NOVEMBER 2012 VOL 23 NO 10
AFRICA www.cvja.co.za
CardioVascular Journal of Africa (official journal for PASCAR)
• Measurement of cardiac troponins using high-sensitivity assays • Electrocardiographic abnormalities in type 2 diabetes • QTc prolongation prior to angiography predicts poor outcome • Statistical profiling of hospital performance • Cardiomyopathies and myocardial disorders in Africa • Telomeres and atherosclerosis
Cardiovascular Journal of Africa . Vol 23, No 10, November 2012
Printed by Tandym Printers
• Workshop highlighting cardiovascular research in South Africa • Simplifying venous thromboembolism management
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...now it’s a stroke. After more than 50 years, a new therapy is now available in South Africa to prevent strokes caused by atrial fibrillation that offers: • 35 % reduced risk of stroke and systemic embolism vs. well-controlled warfarin (p < 0,001) 1,2 • 59 % reduced risk of intracranial bleeding vs. well-controlled warfarin (p < 0,001) 1,2 • 20 % reduced risk of life-threatening bleeding vs. well-controlled warfarin (p = 0,03) 1,2 • Does not require regular INR monitoring3 • Does not interact with food3
Dabigatran etexilate 110 mg/150 mg S4 Pradaxa® 110 mg. Each capsule contains 110 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 42/8.2/0131 S4 Pradaxa® 150 mg. Each capsule contains 150 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 45/8.2/0162 For full prescribing information refer to the package insert approved by the medicines regulatory authority. Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Fax: +27 (011) 787-3766. Cpy. Reg. No. 1966/008618/07. BI Ref. No. 341/2012 (Nov 12) References: 1. Connolly SJ, Ezekowitz MB, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Eng J Med 2009;361:1139–1151. 2. Connolly SJ, Ezekowitz MB, Yusuf S et al. Newly identified events in the RE-LY trial. New Eng J Med 2010;363:1875–1876. 3. Boehringer Ingelheim South African Pradaxa® Package insert.
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1,2
ISSN 1995-1892 (print) ISSN 1680-0745 (online)
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VOL 23, NO 10. NOVEMBER 2012
CONTENTS
Cardiovascular Journal of Africa
531
www.cvja.co.za
Editorial
Measurement of cardiac troponins to detect myocardial infarction using high-sensitivity assays: South African guidelines R Delport • JA Ker
Cardiovascular Topics
533 Prevalence and determinants of electrocardiographic abnormalities in sub-Saharan African individuals with type 2 diabetes A Dzudie • S-P Choukem • AK Adam • AP Kengne • P Gouking • M Dehayem • F Kamdem • MS Doualla • HA Joko • MEE Lobe • YM Mbouende • H Luma • JC Mbanya • S Kingue 538
Follow up in a developing country of patients with complete atrio-ventricular block JCT Tchoumi • S Foresti • P Lupo • R Cappato • G Butera
541
QTc prolongation prior to angiography predicts poor outcome and associates significantly with lower left ventricular ejection fractions and higher left ventricular end-diastolic pressures P van der Bijl • M Heradien • A Doubell • P Brink
546
Statistical profiling of hospital performance using acute coronary syndrome mortality SOM Manda • CP Gale • AS Hall • MS Gilthorpe
552
Cardiomyopathies and myocardial disorders in Africa: present status and the way forward AO Falase • OS Ogah
Review Articles
563 Telomeres and atherosclerosis S Khan • AA Chuturgoon • DP Naidoo
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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 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 10. NOVEMBER 2012
Meeting report
572
2nd South Africa–United Kingdom cardiovascular workshop highlighting cardiovascular research in South Africa R Kelly-Laubscher • G Burger • N Davies • A-M Engelbrecht • K Sliwa • H Strijdom • D Hausenloy • S Lecour
573
South Africa enters a new era in stroke prevention J Aalbers
574
Simplifying venous thromboembolism management: a new and safer era G Hardy
576
Benefits of dabigatran maintained for more than two years J Aalbers
Drug Trends in Cardiology
PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) Case Reports
e1 Infections secondary to pacemaker implantation: a synopsis of six cases AD Kane • MB Ndiaye • S Pessinaba • A Mbaye • M Bodian • MED Driouch • M Jobe • M Diao • M Sarr • A Kane • SA Ba e5
MRI finding of a papillary muscle cyst: a differential diagnosis T Shayingca • S Andronikou • R Truter • E Reid
e7
Successful management of spontaneous aortic dissection type B in the third trimester of pregnancy Y Simsek • C Colak • E Yilmaz • E Celik • N Erdil • O Celik
e10
Single-stage repair of adult aortic coarctation and concomitant coronary artery disease: an unusual surgical approach through median sternotomy MM Ulas • K Ergun • G Lafci • N Sen • A Yalcinkaya • A Irdem • K Cagli
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CONTENT MANAGER
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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: To subscribe to the journal or change your postal address, e-mail wendy@clinicscardive.com 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 10, November 2012
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Editorial Measurement of cardiac troponins to detect myocardial infarction using high-sensitivity assays: South African guidelines With the use of specific cardiac markers with higher sensitivity, new perspectives have emerged on the nature of myocardial necrosis and injury, which are associated with acute coronary syndrome (ACS). The third universal definition of myocardial infarction1 now classifies myocardial infarction (MI), based on the relevant pathology, clinical presentation, prognosis and treatment strategy, as spontaneous MI (type 1), MI secondary to an ischaemic imbalance (type 2), cardiac death due to sudden fatal MI (type 3), and MI associated with revascularisation procedures (types 4 and 5). What has also become evident is the extent of necrosis and injury that is associated with pathologies of other organs and conditions.1-3 The clinical circumstances associated with elevated values of cardiac troponin (c-Tn) due to myocardial injury have been listed,1 and comprise conditions related to primary myocardial ischaemia, conditions related to supply/demand imbalance of myocardial ischaemia, conditions not related to myocardial ischaemia and conditions related to multi-factorial or indeterminate myocardial injury. A shift in focus is apparent, not only from valuing these highly sensitive cardiac biomarkers for their exceptional diagnostic sensitivity and negative predictive value for the diagnosis of MI, but also for their application in ACS risk stratification.1,4-6 Guidelines on the use of high-sensitivity cardiac troponin (hs-cT) markers have recently been set in the consensus statement of the Ethics and Guidelines Standing Committee of the South African Heart Association.7 This editorial aims to appraise these guidelines in the light of more recent research findings and newer guidelines. The committee recommends that high-sensitivity troponin assays be widely adopted as the preferred biomarker for the diagnosis of myocardial infarction, based on evidence of earlier diagnosis of MI, more reliable ruling out of MI, and shortening of the chest pain triage (to four hours compared to former assays). All cardiac troponin measurements are to be reported in ng/l. The first sample is to be collected on first assessment, followed by a second sample after three hours, should the first value be lower than the 99th percentile (URL) of a normal reference population for the specific assay, or between the URL and the WHO-defined URL for MI. Serial measurements are to be reported as percentage change. A specific algorithm for both hs-cTropT and hs-cTropI is proposed for the diagnosis of MI. The Expert Consensus document on the third universal definition of myocardial infarction1 states that sample repeat may be three to six hours later, followed by further sampling depending on uncertainty concerning timing of the initial symptoms and whether the injury was evolving or resolving.4,8,9 Rule-in for MI constitutes a rise and/or fall in values, with one
value above the decision limit (99th percentile value), using an assay with an imprecision (coefficient of variation) ≤ 10% if accompanied by a strong pre-test likelihood, the diagnosis being based mainly on the latter.1 Repeat measurements display the dynamic pattern of troponin values and aid in differentiating between acute and chronic causes of troponin elevation in the circulation.4 The guidelines defined for South Africa (SA)7 differ from those in the Consensus document.1 They state: ‘The percentage change (rise or fall) in hs-cT levels in two samples three hours apart is used to establish a diagnosis of MI when the troponin level is below the WHO cut-off. For troponin I a 50% change in an initial value is diagnostic of MI. In the case of troponin T, a 50% change in an initial value of < 53, or a 20% change in an initial value between 53 and 100 ng/l, is diagnostic of MI.’ They are similar to those set by the study group on biomarkers in cardiology of the ESC Working Group on Acute Cardiac Care, in that the 50% change rule is applied for the second sample,9 but they do not apply the WHO cut-off point and state as prerequisite for rule-in that the values at three hours (and optionally at six hours) be greater than the URI. In the South African guidelines,7 the WHO cut-off values are also taken into consideration for decision making, in that values between the URL and the WHO cut-off values are subject to repeat measurement at three hours, the percentage change being dependent on the first assessment value being smaller than the WHO cut-off values. Of note is that use of change as a measure for rule-in may increase the specificity for MI, but at the cost of a decrease in sensitivity,9-11 and that, as stated by Thygesen et al.,1 ‘It should be clear that dynamic changes are not specific for MI but rather are indicative of active myocardial injury with necrosis’. The validity of the use of the URL12-15 as well as repeated measurements at three hours for rule-in or rule-out of MI3,16-18 have been substantiated in several studies. The selection strategy for the reference population, however, markedly influences the 99th percentile reference values for troponin assays if it does not consider relevant demographic, biological and clinical variables and this affects the diagnostic performance of highly sensitive immunoassays,4,19-21 as suggested in the SA guidelines.7 Furthermore, inter-assay differences concerning reference values for specific populations appear to impact on risk stratification.22-24 A higher cut-off point for the diagnosis on NSTEMI may be appropriate in patients with mildly elevated hs-TnI and without evidence for STEMI,25 and use of absolute change over serial measurements is suggested to perform better and decrease time to rule-in and rule-out of NSTEMI compared with relative change.11,26-29
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The 20% limit of defining a significant increase from the time of first assessment if baseline values are above the URL has been established within the National Academy of Clinical Biochemistry laboratory medicine practice guidelines30 and represents a significant (> 3) standard deviation variation on the basis of a 5–7% analytical imprecision (analytical CV).12,31,32 This increment of increase has been proven to be clinically useful8,32-35 but is assay dependent,16,17,36-38 and remains a challenge that requires further clinical and prospective studies, as concluded by Lippi et al. and others.9,40 The 50% limit of defining a significant increase if baseline values are below the URL does not appear to be based on high-level evidence but purportedly optimises the overall accuracy of MI diagnosis.9,11,27 Other complexities of measurement, as eluded to by Thygesen,9 are the substantial differences between ‘high-sensitivity’ assays and the concern that the manufacturers’ claims for assay precision cannot be achieved in clinical laboratories. Relevant analytical issues alluded to in the SA guidelines are falsely high values because of heterophile antibodies and human autoantibodies interfering with the assay,40-42 and falsely low levels with haemolysis.43,44 In addition, Lippi et al.4 reported interferences being observed, caused by rheumatoid factor, complement, presence of fibrin in serum or plasma after centrifugation of the sample, unsuitable samples (e.g. haemolysed, lipaemic, icteric), and analytical errors (e.g. instrument malfunctioning). Of interest is a report by Gould et al. on carry-over to subsequent samples with certain analysers, potentially leading to false-positive results.45
Conclusion The South African guidelines on the use of high-sensitivity cardiac troponins as biomarkers are timely and of great value, provided that clinicians take up the challenge of applying them clinically. RHENA DELPORT, PhD (Chem Path), MSc, MEd, rhena.delport@up.ac.za Department of Chemical Pathology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa JAMES A KER, MB ChB, MMed (Int), MD, jker@medic.up.ac.za Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
References 1.
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; writing group on behalf of the joint ESC/ACCF/AHA/WHF task force for the universal definition of myocardial infarction. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60(16): 1581–1598. Jaffe AS. Troponin – past, present, and future. Curr Probl Cardiol 2012; 37(6): 209–228. Daubert MA, Jeremias A. The utility of troponin measurement to detect myocardial infarction: review of the current findings. Vasc Health Risk Manag 2010; 6: 691–699. Lippi G, Montagnana M, Aloe R, Cervellin G. Highly sensitive troponin immunoassays: navigating between the scylla and charybdis. Adv Clin Chem 2012; 58: 1–29. Ziebig R, Lun A, Hocher B, et al. Renal elimination of troponin T and
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troponin I. Clin Chem 2003; 49: 1191–1193. Apple FS, Jesse RL, Newby LK, Wu AHB, Christenson RH. NACB and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes, Circulation 2007; 115: e352–e355. Consensus statement of the Ethics and Guidelines Standing Committee of the SA Heart Association. SAHeart 2012; 9: 210–215. MacRae AR, Kavsak PA, Lustig V, et al. Assessing the requirement for the six-hour interval between specimens in the American Heart Association classification of myocardial infarction in epidemiology and clinical research studies. Clin Chem 2006; 52: 812–818. Thygesen K, Mair J, Giannitsis E, et al.; the study group on biomarkers in cardiology of the ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012; 33(18): 2252–2257. Keller T, Zeller T, Peetz D, Tzikas S, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009; 361: 868–877. Reichlin T, Irfan A, Twerenbold R, et al. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation 2011; 124: 136–145. Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF task force for the redefinition of myocardial infarction. Universal definition of myocardial infarction. Eur Heart J 2007; 28: 2525–2538. Mueller M, Celik S, Biener M, et al. Diagnostic and prognostic performance of a novel high-sensitivity cardiac troponin T assay compared to a contemporary sensitive cardiac troponin I assay in patients with acute coronary syndrome. Clin Res Cardiol 2012; 101(10): 837–845. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009; 361: 868–877. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009; 361: 858–867. Keller T, Zeller T, Ojeda F, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. J Am Med Assoc 2011; 306(24): 2684–2693. Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. Highsensitivity cardiac troponin T for early prediction of evolving non-STsegment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin Chem 2010; 56: 642–650. Weber M, Bazzino O, Estrada JJN, Miguel R, Salzberg S, Fuselli JJ, et al. Improved diagnostic and prognostic performance of a new highsensitive troponin T assay in patients with acute coronary syndrome. Am Heart J 2011; 162: 81–88. Keller T, Ojeda F, Zeller T, et al. Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay. Int J Cardiol 2012 May 4. [Epub ahead of print]. Collinson PO, Heung YM, Gaze D, Boa F, Senior R, Christenson R, Apple FS. Influence of population selection on the 99th percentile reference value for cardiac troponin assays. Clin Chem 2012; 58(1): 219–225. Cardinaels EP, Mingels AM, Jacobs LH, Meex SJ, Bekers O, van Dieijen-Visser MP. A comprehensive review of upper reference limits reported for (high-) sensitivity cardiac troponin assays: the challenges that lie ahead. Clin Chem Lab Med 2012; 50(5): 791–806. Mills NL, Lee KK, McAllister DA, et al. Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study. Br Med J 2012; 344: e1533. Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem 2012 Sep 14. [Epub ahead of print]. Lyck Hansen M, Saaby L, Nybo M, et al. Discordant diagnoses of acute myocardial infarction due to the different use of assays and cut-off points of cardiac troponins. Cardiology 2012; 122(4): 225–229.
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Cardiovascular Topics Prevalence and determinants of electrocardiographic abnormalities in sub-Saharan African individuals with type 2 diabetes ANASTASE DZUDIE, SIMEON-PIERRE CHOUKEM, ABDOUL K ADAM, ANDRE P KENGNE, PATRICIA GOUKING, MESMIN DEHAYEM, FÉLICITÉ KAMDEM, MARIE S DOUALLA, HENRY A JOKO, MARIELLE EE LOBE, YVES M MBOUENDE, HENRY LUMA, JEAN-CLAUDE MBANYA, SAMUEL KINGUE
Abstract Aim: This study assessed the prevalence and determinants of electrocardiographic abnormalities in a group of type 2 diabetes patients recruited from two referral centres in Cameroon. Methods: A total of 420 patients (49% men) receiving chronic diabetes care at the Douala General and Yaoundé Central hospitals were included. Electrocardiographic abnormalities were investigated, identified and related to potential determinants, with logistic regressions. Results: The mean age and median duration of diagnosis were 56.7 years and four years, respectively. The main elecDepartment of Internal Medicine, Douala General Hospital, Cameroon ANASTASE DZUDIE, MD, FWHF SIMEON-PIERRE CHOUKEM, MD FÉLICITÉ KAMDEM, MD SOLANGE DOUALLA, MD HENRY A JOKO, MD MARIELLE EE LOBE, MD YVES M MBOUENDE, MD HENRY LUMA, MD
Department of Internal Medicine, Buea Faculty of Health Sciences, Cameroon ANASTASE DZUDIE, MD, FWHF, aitdzudie@yahoo.com SIMEON-PIERRE CHOUKEM, MD
Universite Université des Montagnes, Bangangte, Cameroon ABDOUL K ADAM, MD
Department of Medicine, University of Cape Town and Medical Research Council, Cape Town, South Africa ANDRE P KENGNE, MD, PhD
Diabetes and Endocrine Service, Yaoundé Central Hospital and Faculty of Medicine, Cameroon PATRICIA GOUKING, MD MESMIN DEHAYEM, MD JEAN-CLAUDE MBANYA, MD, PhD
Department of Internal Medicine, Yaoundé Faculty of Medicine, Cameroon SOLANGE DOUALLA, MD HENRY LUMA, MD JEAN-CLAUDE MBANYA, MD, PhD SAMUEL KINGUE, MD
trocardiographic aberrations (prevalence %) were: T-wave abnormalities (20.9%), Cornell product left ventricular hypertrophy (16.4%), arrhythmia (16.2%), ischaemic heart disease (13.6%), conduction defects (11.9%), QTc prolongation (10.2%) and ectopic beats (4.8%). Blood pressure variables were consistently associated with all electrocardiographic abnormalities. Diabetes-specific factors were associated with some abnormalities only. Conclusions: Electrocardiographic aberrations in this population were dominated by repolarisation, conduction defects and left ventricular hypertrophy, and were more related to blood pressure than diabetes-specific factors. Keywords: diabetes mellitus, sub-Saharan Africa, Cameroon, ECG, cardiovascular disease Submitted 28/5/11, accepted 4/7/12 Published online 19/9/12 Cardiovasc J Afr 2012; 23: 533–537
www.cvja.co.za
DOI: 10.5830/CVJA-2012-054
A major threat to the health of diabetes subjects is cardiovascular disease (CVD), which currently accounts for about threequarters of all deaths in diabetes patients in major populations and settings.1 Attempts to maintain cardiovascular health in diabetics include: (1) routine prescription of medications with proven beneficial effects on cardiovascular health, such as statins and aspirin; (2) investigation and treatment of individuals with abnormal levels of modifiable risk factors; (3) monitoring of individuals for infra-clinical changes, which are indicators of future high risk for cardiovascular events, or those with lessadvanced stages of diabetes, whose course could be modified through early intervention.2 The electrocardiogram (ECG) is widely used for monitoring.3 ECG changes appear early in the course of diabetes, and usually include alterations such as sinus tachycardia, QTc prolongation, QT dispersion, changes in heart rate variability, ST–T changes, and left ventricular hypertrophy. These changes and others, detected with the use of a resting ECG, often together with an exercise ECG, are used to detect silent ischaemia, assess prognosis and predict future risk. Because the ECG is a non-invasive and relatively easy test to perform, it is used in the series of investigations conducted as part of the annual clinical evaluation of people with diabetes around the world.3
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The use of this modality however varies substantially, guided essentially by the availability of ECG machines and the cost of such investigations. As a result, the regional office of the International Diabetes Federation (IDF) for Africa recommends ECG monitoring in diabetes only at the secondary or tertiary level of the healthcare system where facilities for performing an ECG are more readily available.4 Therefore in sub-Saharan Africa, the majority of patients with diabetes who receive care in primary healthcare facilities do not have routine ECG screening. Failure to perform regular ECGs means that opportunities to improve cardiovascular health in this population are being missed. Furthermore, our knowledge of the major ECG abnormalities and their determinants in this environment remains very limited. In this study we assessed the distribution of ECG aberrations and investigated their potential determinants in a group of individuals with type 2 diabetes who were receiving chronic care in two referral hospitals in the two largest cities of Cameroon, Central Africa.
Methods The out-patient sections of the Yaoundé Central Hospital’s diabetes and endocrine service, and the Douala General Hospital’s (DGH) internal medicine service and sub-specialties served as settings for recruitment of participants for this study. The Yaoundé Central Hospital (YCH) has been described in detail elsewhere.5,6 The DGH internal medicine and sub-specialities service has an individualised, dedicated endocrine section, which is the main referral centre for endocrine diseases and diabetes in Douala, the second major city of Cameroon (approximately 2.5 million people). Patients with diabetes and its complications, residing in Douala and surrounding regions were the most likely to receive care in our clinic during the study period. Overall, the healthcare system in Cameroon is organised into primary, secondary and tertiary levels. Care at the primary level is provided by nurses and general practitioners and is essentially geared towards acute conditions. Secondary-level facilities provide access to some form of specialist care. Tertiary-level facilities (including YCH and DGH) serve as a referral hospital for primary- and secondary-level health facilities, and for routine consultations and follow up, as in our study. From January 2010, the Yaoundé health service has had three endocrinologists and the Douala health service two. Patients with diabetes who received chronic care in the two study clinics were required to have an annual evaluation as part of their routine care. In addition to a clinical consultation, this evaluation included: (1) an assessment of diabetes control (fasting glucose and haemoglobin A1c levels); (2) an assessment of chronic complications (eyes: fundoscopy, kidney function: albuminuria, serum urea and creatinine levels); (3) a cardiovascular work up including an assessment of lipid profiles (total cholesterol, highdensity lipoprotein cholesterol and triglycerides) and a resting ECG. Participants in this study were recruited from patients presenting for these annual evaluations. The study was approved by the administrative authorities of the two health facilities, and ethical clearance was obtained from the Cameroon National Ethics Committee. Four hundred and twenty individuals with type 2 diabetes
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receiving chronic care in the two study facilities were consecutively enrolled over a two-year period from January 2008 to January 2010. Only the patients’ first consultation during this period was considered, and no other exclusion criteria were applied. The type of diabetes was based on the diagnosis of the attending physician. In addition, patients had to be at least 30 years of age at the time of their first diagnosis of diabetes. Blood pressure (mmHg) was measured on the right arm with the participant in a seated position, after 10 minutes’ rest, with an Omron® MX2 basic electronic device (Omron Healthcare Co, Ltd, Kyoto, Japan) with the appropriate cuff size. The average of two measurements recorded five minutes apart was used in this study. Body weight (kg) was measured in light clothing, using a SECA® scale, and height (m) was measured with a standard stadiometer. The body mass index (BMI) for each patient was calculated as weight/height2 (kg/m2). The waist circumference (cm) was measured with a tape measure on the horizontal plane midway between the lowest rib margin and upper edge of the iliac crest. A 12-lead resting ECG was done on all subjects using the Cardi Max Fx-7302®. All ECG tracings were centrally interpreted by the same investigator who is a cardiologist (AD) and did not know the subjects’ backgrounds. Significant ECG findings such as ST-segment elevation or depression, T-wave aberrations (inversion or tall T wave), bundle branch block, left ventricular hypertrophy (LVH), right and left atrial enlargement, arrhythmias and other changes were noted. LVH was defined according to three different criteria: • Cornell voltage-duration product [(RaVL + SV3) × QRS complex duration] > 2.623 mm × ms in men and > 1.558.7 mm × ms in women,7 • Cornell voltage (SV3 + RaVL > 24 mm in women and 28 mm in men) • Sokolov-Lyon index (SV1 + RV5/6 > 35 mm). Compared with echocardiography, the cut-off values for the Cornell voltage duration product gave the best sensitivity with a specificity of 95%.7 ECG measurements were done with a ruler on the resting ECG tracings, and were expressed as the average of three determinations on consecutive QRS complexes. R-wave amplitude in aVL and S-wave depth in V3 were measured as the distance (mm) from the isoelectric line of their zenith and nadir, respectively. QRS duration was measured from the beginning to the end of the QRS complex. QTc prolongation was defined as a QTc > 460 ms in both men and women. A diagnosis of ischaemic heart disease was made based on the American Heart Association criteria. These criteria include ECG features of significant ST-segment depression, defined as an ST-segment depression > 1 mm in more than one lead, and T-wave inversion. Myocardial infarction was defined as an ST-segment elevation (convex upwards) > 0.08 s, associated with T-wave inversion in multiple leads, and reciprocal ST-segment depression in opposite leads.
Statistical analysis Data were analysed using SPSS® version 17 for Windows (SPSS, Chicago, IL). Differences in means and proportions for participants’ characteristics were assessed using analysis of variance and χ2 tests as applicable, and the influence of likely
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confounders was adjusted for with logistic regressions models. A probability of p < 0.05 was set as the threshold of statistical significance.
Results Of the 420 patients recruited, 207 (49%) were men and 250 (56%) were from the Yaoundé centre. The mean age was 56.7 years and the median duration of diagnosed diabetes was four years (IQR 25th to 75th percentiles: 1–9). TABLE 1. PROFILE OF THE 420 MEN AND WOMEN WITH TYPE 2 DIABETES Men n (%)
Variables
Women n (%)
p
Total n (%)
70
56.7 (9.92)
60
Number (%)
207 (49)
213 (51)
Age (years)
55.9 (9.83)
57.5 (9.96)
0.09
4 (1–9)
Median (range) known duration of diabetes (years)
4 (0–9)
4 (1–8)
0.71
213 (50.7)
Parental history of diabetes
103 (49.7)
110 (51.6)
0.69
32 (7.6)
Smoking
27 (13.1)
5 (2.3)
< 0.001
28.5 (5.2)
Body mass index (kg/m2)
27.2 (4)
29.7 (6)
< 0.001
95.1 (11.9)
Waist circumference (cm)
95.3 (10.8)
94.9 (12.92)
0.71
101.2 (11.8)
98.5 (10)
103.7 (12.9)
< 0.001
0.94 (0.10)
0.96 (0.08)
0.91 (0.11)
< 0.001
142.2 (25.3)
Hip circumference (cm) Waist-to-hip ratio
As expected, anthropometric characteristics were different between men and women. Diabetes control was also poorer in men than in women (all p < 0.04), otherwise men were similar to women with regard to many other characteristics, including history of diabetes, treatment and complications, and cardiovascular risk profile (Table 1). With few exceptions, participants’ characteristics were mostly similar across the participating centres. The few exceptions related to hip circumference (p < 0.001), diastolic blood pressure (p < 0.001), haemoglobin A1c level (p < 0.001), creatinine clearance rate (p = 0.04), the use of ACE inhibitors (p = 0.01) and the presence of neuropathy (p = 0.008).
Percentage (%)
AFRICA
142.8 (23.6) 141.6 (26.91)
0.61
85.1 (13.2)
Diastolic blood pressure (mmHg)
85.6 (12.2)
84.5 (14.15)
0.37
57.1 (18.2)
Pulse pressure (mmHg)
40 30 20 10
Hypertension and treatments Systolic blood pressure (mmHg)
50
0
0.95
211 (50.2)
114 (53.5%)
0.17
186 (44.3)
Any blood pressurelowering medication
83 (40.1)
103 (48.4)
0.09
139 (33.1)
60
ACE inhibitors
70 (33.8)
69 (32.4)
0.84
5 (1.2)
50
2 (1)
3 (1.4)
0.99
118 (28.1)
64 (30)
0.37
69 (16.4)
Calcium channel blockers
33 (15.9)
36 (16.9)
0.79
30 (7.1)
7 (3.4)
23 (10.8)
0.004
185 (49)
Beta-blockers
Lipid profile and lipid-modifying therapies Total cholesterol (mg/dl)
187 (49)
184 (51)
0.57
47 (18)
HDL cholesterol (mg/dl)
47 (19)
48 (18)
0.52
101 (67–141)
0.62
35 (13.2)
16 (7.5)
0.58
1 (0.2) 15 (3.6)
Median (range) triglycerides (mg/dl)
99 (64–142) 102 (68–140)
Lipid modifying therapies
19 (9.2)
Percentage (%)
57.1 (19.49)
97 (46.8)
54 (26.1)
1 (0.5%)
0.32
Cerebrovascular diseases
6 (2.9)
9 (4.2%)
0.46
6 (1.4)
Lower limb occlusive vascular disease
3 (1.4)
3 (1.4%)
0.97
89 (67–111)
88(63–108)
0.23
273 (66)
Median (range) creatinine 91 (70–113) clearance (ml/min/1.73 m2) Diabetes treatment and control Metformin
133 (64.7)
143 (67%)
0.58
185 (44)
Suphonamide
93 (45)
92 (43%)
0.69
9 (2.1)
Acarbose
2 (0.9)
7 (3.3%)
0.19
68 (16.2)
Insulin
37 (17.9)
31 (14.5%)
0.34
177 (81)
Fasting capillary glucose (mg/dl)
185 (85)
169 (77)
0.04
8.2 (2.3)
Haemoglobin A1c (%)
8.5 (2.3)
7.9 (2.2)
0.03
Any diabetic retinopathy
38 (18.3%)
28 (13.1)
0.14
66 (15.7)
Any diabetic nephropathy
30 (14.5%)
37 (17.4)
0.42
67 (15.9)
Any diabetic neuropathy
52 (25.1%)
42 (19.7)
0.18
94 (22.4)
40 30 20
0
AVB
CRBBB CLBBB Conduction changes
LAHB
70 60 Percentage (%)
0 (0.0)
Sinus tachycardia
10
History of cardiovascular disease Coronary heart disease
Sinus arrythmia
70
57.2 (16.8)
ARA II antagonists
Sinus bradycardia
Rythm changes
Hypertension
Diuretics
Atrial fibrillation
50 40 30 20 10 0
Local
Microvascular complications
Women
Non-specific T-wave changes Men
Tall Total
Fig. 1. Rhythm, conduction and T-wave changes in 420 men and women with type 2 diabetes.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
TABLE 2. ECG CHANGES IN 420 MEN AND WOMEN WITH TYPE 2 DIABETES Men n (%)
Variables
Women n (%)
Number (%)
207 (49)
213 (51)
Arrhythmia
31 (15)
37 (17.4)
p
Total n (%)
0.51
68 (16.2) 50 (11.9)
420
Conduction changes
28 (13.5) 22 (10.3)
0.37
Ectopic beats
10 (4.8)
10 (4.7)
0.99
20 (4.8)
T-waves changes
53 (25.6) 35 (16.4)
0.02
88 (20.9)
QTc prolongation
18 (8.7)
25 (11.7)
0.34
43 (10.2)
Ischaemic heart disease
34 (16.4) 23 (10.8)
0.12
57 (13.6) 69 (16.4)
Left ventricular hypertrophy by diagnostic criteria Cornell product
14 (6.7)
55 (25,8)
< 0.001
Sokolov index
17 (8.2)
7 (3.3)
0.03
24 (5.7)
Cornell index
12 (5.8)
5 (2.3)
0.09
17 (4.1)
The distribution of ECG abnormalities was: T-wave aberrations (20.9%), left ventricular hypertrophy according to the Cornell product criteria (16.4%), arrhythmia (16.2%), ischaemic heart disease (13.6%), conduction defects (11.9%), QTc prolongation (10.2%) and ectopic beats (4.8%). Unlike T-wave aberrations and left ventricular hypertrophy, the prevalence of major aberrations was similar in men and women (Table 2). The distribution of subtypes of arrhythmia, conduction defects and T-wave aberrations is shown in Fig. 1. The distribution of subtypes of conduction defects was significantly different in men and women (p = 0.03). Significant predictors of ECG abnormalities are shown in Table 3. Age variables (age at diabetes diagnosis and duration of diagnosed diabetes), and blood pressure variables were the common significant predictors of ECG abnormalities. The presence of diabetic nephropathy was significantly associated with T-wave aberrations [OR: 0.45 (95% CI: 0.24– 0.83)] and ischaemic heart disease [OR: 0.47 (0.23–0.95)]; otherwise, diabetes medications and markers of disease control were not associated with the outcomes. Waist circumference was associated with a 3% (95% CI: 1–6%) higher risk of QTc prolongation, otherwise no other marker of adiposity was associated with the outcomes. Similarly, none of the lipid variables was significantly associated with ECG abnormalities.
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Discussion This study revealed the high prevalence of ECG aberrations in this population of individuals with a short duration of clinically overt type 2 diabetes. While some of these aberrations were benign, others were potential indicators of the presence of serious conditions such as ischaemic heart disease, or were associated with increased future risk of fatal and non-fatal cardiovascular events. The minimal use of preventive treatment for cardiovascular disease in this population highlights the scope for improving cardiovascular health in people with type 2 diabetes in this region. Some aspects of ECG abnormalities in people with diabetes, such as those relating to LVH,8 ischaemic heart disease9 or QTc prolongation10 have been investigated in a few studies on diabetics in Africa. To the best of our knowledge, however, there is no recent study that has investigated the full spectrum of resting ECG aberrations and potential determinants in people with diabetes in this part of the world. In accordance with a previous study in Tanzania,8 we found a 16% prevalence of LVH in our study. Interestingly, blood pressure variables were also the main determinants of LVH, with approximately similar range of effects.8 That more than one in 10 participants in the current study had ECG aberrations suggestive of ischaemic heart disease has relevance in sub-Saharan Africa where cardiovascular diseases are not considered a major priority health issue in people with diabetes.11 In a previous study in the same region, using both resting and exercise ECGs, a prevalence of 7.5% for cardiac ischaemia was found; although this was based on a small sample size.12 Even after accounting for the uncertainties around the estimates from this and other studies in sub-Saharan Africa,9 our findings support a growing prevalence of ECG-diagnosed ischaemic heart disease in diabetes patients in our region over time. This prevalence was similar to that found in stroke survivors in Africa,13 and therefore provides more evidence in support of the high cardiovascular risk of diabetes patients in this part of the world. It is possible that the prevalence of ECG-diagnosed cardiac
TABLE 3. ODDS RATIO AND 95% CONFIDENCE INTERVALS FOR PREDICTORS OF ECG CHANGES Variables Age at diabetes diagnosis (years)
Arrhythmia
Conduction
T-wave changes
1.02 (0.99–1.04) 1.06 (1.02–1.09)* 1.02 (0.99–1.04)
Long QTc 1.02 (0.99–1.06)
IHD
LVH
Ectopic beat
1.00 (0.97–1.03) 1.05 (1.02–1.08)* 1.06 (1.01–1.12)*
Duration of diagnosed diabetes (years)
1.02 (0.97–1.06)
1.01 (0.96–1.07) 1.04 (1.00–1.08)* 1.08 (1.03–1.13)* 1.02 (0.98–1.07) 1.05 (1.00–1.10)* 1.04 (0.97–1.12)
Gender (men vs women)
1.16 (0.69–1.96)
0.66 (0.36–1.22) 0.55 (0.34–0.89)* 1.40 (0.73–2.68)
0.62 (0.35–1.09) 4.86 (2.54–9.25)* 0.84 (0.34–2.12)
Recruitment centre (Yaoundé vs Douala)
0.89 (0.52–1.53)
0.89 (0.48–1.66)
1.28 (0.73–2.26) 3.79 (2.13–6.75)* 2.36 (0.93–5.95)
Presence/history of nephropathy
0.69 (0.34–1.38)
0.76 (0.33–1.73) 0.45 (0.24–0.83)* 0.53 (0.25–1.15) 0.47 (0.23–0.95)* 0.66 (0.31–1.40) 0.52 (0.17–1.66)
Metformin use
1.06 (0.61–1.84)
0.87 (0.46–1.67)
1.04 (0.63–1.73)
1.86 (0.97–3.55)
0.85 (0.46–1.56)
0.89 (0.48–1.64) 0.47 (0.15–1.46)
Suphonylurea use
0.87 (0.51–1.47)
0.90 (0.49–1.65)
0.71 (0.44–1.15)
1.47 (0.76–2.86)
0.58 (0.33–1.02)
1.23 (0.69–1.20) 0.62 (0.25–1.57)
Insulin use
0.60 (0.31–1.18) 3.26 (0.96–11.09) 1.06 (0.54–2.09)
0.51 (0.26–1.11)
1.11 (0.50–2.47)
0.93 (0.40–2.17) 1.44 (0.31–6.75)
Waist circumference (cm)
0.98 (0.96–1.00)
0.98 (0.96–1.00) 1.03 (1.01–1.06)* 1.00 (0.97–1.02)
1.02 (1.00–1.04) 1.01 (0.97–1.04)
Systolic blood pressure (mmHg)
1.00 (0.99–1.01) 1.01 (1.00–1.03)* 1.01 (1.00–1.02)* 1.02 (1.01–1.03)* 1.01 (0.99–1.02)
1.02 (1.01–1.03) 1.01 (0.99–1.02)
Diastolic blood pressure (mmHg)
1.00 (0.98–1.02)
1.01 (0.99–1.04)
1.01 (0.99–1.04) 1.01 (0.98–1.05)
Pulse pressure (mmHg)
1.01 (0.99–1.02
1.02 (1.00–1.04)* 1.02 (1.00–1.03)
Heart rate (beats/min)
1.01 (0.99–1.03)
0.98 (0.96–1.01) 0.98 (0.96–1.00)* 1.05 (1.03–1.08)* 0.99 (0.97–1.01)
0.99 (0.97–1.01) 1.03 (0.97–1.04)
Total cholesterol (mg/dl)
0.60 (0.35–1.04)
1.15 (0.63–2.10)
1.55 (0.96–2.52)
1.22 (0.64–2.36)
1.24 (0.71–2.16) 1.19 (0.48–2.97)
HDL cholesterol (mg/dl)
0.66 (0.15–2.82)
1.39 (0.29–6.51)
2.23 (0.63–7.98)
1.03 (0.17–6.01) 3.82 (0.92–15.96) 1.13 (0.24–2.39) 1.97 (0.19–19.98)
1.01 (0.98–1.03)
1.78 (1.10–2.87)
1.05 (0.55–2.02)
1.01 (0.99–1.03) 1.05 (1.02–1.07)* 1.01 (0.99–1.03) 1.02 (1.00–1.03)
*p < 0.05; IHD, ischaemic heart disease; LVH, left ventricular hypertrophy; all models are adjusted for gender, age and diabetes diagnosis, known duration of diabetes and study centre
1.01 (0.99–1.03) 1.03 (1.01–1.05)* 1.00 (0.98–1.03) 1.27 (0.72–2.24)
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
ischaemia was inflated in our study for at least two reasons: (1) in the absence of a correlation between ECG aberrations and clinical features, some of the observed ST-segment and T-wave changes could have been variants of normal ECGs, as previously described in blacks;14 (2) some of the repolarisation changes could have been secondary to hypertension, which is very common in diabetes patients in this region.5 In a cohort of black and white subjects with no known cardiovascular disease who were participants of the Health, Aging, and Body Composition study (Health ABC study), the presence of major or minor ECG aberrations at baseline was associated with coronary heart disease risk during follow up, independent of classical cardiovascular risk factors.15 The findings of the Health ABC study suggest that the presence of ECG aberrations, including those used to diagnose cardiac ischaemia in our study, should be given consideration as they may indicate an adverse underlying cardiovascular risk profile. Approximately 13% of participants in this study were on a statin, preventive treatment widely recommended for routine use in people with diabetes. No correlation was found between statin use and ECG-diagnosed ischaemic heart disease. This suggests that the use of statins in this population could be almost doubled by using ECG criteria to diagnose for ischaemic heart disease. It was shown in a recent study that the use of recommended preventive therapies for cardiovascular disease risk reduction, based on global risk evaluation, was limited in Africa in people with diabetes and those without.16 Our study had some limitations. In the absence of follow up, we were unable to establish any causal relationship between identified predictors of cardiovascular risk and ECG aberrations. This was a hospital-based study and therefore included participants who may not have been typical of those in the community where the majority of type 2 diabetes persons remain undiagnosed.17 While this could have affected the prevalence of ECG changes found in our study, it was less likely to have affected the direction of associations described, and therefore would not have invalidated the major findings from this study. That ECGs were interpreted by an investigator who was unaware of the clinical background of the patients, which could have affected the prevalence of some of the outcomes. Indeed, using such an approach resulted at best in a description of significant changes, with no assumption about possible correlations between coincident aberrations in the same patient. Our study had some major advantages, including the considerable sample size, which gave us reasonable statistical power to reliably investigate the parameters. We were also able to investigate the full spectrum of resting ECG aberrations, which no previous study has achieved in Africa. The extensive data collection of both clinical and biological profiles enabled a wide range of predictors to be investigated for their possible link with prevalent ECG aberrations.
Conclusion ECG aberrations are frequent in people with diabetes in sub-Saharan Africa. While some may be benign, others are indicators of serious underlying conditions or high future risk
537
for cardiovascular disease. These aberrations have the potential to improve cardiovascular disease risk stratification and the implementation of preventative strategies in people with diabetes in sub-Saharan Africa. The growing prevalence of serious ECG aberrations over time suggests the need for strategies to monitor such changes and their determinants, so as to refine the cardiovascular preventative strategies in sub-Saharan Africa. Elsewhere, dedicated diabetes registries have successfully served these functions.
References 1. 2.
3. 4.
5.
6.
7.
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9. 10.
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14. 15.
16.
17.
International Diabetes Federation. Diabetes Atlas. 4th edn. Brussels: IDF, 2009. International Task Force for Prevention of Coronary Heart Disease, International Atherosclerosis Society. Pocket Guide to Prevention of Coronary Heart Disease. Munster: Born Bruckmeier Verlag GmbH, 2003. International Diabetes Federation. Global Guidelines for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005. IDF Africa Region Task Force on Type 2 Diabetes Clinical Practice Guidelines. Type 2 clinical practice guidelines for sub-Saharan Africa: IDF Afro Region, 2006. Choukem SP, Kengne AP, Dehayem YM, Simo NL, Mbanya JC. Hypertension in people with diabetes in sub-Saharan Africa: revealing the hidden face of the iceberg. Diabetes Res Clin Pract 2007; 77: 293–299. Kengne AP, Djouogo CF, Dehayem MY, Fezeu L, Sobngwi E, Lekoubou A, et al. Admission trends over 8 years for diabetic foot ulceration in a specialized diabetes unit in Cameroon. Int J Low Extrem Wounds 2009; 8: 180–186. Norman JE, Jr., Levy D. Improved electrocardiographic detection of echocardiographic left ventricular hypertrophy: results of a correlated data base approach. J Am Coll Cardiol 1995; 26: 1022–1029. Lutale JJ, Thordarson H, Gulam-Abbas Z, Vetvik K, Gerdts E. Prevalence and covariates of electrocardiographic left ventricular hypertrophy in diabetic patients in Tanzania. Cardiovasc J Afr 2008; 19: 8–14. Lester FT, Keen H. Macrovascular disease in middle-aged diabetic patients in Addis Ababa, Ethiopia. Diabetologia 1988; 31: 361–367. Odusan O, Familoni OB, Raimi TH. Correlates of cardiac autonomic neuropathy in Nigerian patients with type 2 diabetes mellitus. Afr J Med Med Sci 2008; 37: 315–-320. Kengne AP, Amoah AG, Mbanya JC. Cardiovascular complications of diabetes mellitus in sub-Saharan Africa. Circulation 2005; 112: 3592–3601. Mbanya JC, Sobngwi E, Mbanya DS, Ngu KB. Left ventricular mass and systolic function in African diabetic patients: association with microalbuminuria. Diabetes Metab 2001; 27: 378–382. Joubert J, McLean CA, Reid CM, Davel D, Pilloy W, Delport R, et al. Ischemic heart disease in black South African stroke patients. Stroke 2000; 31: 1294–1298. Brink AJ. The normal electrocardiogram in the adult South African Bantu. S Afr J Lab Clin Med 1956; 2: 97–123. Auer R, Bauer DC, Marques-Vidal P, Butler J, Min LJ, Cornuz J, et al. Association of major and minor ECG abnormalities with coronary heart disease events. J Am Med Assoc 2012; 307: 1497–1505. Kengne AP, Njamnshi AK, Mbanya JC. Cardiovascular risk reduction in diabetes in sub-Saharan Africa: What should the priorities be in the absence of global risk evaluation tools? Clin Med: Cardiol 2008; 2: 25–31. Mbanya JC, Kengne AP, Assah F. Diabetes care in Africa. Lancet 2006; 368: 1628–1629.
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Follow up in a developing country of patients with complete atrio-ventricular block JC TANTCHOU TCHOUMI, SARA FORESTI, PIERPAOLO LUPO, RICCARDO CAPPATO, GIANFRANCO BUTERA
Abstract Aim: The purpose of the study was to assess the incidence and survival rate of patients with complete atrio-ventricular block in the cardiac centre of St Elizabeth Catholic General Hospital, Kumbo, Cameroon. Methods: Between 2009 and 2011, 26 patients with complete atrio-ventricular block were diagnosed at our institution. Complete atrio-ventricular block was defined as complete heart block, diagnosed by echocardiographic or electrocardiographic documentation of the dissociation between electrical activity of the atria and ventricles. Hospital charts, electrocardiograms (ECG), echocardiography and chest radiography were reviewed. Results: The triad of symptoms that pointed to the diagnosis of complete atrio-ventricular block was mainly fatigue, shortness of breath on mild physical exertion, and dizziness. The median age at diagnosis was 65 ± 15 years. The escape rhythm showed a narrow QRS complex in 35.2% of patients, whereas wide QRS complexes were seen in 64.8%. In only 15 patients were pacemakers implanted: dual-chamber in 10 and single-chamber in five cases, depending on the availability of the pacemakers. During the observational period, five non-implanted patients died, giving a mortality rate of 45%. We recorded no deaths in patients with pacemakers. Conclusion: In developing countries, natural selection is observed in patients with complete atrio-ventricular block. Lack of infrastructure and early detection, and financial limitations are the main problems faced in the follow up of these patients. Re-organisation of the public health system, new programmes for the prevention of cardiovascular diseases, and government subsidisation are needed in our milieu. Keywords: complete atrio-ventricular block, follow up, cardiac centre Submitted 24/8/11, accepted 30/8/12 Cardiovasc J Afr 2012; 23: 538–540
www.cvja.co.za
DOI: 10.5830/CVJA-2012-059
Cardiac Centre, St Elizabeth Catholic General Hospital, Kumbo, Cameroon JC TANTCHOU TCHOUMI, MD, PhD, tantchouj@yahoo.fr
Department of Electrophysiology, Policlinico San Donato IRCCS, Milan, Italy SARA FORESTI PIERPAOLO LUPO RICCARDO CAPPATO
Department of Pediatric Cardiology and Cardiac Surgery, Policlinico San Donato IRCCS, Milan, Italy GIANFRANCO BUTERA, MD, PhD
Over the past years, cardiac pacing has become the standard mode of therapy for heart block and its complications. The increasing use of cardiac pacemakers (PM) has been encouraged by improved and simplified techniques of permanent pacing, by the development of more dependable electrodes and pulse generators, and by increasing clinical experience and followup data, indicating a favourable effect on the prognosis and improved cardiovascular performance.1 Across Europe in 2005, the number of new implants of pacemakers ranged from 121 to 1 134 per million, and for implantable cardiac defibrillators from 1.18 to 226 per million.2 In countries of sub-Saharan Africa, patients with complete atrioventricular block (CAVB) and other indications for pacing are sent home because of non-availability of facilities for pacemaker implantations, limited availability of pacemakers, and high cost of the implantation procedure. The aim of the study was to assess the incidence and survival in patients with CAVB during a period of 16 months at the cardiac centre of St Elizabeth Catholic General Hospital, Shisong, Cameroon.
Methods CAVB was defined as a complete heart block, diagnosed by echocardiographic or electrocardiographic documentation of the dissociation between electrical activity of the atria and ventricles. Hospital charts, electrocardiogram (ECG), echocardiography and chest radiography were reviewed. We analysed X-rays for cardiomegaly, which was defined as cardiothoracic ratio > 0.5. Between 2009 and 2011, 26 patients with complete atrioventricular block were diagnosed at our institution. Structural heart diseases were diagnosed as follows: eight patients had hypertensive cardiomyopathy, seven had mild mitral valve regurgitation with degenerative aetiology, five had moderate mitral valve regurgitation with post-rheumatic aetiology associated with moderate tricupid valve regurgitation, one case had post-surgical complete atrio-ventricular block, one case had severe pulmonary artery valve stenosis, and the rest of the patients had no cardiac pathology. Local anaesthesia was given in the left subclavicular area using 20 ml of lidocaine. The left subclavian vein was punctured and the guidewire was inserted for monocameral pacemakers. Two punctures were performed when we intended to implant a bicameral pacemaker. A pocket was created at the left subclavian area. Through the 9 and 7 french introducers we sent, respectively, the right atrial and the right ventricular leads in the case of a bicameral pacemaker. Through the 7 french introducer we sent the ventricular lead for a monocameral pacemaker. These introducers were observed by means of radiography. The intra-operative parameters are reported in Table 1. These parameters were optimised three months after the implantation. The leads were anchored with silk 2.0 and the pacemaker was connected. Two layers of stitches were put in: the first, subcutaneous with vicryl 2.0 and the second, intradermic with
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TABLE 1. INTRA-OPERATIVE PARAMETERS
Atrial lead Ventricular lead
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
Sensing (mV) 3.5 ± 0.5 9 ± 0.5
Threshold (V) 0.75 ± 0.5 0.5 ± 0.5
TABLE 3. SYMPTOMS AT FOLLOW UP
Impedance of the lead (Ohm) 768 ± 13 810 ± 9
vicryl 3.0. The post-surgical wound was covered with a plaster. Being a descriptive study, the data are presented as means and standard deviation.
Results Symptoms and signs that pointed to the diagnosis of CAVB are listed in Table 2. Median age at diagnosis was 65 ± 15 years. The escape rhythm showed a narrow QRS complex in 35.2% of patients, whereas a wide QRS complex was seen in 64.8%. In only 15 patients were pacemakers implanted: dual-chamber in 10 and single-chamber in five cases, depending on the payment capacity of patients. Complications observed after implantation were dislodgement of the lead in one patient, haematoma in two cases, and infection of the pocket in one case. During the observational period, five non-implanted patients in NYHA class III died, giving a mortality rate of 45%. The six remaining patients were in NYHA class II. All the implanted patients are alive and in a better clinical condition than the non-implanted patients (Table 3). Chest pains in one patient were intercostal neuralgia, with no ischaemic aetiology. Importantly, before implantation, nine patients were in NYHA class III, and six in class II. After the implantation, 10 were in NYHA class II and five in class I.
Discussion Occasionally, adult patients do not have any symptoms of complete atrio-ventricular block and the diagnosis is made TABLE 2. CLINICAL CHARACTERISTICS OF PATIENTS Total number of patients (n) Age at diagnosis (years) Symptoms dizziness (n) shortness of breath (n) fatigue (n) Adam Stokes attack (n) palpitations (n) No symptoms (n) Co-morbidity hypertension (n) degenerative arthritis (n) diabetes mellitus Referred cases (n) Age at implantation (years) Type of block paroxystic (n) permanent (n) Causes of death Adam Stokes attack (n) cardiovascular accident (n) unknown (n)
26 65 ± 15 19 15 23 6 3 3 16 20 6 2 70 ± 10 6 20 2 1 2
Shortness of breath (n) Dizziness (n) Adam Stokes attack (n) Palpitations (n) Fatigue (n) Death NYHA class II (n) NYHA class I (n)
Implanted patients 2 0 10 5
Non-implanted patients 6 3 3 5 5 5 6 0
by detecting a slow heart rate at a routine examination. The incidence of CAVB seems to be higher in Lome than in the Shisong cardiac centre, being respectively, 1 and 2% (p < 0.02).3 We diagnosed few patients during the observational period, probably due to natural selection. The mortality registered in non-implanted cases was 45%, low compare to the mortality in Togo, which was 59% (p < 0.05).3 In tertiary centres in sub-Saharan Africa, the main cause of death is lack of finances for the procedure. Patients with the pathology must pay before the device will be implanted, the dual-chamber pacemaker being more expensive than the single chamber, which is why in Africa in general more patients have single-chamber pacemakers.4 Besides eliminating the risk of sudden death, reasons for an early PM implantation in patients with CAVB are prevention of morbidity, left ventricular dilatation and dysfunction, and mitral regurgitation. Permanent pacemakers provide effective relief of symptoms and are life-saving in patients with symptomatic heart block. Since pacemakers are only implanted by cardiologists or cardiothoracic surgeons in tertiary hospitals, the rates of pacemaker implantation provide a readily auditable measure of tertiary healthcare.5 In developed countries, patients with a history of complete heart block are almost absent because of the progress in medicine orientated to early detection and treatment of the condition, whereas in developing countries with the lack of finances, infrastructures and human resources, many cases are encountered.6 In this context in Africa, the re-use of pacemakers from charity organisations is a good solution; it can be carried out without increased risk to the patients, provided a proper routine for technical control and sterilisation is followed. Re-use means substantial savings, which could possibly make advanced pacemaker treatment available to all eligible patients irrespective of age. Death is not necessarily the end for heart devices.7,8 In our case, all the pacemakers we used were new. We noted that some of our patients were asymptomatic with very wide QRS complexes, strengthening the hypothesis of natural selection. Electrophysiological and genetic studies are important to understand the mechanism of natural selection. We also found that patients with post-rheumatic heart disease were well represented in our study, causing us to suspect involvement of the conduction tissue in that pathology, as it is the case in patients with Lyme disease.9 The clinical state of implanted patients improved more than that of patients without pacemakers. In developing countries, cardio-stimulation should be made a department of all cardiac
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centres, since many lives are saved using pacemakers as therapy in post-surgical, paroxystic or permanent complete atrioventricular blocks.
Conclusion In undeveloped countries characterised by natural selection of patients with complete atrio-ventricular block, mortality is high. Lack of infrastructure, early detection and financial limitations are the main problems faced in the follow up of these patients. Re-organisation of the public health system, new programmes of prevention of cardiovascular diseases, and government subsidisation are needed in our milieu.
3. 4.
5.
6. 7.
References 1.
2.
Ekpe EE, Aghaji MA, Edaigbini SA, Onwuta CN. Cardiac pacemaker treatment of heart block in Enugu a 5-year review. Niger J Med 2008; 17(1): 7–12. Ector H, Vardas P, on behalf of the European Heart Rhythm Association,
…continued from page 532 25. Gassenmaier T, Buchner S, Birner C, et al. High-sensitive troponin I in acute cardiac conditions: implications of baseline and sequential measurements for diagnosis of myocardial infarction. Atherosclerosis 2012; 222(1): 116–122. 26. Pretorius CJ, Wilgen U, Ungerer JP. Serial cardiac troponin differences measured on four contemporary analyzers: relative differences, actual differences and reference change values compared. Clin Chim Acta 2012; 413(21–22): 1786–1791. Epub 2012 Jul 10. 27. Mueller M, Biener M, Vafaie M, et al. Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem 2012; 58: 209–218. 28. Biener M, Mueller M, Vafaie M, et al. Comparison of a 3-hour versus a 6-hour sampling-protocol using high-sensitivity cardiac troponin T for rule-out and rule-in of non-STEMI in an unselected emergency department population. Int J Cardiol 2012 Oct 10.pii: S0167-5273(12)012430. doi: 10.1016/j.ijcard.2012.09.122. [Epub ahead of print]. 29. Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med 2012; 172(16): 1211–1218. 30. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: use of cardiac troponin and B-type natriuretic peptide or n-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure. Clin Chem 2007; 53: 2086–2096. 31. Thygesen K, Mair J, Katus H, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010; 31: 2197–2206. 32. Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry practice guidelines: clinical characteristics and utilization of biomarkers in acute coronary syndromes. Clin Chem 2007; 53: 552–574. 33. Apple FS, Pearce LA, Smith SW, Kaczmarek JM, Murakami MM. Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Clin Chem 2009; 55: 930–937. 34. Eggers KM, Jaffe AS, Venge P, Lindahl B. Clinical implications of the change of cardiac troponin I levels in patients with acute chest pain – an evaluation with respect to the universal definition of myocardial infarc-
8. 9.
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European Society of Cardiology. Current use of pacemakers, implantable cardioverter defibrillators, and resynchronization devices: data from the registry of the European Heart Rhythm Association. Eur Heart J 2007; Supplement I: I44–I49 Yayehd K, Ganou K, Tchamdja T, et al. Management of high-grade atrioventricular block in Lomé, Togo. Med Trop 2011; 71(6): 637–638. Thomas MO, Oke DA, Ogunleye EO, et al. Bradypacing: indications and management challenges in Nigeria. Pacing Clin Electrophysiol 2007; 30(6): 761–763. Millar RN. Cardiac Arrhythmia Society of South Africa 1998 survey of cardiac pacing in South Africa. Report of the working group on registries of the cardiac arrhythmia society of South Africa (CASSA). Afr Med J 2001; 91(10): 873–876. Zion MM, Marchand PE, Obel IWP. Long-term prognosis after cardiac pacing in atrioventricular block. Br Heart J 1973: 35: 359–364. Linde CL, Bocray A, Jonsson H, et al. Re-used pacemakers – as safe as new? A retrospective case–control study. Eur Heart J 1998; 19(1): 154–157. Mitka M. Death not necessarily the end for heart devices. J Am Med Assoc 2007; 297(2): 144–145. Mohindra R, Pannu HS, Mohan B, Kumar N, et al. Syncope in rheumatic fever. Indian Heart J 2004; 56: 668–669.
tion. Clin Chim Acta 2011; 412(1-2): 91–97. 35. Bonaca M, Scirica B, Sabatine M, et al. Prospective evaluation of the prognostic implications of improved assay performance with a sensitive assay for cardiac troponin I. J Am Coll Cardiol 2010; 55: 2118–2124. 36. Apple FS, Pearce LA, Smith SW, Kaczmarek JM, Murakami MM. Role of monitor-ing changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Clin Chem 2009; 55: 930–937. 37. Mueller M, Biener M, Vafaie M, et al. Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem 2012; 58: 209–218. 38. Apple FS, Jesse RL, Newby LK, Wu AHB, Christenson RH, for the NACB committee members and Apple FS, Christenson RH, Jaffe AS, Mair J, Ordonez-Llanos J, Pagani F, Panteghini M, Tate J, Wu AHB, for the IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD). National Academy of Clinical Biochemistry and IFCC Committee on Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Clin Chem 2007; 53: 547–551. 39. Lippi G, Cervellin G, Plebani M. Sensitive cardiac troponin T assay. N Engl J Med 2010; 362: 1242. 40. Zhu Y, Jenkins MM, Brass DA, Ravago PG, Horne BD, Dean SB, Drayton N. Heterophilic antibody interference in an ultra-sensitive 3-site sandwich troponin I immunoassay. Clin Chim Acta 2008; 395: 181–182. 41. Panteghini M. Assay-related issues in the measurement of cardiac troponins. Clin Chim Acta 2009; 402: 88–93. 42. Savukoski T, Engström E, Engblom J, et al. Troponin-specific autoantibody interference in different cardiac troponin I assay configurations. Clin Chem 2012; 58(6): 1040–1048. 43. Saenger AK, Beyrau R, Braun S, et al. Multicenter analytic al evaluation of a high-sensitivity troponin T assay. Clin Chim Acta 2011; 412: 748–754. 44. Bais R. The effect of sample hemolysis on cardiac troponin I and T assays. Clin Chem 2010; 56(8): 1357–1359. 45. Gould MJ, Wilgen U, Pretorius CJ, Ungerer JP. Probing indiscretions: contamination of cardiac troponin reagent by very high patient samples causes false-positive results. Ann Clin Biochem 2012; 49(Pt 4): 395–398.
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QTc prolongation prior to angiography predicts poor outcome and associates significantly with lower left ventricular ejection fractions and higher left ventricular end-diastolic pressures PIETER VAN DER BIJL, MARSHALL HERADIEN, ANTON DOUBELL, PAUL BRINK
Abstract
Submitted 18/3/12, accepted 30/8/12
Background: QT prolongation on the surface ECG is associated with sudden cardiac death. The cause of QT prolongation in ischaemic heart disease (IHD) patients remains unknown, but may be due to a complex interplay between genetic factors and impaired systolic and/or diastolic function through as yet unexplained mechanisms. It was hypothesised that QT prolongation before elective coronary angiography is associated with an increased mortality at six months. Methods: Complete records of 321 patients who underwent coronary angiography were examined for QT interval corrected for heart rate (QTc), left ventricular ejection fraction (LVEF), left ventricular end-diastolic pressure (LVEDP) and known ischaemic heart disease risk factors. Patients were designated long QTc (LQTc) when they had prolonged QTc intervals or normal QTc (NQTc) when the QTc interval was normal. Patients with atrial fibrillation, bundle branch blocks, no ECG in the 24 hours before angiography, or a creatinine level > 200 μmol/l were excluded. Survival was determined telephonically at six months. Results: Twenty-eight per cent of the total population had LQTc. During follow up, 15 patients (4.7%) died suddenly, 73% of whom had a LQTc. LQTc was significantly associated with mortality (LQTc 12% vs NQTc 1.7%; p < 0.01), and with lower but normal LVEF (LQTc 52.9 ± 15.4% vs NQTc 61.6 ± 13.6%; p < 0.01), higher LVEDP at LVEF > 45% (LQTc 19.2 ± 9.0 mmHg vs NQTc 15.95 ± 7.5 mmHg; p < 0.05), hypercholesterolaemia and a negative family history of IHD. Conclusion: In patients with sinus rhythm and normal QRS width, QTc prolongation before coronary angiography predicted increased mortality at six months. QTc also associated strongly with left ventricular systolic and diastolic dysfunction, hypercholesterolaemia and a negative family history of IHD.
Cardiovasc J Afr 2012; 23: 541–545
Keywords: QT prolongation, sudden death, coronary artery disease
Division of Cardiology, Department of Medicine, Faculty of Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Western Cape, South Africa PIETER VAN DER BIJL, MB ChB, MMed, DA, FCP (SA), pieter. vanderbijl@gmail.com MARSHALL HERADIEN, MB ChB, BSc Hons, MMed, Cert Cardiol (SA) ANTON DOUBELL, MB ChB, MMed, HonsBSc, PhD, FCP (SA) PAUL BRINK, MB ChB, MMed, PhD
DOI: 10.5830/CVJA-2012-060
The QT interval represents ventricular electrical depolarisation and repolarisation on the surface ECG. It increases with age and varies with gender, time of day, season of the year and heart rate.1-3 Bazett’s formula is frequently used to correct the QT interval for heart rate, yielding the QTc interval.4,5 A prolonged QTc interval (LQTc) is a manifestation of a complex interplay between genetic and environmental factors, and is a risk factor for life-threatening dysrhythmias and sudden death. The forme fruste of QT prolongation is congenital long QT syndrome (LQTS), an inherited cardiac ion-channel disease associated with syncope, malignant ventricular tachydysrhythmias and sudden cardiac death. LQTS, by exclusion, occurs in structurally normal hearts.6 Recently, polymorphisms in the gene for NOS1AP, which regulates nitric oxide production and thus coronary perfusion, have been shown to prolong cardiac repolarisation.7-9 Ethnic differences in QT interval have also been reported, LQTc comprising a higher risk among black than white subjects.10 QT prolongation is an independent prognosticator of cardiac and all-cause mortality, especially in the context of cardiovascular disease.11-13 In addition, it is associated with an increased 10-year risk of ischaemic heart disease (IHD) and sudden death in the general population.14 The fact that interventional cardiologists are more interested in the ‘ST’ segment than the ‘QTc’ is underscored by the paucity of QTc studies peri-angiography. In only one study has an LQTc in the period immediately before coronary angiography been directly correlated with outcome, but the authors described QT peak interval instead of QTc.15 LQTc in the presence of coronary artery disease increases the risk of sudden cardiac death by a factor of five.16 IHD is a cause of systolic and diastolic dysfunction of the left ventricle, and both of these are independent predictors of mortality.17,18 QT prolongation is not only inherited, but also linked to cardiac hypertrophy, as frequently observed in hypertensive heart disease.19 However, no reference to an association between left ventricular systolic and diastolic dysfunction and QTc could be identified in the literature. Additionally, the length of the QTc interval appears to be directly related to the number of large coronary arteries that are diseased.20 QT prolongation may also reflect autonomic neuropathy in patients with diabetes mellitus.21,22 It does not, however, provide a reliable measure of the degree of autonomic neuropathy.23 Although smoking has been associated with a LQTc, it has not
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been shown to be an independent cause of a LQTc.24 No clear link is evident in the literature between hypercholesterolaemia and QTc interval. The purpose of our study was to evaluate LQTc as an independent prognostic indicator with regard to mortality and systolic and diastolic dysfunction in the context of IHD. Furthermore, we endeavoured to assess, in a state hospital setting in the Western Cape, whether LQTc correlated with triplevessel coronary artery disease (TVCAD), or was significantly associated with hypercholesterolaemia, diabetes mellitus, smoking, hypertension or a family history of IHD.
Methods The study was approved by the Committee for Human Research, Faculty of Health Sciences, Stellenbosch University. All patients signed informed consent before coronary angiography. All data were collected and recorded as part of routine clinical care. This was a single-centre, prospective study, enrolling a cohort of patients who were eligible for coronary angiography from 2006 to 2009 at Tygerberg Academic Hospital. Due to the time limit imposed by the authors collecting data, rotating through the coronary care unit, not all eligible patients could be enrolled. Patients with atrial fibrillation, bundle branch blocks, no ECG in the 24 hours before angiography, or renal failure (creatinine ≥ 200 μmol/l) were excluded from the study.25,26 QTc intervals were recorded on the last ECG taken during the 24 hours before coronary angiography, and designated long QTc (LQTc) or normal QTc (NQTc). The primary outcome was six-month survival. Secondary outcomes included correlation of QTc intervals with left ventricular ejection fraction (LVEF), left ventricular end-diastolic pressure (LVEDP), TVCAD, diabetes mellitus, smoking, systemic hypertension, a family history of IHD and dyslipidaemia.
Measurement of QT interval As the accuracy of automated measurements of the QT interval is questionable, partly because of inconsistency between manufacturers in terms of the digital algorithms employed in various instruments, the QT intervals were measured manually.5 These values were then compared with the algorithm-based ones. The QT interval was measured from the start of the QRS complex to the end of the T wave, using a Digimatic® digital caliper (0.01-mm scale) with an autostopper (Mitutoyo Corporation, Mita, Japan). When a T wave was biphasic, or nearly so, the QT interval was measured to include the final return to baseline. No U waves were encountered, and therefore no decision as to the endpoint of measurement in such instances had to be taken. The digitally calculated heart rate was obtained from the ECG, and the QTc was computed by means of Bazett’s formula.4,5
Definition of parameters and endpoints The QTc was considered prolonged if > 440 ms in males and > 460 ms in females. The follow-up period started on the day of coronary angiography (day 0), and ended after six months (day 180) had elapsed. Survival was determined telephonically at the end of six months. The LVEF (as an index of systolic function) was determined either by ventriculography at the time
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of coronary angiography or, in the case of ventriculography not having been performed, by transthoracic or trans-oesophageal echocardiography. The LVEDP (as an index of diastolic function) was measured at the time of coronary angiography via a fluidfilled endocardiac catheter. TVCAD was defined as a > 70% stenosis of all three of the following vessels: the right main coronary artery, the left circumflex artery and the left anterior descending coronary artery or the right main coronary artery, in conjunction with the left main stem, as assessed at the time of coronary angiography. The interventional cardiologist decided how to treat stenosed coronaries, i.e. medically, percutaneously or surgically, and the investigators were blinded to subsequent treatment. Diabetes mellitus was defined as symptoms of diabetes plus a random blood glucose concentration of ≥ 11.1 mmol/l, or fasting plasma glucose of ≥ 7.0 mmol/l. This accords with the American Diabetes Association clinical practice recommendations of 2006.27 In addition, patients were considered diabetic if they were taking anti-diabetic medication. Smoking was defined as the use of any tobacco on a daily basis at any stage of the patient’s life. Systemic hypertension was defined as a blood pressure recording of ≥ 140/90 mmHg as per National Cholesterol Education Program Adult Treatment Panel III Guidelines of 2004.28 A family history of IHD was considered positive if it was present in a male first-degree relative of ≤ 55 years, or in a female first-degree relative of ≤ 65 years.28 Hypercholesterolaemia was defined as a total, non-fasting serum cholesterol level > 5 mmol/l. The non-fasting nature was accepted as a result of the short period of hospitalisation of most patients undergoing angiography.
Statistical analysis Data were analysed by the Stellenbosch University Centre for Statistical Consultation (CSC) using STATISTICA version 9 (StatSoft® Inc, Tulsa, OK, USA, 2009). The Kaplan–Meier method was used to create survival curves for NQTc and LQTc groups and a log-rank test was used to compare the two curves and generate a p-value. NQTc and LQTc groups were compared with regard to LVEF, LVEDP and serum cholesterol with a Mann–Whitney U test. Categorical data (diabetes mellitus, smoking, hypertension and family history of IHD) were tested for an association with LQTc using a chi-square test. Statistical significance was defined as p < 0.05.
Results Of the 2 023 patients who were catheterised, 321 were enrolled (80.2% Coloured, 18.8% white, 1.0% black) (mean age 56 ± 12 years; range 24–84) (Fig. 1). One hundred and sixteen patients (36%) were female (mean age 57 ± 10 years; range 29–78) and 205 (64%) were male (mean age 55 ± 12 years; range 24–85) (p = 0.168). Ninety patients (28%) had LQTc. At six months, 15 (4.7%) of the total population had died, 73% of whom had a LQTc. Eleven patients (12%) died in the LQTc group and four (1.7%) in the NQTc group (p < 0.01) (Fig. 2). The hazard ratio was 10.16 (95% CI: 2.91–35.44). LQTc patients had normal LVEF but lower than that of the NQTc cohort (LQTc: 52.9 ± 15.4% vs NQTc: 61.6 ± 13.6%; p < 0.01) (Fig. 3) and higher LVEDP at LVEF > 45% (LQTc: 19.2 ± 9.0 mmHg vs NQTc: 15.9 ± 7.5 mmHg; p < 0.05) (Fig. 4). The
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2 023 catheterised patients considered LVEF (%)
1 702 patients excluded
p < 0.01
65
321 patients enrolled
60 55 50
90 LQTc
45
231 NQTc
Bar = 95% CI NQTc
LQTc QTc interval
79 alive at 6 months
4 dead at 6 months
227 alive at 6 months
Fig. 1. Allocation of study subjects.
LQTc cohort also had significantly higher serum cholesterol levels than the NQTc cohort (Fig. 5). A family history of IHD was significantly less common among those with LQTc (p = 0.045) (Table 1). No association between LQTc and diabetes mellitus, smoking or hypertension could be detected. No association could be demonstrated between TVCAD and NQTc or LQTc (p = 0.96).
Discussion
Cumulative proportion surviving
This study provides further evidence that, regardless of coronary revascularisation, QT prolongation before coronary angiography associated significantly with increased mortality at six months, lower LVEF and higher LVEDP. With regard to IHD risk factors, LQTc patients had higher serum cholesterol values and rarely a family history of IHD. Traditionally, QT prolongation was seldom regarded by interventional cardiologists to be clinically useful, but it has recently been shown that the risk for coronary stenosis increases by 33 to 41% for every 20-ms QTc interval prolongation.29 The ST segment, on the other hand, which forms an integral part of the QT interval, is considered a better marker of underlying coronary artery disease. Interventional cardiologists rely heavily on ST segment shifts during exercise and recovery to identify those patients who need diagnostic coronary angiography. Little attention is given to the QTc interval, especially if it has to be measured or calculated manually. 1.00
p < 0.01
0.98 0.96 0.94 0.92 0.90 0.88 0.86
0
50
100
150
200
Time elapsed (days) NQTc
LQTc
Fig. 2. Cumulative proportion of patients surviving versus time elapsed (Kaplan–Meier).
Fig. 3. Mean LVEF versus QTc interval for NQTc and LQTc groups of patients.
Once coronary angiography has been performed, stents have been inserted and dual anti-platelet therapy (DAT) and beta-blockers have been prescribed, patients are often seen only weeks later for follow up at the outpatient clinic, where they are assessed by a junior colleague. The routine ECG is studied for new Q waves and cardiac arrhythmias. The blood pressure is checked, drug compliance with DAT is reiterated, and the patient is given a six-month follow-up appointment. Our data suggest that more than 10% of patients with QTc prolongation prior to coronary angiography will not return for their six-month appointment because they have died suddenly. The association of LQT with a lower but normal LVEF is interesting. While there is no internationally agreed threshold of a ‘low’ LVEF, it has been characterised in a report of the American Society of Echocardiography and the European Association of Echocardiography by gradation: mild (45–54%), moderate (30–44%) and severe (< 30%) left ventricular dysfunction.30 Only one study reported an association between LQTc and impaired LV function.31 The authors also reported that the QTc interval increased significantly from one- to three-vessel disease. We did not find this correlation between TVCAD and LQTc in our study. The mechanism by which a decreased LVEF results in QT prolongation is unknown, but may involve ion-channel remodelling and/or intracellular calcium transport.32 LVEF is frequently used to prognosticate patients who have suffered a myocardial infarction or who have dilated cardiomyopathy. It is generally accepted that patients with an impaired systolic function have a higher risk for sudden cardiac death, presumably due to malignant ventricular tachydysrhythmias. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), implantable cardioverter-defibrillator (ICD) therapy reduced all-cause mortality by 23% compared with placebo.33 Interestingly, amiodarone, a commonly used anti-arrhythmic agent that also prolongs the QT interval, was ineffective to prevent sudden death in these patients. LVEDP (mmHg)
11 dead at 6 months
p = 0.023
30 20 10 0
Bar = 95% CI NQTc
LQTc QTc interval
Fig. 4. Mean LVEDP (LVEF > 45%) versus QTc interval for NQTc and LQTc groups of patients.
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TABLE 1. ASSOCIATION BETWEEN LQTc AND NQTc GROUPS OF PATIENTS WITH REGARD TO MAJOR RISK FACTORS FOR IHD Risk factor present Yes, n (%) Diabetes mellitus NQTc 62 (29) LQTc 29 (33) Total n 91 Smoking NQTc 116 (56) LQTc 55 (64) Total n 171 Hypertension NQTc 157 (74) LQTc 70 (80) Total n 227 Family history NQTc 74 (36) LQTc 21 (24) Total n 95 *Statistically significant association.
No, n (%)
Total, n
149 (71) 59 (67) 208
211 88 299
92 (44) 31 (36) 123
208 86 294
55 (26) 17 (20) 72
212 87 299
134 (64) 67 (76) 201
208 88 296
p-value
0.54
0.19
Total serum cholesterol (mmol/l)
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6.0
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p = 0.0355
5.8 5.6 5.4 5.2 5.0 4.8 4.6
Bar = 95% CI NQTc
LQTc QTc interval
0.23
0.045*
The association of LQT with an elevated LVEDP (at a normal LVEF – frequently defined as > 45% , and used for the purpose of this study) is striking. Diastolic dysfunction is a relatively new concept when compared with LVEF. The commonest cause of diastolic dysfunction is hypertensive heart disease. Often these patients have thicker, stiffened left ventricles with good systolic function, but impaired relaxation and compliance. Again, exactly how diastolic dysfunction in IHD patients is associated with QT prolongation remains unknown, but recently an association was found between down-regulation of the hERG gene and QT prolongation in rats with cardiac hypertrophy.34 Ion-channels are embedded in a phospholipid bi-layer primarily composed of cholesterol esters. Both congenital LQTS and familial hypercholesterolaemia are more common in South Africans of European descent. Co-segregation of ion-channel disease and hypercholesterolaemia has not yet been described in humans, but in Langendorff-perfused rabbit hearts, hyperlipidaemia led to significant QT prolongation compared with normocholesterolaemia, which can be reversed by administering simvastatin.35
Study limitations This single-centre study in a state hospital setting may be prone to selection bias due to the fact that patients were enrolled only during rotations of the authors collecting the data through the coronary care unit. However, all eligible patients were enrolled during these intervals, leading us to believe that the cohort was truly representative. More than 80% of the studied population were of mixed racial ancestry. One should therefore be careful to draw conclusions about race and QT prolongation. Prescribed medications were not checked and these may well have prolonged the QT interval after discharge. However, this study addressed the relationship between QTc prior to coronary angiography and mortality at six months. The effects of coronary revascularisation on QTc were also not
Fig. 5. Mean total serum cholesterol versus QTc interval for NQTc and LQTc groups of patients.
investigated but it was assumed that significant coronary stenosis would have been treated appropriately by the interventional cardiologist. Mortality in the LQT cohort remained high regardless of coronary revascularisation. Follow up was relatively short owing to the vast extent of the geographical catchment area of the hospital. Genetic screening was also not performed on the study patients. Diastolic pressure was used as an indicator of diastolic function; however, echocardiographic parameters of diastolic function were not assessed.
Conclusion This is the first description of LQTc in a cohort of IHD patients in a South African setting. The study confirms that QTc, which can be determined by a simple, non-invasive, inexpensive method, is an index of subsequent sudden death in patients who undergo coronary angiography for suspected IHD. QTc prolongation before coronary angiography is also a reflection of systolic and diastolic dysfunction (in the context of normal systolic function) of the left ventricle, both of which are independent predictors of mortality rate. Furthermore, LQTc correlates with hypercholesterolaemia and a negative family history of IHD. We are grateful to Khetha Majola and Innocentia Louw for helping with data capturing, Prof Daan Nel of the Centre for Statistical Consultation (CSC), Stellenbosch University, for the statistical analysis, and the Harry Crossley Foundation for generous financial assistance. Elizabeth Schaafsma and Pearl Fredericks were of assistance in data collection and establishment of an electronic database.
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Webster G, Berul CI. Congenital long-QT syndromes: a clinical and genetic update from infancy through adulthood. Trends Cardiovasc Med 2008; 18: 216–224. Jamshidi Y, Nolte IM, Spector TD, Snieder H. Novel genes for QTc interval. How much heritability is explained, and how much is left to find? Genome Med 2010; 2: 35. Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation 2009; 120: 1657–1663. Arking DE, Pfeufer A, Post W. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarisation. Nature Genet 2006; 38: 644–651. Dekker JM, Crow RS, Hannan PJ, et al. Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women - the ARIC study. J Am Coll Cardiol 2004; 43: 565–571. De Bruyne MC, Hoes AW, Kors JA, et al. Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study. Eur Heart J 1999; 20: 278–284. Karjalainen J, Reunanen A, Ristola P, Viitasalo M. QT interval as a cardiac risk factor in a middle aged population. Heart 1997; 77: 543–548. Crow RS, Hannan PJ, Folsom AR. Prognostic significance of corrected QT and corrected JT interval for incident coronary heart disease in a general population sample stratified by presence or absence of wide QRS complex: the ARIC study with 13 years of follow-up. Circulation 2003; 108: 1985–1989. Lee J, Yoo K, Oh Y, et al. Relationship between resting electrocardiographic parameters and estimated 10-year risk for coronary heart disease in healthy adults in the USA. Ann Noninvas Electrocardiol 2010; 15: 315–320. Attar MN, Wong K, Groves DG, et al. Clinical implications of QRS duration and QT peak prolongation in patients with suspected coronary disease referred for elective cardiac catheterization. Ann Noninvas Electrocardiol 2008; 13: 106–102. Chugh S, Reinier K, Singh T, et al. Determinants of prolonged QT interval and their contribution to sudden death risk in coronary artery disease: the Oregon sudden unexpected death study. Circulation 2009; 119: 663–670. Ouzounian M, Lee DS, Liu PP. Diastolic heart failure: mechanisms and controversies. Nature Clin Prac Cardiovasc Med 2008; 5: 375–386. Valera-Roman A, Gonzalez-Juanatey JR, Basante P, et al. Clinical characteristics and prognosis of hospitalised inpatients with heart failure and preserved or reduced left ventricular ejection fraction. Heart 2002; 88: 249–254. Swynghedauw B, Baillard C, Milliez P. The long QT interval is not only inherited but is also linked to cardiac hypertrophy. J Mol Med 2003; 81: 336–345. Krämer B, Brill M, Brühn. A relationship between the degree of coronary artery disease and of left ventricular function and the duration of
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the QT-interval in ECG. Eur Heart J 1986; 7: 14–24. 21. Pappachan JM, Sebastian J, Bino BC, et al. Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis. Postgrad Med J 2008; 84: 205–210. 22. Klupa T, Mroczek T, Galicka-Latała D, et al. Corrected QT interval and diabetic neuropathy of the cardiovascular system. Przegl Lek 1995; 52: 583–587 (abstract). 23. Bravenboer B, Hendriksen PH, Oey LP, et al. Is the corrected QT interval a reliable indicator of the severity of diabetic autonomic neuropathy? Diabetes Care 1993; 16: 1249–1253. 24. Singh K. Effect of smoking on QT interval, QT dispersion and rate pressure product. Ind Heart J 2004; 56: 140–142. 25. Das G. QT interval and repolarization time in patients with intraventricular conduction delay. J Electrocardiol 1990; 23: 49–52. 26. Piotrowicz K, Zareba W, McNitt S, Moss AJ. Repolarization duration in patients with conduction disturbances after myocardial infarction. Am J Cardiol 2007; 99: 163–168. 27. Resnick HE, Foster GL, Bardsley J, Ratner RE. Achievement of American Diabetes Association clinical practice recommendations among U.S. adults with diabetes, 1992–2002: the National Health and Nutrition Examination Survey. Diabetes Care 2006; 29: 531– 537. 28. Grundy SM, Cleeman JI, Merz CNB, et al. National Cholesterol Education Program (NCEP). Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227–239. 29. Truong QA, Banerji D, Ptaszek LM, et al. Utility of nonspecific resting electrocardiographic features for detection of coronary artery stenosis by Computed Tomography in acute chest pain patients: from the ROMICAT trial. Int J Cardiovasc Imaging 2011, 2 Feb. [Epub ahead of print] 30. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7: 79–108. 31. Krämer B, Brill M, Brühn A, Kübler W. Relationship between the degree of coronary artery disease and of left ventricular function and the duration of the QT-interval in ECG. Eur Heart J 1986; 7: 14–24. 32. Qi X, Yeh YH, Chartier D, et al. The calcium/calmodulin/kinase system and arrhythmogenic afterdepolarizations in bradycardia-related acquired long-QT syndrome. Circ Arrhythm Electrophysiol 2009; 2: 295–304. 33. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352: 225–237. 34. Hu C, Yan C, Lin J, Liu S, Li Y. Down-regulation of the human ethera-go-go-related gene in rat cardiac hypertrophy. Am J Med Sci 2011; 341: 119–125. 35. Lee TM, Lin MS, Chou TF, Chang NC. Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits. Am J Physiol Heart Circ Physiol 2005; 288: H1352–1358.
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Statistical profiling of hospital performance using acute coronary syndrome mortality SAMUEL OM MANDA, CHRIS P GALE, ALISTAIR S HALL, MARK S GILTHORPE
Abstract Background: In order to improve the quality of care delivered to patients and to enable patient choice, public reports comparing hospital performances are routinely published. Robust systems of hospital ‘report cards’ on performance monitoring and evaluation are therefore crucial in medical decision-making processes. In particular, such systems should effectively account for and minimise systematic differences with regard to definitions and data quality, care and treatment quality, and ‘case mix’. Methods: Four methods for assessing hospital performance on mortality outcome measures were considered. The methods included combinations of Bayesian fixed- and randomeffects models, and risk-adjusted mortality rate, and rankbased profiling techniques. The methods were empirically compared using 30-day mortality in patients admitted with acute coronary syndrome. Agreement was firstly assessed using median estimates between risk-adjusted mortality rates for a hospital and between ranks associated with a hospital’s risk-adjusted mortality rates. Secondly, assessment of agreement was based on a classification of hospitals into low, normal or high performing using risk-adjusted mortality rates and ranks. Results: There was poor agreement between the point estimates of risk-adjusted mortality rates, but better agreement between ranks. However, for categorised performance, the observed agreement between the methods’ classification of the hospital performance ranged from 90 to 98%. In only two of the six possible pair-wise comparisons was agreement reasonable, as reflected by a Kappa statistic; it was 0.71 between the methods of identifying outliers with the fixedeffect model and 0.77 with the hierarchical model. In the remaining four pair-wise comparisons, the agreement was, at best, moderate. Conclusions: Even though the inconsistencies among the studied methods raise questions about which hospitals performed better or worse than others, it seems that the choice of the definition of outlying performance is less critical than that of the statistical approach. Therefore there is a need to find robust systems of ‘regulation’ or ‘performance monitoring’ that are meaningful to health service practitioners and providers.
Biostatistics Unit, Medical Research Council, Pretoria, South Africa SAMUEL OM MANDA, PhD, samuel.manda@mrc.ac.za
Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom CHRIS P GALE, PhD ALISTAIR S HALL, PhD MARK S GILTHORPE, PhD
Keywords: Bayesian methods, health provider performance, league tables Submitted 11/1/11, accepted 28/9/11 Cardiovasc J Afr 2012; 23: 546–551
www.cvja.co.za
DOI: 10.5830/CVJA-2011-064
Incidents of professional failure and the necessity to improve efficiency and quality of care in the health service have led to increasing demand for quality assurance and audits of medical institutions.1-5 This has allowed quality appraisal and optimal targeting of resources to areas of need. These processes have led to significant improvements in health outcomes; however, variation in hospital performance remains.5,6 A widely used and acceptable method to control variation in health outcomes is based on case mix adjustment.7-9 However, failure to adjust appropriately for differences in case mix may result in unfairly targeting hospitals admitting high-risk patients. Indeed, the identification of hospitals having unusual performance depends on the variables used in the risk-adjustment model.7,8 Furthermore, comparing hospitals on the basis of a riskadjustment model could be erroneous, as the risk model may be wrong, or suffer from incorrect inclusion of prognostic factors.4 More importantly, the disparity in risk-adjusted outcomes may result from a variety of factors including definitions, data quality, structural and institutional management factors, and resource characteristics that have a direct effect on clinical processes.4-6 To this end, differences in case mix should be accounted for in a suitable risk-adjustment model and differences in definitions and data quality kept to a minimum. Any residual variation in outcome between hospitals would therefore reflect hospital quality of care, the basis for medical institutional profiling methods.7-15 However the extent to which these hopes are satisfied remains uncertain. There is a large literature base on statistical methodology for health provider profiling.10-13 Simple methods use ratios of the observed to the expected outcomes (indirect standardisation) or odds ratios from a logistic regression analysis.8,15 A number of studies have shown disagreements between different frequentist or Bayesian methods for profiling hospital performance (Marshall and Spiegelhalter,11 Austin,12 Ohlssen et al.,15 Delong et al.16 and Leyland and Boddy17). In particular, random-effects models are found to be more conservative in classifying institutions as performance outliers.11 There is therefore a need for research to identify statistical models and ways that robustly differentiate between hospitals and remain meaningful to the medical practitioner.12 Normand et al.,10 Marshall and Spiegelhalter,11 Austin12 and Ohlssen et al.15 advocated using hierarchical Bayesian random-effects methods for provider profiling. These methods easily permit data pooling across institutions; thus overcoming uncertainty associated with small institutions, which might be
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outliers by chance alone.12 Estimated performances are stabilised and shrunk towards the population average; the degree of shrinkage being larger for small hospitals than for large hospitals. Bayesian methods provide complete probabilistic information in determining the probability that a hospital-specific riskadjusted rate exceeds a specified threshold.11 Furthermore, a researcher is able to place credible intervals on the derived ranks to quantify the uncertainty associated with institutional ranking before relative performance can be assessed.11,18 In the current study, rather than calibrate the methods, we concentrated on comparing the performance of four methods and assessing how well they agreed with one another, using Marshall and Spiegelhalter,11 and Austin’s approaches.12 The methods were applied to data on short-term mortality in acute coronary syndrome (ACS) patients. The data are part of the Myocardial Infarction National Audit Project (MINAP), which currently reports percentage attainment of standards on five clinical process variables, namely door-to-needle and call-toneedle thrombolysis times, and the use of aspirin, beta-blockers and statins post-acute myocardial infarction (AMI).19,20 A use of the MINAP data for hospital comparison was presented in Gale et al.,5 using funnel plots on the same five process variables. To the best of our knowledge, the present study is the first to use an outcome measure and to control for any variation, specifically for case mix, with contemporary data on ACS. We did not duplicate MINAP tabulations or the Gale et al.5 funnel plot methodology. Instead, we determined (a) whether or not a hospital’s risk-adjusted mortality rate exceeded a specified threshold, and (b) the hospital’s rank, based on its risk-adjusted mortality rate using two statistical models: fixed and hierarchical models, on the number of deaths among patients admitted by the hospital. While this article does not add sufficient new methodological questions on profiling methods, the topic of healthcare performance is timely, important and interesting within the medical and health services domain.
Methods MINAP was established in 1998. It is reported to be the largest and most comprehensive clinical database of ACS care in the world and is a valuable resource for monitoring coronary heart disease audit standards for patients presenting with AMI in England and Wales.20 All hospitals in England and Wales that treat patients with acute AMI submit data to MINAP. The project collects information on the quality of care and outcome of patients. Each patient entry offers details of the patient’s journey, including the method and timing of admission, in-patient investigations, results and treatment, and, if applicable, dates of death from linkage to the Office of National Statistics, United Kingdom. Prospective data are collected locally, electronically encrypted and transferred to a central database. The database may be used for identifying performance indicators to identify examples of good practice. With such data, it is feasible to evaluate contemporary care practices consistent with national guidelines for the management of ACS, investigate whether hospital performance varies between hospitals, identify hospital characteristics predictive of adherence to guidelines, and assess whether adherence to guidelines is associated with mortality rates.7 We examined all 187 069 ACS events entered into the MINAP database from 1 January 2003 to 31 March 2005. We selected
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first (index) admissions reported to MINAP and therefore excluded re-admissions. We then analysed all patients who were aged between 18 and 100 years, who had an admission systolic blood pressure between 49 and 250 mmHg, and an admission heart rate between 20 and 200 beats/min. In total there were 134 hospitals, six of which were discarded from the analyses because of sparse data, i.e. not sufficiently varied (two with one admission, three with fewer than five deaths, one with excessive missing codes on death status). For the remaining 100 686 patients, the overall in-hospital mortality rate was 8.1%, the total mortality rate was 17.8%, and the 30-day mortality rate was 10.2%. Hospital-specific 30-day mortality rates ranged from 5 to 21%, with a median rate of 8.3%.
Statistical models We assumed that Oi is the observed number of 30-day deaths in patients admitted to hospital i (i = 1, …, 128) and Ei is the expected number of deaths, given the case mix of its patients. The number of deaths in the period 1 January 2003 to 31 March 2005 can be assumed to follow a Poisson distribution with unknown mean λi. Therefore Oi ~ Poisson (λi) taking log λi = log Ei + θi where log Ei is an offset that adjusts for the patient effects and θi is a residual representing hospital-specific effect of interest. The expected number Ei is obtained from a logistic regression on the pooled data, adjusting for relevant risk factors, to determine each patient’s predicted probability of 30-day mortality. These probabilities are then summed within a hospital to give the expected number of deaths at that hospital, given its case mix. The hospital-specific effect θi is the log-relative risk or logarithm of the hospital’s standardised mortality ratio (log SMR). Other than to compare hospitals using their SMRs, we used the hospital risk-adjusted 30-day mortality rate (RAMR),7 defined as RAMR = µ30 exp (θi), where µ30 (= 10.2%) is the overall 30-day mortality rate. The RAMR can be thought of as the estimated 30-day mortality rate for a hospital admitting a population of patients identical to the overall case mix.11 We adopted Bayesian methods in estimating a hospital-specific random effect θi to obtain its specific risk-adjusted mortality rate using 10.2 × exp (θi), which we used in this study for institutional profiling. In order to estimate the hospital-specific effect, we firstly assumed that it has a prior normal distribution with mean 0 and variance 1 000. This is the fixed-effects model, and the prior distribution implies that the hospital-specific standardised mortality rate has a prior mean of 1. Secondly, as an alternative, we considered a Bayesian randomeffects model, which, by using hierarchical modelling, pools data across hospitals. This approach produces more reliable estimates of hospital performance, in that genuinely low or high hospital outliers are identified. It reduces the chance of a small hospital being classified as an outlier by chance alone.11 Under the latter modelling approach, it was assumed that the hospital-specific random effects θi were drawn from a normal distribution with an unknown mean µ0 and variance σ02. Therefore, θi ~ Normal (µ0, σ02), where the hyper-parameters µ0 and σ02 were the underlying overall log-standardised mortality ratio and between-hospital variance, respectively. In order to complete the Bayesian implementation of the model, we also needed to specify prior probability distributions for the hyper-parameters µ0 and σ02 for the hospital-specific random effects, θi distribution. The hyper-mean, µ0 was assigned
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a normal distribution with mean of 0 and variance 1 000. The hyper-precision, σ0-2 (inverse of the hyper-variance, σ02) was given a gamma distribution with shape and scale parameters both equal to 0.001; implying that the hyper-precision had a mean of 1 and variance 1 000. This prior translates into a locally uniform distribution on the logarithm of the hyper-variance. We used two ways of identifying outliers; one based on the hospital’s RAMR, and the other based on the rank of RAMR among all the hospitals’ RAMR. Assessments of agreement were initially based on point estimates between each hospital’s ranks, and between risk-adjusted mortality rates. These pairwise agreements could be assessed using Bland–Altman plots.21 However, we used simple two-way scatter plots, where agreement was judged against the line of equality. We concentrated on categorising the different classification outcome measures into low, normal or high mortality risk, and then assessing agreement across the categories. In categorising a hospital’s RAMR, we examined the probability of it exceeding a specified threshold. The overall 30-day mortality rate was 10.2% for our patient cohort. A hospital i is classified as a high outlier if Prob [RAMRi > (1 + σ) 10.2] ≥ 0.75 and, similarly, it is classified as a low outlier if Prob [RAMRi < (1 – σ) 10.2] ≥ 0.75, otherwise the hospital is classified as normal. The threshold value δ can take any value, but values of 10, 15 and 20% are commonly used.18 We conservatively chose δ to be 20%, which has the effect of minimising the number of outlying hospitals, therefore hospital i is a high outlier if Prob (RAMRi > 12.24) ≥ 0.75, and a low outlier if Prob (RAMRi < 8.16) ≥ 0.75. For ranks, we calculated Bayesian point estimates and 95% credible intervals of each hospital’s rank. Hospitals whose 95% intervals fell entirely in the bottom or upper quartile of ranks (i.e. upper limit is ≤ 32.75 or lower limit is ≥ 96.25) were classified as low or high outliers, respectively; otherwise they were normally performing hospitals. With two modelling approaches (the fixed- and random-effects models) plus two ways of classifying hospital performance, we had four different methods for profiling hospitals. In all, there were six possible pair-wise comparisons. For each comparison, we used the kappa (κ) statistic to assess the amount of agreement between the methods. The statistic measures the proportion of observed-to-expected agreement, and we adopted the convention that κ > 0.75 indicates excellent agreement, κ = 0.4–0.75 indicates good agreement, and κ < 0.4 indicates marginal agreement,22 even though κ has been criticised for its limitations. In order to allow for different levels of agreement, we used a weighted κ statistic.
Implementation The computation of the models was done using Markov Chain Monte Carlo methods (MCMC); specifically we used Gibbs sampling as implemented in WinBUGS.23 For each method considered, three parallel Gibbs sampler chains from independent starting positions were run for 50 000 iterations. We monitored 10 randomly chosen random effects, and for hierarchical models also hyper-parameters for convergence. Trace plots of sample values of each of these parameters showed that they were converging to the same distribution. We formally assessed convergence of the three chains using Gelman–Rubin reduction factors,24 and all were estimated near 1.0 by 15 000 iterations. We therefore took 15 000 iterations to
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be in the burn-in period. For posterior inference, we used the remaining 35 000 iterations to give a combined sample size of 105 000.
Results Existing ACS risk scores include a multitude of factors. Patient age, systolic blood pressure (SBP), heart rate (HR) at admission and ECG findings are systematically included in most of the risk-scoring systems.25-27 In a large sample of European patients with ACS, age was found to impact on most of the clinical presentations and on hospital mortality.28 Therefore inclusion of age in a risk model would account for many of the baseline, prior and clinical risk factors. The risk variables that we used in the case mix logistic regression model for the risk adjustment are presented in Table 1, where age cut-off points were based on Resengren et al.,28 and SBP and HR on their fifths. The fitted model had an estimated c-statistic (area under the ROC curve) of 0.798, with a 95% confidence interval of 0.794 to 0.803. The inclusion of co-morbidities (e.g. diabetes and chronic renal failure) resulted in loss of data and minor improvement on the c-statistics. Using only age, SBP and HR, whether continuous or categorised, resulted in a similar value of the c-statistic of 0.777 (0.772–0.781). Using this predictive model of 30-day mortality shown in Table 1, we evaluated the expected number of deaths, Ei in hospital i to obtain its standardised mortality ratio, SMRi = Oi Ei and risk-adjusted mortality rate, RAMRi = 10.2 × SMRi, which ranged from 4.54 to 19.44% with a median of 9.91%. Table 2 shows the top and bottom five ranked hospitals according to their risk-adjusted 30-day mortality rate. The top or bottom ranked 10 hospitals were more or less the same using only age, SBP and HR but with a slightly longer range, 4.14 to 23.32%. Comparisons of agreement between a hospital’s risk-adjusted mortality rates and between ranks of the risk-adjusted mortality rates from fitting the fixed- and random-effects models are shown in Fig. 1A, B. For each plot, lines of equality are shown, and comparisons are based on posterior medians. The observed agreement appears to be very poor between the risk-adjusted mortality rates. On the other hand, for the ranks, the points lie evenly around the line of unity, showing very good agreement. In both plots, agreement is very poor between outcome measures for either low or high outlying hospitals. Furthermore, the plots show that estimated outcome measures are more variable under the fixed-effects model. The problems observed from using point estimates for assessing agreement can be partially nullified by categorising the hospitals into low, normal and high performing. Comparisons based on categories of risk between different methods are shown in Table 3. All methods were able to classify hospitals as lowand high-outcome outliers; however, only seven and 11 from 128 were classified as such under the hierarchical rank and RAMR methods, respectively, while 31 and 33 were outliers under the fixed-effects rank and RAMR methods, respectively. As expected, profiling methods using hierarchical models were more conservative in classifying hospitals as performance outliers than were the non-hierarchical models. The observed agreement in the methods’ classification of hospitals ranged from 90 to 98% of the time, the highest being between the two hierarchical methods. In only one of the six
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TABLE 1. THE RISK-ADJUSTMENT MODEL OF 30-DAY MORTALITY USING BASELINE RISK FACTORS, DISCHARGE ECG FINDINGS AND BIOCHEMICAL MARKERS Risk factor Age group (years) < 55 55–64 65–74 75–84 ≥ 84 SBP (mmHg) < 117 117–132 133–146 147–164 ≥ 165 Heart rate (beats/min) < 62 62–72 73–83 84–98 ≥ 99 Discharge diagnosis ST elevation Non-ST elevation Tropin positive Tropin negative Chest pain Other Total
Number of patients
Number of deaths (%)
Odds ratio (95% CI)
14 116 16 396 21 442 23 006 9 249
233 (1.7) 1.00 549 (3.4) 2.02 (1.72–2.37) 1 703 (7.9) 5.06 (4.38–5.84) 3 656 (15.9) 10.73 (9.33–12.34) 2 259 (24.4) 18.03 (15.61–20.83)
16 609 16 745 16 458 17 072 17 325
3 082 (18.6) 1 716 (10.3) 1 354 (8.2) 1 161 (6.8) 1 087 (6.3)
1.00 0.56 (0.52–0.60) 0.43 (0.40–0.46) 0.33 (0.31–0.36) 0.27 (0.25–0.29)
18 135 15 538 16 836 16 600 17 100
1213 (6.7) 991 (6.4) 1 373 (8.2) 1 905 (11.5) 2 918 (17.1)
1.00 1.10 (0.99–1.20) 1.38 (0.27–1.51) 1.84 (1.70–2.00) 2.55 (2.36–2.75)
29 389 29 462 6 719 6 326 3 136
3 612 (12.3) 3 379 (11.5) 368 (5.5) 58 (0.9) 34 (1.1)
8.59 (6.09–12.11) 5.29 (3.75–7.47) 2.59 (1.81–3.71) 0.67 (0.43–1.02) 1.00
84 209
8 400 (9.98)
4.68 (3.29–6.67)
comparisons was agreement excellent, as reflected by the κ statistic of 0.77. In three cases, the agreement was moderate (0.40 < κ < 0.75). In the remaining two cases, the agreement was only marginal (κ = 0.29–0.32), and these involved comparisons of the random-effects rank and fixed-effects methods. The cross tabulations in Table 3 are in close agreement with those obtained when using only age, SBP and HR in the risk-adjustment model, an indication that our results are insensitive to which factors are included in the risk-adjustment model.
Number of Observed Hospital admissions* deaths Top five 1 737 39 2 167 5 3 232 9 4 209 10 5 2 158 71 Bottom five 124 289 42 125 24 5 126 21 4 127 348 63 128 97 19 *With a valid 30-day status.
16 12 8
4
8
12
16
20
Risk-adjusted mortality rate using fixed-effects model
Expected deaths
RAMR (95% CI)
89.65 10.58 18.99 20.10 123.56
4.54 (3.32–6.21) 4.82 (2.01–11.58) 4.83 (2.52–9.29) 5.07 (2.73–9.43) 5.86 (4.64–7.40)
27.43 3.21 2.50 37.45 9.97
15.62 (11.54–21.13) 15.90 (6.62–38.19) 16.31 (6.12–43.44) 17.16 (13.40–21.96) 19.44 (12.40–30.48)
The results presented here are based on arbitrary choices. In particular, the prior for the between-hospital variation is critical as it dictates how much shrinkage is assumed in the individual hospital estimates.29 However, there is no standard solution to the problem of choosing a prior on the randomeffects variance in hierarchical models. In standard Bayesian analyses, the inverse-gamma prior family is preferred because of its conditional conjugate properties, which allows ease of mathematical derivations. But this prior has been shown to give biased results.30 On the other hand, the threshold values for RAMR have an influence of the number of hospitals classified as outliers. We performed a limited-sensitivity analysis to find out the extent to which the choices impact on the results. We used a uniform (0, 100) prior on the random-effects standard deviation σo and 15% for the threshold value δ. The uniform prior produced exactly the same classifications of the hospitals as the inverse-gamma prior on the random-effects variance. Using a threshold of 15% affected only the 117 hospitals that were previously classified as normal, and now two were classified as low outliers and five as high outliers. Our results were therefore not affected by changes in random-effects variances but slightly so when the threshold value was changed. B
20
4
TABLE 2. OBSERVED, EXPECTED AND RISK-ADJUSTED 30-DAY MORTALITY RATE AFTER ACS ADMISSION, 2003–2005, ENGLAND AND WALES
Risk-adjusted mortality rate using random-effects model
Risk-adjusted mortality rate using random-effects model
A
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115 96 77 58 39 20 1
1
20
39
58
77
96
115
Risk-adjusted mortality rate using fixed-effects model
Fig. 1. Scatter plots of agreements in hospital’s risk-adjusted mortality rate (A) and rank of the risk-adjusted mortality rate (B) between the fixed- and random-effects models. For each plot, the line of equality is shown.
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TABLE 3. CLASSIFICATION OF HOSPITALS UNDER THE FIXED AND HIERARCHAL MODELS Fixed RAMR Fixed rank Hierarchical RAMR Low Normal High Low Normal High Low Normal High Fixed RAMR Low – – – 20 0 0 6 14 0 Normal – – – 7 88 0 0 95 0 High – – – 0 9 4 0 8 5 = 0.71 = 0.46 Fixed rank Low – – – – – – 6 21 0 Normal – – – – – – 0 96 1 High – – – – – – 0 0 4 = 0.44 Hierarchical rank Low 2 0 0 2 0 0 2 0 0 Normal 18 95 8 25 96 0 4 117 0 High 0 0 5 0 1 4 0 0 5 = 0.32 = 0.29 = 0.77
Discussion This study compared the performance of four methods for profiling hospitals and assessed their agreement. The methods included combinations of two Bayesian methods, fixed and hierarchical, and two ways of identifying outliers, rank and exceeding some threshold using a hospital’s risk-adjusted mortality rate; two were based on a hospital’s rank for its riskadjusted mortality rate, obtained from fitting both fixed- and random-effects models. The agreements between the different methods were empirically examined using an extensive dataset of ACS patients. Even though all the methods were able to classify hospitals as low- and high-outcome outliers, profiling methods using random-effects models were more conservative than fixedeffects models in classifying hospitals as having better- or worse-than-expected mortality. These findings were expected on theoretical grounds and support the results from a multitude of prior studies, showing that random-effects models identify fewer performance outliers.8,11 In the present study, the observed agreement in the methods’ classification of hospitals ranged from 90 to 98%, the highest being between the methods within each effects model. The agreement was excellent (κ = 0.77) in only one of the six comparisons. Otherwise, in all the remaining five scenarios, the agreement was, at best moderate (κ < 0.75). Our findings relied on routinely collected clinical data. These types of data suffer from incompleteness and inaccuracy of the variables entered.31 In our preliminary investigation, 11% of the total patients had missing codes on survival status. We did not have full data for admission age, SBP, HR, ECG findings and biochemical markers of the patients. Other risk variables that may have been used also demonstrated missing data, thus limiting the number of risk factors in the case mix adjustment model on this occasion. However, our findings were shown to be robust to which factors were included in the risk-adjustment model. Indeed, difficult-to-obtain key clinical variables add little to the predictive power of ACS risk scores.27 It may well be that the hospital performance variation exhibited in this study was substantially contributed to by the
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variation in definitions and data quality, as alluded to by Lilford et al.4 However, it is unlikely that these issues alone could be attributed to the outcome variation found across the four analytical strategies examined. We did not impute for missing data since other researchers have shown that this does not affect the prediction model or mortality.32 A more elaborate assessment of MINAP data quality and validity on the resulting classification of hospitals is the subject of a British Heart Foundation-funded project within our group undertaken by Gale et al.33 For the present study, it suffices to say that the number of patients analysed and the data used were of sufficient quality to enable a comparison of different methods to assess the hospitals’ performance for 30-day mortality among ACS patients. However, we remain cautious regarding the exact inference made for some hospitals, given their data quality. We performed a limited-sensitivity analysis to different prior specifications of the hospital random-effects variation and threshold values. We found classification of outlying hospitals was not affected by changes in the random-effects variations, but it was slightly affected when the thresholds were changed. A more elaborate sensitivity analysis would alter specification of the hospital random-effects distribution as the assumed normal distribution is not robust and flexible enough to account for outlying hospital effects. Therefore it may be necessary in future research to model the hospital effects more flexibly, for example by heavy-tailed t distributions to investigate both sensitivity and robustness of the results, as in Manda,34 or mixtures or non-parametric Dirichlet distributions, as in Ohlssen.35 The threshold level chosen and the required probability of exceeding this threshold to classify a hospital using the risk-adjusted mortality rate as an outlier were subjective and completely arbitrary. We could have used other thresholds and probabilities, as in Austin,12 which may have generated stronger or weaker levels of agreement between the methods. Furthermore, the requirement that intervals of the ranks must lie entirely in the bottom or top quarters of ranks for the hospital to be classified as an outlier was also arbitrary but has been used before.11,12 Results from any study on profiling hospitals’ performance are predictably used to produce league tables of performance. We are aware of the many criticisms surrounding the statistics used in measuring performance and the subsequent ranking of hospitals. We did not intend to contribute to this controversy. Our aim was to describe and compare the performance of four different Bayesian methods for institutional profiling. In using ranks to compare hospitals, caution should be exercised since most hospitals had considerably overlapping intervals, which made it difficult to obtain reliable ranking, especially for hospitals admitting fewer patients. We follow Normand et al.,10 Marshall and Spiegelhalter,11 Austin12 and Ohlssen et al.18 in advocating the use of Bayesian methods, which when pooling data across hospitals, handles the problem of small hospitals better than frequentist methods, for which a minimum number of patients is required before a hospital can be included.12 However, if we are willing to accept wide confidence intervals, the exact probabilistic methods can be used within a frequentist framework to handle small hospitals (see Luft and Brown36). Furthermore, it is much easier within Bayesian methods to determine uncertainty associated with the ranks, which are very sensitive to sampling variations (see
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Marshall and Spiegelhalter11 and Greenwood18). The main interest of this work was not to find the best model for hospital profiling, but to investigate whether or not the methods agree. In order to inform which method gives a better fit would require other model-checks statistics, such as posterior predictive checks.
Conclusion The main overall finding from our example is that the choice of ways to classify a hospital is less critical than the statistical method used. We suggest profiling hospitals using a hierarchical model and RAMR with an appropriate threshold, which seems to offer more reliable results. However, these methods warrant further investigation, possibly of simulated data sets in which the impact of underlying assumptions (and derivation thereof) may be evaluated. There is a need for robust systems of ‘regulation’ or ‘performance monitoring’, which, with more rigorous work, we hope to achieve in the future. We thank Dr JS Birkhead, clinical director of MINAP, the National Audit of Myocardial Infarction, National Institute for Clinical Outcomes Research, and the Heart Hospital, London, for providing the extract from MINAP. We acknowledge all hospitals in England and Wales for their contribution of data to MINAP. We also thank Darren Greenwood for helpful comments.
References 1.
Department of Health. The new NHS: modern, dependable. The Stationary Office: London, 1997 (Cm 3807). 2. Baker R. Harold Shipman’s clinical practice, 1974–1998. The Stationary Office: London, 2001. 3. Kennedy Inquiry. Report of the public inquiry into children’s heart surgery at the Bristol Royal Infirmary. The Stationary Office: London, 2001. 4. Lilford R, Mohammed MA, Spiegelhalter D, Thomson R. Use and misuse of process and outcome data in managing performance of acute medical care: avoiding institutional stigma. Lancet 2004; 363: 1147–1154. 5. Gale CP, Roberts AP, Batin PD, Hall AS. Funnel plots, performance variation and the Myocardial Infarction National Audit Project 2003– 2004. BMC Cardiovasc Disord 2006; 6: 34. 6. Birkhead JS, Walker L, Pearson M, Weston C, Cunningham AD, Rickards AF. Improving care for patients with acute coronary syndromes: initial results from the National Audit of Myocardial Infarction Project (MINAP). Heart 2004; 90: 1004–1009. 7. Bradley EH, Herrin J, Elbel B, McNamara BL, Magid DJ, Nallamothu BK, et al. Hospital quality for acute myocardial infarction: correlation among process measures and relationship with short-term mortality. J Am Med Ass 2006; 296: 72–78. 8. Stukenborg GJ, Wagner DP, Harrell FE, Oliver MN, Heim SW, Price AL, et al. Which hospitals have significantly better or worse than expected mortality rates for acute myocardial infarction patients? Improved risk adjustment with present-at-admission diagnoses. Circulation 2007; 116; 2960–2968. 9. Grant SW, Grayson AD, Jackson M, Au J, Fabri BM, Grotte G, et al. Does the choice of risk adjustment model influence the outcome of surgeon specific mortality analysis: a retrospective analysis of 14,637 patients under 31 surgeons? Heart 2007: doi:10.1136/hrt.2006.110478. 10. Normand SL, Glickman ME, Gatsonis CA. Statistical methods for profiling providers of medical care: issues and applications. J Am Statist Ass 1997; 92: 803–814. 11. Marshall EC, Spiegelhalter DJ. Institutional performance. In: Leyland AH, Goldstein H (eds). Multilevel Modelling of Health Statistics. Chichester: Wiley 2001: 127–142. 12. Austin C. A comparison of Bayesian methods for profiling hospital
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performance. Medical Decision Making 2002: 163–172. 13. Thomas N, Longford N, Rolph J. Empirical bayes methods for estimating hospital-specific mortality rates. Statist Med 1994; 13: 889–903. 14. Marshall C, Best N, Bottle A, Aylin P. Statistical issues in the prospective monitoring of health outcomes across multiple units. J R Statist Soc Am 2004; 167: 541–559. 15. Ohlssen DI, Sharples LD, Spiegelhalter DJ. A hierarchical modelling framework for identifying unusual performance in health care providers. J R Statist Soc Am 2007; 170: 865–890. 16. DeLong ER, Peterson ED, DeLong DM, Muhlbaier LH, Hackett S, Mark DB. Comparing risk-adjustment methods for provider profiling. Statist Med 1997; 16: 2645–2664. 17. Leyland AH, Boddy FA. League tables and acute myocardial infarcation. Lancet 1998; 351: 555–558. 18. Greenwood D. Reliability of journal impact factor rankings. BMC Med Res Methodol 2007; 7: 48. 19. Birkhead JS, Walker L. National audit of myocardial infarction (MINAP): a project in evolution. Hosp Med 2004; 65: 452–453. 20. Walker L, Birkhead J, Weston C, Pearson J, Quinn T. Myocardial Infarction National Audit Project (MINAP): How the NHS manages heart attacks. Royal College of Physicians. London, 2007. 21. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 327: 307–310. 22. Fleiss J. Statistical Methods for Rates and Proportions. New York: Wiley, 1981. 23. Spiegelhalter DJ, Thomas A, Best NG, Lunn D. BUGS: Bayesian Inference Using Gibbs Sampling, Version 1.4.1, 2004. Medical Research Council Biostatistics Unit, Cambridge University. 24. Gelman A, Rubin DB. Inference from iterative simulations using multiple sequences. Stat Sci 1992; 7: 457–472. 25. Gale CP, Manda SOM, Batin PD, Weston CF, Birkhead JS, Hall AS. Predictors of in-hospital mortality for patients admitted with ST-elevation myocardial infarction: a real-world study using the Myocardial Infarction National Audit Project (MINAP) database. Heart 2007; doi:10.1136/hrt.2007.127068. 26. Gale CP, Manda SOM, Weston CF, Birkhead JS, Batin PD, Hall AS. Evaluation of risk scores for risk stratification of acute coronary syndromes in the Myocardial Infarction National Audit Project (MINAP) Database. Heart 2008: 8. 27. Yan AT, Yan RT, Tan M, Casanova A, Labinaz M, Sridhar K, et al. Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better. Eur Heart J 2007; 28: 1072–1078. 28. Resengren A, Wallentine L, Simoons M, Gitt AK, Behar S, Battler A, Hasdai D. Age, clinical presentation, and outcome of acute coronary syndromes in Euroheart acute coronary syndrome survey. Eur Heart J 2006; 27: 789–795. 29. Normand S-LT, Shahian DM. Statistical and clinical aspects of hospital outcomes profiling. Stat Sci 2007; 22: 206–226. 30. Gelman A. Prior distributions for variance parameters in hierarchical models. Bayesian Anal 2006; 1: 515–533. 31. Mohammed MA, Stevens A. The value of administrative databases. Br Med J 2007; 334: 1014–1015. 32. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, et al. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003; 163: 2345–2353. 33. Gale CP, Manda SOM, Greenwood, West RM, Hall AS. Characterising hospital performance for acute coronary syndromes using the Myocardial Infarction National Audit Project (MINAP) database: Data incompleteness, multiple imputation and development of performance indicators. Research Funded by the British Heart Foundation. 34. Manda SOM. A Bayesian ordinal model for heterogeneity in a multicentre myocardial infarction clinical trial. Statist Med 2002; 21: 2011–3122. 35. Ohlssen D. Bayesian methods for institutional comparisons and performance monitoring. Available at < http://www.ccsr.ac.uk/methods/ festival/programme/bay/ohlssen.pdf >, Accessed July 30, 2007. 36. Luft HS, Brown BW. Calculating the probability of rare events: why settle for an approximation? Hlth Services Res 1993; 28: 419–439.
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Review Articles Cardiomyopathies and myocardial disorders in Africa: present status and the way forward AYODELE O FALASE, OKECHUKWU S OGAH
Abstract A review of heart diseases in Africa shows that the cardiomyopathies continue to be important causes of morbidity and mortality in the population. Hypertension remains the commonest cause of myocardial disease, followed by the cardiomyopathies. Ischaemic heart disease continues to be rare. Of the cardiomyopathies, dilated cardiomyopathy (DCM) is still the commonest. A large proportion of patients diagnosed with DCM in Africa have been shown to be cases of hypertensive heart failure, with varying degrees of myocardial dysfunction. Hypertrophic cardiomyopathy, which in the past was thought to be rare among Africans, has been shown to have the same prevalence as in other parts of the world. Moreover it is now known to be a genetic disorder. Endomyocardial fibrosis has become rare in communities where it used to be common. Its aetiology continues to be elusive. Arrhythmogenic right ventricular cardiomyopathy has been reported among Africans but there are no reports of left ventricular non-compaction or the ion channelopathies from Africa. Lenegre disease and the long-QT syndromes are well-known entities in clinical practice in Africa although long-QT in Africa is associated with potassium deficiency arising from prolonged treatment with diuretics. Left ventricular non-ischaemic aneurysms still occur but are rare. In view of these, a new classification of myocardial disorders was proposed for Africa.
that the commonest cause of heart failure was hypertension. This was followed by diseases that primarily affected the myocardium (labelled myocardial disease in the illustration), then rheumatic heart disease, followed by endomyocardial fibrosis. Recent data (Fig. 1B) among the same ethnic group show that the prevalence of hypertension has doubled, there is no difference in the prevalence of dilated cardiomyopathy, the prevalence of A
Others HHF IHDX CP EMF
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Keywords: cardiomyopathy, Africa, sub-Saharan Africa
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Submitted 6/7/10, accepted 5/6/12
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www.cvja.co.za
DOI: 10.5830/CVJA-2012-046
For the past 60 years, reports from all parts of Africa have shown a remarkable unanimity in the pattern of heart diseases among black Africans.1,2 While ischaemic heart disease is the dominant cardiovascular disease in the Western world, it is rare in black Africans. The typical pattern of heart failure in the sixties in a black African hospital is shown in Fig. 1A.1 From this figure, it is obvious
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Division of Cardiovascular Medicine, Department of Medicine, University College Hospital, Ibadan, Oyo State, Nigeria
AYODELE O FALASE, MD, FWACP, FMCP, FRCP, aofalase@gmail. com OKECHUKWU S OGAH, MB BS, MSC, FWACP
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Fig. 1A. Causes of heart failure in Nigerians at the University College Hospital, Ibadan between 1968 and 1969 (Carlisle and Ogunlesi 1972). B. Causes of heart failure in the same ethnic group in the year 2010 compared with the 1972 data.3 HHF = hypertensive heart failure; RHDX = rheumatic heart disease; DCM = dilated cardiomyopathy; EMF = endomyocardial fibrosis; CP = cor pulmonale; IHDX = ischaemic heart disease.
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ischaemic heart disease remains low, while that of rheumatic heart disease has decreased considerably.3 We are primarily concerned with myocardial diseases and endomyocardial fibrosis in this discourse. We performed a systematic search of Pubmed for published data on cardiomyopathies in sub-Saharan Africa from January 1960 to December 2009. This was supplemented with parallel searches of references of identified journals, as well as a search of specific data sets such as African Index Medicus, African Journals Online (AJOL) and the World Bank database. The search strategy was Africa or sub-Saharan Africa and cardiomyopathy, dilated cardiomyopathy, endomyocardial fibrosis, and peripartum cardiomyopathy. Prior to 1980 there were several descriptions from many geographical areas of the world but mainly from Africa of obscure forms of heart disease that primarily affected the heart muscle. These descriptions were published under several names such as idiopathic cardiomegaly,4 nutritional heart disease,5 cardiovascular collagenosis with parietal endocardial thrombosis,6 and cardiomyopathy.7 The common features of these descriptions were that affected patients presented in congestive cardiac failure with cardiomegaly, the cause of which was not readily apparent. The disease was particularly common in the tropical and sub-tropical countries of the world where it constituted one of the major clinical and health problems.8 Similarly, there were several descriptions from many parts of the world, of another group of myocardial diseases that was characterised by inappropriate massive hypertrophy of the cardiac muscle (HCM). It was first described by Teare in 1958.9 Prior to 1980, it appeared to have a worldwide distribution although initial reports suggested that it was rare in black people. The reason for this might have been due to a high prevalence of hypertensive heart disease, which interfered with the correct diagnosis of the disease.10 HCM too had been described in the past under several names, including idiopathic hypertrophic sub-aortic stenosis, muscular sub-aortic stenosis, obstructive cardiomyopathy and asymmetrical hypertrophy.11 Thirdly, there were before 1980 several descriptions of another group of myocardial disorders of unknown origin, which was characterised by fibrosis of the endomyocardium, particularly the inflow tract, apex and part of the outflow tract of either or both ventricles. The mitral/tricuspid valve apparatus, depending on which ventricular chamber was affected was commonly enmeshed in fibrous tissue, which very often involved the posterior valve leaflet. The anterior valve leaflet was rarely involved. It was called endomyocardial fibrosis (EMF) in those tropical countries that first reported it.12 A
B
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Prior to the description of the tropical forms of EMF, there were also reports of a similar disease that was characterised by the presence of hypereosinophilia. It was first described by Löffler in 1936,13 and was known as Löffler’s endocarditis parietalis fibroplastica. This disease was initially believed to be confined to only the temperate zones of the world and was considered to be a separate illness from the tropical forms of EMF. However several reports have now confirmed its presence in Africa and other countries of the world where the tropical forms of EMF is prevalent.14 Some have even suggested that it is the early form of tropical EMF (Fig. 2).14
Classification of the cardiomyopathies Because of the initial confusion arising from the names given to all these diseases, the inadequacy of previous classifications,15 and to ensure unanimity in their descriptions, a task force was set up by the World Health Organisation and the International Society and Federation of Cardiology (WHO/ISFC) to harmonise the features of the diseases, adopt uniform names for them, and design an acceptable classification. The report of the task force was published in 1980,11 while the full description of each disease was published by the WHO as a report of an expert committee in 1984.10 At the 1980 meeting, it was agreed to adopt the name ‘cardiomyopathy’ for all diseases of the heart muscle of unknown cause. For a disease to qualify as a cardiomyopathy therefore, the patient must have been extensively investigated and no cause found for the malady. Diseases whose causes were known were simply identified by their causative factors, such as alcohol heart disease, myocarditis or viral heart disease. Such diseases were grouped under a separate heading called ‘specific heart muscle diseases’ which was defined as ‘heart muscle diseases of known cause or associated with disorders of other systems’. Since it was considered inappropriate to slot well-known disorders of the myocardium caused by systemic or pulmonary hypertension, coronary artery disease and congenital heart diseases under this group, they were excluded from the classification. It was felt that all diseases of the myocardium would have had to be listed under specific heart muscle diseases if this was not done. In summary, cardiomyopathy was regarded as a disease of exclusion. The meeting further agreed to group the cardiomyopathies into three types. The first two were named to highlight the changes in their structures (hypertrophic and dilated) while the third, unfortunately, in our view, was named to reflect its restrictive haemodynamic features (restrictive). This classification was C
Fig 2.A. Hypertrophic cardiomyopathy; B. dilated cardiomyopathy; C. endomyocardial fibrosis.
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made before arrhythmogenic right ventricular dysplasia was characterised and identified as a separate disease in the literature, hence its omission in the classification. The reaction of clinicians/researchers to this classification was mixed. While everyone agreed with the designation of these diseases as cardiomyopathies, not everyone agreed with its classification. Several classifications followed thereafter but, in so doing, many of them again extended the definition of cardiomyopathies to include any disorder of the myocardium. The report of another task force, set up by the WHO in 199516 to update the 1980 classification, defined the cardiomyopathies as any disease of the myocardium with cardiac dysfunction, although it retained the original three types of cardiomyopathies: hypertrophic, dilated and restrictive. It added a fourth one, arrhythmogenic right ventricular cardiomyopathy (formerly known as arrhythmogenic right ventricular dysplasia). But while it recognised that dilated cardiomyopathy may derive its origin from conditions such as viral myocarditis, it created, under specific cardiomyopathies, an entity known as inflammatory cardiomyopathy, which it defined as ‘myocarditis in association with cardiac dysfunction’. Similarly it also created another entity, known as alcoholic cardiomyopathy, under specific cardiomyopathies after it had agreed that dilated cardiomyopathy may be caused by the consumption of alcohol. Moreover, ischaemic cardiomyopathy was recognised in the report as a separate entity under specific cardiomyopathies, although the same disease was earlier said to be a variety of dilated cardiomyopathy. Finally, the document introduced new names for well-recognised diseases. For example, hypertensive cardiomyopathy was substituted for the well-known and more specific terms, hypertensive heart disease/hypertensive heart failure. The latest classification, sponsored by the American Heart Association,17 agreed to classify the cardiomyopathies in line with ‘the molecular era of cardiovascular disease’. It also agreed that cardiomyopathies should include any disorder of the myocardium and therefore defined them as ‘a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that are frequently genetic. Cardiomyopathies either are confined to the heart or are part of generalised systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability’. The panel made a case for inclusion of the ion channelopathies in the classification of the cardiomyopathies, although it agreed that they are primary electrical diseases with no gross or histopathological abnormalities. As in the 1980 classification, it excluded from the list of cardiomyopathies ‘pathological myocardial processes and dysfunction that are a direct consequence of other cardiovascular abnormalities, such as that which occurs with valvular heart disease, systemic hypertension, congenital heart disease, and atherosclerotic coronary artery disease producing damage secondary to impairment in coronary flow’. The report went further to classify the cardiomyopathies into two major groups ‘based on predominant organ involvement’. These were primary and secondary cardiomyopathies. Primary cardiomyopathies, which may be genetic, non-genetic or acquired, were defined as ‘those solely or predominantly confined to heart muscle and are relatively few in number’. The genetic
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forms included hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular non-compaction, conduction system disease, glycogen storage disorders, mitochondrial myopathies, and ion-channel disorders. The mixed forms were dilated cardiomyopathies and the restrictive (non-hypertrophied and non-dilated) types. In the report, secondary cardiomyopathies were diseases that were associated with systemic illnesses. These were similar to those listed under specific heart muscle disease and specific cardiomyopathies by the 1980 and 1996 reports, respectively.
Classification of the cardiomyopathies in Africa For clinicians working in Africa where the cardiomyopathies are most prevalent, the question that follows is which of these classifications is appropriate for Africa? Before we answer this question, let us briefly review what is currently known about the cardiomyopathies in Africa.
Hypertrophic cardiomyopathy In the pre-echocardiography era, hypertrophic cardiomyopathy (HCM) was hardly diagnosed in Africa. All abnormal electrocardiographs (ECGs) suggestive of left ventricular hypertrophy (LVH) were attributed by clinicians to hypertensive heart disease since hypertension was the dominant cardiovascular disease among Africans and was extremely common in African populations. The widespread use of echocardiographic examination all over Africa changed all this as it showed that HCM indeed occurs among Africans. For instance, HCM was found in 0.2% of 6 680 unselected echocardiograms in Tanzania18 and in 2% of 712 echocardiograms in Lagos, Nigeria.19 Similar reports have also come from South Africa where extensively genetic investigations have confirmed similar findings with other parts of the world.20 In Ghana,21 1.15% of 572 patients referred for echocardiography at the Ghana National Cardiac reference centre had HCM, while Abegaz in Ethiopia discovered that 53 out of 1 240 abnormal echocardiograms performed at the Armed Forces General Hospital had HCM.22 The prevalence rate among populations outside Africa ranged from 0.2 to 0.5%. Interestingly, Maron et al.17 found in their CARDIA study that the prevalence of HCM in blacks was twice that of whites, while more African-Americans performing competitive sports died suddenly compared with their white counterparts. The aetiology of HCM has similarly been sorted out. Investigations all over the world have conclusively shown that HCM is inherited as an autosomal dominant genetic disorder that is caused by mutations in at least 10 different genes that code for sarcomeric proteins.2,15 Mutations in the β-myosin heavy chain gene, myosin-binding protein C and troponin T account for 70 to 80% of all the cases. The total number of mutations is well over 100, and new mutations are being discovered. HCM is therefore no longer a heart muscle disease of unknown cause and this implies that the 1980 report on the cardiomyopathies is no longer valid.
Arrythmogenic right ventricular cardiomyopathy (ARVC) Reports from Africa about this disease have come from only South Africa.20,23 There are familial cases of ARVC as well as
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non-familial ones. Although the disease has been associated with enteroviral and adenoviral myocarditis, it is not considered to be primarily caused by myocarditis. Lately it has been shown that the disease is not confined to the right ventricle as the name suggests, because the left ventricle may be affected in up to 75% of the patients.12
Other genetic disorders of the myocardium Familial and non-familial cases have been described in patients with the recently discovered myocardial disorder known as left ventricular non-compaction (LV non-compaction).12 Characteristic morphological changes of this disease are often found in the left ventricle of those with the disease. There are no reports of LV non-compaction from Africa, possibly because African cardiologists are not yet familiar with its echocardiographic changes. Genetic disorders of the electrical system of the myocardium with or without morphological changes have also been described. They include Lenegre disease,17 a progressive disease of the conduction system of the heart and the ion channelopathies. Among the ion channelopathies are the long-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short-QT syndrome and idiopathic ventricular fibrillation, all of which can cause sudden death. Lenegre disease and the long-QT syndromes are well-known entities in clinical practice in Africa although long-QT is only associated in Africa with metabolic problems, particularly potassium deficiency following prolonged treatment with diuretics. It is however interesting to note the recent report from South Africa,24 which concluded that the genetic forms of long-QT syndrome (LQTS) occurred most commonly among the white Caucasian population of South Africa, with fewer cases from those of mixed ancestry and none from those of black African descent.2 The other ion channelopathies have not been reported from Africa, probably because of lack of sophisticated cardiac electrophysiological studies and a dearth of well-trained personnel required to make the diagnosis.
Dilated cardiomyopathy Next to hypertension, this is the commonest cause of heart failure in black Africans.1,2 In some communities in Africa, DCM is the commonest cause of heart failure. Before the advent of echocardiography, the diagnosis was made on the basis of clinical presentation, chest X-ray, ECG, and sometimes in the large teaching hospitals, cardiac catheterisation and angiography. Echocardiography has made the diagnosis easier and is presently the preferred investigation for making a diagnosis. Affected patients often presented in congestive cardiac failure with functional mitral and tricuspid regurgitation due to myocardial failure, the cause of which was not apparent. ECG changes were variable. Some had low-voltage complexes while others presented with left ventricular hypertrophy. Abnormal intraventricular conduction defects were common, especially left bundle branch block. Chest X-ray usually showed cardiomegaly with failure, while angiography confirmed a dilated left ventricle with poor myocardial contraction and functional mitral regurgitation. DCM is widely regarded as an end-stage myocardial disease from a wide variety of adverse factors. The most common of these insults are briefly considered below.
Hypertension For a long time, several workers in Africa had suspected that many patients who were labelled as having DCM were really hypertensives. And there had been several debates at world conferences where this assertion was actively advanced by many workers. Mokhobo,25 from South Africa advised caution in making a diagnosis of cardiomyopathy since ‘cardiomyopathy and hypertension are both common in black patients and confusion may arise between them’. Lowenthal,24 also from South Africa wrote as follows: ‘these cases are regarded as evidence in favour of the hypothesis that many cases of cryptogenic heart disease (cardiomyopathy, congestive cardiomyopathy, idiopathic cardiomegaly) are in fact hypertensives presenting with normotensive cardiac failure’. From Nigeria, Brockington,26 after extensive studies, came to the conclusion that hypertension and what he called heart muscle disease at the time were similar and that the latter was ‘the late stage of untreated chronic hypertensive heart failure’. Brockington’s view was supported by Celia Oakley at a debate during a conference on cardiomyopathies held in London in 1971 but John Goodwin at the same conference disagreed, asserting that hypertensive heart disease was structurally different from heart muscle disease. The contentious problem in the past had always been the presenting blood pressure. Some patients had a normal blood pressure at presentation but in others the blood pressure was mildly raised, although out of proportion with the degree of the patient’s heart failure. Very often, the hypertension was transient, the blood pressure becoming normal with treatment of the heart failure and staying normal without sustained treatment
Fibrosis Interstitial
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Extravascular compression
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Myocardial fibre necrosis with reparative fibrosis Systolic dysfunction Diastolic dysfunction Heart failure
Fig. 3. The consequences of myocardial fibrosis on the heart of patients with arterial hypertension, modified from Diez et al. Nature Clin Pract Cardiovasc Med 2005; 2(4): 209–216.
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Fig. 4. Representation of progression of the left ventricle in hypertensive patients, from concentric hypertrophy with a small cavity, to concentric hypertrophy with a large cavity, to a destroyed myocardium unable to sustain a high blood pressure.
with diuretics or hypotensive agents. Some investigators had referred to this phenomenon as ‘reactive hypertension’ or ‘Sahli’s Hochdruckstauung’27 because it was thought to be due to intense peripheral vasoconstriction, which occurred in heart failure. Studies from Nigeria in the seventies have however shown that what was called heart muscle disease in the past was not caused by a single disease process.28-33 Over 75% of patients were hypertensives whose hearts had become damaged over time because of poor or lack of control of high blood pressure.34 Progression from a hypertrophied heart (concentric or asymmetric) in Nigerian hypertensives to the stage of flabby heart has been discussed in an earlier publication (Figs 3, 4).34
Alcohol Early reports from Nigeria showed that alcohol consumption played a significant part in the genesis of myocardial damage of patients diagnosed with cardiomyopathies. The authors also suggested that excessive consumption contributed to the heart failure of some of their hypertensives.29,35 This is in agreement with Rees et al.36 who in 1974 suggested from Nairobi that some of their patients with cardiomyopathies were suffering from the combined effects of excessive alcohol consumption and hypertension, and this combination led to congestive cardiac failure. Some of the patients studied in Nigeria had thiamine deficiency and these were linked with protein malnutrition and excess consumption of alcohol. All but one had low-output cardiac failure and they did not respond to thiamine administration.30 By contrast, high-output and low-output cardiac failure caused by thiamine deficiency was shown to have equal prevalence in South African alcoholics.27 Generally, it is now estimated that alcohol is a contributory factor in a significant number (up to 45%) of patients with heart failure of unknown cause in Africa,27 and alcohol also contributes to the heart failure of a significant number of hypertensives.
Myocarditis Studies in the seventies also showed that myocarditis was the cause of a significant number of patients diagnosed at the time as heart muscle disease of unknown cause, especially among young people below the age of 30 years. At that time, it was only possible to investigate the role of Coxsackie B
virus and Toxoplasma gondii in the patients studied, but higher antibody levels were found in the patients compared with control subjects. About 45% of the patients eventually turned out to be hypertensive, implying that myocarditis was playing some part in the genesis of their myocardial damage.28-30,32 A few cases of acute myocarditis caused by Coxsackie B3 virus and Toxoplasma gondii were documented during the four years the patients were followed up. Sub-clinical infection by Toxoplasma gondii is common in Nigeria and several studies have found that virtually everyone living in this community has seroconverted to the organism.32,33 Since then, several studies have confirmed the role of myocarditis in the genesis of myocardial failure all over the world and many more organisms [viruses including the human immunodeficiency virus (HIV), bacteria including mycobacteria, parasites such as Trypanosoma, Toxoplasma gondii and Schistostoma] have been identified as culprits.2 In Africa, many patients with myocardial failure and a positive HIV test have been shown to have not only viral myocarditis (HIV, EpsteinBarr virus, cytomegalovirus, parvovirus, adenovirus and human simplex virus) but also infections from other organisms such as toxoplasmosis and cryptococcus. Endomyocardial biopsies and detection of viral genomes have been crucial in the identification of these agents in the myocardium of the patient.37,38 In an excellent study by Shaboodien,39 a prevalence of 100% infectivity (enterovirus, Epstein-Barr virus, parvovirus, human simplex virus and adenovirus) was found in the hearts of the patients with ‘idiopathic dilated cardiomyopathy’ she biopsied. Unfortunately these advanced techniques are not widely available in Africa outside South Africa. The role of excessive immune activation in the pathogenesis of the disease has also been studied in Africa. A study found that HLA-DR1 and HLA-DRw10 were commoner in patients with DCM.40 Elevated plasma levels of inflammatory cytokine tumour necrosis factor (TNF)-α, C-reactive protein and a plasma marker of apoptosis have also been found in DCM patients,41-43 and those with peripartum cardiomyopathy.44 Leucocyte cytokines were also found to be elevated in these patients. In those with peripartum cardiomyopathy, the level of Fas/Apo-1 was also elevated. These findings had led to studies on the immunomodulatory effect of pentoxifylline in the management of the DCM patients,
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with promising results.45 The process of progression from acute myocarditis to dilated cardiomyopathy was recently elucidated by Kawai.46
Peripartum cardiomyopathy (PCM) PCM commonly occurs during the last trimester of pregnancy and the first six months after delivery. Risk factors that have been reported in the literature are:37,47-50 • black race • advanced maternal age • twin pregnancies • gestational hypertension • long-term tocolysis. Reports from Haiti have shown that partial improvement of systolic function occurred in the first year of follow up.50 In fact a third of their women with PCM recovered fully within five years. Mortality rates were 15% in the first six months and 42% during 25 years of follow up. The Hausas in the northern part of Nigeria have the highest known incidence of PCM in the world – about 13% of all female admissions at the Ahmadu Bello University Teaching Hospital, Zaria.51-54 A wide range of diseases has been advanced as the cause of myocardial damage of these women. They include myocarditis, hypertension, abnormal immune response to pregnancy, impaired cardiac (systemic) microvasculature, increased myocyte apoptosis, cytokine-mediated inflammation, selenium deficiency (Keshan disease), lying on heated mud beds after taking two hot baths in addition to excessive consumption of a special porridge to which as much as 30 g/day of potash (kanwa) has been added (Zaria cases), genetic predisposition, increased adrenergic tone leading to myocardial stunning, and excessive production of prolactin.55 Recent studies have also shown that unbalanced peri/ post partum is linked to proteolytic cleavage of prolactin, which turns it into a potent anti-angiogenic, pro-apoptotic and pro-inflammatory factor. These observations tend to suggest that prolactin cleavage could operate as a specific pathomechanism for the development of PCM.55,56 Bromocriptine has been shown to be beneficial in reducing the raised levels of prolactin found in some of the women, improving their left ventricular function.57 The plasma marker of apoptosis, Fas/Apo-1 has also been shown to be elevated in patients with PCM,42,45 while troponin T levels have been found to be useful in predicting the presence of persistent left ventricular dysfunction in patients.58 Baseline Fas/ Apo-1 levels and higher NHYA at presentation were found to be the only predictors of mortality, while MRI using late gadolinium enhancement can be useful in evaluating the extent of myocardial damage and predict the outcome of the disease.46,59,60 With molecular studies, viral genomic materials of enterovirus, parvovirus B19, human herpes virus 6, Epstein-Barr virus and cytomegalovirus have been identified in the heart muscle of some women with PCM.61-63 On the contrary, Cenac et al.64 found no evidence of viral myocarditis in Niger, West Africa. Sanderson et al.,37 O’Connell et al.65 and Midei et al.66 on the other hand found evidence of myocarditis in biopsy materials of the women they studied. In fact, Midei et al.66 reported that as many as 78% of newly diagnosed patients with PCM seen by his group had myocarditis and resolution was associated with improvement of left ventricular function.
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Familial dilated cardiomyopathy Familial forms of dilated cardiomyopathies have been well summarised by Maron et al.17 It is estimated that they constitute 20 to 35% of cases of DCM. They are genetically heterogenous but the predominant mode of inheritance is autosomal dominant, with X-linked autosomal recessive and mitochondrial inheritance occurring less frequently. Many of the mutant genes that are linked to autosomal dominant DCM also encode the same contractile sarcomeric proteins that are responsible for hypertrophic cardiomyopathy. According to Maron et al.,17 DCM is also caused by a number of mutations in other genes encoding cytoskeletal/sarcolemmal, nuclear envelope, sarcomere and transcriptional co-activator proteins. The most common of these is the lamin A/C gene, which is also associated with conduction system disease, and encodes a nuclear envelope intermediate filament protein. In Africa, the first report of familial DCM was from Uganda where a set of twin brothers was reported to have had the disease.67 Reports of familial cases have also come from South Africa. A case of familial DCM with prominent ventricular arrhythmias was reported by Brink et al.68 while Przybojewski et al.69 described two brothers of Afrikaner ancestry with unexplained DCM. Cases of DCM have been linked with progressive familial heart block types I and II.70-72 There were also reports of DCM in two brothers,68 and a case of microcephaly associated with DCM.72 Mayosi et al.73 has also shown that actin mutations do not play a major role in DCM but a mitochondrial DNA susceptibility gene increases the risk of DCM in the general population. Other studies from South Africa evaluated the role of mutations in signaling pathway proteins, in particular, polymorphisms in the angiotensin-converting enzyme and beta-adrenoreceptor subtypes in the progression of DCM.74
Malnutrition Initial reports of DCM from South Africa suggested that the disease was caused by malnutrition. The patients whom Gillanders5 and Higginson et al.75,76 studied improved when their diet was changed to what was described as a ‘balanced’ one. This view has been discarded as Gillanders’ experiments could not be reproduced. In our study, we found that patients with DCM had significantly lower serum albumin levels compared with controls, irrespective of whether they consumed alcohol or not. This was attributed to hepatic dysfunction caused by congestive cardiac failure.29
Haemosiderosis Consumption of iron in excess from iron-containing beer (Bantu haemosiderosis) has been suggested as a potentially reversible causative factor of DCM.75 It has also been found that the ‘poor correlation of cardiac and hepatic iron deposits with heart disease’ might have led to the under-recognition of dietary iron overload as an important factor in the pathogenesis of DCM.77 High levels of serum ferritin have been found in patients with DCM compared with patients with heart failure from other causes, and about 50% of the patients had ferritin levels above 500 ng/ml.30
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Hb genotype No association was found between Hb genotype and DCM in the patients we studied and there are no reports linking different types of Hb genotypes with DCM.
Summary of studies on DCM in Africa From all these studies, we can conclude as follows: • Hypertension contributes to some of the cases diagnosed clinically as DCM in Africa. Such patients should be identified and reclassified as having hypertensive heart failure with varying degrees of myocardial dysfunction. • Chronic alcohol consumption and myocarditis have also been identified as the causes of myocardial damage in some of the patients clinically diagnosed as cardiomyopathy in Africa and even worldwide. • Familial cases of DCM have been described in Africa but limited research has been done on the continent. • Lack of facilities and technical know-how have also made the routine diagnosis of myocarditis in Africa impossible. Many are therefore missed. • Estimation of markers of inflammation such as C-reactive protein, inflammatory markers such as the tumour necrosis factor α, and the plasma marker of apoptosis (Fas/Apo-1) may perhaps help in making a preliminary diagnosis of myocarditis. This needs to be further explored. • In patients with PCM, abnormal immune response to pregnancy, increased myocyte apoptosis, selenium deficiency, cultural practices such as those of the Zaria women, and prolactin excess/cleavage are other causes that have been advanced by workers in the field. In those with excess prolactin production/cleavage, bromocriptine has been found to improve the cardiac status of these women. • Thiamine deficiency is common among Africans with DCM and it is related to excessive alcohol consumption and/or malnutrition. By itself, it is not an important cause of DCM. • Haemosiderosis has been found in many patients with DCM and is probably due to excessive consumption of alcohol stored in iron containers. Haemosiderosis is reversible.
Implication For a patient’s heart failure to qualify to be labelled as dilated cardiomyopathy according to the 1980 classification of the cardiomyopathies,11 a patient must have been extensively investigated and no cause for his/her disease found. Under this classification, diseases whose causes are known should be named appropriately. From the above, therefore, we can assert that some of the patients diagnosed with DCM in Africa have hypertensive heart disease/failure. Others have alcohol heart disease, viral heart disease or myocarditis, peripartal heart disease and familial dilated heart muscle disease. There are other cases of DCM whose aetiology does not fall into these categories. The prevalence of such cases varies among the different communities of Africa.
Restrictive cardiomyopathy Under the 1980 classification,11 the term restrictive cardiomyopathy was in our view out of place. While hypertrophic and dilated cardiomyopathies referred to structural changes within
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the heart, restrictive cardiomyopathy referred to haemodynamic changes. It would have been more consistent if a term such as fibrotic/obliterative cardiomyopathy was used to describe endomyocardial fibrosis (EMF) and Löeffler’s endomyocardial disease, the two diseases the report had in mind. Moreover, with the advent of echocardiography, it is now known that diastolic problems of the heart are not limited to endomyocardial fibrosis and its variants. They occur in several other diseases, including hypertension and hypertrophic cardiomyopathy, and indeed in infiltrative disorders such as amyloidosis. Under the 1980 classification,11 it was recommended that Löffler’s cardiomyopathy be relabelled eosinophilic endomyocardial disease (EED). Both EED and EMF are characterised by scarring of the endomyocardium of either or both ventricles, which creates cavity obliteration and restriction of filling of the ventricles with blood. While the outflow tract of the affected ventricle is spared, the atrio-ventricular valve becomes enmeshed with scar tissue, which consequently binds down the posterior valve leaflet and leaves the valve perpetually open. Free regurgitation of blood occurs because of this, resulting in an enormously dilated atrium. EED was first described in Europe by Löffler13 in 1936, while EMF was first described by Bedford and Konstam12 in 1946 among Nigerian soldiers who served in the second world war. EMF was similarly reported by Davies78 in East Africa in 1947, although observations had been made about the disease by Arthur Williams79 as far back as 1938. Despite a myriad publications on the two diseases in the world literature, there is still no agreement on their aetiology. In an excellent review, Bukhman et al.80 summarised the causes of EMF, which had been proposed by several authors in the literature as follows: • infection – toxoplasmosis, rheumatic fever, malaria, helminth parasites • allergy – eosinophilia, auto-immunity • malnutrition – protein deficiency, magnesium deficiency • toxic agents – cerium, cassava, thorium, serotonin, plant toxin, vitamin D. In addition to these, the following were considered as probable causes from Ibadan, Nigeria: • vitamin E (tocopherol) deficiency • obstruction of cardiac lymphatics • Schistosoma infestation: Schistosoma ova had been found in EMF lesions of some Nigerian patients. Of all these, only the hypereosinophilic syndrome of Löffler has been shown to be definitely associated with fibrosis and obliteration of the cardiac apex, similar to tropical EMF. The cause of tropical EMF still remains largely unknown. However Löffler’s endomyocardial disease and the tropical forms of EMF, although similar, do not appear to be the same disease, as there are important differences between them. These can be summarised as shown in Table 1. The questions that arise from all these studies are as follows: 1. What causes eosinophils to degranulate and attack the patient’s own tissues? In our view this has not been adequately addressed. It is known that eosinophils are normally deployed by the body to fight parasites and are often elevated in those with allergies, including drug reactions, collagen disorders such as polyarteritis nodosa and some malignancies. But these eosinophils do not harm the patient’s tissues. What therefore
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TABLE 1 . DIFFERENCES BETWEEN TROPICAL EMF AND EED Parameter Tropical EMF EED (Loeffler’s) Constitutional symptoms Absent Present Hypereosinophilic syndrome Absent Present Degranulated and vacuolated eosinophils Few cases Invariably present Cationic proteins Not elevated Elevated Location of lesions RV, LV or BV Invariably BV Geographical distribution Mainly rainforest regions Worldwide Age group Usually children No specific age group Eosinophilic infiltration of other organs Absent Present EMF = endomyocardial fibrosis; EED = eosinophilic endomyocardial disease; RV = right ventricular; LV = left ventricular; BV = biventricular.
programmes/induces them to attack the patient’s tissues and organs and cause the fibrotic reactions seen in the hypereosinophilia of Löffler’s disease? 2. Can filaria worms induce eosinophils to proliferate on a massive scale (i.e. hypereosinophilia), infiltrate major organs of the body, degranulate and attack patients’ tissues and organs during the process of eliminating the invading organisms? 3. Are there other agents – toxins, infections such as Toxoplasma gondii and Schistosoma mansoni – that are capable of damaging the endomyocardium like hypereosinophilia? 4. Can parasites such as filaria worms, ova of common parasites such as Schistosoma, or other organisms such as Toxoplasma gondii get caught within the endomyocardium, cause chronic inflammation and subsequently fibrotic reactions? These parasites are known to lodge in various organs of the body such as the liver and lungs, where they induce fibrotic reactions, and it is often forgotten that they can also lodge within the myocardium of the heart. There may be an eosinophilic reaction to the parasite in such a situation but this will be mild and transient, and not on the same scale as Löffler’s endomyocardial disease. 5. Is the peculiar location of the lesions in EMF and EED due to the mode of blood flow through the ventricles? Studies have shown that there is relative stasis of blood flow within the apices of the ventricles and for this reason most clots congregate at the apices of the ventricles. 6. Is there a consensus with the pathogenesis proposed by Olsen,81 of fibrotic lesions within the endomyocardium of patients with EMF/EED? His studies showed that the process of development of EMF/EED goes through the following phases: –– necrotic phase with active myocarditis, inflammatory infiltrates and eosinophils –– thrombotic phase with endocardial thickening, thrombosis and decrease in the number of inflammatory cells –– fibrotic phase involving the endocardium, replacement of tissues by collagen and superficial thrombosis. 7. What is the implication of the recent observations in Uganda by Freers et al.,82-84 which showed that fibrosis in patients with EMF is not confined to the endomyocardium but also occurs in other tissues such as the peritoneum, pleura, liver and pericardium. Does it conform to the parasitic theory put forward in (4) above? 8. Are there others markers specific for Löffler’s endomyocardial disease that could make the diagnosis of the disease easier in Africa?
Answers to these questions will help researchers in Africa make significant progress in finding the cause(s) of EMF. The greatest problem we have with the disease at present is that we do not know how the illness begins. Several investigators have described what they believe are the early illnesses of the disease but these are not convincing. Yet, it is during the early stages of the disease that we can find its cause and define its pathogenesis. The EMF cases seen in our wards in Africa are already in the chronic stages of the disease, when the cause is difficult or impossible to find. By going to the villages where there is poverty and a high incidence of EMF, and by using an echocardiogram to aid their study, the research team presently working in Mozambique85 has a unique opportunity to help us find the cause of the disease (Fig. 5).
Left ventricular non-ischaemic ventricular aneurysms These are ventricular aneurysms that occur in black people living in the tropics, particularly those who live in the equatorial rainforest belt of Africa, and are not due to or associated with coronary artery occlusion.86-88 They belong to the group of forgotten tropical cardiomyopathies. Although they are now rare, they still occur. Sporadic cases of such aneurysms have been described in the past from the United States of America, France, Sweden, South Africa and the West Indies, mainly among black people living in those countries. It was first reported in 1813 by Corvisart, in a black man who died of the disease in France in 1796. The aneurysms are often sub-valvular in location, more commonly affecting the mitral and aortic valve rings. Sub-mitral aneurysms tend to be very large, often creating mitral regurgitation; sub-aortic aneurysms on the other hand tend to be smaller and may cause left and right ventricular outflow [no infarctions, no arteritic lesions]
Tricuspid posterior cusp
Semilunar valves uninvolved
Secondary elastomyofibrosis Mitral posterior cusp Fibrosed endocardium
R.V.
L.V.
Thick mass junction of inflow–outflow tract
Normal coronary artery Mural thrombus (41%) Fibrosed myocardium
Fig. 5. Davies’ representation of endomyocardial fibrosis.
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obstruction with aortic and pulmonary regurgitation. Sometimes the aneurysms are annular, extending in a circular direction around the heart and may extend laterally, superiorly and anteriorly. Left atrial aneurysms may be found in some patients. Atrio-ventricular conduction abnormalities, including complete heart block are common. The cause of the aneurysms is unknown, although the pathological findings and the presence of fibrinous pericarditis support the theory that the out-pouchings are initiated by myocarditis.
Proposed new classification Earlier, we posed this question ‘which of the several classifications of myocardial disorders is suitable for Africa?’ The problem
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is that there is no agreement at present on the definition of cardiomyopathy. While some regard it as ‘any disorder of the myocardium’, others believe that it should be defined as heart muscle disease of unknown cause. Yet others believe that it should be defined as ‘any disease of the myocardium with cardiac dysfunction’. This last definition implies that patients with hypertensive heart disease/failure will be described as hypertensive cardiomyopathy and those with aortic valve disease for example, aortic valve cardiomyopathy. While waiting for another consensus meeting to resolve this difficulty, we wish to propose the following classification (Table 2). It is our view that this could stimulate the continental society (PASCAR) to set up an expert committee to look into this subject.
TABLE 2. PROPOSED CLASSIFICATION OF MYOCARDIAL DISORDERS FOR AFRICA 1.
DISEASES THAT ARISE WITHIN THE CARDIOVASCULAR SYSTEM GENETIC A. DISORDERS OF THE MYOCYTES (i) Non-dilated types: • Hypertrophic cardiomyopathy • LV non-compaction (ii) Dilated types: • Arrhythmogenic right ventricular cardiomyopathy • Familial dilated cardiomyopathy B. DISORDERS OFTHE ELECTRICAL STRUCTURES (i) Conduction system disease Structural types: Lenegre disease Non-structural types: ion channelopathies • Long-QT syndrome • Brugada syndrome • Catecholaminergic polymorphic ventricular tachycardia • Short-QT syndrome • Idiopathic ventricular fibrillation NON-GENETIC (i) Hypertrophic • Hypertensive heart disease (concentric, asymmetric) • Chronic rheumatic heart diseases (obstructive forms such as aortic/ pulmonary stenosis • Chronic lung disease, pulmonary embolism, primary pulmonary hypertension. These affect only the right ventricle and can dilate in untreated cases • Congenital heart diseases – obstructive types (ii) Dilated • Hypertensive heart disease/failure (of different grades and severity) • Alcohol heart disease • Myocarditis e.g. viral, bacterial, protozoal, rickettsial • Chronic rheumatic heart diseases (regurgitant forms such as mitral/ aortic/tricuspid/pulmonary regurgitation • Ischaemic cardiomyopathy (iii) Associated with pregnancy • Peripartum heart disease (iv) Fibrotic/obliterative • Löeffler’s endomyocardial disease • Endomyocardial fibrosis (v) Unknown cause • Dilated cardiomyopathy • Left ventricular non-ischaemic ventricular aneurysms
2.
DISEASES THAT ARISE OUTSIDE THE CARDIOVASCULAR SYSTEM INFILTRATIVE • Amyloidosis (primary, familial autosomal dominant, senile, secondary forms) • Gaucher disease • Hurler’s disease • Hunter’s disease STORAGE • Haemochromatosis • Fabry’s disease • Glycogen storage disease (type II, Pompe) • Niemann-Pick disease TOXICITY • Drugs • Heavy metals • Chemical agents GRANULOMA • Sarcoidosis ENDOCRINE • Diabetes mellitus • Hyperthyroidism • Hypothyroidism • Hyperparathyroidism • Phaeochromocytoma • Acromegaly CARDIOFACIAL • Noonan syndrome • Lentiginosis NEUROMUSCULAR/NEUROLOGICAL • Friedreich’s ataxia • Duchenne-Becker muscular dystrophy • Emery-Dreifuss muscular dystrophy • Myotonic dystrophy • Neurofibromatosis • Tuberous sclerosis NUTRITIONAL DEFICIENCIES • Beri beri (thiamine) • Pellagra • Scurvy • Selenium • Carnitine • Kwashiorkor AUTOIMMUNE/COLLAGEN • Systemic lupus erythematosus • Dermatomyositis • Rheumatoid arthritis • Scleroderma • Polyarteritis nodosa ELECTROLYTE IMBALANCE CONSEQUENCE OF CANCER THERAPY • Anthracyclines: doxorubicin (adriamycin), daunorubicin • Cyclophosphamide • Radiation
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The classification we are proposing is a modification of that of Maron et al.17 but we believe that the diseases should be named according to what caused them. All myocardial disorders are included under the classification we are proposing, while less emphasis was placed on the term cardiomyopathy, which, as observed earlier, has now acquired several meanings. It was, however, retained for only those diseases for which the term has become part of the general usage, for example hypertrophic cardiomyopathy. The name dilated cardiomyopathy was used for only those diseases that are characterised by dilatation of the left ventricle with systolic dysfunction, whose cause could not be determined after all the necessary investigations had been performed.
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48. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006; 368: 687–693. 49. Ntusi NB, Mayosi BM. Aetiology and risk factors of peripartum cardiomyopathy: a systematic review. Int J Cardiol 2009; 131: 168–179. 50. Fett JD. Peripartum cardiomyopathy. Insights from Haiti regarding a disease of unknown etiology. Minn Med 2002; 85: 46–48. 51. Sanderson JE, Adesanya CO, Anjorin FI, Parry EH. Postpartum cardiac failure – heart failure due to volume overload? Am Heart J 1979; 97: 613–621. 52. Ford L, Abdullahi A, Anjorin FI, et al. The outcome of peripartum cardiac failure in Zaria, Nigeria. Q J Med 1998; 91: 93–103. 53. Adesanya CO, Anjorin FI, Adeoshun IO, Davidson NM, Parry EH. Peripartum cardiac failure. A ten year follow-up study. Trop Geogr Med 1989; 41: 190–196. 54. Davidson NM, Parry EH. Peri-partum cardiac failure. Q J Med 1978; 47: 431–461. 55. Hilfiker-Kleiner D, Sliwa K, Drexler H. Peripartum cardiomyopathy: recent insights in its pathophysiology. Trends Cardiovasc Med 2008; 18: 173–179. 56. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007; 128: 589–600. 57. Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-ofconcept pilot study. Circulation 2010; 121: 1465–1473. 58. Hu CL, Li YB, Zou YG, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy. Heart 2007; 93: 488–490. 59. Caballero-Borrego J, Garcia-Pinilla JM, Rueda-Calle E, de TeresaGalvan E. [Evidence of gadolinium late-enhancement on cardiac magnetic resonance imaging in a patient with peripartum cardiomyopathy]. Revista espanol Cardiol 2008; 61: 219–220. 60. Kawano H, Tsuneto A, Koide Y, et al. Magnetic resonance imaging in a patient with peripartum cardiomyopathy. Int Med (Tokyo, Japan) 2008; 47: 97–102. 61. Kuhl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112: 1965–1970. 62. Rabausch-Starz I, Schwaiger A, Grunewald K, Muller-Hermelink HK, Neu N. Persistence of virus and viral genome in myocardium after coxsackievirus B3-induced murine myocarditis. Clin Exp Immunol 1994; 96: 69–74. 63. Bultmann BD, Klingel K, Nabauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005; 193: 363–365. 64. Cenac A, Gaultier Y, Devillechabrolle A, Moulias R. Enterovirus infection in peripartum cardiomyopathy. Lancet 1988; 2: 968–969. 65. O’Connell JB, Costanzo-Nordin MR, Subramanian R, et al. Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol 1986; 8: 52–56. 66. Midei MG, DeMent SH, Feldman AM, Hutchins GM, Baughman KL. Peripartum myocarditis and cardiomyopathy. Circulation 1990; 81: 922–928. 67. Owor R, Rwomushana RJ. Familial congestive cardiomyopathy in Uganda. East Afr Med J 1975; 52: 372–375.
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68. Brink AJ, Torrington M, van der Walt JJ. Hereditary dysrhythmic congestive cardiomyopathy. S Afr Med J 1976; 50: 2119–2123. 69. Przybojewski JZ, van der Walt JJ, van Eeden PJ, Tiedt FA. Familial dilated (congestive) cardiomyopathy. Occurrence in two brothers and an overview of the literature. S Afr Med J 1984; 66: 26–30. 70. Brink AJ, Torrington M. Progressive familial heart block – two types. S Afr Med J 1977; 52: 53–59. 71. Van der Merwe PL, Weymar HW, Torrington M, Brink AJ. Progressive familial heart block. Part II. Clinical and ECG confirmation of progression – report on 4 cases. S Afr Med J 1986; 70: 356–357. 72. Fernandez P, Moolman-Smook J, Brink P, Corfield V. A gene locus for progressive familial heart block type II (PFHBII) maps to chromosome 1q32.2-q32.3. Hum Genet 2005; 118: 133–137. 73. Mayosi BM, Khogali S, Zhang B, Watkins H. Cardiac and skeletal actin gene mutations are not a common cause of dilated cardiomyopathy. J Med Genet 1999; 36: 796–797. 74. Watkins DA, Mayosi BM. The contribution of South Africans to the subject of dilated cardiomyopathy with reference to cardiovascular collagenosis with parietal endocardial thrombosis: a clinicopathologic study of forty cases. Cardiovasc J Afr 2009; 20: 11–16. 75. Higginson J, Gillanders AD, Murray JF. The heart in chronic malnutrition. Br Heart J 1952; 14: 213–24. 76. Svoboda D, Grady H, Higginson J. The effects of chronic protein deficiency in rats. II. Biochemical and ultrastructural changes. Lab Invest 1966; 15: 731–749. 77. Swift PJ. Dietary iron overload as a cause of idiopathic cardiomyopathy in South African blacks: the role of free iron radicals. S Afr Med J 1996; 86: C17–C21. 78. Davies JNP. Endocardial fibrosis in Africans. East Afr Med J 1948; 25: 10. 79. William A. Heart disease in the native population of Uganda. East Afr Med J 1938; 15: 279. 80. Bukhman G, Ziegler J, Parry E. Endomyocardial fibrosis: still a mystery after 60 years. PLoS Negl Trop Dis 2008; 2: e97. 81. Olsen EG. The role of biopsy in the diagnosis of myocarditis. Herz 1985; 10: 21–26. 82. Freers J, Amandua J, Mugerwa R. Endomyocardial fibrosis and eosinophilia. Lancet 1993; 342: 1233. 83. Freers J, Masembe V, Schmauz R, Mayanja-Kizza H. Endomyocardial fibrosis syndrome in Uganda. Lancet 2000; 355: 1994–1995. 84. Freers J, Mayanja-Kizza H, Rutakingirwa M, Gerwing E. Endomyocardial fibrosis: why is there striking ascites with little or no peripheral oedema? Lancet 1996; 347: 197. 85. Mocumbi AO, Ferreira MB, Sidi D, Yacoub MH. A population study of endomyocardial fibrosis in a rural area of Mozambique. N Engl J Med 2008; 359: 43–49. 86. Abrahams DG, Barton CJ, Cockshott WP, Edington GM, Weaver EJ. Annular subvalvular left ventricular aneurysms. Q J Med 1962; 31: 345–360. 87. Edington GM, Williams AO. Left atrial aneurysms associated with annular subvalvular left ventricular aneurysms. J Pathol Bacteriol 1968; 96: 273–83. 88. Cockshott WP. Annular subvalvar left ventricular aneurysms. Cardiologia 1968; 52: 109–112.
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Telomeres and atherosclerosis SAJIDAH KHAN, ANIL A CHUTURGOON, DATSHANA P NAIDOO
Abstract In humans and other multicellular organisms that have an extended lifespan, the leading causes of death are atherosclerotic cardiovascular disease and cancer. Experimental and clinical evidence indicates that these age-related disorders are linked through dysregulation of telomere homeostasis. Telomeres are DNA protein structures located at the terminal end of chromosomes and shorten with each cycle of cell replication, thereby reflecting the biological age of an organism. Critically shortened telomeres provoke cellular senescence and apoptosis, impairing the function and viability of a cell. The endothelial cells within atherosclerotic plaques have been shown to display features of cellular senescence. Studies have consistently demonstrated an association between shortened telomere length and coronary artery disease (CAD). Several of the CAD risk factors and particularly type 2 diabetes are linked to telomere shortening and cellular senescence. Our interest in telomere biology was prompted by the high incidence of premature CAD and diabetes in a subset of our population, and the hypothesis that these conditions are premature-ageing syndromes. The assessment of telomere length may serve as a better predictor of cardiovascular risk and mortality than currently available risk markers, and anti-senescence therapy targeting the telomere complex is emerging as a new strategy in the treatment of atherosclerosis. We review the evidence linking telomere biology to atherosclerosis and discuss methods to preserve telomere length. Keywords: coronary artery disease, molecular and cellular cardiology Submitted 11/4/12, accepted 4/7/12 Cardiovasc J Afr 2012; 23: 563â&#x20AC;&#x201C;571
www.cvja.co.za
DOI: 10.5830/CVJA-2012-056
Atherosclerosis is an age-related disorder.1 Premature biological ageing, an entity separate from chronological ageing, may contribute to its pathogenesis. Cellular senescence, which is defined as the finite replicative lifespan of cells leading to irreversible growth arrest, plays a critical role in the pathogenesis of atherosclerosis.2-4 A central feature of atherosclerosis is vascular endothelial cell dysfunction. The histology of atherosclerotic plaques has been
Department of Cardiology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa SAJIDAH KHAN, MB ChB, FCP (SA), khans19@ukzn.ac.za; sajidahkha@ialch.co.za DATSHANA P NAIDOO, MD
Discipline of Medical Biochemistry, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa ANIL A CHUTURGOON, PhD
comprehensively studied and has demonstrated that endothelial and vascular smooth muscle cells in atherosclerotic lesions display changes of senescence.5,6 In stable atherosclerotic plaques there are few senescent cells, whereas in advanced, complicated plaques, senescent cells accumulate because of high cell turnover and increase the risk of acute coronary syndromes.7 The biological mechanism that triggers the onset of cellular senescence is thought to be telomere shortening. Telomeres are DNA protein structures located at the extreme ends of the chromosomes.They cap and protect the ends of chromosomes. Whereas the DNA molecule carries the genetic code and is about 100 million base pairs long, the telomeric ends are non-coding and are between 5 000 and 15 000 base pairs long: 15 000 at the time of human conception and around 5 000 at the time of death.8 During DNA replication, the very end sequences of the telomere are not fully copied due to the inability of DNA polymerase to completely replicate the chromosome to its very end. This is termed the end-replication problem. As a result, between 50 and 200 nucleotides are lost with each cycle of cell replication, leading to progressive telomere shortening.9 When telomere length reaches a critical threshold, the cell becomes incapable of further replication and enters a phase of cellular growth arrest termed replicative senescence. On average, cells reach senescence after 50 divisions. The senescent phase may then progress to cell death or apoptosis. Cellular senescence and the apoptotic cascade are mediated by cell cycle checkpoint pathways, regulated mainly by p53/p21, which are best recognised as tumour suppressor proteins.2 This process is responsible for physiological ageing and gives rise to the morphological and functional changes that accompany the decline in organ function seen with age, e.g. endothelial cell senescence in atherosclerotic plaques or beta-cell senescence in diabetes mellitus.4,10,11 However, a limited number of cells (about one in 10 million) are able to reactivate the enzyme telomerase. In the presence of telomerase, cells are able to replicate and in this way telomere integrity is maintained. Telomerase activity is lacking in somatic cells but is preserved in reproductive and stem cells. High telomerase activity has also been detected in about 90% of human cancer samples. The high telomerase activity is thought to be responsible for the indefinite cell proliferation and cellular immortalisation seen with cancer.12-15 Inducing cell senescence and apoptosis is therefore an important mechanism for the suppression of cancer. Studies have shown that telomere length is not only determined by cell replication and lifespan, but is also influenced by heredity and exposure to environmental risk factors. The healthy offspring of parents with coronary artery disease have shorter telomeres than the offspring of normal subjects.16,17 The traditional risk factors for atherosclerosis have been shown to lower the threshold for cardiovascular disease by hastening biological aging.18 Risk factors such as smoking,19,20 obesity,19 insulin resistance,21,22 and type 2 diabetes23-26 are associated with accelerated telomere shortening.
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Diabetic patients, more than any other subset, show the greatest difference in telomere length compared to non-diabetics.26 Type 2 diabetes is considered a cardiovascular risk equivalent.27,28 It is postulated that telomere shortening induces pancreatic β-cell senescence. Like atherosclerosis, diabetes is thought to be a premature-ageing syndrome.26 The study of telomeres may therefore provide in a single marker, the combined influence of genetics, environmental risk and ageing in predicting risk and identifying susceptible individuals prone to developing coronary artery disease. This is especially relevant in our community, which has a high incidence of both premature coronary artery disease and type 2 diabetes.29,30
Structure and function of the telomere complex Telomeres have a dynamic structure that is thought to switch between a closed, protected state and an open, extendable state, which allows the DNA terminus to undergo replication. The protected state is necessary for safeguarding the integrity of genomic material, whereas the extendable state allows the enzyme telomerase to extend short telomeres (Figs 1, 2).31 Telomere components include: • The DNA component: this consists of tandem repeats of the hexanucleotide 5′-TTAGGG-3′ (T = thymine, A = adenine, G = guanine) and has a high guanine content. The bulk of telomeric DNA is arranged in the double-stranded configuration, which then ends in a single-stranded extension. The single-stranded overhang folds back to form a terminal loop, which prevents the end of the telomere from being recognised as a damaged, broken end. Telomere shortening is thought to destabilise this loop.8,14,31 • Shelterin proteins: these proteins bind and protect the loop structure and are termed shelterin because they shelter the chromosome end.32 An inability to form the terminal loop will leave the chromosome ends uncapped, resembling a DNA break and provoking DNA repair mechanisms. The shelterin complex consists of six proteins, which have specific func-
telomere
nucleus
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tions in telomere replication and end protection. The six proteins are: TRF1 and TRF2: telomere repeatbinding factors 1 and 2, which are the two major proteins; POT1: protection of telomeres 1; TPP1: tripeptidyl peptidase 1; TIN2: TRF1-interacting protein 2; and RAP1: repressor activator protein 1. Whereas the shelterin proteins are a constant fixture at the telomere end, other accessory proteins are intermittently recruited to the telomere. These proteins include the tankyrases tank 1 and 2, Ku 70/86 and poly-ADP ribose polymerase-1 (PARP-1), which influence the control of telomere length and repress the DNA damage response.31,33,34 • The CST complex: an additional telomere-associated complex, known as the CST, has recently been identified. It binds single-stranded DNA and appears important for both telomere protection and replication.31 • Telomerase: in order for cellular repair to take place as well as for species survival, stem cells and reproductive cells need to be able to proliferate without the penalty of progressive telomere shortening.31 These cells, unlike somatic cells, contain the enzyme telomerase, which is capable of adding DNA sequences to the chromosome terminus to compensate for the loss sustained during replication. Telomerase is made of Terc – the RNA component that serves as a template for the synthesis of new telomeric DNA, and TERT – a reverse transcriptase which is the catalytic subunit representing the rate-limiting step in telomerase activity.12,14,33,35 A variety of accessory proteins have important roles in telomerase biogenesis and localisation.
Telomere homeostasis Telomere length in proliferating cells is influenced by the following factors. • Factors that shorten telomeres: –– telomere attrition during cell division –– DNA damage due to oxidative stress caused by environmental risk factors –– specific exonucleases involved in the degradation of RNA primers used for DNA replication –– deficiency of Rad 54, which is involved in DNA repair –– histones: methylation of histones H3 and H4 diminishes telomerase activity.36 TPP1POT1
chromosome
shelterin complex TRF1
doublestranded DNA
single-stranded DNA
Fig. 1. A simplified scheme depicting the structure of the telomere and its location on the chromosome in the cell. Reproduced with permission.126
TRF2
RAP1 TIN2
T-loop
telomere
Fig. 2. Scheme showing the terminal end of the telomere concealing the terminal single-stranded part with the help of the shelterin complex. Reproduced with permission.126
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• Factors that maintain telomere length: –– Telomerase: in addition to the level of telomerase within a cell, telomere length is also dependent on the delivery of telomerase to the telomere by Cajal bodies, telomerase access to the DNA terminus and the presence of molecules that stimulate or inhibit telomerase activity.31 –– A recombination process known as alternative lengthening of telomeres or ALT (10% of cancers maintain their telomere length by ALT).35,37 The two major mechanisms responsible for telomere shortening are the end-replication problem, and more importantly, the oxidative DNA damage induced by environmental risk factors. Telomere shortening due to the end-replication problem is relatively small and constant in each cell, irrespective of telomere length, whereas telomere shortening induced by oxidative stress is proportional to telomere length, as longer telomeres are larger targets for free radicals.38-40 Variability in telomere length is also noted at birth and is influenced by heredity, race and gender. Telomere length has been shown to be shorter in healthy offspring of patients with coronary artery disease (CAD).16,17 This finding offers some explanation for the increased familial risk of CAD and also implies that shorter telomeres are likely a primary abnormality in the pathogenesis of the disease.41 African-Americans have longer telomeres than whites and Indians,42-44 and females have longer telomeres than their male counterparts.45
Mechanisms of disease: a balance between injury and repair Mechanism of injury: oxidative stress Oxidative stress is the unifying pathophysiological mechanism responsible for ageing and age-related disorders.46-49 It is defined as an increase in the intra-cellular concentration of reactive oxygen species (ROS). ROS are generated during regular metabolism because of incomplete oxygen reduction in the mitochondrial electron transport chain – a one-electron reduction of oxygen forms superoxide (O2-), a two-electron reduction forms hydrogen peroxide (H2O2), and a three-electron reduction forms the hydroxyl radical (OH). Many other ROS species can be derived from superoxide and hydrogen peroxide. These ROS initiate processes involved in atherogenesis through several enzyme systems including xanthine oxidase, NADPH (nicotinamide adenine dinucleotide phosphate) oxidases and nitric oxide synthase.50 The ROS damage all components of the cell including proteins, lipids and DNA. The exact mechanism of damage is via: • Decreased availability of nitric oxide (NO), which results in defective endothelial vasodilation. Nitric oxide is an antiatherosclerotic agent that protects vascular cells from apoptosis.51-53 • Inflammation: ROS increase the production of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), which in turn can also increase the production of ROS. TNF-α activates two transcription factors: nuclear factor kappa-β (NF-κβ) and activator protein-1 (AP-1), which increase the expression of pro-inflammatory genes. Cytokines stimulate the synthesis of acute-phase reactants such as C-reactive protein (CRP) by the liver. ROS also increase the expression of cellular adhesion molecules on the endothelial cell surface.
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These molecules, intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM-1), enhance monocyte adhesion to endothelial cells and lead to the formation of atherosclerotic plaques.54-58 • Modification of lipoproteins and lipids: ROS contribute to the formation of lipid peroxides, which bind to proteins to form advanced lipoxidation end products (ALEs).59 Oxidised LDL and ALE-containing LDL are pro-atherogenic. In vitro studies have shown that LDL cholesterol (LDL-C) is not atherogenic in itself but it is the oxidative modification of LDL-C that plays a critical role in the pathogenesis of atherosclerosis.60,61 In the early phase of atherosclerosis, oxidised-LDL (ox-LDL) contributes to inflammation by enhancing expression of chemokines such as the monocyte chemo-attractant protein-1. Ox-LDL decreases the bioavailability of nitric oxide. The proatherogenic effects are exerted by influencing the phosphoinositol-3 (PI3) kinase/Akt signalling pathway.62 This pathway has an important regulatory role in cellular proliferation and survival. Of the three known isoforms of Akt, Akt 1 is most relevant in regulating cardiovascular cell growth and survival and Akt 2, which is highly expressed in muscle and adipocytes, contributes to regulation of glucose homeostasis. These isoforms are activated by growth factors, extra-cellular stimuli such as pro-atherogenic factors and by oncogenic mutations in upstream regulatory proteins. Akt mediates downstream signalling pathways through phosphorylation of a host of substrates. Thus far, more than a hundred substrates for Akt have been identified, indicating that it has widespread biological effects. Dysregulation of Akt is associated with cardiovascular disease, diabetes, cancer and neurological disorders. Our current understanding of its role in cardiovascular disease is incomplete and studies explaining its effects describe conflicting mechanisms. Breitschopf et al. have demonstrated that pro-atherogenic factors such as ox-LDL, TNF-α and hydrogen peroxide promoted endothelial cell senescence by inactivation of the PI3/Akt pathway. Akt was shown to maintain telomerase activity by phosphorylation of its TERT subunit, and inactivating Akt reduced telomerase activity, leading to accelerated endothelial cell senescence.63 On the other hand, Miyauchi et al. demonstrated that activation of Akt promotes senescence and arrests cell growth via the p53/p21-dependent pathway and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Akt achieved growth arrest by phosphorylating and inhibiting a forkhead transcription factor (FOXO 3a), which influences p53 activity by regulating levels of ROS.64 Rosso et al. confirmed the latter mechanism by demonstrating that endothelial progenitor cells cultured in the presence of ox-LDL in a diabetic milieu underwent senescence and growth arrest by activation of the Akt pathway via accumulation of p53/p21.65 Miyauchi et al. commented that the divergent observations may be explained by the different cell types used in studies. They used primary human endothelial cells, whereas most other studies examined immortal cells in which the normal cell cycle machinery may have been impaired. In addition, Akt may promote cell proliferation or senescence depending on other factors such as the duration and extent of its activation. It has been noted that activation of Akt in itself is insufficient to cause cancer unless combined with other oncogenic stimuli.
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There is currently much interest in the development of Akt inhibitors for the treatment of cancer and it remains to be seen what effects such therapy would have on the cardiovascular system. In addition to Akt signalling, mitogenic stimuli may activate Ras signalling, which has also been shown to participate in the divergent processes of both cell proliferation and senescence.66
Oxidative stress and telomere shortening Exposure of DNA to oxidative stress produces higher levels of stress biomarkers in telomere sequences than in non-telomere sequences. 8-oxodG (8-oxo-7,8-dihydro-2-deoxyguanosine) is a sensitive biomarker for oxidative stress on DNA. Progressive increases in 8-oxodG have been shown to correlate with decreasing telomere length. The high guanine (-GGG) content of telomeres makes them particularly sensitive to damage by oxidative stress.47,67 This site specificity for guanine is due to several reasons. Firstly, guanine is the most easily oxidised DNA base as its oxidation potential is lower than that of the other three bases (adenine < cytosine < thymine). A second factor is the distribution of electrons on the DNA base. The highest occupied molecular orbital that accommodates electrons with the greatest energy determines the reactivity of DNA bases. Many of these electrons are located on the 5′-G of the GG sequence and therefore this guanine is more likely to be oxidised. A third reason is that the ROS have different redox potentials, which may determine site specificity. For example, the free hydroxyl radicals cause DNA damage without a marked site specificity, whereas the benzoyloxyl radicals specifically cause damage to the 5′-G in GG sequence.68-70 In addition to the direct effects of ROS, telomeres, unlike the rest of the genome, appear less efficient in repairing oxidative damage.71 An important consequence of oxidative stress is the initiation of an inflammatory response.
Inflammation and telomere shortening Chronic systemic inflammation is responsible for an increase in peripheral white blood cell turnover, which in turn leads to an exaggerated telomere attrition rate.55 The increased white cell consumption induces haematopoietic stem cells to divide, thereby shortening their telomere length as well. Exposure to TNF-α also reduces telomere length by negative regulation of telomerase activity.57 DNA sampling for telomere length quantification is generally sourced from circulating white blood cells rather than human vascular tissue. It has been suggested that white blood cell telomere attrition is a consequence of systemic inflammation rather than being indicative of vascular endothelial cell ageing. The study by Wilson et al. demonstrated that telomere attrition in circulating blood leucocytes reflects similar changes in the vasculature and is an acceptable surrogate for vascular ageing in population studies.72
Mechanisms of repair: stem cells and endothelial progenitor cells The atherosclerotic process is characterised by endothelial cell dysfunction. Repair of the endothelium is dependent on
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the presence of endothelial progenitor cells, which migrate to sites of vascular injury to initiate repair. Endothelial progenitor cells are produced by haematopoietic stem cells, which, due to their higher telomerase activity, have a greater proliferative capacity. Exhaustion of the progenitor cell or stem cell pool is an important factor in endothelial cell dysfunction. Telomere length in haematopoietic stem cells (HSC) is a reflection of progenitor cell reserves, and shortened telomere length in these cells is indicative of diminished reparative capacity.41,42 The onset of atherosclerotic disease is therefore dependent on the balance between injury and repair of the endothelium – injury from oxidative stress and inflammation, and repair, which depends on haematopoietic stem cell reserves, as reflected by HSC telomere length.41
Telomeres and atherosclerosis risk factors Smoking Cigarette smoking is associated with increased oxidative stress.73 Although there is variability in the findings of different epidemiological studies, the following studies recorded an association between smoking and telomere shortening. Nawrot et al., reporting on the Flemish study on environment, genes and health outcomes, found shorter telomeres in smokers compared to non-smokers.45 The study by Valdes et al. showed that women who had never smoked had longer telomeres than former smokers, and both had longer telomeres than current smokers (531 never smokers, 369 ex-smokers and 203 current smokers). They also demonstrated a dose-dependent relationship between smoking and telomere shortening. Each pack-year smoked was equivalent to the loss of an additional five base pairs of telomere length, or 18% of the average annual loss in telomere length, compared to the rate in the overall cohort.19 The dose-effect relationship was subsequently replicated by Morla et al. who studied a cohort of male smokers with and without chronic obstructive pulmonary disease (50 smokers, 26 never smokers) in whom telomere shortening correlated with cumulative exposure to tobacco smoking.20
Hypertension Since systolic blood pressure rises with age, and diastolic blood pressure plateaus, Jeanclos et al. postulated that arterial pulse pressure may correlate with biological age. Among 49 twin pairs (mean age 37 years) in the Danish Twin Register, they showed a significant inverse correlation between pulse pressure and telomere length, i.e. wider pulse pressure was associated with shorter telomere length.74 The Framingham Heart Study found shorter telomere lengths in hypertensive males (n = 171) compared to their normotensive peers (n = 156) but the shorter telomere length was largely due to insulin resistance.21 Benetos et al. examined the relationship between telomere length and carotid artery atherosclerosis in 163 treated hypertensive males and found that telomere length was shorter in hypertensive men with carotid plaques compared to hypertensive men without plaques.75
Obesity Increased caloric intake and obesity are recognised to shorten lifespan. Adipose tissue is not only a source of ROS and
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pro-inflammatory cytokines but also secretes a host of bioactive molecules including angiotensinogen, leptin, resistin, adiponectin and PAI-1, which influence the function and structural integrity of the cardiovascular system.76,77 These adipocytokines influence glucose metabolism, blood pressure regulation, lipid metabolism, the coagulation system and endothelial function to accelerate the process of atherosclerosis. Obesity is strongly associated with cardiovascular disease and promotes the clustering of risk factors such as dyslipidaemia, hypertension, diabetes and the metabolic syndrome. Obese individuals experience substantially elevated morbidity and mortality from all forms of cardiovascular disease.78,79 A retrospective analysis of the Bogalusa Heart Study examined the relationship between weight change and telomere dynamics over a period of 10 to 12 years in 70 young adults. The study showed that weight gain was associated with accelerated telomere attrition and that a rise in insulin resistance accounted for the relationship between the increase in body mass index (BMI) and telomere attrition rate.22 In the study by Valdes et al. of 1 122 healthy adult female twins (45 monozygotic and 516 dizygotic pairs, mean age 47 years), it was found that the telomeres of obese twins were 240 base pairs shorter than those of the lean sibling. The difference in telomere length between the lean and the obese corresponded to 8.8 years of ageing.19 The study also suggested that the mechanism by which obesity affects telomere length is through increased leptin levels rather than BMI per se. Obesity is associated with high serum concentrations of leptin, which is linked to NF-κB activation, a mediating factor in the production of ROS and inflammatory cytokines.80 Nordfjall et al. confirmed the negative association between BMI and telomere length but in their study, this finding applied only to female participants.81
Insulin resistance Insulin resistance is pro-atherogenic and increases the risk of CAD even without the presence of hyperglycaemia.82 The mechanisms involved in atherogenesis include both systemic effects such as dyslipidaemia, hypertension and a pro-inflammatory state as well as direct effects on vascular endothelial cells, smooth muscle cells and macrophages. These three cell types have insulin receptors and effects are mediated via down-regulation of insulin signalling pathways such as the Akt pathway. In early atherosclerosis, insulin resistance causes decreased nitric oxide production and an increase in VCAM-1, which are responsible for impaired vasodilation and inflammation. In advanced plaques, insulin resistance triggers apoptosis of cells via the Akt pathway.83-86 Apoptosis of smooth muscle cells causes fibrous cap thinning, whereas apoptosis of macrophages leads to plaque necrosis, both being pathological processes that precipitate acute coronary syndromes.
Diabetes In the setting of type 2 diabetes, insulin resistance and hyperglycaemia have additive effects that accelerate the process of atherosclerosis. Hyperglycaemia is associated with the activation of several molecular pathways that include the production of advanced glycation end products (AGEs),87,88 activation of protein kinase C, increased activity of both the
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polyol as well as the hexosamine pathways.89,90 These pathways are interdependent and induce cellular damage through the final common mechanism of increased oxidative stress. It is well established that hyperglycaemia, even in the pre-diabetic state, induces oxidative stress91-94 and ultimately leads to cellular senescence. Cellular senescence and apoptosis occur not only in vascular endothelial and smooth muscle cells but in multiple cell lines, including endothelial progenitor cells.95,96 Type 2 diabetes can therefore be considered a premature-ageing syndrome. In recent years several cross-sectional clinical studies have been published that demonstrate an association between shorter telomere length and type 2 diabetes (T2D).23-26,97-99 The studies suggest that there is a gradation in the severity of telomere shortening. Shorter telomere lengths were noted in patients with impaired glucose tolerance compared to controls, even shorter lengths in those with diabetes, and the shortest lengths were observed in patients with the combination of pre-diabetes/ diabetes and atherosclerotic vascular disease, compared to those with diabetes or cardiovascular disease alone.100 Satoh et al. showed that CAD patients with the metabolic syndrome had shorter telomeres than CAD patients without the metabolic syndrome.97 Adaikalakoteswari et al. found that among diabetic patients, those with atherosclerotic plaques had shorter telomeres.98 The study by Olivieri et al. demonstrated that diabetic patients with myocardial infarction had shorter telomeres than diabetic subjects without myocardial infarction,99 and the study by Salpea et al. showed that among diabetic subjects, those with CAD had significantly shorter telomeres.26 Based on these observations, it has been postulated that critically shortened telomeres, due to a combination of inherited short telomeres and oxidative stress-induced telomere attrition, caused by the common risk factors between diabetes and cardiovascular disease, indicates greater cellular ageing in vascular endothelial cells and pancreatic beta-cells, and may be a useful biomarker of tissue ageing and disease progression.100
Atherosclerosis and coronary artery disease Minamino et al. have shown that endothelial cells with characteristic features of senescence are present in atherosclerotic regions of human coronary arteries. They demonstrated that inhibiting telomere function induced senescence in endothelial cells, whereas introducing telomerase suppressed senescence and extended the lifespan of these cells.3 Ogami et al. have shown that the telomeres of coronary endothelial cells were shorter in patients with CAD compared to age-matched subjects without CAD and that in the CAD patients, telomere length was shorter in endothelial cells at atherosclerotic sites compared to non-atherosclerotic sites.101 Chang and Harley have shown that endothelial cells in regions of the vascular tree that are subjected to greater haemodynamic stress demonstrated more pronounced telomere attrition than endothelial cells from areas with less shear stress. For example, telomere attrition rate in the iliac arteries was –147 base pairs per year compared to the internal mammary arteries at –87 base pairs per year.102 Okuda et al. also demonstrated that telomere attrition was higher in the intima of the distal abdominal aorta compared to the proximal abdominal aorta, again indicating that areas of the vasculature that undergo greater shear wall stress have
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higher cellular turnover rates and consequently shorter telomere length.103 This variable telomere attrition rate indicates the significant impact of environmental stress on telomere length. Population studies have demonstrated a link between telomere length and CAD.104,105 In the pioneering study by Samani et al. of 10 cases and 20 control subjects, it was observed that mean telomere length was significantly shorter in patients with severe triple-vessel CAD compared with matched subjects who had normal coronary angiograms.106 A retrospective registry analysis of 383 patients (203 cases, 180 controls) showed that patients with premature myocardial infarction had significantly shorter mean telomere lengths. In this study the difference in telomere length between cases and chronologically age-matched controls demonstrated a biological age gap in excess of 11 years. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold in subjects with shorter-than-average telomeres.107 In another study of 143 normal blood donors over the age of 60 years, it was shown that subjects with shorter telomeres had poorer survival, with a 3.18fold higher mortality rate from heart disease.108 In a sub-study of the West of Scotland Primary Prevention Study (WOSCOPS) that compared telomere lengths at recruitment in 484 individuals who went on to develop coronary heart disease events with those from 1 058 age-matched controls who remained free of CAD, it was shown that subjects with shorter telomere length at the time of recruitment had a significantly higher risk of developing subsequent coronary heart disease.109 In a case-control sub-study of the Cardiovascular Health Study that examined 419 older subjects, it was found that individuals 73 years or younger had a threefold increased risk of myocardial infarction and stroke for each one kilobase decrease in telomere length.110 Farzaneh-Far et al. measured telomere length in 780 patients with stable angina in a prospective cohort study. During a mean follow up of 4.4 years, shorter telomere length was significantly associated with all-cause mortality, independent of age, clinical and echocardiographic variables.111 Zee et al. using samples collected at baseline in the prospective Physicianâ&#x20AC;˛s Health Study from a cohort of 14 916 initially healthy men, of whom 337 went on to develop myocardial infarction, demonstrated that participants with shorter telomere length at baseline had a significantly increased risk of incident myocardial infarction compared to age- and smoking-matched controls who remained free of vascular disease over a mean follow up of 3.85 years.112 Finally, in the prospective population-based Bruneck study, baseline telomere length was a significant risk predictor for subsequent myocardial infarction and stroke, independent of standard risk factors. Of note in this study was that telomere length was strongly associated with advanced pathology and acute vascular syndromes but not early atherosclerosis.7
Mechanisms to preserve telomere length Telomerase has been shown to be activated by lifestyle choices that include a healthy diet, stress relief through meditation, chronic high-intensity aerobic physical exercise as well as by pharmacological agents.113,114 Exercise has been associated with improved cardiovascular health and longevity. La Rocca et al. in a recent study have
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shown that maintaining high levels of aerobic fitness preserved telomere length.115 They examined young and old individuals and compared sedentary subjects who exercised fewer than two days per week for less than 30 min per day with active ones who had exercised five days per week for more than 45 min per day for five years. Telomere length was preserved in the older adults who performed chronic, vigorous exercise and was positively correlated with maximum aerobic capacity as assessed by higher VO2max levels. The molecular mechanisms exploring the protective effects of exercise on the heart has been studied in experimental animals. Exercise has been shown to promote cell survival by increasing the activity of telomerase and the expression of TRF2. The up-regulation of telomerase was mediated via insulin-like growth factor 2 and endothelial nitric oxide synthase. Exercise was also shown to decrease levels of markers of cellular growth arrest and apoptosis, such as p16, cell cycle-checkpoint kinase 2 and p53. Molecules that enhance low residual telomerase activity or re-express silenced telomerase may help preserve telomere length. Natural products such as derivatives from the Chinese Astragalus plant, Ginko biloba and resveratrol have been shown to activate telomerase, the latter two via PI3k/Akt signalling pathways. The anti-oxidants N-acetylcysteine and Îą-tocopherol enhance telomerase activity.116,117 Farzaneh-Far et al. demonstrated in a prospective study of patients with stable CAD, an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over five years.118 Aspirin, ACE inhibitors and particularly statin therapy have been shown to positively impact on the vascular endothelium via anti-senescence effects. Over and above its anti-thrombotic and anti-inflammatory effects, aspirin has been shown to decrease the formation of dimethylarginine, an endogenous inhibitor of nitric oxide synthase, thereby reducing oxidative stress and delaying endothelial cell senescence.119 ACE inhibitors, particularly those containing the sulfhydryl group, have been shown to delay endothelial cell senescence by activating Akt phosphorylation, increasing the expression of nitric oxide synthase and up-regulating telomerase.120 Several studies have suggested that the survival benefit attributed to statin therapy may be linked to its effects on telomere biology. Spyridopoulos et al. have shown that statins enhance the migratory capacity of endothelial progenitor cells by up-regulation of TRF2, the telomere-binding protein that stabilises telomere structure at the t-loop.121 Satoh and co-workers demonstrated that intensive statin therapy over 12 months, through its anti-oxidant effects, prevents endothelial progenitor cell telomere erosion in patients with CAD.122 A recent publication by Saliques et al. who studied patients presenting with acute myocardial infarction, showed that prior statin therapy was independently associated with significantly longer telomere length in subjects below the age of 64 years.123
Conclusion Our interest in telomere biology stems from the high incidence of both premature CAD and type 2 diabetes mellitus witnessed in the population that we serve. Patients with CAD who have diabetes have worse outcomes than those without diabetes. This, coupled with the fact that the initial presentation in a
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substantial majority of our young patients is with myocardial infarction, which carries a worse prognosis than stable CAD, further contributes to adverse long-term outcomes. Indications are that revascularisation procedures are not as efficacious in this population. The availability of quantitative polymerase chain reaction, which is a simpler, less labour-intensive and cheaper method requiring smaller quantities of DNA compared to the standard method of southern blot analysis, has made it feasible for us to determine telomere length in our patients.124,125 The study of telomere dynamics may serve several functions. Firstly, measuring telomere length in the early years of life may indicate a genetic predisposition and help target susceptible individuals. Studies on the genetic contribution to premature CAD with genome-wide association scans have yielded little thus far, whereas an assessment of telomere length provides a more universal insight into the genetics of CAD. Secondly, telomere length is a measure of cumulative DNA damage from multiple environmental risk factors over an individual’s lifespan and is likely a better predictor of CAD than the currently available risk markers, which are single, point measurements in time. Thirdly, although the development and progression of atherosclerosis occurs over decades, the process is clinically silent until the manifestation of full-blown disease. The rate of telomere shortening is accelerated prior to the onset of clinical disease, so longitudinal assessments of telomere length may be of predictive value. Finally, novel therapies aimed at delaying cellular senescence by manipulation of the telomere/telomerase complex may be of benefit.
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Meeting Report 2nd South Africa–United Kingdom cardiovascular workshop Highlighting cardiovascular research in South Africa It has been predicted that by the year 2030, the prevalence of death from cardiovascular disease (CVD) will have increased significantly.1 The perception that CVD is not relevant to developing countries needs to be redressed. In fact, South Africa (SA) is undergoing a more rapid increase in the prevalence of CVD than the developed countries, mainly due to urbanisation and the threatening increase in incidence of obesity and diabetes.2 Therefore there is a need for cutting-edge research with the potential to produce better therapies for the treatment of CVD in Africa. To facilitate this cutting-edge research, it is imperative that we create a skills base capable of producing such research. The UK–SA workshops are events that we feel facilitate this process by establishing north–south collaboration, enticing promising young cardiovascular scientists to South Africa, and introducing our own students to a large network of scientists and opportunities for development. The second UK–SA cardiovascular research workshop was held in Cape Town, South Africa in August 2012. The workshop was hosted by the South African Society for Cardiovascular Research (SASCAR), a special-interest group of the South African Heart Association, at the Chris Barnard building, University of Cape Town (UCT). The main organisers of this event were Prof Sandrine Lecour, head of the cardioprotection group at the Hatter Institute for Cardiovascular Research in Africa, UCT, and Dr Derek Hausenloy, British Heart Foundation senior clinical research fellow at the Hatter Institute, University College London. The purpose of this joint UK–SA cardiovascular research workshop was to highlight the work of our young clinical and basic science researchers and to promote fruitful cardiovascular research collaborations between the UK and South Africa through the auspices of the European Society of Cardiology (ESC), the University of Cape Town and
the SASCAR. The main research themes of the workshop represented the major overlapping research interests in the UK and South Africa, and included novel cardioprotective therapeutic approaches, cardiomyopathies, cardiovascular risk factors, clinical cardiovascular research, signalling pathways in cardioprotection and myocardial ischaemia–reperfusion injury. There were also presentations on problems more relevant locally, such as rheumatic heart disease, myocarditis in HIV-associated cardiomyopathies, and the effects of antiretroviral therapy on cardiac contractile function. The workshop had over 65 delegates, including invited faculties from Europe, the USA and South Africa, five invited and sponsored cardiovascular research PhD students from academic institutions in Europe, and approximately 50 South African cardiovascular researchers and students. At the beginning of the week, the five invited European students had the opportunity to visit and spend time in research laboratories in South Africa. The workshop took place on a Thursday and Friday and each of the European and South African students had the opportunity to present their work. The SA–UK workshop targets clinical and basic science PhD students in their later years of study. This is a critical time when students are trying to decide what they will do after completing their PhD. Unfortunately some very good scientists leave cardiovascular research after obtaining a PhD because they do not see any opportunities available to them. The SA–UK workshop introduces them to a network of potential national and international postdoctoral supervisors. Some may suggest that introducing students to opportunities abroad may contribute to the so-called ‘brain drain’. However, it has recently been suggested that this brain drain can be turned into a ‘brain gain’. According to Meyer and Brown,3 ‘There are two ways to implement the brain gain: either through
the return of the expatriates to the country of origin (return option) or through their remote mobilisation and association to its development (diaspora option)’. Postdoctoral experience abroad may introduce students to new ideas and techniques not available in South Africa. When these young researchers return, they bring some of these new techniques and ideas with them. Likewise, foreign students coming to South Africa for a postdoctoral position often bring new skills and ideas to South African laboratories. Although the main aim of the workshop was to foster international collaboration, PhD students were also exposed to local opportunities. This was mainly through networking with local scientists at the workshop dinner. They also had the opportunity to listen to plenary talks by some of the most successful upcoming local researchers from the University of Cape Town (Prof Edward Sturrock, Dr Gasnat Shaboodien, Dr Liezl Zuhkl and Prof Sandrine Lecour), the University of Stellenbosch (Prof Faadiel Essop and Prof Hans Strijdom), and the University of KwaZulu-Natal (Prof Sajidah Khan). Based on their presentations, there was a prize for the best South African and European PhD students. Ms Kathleen Reyskens from the University of Stellenbosch won the South African prize for her work on the effects of antiretroviral treatment on the heart. Ms Uma Mukherjee from the Hatter Institute at University College London won the European prize for her work on a molecule called DJ-1. The student presentations were accompanied by plenary lectures from experts in cardiovascular research, and an ESC nucleus meeting of the working group in cellular biology of the heart, titled Frontiers in Cardioprotection, formed part of the programme. Finally, the meeting was concluded with a presentation by Prof Lionel Opie on how to become a successful researcher.
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One of the highlights of the second joint meeting was that it extended past the UK borders, with the participation of other European PhD students and cardiovascular researchers. The next UK– SA (or UK–EU) workshop will be held in France in two years’ time. The event was funded by UCT and the European Society for Cardiology, a European exchange programme (PROMISE), and industrial partners (SANOFI, Abcam).
ROISIN KELLY-LAUBSCHER, Roisin.kelly@uct.ac.za Department of Human Biology, University of Cape Town, South Africa
GIDEON BURGER Lasec, Cape Town, South Africa NEIL DAVIES Cardiovascular Research Unit, University of Cape Town, South Africa ANNA-MART ENGELBRECHT Department of Physiological Sciences, University of Stellenbosch, South Africa KAREN SLIWA SANDRINE LECOUR Hatter Institute for Cardiovascular Disease in Africa, University of Cape Town, South Africa HANS STRIJDOM Division Medical Physiology, University of Stellenbosch, South Africa
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DEREK HAUSENLOY Hatter Cardiovascular Institute, University College, London, United Kingdom
1.
2.
3.
Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K. The burden and costs of chronic diseases in low-income and middle-income countries. Lancet 2007; 370(9603): 1929–1938. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009; 374(9693): 934–947. Meyer JB, Brown M. Scientific diasporas: a new approach to the brain drain. Management of Social Transformations Discussion Paper 1999: 41.
Drug Trends in Cardiology South Africa enters a new era in stroke prevention Boehringer Ingelheim chose World Stroke Day on 29 October to launch its novel anticoagulant, Pradaxa (dabigatran) in South Africa. It promises to revolutionise stroke prevention in patients with atrial fibrillation (AF). Speaking at the launch, Dr Kevin Ho, medical director of Boehringer Ingelheim, said that AF affects one in four individuals over the age of 40 years and that the aging population worldwide will see the number of AF sufferers double in the next 30 years. AF increases the risk of stroke (mainly ischaemic) fivefold. Current therapies such as warfarin and aspirin have limitations to their use. Pradaxa promises to address unmet needs consequent thereon.
According to Dr IWP Obel, an electrophysiologist based at the Netcare Milpark Hospital, Johannesburg, the statistics are stark. ‘Without preventive treatment, one in 20 AF patients will suffer a stroke. The condition is responsible for nearly one-third of all strokes, and stroke is the leading complication of AF.’ Aspirin offers insufficient protection in high-risk patients and is associated with limited stroke-risk reduction. Warfarin’s narrow therapeutic window, many food– drug and drug–drug interactions and slow onset–offset of action hamper its use. It requires regular coagulation monitoring, a major issue for patients, and also carries a high risk of inducing bleeding. ‘This unpredictable response means
that it is both underused and wrongly used’, he continued. ‘Only half of eligible patients receive warfarin, and this is especially the case in elderly patients where AF is common. Most ischaemic strokes occur in patients who are inadequately anticoagulated.’ The goals of anticoagulation therapy are to prevent ischaemic stroke and minimise the risk of haemorrhagic stroke/ intracranial haemorrhage. ‘New agents such as Pradaxa, which has a predictable mode of action and does not require monitoring, can help us achieve these goals’, Dr Obel concluded. J Aalbers
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Simplifying venous thromboembolism management: a new and safer era
Honorary consultant vascular physician, Department of Vascular Surgery, King’s College Hospital, London
Dr Cohen is a vascular physician and epidemiologist involved in clinical work, designing, managing and analysing clinical trials from phase I to IV. He is the chairman and member of many international steering committees for multicentre trials, and epidemiological and pharmaco-economic studies. He has participated in cardiovascular clinical trials on anticoagulants, thrombolytic agents, and antiplatelet, antihypertensive and lipid-lowering drugs. He has undertaken numerous meta-analyses, economic analyses and large epidemiological studies. Dr Cohen has written or co-authored numerous articles and abstracts since 1990; many in the Lancet, New England Journal of Medicine, Annals of Internal Medicine, Archives of Internal Medicine and British Medical Journal. He is also a member of a number of international
special-interest societies and serves as an educational supervisor at the Royal College of Physicians. Dr Cohen is an advisor on the prevention of venous thromboembolism (VTE) to the UK Government Health select committee, the all-party working group on thrombosis, the Department of Health and the National Health Services. He is also an advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity, the Coalition to Prevent Venous Thromboembolism. His main interests continue to be in the screening and prevention of vascular disease. He specialises in the primary and secondary prevention of cardiovascular disease, prevention of stroke and coronary artery disease, and prophylaxis and treatment of venous thromboembolism.
During the course of October, Bayer hosted a lecture tour in major centres throughout South Africa on venous thromboembolism (VTE) management. Spanning the interests of a healthcare team approach to the management of VTE, lectures were presented by the eminent vascular physician Dr Cohen and our South African counterparts; haematologist Prof Peter Jacobs and specialist vascular surgeon Dr James Tunnicliffe. VTE is a ubiquitous condition seen across all specialities. It is the third most common cause of mortality, with 10% of all deaths associated with or caused by VTE. VTE is also the third most common cardiovascular disease, with more than one-third of cases representing recurrent VTE. Deep-vein thrombosis (DVT) and pulmonary embolism (PE) commonly occur in the community, as well as pre- and post-hospitalisation for acute medical illness or surgery. Patients undergoing major orthopaedic surgery are particularly at risk. In the absence of thromboprophylaxis, DVT develops in 40 to 60% of patients undergoing total knee or total hip replacement; and in 10 to 40% of medical and general surgery patients. In an interview with Dr Cohen, the context of VTE management in resource-
limited settings such as sub-Saharan Africa was discussed. ‘The chronic nature of VTE and its complications, such as post-thrombotic syndrome and pulmonary hypertension, place an enormous burden on the healthcare system’, he said. Data presented in his lecture indicated that post-thrombotic syndrome occurs in 20 to 50% of patients after symptomatic deep-vein thrombosis (DVT). Of pulmonary embolism (PE) patients, 4% will develop pulmonary hypertension, which is difficult to manage. Morbidity at eight years post-VTE is 45% for DVT and 55% for PE. ‘Diagnosis can be difficult and VTE is often missed as a cause of death’, Dr Cohen stated, placing a further morbidity burden on the healthcare system. ‘Diagnosis of DVT requires a comprehensive history and clinical examination.’ Half of DVT cases are asymptomatic, and for diagnosis, Dr Tunnicliffe and Dr Cohen were in agreement that compression ultrasound at two sites is not sufficient. Imaging is also difficult in the obese patient. It is therefore essential to perform a good evaluation. Dr Cohen advised that the primarycare physician request the radiologist to view intervening segments from the traditional two-point compression. ‘In the
UK, it is standard to look from groin into calf and also to look up into the abdomen if nothing presents in the lower limb’, he said. Furthermore, limitations of current therapies, which are inconvenient and cumbersome, may contribute to suboptimal treatment of VTE and subsequent complications including recurrences. Currently recommended treatments for VTE include unfractionated heparin (UFH), low-molecular weight heparin (LMWH), fondaparinux and vitamin K antagonists (VKAs), usually warfarin. UFH, LMWH and fondaparinux require parenteral administration, while the oral VKAs have a slow onset of action, require regular coagulation monitoring and have numerous drug and food interactions. ‘These limitations make the management of patients with VTE difficult and they negatively affect quality of life’, stated Dr Cohen in introducing the new anticoagulant agents that could overcome these considerations. ‘In many countries rivaroxaban is now used for VTE management. The use of one drug to manage blood clots without the need for therapeutic dose monitoring is ideal.’ This furnishes the advantages of improving adherence and reducing overall treatment costs by negating the need for dose
Alexander (Ander) T Cohen, MB BS, MSc, MD, FRACP
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monitoring. Trial data in support of rivaroxaban include the EINSTEIN DVT study, which indicated that symptomatic recurrent VTE for the rivaroxaban arm was non-inferior to standard therapy of enoxaparin plus VKA. The EINSTEIN PE trial, the only currently published study of a singleagent approach specifically for the treatment of symptomatic PE, revealed that rivaroxaban was non-inferior to enoxaparin plus VKA for the prevention of symptomatic recurrent VTE. In the EINSTEIN Extension study, rivaroxaban was significantly superior to placebo with regard to symptomatic recurrent VTE and was associated with a relative risk reduction of 82%. Major bleeding was infrequent and occurred in 0.7% of patients. Dr Cohen concluded by saying that the novel oral anticoagulants have been shown to be effective and have good safety in the treatment of VTE. Only oral rivaroxaban, given in a dose of 15 mg twice daily for three weeks for acute therapy, followed by 20 mg once daily, provides a simple single-drug approach
MARK YOUR CALENDAR
Dr Cohen
for short-term treatment and continued prevention of VTE. A single-agent approach also allows for the simplifying of complicated guidelines. An example is the American College of Chest Physicians (ACCP) 9th antithrombotic guidelines, consisting of 117 different recommendations. Dr Tunnicliffe presented a surgeon’s perspective on VTE interventions, initially emphasising that the surgeon does not see VTE early enough and that aggressive early intervention may prevent early PE death. He noted that while anticoagulants will prevent propagation of clot and prevent PE, the existing clot is still a concern. Spontaneous lysis is often incomplete, with residual obstruction resulting in vascular hypertension. ‘Anticoagulation alone is
probably insufficient in most cases of proximal DVT’, stated Dr Tunnicliffe, recommending clot removal when anticoagulation proves inadequate. He also noted that the long-term outcomes of anticoagulation in the young were not promising. A thrombectomy under general anaesthetic entails catheter extraction of the clot through a groin incision. Operative mortality is very low, although there is a risk of groin complications, rethrombosis and very rarely, PE. Cost is a consideration as the hospital stay may exceed 10 days. Prof Jacobs pondered on the practical realities of VTE. Of primary concern is the pre-emptive avoidance of the first clot. In terms of the initial event, it is essential to ascertain whether the clot was provoked or idiopathic in origin, in order to appropriately intervene. A good family history will often give clues to causation. Prof Jacobs emphasised the need for simple referral guidelines. He concluded that ‘most underestimate the impact of smoking on the vascular system.’ G Hardy
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
‘Only oral rivaroxaban, given in a dose of 15 mg twice daily for three weeks for acute therapy, followed by 20 mg once daily, provides a simple single-drug approach for short-term treatment and continued prevention of VTE.’
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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Benefits of dabigatran maintained for more than two years Prevention of stroke in patients with non-valvular atrial fibrillation was sustained over more than two years’ use of the novel oral anticoagulant drug, dabigatran, according to data from the first long-term study of these new agents. The results from the RE-LY-ABLE (Long-term Multi-centre Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) study1 were presented at the American Heart Association (AHA) scientific sessions 2012. RE-LY-ABLE is an extension of the previously published RE-LY study, following which, 5 851 patients continued to receive dabigatran 110 or 150 mg bid (Table 1).1 Presenting the results, Prof Stuart Connolly, director of Cardiology at McMaster University, Hamilton, Canada, said: ‘RE-LY-ABLE shows the results seen in RE-LY continue to be observed during long-term follow up. We see similar rates of stroke or systemic embolism and comparable rates of major bleeding, with similar rates of intracerebral bleeding and intracranial haemorrhage’ (Table 2). ‘Most patients with atrial fibrillation (AF) need life-long anticoagulation treatment to be protected from ischaemic stroke. The unique long-term data we now have for dabigatran are reassuring for both patients and physicians’, said Prof Connolly. He added that the combined data of RE-LY and RE-LY-ABLE provide more than four years of information on efficacy and safety. 2,3 RE-LY-ABLE showed that there was a consistent reduction in ischaemic and haemorrhagic stroke with both doses of dabigatran versus a blinded control group (Table 3). Additionally, the incidence of major bleeding was 3.74% per year in patients receiving dabigatran 150 mg bid
TABLE 1. THE RE-LY-ABLE STUDY Purpose RE-LY-ABLE (Long-term Multi-centre Extension of Dabigaran Treatment in Patients with Atrial Fibrillation study) included patients who completed the RE-LY trial and were recruited into a cluster-randomised trial to evaluate the long-term effects of continued treatment with dabigatran. Objective To establish the long-term safety of dabigatran and to assess its efficacy on the prognosis, cardiovascular risk profile and quality of care in patients with atrial fibrillation.
and 2.99% per year in those treated with 110 mg bid compared with controls. Rates of intracranial bleeding were 0.33 and 0.25% per year in the 150- and 110-mg groups, respectively. The rate of myocardial infarction was 0.69% per year in patients treated with 150 mg bid and 0.72% per year in the 110-mg bid group. ‘This is consistent with the results seen in RE-LY’, Prof Connolly said. Based on these data, Prof Connolly commented, ‘The consistent incidence of ischaemic and haemorrhagic stroke as well as rates of intracranial bleeding observed indicate that dabigatran provides on-going protection of the brain. Furthermore, both doses of dabigatran had similar net clinical benefit and mortality rates. In RE-LYABLE, the safety profile of dabigatran was consistent with the findings from the RE-LY trial.’ Commenting after the presentation, Prof Gregory Lip, professor of Cardiovascular Medicine at the University of Birmingham, UK said, ‘The results of RE-LY-ABLE will be a valuable contribution to evidencebased decision making in the selection of a treatment for patients with AF over the longer term. Despite the prevalence of AF and the five-fold increase in the risk of stroke, there remains significant scope for improvement in reducing the risk of stroke in the AF population. RE-LY-ABLE will serve to give added confidence to physicians in their prescribing decisions when managing this increasingly prevalent condition over the long term.’
Net benefit analysis Prof Connolly also presented a net benefit analysis at the AHA of all 12 091 dabigatrantreated patients in both RE-LY and RE-LYABLE. This showed that in patients treated over more than four years, the hazard ratio for stroke and systemic embolism was 0.81 (95% CI = 0.66–0.96), with rates of 1.25% per year if patients received dabigatran 150 mg bid and 1.50% per year in the 110-mg bid group. Prof Connolly commented: ‘There is now convincing data that there is no difference in total mortality between the two doses of dabigatran over a mean follow up of 4.3 years. Discussing this net clinical benefit, Prof John Eikelboom, Department of Medicine, McMaster University, Hamilton, Canada, said ‘Both high (150-mg bid) and low (110-mg bid) doses (of dabigatran) provide similar net benefit over warfarin. The higher dose achieved this clinical benefit through (superior) stroke prevention while the lower dose achieved it through a reduction in bleeding. So, the picture here is one of complete internal consistency. Clinicians can be confident that if they start a patient on dabigatran, it will remain a good decision three to four years later.’ J Aalbers 1.
2. 3.
Connolly SJ, et al. Presented 7 November 2012 at the American Heart Association Scientific Sessions 2012.11.15. Connolly SJ, et al. N Engl J Med 2009; 361: 1139–1151. Connolly SJ, et al. N Engl J Med 2010; 363: 1875–1876.
TABLE 2. PATIENTS IN RE-LY AND RE-LY-ABLE Treatment Randomised to RE-LY Completed RE-LY and still receiving dabigatran Patients enrolled into RE-LY-ABLE Completed RE-LY-ABLE and still receiving dabigatran Continued in RE-LY-ABLE beyond 28-month visit
Dabigatran 150 mg bid, n (%) 6015 4492 (75) 2914 (86) 2511 (86) 1082 (44)
Dabigatran 110 mg bid, n (%) 6076 3397 (75) 2937 (87) 2508 (85) 1104 (44)
TABLE 3. OUTCOMES WITH TWO DABIGATRAN DOSES COMPARED IN RE-LY-ABLE Event Stroke/systemic embolism Major bleed Intracranial bleed Death Stroke, systemic embolism, MI, pulmonary embolism, major bleed or death
Dabigatran Dabigatran 150 mg (%/year) 110 mg (%/year) 1.46 1.60 3.74 2.99 0.33 0.25 3.02 3.10 7.36 6.89
Hazard ratio (95% CI) 0.91 (0.69–1.20) 1.26 (1.04–1.53) 1.31 (0.68–2.51) 0.97 (0.80–1.19) 1.07 (0.94–1.22)
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Case report Infections secondary to pacemaker implantation: a synopsis of six cases AD KANE, MB NDIAYE, S PESSINABA, A MBAYE, M BODIAN, MED DRIOUCH, M JOBE, M DIAO, M SARR, A KANE, SA BA
Abstract Introduction: Permanent cardiac pacing is a technique whose indications have increased in the last 20 years. As with any foreign body, pacemaker implantation is associated with the risk of infection. The objective of this study was to describe the clinical, paraclinical and treatment options of infections secondary to pacemaker implantation at the Cardiology Department of the Aristide le Dantec Teaching Hospital (CHU Aristide le Dantec) in Dakar, Senegal. Methods: We conducted a retrospective study over a period of three years (from January 2005 to December 2007) during which pacemaker implantation was carried out in 107 patients. All patients with local and/or systemic signs of infection were included in our study. Results: The prevalence of infection in patients with pacemakers was 5.6% in our series and infection occurred in three women and three men, with a mean age of 66.2 years (range 23–83). The delay time for the onset of clinical signs of infection was 6.6 months, with a range of eight days to 12 months. The clinical signs were externalisation of the pacemaker with suppuration (five cases), fever (one case) and inflammatory signs (one case). Factors favouring the occurrence of infection were co-morbidity (four cases), pre-operative length of stay (average eight days), use of temporary cardiac pacing (three cases), the number of people in the theatre (average 4.5), postoperative haematoma (one case) and repeating the surgical procedure (three cases). Staphylococcus epidermidis (two cases), Staphylococcus aureus (two cases) and Klebsiella pneumoniae (one case) were the organisms isolated at the local site. Transthoracic echocardiography showed no objective signs of endocarditis. The treatment was antibiotic therapy for an average duration of 50.4 days after debridement of the infected site (six cases). We noted four recurrences at six months and one death from sepsis at 12 months. Cardiology Department, Aristide Le Dantec Teaching Hospital, Dakar, Senegal AD KANE, MD, damskane@hotmail.com MB NDIAYE, MD S PESSINABA, MD A MBAYE, MD M BODIAN, MD MED DRIOUCH, MD M JOBE, MB ChB M DIAO, MD M SARR, MD A KANE, MD SA BA, MD
Conclusion: Infections secondary to pacemaker implantation are rare but serious. Their management is difficult and requires the removal of the implanted material, hence the importance of prevention of infection, or the removal and re-implantation of the pacemaker at another site in cases of infection. This is particularly important in our region where pacemakers are very expensive. Keywords: pacemaker, infection, Dakar Submitted 16/3/11, accepted 2/5/12 Cardiovasc J Afr 2012; 23: e1–e4
www.cvja.co.za
DOI: 10.5830/CVJA-2012-035
Permanent cardiac pacing is a technique whose indications have increased in the last 20 years.1 It is increasingly common in Africa in general and in Senegal in particular. As with any foreign body, pacemaker implantation is associated with risk of infection of various degrees of severity, possibly leading to bacteraemia and endocarditis.2 These infections are associated with a significant morbidity and mortality. The objectives of this study were to describe the epidemiological and clinical aspects, predisposing factors, and the bacterial population associated with infection, as well as the management of infections secondary to pacemaker implantation at the Cardiology Department of the Aristide le Dantec Teaching Hospital, Dakar, Senegal.
Methods We conducted a retrospective study over a period of three years from January 2005 to December 2007. During this period permanent cardiac pacemakers were implanted in 107 patients at the Cardiology Department of Aristide le Dantec Teaching Hospital in Dakar. The inclusion criteria were: the externalisation of the pacemaker box or leads by scar dehiscence or skin necrosis; local inflammatory signs (redness, swelling, pain, localised heat) with or without externalisation of the pacemaker; local signs of infection (skin necrosis, abscesses, purulent discharge) with or without externalisation of the pacemaker; and local mechanical signs (isolated pain, protrusion of a part of the pacemaker box or lead). The parameters studied were age, gender, indication for cardiac pacing, predisposing factors (diabetes, cancer, long-term treatment with corticosteroids or anticoagulants, presence of postoperative haematoma, number of times the operation was repeated, implantation with more than two leads, fever occurring
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within 24 hours of implantation, use of a temporary pacemaker, early re-operation, pre-operative length of stay), clinical and laboratory signs, treatment and evolution. The data were entered and analysed using Epi Info version 3.5.1. We used Microsoft Excel 2007 for the quantitative data and to calculate averages.
Results Infection was noted in six patients, including three women and three men, with a mean age of 66.2 years and a range of 23 to 83 years. This represented 5.6% of patients implanted with pacemakers during the study period. The indication for implantation was complete atrio-ventricular block in all cases. Table 1 summarises the observations of the six patients. Factors associated with the occurrence of infection were diabetes and dermatosis, the average duration of pre-operative hospital stay which was eight days (range from 24 hours to 36 days), use of a temporary pacemaker (three patients), the number of people in the ward (between four and five, average 4.5), postoperative haematoma (one case), and repeating the procedure (change of pacemaker box: one case, repositioning of leads: one case, and re-placement of pacemaker box: one case). The delay time of onset of clinical signs of infection was 6.6 months, with a range of eight days to 12 months. The clinical signs were represented by the externalisation of the pacemaker pouch (Fig. 1) with skin necrosis, suppuration in five cases and signs of inflammation in one case. Haematologically, there was leukocytosis (one case), positive C-reactive protein (three cases), raised erythrocyte sedimentation rate (five cases) and anaemia due to inflammation (one case). There was no blood culture for any of the patients. Local culture
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samples were positive in five patients and negative in one patient. The bacteria found were Staphylococcus epidermidis (two cases), Staphylococcus aureus (two cases) and Klebsiella pneumoniae (one case). Transthoracic echocardiography showed no objective signs of endocarditis. Transoesophageal echocardiography was not performed. As for the treatment, all patients had received intravenous antibiotics prior to oral intake. The average duration of antibiotic therapy was 50.4 days. Surgical treatment was conservative: debridement and cleaning of the infection focus, repositioning of the same pouch (five cases) and evacuation of the pus with cleaning of the infection focus (one case). After six months there was a recurrence in four patients. They had local infection associated with externalisation of the pacemaker box. The treatment was again with antibiotics and conservative surgery. At 12 months, these four patients had another recurrence. Two patients had their pacemakers implanted onto the contralateral site, one patient had conservative surgery and one died of septicaemia.
Discussion Infectious complications after implantation of a pacemaker or defibrillator are numerous and often have serious consequences.3 Because of the steady increase in the number of long-lasting devices implanted each year, the incidence of these complications is expected to rise over the coming years.3 The overall rate of infection after pacemaker implantation was estimated in 2007 to be 1.6%.4 The incidence of localised infection in the pacemaker pouch was estimated at 1.33 per 1 000 in the USA.5 In an update published in 2008, the frequency of pacemaker infections ranged from less than 1% to more
TABLE 1. SUMMARY OF DATA OF SIX PATIENTS Number Age of leads Date and type of No (years) Gender in place last intervention 1 23 M 2 March 2005 first implantation
Onset of complication after last implantation Type of complication Pathogen 8 months Infection of pacemaker Staphylococcus pouch + externalisation epidermis of box
2
83
M
1
January 2006 replacement of box
5 months
3
76
M
1
February 2007 8 months first implantation
4
73
F
1
October 2007 8 days first implantation
5
74
F
1
6
68
F
2
December 2005 re-implantation of box March 2005 repositioning of lead
6 months
12 months
Treatment Antibiotics + repositioning of box
Infection of pacemaker Staphylococcus Antibiotics + pouch + externalisation epidermis repositioning of box of box
Infection of pacemaker Negative pouch + externalisation culture of box Infection of pouch Staphylococcus aureus
Antibiotics + repositioning of box Antibiotics + repositioning of box Infection of pacemaker Staphylococcus Antibiotics + pouch + externalisation aureus repositioning of box of box Infection of pacemaker Klebsiella Antibiotics + pouch + externalisation pneumoniae repositioning of box of box
Outcome Treatment failure with recurrence of infections Good evolution after removal of pacemaker and transferred to the contralateral site Treatment failure with re-infection Good evolution after removal of pacemaker and transferred to the contralateral site Good evolution at 6 months Good evolution at 6 months Treatment failure four times Treatment failure with recurrence of infection with Staphylococcus aureus Died of septic shock
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Fig. 1. Externalisation of the pacemaker pouch.
than 10% whatever the form.6 In our study, the incidence was 5.6%. This frequency distribution is due to the heterogeneity in definitions of pacemaker infection. The factors predisposing to the occurrence of infection after implantation of a pacemaker are diabetes, cancer, long-term treatment with corticosteroids or anticoagulants, the presence of postoperative haematoma, surgeon’s inexperience, and the number of times the operation is repeated.7,8 Other factors were also implicated, such as the implantation of more than two wires,9 fever occurring within 24 hours of implantation, using a temporary pacemaker, early re-operation,10 and the placement of the pacemaker box in the abdomen.11 In our study, the risk factors found were: diabetes, dermatosis, the long duration of pre-operative stay, the use of temporary pacing, the number of people concurrently in the ward (between four and five, average 4.5), postoperative haematoma and repeating the operative procedure. The mechanisms of infection were contamination of the surgical site at the time of implantation12 or haematogenous spread from a remote focus, identified or not.13 The average time of onset of symptoms varied, according to the authors, between six and 34.5 months.14,15 We found the average time of onset to be 6.6 months in our study. The clinical signs of infection of pacemaker varied according to the location of the infected portion, from only localised signs of a sagging in the pocket in about 70% of cases, local and general signs in 20% of cases, to general symptoms in 10% of cases.16 The clinical presentation of infective endocarditis with a pacemaker is right heart endocarditis with fever and pulmonary symptoms secondary to septic emboli. None of our patients showed signs of endocarditis but all had local signs of infection. The microbiological diagnosis relies on sample collection from a potentially infected site, repeated blood cultures, and samples of different pre-operative implanted parts. In all patients, a sample from the site of the pacemaker pouch was collected. Staphylococcus, mostly coagulase negative, was involved in 50 to 90% of cases.3 We found Staphylococcus in 80% of cases, namely Staphylococcus aureus (40%) and Staphylococcus epidermidis (40%). Moreover, mixed infections are not uncommon. There can be associations of a staphylococcus with other bacteria or fungi, or a combination of two different strains
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of staphylococci.17 The strong presence of skin bacteria is an additional argument in favour of contamination during handling of the pacemaker. Echocardiography is the key to the morphological diagnosis of endocarditis on pacemaker leads by visualising the vegetations. Different morphologies of vegetations have been described: floating ribbons, large rounded lesions, more or less pedunculated, multilobed vegetations, and a sleeve around the lead.3 The sensitivity of transoesophageal echocardiography in detecting vegetations is above 90% while that of transthoracic echocardiography is above 30%.13 In our study, no patient received transoesophageal echocardiography. This would explain the fact that we did not see any vegetations. The management of pacemaker infection is difficult and has been the subject of several studies. In infective endocarditis secondary to pacemaker leads, all authors agree that removing the implanted material is necessary for treatment.18 On the other hand, in local infections, opinions on how to treat are divided. Some advocate conservative treatment19 while others suggest radical treatment.17 However, current recommendations call for a complete removal of implanted material in all types of infection, whatever the clinical presentation.19 In our study, we used conservative treatment and we had four out of six recurrences. Mortality was one in six (16.7%) patients. This highlights the importance of complete removal and re-implantation of a new device or a sterilised, used pacemaker, especially in our circumstances.
Conclusion Infections secondary to pacemaker implantation are rare but serious. The risk factors found were diabetes, dermatoses, longer duration of in-hospital pre-operative stay, use of a temporary pacemaker, the number of patients in the ward, postoperative haematoma and re-operation. The management of infection is difficult and can lead to removal of the implanted device. Hence the importance of prevention, especially in our country where pacemakers are still very expensive.
References 1.
2.
3. 4. 5.
6. 7.
8. 9.
Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation 2007; 116: 1349–1355. Selton-Suty C, Doco-Lecompte T, Freysz L, et al. L’endocardite sur matériel de stimulation intracardiaque. Ann Cardiol Angeiol 2008; 57: 81–87. Camus C, Donal E, Bodi S, et al. Infections liées aux pacemakers et défibrillateurs implantables. Med Mal Infect 2010; 40: 429–439. Catanchin A, Murdock CJ, Athan E. Pacemaker infections: a 10-year experience. Heart Lung Circ 2007; 16: 434–439. Uslan DZ, Sohail MR, St Sauver JL, et al. Permanent pacemaker and implantable cardioverter defibrillator infection: a population-based study. Arch Intern Med 2007; 167: 669–675. Kearney RA, Eisen HJ, Wolf JE. Nonvalvular infections of the cardiovascular system. Ann Intern Med 1994; 121: 219–230. Villamil Cajoto I, Rodriguez Framil M, van den Eynde Collado A, et al. Permanent transvenous pacemaker infections: an analysis of 59 cases. Eur J Intern Med 2007; 18: 484–488. Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis 2007; 45: 166–173. Marschall J, Hopkins-Broyles D, Jones M, et al. Case-control study of surgical site infections associated with pacemakers and implantable cardioverter-defibrillators. Infect Control Hosp Epidemiol 2007; 28:
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1299–1304. 10. Klug D, Vaksmann G, Jarwé M, et al. Pacemaker lead infection in young patients. Pacing Clin Electrophysiol 2003; 26: 1489–1493. 11. Dumont E, Camus C, Victor F, et al. Suspected pacemaker or defibrillator transvenous lead infection. Prospective assessment of o TEE-guided therapeutic strategy. Eur Heart J 2003; 24: 1779–1787. 12. Leprince P, Nataf P, Cacoub P, et al. Septicémies et endocardites sur sondes endocavitaires et stimulateur cardiaque : indications chirurgicales et résultats. Arch Mal Coeur 1995; 88: 241–246. 13. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverter defibrillator infections. J Am Coll Cardiol 2007; 49: 1851–1859. 14. Martinez JG. Pacemaker pocket infection. Pace 1999; 22: 691–692. 15. Lewis AB, Heyes DL, Holmes DR, et al. Update on infections involving permanent pacemakers: characterization and management. J Thorac
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Cardiovascular Surg 1985; 89: 758–763. 16. Vogt PR, Sagdic K, Lachat M, et al. Surgical management of infected permanent transvenous pacemaker systems : ten years experience. J Cardiac Surg 1996; 11(3): 180–186. 17. Yamada M, Takeuchis S, Shiojiri Y, et al. Surgical lead-preserving procedures for pacemaker pocket infection. Ann Thorac Surg 2002; 74: 1494–1799. 18. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverter defibrillator infections. J Am Coll Cardiol 2007; 49: 1851–1859. 19. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society. Eur Heart J 2009; 30(19): 2369–413.
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Case Report MRI finding of a papillary muscle cyst: a differential diagnosis THANDAZA SHAYINGCA, SAVVAS ANDRONIKOU, RENE TRUTER, EMILE REID
Abstract Cystic lesions of the papillary muscle in the form of myxoma, hydatid cyst, papillary fibroelastoma, blood-filled cysts and endodermal heterotopia are rare causes of embolic stroke. In view of the potential complications caused by these lesions, surgery is often advocated but there is no consensus on which patients qualify. We examined a differential diagnosis of a papillary muscle cystic lesion in a patient presenting with features of embolic disease and identified the imaging features on MRI that directed management. Keywords: papillary muscle, myxoma, hydatid, fibroelastoma Submitted 7/12/11, accepted 3/9/12 Cardiovasc J Afr 2012; 23: e5–e6
www.cvja.co.za
DOI: 10.5830/CVJA-2012-062
The papillary muscles are a specialised form of the trabeculae carnae. They connect to the chordae tendinae, which attach to the tricuspid valve in the right ventricle and the mitral valve in the left ventricle, and act to prevent regurgitation by bracing the atrio-ventricular valves against prolapse. Cystic lesions of the papillary muscle in the form of myxoma, hydatid cyst, papillary fibroelastoma, blood-filled cysts and endodermal heterotopia are rare causes of embolic stroke.1 In view of the potential complications caused by these lesions, surgery is often advocated but there is no consensus on which patients qualify. We examined a differential diagnosis of a papillary muscle cystic lesion in a patient presenting with features of embolic disease, and identified the imaging features on MRI that directed management.
Case report A 50-year-old female investigated for recurrent transient ischaemic attacks (TIA) underwent cardiac MRI following an
echocardiogram, which suggested a possible aneurysm of the free wall of the left atrium. MRI (T1, STIR, T2 ciné gradient protocols and post-contrast viability studies at different levels) showed normal anatomical and ventriculo-atrial connections, and normal concordance. MRI further demonstrated an abnormal hyper-intense (STIR and T2 gradient echo) lesion in relation to the posterior ventricular papillary muscle. The lesion was cystic with subtle post-contrast enhancement. No involvement of the surrounding ventricular wall or motion abnormality was demonstrated. A differential diagnosis of myxoma, fibroelastoma, and even a papillary muscle pseudoaneurysm was considered. The patient was subsequently referred for a transoesophageal echocardiographic (TEE) assessment, which confirmed a 15 × 12-mm central lucent mass at the posterior-medial papillary muscle, and mild central mitral valve regurgitation. The subtle gadolinium enhancement made a neoplasm less likely, prompting the adoption of a conservative approach to therapy, using anticoagulation and a planned follow-up MRI after six months.
Discussion The significance of the papillary muscle in cardiac function was appreciated more than a century ago. Diseases of the papillary muscle are mostly subtle, therefore causing a delay in presentation, and they are mostly discovered at post mortem. In this case report we present a differential diagnosis of a cystic lesion in a patient who presented with TIA. Myxomas are the most common primary tumours of the heart and arise from the endocardium.2 They tend to present as cavitary gelatinous masses that arise adjacent to the fossa ovalis in the left atrium and are typically pedunculated but can also arise in a a
b
Department of Radiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa THANDAZA SHAYINGCA, MD, thandaza@gmail.com SAVVAS ANDRONIKOU, MD
Schnetler Corbett and Partners, Private radiology practice, Cape Town, South Africa RENE TRUTER, MD
Private practice, Cape Town, South Africa EMILE REID, MD
Fig. 1. Axial MRI demonstrating an abnormal hyperintense (a) T2 gradient echo, and enhancing (b) corresponding post-gadolinium lesion in relation to the posterior ventricular papillary muscle (arrows).
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a
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b
Fig. 2. Coronal MRI demonstrating an abnormal hyperintense (a) T2 gradient echo, and enhancing (b) corresponding post-gadolinium lesion in relation to the posterior ventricular papillary muscle.
Fig. 3. Sagital MRI demonstrating an abnormal hyperintense (a) T2 gradient echo, and enhancing (b) corresponding post-gadolinium lesion in relation to the posterior ventricular papillary muscle.
sessile manner. The majority of patients are usually in the 30- to 60-year age group, with a female predominance.3 The clinical spectrum can be wide, with most affected individuals presenting with one or more of a triad of symptoms, including embolic phenomena (as in our patient), intracardiac flow obstruction (congestive heart failure) and constitutional symptoms.4 Myxomas generally have a variable appearance on MRI. They are hypo-intense relative to the myocardium and appear heterogenous on T1- and T2-weighted images due to areas of necrosis, haemorrhage or calcification. Gadoliniumenhanced MRI generally demonstrates mass perfusion.5 The subtle enhancement of the cyst in our patient did not support the diagnosis of myxoma. Hydatid disease is a parasitic infestation by Echonicoccus granulosus, which forms cysts. Cardiac involvement is rare, seen in approximately 0.5–2% of all cases of hydatid disease in humans.6 An extremely rare localisation of the cyst is in a papillary muscle, which may sometimes require excision of the valve.7 The increase in volume and compression of the adjoining heart structures is responsible for the appearance of symptoms such as chest pain, palpitation, dizziness, lethargy, dyspnoea and syncope. The clinical presentation of cardiac hydatidosis may be non-specific, mimicking valvular lesions, intracardiac mass, or even heart failure. Although an unusual location for a hydatid cyst, this diagnosis is possible for the population in our geographic location. Papillary fibroelastoma is the third most common primary tumour of the heart,2 and is most likely to involve the cardiac valves. A papillary fibroelastoma is generally considered benign but can be associated with heart attack, stroke and sudden cardiac death.8 Symptoms due to papillary fibroelastomas are generally the result of mechanical effects or due to embolisation of a part of the tumour. Blood-filled cysts are congenital and located on the endocardium, particularly along the lines of closure of the heart valves. These thin-walled cysts contain non-organised blood or sero-sanguinous fluid.9 Intra-cardiac blood-filled cysts are typically asymptomatic. These cysts have been described on the mitral valve, papillary muscles and aortic valve. Cardiac MRI also could be valuable to differentiate a blood-filled cyst from other masses. On pre-contrast examinations, blood-filled cysts are iso-intense compared to myocardium on T1-weighted images, and hyper-intense on T2-weighted images. The cyst in our patient did not show signs characteristic of blood.
There is no consensus regarding the optimal management of these cystic papillary mass lesions. In view of the possible complications, surgical removal should be given serious consideraton. There are however no randomised data available to advocate surgical intervention,10 even though some studies show that patients who have undergone surgical treatment have remained free of cerebral events.11 Our patient was started on anticoagulation therapy and followed up with an MRI after six months, with the assumption that the lesion was not a neoplasm, based on the imaging findings.
Conclusion Cystic papillary muscle lesions are rare but important causes of embolic strokes. MRI plays a significant role in charecterising cardiac lesions in order to exclude neoplasms and to plan management, thereby avoiding unnecessary surgery.
References 1.
Shing M, Rubenson DS. Embolic stroke and cardiac papillary fibroelastoma. Clin Cardiol 2001; 24: 346–347. 2. Ragland MM, Tak T. The role of echocardiography in diagnosing space occupying lesions of the heart. Clin Med Res 2006; 4: 22–32. 3. Fisher J. Cardiac myxoma. Cardiovasc Rev Rep 1983; 4: 1195–1199. 4. Basso C, Valente M, Poletti A, Casarotto D, Thiene G. Surgical pathology of primary cardiac and pericardial tumors. Eur J Cardiothorac Surg 1997; 12: 730–737. 5. Murphy MD, McRae GA, Fanburg-Smith JC, Levine AM, Aboulafia AJ. Imaging of soft tissue myxoma with emphasis on CT and MR and comparison of radiologic and pathologic findings. Radiology 2002; 225: 215–224. 6. Dighiero J, Cabanal EJ, Aguirre CV, Horjales JO. Echinococcus disease of the heart. Circulation 1958; 17(1): 127–132. 7. Sensoz Y, Ozkokeli M, Ates M, Akcar M. Right ventricle hydatid cyst requiring tricuspid valve excision. Int J Cardiol 2005; 101(2): 339–341. 8. Takahiro K, Kazunori t, Ryoichi O, Hatsue I, Osamu T, Kazumo M. Cardiac papillary fibroelastoma as a cause of embolic stroke: ultrasound and histopathological charecteristics. Inter Med 2009; 48: 77–80. 9. Arnold IR, Hubner PJB, Firmin RK. Blood filled cyst of the papillary muscle of the mitral valve producing severe left ventricular outflow tract obstruction. Br Heart J 1990; 63: 132–133. 10. Alessi A, Carvalho RG, Praoma DB. Fibroelasoma of the mitral valve as a cause transient ischaemic stroke. Arg Bras Cardiol 2001; 77: 81–84. 11. Gowda RM, Khan LA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases. Am Heart J 2003; 146: 404–410.
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Case Report Successful management of spontaneous aortic dissection type B in the third trimester of pregnancy YAVUZ SİMSEK, CENGİZ COLAK, ERCAN YİLMAZ, EBRU CELİK, NEVZAT ERDİL, ONDER CELİK
Abstract
Case report
Acute aortic dissection is a life-threatining disease that requires immediate surgical intervention. Although aortic dissection is a rare condition during pregnancy, it is of high risk for both mother and foetus. Most cases of aortic dissection during pregnancy have certain risk factors, including Marfan syndrome and congenital heart diseases. In this study, we report on a case of acute aortic dissection developing spontaneously at 32 weeks of gestation. The patient delivered a baby through cesarean section, and medical management of the dissection was commenced. Both mother and neonate survived and recovered well.
A 36-year-old gravidy 4, parity 3 patient at 32 weeks of gestation was referred to our emergency clinic with the symptom of excrutiating back pain, which had migrated to the left scapular area, and had begun two hours earlier. This was accompanied by nausea and minimal dyspnoea. No other symptoms were noted at the time. The patient had not been taking any medications aside from multivitamin pills. She was a non-smoker and had no prior surgeries. The patient’s vital signs were as follows: blood pressure 190/110 mmHg, pulse rate 90 beats/min with normal heart sounds, axillary temperature was 37°C, and respiration rate 18 breaths/min. The lung sounds were clear during auscultation. The results of other physical and neurological examinations were unremarkable. Peripheral pulse examination was normal in general, except for the diagnosis of a weak pulse at the left femoral artery, and loss of pulse at the more distal part of the left lower extremity. Nevertheless, no evidence of ischaemia was noted in the affected extremity. A bimanual pelvic examination was unremarkable, with a closed and unraped cervix. Obstetric ultrasonography showed a single live foetus at 32 weeks of gestation with normal amniotic fluid and placenta. The transvaginal sonography revealed normal pelvic anatomy and minimal free fluid in the Douglas pouch. Laboratory investigations showed the following concentrations: alanine aminotransferase (ALT) 26 IU/l, aspartate aminotransferase (AST) 28 IU/l, lactate dehydrogenase (LDH) 220 U/l, total bilirubin 0.2 mg/dl, γ-glutamyl transferase (GGT) 10 IU/l, and alkaline phosphatase (ALP) 84 IU/l. The prothrombin time (PT) was 11.5 s, with an international normalised ratio (INR) of 0.8. The patient had normal serum cardiac enzyme, glucose and lipase levels. Routine urine examination was normal. Chest radiography showed no significant cardiac or thoracic findings. Echocardiography revealed normal left ventricular functions, with normal anatomy of the valves. Neither pericardial effusion nor any sign of aortic dissection was seen. A presumptive diagnosis of aortic dissection was made and the patient was informed. An emergency thoraco-abdominal computed tomography (CT) scan was performed and an aortic dissection beginning from the arc and extending to the infrarenal segment of the descending aorta was diagnosed (type B) (Fig. 1). The left common carotid artery and left subclavian artery were anatomically normal. Subsequently, sonography and Doppler scan of her lower extremities were performed on the suspicion of peripheral
Keywords: aortic diseases, pregnancy, hypertension, therapy Submitted 28/3/12, accepted 3/9/12 Cardiovasc J Afr 2012; 23: e7–e9
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DOI: 10.5830/CVJA-2012-063
Acute aortic dissections (AAD) affect predominantly male patients, with a male-to-female ratio of 3:1.1 In general, pregnancy is considered a risk factor and nearly half of the cases of dissection in young women occur during pregnancy, most commonly in the third trimester.2 The occurence of AAD during pregnancy can be life threatening for both mother and foetus. Most reported cases are associated with recognisable risk factors, including connective tissue disease (e.g. Marfan’s syndrome), systemic hypertension and congenital heart diseases (e.g. coarctation of the aorta and bicuspid aortic valve).3 The Stanford classification divides dissections into two types, type A and B. Most reported cases of aortic dissection during pregnancy are type A.4 We report here on the diagnosis and management of a case of AAD type B in the third trimester of pregnancy in a parous woman without any identifiable risk factors. We discuss the topic below, with a relevant literature review. Department of Obstetrics and Gynaecology, Inonu University Faculty of Medicine, Malatya, Turkey YAVUZ SİMSEK, MD, dryavuzsimsek@gmail.com ERCAN YİLMAZ, MD EBRU CELİK, MD ONDER CELİK, MD
Department of Cardiovascular Surgery, Inonu University Faculty of Medicine, Malatya, Turkey CENGİZ COLAK, MD NEVZAT ERDİL, MD
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Fig. 1. Contrast-enhanced CT scan obtained after admission revealed the normal appearance of the ascending aorta (A). The arrows indicate a large dissection line in the descending aorta distal to the left subclavian artery (type B).
vascular obstruction. The results showed patent bilateral femoral and popliteal arteries with normal compressibility. The patient was transferred to the intensive care unit of cardiovascular surgery. During her follow up, the increased blood pressure was unresponsive to high-dose combined parenteral antihypertensive therapy (10 µg/kg/min nitroprusside plus 10 µg/kg/min esmolol). The patient’s pain had not subsided and had even increased after her admission. The patient and her family were informed about the condition and the risk of aortic rupture. A written informed consent was obtained and a cesarean section was performed 12 hours after her admission, in order to protect both mother and foetus from the catastrophic consequences of aortic rupture and to control the patient’s pain and severely increased blood pressure. A male foetus weighing 1.45 kg was delivered. On postoperative follow up, the blood pressure had lowered and the pain had subsided. On postoperative day 3, repeated thoraco-abdominal CT scans showed stability of the pre-existing dissection line. The pulselessness in the patient’s left leg had also recovered after the delivery. Conservative management of the patient was therefore decided on. A blood test for karyotyping was made in order to exclude the diagnosis of Turner syndrome and a 46 XX normal karyotype was obtained. The patient has maintained good general condition and cardiovascular function four months postoperatively and to date.
Discussion It is well known that during the third trimester, there are maximal increases in stroke volume, heart rate and cardiac output, and in left ventricular wall mass and end-diastolic dimensions. In addition, oestrogen reportedly inhibits collagen and elastin deposition in the aorta, while progestogen accelerates deposition of non-collagen proteins in the aorta.5 These hormonal effects lead to a fragmentation of the reticulin fibers, diminished concentration of acid mucopolysaccharides, and loss of the normal corrugation of the elastic fibers.6 These haemodynamic changes occur in every pregnancy and it is hypothesised that aortic dissection may have some aetiological factors, such as an inborn defect in the arterial wall.1,2 Most of the reported cases had some predisposing risk factors, including Marfan syndrome, Turner syndrome and
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congenital heart diseases. In the present case, however, none of the above risk factors were present and acute dissection of the aorta developed spontaneously. Although the clinical presentations of AAD are well defined, the diagnosis is often overlooked. A study evaluating the clinico-pathological features of patients with aortic dissection over a 27-year period shows that misdiagnosis occurred in 85% of patients presenting with acute dissection.6 This interesting finding has been confirmed by a number of case reports in which the diagnosis was initially missed during pregnancy and the peripartum period.2,7,8 Although suggested by the clinical findings, a reliable diagnosis of aortic dissection must be confirmed by specific imaging methods, including echocardiography, contrastenhanced CT, aortography and magnetic resonance imaging. Transthoracic echocardiography was suggested for the initial screening of patients with suspected aortic dissection.6 Although the sensitivity and specificity can be up to 75 and 90%, respectively, in type A dissections, the diagnostic value of this procedure is of limited value in the case of type B dissections. Our presenting patient’s symptoms and examination findings were suggestive of aortic dissection. A rapid diagnosis was made within 12 hours after her admission by thoraco-abdomianl CT scan. Aortic dissections are divided into two types according to the Stanford classification system: type A always involves the ascending aorta, while type B begins in the descending aorta distal to the left subclavian artery.4 In the International Registry of Acute Aortic Dissection (IRAD), 62% of dissections are type A and 38% are type B.9 Patients with type B dissections tend to be older, heavy smokers with chronic lung diseases, and more often have generalised atherosclerosis and hypertension, compared with patients who have proximal aortic dissections. The diagnosis of acute type B dissection in pregnancy is rare.10 A high incidence of foetal intra-uterine demise or subsequent neonatal fatality has been linked to type B dissections.9 In the presenting case, however, early delivery of the foetus and medical management of the mother were adequte to save both mother and baby’s life. The treatment of type B dissections is medical, with close follow up of high blood pressure. Surgical treatment should be reserved for patients who have persistent pain, uncontrolled hypertension, occlusion of a major arterial trunk, frank aortic leaking or rupture, or development of a localised aneurysm.6,9 Similarly, in the present case, a primary caesarean section followed by conservative management of the dissection was the treatment of choice. Nevertheless, patients with uncomplicated distal dissections treated for blood pressure control have an in-hospital mortality of 10%.6,10 The priority indication for termination of pregnancy in this case was aimed at sparing the lives of both the mother and foetus, since the elimination of the negative impact of pregnancy-related haemodynamic changes on the AAD enhanced the chance of maternal and foetal survival. Our approach to the present case was consistent with data described in the literature, in which the best survival rates (mother and foetus) are based on gestational age.7-10 Therefore, if the dissection presents after 32 weeks, when the foetus has viability, pregnancy termination with or without surgical repair should be performed.
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Conclusion AAD during pregnancy is a rare, under-diagnosed cardiovascular complication with a high mortality rate. Further investigations, including chest CT scan, should be considered in patients with severe and progressive chest or back pain. Appropriate prenatal counselling, including documentation of maternal and foetal risks, and the decision to deliver by a multispeciality team is needed for proper management of pregnant patients with AAD.
References 1. 2.
3. 4.
Grubb KJ, Kron IL. Sex and gender in thoracic aortic aneurysms and dissection. Semin Thorac Cardiovasc Surg 2011; 23(2): 124–125. Thalmann M, Sodeck GH, Domanovits H, Grassberger M, Loewe C, Grimm M, et al. Acute type A aortic dissection and pregnancy: a population-based study. Eur J Cardiothorac Surg 2011; 39(6): e159–163. Parlakgumus HA, Haydardedeoglu B. A review of cardiovascular complications of pregnancy. Ginekol Pol 2010; 81(4): 292–297. Daily PO, Trueblood HW, Stinson EB, Wuerflein RD, Shumway NE.
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Management of acute aortic dissections. Ann Thorac Surg 1970; 10(3): 237–247. 5. Rossiter JP, Repke JT, Morales AJ, Murphy EA, Pyeritz RE. A prospective longitudinal evaluation of pregnancy in the Marfan syndrome. Am J Obstet Gynecol 1995; 173: 1599–1606. 6. Mészáros I, Mórocz J, Szlávi J, Schmidt J, Tornóci L, Nagy L, et al. Epidemiology and clinicopathology of aortic dissection. A populationbased longitudinal study over 27 years. Chest 2000; 117: 1271–1278. 7. Mayet J, Thorpe-Beeson G, Pepper J, Somerville J. Aortic dissection and triplets: treble the trouble. Br J Obstet Gynaecol 1999; 106: 601–604. 8. Wahlers T, Laas J, Alken A, Borst HG. Repair of acute type A aortic dissection after Caesarean section in the thirty-ninth week of pregnancy. J Thorac Cardiovasc Surg 1994; 107: 314–315. 9. Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The International Registry of Acute Aortic Dissection (IRAD): New insights into an old disease. J Am Med Assoc 2000; 283: 897. 10. Immer FF, Bansi AG, Immer-Bansi AS, McDougall J, Zehr KJ, Schaff HV, et al. Aortic dissection in pregnancy: analysis of risk factors and outcome. Ann Thorac Surg 2003; 76: 309–314.
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Case Report Single-stage repair of adult aortic coarctation and concomitant coronary artery disease: an unusual surgical approach through median sternotomy MAHMUT MUSTAFA ULAS, KUMRAL ERGUN, GOKHAN LAFCI, NIHAT SEN, ADNAN YALCINKAYA, AHMET IRDEM, KERIM CAGLI
Abstract Surgical repair of postductal aortic coarctation associated with severe coronary artery disease is in most cases a difficult decision to make. As staged procedures are associated with a higher rate of morbidity and mortality, simultaneous operative management of both pathologies is desirable. We describe a case of a 51-year-old man who was referred to our department for surgical treatment of postductal aortic coarctation and concomitant coronary artery disease, which we managed with single-stage surgery through median sternotomy. Keywords: single-stage surgical management, aortic coarctation, coronary bypass surgery Submitted 28/12/10, accepted 3/9/12 Cardiovasc J Afr 2012; 23: e10–e12
Cold cardioplegic arrest of the myocardium was maintained by infusion of cold cardioplegia into the aortic root and coronary sinus. The patient was cooled down to 30°C rectal temperature. After cross clamping, during the cooling period we performed coronary surgery. First, we carried out sequential graftings with the saphenous vein. The distal anastomosis to the right posterior descending artery was completed; then the proximal sequential anastomosis to the right acute marginal artery, and finally the proximal anastomosis to the ascending aorta was done. Second, the distal anastomosis to the obtuse marginal branch and the proximal sequential anastomosis to the diagonal artery were carried out, and then the proximal anastomosis to the ascending aorta. Finally, the (left internal thoracic artery) LITA–LAD (left anterior descending artery) anastomosis was
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DOI: 10.5830/CVJA-2012-061
Case report A 51-year-old man was referred to our department with unstable angina and uncontrolled hypertension. Echocardiography demonstrated severe postductal aortic coarctation with 114 mmHg peak gradient at rest. CT angiography localised the aortic coarctation (Fig. 1) and coronary angiography demonstrated severe multi-vessel coronary artery disease. We decided to perform coronary surgery first and then carry out the coarctation repair. Surgery was performed via a standard median sternotomy. The patient was anticoagulated with 1 mg/kg of heparin. Cardiopulmonary bypass was instituted using right atrial and ascending aortic cannulation.
Cardiovascular Clinic, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey MAHMUT MUSTAFA ULAS, MD GOKHAN LAFCI, MD ADNAN YALCINKAYA, MD AHMET IRDEM, MD KERIM CAGLI
Cardiology Clinic, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey KUMRAL ERGUN, MD NIHAT SEN, MD
Fig. 1. CT angiography demonstrating localisation of the aortic coarctation.
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Fig. 2. A view of retraction of the arcus aorta and pulmonary artery after coronary bypass.
completed and a bulldog clamp was left on the LITA graft. After all anastomoses were completed, the aorta was mobilised extensively, the left pleura was opened, and a tape was passed around the left pulmonary artery to retract it inferiorly. The patient was turned to the right side and mini retractors were used for maximum exposure. The arcus aorta was pulled up and to the right, and the pulmonary artery was retracted inferiorly (Fig. 2). After gentle retraction, the coarctation segment, left vagus nerve, recurrent laryngeal nerve and ligamentum arteriosum were seen. The ligamentum arteriosum was divided and oversewn. Large intercostal branches were identified and encircled in preparation for snaring. The aorta was clamped just distal to the left subclavian artery and distal to the coarctation. The aorta was then incised longitudinally across the lesion and a wide Dacron patch of appropriate size was sewn with fine, continuous prolene sutures to the aortic edges (Fig. 3). Cross-clamp time was 95 minutes. After declamping, cardiopulmonary bypass was discontinued uneventfully. Two months later, the patient was asymptomatic and control echocardiography revealed a mean 12 mmHg gradient (Fig. 4).
Fig. 3. A view at the end of the operation.
caused by myocardial infarction, indicating the significant role that myocardial disease plays in these patients. The mortality and morbidity of a staged surgical approach is significant. On the other hand, correction of the cardiac lesion alone is associated with increased postoperative renal failure and paraplegia as a result of inadequate perfusion of the distal organs.
Discussion Coarctation of the aorta generally presents in childhood. However, a significiant number of patients will present with primary coarctation later in life. A direct approach to repairing coarctation may entail enormous difficulties in adults.1 Severe lung disease, large collateral formation, concomitant cardiac pathologies, and lung dysfunction from a thoracotomy all present technical challenges. Surgery to repair only coarctation presenting in adulthood is associated with significantly higher hospital and late cardiovascular mortality.2 The majority of these deaths are
Fig. 4. Postoperative echocardiographic findings.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
Therefore one of the main indications for single-stage repair is coarctation with serious triple-vessel coronary artery disease.
Conclusion Coarctation of the aorta with concomitant coronary artery disease can be simultaneously repaired, safely and effectively through median sternotomy when patients present in adulthood. Since it is a protracted and difficult procedure, the surgeon must be experienced. However the rates of morbidity and mortality are higher with this procedure. We did not reposition the patient for
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the second stage of the operation therefore the risk of infection was less.
References 1.
2.
Liberthson RR, Pennington DC, Jacobs ML, Dagget WM. Coarctation of the aorta:review of 243 patients and clarification of management problems. Am J Cardiol 1979; 43: 835–840. Stewart AB, Ahmed R, Travill CM, Newman CG. Coarctation of the aorta:long term follow-up and prediction of outcome after surgical correction. Circulation 1989; 80: 840–845.
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...now it’s a stroke. After more than 50 years, a new therapy is now available in South Africa to prevent strokes caused by atrial fibrillation that offers: • 35 % reduced risk of stroke and systemic embolism vs. well-controlled warfarin (p < 0,001) 1,2 • 59 % reduced risk of intracranial bleeding vs. well-controlled warfarin (p < 0,001) 1,2 • 20 % reduced risk of life-threatening bleeding vs. well-controlled warfarin (p = 0,03) 1,2 • Does not require regular INR monitoring3 • Does not interact with food3
Dabigatran etexilate 110 mg/150 mg S4 Pradaxa® 110 mg. Each capsule contains 110 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 42/8.2/0131 S4 Pradaxa® 150 mg. Each capsule contains 150 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 45/8.2/0162 For full prescribing information refer to the package insert approved by the medicines regulatory authority. Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Fax: +27 (011) 787-3766. Cpy. Reg. No. 1966/008618/07. BI Ref. No. 341/2012 (Nov 12) References: 1. Connolly SJ, Ezekowitz MB, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Eng J Med 2009;361:1139–1151. 2. Connolly SJ, Ezekowitz MB, Yusuf S et al. Newly identified events in the RE-LY trial. New Eng J Med 2010;363:1875–1876. 3. Boehringer Ingelheim South African Pradaxa® Package insert.
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CardioVascular Journal of Africa (official journal for PASCAR)
• Measurement of cardiac troponins using high-sensitivity assays • Electrocardiographic abnormalities in type 2 diabetes • QTc prolongation prior to angiography predicts poor outcome • Statistical profiling of hospital performance • Cardiomyopathies and myocardial disorders in Africa • Telomeres and atherosclerosis
Cardiovascular Journal of Africa . Vol 23, No 10, November 2012
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• Workshop highlighting cardiovascular research in South Africa • Simplifying venous thromboembolism management