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MARCH / APRIL 2010 VOL 21 NO 2

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CardioVascular Journal of Africa (official journal for PASCAR)

• Bioequivalence: tried and tested • Correlates of left ventricular mass in hypertensive Nigerians • Exercise treadmill test and echocardiographic left ventricular geometry in Nigerian normotensive diabetics • Inflammation and dyslipidaemia in North Indian males with coronary artery disease • Amiodarone-induced QT prolongation in a newly transplanted heart

Cardiovascular Journal of Africa . Vol 21, No 2, March/April 2010

Printed by Durbanville Commercial Printers Tel: 021 946 4074

• The unicuspid aortic valve


It's the shell that makes R

safer.

Safety-Coated R

81mg The ORIGINAL low dose aspirin for optimum cardio-protection pH

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.


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

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VOL 21, NO 2. MARCH / APRIL 2010

CONTENTS

Cardiovascular Journal of Africa

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www.cvja.co.za

Editorial

Bioequivalence: tried and tested R Schall • L Endrenyi

Cardiovascular Topics

72 AMP kinase activation and glut4 translocation in isolated cardiomyocytes I Webster • SO Friedrich • A Lochner • B Huisamen 79

Correlates of left ventricular mass in hypertensive Nigerians: an echocardiographic study OS Ogah • A Bamgboye

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Medication adherence, self-care behaviour and knowledge on heart failure in urban South Africa: the Heart of Soweto study V Ruf • S Stewart • S Pretorius • M Kubheka • C Lautenschläger • P Presek • K Sliwa

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Blood pressure response to an exercise treadmill test, and echocardiographic left ventricular geometry in Nigerian normotensive diabetics EA Ajayi • MO Balogun • OA Akintomide • RA Adebayo • OE Ajayi • RT Ikem • SA Ogunyemi • AT Oyedeji

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Factors associated with mortality when chronic beta-blocker therapy is withdrawn in the peri-operative period in vascular surgical patients: a matched case–control study BM Biccard

103 Inflammation and dyslipidaemia: a possible interplay between established risk factors in North Indian males with coronary artery disease B Goswami • M Rajappa • B Singh • PC Ray • S Kumar • V Mallika

INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors Editor-in-Chief (South Africa) PROF AJ BRINK Assistant Editor Prof JAMES KER (JUN) Regional Editor (Cameroon) Prof JC Mbanya Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Editorial Board

prof PA Brink Experimental & Laboratory Cardiology PROF V CORFIELD Molecular Cardiology PROF R DELPORT Chemical Pathology PROF MR ESSOP Haemodynamics, Heart Failure & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure PROF J KER (SEN) Hypertension, Cardiomyopathy, Cardiovascular Physiology

DR J LAWRENSON Paediatric Heart Disease PROF A LOCHNER Biochemistry/Laboratory Science PROF BM MAYOSI Chronic Rheumatic Heart Disease DR MT MPE Cardiomyopathy PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society PROF MM SATHEKGE Nuclear Medicine/Society PROF YK SEEDAT Diabetes & Hypertension PROF H DU T THERON Invasive Cardiology

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 PETER SCHWARTZ Italy (Dysrhythmias) PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

Publishing Consultant Mike Gibbs


Case Reports

109 Amiodarone-induced QT prolongation in a newly transplanted heart associated with recurrent ventricular fibrillation ER Schwarz • LS Czer • SA Simsir • RM Kass • A Trento

VOL 21, NO 2. MARCH / APRIL 2010

CONTENTS

113 The unicuspid aortic valve SM Yuan • H Jing • J Lavee 115

Drug Trends

Focus on the American College of Cardiology Congress, 2010

Reduced blood pressure variability in ASCOT-BPLA trial favours use of amlodipine/ perindopril combination to reduce stroke risk

Comparison of ivabradine plus β-blockers versus β-blocker therapy only

INVEST study warns on too-low BP in diabetic patients with CAD ACCORD LIPID study results strengthen guideline approach of adding fenofibrate to therapy of dyslipidaemic type 2 diabetic patients 120

Combination therapy in hypertension: new recommendations

123 The use of anticoagulants for venous thrombo-embolism 124 Opinions in hypertension management: Angiotensin receptor blockers in hypertension patients: earlier use of these bettertolerated medications is warranted

Supplement

International Symposium: Integrated Approach to Disease Management: Endocrinology, Metabolic Disorders and Cardiac Consequences Cape Town, 6–7 March 2010

It's the shell that makes

Abstracts of the 7th Scientific Congress of the Cameroon Cardiac Society (CCS) 17–19 March 2010, Yaoundé, Cameroon, published electronically

safer.

Safety-Coated R

81mg The ORIGINAL low dose aspirin for optimum cardio-protection pH

Assistant Editor Special Assignments julia aalbers Tel: 021 976 4378 Fax: 086 610 3395 e-mail: jaalbers@icon.co.za

Production Editor SHAUNA GERMISHUIZEN Tel: 021 785 7178 Fax: 086 628 1197 e-mail: shaunag@xsinet.co.za

Editorial Assistant & Circulation ELSABÉ BURMEISTER Tel: 021 976 8129 e-mail: elsabe@cvja.co.za

Production Co-ordinator

WENDY WEGENER Tel: (021) 976-4378 e-mail: wendy.icon@wol.co.za

GAUTENG CONTRIBUTOR

PETER WAGENAAR Cell 082 413 9954 e-mail : skylark65@myconnection.co.za

Editorial BOARD

The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published six times a year, the deemed publication date being the seventh day of the second designated month, i.e. 7 February, 7 April, 7 June, 7 August and 7 October. Copyright: Clinics Cardive Publishing, Pty, Ltd. Layout: Martingraphix Printer: Durbanville Commercial Printers

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.

All submissions to CVJA are to be made online via www.cvja.co.za Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances. Postal address: PO Box 1013, Durbanville, 7551 Tel/Fax: 021 976 8129 Int.: +27 21 976 8129 e-mail: info@cvja.co.za 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 jaalbers@icon.co.za User ID: cvja8 Password: cvja8

Subscriptions for six issues: South Africa: R300 (excl VAT) Other African countries: $30 Overseas: Institutions: R845 ($82) Individuals: R1 080 ($105) 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.


IntroducIng rEVAtIo® A wEll EstAblIshEd PdE-5 InhIbItor rEgIstErEd for usE In PulmonAry ArtErIAl hyPErtEnsIon (PAh) REVATIO® helping your patients to do more... • Significantly improves exercise capacity (p<0.001) (1) • Significantly reduces mean pulmonary arterial pressure (p=0.04) (1) • Significantly improves physical functioning and general health (p<0.001) (2) ...without holding them back • Convenient oral dosing: 20 mg tds with or without meals • Adverse events are generally transient and mild to moderate (1,3) • Low discontinuation rate comparable to placebo • No monthly liver function testing required (3)

References: 1. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005;353(20):2148-2157. 2. Pepke-Zaba J, Gilbert C, Collings L, Brown MCJ. Sildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension. Chest 2008;133:183-189. 3. Croom KF, Curran MP. Sildenafil. A Review of its Use in Pulmonary Arterial Hypertension. Drugs 2008;68(3):338-397. S4 REVATIO® Film-coated tablets (Reg. No. A40/7.1.5/0131). COMPOSITION: Each tablet contains 20 mg of sildenafil, as the citrate. PHARMACOLOGICAL CLASSIFICATION: A 7.1.5 Vasodilators – peripheral. INDICATIONS: Treatment of pulmonary arterial hypertension. REVATIO has been shown to improve exercise ability and to reduce mean pulmonary arterial pressure. CONTRA-INDICATIONS: Known hypersensitivity to any component of the tablet. Patients concurrently using nitric oxide donors or organic nitrates in any form. Concomitant use with ritonavir, erythromycin, saquinavir, ketoconazole and itraconazole. Severe hepatic or renal function. Pregnancy and Lactation. WARNINGS: No controlled clinical data in MI, stroke, or life-threatening arrhythmia within the last 6 months; resting hypotension (BP <90/50) or hypertension (BP >170/110); cardiac failure or CAD causing unstable angina and retinitis pigmentosa. Physicians should carefully consider whether patients with underlying CVD could be affected adversely by transient decreases in supine BP, especially in combination with sexual activity. Serious events, including MI, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, and hypertension have been reported. Most patients had pre-existing CV risk factors. Use with caution in patients with anatomical deformation of the penis, or conditions which may predispose to priapism. Patients taking alpha-blocker therapy may lead to symptomatic hypotension. Administer with caution to patients with bleeding disorders or active peptic ulceration. Decreased vision or loss of vision, has been reported. Exercise caution before driving, operating hazardous machinery or performing hazardous tasks. DOSAGE AND DIRECTIONS FOR USE: 20 mg three times a day approximately 6 to 8 hours apart with or without food. Dose adjustments may be required when co-administered with bosentan or other CYP3A4 inducers. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Most commonly reported side-effects included headache, flushing, dyspepsia, back pain, diarrhoea and limb pain. Other common side-effects include cellulitis, influenza, sinusitis, anaemia, fluid retention, insomnia, anxiety, migraine, tremor, paraesthesia, burning sensation, hypoaesthesia, visual acuity reduced, retinal haemorrhage, visual disturbance, photophobia, diploplia, chromatopsia, cyanopsia, abnormal sensation in eye, eye irritation, vertigo, bronchitis, epistaxis, rhinitis, cough, gastritis, gastroenteritis, gastro-oesophageal reflux disease, haemorrhoids, abdominal distension, alopecia, erythema, myalgia, gynaecomastia, pyrexia and weight increase. A sudden unilateral or bilateral decrease or loss of hearing (sensorinearal deafness) with or without associated vestibular symptoms has been reported. LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. Reg. No.: 1954/000781/07. P.O. Box 783720, Sandton 2146. Tel. No.: 0860 PFIZER (734937). PI Ref: 13/07/09. Please refer to the detailed package insert for full prescribing information. 01/01/REV/10/JA


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Editorial Bioequivalence: tried and tested Two drug products are considered bioequivalent ‘if their bioavailabilities ... are similar to such a degree that their effects, with respect to both efficacy and safety, will essentially be the same’.1 The bioequivalence of two drug products is generally demonstrated through a clinical study in healthy volunteers, the so-called bioequivalence study. If bioequivalence is shown for two drug products, therapeutic equivalence of the drug products is implied. Chow and Liu2 call this assumption, namely that bioequivalence implies therapeutic equivalence, the ‘fundamental bioequivalence assumption’. Most drug products on the market today have been subjected to bioequivalence assessment at various stages in their development. As is well known, generic drug products require the demonstration of bioequivalence to the relevant innovator product for regulatory approval. What is perhaps less well known is that most innovator products, too, require some form of bioequivalence testing. New drugs typically undergo pharmacokinetic dose-proportionality studies, and drug–drug and drug– food interaction studies, all of which use the bioequivalence concept. The site of development and production of the drug product could be changed. Most importantly, when the innovator formulation to be marketed is different from the formulation used previously in pivotal efficacy trials, as is often the case, bioequivalence of the marketed formulation to the clinical trial formulation must be shown. In this sense, many innovator drug products on the market are in fact ‘generic copies’ of the clinical trial formulation for which therapeutic efficacy and safety had been shown in patients. Consumers of drug products, therefore, of both generic and innovator products, need assurance on the question whether bioequivalence implies therapeutic equivalence. All drug manufacturers of either generic or innovator products need to know whether the bioequivalence concept and bioequivalence methodology serve their products well during development. On both these questions relatively recent developments have shed some light.

History of the bioequivalence concept Public concern and ongoing discussion about bioequivalence started in the early 1970s with reports about digoxin intoxications. At the time, generic digoxin formulations were increasingly prescribed in the United States, and a change in the manufacturing process of a company in Great Britain led to an unintentional increase in the bioavailability of one brand of digoxin tables.3,4 It became clear that drug products that are pharmaceutically equivalent, that is, products that contain the same drug in the same dose, are not necessarily bioequivalent.5 Over the years, various regulatory guidelines on the design, conduct and statistical analysis of bioequivalence studies have been published. Many years of research, discussion and controversy culminated in the seminal Food and Drug Administration’s

(FDA) 1992 guidance6 on the statistical analysis of bioequivalence studies. That guidance established such well-known concepts as the pharmacokinetic characteristics for rate and extent of drug absorption and the statistical decision rule for the demonstration of bioequivalence (90% confidence interval for the test/reference ratio of mean bioavailability must fall completely in the bioequivalence acceptance range of 80–125%.)

Switchability of drug products: the individual bioequivalence intermezzo With the publication of the 1992 FDA guidance,6 one might have thought that agreement had been reached, finally, among researchers and regulators on the central concepts of bioequivalence. Ironically, almost exactly around that time, the new concept of individual bioequivalence7 was formulated and sparked a new era of research and discussion, and probably more controversy than ever before. Two US biostatisticians, Anderson and Hauck,7 pointed out that the traditional way of bioequivalence assessment, as circumscribed, for example, in the contemporary 1992 FDA guidance, ensured merely that the bioavailability of two drug products was similar (‘equivalent’) on average. They raised the following clinically very relevant question: does equivalence of average bioavailability, which they termed average bioequivalence, ensure that the bioavailability of two drug products is equivalent in individual patients? In other words, does average bioequivalence imply switchability of drug products in individual patients? Following the groundbreaking article of Anderson and Hauck, numerous statistical approaches to individual bioequivalence were published (Schall8 provides a unified view of most of the approaches; see also the reviews of Hauschke, Steinijans and Pigeot9 and Chow and Liu2). Eventually, in 2001, the individual bioequivalence concept was adopted in an FDA guidance.10 However, ‘responses [to the guidance] were doubt-filled as to whether the new bioequivalence criteria really provided added value compared to average bioequivalence’.9 Crucially and rather illuminating on the question of the general validity of the fundamental bioequivalence assumption was the observation that ‘there has been no published evidence of clinical failure with a formulation demonstrated to be equivalent to the reference product under average bioequivalence’.11,12 Individual bioequivalence was called a ‘theoretical’ solution to a ‘theoretical’ problem.13 In response to the widespread criticism and doubts, in 2003 the FDA omitted the individual bioequivalence concept from a subsequent guidance,14 and returned, almost full circle, to the conventional (average) bioequivalence concept of the 1992 guidance.6

Bioequivalence and therapeutic equivalence The concept of individual bioequivalence proved to be an inter-


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mezzo but it proved to be useful after all. Critical and clinically relevant questions were asked about the traditional concept of average bioequivalence, and this concept emerged strongly. In particular, the crucial question, namely whether bioequivalence implied therapeutic equivalence, was answered in the affirmative. In a highly competitive market and litigious society such as the United States one would expect cases of therapeutic inequivalence of bioequivalent products to be publicised quickly and widely. Nevertheless, Rheinstein15 could state in 1990 that ‘To date, there is no evidence of therapeutic inequivalence in a properly manufactured generic drug which has been approved as bioequivalent by the FDA’. A literature search conducted by Gould11 10 years later to answer the question whether average bioequivalence implied switchability of drug products in practice came to the same conclusion: essentially no evidence of therapeutic failure of bioequivalent products could be found. Chow and Liu2 reported how in the United States innovator companies file citizen petitions in order to convince the regulatory agency (FDA) that a generic copy of a brand-name drug will not achieve therapeutic equivalence even if the generic has been shown to be bioequivalent to the brand name drug. Those authors cite no case of a generic that has been approved as bioequivalent by the FDA but has been shown to be therapeutically inequivalent to the innovator. [However, it should be noted that there are classes of drugs whose safety are particularly sensitive to the conditions of administration. For example, responses to immunosuppressants, and the contrasts between different drug products can vary with time after transplantation, the target organ, ethnicity and concomitant disease conditions (e.g. diabetes) of the patients.16] In summary, the fundamental bioequivalence assumption, namely that bioequivalent products are therapeutically equivalent and can be used interchangeably, has survived strong scrutiny; scrutiny that was inter alia a by-product of the discussion of and research on the individual bioequivalence concept. The conventional concept of average bioequivalence seems to have served the consumers of drugs rather well.

Highly variable drugs and widening the bioequivalence acceptance range, or scaling What about the concerns that the producers of drugs might have with the bioequivalence concept? It is well known that the conventional approach of average bioequivalence, with an 80–125% acceptance range, can make it very difficult to show bioequivalence for drug products with highly variable bioavailability (so-called ‘highly variable drugs’ or drug products). For such drugs, sample sizes of 100 subjects and higher can be required to demonstrate bioequivalence. ‘A feature of the difficulties involving the determination of bioequivalence of highly variable drugs is that, under typical conditions, a drug product may not be found bioequivalent to itself.’17 This is clearly unsatisfactory, in particular to producers of drug products who face inordinate costs when conducting bioequivalence studies for highly variable drugs. A potential solution to the problem of highly variable drugs is suggested by the observation that most highly variable drugs have a wide therapeutic index. If such a drug indeed has a wide therapeutic index, it should be clinically acceptable to widen the bioequivalence acceptance range for it. Various ways of

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appropriately widening the acceptance range for highly variable/ wide therapeutic-index drugs have recently been discussed and investigated.17,18 The approach that currently seems to be favoured by FDA scientists and researchers in the field is that of scaled average bioequivalence.17,18 Without going into the methodological and statistical details, the scaled average bioequivalence concept effectively widens the conventional acceptance range for bioequivalence, namely 80–125%, proportionally to the within-subject standard deviation of the bioavailability of the reference product. Therefore, the more variable the bioavailability of the reference drug product, the wider the effective acceptance range for bioequivalence. Interestingly, the basic concept of scaling the bioequivalence criterion had already been proposed early in the development of characteristics for individual bioequivalence,8,19,20 so that the scaled average bioequivalence concept can be viewed as another by-product of the research into individual bioequivalence. While there still are some problems with the scaled average bioequivalence concept,17 at present it seems to be the most promising and practical approach for handling the problem of highly variable drugs in bioequivalence.

Narrow therapeutic index drugs and narrowing the bioequivalence acceptance range The mirror image of highly variable drugs with wide therapeutic index is narrow therapeutic-index drugs whose variability typically is low. If it is reasonable to widen the bioequivalence acceptance range for highly variable drugs with wide therapeutic index, it seems equally reasonable to narrow the bioequivalence acceptance range for drugs with low variability and narrow therapeutic index. Such a narrowing of the bioequivalence acceptance range for narrow therapeutic-index drugs could increase assurance, particularly of the safety of generics in this drug class, without imposing an undue burden, financial or otherwise, on the sponsors of bioequivalence studies for such drugs. Indeed, the new European bioequivalence guideline21 envisages that ‘in specific cases of products with narrow therapeutic index, the acceptance interval for AUC should be tightened to 90–111.11%’.

Conclusion The standard approach to bioequivalence assessment, namely conventional average bioequivalence, has proven itself under strict scrutiny over more than 20 years. Drug products that under a proper regulatory regime have been approved as bioequivalent to a reference product can generally be assumed to be therapeutically equivalent to that reference product. The bioequivalence limits could be widened relative to the conventional acceptance range of 80–125% for handling the problem of highly variable drugs, and could be narrowed for narrow therapeutic-index drugs. For highly variable drugs, scaled average bioequivalence provides an alternative, effective approach to the comparison of drug products. ROBERT SCHALL, schallr@ufs.ac.za Department of Mathematical Statistics and Actuarial Science, University of the Free State, Bloemfontein, South Africa LASZLO ENDRENYI Department of Pharmacology, University of Toronto, Ontario, Canada


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References 1. CPMP. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. London: Committee for Proprietary Medicinal Products, 2001. http://www.egagenerics.com/doc/emea_bioequiv-1401-98.pdf 2. Chow S-C, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies, 3rd edn. Boca Raton: CRC Press, 2009. 3. Lindenbaum J, Mellow MH, Blackstone MO, Butler VP (jun). Variation in biologic availability of digoxin from four preparations. N Engl J Med 1971; 285: 1244–1347. 4. Schulz H-U, Steinijans VW. Striving for standards in bioequivalence assessment: a review. Int J Clin Pharm Ther Toxicol 1991; 29: 293–298. 5. Skelly KP, Knapp G. Biologic activity of digoxin tablets. J Am Med Ass 1973; 224: 243. 6. FDA. Statistical Procedures for Bioequivalence Studies using a Standard Two Treatment Cross-over Design. Washington DC: FDA, CDER, 1992. 7. Anderson S, Hauck WW. Consideration of individual bioequivalence. J Pharmacokinet Biopharm 1990; 18: 259–273. 8. Schall R. A unified view of individual, population, and average bioequivalence. In: Blume HH, Midha KK, ed. BIO-International 2. Bioavailability, Bioequivalence and Pharmacokinetic Studies. Stuttgart: Medpharm Scientific, 1995: 91–106. 9. Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development. Methods and Applications. Chichester: Wiley, 2007. 10. FDA. Statistical Approaches to Establishing Bioequivalence. Guidance for Industry. Washington DC: FDA, CDER, 2001. http://www.fda.gov/ cder/guidance/ 11. Gould AL. A practical approach for evaluating population and individual

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bioequivalence. Stat Med, 2000; 19: 2721–2740. 12. Barret JS, Batra V, Chow A, Cook J, Gould AL, Heller A, et al. PHARMA perspective on population and individual bioequivalence. J Clin Pharmacol 2000; 40: 561–570 13. Patterson S. A review of the development of statistical design and analysis techniques for assessing in vivo bioequivalence: Part two. Ind J Pharm Sc 2001; 63: 169–186. 14. FDA. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General considerations. Guidance for Industry. Washington DC: FDA, CDER, 2003. http://www.fda.gov/cder/guidance/ 15. Rheinstein PH. Therapeutic inequivalence. Drug Safety 1990; 5(Suppl 1): 114–119. 16. Pollard S, Nashan B, Johnston A, Hoyer P, Belitsky P, Keown P, Helderman H. A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporine A. Clin Ther 2003; 25: 1654–1669. 17. Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet 2009; 48: 725–743. 18. Haidar SH, Davit B, Chen M-L, et al. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res 2008; 25: 237–241. 19. Sheiner LB. Bioequivalence revisited. Stat Med 1992; 11: 1777–1788. 20. Schall R, Luus HG. On population and individual bioequivalence. Stat Med 1993; 12: 1109–1124. 21. CHMP. Guideline on the Investigation of Bioequivalence. London: Committee for Medicinal Products for Human Use, 2008. http://www. emea.europa.eu/pdfs/human/qwp/140198enrev1fin.pdf

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Cardiovascular Topics AMP kinase activation and glut4 translocation in isolated cardiomyocytes INGRID WEBSTER, SVEN O FRIEDRICH, AMANDA LOCHNER, BARBARA HUISAMEN

Summary Activation of AMP-activated protein kinase (AMPK) results in glucose transporter 4 (GLUT4) translocation from the cytosol to the cell membrane, and glucose uptake in the skeletal muscles. This increased activation of AMPK can be stimulated by a pharmacological agent, AICAR (5′-aminoimidazole-4-carboxamide ribonucleoside), which is converted intracellularly into ZMP (5′-aminoimidazole-4-carboxamideribonucleosidephosphate), an AMP analogue. We utilised AICAR and ZMP to study GLUT4 translocation and glucose uptake in isolated cardiomyocytes. Adult ventricular cardiomyocytes were treated with AICAR or ZMP, and glucose uptake was measured via [3H]-2-deoxyglucose accumulation. PKB/Akt, AMPK and acetyl-CoA-carboxylase phosphorylation and GLUT4 translocation were detected by Western blotting or flow cytometry. AICAR and ZMP promoted AMPK phosphorylation. Neither drug increased glucose uptake but on the contrary, inhibited basal glucose uptake, although GLUT4 translocation from the cytosol to the membrane occurred. Using flow cytometry to detect the exofacial loop of the GLUT4 protein, we showed ineffective insertion in the membrane under these conditions. Supplementing with nitric oxide improved insertion in the membrane but not glucose uptake. We concluded that activation of AMPK via AICAR or ZMP was not sufficient to induce GLUT4-mediated glucose uptake in isolated cardiomyocytes. Nitric oxide plays a role in proper insertion of the protein in the membrane but not in glucose uptake. Keywords: AMPK, AICAR, GLUT4, GLUT4 exofacial loop, cardiomyocytes Submitted 9/3/09, accepted 19/6/09 Cardiovasc J Afr 2010; 21: 72–78

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Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa INGRID WEBSTER, MSc SVEN O FRIEDRICH, PhD AMANDA LOCHNER, PhD, DSc BARBARA HUISAMEN, PhD, bh3@sun.ac.za

MRC Cape Heart Centre, Tygerberg, South Africa AMANDA LOCHNER, PhD, DSc BARBARA HUISAMEN, PhD

AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis in the cell1 by recognising ATP depletion,2 initiating changes to restore cellular ATP levels and inhibiting ATP-utilising anabolic pathways.3 In heart and skeletal muscle, AMPK plays an important role in accelerating fatty acid oxidation, FAT/CD36 translocation and fatty acid uptake, as well as glut4 translocation, glucose uptake and glycolysis.4,5 AMPK is activated by cellular stress, which alters the AMP:ATP ratio – this can be nutrient stress, lack of oxygen or exercise-induced stress.4,6 The AMPK signalling pathway provides an alternative to the insulin-dependant glucose uptake pathway in muscle. Insulinstimulated activation of glut4 translocation via activation of phosphatidyl-inositol-3 kinase (PI3-K) and PKB/Akt has been extensively researched. Resistance of muscle to the effects of insulin is a hallmark of pre-diabetes. This reduction in insulin sensitivity is reflected in decreased insulin-stimulated glucose uptake.7 Since AMPK activates glucose uptake via a distinctly different signalling pathway than insulin, it may present a mechanism to manipulate pharmacologically to treat this disease. Indeed, in insulin-resistant humans and rodents, regular exercise, known to activate AMPK, enhances insulin sensitivity.8-12 Repeated activation of AMPK may therefore be a mechanism to improve insulin sensitivity.13 Furthermore, it was demonstrated that activation of AMPK is responsible for glucose uptake by hearts subjected to ischaemia, underscoring the importance of this kinase in the pathophysiology of the heart.14 AICAR (5′-aminoimidazole-4-carboxamide ribonucleoside) is an adenosine analogue which is taken up into the cells and converted to the monophosphorylated nucleotide, ZMP (5′-aminoimidazole-4-carboxamide-ribonucleosidephosphate), by adenosine kinase.6,15 It was described as a specific activator of AMPK16 in intact cells. In has also been found that ZMP, an analogue of AMP, mimics the effects of AMP on allosteric activation of AMPK,17 and the promotion of phosphorylation and activation of AMPK by the AMPK kinase, LKB118 without changing the ATP:ADP or ATP:AMP ratio in the cell.16 There are numerous studies showing that AICAR increases AMPK phosphorylation as well as glucose uptake in skeletal muscle, the latter mediated via GLUT4 translocation.19-21 There are, however, only a few studies to date showing effects of AICAR on glucose uptake in the heart, some utilising papillary muscle,14 whereas Jing and Holman used oligomycin to activate AMPK in cardiomyocytes.22 GLUT4 protein in the heart is largely confined to an intracellular vesicle storage site in the basal, non-stimulated state.23,24 It becomes recruited to the cell surface under the influence of insu-


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lin25-27 or stimuli such as contraction or hypoxia. GLUT4 vesicles respond to insulin in a marked and dramatic way, increasing GLUT4 levels in the membrane up to nine times that of basal levels.28 The protein is recycled via endocytosis in clathrincoated vesicles.29 It has, however, been recognised that translocation of GLUT4 to the membrane, and glucose uptake by the GLUT4 transporters are not always reconcilable. There is a marked discrepancy between glucose uptake and translocation of GLUT4.30 Although our understanding of the regulation of GLUT4 translocation from the intracellular to the membrane compartments has expanded rapidly over the past years,31 the exact mechanisms governing these events, especially at the site of fusion with the cell membrane, is not fully understood. Events elicited by stimulation with insulin have been the focus of intense research, whereas less is known of those elicited by AMPK activation. However, stimulation with activators of AMPK share some of the downstream signalling events of the insulin pathway.32,33 We used isolated, adult ventricular myocytes stimulated with AICAR and ZMP to correlate glucose uptake and GLUT4 translocation after AMPK activation. The results demonstrated that in cardiomyocytes, activation of AMPK was not sufficient to affect GLUT4 insertion into the cell membrane and therefore glucose uptake.

Methods Materials

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genase perfusion, essentially as described previously.34 Isolated cells were filtered through a nylon mesh (200 × 200 µm) and gently spun down (3 min, 100 rpm). The resulting pellet was resuspended in HEPES buffer (10 mM HEPES pH 7.4, 6 mM KCl, 1 mM Na2HPO4, 0.2 mM NaH2PO4, 1.4 mM MgSO4, 128 mM NaCl, 5.5 mM glucose, 2 mM pyruvate, containing 1.25 mM CaCl2, 2% BSA (fraction V, fatty acid free) and the cells were allowed to recover for 60 min on a slowly rotating platform. Osmotic fragility coupled to trypan blue exclusion (TBE) and cell morphology were used as indices for assessment of cell viability.35 Viable cells varied between 70 and 80% and all cell isolates of less than 70% viability were discarded. At the end of experimentation, the viability of cell preparations was determined with propidium iodide.

Propidium iodide staining Propidium iodide (PI) staining was used to assess cell membrane permeability. Nuclear staining by PI was assessed with flow cytometric (FACS) analysis. Cardiac myocytes were incubated with 10 μM PI for 15 min before analysis. Data are expressed as mean fluorescence intensity as a percentage of control. FACS analysis was done with a FACSCalibur using Cellquest 3.3 software (Becton Dickinson, San Jose, California, USA).

Detection of glucose uptake

AICAR, ZMP, insulin and Triton X-100 were obtained from Sigma, type 2 collagenase was from Worthington, bovine serum albumin (BSA) fraction V, fatty acid-free from Roche Diagnostics and 2-deoxy-D-[3H]glucose from New England Nuclear. The ECL Western blotting detection reagents, antirabbit Ig, horseradish peroxidase-linked whole secondary antibody were from Amersham Biosciences, UK Ltd, GLUT4 (H-61): sc-7938 rabbit polyclonal antibody was from Santa Cruz Biotechnology Inc., phospho-PKB/Akt (Ser473), phosphoAMPK-α (Thr172) and Phospho-ACC antibodies were from Cell Signalling technology. The anti-GLUT4 (exofacial loop) was purchased from Chemicon International (Temecula, California, USA), and Zenon Alexa Fluor 488 Rabbit IgG Labeling Kit was acquired from Molecular Probes (Eugene, Oregon, USA). Paraformaldehyde was purchased from Merck (Cape Town, RSA) and Dulbecco’s phosphate-buffered saline (PBS) from Gibco (Grand Island, New York, USA).

Myocyte uptake of 2-deoxy-D-[3H] glucose (2DG) was measured as described previously.34 Cardiomyocytes (approximately 0.5 mg protein) were placed in a total volume of 750 µl assay medium containing (in mmol/l): KCl 6, Na2HPO4 1, NaH2PO4 0.2, MgSO4 1.4, NaCl 128, HEPES 10, CaCl2 1.25 plus 2% BSA (fraction V, fatty acid free) pH 7.4, 37°C, equilibrated with oxygen. Cells were equilibrated for 15 min in a shaking water bath (180 strokes/min) with or without phloretin (400 µM) for measurement of non-carrier-mediated glucose uptake. They were stimulated with or without insulin (15 min × 100 nM), AICAR (30 min × 1 mM) or ZMP (30 min × 1 mM) as indicated. Glucose uptake was initiated by the addition of 2-deoxy-D-[3H] glucose (1.5 µCi/ml; final 2-deoxy-D-glucose concentration 1.8 µM) and allowed to progress for 30 min before the reaction was stopped with phloretin (final concentration 400 µM). The cells were then centrifuged and the pellet was washed twice with HEPES buffer and dissolved in 1 ml 0.5 N NaOH. An aliquot of this solution was then used to assay protein concentration by the method of Lowry,36 and the rest was counted for radioactivity.

Animals

Preparation of lysates for Western blotting

Male Wistar rats weighing between 250 and 300 g were used in all experiments. Animals were bred and kept in the AAALACaccredited facility of this institution. The project was approved by the Ethics committee of the Faculty of Health Sciences, University of Stellenbosch and conformed to the Guide for the Care and Use of Laboratory Animals of the NIH (Publication No. 85-23, revised 1996). Animals were anaesthetised with sodium pentobarbital (160 mg/kg) before experimentation.

Cardiomyocytes were removed after stimulation with insulin, AICAR or ZMP as described above and placed on ice. The cells were centrifuged and washed three times with ice-cold HEPES buffer without albumin and lysed in 100 µl of lysis buffer (25 mM HEPES, 50 mM β-glycerophosphate, 1 mM EGTA, 1% Triton X-100, 10 mM p-nitrophenyl phosphate, 1 mM Na3VO4, 2.5 mM MgCl2, 10 µg/ml aprotonin, 10 µg/ml leupeptin, 1 mM phenylmethylsulphonyl fluoride and 1 mM 1-4-dithiothreitol, pH 7.4). The lysates were centrifuged at 15 000 × g for 10 min and the supernatants diluted with Laemmli sample buffer for SDS-PAGE. An aliquot of the supernatant was used for protein determination.37

Preparation of cardiomyocytes Rod-shaped ventricular cardiomyocytes were obtained by colla-


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Western blotting After boiling for five minutes, equal amounts of sample protein from the various fractions were separated on a 10% SDS-PAGE and transferred to ImmobilonTM-P membranes. Transfer and equal loading were confirmed using the reversible stain, Ponceau red. Non-specific binding sites were blocked with 5% fat-free milk powder in TRIS-buffered saline (TBS) for two hours at room temperature and then incubated with either the phosphoAkt (Ser473), GLUT4 (H-61): sc-7938 or phospho-AMPK (Thr172) primary antibody [1:1000 dilution in TBS plus 0.1% Tween-20 (TBST)] for 16 hours at 4°C. After washing with TBST, the membranes were treated for one hour with 1:4000 dilution of anti-rabbit Ig, horseradish peroxidase-linked whole antibody and the bands were visualised with the ECL method.

Membrane fractionation for measurement of GLUT4 translocation In order to determine GLUT4 translocation, cardiomyocytes were fractionated into a sarcolemmal membrane and a cytosolic compartment, essentially as described by Takeuchi et al.38 After stimulation with the various compounds, the cardiocytes were washed twice with ice-cold HEPES buffer without albumin and then sonicated on ice in TES buffer containing (in mM): TrisHCl 20, pH 7.5, EDTA 2, EGTA 0.5, sucrose 330 PMSF 1 and 25 µg/ml leupeptin. The homogenate was centrifuged to remove particulate debris (1000 × g at 4°C for 10 min). The supernatant was further fractionated by ultracentrifugation for 90 min at 40 000 × g at 4°C (Beckman, Ti50). The supernatant obtained was considered to represent the cytosolic fraction. The pellet was suspended in the aforementioned buffer minus sucrose but containing 1% (vol/vol) Triton X-100 plus 1% SDS and rotated at 4°C for 30 min. Afterwards the suspension was ultracentrifuged at 40 000 × g for one hour at 4°C (Beckman, Ti50), and the supernatant used as the membrane fraction. Protein concentration was determined using the method of Bradford,37 samples were diluted in Laemmli sample buffer, boiled for 5 min and stored at –20°C. GLUT4 content and distribution were determined by Western blotting and suitable antibodies.

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or two-way ANOVA followed by a Bonferroni correction or with the Students t-test where applicable, using GraphPad Prism 5; p < 0.05 was considered as significant.

Results AMPK activation To determine whether the two pharmacological substances AICAR and ZMP could exert physiological effects via activation 4 Arbitrary Densitometry Units

74

**

3

**

*

2

1

0

Basal AICAR

ZMP Anoxia

pAMPK pACC Aicar

+

ZMP

+

Anoxia

+

Detection of GLUT4 exofacial loop Approximately 100 000 cardiomyocytes per sample were used and washed once with PBS. After that, the cells were stained with 1 µg GLUT4 antibody coupled to Alexa Fluor 488 according to the manufacturer’s instructions, and washed with PBS. A fixing step with 1 ml PBS containing 1% paraformaldehyde (PFA) for 15 min at room temperature followed. Samples were centrifuged at 4 × g for 5 min. Flow cytometric analysis was done with a FACSCalibur using Cellquest 3.3 software (Becton Dickinson, San Jose, California, USA). A forward-scatter against side-scatter plot was used to distinguish the cells from the debris, as described previously.39 The fluorescence signal of the labelled antibody bound to GLUT4 was detected in the FL-1 channel using logarithmic amplification. Positive cells were defined by a fixed gate and expressed as a percentage of the total cell population.

Statistical analyses Results are presented as mean ± SEM. The significance of the differences between groups was analysed with either a one-way

Fig. 1. A: Lysates of cardiomyocytes were prepared after stimulation for 30 min with either AICAR (1 mM) or ZMP (1 mM) as described in Methods; 50 µg of protein were loaded per lane, separated and, after Western blotting, probed with an antibody against the Thr172phosphorylated form of AMPK. Cells made anoxic by bubbling nitrogen through the incubation medium were used as a positive control. After visualisation, blots were analysed with laser scanning densitometry. B: A representative Western blot of phosphorylation of AMPK and ACC as substrate of AMPK to demonstrate activation. C: A Ponceau red-stained membrane to show equal loading of proteins. All values are expressed as mean ± SEM (n = 4); *p < 0.05 vs basal level; **p < 0.01 vs basal level.


*

10

2.0

Fold stimulation

8

* #

2

*

#

**

0.5

0.0 Basal Insulin AICAR

ZMP

Basal Insulin AICAR

ZMP

46 kDa

30

Percentage

**

1.0

4

20

10

0

**

1.5

6

0

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Arbitrary densitometry units

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Control Insulin AICAR

ZMP

Fig. 2. A: Glucose uptake of cardiomyocytes as measured by the accumulation of 2-deoxy-D-[3H] glucose over a 30-min incubation period after stimulation with 1 mM AICAR, 1 mM ZMP or 100 nM insulin. Values are given as multi-fold stimulation over a baseline of 1. B: PI staining of the cells was performed after treatment with insulin, AICAR and ZMP to demonstrate cell viability. All values are expressed as mean ± SEM (n = 8 individual preparations, assayed in duplicate). *p < 0.05 vs basal level; #p < 0.05 vs insulin.

of AMPK, the ability of these compounds to elicit phosphorylation of the kinase was determined. This was accomplished by measuring AMPK activation in terms of its phosphorylation on Thr172 via Western blotting and a specific antibody. In cardiomyocytes treated with AICAR (1 mM for 30 min) and ZMP (1 mM for 30 min) it was found that both substances resulted in significant phosphorylation of AMPK (Fig. 1A). Cells made anoxic by incubation in medium equilibrated with nitrogen were used as a positive control. To ascertain that the phosphorylated kinase was active, the phosphorylation of one of its downstream substrate proteins, acetyl-Co-A carboxylase (ACC) was determined on the same samples. Fig. 1B is a representative blot showing phosphorylation of AMPK and ACC after stimulation with both AICAR and ZMP, while Fig. 1C is a representative Ponceau red-stained membrane showing equal loading of protein.

AICAR

+

ZMP

+

Insulin

+

Fig 3. A: Sarcolemmal membrane distribution of GLUT4 in basal, insulin- (100 nM), AICAR- (1 mM) and ZMP- (1 mM) treated cardiomyocytes. GLUT4 was determined via Western blotting as described in Methods, on membrane fractions obtained by differential centrifugation and analysed with laser scanning densitometry. All values are expressed as mean ± SEM, (n = 5–10 individual preparations); **p < 0.01 vs basal. B: A representative Western blot to show content of GLUT4 in the membrane fraction of cardiomyocytes treated with AICAR (1 mM), ZMP (1 mM) or insulin (100 nM).

Javaux et al.40 reported in 1995 that rabbit cardiomyocytes were unable to phosphorylate AICAR to ZMP. Because of the observed inability of AICAR to elicit glucose uptake in rat cardiomyocytes, we tested the ability of ZMP to affect glucose uptake. As seen in Fig. 2A, ZMP also significantly lowered basal glucose uptake levels 0.6 ± 0.22-fold (p < 0.05). To ascertain that this was not because AICAR or ZMP influenced cell viability, PI staining was performed at the end of the experimental protocol. Fig. 2B shows that cell viability was not affected by either substance.

GLUT4 translocation in cardiomyocytes Because of the observed activation of AMPK by AICAR and ZMP, but not of glucose uptake, we assessed GLUT4 translocation under these conditions, fractionating the cells into cytosolic and membrane compartments, and then probing Western blots of the separated proteins with a specific GLUT4 antibody. As shown in Fig. 3A and B, a significant increase in GLUT4 could be seen between basal and stimulated cells in the membrane compartment (1.01 ± 0.01 arbitrary densitometry units vs insulin 1.45 ± 0.2, AICAR 1.29 ± 0.10 and ZMP 1.56 ± 0.1).

Glucose uptake

Determination of GLUT4 exofacial loop

Insulin (100 nM) increased glucose uptake significantly [7.0 ± 0.71-fold (p < 0.05)] from basal levels in the cardiomyocytes, whereas AICAR (1 mM) diminished glucose uptake 0.6 ± 0.1-fold (p < 0.05) from basal levels (Fig. 2A).

In order to understand this discrepancy, we used an antibody directed against the exofacial loop of the GLUT4 protein, coupled to flow cytometry, to determine whether the protein was properly inserted into the membrane.41 As seen in Fig. 4, these


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8

Fold stimulation

% Glut4 positive myocytes

150

100

50

* 0

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Basal SNP Insulin AICAR AICAR+SNP

Fig 4. A. Cardiomyocytes were stimulated as described in Methods, with 1 mM AICAR, 100 nM insulin and 100 µM SNP. GLUT4 protein was visualised with Alexa Fluor 488 coupled to an antibody directed against the exofacial loop of the protein. Positive cells were defined by a fixed gate and expressed as a percentage of the total cell population. All values are expressed as mean ± SEM (n = 4 individual preparations); *p < 0.05 vs basal level.

results clearly demonstrate that AICAR stimulation of GLUT4 translocation resulted in a protein not exposed on the outside of the cell. In addition, it was demonstrated that insulin treatment led to exposure of GLUT4 on the outside of the cardiomyocyte while AICAR treatment, in accordance with the diminished glucose uptake seen in Fig. 2A, attenuated the amount of protein that could be recognised by the antibody on the outer surface of the cell. It is postulated that activation of PI-3-kinase or PKB/Akt plays an important role in the docking and fusion of GLUT4 vesicles in insulin-stimulated glucose uptake.31,42 However, neither AICAR nor ZMP resulted in phosphorylation of PKB/ Akt (results not shown). It has also been described that nitric oxide (NO) is important in AMPK-mediated glucose uptake and GLUT4 translocation.43 Because myocytes produce much less NO than endothelial cells,44 we tested the effects of an NO donor, sodium nitroprusside (SNP) in combination with AICAR on the exposure of GLUT4 on the outside of cardiomyocytes, using the flow cytometric method. As shown in Fig. 4, SNP (100 µm) had no effect on the number of myocytes with the exofacial loop of GLUT4 exposed on the outside under control conditions. However, giving SNP together with AICAR led to enhanced exposure of GLUT4 on the outer surface of the cell. Contrary to expectation, this was not accompanied by enhanced glucose uptake (Fig. 5).

Discussion In this study we aimed to determine whether the pharmacological substance, AICAR, known to activate AMPK in skeletal muscle, also exerted similar effects on AMPK activation, glucose uptake and GLUT4 translocation in isolated, adult ventricular cardiac myocytes. Our results showed significantly increased AMPK phosphorylation of Thr172 in these cells after stimulation with AICAR (Fig. 1), corroborating findings in EDL skeletal muscle45 and hypothalamic cells.46 However, Longnus et al.47 were unable to detect AMPK activation with AICAR in ventricular tissue. In view of the conclusion of Javaux et al.40 that in cardiomyocytes, AICAR is probably not phosphorylated to ZMP, we similarly

6

***

***

4

2

0

Basal

SNP

Insulin

Insulin + SNP

AICAR

AICAR + SNP

Fig 5. Cardiomyocytes were stimulated as described in Fig. 4 where after they were allowed to accumulate 2-DG for a period of 30 min to determine glucose uptake. All values are expressed as mean ± SEM (n = 4 individual preparations); ***p < 0.0001 vs basal level, SNP, AICAR and AICAR + SNP.

tested the effect of ZMP and found increased phosphorylation of Thr172 also by this substance. Therefore, both AICAR and ZMP can increase phosphorylation of AMPK in isolated cardiomyocytes. An increase in AMPK activity leads to stimulation of glucose uptake in skeletal muscle.48,49 However, the significant AMPK phosphorylation noted in our study was not accompanied by a concomitant increase in cardiomyocyte glucose uptake (Fig. 2A). On the contrary, there was a significant decrease in glucose uptake seen in both the AICAR- and ZMP-treated cells. This finding underscores the work by Jessen et al.50 which showed that basal glucose transport in AICAR-exposed animals was significantly lower in all muscles when compared to controls or exercised animals. Additionally, Al-Khalili et al.51 found that both chronic and short-term exposure to AICAR induced AMPK activation in primary human skeletal myocytes but no subsequent increase in glucose uptake. In contrast to the above, Russell et al.,14 using a slightly longer incubation time, showed that in heart papillary muscle, incubations with AICAR increased glucose uptake almost twofold and led to AMPK phosphorylation and GLUT4 translocation. Papillary muscle, of course, also contains endothelial and endocardial cells. Both insulin25,34 and AMPK52,54 stimulate glucose uptake by translocation of GLUT4 to the cell membrane. In view of the findings of Russell and co-workers,14 we quantified GLUT4 movement to the cell membrane after various stimuli. Fractionating cells into cytosol and sarcolemmal membranes, insulin, AICAR and ZMP treatment resulted in significantly more GLUT4 associated with the cell membrane (Fig. 3). Therefore neither AICAR nor ZMP could stimulate glucose uptake in isolated cardiomyocytes, whereas both substances were able to phosphorylate AMPK and elicit translocation of the GLUT4 transporter from the cytosol to the cell membrane. The concept that GLUT4 translocation and activation to transport glucose are two independent although interrelated occurrences that can be separated from one another has been put forward by Furtado et al.30 To substantiate this statement, it was demonstrated that intracellular delivery of PIP3 results in GLUT4


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translocation and incorporation into the membrane, while no associated glucose uptake was detected.57 In addition, Funaki and co-workers created a cell-permeable phosphoinositide-binding peptide that could induce GLUT4 translocation to the plasma membrane in adipocytes without increasing glucose uptake.58 We used an antibody directed against the exofacial loop of the GLUT4 protein, coupled to a flow cytometric method to determine the amount of GLUT4 exposed on the outer surface of cardiocytes after stimulation with either insulin or AICAR. This method clearly demonstrated enhanced exposure with insulin but attenuated exposure with AICAR, similar to the profile of glucose uptake (Fig. 4). As this was in contrast to the results obtained by Davey et al.59 showing that ischaemia causes a marked translocation of GLUT 4 to the sarcolemmal membrane in whole beating hearts, we speculated on the possible role of NO in this process. AMPK phosphorylates endothelial nitric oxide synthase (eNOS) on Ser1177.60 According to Li et al.,61 this activation modulates glucose uptake and GLUT4 translocation in heart muscle. Although cardiomyocytes also contain NOS, isolated cardiocytes produce very little NO in comparison to cardiac endothelial cells.44 We therefore argued that the lack of NO formation and subsequent activation of the cGMP pathway may be responsible for the lack of glucose uptake in our cells. To test this, we supplemented the cells with NO with the addition of SNP. This demonstrated that indeed, simultaneous stimulation with SNP and AICAR resulted in significantly more GLUT4 protein now detectable with the antibody against the exofacial loop of the protein. However, contrary to our expectations, glucose uptake was not affected, underscoring the concept that there still has to be activation of the GLUT4 transporter after insertion into the membrane. These results then reinforce the finding of Li et al.61 that more signals than NO in addition to AMPK are necessary to induce glucose uptake. The results obtained in this study therefore argue that other, hitherto unidentified factors besides AMPK activation and GLUT4 translocation are necessary to induce glucose transport via this pathway. We furthermore concluded that these signals were not activated in the isolated cardiomyocytes via activation of AMPK, although they were active in beating cardiac muscle. Both AICAR and ZMP have proved valuable tools in this study.

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27. Becker C, Sevilla L, Tomàs E, Palacin M, Zorzano A, Fischer Y. The endosomal compartment is an insulin-sensitive recruitment site for GLUT4 and GLUT1 glucose transporters in cardiac myocytes. Endocrinolgy 2001; 142(12): 5267–5276. 28. Holloszy JO. A forty-year memoir of research on the regulation of glucose transport into muscle. Am J Physiol Endocrinol Metab 2003; 284: E453–E467. 29. Hou J C and Pessin JE. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol 2007; 19: 466–473. 30. Furtado LM, Somwar R, Sweeney G, Niu W, Klip A. Activation of the glucose transporter GLUT4 by insulin. Biochem Cell Biol 2002; 80(5): 569–78. 31. Ishiki M, Klip A. Mini-review; recent developments in the regulation of glucose transporter-4 traffic: new signals, locations. Endocrinology 2005: 146: 5071–5078. 32. Koumanov F, Jun B, Yang J, Holman GD. Insulin signaling meets vesicle traffic of GLUT 4 at a plasma-mambrane-activated fusion step. Cell Metab 2005; 2: 179–189. 33. Arias EB, Kim J, Funai K, Cartee GD. Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle. Am J Physiol Endocrinol Metab 2006; 292: E1191–E1200. 34. Donthi R, Huisamen B, Lochner A. The effect of vanadate and insulin on glucose transport in isolated adult rat cardiomyocytes. Cardiovasc Drugs Ther 2000; 14: 463–470. 35. Armstrong S, Downey JM, Ganote CE. Preconditioning of isolated rabbit cardiomyocytes: induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C. a protein kinase C inhibitor. Cardiovasc Res 1994; 28: 72–77. 36. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin Phenol reagent. J Biol Chem 1951; 193(1): 265–275. 37. Bradford MM. A sensitive method for the quantification of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 71: 248–254. 38. Takeuchi K, McGowan FX Jr, Glynn P, Moran AM, Rader CM, Cao-Danh H, et al. Glucose transporter upregulation improves ischemic tolerance in hypertrophied failing heart. Circulation 1998; 98(19 Suppl): II-234–II-239. 39. Strijdom H, Muller C, Lochner A. Direct intracellular nitric oxide detection in isolated adult cardiomyocytes: flow cytometric analysis using the fluorescent probe, diaminofluorescein. J Mol Cell Cardiol 2004; 37(4):897–902. 40. Javaux F, Vincent MF, Wagner DR, Van den Berghe G. Cell-type specificity of inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside. Lack of effect in rabbit cardiomyocytes and human erythrocytes, and inhibtion in FTO-2B rat hepatoma cells. Biochem J 1995; 305(Pt 3): 913–919. 41. Dimitriades G, Maratou E, Boutati E, Psarra K, Papasteriades C, Raptis SA. Evaluation of glucose transport and its regulation by insulin in human monocytes using flow cytometry. Cytometry Part A 2005; 64A: 27–33. 42. Tanti JF, Grillo S, Grémeaux T, Coffer PJ, Van Obberghen E, Le Marchand-Brustel Y. Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes. Endocrinology 1997; 138(5): 2005–2010. 43. Fryer LGD, Hajduch E, Rencurel F, Salt IP, Harinder S, Hundal D, et al. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 2000; 49: 1978–1985. 44. Strijdom H, Jacobs S, Hattingh S, Page C, Lochner A. Nitric oxide production is higher in rat cardiac microvascular endothelial cells than ventricular cardiomyocytes in baseline and hypoxic conditions: A comparative study. FASEB J 2006; 20(2): 314–316. 45. Lemieux K, Konrad D, Klip A, Marette A. The AMP-activated protein

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kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle. FASEB J 2003; 17(12): 1658–1665. 46. Perrin C, Knauf C, Burcelin R. Intracerebroventricular infusion of glucose, insulin and the AMP-activated kinase activator AICAR controls muscle glycogen synthesis. Endocrinology 2004; 145(9): 4025–4033. 47. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF. 5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 2003; 284(4): R936–R944. 48. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 1997; 273(6 Pt 1): E1107–E1112. 49. Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ. Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 1998; 47(8): 1369-73. 50. Jessen N, Pold R, Esben S. Buhl, ES. Jensen LS, Schmitz O, et al. Effects of AICAR and exercise on insulin-stimulated glucose uptake, insulin signalling and GLUT4 content in rat skeletal muscles. J Appl Physiol 2002; 10: 1152. 51. Al-Khalili L, Krook A, Zierath JR, Cartee GD. Prior serum- and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake. Am J Physiol Endocrinol Metab 2004; 287: E553–E557. 52. Fryer LGD, Hajduch E, Rencurel F, Salt IP, Harinder S, Hundal D, et al. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 2000; 49: 1978–1985. 53. Berger J, Hayes N, Szalkowski DM, Zhang B. PI 3-kinase activation is required for insulin stimulation of glucose transport into L6 myotubes. Biochem Biophys Res Commun 1994; 205(1): 570–576. 54. Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ. Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 1998; 47(8): 1369–1373. 55. Fisher JS, Gao J, Han DH, Holloszy JO, Nolte LA. Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol 2002; 282: E18–E23. 56. Beauloye C, Marsin AS, Bertrand L, Krause U, Hardie DG, Vanoverschelde JL, et al. Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenine nucleotides. FEBS Letts 2001; 505(3): 348–352. 57. Sweeney G, Garg RR, Ceddia RB, Li D, Ishiki M, Somwar R, et al. Intracellular delivery of phosphatidylinositol (3,4,5)-trisphosphate causes incorporation of glucose transporter 4 into the plasma membrane of muscle and fat cells without increasing glucose uptake. J Biol Chem 2004; 279(31): 32233–32242. 58. Funaki M, Randhawa P, Janmey PA. Separation of insulin signalling into distinct GLUT4 translocation and activation steps. Mol Cell Biol 2004; 24(17): 7567–7577. 59. Davey KAB, Garlick PB, Warley A, Southworth R. Immunogold labelling study of the distribution of GLUT-1 and GLUT-4 in cardiac tissue following stimulation by insulin of ischemia. Am J Physiol Heart Circ Physiol 2006; 292: 2009–2019. 60. Thors B, Halldórsson H, Thorgeirsson G. Thrombin and histamine stimulate endothelial nitric-oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3K-Akt. FEBS Letts 2004; 573: 175–180. 61. Li J, Hu X, Selvakumar P, Russel RR III, Cushman SW, Holman GD, Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol 2004; 287: E834–E841.


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Cardiovascular Topics Correlates of left ventricular mass in hypertensive Nigerians: an echocardiographic study OKECHUKWU S OGAH, AFOLABI E BAMGBOYE

Summary Background: Studies have shown that left ventricular mass, diagnosed by echocardiography, correlated poorly with blood pressure, even when the 24-hour ambulatory blood pressure monitoring was taken into account in the analysis. This may be partly because there are other determinants of left ventricular mass such as age, gender, neurohormonal factors and heredity. Knowledge of the correlates of left ventricular mass could help design individual and population strategies to prevent or reverse left ventricular hypertrophy. To the best of our knowledge, there is a paucity of such studies in native Africans. Hence the purpose of this study was to define the correlates of left ventricular mass in hypertensive Nigerians. Methods: The study was a retrospective analysis of prospectively collected data in 285 hypertensive subjects. Echocardiographic left ventricular mass was determined using the standard formula. Stepwise multiple regression analysis was used to determine the independent predictors of left ventricular mass with a probability value to enter and remove of p < 0.05. Results: There were 153 men (53.7%) and 132 women (46.3%) in the study. The mean age of all subjects was 58.2 ± 13.7 years. There was no significant gender difference in most of the echocardiographic parameters. In a stepwise multiple regression analysis, left ventricular wall tension, left ventricular wall stress, left atrial size, diastolic blood pressure, alcohol consumption and a family history of hypertension were the independent predictors of left ventricular mass in this population. The optimum multivariate linear regression main effects had an adjusted model, r2 of 0.945, thus explaining about 95% of left ventricular mass variability. Conclusion: Mechanical or haemodynamic factors possibly interacting with genetic and social factors are the likely determinants of left ventricular mass in hypertensive Nigerians. Therefore modulation of some of these factors pharmacologically or non-pharmacologically will be of benefit in the management of this patient population. Department of Medicine, Federal Medical Centre, Idi-Aba, Abeokuta, Nigeria OKECHUKWU S OGAH, MB BS, Dipl, MSc, FWACP, osogah56156@yahoo.com

Departments of Epidemiology, Medical Statistics and Environmental Health (EMSEH), College of Medicine, University of Ibadan, Nigeria AFOLABI E BAMGBOYE, PhD

Keywords: hypertension, left ventricular mass, correlates, determinants, Nigeria Submitted 22/6/09, accepted 13/8/09 Cardiovasc J Afr 2010; 21: 79–85

www.cvja.co.za

Left ventricular hypertrophy (LVH) has been shown to be a significant risk factor for adverse outcomes both in patients with hypertension and in the general population.1,2 Although for many years LVH was thought to be a beneficial compensatory mechanism for maintaining wall stress in left ventricular (LV) pressure and volume overloads, epidemiological studies using electrocardiography (ECG) and more recently echocardiography (ECHO) have elucidated the profound independent risk of LVH for congestive heart failure (CHF),3,4 coronary artery disease (CAD),5,6 life-threatening arrhythmias7 and cardiac mortality.1-4 Studies have shown that, among other things, increased left ventricular mass (LVM) is associated with a significant excess of cardiovascular morbidity and mortality.8 This is independent of the co-existence of coronary artery disease and hypertension.8 There is a threefold increase in the mortality rate in persons with either of these conditions in addition to increased LVM.8 The risks of coronary, peripheral or cerebral vascular disease are also raised even among normotensive individuals with LVH.1,3,4 LVH defined by ECG has been shown to be an independent risk factor for cardiovascular events.4 More recently LVH defined by echocardiography, a more sensitive diagnostic tool, has similarly been shown to increase cardiac risk.9 Recent data from the LIFE study (Losartan Intervention For Endpoint reduction in hypertension) revealed a close correlation between microalbuminuria and ECG-determined LVH.10-12 Regression of LVH has also been shown to be possible using either antihypertensive drugs (except hydralazine and minoxidil) or non-pharmacological lifestyle modifications. Therefore an understanding of the factors promoting increased LVM in hypertensive Nigerians may permit the development of strategies aimed primarily at preventing LVH or promoting regression more effectively. Moreover, to the best of our knowledge, no work of this nature has been carried out in this environment. The objectives of the present study were to assess the nonhaemodynamic and haemodynamic correlates of LVM among hypertensive Nigerians seen at the University College Hospital (UCH), Ibadan, Nigeria.

Methods The study was carried out at the Medical Outpatient Unit of the University College Hospital, Nigeria. It was a retrospective anal-


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ysis of prospectively collected data. Eligible patients were men and women aged 18 years and older with established hypertension, who were attending the hypertension clinic at the hospital. Diagnosis of hypertension was based on systolic blood pressure of ≥ 140 mmHg and diastolic blood pressure of ≥ 90 mmHg or those on antihypertensive therapy.13 Subjects with a previous history or symptoms of ischaemic heart disease, echocardiographic evidence of regional wall motion abnormalities, or established congestive heart failure were excluded from the study. Other exclusion criteria included patients with hypertrophic cardiomyopathy, left bundle branch block and those with incomplete echocardiography reports. Ethical approval was obtained from the institution’s ethical review board. The estimated minimum sample size was 255 hypertensive subjects. The calculation of the minimum sample size was based on the prevalence of echocardiographic LVH in hypertensive subjects at the UCH, Ibadan, which was between 16.5 and 25.8% depending on the cut-off value used in defining LVH.14 The study power was 80% (20% beta error) and the alpha error was set at 5% (0.05).

Clinical evaluation Baseline clinical and demographic characteristics were obtained from the subjects’ case notes. These included date of birth (age), gender, history of diabetes, history of smoking, duration of their hypertension, and family history of hypertension. Also obtained were the blood pressure, pulse rate, body weight and height at the time of echocardiography. Body mass index (BMI) was calculated using the formula: weight

Calculation of echocardiographically derived variables Left ventricular mass was calculated using the formula that has been shown to yield values closely related (r = 0.90) to necropsy LV weight and which has good inter-study reproducibility.18 LVM (ASE) = 0.8 [1.04 (IVSTd + LVIDd + PWTd) 3 + 0.6 g Relative wall thickness was calculated as twice the posterior wall thickness/LV internal dimension in diastole. Relative wall thickness of 0.43 or greater was considered abnormal.19 LV hypertrophy was considered present when LV mass exceeded 51 g/m2.7 in both men and women.

Haemodynamics Left ventricular volumes were estimated using the formula of Teichholz et al.20 These include: LV end-diastolic volume, LV-end systolic volume, stroke volume and cardiac output. These measurements have been validated with the invasive Doppler echocardiographic method.21 LV end-diastolic volume (EDV) (ml) = 7[LV internal in diastole (LVIDd) + 2.4] × LVIDd LV end-systolic volume (ESV) (ml) = 7[LV internal in systole (LVIDs) + 2.4] × LVIDs Stroke volume (SV) (ml) = EDV – ESV Cardiac output (CO) (ml) = SV × heart rate (HR)

​ height2   ​ BMI (kg/m2) = _____

Mean arterial blood pressure (MAP) (mmHg) was calculated as: diastolic BP + 1/3 pulse pressure

Body surface area (BSA) was calculated using the formula of Dubois:15

  ​ Total peripheral resistance was assessed as: ​ ________ CO   

BSA (m2) = 0.0001 × 71.84 × [weight (kg)]0.425 × [height (cm)]0.725

Pulse pressure (mmHg) was estimated as: SBP – DBP

MAP × 80

100 × (LVIDd – LVIDs)

Echocardiography All the echocardiograms were performed with the use of a commercially available echo-machine (ALOKA SSD-1, 700) and a 3.5-MHz linear array transducer. This was performed on each subject in the left lateral decubitus position. All measurements were made according to the American Society of Echocardiography leading edge-to-leading edge criteria.16 LV measurement was obtained at end-diastole and end-systole. The LV measurements recorded included interventricular septal thickness at end-diastole (IVSTd), posterior wall thickness at end-diastole (PWTd), and the LV internal dimensions at end-systole (LVIDs) and end-diastole (LVIDd). Other parameters obtained were left atrial diameter, aortic root diameter, indices of LV diastolic function [early-filling velocity (E-velocity), latefilling velocity (A-velocity) and deceleration time (DT)]. Two experienced cardiologists performed the echocardiography. In our laboratory, the intra-observer concordance correlation coefficient ranged from 0.76 to 0.98 while that of the interobserver concordance ranged from 0.82 to 0.96.17

Fractional shortening (%) = ​ _________________   ​ LVIDd    100 × (EDV – ESV)

Ejection fraction (%) = ​ ______________ EDV     ​  The ratio of pulse pressure to stroke volume was used as an indirect estimate of global arterial stiffness.22,23 LV peak wall stress (dynes/cm2) was calculated as: 0.86 × (0.334 × SBP × LVIDd)

​ _______________________         (PWTd × 1 + PWTd) – 2 LVIDd ​ 1.333 × SBP × LVIDs

LV systolic wall tension (dynes) = ​ ________________ 2     ​ 

Statistical analysis SPSS version 11.0 (SPSS, Inc, Chicago Illinois) was used for statistical analysis. Continuous variables were expressed as mean ± SD and categorical variables as percentages. We assessed differences in categorical variables by Chi-square analysis while the unpaired t-test was used for comparison of continuous variables between men and women.


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To determine the independent predictors of LV mass, multiple regression models were created. Univariate regression was first performed for each continuous and categorical variable. Thereafter variables having a significant correlation with LVM were entered in stepwise multiple regression models. In the final model, variables that exhibited a high degree of collinearity were added or deleted iteratively. This was to achieve a model with consistency and conciseness. The probability value to enter and remove was set at p ≤ 0.05.

Results Of the 285 subjects enrolled, there were 153 men (53.7%) and 132 women (46.3%); overall mean age was 58.2 ± 13 years. Of these, 146 patients were presenting for the first time at the hypertension clinic (51.2%). About 70.2% of the subjects were on thiazide diuretics and 56% were on calcium channel blockers. Angiotensin receptor

blockers and beta-blockers were prescribed for 44.6 and 13.7% of the subjects, respectively. More than 60% of the subjects were receiving two or more classes of drugs. The clinical and demographic characteristics of the subjects are shown in Table 1. There was no significant difference in the mean age between the genders. The men were taller than the women (p = 0.0006) while the women were heavier than the men (BMI, 27.2 ± 5.6 vs 25.6 ± 4.8 for women and men, respectively. About 64% of the women were overweight compared to 51% of the men. The duration of hypertension was longer in the men than the women. A history of alcohol consumption was also commoner in men. A positive family history of hypertension was obtained in 43 subjects and more often in men. There was no significant difference in blood pressure, heart rate, history of cigarette smoking, presence of diabetes mellitus, marital status and origin of subjects between the two genders. Table 2 depicts the biochemical characteristics of the subjects.

TABLE 1. BASELINE CHARACTERISTIC OF 285 HYPERTENSIVE SUBJECTS SEEN AT UCH, IBADAN, ACCORDING TO GENDER Parameter All subjects (n = 285) Women (n = 132) Men (n = 153) p-value Age (years) 58.2 ± 13.7 57.6 ± 13.2 58.8 ± 14.1 0.468 Body weight (kg) 69.7 ± 13.5 70.3 ± 15.1 69.1 ± 11.9 0.436 Height (cm) 162.8 ± 8.7 161.0 ± 8.5 164.5 ± 8.6 0.0006 2 26.3 ± 5.0 27.2 ± 5.6 25.6 ± 4.8 0.00081 BMI (kg/m ) 1.74 ± 0.18 1.74 ± 0.19 1.75 ± 0.62 0.428 BSA (m2) SBP (mmHg) 153.2 ± 29.5 150.7 ± 24.3 155.3 ± 33.2 0.193 DBP (mmHg) 94.2 ± 18.0 92.0 ± 14.5 96.0 ± 20.5 Pulse press (mmHg) 59.0 ± 21.9 58.7 ± 19.8 59.3 ± 23.5 0.815 MAP (mmHg) 113.8 ± 20.0 111.6 ± 15.8 115.8 ± 22.8 0.080 Heart rate (beats/min) 80.3 ± 19.2 82.2 ± 18.4 78.3 ± 19.8 0.133 Duration of hypertension 4.0 ± 7.4 2.55 ± 5.9 5.19 ± 8.20 0.004 (range in years) (0–30) (0–30) (0–30) Alcohol consumers 70 25 45 0.028 Cigarette smokers 31 11 20 0.138 Diabetes mellitus 17 8 9 0.572 Family history of hypertension 43 17 30 0.085 Overweight/obese (%) 159 (55.8) 84 (63.6) 77 (51) 0.035 Married (%) 249 (87.4) 111 (84.1) 138 (90.2) 0.162 BMI = body mass index, BSA = body surface area, SBP = systolic blood pressure, DBP = diastolic blood pressure, MAP = mean arterial blood pressure. TABLE 2. THE BIOCHEMICAL PARAMETERS OF HYPERTENSIVE SUBJECTS SEEN AT UCH, IBADAN, ACCORDING TO GENDER Parameter All subjects Women Men Sodium (mmol/l) 138.4 ± 6.4 138.8 ± 5.0 138.1 ± 7.1 Potassium (mmol/l) 3.77 ± 0.67 3.65 ± 0.63 3.78 ± 0.59 Creatinine (mg/dl) 1.57 ± 1.31 1.26 ± 0.32 1.79 ± 1.67 Uric acid (mg/dl) 7.4 ± 2.9 6.63 ± 2.27 7.91 ± 3.14 Fasting blood glucose (mg/dl) 111.1 ± 49.4 111.3 ± 38.5 110.9 ± 57.1 2-hour postprandial glucose (mg/dl) 135.2 ± 74.4 129.6 ± 55.3 140.3 ± 88.7 Total cholesterol (mg/dl) 190.7 ± 52.3 195.6 ± 43.5 186.9 ± 58.2 TG (mg/dl) 82.6 ± 7.9 113.5 ± 79.2 117.8 ± 85.7 HDL (mg/dl) 43.7 ± 20.0 47.02 ± 23.4 41.2 ± 20.8 LDL (mg/dl) 124.6 ± 50.0 128.6 ± 45.8 121.5 ± 53.1 TG = triglycerides, HDL = high-density lipoprotein cholesterol, LDL = low density lipoprotein cholesterol.

p-value 0.488 0.202 0.0064 0.066 0.962 0.489 0.391 0.782 0.180 0.470


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Echocardiographic findings Tables 3 and 4 summarise the echocardiographic parameters. Except for septal wall thickness and indices of LV systolic function (ejection fraction and fractional shortening), which where higher in men, all the parameters were similar in the men and women. When the subjects were grouped into those with increased LV mass (left ventricular hypertrophy) and those with normal LV mass, significant differences were found in their clinical, biochemical and echocardiographic characteristics. Hypertensive subjects with left ventricular hypertrophy were found to be older, heavier and had higher baseline systolic, diastolic and mean arterial blood pressures. Their resting heart rate was also significantly higher. They had higher serum sodium, lower serum potassium (0.015), higher serum creatinine and higher uric acid levels. This group also had higher fasting blood glucose and lipid profiles (total cholesterol, triglycerides and LDL cholesterol). Accordingly they also had lower mean HDL cholesterol levels. Comparison of their echocardiographic variables revealed

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that subjects with increased LV mass (LVH) had larger aortic root diameters, left atrial diameters and LV wall thickness. LV internal dimensions (both in systole and diastole), LV enddiastolic and end-systolic volumes, stroke volume and cardiac output were also higher in the group with LVH. On the other hand, subjects with increased LVM had lower indices of LV systolic function (ejection fraction and fractional shortening), relative wall thickness, total peripheral resistance and pulse pressure–stroke volume ratio. These were all statistically significant. There was no difference in the indices of LV diastolic function (E-velocity, A-velocity, E/A ratio and deceleration time).

Determinants of LV mass As shown in Table 5, LV mass correlated fairly well with duration of hypertension (r = 0.123), alcohol consumption (r = 0.209), cigarette smoking (r = 0.190), presence of diabetes mellitus (r = 0.187), body weight (r = 187) and height (r =

TABLE 3. THE ECHOCARDIOGRAPHIC PARAMETERS OF 285 HYPERTENSIVE SUBJECTS SEEN AT UCH, IBADAN Parameter All subjects Women Men p-value Aortic root diameter (cm) 2.87 ± 0.43 2.84 ± 0.40 2.89 ± 0.46 0.354 LA (cm) 3.52 ± 0.72 3.48 ± 0.67 3.56 ± 0.76 0.378 Septum (cm) 1.07 ± 0.28 1.03 ± 0.207 1.11 ± 0.33 0.013 PWTd 0.997 ± 0.22 0.996 ± 0.211 0.998 ± 0.228 0.947 LVIDd 4.86 ± 0.95 4.84 ± 0.91 4.87 ± 0.99 0.817 LVIDs 3.34 ± 0.96 3.39 ± 0.93 3.30 ± 0.99 0.457 E-velocity 0.59 ± 0.22 1.123 ± 0.76 1.03 ± 0.70 0.757 A-velocity 0.61 ± 0.19 58.7 ± 19.8 59.3 ± 23.5 0.0806 E/A ratio 1.07 ± 0.58 1.02 ± 0.46 1.11 ± 6.65 0.190 Deceleration time 199.7 ± 60.8 196.1 ± 61.3 202.5 ± 60.5 0.426 LA = left atrial diameter, PWTd = posterior wall thickness in diastole, LVIDd = LV internal diameter in diastole, LVIDs = LV internal diameter in systole, E = early left ventricular filling phase, A = late left ventricular filling phase. TABLE 4. THE ECHOCARDIOGRAPHICALLY DERIVED PARAMETERS IN 285 HYPERTENSIVE MEN AND WOMEN SEEN AT UCH, IBADAN Parameter All subjects Women LVM 188.7 ± 82.4 180.7 ± 67.0 50.8 ± 22.1 49.6 ± 16.6 LVM/height2.7 LVM/BSA 116.0 ± 49.9 104.2 ± 37.3 LVM/hypertension 108.6 ± 46.9 111.7 ± 39.1 Relative wall thickness 0.43 ± 0.13 0.428 ± 0.13 LVH/no LVH 111/174 58/74 Fractional shortening (%) 32.0 ± 9.2 30.7 ± 9.96 Ejection fraction (%) 58.9 ± 13.4 57.0 ± 14.2 End-diastolic volume (ml) 116.6 ± 54.9 115.3 ± 50.6 End-systolic volume (ml) 51.5 ± 38.7 52.6 ± 36.4 Stroke volume (ml) 65.2 ± 25.7 62.7 ± 25.2 1.74 ± 0.18 1.735 ± 0.191 Stroke index (ml/m2) Cardiac output (ml) 5275 ± 2636 5192 ± 2606 3.04 ± 1.50 300.94 ± 1472.2 Cardiac index (ml/m2) Total peripheral resistance (dynes/ml) 0.027 ± 0.015 0.027 ± 0.16 Pulse pressure–stroke volume ratio 1.07 ± 0.73 1.13 ± 0.75 2 338.6 ± 119.9 335.9 ± 106.0 Wall stress (dynes/cm ) 186.5 ± 75.9 181.7 ± 68.3 Wall tension (dynes/cm2) LVM = left ventricular mass, LVH = left ventricular hypertrophy, BSA = body surface area.

Men 195.7 ± 93.3 51.9 ± 26.0 112.5 ± 53.8 119.8 ± 57.6 0.428 ± 0.14 53/100 33.0 ± 8.75 60.5 ± 12.6 117.7 ± 58.4 50.5 ± 40.6 67.2 ± 26.1 1.751 ± 0.162 5348 ± 2669 3072.8 ± 152.40 0.026 ± 0.013 1.03 ± 0.70 340.9 ± 131.0 190.7 ± 82.0

p- value 0.124 0.394 0.141 0.172 0.985 0.145 0.033 0.027 0.711 0.651 0.140 0.428 0.623 0.725 0.497 0.247 0.724 0.319


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TABLE 5. CORRELATION OF LV MASS WITH CLINICAL, BIOCHEMICAL AND OTHER ECHOCARDIOGRAPHIC VARIABLES IN 285 HYPERTENSIVE SUBJECTS SEEN AT UCH, IBADAN Parameter Age (years) Gender (male vs female)* Duration (years) Alcohol consumption (yes/no)* Cigarette smoking (yes/no)* Family history of hypertension (yes/no)* Diabetes mellitus (yes/no)* Weight (kg) Height (cm) Body mass index (kg/m2) Body surface area (m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Mean arterial pressure (mmHg) Sodium (mmol/l) Potassium (mmol/l) Creatinine (mg/dl) Uric acid (mg/dl) Fasting blood glucose (mg/dl) 2-hour postprandial glucose (mg/dl) Total cholesterol (mg/dl) Triglycerides (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Heart rate (beats/min) Aortic root diameter (cm) Left atrial diameter (cm) Septal wall thickness (cm) LV posterior wall thickness (cm) LV end-diastolic diameter (cm) LV end-systolic diameter (cm) Relative wall thickness (cm) Fractional shortening (%) Ejection fraction (%) End-diastolic volume (ml) End-systolic volume (ml) Stroke volume (ml) Stroke index (ml/m2) Cardiac output (ml) Cardiac index (ml/m2) Total peripheral resistance Pulse pressure–stroke volume ratio Wall stress (dynes/cm2) Wall tension Mitral early velocity (E) Mitral late velocity(A) E/A ratio Deceleration time *Values were entered as dummy variables.

r

r2

p-value

0.061 0.091 0.123 0.209 0.190 0.074 0.139 0.187 0.195 0.065 0.228 0.200 0.235 0.076 0.239 0.017 –0.123 0.225 0.362 0.071 0.046 0.121 –0.013 –0.063 0.109 0.092 0.238 0.514 0.588 0.426 0.718 0.694 –0.126 –0.380 –0.415 0.727 0.989 0.518 0.228 0.458 0.414 –0.329 –0.284 0.670 0.255 0.089 –0.050 0.110 –0.072

0.004 0.008 0.015 0.044 0.36 0.005 0.019 0.035 0.038 0.004 0.052 0.040 0.050 0.006 0.057 0.0002 0.015 0.051 0.131 0.005 0.002 0.015 0.0001 0.004 0.012 0.009 0.056 0.264 0.346 0.182 0.516 0.482 0.016 0.144 0.172 0.528 0.471 0.269 0.052 0.210 0.171 0.108 0.018 0.449 0.065 0.008 0.002 0.012 0.005

0.302 0.124 0.046 0.0004 0.0012 0.214 0.0185 0.0016 0.0010 0.280 0.001 0.0007 < 0.0001 0.203 < 0.0001 0.831 0.118 0.002 0.0002 0.420 0.658 0.189 0.886 0.516 0.268 0.123 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.034 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.005 0.168 0.443 0.090 0.279

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0.195). LV mass was also positively related with body surface area (r = 0.228), systolic BP (r = 0.200) diastolic BP (r = 0.235) and mean arterial BP (r = 0. 239). Serum creatinine (r = 0.225), serum uric acid (r = 0.362), aortic root diameter (r = 0.238), left atrial diameter (r = 0.514), LV end-diastolic volume (r = 0.727) and LV end-systolic volume (r = 0.989) were all positively and directly related to LV mass. All the haemodynamic parameters also showed a relationship with LV mass. The relationship was mostly positive except for fractional shortening (r = –0.380), ejection fraction (r = –0.415), total peripheral resistance (r = –0.329) and pulse pressure/stroke volume ratio (r = –0.284), which showed a negative relationship with LV mass. LVM was not significantly related to indices of LV diastolic function. However the relationship with A-velocity and deceleration time was negative In a stepwise multivariate linear regression analysis, the independent predictors of LV mass were LV wall tension, left atrial diameter, LV wall stress, LV end-diastolic volume, diastolic blood pressure, family history of hypertension, and alcohol consumption. These variables explained about 95% of the variability in LV mass (Table 6). A sub-analysis of the newly presenting hypertensive subjects did not yield additional or different information.

Discussion Left ventricular mass is a powerful and independent risk factor for cardiovascular events. In this study, the prevalence of echocardiographically defined LVH in subjects aged 20 to 94 years was 38.9%. Previous studies have reported prevalences ranging from 15 to 64%.24-26 In a study of 50 untreated hypertensive and 50 normotensive subjects, Ganau et al.27,28 showed that systolic BP, stroke–volume index and end-systolic stress/volume index ratio were strong determinants of indexed LVM. Another study by Jones and colleagues29 also observed that changes in haemodynamic load may induce LVH and abnormal LV remodelling in hypertension. These parameters were determined in the present study, where it was found that LVM correlated with end-diastolic volume, end-systolic volume, stroke volume, stroke index, cardiac output and cardiac index. LVM was also found in this study to be related to total peripheral resistance, pulse pressure/stroke volume ratio, LV wall tension and LV wall stress. Dahan and colleagues30 reported LV end-diastolic volume and end-systolic meridional stress-to-volume ratio as the main determinants of LVM in a population of patients on haemodialysis. A recent comprehensive report by Chen and co-workers31 TABLE 6. INDEPENDENT PREDICTORS OF LV MASS IN HYPERTENSIVE SUBJECTS SEEN AT UCH, IBADAN Variable b SE Wall tension 0.277 0.0 Left atrial diameter 17.55 5.74 Wall stress –0.794 0.067 LV end-diastolic volume 1.465 0.118 Diastolic BP 0.557 0.215 Family history of hypertension 18.10 7.87 r2 = 0.952 (adjusted 0.945), F = 138.77, p = 0.000.

Beta p-value 0.324 0.000 0.131 0.004 –0.691 0.000 0.941 0.000 0.122 0.012 0.082 0.026


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is also in keeping with our findings. Major predictors of LVM in our model included LV wall tension, left atrial size, LV wall stress, LV end-diastolic diameter, diastolic BP, family history of hypertension and alcohol consumption. Parameters that cause the left ventricle to remodel can be categorised as those that affect the external or internal LV loads. To date, it is still unclear how many vascular parameters affect cardiac load. The vascular or haemodynamic parameters may affect blood pressure, properties of the arterial wall, or size of the arteries. For example, systolic blood pressure imposes external load on the left ventricle. It is a reflection of the ejection force of the heart and is influenced by factors such as arterial wall stiffness and transmission speed. On the other hand, diastolic blood pressure determines the LV end-diastolic pressure, which is the pressure required for the aortic valve to open. It affects the internal load of the left ventricle. In our model, diastolic blood pressure was found to be an independent determinant of LV mass. Its role as a predictor of LVM stems from the fact that stretch on the cardiac myocytes is a stimulant for cardiac hypertrophy. It causes activation of intracellular messengers, changes in ionic homeostasis, and increased synthesis of various proteins as well as growth factors.32 All these can result in cardiac muscle hypertrophy. The same applies to the role of LV wall tension and wall stress as a predictor of LV mass. The association between alcohol consumption and LV mass is not well established. A previous report on a Caucasians population has shown that heavy drinking has a positive but weak association with LV mass.33 On the contrary, Sax et al.34 did not observe any relationship between alcohol consumption and LVM. Our finding that a family history of hypertension is a strong predictor of LV mass corroborates the report of other workers. It has been demonstrated that LV mass is significantly elevated in normotensive offspring of hypertensive parents, and siblings of people with LVH.35 Moreover, studies on twins have shown some influence of genetics on LV mass, which was independent of other factors.36 This may not be unconnected with higher ambulatory blood pressure loads.

Negative observations We did not observe the independent relationship between body mass index and LVM previously reported by other workers.37,38 BMI showed a weak correlation with LVM in the univariate regression analysis. On the other hand, there was a strong association between BSA and LV mass in this study as reported by some workers, but not an independent determinant. This study did not find age as an independent determinant of LVM as previously reported.24,39 Its correlation with LV mass was also weak in the univariate analysis (r = 0.061). There was little gender difference in the echocardiographic parameters. Gender also correlated weakly with LV mass. Two possible reasons are that (1) the influence of gender on LV mass could have been accounted for by other factors such as height, weight and body surface area; (2) the choice of a non-genderspecific partition value for the definition of LVH in this study could have obliterated any gender difference. Some workers have reported gender as a determinant of LV mass.40,41 Aortic root diameter did not enter our model as a predictor of LVM. The study by Chan et al.31 has reported aortic root diameter as one of the five strongest determinants of LV mass in

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their subjects, apart from stroke volume, systolic BP, BMI and end-systolic meridional stress-to-volume ratio. Although total peripheral resistance showed a strong relationship with LVM in the univariate analysis, it was not an independent predictor of LVM. This corroborates some studies that showed that vascular resistance is not a good index of haemodynamic loading.42 We also confirmed the rather surprising, inappropriate and negative relationship between LV mass and indexes of arterial stiffness noted earlier by Chan et al.31

Limitations of the study The first limitation of the study was the fact that it was retrospective and cross-sectional. It can only claim association but not causality. Secondly, clinic or casual blood pressure was measured in the subjects. Many studies have shown that ambulatory blood pressure is more closely associated with LV mass than clinic blood pressure. Thirdly, other variables such as insulin resistance, blood viscosity, and carotid intima–media thickness that have been documented as determinants of LV mass were not assessed in this study. Fourthly, this study did not correlate ECG findings with ECHO findings. The authors will explore this in future research. Lastly, there may be concern about the independence of the haemodynamic parameters, which were derived from some M-mode measurements also used in the calculation of LV mass. This concern has been addressed in the recent report by Chan et al.31 They tested the reliability of M-mode parameters by comparing them with those obtained with the two-dimensional echocardiographic truncated ellipsoid formula, which were devoid of M-mode-derived parameters in 1 238 subjects. They noted a lower overall model variance (0.59 vs 0.74) but with the same top predictors of LV mass contributing to 98% of the total variance.

Conclusion This study found that the most important determinants of LV mass were LV wall tension, left atrial size, LV wall stress, diastolic BP, a family history of hypertension, and alcohol consumption. These factors appeared to explain about 95% of the variability in LV mass in hypertensive Nigerians seen at the University College Hospital, Ibadan. Mechanical or haemodynamic factors, possibly interacting with genetic and social factors are the likely determinants of LV mass in Nigerian hypertensive men and women. Therefore modulation of these factors pharmacologically or non-pharmacologically will be of benefit in the management and control of hypertension in this population. The implications of this study are that measures that effectively modulate wall stress and wall tension as well as blood pressure control, for example antihypertensive therapy, can cause early regression of LVH. Early screening of relatives of hypertensive subjects may provide an effective blood pressure-control programme. Non-pharmacological treatment such as avoidance of excessive alcohol consumption may be an effective tool in a blood pressure-control programme. However, based on the recent findings by the LIFE study,10-12 which showed a correlation between ECG and ECHO findings, as well as the recommendation of the World Heart Organisation, ‘echocardiography in hypertensive patients in sub-Saharan Africa should be used only for research purposes and is not cost effective in resource-poor countries’.


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References 1. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart study. N Engl J Med 1990; 322: 1561. 2. Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension. J Am Coll Cardiol 1998; 31(2): 383–390. 3. Levy D. Clinical significance of left ventricular hypertrophy: insights from the Framingham study. J Cardiovasc Pharmacol 1991; 17(Suppl 2): S1–6. 4. Levy D, Salomon M, D’Agostino RB, Belanger AJ, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994; 90(4): 1786–1793. 5. Galderisi M, Lauer MS, Levy D. Echocardiographic determinants of clinical outcome in subjects with coronary artery disease (the Framingham Heart Study). Am J Cardiol 1992; 70(11): 971–976. 6. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart study. Ann Intern Med 1989; 110(2): 101–107. 7. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987; 60(7): 560–565. 8. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart study. N Engl J Med 1990; 322(22): 1561– 1566. 9. Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic value of left ventricular mass and geometry in systemic hypertension with left ventricular hypertrophy. Am J Cardiol 1996; 78(2): 197–202. 10. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359(9311): 995–1003. 11. Kjeldsen SE, Dahlof B, Devereux RB, et al. Lowering of blood pressure and predictors of response in patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint. Am J Hypertens 2000; 13(8): 899–906. 12. Wachtell K, Olsen MH, Dahlof B, et al. Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. J Hypertens 2002; 20(3): 405–412. 13. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (The JNC 7 Report). J Am Med Assoc 2003; 289(19): 2560–2572. 14. Adebiyi AA, Ogah OS, Aje A, et al. Echocardiographic partition values and prevalence of left ventricular hypertrophy in hypertensive Nigerians. BMC Med Imaging 2006; 6: 10. 15. Du Bois D, Du Bois E. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916; 17: 863–867. 16. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458. 17. Adebiyi AA, AJE A, Ogah OS, et al. Correlates of left atrial size in Nigerian hypertensives. Cardiovasc J South Afr 2005; 16(3): 201–204. 18. Devereux RB, E.M L, Casale PN, et al. Standardization of M-Mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 1984; 4: 1222. 19. Roman MJ, Pickering TG, Schwartz JE, Pini R, Devereux RB. Association of carotid atherosclerosis and left ventricular hypertrophy. J Am Coll Cardiol 1995; 25(1): 83–90. 20. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determination: echocardiographic–angiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976;

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37: 7–11. 21. Devereux RB, Roman MJ, Paranicas M, et al. Relation of Doppler stroke distance and aortic annular diameter to left ventricular stroke volume in normotensive and hypertensive American Indians: the strong Heart study. Am J Hypertens 1997; 10: 619–628. 22. Ferguson JJ, Julius S, Randall OS. Stroke volume:pulse pressure relationships in borderline hypertension: a possible indicator of decreased arterial compliance. J Hypertens 1984; 2(Suppl 3): 397–399. 23. Randall OS, Westerhof N, VanDen Bos GC, Alexander B. Reliability of stroke volume to pulse pressure ratio for estimating and detecting changes in arterial compliance. J Hypertens 1986; 4(Suppl 5): S293–S296. 24. Liebson PR, Granditis G, Prineas R, et al. Echocardiographic correlates of left ventricular structure among 844 mildly hypertensive men and women in the Treatment Of Mild Hypertension Study (TOHMS). Circulation 1993; 87: 476. 25. Tingleff J, Munch M, Jakobsen TJ, et al. Prevalence of left ventricular hypertrophy in a hypertensive population. Eur Heart J 1996; 17(1): 143–149. 26. Tingleff J, Munch M, Jakobsen TJ, et al. [Prevalence of left ventricular hypertrophy in Danish patients with hypertension]. Ugeskr Laeger 1997; 159(37): 5529–5533. 27. Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992; 19(7): 1550–1558. 28. Ganau A, Saba PS, Roman MJ, de Simone G, Realdi G, Devereux RB. Ageing induces left ventricular concentric remodelling in normotensive subjects. J Hypertens 1995; 13(12 Pt 2): 1818–1822. 29. Jones EC, Devereaux RB, O’Grady MJ, et al. Relation of haemodynamic load to arterial and cardiac size. J Am Coll Cardiol 1997; 29:1303–1310. 30. Dahan M, Siohan P, Viron B, et al. Relationship between Left ventricular hypertrophy, myocardial contractility, and load conditions in haemodialysis patients: an echocardiographic study. Am J Kidney Dis 1997; 30: 780–785. 31. Chen C, Ting C, Lin S, et al. Which arterial and cardiac parameters best predict left ventricular mass? Circulation 1998; 98: 422–428. 32. Lakatta EG. Similar myocardial effects of aging and hypertension. Eur Heart J 1990; 11(Suppl G): 29–38. 33. Manolio TA, Levy D, Garrison RJ, Castelli WP, Kannel WB. Relation of alcohol intake to left ventricular mass: The Framingham Study. J Am Coll Cardiol 1991; 17(3): 717–721. 34. Sax FL, Brush JE, Cannon RO, et al. Impaired left ventricular filling in symptomatic compared to asymptomatic hypertensive patients (abstract). J Am Coll Cardiol 1988; 11: 81A. 35. Schunkert H. Obesity and target organ damage: the heart. Int J Obes Relat Metab Disord 2002; 26(Suppl 4): S15–20. 36. Post WS, Larson MG, Myers RH, Galderisi M, Levy D. Heritability of left ventricular mass:The Framingham Heart study. Hypertension 1997; 30: 1025–1028. 37. Messerli FH. Clinical Determinants and Manifestations of Left Ventricular Hypertrophy. New York: Yorke Medical Books, 1987. 38. Rasooly Y, Sasson Z, Gupta R. Relation between body fat distribution and left ventricular mass in men without structural heart disease or systemic hypertension. Am J Cardiol 1993; 71: 1477. 39. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham study). Am J Cardiol 1989; 64: 1066. 40. Marcus R, Krause L, Weder AB, Dominguez-Meja A, Schork NJ, Julius S. Sex-specific determinants of increased left ventricular mass in the Tecumseh Blood Pressure Study. Circulation 1994; 90(2): 928–936. 41. Koenig H, Goldstone A, Lu CY. Testosterone-medicated sexual dimorphism in the rodent heart: Ventricular lysosomes, mitochondria, and cell growth are modulated by androgens. Circ Res 1982; 50: 782. 42. Devereaux RB. Towards a more understanding of left ventricular afterload. J Am Coll Cardiol 1991; 17: 122–124.


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Cardiovascular Topics Medication adherence, self-care behaviour and knowledge on heart failure in urban South Africa: the Heart of Soweto study VERENA RUF, SIMON STEWART, SANDRA PRETORIUS, MAUREEN KUBHEKA, CHRISTINE LAUTENSCHLÄGER, PETER PRESEK, KAREN SLIWA

Summary Background: There is a paucity of data on treatment adherence in patients with chronic heart failure (CHF) in Africa. Methods: We examined the pattern of treatment adherence, self-care behaviour and treatment knowledge in 200 consecutive patients with CHF attending the Chris Hani Baragwanath Hospital, Soweto, South Africa via a combination of questionnaire (100%, n = 200) and pill count (41%, n = 82). Results: Mean age was 56 ± 14 years, 157 were black African (79%) and 109 (55%) were male. CHF-specific treatment included loop diuretics (93%), beta-blockers (84%), ACE inhibitors (74%), spironolactone (64%) and cardiac glycosides (24%); mean number of medications was 6 ± 2. Overall, 71% (58 of 82) adhered to their prescribed CHF regimen and individual medication adherence ranged from 64 to 79%. Behavioural adherence varied from 2.5 to 98%. Patient treatment knowledge was poor; 56% could not name medication effects or side effects. However, an average knowledge score of 69% was achieved on 10 questions concerning CHF management. Conclusion: As in other regions of the world, non-adherence to complex CHF treatment is a substantial problem in Soweto. Our data confirm the need for a dedicated CHF management programme to optimise CHF-related outcomes in a low-resource environment. Soweto Cardiovascular Research Unit, Department of Cardiology, Chris Hani-Baragwanath Hospital, Soweto, Johannesburg, South Africa VERENA RUF, MD SIMON STEWART, PhD, FCSANZ, NFESC, FAHA SANDRA PRETORIUS, RD (SA) MAUREEN KUBHEKA, B Curr KAREN SLIWA, MD, PhD, Sliwa-hahnlek@mdh-africa.org

Baker Heart Research Institute, Melbourne, Australia SIMON STEWART, PhD, FCSANZ, NFESC, FAHA

Institute for Medical Epidemiology, Biometrics and Computer Science, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany CHRISTINE LAUTENSCHLÄGER, PhD

Institute of Pharmacology, Division of Clinical Pharmacology, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany VERENA RUF, MD PETER PRESEK, MD

Keywords: medication adherence, self-care behaviour, knowledge, heart failure, Africa Submitted 12/3/09, accepted 14/8/09 Cardiovasc J Afr 2010; 21: 86–92

www.cvja.co.za

Although the population burden and individual impact of chronic heart failure (CHF) has been well described in the western world,1 it has been less well described on the African continent.2,3 Significantly, CHF represents an emerging problem in low- to middle-income countries in sub-Saharan Africa undergoing epidemiological transition.3 For example, CHF is already an important cause of morbidity and mortality in black South Africans and it is conceivable that the incidence of CHF will increase over time.4 In addition to the need for a series of studies in Africa that parallel the detailed documentation of the epidemic of heart failure in the western world,5 we also need to better understand the individual experiences of those affected by heart failure in African communities. In this context, one of the key issues that determine individual outcomes is patient knowledge and adherence to prescribed gold-standard, non-pharmacological and pharmacological treatments.6 Results from high-income countries have shown that poor adherence to medical recommendations remains a substantial problem among people with CHF who must follow a multicomponent treatment regimen that includes medications, dietary restrictions and exercise recommendations.7 Overall, it has been estimated that between one-third and one-half of all patients with chronic heart conditions have difficulty adhering to their prescribed medication regimen in the western world, contributing to impaired quality of life, high healthcare costs linked to increasing rates of hospital re-admissions and out-patient hospital care, in addition to premature mortality.8 Importantly, increased CHF-related knowledge is associated with better treatment adherence.9 However, despite its potential clinical importance (there is no reason to suspect African patients are immune to this problem), there is a paucity of data on treatment adherence in patients with heart disease in the African context.10-12

Methods It is within the above context that we examined patterns of adherence to prescribed pharmacological and non-pharmacological therapy in a large cohort of black African patients in Soweto, diagnosed with CHF. We also examined their understanding of


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prescribed treatment and the overall purpose of CHF management. This represents a key substudy of the previously described Heart of Soweto study,3,13 which is currently mapping the emergence and spectrum of heart disease in a black urban population. This study benefits from the unique setting at the Chris HaniBaragwanath Hospital, representing the only tertiary-care centre for the population of Soweto and surrounding communities. Soweto, a township situated in the south west of Johannesburg, South Africa, has a population of 1.1 million, which has undergone economic development, enabling a large proportion of its population to achieve a more affluent lifestyle. The township comprises people from different ethnic backgrounds, however the black African population is predominant. As Chris Hani-Baragwanath Hospital is the only point of specialist cardiac care for the population of Soweto, the cardiology clinic probably attends to nearly every patient presenting with symptoms evolving from a cardiac condition. The population of the cardiology out-patient department consists of patients with a suspected cardiac disorder, seen and referred by 12 local Soweto primary-care clinics. Other patients are initially seen at the general medicine out-patient facilities, specialist medical registrar clinic, diabetes clinic or are in-patients admitted to any other ward of the Chris Hani-Baragwanath hospital and need a cardiac consultation. During November 2006 and April 2007, we recruited 200 consecutive patients with a confirmed diagnosis of CHF presenting at the cardiology clinic. For the purpose of this study, patients were included if they had a confirmed diagnosis of CHF by an attending cardiologist, based on typical clinical symptoms (shortness of breath, oedema, fatigue) and a documented left ventricular ejection fraction (LVEF) of ≤ 45% using echocardiography. Non-English-speaking patients were excluded only if a translator was unavailable. Patients were approached in the out-patient cardiology clinic and invited to participate. Data were collected after an informed consent form was signed. Prior to study commencement, the relevant local Ethics of Human Research Committee approved the study. The study conforms to the standard statements on ethics outlined by the Declaration of Helsinki. During a pilot study consisting of 20 participants, a ‘medication adherence and knowledge on heart failure’ survey specific to this predominantly black African community was developed in October 2006. The questionnaire was then applied to the above study population on a one-to-one basis in an interview of approximately 20 minutes. All interviews were executed by the same investigator (VR) and if needed, a translator assisted the applicant. A pill count of prescribed CHF treatment was conducted in those 82 patients (41%) who returned for a scheduled one-month post-interview appointment. If appropriate, a telephone reminder was made two days prior to this appointment; however, contact details were available for few patients. The medication adherence and knowledge on heart failure survey addresses the following sections: demographic and clinical data, medication adherence, self-care behaviour (adherence to follow-up appointments, weighing behaviour, dietary restriction, regular physical activity, smoking abstinence and alcohol intake), knowledge concerning CHF medication and overall CHF management. Questionnaires in other studies included the same sections,7,9,14 however the answer possibilities in our ques-

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tionnaire were mostly dichotomous (yes or no) instead of offering a range of answers (no, a little, some, a lot). In accordance with previous studies of this type,7,14 we defined treatment adherence as ≥ 75% of the prescribed pills taken. Similarly, we defined appointment adherence as being present at ≥ 75% of the assigned appointments consisting of quarterly check-ups and monthly medication refills at the hospital pharmacy. In accordance with the European Society of Cardiology guidelines,6 we defined behavioural adherence as daily weight monitoring, daily intake of five servings of fruit and vegetables, drinking less than two litres of fluids per day, being physically active, with compensated CHF two to three times per week, refraining from smoking and keeping a moderate alcohol intake (one beer, one to two glasses of wine per day).

Statistics Descriptive statistics and measures of frequency were conducted in Microsoft EXCEL® and were used to describe the study population and various adherences. Data are presented as means ± standard deviation or percentages. To compare groups we used χ2 analyses for discrete variables and the Student’s t-test for continuous variables. Binary logistic regression models were performed in SPSS 11.5 to determine variables predicting adherence. Determinants for medication adherence were presented by odds ratio (OR) and 95% confidence intervals (CI), where an OR = 1 indicated no influence on medication adherence. Significance was accepted at the two-sided level of 0.05.

Results The overall demographic and clinical profile of the study cohort is presented in Table 1. Overall, black Africans predominated [n = 157 (79%)] and there were more men [n = 109 (55%)] than women [n = 91 (45%)] with no difference in age profile (mean age 56 ± 13 vs 56 ± 15 years). Apart from black African patients there were Asian Indians (n = 10), coloureds (n = 8) and white Africans (n = 25), which we combined as ‘other races’. Almost half of the patients were retired and nearly all lived in a shared household. Black Africans were significantly more likely to have no or standard education than the other races combined [128 (82%) vs 24 (56%), p = 0.001]. When questioned about their self-perceived level of social support, black Africans were less likely to report having ‘a lot of’ practical support than other races combined [91 (58%) vs 33 (78%), p = 0.038], however there was no major difference found in respect of reported emotional support.

Clinical profile Overall, 90% of our study patients were classified as New York Heart Association functional class (NYHA) II and III at the point of being diagnosed with CHF. Overall, the mean left ventricular ejection fraction was 32 ± 8%. Black Africans were less likely to live longer than five years with CHF than the other races combined [61 (39%) vs 23 (53%), p = 0.085] and additionally, they were more likely to have been admitted to hospital before the point of investigation due to their CHF [135 (86%) vs 34 (79%), p = 0.188]. However, that did not reach statistical significance. As represented in Fig. 1, the three most common underlying


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TABLE 1. SOCIODEMOGRAPHIC AND CLINICAL PROFILE

Education profile None Standard 1–5 Standard 6–10 Matriculation/post matriculation Employment status Employed Unemployed Retired Living environment Alone Perceived practical support Not at all A little or some A lot Perceived emotional support Not at all A little or some A lot Clinical profile Mean LVEF (%) ± SD NYHA class II/III NYHA class IV Newly diagnosed HF Treated for HF > 1 year Prior admission for HF Prescribed treatment Beta-blocker ACE inhibitor Loop diuretic Spironolactone Cardiac glycoside

Total (%) (n = 200)

Men (%) (n = 109)

Women (%) (n = 91)

Black African (%) (n = 157)

Other races (%) (n = 43)

16 (8.0) 43 (22) 93 (47) 42 (21)

9 (8.3) 18 (17) 49 (45) 30 (28)

7 (7.7) 25 (28) 44 (48) 12 (13)

14 (8.9) 42 (27) 72 (46) 25 (16)

2 (4.6) 1 (2.3) 21 (49) 17 (40)

54 (27) 57 (29) 89 (45)

37 (34) 30 (27) 42 (39)

17 (19) 27 (30) 47 (51)

39 (25) 49 (31) 69 (44)

15 (35) 8 (19) 20 (47)

18 (9.0)

12 (11)

6 (6.6)

13 (8.3)

5 (12)

36 (18) 36 (18) 124 (62)

21 (19) 17 (16) 68 (62)

15 (17) 19 (21) 56 (62)

28 (18) 34 (22) 91 (58)

8 (19) 2 (4.6) 33 (77)

16 (8.0) 41 (21) 137 (69)

14 (13) 23 (21) 66 (61)

2 (2.2) 18 (20) 71 (78)

12 (7.6) 32 (20) 108 (69)

4 (9.3) 9 (21) 29 (67)

32 ± 8 180 (90) 5 (2.5) 60 (30) 140 (70) 169 (85)

32 ± 8 97 (89) 2 (1.8) 32 (29) 77 (71) 92 (86)

33 ± 8 83 (91) 3 (3.3) 28 (31) 63 (69) 77 (85)

32 ± 8 141 (90) 4 (2.5) 21 (13) 136 (87) 135 (86)

34 ± 7 39 (91) 1 (2.3) 6 (14) 37 (86) 34 (79)

168 (84) 148 (74) 185 (93) 127 (64) 47 (24)

93 (85) 79 (72) 97 (89) 68 (62) 25 (23)

75 (82) 69 (76) 88 (97) 59 (65) 22 (24)

129 (82) 117 (75) 150 (96) 103 (66) 41 (26)

39 (91) 31 (72) 35 (81) 24 (56) 6 (14)

aetiologies for CHF in our study population were idiopathic cardiomyopathy (CMO), ischaemic CMO and hypertensive heart failure. Of the 24% diagnosed with ischaemic CMO, 45% were black African and 55% were other races combined (thereof 12% Asian Indians, 10% coloureds and 33% white Africans). Other causes of CHF included post partum CMO (5% of patients), a condition more commonly found in Africa.2

Treatment adherence Standard CHF treatment included beta-blockers (84%), ACE inhibitors (74%), loop diuretics (93%), spironolactone (64%) and cardiac glycosides (24%). Other medications commonly prescribed in patients with CHF included potassium supplements (54%), aspirin (47%), lipid-lowering agents (33%), warfarin (19%), hypoglycaemic agents, thiamine supplements and calcium antagonists (14%), and the anti-arrhythmic agent amiodarone (7%). Study participants were prescribed a mean of 6 ± 2 individual medications. Overall, 82% of the study participants reported that they were compliant with their prescribed medication (Fig. 2) and 16% acknowledged not taking ≥ 75% of their prescribed CHF

treatment. There was a difference between men and women with 85 versus 75% of participants, respectively, rating themselves as medication compliant. Although adherence to follow-up appointments given by the attending cardiologist was good (Fig. 2), there was a poor adherIdiopathic CMO 31%

Arrhythmia 5% Peripartal CMO 5%

Other 2%

Valvular Inflammable CMO CMO 7% 4%

Ischemic CMO 24%

Hypertensive HF 22%

Fig.1. Aetiology of CHF in the total study population.


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100

% of compliant patients

80

98

95 84

82 71

60

56

38

40

20

0

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13 2,5 Appointment Medication Self-reported Daily adherence adherence medication weight adherence monitoring

Fruit intake

Fluid intake

Physical activity

Smoking restriction

Moderate alcohol intake

Fig. 2. Reported adherence to self-care behaviour. Appointment adherence was achieved when being present at ≥ 75% of assigned appointments consisting of quarterly check-ups and monthly medication refills at the hospital pharmacy. Medication adherence represents the number of patients who took ≥ 75% of their medication, determined through pill counts. Adhering to fruit intake meant five servings of fruit per day and adherence in fluid intake was accomplished when drinking less than two litres per day. Regular physical activity was achieved when study participants walked moderately for 20 to 30 minutes three to four times a week. A moderate alcohol intake meant one beer or one to two glasses of wine per day.

ence to the appointment given for the pill count with only 82 of 200 patients returning (41%). These pill counts revealed that 71% were clearly compliant and 22% non-compliant with their overall prescribed HF regimen (a pill count was not possible in 7% of this subgroup of participants). Fig. 3 shows that the highest adherence rates were for ACE inhibitors and spironolactone compared to the lowest for loop diuretics. Participants reported skipping their loop diuretic (furosemide) most often, with forgetfulness and avoidance of side effects being the most common reasons for non-adherence overall.

this regard. Daily weight monitoring was associated with the lowest rate of adherence (only 19% of participants having a scale at home), while avoiding alcohol intake was associated with the highest rate of adherence. From a dietary behaviour perspective, 87% of participating patients were non-compliant concerning daily intake of fruit. However, 64% of participants reported having difficulty affording fresh fruit. From a smoking perspective, there were 31 (16%) current smokers and 59 (30%) former smokers. 100

Determinants for treatment adherence

80 % of compliant patients

There were no statistically significant factors linked to treatment non-adherence on the basis of multiple logistic regression analysis. However, those participants reporting less than three of the symptoms commonly found in patients with CHF were 4.5-fold (95% CI: 0.95–21.7; p = 0.058) more likely to be designated as compliant, demonstrating the importance of treatment for symptom control and likely clinical benefit of prescribed treatment. At the same time, men tended to be more compliant than women (OR 1.8, 95% CI: 0.61–5.14; p = 0.294) without approaching significance.

78

79

79 64

67

60

40

20

Self-care behavioural adherence Fig. 2 demonstrates adherence to different self-care behaviours. Overall, 95% of all study participants kept ≥ 75% of their followup appointment schedule and were consequently designated as compliant. Overall, 81% adhered to 100% of their follow-up appointment schedule. There was no difference found between men and women and no major difference between the races in

0

Beta blocker n = 49

ACE inhibitor n = 42

Loop diuretic n = 42

SpironoCardiac lactone Glycoside n = 33 n = 14

Fig. 3. Adherence to individual medication. n = number of conducted pill counts


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80 70

70

60

60 % of given health education

73

70

50 39

40

36

30 20 8

10 0

Daily weight monitoring

Healthy diet

Fluid intake

Moderate alcohol intake

Regular physical activity

Smoking restriction

Information on HF

Fig. 4. Percentage of health education given on various aspects of self-care behaviour and heart failure. Health education on daily weight monitoring was given if a patient knew about this way of HF management. Health education given on a healthy diet was accomplished when a patient was informed on the positive effect of a diet rich in vegetables and fruits. Health education on fluid intake was given if a patient knew that there is a restriction of < two litres per day. Health education on alcohol restriction meant informing patients to aim for a moderate alcohol intake (one beer or one to two glasses of wine per day). Health education on physical activity was provided to those with stable CHF and smokers were told about the benefits of refraining from smoking. Information on HF consisted of information about the nature of the syndrome.

Health education The medication adherence and knowledge on heart failure survey contained questions in several sections on health education provided by a doctor or a nurse. According to the patientâ&#x20AC;&#x2122;s responses, the least amount of education was provided in relation to daily weight monitoring, with only 8% of participants remembering this component of education. Dietary management was also less memorable than education focusing on alcohol, smoking and CHF in general (Fig. 4).

Knowledge on heart failure medication and management Overall, patient knowledge concerning their prescribed CHF medication was poor: 56% could not name the effect or any side effects of their medication. On average, only 10% of effects and side effects of pills taken could be named by all participating patients. However, in those patients who self-reported receiving health education on CHF (70%, Fig. 4), the average knowledge on CHF medication was twice as high as in patients without health education. An average score of 69% was achieved on 10 questions concerning CHF management. Percentages on correct answers for each of the 10 questions varied between 29 and 89%. Again, patients who received education on CHF management had a higher average knowledge (70%) than patients who had not received information on CHF management (65%).

Discussion To our knowledge, this represents the largest report to date on

the pattern of treatment adherence and knowledge in predominantly black African patients with CHF emanating from South Africa. Indeed, it is one of the largest overall reports relating to CHF from the continent.11 This is particularly significant given our recent reports of a higher-than-expected burden of CHF in the urban South African community of Soweto,13 and the likelihood of an increase in both traditional and affluent forms of the syndrome due to epidemiological transition.13 How do our data compare with data derived from western cohorts? Our findings on medication adherence are generally lower than reports emanating from high-income countries.8 However, a study conducted in Zimbabwe attained results that supported our findings:11 Bhagat and Mazayi-Mupanemunda found that 73% of the 22 investigated heart failure patients were considered compliant with their prescribed medication.11 Although adherence rates from several studies in the western world vary from 71 to 99%, over half of the listed studies had an adherence rate above 80%.14-20 Alternatively, studies from Sweden (71%) and the USA (73%) have reported similar rates to the current study.15,20 When looking at individual medication adherence to the five basic medications prescribed for CHF, our results ranged from 64 to 79%. In a UK study, Struthers et al. found that 18, 34 and 58% of patients had adherence rates of < 70%, < 85% and 100%, respectively, to prescribed ACE inhibitors.21 In contrast, Monane et al. found that only 10% of their study patients were fully compliant with prescribed digoxin therapy during one year of follow-up.22 With regard to adherence to appointment schedules, patients


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in this study were similar to most other reports (i.e. > 90% appointment adherence).7,14 Alternatively, our data on daily weight monitoring were generally lower than that of other reports (ranging from 12 to 75%).23,24 The fact that only 19% of our study patients had a scale at home is an important factor in this regard. In respect of fluid management, 56% of our study patients reported adhering to the recommended fluid intake of less than two litres per day. In comparison, Artinian et al. (23%)18 and Jaarsma et al. (37%)19 reported lower, while van der Wal (73%)25 reported higher adherence rates to fluid restriction. With 38% of participating patients performing some form of regular exercise (especially walking 20 to 30 min per day), our results were lower than results from other studies (equivalent range 39 to 67%).7,8,14,19,26 Concerning smoking abstinence, 16% of our participating patients persisted in smoking tobacco. In comparison Evangelista et al. and Carlson et al. found less than 10% of their study patients to be non-compliant in this regard,7,14,26 whereas higher smoking rates have been reported by Artinian et al. (46%) and also by Evangelista et al. (55%) in a study on veterans with CHF.18,27 Overall, 98% of all study participants were compliant with regard to reduced alcohol intake. This result is higher than in studies led by Evangelista et al. where adherence to alcohol limitation varied between 64 and 94%,7,14,27 compared to 56% in a cohort studied by Artinian et al.18 Our finding that men tended to be more compliant with prescribed medication is both supported15,28 and refuted22,29 by other studies, with no clear pattern in the literature. Although it is logical to suggest that those with greater symptoms are more likely to be non-compliant, this association is not a regular feature in the literature. It is now largely accepted that greater CHF-related knowledge has a positive impact on adherence behaviours.9,25 Unfortunately, our data imply that patient education at the cardiology out-patient department of the Chris Hani-Baragwanath Hospital is suboptimal in respect of a number of key educational areas. A similar result was found in another study from South Africa focusing on patients with hypertension.12 There were some encouraging results with regard to the provision of CHF information, but this may be due to the fact that study participants had to decide only whether a statement on CHF management was correct or incorrect. In a study lead by Ni et al., the percentage of patients choosing the correct answer on eight questions concerning CHF management varied between 43 and 90% versus a range of 29 to 89% in our study.9 By self-report, 68% of our patients said they knew a little or nothing about CHF. Ni et al. found that only 38% of their study participants reported that they knew only a little or nothing about CHF.9 It is clear from this and other studies from the western world that poor adherence to treatment and CHF-related self-care behaviour exposes the patient to an increased risk of clinical instability and increased symptoms.16,30 This can result in higherthan-expected hospital admission rates, which place a substantial (cost) burden on the healthcare system.16,31 In order to prevent the deterioration of the patientâ&#x20AC;&#x2122;s condition, adherence to medication and other self-care behaviour needs to be ameliorated. In the western world, CHF management programmes have had a positive effect on outcomes of adherence, using various strategies.19,32,33 These data certainly support the potential for CHF

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management programmes to improve health behaviours and outcomes in South Africa. We plan to use these data to undertake one of the first randomised, controlled trials of CHF management in Africa with interventions suited to the local culture and environment.

Limitations There are a number of study limitations that require comment. Although, pill counts are a fairly objective method to measure medication adherence, it is still prone to errors such as the assumption that a pill was truly taken if it is not in the medication box. Serum bioassays or electric monitoring advices may be more objective and thus more accurate.14 However, in our settings, pill counts and interviews were the only options for measuring adherence. As we also based our adherence figures on the results from the pill counts, the findings may be biased, given that those patients who returned for the pill count were already more likely to be compliant in following instructions and were therefore more prone to follow advice concerning medication adherence. Similarly, as the interview took place before the pill count, patients might have paid more attention to taking their medication regularly during the following month. As a result, medication adherence may be overestimated in our study. In future studies, pill counts could be conducted at one, three and six months after the interview to obtain more accurate results. As self-reporting is always subjective and biased, adherence rates to self-care behaviour and the measured knowledge on CHF and its management may have been affected. We also defined behavioural adherence in accordance with the European Society of Cardiology guidelines, even though they might not be applicable to our study population, considering the different disease profiles, cultural and socio-economic profiles and financial backgrounds. Another limitation to our study was the diversity of languages in South Africa (11 official languages). A translator was used in various interviews. Finally, it is difficult to ascertain how representative these data are in relation to other African centres. For example, there was a relatively large number of patients with ischaemic CMO, a generally uncommon cause of CHF in Africa. However, we have recently reported a rise in such cases,34 and the other common causes of CHF in Africa (idiopathic CMO and hypertensive heart failure) were well represented. Given that this was a relatively small group of patients (although large for Africa), we were most probably underpowered to fully explore predictors of nonadherence. Despite these limitations, our study is the first study of this dimension on medication adherence in South Africa. These data indicate the need for interventions that have already been established in the western world to improve health outcomes. These data therefore support the need for culturally sensitive and affordable CHF management programmes that can improve treatment adherence and optimise self-care behaviours and knowledge, in order to improve CHF-related health outcomes overall in South Africa.

Conclusion As in many other regions of the world, non-adherence to complex


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CHF treatment is a substantial problem in Soweto. Additionally, as education on heart failure is not optimal, knowledge on heart failure medication and management is poor. These data confirm the need for a dedicated heart-failure programme in a lowresource set up to optimise CHF management and outcomes. We thank Phutuma Mathusi who contributed to the collection of the data. We acknowledge the financial support of the University of the Witwatersrand and the Medtronic Foundation.

References 1. McMurray JJ, Stewart S. Epidemiology, aetiology and prognosis of heart failure. Heart 2000; 83: 596–602. 2. Sliwa K, Damasceno A, Mayosi B. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005; 112: 3577–3583. 3. Stewart S, Wilkinson D, Becker A, et al. Mapping the emergence of heart disease in a black urban population in Africa: The Heart of Soweto Study. Int J Cardiol 2006; 101: 101–108. 4. Damesceno A, Cotter G, Sliwa K, Mayosi BM. Heart failure in sub-Saharan Africa: Time for Action. J Am Coll Cardiol 2007; 50; 1688–1693. 5. Inglis SC, Stewart S, Papachan A et al. Anaemia and renal function in heart failure due to idiopathic dilated cardiomyopathy. Eur J Heart Fail 2007; 9: 384–390. 6. Swedburg K, Cleland J, Dargie H, et al. ESC Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). The Task Force for the diagnosis and treatment of CHF of the European Society of Cardiology. Eur Heart J 2005; 26: 1115–1140. 7. Evangelista LS, Doering LV, Westlake C, Hamilton M, Fonarow GC. Compliance behaviours of elderly patients with advanced heart failure. J Cardiovsac Nurs 2003; 18: 197–206. 8. Munger MA, Van Tassell BW, LaFleur J. Medication nonadherence: an unrecognized cardiovascular risk factor. Med Gen Med 2007; 9: 58. 9. Ni H, Naumann D, Burgess D, Wise K, Crispell K, Herschberger RE. Factors influencing knowledge of and adherence to selfcare among patients with heart failure. Arch Intern Med 1999; 159: 1613–1619. 10. Ohene Buabeng K, Matowe L, Plange-Rhele J. Unaffordable drug prices: the major cause of non-compliance with hypertension medication in Ghana. J Pharm Pharm Sci 2004; 7(3): 350–352. 11. Bhagat K, Mazayi-Mupanemunda M. Compliance with medication in patients with heart failure in Zimbabwe. East Afr Med J 2001; 78(1): 45–48. 12. Shiri C, Srinivas SC, Futter W, Radloff SE. The role of insights into and beliefs about medicines of hypertensive patients. Cardiovasc J Afr 2007; 18: 353–357. 13. Sliwa K, Wilkinson D, Hansen C, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study. Lancet 2008; 371: 915–922. 14. Evangelista LS, Berg J, Dracup K. Relationship between psychosocial variables and compliance in patients with heart failure. Heart Lung 2001; 30: 294–301. 15. Roe CM, Motheral BR, Teitelbaum F, Rich MW. Compliance with and dosing of angiotensin-converting inhibitors before and after hospitalization. Am J Health Syst Pharm 2000; 57: 139–145. 16. Van der Wal MHL, Jaarsma T, van Veldhuisen DJ. Non-compliance in

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patients with heart failure; how can we manage it? Eur J Heart Fail 2005; 7(4): 5–17. 17. Schwarz KA, Elman CS. Identification of factors predictive of hospital readmissions for patients with heart failure. Heart Lung 2003; 32: 88–99. 18. Artinian NT, Magnan M, Sloan M, Lange MP. Self-care behaviours among patients with heart failure. Heart Lung 2002; 31: 161–172. 19. Jaarsma T, Abu-Saad HH, Dracup K, Halfens R. Self-care behaviour of patients with heart failure. Scand J Caring Sci 2000; 14: 112–119. 20. Cline CM, Bjorck-Linne AK, Israelsson BY, Willenheimer RB, Erhardt LR. Non-compliance and knowledge of prescribed medication in elderly patients with heart failure. Eur J Heart Fail 1999; 1: 145–149. 21. Struthers AD, Anderson G, Mac Fadyen RJ, Fraser C, Mac Donald TM. Non-adherence with ACE inhibitor treatment is common in heart failure and can be detected by routine serum ACE activities assays. Heart 1999; 82: 584–588. 22. Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Avorn J. Non-compliance with congestive heart failure therapy in the elderly. Arch Intern Med 1994; 154: 433–437. 23. Bushnell FK. Self-care teaching for congestive heart failure patients. J Gerontol Nurs 1992; 18: 27–32. 24. De Lusignan S, Wells S, Johnson P, Meredith K, Leathan E. Compliance and effectiveness of 1 year’s home telemonitoring. The report of a pilot study of patients with chronic heart failure. Eur J Heart Fail 2001; 3: 723–730. 25. Van der Wal MHL, Jaarsma T, Moser DK, Veeger NJGM, van Gilst WH, Van Veldhuisen DJ. Compliance in heart failure patients: the importance of knowledge and beliefs. Eur Heart J 2006; 27: 434–440. 26. Carlson B, Riegel B, Moser DK. Self-care abilities of patients with heart failure. Heart Lung 2001; 30: 351–359. 27. Evangelista LS, Doering LV, Dracup K. Usefulness of a history of tobacco and alcohol use in predicting multiple heart failure readmissions among veterans. Am J Cardiol 2000; 86: 1339–1342. 28. Opasich C, Rapezzi C, Lucci D et al. Precipitating factors and decisionmaking process of short-term worsening heart failure despite “optimal” treatment. Am J Cardiol 2001; 88: 382–387. 29. Struthers AD, Anderson G, Donnan DT, Mac Donald T. Social deprivation increases cardiac hospitalization in chronic heart failure independent of disease severity and diuretic non-adherence. Heart 2000; 83: 12–16. 30. Stewart S, Horowitz JD. Detecting early clinical deterioration in chronic heart failure patients post-acute hospitalisation-a critical component of multidisciplinary, home-based intervention? Eur J Heart Fail 2002; 4: 345–351. 31. McMurray JJ, Stewart S. The burden of heart failure. Eur Heart J 2002; 4(Suppl D): D50–D58. 32. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: A systematic review of randomized trials. J Am Coll Cardiol 2004; 44(4): 810–819. 33. Roccafort R, Demers C, Baldassarre F, Koon T, Yusuf S. Effectiveness of comprehensive disease management programmes in improving clinical outcomes in heart failure patients. A meta-analysis. Eur J Heart Fail 2005; 7: 1133–1144. 34. Stewart S, Wilkinson D, Hansen C, et al. A predominance of heart failure in the Heart of Soweto Study cohort: emerging challenges for urban African communities. Circulation 2008; 118: 2360–2367.


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Cardiovascular Topics Blood pressure response to an exercise treadmill test, and echocardiographic left ventricular geometry in Nigerian normotensive diabetics EA AJAYI, MO BALOGUN, OA AKINTOMIDE, RA ADEBAYO, OE AJAYI, RT IKEM, SA OGUNYEMI, AT OYEDEJI

Summary Objectives: This study evaluated normotensive diabetic patients’ blood pressure response to graded exercise and their echocardiographic pattern of left ventricular geometry. Methods: A descriptive, cross-sectional, hospital-based study was carried out on 30 normotensive type 2 diabetic patients and 34 controls, aged 30 to 60 years. The outcome measures were to determine the exercise-related variable, blood pressure response, and left ventricular geometry by means of echocardiography. Results: Nineteen (29.7%) and 11 (17.2%) normotensive diabetic subjects had normal left ventricular geometry and concentric left ventricular remodelling, respectively. None of the subjects had concentric or eccentric left ventricular hypertrophy. On this basis, the normotensive diabetic subjects were divided to two groups: G1 (normal) and G2 (concentric left ventricular remodelling). The groups had comparable mean age, body mass index (BMI), fasting blood glucose (FBG) and two-hour post-prandial blood glucose values, and heart rate, systolic (SBP) and diastolic blood pressure (DBP) at rest. G2 patients had higher mean duration of diabetes than G1 subjects (69.0 ± 9.48 vs 18.7 ± 8.7 months; p = 0.007). Peak systolic blood pressure was significantly higher in G2 than G1 subjects (213.6 ± 20.1 vs 200.0 ± 15.3 mmHg; p = 0.04). Although there was no statistically significant difference in the left ventricular (LV) mass index between the groups, G2 patients had significantly higher relative wall thicknesses than G1 patients (0.53 ± 0.03 vs 0.41 ± 0.04; p < 0.001). Conclusion: Normotensive diabetic subjects with concentric left ventricular remodelling have increased blood pressure reactivity to exercise. It is probable, as suggested in earlier Department of Internal Medicine, University Teaching Hospital, Ado Ekiti, Nigeria

EA AJAYI, FWACP, lifecareado@gmail.com, adekunze@yahoo.com

Department of Medicine, Obafemi Awolowo University Teaching Hospital, Ile Ife, Nigeria MO BALOGUN, FWACP, FMCP OA AKINTOMIDE, FWACP RA ADEBAYO, FWACP OE AJAYI RT IKEM, FMCP SA OGUNYEMI, FMCP AT OYEDEJI, FMCP

studies, that increased blood pressure reactivity to exercise is an indicator of target-organ damage, particularly in normotensive diabetics. Keywords: diabetes, exercise, blood pressure response, left ventricular geometry Submitted 9/9/09, accepted 4/10/09 Cardiovasc J Afr 2010; 21: 93–96

www.cvja.co.za

Stress increases blood pressure, and variable individual blood pressure responses have been evaluated with regard to prediction of new-onset hypertension, target-organ damage and incident cardiovascular disease or death.1 The significance of blood pressure reactivity to exercise has been evaluated, with variable results, in studies on the association between the blood pressure response to exercise and either left ventricular mass or left ventricular geometry in hypertensive patients.2,3 The exaggerated exercise blood pressure (BP) values in these hypertensive adults have been attributed to impaired endothelial vasodilator function.4 Arterial stiffness is also related to type 2 diabetes,5 mainly due to an impaired endothelial vasodilator function, which in turn is associated with increased afterload,5 leading to an elevated systolic blood pressure (SBP).6 These processes consequently lead to structural alterations in the diabetic heart. In normotensive diabetic patients, early and asymptomatic functional and structural abnormalities may alter the normal response to exercise, as already observed in elderly7 and non-diabetic hypertensive patients.3 However, not much is known about the relationship between blood pressure response to exercise and sub-clinical cardiac end-organ damage in normotensive diabetics, particularly in Nigeria. In light of the above, we set out to investigate the relationship between blood pressure response to graded exercise in normotensive diabetics and their echocardiographic pattern of left ventricular geometry, as evidence of cardiac end-organ damage.

Methods Thirty normotensive type 2 diabetic subjects (male = 15; female = 15) and 34 normal controls (male = 17; female = 17) aged 30 to 60 years were recruited through the medical out-patient department of Obafemi Awolowo University Teaching Hospitals complex (OAUTHC), Ile Ife, Nigeria. Ethical clearance for the study was approved by the Ethics and Research Committee of the Hospital in conformity with ethical guidelines of the 1975


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Estimated LV mass index (g/m2) = 0.80 [1.04 (LVIDD + PWT + IVST)3 – (LVIDD)3] + 0.6 g/BSA

Declaration of Helsinki, and all participants gave written consent to participate. Demographic parameters of the subjects were noted and recorded. All subjects were clinically examined to evaluate their body mass index (BMI) and cardiovascular status at rest. Subjects were considered diabetic if they had fasting plasma glucose (FBG) values ≥ 126 mg/dl (7.0 mmol/l)8 or if they used hypoglycaemia medication. Fasting plasma glucose and twohour post-prandial plasma glucose (2HPP) values were obtained 24 hours prior to the procedures. A resting 12-lead ECG was done to exclude patients with baseline ST-segment abnormalities and bundle branch block. Also excluded were patients with coexisting hypertension or who were on antihypertensive(s), those with established chronic renal failure or serum creatinine levels > 1.5 mg% (132 µmol/l), congestive heart failure, valvular heart disease and other diseases known to influence LV function, such as thyroid disease and severe obesity. All the subjects underwent treadmill-symptom limited maximal exercise using the Bruce protocol.9 The protocol continued until one of several endpoints was reached. These included if the patient achieved the age-predicted maximum heart rate; requested that the exercise be terminated; developed severe chest pain, fatigue, leg discomfort or dyspnea; developed frequent premature ventricular beats; developed a systolic blood pressure > 250 mmHg or a drop in the pre-test systolic blood pressure > 10 mmHg; or developed any other problems necessitating termination of exercise. The subjects also had transthoracic two-dimensional (2D) and 2D derived M-mode echocardiography performed, according to standard procedure,10 with simultaneous electrocardiographic recordings while in the left lateral decubitus position, using a standard ultrasound machine (Sonoline G60S Ultrasound Imaging System) with 4.2-MHz transducer. Left ventricular enddiastolic measurements were taken during at least three cycles11 and included left ventricular internal diameter (LVIDD), posterior wall thickness (PWT) and interventricular septal thickness (IVST). Left ventricular mass was estimated from the American Society of Echocardiography’s formula11:

The diabetic subjects and controls had comparable ages and BMIs (48.37 ± 6.96 vs 48.35 ± 6.13 years; p = 0.197 and 24.82 ± 3.66 vs 24.38 ± 1.94 kg/m2; p = 0.861, respectively). Diabetic subjects had significantly higher FBG values than the controls (8.94 ± 2.13 vs 4.75 ± 0.37 mmol/l; p ≤ 0.001). As shown in Table 1, normotensive diabetic subjects had higher exercise-induced haemodynamic parameters of peak systolic (pSBP) and peak diastolic blood pressure (pDBP) but lower peak heart rates (pHR). There was no statistically significant difference in left ventricular mass index (LVMI). Nineteen (29.7%) and 11 (17.2%) normotensive diabetic subjects had normal left ventricular geometry and concentric left ventricular remodelling, respectively. None of the normotensive diabetic subjects had concentric or eccentric left ventricular hypertrophy. Thirty (46.8%) and four (6.3%) controls had normal left ventricular geometry and concentric left ventricular remodelling, respectively. None of the subjects had concentric or eccentric left ventricular hypertrophy. The normotensive diabetic subjects were then divided into two groups: G1 (normal) and G2 (concentric left ventricular remodelling) on this basis. The groups had comparable mean ages, BMIs, FBG and two-hour post-prandial blood glucose values,

TABLE 1. HAEMODYNAMIC RESPONSE AND ECHOCARDIOGRAPHIC PATTERN OF THE STUDY POPULATION

TABLE 2. CLINICAL AND DEMOGRAPHIC PATTERN OF G1 AND G2 SUBJECTS

Normotensive p-value diabetics Controls (Student’s Parameters (n = 30) (n = 34) t-test) rHR (per min) 91.37 ± 16.10 83.29 ± 5.36 0.038 rDBP (mmHg) 73.03 ± 5.46 71.94 ± 3.13 0.713 rSBP (mmHg) 117.13 ± 6.36 113.62 ± 4.51 0.044 pHR (per min) 166.00 ± 15.61 179.03 ± 9.10 < 0.001 pDBP (mmHg) 95.67 ± 9.35 89.12 ± 7.12 < 0.001 pSBP (mmHg) 205.00 ± 18.15 185.41 ± 10.81 < 0.001 Exercise capacity (METs) 8.07 ± 1.47 8.11 ± 0.88 0.992 93.97 ± 17.04 90.55 ± 17.09 0.512 LVMI (g/m2) IVST (mm) 10.24 ± 1.36 9.45 ± 1.44 0.084 PWT (mm) 9.70 ± 1.51 9.43 ± 1.50 0.771 RWT 0.45 ± 0.68 0.41 ± 0.07 0.038 Statistical significance at p < 0.05; Values are expressed as mean ± SD; rHR = resting heart rate, pHR = peak heart rate.

Upper normal limits for LV mass index were 134 and 110 g/m2 in men and women, respectively.12 Relative wall thickness (2 × posterior wall thickness/LV diastolic diameter) was calculated.13 A partition value of 0.45 for relative wall thickness was used for both men and women.14 Patients with increased LV mass index and increased relative wall thickness were considered to have concentric hypertrophy, and those with increased LV mass index and normal relative wall thickness were considered to have eccentric hypertrophy. Those with normal LV mass index and increased or normal relative wall thickness were considered to have concentric remodelling or normal geometry, respectively.

Results

Normal LV Concentric p-value geometry LV remodel- (Student’s (n = 19) ling (n = 11) t-test) 48.68 ± 7.7 47.82 ± 5.7 0.749

Parameters Age Gender M: n (%) 7 (36.8%) 8 (72.7%) F: n (%) 12 (63.2%) 3 (27.3%) 24.8 ± 4.1 24.8 ± 2.9 BMI (kg/m2) Duration of diabetes (months) 18.7 ± 8.7 69.0 ± 9.48 FBG (mmol/l) 9.8 ± 2.03 8.1 ± 1.9 2HPP (mmol/l) 12.2 ± 1.9 13.8 ± 3.5 rHR (bpm) 92.1 ± 18.2 90.1 ± 12.4 rDBP (mmHg) 72.4 ± 5.8 74.2 ± 4.9 rSBP (mmHg) 118.5 ± 6.5 114.7 ± 5.6 rPP (mmHg) 46.2 ± 8.7 40.6 ± 3.9 Statistical significance at p < 0.05; *Chi-square. Values are expressed as mean ± SD.

0.058* 0.992 0.007 0.082 0.236 0.748 0.390 0.116 0.052


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TABLE 3. EXERCISE-INDUCED HAEMODYNAMIC FACTORS Normal LV geometry Parameters (n = 19) pHR (bpm) 167.8 ± 10.9 pDBP (mmHg) 94.2 ± 7.7 pSBP (mmHg) 200.0 ± 15.3 ΔHR (bpm) 75.7 ± 18.4 ΔDBP (mmHg) 21.5 ± 14.1 ΔSBP (mmHg) 81.5 ± 14.1 ΔPP (mmHg) 105.8 ± 9.6 HR reserve 0.97 ± 0.16 Exercise capacity (METs) 8.5 ± 1.5 Statistical significance at p < 0.05 Values are expressed as mean ± SD.

Concentric LV remodelling (n = 11) 162.8 ± 21.7 98.2 ± 11.7 213.6 ± 20.1 72.7 ± 28.1 24.0 ± 13.3 98.9 ± 20.1 115.5 ± 11.3 0.87 ± 0.03 7.4 ± 1.1

p-value (Student’s t-test) 0.405 0.270 0.045 0.725 0.596 0.010 0.019 0.222 0.042

heart rates, and SBP and DBP at rest (Table 2). G2 patients had a higher mean duration of diabetes than G1 (69.0 ± 9.48 vs 18.7 ± 8.7 months; p = 0.007). The patients’ characteristics at rest were not statistically significantly different (Table 2). As shown in Table 3, peak systolic blood pressure was significantly higher in G2 subjects than in G1 (213.6 ± 20.1 vs 200.0 ± 15.3 mmHg; p = 0.04). The difference between resting systolic and peak systolic blood pressure (ΔSBP) as well as resting pulse pressure and pulse pressure during exercise (ΔPP) followed a similar trend to that of peak systolic blood pressure. Exercise capacity in G2 subjects was significantly lower than in G1 by 12.94% (7.4 ± 1.1 vs 8.5 ± 1.5 METs; p = 0.042). Although, there was no statistically significant difference between the LV mass index in the two groups, G2 subjects had significantly higher relative wall thicknesses than those in G1 (0.53 ± 0.03 vs 0.41 ± 0.04; p < 0.001) (Table 4).

Discussion The relationship of blood pressure response to exercise and endorgan damage in hypertensive subjects is not clear. Studies on this subject in diabetics are few, especially among blacks, who unfortunately are at higher risk of developing cardiovascularrelated complications than their Caucasian counterparts.15 This study is the first in Nigeria to assess the relationship between blood pressure response to exercise and abnormal LV geometry. In this study, gender, age and BMI were comparable among the patients with normal LV geometry and those with LV concentric remodelling. The longer duration of diabetes in patients with concentric LV remodelling supports the earlier assertion that the longer the duration of diabetes, the more the likelihood that the patient will develop cardiovascular complications. This was despite the fact that short-term (FBG, two-hour post-prandial blood glucose) glycaemic control was similar in both groups in this study, suggesting that blood pressure response during exercise may not have been much influenced by blood glucose exposure. It has been suggested that blood pressure response may be related to blood glucose control.16 Marfella et al. reported that in the resting state, the presence of hyperglycaemia led to an increase in SBP and DBP independently of endogenous insulin in 20 patients with type 2 diabetes. A reduced availability of nitric oxide was suggested as a possible explanation.16

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TABLE 4. ECHOCARDIOGRAPHIC PARAMETERS OF G1 AND G2 SUBJECTS Normal LV geometry Parameters (n = 19) 81.1 ± 13.4 LVMI (g/m2) IVST (mm) 9.8 ± 1.2 PWT (mm) 9.0 ± 1.3 RWT 0.41 ± 0.04 Statistical significance at p < 0.05 Values are expressed as mean ± SD.

Concentric LV remodelling (n = 11) 88.9 ± 21.8 11.1 ± 1.3 10.9 ± 1.1 0.53 ± 0.03

p-value (Student’s t-test) 0.233 0.010 < 0.001 < 0.001

In our study, the peak systolic blood pressure during exercise was significantly higher in patients with LV concentric remodelling than in those with normal LV geometry. This however was not the case with peak diastolic blood pressure. This was reflected in the significant change in pulse pressure (ΔPP) observed during exercise. Pulse pressure provides a crude guide to stiffness of the large conduit arteries.17 Physiological parameters related to blood pressure regulation and potential contributors to reduced exercise capacity in type 2 diabetic individuals include reduced LV systolic volume, altered myocardial and diastolic functions and increased arterial stiffness.5,18 The elevated peak exercise SBP observed in patients with concentric left ventricular remodelling in this study was probably partly associated with arterial stiffness, as reflected by the higher ΔPP.5,6 Exercise capacity was also reduced in patients with LV concentric hypertrophy in our study. This may provide additional explanation for reduced exercise tolerance in normotensive diabetes patients. It has been suggested that the voltage on the ECG of left ventricular hypertrophy may be an early marker of impaired exercise capacity.19 Previous studies have shown that left ventricular hypertrophy independently predicted reduced exercise capacity.20 This study has shown that type 2 diabetic patients with increased peak systolic blood pressure had increased arterial stiffness, higher LVMI, abnormal LV geometry and reduced exercise capacity.

Conclusion Normotensive diabetics with concentric left ventricular remodelling have increased systolic blood pressure reactivity to exercise. It is probable, as suggested in earlier studies, that increased blood pressure reactivity to exercise is an indicator of target-organ damage, especially in normotensive diabetics.

References 1. Gottdierer JS, Brown J, Zoltick J, Fletcher RD. Left ventricular hypertrophy in men with normal blood pressure: relation to exaggerated blood pressure response to exercise. Ann Intern Med 1990; 112: 161–166. 2. Al’Absi M, Devereux RB, Lewis CE, et al. Blood pressure responses to acute stress and left ventricular mass. Am J Cardiol 2002; 89: 536–540. 3. Rostrup M, Smith G, Bjo¨ rnstad H, Westheim A, Stokland O, Eide I. Left ventricular mass and cardiovascular reactivity in young men. Hypertension 1994; 23(Suppl I): I168–I171. 4. Stewart KJ, Sung J, Silber HA, et al. Exaggerated exercise blood pressure is related to impaired endothelial vasodilator function. Am J Hypertens 2004; 17(4): 314–320. 5. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation 2000; 101: 2271–2276.


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6. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998; 32: 1221–1227. 7. Berne RM, Levy MN. Peripheral circulation and its control. Physiology, 4th edn. Sydney: Mosby, 1998, Vol. 1: 1130. 8. World Health Organization. Second Report of the Expert Committee on Diabetes. Geneva. World Health Org, 1980; (Tech Rep Ser 646). 9. Bruce RA. Exercise testing of patients with coronary disease. Principles and normal standards for evaluation. Ann Clin Res 1971; 3: 323–332. 10. Devereux RB, Liebson PR, Horan MJ. Recommendations concerning use of echocardiography in hypertension and general population research. Hypertension 1987; 9(Suppl II): 97–104. 11. Sahn DJ, DeMaria A, Kisslo J. Recommendations regarding quantitation in M-mode electrocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083. 12. Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987; 59: 956–960. 13. Reichek M, Devereux RB. Reliable estimation of peak left ventricular systolic pressure by M-mode echocardiographic determined end-diastolic relative wall thickness. Identification of severe valvular aortic stenosis

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in adult patients. Am Heart J 1982; 103: 202–209. 14. Iwashima Y, Horio T, Kuroda S, Takishita S, Kawano Y. Influence of plasma aldosterone on left ventricular geometry and diastolic function in treated essential hypertension. Hypertens Res 2002; 25: 49–56. 15. Chaturvedi N, McKeigue PM, Marmot MG. Resting and ambulatory blood pressure differences in Afro-Caribbeans and Europeans. Hypertension 1993; 22: 90–96. 16. Marfella R, Nappo F, De Angelis L, Paolisso G, Tagliamonte MR, Giugliano D. Hemodynamic effects of acute hyperglycemia in type 2 diabetic patients. Diabetes Care 2000; 23: 658–663. 17. Beltran A, McVeigh G, Morgan D, et al. Arterial compliance abnormalities in isolated systolic hypertension. Am J Hypertens 2001; 14: 1007–1011. 18. Kizu A, Koyama H, Tanaka S, Maeno T, Komatsu M, Fukumoto S, et al. Arterial wall stiffness is associated with peripheral circulation in patients with type 2 diabetes. Atherosclerosis 2003; 170: 87–91. 19. Balogun MO, Eniola A. Exercise induced ventricular arrhythmias in Nigerian patients with hypertension. Trop Cardiol 1995; 21: 53–58. 20. Okura H, Inoue H, Tomon M, Nishiyama S, Yoshikawa T, Yoshida K, et al. Impact of Doppler-derived left ventricular diastolic performance on exercise capacity in normal individuals. Am Heart J 2000; 139: 716–722.

Boehringer Ingelheim launches Care foundation and get-together of its sponsored medical students Boehringer Ingelheim launched its collective Corporate Social Investment (CSI) initiatives under one umbrella, the Care foundation, at a special function in Cape Town recently. Consisting of a number of initiatives, including the provision of anti-retrovirals free of charge for use in the prevention of mother-to-child transmission of HIV, HIV education programmes, and a fully sponsored programme for medical students

from disadvantaged backgrounds, the Care Foundation will have the support of patrons Prof Rolf Krebs, former chairman of the Board of Managing Directors, Boehringer Ingelheim GmBH, and Mr Paul Stewart, previously CEO of Boehringer Ingelheim South Africa and now corporate senior vice-president, PM/ CHC Emerging Markets, Boehringer Ingelheim GmBH. Prof Rolf Krebs pointed out that

From left to right: Sheldon Marais (current student), Dirk van Niekerk (country chairman, Boehringer Ingelheim, SA), Siphesihle Khwela (current student), Prof Rolf Krebs (patron of the Boehringer Ingelheim Care foundation), Mlekeleli Gumbu (current student).

education and leadership are key to South African and African ambitions. ‘This programme with its already-qualified 22 students can provide leadership in health policy and delivery that is so essential to improving the lives of South Africans. We have to be the leaders’, he warned. Eighty per cent of these medical students sponsored by Boehringer Ingelheim are still practicing in South Africa. To date, Boehringer Ingelheim has invested R6.4 million in the programme, which includes sponsorship of academic and residence fees for the seven-year study period. In line with its ongoing vision to add value to the lives of its patients, its people and its communities, the company has committed to continue the programme indefinitely and ensure that there will be 12 students participating in the programme at all times. Dirk van Niekerk, country chairman of Boehringer Ingelheim South Africa, commented: ‘Doctors and pharmacists are the lifeblood of the health industry. At the forefront of improving the lives of their patients, they play a crucial role in the communities they serve – and yet, up to 1994, there were few or no doctors from previously disadvantaged communities in South Africa, as a result of political barriers, inadequate secondary education and poverty.’


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Cardiovascular Topics Factors associated with mortality when chronic betablocker therapy is withdrawn in the peri-operative period in vascular surgical patients: a matched case–control study BRUCE M BICCARD

Summary Background: Withdrawal of chronic beta-blockade following vascular surgery is associated with peri-operative mortality. The aim of this study was to examine risk factors associated with mortality in patients where chronic beta-blockade was withdrawn. Methods: Two matched case–control studies were conducted, one of patients withdrawn from beta-blockade who survived and the other of patients who were maintained on beta-blockade and survived. Each case was matched with two controls. Three potential risk factors were analysed: the increase in heart rate postoperatively, the use of inotropes, and whether withdrawal for the first three postoperative days was more predictive than withdrawal for a single day. Multivariate conditional logistic regression was conducted. Results: The only independent predictor of in-hospital mortality was a change in the mean daily heart rate of ≥ six beats per minute from the day of surgery to the third postoperative day, or death or discharge if this happened before the third day (OR 13.7, 95% CI: 1.7–110, p = 0.014). The area under the curve for the receiver operating characteristic curve was 0.787. Conclusion: Use of a postoperative heart rate threshold may be clinically useful as an ‘early warning system’ in patients withdrawn from chronic beta-blockade in the peri-operative period. Keywords: mortality, cardiac, surgery vascular, pharmacology beta-blockers

documented withdrawal of chronic beta-blockade following mixed vascular surgical procedures have reported extremely poor outcomes; with an in-hospital mortality of 24 to 50%, an early cardiovascular mortality of 29%, a peri-operative myocardial infarction rate of 50% and a one-year mortality following surgery of 38%.2,3 A meta-analysis of these two studies shows that the OR for mortality when chronic beta-blockade is withdrawn in the peri-operative period in vascular surgical patients is 26.32, 95% CI: 8.95–77.44, p < 0.0001. Despite the significantly increased risk of mortality, the total number of cases reported is small (n = 29) and no attempt has been made to identify risk factors associated with mortality in patients in whom chronic beta-blockade is withdrawn in the peri-operative period. Chronic beta-blockade results in beta-adrenergic receptor up-regulation and a lowering of the ischaemic threshold,1 with myocardial ischaemia evident at lower myocardial oxygen demands. Withdrawal of chronic betablockade in the peri-operative period and an associated increase in heart rate therefore probably contributes to the increased all-cause and cardiovascular mortality, secondary to myocardial ischaemia. The relationship between postoperative heart rate and chronic beta-blockade withdrawal as an independent predictor of postoperative mortality following vascular surgery has recently been confirmed.4 The aim of this study was to examine clinically useful predictors of mortality in patients withdrawn from chronic betablockade in the peri-operative period. As it would be unethical to investigate this problem prospectively, a case–control study design was utilised.

Submitted 22/7/09, accepted 13/10/09 Cardiovasc J Afr 2010; 21: 97–102

www.cvja.co.za

A history of chronic beta-blockade has been associated with a significantly increased incidence of peri-operative myocardial infarction in non-cardiac surgical patients [odds ratio (OR) 2.14, 95% confidence interval (CI): 1.29–3.56].1 Case series that have Department of Anaesthetics, Nelson R Mandela School of Medicine and Inkosi Albert Luthuli Central Hospital, Durban, South Africa BRUCE M BICCARD, MB ChB, FFARCSI, FCA (SA), MMed Sc, biccardb@ukzn.ac.za

Methods Local ethical approval was granted by the Ethics Committee of the Nelson R Mandela School of Medicine for this study. An existing database of all vascular surgical patients over 39 years of age admitted for both elective and emergency vascular surgery at Inkosi Albert Luthuli Central Hospital between June 2003 and June 2007 was used for this study. Only the most recent surgical procedure per patient is recorded in the database. Therefore the mortality reported in this article represents the mortality per patient and not per procedure. More recent data has not been included as this is prospectively being collected for a Medical Research Council-funded observational study.


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Demographic data associated with peri-operative cardiac risk,5 and physiological6 and surgical procedural data7 associated with in-hospital mortality were extracted from the hospital computerised database. The following clinical risk factors are included in the database: history of ischaemic heart disease (or pathological Q waves on ECG), history of congestive heart failure, diabetes, serum creatinine > 180 µmol.l-1, age, gender, pre-operative and postoperative haemoglobin and blood glucose levels, and a history of hypertension. The vascular surgical procedural factors included the type of surgery, duration of surgical operating time, and whether surgery was undertaken out of elective surgical working hours. Therefore this study includes both elective and emergency surgical patients. The physiological data included the mean daily heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) calculated from recorded nurses’ observations during the hospital admission. A history of pre-operative chronic betablocker therapy and in-hospital drug administration was also recorded in the database. It was therefore possible to identify patients who did not have their beta-blocker therapy prescribed during their hospital admission. The cause of in-hospital deaths reported in the database were determined using the stringent criteria of a previous study.8 Cardiac deaths were defined as a postoperative cardiac event being the primary event, which subsequently resulted in death. These cardiac events included cardiac arrest, myocardial infarction or cardiac failure. A primary cardiac arrest was defined as a witnessed cardiac arrest associated with ventricular fibrillation, ventricular tachycardia or asystole in a patient who was previously considered stable. Myocardial infarction was defined as postoperative clinical signs or symptoms consistent with myocardial ischaemia and either an associated diagnostic rise in troponin T or creatinine kinase-MB, or electrocardiographic (ECG) changes consistent with acute myocardial infarction. Primary postoperative cardiac failure was defined as clinical signs and symptoms consistent with acute pulmonary oedema requiring inotropic support without an obvious precipitant. All patients in the database in whom chronic beta-blockade was not administered on any of the first three postoperative days were identified. Those patients who died during the hospital admission were identified as ‘cases’. These patients were matched in two separate case–control studies: the first matched ‘cases’ with patients who were withdrawn from chronic betablockade but survived, and the second matched ‘cases’ with patients who were continued on chronic beta-blockade in the peri-operative period and survived. To identify matching patients, all the patients were stratified according to age. The matched controls for the cases that died were the two patients nearest in age to the case, who were matched for the presence or absence of the following risk factors (serum creatinine >180 µmol.l-1, surgery out of hours, and a mean daily postoperative SBP of > 179 or < 90 mmHg). These three risk factors were previously identified as independent predictors of all-cause in-hospital mortality in our vascular surgical patients.4 These three variables were chosen as two of them were the strongest predictors of mortality in the postoperative model (serum creatinine and surgery out of hours) and the third variable was known to interact with postoperative heart rate (SBP > 179 or < 90 mmHg).4 The reason for withdrawal of chronic beta-blockade was iden-

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tified by analysis of case notes. Attention to beta-blocker-associated side effects including bradycardia, hypotension, and perioperative complications requiring inotropic support were analysed. If there was no obvious clinical indication for withdrawal, then the reason for withdrawal was classified as ‘unknown’.

Statistical analysis All demographic and possible risk factors were summarised by group (case versus control) using descriptive statistics. Mean [standard deviation (SD)] or median (interquartile range) was used where appropriate for continuous variables and frequency (proportion) for categorical variables. Conditional logistic regression was used to compare case and control groups for each variable and to take into account matching in the comparison. Categorical data of mortality associated with chronic betablockade and withdrawal of beta-blockade were analysed using the Fisher’s exact test. Three risk factors possibly associated with mortality following withdrawal of chronic beta-blockade were examined using conditional logistic regression. Firstly, whether complete withdrawal of beta-blockers for the first three days was associated with mortality when compared with withdrawal for only a single day. Secondly, whether the administration of postoperative inotropes was associated with mortality. Thirdly, whether the change in mean daily heart rate from the day of surgery to the third postoperative day was associated with mortality. Where patients died or were discharged before the third postoperative day, mean daily heart rate for the last day in hospital was used. If the change in mean daily heart was found to an important univariate predictor, then a dichotomous heart rate variable was to be derived from constructing a receiver operating characteristic (ROC) curve and identifying the optimal cut-off point for the change in mean daily heart rate from the day of surgery to the ‘last mean daily heart rate’. The variables with the strongest association with postoperative mortality following chronic beta-blocker withdrawal were entered into a multivariate conditional logistic regression. A p-value less than the Bonferroni adjusted α (0.017 = 0.05/number of possible risk factors) indicated statistical significance. An independent samples t-test was conducted to compare heart rates between cases and controls as the heart rate was normally distributed. P-value, OR and CI are presented for all comparisons. SPSS 15.0 for Windows (6 Sept 2006) was used for data analysis.

Results Out of 829 vascular surgical patients, 195 patients on chronic beta-blockade were identified (23.5%). Both chronic betablockade and withdrawal of chronic beta-blockade were associated with significantly higher in-hospital mortality rates (Tables 1 and 2). Fifty per cent of the patients who were withdrawn from chronic beta-blockade were classified as having primary cardiac deaths. Of the 21 patients who were withdrawn from chronic betablockade and died, seven were excluded from the matched case– control studies, as four had missing haemodynamic data, and for three cases it was impossible to identify adequate controls for matching. The remaining fourteen cases were adequately matched with two sets of 28 controls. For both the case–control


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study of matched survivors who were withdrawn from chronic beta-blockade and the case–control study of matched survivors who continued chronic beta-blockade, 27 controls were matched on all three risk factors, and one control was matched for two risk factors. The patient characteristics of the 14 cases withdrawn from chronic beta-blockade and died are presented in Table 3. All 14 patients were withdrawn from chronic atenolol therapy. The demographic, clinical, surgical and physiological data of the cohorts were similar with the exception of a history of hypertension, which was more frequent in the matched control group of survivors withdrawn from chronic beta-blockade (Table 4). The conditional logistic regression identified that the postoperative change in heart rate had the strongest association with postoperative mortality in the matched cohort of withdrawn survivors (Table 5). The ROC curve showed the optimal cut-off point to be a mean increase in heart rate of ≥ six beats per minute from the day of surgery to the ‘last mean daily heart rate’. This had a sensitivity of 84.6% and a specificity of 71.4% and an area under the curve of 0.787 (Fig. 1). For the cohort that was maintained on chronic beta-blockade, the same cut-off point had a sensitivity of 76.9% and a specificity of 65.4%. The area under the curve was 0.778. The optimal cut-off point for this group was a mean increase in heart rate of > 5.8 beats per minute with an TABLE 1. A HISTORY OF CHRONIC BETA-BLOCKADE AND PER PATIENT IN-HOSPITAL MORTALITY Chronic No chronic beta-blockade beta-blockade Mortality 28/195 (14.4%) 54/634 (8.5%) CI: confidence interval; p = 0.02

Odds ratio (95% CI) 1.80 (1.11–2.93)

TABLE 2. WITHDRAWAL OF CHRONIC BETA-BLOCKADE AND PER PATIENT IN-HOSPITAL MORTALITY Withdrawal Administration of chronic of chronic Odds ratio beta-blockade beta-blockade (95% CI) Mortality 21/108 (19.4%)* 6/86 (7.0%) 3.22 (1.24–8.38) *The data on one death is excluded as this patient died intra-operatively. CI: confidence interval; p = 0.01.

84.6% sensitivity and 65.4% specificity. No interaction was demonstrated between an increase in heart rate of ≥ six beats per minute and non-administration of beta-blockade within the first three postoperative days. Entering both these variables into the multivariate analysis found only the increase in heart rate to be independently associated with postoperative mortality following withdrawal of chronic beta-blockade in vascular surgical patients (OR 13.7, 95% CI: 1.7–110, p = 0.014). In the case–control study of patients maintained on chronic beta-blockade, neither the withdrawal of chronic betablockade for all three postoperative days nor the increase in heart rate were independent predictors of mortality. The heart rate characteristics of the cases and controls of the case–control study of patients withdrawn from chronic beta-blockade are presented in Table 6. 1.0

0.8

Sensitivity

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0.6

0.4

0.2

0.0

0.0

0.2

0.4 0.6 Specificity

0.8

1.0

Fig. 1. The receiver operating characteristic curve for the relationship between the increase in mean daily heart rate following withdrawal of chronic beta-blockade and in-hospital mortality.

TABLE 3. PATIENT CHARACTERISTICS OF ‘CASES’ WITHDRAWN FROM CHRONIC BETA-BLOCKADE Patient Postoperative days Reason for withdrawal number withdrawn (n)* of beta-blockade 1 1 Peri-operative inotropes 2 3 Unknown 3 3 Unknown 4 2 Unknown 5 1 Peri-operative inotropes 6 3 Peri-operative inotropes 7 3 Unknown 8 2 Unknown 9 1 Unknown 10 1 Peri-operative inotropes 11 3 Unknown 12 3 Unknown 13 3 Postoperative ventilation 14 3 Bradycardia *Within the first three postoperative days

Postoperative day of death 15 26 11 2 1 6 8 2 30 1 3 3 13 6

Cause of death Cardiac: myocardial infarction Cardiac: cardiac arrest Non-cardiac: abdominal compartment syndrome Non-cardiac: cerebrovascular accident Non-cardiac: massive haemorrhage Cardiac: myocardial infarction Non-cardiac: respiratory failure Cardiac: myocardial infarction Cardiac: cardiac failure Cardiac: myocardial infarction Cardiac: myocardial infarction Non-cardiac: indeterminate Non-cardiac: respiratory failure Cardiac: myocardial infarction


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TABLE 4. DEMOGRAPHIC DATA, CARDIAC AND SURGICAL RISK FACTORS AND POSTOPERATIVE PHYSIOLOGICAL DATA FOR CASE AND MATCHED CONTROL COHORTS. VALUES ARE MEAN (SD), MEDIAN (IQR) OR NUMBER (PROPORTION) Controls (withdrawn survivors) (n = 28)

Controls (continued survivors) (n = 28)

Matched case–control for beta- Matched case control for betablocker-withdrawn survivors blocker-continued survivors

Cases Characteristic (n = 14) p-value* OR* 95% CI* p-value* OR* 95% CI* Pre-operative risk factors Age 63.5 (± 7.5) 63.4 (± 7.0) 63.1 (± 7.7) Gender (male) 11 (78.6%) 15 (53.6%) 18 (64.3%) 0.11 5.72 0.66–49.4 0.33 2.30 0.43–12.24 Diabetic 3 (21.4%) 16 (57.1%) 11 (39.3%) 0.07 0.29 0.78–1.11 0.62 0.68 0.15–3.10 Hypertensive 9 (64.3%) 27 (96.4%) 24 (85.7%) 0.04 0.10 0.01–0.86 0.13 0.27 0.05–1.47 Smoker 9 (64.3%) 16 (57.1%) 13 (46.4%) 0.66 1.34 0.36–5.17 0.31 1.92 0.54–6.80 Ischaemic heart disease 10 (71.4%) 24 (85.7%) 21 (75%) 0.33 0.50 0.13–2.0 0.77 0.78 0.15–4.20 Congestive cardiac failure 0 (0%) 1 (3.6%) 1 (3.6%) 0.68 0.03 0–939855 0.68 0.26 0–939855 Stroke 2 (14.3%) 3 (10.7%) 4 (14.3%) 0.73 1.44 0.19–11.12 † 3 (21.4%) 5 (17.9%) 5 (17.9%) Creatinine > 180 µmol.l-1 12.3 (± 1.9) 13.1 (± 2.1) 0.41 0.31 0.02–5.22 0.40 0.27 0.01–5.72 Pre-operative haemoglobin (g.dl-1) 8.8 (± 2.5) 8.5 (± 3.7) 6.9 (± 2.9) 8.9 (± 4.2) 0.35 1.16 0.85–1.58 0.37 1.27 0.76–2.13 Pre-operative glucose (mmol.l-1) Pre-operative chronic medical therapy No statin therapy 12 (85.7%) 19 (67.9%) 16 (57.1%) 0.18 4.59 0.50–42.40 0.92 4.00 0.80–20.01 Surgical risk factors Supra-inguinal surgery 7 (50%) 17 (60.7%) 17 (60.7%) 0.51 0.63 0.17–2.42 0.51 0.63 0.17–2.42 Duration of surgery (minutes) 105 (65–190) 103 (76–149) 108 (58–164) 0.75 1.002 0.99–1.01 0.50 1.003 0.99–1.01 Surgery out of hours 1 (7.1%) 2 (7.1%) 2 (7.1%) Postoperative physiological data and risk factors SBP < 100 or > 179 mmHg 2 (14.3%) 4 (14.3%) 4 (14.3%) 9.7 (± 2.4) 10.5 (± 2.1) 0.92 0.97 0.55–1.72 0.78 1.05 0.76–1.44 Postoperative haemoglobin (g.dl-1) 10.7 (± 3.3) 10.1 (± 3.9) 9.3 (± 4.3) 8.2 (± 3.8) 0.63 0.92 0.65–1.30 0.75 1.04 0.80–1.36 Postoperative glucose (mmol.l-1) *Not reported for variables used for matching †: no model fitted; SBP: systolic blood pressure; SD: standard deviation; IQR: interquartile range. TABLE 5. CONDITIONAL LOGISTIC REGRESSION OF THE THREE PREDETERMINED RISK FACTORS FOR MORTALITY FOLLOWING WITHDRAWAL FROM CHRONIC BETA-BLOCKADE Matched beta-blockerMatched beta-blockerwithdrawn survivors cohort continued survivors cohort Odds ratio 95% CI p-value Odds ratio 95% CI p-value

Characteristic Heart rate characteristics Heart rate difference: day of surgery to last HR 1.10 1.01–1.18 0.03 1.09 1.004–1.18 0.04 Mean HR increase of ≥ six beats per minute from day of surgery* 13.66 1.70–110.09 0.014 6.06 1.27–28.93 0.024 Beta-blocker administration No beta-blocker administration in first three days versus any administation 4.92 1.01–23.97 0.05 169.5 0.9–32943 0.06 Inotrope administration Institution of peri-operative inotropic support 4.00 0.73–21.84 0.11 8.00 0.89–71.6 0.06 CI: confidence interval; HR: heart rate. *Optimal cut-off point from receiver operating characteristic curve from the withdrawn survival cohort. TABLE 6. HEART RATE CHARACTERISTICS OF MATCHED CASE–CONTROL STUDY OF PATIENTS WITHDRAWN FROM CHRONIC BETA-BLOCKADE Mean HR (SD) t-test Day of surgery Last HR Day of surgery Last HR Died 72 (18) 92 (21) 0.66 0.047 Survived 75 (14) 80 (18) HR: heart rate; SD: standard deviation; last HR: mean heart rate on third postoperative day or last day in hospital if earlier than the third postoperative day.

Discussion The sample size of vascular surgical patients who were with-

drawn from chronic beta-blockade in this study was nearly 1.5 times greater than the total number of cases previously reported in the published literature. This study therefore adds substantially to the data on this important peri-operative problem. It confirms that withdrawal of chronic beta-blockade is potentially lethal. It is, however, the first study to demonstrate that withdrawal of a single dose of beta-blocker within the first 72 hours postoperatively is significantly associated with in-hospital mortality. It is also the first study to specifically address predictors of mortality in patients who are withdrawn peri-operatively from chronic beta-blockade, and to confirm that the response of the heart rate between the day of surgery and the third postoperative day is independently associated with mortality. This study therefore suggests that rate-mediated ischaemia is


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critical to survival once beta-blockers are withdrawn in the perioperative period.1 An increase in the mean heart rate of ≥ six beats per minute following withdrawal of chronic beta-blockade was found to be independently associated with peri-operative mortality in vascular surgical patients. The positive likelihood ratio (LR) is 3 and the negative LR is 0.2. For a test to be clinically useful, it should have a positive LR exceeding 5 to 10 and a negative LR of less than 0.2.9,10 Based on the heart rate threshold identified in this study and the associated LR, we can conclude that patients who have a heart rate increase of less than six beats per minute following withdrawal of chronic beta-blockade are likely to survive, as the LR is within the clinically useful range. When the heart rate increases by at least six beats per minute, then the discrimination is not as accurate. Therefore although this heart rate increase is an independent predictor of mortality when chronic beta-blockade is withdrawn, it is still clinically inaccurate, reflecting the uncertainty associated with this predictor. This poor positive discrimination is not an unusual problem with peri-operative risk prediction.9 Indeed, none of the positive results of the current special investigations for vascular surgery appear to be accurate enough for positive discrimination.11 The poor positive discrimination of this heart rate threshold should however not be considered an important limitation, especially when one considers how this heart rate threshold may impact on peri-operative anaesthetic practice. When patients on chronic beta-blockade present for surgery, keeping the heart rate below the ischaemic threshold is a central tenant. This target could be identified by determining the ischaemic threshold from pre-operative Holter monitoring or by arbitrarily selecting a heart rate threshold.1 Certainly, with a negative LR of 0.2, the heart rate threshold presented in this article is clinically useful. If an anaesthetist could successfully control the heart rate below this threshold, then it would probably be unnecessary to conduct a pre-operative Holter in order to determine an ischaemic threshold. However, what should we do with patients in whom chronic beta-blockade is withdrawn and who have an increase in heart rate ≥ six beats per minute? As we cannot accurately predict which patients will die using this threshold, but as we do know that this group is at a significantly increased risk of in-hospital mortality, we could use this threshold as an ‘early warning system’. It would be reasonable to attempt to re-institute betablockade as soon as possible if not contra-indicated. Transfer of the patient to a high-care facility, serial monitoring of troponins, repeat ECG12 and an attempt to institute other negatively chronotropic therapy if beta-blockade is contra-indicated should all be considered. Although withdrawal of chronic beta-blockade is clearly undesirable,1-3 it does occur, either inadvertently, or as a considered decision based on perceived contra-indications or peri-operative complications considered to be related to beta-blocker administration. The findings of this study may be useful in identifying patients at risk and initiating management and therapy that may decrease the high associated morbidity and mortality. There were limitations to this study. One-third of the patients who were withdrawn from beta-blockade were excluded from the study because of missing data. It is possible that these patients could have had a meaningful impact on the statistical analysis. In over 50% of the patients who had beta-blockers withdrawn and

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died, there was no obvious reason for the withdrawal (Table 3). Clearly, such a high withdrawal rate with no obvious indication needs to be studied and the reasons for withdrawal elicited, as omission of chronic beta-blockade is potentially life threatening. It is important to note that even in chronically beta-blocked patients, there is a significant circadian rhythm to the mean heart rate with the nocturnal heart rate being lower than the daily heart rate.13 The ischaemic threshold is significantly decreased in the early morning.14 It is likely that a number of factors contribute to increased myocardial oxygen demand in the morning, including heart rate, blood pressure, autonomic and humeral physiological changes.15 The use of a mean daily heart rate, as used in this study, has limitations due to the variation of the ischaemic threshold through the course of a day. It is likely that the optimal cut-off point for the change in heart rate is lower than six beats per minute in the morning and possibly higher in the evening. This will, however, only be adequately addressed with a perioperative study using continuous Holter monitoring. We also did not have data on the dosage of chronic betablockade that all the patients in this study received, which may be an important determinant of the ischaemic threshold.16 Higher doses are associated with a lower ischaemic threshold, making it possible that an increase in heart rate of ≥ six beats per minute may be too high for patients on a high dose of chronic beta-blockade. This then is another area that requires further investigation, particularly if a heart rate-based cut-off point is to be used. Furthermore, there were statistical limitations to this study. The large confidence intervals for the OR of mortality associated with an increase in postoperative heart rate (95% CI: 1.7–110) are of limited clinical utility. There are two possible explanations for the large confidence interval: firstly, the sample size was small and secondly, it is possible that the retrospective data collection in this study may have increased the variability of the heart rate data collected. A small sample size results in less precision around an estimate of risk (and hence a larger confidence interval) and increased variability within a group decreases the reliability of the findings, and again, increases the width of the confidence intervals.17 It is important to note that despite the wide confidence intervals in this study, the postoperative increase in heart rate was still significantly associated with mortality. It appears therefore that this was an important observation, although it is difficult to precisely quantify its risk. Is it clinically plausible that a heart rate change of only six beats per minute can explain an associated increased mortality? It probably is, for a number of reasons. Firstly, a Holter study of patients with stable coronary artery disease patients receiving beta-blocker therapy for two weeks has shown that silent myocardial ischaemia is evident with an increase in heart rate of as little as 12.3 (± 1.4) beats per minute from the mean resting heart rate, immediately prior to the onset of myocardial ischaemia.18 Secondly, beta-blockade has been shown to significantly decrease the ischaemic threshold,16 and that increasing doses of beta-blocker are associated with further significant reduction in the ischaemic threshold.16 Thirdly, the ischaemic threshold is associated with the duration of the heart rate increase, where a lower ischaemic threshold is evident if the heart rate increase is prolonged.19 Furthermore, there is an increased frequency of myocardial ischaemia at lower heart rates in patients on beta-


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blocker therapy.19 As heart rate tends to increase in the first three postoperative days,20 it is likely therefore that a heart rate change of as little as six beats per minute may be associated with significant myocardial ischaemia in vascular surgical patients who were chronically beta-blocked and then withdrawn from therapy.

Conclusion An increase in the mean daily heart rate of ≥ six beats per minute is independently associated with in-hospital mortality following the withdrawal of chronic beta-blockade in vascular surgical patients. It is possible that re-institution of beta-blockade or other techniques of rate control in these patients may improve survival. The relationship between the postoperative heart rate and both the dose of chronic beta-blockade and circadian rhythm needs further investigation.

References 1. Giles JW, Sear JW, Foex P. Effect of chronic beta-blockade on perioperative outcome in patients undergoing non-cardiac surgery: an analysis of observational and case control studies. Anaesthesia 2004; 59(6): 574–583. 2. Shammash JB, Trost JC, Gold JM, Berlin JA, Golden MA, Kimmel SE. Perioperative beta-blocker withdrawal and mortality in vascular surgical patients. Am Heart J 2001; 141(1): 148–153. 3. Hoeks SE, Scholte Op Reimer WJ, van Urk H, Jorning PJ, Boersma E, Simoons ML, et al. Increase of 1-year mortality after perioperative betablocker withdrawal in endovascular and vascular surgery patients. Eur J Vasc Endovasc Surg 2007; 33(1): 13–19. 4. Biccard BM, Pooran RR. Validation of a model to predict all-cause in-hospital mortality in vascular surgical patients. Cardiovasc J Afr 2008; 19(6): 303–308. 5. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100(10): 1043–1049. 6. Goldhill DR, McNarry AF. Physiological abnormalities in early warning scores are related to mortality in adult inpatients. Br J Anaesth 2004; 92(6): 882–884. 7. Leung JM, Dzankic S. Relative importance of preoperative health status versus intraoperative factors in predicting postoperative adverse outcomes in geriatric surgical patients. J Am Geriatr Soc 2001; 49(8):

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1080–1085. 8. Biccard BM, Bandu R. Clinical risk predictors associated with cardiac mortality following vascular surgery in South African patients. Cardiovasc J Afr 2007; 18(4): 216–220. 9. Ridley S. Cardiac scoring systems – what is their value? Anaesthesia 2003; 58(10): 985–991. 10. Coetzee JF. Evaluating diagnostic tests. S Afr J Anaesthes Analges 2004(November): 7–15. 11. Kertai MD, Boersma E, Bax JJ, Heijenbrok-Kal MH, Hunink MG, L’Talien G J, et al. A meta-analysis comparing the prognostic accuracy of six diagnostic tests for predicting perioperative cardiac risk in patients undergoing major vascular surgery. Heart 2003; 89(11): 1327–1334. 12. Rinfret S, Goldman L, Polanczyk CA, Cook EF, Lee TH. Value of immediate postoperative electrocardiogram to update risk stratification after major noncardiac surgery. Am J Cardiol 2004; 94(8): 1017–1022. 13. Burger AJ, Kamalesh M. Effect of beta-adrenergic blocker therapy on the circadian rhythm of heart rate variability in patients with chronic stable angina pectoris. Am J Cardiol 1999; 83(4): 596–598, A8. 14. Figueras J, Lidon RM. Early morning reduction in ischemic threshold in patients with unstable angina and significant coronary disease. Circulation 1995; 92(7): 1737–1742. 15. Li JJ. Circadian variation in myocardial ischemia: the possible mechanisms involving in this phenomenon. Med Hypoth 2003; 61(2): 240–243. 16. Tzivoni D, Medina A, David D, Barzilai Y, Brunel P. Effect of metoprolol in reducing myocardial ischemic threshold during exercise and during daily activity. Am J Cardiol 1998; 81(6): 775–777. 17. Gardner MJ, Altman DG. Statistics with Confidence – Confidence Intervals and Statistical Guidelines. London: British Medical Journal, 1989. 18. Stone PH, Gibson RS, Glasser SP, DeWood MA, Parker JD, Kawanishi DT, et al. Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group. Circulation 1990; 82(6): 1962–1972. 19. McLenachan JM, Weidinger FF, Barry J, Yeung A, Nabel EG, Rocco MB, et al. Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease. Circulation 1991; 83(4): 1263–1270. 20. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341(24): 1789–1794.

Save these dates SCM 2010: 2nd Lugano Stem Cell Meeting: 22–23 June 2010 Cardiocentro Ticino, Lugano, Switzerland MTE 2010 (Meet the Experts): 6th Interventional Symposium on High-Risk Coronary Interventions: 23–25 June 2010 Cardiocentro Ticino, Lugano, Switzerland To register or for more information email congressi@cardiocentro.org


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Cardiovascular Topics Inflammation and dyslipidaemia: a possible interplay between established risk factors in North Indian males with coronary artery disease BINITA GOSWAMI, MEDHA RAJAPPA, BHAWNA SINGH, PC RAY, SURESH KUMAR, V MALLIKA

Summary Objectives: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the developed world and is rapidly assuming epidemic proportions in developing countries, including India. This has led to extensive research to determine the risk factors and the pathways that may predispose to the elevated risk of this disease. Important among them include lipoproteins, homocysteine, lipoprotein (a), pro-inflammatory cytokines and others. The following study was undertaken to determine a possible inter-relationship between inflammation and dyslipidaemia, which are important risk factors for CAD in the atherosclerosis-prone North Indian male population. Methods: The study groups comprised 150 clinically assessed North Indian male patients with acute myocardial infarction (AMI), diagnosed on electrocardiographic and biochemical criteria, and 150 healthy controls. Apolipoprotein-AI (Apo-AI), apolipoprotein-B (Apo-B) and C-reactive protein (CRP) levels were estimated using kits based on the immunoturbidimetric assay from Randox, UK. Tumour necrosis factor-α (TNF-α) and lipoprotein (a) were assayed using commercially available ELISA kits from Diaclone Research, Belgium and Innogenetics, Belgium, respectively. Results: The patients with AMI showed highly significant elevations in the levels of total serum cholesterol, triglycerides, LDL cholesterol, Apo-B and a significant decline in HDL cholesterol, compared with healthy controls. Significantly elevated serum levels of inflammatory markers, TNF-α and Department of Biochemistry, GB Pant Hospital, New Delhi, India BINITA GOSWAMI, MD, DNB, binitadr@yahoo.co.in BHAWNA SINGH, MD V MALLIKA, MD

Department of Ocular Biochemistry, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India MEDHA RAJAPPA, MD, DNB, MNAMS, linkmedha@gmail.com

Department of Biochemistry, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi, India PC RAY, MD

Department of Medicine, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi, India SURESH KUMAR, MD

CRP were seen in patients with AMI, compared to the control subjects. A significantly positive correlation of TNF-α was observed with lipoprotein (a) in patients with CAD. Conclusion: The data clearly underlines a possible interplay between inflammation and dyslipidaemia in the pathogenesis of CAD in the Indian context. This insight into the aetiopathogenesis of CAD will prove highly beneficial for devising better preventive measures and pharmacological interventions for CAD. Keywords: coronary artery disease, C-reactive protein, tumour necrosis factor-α, apolipoprotein-AI, apolipoprotein-B Submitted 17/11/09, accepted 3/2/10 Cardiovasc J Afr 2010; 21: 103–108

www.cvja.co.za

The last century has seen a rapid increase in the global prevalence of coronary artery disease (CAD). Results from the Global Burden of Disease study estimated that India is facing the greatest burden due to CAD.1-3 It has been projected that by the year 2010, 60% of the world’s patients with heart disease will be in India. Moreover, in India about 50% of CAD-related deaths occur in people younger than 70 years of age, compared with only 22% in the west.4 Another interesting feature of CAD among Indians is the lower prevalence of conventional risk factors, such as hypertension, obesity, cigarette smoking, hypercholesterolemia, and others. The explanation for this paradox has been a matter of intense research in the last few decades.5 In the recent past, newer risk factors such as lipoprotein (a) [Lp(a)], homocysteine, apolipoproteins, pro-inflammatory mediators, hypercoagulability, platelet aggregation, and insulin resistance have caught the attention of clinicians and researchers as the probable conglomeration of novel risk factors responsible for CAD in Indians.6 Hence it is clear that both nature (genetic predisposition) and nurture (environmental or lifestyle factors) are responsible for the disease burden in Asians.7 Atherosclerosis, a progressive disease characterised by the accumulation of lipids and fibrous elements in the large arteries, constitutes the single most important contributor to this growing burden of CAD. The hypotheses regarding the pathophysiology of this important malady have evolved substantially over the last few decades. The link between lipids and atherosclerosis has dominated the thinking up to the 1970s, based on strong experimental and clinical relationships between hypercholesterolaemia and atheroma formation. The emerging knowledge on vascular biology led to a focus on growth factors and the proliferation of


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smooth muscle cells in the 1970s and 1980s. A fusion of these views led to the concept of the atheroma as a graveyard of acellular lipid debris enrobed in a capsule of proliferated smooth muscle cells.8 Over the past decade, however, it has been appreciated that inflammation plays a prominent role in atherosclerosis and its complications. Whereas most clinicians previously regarded atheroma as a bland lesion, the current notion that inflammation and immune response contribute to atherogenesis has garnered increased interest.9 A picture emerges of a chronic disease that, from its origin to its ultimate complications, involves inflammatory cells (T cells, monocytes, macrophages), inflammatory proteins (cytokines, chemokines) and inflammatory responses from vascular cells.10 Both infection and inflammation induce the systemic host response known as the acute-phase response (APR) and produce many abnormalities that could increase the risk of developing atherosclerosis, including alterations in lipid and lipoprotein metabolism, which is often mediated by cytokines, particularly TNF-α, IL-1 and IL-6.11 Hence, atherosclerosis is increasingly being recognised as a complex phenomenon involving the interaction of several mechanisms: dyslipidaemia, inflammation, thrombosis and other dysfunctional metabolic syndromes.12 This study attempts to evaluate the contribution of dyslipidaemia and inflammation in the pathogenesis of myocardial infarction and to study a possible interplay between these risk factors in the pathophysiology of CAD.

Methods The study population comprised 150 consecutive male firsttime acute myocardial infarction patients without past or family history of coronary events, presenting to the medical emergency of Lok Nayak Hospital, New Delhi. Acute myocardial infarction was diagnosed based on clinical, electrocardiographic and biochemical criteria. Patients with a history suggestive of hepatic or renal disease were excluded. Use of lipid-lowering drugs also led to exclusion from the study group. The patients were enrolled in the study group after giving informed consent and filling in a structured questionnaire, including details of classical risk factors such as family history of CAD, hypertension and smoking. Any patient with a history of diabetes, hypertension, past or family history of CAD were excluded from the study. The study evaluated the role of inflammation and dyslipidaemia in those patients without apparent risk. The role of smoking could not be excluded from the study groups, as it is very common in India. Body mass index (BMI) values were derived from Quetelet’s formula (weight in kg/height in m2). Approval was obtained from the ethical committee of the institution before commencing the study. Also enrolled were 150 non-diabetic, age-matched healthy controls who satisfied the following criteria: normal glucose tolerance test, absence of angina (Rose questionnaire), absence of history of any vascular disease [acute myocardial infarction (AMI), stroke or intermittent claudication] and normal 12-lead resting electrocardiograms. A patient was diagnosed with AMI if there was a clinical history of ischaemic-type chest pain lasting for more than 20 minutes, substantiated by electrocardiographic evidence of Q waves, ST elevation/depression, and a rise in

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cardiac troponins/CK-MB.13 Arterial hypertension was diagnosed in patients with resting blood pressure values above 140/90 mmHg measured repetitively (at least twice).14 Diabetes was diagnosed based on the criteria of the American Diabetes Association expert committee on diagnosis and classification of diabetes mellitus, i.e., fasting plasma glucose ≥ 126 mg/dl, two hours post-load glucose ≥ 200 mg/dl or two random plasma glucose values ≥ 200 mg/dl.15 A fasting blood sample was taken and serum was separated and stored at –70°C until the assays were performed. Total cholesterol and triglycerides were measured using commercially available kits on the Olympus AU400 (Hamburg, Germany) auto-analyzer. High-density lipoprotein (HDL) cholesterol was determined, after precipitation of Apo-B-containing particles by phosphotungstic acid-MgCl2. Low-density lipoprotein (LDL) cholesterol was calculated for subjects with fasting serum triglyceride levels < 400 mg/dl, using Friedwald’s formula.16 Apo-B and Apo-AI were assayed using commercial kits based on an automated immunoturbidimetric method (Randox, UK). C-reactive protein (CRP) was quantitated in the serum using immunoturbidimetric assay kits from Randox, UK. TNF-α levels were measured using commercial ELISA kits from Diaclone Research, Belgium. Lp(a) levels were estimated using enzymelinked immunosorbent assay [Innotest Lp(a), Innogenetics, Belgium]. This method uses mouse monoclonal anti-Lp(a) as solid-phase antibody and sheep anti-Apo-B polyclonal antibody labelled with horseradish peroxidase (HRP) as capturing antibody.

Statistical analysis All the values are expressed as mean ± SD. Continuous variables were compared with the Student’s t-test. As the parameters followed a non-Gaussian distribution in the study population, Spearman’s rank correlation was used to look for association between different variables in the study group. Univariate logistic regression analysis was performed to ascertain the role of the different risk factors for CAD in our study. A p-value < 0.05 was considered significant. Statistical analyses were performed with SPSS for windows version 12 (SPSS Inc).

Results The clinical characteristics of the study group are shown in Table 1. Significantly elevated levels of total cholesterol, triglycerides, LDL cholesterol and Apo-B were observed in patients with AMI, compared with healthy control subjects (Table 2). The patients with AMI also exhibited lower HDL cholesterol and Apo-AI, compared with controls (Table 2). However, there was no statistically significant difference between Apo-AI levels of patients and controls. Serum levels of inflammatory markers such as CRP and TNF-α were measured in the study population and they exhibited a highly significant difference between the patients with AMI and the controls. Spearman’s rank correlation showed a highly significant positive correlation between TNF-α and lipoprotein (a), while a similar correlation was observed between CRP and lipoprotein (a) (Table 3). The positive correlation between TNF-α (a pro-inflammatory cytokine) and lipoprotein (a) levels indicates a probable interrelationship between dyslipidaemia and


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inflammation in the pathogenesis of CAD. Table 4 depicts the odds ratio of the various risk factors analysed by univariate regression analysis. The odds ratio is the measure of the increase in risk of the disease per unit increase of the parameter. In univariate analysis, Lp(a) among the lipid parameters and CRP among the inflammatory parameters emerged as the strongest risk factors. Lp(a) had an odds ratio of 1.217 (95% confidence interval of 1.159–1.279) and CRP had an odds ratio of 2.996 (95% confidence interval of 2.216–4.049)

Discussion The CAD rate in Asian Indians has been increasing rapidly and has reached alarming levels.1-3,5 It is this CAD-prone North Indian population that constitutes the study population in this research. In the last decade, substantial improvements have occurred in the assessment of cardiovascular risk. A better appreciation of the atherogenic effects of well-known cardiovascular risk factors has been accompanied by understanding the sum of these factors; i.e. the global risk profile provides a better predictive power than any single risk factor. In addition, a number of more recently identified and less well-known factors have received intense investigation over the past few years.17-19 The current view of atherosclerosis is a chronic inflammatory process, developing in response to some metabolic disorders, infections and environmental processes, which initiates and promotes lesion development to the point of acute thrombotic complications and clinical events.19,20 Clearly, inflammation begets more inflammation.21 Substantial advances in basic and experimental science have illuminated the role of inflamma-

tion and the underlying cellular and molecular mechanisms that contribute to atherogenesis.22-24 Many individuals develop CAD in the absence of abnormalities in the lipoprotein profile. The availability of effective therapies for preventing even a first myocardial infarction renders imperative the need to identify at-risk individuals, for concerted intervention, before problems manifest. Based on the evidence supporting the role of inflammation in the pathogenesis of atherosclerosis, inflammatory markers have garnered substantial interest as markers of atherosclerotic risk and add to the information available from traditional measures such as lipid profiles.25,26 In the present study, the roles of CRP and TNF-α were evaluated as markers of the underlying inflammatory process in North Indian patients with acute myocardial infarction, and their serum levels were significantly elevated in the CAD-prone North Indian patients with AMI, compared to controls. One of these markers, CRP, has proven remarkably robust as a marker of cardiovascular risk. Plasma CRP, an acute-phase reactant produced primarily by the liver in response to inflammatory cytokines such as IL-6, prospectively identifies asymptomatic individuals at risk for coronary events.27 The pro-atherogenic functions of CRP include induction of production of inflammatory cytokines and chemotaxis of monocytes, increased expression of cell adhesion molecules, down-regulation of endothelial TABLE 3. SPEARMAN CORRELATION OF THE INFLAMMATORY MARKERS WITH THE LIPID PARAMETERS IN PATIENTS WITH AMI Inflammatory parameter TNF-α v/s

TABLE 1. CLINICAL CHARACTERISTICS OF STUDY GROUPS

Age (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Smoking (n) Alcohol intake (n) Past history of CAD Family history of CAD

AMI patients (n = 150) 55.1 ± 9.6 23.2 ± 4.2 128 ± 9.4 78 ± 4.5 10 6 0 0

Controls (n = 150) 53.7 ± 10.2 22.5 ± 3.9 121 ± 10.1 75 ± 5.2 6 4 0 0

Patients (n = 150) 188.6 ± 40.15 143.3 ± 64.83 38.2 ± 6.29 133.9 ± 32.11 40.2 ± 6.54 107 ± 19.37 99.6 ± 23.55 86.9 ± 14.76 5.01 ± 1.99

Controls (n = 150) 145.5 ± 29.71 123.2 ± 41.92 43.2 ± 5.57 79.7 ± 20.23 10.5 ± 2.34 109.1 ± 18.69 76.9 ± 22.62 15.2 ± 4.23 1.20 ± 0.28

r-value 0.058 –0.076 0.175 –0.127 –0.031 0.018 0.698 0.070 0.159 0.047 –0.023 0.107 –0.070 0.714

p-value NS NS NS NS NS NS 0.003 NS NS NS NS NS NS 0.001

NS: not significant.

TABLE 2. BIOCHEMICAL PARAMETERS IN THE STUDY GROUPS Parameter Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) LDL (mg/dl) Lp(a) (mg/dl) Apo-A (mg/dl) Apo-B (mg/dl) TNF-α (pg/ml) CRP (mg/l) NS: not significant.

CRP v/s

Lipid parameters Cholesterol Triglycerides LDL HDL Apo-AI Apo-B Lp(a) Cholesterol Triglycerides LDL HDL Apo-AI Apo-B Lp(a)

p-value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 NS < 0.001 < 0.001 < 0.001

TABLE 4. UNIVARIATE REGRESSION ANALYSIS OF RISK FACTORS FOR CAD Parameter Cholesterol Triglycerides LDL HDL Apo-AI Apo-B Lp(a) TNF-α CRP

Exp (β) 1.032 1.007 1.032 0.899 0.991 1.040 1.217 1.108 2.996

95% CI 1.021–1.044 1.002–1.013 1.020–1.043 0.855–0.945 0.977–1.006 1.025–1.056 1.159–1.279 1.055–1.163 2.216–4.049

p-value 0.000 0.012 0.000 0.000 0.258 0.000 0.000 0.000 0.000


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nitric oxide synthase expression and activity, increased uptake of LDL-C by macrophages, and stimulation of tissue factor production by peripheral blood monocytes.28-32 CRP elevation indicates the systemic nature of progressive atherosclerotic disease, which suggests that patients with enhanced inflammation are generally at high risk for progression of atherosclerotic disease and may exhibit multiple vulnerable lesions. The concept of early identification of vulnerable patients who are susceptible to cardiovascular adverse events seems appealing, and measurement of inflammatory biomarkers may be a potent adjunctive tool for this purpose.33 Earlier studies such as the OACIS (Osaka Acute Coronary Insufficiency study) and the Quebec Cardiovascular study have shown that CRP levels were significantly raised in the study group, compared to age- and gender-matched controls.34,35 The JUPITER trial has firmly established the utility of CRP as a biomarker to identify populations that will benefit from preventive therapy. Robert Glynn, the statistician associated with the project, has conservatively estimated that hsCRP screening followed by high-dose statin therapy over a five-year period can prevent more than 250 000 heart attacks, strokes, revascularisation procedures and premature vascular deaths in the USA alone. CRP has now emerged as a new diagnostic and therapeutic modality for the management of coronary artery disease and stroke.36 Our study echoes the same finding. CRP plays a major role in regulating lipoprotein metabolism. It promotes uptake of native LDL-C. CRP has also been shown to significantly reduce cholesterol efflux from THP-1 (human myelogenous leukaemia cell line) and peripheral blood mononuclear cells to apoA-I or HDL.37 CRP also decreases the expression of ATP-binding membrane cassette transporter A1 (ABCA1) and ABCG1.38 TNF-α is a pro-inflammatory cytokine produced primarily by activated monocytes/macrophages in response to a variety of stimuli.39 Recently, TNF-α has been implicated in the pathogenesis as well as the progression of atherosclerotic plaques in a number of ways.40 The possible mechanisms postulated include the enhanced surface expression of ICAM-1, VCAM-1, and Eand P-selections on endothelial cells.41 It also leads to increased chemokine and scavenger receptor expression.42,43 Hirschl et al. concluded that the extent of changes in serum TNF-α concentration is significantly related to estimates of infarct extent, obtained scintigraphically.44 In a study involving South Indian patients with CAD (acute myocardial infarction, unstable and stable angina), Rajappa et al. found that the ratios of pro-/anti-inflammatory cytokines in all the study groups increased significantly when patients with unstable angina were compared to other groups.45 Ridker et al. concluded that inflammation plays a major role in the acute coronary syndromes and that TNF-α gene and protein expression persisted in the myocytes over time, which suggests a possible long-term role of this cytokine in vascular remodelling.39 Wojciech et al. conducted a study on the role of inflammation in promotion of left ventricular (LV) diastolic dysfunction. The investigators concluded that plasma levels of TNF-alpha and IL-6 were elevated and there was an association between immuno-inflammatory activation, reflected by plasma levels of cytokines, and LV diastolic dysfunction.46 The findings of our study further substantiate the evidence in favour of the pro-atherogenic functions of TNF-α. We demonstrated the superiority of

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the TNF-α /IL-10 ratio in risk stratification of CAD patients in a previous study.47 Lp(a) is a complex of apolipoprotein (a) and LDL-C. Apolipoprotein (a) is an atherothrombogenic moiety that can competitively inhibit plasminogen activity, leading to impaired fibrinolysis.48 Lp(a) has also been implicated in enhanced oxidation and foam cell formation. Lp(a) functions as a dual pathogen that is thrombogenic, one through its LDL-like characteristics and the other through its plasminogen-like properties.49,50 It forms a link between genetics and two major explanations of the pathogenesis of atherosclerosis: the fibrin-deposition theory of Rokitansky and the lipid hypothesis of Virchow.51,52 Recently, it has been proposed that in settings of enhanced oxidative stress and elevated Lp(a) levels, a pro-inflammatory milieu may predominate that contributes to the clinical expression of CAD.53,54 Lipoprotein (a) has a prothrombic role in the pathogenesis of CAD due to its structural homology with plasminogen and it has been hypothesised that the former interferes with plasminogen activation and creates a thrombogenic milieu. It has a tendency to self-aggregate and hence, a greater capacity to bind to glycosaminoglycans and other structures in the vascular wall. Lp(a) binds avidly to endothelial cells, macrophages, fibroblasts and platelets, as well as to the sub-endothelial matrix; and promotes proliferation of vascular smooth muscle cells and chemotaxis of human monocytes. Due to its unique structural homology with plasminogen, Lp(a) competes with plasminogen for binding to plasminogen receptors, fibrinogen and fibrin. It also induces the production of plasminogen activator inhibitor 1 (the main inhibitor of the fibrinolytic system) and inhibits the secretion of tissue-plasminogen activator by endothelial cells.55-58 All these effects may be potentiated by concomitant dyslipidaemia.59 Anuurad et al. found that the presence of inflammation as detected by increased levels of CRP and fibrinogen resulted in increased Lp(a) levels among African-Americans.60 It was shown that a combination of high Lp(a) levels with a high level of either CRP or fibrinogen was associated with an increased risk for CAD. These results suggest the possibility of an interaction between Lp(a) and inflammatory markers and, furthermore, that the presence of inflammation modulates the risk-factor properties of Lp(a).60 Quantification of apolipoproteins A and B provides a measure of the total number of anti-atherogenic and pro-atherogenic particles in plasma.61 The Quebec Heart study demonstrated accelerated CAD in patients with hyperapolipoproteinaemia-B.62 Our study also showed a significant rise in the atherogenic apolipoprotein B levels in AMI patients in the atherosclerosis-prone North Indian population, compared with control subjects, and indicates that the measurement of apo-B concentration can more accurately delineate coronary artery disease than LDL cholesterol measurement alone. Yet another finding of our study was the highly significant positive correlation between TNF-α and lipoprotein (a) in the CAD-prone North Indian patients with acute myocardial infarction. The positive correlation between these two parameters throws some light on the complex interaction between inflammation and dyslipidaemia in the pathogenesis of atherosclerosis and its ultimate clinical manifestation, namely, acute coronary syndrome that includes myocardial infarction. The apo(a) gene


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contains response elements for inflammatory factors such as IL-6.63 Ramharack et al. reported that Lp(a) and apo(a) mRNA levels in primary monkey hepatocyte culture were responsive to cytokines.64 During inflammation, the lipid changes that are observed are not only quantitative but also qualitative, with changes in the composition of lipoproteins. Therefore, the proportion of triglycerides, phospholipids and cholesterol is increased in VLDL, IDL and LDL particles, whereas the proportion of cholesterol and triglycerides decreases in HDL particles.65 TNF-α administration in rodents led to an increase in HMG CoA reductase mRNA levels.66 In addition to the changes in LDL-C levels observed, a change in LDL size and susceptibility to oxidation of these particles was also observed. TNF-α levels in humans correlated negatively with particle peak size.67 Infection and inflammation was associated not only with a decrease in HDL cholesterol levels but also with a change in the composition. HDLs that circulated during infection and inflammation were depleted in cholesterol esters but enriched in free cholesterol, triglyceride and sphingolipids.68 In addition, HDL-associated Apo-AI1 and paraoxonase, lecithin:cholesterol acyl transferase (LCAT), cholesterol ester transport protein (CETP), hepatic lipase (HL), and phospholipid transfer protein (PLTP) levels decreased but Apo-B and serum amyloid A levels increased.69,70 Because of these changes in HDL metabolism, it is postulated that the main function of HDL, namely its role in protecting LDL against oxidation and reverse cholesterol transport, may be decreased in APR. The present study highlights significantly higher levels of inflammatory mediators such as CRP and TNF-α in the North Indian male patients with acute myocardial infarction, compared with control subjects, and a highly significant positive correlation between Lp(a) and TNF-α levels in male patients in the atherosclerosis-prone Indian population, clearly pointing to a role in the interplay of inflammation and dyslipidaemia in the pathogenesis of CAD in the atherosclerosis-prone North Indian population. The strength of this work lies in the fact that the CAD-prone North Indian population constituted the study population and there was a large sample size involved. However, the present study has a few limitations, which include the lack of follow-up data due to patients’ incompliance and administrative constraints, which could have provided precious information about the role of these mediators as markers for risk stratification and prognosis. Accumulating data indicate that information gained from the link between inflammation, dyslipidaemia and atherosclerosis can yield predictive and prognostic information of considerable clinical utility. New insights into the interplay between dyslipidaemia and inflammation in atherosclerosis may aid in identifying innovative therapeutic strategies to improve outcomes of individuals at risk for or affected by this scourge growing worldwide. We therefore stand on the threshold of clinical application of the interplay between dyslipidaemia and inflammation in atherosclerosis, which could fundamentally alter the way in which we practice preventive medicine, and prove immeasurably beneficial to the public as well.

References 1. Murray CJ, Lopez AD. Global mortality, disability and the contribution of risk factors: Global Burden of Disease study. Lancet 1997; 49:

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1498–1504. 2. Achari V, Thakur AK. Association of major modifiable risk factors among patients with CAD – a retrospective analysis. J Assoc Physicians India 2004; 52: 103–108. 3. Mckeigne PM, Miller GJ, Marmot MG. Coronary artery disease in south Asians overseas: a review. J Clin Epidemiol 1989; 41: 597–598. 4. Gaziano TA, Reddy KS, Paccaud F. Cardiovascular disease. In: Jamison DT, Breman JG, Measham AR. Disease Control Priorities in the Developing World. Oxford: Oxford University Press, 2006: 645–662. 5. Enas EA, Senthikumar A. Coronary artery disease in Asian Indians. An update and review. Internet J Cardiol 2001; 1: 1–42. 6. Rajappa M, Sharma A. Biomarkers of cardiac injury: An update. Angiology 2005; 56: 677–691. 7. Braundwald E. Heart Disease. A Textbook of Cardiovascular Medicine, 5th edn. New York: WB Saunders, 1997; Vol 2: 1105–1160. 8. Mallika V, Goswami B, Rajappa M. Atherosclerosis – pathophysiology and role of novel risk factors: a clinico-biochemical perspective. Angiology 2007; 58: 513–522. 9. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135–1143. 10. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndrome. Am J Cardiol 2001; 88(Suppl): 10K–15K. 11. Khovindhunkit W, Kim MS, Memon RA. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004; 45: 1169–1196. 12. Harb TS, Zareba W, Moss AJ, Ridker PM, Rifai N, Marder WJ, et al. Association between inflammatory markers, hemostatic and lipid factors in post infarction patients. Am J Cardiol 2003; 91: 1120–1123. 13. Alpert JS, Thygesen K, Antman E, Barband JP. Myocardial infarction redefined – a consensus document of the joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–969. 14. Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, Nikowitsch R, et al. Inflammation and Carotid Artery – Risk for Atherosclerosis study (ICARAS). Circulation 2005; 111: 2203–2209. 15. American Diabetic Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183–1201. 16. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502. 17. Yusuf S, Ounpuu S, Anand S. Global burden of cardiovascular disease: A review of evidence. In: Sethi KK, ed. Coronary Artery Disease in Indians: A Global Perspective. Mumbai: Cardiological Society of India, 1998: 11–25. 18. Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol 1992; 70: 945–949. 19. Wood D. Established and emerging cardiovascular risk factors. Am Heart J 2001; 141: S49–57. 20. Libby P. Vascular biology of atheroscterosis overview and state of the Art. Am J Cardiol 2003; 91(Suppl): 3A–6A. 21. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–809. 22. Buja LM. Does atherosclerosis have an infectious etiology? Circulation 1996; 94: 872–873. 23. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–120. 24. Rader DJ. Inflammatory markers of coronary risk. N Engl J Med 2000; 343; 1179–1182. 25. Alexander RW. Inflammation and coronary heart disease. N Engl J Med 1994; 331: 468–469. 26. McGovern PG, Pankow JS, Shahar E for the Minnesota Heart survey investigations. Recent trends in acute coronary heart disease mortality, morbidity, medical care and risk factors. N Engl J Med 1996; 334: 884–890. 27. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; l11(12): 1805–1812. 28. Torzewski M, Rist C, Mortensen RF, Zwaka TP. C-reactive protein in the arterial intima: role of C-reactive protein receptor dependent monocyte


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recruitment in atherogenesis. Arterioscler Thromb Vasc Biol 2000; 20: 2094–2099. 29. Fichtscherer S, Rosmbingr G, Walter DH, Breur S. Elevated C-reactive protein and improved endothelial reactivity in patents with coronary artery disease. Circulation 2000; 102: 1000–1016. 30. Venugopalan SK, Devaraj S, Yuhana I, Shaul P. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002; 106: 1439–1441. 31. Zwaka TP, Hombach V, Torzewski J. C-reactive protein mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001; 103: 1194–1197. 32. Cermark J, Key N, Bach R, Balla J. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513–520. 33. Buffon A, Biasucci LM, Liuzzo G, D’onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 5–12. 34. Kinjo K, Sato H, Ohnishi Y, Hishida E. Impact of high sensitivity C-reactive protein on predicting long term mortality of acute myocardial infarction. Am J Cardiol 2003; 91: 931–935. 35. St Pierre AC, Bergeron J, Pirro M, Cantin B. Effect of plasma C-reactive protein levels in modulating the risk of coronary heart disease associated with small dense, low density lipoproteins in men. Am J Cardiol 2003; 91: 555–558. 36. Koenig W. Is hs CRP back on board? Implications from the JUPITER trial. Clin Chem 2009; 55(2): 216–218. 37. Devraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombosis. Clin Chem 2009; 55(2): 229–238. 38. Wang X, Liao D, Bharadwaj U, Li M, Yao Q, Chen C. C-reactive protein inhibits cholesterol efflux from human macrophage derived foam cells. Arterioscler Thromb Vasc Biol 2008; 28: 519–526. 39. Ridker PM, Rifai N, Pfiffer M, Sacks F. Elevation of tumour necrosis factor α and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149–2153. 40. Gotsman I, Stabholz A, Planer D, Pugatsch T, Lapidus L, Novikov Y, et al. Serum cytokine tumor necrosis factor-alpha and interleukin-6 associated with the severity of coronary artery disease: indicators of an active inflammatory burden? Isr Med Assoc J 2008; 10: 494–498. 41. Oden M. Tumour necrosis factor α as a myocardial depressant substance. Int J Cardiol 1993; 42: 231–238. 42. Pwdil R, Pidrman V, Krejsek J. Gregor J. Cytokines and adhesion molecules in the course of acute myocardial infarction. Clin Chem Acta 1999; 280: 127–134. 43. Stampfer MJ, Sacks FM, Salvini S, Willett WC. A prospective study of cholesterol, apolipoprotein and the risk of myocardial infarction. N Engl J Med 1991; 325: 375–381. 44. Hirschl MM, Gwechenberger M, Binder T, Binder M. Assessment of myocardial injury by serum tumour necrosis factor alpha measurements in acute myocardial infarction. Eur Heart J 1996; 17: 1852–1859. 45. Rajappa M, Sen SK, Sharma A. Role of pro-/anti-inflammatory cytokines and their correlation with established risk factors in South Indians with coronary artery disease. Angiology 2009; 60: 419–426. 46. Wojciech K, Roksolana D, Monika PK, Alina O, Walentyna M. Plasma levels of TNF-α, IL-6, and IL-10 and their relationship with left ventricular diastolic function in patients with stable angina pectoris and preserved left ventricular systolic performance. Coron Artery Dis 2008; 19(6): 375–382. 47. Goswami B, Rajappa M, Mallika V, Shukla DK, Kumar S. TNF-α/IL-10 ratio and C-reactive protein as markers of the inflammatory response in CAD-prone North Indian patients with acute myocardial infarction. Clin Chim Acta 2009; 408: 14–18. 48. Scanu AM. Lipoprotein (a): a genetic risk factor for premature coronary artery disease. J Am Med Assoc 1992; 267: 3326–3329. 49. Luthra K, Misra A, Srivastava LM. Lipoprotein (a): Biology and role in atherosclerotic vascular disease. Curr Sci 1999; 76: 1553–1560. 50. Rhoads GG, Dahlen G, Berg K, et al. Lipoprotein (a) as a risk factor for myocardial infarction. J Am Med Assoc 1986; 256: 2540–2544.

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51. Rajappa M, Sridhar MG, Balachander J, Sethuraman KR. Lipoprotein (a) and comprehensive lipid tetrad index as a marker for coronary artery disease in NIDDM patients in South India. Clin Chim Acta 2006; 372: 70–75. 52. Dahlen G. Lipoprotein (a) in cardiovascular disease: review article and viewpoint. Atherosclerosis 1994; 108: 111–126. 53. Singh RB, Ghosh S, Niaz MA. Epidemiologic study of diet and coronary risk factors in relation to central obesity and insulin levels in rural and urban populations of North India. Int J Cardiol 1995; 47: 245–255. 54. Watts GF, Gwjlym RM, Mazurkiewicz J, et al. Independent correlation between plasma lipoprotein (a) and angiographic coronary artery disease in NIDDM. Diabetes Care 1995; 18: 234–236. 55. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, et al. A study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. J Am Med Assoc 1996; 276: 882–888. 56. St-Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, et al. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 2005; 25: 553–559. 57. Bjornheden T, Babyi A, Bondjers G, Wiklund O. Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system. Atherosclerosis 1996; 123: 43–56. 58. Tribble DL, Rizzo M, Chait A, Lewis DM, Blanche PJ, Krauss RM. Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins. Am J Med 2001; 110: 103–110. 59. Galeano NF, Al-Haideri M, Keyserman F, Rumsey SC, Deckelbaum RJ. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J Lipid Res 1998; 39: 1263–1273. 60. Anuurad E, Rubin J, Chiem A, Tracy RP, Pearson TA, Berglund L. High levels of inflammatory biomarkers are associated with increased allelespecific apolipoprotein(a) levels in African-Americans. J Clin Endocrin Metabol 2008; 93(4): 1482–1488. 61. Goswami B, Mallika V, Rajappa M, Kumar S, Shukla DK. Apo-B/ Apo-A-I ratio: a better discriminator of coronary artery disease risk than other conventional lipid ratios in Indian patients with acute myocardial infarction. Acta Cardiol 2008; 63: 749–755. 62. Lamarche B, Despres JP, Moorjani S, Cantin B, Dagenais GR, Lupien PJ. Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular study). Am J Cardiol 1995; 75: 1189–1195. 63. Berglund L, Ramakrishnan R. Lipoprotein (a). An elusive cardiovascular risk factor. Arterioscler, Thrombosis, Vasc Biol 2004; 24: 2219. 64. Ramharack R, Barkalow D, Spahr MA. Dominant negative effect of TGF-ß1 and TNF- on basal and IL-6-induced lipoprotein (a) and apolipoprotein (a) mRNA expression in primary monkey hepatocyte cultures. Arterioscler, Thrombosis, Vasc Biol 1998; 18: 984–990. 65. Cabana VG, Seigel JN, Sabesin SM. Effect of acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins. J Lipid Res 1989; 30: 39–49. 66. Hardardottir I, Grunfeld C, Feingoid KR. Effects of endotoxin and cytokines on lipid metabolism. Curr Opin Lipidol 1994; 5: 207–215. 67. Skoog T, Dichtl W, Boguist S. Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle aged men. Eur Heart J 2002; 23: 376–383. 68. Feingold KR, Memon RA, Moser AH, Grunfeld C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998; 139: 307–315. 69. Feingold KR, Judy K, Shigenaga LG, et al. Infection and inflammation decrease apolipoprotein M expression. Atherosclerosis 2008; 199: 19–26. 70. Ly H, Franconi OL, Fielding CJ. Endotoxin and TNF lead to reduced LCAT activity and decreased hepatic LCAT-mRNA levels in Syrian hamsters. J Lipid Res 1995; 36: 1254–1263.


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Case Report Amiodarone-induced QT prolongation in a newly transplanted heart associated with recurrent ventricular fibrillation ERNST R SCHWARZ, LAWRENCE S CZER, SINAN A SIMSIR, ROBERT M KASS, ALFREDO TRENTO

Summary Anti-arrhythmic drugs such as amiodarone have the potential to prolong QT intervals, which can result in torsades de point arrhythmia. It is unknown whether amiodarone, given to a recipient prior to cardiac transplantation, can cause arrhythmia in a newly transplanted donor heart. We report on a case of a 71-year-old male patient who had received intravenous and oral amiodarone prior to transplantation, which was associated with QT prolongation in the transplanted heart after re-exposure to the drug during subsequent episodes of ventricular fibrillation. An ICD was implanted, which has not been described that soon after cardiac transplantation. Amiodarone, given to a recipient, might cause QT prolongation in a donor heart after transplantation, possibly due to its long half-life and increased bioavailability caused by interaction with immunosuppressive drugs. Keywords: ventricular fibrillation, QT prolongation, antiarrhythmic drugs, heart transplantation Submitted 3/7/09, accepted 19/8/09 Cardiovasc J Afr 2010; 21: 109–112

www.cvja.co.za

Cardiac transplantation represents the ultimate therapeutic solution for end-stage heart failure. Currently, approximately 2 200 heart transplantations are performed in the USA per year.1 Survival rates at one, five and 10 years after cardiac transplantation are reported as 87, 77 and 57%, respectively. The average life expectancy after cardiac transplantation is approximately 10 years in adults (9.16 years in a recent study2). Quality of life in patients 10 years after heart transplantation has been described as similar to that in the general population.2 Arrhythmias early after transplant surgery, in particular paroxysmal atrial fibrillation, have been described in 5% of cases,3 even independent of evidence of cellular or humoral rejection. In a large retrospective analysis, cardiac transplantation – in Cedars Sinai Heart Institute, Division of Cardiology, Division of Cardiothoracic Surgery, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, and University of California Los Angeles, (UCLA), Los Angeles, USA ERNST R SCHWARZ, MD, PhD, Ernst.schwarz@cshs.org LAWRENCE S CZER, MD SINAN A SIMSIR, MD ROBERT M KASS, MD ALFREDO TRENTO, MD

contrast to CABG surgery in low-risk patients – was considered the strongest independent predictor of freedom from postoperative atrial fibrillation (odds ratio 96; 95% confidence interval: 13–720).4 The incidence of atrial fibrillation, atrial flutter and supraventricular tachycardia after cardiac transplantation was reported as 0.33, 2.8 and 1.3%, respectively.4 Early postoperative supraventricular arrhythmias are usually of a transient nature and rarely require specific anti-arrhythmic therapy. In contrast, the potential pro-arrhythmogenic effects of antiarrhythmic drugs are well known.5 QT prolongation with subsequent torsade de point arrhythmias, in particular after amiodarone therapy potentially resulting in ventricular fibrillation, has been described repeatedly.6-8 We report on a patient with end-stage heart failure treated with intravenous amiodarone followed by oral amiodarone prior to cardiac transplantation. With a single intravenous re-exposure to the drug after transplantation for an episode of atrial fibrillation, the patient developed QT prolongation with subsequent ventricular fibrillation, requiring ICD implantation soon after transplant. This has not been reported before.

Case report The patient was a 71-year-old male with a long-standing history of cardiovascular disease, coronary artery disease, status post myocardial infarction 14 years ago, who underwent coronary artery bypass grafting seven years earlier with a mammary graft to the left anterior descending artery, a vein graft to the diagonal branch, a vein graft to the marginal branch, and a vein graft to the right coronary artery. Over the past five years, the patient had developed symptomatic heart failure, most likely due to myocardial ischaemia. Echocardiography demonstrated severe left ventricular dysfunction with an ejection fraction of 16% and severe mitral regurgitation. Coronary angiography showed occlusion of all grafts except the mammary artery graft. Due to severe coronary sclerosis in the native coronary arteries, no interventional or surgical options for revascularisation were considered. After repeated outside hospital admissions for acute decompensated heart failure, the patient was referred in congestive heart failure New York Heart Association class IV, stage D, for advanced heart failure therapy. The patient had a left bundle branch block and a cardioverter/defibrillator/biventricular pacemaker (CRTD) device was implanted for cardiac resynchronisation therapy and sudden death prophylaxis. Due to persistent symptoms of heart failure


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Fig. 1. ECG 1 of the patient’s heart directly prior to surgery (January 4), after treatment with amiodarone, showing sinus tachycardia with a rate of 134/min, right axis deviation and left bundle branch block. QT duration is 346 msec.

Fig. 2. ECG 2 of the same patient seven days after transplantation (January 11) of the donor heart, showing paroxysmal atrial fibrillation and heart rate approximately 105/min. QT duration is 344 msec.

Fig. 3. ECG 3 of the recipient after cardiac transplantation (January 13) with sinus rhythm, heart rate 60/min and prolonged QT interval of 550 msec. Shortly thereafter, the patient developed ventricular fibrillation.

despite optimised medical and electrical therapy, the patient was evaluated for cardiac transplantation. A right heart catheterisation revealed a PA pressure of 68/38 mmHg with a mean of 49 mmHg and pulmonary capillary wedge pressures of 41/64 mmHg with a mean of 49 mmHg, and a cardiac output of 1.63 l/ min with a cardiac index of 0.89 l/min/m2. Continuous intravenous (IV) inotropic therapy using dobutamine was initiated at 5 mcg/kg/min in combination with IV diuretics. The cardiac index improved to 1.8 l/min/m2, and with persistent symptoms of heart failure after completing the evaluation process, the patient was listed for cardiac transplantation as a status IB. Even before dobutamine therapy, the patient had recurrent episodes of ventricular tachycardia, supraventricular tachycardia and intermittent atrial fribrillation. Amiodarone therapy was initiated with an initial bolus of 150 mg IV, followed by continuous infusion of 1 mg/min for six hours, followed by 0.5 mg/min for 18 hours as a continuous infusion, and then changed to oral

amiodarone 200 mg given twice daily 12 hours apart. The patient’s rhythm stabilised (Fig. 1) and after 10 days, orthotopic cardiac transplantation was performed successfully. The donor heart was from a 36-year-old male without any prior cardiovascular history or prior anti-arrhythmic therapy. The donor’s ECG was without any abnormalities. On postoperative day seven, the recipient developed paroxysmal atrial fibrillation (Fig. 2). A single amiodarone bolus of 150 mg was given, followed by an infusion of 0.5 mg/min and the patient converted to sinus rhythm. Subsequently, the patient demonstrated prolonged QT interval on ECG (550 msec, QTc 544 msec, Fig. 3) and developed torsade de pointes, which degenerated into ventricular fibrillation, with successful external defibrillation. Amiodarone was discontinued, electrolytes were in the normal range but IV magnesium was started for a borderline low magnesium level of 1.5 mg/dl. Despite shorter but still prolonged QT intervals the following day (454 ms, QTc 517 msec) with normal


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electrolytes, the patient had another episode of ventricular fibrillation, which required external defibrillation. Subsequent ECGs demonstrated normalised QT intervals. Cardiac function, assessed by transthoracic two-dimensional echocardiography was normal, and a coronary angiogram demonstrated normal coronary arteries without angiographic evidence of any obstructive disease, coronary spasm or embolus. Right ventricular endomyocardial biopsies did not reveal any signs of acute cellular or humoral rejection. We hypothesise that amiodarone given to the recipient for a prolonged time prior to transplantation, followed by re-exposure to intravenous amiodarone with increased bioavailability due to concomitant tacrolimus therapy after transplantation might have caused prolonged QT interval in the donor heart with subsequent ventricular arrhythmia. After considering a watch-and-wait approach versus a temporary wearable defibrillator vest (which was rejected by the patient) it was decided to proceed with implantation of a single-chamber ICD as primary prevention of sudden death 14 days after cardiac transplantation. The patient was discharged in a stable condition and so far, has had no further arrhythmic events.

Discussion We report recurrent ventricular fibrillation in a patient soon after cardiac transplantation without evidence of electrolyte abnormalities, myocardial ischaemia, humoral or cellular rejection or graft dysfunction. ECG revealed a prolonged QT interval, which occurred after a brief re-exposure to intravenous amiodarone after the recipient had had prolonged IV and oral amiodarone in the days prior to transplantation. Even though not proven without doubt, it is likely that previous amiodarone therapy induced QT prolongation in the transplanted donor heart due to its long half-life, even after the drug was stopped.9,10 The brief intravenous re-exposure might have boosted amiodarone levels, however, unlike oral amiodarone, IV amiodarone alone is rarely associated with significant QT prolongation and even more rarely with torsade de pointes. Other potential reasons for the QT prolongation cannot be ruled out completely. A cross check of drugs known to prolong QT intervals, such as albuterol, alfuzosin, amantadine, amitriptyline, amphetamines, arsenic, astemizole, atazanavir, atomoxetine, azythromycin, chloroquine, clomipramine, dolasetron, metaproterenol, moxifloxacin, phentermine, and phenylpropanolamine revealed that none of those had been reported to be taken by the recipient or the donor in the past. There was no significant bradycardia and no relevant electrolyte abnormalities that could have caused either QT prolongation or ventricular arrhythmia. No evidence for myocardial ischaemia, graft dysfunction or rejection was evident. The donor had no known history of long QT syndrome or any cardiovascular disorder and had died of non-cardiac reasons. Therefore, we believe that the QT-prolonging and pro-arrhythmic potential of extended amiodarone therapy prior to transplant caused the events in the case described here. In general, the occurrence of QT prolongation with subsequent ventricular fibrillation in the absence of ischaemia or graft rejection is extremely rare early after cardiac transplantation, and in fact, has not been reported so far, to the best of our knowledge. Also, we did not find any reports in the literature of either ventricular fibrillation or ICD implantation in the early

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postoperative period after heart transplantation or on potential anti-arrhythmia-induced QT prolongation. Serum levels of amiodarone, even though not measured, could have been increased by a potential drug interaction with tacrolimus,11 which was given as part of the immunosuppressive regime after transplantation. Similarly, this has been described with cyclosporine,12 and both drugs can contribute to higher bioavailability of amiodarone. MacDonald et al. demonstrated that patients who received amiodarone before transplantation had significantly lower heart rates at one and four weeks after transplantation and required prolonged atrial pacing (7.3 ± 1.4 versus 3.4 ± 0.8 days, p < 0.02). In a relatively small study of 19 patients on amiodarone compared to 31 controls, no effect of prior amiodarone therapy on early allograft function or on clinical outcome was detected.13 Even though some authors in the past have recommended continuing amiodarone after cardiac transplantation because of serious side effects after discontinuation of the drug,14 this is not recommended anymore. Moreover, there is also controversy about the use of beta-adrenergic blockers (early) after transplantation,15 but there are no data from controlled large-scale studies. Since we believed that the arrhythmia was most likely caused by amiodarone, we recommended waiting until the drug was completely cleared, as demonstrated by continuous monitoring. Also, a wearable defibrillator vest was discussed, but neither was accepted by the patient and therefore, a single-chamber ICD was implanted for the prevention of sudden death. This has not been reported that early after transplantation before. In contrast, ventricular arrhythmias and the need for antiarrhythmic therapy, including ICD implantation has been described late after cardiac transplantation. Arrhythmic events in the post-transplant population are most often associated with graft dysfunction secondary to chronic allograft vasculopathy and subsequent myocardial ischaemia, with an increased risk of sudden death years after transplant.16 The usefulness of ICD implantation has been described in 10 out of 493 heart transplant recipients,17 which is not as common as ICD implantation in heart failure patients awaiting cardiac transplantation.18-20

Conclusion The potential arrhythmogenic effects of anti-arrhythmic drugs such as amiodarone should be considered, even after cessation of the drug, and even in the transplanted donor heart. Because of the potential drug interactions with immunosuppressive agents such as tacrolimus, the QT interval in the transplanted heart should be monitored closely in patients who had received amiodarone prior to transplantation.

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cases. Ann Thorac Surg 2008; 85: 56–58. 4. Khan M, Kalahasti V, Rajagopal V, Khaykin Y, Wazni O, Almahameed S, et al. Incidence of atrial fibrillation in heart transplant patients: longterm follow-up. J Cardiovasc Electrophysiol 2006; 17: 827–831. 5. Lazzara R. Antiarrhythmic drugs and torsade de pointes. Eur Heart J 1993; 14(Suppl H): 88–92. 6. McComb JM, Logan KR, Khan MM, Geddes JS, Adgey AA. Amiodaroneinduced ventricular fibrillation. Eur J Cardiol 1980; 11: 381–385. 7. Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992; 86: 1376–1382. 8. Schrickel J, Bielik H, Yang A, Schwab JO, Shlevkov N, Schimpf R, et al. Amiodarone-associated ‘torsade de pointes’. Relevance of concomitant cardiovascular medication in a patient with atrial fibrillation and structural heart disease. Z Kardiol 2003; 92: 889–892. 9. Zipes DP, Prystowsky EN, Heger JJ. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects. J Am Coll Cardiol 1984; 3: 1059–1071. 10. [No authors listed]. Adverse effects of amiodarone: even after the end of treatment. Prescrire Int 2006; 15: 62. 11. Nalli N, Stewart-Teixeira L, Dipchand AI. Amiodarone-sirolimus/ tacrolimus interaction in a pediatric heart transplant patient. Pediatr Transplant 2006; 10: 736–739. 12. Chitwood KK, Abdul-Haqq AJ, Heim-Duthoy KL. Cyclosporineamiodarone interaction. Ann Pharmacother 1993; 27: 569–571. 13. Macdonald P, Hackworthy R, Keogh A, Sivathasan C, Chang V, Spratt P.

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The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function. J Heart Lung Transplant 1991; 10: 743–749. 14. Preuner JG, Lehle K, Keyser A, Merk J, Rupprecht L, Goebels R. Development of severe adverse effects after discontinuing amiodarone therapy in human heart transplant recipients. Transplant Proc 1998; 30: 3943–3944. 15. Verani MS, Nishimura S, Mahmarian JJ, Hays JT, Young JB. Cardiac function after orthotopic heart transplantation: response to postural changes, exercise, and beta-adrenergic blockade. J Heart Lung Transplant 1994; 13: 181–193. 16. Weiss MJ, Madsen JC, Rosengard BR, Allan JS. Mechanisms of chronic rejection in cardiothoracic transplantation. Front Biosci 2008; 13: 2980–2988. 17. Ptaszek LM, Wang PJ, Hunt SA, Valantine H, Perlroth M, Al-Ahmad A. Use of the implantable cardioverter-defibrillator in long-term survivors of orthotopic heart transplantation. Heart Rhythm 2005; 2: 931–933. 18. Lorga-Filho A, Geelen P, Vanderheyden M, Malacky T, Primo J, Goethals M, et al. Early benefit of implantable cardioverter defibrillator therapy in patients waiting for cardiac transplantation. Pacing Clin Electrophysiol 1998; 21: 1747–1750. 19. Grimm M, Grimm G, Zuckermann A, Wieselthaler G, Feuerstein M, Daneschvar H, et al. ICD therapy in survivors of sudden cardiac death awaiting heart transplantation. Ann Thorac Surg 1995; 59: 916–920. 20. Podczeck A, Hief C, Jakl G, Frohner K, Nürnberg M, Kaltenbrunner W, et al. [Efficacy of the implantable cardioverter-defibrillator in patients on the waiting list for heart transplantation.] Wien Klin Wochenschr 1995; 107: 485–488.

Innovative approaches offer more at 2010 South African Heart Association congress, 8–11 August, Sun City The organisers of the 2010 South African Heart Association congress (SAHA) are offering an innovative programme with sessions in cardio-oncology (a first for South Africa), women’s cardiovascular health, ethics, and South African scientific contributions within the plenary sessions. Parallel sessions, although necessary to cope with special-interest groups, will be kept to a minimum. Interventional cardiology will be well covered. The August timing of the congress has not deterred international interest and 16 overseas experts in the clinical, interventional and community health fields will participate in the convention. The popular Mayo Clinic echocardiography workshop will be held on 8 August and will focus on new topics not dealt with in earlier workshops held in South Africa. The congress organising committee, under the chairmanship of Dr Eric Klug, has kept price increases to a minimum. ‘We are also providing incentives to delegates to register early and as members of SAHA, thereby obtaining cheaper access.’ As the congress also includes a long weekend, family packages will be available. An across-the-board subsidy for registration is being considered. The theme Holistic Healthcare, inspired by Dr Braunwald’s

previous appeals for improved overall care in cardiovascular medicine, will be patient focused. ‘Our vision for this meeting is to use creative means to enhance the clinician’s day-to-day skills, with the end result that the patient sees our combined efforts as co-ordinated, evidence based, sympathetic and ethical. We aim to share frankly our experiences of success and failure in special sessions devoted to how I do it and lessons I have learned, Dr Klug said. A thought-provoking soapbox session on the last day will include seven succinct presentations on controversial topics in cardiovascular medicine. A wonderful social programme is also being arranged. SO DO NOT MISS THIS RAND-BASED OPPORTUNITY TO HAVE THE BEST OF INTERNATIONAL CONTRIBUTIONS, THE BEST AFRICA HAS TO OFFER. GO TO THE WEBSITE TO SEE THE FULL PROGRAMME AND REGISTER NOW!! www.saheart.co.za


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Case Report The unicuspid aortic valve SHI-MIN YUAN, HUA JING, JACOB LAVEE

Summary The unicuspid aortic valve is a very rare congenital anomaly, which usually presents as aortic stenosis, incompetence, or a combination of both. Other congenital disorders may accompany this phenomenon and aortic dilatation and left ventricular hypertrophy are frequent complications. We present a case report of a young, symptomatic patient with a unicuspid aortic valve, complicated by dilatation of the aortic root and ascending aorta, with left ventricular hypertrophy. The patient recovered fully after a Bentall procedure. Keywords: aortic dilatation, echocardiography, unicuspid aortic valve Submitted 20/7/09, accepted 13/10/09 Cardiovasc J Afr 2010; 21: 113–114

www.cvja.co.za

The unicuspid aortic valve is a rare congenital cardiovascular anomaly, which is often misdiagnosed as a bicuspid aortic valve.1 The true incidence of the unicuspid aortic valve may be underestimated in the asymptomatic population.2 The clinical and diagnostic implications of this anomaly have been reviewed before.2-6

Case report These images (Fig. 1A–1D) are those of a 32-year-old male who presented with intermittent chest pain. Clinically, a combined systolic and diastolic murmur was audible over the left parasternal region. Chest radiography demonstrated a dilated ascending aorta. Echocardiography additionally revealed a unicuspid aortic valve – with one raphe and commissure. Severe aortic regurgitation with mild aortic stenosis, resulting in left ventricular hypertrophy was also present. At operation, the aortic valve was unicuspid and severely regurgitant with an eccentric orifice, with one commissural attachment at the left- and non-coronary commissural, and one raphe at the right- and left-coronary commissural positions, with leaflet thickening and calcification. Aortic dilatation involving the aortic root and ascending aorta was an additional operative

Department of Cardiac and Thoracic Surgery, The Chaim Sheba Medical Center, Tel Hashomer, Israel SHI-MIN YUAN, MD, PHD JACOB LAVEE, MD, Jacob.lavee@sheba.health.gov.il

Department of Cardiothoracic Surgery, Jinling Hospital, School of Clinical Medicine, Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China SHI-MIN YUAN, MD, PHD HUA JING, MD, dr.jing@163.com

finding. The patient underwent a Bentall procedure and had an uncomplicated post-operative course.

Discussion The unicuspid aortic valve is a rare congenital malformation seen in 0.019% of patients during echocardiographic evaluation and in 5.59% of patients during aortic valve replacement.2,3 The unicuspid aortic valve can be categorised into two types: acommissural pin-hole shaped, and unicommissural slit-shaped.1 The acommissural type has no lateral attachment to the aorta with a central orifice, and the unicommissural type has one attachment with an eccentric orifice.3 Patients with a unicuspid aortic valve are always very young at the time of diagnosis or surgery, ranging from 14 to 75 years old.1,4 The typical age of unicuspid aortic valve patients at presentation is the third to the sixth decade, indicating an earlier onset and a higher rate of progression of aortic stenosis in comparison to patients with a tricuspid aortic valve. Collins et al.5 have shown in a retrospective analysis that a decreased number of aortic cusps are associated with an increased occurrence of pathological changes of these cusps and the ascending aorta. Severe aortic stenosis or mixed stenosis and regurgitation is the predominant disorder that accompanies patients with a unicuspid aortic valve.6 Left ventricular dilatation might be present at the time of diagnosis.7 Similar to the bicuspid aortic valve, the unicuspid aortic valve is prone to be associated with dilatation or dissection of the aorta, involving the aortic root,8 ascending aorta,9 or aortic arch,10 which typically requires surgical intervention. Other associated disorders include aortic coarctation, an aberrant right subclavian artery,1 and a single coronary artery and ventricular septal defects.8 Recently, magnetic resonance imaging, cardiac computed tomography, and multislice tomography angiography were also applied as auxiliary diagnostic tools in such patients by virtue of their promising assessment of aortic valve morphology, including the exact morphology of the aortic valve and the severity of the aortic stenosis and regurgitation.1,11,12 However, echocardiography remains a reliable method for the pre-operative diagnosis of a unicuspid aortic valve, preferable to the radiological diagnostic tools mentioned above. Echocardiographic imaging allows diagnostic accuracy of aortic valve morphology in most patients. The commissural attachment zone, the valvular orifice, the free edge of the leaflet, and the configuration of the aortic valve can be clearly visualised. Besides, echocardiography can even distinguish true from false unicuspid aortic valves.2 Aortic valve repair, including bicuspidisation, can be performed with low risk and excellent operative results.9


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A

B

C

D

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Fig. 1. Transthoracic echocardiaography showing a unicuspid aortic valve with a raphe at the 11 o’clock position (upper arrow) and a clear commissure at the 4–5 o’clock position (lower arrow) on a short-axis view during systole (A), and diastole (B). The aortic valve in an integral movement and in a dome-shaped configuration during systole (C) and diastole (D), and left ventricular hypertrophy and dilated aortic root extending 3.8 cm in diameter could be seen from the parasternal long axis view (C, D). AV: aortic valve; LV: left ventricle.

References 1. Dursun M, Yilmaz S, Sayin OA, Ugurlucan M, Ucar A, Yekeler E, Tunaci A. Combination of unicuspid aortic valve, aortic coarctation, and aberrant right subclavian artery in a child: MR imaging and CTA findings. Cardiovasc Intervent Radiol 2007; 30: 547–549. 2. Novaro GM, Mishra M, Griffin BP. Incidence and echocardiographic features of congenital unicuspid aortic valve in an adult population. J Heart Valve Dis 2003; 12: 674–678. 3. Falcone MW, Roberts WC, Morrow AG, Perloff JK. Congenital aortic stenosis resulting from a unicommisssural valve. Clinical and anatomic features in twenty-one adult patients. Circulation 1971; 44: 272–280. 4. Roberts WC, Ko JM. Clinical and morphologic features of the congenitally unicuspid acommissural stenotic and regurgitant aortic valve. Cardiology 2007; 108: 79–81. 5. Collins MJ, Butany J, Borger MA, Strauss BH, David TE. Implications of a congenitally abnormal valve: a study of 1025 consecutively excised aortic valves. J Clin Pathol 2008; 61: 530–536. 6. Singh D, Chee TS. Incidental diagnosis of unicuspid aortic valve in an

asymptomatic adult. J Am Soc Echocardiogr 2008; 21: 876.e5. 7. Murphy BA, Groban L, Kon ND. Diagnosis of a unicuspid aortic valve using transesophageal echocardiography. J Cardiothorac Vasc Anesth 2003; 17: 82­–83. 8. Ishigami H, Iwase M, Hyoudo K, Aoyama I, Ito M, Tajima K, et al. A case of unicuspid aortic valve associated with a single coronary artery and ventricular septal defect. J Med Ultrason 2005; 32: 65–70. 9. Schäfers HJ, Aicher D, Riodionycheva S, Lindinger A, Rädle-Hurst T, Langer F, Abdul-Khaliq H. Bicuspidization of the unicuspid aortic valve: a new reconstructive approach. Ann Thorac Surg 2008; 85: 2012–2018. 10. Bansal A, Arora S, Traub D, Haybron D. Unicuspid aortic valve and aortic arch aneurysm in a patient with Turner syndrome. Asian Cardiovasc Thorac Ann 2008; 16: 266–267. 11. Debl K, Djavidani B, Buchner S, Poschenrieder F, Heinicke N, Schmid C, et al. Unicuspid aortic valve disease: a magnetic resonance imaging study. Rofo 2008; 180: 983–987. 12. Gibbs WN, Hamman BL, Roberts WC, Schussler JM. Diagnosis of congenital unicuspid aortic valve by 64-slice cardiac computed tomography. Proc (Bayl Univ Med Cent) 2008; 21: 139.


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Drug Trends in Cardiology Focus on the American College of Cardiology Congress, 2010 Reduced blood pressure variability in ASCOT-BPLA trial favours use of amlodipine/perindopril combination to reduce stroke risk Lower within-individual visit-to-visit variability in blood pressure readings in the amlodipine/perindopril combination treatment arm of the ASCOT study has been shown to account for the more effective stroke reduction rate with this combination compared to atenolol and diuretic-based therapies, despite overall similar blood pressure lowering. This finding was presented at the late-breaking clinical trial session of the American College of Cardiology congress and was published simultaneously in the Lancet Neurology edition online.1 ‘These findings have major clinical implications for the management of patients with hypertension’, said Peter Sever, FRCP, a professor of clinical pharmacology and therapeutics and co-director of the International Centre for Circulatory Health, Imperial College, London. ‘This data convincingly demonstrates that patients with more variation in their blood pressure levels are at greatest risk of future heart attacks and strokes, and that reducing variability is a key goal of treatment.’2 For the ASCOT-BPLA study, researchers recruited 19 257 patients with high blood pressure, averaging 164/95 mmHg at rest. Patients were randomly assigned to treatment with the calcium channel blocker amlodipine with or without the ACE inhibitor perindopril, or to treatment with the beta-blocker atenolol with or without the diuretic bendroflumethiazide. During 5.5 years of follow up, blood pressure variability was determined by comparing multiple blood pressure readings taken at each visit and at several different visits. The Medical Research Council (MRC) trial of 4 396 elderly hypertensive patients

treated with atenolol, a diuretic combination, or placebo, were also evaluated for blood pressure variability and the results were included in this study.3 Researchers found that between-visit blood pressure variability was significantly greater among patients treated in the atenolol arm than those in the amlodipine/ perindopril arm of ASCOT. In addition, when researchers compared patients at the highest one-tenth for between-visit blood pressure variability to those at the lowest one-tenth, they found a strong link with increased risk of stroke. In the beta-blocker group, patients with high blood pressure variability faced a risk of stroke 4.06 times that of those with low blood pressure variability. In the amlodipine/perindopril group, the risk of stroke was 3.8 times higher among patients with high blood pressure variability. A similar pattern linked high blood pressure variability to an increased risk for heart attack and other coronary events. The overall risk of stroke was 22% lower among patients treated with amlodipine/ perindopril when compared to those treated with the beta blocker/thiazide diuretic, a difference that could be entirely explained by differences in blood pressure variability, researchers found. In the ASCOT-BPLA trial, the researchers were also able to look at within-visit variability and variability on 24-hour ambulatory blood pressure monitoring (ABPM). In the ABPM substudy, reduced variability in daytime systolic blood pressure (SBP) in the amlodipine group (p < 0.0001) partly accounted for the reduced risk of vascular events, but reduced visit-to-visit variability in clinic SBP had a greater effect.

In the MRC trial, all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo and diuretic groups during initial follow up (all p < 0.0001). Subsequent temporal trends in variability in blood pressure during follow up in the atenolol group correlated with trends in stroke risk. ‘The greater reduction in variability among patients treated with amlodipine and perindopril may be best explained by their more profound effects on blood vessel relaxation, compared to beta-blockers’, Sever said. He and his co-investigators believe that clinical guidelines and future drug trials must take into account the importance of blood pressure variability in the management of patients, not simply the extent to which a drug lowers average levels of blood pressure. This aspect will need to be reported on in more detail in future trials. The hypothesis that erratic blood pressure levels could be an important factor in determining the risk of future strokes was originally proposed by Peter M Rothwell, MD, PhD, of the Stroke Prevention Research Unit, University Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK. J Aalbers, Special Assignments Editor 1. Rothwell PM, et al. Effects of beta-blockers and calcium channel blockers on withinindividual variability in blood pressure and risk of stroke. Lancet Neurol 2010, March DOI: 10.1016/51474-4422(10)70066-1. 2. ACC report. ACC congress 2010. 3. MRC working party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1992; 304: 405–412.


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Comparison of ivabradine plus β-blockers versus β-blocker therapy only 60 p < 0.001 p < 0.001

50 Change in ETT criteria (s)

A study of patients with stable angina and moderate left ventricular systolic dysfunction has shown that the addition of ivabradine to bisoprolol produced additional anti-anginal and anti-ischaemic effects that were not achieved with up-titration of bisoprolol.1 This indicative study is of importance to clinicians as they are frequently faced with patients on β-blockers who are not able to tolerate the full target dose, as defined from evidencebased clinical trials. Ivabradine is a novel agent that reduces heart rate (HR) by selective and specific inhibition of the If current in sino-atrial cells, leading to prolongation of the slow diastolic depolarisation phase of the action potential. Placebo-controlled studies in angina patients have shown that ivabradine improves exercise tolerance, lengthens time to ischaemia, and has anti-anginal and anti-ischaemic efficacy similar to that of atenolol or amlodipine. The ASSOCIATE study in stable angina patients receiving the beta-blocker atenolol has demonstrated that ivabradine reduces HR and improves exercise capacity (Fig. 1). This study, presented at the ACC congress, included 29 patients with chronic stable angina (class II) who had had a myocardial infarction more than three months before and had moderate left ventricular systolic dysfunction on stable therapy, including bisoprolol 5 mg once daily. Therapy included aspirin, and statins enalapril and furosemide in cases with congestive heart failure.

p < 0.001

40 p = 0.005

20

p < 0.001

p < 0.001

30

p = 0.018

p = 0.017

10

0

M2

M4

Total exercise duration

M2

M4

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Time to limiting angina

M4

Time to angina onset

Ivabradine

M2

M4

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Placebo

Fig. 1. Change in exercise tolerance test criteria between baseline and M2 visit and between baseline and end of study (M4) in the full analysis set. (Ammended from Eur Heart J 9 Jan, 2009).

Over a period of two months, resting heart rate was reduced in both groups to similar levels (60 bpm). However more patients in the ivabradine-treated group (7.5 mg twice daily) showed improvements in angina and more patients moved from angina class II to angina class I than those who received the up-titrated bisoprolol dose (10 mg once daily). Importantly, walking distance and exer-

cise tolerance improved in the ivabradine group while no improvement occurred in the bisoprolol-treated group. J Aalbers, Special Assignments Editor 1. Ekaterina N, et al. Anti-ischemic efficacy of ivabradine in combination with bisoprolol versus up-titration of bisoprolol. E-Abstract 1217-1322, ACC congress 2010.

ACCORD LIPID study results strengthen guideline approach of adding fenofibrate to therapy of dyslipidaemic type 2 diabetic patients Type 2 diabetic patients treated with statins but still experiencing elevated serum levels of triglycerides (2.3 mmol/l or higher) and low HDL cholesterol (0.8 mmol/l or lower), a pre-specified subgroup, benefited from the addition of fenofibrate to their treatment regimen. Risk of cardiovascular events was reduced by 31% in those patients, translating to a need-to-treat 20 patients for five years to

prevent one cardiovascular event.1 Prof Frank Sacks, Harvard School of Public Health and Brigham and Women’s Hospital, Boston, USA pointed out that the ACCORD LIPID study has reinforced the residual-risk hypothesis. ‘Interestingly, those patients whose LDL cholesterol was below 3 mmol/l, essentially at target, showed a tendency to receive greater benefit from the addition of fenofibrate.

Importantly, the atherogenic dyslipidaemia group was a pre-specified group in this trial.’ ‘Previous studies had raised possible concerns about the importance of the observed increase in serum creatinine levels in patients on fenofibrate. The ACCORD LIPID trial has shown convincingly that fenofibrate is safe, with no significant difference in the incidence of


Providing Synergy , Prolonging Time 1

2*


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end-stage renal disease or need for dialysis. There was also no increase in severe muscle aches/pains or rhabdomyolysis, or evidence of liver damage’, Prof Sacks noted. There was, however, a significant reduction in micro- and macroalbuminuria in the fenofibrate group, indicating that diabetic nephropathy may be improved in these patients. The ACCORD trial was an independent trial conducted by NIH specialist institutes and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Fenofibrate administration was masked and administered at a dose of 160 mg per day; adjusted according to the estimated

glomerular filtration rate. A total of 5 518 patients were enrolled in the ACCORD LIPID arm. The pre-specified primary outcome was the first occurrence of a major cardiovascular event, including non-fatal myocardial infarction, non-fatal stroke or death from cardiovascular causes. Mean duration of follow up was 4.7 years for the primary outcome. The results showed that the combination was not better than simvastatin alone in reducing the primary outcome in the majority of the recruited high-risk patients with type 2 diabetes. ‘While patients with atherogenic dyslipidaemia only represented 17% of the

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ACCORD LIPID population, in everyday clinical practice, the size of the problem is significantly greater. We are now quantifying this in the R³i-funded REsiduAl risk LIpids and Standard Therapies (REALIST) study, which is being conducted at Harvard Medical School and over 20 well-known academic centres worldwide’, said Prof Frank Sacks, vice president of the R3i. J Aalbers, Special Assignments Editor 1. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. New Engl J Med March 14, 2010 (10.1056/NEJMoa1001282)

INVEST study warns on too-low BP in diabetic patients with CAD The INVEST (INternational VErapamil SR-Trandolapril) study, a very large international study of hypertensive patients, has shown that patients with type 2 diabetes and coronary artery disease do not benefit from tightening systolic blood pressure levels to below 130 mmHg, and this may in some cases be harmful. INVEST, initiated in the mid-nineties, continues to contribute to the improved management of patients with CAD and this latest evaluation of the 6 400 patients with diabetes and CAD included in the INVEST cohort is the first study to critically evaluate the effects of systolic blood pressure lowering in patients with both diabetes and documented CAD. These results are likely to require guideline committees, including the local SEMDSA’s guideline committee, to include a warning that blood pressure need not be driven below 130 mmHg in diabetic patients as this does not result in any further cardiovascular benefit. This finding is particularly pertinent to drug selection and the use of verapamil SR/trandolapril, which was successful with more than 70% of INVEST patients reaching the target blood pressure of less than 140/90 mmHg. The verapamil SR/ trandolapril therapy group also experienced significantly fewer cases of newonset diabetes than those patients treated with atenolol/hydrochlorothiazide.

‘Current guidelines suggest “lower is better” with regard to blood pressure’, said Rhonda M Cooper-DeHoff, PharmD, MS, and associate professor of pharmacy and medicine at the University of Florida, Gainesville. ‘The INVEST data suggest that in patients with both diabetes and coronary artery disease, there is a blood pressure threshold below which cardiovascular risk increases’. For the study, INVEST randomly assigned 6 400 patients with diabetes and CAD to blood pressure-lowering therapy based on either a calcium channel blocker or a beta-blocker, plus an angiotensin converting enzyme (ACE) inhibitor and/ or a thiazide diuretic. The target was a blood pressure of < 130/< 85 mmHg. For the analysis, patients were categorised according to the degree of blood pressure control actually achieved. Patients with a systolic blood pressure of 140 mmHg or higher, almost onethird of patients, were classified as ‘not controlled’. Those with a systolic blood pressure below 130 mmHg were classified as ‘tight control’ and those with a systolic blood pressure in between (≥ 130 mmHg, but < 140 mmHg) were classified as ‘usual control’. During a follow-up period equivalent to more than 16 893 patient-years, researchers found that patients in the notcontrolled group had nearly a 50% higher

combined risk of death, heart attack or stroke when compared with the usual-care group. However, those in the tight-control group had a similar risk to those in the usual-control group. Further analysis showed that lowering systolic blood pressure below 130 mmHg significantly increased the risk of allcause death when compared to usual care, an increase that became apparent about 30 months into the study and persisted for an additional five years of follow up. When researchers then analysed blood pressure in 5-mmHg increments in the tight-control group, they discovered that a systolic blood pressure below 115 mmHg was associated with increased mortality. ‘Diabetic patients with CAD in whom blood pressure is not controlled have increased risk for unfavourable cardiovascular outcomes, so the message to lower systolic blood pressure below 140 mmHg is still important’, Cooper-DeHoff said. ‘However, it is not necessary to lower systolic blood pressure below 130 mmHg to reduce that risk. Most importantly, reducing systolic blood pressure below 115 mmHg may be associated with increased mortality.’ J Aalbers, Special Assignments Editor 1. American College of Medicine. Press release.


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Combination therapy in hypertension: new recommendations The recent publication of the American Hypertension Society (ASH) position paper on combination therapy in the treatment of hypertension is essential reading for all physicians and for South African medical aid funders.1 As all agree that the goal of antihypertensive therapy is to reduce the risk of vascular events, it is essential that effective and easy-to-use antihypertensives with outcomes data be used early in therapy. Available data from clinical trials and meta-analyses have shown that at least 75% of patients will require combination therapy to achieve contemporary targets. The increasing prevalence of obesity, the metabolic syndrome and type 2 diabetes is likely to increase this percentage even higher, the position paper notes. When choosing combination therapy, the position paper points to the physician making a deliberate choice as to which combination for which patient. The physician needs to consider efficacy, tolerability and adherence aspects when prescribing combination therapy. In efficacy terms, rational combination therapy is based on evidence that the combination lowers blood pressure more significantly than its individual components. The blood pressure reduction should be smooth and continuous, meeting pharmacokinetic criteria for once-a-day usage. Dose-dependent effects of the combination should be less than those induced by higher dosage of the monotherapy. Funders need to take note that co-payment by the medical aid member will reduce compliance and reduce the protective effect of the antihypertensive medication on future vascular events. The ASH position paper identifies twodrug combinations that meet the three criteria outlined above (a single pill with three or more drugs were not reviewed) and these are regarded as preferred combinations. Others that have less evidence to support efficacy, safety or tolerance are also identified. RAAS inhibitor and diuretic This combination is classified as preferred, whether an ACE inhibitor or an angiotensin receptor blocker (ARB), is used with a low-dose diuretic. Most combinations contain hydrochlorothiazide, but chlorthalidone is also identified as

the most-used diuretics in US outcomes trials, although combinations with this diuretic are not currently available. RAAS inhibitor and calcium channel blocker The combination of an ACE inhibitor or ARB with a calcium channel blocker (CCB) results in fully additive blood pressure reduction and improves tolerability. The ACCOMPLISH trial2 (Avoiding Cardiovascular events through COMbination therapy in patients living with Systolic Hypertension) showed beneficial cardiovascular outcomes of this ACE inhibitor/CCB combination compared with the ACE inhibitor/diuretic. Most of the patients in this trial were diabetic, with evidence of underlying ischaemic disease. The position paper considers ARB/CCB combinations equivalent to ACE inhibitor/CCB combinations. Renin inhibitor and ARBs This combination, although without outcome data, has achieved partially additive blood pressure reduction and is well tolerated. In a study of maximum approved doses of valsartan and aliskiren,3 a 30% additional blood pressure response was seen compared to monotherapy. The sideeffect profile matched that of placebo. CCB and diuretics This combination also results in partially additive blood pressure reduction and performed well in outcome studies.4 It is classified in the position paper as acceptable, perhaps because it does not meet the criteria of reduced side-effect profile of the combination compared to the individual drugs. β-blockers and diuretics The position paper notes that there is evidence, mainly with the first-generation β-blocker, atenolol, that β-blockers are less effective than diuretics, ACE inhibitors, ARBs and CCBs. β-blockers attenuate the RAAS activation that accompanies the use of thiazide diuretics, and their combination results in fully additive blood pressure reduction. Addition of the diuretic improves the efficacy of β-blockers in black patients and others with low-renin hypertension.5 These combinations are classed as acceptable with known side effects, such as increased risk of glucose intolerance, fatigue and sexual dysfunction.

Take-home message

•• Use combination therapy routinely to achieve blood pressure targets •• Use only preferred or acceptable two-drug combinations •• Initiate combination therapy routinely in patients who require ≥ 20/10 mmHg blood pressure reduction to achieve target blood pressure •• Initiate combination therapy in stage 1 patients (at the physician’s discretion), especially when the second agent will improve the side-effect profile of initial therapy •• Use combinations rather than separate individual agents in circumstances where convenience outweighs other considerations.

Thiazide diuretics and potassiumsparing diuretics The use of spironolactone/HCTZ in obese patients is especially noted, as is the fact that the combination should be used only in people with relatively well-preserved kidney function (eGFR > 50 ml/min). CCBs and β-blockers The pharmacological effects of these two drug classes are complementary and result in additive blood-pressure reduction. The combination should be with a dihydropyridine CCB and not a non-dihydropyridine CCB such as verapamil or diltiazen because of their additive effects on heart rate and A–V conduction. This position paper places ACE inhibitors and ARBs, RAAS inhibitors and β-blockers, and the combination of β-blockers and centrally acting agents in the category of lower efficacy. It concludes that early use of a combination reduces counter-regulatory responses of monotherapy and brings blood pressure to target in a shorter period of time. J Aalbers, Special Assignments Editor 1. Gradman AH, Basile JN, Carter BL, Bakris GL, on behalf of the American Society of Hypertension writing group. J Am Soc Hypertens 2010; 4(1): 42–50 2. Jamerson K, Weber MA, Bakris GL Dahlof B, Pitt B, Shi V, et al; for the ACCOMPLISH trial investigators. N Engl J Med 2008; 359: 2417–2428. 3. Oparil S, Yarrows SA, Patel S, et al. Lancet 2007; 370: 221–229. 4. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; for the VALUE trial group. Lancet 2004; 363: 2022–2031. 5. Gradman AH. Drug combinations. In: Isso Jl (jun), Black HR, Sica DA, eds. Hypertension Primer. 4th edn. Philadelphia PA: Lippincott, Williams and Wilkins, 2008.


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BETTER BP CONTROL AND ACTIVE CARDIOVASCULAR RISK REDUCTION WITH ADALAT® XL 2 ADALAT® XL • significantly lowers blood pressure while reducing cardiovascular risk3 • can be safely used for the long-term treatment of patients with coronary disease and angina pectoris4 • is effective and safe in a broad spectrum of patients3 ADALAT® XL 20 • provides a low nifedipine dose for initial therapy or combination therapy and allows for greater flexibility in dosing1

Long-term commitment to Life References: 1. ADALAT® XL package insert. 2. Constance C. Which CCB is the better choice? Clinicians Corner 2003;Volume 1. 3. Heagerty AM. Nifedipine gastrointestinal therapeutic system – Hypertension management to improve cardiovascular outcomes. Int J Clin Pract 2005;59:1112-1119. 4. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomized, controlled trial. Lancet August 31, 2004. S3 ADALAT® XL 20 Tablets. Each tablet contains 20 mg nifedipine. Reg. No.: A39/7.1/0634. S3 ADALAT® XL 30 Tablets. Each tablet contains 30 mg nifedipine. Reg. No.: Y/7.1/314. S3 ADALAT® XL 60 Tablets. Each tablet contains 60 mg nifedipine. Reg. No.: Y/7.1/315. For full prescribing information refer to the package insert approved by the medicines regulatory authority. ZA.GM.ADAL.11-2009.0012

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The use of anticoagulants for venous thrombo-embolism Pulmonary embolism is a life-threatening condition with mortality as high as 17.5% within three months of onset.1 Pulmonary embolism is also the most common preventable cause of hospital death. Despite these unacceptably high risks, the effective use of anticoagulants to prevent venous thrombo-embolisms (VTEs) remains inconsistent. Communication and education around the risk of VTE as a result of major orthopaedic surgery, particularly hip- and kneereplacement surgery, remains a concern. Talib Abdool-Carrim, professor of vascular surgery at Milpark Hospital, says to date this communication has been inadequate. ‘I believe medical professionals need to be constantly reminded, as only about 50% of hospital doctors are giving out guidelines for prophylactics, and we need to practice in line with the ACCP and South African guidelines. However, the use of anticoagulants for these patients has increased from a specialist perspective’, Prof Abdool-Carrim says. Orthopaedic surgeon Dick van der Jagt believes medical professionals in South Africa are constantly being informed about prophylaxis for these patients, but that this communication needs to be repeated on an ongoing basis to prevent complacency setting in. ‘Every patient needs to be assessed to determine their individual risk profile, and given appropriate prophylaxis against VTEs’, he says. Prof Mervyn Mer, critical care specialist and one of the authors of the South African Guidelines for Prophylactic Anticoagulation agrees that communication around this issue needs to be optimised. ‘There’s no doubt that extended prophylaxis should be given to high-risk hip- and knee-replacement patients, and that it should be used in conjunction with mechanical devices such as pneumatic compressive devices which are applied to the lower limbs. These are a useful addition to prophylaxis agents as they assist in moving blood around and prevent stasis. These devices are not ideally optimal when used alone but do further decrease

the chance of VTEs’, Prof Mer says. According to Prof Abdool-Carrim, anticoagulants reduce the risk of VTEs by up to 80%. ‘There is enormous data to support the efficacy of anticoagulants in reducing the risk of VTE’, Prof Mer says. ‘It is not 100% guaranteed, but the risk is reduced so substantively that the omission of anticoagulants would compromise the medical practitioner and be difficult to defend. The use of anticoagulants to reduce the risk of VTE has become the number 1 focal point in US hospitals, with specialists being called upon to justify their actions should these agents be omitted.’ The new ACCP guidelines recommend the use of anticoagulants for a minimum of 10 days for knee-replacement surgery and up to 35 days for hip-replacement surgery. The new South African guidelines are fully aligned with the ACCP recommendations and have even extended the time period for knee-replacement surgery to two weeks. ‘In general, prophylaxis should be used whenever a patient is immobile, and should be continued until the patient is mobile again’, Prof Mer says. According to Prof Abdool-Carrim, adequate prophylaxis is not always prescribed for hip and knee replacements or other major surgeries. Dr van der Jagt concurs, saying many patients only receive anticoagulants while in hospital. ‘However, this is often because medical aids will not cover the treatment outside of hospital care, and a high percentage of patients cannot afford to fund it themselves. The guidelines are clear, but unfortunately medical aids are more interested in their bottom lines’, he says. The South African Guidelines for Prophylactic Anticoagulation allude to only currently registered agents, but are updated as the industry evolves. These guidelines have been endorsed by a number of societies including those of orthopaedic surgeons, vascular surgeons, anaesthesiologists, critical care specialists and pulmonary specialists. For the

first time in South Africa, the guidelines include the input of two highly regarded international specialists in the field who have contributed independently to the guidelines to avoid any local bias. Without anticoagulation treatment, patients undergoing major orthopaedic surgery have up to a 60% chance of developing a VTE.1 Recent advances in the field, however, indicate a brighter future as treatment has evolved from warfarin to intravenous heparin to the new oral anticoagulants which are due to be released onto the market soon. According to Dr van der Jagt, the new oral anticoagulants offer a number of benefits over existing treatments: they are simple to administer, easy to manage and don’t need to be constantly monitored. In line with the trend to safely administer effective prophylaxis against VTEs, the oral agents also eliminate the need for injections and cut down on hospital costs as well as hospital-acquired infections by enabling patients to continue with the drugs at home. Commenting on the future direction of these treatments, Prof Mer says the next step lies in the development of particular antidotes and the ability to measure the effects of these agents. ‘We need the ability to measure and monitor each patient’s requirements rather than using a fixed dose for most people’, he says. ‘The future for the prevention of VTEs is definitely looking positive’, Prof AbdoolCarrim added. A further benefit of the new oral anticoagulant agents is that they offer minimal drug–drug and drug–food interactions, making the use of extended anticoagulation therapy more practical. ‘Some of the existing treatments do present a problem with drug–drug and drug–food interactions’, Dr van der Jagt says. ‘Choose a preferred oral anticoagulant which will effectively reduce the risk of clotting without severely increasing the risk of bleeding.’ 1. MIMS Desk Reference. Avusa Media Ltd, 2008; 43: 196.


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Opinions in Hypertension Management Angiotensin receptor blockers (ARBs) in hypertension patients: earlier use of these bettertolerated medications is warranted All patients with hypertension are at increased risk for vascular events and hypertension is widely regarded as one of the most important risk factors for cardiovascular disease.1 At all ages, there is a positive and graded relationship between usual blood pressure and the risk of cardiovascular and stroke mortality.2 The role of the renin–angiotensin– aldosterone system (RAAS), even in the early stages of the cardiovascular continuum, is well-established, with positive results being obtained in clinical trials of cardiovascular event reduction using specific RAAS blockers. In hypertension management, tolerability is key to patient compliance and the long-term reduction of cardiovascular events. ARBs with placebo-like tolerability and efficacy in reducing cardiovascular and cerebrovascular events should be favoured in guidelines.3 ARBs reduce blood pressure at least to the same extent as ACE inhibitors and more so in some cases. For example, the largest study undertaken to compare an ARB

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with an ACE inhibitor, the 1 600-patient Prospective Randomized Investigation of the Safety and efficacy of Micardis versus ramipril using Ambulatory blood pressure monitoring (PRISMA) study found greater blood pressure reductions from telmisartan than ramipril.4 There is significant evidence of within-class differences among ARBs with respect to their plasma half-lives, lipophilicity and receptor-binding affinity. Drugs in the ARB class also differ in their antihypertensive efficacy.5 Clinicians should evaluate these aspects carefully when selecting ARBs for individual patients. There is also increasing evidence that, as with ACE inhibitors, ARBs confer benefits beyond their blood pressurelowering effects by reducing morbidity and mortality in cardiovascular, renal and cerebrovascular outcomes through renin– angiotensin system (RAS) blockade.6

Hypertensive patients at increased risk Telmisartan is the only ARB that has demonstrated therapeutic equivalence to the ACE inhibitor ramipril in hypertensive patients at increased vascular risk. The patient population in this study (ONTARGET) is of particular interest as it is representative of the majority of hypertensive patients seen in everyday clinical practice. The findings from this study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross section of highrisk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.7

Implications for practice In clinical practice, ARBs are linked to greater patient adherence and to better blood pressure control. For this reason, first-line ARBs can offer improved efficacy, greater compliance and reduced healthcare utilisation, which offset higher acquisition costs. Importantly, all ACE-intolerant patients who are at risk of diabetes, myocardiaI infarction, stroke or peripheral arterial disease should be switched to the ARB with proven benefit. J Aalbers, Special Assignments Editor 1. Verdecchia Paolo, et al. Comparative assessment of angiotensin receptor blockers in different settings. Vasc Hlth Risk Mngmt 2009; 5: 939–948. 2. Leurington, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360(9349): 1903–1913. 3. Neldam S. Choosing an angiotensin-receptor blocker: blood pressure lowering, cardiovascular protection or both? Future Cardiol 2010; 6(1): 129–135. 4. Williams B, Lacourciere Y, Schumacher H, Gosse P, Neutel JM. Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials. J Hum Hpertens 2009; 23(9): 610–619. 5. Lacourciere Y, Krezesinski JM, White WB, Davidai G, Schumacher H. Sustained antihypertensive activity of telmisartan compared with Valsartan. Blood Pres Monit 2004; 9: 203–210. 6. Carson P,Giles T, Higgenbotham M, et al. Angiotensin receptor blockers: evidence for preserving target organs. Clin Cardiol 2001; 24; 183–190. 7. Drug Trends in Cardiology. ONTARGET proves telmisartan efficacy to ramipril in cardiovascular protection of patients at high risk and without heart failure. Cardiovasc J Afr 2008; 19(2): 108.


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Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.


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