troponins are not elevated, is another justification for evaluation of PAPP-A level as a novel marker of plaque vulnerability. The comparison of PAPP-A and hs-CRP levels with the established biomarker troponin T needs to be evaluated and the results substantiated by studies carried out in large, population-based studies.

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Oral health of patients with severe rheumatic heart disease BREMINAND MAHARAJ, AHMED C VAYEJ

Abstract In order to determine whether adequate attention is paid to the maintenance of good oral health in patients at risk of developing infective endocarditis, we studied 44 black patients with severe rheumatic heart disease before they had cardiac surgery. Plaque and gingival index scores were calculated and panoramic radiographs were done in all patients.

There were 17 males and 27 females (mean age: 30.6 years).

The plaque and gingival index scores were classified as poor in 31.8 and 54.6% of patients, respectively. Panoramic radiographic findings included caries in 56.8% of patients, peri-apical pathology in 18.1% and retained roots in 22.7% of patients. This study demonstrates that inadequate attention is paid to the maintenance of good oral health in patients with severe rheumatic heart disease. The oral and dental care of patients at risk of developing infective endocarditis needs to be improved.

Keywords: oral health, rheumatic heart disease, periodontal health Submitted 30/11/11, accepted 8/2/12 Cardiovasc J Afr 2012; 23: 336–339

www.cvja.co.za

and dental literature on the prevention of infective endocarditis, Barco stated: ‘Finally, and most importantly, dental and periodontal health is the best long-term prevention of infection from the oral cavity for such patients at risk of infective endocarditis’.12 Most national guidelines on infective endocarditis prophylaxis stress the maintenance of optimum oral health. The 1997 recommendations of the American Heart Association stated that individuals who are at risk of developing infective endocarditis should establish and maintain the best possible oral health to reduce potential sources of bacterial seeding. They also stated that optimal oral health is maintained through regular professional care.13 The Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy has emphasised the need for regular dental attendance for the management of dental health in patients susceptible to infective endocarditis.14,15 More recent guidelines have stressed the importance of this aspect of prophylaxis.16,17 The aim of this study was to determine by clinical and radiological examination whether adequate attention is paid to the maintenance of good oral health in black patients who are at risk of developing infective endocarditis.

DOI: 10.5830/CVJA-2012-009

There are many case reports of the failure of antibiotic prophylaxis to prevent infective endocarditis.1 Wahl suggested, however, that ‘failures of prophylaxis’ were actually successful, and that patients had developed endocarditis before or after the dental procedure because of poor oral hygiene.2 Individuals who have poor oral health are at high risk of developing spontaneous bacteraemia.3 The literature indicates that most cases of infective endocarditis are not related to procedures.4,5 Eykyn stated that it is becoming increasingly clear that poor dental hygiene rather than dental procedures are responsible for most, if not all, cases of viridans streptococcal endocarditis.6 In the study by Pogrel and Welsby, oral sepsis was associated with infective endocarditis in 12% of cases.7 Guntheroth pointed out that bacteraemia was found in 11% of patients with oral sepsis and no intervention.8 A number of authors have stressed proper oral hygiene as a far more important preventative measure than chemoprophylaxis against infective endocarditis.2,3,8-11 In his review of the medical

Department of Therapeutics and Medicines Management, University of KwaZulu-Natal, Durban, South Africa BREMINAND MAHARAJ, MB ChB, FCP (SA), MD, PhD, FRCP (London), maharajb4@ukzn.ac.za

Programme: Oral Health, Department of Health, KwaZuluNatal, Durban, South Africa AHMED C VAYEJ, BDS

Methods Black patients who had been evaluated by a cardiologist at the cardiac unit at the Wentworth Hospital, Durban, and assessed as having severe rheumatic heart disease requiring valvular surgery, were studied. Patients were examined during the week preceding their cardiac surgery in the cardio-thoracic unit of this hospital after informed consent had been obtained. The study was approved by the Ethics committee of the Nelson R Mandela School of Medicine, University of Natal, Durban.

For each patient, the age, gender and nature of the valvular abnormality were recorded. Plaque and gingival index scores were calculated after careful clinical examination, and rotational panoramic radiographs were done in all patients.18-20 Each radiograph was examined without magnification using a standard viewing box in a horizontal position. Two observers examined all radiographs; differences in interpretation were resolved by consensus.

Recording sheets were compiled and the presence of the following lesions was recorded: caries, missing teeth, impacted teeth, hypercementosis, peri-apical radiolucencies, attrition, fractured teeth, unerupted teeth, and retained roots. Definitions used for all the radiographic lesions are listed in Table 1.

Results A total of 44 black patients with severe rheumatic heart disease were studied. There were 17 males and 27 females, with ages ranging from 13 to 50 years (mean age: 30.6 years).

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The distribution of valvular lesions is shown in Table 2. The distribution of scores obtained after calculation of the plaque and gingival index scores are shown in Tables 3 and 4.

Seven (15.9%) patients had normal panoramic radiographs.

No patients were edentulous. The nature of radiographic abnormalities and their relative frequency are shown in Table 5.

The panoramic radiographs, shown in Figs 1 to 4, illustrate some of the abnormalities that were detected.

Discussion The plaque and gingival index scores were classified as good in only 13.6 and 15.9%, respectively of patients with severe rheumatic heart disease who were scheduled to have cardiac surgery. None of the patients had a score that would have placed their indices in the excellent category, while 31.8 and 54.6% of TABLE 3. PLAQUE INDEX: DISTRIBUTION OF SCORES

TABLE 1. DEFINITIONS USED FOR RADIOGRAPHIC LESIONS19-21 Missing teeth Unerupted teeth Impacted teeth

Hypercementosis Peri-apical radiolucency Caries Attrition

All permanent teeth not on the radiograph Teeth that had not reached the occlusal plane and which were not impeded from doing so Teeth with fully or incompletely formed roots, impeded by hard tissue from reaching their correct relationship to the occlusal plane and surrounding bone Formation of excessive cementum on tooth roots Radiolucency associated with the apex of a tooth root Radiolucent areas in a tooth Wearing away of a tooth where teeth rub together

Tooth fracture Retained roots

Fracture of the crown and/or root of the tooth Roots which cannot be restored because of insufficient remaining healthy tooth tissue and/or supporting tissue Interdental bone loss Lack of continuity of lamina dura

TABLE 2. DISTRIBUTION OF VALVULAR LESIONS (n = 44) Valvular lesions Isolated mitral stenosis Isolated mitral regurgitation Mitral stenosis plus regurgitation (mixed mitral valve disease) Aortic regurgitation Aortic regurgitation plus aortic stenosis (mixed aortic valve disease) Mixed mitral valve disease plus mixed aortic valve disease

No. of patients 8 3 16 3 3

Rating Excellent Good Fair Poor

Score 0 0.1–0.9 1.0–1.9 2.0–3.0

Patients Number 0 6 24 14

Percent 0 13.6 54.6 31.8

TABLE 4. GINGIVAL INDEX: DISTRIBUTION OF SCORES Rating Excellent* Good Fair Poor *Healthy tissue

Score 0 0.1–0.9 1.0–1.9 2.0–3.0

Patients Number 0 7 13 24

Percent 0 15.9 29.5 54.6

TABLE 5. TYPES AND FREQUENCIES OF RADIOGRAPHIC ABNORMALITIES Patients Abnormality Caries Missing teeth Peri-apical radiolucencies Impacted teeth Unerupted teeth Hypercementosis Tooth fracture Attrition Retained roots Interdental bone loss

Number 25 24 8 11 9 5 1 8 10 6

Percent 56.8 54.5 18.1 25.0 20.5 11.4 2.3 18.2 22.7 13.6

11

Fig. 1. Panoramic radiograph showing few abnormalities. This radiograph shows complete dentition, with no unerupted or impacted teeth. Interdental bone loss is minimal. A large carious lesion (a) is present in the right second mandibular molar tooth. A peri-apical radiolucency (c) is also present at the apex of the same tooth.

This is indicative of a peri-apical abscess or granuloma.21 The overall condition of the teeth of this patient is good.

Fig. 2. Panoramic radiograph showing more abnormalities than Fig. 1. This radiograph shows three impacted third molar teeth (g). The right first maxillary molar tooth is missing (b). The crown of the left second mandibular molar tooth is missing and retained roots are present (f). The same tooth also shows a peri-apical radiolucency (c) with a well-defined calcified margin indicating possible peri-apical cyst formation.21 The retained root of the right second maxillary incisor tooth is also seen (f).

The occlusal surfaces of the right mandibular first and second molar teeth show attrition (d).

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Fig. 3. Panoramic radiograph showing more abnormalities than Fig. 2. This radiograph shows edentulous areas (i.e. loss of teeth) involving the right mandibular molar region and the left maxillary incisor and canine regions (b). A retained root of the right maxillary canine tooth is also present (f). Interdental bone loss is seen between the left mandibular premolar and molar teeth (e). A peri-apical radiolucency is associated with the left first mandibular molar tooth (c). The overall condition of the teeth of this patient is poor.

Fig. 4. Panoramic radiograph showing many abnormalities. This radiograph shows multiple retained roots (f) and missing teeth (b) in both mandibular and maxillary arches. The right mandibular first molar tooth shows a large carious lesion with loss of crown enamel (a). The left mandibular canine teeth and the left mandibular first premolar tooth show caries interproximally (a). Periapical radiolucencies are noted in relation to the right and left mandibular molar teeth (c). The overall condition of the teeth of this patient is extremely poor.

patients had gingival and plaque index scores that were rated as poor.

Abnormalities were detected in the panoramic radiographs of 84.1% of patients. The most frequent lesion was caries, present in 56.8% of patients, followed by missing teeth in 54.5%, and impacted teeth in 25% of patients. Retained roots were present in 22.7% and peri-apical pathology was detected in 18.1% of patients. Although seven (15.9%) patients had a normal panoramic radiograph, only one also had both plaque and gingival index scores that were good.

Thom and Howe reported on their study in which 50 patients, all with severe heart disease, were examined clinically and radiologically to ascertain their dental status.22 Their study differs from ours in a number of respects. Firstly, they included four patients with congenital heart disease (ventricular septal defect).

Secondly, they used full-mouth intra-oral peri-apical radiographs, whereas our study used rotational panoramic radiography.

Thirdly, they decided whether the patients were ‘dentally fit’ and whether they had periodontal disease, although diagnostic criteria were not given. We studied oral health with particular reference to oral hygiene. Fourthly, their study included edentulous patients whereas ours did not have any edentulous patients. Fifthly, their study was done in a developed country.

Nevertheless, comparisons can be made with our study.

Furthermore, their findings and conclusions are applicable to developing countries. Thom and Howe reported that 20.5% of patients were dentally fit.22 By contrast, only one patient in our group had a normal panoramic radiograph, a plaque index score that was rated as good, and a gingival index score that was good – the latter indicating mild gingival inflammation. Periodontal disease was present in 46% of their patients. Using only the clinical examination, 86.5% of our patients had a fair or poor gingival index. The relative frequency of caries, retained roots and impacted teeth in their study was 20, 34 and 6%, respectively, while in our study it was 56.8, 22.7 and 25%, respectively.

These authors divided their patients into one group (n = 11)

that visited the dentist regularly (group A) and another group (n = 39) that visited the dentist irregularly (group B). They found that all clinical and radiographic abnormalities were more frequent in group B [dentally unfit (36.4 vs 82.1%), retained roots (9.1 vs 41%), caries (0 vs 25.6%), periodontal disease (35 vs 51.3%) and impacted teeth (0 vs 77%)]. Although statistical tests were not done in this study, the findings indicate that regular dental care is beneficial.

Holbrook et al. performed a mirror-and-probe examination of teeth and soft tissue of 100 patients with a cardiac valvular lesion attending a cardiac clinic; six had a history of infective endocarditis.23 They found that only 40.5% of the 42 patients with teeth could be regarded as having satisfactory dental health; the remaining patients had either chronic periodontal infection or an abscess, or both. The dental health of edentulous patients was also poor – 53.9% had ill-fitting dentures and 28.9% had diseases of the mouth that could produce bacteraemia.

Smith and Adams published a report on the dental health of 81 at-risk patients attending a cardiology out-patient clinic.24 This investigation consisted of a clinical examination and completion of a questionnaire. Edentulous patients were included in the study because of several reports in the literature of edentulous patients suffering from infective endocarditis.25-27 The criteria used to classify a patient as dentally unfit were provided.

Forty-eight (59.3%) patients were dentally fit; 25 of these patients were edentulous. The dentally unfit group comprised 33 (40.7%) patients, of whom four were edentulous. These workers commented that the prevalence of periodontal disease in their patients was high; however, no figures were given. The articles

by Thom and Howe, Holbrook and co-workers, and Smith and Adams, which were based on studies done in the UK, also indicated that a number of edentulous patients were dentally unfit.22-24 In a study of 38 children with congenital heart disease, dental examination revealed dental caries in 39% of the children.28 In another study, 42.4% of 170 children with congenital heart

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disease had dental caries.29 Untreated dental caries were found in 36% of 28 children with previous infective endocarditis or a prosthetic heart valve.30

Conclusion Our study demonstrates that inadequate attention is paid to the maintenance of good oral health in black patients with severe rheumatic heart disease requiring cardiac surgery. It is very likely that within our healthcare system, the oral health of patients with less severe rheumatic heart disease who are not attending specialist cardiac facilities is also suboptimal. This important aspect of the prevention of infective endocarditis needs greater attention.16,17

References 1.

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Durack DT, Kaplan EL, Bisno AL. Apparent failures of endocarditis prophylaxis. Analysis of 52 cases submitted to a national registry. J Am Med Assoc 1983; 250: 2318–2322.

Wahl MJ. Myths of dental-induced endocarditis. Arch Intern Med 1994; 154: 137–144.

Montazem A. Antibiotic prophylaxis in dentistry. Mt Sinai J Med 1998; 65: 388–392.

Drangsholt MT. A new causal model of dental diseases associated with endocarditis. Ann Periodontol 1998; 3: 184–196.

Durack DT. Prevention of infective endocarditis. N Engl J Med 1995; 332: 38–44.

Eykyn SJ. Infective endocarditis: some popular tenets debunked? Heart 1997; 77: 191–193.

Pogrel MA, Welsby PD. The dentist and prevention of infective endocarditis. Br Dent J 1975; 139: 12–16.

Guntheroth WG. How important are dental procedures as a cause of infective endocarditis? Am J Cardiol 1984; 54: 797–801.

Bayliss R, Clarke C, Oakley C, et al. The teeth and infective endocarditis. Br Heart J 1983; 50: 506–512.

Oakley C, Somerville W. Prevention of infective endocarditis. Br Heart J 1981; 45: 233–235.

Lockhart PB. An analysis of bacteremias during dental extractions. A double-blind, placebo-controlled study of chlorhexidine. Arch Intern Med 1996; 156: 513–520.

Barco CT. Prevention of infective endocarditis: a review of the medical and dental literature. J Periodontol 1991; 62: 510–523.

Dajani AS, Taubert KA, Wilson W et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. J Am

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Med Assoc 1997; 227: 1794–1801.

14. Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy. Antibiotic prophylaxis of infective endocarditis. Lancet 1990; 335: 88–89.

15. Simmons NA, Ball AP, Cawson RA, et al. Antibiotic prophylaxis and infective endocarditis. Lancet 1992; 339: 1292–1293.

16. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–1754.

17. National Institute for Health and Clinical Excellence. Prophylaxis against infective endocarditis. 2008. www.nice.org.uk/CG064.

18. Wilkins EM. Clinical Practice of the Dental Hygienist. 4th edn.

Philadelphia: Lea & Febiger; 1976: 273–283.

19. Wilkins EM. Clinical Practice of the Dental Hygienist. 5th edn.

Philadelphia: Lea & Febiger; 1983: 299–301.

20. Finkelstein MB, Lownie JF, Cleaton-Jones PE. Pathological conditions detected on panoramic radiographs of two Johannesburg populations. J Dent Assoc S Afr 1988; 43: 111–114.

21. Kerr DA, Ash MM Jr. Oral Pathology. 4th edn. Philadelphia: Lea & Febiger, 1978.

22. Thom AR, Howe GL. The dental status of cardiac patients. Br Heart J 1972; 34: 1302–1307.

23. Holbrook WP, Willey RF, Shaw TR. Dental health in patients susceptible to infective endocarditis. Br Med J 1981; 283: 371–372.

24. Smith AJ, Adams D. The dental status and attitudes of patients at risk from infective endocarditis. Br Dent J 1993; 174: 59–64.

25. Cameron IW. Subacute bacterial endocarditis in an edentulous patient.

A case report. Br Dent J 1971; 130: 404–406.

26. Croxson MS, Altmann MM, O’Brien KP. Dental status and recurrence of streptococcus viridans endocarditis. Lancet 1971; i: 1205–1207.

27. Simon DS, Goodwin JF. Should good teeth be extracted to prevent streptococcus viridans endocarditis? Lancet 1971; i: 1207–1209.

28. Balmer R, Bu’Lock FA. The experiences with oral health and dental prevention of children with congenital heart disease. Cardiol Young 2003; 13: 439–443.

29. Rai K, Supriya S, Hegde AM. Oral health status of children with congenital heart disease and the awareness,attitude and knowledge of their parents. J Clin Pediatr Dent 2009; 33: 315–318.

30. Balmer R, Booras G, Parsons J. The oral health of children considered very high risk for infective endocarditis. Int J Paediatr Dent 2010; 20: 173–178.

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An investigation of the frequency of bacteraemia following dental extraction, tooth brushing and chewing BREMINAND MAHARAJ, YACOOB COOVADIA, AHMED C VAYEJ

Abstract We conducted a study to determine the frequency of bacteraemias following dental extraction and common oral procedures, namely tooth brushing and chewing, and the relationship between bacteraemia and oral health in black patients.

Positive blood cultures were detected in 29.6% of patients after dental extraction, in 10.8% of patients after tooth brushing and in no patients after chewing. No relationship between the state of oral health, which was assessed using the plaque and gingival indices, and the incidence of bacteraemia was found. The duration of bacteraemia was less than 15 minutes. One patient had a positive blood culture prior to dental extraction; his oral health status was poor. Our study confirmed that bacteraemia occurs after tooth brushing.

Keywords: bacteraemia following dental procedures Submitted 30/11/11, accepted 24/2/12 Cardiovasc J Afr 2012; 23: 340–344

www.cvja.co.za

DOI: 10.5830/CVJA-2012-016

Dental treatment has been regarded as a major cause of infective endocarditis, mainly because of the high frequency of bacteraemia after various oral procedures and the high recovery rate of viridans streptococci from the blood of patients with infective endocarditis.1-3 Awareness of the relationship between infective endocarditis and dental extraction dates back to 1909, when Horder noted the association between Streptococcus viridans in the oral cavity and infective endocarditis in patients with heart disease.4 Bacteria may invade the bloodstream after a wide variety of clinical procedures.5 Lewis and Grant postulated that healthy persons frequently have innocuous, transient bacteraemia and that the defective heart valve may trap and retain these organisms, resulting in infective endocarditis.6 Okell and Elliot noted streptococcal bacteraemia following dental extraction in 61% of their patients.7 Many investigators have assessed the incidence of transient bacteraemia following various oral procedures. The frequency of positive blood cultures has ranged from zero to 85% (mean:

Department of Therapeutics and Medicines Management, University of KwaZulu-Natal, Durban, South Africa BREMINAND MAHARAJ, MB ChB, FCP (SA), MD, PhD, FRCP (London), maharajb4@ukzn.ac.za

Department of Medical Microbiology, University of KwaZuluNatal, Durban, South Africa YACOOB COOVADIA, MB ChB, FCPath (Micro)

Programme: Oral Health, Department of Health, KwaZuluNatal, Durban, South Africa AHMED C VAYEJ, BDS

40%) for dental extraction, from eight to 79% (mean: 35%) for dental scaling, from 36 to 88% (mean: 58%) for periodontal surgery, from seven to 50% (mean: 25%) for tooth brushing or irrigation, and from zero to 51% (mean: 38%) for chewing.5,8 Bacteraemia has been detected following flossing,9 procedures used for conservative dentistry,2 intra-oral suture removal,10 and endodontic treatment.11 Although viridans streptococci are the micro-organisms most frequently isolated in these studies, considerable differences in frequency, type and magnitude (colony counts per millimetre of blood) of post-procedure bacteraemia have been reported.

This is mainly the result of diversities in the type of surgical procedures (e.g. single vs multiple dental extraction), time of blood sampling, volume of blood cultured, and the methods used to isolate and identify the micro-organisms, which hinder the interpretation and comparison of results. The reports published before the 1960s may also have underestimated the incidence of transient bacteraemia, since no refined anaerobic culture techniques were available.12 Because some of the earlier investigations on antibiotic prophylaxis had failed to show eradication of bacteria, and the state of oral health had not been controlled in these studies,13,14 we decided that it would be important to rule out the possible influence of oral health on post-extraction bacteraemia. Also, the frequency of bacteraemia following other common oral procedures, which have been recorded to produce bacteraemia, had not been evaluated in black patients.

This study was designed to determine: • the relative frequency of bacteraemia following tooth extraction, tooth brushing and chewing in black patients • whether the state of oral health influenced the occurrence of bacteraemia after these procedures • the duration of bacteraemia after these procedures.

Methods Adult black patients attending the Dassenhoek Dental Clinic in Marianhill near Durban were included in the study, after informed consent had been obtained. They were healthy, had no history of cardiovascular disease and had not received antibiotics in the previous two weeks.

Any patient found to have a dental abscess was excluded.

In addition, in the extraction part of the study, any patient who needed more than one tooth extracted or required general anaesthesia was excluded.

The age and gender of each patient was recorded. The oral health status was evaluated by clinical examination and calculation of the plaque and gingival index scores, and rated as excellent, good, average and poor in each patient.15,16 One dental surgeon performed the oral health status evaluation throughout the study.

This study was approved by the Ethics Committee of the Nelson R Mandela School of Medicine, University of Natal.

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The frequency of bacteraemia following dental extraction In this part of the study, only one tooth was extracted per patient.

The same dental surgeon performed the procedure using dental forceps; no surgical procedures were used in any patient.

The skin at the site of the venepuncture was prepared using 0.5% chlorhexidine in 70% alcohol. Using standard aseptic techniques, 8–10 ml of blood was drawn immediately prior to and at two, five, 15 and 30 minutes after the extraction in each patient.

Three to 5 ml of blood was injected directly into BACTEC (Becton Dickinson, Maryland, USA) blood culture vials type 6b (aerobic) and 7d (anaerobic), respectively, after the used needle was replaced with a new, sterile needle and the rubber septum on the BACTEC vials was disinfected with alcohol.

The blood culture bottles were transported to the Microbiology Department, King Edward VIII Hospital, Durban within two hours of collection and were immediately incubated at 37°C. In the case of the aerobic bottles, this also included agitation on BACTEC shakers for the first 24 hours.

The blood culture vials were tested on days one, three, five and seven, and positive vials were sub-cultured and Gram-stained smears were prepared. The aerobic vials were sub-cultured onto chocolate, blood and MacConkey agar plates, which were incubated for 48 hours in air plus 10% CO2. The anaerobic vials were sub-cultured onto 10% blood agar plates with and without amikacin, which were incubated for 48 to 72 hours in anaerobic gas pak (Becton Dickinson, USA) jars with appropriate controls.

The organisms isolated were further identified using conventional laboratory methods and the identity of streptococcal isolates was confirmed using the API Strep 20 (API, France) system.17

The frequency of bacteraemia following tooth brushing In this part of the study, patients were instructed on the proper technique of tooth brushing by the dental surgeon. Thereafter they brushed their teeth for about five minutes using a new soft toothbrush and toothpaste.

The skin preparation and the techniques for blood collection and blood culture were similar to the first part of the study.

The timing of the blood sampling was immediately prior to, immediately after, and at five and 15 minutes after tooth brushing.

TABLE 1. ORGANISMS CULTURED AFTER DENTAL EXTRACTION Aerobic cultures No. Anaerobic cultures No. Streptococcus mitis 5 Streptococcus mitis 5 Streptococcus sanguis 4 Streptococcus sanguis 1 Streptococcus anginosus group 4 Streptococcus anginosus group 4 Streptococcus species 6 Viridans streptococci 1 Staphylococcus epidermidis 1 Streptococcus species 5 Enterococcus faecalis 2 Staphylococcus epidermidis 2 Moraxella catarrhalis 1 Enterococcus faecalis 1 Neiserria sicca 1 Moraxella catarrhalis 1 Corynebacterium ulcerans 1 Neiserria sicca 1 Corynebacterium xerosis 1 Corynebacterium ulcerans 1 Corynebacterium xerosis 1 Prevotella melaninogenica 1 Capnocytophaga species 1 Gram-negative bacilli 1

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The frequency of bacteraemia following chewing In this part of the study, patients were asked to chew an apple.

The skin preparation and the techniques for blood collection and blood culture were similar to the first part of the study.

The timing of the blood sampling was immediately prior to commencement of chewing, when half the apple had been eaten, when the whole apple had been eaten, and five minutes later.

Statistical analysis In each part of the study, the patients with plaque and gingival index scores rated as excellent, good, average and poor were placed in their respective groups and the number of patients with positive blood cultures in each group was compared using the Chi-square test. A p-value < 0.05 was chosen as the level of significance.

Results The frequency of bacteraemia following dental extraction A total of 108 black patients participated in the study. There were 60 males and 48 females. Their ages ranged from 16 to 66 years (mean 29.5).

No patient had a plaque or gingival index score that was rated as excellent. One patient who had a plaque and gingival index score rated as poor had a bacteraemia prior to dental extraction.

Bacteroides fragilis was detected on anaerobic culture.

Post-extraction bacteraemia was detected in 32 (29.6%) patients and was transient in all patients. No bacteria were detected at 15 or 30 minutes. The organisms cultured after dental extraction are listed in Table 1. The number of patients who had positive blood cultures in the groups with good, fair and poor plaque and gingival index scores are shown in Tables 2 and 3.

The frequency of bacteraemia following tooth brushing Seventy-four black patients, 39 males and 35 females, entered the study. Their ages ranged from 16 to 63 years (mean 26.6).

No patient had a plaque or gingival index score that was rated as excellent.

No bacteraemia was detected prior to tooth brushing.

Bacteraemia was detected in eight (10.8%) patients after tooth TABLE 2. PATIENTS WITH POSITIVE CULTURES AFTER DENTAL EXTRACTION IN RELATION TO PLAQUE INDEX* Plaque index score No. in group No. positive % positive Good 36 10 27.8 Fair 37 12 32.4 Poor 35 10 28.6 *Differences between the groups were not statistically significant.

TABLE 3. PATIENTS WITH POSITIVE CULTURES AFTER DENTAL EXTRACTION IN RELATION TO GINGIVAL INDEX* Gingival index score No. in group No. positive % positive Good 38 9 23.7 Fair 34 12 35.3 Poor 36 11 30.6 *Differences between the groups were not statistically significant.

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brushing. The duration was less than 15 minutes. The organisms cultured after tooth brushing are listed in Table 4. The number of patients who had positive blood cultures in the groups with good, fair and poor plaque and gingival index scores are shown in Tables 5 and 6.

The frequency of bacteraemia following chewing There were 32 black patients, 20 males and 12 females, in this part of the study. Their ages ranged from 16 to 45 years (mean 25). Both the plaque and gingival index scores were rated as good, fair and poor in 11, 12 and nine volunteers, respectively.

None of the blood cultures taken before, during and following mastication yielded any bacterial growth. Based on this preliminary analysis, it was decided to terminate the study. The target number in this part of the study was 60 patients.

Discussion There are conflicting data regarding the degree of oral disease necessary to produce bacteraemia after oral procedures. Okell and Elliott found that the occurrence and degree of bacteraemia after dental extraction depended upon the severity of gum disease,7 whereas McEntegart and Porterfield found that the incidence of post-extraction bacteraemia was unrelated to the extent of oral sepsis.18 In children, Peterson and Peacock found that the incidence of bacteraemia following dental extraction was unrelated to the local disease,19 while Speck et al. found that bacteraemia was more common after extraction of abscessed teeth.20 Cobe reported that the occurrence of periodontal disease had little effect on the incidence of bacteraemia after tooth brushing,21 whereas the data of Sconyers et al. suggested that there was a relationship between the frequency of bacteraemia after tooth brushing and oral health.22,23 Cobe also found no relationship between periodontal disease and the occurrence of bacteraemia after chewing.21 Attempts to establish a relationship between bacteraemia and oral disease from published reports have been extremely difficult.

The first problem relates to terminology. Cooke noted that it was only in the 1960s that the all-embracing term ‘oral disease’ was replacing the older and equally vague term ‘oral sepsis’ and that these had clouded the interpretation of any relationship between specific oral disease such as gingivitis and periodontitis, and bacteraemia.24 Furthermore, terms such as ‘dental sepsis’ and ‘moderate’ and ‘severe gum disease’ were not defined.

The second problem relates to the diversities in the type of surgical procedures (e.g. single vs multiple dental extractions), time of blood sampling, volume of blood cultured and the methods used to isolate and identify the micro-organisms. This hindered interpretation and comparison of the results.12 In our study, we were unable to find a relationship between the plaque and gingival index scores, which are indicators of oral health status, and bacteraemia following dental extraction.

TABLE 4. ORGANISMS CULTURED AFTER TOOTH BRUSHING Aerobic cultures Streptococcus sanguis Streptococcus salivarius Viridans streptococci

No. 2 1 2

Anaerobic cultures Streptococcus sanguis Streptococcus salivarius Bacillus species Corynebacterium species

No. 2 1 1 1

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Bacteraemia occurred after dental extraction in 27.8, 32.4 and 28.6% of black patients with good, fair and poor plaque index scores, and in 23.7, 35.3 and 30.6% of patients with good, fair and poor gingival index scores, respectively. These differences were not statistically significant.

Coulter et al. found that there was no relationship between the incidence or the intensity of post-extraction bacteraemia and either the amount of plaque around the gingival margin or the gingival condition in children.25 Lewis et al. reported that there was no correlation between oral health status and positive blood cultures after dental extraction in black patients in the abstract of their article.26 However, in their discussion they stated that although the majority of their subjects were considered to have poor oral health, it was not possible to draw any definite conclusion about the relationship between oral health and post-extraction bacteraemia. Lockhart27 and Lockhart et al.28 found that the degree or severity of oral disease did not correlate with the results of blood culture.

In our study, 29.6% of our patients developed bacteraemia after dental extraction. The frequency of positive blood cultures after dental extraction ranged from zero to 85% (mean 40%).8 Using a lysis-filtration technique to process blood samples, Heimdahl et al. observed bacteria in 100% of patients after dental extraction.29 Using molecular techniques, Lockhart et al. found that the cumulative incidence of infective endocarditisrelated bacteraemia was 60.4%.28 Lewis et al. studied 60 black patients and detected bacteraemia in 65% of patients after dental extraction.26 Streptococci accounted for 35.7% of their positive blood cultures. In our study, streptococci made up 76.9% of the bacteria isolated. These data are in keeping with published reports, which indicate that viridans streptococci are the most frequent micro-organisms cultured after extraction.5,12 None of our patients had positive blood cultures at 15 and 30 minutes after extraction. The duration of bacteraemia after dental extraction is relatively brief, less than 30 minutes.8 Some investigators have found blood cultures positive for organisms further on in time but they drew blood specimens following surgical procedures of different durations.27 In our study, tooth brushing produced bacteraemia in 10.8% of black patients and the duration was less than 15 minutes in all patients. Bacteraemia was detected in the studies by Cobe (24.2% positive),21 Rise et al. (26.0% positive),30 Schlein et al.

(25% positive),31 Roberts et al. (38.5% positive),2 Sconyers et al.

TABLE 5. PATIENTS WITH POSITIVE CULTURES AFTER TOOTH BRUSHING IN RELATION TO PLAQUE INDEX* Plaque index score No. in group No. positive % positive Good 24 2 8.3 Fair 24 1 4.2 Poor 26 5 19.2 *Differences between the groups were not statistically significant

TABLE 6. PATIENTS WITH POSITIVE CULTURES AFTER TOOTH BRUSHING IN RELATION TO GINGIVAL INDEX* Gingival index score No. in group No. positive % positive Good 24 2 8.3 Fair 25 2 8 Poor 25 4 16 *Differences between the groups were not statistically significant.

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(16.1% positive),22 Kinane et al. (3%)32 and Forner et al. (10%)33 but not in the studies by Sconyers et al.,23 Berger et al.34 and Hartzell et al.35 Streptococci were the predominant organisms isolated in these studies as well as in our study.

In our study, bacteraemia was unrelated to oral health status.

The frequency of bacteraemia in the study by Bhanji et al. was 46%.36 They found no correlation between the plaque and gingival scores and the occurrence of bacteraemia. However, using molecular techniques, Lockhart et al. reported that the cumulative incidence of infective endocarditis-related bacteraemia was 22.5% and that the incidence was significantly related to the state of oral hygiene and gingival disease parameters.28 Chewing did not produce bacteraemia in our study. Similar results were obtained by Robinson et al.37 in patients chewing wax, and by Cobe21 in patients chewing gum. On the other hand, bacteraemia was detected after chewing bubble gum in 22% of patients by Diener et al.,38 after chewing paraffin in 55% of patients by Murray and Moosnick,39 after chewing hard candy in 17.4% of patients by Cobe,21 and after chewing bubble gum in 20% of patients by Forner et al.33 One patient in our study had a bacteraemia prior to dental extraction. His plaque and gingival index scores were rated as poor. Bacillus fragilis was isolated. Reith and Squier obtained positive blood cultures from 12% of 99 patients with no demonstrable focus of infection.40 Okell and Elliott found that 10.9% of 110 patients with pyorrhoeal disease had a streptococcal bacteraemia before any operative procedures.7 Rogosa et al.41 and Roberts et al.2 found positive blood cultures unrelated to dental procedures.

In a study of different antibiotic regimens in the prevention of bacteraemia after dental extraction , Diz Dios et al. reported that positive blood cultures were present prior to the dental extraction in all four of their study groups (range: 5–12.5%).42 On the other hand Cobe,21 Peterson and Peacock,19 and Hall et al.43 found no growth in pre-procedure blood cultures.

Our study confirmed that bacteraemia occurs after tooth brushing. In the past, emphasis was placed on antibiotic prophylaxis prior to dental procedures, especially dental extraction.

Only 4% of the 1 322 patients with infective endocarditis studied by Guntheroth had extractions in the previous two months.8 He noted that bacteraemia occurred in 40% of patients after dental extraction, in 25% after tooth brushing or oral irrigation, and in 38% with normal chewing. He concluded that in a hypothetical month ending with a dental extraction, the number of exposures to bacteraemia is almost 1 000 times more for ‘physiological sources’ (e.g. tooth brushing and chewing) than from a dental extraction. He stated that the physiological sources of bacteraemia would explain the occurrence of endocarditis due to viridans streptococci in patients who did not have dental extractions.

Roberts also reported that the cumulative exposure to bacteraemia from everyday procedures such as tooth brushing was significantly greater than that following invasive procedures such as dental extraction.44

Conclusion The emphasis in the prevention of infective endocarditis has now shifted from the use of antibiotics prior to dental procedures

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to the maintenance of good oral health in patients at risk of developing infective endocarditis.45,46

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Van der Meer JTM, van Vianen W, Hu E, et al. Distribution, antibiotic susceptibility and tolerance of bacterial isolates in culture-positive cases of endocarditis in The Netherlands. Eur J Clin Microbiol Infect Dis 1991; 10: 728–734.

Roberts GJ, Holzel HS, Sury MRJ, et al. Dental bacteremia in children.

Pediatr Cardiol 1997; 18: 24–27.

Montazem A. Antibiotic prophylaxis in dentistry. Mt Sinai J Med 1998; 65: 388–392.

Horder TJ. Infective endocarditis; with an analysis of 150 cases and with special reference to the chronic form of the disease. Q J Med 1909; 2: 289–324.

Everett ED, Hirschmann JV. Transient bacteremia and endocarditis prophylaxis. A review. Medicine 1977; 56: 61–77.

Lewis T, Grant RT. Observations relating to subacute infective endocarditis. Heart 1923; 10: 21–77.

Okell CC, Elliott SD. Bacteriaemia and oral sepsis with special reference to the aetiology of subacute endocarditis. Lancet 1935; ii: 869–872.

Guntheroth WG. How important are dental procedures as a cause of infective endocarditis? Am J Cardiol 1984; 54: 797–801.

Lineberger LT, De Marco TJ. Evaluation of transient bacteremia following routine periodontal procedures. J Periodontol 1973; 44: 757–762.

King RC, Crawford JJ, Small EW. Bacteremia following intraoral suture removal. Oral Surg Oral Med Oral Pathol 1988; 65: 23–28.

Debelian GJ, Olsen I, Tronstad L. Bacteremia in conjunction with endodontic therapy. Endod Dent Traumatol 1995; 11: 142–149.

Hall G, Heimdahl A, Nord CE. Bacteremia after oral surgery and antibiotic prophylaxis for endocarditis. Clin Infect Dis 1999; 29: 1–10.

Shanson DC, Cannon P, Wilks M. Amoxycillin compared with penicillin V for the prophylaxis of dental bacteraemia. J Antimicrob Chemother 1978; 4: 431–436.

Hess J, Holloway Y, Dankert J. Incidence of postextraction bacteremia under penicillin cover in children with cardiac disease. Pediatrics 1983; 71: 554–558.

Wilkins EM. Clinical Practice of the Dental Hygienist. 4th edn.

Philadelphia: Lea & Febiger, 1983: 299–301.

Wilkins EM. Clinical Practice of the Dental Hygienist. 4th edn.

Philadelphia: Lea & Febiger, 1976: 273–283 Cowan ST. Cowan and Steele’s Manual for the Identification of Medical Bacteria. 2nd edn. Cambridge: Cambridge University Press, 1974: 238.

McEntegart MG, Porterfield JS. Bacteraemia following dental extractions. Lancet 1949; ii: 596–598.

Peterson LJ, Peacock R. The incidence of bacteremia in pediatric patients following tooth extraction. Circulation 1976; 53: 676–679.

Speck WT, Spear SS, Krongrad E, et al. Transient bacteremia in pediatric patients after dental extraction. Am J Dis Child 1976; 130: 406–407.

Cobe HM. Transitory bacteremia. Oral Surg 1954; 7: 609–615.

Sconyers JR, Crawford JJ, Moriarty JD. Relationship of bacteremia to toothbrushing in patients with periodontitis. J Am Dent Assoc 1973; 87: 616–622.

Sconyers JR, Albers DD, Kelly R. Relationship of bacteremia to toothbrushing in clinically healthy patients. Gen Dent 1979; 27: 51–52.

Cooke BED. Relation between oral disease and acute bacterial endocarditis. Proc R Soc Med 1970; 63: 263–266.

Coulter WA, Coffey A, Saunders IDF, Emmerson AM. Bacteremia in children following dental extraction. J Dent Res 1990; 69: 1691–1695.

Lewis HJ, Culligan GA, Pochee E, et al. A microbiological investigation of post-extraction bacteraemia in black subjects. J Dent Assoc S Afr 1987; 42: 205–208.

Lockhart PB. An analysis of bacteremias during dental extractions. A double-blind, placebo-controlled study of chlorhexidine. Arch Intern Med 1996; 156: 513–520.

Lockhart PB, Brennan MT, Thornhill M, et al. Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia. J Am Dent

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Assoc 2009; 140: 1238–1244.

29. Heimdahl A, Hall G, Hedberg M, et al. Detection and quantitation by lysis-filtration of bacteremia after different oral surgical procedures. J Clin Microbiol 1990; 28: 2205–2209.

30. Rise E, Smith JF, Bell J. Reduction of bacteremia after oral manipulations. Arch Otolaryngol 1969; 90: 198–201.

31. Schlein RA, Kudlick EM, Reindorf CA, et al. Toothbrushing and transient bacteremia in patients undergoing orthodontic treatment. Am J Orthod Dentofacial Orthop 1991; 99: 466–472.

32. Kinane DF, Riggio MP, Walker KF, et al. Bacteraemia following periodontal procedures. J Clin Periodontol 2005; 32: 708–713.

33. Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol 2006; 33: 401–407.

34. Berger SA, Weitzman S, Edberg SC, Casey JI. Bacteremia after the use of an oral irrigation device. A controlled study in subjects with normalappearing gingiva: comparison with use of toothbrush. Ann Intern Med 1974; 80: 510–511.

35. Hartzell JD, Torres D, Kim P, Wortmann G. Incidence of bacteremia after routine tooth brushing. Am J Med Sci 2005; 329: 178–180 36. Bhanji S, Williams B, Sheller B, et al. Transient bacteremia induced by toothbrushing: a comparison of the Sonicare toothbrush with a conventional toothbrush. Pediatr Dent 2002; 24: 295–299 37. Robinson L, Kraus FW, Lazansky JP, et al. Bacteremias of dental origin.

II. A study of factors influencing occurrence and detection. Oral Surg 1950: 3: 923–936.

38. Diener J, Schwartz SM, Shelanski M, Steinberg G. Bacteremia and oral sepsis with particular reference to the possible reduction of systemic disease originating from the oral cavity. J Periodontol 1964; 35:

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236–241.

39. Murray M, Moosnick F. Incidence of bacteriemia in patients with dental disease. J Lab Clin Med 1941; 26: 801–802.

40. Reith AF, Squier TL. Blood cultures of apparently healthy persons. J Infect Dis 1932; 51: 336–343.

41. Rogosa M, Hampp EG, Nevin TA, et al. Blood sampling and cultural studies in the detection of postoperative bacteremias. J Am Dent Assoc 1960; 60: 171–180.

42. Diz Dios P, Carmona IT, Posse JL, et al. Comparative efficacies of amoxicillin, clindamycin, and moxifloxacin in prevention of bacteremia following dental extractions. Antimicrob Agents Chemother 2006; 50: 2996–3002.

43. Hall G, Hedström SA, Heimdahl A, Nord CE. Prophylactic administration of penicillins for endocarditis does not reduce the incidence of postextraction bacteremia. Clin Infect Dis 1993; 17: 188–194.

44. Roberts GJ. Dentists are innocent! “Everyday” bacteraemia is the real culprit: A review and assessment of the evidence that dental surgical procedures are a principal cause of bacterial endocarditis in children.

Pediatr Cardiol 1999; 20: 317–325.

45. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–1754.

46. National Institute for Health and Clinical Excellence. Prophylaxis against infective endocarditis. 2008. www.nice.org.uk/CG064.

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Your Life and Your Heart Focus on omega-3 PUFAs in heart failure The therapeutic use of omega-3 polyunsaturated fatty acids (PUFAs) has been acknowledged for the first time, as being of value in reducing the risk of hospitalisation for cardiovascular disease and death, in the latest heart failure guidelines released by the European Society of Cardiology (ESC).1 Importantly, the level of evidence for this form of nutritional supplement was evaluated as support for this new ESC recommendation. The heart failure guidelines also note the need for the selection of quality formulations and a dosage of at least 1 g daily.

Supporting evidence was mainly from the GISSI-HF trial – a trial of 6 975 patients with NYHA class II–IV symptoms and an ejection fraction ≤ 40%, which has shown that omega-3 PUFA treatment led to a relative risk reduction (RRR) of 8% in the co-primary composite outcome of death or cardiovascular hospitalisation in the adjusted analysis.

There was no reduction in heart failure hospitalisation, but there was a 10% RRR in cardiovascular mortality and 7% RRR in overall cardiovascular hospitalisation.2 The ranking of the use of omega-3 PUFAs above that of statins, which are not recommended and are of unproven benefit for heart failure patients, certainly raises the profile of this nutritional supplement

in cardiological use. Cardiologists are aware of the large GISSI-Prevensione trial3 of more than 11 000 post-myocardial infarction patients treated with omega-3 PUFAs, which also showed a reduction in cardiovascular death.

The Cardiovascular Journal of Africa published an evaluation of South Africanformulated omega-3 supplements by the South African Medical Research Council (MRC), indicating inadequate regulatory structure to check claimed levels of EPA and/or DHA in these products.4 This is an important factor to consider when advising patients on which omega-3 formulations are subject to international regulatory scrutiny. The need to reduce side effects such as nausea and minor gastrointestinal disturbances is also better addressed by formulations that seek to avoid any possible fish oil aftertaste.

Primary prevention with omega3 PUFAs The use of omega-3 supplements early as a health-maintenance strategy in order to prevent the development of cardiovascular disease is widely accepted, although a recent trial in patients with early type 2 diabetes was not able to show cardiovascular benefits over a six-year period, despite a drop in serum

AFRICA Cardiovascular Journal of Africa special reports and podcasts ESC congress, Munich, 2012 The Cardiovascular Journal of Africa will be attending the 2012 ESC congress and reporting on the latest developments. A new innovation is the introduction of podcasts, where we will interview major presenters and publish these interesting interviews on our website.

If you would like your symposium or poster presentation to be covered, please contact Julia Aalbers at julia@clinicscardive.com.

triglyceride levels.5 A larger Danish study of 57 000 middle-aged men and women who were healthy and cancer free was, however, able to show a lower risk of acute coronary syndromes in the men with a high fatty fish intake over a mean follow-up period of more than seven years.6 Julia Aalbers

References 1.

2.

3.

4.

5.

6.

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J. DOI:10.1093/eurheartj/ ehs 104.

Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 PUFA in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind placebocontrolled trial. Lancet 2008; 372: 1223– 1230.

Dietary supplementation with n-3 PUFA and vitamin E, after MI results of the GISSI-Prevenzione trial. Lancet 1999; 354: 447–455.

Opperman M, Marais DW, Benade AJS. Analysis of omega-3 fatty acid content of South African fish oil supplements.

Cardiovasc J Afr 2011; 22(6): 324–329.

The ORIGIN trial investigators n-3 fatty acids and cardiovascular outcomes in patients with dyslycaemia. N Eng J Med 2012. DOI:10:1056/NEJMoa/203858.

Bjerregaard LJ, Joensen AM, Dethlefsen C, et al. Fish intake and acute coronary syndrome. Euro Heart J 2010; 31: 29–34.

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In Memoriam Prof Andrzej Michael Okreglicki, 1960–2012

It was with shock and great sadness that we learned of the sudden death of Prof Andrzej Michael Okreglicki, better known as AO. He was killed in a car accident while returning from a 100-mile run in Cornwall, UK on Sunday 24 June.

At the time of his death he was associate professor in the Division of Cardiology, Department of Medicine, University of Cape Town, president of the Cardiac Arrhythmia Society of South Africa (CASSA) and a member of the Education Standing Committee of the South African Heart Association. He was co-founder of PACE (Prevent Arrhythmic Cardiac Events), an advocacy organisation for lay persons.

AO qualified with an MB BCh with honours at the University of Cape Town (UCT) in 1983. After completing his internship at Groote Schuur Hospital (GSH) in 1984, he spent two years as a medical officer in Nqutu and Mseleni in KwaZulu. He joined the Cardiac Clinic at GSH in 1987 as a senior house officer.

After completing his registrarship and obtaining his FCP (SA) in 1992, he came back as a senior registrar to train in Cardiology, earning his MMed (UCT) in 1996.

During this time, he became interested in cardiac electrophysiology, which led to further training and experience in Newcastle-upon-Tyne, UK, and Rochester, New York. He returned to the Cardiac Clinic as a consultant in 1999, having gained wide and valuable experience in electrophysiology, pacing and implantable cardioverter defibrillators. This experience proved invaluable in improving and expanding the arrhythmia and electrophysiology service at Groote Schuur, the only such service at a public hospital in South Africa. As a result, he dealt with referrals from all over southern Africa.

Since taking charge of electrophysiology and pacing in 2006, his passion and enthusiasm has inspired at least six young people to embark on training in electrophysiology. It is these protégés who are his major legacy. They will have to take over and maintain the very high standards he set, but his passing has left a huge void that will be difficult to fill.

AO was a unique person and a man of many parts. He was much more than an electrophysiologist. Very few in that field shared his ability to cope with so many different aspects of medicine and cardiology, from bedside skills to dealing with emergencies, and being a very capable plumber as well as cardiac electrician. In addition to his clinical skills, he was the ‘Mr Fixit’ and ‘MacGyver’ for the clinic, the one who knew how to get the projector to work with a visiting speaker’s computer. He redesigned the auditorium, catheter laboratory and physical layout of the department.

His quiet manner belied a strong will and determination that things should be done the right way, but without unnecessary confrontation. He earned the love and respect of all his fellow workers, from consultants to cleaners.

He was renowned for his endurance during difficult procedures, carrying on and achieving a successful outcome long after most of us would have given up.

This same determination and endurance also manifested itself in his long-distance

running, starting with his first Comrade’s Marathon 10 years ago. He had completed the last of his many 100-mile endurance races the day before his death. His mental toughness was probably more important than physical prowess as the key to his success in these endeavours.

As a teacher, AO was outstanding and enthusiastic, as well as being patient with those slow to see what he saw in a difficult ECG. He was tireless in running CASSA workshops for general practitioners and others throughout the Cape, and his ECG workshops at SA Heart congresses always attracted a large audience. At a personal level, having previously been his teacher, I found myself continually learning new insights and fresh approaches to cardiac arrhythmias from AO. He single-handedly took on the task of providing an electrophysiology service at Inkosi Albert Luthuli Hospital in Durban, with regular visits every few months to deal with cases and to teach and stimulate the doctors there. As the only electrophysiologist in the fulltime employ of an academic hospital, he took responsibility for all local training in cardiac electrophysiology.

He organised sponsorship for a two-year electrophysiology fellowship at GSH. The first incumbent completes his training in November.

Under the auspices of the Pan-African Society of Cardiology (PASCAR) he developed a six-month programme to train physicians, nurses and technologists from the rest of Africa in the skills of basic life-saving cardiac pacing for heart block, presently available in only four of 56 African countries. The first candidate is due to start in January next year.

With his career tragically cut short, South Africa has lost a national treasure in a field that is still desperately short of qualified practitioners. Those of us who knew him have lost a friend and colleague who will be sorely missed. He is survived by his parents and brother, Stefan Antoni.

Rob Scott Millar

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Conference Report Hypertension, chronic kidney disease, atrial fibrillation and the newer anticoagulants: Prof Brian Rayner comments Prof Brian Rayner, head of Nephrology at Groote Schuur Hospital and the University of Cape Town, presented this Bayer-sponsored lecture. He began by stating that it is highly likely that the practitioner will encounter older patients with atrial fibrillation (AF), concomitant hypertension and chronic kidney disease (CKD), requiring anticoagulation therapy.

A sophisticated inter-relationship exists between these clinical conditions.

AF is commonly associated with increased morbidity and mortality, primarily related to embolic stroke. In the absence of mitral valve disease, the dominant risk factors for AF are hypertension and older age; both of which are CHADS2 determinants in assessing the need for anticoagulation. Additionally, hypertension and ageing are risk factors for the development of CKD, which in itself is a risk factor for AF.

Atrial fibrillation The co-existence of AF and hypertension doubles the risk of overall mortality, stroke, heart failure and hospitalisation; in addition to affecting quality of life and impairing cognitive function. In these patients, the primary clinical goal is to TABLE 1. UPDATED CKD CLASSIFICATION

Stage 1

2

3a 3b

4

5

GFR (ml/min/ 1.73 m2) Description ≥ 90 Normal or increased GFR, with other evidence of kidney damage present for ≥ three months 60–89 Slight decrease in GFR, with other evidence of kidney damage present for ≥ three months 45–59 Moderate decrease in GFR 30–44 for ≥ three months with or without other evidence of kidney damage 15–29 Severe decrease in GFR, with or without other evidence of kidney damage < 15 Established renal failure

reduce blood pressure.

There is some evidence that drugs blocking the renin-angiotensinaldosterone system reduce the risk of new-onset AF, particularly in high-risk patients (those with left ventricular dysfunction, left ventricular hypertrophy and post-myocardial infarction). Betablockers are effective for rate control but there is a dearth of evidence for the use of beta-blockers and other agents in new-onset AF.

Chronic kidney disease Prof Rayner expressed the opinion that South Africa is in the early stages of an escalating CKD epidemic, fuelled by the high prevalence of hypertension and diabetes mellitus. CKD is defined by glomerular filtration rate (GFR); usually estimated from serum creatinine level. The Modification of Diet in Renal Disease (MDRD) equation is usually used in South Africa. Prof Rayner emphasised that CKD classification (Table 1) is an epidemiological tool and not a gold standard, and that the need to consider the individual patient should not be overlooked.

Relationship with cardiovascular disease The relationship between cardiovascular disease (CVD) and CKD is a complex one. In dialysis patients, 52% of deaths are due to non-vascular causes. The remainder of deaths are attributable to acute myocardial infarction (8%), stroke (5%), cardiac arrest/arrhythmia (27%), other cardiovascular diseases (3%), and other cardiac complications (5%).

CVD and CKD share traditional risk factors including hypertension and ageing; however, a number of ‘uraemia-specific’ risk factors contribute to CVD. These are anaemia, phosphate retention, hyperparathyroidism, vascular calcification, uraemic toxins, hyperhomocysteinaemia and volume overload. The combination of volume and pressure overload, as well

as sympathetic overactivity result in left ventricular hypertrophy.

CKD (stages 3 to 5) is an independent risk factor for new-onset AF in hypertensive patients (8.3% with and 3.4% without CKD). The worse the GFR, the greater the AF risk. Similarly, the presence of proteinuria also increases AF risk.

CKD results in altered cytokine production, manifesting increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines, which may promote accelerated atherosclerosis. As opposed to traditional atherosclerosis, medial calcification results in vascular thickening. Prof Rayner recommended lateral lumbar X-ray for assessment.

Anticoagulation in patients with AF, hypertension and CKD Kidney function is an important determinant of the pharmacokinetics of a variety of drugs. This is of particular concern with the use of anticoagulants, which have a narrow therapeutic/toxic range.

Anticoagulants are potent therapies used to prevent thromboembolism; as a result, all anticoagulants may cause potentially life-threatening bleeds.

Patients at a higher risk of bleeding include those with renal and hepatic impairment and those concomitantly receiving systemic azole-antimycotics, HIV protease inhibitors, drugs affecting haemostasis, and agents that are strong inhibitors of the CYP3A4 and P-GP pathways.

Care also needs to be taken in the anticoagulation of patients with other haemorrhagic risk factors such as uncontrolled severe arterial hypertension, active or recent gastrointestinal ulceration, recent intracranial or intracerebral haemorrhage, and bronchiectasis or a history of pulmonary bleeding. It is therefore essential for the practitioner to understand the risks and benefits of

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anticoagulation in older patients with AF, hypertension and CKD.

Federal Drug Administration suggest bleeding risk for dabigatran to be higher (505 cases) than warfarin (176 cases) in the first quarter of 2012. The RELY study patients were younger, heavier and with better kidney function. Rivaroxaban (15 or 20 mg QD) was found to be non-inferior to warfarin on intention-to-treat analysis but superior in on-treatment analysis, displaying a similar rate of major bleeds.

Dabigatran is excreted 80% unchanged in the urine, with the pharmacokinetics of dabigatran highly influenced by renal function. It is currently contra-indicated in CKD stages 4 and 5 and a dose reduction is required in CKD stage 3.

Rivaroxaban is excreted one-third unchanged in the urine, with concentrations and half-life less influenced by renal function. Reduction of the 20-mg rivaroxaban dose to 15 mg is recommended in CKD stage 3, and it should be used with caution in stage 4 patients. Rivaroxaban is not recommended for use in CKD stage 5.

Currently approved registration for the use of rivaroxaban in adults in the European Union include the prevention of vascular thromboembolism in patients undergoing elective hip- or knee-replacement surgery (registered for such use in South Africa), treatment and prevention of recurrent deep-vein thrombosis and pulmonary embolism following an acute deep-vein thrombosis, and prevention of stroke and

Warfarin Warfarin has been the mainstay of anticoagulation in AF patients. However, large observational studies have suggested that compared to placebo, warfarin is associated with increased risk of both haemorrhagic and ischaemic stroke in advanced CKD and is contra-indicated in stages 4 and 5. Another concern is that warfarin blocks vitamin K2, which may be important in the prevention of vascular calcification.

New oral anticoagulants Prof Rayner continued by discussing trials in which the new agents were comparators against warfarin. The RELY (dabigatran), ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban) trials showed that in non-valvular AF, the new agents were non-inferior or superior to warfarin.

Results from RELY indicated dabigatran 110 mg bid was non-inferior to warfarin, with 20% fewer major bleeds; whereas the 150-mg bid dose was superior to warfarin, although it displayed a similar rate of major bleeds.

Of note are recent reports of a greater bleeding risk in the elderly with the use of dabigatran as opposed to warfarin.

Adverse drug reactions reported to the

systemic embolism in non-valvular AF patients with another risk factor such as age or hypertension.

Management of bleeding complications Prof Rayner commented on the management of bleeding complications in the anticoagulated patient. The next dose should be delayed or, if appropriate, treatment should be interrupted.

Individualised bleeding management may include symptomatic treatment such as mechanical compression, surgical intervention and fluid replacement; and haemodynamic support such as blood products or blood components. For lifethreatening bleeding, use of specific procoagulant agents such as prothrombin complex concentrate (PCC), a PCC and factor VIIa should be considered; although there is currently limited clinical experience with these measures.

Prof Rayner’s concluding statements were that the new anticoagulants are an exciting development. The lack of need for dose monitoring of the new agents does not however imply a reduction in haemorrhagic risk. He emphasised responsible prescribing, the importance of weighing risk against benefit, and the importance of understanding the effects of renal dysfunction on these agents.

Glenda Hardy

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www.cvja.co.za – subscription is 200 ZAR for 24/7 access to the CVJAfrica since 2001. www.diabetesjournal.co.za – subscription is 200 ZAR for 24/7 access to the SAJDVD.

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Faculty of Consulting Physicians of South Africa (FCPSA) Saving brain with dabigatran

Dr Ken Butcher is associate professor of Neurology at the University of Alberta, Canada. His major clinical and research interests include acute stroke care. He holds a Canada research chair in Cerebrovascular Disease, and the Heart and Stroke Foundation of Alberta professorship in Stroke Medicine.

At the FCPSA 2012 congress, Dr Butcher stressed from the outset the urgency of rapid diagnosis in stroke/transient ischaemic attack (TIA). The presentation of ischaemic and haemorrhagic stroke has complete overlap, with Dr Butcher noting that ‘one is blind until imaging is performed’.

Patients with focal neurological deficits (speech issues and weakness) undoubtedly require a scan, but so too do those whose symptoms resolve en route. This is supported by the finding that 50% of TIA patients have evidence of ischaemic infarction on MRI. Early recurrent stroke is also common after a TIA or minor stroke.

Lacunar infarcts (LACI) are classically hypothesised to occur as a result of lipohyalinosis, whereas the cortical infarcts (PACI) are thought to occur as a result of artery–artery and cardioembolism. Nonetheless, the mechanism cannot be reliably determined based on infarct pattern, making it necessary to investigate for all possible aetiologies, including cardio-embolism, which is most often secondary to atrial fibrillation (AF).

‘AF is a major stroke risk factor, equating to a five-fold increase in risk’, Dr Butcher said. In terms of cardio-embolic stroke, thrombi tend to be fairly large, although they often break up. Emboli will more often go to the left hemisphere, but can end up in any arterial territory within the brain. Cardio-embolic strokes tend to be larger, and associated with greater disability and higher mortality rates.

‘In my practice, virtually all patients with AF require anticoagulation, as they have suffered a TIA/stroke, putting them at high risk for recurrence. Even patients ‘Thrombin time is directly related to dabigatran concentration, which is incredibly useful when considering thrombolysis in a patient taking dabigatran’ – Ken Butcher

‘Using the 110-mg dabigatran dose is viable as you have not lost efficacy compared to warfarin. Although the 150-mg dose is preferred in younger patients with normal renal function, I would still use it in situations where this is the only dosage available’ – Ken Butcher

with lower risk-stratification scores (CHADS) are at significant risk for stroke and most should be anticoagulated. The stroke risk in paroxysmal AF patients is also just as significant.’

‘Dabigatran binds both free and clot-bound thrombin, making it a very powerful anticoagulant. Cardiologists note that patients on dabigatran undergoing percutaneous coronary intervention (PCI) with stenting, experience fewer clots than patients on other therapies’, he said. Baremetal stents are recommended for these patients, in order to avoid exposure to triple antithrombotic therapy for more than one month.

Presenting the RE-LY study,1 Dr Butcher noted the well-balanced cohort in each of the three arms: warfarin, and dabigatran 110 and 150 mg bid. The 150-mg dose was clearly superior, and so has become the default dose or dose of choice.

‘The relative risk reduction (RRR) in stroke and systemic emboli was 34% while the absolute risk reduction was 0.59%. Although seemingly small, it translates to a number needed to treat (NNT) of 169 patients per year to avert a cerebrovascular event. This translates into significant numbers over the lifetime of a patient, and even greater cost benefits from a population health perspective’, Dr Butcher stressed.

The amazing aspect is that these benefits do not come with an increase in major bleeds. ‘More importantly, most of the improved safety related to fewer intracranial haemorrhages. I interpret this to mean that there is something about warfarin that is bad for the brain. This is likely related to knocking out all of the vitamin K-dependent clotting factors with warfarin therapy, which does not occur with the novel oral anticoagulants.

The improved safety profile of dabigatran occurred across all sites of intracranial bleeds whether subdural, intracerebral or

subarachnoid’, Dr Butcher pointed out.

The real side effect of warfarin is dyspepsia. ‘I use a proton pump inhibitor with these drugs to provide cytoprotection, particularly in the elderly.

In most patients, the dyspepsia is not severe’, he added.

Referring to the two major arguments related to not choosing to use these new agents, Dr Butcher noted the most frequently cited issues were cost and reversibility. With regard to cost, the Canadian experience is that the drug is available at a cost equivalent to that of clopidogrel.

‘When I discuss this aspect with patients, they are often amenable to bear the costs of these agents, which are more beneficial for them in terms of lifestyle.

In Canada, we have had availability for 18 months without funding from the medical aids or State and have been able to get re-imbursement only two months ago. Despite this, dabigatran is frequently chosen by AF patients after discussion.’

The societal cost of stroke is self-evident across the world.

Dr Butcher then presented a number of cases of warfarin-associated intracranial haemorrhages,2 noting that they expand and are not easy to reverse, even using prothrombin complex concentrates (PCCs). ‘So, if warfarin was readily reversible, without mortality or morbidity, the sceptics would have a better argument about the current lack of a dabigatran antidote’, he said.

‘We do have a plan for patients with smaller haematomas on the new anticoagulants. That is to use a five-factor PCC which is a combination of various coagulation factors, such as factor II, VIIa and X, with activated charcoal.’3 With regard to aspects such as myocardial infarction (MI) with these new agents, Dr Butcher noted that he prescribes dabigatran to prevent ischaemic stroke and not MI. ‘It is a spurious argument not to use dabigatran due to the risk of ischaemic heart disease, as most cardiologists have not accepted the ‘It is in the company’s interest to ensure the drug is as affordable as possible so that it can be used widely’ – Kevin Ho, medical director

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

fact that warfarin is an excellent cardioprotectant.’

‘For years we were told that warfarin was insufficient protection for the heart, despite some evidence to the contrary (the ASPECTS study group trial in the UK), and that antiplatelets were required in AF patients with coronary artery disease’, he said. ‘I only add aspirin (81 mg) in those patients with coronary heart disease, unstable angina or stents’, Dr Butcher said, noting that dual use did increase the bleeding risk.

Referring to clinical practice, Dr Butcher noted that after a TIA he provides dabigatran immediately, while with a

large stroke it is customary to wait about a week, rescan and then put the patient on dabigatran, provided spontaneous haemorrhagic transformation has not occurred. He stressed that this practice is off-label, as the trial evidence of RE-LY was based on 14 days’ post-stroke administration of dabigatran.

With regard to patients on dabigatran undergoing surgery, Dr Butcher encouraged physicians to stay involved with the patient and not to stop the drug too early. ‘Bridging the patient with low-molecular weight heparin is not required, but may be useful in situations where surgeons are uncomfortable

351

with the newer agents. Guidelines for dabigatran usage in this situation are currently being developed.’

Julia Aalbers, Glenda Hardy 1.

2.

3.

Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151.

Dawlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial haemorrhage despite anticoagulation reversal. Stroke 2012; May 3 (e-published).

Kaatz S, Kouides PA, Garcia DA, et al.

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87(Supp1): S141–145.

Managing neuropathic pain: first expert recommendation for South Africa places emphasis on stepwise pharmacological intervention Neuropathic pain, initiated or caused by a primary lesion or disease in the peripheral or central nervous system, is best treated by first defining the aetiology, then treating the primary cause such as diabetes or rheumatoid arthritis, and thirdly, initiating appropriate and adequate doses of painrelieving medication. ‘Frequently, patients are referred to us at the Pain Clinic with appropriate pain-relieving therapy, but at very timid doses’, Dr Milton Raff, Christiaan Barnard Memorial Hospital said at the recent FCPSA congress.

In his presentation, Dr Raff dealt with the basics of the physiology of pain, stressing the transmission mechanism of pre-synaptic neurons releasing neuro-

transmitters, reaching the receptor on the post-synaptic neuron in onward transmission to the spinal cord, cortex and the limbic brain, which integrates pain awareness with subjective factors such as fear, anxiety and sleep disturbance. ‘At each physiological level, we have agents to target the pain mechanism (Table 1) but we must appreciate that one aetiology does not cause one symptom but causes a cluster of symptoms that are shared with other aetiologies, requiring more than one therapeutic approach’, Dr Raff noted.

With regard to neuropathic pain, there are four main drug classes that can be used: carbamazepine as a sodium channel blocker plus anti-depressants; the alpha-2

TABLE 1. PATHOPHYSIOLOGICAL TARGETS IN PAIN MANAGEMENT Peripheral activation (mainly prostaglandin mediated) Factors affecting transmission e.g. increased sodium channels Conduction via afferent neurons to dorsal horn (alpha-2 delta subunit) Dorsal horn receptors (NMDA receptors) Spinal cord (COX-3 mediated and other mediators) Brain (µ, κ, δ receptors) Modulation of the feedback mechanism (serotonin and noradrenaline mediated)

NSAIDS, COXibs Carbamazepine, lignocaine Pregabalin, gabapentin Ketamine (anaesthesia) Gabapentinoids NSAIDS, paracetamol Opioids Tramadol SNRIs (selective noradrenaline reuptake inhibitors) SSRIs (selective serotonin reuptake inhibitors)

delta-ligands (pregabalin and gabapentin); SNRIs; and opioids. ‘The difficulty is that there are no predictors to guide choice and no head-to-head studies to compare agents’, Dr Raff pointed out. This has led to the development of a stepwise pharmacological approach of using agents, first developed by Dickenson,1 and latterly followed by international agencies such as the European Federation of Neuroscience guidelines.2 Recent South African guidelines have been published,3 with input from an expert panel consisting of specialists from the fields of psychiatry, neurology, neurosurgery, anaesthesiology, family medicine and basic science (Table 2).

The expert panel makes the following recommendations: • First-line therapy is the alpha-2 deltaligands (pregabalin or gabapentin), TCAs (tricyclic antidepressants) or the SNRIs (duloxetine and venlafaxine).

• Second-line therapy consists of a combination of these drugs.

• Third-line therapy involves the use of tramadol and the opioids (morphine, oxycodone, fentanyl).

‘Interestingly, our so-called proven use of tricyclic antidepressants with their known wide spectrum of side effects is based on a very small study of 79 cases’, Dr Raff said.

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TABLE 2. SUMMARY OF THERAPEUTIC AGENTS FOR PERIPHERAL AND DIABETIC NEUROPATHY IN SOUTH AFRICA α2 δ-ligands Pregabalin

Gabapentin

Contraindications/precautions/drug interactions

Other benefits

No significant drug interactions Linear pharmacokinetics Dose reduction required in renal insufficiency Dosage reduction required in renal insufficiency No clinically significant drug interactions

Improvement of sleep disturbance Anxiolytic Improvement of sleep disturbance

SNRIs Duloxetine

Contraindicated in severe hepatic impairment, end-stage renal disease, alcohol abuse, concomitant use of tramadol and Improvement of MAOIs major depression Low initial doses for mild to moderate hepatic and renal impairment disorder and Caution required in patients with history of mania, seizures, acute narrow-angle glaucoma generalised Glucose monitoring required as worsening glycaemic control seen in diabetic patients anxiety disorder Drug interactions with tramadol, TCAs, SSRIs and SNRIs. Inhibition of metabolism of drugs metabolised by CYP2D6 Suicide risk (black-box warning, in line with other antidepressants) Venlafaxine Caution required in patients with cardiac disease Risk of hypertension, hence regular blood pressure monitoring required Lower dose may be necessary in patients with renal impairment (GFR = 10–70 ml/min) or cirrhosis of the liver Use with caution in patients with history of seizures and history of mania Drug interactions with tramadol, TCAs, SSRIs and SNRIs. Inhibition of metabolism of drugs metabolised by CYP2D6 Suicide risk (black-box warning, in line with other antidepressants) TCA: Contraindicated with MAOI use, antihypertensives, patients with myocardial infarction/heart block, untreated narrowImprovement of amitriptyline angle glaucoma major depression Use with caution in patients with glaucoma, cardiovascular disease, especially in elderly patients, hyperthyroidism, disorder impaired liver function, epilepsy, urinary retention, prostatic hypertrophy, constipation, mania Tramadol High risk of addiction and abuse, psychomotor impairment possible Rapid onset of Use with caution in patients with history of substance abuse, suicide risk, seizure disorder and in elderly patients analgesic benefit because of risk of confusion Contraindicated with concomitant use of SSRI, SNRI, TCA Strong High risk of addiction and abuse, psychomotor impairment possible Rapid onset of opioids Use with caution in patients with history of substance abuse, suicide risk and in elderly patients because of risk of analgesic benefit confusion Contraindicated with concomitant use of SSRI, SNRI, TCA SNRIs = serotonin–noradrenalin reuptake inhibitors; MOAIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants; SSRIs = selective serotonin reuptake inhibitors.

‘Gabapentin works, despite a host of side effects including dizziness, somnolence and peripheral oedema.

Pregabalin is effective, but it is essential to use a therapeutically adequate twicedaily dose, between 75 and 150 mg bid’, Dr Raff noted.

Duloxetine at a dosage of 60 mg daily is the recommended dose and there is more evidence for its use in painful diabetic neuropathy (PDN) than there is for venlafaxine use.

Oxycodone in controlled-release format is now available in South Africa.

‘It can however take up to four weeks to provide pain relief and patients must be prepared for this treatment delay’, he noted. ‘Tramadol has adequate but not large studies supporting its third-line use.’

The therapeutic rationale for postherpetic neuralgia (PHN) is treatment

with gabapentin, pregabalin, TCAs, and strong opioids as they have evidence of efficacy for PHN. The first-, second- and third-line therapy is therefore essentially the same for PNP and DPN. Trigeminal neuralgia therapy options are sparse with only carbamazepine and oxcarbazepine achieving positive outcomes.

Therapy for central neuropathic pain from spinal cord injuries and stroke is a neglected field with few clinical trials. South African guidelines suggest carbamazepine, pregabalin or amitryptiline but note that there is limited supporting evidence in this category of patients.

‘Non-pharmacological treatments, if they work for the patient, should be positively regarded by the attending physician’, Dr Raff concluded.

New South African guidelines for the management of neuropathic pain are available on the South African Medical Journal website: www.samj.org.za/index. php/smj/article/download/5472/4036.

Julia Aalbers 1.

2.

3.

Dickenson AH, et al. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple aetiologies. Pain 2005; 113(3): 251–254.

Ahal N, et al. EFNS guidelines on the Pharmacological treatment of neuropathic pain. 2010 revision. Eur J Neurol 2010; 17: 1113–e88.

Chetty S, Baalbergen E, Bhigjee AI, Kamerman P, Ouma J, et al. Clinical practice guidelines from management of neuropathic pain: expert panel recommendations for South Africa. S Afr Med J 2012; 102(5): 312–325.

LYRICA® - early and sustained

relief in the treatment of Neuropathic Pain*5,6,7

Early onset - reduction of pain within first week5,6 Sustained pain relief7 Simple BD dosing

*South African Registration: - Diabetic Peripheral Neuropathy - Postherpetic neuralgia International Guidelines: 1. US: Postherpetic neuralgia 2. Canada: Chronic Neuropathic Pain 3,4. EU: Neuropathic Pain

References: 1. Dubinksy RM, Kabbani H, El-Chami Z, Boutwell C, Ali H. Practice Parameter: Treatment of postherpetic neuralgia – An evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004; 63:959-965. 2. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CPN, Sessle BJ, et al. Pharmacological management of chronic neuropathic pain - Consensus statement and guidelines from the Canadian Pain Society. Pain Res Manage 2007; 12(1):13-21. 3. Attal N, Cruccu G, Haanpää M, Hansson P, Jensen TS, Nurmikko T, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006; 13:1153-1169. 4. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007; 132:237-251. 5. Freeman R, Durso-DeCruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomised, controlled trials across a range of doses. Diabetes Care 2008; 31(7):1448-1454. 6. Sabatowski R, Gálvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, et al. The 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomized, placebo-controlled trial: Pain 2004; 109:26-35. 7. Stacey BR, Dworkin RH, Murphy K, Sharma U, Emir B, Griesing T. Pregabalin in the Treatment of Refractory Neuropathic Pain: Results of a 15-Month Open-Label Trial. Pain Med Mar 11, 2008. [Epub ahead of print].

S5 LYRICA® 25 mg, 75 mg and 150 mg capsules. (Reg. No’s: A39/2.5/0264, 0266, 0268). Each hard capsule contains 25 mg, 75 mg, or 150 mg of pregabalin respectively. LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. Reg. No. 1954/000781/07. P O Box 783720, Sandton, 2146. Tel. No.: 0860 PFIZER (734937). Please refer to detailed package insert for full prescribing information (PI Ref 02/02/10).

06/LYR/08/11/JA. 17767

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Where Power meets Functionality in Pain Management

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POWER Powerful ul pain reduction

2,3,4

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LEPETTA 083 415 6431 L789

Demonstrated safety and tolerability profile5,6

S3 CELEBREX® 100 mg and 200 mg Capsules. (Reg. No’s: 33/3.1/0332, 0333). Each capsule contains 100 mg and 200 mg celecoxib respectively. LICENCE HOLDER: Pzer Laboratories (Pty) Ltd. Reg No. 1954/000781/07.

P O Box 783720, Sandton, 2146. Tel. No.: 0860 PFIZER (734937). Please refer to detailed package insert for full prescribing information. (PI Ref 11/12/08). 5/CEL/1/11/TA. References: 1. Celebrex p prescribing g information, ((PI ref: 11/12/2008). ) 2. Frampton p JE, Keating g GM. Celecoxib: A Review of its Use in the Management g of Arthritis and Acute Pain. Drugs g 2007;67(16):2433-2472. ( ) 3. Petri M, Hufman SL, Waser G, Cui H, Snabes MC, Verburg g KM. Celecoxib effectively y treats p patients with acute shoulder tendinitis/bursitis. J Rheumatol 2004;31(8):1614-1621. ( ) 4. Derry y S, Barden J, McQuay y HJ, Moore RA. Single g dose oral celecoxib for acute p postoperative p p pain in adults. Cochrane Database Syst y Rev. 2008;(4):CD004233. ( ) 5. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 y yg inhibitor, on platelet function in healthy p y adults: a randomized, controlled trial. J Clin Pharmacoll 2000;40:124-132. 6. Nadarajah j A, Abrahan L, Lau FL, Hwang g LJ, Fakir-Bolte C. Efcacy y and tolerability y of celecoxib compared p with diclofenac slow release in the treatment of acute ankle sprain p in an Asian p population. p Singapore g p Med J 2006;47(6):534-542. ( ) 7. Zhao SZ, McMillen JI, Markenson JA, Dedhiya y SD, Zhao WW, Osterhaus JT et al. Evaluation of the Functional Status Aspects p of Health-Related Qualityy of Life of Patients with Osteoarthritis Treated with Celecoxib. Pharmacotherapyy 1999;19(11):1269-1278. 8. Rozenberg S, Meric G, Jeanpetit Y. [Changes in quality of life in patients with osteoarthritis treated with celecoxib: the Qualice study.] Presse Med d 2008;37:571-578.

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

Rheumatoid arthritis management options for 2012 The fundamental approach in managing rheumatoid arthritis is to treat early to reduce functional loss and to treat aggressively to achieve a low disease activity rate. ‘This is because international research has shown that in 70% of rheumatoid arthritis patients, irreversible damage has occurred in the first three years of the disease’, Prof Simon Huang, clinical associate professor, Division of Rheumatology, University of British Columbia, Canada noted in his presentation at the FCPSA congress.

‘We need to treat aggressively as early as possible with disease modifying antirheumatic drugs (DMARDs) and treat to target’, he stressed.

The objective of therapy is to achieve remission of symptoms with low disease activity, being defined as less than or one painful joint, less than or one swollen joint and C-reactive protein (CRP) levels less than 1 mg/l. These classification criteria were reviewed in 2010 in a joint American/European effort to focus attention on the important need for earlier diagnosis and therapy.1 ‘Drug therapy should be assessed every three to six months with adaptations to therapy being introduced if diseasemodifying targets of remission/low activity are not reached’, Prof Huang stressed.

The European guidelines compiled by the European League Against Rheumatism (EULAR) also aimed to set practical recommendations to guide effective therapeutic choices.2 Their stepped-up approach is summarised in Fig. 1. In the USA, guidelines are also adopting a more aggressive therapeutical approach.

‘With regard to the traditional, non-biologic DMARDs, all are slow acting. Methotrexate should be uptitrated regularly and patients monitored every one to three months for individual side effects. In South Africa, the presence of HIV infection may reduce the general “gold standard” status of methotrexate, as its use is contra-indicated in chronic hepatitis B and C, and likely also in HIV infection.’

In terms of biological DMARDs, it is important to note that the tissue necrosis factor inhibitors (TNF-I) are regarded as first-line biological agents and those that are receptor-type inhibitors, which

Phase I No contraindication for methotrexate

Start methotrexate

Failure phase I: go to phase II

Contraindication for methotrexate

Clinical diagnosis of rheumatoid arthritis

±

Combine with shortterm low- or high-dose glucocorticoids Achieve target* within 3–6 months

No

±

Start leflunomide, intramuscular gold or sulfasalazine

Yes

Continue

Phase II Prognostically unfavourable factors present such as RF/ACPA, esp. at high levels; very high disease activity; early joint damage Add a biological drug (especially a TNF-inhibitor)

Failure phase II: go to phase III

Failure or lack of efficacy and/or toxicity in phase I

Start a second synthetic DMARD: leflunomide, sulfasalzine, methatrexate or intramustcular gold as monotherapy or eventually as combination therapy (with or without addition of glucocorticoids as above)

Achieve target* within 3–6 months

No

Achieve target* within 3–6 months

No

Prognostically unfavourable factors absent

Yes

Continue

Achieve target* within 3–6 months

Yes

No

Continue

Phase III Biological agent ± synthetic DMARD

Failure or lack of efficacy and/or toxicity in phase II

Change the biological treatment: Switch to second TNF-blocking drug (+ DMARD) or Replace TNF-blocking drug by abatacept (+DMARD) or rituximab (+ DMARD) or locilizumab (± DMARD)

Fig. 1. Algorithm based on the European League Against Rheumatism recommendations on rheumatoid arthritis management. DMARD, diseasemodifying anti-rheumatic drug; RF/ACPA, rheumatoid factor/anti-citrullinated peptide antibodies; TNF, tumour necrosis factor. *The treatment target is clinical remission or, if remission is unlikely to be achievable, at least low disease activity.

interfere in cell-to-cell transmission, are preferable for use with co-infections.

‘Patients with heart disease should not be given TNF inhibitors’, Prof Huang said.

Julia Aalbers 1.

2.

Aletaha D, Neogi T, Silman AJ, Funovits J, et al. 2010 Rheumatoid arthritis classification criteria. Arthritis Rheum 2010; 62(9): 2569–2581.

Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, et al. EULAR

3.

recommendations for the management of rheumatoid arthritis with synthetic and biologic disease-modifying anti-rheumatic drugs. Ann Rheum Dis 2010; 69(6): 964–975.

Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease modifying anti-rheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012; 64(5): 625–639.

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Benefit versus risk in the use of non-selective NSAIDs and selective COX-2 inhibitors The use of COX-2 inhibitors (COXibs) as therapy for both acute and chronic musculoskeletal disease is well established in South African therapeutic guidelines. These agents need to be used to support the objective of reducing symptoms and attaining a low activity status.1,2 Celecoxib, the widely-used COX-2 inhibitor, has official indications for symptomatic relief in rheumatoid arthritis and osteoarthritis, and also evidence of efficacy in acute low-back pain,3 acute ankle sprains,4 acute shoulder pain, and dysmenorrhoea.5 A recent Cochrane systemic review has also shown the efficacy of celecoxib therapy for acute post-operative pain.6 While it is well accepted that celecoxib is less likely to cause gastrointestinal bleeds and symptoms than non-selective traditional antiinflammatories, the difference in cardiovascular safety is still of concern to some cardiologists and physicians.

Prof Huang addressed the risk-benefit profile of non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) in a series of symposia sponsored by

MARK YOUR CALENDAR

celecoxib or the NSAIDS are used.

‘These agents should be used at the lowest effective dosage, after careful evaluation of the gastrointestinal, cardiovascular and renal risks of the individual patient’, he concluded.

Julia Aalbers 1.

2.

3.

4.

5.

6.

7.

South African Acute Pain Guidelines. S Afr J Anaesthesia Analgesia 2009; 15(6): 1–120. www.saraa.co.za.

Petri M, Hufman SL, Waser G, et al.

Celecoxib effectively treats patients with acute shoulder tendinitis/bursitis. J Rheumatol 2004; 31(8): 1614–1620.

Cardenas-Estrade E, et al. Efficacy and safety of celecoxib in the treatment of acute pain due to ankle sprain in a Latin American and Middle Eastern Population.

J Int Med Res 2009; 37(6): 1937–1951.

Daniels S, et al. Celecoxib in the treatment of primary dysmenorrhea. Clin Ther 209; 31(6): 1192–1208.

Derry S, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev 2010; 14(3): CD004233.

Hermandez-Diaz S, et al. Non-steroidal anti-inflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmecol Toxicol 2006; 98(3): 266–274.

17-22 FEBRUARY 2013 CAPE TOWN, SOUTH AFRICA

COME TO CAPE TOWN...

6th

Paediatric Cardiology & Cardiac Surgery

Conference Secretariat Contact the conference secretariat or visit www.pccs2013.co.za Event Dynamics P.O Box 6761, Roggebaai, 8012, South Africa Telephone: +27(0) 21 408 9796 Fax: +27(0) 21 408 9954 E-mail: info@pccs2013.co.za

Hosted by:

SOUTH AFRICAN HEART ASSOCIATION

Pfizer, following on the FCPSA annual congress held in Cape Town recently.

Referring to the Harvard-based study conducted by Hermandez-Diaz and co-workers,7 Prof Huang noted that smoking, diabetes and hypertension cause many more cardiovascular-related problems than either the non-aspirin NSAIDs or the COXibs.

‘In Diaz’s systematic review of the use of NSAIDS and the risk of acute myocardial infarction (MI), there was an increased MI risk observed for diclofenac and rofecoxib. The relative risk ratio (RRR) however for celecoxib (0.96) was very similar to that of naproxen (0.98), which has been regarded as the safest NSAID to use in at-risk cardiovascular patients.’

‘The available evidence supports the view that celecoxib and nsNSAIDs, used with or without proton pump inhibitors, are equally effective. The risks related to the cardiovascular and renal vascular systems are similar’, he commented.

Dr Huang noted that to minimise any potential risks, normal good clinical practice should be in place when either

A trendy, sophisticated, multi-cultural city at the foot of Africa in a diverse and beautiful natural environment. Cape Town is a destination with irresistable appeal.

South Africa has a compelling history and with its abundance of game reserves offers visitors a uniquely different cultural and tourist experience.

The most distinguished international faculty available makes the “6th World Congress” an attractive, interactive and unique meeting place for clinicians, scientists health care managers and policy developers from all across our world.

PROGRAMME TRACKS •Surgery, anaesthesia and intensive care •Catheter interventions from fetus to adult •Health systems and heart disease •Adults with congenital and acquired heart disease •Cardiology and the imaging revolution

www.pccs2013.co.za

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Drug Trends in Cardiology ORIGIN trial shows safety and efficacy of insulin glargine No adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use The ORIGIN trial, a large trial in patients with high cardiovascular risk and dysglycaemia, using an intervention of initial basal insulin (glargine) in impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or early-stage type 2 diabetes, has shown no cardiovascular benefits or adverse cardiovascular outcomes. However a reduction of progression to diabetes did occur in patients with IFG or IGT who were treated with insulin, actively targeting normoglycaemia of < 5.3 mmol/l, compared to those treated with standard care and mainly oral agents.1 Importantly, the long-term use of insulin glargine was shown to be efficacious in lowering glucose levels safely over the six-year period. There was no increase in the incidence of cancer or cardiovascular events in the more than 5 000 patients treated over this extended period.

The trial showed that better glucose control was achieved using a daily injection of basal insulin (with or without oral agents) in high-risk patients who self-titrated their insulin dosage to a fasting plasma glucose (FPG) level of < 5.3 mmol/l compared to those offered standard care. However, in both groups, a mean HbA1c level of â&#x2030;¤ 6.5% was achieved over the duration of the study.

In those in the glargine arm of the study, the median insulin dose rose from 0.31 U/kg by year one to 0.40 U/kg by year six. Importantly, 83.6% (5 230 patients) were adherent to their insulin glargine therapy at year six; 19% did

however permanently discontinue their insulin therapy. In the standard-care group, 11% of patients were using insulin at the end of the study.

With regard to the co-primary composite cardiovascular outcomes of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke, and secondly, the composite of these events plus either a revascularisation procedure or hospitalisation for heart failure, there was no significant difference between the two groups.

Compared to standard care, insulin glargine, titrating towards normoglycaemia, had a neutral outcome with regard to cardiovascular outcomes.

There was also no significant difference with regard to microvascular events. Of particular importance was that there was no significant difference in the incidence of any cancer, death from cancer or cancer at specific sites (Table 1).

The incidence of a first episode of severe hypoglycaemia was a modest 1.00 per 100 person-years in the insulin glargine-treated group, and 0.31 per 100 person-years in the standard-care group (p < 0.001). Participants in the insulin glargine group gained a median of 1.6 kg whereas the standard-care group lost a median of 0.5 kg.

Reduction in progression to diabetes In the sub-population of 1 456 participants without diabetes, but with IFG/IGT

TABLE 1. CANCER INCIDENCE IN THE ORIGIN TRIAL Cancer by site Hazard ratio Breast 1.01 Lung 1.21 Colon 1.09 Prostate 0.94 Melanoma 0.88 Other 0.95 Amended from supplementary data, reference 1.

Insulin glargine n (%) 28 (0.4) 80 (1.3) 76 (1.2) 88 (2.1) 15 (0.2) 233 (3.7)

Standard care n (%) 28 (0.4) 66 (1.1) 70 (1.1) 89 (2.2) 17 (0.3) 245 (3.9)

and other cardiovascular risks at randomisation, 737 were assigned to insulin glargine and 719 to standard care. Those assigned to insulin glargine were 28% less likely to develop diabetes, as defined by oral glucose tolerance tests performed on 65% of this cohort.

Dr Landi Lombard, specialist physician, diabetologist, Kuilsriver, Cape Town and editor of the South African Journal of Diabetes and Vascular Disease attended the American Diabetes Association meeting and commented The ORIGIN trial had two main arms.

The first assessed the use of 1 g of omega-3 fatty acid supplementation in this cardiovascular high-risk group, versus placebo. This was based on many previous trials showing potential benefit, and the GISSI trial showing statistically significant benefit of this therapy in postmyocardial infarction patients, with a 15% reduction in all-cause mortality.

A recent meta-analysis supported these results and showed a 9% cardiovascular mortality benefit. Unfortunately this was not supported in the ORIGIN trial, which showed no benefit. The absence of benefit was found in both primary and secondary outcomes and also in all the subgroup analyses. This is obviously very disappointing, with only a very small reduction shown in triglyceride levels. There is no positive take-home message here and I cannot recommend the use of omega-3 fatty acids in this study population.

The second arm of the study assessed insulin glargine versus standard care for IFG, IGT or early diabetes in high-risk cardiovascular patients. This arm of the study was unfortunately also negative. No cardiovascular benefits could be shown for the primary or secondary endpoints despite a 3% per year event rate.

These results were very disappointing

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and suggest no cardiovascular benefits from early insulin initiation in high-risk patients with early diabetes. This strategy can therefore also not be recommended for cardiovascular protection, but should be used on merit for diabetes control.

However, it is important to note is that the early use of insulin glargine targeting normoglycaemia of < 5.3 mmol/l had no adverse effect with regard to cardiovascular outcomes.

There were however two positive outcomes/conclusions from this part of the trial. The first was the safety of glargine insulin, which this study has now proven beyond any doubt to be a safe insulin. Glargine now has more safety data than most other medicines and much more than any other insulin (10 years), with no sign at all to suggest increase in cancer risk. The risk of hypoglycaemia in the study was also fairly low and weight gain was only 1.6 kg over the 6.2 years of average follow up.

The second positive outcome was that the glargine group slowed progression from dysglycaemia to diabetes in the subgroup with IGT and IFG (n = 1 456), with a 28% risk reduction despite a 1.6-kg weight gain. The question remains if this would be a cost-effective intervention

to consider in these patients, and further study will be required.

As in the UKPDS study, an 8.5-year extension of follow up proved to be invaluable with regard to microvascular outcomes. In that light, a further two years of follow up has already been announced, which might generate further interesting data. Currently, I don’t think this strategy can be used in general practice as routine management.

Dr Larry Distiller, Centre for Diabetes Education, Houghton, Johannesburg It is probably not surprising that there was no demonstrable reduction in cardiovascular outcomes in patients on glargine insulin compared to the standardcare group. Firstly, although these were ostensibly ‘new-onset’ diabetes patients, all were at high risk, with documented cardiovascular disease at the time of selection, and, as with the ADVANCE, ACCORD and VADT trials, one would not expect a reversal of cardiovascular event rates in just seven years in patients with documented vascular disease.

Secondly, the difference in HbA1c levels achieved between the standard-care

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and glargine group was just 0.3%, with both groups achieving mean HbA1c levels ≤ 6.5%. Unless one was to anticipate a specific protective effect of insulin itself, one would not anticipate a different outcome between the two groups based on differences in glycaemic control alone.

The positive aspects of this study are that tight glycaemic targets are achievable without increasing cardiovascular mortality, even in high-risk patients, and that glargine insulin can be used safely as a therapeutic option in both high-risk and recently diagnosed diabetes. The weight gain documented and the amount of hypoglycaemia experienced is acceptable and not excessive.

It is unlikely that the outcomes reported in this trial will have any significant impact on the current approaches to the management of diabetes in the clinical setting.

Dr Landi Lombard, Dr Larry Distiller, Julia Aalbers 1.

The ORIGIN trial investigators. Basal insulin and CV and other outcomes in dysglycemia. N Eng J Med. Epub 11/6/2012. DOI: 10.1056/NEJMoa1203858.

Advertorial Lantus®: our commitment to safety Introduction As an ethical pharmaceutical company with a long-standing commitment to diabetes, the safety and wellbeing of people with diabetes is of paramount importance to Sanofi. Lantus® [insulin glargine (rDNA) injection] is already supported by a wealth of available data1 resulting from more than 80 000 patients enrolled in clinical trials and over 47 million patient-years2 of treatment exposure to insulin glargine, which showed no increased cancer risk with Lantus®.1 Nevertheless, the company is committed to contributing to the generation of knowledge on the safety of insulin, including insulin glargine. Further to the debate on the potential relationship between insulin and cancer since 2009, and the safety of insulin glargine in this context, we are taking an active stance to provide accurate and meaningful scientific information.

To this effect, Sanofi is working closely

with prominent scientists, health authorities (EU, US and others), scientific associations (including the American Diabetes Association) and the American Cancer Society.

At the American Diabetes Association 72nd scientific sessions, we released new results of a large-scale epidemiological programme to evaluate cancer risk in diabetes and generate comprehensive insulin glargine exposure data from large databases.

Sponsored by Sanofi and conducted by independent researchers in the northern European countries, at Kaiser Permanente in northern and southern California, and at the University of North Carolina in the United States, it is the largest observational programme designed for this purpose to date.

Lantus® and cancer risk allegations The role of (any) insulin and its potential

relation to cancer has been a matter of scientific debate, where some studies published since 2009 have shown an association and others have not.

In June 2009, Diabetologia published four papers suggesting a possible relationship between insulin analogs, such as insulin glargine, and an increased risk of cancer. The publications generated debate and concern over the safety of such insulin treatments.

Limitations of the Diabetologia papers In January 2011, the US Food and Drug Administration (FDA) announced that it had reviewed the four published papers and determined that the evidence presented was inconclusive.3 Methodological limitations included: • Insufficient information on patients’ prior and subsequent use of insulin products • Inadequate control of confounding risk

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factors for cancer (e.g. smoking, family history of cancer and obesity) • Insufficient duration of patient follow up.

In light of the shortcomings in study design, the FDA did not conclude that insulin glargine increased the risk of cancer and the review determined that prescription of insulin glargine by healthcare professionals and its use by people with diabetes should remain unchanged.3 Drug regulatory agencies in the US (FDA), the EU (EMA) and others have conducted a review of insulin glargine data and have not required changes in the package insert regarding its use.3,4 These agencies have recommended that patients maintain their treatment as prescribed. The ADA/ACS Consensus statement on this matter concludes that further research is needed to clarify these issues.5 The Sanofi Epidemiological Programme Rationale In September 2009, the company announced it was collaborating with independent experts on an epidemiological programme aimed at generating methodologically robust information on a potential association between cancer risk and insulin treatment options.

The epidemiological programme comprises three major studies designed to overcome the methodological limitations of the Diabetologia papers and to provide further evidence about the safety of insulin glargine with respect to oncology outcomes.

The three studies • Northern European (prescription) database study • US database study (northern and southern California Kaiser-Permanente Diabetes Registries) • International Study of Insulin and Cancer (ISICA) The studies have been designed independently of the company by the lead investigators and endorsed by the EMA and FDA. They use state-of-the-art biostatistical methodology with protocols that have been discussed with a senior-level biostatistics advisory group and European regulators.

Results At the American Diabetes Association’s (ADA) 72nd scientific sessions, Sanofi announced results from the US and northern European observational database studies providing further evidence that there was no increased risk of cancer in people with diabetes treated with insulin glargine, compared to those treated with other insulins.

These findings reinforce the established safety profile of insulin glargine, complementing the existing wealth of data already available. Endorsed by the EMA and FDA, the epidemiological programme is the largest observational programme designed for this purpose to date.

Northern European database study The northern European study, conducted in Denmark, Finland, Norway, Scotland and Sweden is the largest study of its kind comprising 447 821 people with diabetes using insulin, over 1.5 million person-years of observation.

The average follow-up time is longer than any other follow-up study, at 3.1 years for those on insulin glargine and 3.5 years for other insulins. This study looked at the risk for all cancers, as well as individually for breast, lung, pancreas, colorectal and prostate cancers.

The study was led by Peter Boyle, president of the International Prevention Research Institute based in Lyon, France.

In answering the primary hypothesis, among all users of insulin, and similarly among users of human insulin, this observational study found: • no evidence of an increased risk of breast cancer in women, prostate cancer in men and colorectal cancer in men and women • no evidence of an increased risk in users of insulin glargine vs other insulins relative to the pre-specified secondary hypothesis (risk of all forms of cancer combined) and the exploratory hypothesis (risk of lung or pancreatic cancer) • in conclusion, the study showed no increased risk for cancer in association with the use of insulin glargine compared to users of other insulins.

The Committee for Medicinal Products for Human Use (CHMP) in Europe expressed that the northern European study results add important knowledge for understanding the safety of insulin glargine.

US study (Kaiser-Permanente Collaboration) The main analyses of this US database study (using the northern and southern California Kaiser Permanente diabetes registries included 115 000 patients with median duration of 1.2 years for glargine use and 1.4 years for neutral protamine Hagedorn (NPH) among all insulin users (insulin glargine and NPH insulin). They examined cancer risk in people treated with each of these insulins as well as those who had switched from one to the other.

Results from the US database study, led

by John Buse, former president of the ADA, and director of the Diabetes Care Center at the University of North Carolina, were also presented at ADA 2012.

The main analyses among all insulin users (insulin glargine and NPH insulin) showed: • no association between use of insulin glargine and increased risk of breast cancer, prostate cancer or colorectal cancer (primary endpoints) • no association between insulin glargine use and increased risk of all cancers combined (secondary endpoints).

In the sub-analysis of NPH insulin users switching to insulin glargine: • no association with an increased risk of breast, prostate, colorectal or all cancers

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combined.

Among new users of insulin: • no association between insulin glargine use – or duration of insulin glargine use – and risks for prostate, colorectal or all cancers combined.

In a sub-analysis using one specific methodology (counting of dose), there was a suggestion of a very modest increase of breast cancer in patients with two or more years of insulin glargine use. When another methodology was adopted (counting of prescriptions), no such suggestion existed.

Principal investigator Laurel Habel, PhD, research scientist at the Kaiser Permanente Northern California Division of Research, noted that results of their study should be viewed cautiously, given the relatively short duration of glargine use and the large number of associations examined.

Additionally, the US database study was complemented by findings from researchers at the University of North Carolina, using the healthcare database MedAssurant (43 306 patients on glargine and 9 147 on NPH; mean duration of treatment: 1.2 years for glargine group and 1.1 years for NPH group). There was no evidence of an increased risk for cancer, and specifically for breast cancer.

As with the results of the northern European Study and data from the US Kaiser Permanente, the MedAssurant study showed no association between use of insulin glargine and increased risk of the cancers evaluated among all insulin users tested.

International Study of Insulin and Cancer Additional results are expected from another observational study, the International Study of Insulin and Cancer (ISICA), led by Lucien Abenhaim, professor of Public Health at the University of Paris and former director general for Health in France, which will be completed in 2012.

References 1. Home P, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 2009: 52(9): 2499–2506.

2. Safety Monitoring Report, April 2012.

3. US Food and Drug Administration. FDA drug safety communication: update to ongoing safety review of Lantus® (insulin glargine) and possible risk of cancer. Available at: http://www.fda.gov/Drugs/ DrugSafety/ucm239376.htm. Date accessed: June 2012.

4. European Medicines Agency 2009. European Medicines Agency update on safety of insulin glargine – update. Available at: http://www. ema.europa.eu/ema/index.jsp?curl=pages/news_ and_events/news/2009/11/news_detail_000066. jsp&murl=menus/news_and_events/news_and_ events.jsp&mid=WC0b01ac058004d5c1. Date accessed: June 2012.

5. Giovannucci E et al. Diabetes and Cancer. A consensus report. Diabetes Care 2010: 33(7): 1674–1685

Press release from Sanofi. Released at ADA 72nd congress, Philadelphia, USA, 2012

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SHIf T: ivabradine’s additional clinical benefits regardless of background beta-blocker dose In systolic heart failure, reduction in relatively high heart rates improves clinical outcomes when achieved with beta-blockers, and even more so when the sinus node inhibitor ivabradine is also added.1 The mechanism for the effect of beta-blockers in systolic heart failure is unclear but there is an association between improvement of outcomes and degree of drug-induced heart rate reduction.

In the Systolic Heart failure treatment with the If inhibitor Trial (SHIfT), reduction of heart rate by ivabradine, administered in addition to beta-blockers when heart rate exceeded 70 beats/min on beta-blockers alone, reduced subsequent adverse outcomes. A remaining clinical question is whether beta-blocker dose at randomisation impacts on the effect of ivabradine. Investigators explored this question using the SHIfT database, assessing the impact of background betablocker dose on response to ivabradine.

In May 2012, the Heart Failure congress of the European Society of Cardiology (ESC) Heart Failure Association was held in Belgrade, Serbia. At the congress, the sub-analysis of SHIfT was presented

by Prof Karl Swedberg (University of

Gothenburg, Sweden) and simultaneously published online in Journal of the American College of Cardiology.2 The analysis indicates that the effects of ivabradine on the primary clinical outcome of SHIfT and its components were not significantly impacted on by beta-blocker dose. The primary endpoint and heart failure hospitalisations were significantly reduced by ivabradine in all subgroups with < 50% of target betablocker dose including no beta-blocker.

No suggestion of a significant trend was apparent when the analysis was restricted to those taking a beta-blocker.

The placebo-corrected treatment effect of ivabradine on heart rate was significantly related to baseline heart rate but not to beta-blocker dose. Therefore baseline heart rate was the most important contributor to the treatment effect.

When a heart failure patient’s heart rate is greater than 70 beats/min ‘reduction in heart rate with ivabradine will provide additional clinical benefit regardless of beta-blocker dose’, said Prof Karl Swedberg when presenting the analysis.3 ‘The magnitude of heart rate reduction with ivabradine beyond that achieved

HEALTHCARE

by beta-blockers primarily determines subsequent outcomes’.

The clinical implications of these findings reflect the importance of heart rate. Among patients with systolic heart failure, the dose to which a beta-blocker can be titrated is dependent on patient co-morbidities and other demographics.

By adding the heart rate-lowering agent ivabradine in patients whose heart rate exceeds 70 beats/min despite beta-blockade (as well as among those who cannot tolerate beta-blockade), the additional heart rate reduction is beneficial. The magnitude of heart rate reduction by ivabradine beyond what is achieved by a beta-blocker rather than background beta-blocker dose, primarily determines subsequent outcome.

1.

2.

3.

Swedberg K, Komadja M, Bӧhm M, et al.

J Am Coll Cardiol. 2012: 59: 1938–1945.

Swedberg K, et al. Effects on outcome of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose? J Am Coll Cardiol 2012, e-pub. DOI : 10:1016/j. jacc.2012.01.020.

Heartwire website.

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Cardiovascular Topics p53 negatively regulates the osteogenic differentiation of vascular smooth muscle cells in mice with chronic kidney disease KL LI, J CHEN, ZH LI, J ZHAN, L ZHAO, YN HE

Abstract Aim: To investigate the osteogenic differentiation of vascular smooth muscle cells (VSMCs) in mice with chronic kidney disease (CKD) and to evaluate the effects of p53 on the osteogenic differentiation of the VSMCs. Methods: Experimental models of CKD-associated vascular calcification generated by five-sixth (5/6) nephrectomy (Nx) and a high-phosphate (HP) diet were used in p53+/+ and p53–/– mice. Following 5/6 Nx, aortic calcification, markers of osteogenic differentiation, VSMCs and p53 protein in aortic tissues were studied.

Results: Aortic calcification was observed after eight weeks following 5/6 Nx in mice of both genotypes, and expression of the markers of osteogenic differentiation in the VSMCs was increased. These changes were continuously observed up to 12 weeks after 5/6 Nx, and particularly after 5/6 Nx + HP. Compared with p53+/+ mice, aortic calcification in p53–/– mice was more severe (p < 0.001). Expression of the markers of osteogenic differentiation was noticeably increased (p < 0.001), while expression of the marker of VSMCs had decreased (p < 0.001). Statistical analysis demonstrated that the markers of osteogenic differentiation were negatively correlated with p53, and the marker of VSMCs was positively correlated with p53 (p < 0.001).

Conclusion: p53 has the potential to negatively regulate the osteogenic differentiation of VSMCs in CKD mice.

Keywords: chronic kidney disease, mouse, osteogenic differentiation, P53, vascular smooth muscle cells Submitted 1/3/11, accepted 22/11/11 Published online 1/12/11 Cardiovasc J Afr 2012; 23: e1–e9

www.cvja.co.za

DOI: 10.5830/CVJA-2011-069

Department of Nephrology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China KL LI, MD ZH LI, MD J ZHAN, MD YN HE, MD, heynmail@yahoo.com

State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China J CHEN, MD L ZHAO, MD

It is increasingly apparent that individuals with chronic kidney disease (CKD) are more likely to die of cardiovascular disease (CVD) than to develop kidney failure,1,2 and CVD accounts for approximately 50% of the premature deaths in dialysis patients.3,4 Vascular calcification is more prevalent and more severe in patients with stage V CKD (CKD-V),5 and the extent of vascular calcification has been identified as an independent risk factor for cardiovascular death in patients on haemodialysis.3 Calcification can be found in atherosclerotic plaques and in the vascular media, vascular smooth muscle cells (VSMCs) and elastic laminae of large elastic and medium muscular arteries, as well as in the cardiac valves.1,6 Recent evidence indicates that vascular calcification is an active, cell-mediated process. Osteoblast differentiation corebinding factor α-1 (RUNX2) and several bone-associated proteins, such as bone morphogenetic protein-2 (BMP-2) and osterix (Osx), and alkaline phosphatase (ALP) are present in histological sections of arteries as well as in uraemic serum obtained from patients with CKD-V. This supports the theory that VSMCs can dedifferentiate or transform into osteoblastlike cells. The dedifferentiation of VSMCs via up-regulation of core-binding factor a1 (Cbfa1) may be the first step in the process of calcification of the arteries.5,7,8 In addition, it is likely that circulating inhibitors of calcification are also important, but to date, the process is not clearly understood, particularly the effect of cell cycle regulatory proteins (p53 for example) on the osteogenic differentiation of VSMCs. Activation of the tumour suppressor p53 induces cellular programmes, including cell cycles, to shut down and undergo apoptosis or senescence, which prevents the accumulation of genetically altered cells.9-11 Recent studies have found that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia. Murine double-minute (Mdm2)mediated inhibition of p53 function is a prerequisite for RUNX2 activation, osteoblast differentiation and proper skeletal formation.12 In atherosclerosis, p53 not only arrests growth and promotes cell senescence and apoptosis, but also protect against trans-differentiation of bone marrow stromal cells into VSMCs, protects against apoptosis, and alters the mode of cell death within the plaque.

In a previous study, we found that vascular calcification was extensively present in patients with CKD-V on maintenance haemodialysis, and it was accompanied by decreased expression of p53 in VSMCs. This result indicates that inhibition of expression p53 in VSMCs may be involved in the pathogenesis

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of vascular calcification.13 To further investigate the effects of p53 on the osteogenic differentiation of VSMCs, we used wild-type (p53+/+) and p53-deficient (p53–/–) mice in this study to construct animal models of CKD-associated vascular calcification. Some of the mice were subjected to five-sixth (5/6) nephrectomy (Nx) and a high-phosphate (HP) diet. At different time points following 5/6 Nx, we studied histological changes in the kidney, aortic calcification, the markers of osteogenic differentiation (such as BMP-2, RUNX2, Osx and ALP), a special marker of VSMCs [alpha smooth muscle actin (α-SMA )], and the expression of p53 protein in the aortic tissue. The effects of p53 on the osteogenic differentiation of VSMCs were evaluated.

Methods p53–/– mice (F2) in C57BL/6 background mice (F2) were obtained from the NIH and housed in a pathogenfree environment. p53+/– mice were crossed with p53+/– mice to generate homozygous p53–/– and p53+/+ littermates.

Genotyping of the mice was performed by polymerase chain reaction analysis of DNA extracted from the tail tips, as reported

by Donehower.10,14 Male p53–/– and p53+/+ mice aged two months were used in this study.

The experiments were carried out in accordance with the Research Council and Animal Care and Use Committee of the Research Institute of Surgery, Daping Hospital, Third Military Medical University (Chongqing, China). Experiments conformed to the guidelines of the ethical use of animals. The animal study protocol was reviewed and approved by the Animal Ethics Committee of Chongqing. Efforts were made to minimise animal suffering and the number of mice used.

We used a well-established murine model of a CKD-associated vascular calcification model. Briefly, male mice weighing 19 to 24 g were housed with a 12-hour light and dark cycle and allowed free access to food and water. All animals were anesthetised with sodium pentobarbital (50 mg/kg i.p.) and then placed on a warming table to maintain a rectal temperature of 37°C. 5/6 Nx as a model of CKD was achieved in a two-step surgical procedure.3,15,16 The left kidney was exposed by a flank incision and the upper and lower poles of the right kidney were resected.

Two weeks later the left kidney was removed. The mouse was allowed to recover in a warmed cage, and food and water were given ad libitum. The day after the 5/6 Nx, the animals received standard HP diet (Altromin C1049, Germany, containing 1.65% phosphate, 0.24% sodium, 0.95% calcium, 0.07% magnesium, 0.7% potassium and 17% protein).

Experimental design Mice were randomly assigned to six experimental groups: (1) p53+/+ mice sham-operated on a normal diet (0.6% Ca and 0.6% P) were used as the control (group 1, n = 10) with the p53+/+ group, (2) p53–/– mice sham-operated on a normal diet were used as the control (group 2, n = 10) with the p53–/– group, (3) 5/6 Nx of p53+/+ mice on a normal diet (group 3, n = 10), (4) 5/6 Nx of p53–/– mice on a normal diet (group 4, n = 10), (5) 5/6 Nx of p53+/+ mice + HP diet (group 5, n = 10), and (6) 5/6 Nx of p53–/– mice + HP diet (group 6, n = 10).

Food consumption in groups 1 to 4 was the same, and that in groups 5 and 6 was the same. The high mortality in 5/6 Nx

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mice precluded maintaining them for more than 12 weeks in this study. At eight and 12 weeks following 5/6 Nx, the mice were anaesthetised with intraperitoneal pentobarbital (five animals at each time point in each group). Blood was collected by retroorbital bleeding. The mice were killed by cervical dislocation and the kidneys and aortic tissue were collected. Each kidney or aorta was cut into three parts medially for the following analyses.

Analyses Paraffin-embedded sections of 4 µm were prepared and stained with haematoxylin and eosin (HE) stain and then examined in a blinded manner by two examiners, with each section evaluated twice. Glomerular cell number was determined by counting the nuclei within the glomerular tuft. Glomerular sclerosis was graded as follows: 0 = none; +1 = sclerotic changes in < 25% of the glomerulus; +2 = 25– 50% sclerosis; +3 = > 50% sclerosis.17 The mean score per glomerulus in each kidney was determined as the sclerosis index.

Tubulo-interstitial fibrosis was defined as tubular atrophy, dilation and intratubular casts, as well as cellular infiltration and widening of the interstitium. It was scored semi-quantitatively according to the method of Shih et al.18 as follows: 0 = normal; 0.5 = small focal area injured; 1 = less than 10% of the cortex injured; 2 = 10–25% of the cortex injured; 3 = 25–75% of the cortex injured; and 4 = > 75% of the cortex injured.

Measurements of body weight and blood pressure, and the levels of haemoglobin, blood urea nitrogen (BUN), phosphate (Pi) and calcium (Ca) were performed as described by Bro et al.17 Parathyroid hormone (PTH) level was determined by a commercial ELISA test (BioSource, Belgium).

Mineral deposition (calcification) was assessed under the light microscopic using the von Kossa assay. Dewaxed and rehydrated sections (4 µm) of artery tissue were placed in 5% silver nitrate solution for 30 min in the dark, then into revelator solution (Kodak) for 5 min. They were fixed in 5% sodiumthiosulfate solution for another 5 min. Finally the sections were counterstained with 2% eosin.

Calcium deposits appeared as black areas.19,20 For the vascular calcification score, sections were graded from 0 to 4+ for von Kossa staining,21 where 0 = no calcification; 1 = spots; 2 = single segments of black staining; 3 = multiple segments; and 4 = diffuse, circumferential staining. The calcification score was obtained by averaging all the scores from all sections.

The determination of BMP-2, RUNX2 and Osx in the aortic tissue was performed on cryostat sections (4 µm) using indirect immunofluorescence staining. Briefly, the sections were fixed with 4% formaldehyde/PBS (pH 7.4) and treated with 3% H2O2 in methanol for 10 min to inactivate endogenous peroxidase.

After washing in PBS, the sections were microwaved in 10 mM citrate buffer (pH 6.0) for 10 min to retrieve the antigen.

Sections were then incubated with 1.5% normal goat serum for 15 min, followed by incubation with primary antibodies, BMP-2 antibody (1:200, code: sc-6895, Santa Cruz, USA), RUNX2 antibody (1:200, code: sc-12488, Santa Cruz, USA), or Osx antibody (1:200, code: sc-22536-R, Santa Cruz, USA) at 37°C for three hours.

After removal of the unbound primary antibody and rinsing with PBS, the sections were incubated with fluorescein isothiocyanate-conjugated (FITC) antibody (code: AP186F,

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Chemicon, Germany) diluted 1:100 in PBS at 37°C for 30 min.

The slides were washed three times with PBS and stained with propidium iodide (Sigma) and Hoechst 33342 (Sigma). Negative controls consisted of substituting the primary antibody with PBS. Immunofluorescent images were visualised under a confocal microscope (LSM 510 META, Carl Zeiss, Jena, Germany).

Positive results were identified by a green fluorescence.

Immunostaining for p53, ALP and α-SMA in the aorta tissue was performed on cryostat sections (4 µm) using the standard avidin–biotin complex method. Sections were processed as previously described.10 Anti-mouse p53 polyclonal antibody (1:200, code: SC-6243, Santa Cruz, USA), anti-ALP (1:200, GmbH, Germany) and monoclonal mouse anti-α-SMA (1:200, Sigma-Aldrich Co, St. Louis, MO, USA) were used as primary antibodies. Sections were incubated with primary antibody at 37°C for three hours.

After removal of unbound primary antibody and rinsing with PBS, the sections were incubated with avidin-biotinylated horseradish peroxidase (code: pk-7200, Vectastain Elite ABC kit; Vector Laboratories) for 60 min. The slides were washed again in PBS, then visualisation was performed using the diaminobenzidine (DAB) substrate–chromogen system (code: 3468, Dako, Glostrup, Denmark) and counterstained with 1% methylene green.

Finally, sections were washed with tap water, dehydrated and mounted. Negative controls consisted of substituting the primary antibody with PBS. A brown colour indicated a positive result.

The Western blot analysis was carried out for determination of p53, BMP-2, RUNX2, Osx, ALP and α-SMA in the aortic tissue.

Pieces of dissected aortic tissue were immersed in lysis buffer (50 mM Tris-HCl, pH 7.4, 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, 100 mM NaCl, 0.1 mM sodium orthovanadate, 1 mM sodium fluoride, 10 μg/ml aprotinin, 10 μg/ml leupeptin, 10 μg/ml pepstatin, and 10 μg/ml PMSF), homogenised with a dounce homogeniser, and then incubated on ice for 30 min.

After centrifuging at 20 000 × g and 4°C for 30 min, the protein concentration of the collected supernatant was determined by BCA kit (code: 23250, Pierce, Rockford, IL).

Samples of 40-μg protein were mixed with two × loading buffer containing 125 mM Tris-HCl (pH 6.8), 5% glycerol, 2% sodium dodecyl sulfate (SDS), 2% β-mercaptoethanol and 0.001% bromophenol blue and were electrophoresed on 13% sodium dodecyl sulfate-polyacrylamide gels for BMP-2 and ALP, or on 10% gels for p53, RUNX2, Osx and α-SMA. The proteins were transferred overnight to polyvinylidine difluoride (PVDF) membranes (Millipore, Bedford, MA) using a Bio-Rad Western blot apparatus.

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After the proteins were transferred, the blots and gels were stained with Coomassie blue to check for complete protein transference and equal loading. Membranes were blocked in 5% skimmed milk and hybridised to the following primary antibodies against p53, BMP-2, RUNX2, Osx, ALP and α-SMA as mentioned above (1:2 000) in anti-glyceraldehyde3-phosphate dehydrogenase (GAPDH) mAb (1:2 000; code: sc-47724, Santa Cruz, USA). The membranes were washed in 20 mM Tris, pH 7.5, 150 mM NaCl, 0.05% (v/v) Tween-20, and hybridised to the corresponding horseradish peroxidaseconjugated secondary antibodies, goat anti-rabbit IgG-HRP (code: SC-2004, Serologicals Corporation) 1:3 000 or goat antimouse IgG-HRP (code: 12-349, Serologicals Corporation) 1:3 000 at room temperature for one hour.

Chemiluminescence detection was performed using Supersignal (code: 34080, Pierce, IL, USA) according to the manufacturer’s instructions and images were acquired on X-ray film. Quantitative densitometry was performed on the identified bands using a computer-based measurement system.

Statistical analysis Results are expressed as mean ± SEM. Data analysis was performed using SPSS (SPSS Inc, Chicago, IL, Version 11.0). Means of total cell number per glomerulus, glomerular sclerosis index score and tubulo-interstitial fibrosis index score (histological index score), as well as body weight, blood pressure and serum chemistry parameters in non-size matched experimental groups were compared using Kruskal-Wallis non-parametric tests.

To determine the differences in vascular calcification and the expression levels of the proteins in p53+/+ and p53–/– mice at different time points after 5/6 Nx, the Fisher exact test was used.

For calculating the correlation between the expression of p53 protein and vascular calcification or osteogenic differentiation proteins, linear correlation analysis was done on the Western blot data. Statistical significance was defined as p < 0.05.

Results The morphology of the kidney was normal in groups 1 and 2 eight and 12 weeks after 5/6 Nx (data not shown). The appearance of abnormalities, including glomerular hypertrophy, cellular proliferation, glomerular sclerosis, intratubular casts, tubular dilation and atrophy, and intertubular cell infiltration and matrix accumulation occurred in groups 3 and 4, as well as in groups 5 and 6 at eight weeks, and became progressively worse

TABLE 1. EFFECTS OF 5/6 NX AND HP TREATMENT ON BODY WEIGHT, BLOOD PRESSURE AND SERUM CHEMISTRY IN P53+/+ AND P53–/– MICE AT 12 WEEKS p53+/+ mice p53–/– mice Sh 5/6 Nx 5/6 Nx + HP Sh 5/6 Nx 5/6 Nx + HP 16.8 ± 2.2a 22.6 ± 1.3 18.5 ± 2.1a 18.8 ± 2.5a Body weight (g) 12.1 ± 1.4 17.3 ± 1.7a a a a Blood haemoglobin (mmol/l) 10.6 ± 0.6 8.4 ± 0.4 8.2 ± 0.3 10.8 ± 0.5 8.7 ± 0.4 8.6 ± 0.2a b b b Plasma urea (mmol/l) 12.5 ± 1.3 27.7 ± 4.5 29.1 ± 3.8 13.8 ± 2.1 30.2 ± 5.7 32.8 ± 4.2b a cd a Plasma calcium (mmol/l) 2.1 ± 0.2 2.8 ± 0.1 3.7 ± 0.2 2.3 ± 0.2 3.1 ± 0.3 4.1 ± 0.3cd c cd c Plasma phosphate (mmol/l) 2.7 ± 0.3 3.6 ± 0.2 4.8 ± 0.4 3.0 ± 0.4 3.8 ± 0.4 5.0 ± 0.3cd PTH (ng/ml) 67 ± 22 685 ± 221b 843 ± 301be 72 ± 27 702 ± 237b 862 ± 325be Results are expressed as group mean ± SEM at 12 weeks after 5/6 nephrectomy (5/6 Nx) or sham-operation (Sh), n = 5 per group. a p < 0.05, bp < 0.001, cp < 0.01 vs untreated Sh. dp < 0.01, ep < 0.001 vs 5/6 Nx mice. PTH = parathyroid hormone.

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by week 12. No obvious difference was found when the HP diet was combined with 5/6 Nx compared with 5/6 Nx only (group 5 vs 3 and 6 vs 4, p > 0.05), and no significant difference was observed between groups 3 and 4, and groups 5 and 6 at the same time points (Fig. 1).

I A

C

Compared with sham surgery, 5/6 Nx in both p53+/+ and p53–/– mice caused more than twofold increases in BUN concentrations at eight weeks following 5/6 Nx, which remained elevated throughout the study. Similarly, 5/6 Nx also had significant effects on haemoglobin, plasma Ca, Pi and PTH levels and body weight, but not on mean systolic arterial blood pressure (Table 1). Plasma BUN, haemoglobin, plasma Ca, Pi and PTH levels, body weight and BP were similar in p53+/+ and p53–/– mice after 5/6 Nx (group 3 vs 4), as well as in p53+/+ and p53–/– mice after 5/6 Nx + HP (group 5 vs 6). However plasma Ca, Pi and PTH levels were significantly higher in mice after 5/6 Nx + HP compared with those in mice after 5/6 Nx only (group 5 vs 3 and 6 vs 4, p < 0.001 at each time) (Table 1).

Histopathological analysis of vascular calcification in the aorta D

B

In groups 1 and 2, no mineral deposition was noted in the 5/6 I A

C

B

D

60 50

NS

NS

40 30 20 10 0

Nx

Nx + HP p53+/+

Score

5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0

Nx

p53–/–

Nx + HP

II

NS

NS

NS

NS

Nx

Nx + HP

Sclerosis index p53+/+

Nx

Nx + HP

Tubulointerstitial fibrosis p53–/–

Fig. 1. I: Histological appearance of the kidney in A and C: p53+/+ mice, and B and D: p53–/– mice at 12 weeks after 5/6 Nx or 5/6 Nx + HP diet. A and B: Nx mice, C and D: Nx + HP mice (HE staining, original magnification: × 200). II: Quantification of glomerular cell number, sclerosis index and tubulo-interstitial fibrosis in mice at 12 weeks after Nx or Nx + HP. Values are means ± SEM; n = 5 per group.

NS = no significant difference vs p53–/– mice.

5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0

Vascular calcification (score)

Total cell number/glomerulus

II

ab a

Nx

Nx + HP p53+/+

p53–/–

Fig. 2. Ⅰ: Histopathological analysis of vascular calcification in the aorta at 12 weeks after Nx or Nx + HP (original magnification, × 200) with von Kossa staining. A and C: p53+/+ mice, and B and D: p53–/– mice. Ⅱ: Evaluation of the vascular calcification score in p53+/+ and p53–/– mice at 12 weeks after 5/6 Nx or 5/6 Nx + HP. Values are means ± SE; n = 5 per group. ap < 0.001 vs p53+/+ mice, b p < 0.01 vs Nx mice.

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Nx mice but scattered spots of black-stained material were found in the arterial media layer (Fig. 2A, B) at 12 weeks. In the 5/6 Nx + HP mice, diffuse or massive mineral deposition was detected in the media layer (Fig. 2C, D) at 12 weeks, and the calcification in p53–/– mice was much more severe than in the p53+/+ mice. The aorta in the 5/6 Nx mice had mild/ moderate calcification, whereas the aorta in the 5/6 Nx + HP mice, particularly the p53–/– mice, had severe calcification.

The score showed that vascular calcification in the p53–/– mice had increased significantly compared with that in the p53+/+ mice. Vascular calcification in the 5/6 Nx + HP mice was also increased compared with that in the 5/6 Nx only mice (Fig. 2).

In groups 1 and 2, almost no positive staining of p53, BMP-2, RUNX2, Osx and ALP protein was found in the VSMCs of the aorta, but expression of α-SMA was detected. In group 4 and particularly group 6, positive staining of BMP-2 (Fig. 3C, D), RUNX2 (Fig. 3G, H), Osx (Fig. 3K, L) and ALP protein (Fig. 4G, H) was always detected in the VSMCs. However, no p53 (Fig. 4C, D) and only weak staining of α-SMA (Fig. 4K, L) was detected in the same tissues. This pattern presented at eight weeks after 5/6 Nx, and became significantly increased 12 weeks after 5/6 Nx. On the other hand, weak positive staining of BMP-2 (Fig. 3B, A), RUNX2 (Fig. 3F, E), Osx (Fig. 3J, I) and

P53(+/+) mice R p-value –0.725 < 0.001 0.569 < 0.001 0.457 < 0.001 0.510 < 0.001 0.670 < 0.001 –0.582 < 0.001

Protein p53 BMP-2 RUNX2 Osx ALP α-SMA

p53(–/–) mice R p-value 0.677 0.594 0.618 0.773 –0.755

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

ALP proteins (Fig. 4F, E), and enhanced positive staining of p53 (Fig. 4B, A) and α-SMA (Fig. 4J, I) was detected in group 5, and particularly in group 3. Quantitative analysis of these proteins was performed using the Western blot analysis, and this showed changes similar to those found by the immunohistochemistry and indirect immunofluorescence analyses (Figs 5, 6).

Statistical analysis showed that changes in vascular calcification were positively correlated with the levels of expression of BMP-2, RUNX2, Osx and ALP, but negatively correlated with the levels of expression of p53 and α-SMA. p53–/– mice

p53+/+ mice

A

TABLE 2. LINEAR CORRELATION BETWEEN VASCULAR CALCIFICATION AND CALCIFICATION-RELATED PROTEINS IN VSMCS AFTER 5/6 NEPHRECTOMY

B

C

D

E

F

G

H

I

J

K

L

BMP–2

RUNX2

OsX

Nx

Nx + HP

Nx

Nx + HP

Fig. 3. Indirect immunofluorescence staining analysis for BMP-2, RUNX2 and Osx in the aorta at 12 weeks after 5/6 Nx or 5/6 Nx + HP (original magnification, × 200). Positive staining of BMP-2, RUNX2 and Osx protein was detected in VSMCs, clumping or a green line demonstrated the expression of protein, but in p53+/+ or 5/6 Nx mice, a weaker signal was detected compared with those in p53–/– or 5/6 Nx + HP mice.

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p53–/– mice

p53+/+ mice

A

B

C

D

E

F

G

H

I

J

K

L

p53

ALP

a-SMA

Nx

Nx

Nx + HP

Nx + HP

Fig. 4. Immunohistochemistry analysis for p53, ALP and α-SMA in the aorta at 12 weeks after 5/6 Nx or 5/6 Nx + HP (original magnification, × 200). In p53–/– mice with 5/6 Nx + HP, ALP expression was high, but α-SMA was low, and no p53 was detected, while related heavy mineral deposition was also detected. On the other hand, a weak positive staining of ALP, and enhanced positive staining of p53 and α-SMA was detected in p53+/+ mice, while moderate mineral deposition could be detected. A brown colour indicated the presence of proteins and a black colour indicated mineral deposition.

Correlation coefficients (R) and p-values are shown in Table 2. The levels of expression of BMP-2, RUNX2, Osx and ALP were significantly negatively correlated with those of p53 and α-SMA. Correlation coefficients and p-values are shown in Tables 3 and 4.

Discussion Although circulating calcium and phosphate concentrations have been correlated with the progression of vascular calcification in longitudinal studies of dialysis patients,22,23 they only partly account for the calcification. It is clear then that vascular TABLE 3. LINEAR CORRELATION BETWEEN P53 PROTEIN AND OTHER CALCIFICATION-RELATED PROTEINS IN VSMCS FROM P53+/+ MICE AFTER 5/6 NEPHRECTOMY Protein BMP-2 RUNX2 Osx ALP

R –0.671 –0.586 –0.622 –0.703

p-value < 0.001 < 0.001 < 0.001 < 0.001

calcification is controlled by factors other than circulating calcium and phosphate levels.

In a previous study, we found that the expression of p53 was inhibited in VSMCs from patients on maintenance haemodialysis, while vascular calcification was widely present.13 In line with these findings, Ohmi et al.24 found that VSMCs from p53 knock-out mice aortas revealed an extended bipolar shape and expressed h-caldesmon and calponin, as well as a smooth muscle actin as protein markers of differentiated smooth muscle. This TABLE 4. LINEAR CORRELATION BETWEEN a-SMA AND OTHER CALCIFICATION-RELATED PROTEINS IN VSMCS AFTER 5/6 NEPHRECTOMY Protein p53 BMP-2 RUNX2 Osx ALP

P53(+/+) mice R p-value 0.664 < 0.001 –0.585 < 0.001 –0.502 < 0.001 –0.569 < 0.001 –0.742 < 0.001

p53(–/–) mice R p-value –0.629 –0.610 –0.716 –0.758

< 0.001 < 0.001 < 0.001 < 0.001

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p53–/– Mice

p53+/+ Mice

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p53+/+ Mice

p53–/– Mice

p53–/– Mice

p53+/+ Mice

p53+/+ Mice

p53–/– Mice

p53

53 kd

p53

53 kd

Osx

45 kd

Osx

45 kd

GAPDH

36 kd

GAPDH

36 kd

GAPDH

36 kd

GAPDH

36 kd

BMP-2

16 kd

BMP-2

16 kd

ALP

12 kd

ALP

12 kd

GAPDH

36 kd

GAPDH

36 kd

GAPDH

36 kd

GAPDH

36 kd

RUNX2

55 kd

RUNX2

55 kd

a-SMA

42 kd

a-SMA

42 kd

36 kd

GAPDH

36 kd

GAPDH

36 kd

GAPDH

GAPDH Nx

Nx + HP

2.5

2

NS

1.5

aNS

a

aNS

a

NS

Nx

Nx + HP p53

Nx

NS

Nx + HP BMP-2

p53+/+

ac

2

Nx

Nx + HP RUNX2

p53–/–

Fig. 5. Western blot analysis for p53, BMP-2 and RUNX2 in the aorta at 12 weeks after 5/6 Nx or 5/6 Nx + HP. A densitometry graph shows the expression levels of each calcification-related protein identified by Western blot analysis in the aorta. The graph indicates the relative band density when levels of GAPDH protein expression in each sample were calculated as 100%. Values are means ± SE; n = 5 per group. ap < 0.001 vs p53–/– mice, NS = no significant difference vs 5/6 Nx mice with the same genetype.

implies that p53–/– VSMCs have the potential to transform to osteoblast-like cells, and that p53 may inhibit the transformation of VSMCs to osteoblast-like cells. We therefore propose that the inhibition of expression of p53 in VSMCs may be involved in the pathogenesis of the osteogenic differentiation of VSMCs in CKD. To test this hypothesis, we used the experimental model of CKD-associated vascular calcification in p53+/+ and p53–/– mice with 5/6 Nx and HP diet. At eight and 12 weeks after 5/6 Nx, aortic calcification, and markers of osteogenic differentiation, smooth muscle-specific protein and p53 proteins in the aortic tissue were studied, and the effects of p53 on osteogenic differentiation of VSMCs were assessed.

We found that changes in kidney histopathology and plasma BUN levels showed no significant difference between the p53+/+ and p53–/– mice at eight and 12 weeks following 5/6 Nx, which indicates that both p53+/+ and p53–/– mice developed to the same stage of CKD at the same time following 5/6 Nx. There were no obvious differences in deposition of serum calcium phosphate between groups 1 and 2, groups 3 and 4, and groups 5 and 6, which indicated that the disruption by p53 had no effect on the calcium–phosphate homeostasis.

In sham-operated mice, mineral deposition was not assessed.

In p53+/+ mice with 5/6 Nx, and particularly with 5/6 Nx + HP, scattered mineral deposition was found in the arterial media layer. In p53–/– mice with 5/6 Nx, and particularly with 5/6 Nx + HP, diffuse or large-scale mineral deposition was detected in

c

a

1

Nx

Nx + HP p53

a

c

b

0.5 0

a

ab

1.5

1

0.5

Calcification-related protein/GAPDH

Calcification-related protein/GAPDH

2.5

0

36 kd

Nx

Nx + HP

Nx

Nx + HP BMP-2

p53+/+

Nx

ac

Nx + HP RUNX2

p53–/–

Fig. 6. Western blot analysis for Osx, ALP and α-SMA in the aorta at 12 weeks after 5/6 Nx or 5/6 Nx + HP. A densitometry graph shows the expression levels of each calcification-related protein identified by Western blot analysis in the aorta. The graph indicates the relative band density when levels of GAPDH protein expression in each sample were calculated as 100%. Values are means ± SE; n = 5 per group. ap < 0.001 vs p53–/– mice, b p < 0.05, cp < 0.01 vs 5/6 Nx mice with the same genetype.

the media layer. Therefore the aortas of p53+/+ and p53–/– mice with 5/6 Nx had mild/moderate calcification, and the aortas of p53–/– mice with 5/6 Nx + HP had severe calcification.

The vascular calcification score showed that in p53–/– mice and in mice with 5/6 Nx + HP, vascular calcification was significantly increased compared with that in p53+/+ mice and in mice with 5/6 Nx only. This result suggests that (1) the vascular calcification may be inhibited by p53 in CKD mice, and (2) the 5/6 Nx plays a vital role in vascular calcification, and the HP diet aggravates vascular calcification.

Our further investigation showed that almost no positive staining of p53, RUNX2, Osx and ALP proteins was found in the VSMCs from sham-operated mice, but expression of α-SMA was detected. In p53–/– mice, positive-staining of RUNX2, Osx and ALP proteins was detected in VSMCs, but no p53 and only weak staining of α-SMA was detected in the same tissue.

This pattern presented at eight weeks after 5/6 Nx, and became more apparent at 12 weeks after 5/6 Nx. On the other hand, weak positive staining of RUNX2, Osx and ALP proteins, and enhanced positive staining of p53 and α-SMA was detected in p53+/+ mice.

Statistical analysis indicated that changes in vascular calcification were positively correlated with levels of expression of RUNX2, Osx and ALP, but negatively correlated with levels of expression of p53 and α-SMA. Levels of expression of RUNX2, Osx and ALP were significantly negatively correlated with levels of expression of p53 and α-SMA. These results indicate

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that p53 has an inhibitory effect on osteogenic differentiation of VSMCs in CKD mice, as evidenced by an increase in markers of osteogenic differentiation and a decrease in expression of the smooth muscle-specific marker. However, the mechanisms by which p53 inhibited osteogenic differentiation of VSMCs were not clear.

We then investigated the possible mechanisms whereby p53 inhibited osteogenic differentiation of VSMCs in CKD mice. Previous studies suggest that vascular calcification and bone formation may share common regulatory mechanisms.25-28 In bone, BMP-2 promotes osteoblast differentiation and mineralisation. BMP-2 is a potent osteogenic protein required for osteoblast differentiation and bone formation, which has been implicated in vascular calcification.25 BMP-2 promoted transition of the osteochondrogenic phenotype of VSMCs, also evidenced by an increase in marker expression of RUNX2 and a decrease in marker expression of VSMC.25 Runx2 is a transcription factor critical for osteogenesis and bone formation and is expressed during ectopic vascular calcification. A study by Tanaka et al.29 demonstrated that RUNX2 could repress myocardin-induced differentiation and concomitantly promote the osteogenic conversion of VSMCs. The expression level or activity of the RUNX2 protein is critical for the osteoblastic differentiation of VSMCs. Osx is genetically downstream of RUNX2.30 The studies by Wang et al.31 and Lengner et al.12 provide compelling evidence that p53 suppresses osteoblast differentiation by repressing the expression of either RUNX2 or Osx. The subtle discrepancy that exists between the two studies (whether RUNX2 or Osx is the target of p53 action) may be related to how p53 activity is targeted and whether this mechanism alters the stage of cell differentiation. In either case, the concept is that the absence of a tumour-suppressor gene can enhance cell proliferation while favouring differentiation.30 Fujita et al.32 found that BMP-2 could induce new bone formation in vivo by the BMP–p53–Cbfa1–Osterix axis in the osteoblast lineage. p53 is a negative regulator of Osx, and osteoblasts deficient in p53 exhibited an enhanced ability to promote osteoblast-dependent osteoclastogenesis.32 In our study, no expression of BMP-2 was found in the VSMCs from sham-operated mice, but in the VSMCs from p53–/– mice, positive staining of BMP-2 proteins was increased along with the increase in expression of RUNX2, Osx and ALP. Conversely, positive staining of BMP-2 proteins was decreased along with the decrease in expression of RUNX2, Osx and ALP in p53+/+ mice. The level of expression of BMP-2 correlated negatively with that of p53, while α-SMA correlated negatively with the level of expression of calcification-related proteins and positively with that of p53 (Tables 2, 3, 4).

From the data above, our results imply that p53 may repress osteogenic differentiation of VSMCs in CKD by inhibiting the expression of BMP-2 and/or RUNX2 and Osx protein directly.

This indicates that the BMP–p53–Cbfa1(RUNX2)–Osterix axis in osteoblast-dependent osteoclastogenesis is involved in the mechanism of osteogenic differentiation of VSMCs in CKD mice.

Clinically, a percentage of CKD patients in dialysis do not have vascular calcification and also do not show development or progression of calcification, implying that there are most likely genetic factors that predispose to protection from vascular

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calcification. p53 may play a role in these patients. The precise molecular targets of p53 in these mechanism remains to be elucidated in further in vitro study.

Conclusion We found that a p53 deficiency resulted in phenotype changes and elevated phosphate-induced mineralisation in VSMCs from 5/6 Nx mice. The effect of p53 repressing osteogenic differentiation of VSMCs is most likely to be mediated in part by down-regulation of BMP-2 expression and/or expression of RUNX2 and Osx directly. This study has provided a possible novel mechanism to show that p53 could be a negative regulator of osteogenic differentiation of VSMCs in CKD mice. It raises an interesting question regarding future therapeutic strategies for vascular calcification in CKD patients by up-regulating the expressson of p53.

This study was supported by the Natural Science Foundation Project of CQ CSTC (no. CSTC, 2008BB5275).

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Nonomura Y. A novel aortic smooth muscle cell line obtained from p53 knock out mice expresses several differentiation characteristics.

Biochem Biophys Res Commun 1997; 238: 154–158.

Li X, Yang HY, Giachelli CM. BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. atherosclerosis. Atherosclerosis 2008; 199: 271–277.

Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001; 89: 1147–1154.

Chen NX, O’Neill KD, Duan D, Moe SM. Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int 2002; 62: 1724–1731.

Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 2006; 98: 905–912.

Tanaka T, Sato H, Doi H, Yoshida CA, Shimizu T, Matsui H, et al.

Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells. Mol Cell Biol 2008; 28: 1147–1160.

Zambetti GP, Horwitz EM, Schipani E. Skeletons in the p53 tumor suppressor closet: genetic evidence that p53 blocks bone differentiation and development. J Cell Biol 2006; 172: 795–797.

Wang X, Kua HY, Hu Y, Guo K, Zeng Q, Wu Q, et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J Cell Biol 2006; 172: 115–125.

Fujita K, Janz S. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF.Mol Cancer 2007; 6: 1–13.

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Case Report Successful emergency double valve repair operation during acute aortic dissection type A TAYLAN ADADEMIR, ALTUG TUNCER, MEHMET OZKOKELI, AHMET SASMAZEL, HASAN ERDEM, RAHMI ZEYBEK

Abstract Reconstructive valve surgery in acute aortic dissection type A (AADTA) remains challenging. We describe a case of successful combined repair of the aortic and mitral valves, and replacement of the ascending aorta after AADTA with aortic and mitral insufficiency. Mitral valve repair was achieved by quadrangular resection of the posterior leaflet, combined with ring annuloplasty. Aortic valve repair was achieved by Cabrol commissural sutures with resuspension of the annulus. The postoperative clinical course was uneventful and an echocardiogram revealed competent mitral and aortic valves.

Mitral and aortic valve repair is an option in AADTA with mitral and aortic valve insufficiency.

Keywords: acute aortic dissection type A, aortic valve repair, mitral valve repair, Cabrol Submitted 30/3/11, accepted 13/9/11 Cardiovasc J Afr 2012; 23: e10–e11

www.cvja.co.za

DOI: 10.5830/CVJA-2011-056

Case report A 50-year-old woman with a history of moderate degenerative mitral valve insufficiency (MI) was admitted to an outlying hospital with sudden onset of severe back pain. She was referred to our hospital with a diagnosis of acute aortic dissection type A (AADTA), based on clinical and echocardiographic findings.

On physical examination, she was tachypnoeic (respiratory rate 33 per min) and tachycardic (117 per min). Her systolic blood pressure was 150 mmHg on her right arm, which was 25 mmHg higher than that of the left arm. Bilateral carotid and femoral pulses were palpable. Chest auscultation revealed fine inspiratory rales at the basal zones of both lungs and a systolic murmur was noted in the precordium.

Radiography of the chest showed an increased opacity of both lower lobes. The electrocardiogram did not demonstrate any specific changes. Transthoracic echocardiography (TTE)

revealed an intimal flap in the ascending aorta, severe mitral and aortic insufficiency (AI) and minimal pericardial effusion.

Computed tomography of the chest confirmed the diagnosis of AADTA by visualising an intimal flap just above the sinotubular junction and a slightly dilated ascending aorta.

The patient was immediately taken to the operating theatre. Cardiopulmonary bypass was established with arterial cannulation in the right axillary artery. After median sternotomy and bicaval venous cannulation, the patient was slowly cooled to 24°C. The ascending aorta was cross-clamped just proximal to the brachiocephalic artery and aortotomy was performed.

Antegrade direct blood cardioplegia was used selectively to each coronary ostium to arrest the heart and it was repeated every 20 minutes. Aortotomy confirmed a type A dissection with an intimal tear situated 2 cm distal to the ostium of the right coronary artery. Severe aortic insufficiency was detected.

The mitral valve was exposed through a standard left atriotomy. The mitral annulus was dilated, with a posterior mitral leaflet prolapse. The prolapsed posterior mitral leaflet (P2) was removed by excising a quadrangular portion of the leaflet. Direct suturing of the leaflet remnants restored posterior leaflet continuity. Ring annuloplasty was also performed with a St Jude mitral ring (No 31). Cabrol commissure sutures (Fig. 1) with resuspension of the valve were used to repair the aortic insufficiency. The proximal part of the graft was anastomosed to the ascending aorta 1 cm distal to the coronary ostiums.

The brachiocephalic artery was selectively clamped and cross clamped and the ascending aorta was removed.

Cardiopulmonary bypass flow was decreased to 10 ml/min/m2 and the hemi-arc was replaced by a 30-mm Dacron graft

Kartal Kosuyolu Yuksek Ihtisas Heart Education and Research Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey TAYLAN ADADEMIR, MD, taylanadademir@gmail.com ALTUG TUNCER, MD MEHMET OZKOKELI, MD AHMET SASMAZEL, MD HASAN ERDEM, MD RAHMI ZEYBEK, MD, PhD

Fig. 1. The Cabrol suture narrows the intercommissure angle, and the valvular apparatus just above the annulus brings the body of the aortic valve leaflets closer together and improves the critical area of coaptation.

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(Hemashield, Meadox Medicals Inc) during low-flow cerebral perfusion. After completion of the distal anastamosis, the brachiocephalic artery was unclamped and cardiopulmonary bypass was maintained at 4.5 l/min/m2 to rewarm the patient.

Intra-operative transoesophageal echocardiography showed no residual AI or MI. The total cardiopulmonary bypass time was 126 minutes. The total aortic cross-clamp time was 76 minutes, with 10 minutes low-flow cerebral perfusion time.

The postoperative course was uneventful, and the patient was discharged on postoperative day 10. One-month follow-up transthoracic echocardiography documented neither AI nor MI.

Discussion Acute aortic dissection type A is a life-threatening disease.

Complications such as aortic rupture, cardiac tamponade and acute aortic regurgitation require immediate surgical intervention.

Replacement of the aortic valve, root and ascending aorta with a composite graft carrying a mechanical valvular prosthesis is one of the most commonly used treatment options, especially if the aortic root is severely impaired. However it is accompanied by the disadvantages of mechanical valve prostheses, such as thromboembolic events and haemorrhage due to lifetime anticoagulation.

There are several aortic valve-sparing operations for replacement of the ascending aorta to overcome the shortcomings of a mechanical prosthesis. The Cabrol type of commissure sutures with or without resuspension of the valve is one that is perfectly suited to patients with AADTA.1,2 The advantages of mitral valve repair over prosthetic valve replacement, such as better preservation of left ventricular function and lower incidence of valve-related events, are well documented. Nowadays, the procedure is the gold standard, especially for degenerated MI.3 In contrast to mitral valve repair, aortic valve repair still poses significant technical challenges. Svensson et al.2 reported on 388 aortic root-preserving procedures, of which 140 (36.1%) were after AADTA. They performed 197 leaflet repair procedures, of which 158 (80.7%) were Cabrol/Trusler type of commissure sutures, with excellent early results.

Kallenbach et al.4 reported the results of 22 emergency valve-sparing aortic root reconstructions with a re-implatation technique. There was 14% peri-operative deaths but excellent results during follow up. Thirty-six patients with valve-sparing aortic root remodeling/re-implantation for AADTA were reported

by Erasmi et al.,5 with excellent mid-term aortic valve function.

Our case is unique in that in the above reports, there were no concomitant mitral valve repairs or replacement.

In contrast, mitral valve insufficiency is present in 68 to 91% of patients with Marfan’s syndrome, who are more prone to aortic dissection.6 Forteza et al.7 reported on 37 aortic valvesparing procedures in patients with Marfan’s syndrome, where six (16%) concomitant mitral valve repairs were done, with good short- and midterm results. In their series, none were diagnosed with AADTA. Another report from Kallenbach et al. described 59 aortic valve-sparing procedures in Marfan’s syndrome patients, of whom seven had mitral valve repair. There were also four AADTA patients in the report but they did not mention the concomitance of double valve repair in any of the acute dissection patients.8

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There are only a few reports of combined aortic and mitral valve repair and durability, even under elective conditions.

Gillinov et al.9 reported acceptable late survival, an excellent freedom from valve-related morbidity, but limited long-term durability, with a 10-year freedom from re-operation of 65%.

The risk factors they reported for valve-related re-operation were aortic stenosis, rheumatic valve disease and anterior mitral leaflet pathology. Kazui et al.10 reported excellent early results with a 100% 30-day survival rate and no valve-related morbidity during one year of follow up.

In our institution, mitral valve repair is attempted first, regardless of the aetiology of the mitral insufficiency, and the Cabrol commissure sutures have been the mainstay of aortic valve repair, particularly after AADTA. AADTA dilates the aortic root and annulus, separates the aortic valve leaflets, and makes the valve incompetent. The Cabrol suture narrows the intercommissure angle and the valvular apparatus just above the annulus, brings the body of the aortic valve leaflets closer together, and improves the critical area of coaptation. The suture alone will result in a competent valve when combined with resuspension of the valve.

Surgeons are generally more familiar with valve replacement than reconstruction. Prolonged operation time, with expansion of aortic cross clamp and extracorporeal circulation time, is another potential drawback for the application of reconstructive techniques, particularly with AADTA. The benefits of double valve repair (low risk of valve-related complications such as endocarditis, thromboembolism and haemorrhage, and better preservation of left ventricular function) should be pointed out during the ongoing discussions and surgeons should gain experience with reconstructive techniques in elective cases.

Conclusion We believe that valve repair should be attempted, even under emergency conditions, and double valve repair should be carried out whenever possible.

References 1.

Fraser CD Jr, Cosgrove DM. Surgical techniques for aortic valvuloplasty. Tex Heart Inst J 1994; 21: 305–309.

2. Svensson LG, Deglurkar I, Ung J, et al. Aortic valve repair and root preservation by remodeling, reimplantation, and tailoring: technical aspects and early outcome. J Card Surg 2007; 22: 473–479.

3. Adams DH, Anyanwu AC, Rahmanian PB, et al. Current concepts in mitral valve repair for degenerative disease. Heart Fail Rev 2006; 11: 241–257.

4. Kallenbach K, Pethig K, Leyh RG, et al. Acute dissection of the ascending aorta: first results of emergency valve sparing aortic root reconstruction. Eur J Cardiothorac Surg 2002; 22: 218–222.

5. Erasmi AW, Stierle U, Bechtel JFM, et al. Up to 7 years’ experience with valve-sparing aortic root remodeling/reimplantation for acute type A dissection. Ann Thorac Surg 2003; 76: 99–104 6. Pyeritz RE, Wappel MA. Mitral valve dysfunction in the Marfan’s syndrome. Am J Cardiol 1983; 74: 797–807.

7. Forteza A, De Diego J, Centeno J, et al. Aortic valve-sparing in 37 patients with Marfan syndrome: midterm results with David operation.

Ann Thorac Surg 2010; 89: 93–96.

8. Kallenbach K, Baraki H, Khaladj N, et al. Aortic valve-sparing operations in marfan syndrome: What do we know after a decade? Ann Thorac Surg 2007; 83: 764–768.

9. Gillinov AM, Blackstone EH, White J, et al. Durability of combined aortic and mitral valve repair. Ann Thorac Surg 2001; 72: 20–27.

10. Kazui T, Kin H, Izumoto H, et al. Combined aortic and mitral valve repair. Asian Cardiovasc Thoraca Ann 2003; 11: 319–322.

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Case Report Dilated cardiomyopathy secondary to coarctation of the aorta was completely resolved after stent implantation MUSTAFA TARIK AĞAÇ, ZEYDIN ACAR, RAMAZAN AKDEMIR, LEVENT KORKMAZ, ABDÜLKADIR KIRIŞ, ALI RIZA AKYÜZ, HAKAN ERKAN

Abstract

Case report

Although rare in adults, coarctation of the aorta can present as an occult cause of cardiomyopathy. In this case report, we describe a 55-year-old man who presented to our clinic with new-onset symptoms of heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed systolic function. Cardiac catheterisation showed no critical coronary artery disease but a severe aortic coarctation just distal to the origin of the left subclavian artery, with a peak-to-peak systolic pressure gradient of 40 mmHg. We successfully implanted a balloon-expandable stent with good angiographic results. The procedure resulted in immediate clinical improvement. Six-months after stent implantation, the patient was free of symptoms and an echocardiographic examination showed completely normalised cardiac size and systolic function.

A 55-year-old man was admitted to our hospital with a one-week history of increasing dyspnoea, orthopnoea and nocturnal dyspnoea. He had noticed a gradual limitation in exercise tolerance over the previous two years. His medical history revealed only systemic arterial hypertension of 22 years’ duration, which was poorly controlled despite concurrent use of three antihypertensive medications.

On physical examination, his blood pressure was 190/100 mmHg. There was a differential blood pressure of 30 mmHg between the upper and lower extremities. There were basal rales in the lower lung fields and auscultation showed rapid heart sounds with S3 gallop. A harsh II/VI systolic murmur was heard along the left scapular border.

Echocardiography revealed a dilated left ventricle with end-diastolic (LVEDD) and end-systolic diameters (LVESD) of 60 and 53 mm, respectively. Left ventricular contraction was diffusely hypokinetic, with a calculated ejection fraction (EF) of 30% (Video 1). Continuous-wave Doppler interrogation revealed a peak velocity of 2.9 m/s along the descending aorta. No significant valvular dysfunction was noted. Cardiac catheterisation showed normal coronary arteries, but a severe funnel-shaped aortic coarctation was detected just distal to the origin of the left subclavian artery (Fig. 1, Video 2) with a peakto-peak systolic pressure gradient of 40 mmHg.

Keywords: aortic coarctation, dilated cardiomyopathy, heart failure, stent implantation Submitted 12/2/11, accepted 21/9/11 Cardiovasc J Afr 2012; 23: e12–e13

www.cvja.co.za

DOI: 10.5830/CVJA-2011-061

In patients referred for evaluation of heart failure, it is important to exclude reversible causes. This includes consideration of mechanical causes, such as aortic stenosis, which may produce a clinical picture resembling dilated cardiomyopathy, for which surgical correction is possible.

Similarly, increased afterload in the setting of aortic coarctation may produce heart failure.1,2 In the present report, we describe an adult patient presenting in the fifth decade of life with dilated cardiomyopathy secondary to occult, congenital coarctation of the aorta, who recovered completely after stent implantation.

Ahi Evren Chest, Heart and Vascular Surgery Hospital, Soğuksu Mah, Trabzon, Turkey MUSTAFA TARIK AĞAÇ, MD, tarikagac@gmail.com ZEYDIN ACAR, MD RAMAZAN AKDEMIR, MD LEVENT KORKMAZ, MD ABDÜLKADIR KIRIŞ, MD ALI RIZA AKYÜZ, MD HAKAN ERKAN, MD

Fig. 1. Aortography in the left anterior oblique view showing severe funnel-shaped aortic coarctation just distal to the origin of the left subclavian artery.

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Upon stabilisation of the patient’s general condition, percutaneous stent implantation was scheduled. Vascular access was gained by placing 6F sheats in the right femoral and brachial arteries. Aortic coarctation was crossed retrogrately with a 0.032-inch, 260-cm-long guidewire through a 6F multipurpose catheter, which was withdrawn and exchanged with a long 12F sheath (Cook Europe, Bjaeverskov, Denmark). A 45-mm-long CP stent (Numed Inc, Hopkinton, NY, USA) manually mounted in a 24 × 40-mm BIB balloon (Numed Inc, Hopkinton, NY, USA) was then introduced through a long sheath and succesfully deployed with angiographic control through the right subclavian artery (Fig. 2).

Post-prosedural angiography confirmed that the stent placement was adequate and that anatomical results were excellent (Fig. 3). The patient was discharged free of symptoms on the second post-procedural day.

At the six-month follow-up examination, the patient was completely asymptomatic. Echocardiography showed a normal-

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sized left ventricle (LVEDD: 55 mm, LVESD: 39 mm) with normal systolic function (EF: 56%) (Videos 3, 4).

His blood pressure was 130/80 mmHg. Control of his hypertension was achived with an angiotensin converting enzyme inhibitor and low-dose thiazide diuretic combination.

Discussion Aortic coarctation is the fifth most common congenital heart disease and accounts for 5 to 8% of all congenital cardiac anomalies.3 Heart failure is one of the most frequent complications and cause of death in the natural history of aortic coarctation.4 Aortic coarctation should be considered in the differential diagnosis of cardiomyopathy in adults.

Similar to aortic stenosis, long-standing afterload excess in the setting of coarctation may be the mechanism of the failing heart. In patients with aortic stenosis and severe heart failure, favourable effects on left ventricular function have been demonstrated following the relief of afterload excess by aortic valve replacement.5 Likewise, improvements may be expected in patients with aortic coarctation and cardiomyopathy following surgical or percutaneus correction.

While surgical series of coarctation repair include adult patients with heart failure, no objective data on pre- and postoperative left ventricular systolic function are included.6 A few case reports have been published in the literature demonstrating some degree of improvement in clinical and echocardiographic parameters following the relief of coarctation.1,7,8 However, it is not known whether correction of coarctation would reverse all indices of heart failure, in other words ‘cure heart failure’.

Conclusion

Fig. 2. Introduction of a CP stent mounted in a BIB balloon under angiographic guidence. Contrast was administered through a catheter in the right subclavian artery.

We belive that our experience is unique and shows complete normalisation of left ventricular size and function with full functional recovery following correction of coarctation with stent implantation.

References 1.

2.

3.

4.

5.

6.

7.

8.

Fig. 3. Angiography following stent deployment.

Pauly DF, Morss SE, Tanio JW, Irani K, Cameron DE, Schulman SP, Hare JM. Reduced left ventricular dimension and normalized atrial natriuretic hormone level after repair of aortic coarctation in an adult.

Clin Cardiol. 1999; 22(3): 233–235.

Morgan DJ, Hall RJ. Occult aortic stenosis as cause of intractable heart failure. Br Med J 1979; 1: 784–787.

Cetta F, Lichtenberg RC, Clark SE. Adults with congenital heart disease. Comprehensive Ther 1992; 18(2): 33–37 Campbell M. Natural history of coarctation of the aorta. Br Heart J 1970; 32(5): 633–640.

Connolly HM, Oh JK, Schaff HV, Roger VL, Osborn SL, Hodge DO, Tajik AJ. Severe aortic stenosis with low transvalvular gradient and severe left ventricular dysfunction: result of aortic valve replacement in 52 patients. Circulation 2000; 101(16): 1940–1946.

Brouwer RM, Erasmus ME, Ebels T, Eijgelaar A. Influence of age on survival, late hypertension, and recoarctation in elective aortic coarctation repair. Including long-term results after elective aortic coarctation repair with a follow-up from 25 to 44 years. J Thorac Cardiovasc Surg 1994; 108(3): 525–531.

Alcibar J, Peña N, Oñate A, Gochi R, Barrenechea JI. Stent implantation in an adult with coarctation of the aorta in the presence of advanced secondary heart failure. Tex Heart Inst J 1999; 26(2): 143–147.

Kim W, Jeong MH, Shim WH, Ahn YK, Kang JC. A successful stenting of the coarctation of aorta in a patient presented with acute pulmonary edema. Int J Cardiol 2006; 113(2): 267–269.

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Case Report A rare case of spontaneous rectus sheath haematoma in a patient with mechanical prosthetic aortic and mitral valves AHMET AYKAN, ALİ OGUZ, MUSTAFA YİLDİZ, MEHMET ÖZKAN

Abstract Every year nearly 300 000 patients have heart valve operations and mostly prosthetic valves are inserted. Coumadin is the mainstay of therapy in these individuals but it has many side effects, mostly related to its anticoagulant effect.

Rectus sheath haematoma (RSH) is a rare complication of abdominal trauma, surgery and excessive strain, however, anticoagulant agents may predispose to this condition without any precipitating event. Reversal of anticoagulation and resuscitation with fluids and blood products are necessary but anticoagulation is crucial in patients with prosthetic valves, as they have acquired thrombotic diathesis. Herein we report on a case of spontaneous RSH in a patient with prosthetic mitral and aortic valves and a history of prosthetic valve thrombosis. He was successfully managed medically.

Keywords: rectus sheath, haematoma, prosthetic valve, warfarin Submitted 23/3/11, accepted 22/11/11 Cardiovasc J Afr 2012; 23: e14–e15

www.cvja.co.za

DOI: 10.5830/CVJA-2011-070

Rectus sheath haematoma (RSH), secondary to abdominal trauma, surgery and excessive strain, is a rare complication.

Its incidence without any precipitating event is increasing with the growing use of antiplatelet and anticoagulant agents.1 Management of RSH in patients with prosthetic mechanical heart valves is a challenge as anticoagulation in these subjects is crucial, whereas keeping them on anticoagulation may cause death.

or urine.

He had had mechanical prosthetic mitral and aortic valve surgery for rheumatic heart disease five years earlier and had a history of prosthetic mitral valve thrombosis, which was successfully treated with thrombolytic therapy. He was on coumadin.

Physical examination revealed mild abdominal swelling, ecchymosis of the abdomen (positive Cullen’s sign) radiating to both flanks (positive Gray Turner’s sign) and a palpable mass on both sides of the umbilicus (Fig. 1). He had tenderness and mild guarding in the lower quadrants with positive Fothergill’s and Carnett’s signs. The bowel sounds were normal. He had tachycardia (120 beats/min) and hypotension (75/40 mmHg).

Blood tests revealed mild leucocytosis accompanied by anaemia (8.2 g/dl). His INR was 3.0. His abdominal X-ray was normal and the stool occult blood test was negative.

Transthoracic echocardiography was normal with normalfunctioning prosthetic heart valves and a left ventricular ejection fraction of 65%. Abdominal ultrasonography showed a large right-sided RSH, 12 × 22 cm in size.

The patient was transferred to the intensive care unit and 1 mg intravenous vitamin K and three units of fresh frozen plasma were administered to reverse anticoagulation. Meanwhile his current medication was immediately stopped and he was resuscitated with crystaloids and packed red blood cells.

Over the next 12 hours the patient’s symptoms improved

Case report A 36-year-old male patient was admitted to the emergency department with a two-day history of abdominal pain, poor appetite, dizziness, fatigue and discolouration of the abdomen and flank. He had had no recent trauma or surgery. His bowel habits were normal and there was no discolouration of the faeces

Department of Cardiology, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey AHMET AYKAN, MD, ahmetaykan@yahoo.com ALİ OGUZ, MD MUSTAFA YİLDİZ, MD, PhD MEHMET ÖZKAN, MD

Fig. 1. Ecchymosis of the abdomen and flank area is evident.

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gradually. A total of six units of red blood cells and three units of fresh frozen plasma was administered to the patient. After 24 hours, the haematocrit and haemogram were steady without the need for further resuscitation.

We waited 12 hours and then cautiously started intravenous heparin administration, with close monitoring of the patient as he had prosthetic heart valves which had thrombosed a year earlier.

Coumadin was started on the second day of hospitalisation and effective coumadinisation was achieved on the 10th day, so the heparin infusion was stopped.

Transoesophageal echocardiography revealed normalfunctioning prosthetic mechanical mitral and aortic valves with no thrombus. The patient was discharged on coumadin.

Discussion Abdominal trauma, abdominal surgery, pregnancy, collagen vascular disorders, coagulopathies, anticoagulant therapy and strenuous exercise may cause RSH. Some patients may experience RSH without any prior history, which is termed spontaneous RSH.1,2 It is more frequently observed in females and older patients.1 Injury of the superior epigastric artery causes RSH above the arcuate line, and is usually self-limiting with a unilateral small mass. However, when the inferior epigastric artery is injured, it may bleed profusely and the haematoma may cross the midline and extend into the pelvic cavity. Patients usually present with acute abdominal pain, often associated with nausea, fever and vomiting. Tenderness and swelling of the abdominal wall is usually noticed in the physical examination, and when the bleeding is profound, signs of hypovolaemic shock such as tachycardia and hypotension may be seen. Fothergill’s and Carnett’s signs may also be observed.3,4 Gray Turner’s and Cullen’s signs may be noted later.

Ultrasonography is a useful initial diagnostic modality due to its low cost, availability and portability.5 Computed tomography however is superior to ultrasonography for diagnosis.5 Management of RSH depends on the severity of the situation.

Conservative therapy is usually sufficient, as RSH is mostly self-limiting. Urgent reversal of coagulopathy is the mainstay of therapy when anticoagulants are being used. If there is haemodynamic compromise, blood transfusion is mandatory.

Interventional procedures are rarely required but in that case,

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coil or gel foam embolisation of the epigastric arteries can be successfully performed.6 Spontaneous resolution of the haematoma takes several weeks. Anticoagulation must be prevented unless it is essential.

Our patient experienced spontaneous RSH, probably predisposed by taking coumadin. Fresh frozen plasma and vitamin K were administered to reverse the anticoagulation and the patient was resuscitated with blood and fluids to achieve haemodynamic stability.

The timing of anticoagulation is important in patients suffering from major bleeding because administration of anticoagulants may restart the bleeding. In patients with thrombotic diathesis, this anticoagulant-free period may induce thrombosis, as in patients who have had prior prosthetic valve thrombosis.

After achieving steady haemoglobin and haematocrit levels, we waited 12 hours before restarting anticoagulation. The patient was discharged uneventfully after transoesophageal echocardiography, which showed normal-functioning prosthetic mitral and aortic valves.

Conclusion Patients with mechanical heart valves experience problems due to both the mechanical valves and the medication. Coumadin is the mainstay of therapy in these individuals but it predisposes to bleeding, as in our patient. Management of the bleeding is problematic as the coumadin must be stopped and its effects reversed, despite risking thrombosis of the heart valves. This process needs fine adjustment and close follow up.

References 1.

2.

3.

4.

5.

6.

Cherry WB, Mueller PS. Rectus sheath hematoma. Review of 126 cases at a single institution. Medicine 2006; 85: 105–110.

Zainea GG, Jordan F. Rectus sheath hematomas; their pathogenesis, diagnosis and management. Am J Surg 1988; 54: 630–633.

Osinbowale O, Bartholomew JR. Rectus sheath hematoma. Vasc Med 2008; 13: 275–279.

Thomson H, Francis DM. Abdominal-wall tenderness: A useful sign in the acute abdomen. Lancet 1977; 2: 1053–1054.

Moreno Gallego A, Aguayo JL, Flores B, et al. Ultrasonography and computed tomography reduce unnecessary surgery in abdominal rectus sheath hematoma. Br J Surg 1997; 84: 1295–1297.

Rimola J, Perendreu J, Falcó J, et al. Percutaneous arterial embolization in the management of rectus sheath hematoma. Am J Roentgenol 2007; 188(6): 497–502.

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Case Report Sustained idiopathic ventricular tachycardia originating from the posteroseptal tricuspid annulus TURGAY CELIK, BARİS BUGAN, SEDAT KOSE, U CAGDAS YUKSEL, ATİLA IYISOY, H KUTSİ KABUL, HURKAN KURSAKLIOGLU, ERSOY ISIK

Abstract

Keywords: tricuspid annulus, idiopathic ventricular tachycardia

Tricuspid annular ventricular tachycardia (VT) is a rarely encountered entity. Despite abundant data on idiopathic VTs, the prevalence and clinical characteristics of this infrequent form are not well defined and the efficacy of radiofrequency (RF) catheter ablation treatment remains unknown. We report on a case of a 44-year-old male presenting with symptomatic sustained idiopathic VT originating from the posteroseptal tricuspid annulus.

Submitted 16/2/10, accepted 16/2/12

Department of Cardiology, School of Medicine, Gulhane Military Medical Academy, Etlik, Ankara, Turkey

TURGAY CELIK, MD, benturgay@yahoo.com SEDAT KOSE, MD U CAGDAS YUKSEL, MD ATİLA IYISOY, MD H KUTSİ KABUL, MD HURKAN KURSAKLIOGLU, MD ERSOY ISIK, MD

Department of Cardiology, Malatya Army District Hospital, Malatya, Turkey BARİS BUGAN, MD

Cardiovasc J Afr 2012; 23: e16–e18

www.cvja.co.za

DOI: 10.5830/CVJA-2012-010

Idiopathic ventricular tachycardias (VT) and premature ventricular contractions (PVC) mostly originate from the right ventricular outflow tract (RVOT). In contrast to abundant data on VTs originating from the RVOT, idiopathic VT/PVCs originating from the tricuspid annulus have been reported in only a few cases. Anatomical localisation of arryhthmogenic foci and the electrophysiological characteristics of this infrequent tachycardia are obscure and the efficacy of radiofrequency (RF) catheter ablation of idiopathic VT/PVCs therapy remains unknown.1 We report a case of a 44-year-old male presenting with symptomatic sustained idiopathic VT originating from the posteroseptal tricuspid annulus.

Case report A 44-year-old male was admitted to our hospital with palpitations, dyspnoea on exertion, and a syncopal attack. His medical history

Fig. 1. A 12-lead ECG showing the sustained ventricular tachycardia with QRS morphology of left bundle branch block with a leftward axis.

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A

B

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was unremarkable and he had no previous health problems. The patient’s symptoms started two days earlier and worsened over time. The palpitations became sustained and he started suffering from shortness of breath.

The initial 12-lead electrocardiogram (ECG) showed sustained wide QRS-complex tachycardia consistent with VT with left bundle branch block (LBBB) with a leftward axis (Fig. 1). The physical examination was otherwise unremarkable.

Echocardiography revealed a normal left ventricular systolic function with an ejection fraction of 65%, and no structural heart disease.

The LBBB pattern and the leftward axis during VT suggested the inferior wall to be the source of arrhythmia. The patient underwent an electrophysiological study (EPS). Electroanatomical mapping indicated the posteroseptal portion of the tricuspid annulus as the earliest ventricular activation site during clinical tachycardia. The intracardiac electrocardiographic recordings at that region demonstrated a distinct, sharp ventricular activation 27 ms before the onset of QRS (Fig. 2).

After delivering several RF energy applications (70°C, 50 W) to the earliest ventricular activation site, the tachycardia suddenly ceased (Fig. 3). No spontaneous VT/PVCs were observed after the procedure, and provocation with isoproterenol failed to induce any tachycardia after the procedure.

His surface ECGs were completely normal in the two days before discharge and the patient was discharged from hospital without anti-arrhythmic medications. During the subsequent six-month follow up, he remained asymptomatic and no ventricular ectopic activity originating from the posterior tricuspid annulus was deteceted in 24-hour Holter recordings.

Discussion

C

Fig. 2. Intracardiac recordings. A: During the tachycardia, the ventricular potential recorded by the distal ablation catheter (ABLd) preceded the onset of the QRS complex by 27 ms. B: Radiographs obtained in the left anterior oblique, and C: right anterior oblique projections show the ablation sites. The distal electrode of the ablation catheter (ABL) was positioned at the posteroseptal portion of the tricuspid annulus.

Idiopathic right ventricular tachycardia mostly originates from the septal region of the RVOT, and the ECG shows LBBB rightward axis morphology. Idiopathic VT/PVCs in the absence of any underlying structural disease are considered to be benign.1 However, occasionally VT/PVCs originating from the right ventricle may be the first and only manifestation of arrhythmogenic right ventricular dysplasia, often a familial disease that can cause sudden death.

Tricuspid annular VT is a rarely encountered entity. Tada et al.2 reported that 8% of idiopathic VT/PVCs originate from the tricuspid annulus. Their well-designed study demonstrated that the anteroseptal annulus was the most common site to host arrhythmogenic foci around the tricuspid annulus.2 They reported that ECG findings were useful in identifying the precise origin of the VT/PVCs arising from the tricuspid annulus.2 In our case, LBBB morphology accompanied with leftward axis deviation on the surface ECG suggested that the arrhythmogenic focus was the posteroseptal tricuspid annulus.

Tada et al.2 demonstrated that VT/PVCs originating from the tricuspid annulus had LBBB block, QRS morphology and positive QRS polarity in leads I, V5 and V6. No negative deflection was observed in lead I. Since VT/PVCs originating from the tricuspid annulus were initiated from the right anterior wall of the heart, an rS or QS pattern in lead aVR was observed on the surface ECG, similar to RVOT VT/PVCs. However, in lead aVL, a QS or rS pattern was rare (8%), and the QRS polarity in lead aVL was positive in almost all VT/PVCs originating from

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Fig. 3. Intracardiac recordings. After RF energy applications, the tachycardia completely disappeared.

the annulus (89%).

Lack of positive QRS polarities in the inferior leads, positive QRS polarity in lead aVL, and a greater Q-wave ratio in leads aVR to aVL were surface ECG characteristics of VT/PVCs originating from the annulus, which were significantly different from those of VT/PVCs originating from RVOT. Both right and left ventricles were activated almost simultaneously, as the origin of the VT/PVCs was the septum, which caused early precordial transition on the surface ECG.2 The QRS morphology in our patient was similar to those reported by Tada et al.2 for posterior tricuspid annular VT/PVCs. In their series, among the 38 VT/PVCs originating from the annulus, three originated from the posterior septum. However, in contrast to our case, these patients did not demonstrate sustained VTs but only isolated PVCs from the region of the tricuspid annulus.2 Tada and co-workers reported that 66% were treated with RF catheter ablation. The success rates of RF catheter ablation for VT/PVCs originating from the free-wall portion of the annulus and septum were 90 and 57%, respectively.1 We therefore treated our case with RF catheter ablation.

Arrhythmias originating anywhere in the right ventricle raise concerns about the presence of arrhythmogenic right ventricular cardiomyopathy (ARVC). We performed a cardiac magnetic resonance imaging study, which revealed a structurally normal heart in our patient. While ARVC could not be completely excluded, our case was much more likely to be one of idiopathic

tachycardia, based on the observations of a normal-sized right ventricle, lack of epsilon waves or inverted T waves in the precordial leads, absence of fractionated electrograms at or around the ablation site, suppression of arrhythmia during exercise, single QRS morphology of the arrhythmia, and the success of focal ablation.3 Other than one minor ARVC criterion, our patient did not fulfil any of the major ARVC criteria, which also supported the diagnosis of idiopathic VT.

Conclusion We present a sporadic case of sustained idiopathic VT originating from the posteroseptal tricuspid annulus. Surface ECG is a reliable tool that can be used to localise the anatomical origin of the VT/PVCs.

References 1.

2.

3.

Sergio L. Pinski. The Right Ventricular Tachycardias. J Electrocardiol 2000; 33: 103–114.

Tada H, Tadokoro K, Ito S, Naito S, Hashimato T, Kaseno K, Miyaji K, et al. Idiopathic ventricular arrhythmias originating from the tricuspid annulus: prevalence, electrocardiographic characteristics, and results of radiofrequency catheter ablation. Heart Rhythm 2007; 4: 7–16.

O’Donnell D, Cox D, Bourke J, Mitchell L, Furniss S. Clinical and electrophysiological 7575 differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. Eur Heart J 2003; 24: 801–810.

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Case Report LEOPARD syndrome PL MASSOURE, C LATREMOUILLE, G LAMBLIN, F LECA

Abstract LEOPARD syndrome (LS) is a rare hereditary disorder, characterised mainly by skin, facial and cardiac abnormalities. We report on the case of a six-­year-old Djiboutian with typical features of LS. Multiple cardiovascular problems are described, including pulmonary infundibular, valvular and supra-valvular stenosis. A favourable course was observed after successful cardiac surgery. This is the first reported case of LS from the horn of Africa.

A

Keywords: LEOPARD syndrome, pulmonary stenosis, ventricular hypertrophy Submitted 21/8/10, accepted 22/2/12 Cardiovasc J Afr 2012; 23: e19–e20

www.cvja.co.za

DOI: 10.5830/CVJA-2012-011

LEOPARD syndrome (LS), a rare syndrome comprising multiple congenital anomalies of the skin, face and heart, is probably underdiagnosed in Africa. Characteristic cardiovascular anomalies range from benign to life threatening. We report on the case of a six-­year-old Djiboutian who presented with typical features of LS.

B

Case report A six-year-old Djiboutian presented with progressive exercise dyspnoea and flat black-brown lentigines on the face, neck and torso (Fig. 1A). Physical examination revealed height and weight below the third percentile, ocular hypertelorism and bilateral cryptorchism. A grade 3/6 systolic murmur was heard at the left second intercostal space.

An ECG showed normal sinus rhythm (Fig. 1B) with right ventricular hypertrophy and long QTc (480 ms). Transthoracic echocardiography confirmed right ventricular hypertrophy, especially of the septum and free right ventricular wall, and revealed pulmonary infundibular, annular and supravalvular stenosis (Fig. 2A). Peak pressure gradient between the right ventricle and the pulmonary trunk was 148 mmHg (Fig. 2B).

There was no other cardiac abnormality.

Service de Médecine, Hôpital Bouffard, Djibouti, Armées PL MASSOURE, MD, plmassoure@aol.com G LAMBLIN, MD

Hôpital Européen Georges Pompidou, Paris, France C LATREMOUILLE, MD

Mécénat Chirurgie Cardiaque – Enfants du Monde, Paris, France F LECA, MD

Fig. 1. A: Six-year-old Djiboutian with multiple lentigines on the face, neck and torso. B: ECG of the patient: sinus rhythm, deep Q waves, right ventricular hypertrophy and repolarisation abnormalities (long QTc: 480 ms).

LEOPARD syndrome was diagnosed. There was no other case in his family. Genetic analyses were not performed.

Surgical procedure consisted of a resection of the fibrotic stenosis in the right ventricular outflow tract, and widening of the pulmonary annulus and the first centimetre of the pulmonary trunk with a pericardial patch. A postoperative echocardiogram showed a residual 24-mmHg pressure gradient between the right ventricle and the pulmonary trunk.

After three months of follow up, the patient was asymptomatic.

Conduction abnormalities or rhythm disturbance were not shown on consecutive postoperative ECG recordings.

Orchidopexy and protection from the sun’s ultraviolet A and B rays were recommended. The patient’s parent were advised to avoid drugs known to prolong the QT interval.

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012

A

Right Ventricle RVOT

Pulmonary Trunk

B

Vmax VP 6.09m/s VP GPmax 148.5mmHg VP Vmoy 4.28m/s VP GPmoy 4.28m/s ITV VP 154.1cm HR 75bpm

AFRICA

based on multiple lentigines with two or more cardinal features.1 In the absence of lentigines, three or more other features in the patient and the presence of an affected close relative are diagnostic.

The coexistence of lentigines and cardiac disease was first reported by Walter et al. 2 in 1966. The defect associated with development of the syndrome has been located on chromosome 12 and the responsible gene is protein tyrosine phosphatase non-receptor 11 (PTPN 11). LS is one of the so called neuro-cardio-facial-cutaneous syndromes, such as Noonan syndrome, neurofibromatosis type 1, Costello syndrome and cardiofaciocutaneous syndrome. These overlapping disorders may represent a differential diagnosis in less complete forms than reported here. ECG abnormalities occur in about 75% of the patients, including left, right or bi-ventricular hypertrophy, Q waves, prolonged QTc and repolarisation abnormalities.3 Pulmonary stenosis (valvular dysplasia, pulmonary annulus dysplasia and/or infundibular stenosis) is noted in 20% of persons with LS. A pre-operative image of the nature of the right ventricular outflow tract obstruction will determine the form of operative procedure adopted. Valvulectomy, valvulotomy or valvuloplasty are possible options.1 Infundibular and valvular stenosis are common but supravalvular stenosis, as reported here, appears to be unusual. Mitral or aortic valvular anomalies, obstruction of the left ventricular outflow tract and dilatation of the coronary arteries have seldom been described in LS and were not observed here.

Right ventricular hypertrophy may also accompany left ventricular hypertrophy and pulmonary stenosis in about 30% of patients with LS.4 Hypertrophic cardiomyopathy (HCM) may appear later in life and may be life threatening. Careful follow up of young patients is necessary to detect cardiac conduction abnormalities (25% of the patients) and the onset of HCM.

Conclusion Fig. 2. A: Two-dimensional echocardiography of the right ventricular outflow tract (RVOT), pulmonary annulus and pulmonary trunk showing a fibrotic stenosis (later confirmed at surgery). B: Severe pulmonary stenosis revealed by continuous Doppler: a 148-mmHg peak pressure gradient was measured between the right ventricle and the pulmonary trunk.

LS is probably underdiagnosed. Approximately 200 cases have been reported in the world and very few in Africa.1,5 To the best of our knowledge, this is the first case reported in the horn of Africa.

References 1.

Discussion

2.

LEOPARD is an acronym for the major features of this rare, dominant, autosomal genetic disease, including multiple Lentigines (appearing at four to five years and increasing in the thousands until puberty, independent of sun exposure), ECG conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. As shown here, the diagnosis of LS is

3.

4.

5.

Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. Orphanet J Rare Dis 2008; 27: 1750–1772.

Walter RJ, Polanski BJ, Grots IA. Electrocardiographic abnormalities in a family with generalized lentigo. N Engl J Med 1966; 275: 1220–1225.

Limongelli G, Pacileo G, Marino B, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol 2007; 100: 736–741.

Limongelli G, Sarkozy A, Pacileo G, et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet 2008; 46: 620–628.

Kubeyinje EP, Onunu AN, Obasohan AO. Multiple lentigines syndrome in a Nigerian family. Trop Geogr Med 1993; 45: 135–137.

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