CVJA Volume 22, Issue 4

AFRICA

JULY / AUGUST 2011VOL 22 NO 4

CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

Cardiovascular Journal of A

frica . Vol 22, No 4, July/A

ugust 2011

• Management of hypertension at primary level

• Mitochondrial proteins in a mouse model

• Colour M-mode evaluation of myocardial performance

• Health practitioners’ management of hypertension

• Heart disease in Sudan

• Time to revise antiretroviral therapy guidelines

• Subclavian crush syndrome

• Left ventricular outflow tract obstruction of acute myocardial infarction

• Waist-to-height ratio in children with high blood pressure

• The evolution of heart rate

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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)

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...without holding them back• Convenient oral dosing: 20 mg tds with or without meals• Adverse events are generally mild to moderate (1,3)

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For full prescribing information, refer to the package insertReferences: 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.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. 23/REV/11/10/JA

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

Assistant EditorPROF JAMES KER (jun) (South Africa)

Regional Editor (Cameroon)PROF JC MBANyA

Regional Editor (Kenya)DR F BuKAChI

Regional Editor (South Africa)PROF R DELPORT

Editorial BoardPROF PA BRINKExperimental & Laboratory CardiologyPROF R DELPORTChemical PathologyPROF MR ESSOPhaemodynamics, heart Failure & Valvular heart DiseaseDR OB FAMILONIClinical CardiologyDR V GRIGOROVInvasive Cardiology & heart FailurePROF J KER (sen)hypertension, Cardiomyopathy, Cardiovascular PhysiologyDR J LAWRENSONPaediatric heart Disease

PROF A LOChNERBiochemistry/Laboratory SciencePROF BM MAyOSIChronic Rheumatic heart DiseaseDR MT MPECardiomyopathyPROF DP NAIDOOEchocardiographyPROF B RAyNERhypertension/SocietyPROF MM SAThEKGENuclear Medicine/SocietyPROF yK SEEDATDiabetes & hypertensionPROF h Du T ThERONInvasive Cardiology

intErnational advisory BoardPROF DAVID CELEMAJERAustralia (Clinical Cardiology)PROF KEITh COPELIN FERDINANDuSA (General Cardiology)DR SAMuEL KINGuECameroon (General Cardiology)DR GEORGE A MENSAhuSA (General Cardiology)PROF WILLIAM NELSONuSA (Electrocardiology)DR uLRICh VON OPPELWales (Cardiovascular Surgery)PROF PETER SChWARTZItaly (Dysrhythmias)PROF ERNST VON SChWARZuSA (Interventional Cardiology)

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

Cardiovascular Journal of Africa www.cvja.co.za

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Editorial172 dismal management of hypertension at primary level: does it reflect a failure of patients,

a failure of the system or a failure of doctors?NBA Ntusi

CardiovasCular toPiCs175 Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetes

MF Essop • WA Chan • S Hattingh

179 late surgical treatment of tetralogy of Fallot JCT Tchoumi • JC Ambassa • A Giamberti • S Cirri • A Friqiola • G Butera

182 Colour M-mode superiority in evaluation of improvement in myocardial performance indices following successful percutaneous coronary intervention (PCi)R Sattarzadeh • M Maleki • A Jamalian • A Amirpour • A Firuzi • N Samiei • ME Zadeh • A Ghorbani, A Tavoosi

186 health practitioners’ state of knowledge and challenges to effective management of hypertension at primary levelA Parker • B Nagar • G Thomas • M Badri • NBA Ntusi

190 WilliaM nElson ECg Quiz

rEviEW artiClE191 the state of heart disease in sudan

A Suliman

CasE rEPorts197 Progressive human immunodeficiency virus-associated vasculopathy: time to revise

antiretroviral therapy guidelines? NBA Ntusi • D Taylor • NG Naidoo • M Mendelson

201 subclavian crush syndrome: a cause of pacemaker lead fractureF Femenia • JCL Diez • M Arce • A Baranchuk

Managing EditorJuLIA AALBERSTel: 021 976 4378Fax: 086 610 3395e-mail: [email protected]

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Editorial assistant & CirCulationELSABÉ BuRMEISTERTel: 021 976 8129e-mail: [email protected]

ProduCtion Co-ordinatorWENDy WEGENERTel: (021) 976-4378e-mail: [email protected]

gautEng ContriButorPETER WAGENAARCell 082 413 9954e-mail : [email protected]

Editorial BoardThe 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.

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The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

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1203 diagnosis of a congenitally corrected transposition of the great arteries in a 50-year-old

multiparous womanR Jalalian • S Masoumi • A Ghaemian

205 Cardiogenic shock due to left ventricular outflow tract obstruction of acute myocardial infarction: an under-diagnosed complicationKY Karabay • G Kocabay • A Kalayci • H Tanboga • M Mert • C Kirma

206 snake-like thrombus in the right atrium causing pulmonary embolismCY Karabay • G Kocabay • A Kalayci • R Zehir • M Mert • C Kirma

short CoMMuniCation208 the sensitivity of waist-to-height ratio in identifying children with high blood pressure

BS Motswagole • HS Kruger • M Faber • JM Van Rooyen • JH De Ridder

iMagEs in Cardiology212 Malignant convulsive vasovagal syncope

B Amasyali

213 Cardio nEWs

lEttErs to thE Editor217 torsades de pointes

228 Torulopsis glabrata endocarditis in a retro-positive individual

drug trEnds214 the evolution of heart rate: past, present and future

P Wagenaar

216 new data support ivabradine use in chronic heart failure J Aalbers

218 Fda approves rivaroxaban for prevention of deep-vein thrombosis in surgeryJ Aalbers

220 south africa’s poor warfarin control raises questions of benefit above other anticoagulant therapies in atrial fibrillationJ Aalbers

223 obesity and platelet reactivity: the relationship remains uncertainJ Aalbers

224 arBs in cardiovascular and renal protection in high-risk patientsJ Aalbers

227 safe use of ezetimibe plus simvastatin in high-risk vascular patients (with chronic kidney disease and Pad)J Aalbers

References: 1. CRESTOR® package insert 2. Jones P, Davidson MH, Stein EA, et al. Comparison of the Effi cacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR* Trial). Am J Cardiol 2003;92:152-160. 3. Schuster H, Barter PJ, Stender S, et al. Effects of switching statins on achievement of lipid goals. Measuring Effective Reduction in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J 2004;147:705-712. 4. Rosenson RS. Statins: can the new generation make an impresssion? Expert Opin Emerg Drugs 2004;9(2):269-279. 5. Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosuvaststin. Am J Cardiol 2004;94:882-888.

S4 CRESTOR® 5 (Tablet) Each CRESTOR® 5 tablet contains 5 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 10 (Tablet) Each CRESTOR® 10 tablet contains 10 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 20 (Tablet) Each CRESTOR® 20 tablet contains 20 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 40 (Tablet) Each CRESTOR® 40 tablet contains 40 mg of rosuvastatin as rosuvastatin calcium. PHARMACOLOGICAL CLASSIFICATION: A. 7.5 Serum-cholesterol reducers INDICATIONS: Primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate. Indicated in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments. CRESTOR® 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of CRESTOR® or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated. REGISTRATION NUMBERS: CRESTOR® 5: 41/7.5/0298, CRESTOR® 10: 36/7.5/0349, CRESTOR® 20: 36/7.5/0350, CRESTOR® 40: 36/7.5/0351. DETAILS OF THE REGISTERED LICENCE HOLDER: AstraZeneca Pharmaceuticals (Pty) Ltd Reg No. 1992/005854/07. No. 5 Leeuwkop Road, Sunninghill, 2157, South Africa. Tel: 011 797 6000. Fax: 011 797 6001. www.astrazeneca.co.za. For full details relating to any information mentioned above please refer to the package insert of CRESTOR® 5 mg, 10 mg, 20 mg and 40 mg. CRESTOR® is a registered trademark of AstraZeneca group. Licensed from Shionogi & Co Ltd, Osaka, Japan. EPI Date: 13/05/2008. Date compiled: March 2011.

16162

Help your patients love themselves a little more.

CRESTOR® 5 mg is suitable for select patients who need less aggressive lipid lowering1

CRESTOR® is the more effective statin at lowering LDL-C and raising HDL-C2

CRESTOR® 10 mg will get most patients to LDL-C goal1,3

CRESTOR® is well-tolerated and has a favourable benefi t-risk profi le4,5

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 4, July/August 2011172 AFRICA

Editorial

dismal management of hypertension at primary level: does it reflect a failure of patients, a failure of the system or a failure of doctors?NBA NTuSI

‘My great concern is not whether you have failed, but whether you are content with your failure.’

Abraham Lincoln

Hypertension is a major but modifiable risk factor for cardio-vascular disease (CVD). About 25% of adults in the world have hypertension and this is expected to increase in the coming years.1 In sub-Saharan Africa (SSA), the number of hypertensive adults is projected to rise from 80 million in 2000 to 150 million by 2025.2

In SSA, not only is hypertension common, but it is frequent-ly misdiagnosed. This is of great economic relevance as it commonly affects the young, and causes serious complica-tions.3,4 Persistently elevated blood pressure is associated with poor outcomes, including left ventricular hypertrophy, heart failure, stroke, premature coronary artery disease, chronic kidney disease, intra-cerebral haemorrhage, retinopathy, vascular dementia and acute life-threatening emergencies. Moreover, the management of hypertension remains sub-optimal worldwide.

Data from the National Health and Nutrition Examination Survey (NHANES) and the United States Census Bureau from 1999 to 2000 revealed that only 29 to 31% of adult hyperten-sives were controlled, with the prevalence of poor control being higher in older people and blacks.5 Multiple patient-, system- and physician-related factors contribute to the poor management of hypertension, despite the publication of best-practice guidelines for management of high blood pressure by different professional societies.

In this issue of the journal, Parker and colleagues report on a study conducted in Cape Town, South Africa, showing that these doctors’ knowledge on the management of hypertension and of the South African hypertension guidelines was poor, with 62.5% of the doctors surveyed attempting to treat hypertension to target, and only 50% recommending lifestyle modifications to their patients.6 Furthermore, physician inertia was rife, as the participating doctors estimated that about 35% of their hyperten-sive patients were controlled on the treatment prescribed, and yet therapy was not routinely up-titrated for the majority of patients.

Factors identified by these doctors as impacting on optimal management of hypertension at primary level included poor patient adherence to prescribed treatment, communication diffi-culties (as the doctors did not always speak the language of the patients), heavy patient workloads and staff shortages, and patient loss to follow up.

hypertension in south africaHypertension in South Africa was responsible for 46 888 deaths (9% of all deaths) and 2.4% of disability-adjusted life years in 2000.7 Risk factors for high blood pressure in South Africa include low educational attainment, older age, increased weight, excess use of alcohol and a family history of hypertension or stroke.8

Hypertension in black South Africans differs in its clini-cal presentation, epidemiology and complications from that of white South Africans and hypertensive patients from developed countries. Black South Africans, particularly the young, typi-cally have malignant hypertension complicated by hypertensive nephrosclerosis, stroke, hypertensive heart disease, heart failure more commonly, and coronary artery disease less frequently.8,9 Furthermore, the mortality from stroke is twice as high among blacks compared to other race groups.10

Poor control of hypertension at primary level in south africaPoor management of hypertension by despondent primary healthcare workers in South Africa has previously been docu-mented.11,12 Rayner et al.13 and Steyn et al.14 have reported that only 39.8 and 42.1%, respectively, of South African primary healthcare hypertensive patients were adequately controlled. Furthermore, Schoeman and Rayner, from a cross-sectional analysis of South African hypertensive patients in general prac-tice have demonstrated that physician inertia is common, with 30.7% of hypertensive patients on monotherapy, 42.8% on two drugs and only 26.5% receiving more than two agents.15

risk factors for hypertensionEssential (primary) hypertension is responsible for the majority of cases of elevated blood pressure, where it is found to be more severe and more common in blacks, older people and obese women. High salt intake, excessive alcohol use, physical inactiv-ity and dyslipidaemia remain important additional risk factors. Several other factors are risk factors/causes of secondary hyper-tension (as summarised in Table 1).

refractory hypertensionMultiple factors contribute to poor control of hypertension. Refractory hypertension is an indication for referral of hyper-tensive patients from primary-care centres to a higher level of

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 4, July/August 2011AFRICA 173

care for further investigation and modification of therapeutic strategy. Refractory hypertension is defined as poorly controlled blood pressure in a patient receiving three or more antihyperten-sive agents prescribed at optimal doses, one of which must be a diuretic.16 However, before diagnosing refractory hypertension, it is important to exclude pseudo-resistance, which may emanate from patient non-adherence to prescribed therapy, ‘white coat’ hypertension or inaccurate measurement of blood pressure, among other factors.

Risk factors for refractory hypertension include presence of left ventricular hypertrophy, older age, obesity, African race, chronic kidney disease, diabetes mellitus and obstructive sleep apnoea.16 Table 2 summarises the important conditions that need to be considered in the investigation of a patient with refractory hypertension.

Compelling indications for treatment of hypertensionIn the report by Parker and colleagues,6 knowledge of the compel-ling indications for the management of hypertension was found to be quite poor among the primary healthcare doctors studied. The South African hypertension guidelines provide a rational and evidence-based approach for the management of individuals with hypertension.17 In the presence of certain conditions, the first-line recommended agents vary, as discussed below.• Angiotensin converting enzyme (ACE) inhibitors should be

first-line agents in the presence of heart failure, asymptomatic left ventricular dysfunction, diabetes mellitus, coronary artery disease and proteinuric kidney disease.

• Angiotensin II receptor blockers (ARBs) have similar indica-tions as ACE inhibitors, and may be preferable where there is electrocardiographic evidence of left ventricular hypertrophy or intolerance to ACE inhibitors.

• Diuretics are the usual recommended first-line therapy in the absence of compelling indications, and are useful agents in the presence of volume overload. Chlorthalidone is the preferred thiazide diuretic for essential hypertension, but is not available in most African countries.

• Calcium channel blockers (CCBs) have no absolute indica-tions, but may be useful for rate control in atrial fibrillation and in patients with angina pectoris. CCBs are preferable to beta-blockers in those with obstructive airway disease.

• Beta-blockers may be considered as first-line treatment (but are usually given in combination with an ACE inhibi-tor) after acute myocardial infarction, in stable patients with heart failure, asymptomatic left ventricular dysfunction, for rate control in atrial fibrillation, and for symptom control in ischaemic heart disease. In the absence of these conditions, beta-blockers should not be first line or given as monotherapy, especially in patients older than 60 years, where they have been associated with higher rates of stroke, coronary artery disease and all cardiovascular events, compared to other anti-hypertensives.18

• Alpha-blockers are not recommended as first-line agents or as monotherapy because of the increased risk of heart failure and increased cardiovascular events associated with their use.

recommendationsDoctors should aim to treat all hypertensive patients to target, as hypertension is a modifiable risk factor for CVD. It is the amount of blood pressure reduction that determines the absolute reduc-tion in cardiovascular risk and not the choice of antihypertensive therapy. Hence, the aim should be to lower blood pressure at all costs. The management strategy should take into account the patient’s individual needs and preferences.

People with hypertension should have the opportunity to make informed decisions about their care and treatment, as this will likely increase their adherence to the prescribed medica-tion. Good communication between healthcare professionals, especially doctors, and patients is essential. Care of people with hypertension needs to be supported by provision of evidence-based information such as the South African hypertension guidelines.17

Lifestyle interventions need to be offered to all patients. These include weight loss, smoking cessation, moderation of alcohol intake, increased physical activity, reduced dietary intake of salt, saturated fats and cholesterol, and adequate dietary intake of potassium, calcium and magnesium. Each of these lifestyle changes has been shown to reduce blood pressure and improve overall well-being. However, there is no evidence for the routine prescription of calcium, potassium and magnesium supplements to aid the management of hypertension. Furthermore, excessive

TABLE 2. CONDITIONS ASSOCIATED WITH REFRACTORY HYPERTENSION

1. Sub-optimal antihypertensive therapy

2. Extracellular volume expansion

3. Poor adherence to medical and dietary therapy

4. Secondary hypertension

5. Undiagnosed kidney disease

6. Primary aldosteronism

7. Ingestion of substances that elevate blood pressure (alcohol, herbal remedies, oral contraceptive pill, anti-depressant medica-tions, non-steroidal anti-inflammatories)

8. Office or ‘white coat’ hypertension

9. Lifestyle and diet (e.g. high salt intake)

10. Pseudohypertension

TABLE 1. RISK FACTORS FOR HYPERTENSION

Essential hypertension Secondary hypertension

More common and more severe in blacks, older people and women

Primary renal disease

High salt intake Renovascular disease

Hypertension in parents Primary aldosteronism

Excess alcohol intake Phaeochromocytoma

Obesity Cushing’s syndrome

Physical inactivity Pregnancy

Dyslipidaemia (independent of obesity)

Sleep apnoea

Certain personality traits (e.g. Type A personality)

Drugs (e.g. oral contraceptive pill, non-steroidal anti-inflamma-tory drugs)

High intake of fructose from sweetened beverages

Other endocrinopathies (e.g. hyperthyroidism, hypothyroidism, hyperparathyroidism, acromegaly, etc)

Multiple genetic polymorphisms Aortic coarctation


use of caffeine- and fructose-rich substances and beverages should be discouraged.

Every consultation with a hypertensive patient needs to be seen as an opportunity for health promotion and general cardio-vascular risk assessment. Such assessment would include look-ing for hypertensive damage to target organs and involves a urine dipstick, a 12-lead ECG and blood tests for plasma glucose, electrolyte, creatinine and urea, and cholesterol levels. Education about and screening for cardiovascular disease at primary health centres should be increased.

Doctors working at primary healthcare level should regularly consider the use of specialist services if blood pressure remains elevated. Likewise, the publication of guidelines by specialists is not sufficient. There should be multiple opportunities for on-going education of all levels of doctors, on management of hypertension and for engagement between primary-level doctors and specialists. Medical outreach is one strategy for facilitating such interaction. Opportunities exist for engagement between healthcare professionals, academia, industry and civil society and need to be encouraged.19

ConclusionDetection and management of hypertension in South Africa remains sub-optimal. Doctors working alone have failed in their endeavour to improve the health of hypertensive patients and the prevention of premature mortality in this group of patients. The management of hypertension presents both complex challenges and opportunities. Doctors should not be content with their failure, but rather use their power and foresight, in collaboration with partners from various sectors, to deliver the promise of ‘a better health for all’.

Dr Ntusi receives funding from the Medical Research Council of South Africa, the Discovery Foundation, and the Nuffield Foundation.

NTOBEKO BA NTuSI, MB ChB, [email protected]

Department of Medicine, university of Cape Town and Groote Schuur hospital, Cape Town, South Africa; Department of Cardiovascular Medicine, university of Oxford and John Radcliffe hospital, Oxford, united Kingdom

References1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hyper-

tension: analysis of worldwide data. Lancet 2005; 365: 217–223.

2. Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden of disease. Lancet 2002; 360: 1347–1360.

3. Ntusi NBA, Mayosi BM. Epidemiology of heart failure in sub-Saharan Africa. Expert Rev Cardiovasc Ther 2009; 7: 169–180.

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

5. Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004; 44: 398–404.

6. Parker A, Nagar B, Thomas G, et al. Health practitioners’ state of knowledge and challenges to effective management of hypertension at primary level. Cardiovasc J Africa 2011; 22(4): 00–00.

7. Norman R, Gaziano T, Lauscher R, et al. South African Comparative Risk Assessment Collaborative Group. Estimating the burden of disease attributable to hypertension in South Africa in 2000. S Afr Med J 2007; 97: 692–698.

8. Rayner B. Hypertension: detection and management in South Africa. Nephron Clin Pract 2010; 116: c269–c273.

9. Stewart S, Libhaber E, Carrington M, et al. The clinical consequences and challenges of hypertension in urban-dwelling black Africans: insights from the Heart of Soweto Study. Int J Cardiol 2009; 146: 22–27.

10. Mayosi BM, Fisher AJ, Lalloo UG, et al. The burden of non-communi-cable diseases in South Africa. Lancet 2009; 374: 934–947.

11. Steyn K, Levitt NS, Patel M, et al. Hypertension and diabetes: Poor care for patients at community health centres. S Afr Med J 2008; 98: 618–622.

12. Lunt DWR, Edwards PR, Steyn K, et al. Hypertension care at a Cape Town community health centre. S Afr Med J 1998; 88: 544–548.

13. Rayner B, Blockman M, Baines D, et al. A survey of hypertensive practices at two community health centres in Cape Town. S Afr Med J 2007; 97: 280–284.

14. Steyn K, Levitt N, Fourie J, et al. Treatment status and experiences of hypertension patients at a large health centre in Cape Town. Ethn Dis 1999, 9: 441–450.

15. Rayner B, Schoeman HS. A cross-sectional study of blood pressure control in hypertensive patients in general practice (the I-TARGET study). Cardiovasc J Africa 2009; 20: 224–227.

16. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403–1419.

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

18. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). Eur Heart J 2007; 28: 1462–1536.

19. Mpako-Ntusi T, Ntusi NBA. The challenges of cardiovascular medi-cine in sub-Saharan Africa: opportunities for engagement between academia, industry and civil society. Global Forum Update on Research for Health 2009; 6: 72–77.


Cardiovascular topics

Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetesMF ESSOP, WA ChAN, S hATTINGh

abstractObjective: Impaired mitochondrial function may contribute to the onset of contractile dysfunction with insulin resistance/type 2 diabetes. Our aim was therefore to determine altera-tions in the mitochondrial proteome of a mouse model of obesity/type 2 diabetes. Methods: Mitochondrial proteins were isolated from hearts collected from 18- to 20-week-old female db/db mice and compared to matched controls. We performed two-dimen-sional polyacrylamide gel electrophoresis to determine differ-entially expressed proteins. Peptides of interest were further analysed by mass spectrometry and Mascot software was employed to identify protein matches.Results: Our data showed that ATP synthase D chain, ubiquinol cytochrome-C reductase core protein 1 and elec-tron transfer flavoprotein subunit alpha peptide levels were altered with obesity. Moreover, we found coordinate down-regulation of contractile proteins in the obese heart, i.e. α-smooth muscle actin, α-cardiac actin, myosin heavy-chain αand myosin-binding protein C. Conclusion: We propose that decreased contractile protein levels may contribute to contractile dysfunction of hearts from diabetic mice.

Keywords: heart, proteomics, obesity, diabetes, contractile proteins

Submitted 9/4/10, accepted 12/7/10

Published online 11/9/10

Cardiovasc J Afr 2011; 22: 175–178 www.cvja.co.za

DOI: 10.5830/CVJA–2010–058

Type 2 diabetes is characterised by metabolic perturbations that may contribute to cardiac contractile dysfunction in the absence of atherosclerosis or hypertension, i.e. diabetic cardio-

myopathy.1 For example, previous studies reported mitochondrial dysfunction in the hearts of ob/ob and db/db transgenic mice, well-described rodent models of obesity and type 2 diabetes.2,3 Here it was proposed that reduced peptide levels of mitochon-drial respiratory chain complexes I, III and V in ob/ob mice, and lower expression of the F1 α-subunit of ATP synthase in db/db mice may contribute to decreased mitochondrial oxidative phos-phorylation capacity. In addition, increased myocardial oxygen consumption (MVO2) of diabetic hearts resulted in reduced cardiac efficiency in diabetic mice, proposed to occur as a result of fatty acid-induced uncoupling of myocardial mitochondrial oxidative phosphorylation.4 We also recently found that obese rats displayed increased myocardial damage and attenuated respiratory capacity in response to acute oxygen deprivation.5

Together, these studies show that impaired mitochondrial function plays a pivotal role in the onset of contractile dysfunction associated with insulin resistance and type 2 diabetes. However, the complete identity of mitochondrial peptides involved in this process remains unclear. The aim of this study was therefore to determine alterations in the mitochondrial proteome in a trans-genic mouse model of obesity and type 2 diabetes, investigating the hypothesis that db/db mouse hearts display lower expres-sion of contractile and mitochondrial energy metabolic proteins compared to wild types.

Methods To investigate our hypothesis we employed 18- to 20-week-old female leptin receptor-deficient (db/db) (BKS.Cg-m+/+Leprdb/J strain) and heterozygous (db/+) mice. Mice were obtained from Jackson Laboratory (Bar Harbor, Maine) and exposed for one week to a reverse 12-hour light 12-hour dark cycle with free access to standard mouse chow and water. The reverse cycle was employed since mice are most metabolically active during the night period, and it allowed us to easily sacrifice mice in the middle of their night phase during our normal laboratory work-ing hours.

All animal experiments were approved by the University of Cape Town’s Animal Research Ethics Committee (approval number 03/030) and the investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Mitochondrial isolation procedure On the day of the experiment, mice were anesthetised using sodium pentobarbital (50 mg/kg intra-peritoneally) and heparin-

Cardio-Metabolic research group (CMrg), department of Physiological sciences, stellenbosch university, stellenbosch, south africaMF ESSOP, PhD, [email protected]

hatter institute for Cardiovascular research, Faculty of health sciences, university of Cape town, south africaWA ChAN, MSc

department of Medical Physiology, stellenbosch university Faculty of health sciences, tygerberg, south africaS hATTINGh, MSc


ised to prevent blood clotting. Mitochondria were isolated from mouse heart tissues (for both obese and age-matched lean controls) using a mitochondrial isolation kit (Sigma-Aldrich, St. Louis MO) that allows for rapid isolation of enriched mitochon-drial fractions for proteomic studies.6,7 Approximately 120 mg of left ventricular tissue was dissected out from control and obese mice and weighed, cut into smaller pieces and resuspended in 10 volumes of extraction buffer A (10 mM HEPES: pH 7.5, 200 mM mannitol, 70 mM sucrose, 1 mM EGTA).

We added 0.25 mg/ml trypsin followed by incubation on ice for three minutes. After the samples were centrifuged for 15 seconds in a microfuge, the supernatant was removed by aspira-tion, eight volumes of extraction buffer A (containing 0.25 mg/ml trypsin) was added to the pellet and it was incubated on ice for 20 minutes. To quench proteolytic reactions, an albumin solu-tion was added to a final concentration of 10 mg/ml. Samples were thereafter centrifuged for 15 seconds in a microfuge, the supernatant was aspirated, and the pellet was washed with eight volumes of extraction buffer A and re-centrifuged for 15 seconds. The latter step was repeated once more, where after the pellet was homogenised 20 to 30 times using a glass homogen-iser.

The homogenised sample was subsequently centrifuged at 1 000 × g for five minutes, and the supernatant was collected and re-centrifuged at 3 500 × g for 10 minutes. The mitochon-drial pellet was resuspended (10 mM HEPES: pH 7.4, 250 mM sucrose, 1 mM ATP, 0.08 mM ADP, 5 mM sodium succinate, 2 mM K2HPO4, 1 mM DTT) and protein concentrations were determined using the Bradford assay. We typically obtained 1 000 µg of mitochondrial proteins for our proteomic analyses.

The ReadyPrep 2D CleanUp kit (Bio-Rad, Hercules CA) was used to concentrate mitochondrial proteins by precipitation and also to wash away compounds that may have interfered with the isoelectric focusing (IEF) step. After precipitation, proteins were washed and then resuspended in an IEF/2D-compatible sample buffer [8 M urea, 2% CHAPS, 50 mM DTT, 0.2% (w/v) Bio-Lyte 3/10 ampholyte, 0.002% (w/v) bromophenol blue] and protein concentrations were determined using the RC/DC assay (Bio-Rad, Hercules CA). The complete mitochondrial isolation procedure was performed at 4ºC with ice-cold solutions.

Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) The first dimension was performed using the PROTEAN-IEF cell (Bio-Rad, Hercules CA). Samples containing 100 µg mito-chondrial protein were loaded onto 11-cm immobilised pH gradient strips (pH 5–8) (Bio-Rad, Hercules CA). Three experi-ments were performed for each condition (i.e. control vs obese). Strips were rehydrated under passive conditions for 12 hours at 20ºC and focused at 200 V for 20 minutes. Thereafter they were linearly increased over two hours to a maximum of 8 000 V and then run (rapid ramping) to accumulate a total of 40 000 V/h. Prior to the second dimension, the immobilised pH gradient strips were first equilibrated for 15 minutes in a buffer contain-ing 0.375 M Tris-HCL (pH 8.8), 6 M urea, 2% SDS, 20% glyc-erol and 2% (w/v) DTT, followed by equilibration for another 15 minutes in a buffer containing 0.375 M Tris-HCL (pH 8.8), 6 M urea, 2% SDS, 20% glycerol and 2.5% (w/v) iodoacetamide.

Subsequently, the strips were embedded in 0.5% low-melting point agarose containing 0.003% bromophenol blue (Bio-Rad, Hercules CA) on the top of Criterion XT 4–12% precast Bis Tris gels (Bio-Rad, Hercules CA), containing a 4% stacking gel. Electrophoresis was performed at 200 V; constant for 55 minutes. Gels were stained overnight with Brilliant Blue G colloidal concentrate (Sigma-Aldrich, St. Louis MO) in order to visualise the protein spots.

Identification of mitochondrial proteins To obtain gel images, the gels were scanned with a GS-800 cali-brated densitometer (Bio-Rad, Hercules CA) using the Quantity One-4:5.2 (basic) software program (Bio-Rad, Hercules CA). The gel images were subsequently analysed using the PDQuest version 8 software program (Bio-Rad, Hercules CA) to identify differentially expressed protein spots on the gels from control and obese mice samples.

Protein spots of interest (i.e. only differentially expressed ones) were manually excised, de-stained and subjected to in-gel digestion by trypsin, followed by ElectroSpray-Injection-Quadrupole Time of Flight (ESI-Q-TOF) mass spectrometry.

Fig. 1. two-dimensional PagE patterns of mitochondrial proteins. heart mitochondria were isolated from normal and obese female mice and purified from interfering substances with the first-dimension separation. Proteins were separated by two-dimensional PagE and detected by Coomassie staining. the spots containing proteins that were subsequently identified are numbered. a: control and B: obese. Molecular weight is given in kda.


Data from the mass spectrometry analysis were processed and employed to create PKL files, which were used to search against the MASCOT software program (www.matrixscience.com). The latter searched the SwissProt database to identify peptide protein matches.

Statistical analysis Due to the small heart sizes, we pooled (for each experi-ment) two hearts for control and obese mice, respectively, for mitochondrial isolation. For this study we performed three independent mitochondrial isolation experiments as described above. Subsequently, three independent gels were performed per mitochondrial isolation experiment for db/db and db/+ mouse hearts, and only changes found in two or more experiments were selected for further analysis. Data are presented as increased or decreased fold change versus matched controls. Statistical differ-ences between groups were calculated using the Student’s t-test. Statistical significance was considered when p < 0.05.

results Two-dimensional PAGE analysis highlighted several differences between obese db/db mouse hearts versus matched db/+ controls

(Fig. 1). Proteins of interest were further analysed by mass spectrometry and peptides were identified using software as described in the methods section. We divided altered mitochon-drial protein expression into two broad groupings, i.e. regulating mitochondrial energy metabolism (Table 1), and forming part of the myocardial contractile apparatus (Table 2).

Seven proteins regulating mitochondrial energy metabolism were differentially expressed (statistically significant) between obese and control hearts. These data show both up- and down-regulation of key regulators of electron transfer in the electron transport chain (ETC) and mitochondrial ATP production. However, expression of only three proteins, i.e. ATP synthase D chain (increased 2.5-fold), ubiquinol cytochrome-C reductase core protein 1 (decreased 2.1-fold) and electron transfer flavo-protein subunit alpha (increased 5.9-fold) were altered in at least two independent experiments.

Interestingly, we also found differentiated expression for several contractile/cytoskeletal proteins (Table 2), although only four displayed decreased expression in at least two independ-ent experiments. Here α-smooth muscle actin, α-cardiac actin, myosin heavy-chain (MHC) α and myosin-binding protein C (MyBP-C) protein levels were coordinately down-regulated in obese versus control hearts.

TABLE 1. PROTEINS IDENTIFIED IN OBESE FEMALE MICE: MITOCHONDRIAL ENERGY METABOLISM

Spot SSP Mr (Da) pIMascot score Protein name

Swiss prot acces-sion number

% Sequence coverage

No of peptides

Fold increase or decrease

Functional group or function

1 2305 56265 5.19 873 ATP synthase subunit beta,

P56480 44 18 2.7 ATP synthesis, (catalytic subunit)

2* 5002 18664 5.52 273 ATP synthase D chain Q9DCX2 70 11 2.5 ATP synthesis, (rota-tional mechanism)

3* 6003 53420 5.75 280 Ubiquinol cytochrome-C reductase core protein 1

Q9CZ13 21 7 –2.1 Electron transport

4 8406 59830 9.22 693 ATP synthase subunit alpha

P56757 30 15 14.9 ATP synthesis (regu-latory subunit)

5 3101 27640 5.19 297 NADH dehydrogenase flavoprotein 2

Q9D6J6 45 9 –1.8 Electron transfer

6 2903 80724 5.51 563 NADH ubiquinone oxido-reductase 75 kDa subunit

Q91VD9 26 18 –2 Electron transfer

7* 9302 35360 8.62 623 Electron transfer flavopro-tein subunit alpha

Q99LC5 51 15 5.9 Electron transfer

Data represent differentially expressed proteins between control and obese female mice. Only proteins that were significantly different are reported (p < 0.05). The SSP number is assigned by the PDQuest software program (Bio-Rad, Hercules CA). *Proteins identified in two or more independent experiments.

TABLE 2. PROTEINS IDENTIFIED IN OBESE FEMALES: CONTRACTION/CYTOSKELETAL

Spot SSP Mr (Da) pIMascot score Protein name

Swiss prot acces-sion number

% Sequence coverage

No of peptides

Fold increase or decrease

Functional group or function

8 0203 32718 4.69 429 Tropomyosin 1, alpha chain

P58771 34 11 2.5 Striated muscle contraction

9* 3201 42381 5.23 268 Actin, smooth muscle P62737 22 7 –2.3 Structural constitu-ent of cytoskeleton

10* 3203 42334 5.23 318 Actin, alpha cardiac P68033 35 10 –4.0 Structural constitu-ent of cytoskeleton

11* 7002 224349 5.57 225 Myosin heavy chain QO2566 2 6 –3.8 Muscle contraction

12* 5401 141799 6.06 179 Myosin binding protein C, cardiac

O70468 6 9 –1.9 Muscle contraction

13 0206 22390 5.03 283 Myosin light chain P05977 33 8 1.7 Muscle contraction

Data represent differentially expressed proteins between control and obese female mice. Only proteins that were significantly different are report-ed (p < 0.05). The SSP number is assigned by the PDQuest software program (Bio-Rad). *Proteins identified in two or more independent experi-ments.


discussion We previously found a significant increase in body weight and fasting blood glucose levels for 18- to 20-week-old db/db female mice versus matched controls.8 For the current study, 2D-PAGE illustrated differences between control and obese hearts for female mice that we broadly categorised into two groups, i.e. related to energy metabolism and contraction/cytoskeleton. Here we identified changes in several proteins that play a role in mitochondrial energy metabolism, although only three, i.e. ATP synthase D chain, ubiquinol cytochrome-C reductase core protein 1 and electron transfer flavoprotein subunit alpha were identified as real changes.

ATP synthase D chain peptide levels were up-regulated for the db/db mouse versus controls. ATP synthase D chain is a non-enzymatic component of the F0 channel of the F1F0 ATP synthase that links the flow of protons (from within the inter-mitochon-drial membrane space) through its F0 channel to ATP synthesis that occurs on F1. We propose that this may represent an adaptive mechanism by the obese female heart to increase proton transfer and thereby enhance mitochondrial ATP production. In agree-ment with this notion, we found a marked induction of electron transfer flavoprotein subunit alpha. The latter usually serves as an electron acceptor for dehydrogenases, and plays a role in the transfer of electrons along the mitochondrial ETC.

Conversely, we found a decrease in peptide levels of ubiquinol cytochrome-C reductase core protein 1, a subunit of complex III of the electron transfer chain that catalyses transfer of electrons from coenzyme Q to cytochrome C. These data suggest that despite attempts by hearts from the obese animals to augment mitochondrial ATP production, decreased ubiquinol cytochrome-C reductase core protein 1 peptide levels likely contribute to impaired mitochondrial ATP production. In agreement, we previ-ously found diminished cardiac respiratory capacity in female db/db mice compared to matched controls.8 It is likely that ATP synthase D chain and electron transfer flavoprotein subunit alpha may also be down-regulated with prolonged persistence of the diabetic phenotype.

We also found coordinated down-regulation of key contrac-tile/cytoskeletal proteins in the obese heart, i.e. α-smooth muscle actin, α-cardiac actin, MHCα and MyBP-C. Together these peptides play a crucial role in ensuring sustained myocardial contractile function and cytoskeletal support.9 The contractile proteins identified in this study were associated with the isolated mitochondrial fraction and likely represent proteins closely asso-ciated with interfibrillar mitochondria. These data are consistent with previous work that found an MHC isoform switch during the onset of diabetes, i.e. decreased MHCα and increased MHCβexpression.10 MyBP-C is a thick filament-associated protein and provides an additional regulatory step to myocardial contrac-tion.11 MyBP-C gene mutations can cause hypertrophic cardio-myopathy,11 while its absence (cMyBP-C null mice) significantly attenuates in vivo left ventricular function.12

Together our data are in agreement with an earlier study that found increased contractile dysfunction with older db/db female mice (aged 16–18 weeks).13 We therefore propose that it is likely that lower contractile protein expression may indeed contribute

to impaired contractile function observed in the diabetic heart. However, additional studies are required to confirm these chang-es within the cytosolic fraction of hearts from diabetic animals.

ConclusionThis study found that diabetic mouse hearts displayed altered expression of mitochondrial metabolic peptides together with the coordinated down-regulation of several cardiac contractile/cytoskeletal proteins. We propose that attenuated contractile protein expression may contribute to the onset of diabetic cardio-myopathy.

The authors acknowledge the contributions of the biological mass spec-trometry and proteomics facility in the Department of Biological Sciences, University of Warwick. Research work was supported by the National Research Foundation and the South African Medical Research Council (awarded to MFE).

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11. Flashman E, Redwood C, Moolman-Smook J, Watkins H. Cardiac myosin binding protein C: its role in Physiology and disease. Circ Res 2004; 94: 1279–1289.

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13. Aasum E, Hafstad AD, Severson DL, Larsen TS. Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes 2003; 52: 434–441.


late surgical treatment of tetralogy of Fallot JCT TChOuMI, JC AMBASSA, A GIAMBERTI, S CIRRI, A FRIGIOLA, G BuTERA

abstractAim: To study early post-operative results and follow up of patients over a year old, operated on for tetralogy of Fallot (ToF).Methods: This retrospective analysis included 22 patients (14 male and eight female) with a mean age of 9.18 ± 6.5 years (range 13.5 months to 26 years), who underwent complete repair of ToF between April 2003 and June 2009. Data from patients’ records, pre-operative cardiac catheterisation studies, operative intervention, and pre-operative and post-operative two-dimensional echocardiographic studies were reviewed. All patients underwent complete repair including closure of ventricular septal defect (VSD). A trans-annular patch was used in 12 patients while an infundibular patch was used in 10 others. Patients were evaluated one, three, six and 12 months after surgery, and annually thereafter. The duration of follow up was from eight months to six years post surgery.Results: Classical ToF was found in 10 patients. Twelve cases had associated anomalies: two patients with hypoplastic pulmonary artery branches, two with arterial duct malfor-mations, and eight had proximal stenosis of the left branch of the pulmonary artery. NHYA class distribution was as follows: class I: two patients; class II: five subjects; class III: 10 patients; class IV: five subjects. The mean stay in hospital was 15 ± 7 days. Two patients (9%) died during the early post-surgical period. At a mean follow-up interval of 32 ± 9 months, all patients were asymptomatic and in NYHA class I. No late deaths occurred. In three patients, we registered isolated monomorphic ventricular extrasystoles. The right ventricle outflow tract (RVOT) pressure gradient was 29 ± 1.5 mmHg in the acute post-surgical period and it did not change significantly during follow up. The right ventricular function was defined as normal in 95% of the patients in the study and was mildly depressed in 5%. Conclusion: Even if treated later in life, our study showed very good surgical results of patients with ToF.

Keywords: tetralogy of Fallot, older patients, follow up



DOI: 10.5830/CVJA–2010–057

Tetralogy of Fallot (ToF) is the most common cause of cyanotic congenital heart disease.1 The best age for ToF repair remains controversial and the strategy employed may influence the tech-nique of operation.2 Early repair of ToF has many advantages. It

abolishes the secondary effects of increasing cyanosis on vital

organs and its adverse effects on cognitive and psychomo-tor development of the patient. The relief of right ventricular

outflow obstruction eliminates the secondary right ventricular

hypertrophy and maintains the systolic and diastolic properties

of the ventricle when compared with either two-stage repair or repair later in life.3 Supporters of primary neonatal repair cite factors such as prevention of time-related end-organ damage from cyanosis, removal of stimulus for right ventricular hyper-trophy and fibrosis, improved lung development (vascular and alveolar), avoidance of deleterious effects and risks of palliative shunts, and psychosocial-economic issues (for the family and care givers).4

In large centres worldwide, correction is performed between six and nine months of age.5 However, in developing countries, early repair may be difficult due to many factors, including facilities for diagnosis, cultural background of patients, and availability of surgical centres. The purpose of this retrospec-tive investigation was to study the early results and follow up in patients with ToF operated on when older than a year and coming from a developing country.

Methods This retrospective analysis included 22 patients (14 males and eight females) with a mean age of 9.18 ± 6.5 years (range 13.5 months to 26 years) who underwent complete repair of ToF between April 2003 and June 2009. All subjects came from Cameroon and were evaluated in the Cardiac Centre of the Saint Elizabeth Hospital in Shisong. Data from patients’ records, pre-operative cardiac catheterisation studies, operative intervention,

and pre- and postoperative two-dimensional echocardiographic studies were reviewed.

All patients were operated on in the paediatric surgical unit of San Donato teaching hospital in Shisong, and the project was supported by the Tertiary Sisters of St Francis and two non-governmental, non-profit organisations, Cuore Fratello (www.cuorefratello.org) and Associazione Bambini Cardiopatici nel Mondo (www.bambinicardiopatici.it).

The ethics committee of the hospital approved the study. A consent form was signed by patients, or their parents when patients were unable to sign. It is significant that during the peri-od of the study while awaiting surgery, 25 patients aged between seven months and 15 years (nine males) died due to ToF-related complications.

The operative technique to repair ToF has been described previously.6 RVOT reconstruction included a trans-annular patch in the pericardium with a monocusp made of goretex. Some subjects needed a trans-infundibular patch without any surgical treatment of the pulmonary valve.6

st Elizabeth Catholic general hospital, Cardiac Centre, shisong, CameroonJCT TChOuMI, MD, PhD, [email protected] AMBASSA, MD

Policlinico san donato irCCs, Pediatric Cardiology, Cardiac surgery and guCh unit, Milan, italyA GIAMBERTI, MDS CIRRI, MDA FRIGIOLA, MDG BuTERA, MD, PhD


Patients were evaluated at one, three, six and 12 months, and then annually after surgery. Postoperative evaluation included a complete physical examination, an electrocardiogram, and two-dimensional and Doppler echocardiography in all patients.

Statistical analysisStatistical analyses were performed using the χ2 test and the

Wilcoxon rank sum test for non-parametric variables. A paired

t-test was used for continuous variables. The results were calcu-lated as the mean ± standard deviation. All statistical analyses were performed using the SPSS 11 program.

resultsClassical ToF was found in 10 patients. Twelve cases had associ-ated anomalies (two patients with hypoplastic pulmonary artery branches, two with arterial duct malformations, and eight had proximal stenosis of the left branch of the pulmonary artery). NYHA class distribution was as follows: class I: two patients; class II: five subjects; class III: 10 patients; class IV: five subjects.

Five patients (25%) were symptomatic, with more than one episode of hypoxic spells or persistent hypoxaemia (arterial oxygen saturation less than 80%). Among these was one boy with hypotony of the lower limbs because of prolonged immobility due to the hypoxic spells during mild physical exertion.

Early postoperative course Complete repair was carried out on 22 patients. Closure of the ventricular septal defect (VSD) with the insertion of a trans-annular patch was performed in 12 subjects, and closure of the VSD with the insertion of an infundibular patch was performed in 10 patients. The acute post-surgical complications were mild pericardial effusion detected in four cases and pleural effusion in three cases. The dosage of diuretic was increased in these, with good results. In one case there was chylothorax, which was treated with diet. There were no cases of arrhythmia. We did not observe any differences in follow-up results regarding age of the children at surgery, nor for surgical technique.

The mean hospital stay was 15 ± 7 days and the range was between 10 and 20 days. In the intensive care unit, the mean stay was 5 ± 3 days. The chest tubes for drainage were removed in the general children’s ward, mostly on the seventh to eighth postop-erative day. The mean oxygen saturation of the patients changed from 67 ± 5% before surgery to 90 ± 2.5% after the correction.

A five-year-old boy and a girl died in the acute post-surgical period (9%). The cause of death was profuse bleeding from a poorly controlled collateral vessel.

Follow-up dataThe duration of follow up was from eight months to six years.Electrocardiographic data: All patients were in regular sinus rhythm. First-degree atrio-ventricular block was observed in two patients in the acute post-surgical period and thereafter. Right bundle branch block and right ventricular hypertrophy present before surgery persisted in 88% of patients. In three patients we detected isolated monomorphic ventricular extra-systoles. Echocardiographic data: There were no significant differences

in RVOT gradients and right ventricular (RV) pressures during follow up in all patients except one, who developed mild to moderate RVOT obstruction, with a pressure gradient of 25 to 35 mmHg proximal to the patch. The mean RVOT pressure gradient was 29 ± 1.5 mmHg in the acute post-surgical period. Three months later, it was 27.6 ± 1.7 mmHg. The RVOT pres-sure at one year was 26.8 ± 1.1 mmHg (p ≤ 0.05) compared to the acute post-surgical reading. After two years, the mean RVOT pressure was constant at around 26.2 ± 2.9 mmHg (p > 0.6). This was maintained for about two years, until the last follow-up measurements.

Right ventricular function was defined as normal in 95% of the patients in the entire study and mildly depressed in 5%. A

mild to moderate degree of pulmonary regurgitation was evident

in three patients, associated with mild triscupid regurgitation and a mild right ventricular dilatation.

A diagnostic cardiac catheterisation was done prior to surgery in only three cases, for better visualisation of the coronary arter-ies, pulmonary arterial trunk and pulmonary branches. Proximal

left pulmonary artery stenosis with a pressure gradient of 20

mmHg was found in one patient a week after surgery. A success-ful dilatation was done in the catheterisation laboratory.

discussionAlthough the presentation of ToF in adults is becoming a rarity in Western countries, it is still common in developing countries. In our study we aimed to analyse the early results and follow up of older Cameroonian patients operated on for ToF. All our patients had surgery after 12 months of age, with a good outcome.

In the literature, correction is usually performed before one year of age and some authors advocate very early repair, before six months of age. However, Vohra et al.5 found that early primary repair of ToF was comparable to later repair. Ooi et al.7 showed that early definitive repair of ToF can be performed safely on patients under six months old. Both approaches are supported by clinical reports of excellent early results.8 However, in our cases, because of lack of adequate medical facilities and poverty of patients, the diagnosis and surgery were performed late.

In our cohort of ToF patients, the most commonly occur-ring problems before surgery were hypotony of the lower limbs and stiffness caused by immobility due to hypoxic spells. After surgery, we observed pulmonary and triscupid regurgitation and residual obstruction of the RVOT. It is important to mention that hypoxic spells during mild physical exertion are an incapacitat-ing factor in our context, leading to stiffness and hypotony of the lower limb muscles, which will need later physiotherapy.

Late diagnosis and late surgical intervention are probably the reasons why early mortality in our series was 9%, which is quite elevated when compared to data by Wu9 (0.9% death rate in patients aged between one and 37 years) or Ghavidel et al.10

(1.9% in adult patients with ToF). In our case, the cause of death was poorly controlled severe bleeding from the collaterals. It is well known that deeply cyanosed patients have a well-developed collateral circulation. Furthermore, the presence of combined chronic latent diseases (tropical infections) on admission could have influenced the acute post-surgical period.

The length of the chest tube for drainage was notably longer in our series than in ToF subjects treated between six and 12


months of age. Furthermore, post surgery, hypotony of the lower limbs was present in one patient who had a longer hospital stay to enable the lower limbs to recover their function. These factors accounted for the longer length of hospital stay in our series.

During follow up, no deaths were registered. All patients were in NYHA class I. Similar data were reported by Bisoi et al.,11 who stated that total correction of ToF in teenagers and adults offers the best option for long-term, symptom-free survival.

No malignant rhythm disturbances were recorded on ECG. Right ventricular hypertrophy with a right bundle branch block (RBBB) recorded on ECG persisted after surgery. Bouzas12 showed that the presence of RBBB in post-TOF repair is extremely common and may mask the presence of RV hyper-trophy. Progressive lengthening of the QRS duration with time reflects RV enlargement and potential RV failure.

We observed a drop, although not statistically significant, in the RVOT pressure from the acute post-surgical period. No difference in RVOT pressure was registered between the patients with annuloplasty and infundibuloplasty. No restrictive Doppler pattern was observed in assessing the right ventricle, contrary to the study of Cardoso and Miyague,13 who reported that restric-tive right ventricular physiology was present in most patients undergoing repair of ToF with a trans-annular patch. This may be a transient phenomenon of incomplete adaptation of the right ventricle to volume and pressure modifications.

Over six years of follow up, right ventricular function was mildly depressed in 5% of cases, and mild to moderate pulmonary regurgitation was evident in 13.7%. Pulmonary regurgitation (PR) is related to the use of a trans-annular patch during RVOT reconstruction and aggressive infundibulectomy involving the pulmonary valve annulus. Although PR is report-edly well tolerated in several clinical studies, long-term follow up has shown that this can lead to considerable disability. The adverse effects of PR include progressive dilatation of the RV, reduced exercise capacity, arrhythmia and sudden death. The right ventricular function and pulmonary valve of these patients will need close monitoring to anticipate pulmonary or tricuspid valve replacement.

Our study had two limitations. First, we had a limited number of patients enrolled. Second, longer follow up is needed.

ConclusionThe study showed good early results in the post-surgical follow up of older patients with ToF. The right ventricular function and pulmonary valve will need close surveillance, and timely and appropriate interventions must be taken to optimise outcomes.

We thank Associazione Bambini Cardiopatici nel Mondo, Cuore Fratello and the Tertiary Sisters of St Francis for their collaboration in saving the lives of Cameroonian children.

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12. Bouzas B, Kilner PJ, Gatzoulis MA. Pulmonary regurgitation: not a benign lesion. Eur Heart J 2005; 26: 433–439.

13. Cardoso SM, Miyague NI. Right ventricular diastolic dysfunction in the postoperative period of the tetralogy of Fallot. Arq Bras Cardiol 2003; 80(2): 198–201


Colour M-mode superiority in evaluation of improvement in myocardial performance indices following successful percutaneous coronary intervention (PCi)R SATTARZADEh, M MALEKI, A JAMALIAN, A AMIRPOuR, A FIRuZI, N SAMIEI, M ESMAEILZADEh, A GhORBANI, A TAVOOSI

abstractAim: This study aimed at evaluating the early effects of successful elective percutaneous coronary intervention (PCI) on systolic and diastolic function.Methods: We consecutively studied the systolic and diastolic function in 21 patients with stable coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) > 40% before and 48 hours after successful elective PCI. Results: Tei index and systolic indices (LVEF, regional wall motion abnormality score, tricuspid annular plane systolic excursion and peak systolic velocity of mitral and tricuspid annulus) did not change significantly. Among the diastolic indices, only velocity propagation (Vp) improved significant-ly (from 42.9 ± 10.8 to 51.8 ± 10.7, p-value = 0.008) following PCI. Diastolic velocities, E/A ratio, deceleration time (DT), early and late diastolic velocities of mitral annulus in TDI, pulmonary vein systolic (PVs) and diastolic flow velocity (PVd) did not show significant improvement.Conclusion: Propagation velocity of mitral inflow was the earliest index to recover following successful PCI in patients with stable CAD.

Keywords: percutaneous coronary intervention, echocardiogra-phy, coronary artery disease, systolic function, diastolic function



DOI: 10.5830/CVJA–2010–061

Percutaneous coronary intervention (PCI) is a very common revascularisation procedure performed in patients with stable coronary artery disease (CAD).1 PCI has shown promise in terms of reduction of symptoms and improvement in quality of life.2,3 However, physiological cardiac changes following improvement of anatomical blood flow after PCI are still unclear.

Echocardiography provides a feasible and non-invasive tech-nique for assessment of global and regional myocardial func-tion.4 Results of echocardiographic assessment of systolic and diastolic ventricular function following successful elective PCI have been contradictory and confusing.5-9 However, the tech-niques used in previous studies were mainly based on qualitative and semi-quantitative assessment of myocardial function, and information on quantification of regional and global myocardial function with the recently introduced technique, tissue Doppler imaging (TDI),10-12 following PCI is limited.

The present study was designed to evaluate the early effects of successful elective PCI on systolic and diastolic function glob-ally and regionally through thorough echocardiographic exami-nations, including two-dimensional (2-D), M-mode, colour Doppler and TDI.

MethodsOur study participants were recruited from 31 consecutive patients with stable CAD who were scheduled for elective PCI in Rajaie Heart Centre. Patients were considered for inclusion if they had angiographically documented coronary artery stenosis > 70% in diameter in the culprit lesion by visual assessment, and documented ischaemia. Ischaemia was documented using stress testing in patients with typical stable angina, according to the Canadian Cardiovascular Society (class I or II).

Exclusion criteria were bundle branch block, pacemaker implantation, left ventricular ejection fraction (LVEF) < 40%, valvular heart disease, cardiomyopathy, history of coronary artery bypass grafting (CABG), refractory angina or acute myocardial infarction (MI) requiring emergency revascularisa-tion, and left main stem disease.

All patients were evaluated by an experienced echocardiolo-gist, using conventional (2-D, M-mode and colour Doppler) and tissue Doppler echocardiography examinations one day before and 48 hours after successful PCI, in order to assess cardiac systolic and diastolic function. Successful revascularisation was defined as a residual stenosis of < 30% in luminal diameter with TIMI flow grade 3. Patients with unsuccessful PCI (10 people) were excluded.

All patients were on an optimal medical regimen consisting of nitrates, aspirin, β-blockers, angiotensin converting enzyme inhibitors and lipid-lowering agents (statins) along with a low-fat diet on an individual basis.

department of Cardiology, tehran university of Medical sciences, imam Khomeini hospital, tehran, iranR SATTARZADEh, MD

department of Cardiology, shaheed rajaie Cardiovascular Medical and research Centre, iran Medical university, tehran, iranM MALEKI, MD, FACCA JAMALIAN, MD A AMIRPOuR, MDA FIRuZI, MDN SAMIEI, MDM ESMAEILZADEh, MD, FCAPSC

digestive diseases research Centre, tehran university of Medical sciences, shariati hospital, tehran, iranA GhORBANI, MD

department of Cardiology, tehran university of Medical sciences, imam Khomeini hospital, tehran, iranA TAVOOSI, MD, [email protected]


The institutional review board of the hospital approved the study protocol. All participants gave written informed consent. This investigation was in accordance with the Declaration of Helsinki.

Direct stenting or stenting after successful angioplasty was performed in all the participants according to published guide-lines.13 All patients received heparin to a target activated throm-bin time level of 200–300 sec, and also clopidogrel in standard doses.

Echocardiographic data were obtained using a commer-cially available ultrasound system Vivid-3 (GE) equipped with a 3-MHz transducer. Measurements were obtained by averaging values recorded in three consecutive cycles, according to the current American Society of Echocardiography guidelines.14

For two-dimensional and M-mode echocardiography, 2-D images were obtained in standard parasternal and apical views. All patients were examined at rest in the left lateral decubitus position.

The LV end-diastolic and end-systolic dimensions (LVEDD and LVESD) were measured at the level of the mitral leaflet tips from the parasternal long-axis with two-dimensional targeted M-mode echocardiography. LVEF was calculated from the apical two- and four-chamber views using the modified Simpson’s rule.

The regional wall motion abnormality (RWMA) score of the LV was assessed for each LV segment individually, and the wall motion abnormality score index (WMSI) was obtained using the 16-segment model, according to the American Society of Echocardiography recommendations.14 Higher scores were considered for more severe wall motion abnormalities (1: normal, 2: hypokinesis, 3: akinesis, 4: dyskinesis, 5: aneurysmal).

For RV systolic functional assessment, the tricuspid annular plane systolic excursion (TAPSE) was measured using two-dimensionally guided M-mode imaging from the apical four-chamber view.

Mitral inflow velocities were measured with pulsed-wave colour Doppler echocardiography, with the sample volume positioned between the tips of the mitral leaflets in the apical four-chamber view. Peak early diastolic velocity (E), peak late diastolic velocity (A), E/A ratio and deceleration time (DT) were obtained.

Mitral inflow propagation velocity (Vp) was measured as the maximum slope of the first aliasing velocity during early filling from the mitral valve plane to 4 cm distal to the LV cavity in the apical four-chamber view using colour M-mode Doppler.

Pulmonary vein systolic flow velocity (PVs) and diastolic flow velocity (PVd) were measured from the apical four-cham-ber by placing a sample volume in the right upper pulmonary vein with Doppler echocardiography. Isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT) and ejection time (ET) were assessed by simultaneously measuring the flow into the LV outflow tract and the mitral inflow, using Doppler echocardiography. The index of myocardial performance (IMP or Tei index) was calculated by dividing the sum of IVRT and IVCT by ET.

Pulsed-wave TDI was performed by activating the tissue Doppler function in the same echocardiographic machine. Mitral annulus velocities (myocardial systolic and diastolic velocities) were measured using the pulsed-wave TDI technique, by placing a 1–2-mm sample volume at the levels of septal, lateral, inferior, anterior and posterior annulus.

Peak systolic velocity of the mitral annulus (Sa), and early (Ea) and late diastolic (Aa) velocities of the mitral annulus were determined from septal, lateral, inferior, anterior and posterior aspects. Peak systolic velocity of the tricuspid annulus (TA-Sa) was also derived from pulsed Doppler tissue imaging of the lateral tricuspid annulus.

Statistical analysisContinuous variables are presented as means ± standard devia-tions (SD) and categorical data are expressed as frequencies and percentages. Comparisons of continuous variables pre and post PCI were carried out using the paired-samples t-test. The Wilcoxon signed rank test was used to test for the difference between the mean RWMA scores before and after PCI. The statistical software SPSS-13 (Chicago, IL, USA) for Windows was used for all analyses; p-values < 0.05 were considered statis-tically significant.

resultsA total of 21 patients who had had successful PCI were consid-ered for the study analysis. Baseline characteristics of partici-pants are summarised in Table 1. LVEF, RWMI and peak systolic velocities remained unchanged 48 hours following elective PCI (Table 2). The index of myocardial performance did not change (Table 2). Vp improved significantly early after PCI (p = 0.008). Other diastolic indices did not show improvement (Table 3).

discussionThis study presents a comprehensive echocardiographic assess-ment of regional and global myocardial function, both systolic and diastolic, following blood flow restoration with PCI elec-tively performed in patients with stable CAD. Our findings indicate that the propagation velocity of early flow into the LV cavity (Vp), measured by colour M-mode Doppler, was the most sensitive index to recover after successful PCI.

LV ejection fraction calculated by the biplanar Simpson’s method, along with other parameters of myocardial systolic function including the regional wall motion index evaluated by 2-D and TDI-derived systolic myocardial velocities at the mitral (Sa) and tricuspid annulus (TA-Sa), did not change significantly

TABLE 1. BASELINE CHARACTERISTICS OF THE PATIENTS

Study population (n = 21)*

Age (years) 54.05 ± 10.08

Male (%) 14 (66.6)

BMI (kg/m2) 25.72 ± 3.97

Heart rate 76.05 ± 11.36

LVESD (cm) 3.27 ± 0.53

LVEDD (cm) 5.03 ± 0.42

Angiographic results (%)

Mono-vessel involvement 12 (57.1)

Two-vessel involvement 6 (28.6)

Three-vessel involvement 3 (14.3)

*Means ± standard deviation. BMI: body mass index; LVESD: left ventricular end-systolic diameter; LVEDD: left ventricular end-diastolic diameter.


early after PCI. Previous studies have shown different results regarding systolic functional improvement following PCI. In a study performed in 41 patients with stable CAD, successful elective PCI did not improve ejection fraction at the one-day and six-month follow up.5

However, in another study, peak systolic velocities of three annular sites, but not the ejection fraction, showed substantial improvement.6 It was also shown in 32 patients that resting EF and WMSI improved significantly after three to five days and six months, following successful elective PCI.7 In addition, the index of myocardial performance (Tei index), which reflects both systolic and diastolic myocardial performance, did not improve in our study.

It is postulated that patients with severely depressed ventricu-lar dysfunction (LVEF < 40%) benefit most from revascularisa-tion.15 Therefore the possible explanation for these findings could be the fact that the patients included in our study had LVEF > 40% at baseline and therefore experienced little improvement.

Among various echo-technique parameters assessing diastolic function, only colour M-mode Vp was found to have improved significantly 48 hours after PCI. There have been various reports on improvements observed in diastolic parameters following PCI. Diller et al.16 analysed the results of successful elective PCI, using TDI before PCI as well as one day and six weeks after the procedure, on systolic and diastolic function in 24 consecutive patients with CAD and normal systolic function. They found that all tissue Doppler measurements of early diastolic func-tion improved significantly after PCI, and systolic peak veloc-ity improved in the septal, lateral, inferior and right ventricular areas.16

A study performed on 31 patients with chronic CAD showed that most echocardiographic diastolic indices, including IVRT, EDT, E/A ratio, IVCT and diastolic indices of both the mitral and tricuspid annulus sites on TDI improved significantly 24

hours following elective PCI.6 In another study, LV diastolic filling improved marginally within 10 days of PCI and persisted up to 30 days.8 By contrast, in a study in 15 patients with single anterior descending coronary artery stenosis and normal systolic function, abnormalities in early and late LV filling velocities lasted as long as three months after PCI.9

There is evidence that abnormalities in diastolic function may precede systolic dysfunction during myocardial ischaemia.17 It has been shown that early LV diastolic function becomes severe-ly impaired during ischaemia.18 The early ventricular relaxation is a highly energy-dependent process.19 Therefore, the restora-tion of blood flow following PCI might affect diastolic function earlier than systolic function.

Vp, which was initially proposed by Brun et al.20 as a sensitive non-invasive indicator of impaired diastolic relaxation, repre-sents the rate of change in velocity of blood flow in early diastole and indicates the time difference between maximal velocity at the apex level and the mitral leaflet tips. It is a unique measure for accurate and reliable assessment of ventricular relaxation, since it is independent of preload.21

The reason for persistence of abnormal indices of LV perfor-mance (other than Vp) may be the duration of disease before PCI.22 These indices may have been improved if patients had undergone PCI earlier during the course of their disease. Hence we say ‘time is muscle’. However, it is believed, based on the ‘open artery theory’, that even late reperfusion provides benefi-

TABLE 2. EARLY ECHOCARDIOGRAPHIC INDICES OF VENTRICULAR SYSTOLIC FUNCTION BEFORE AND AFTER SUCCESSFUL PCI IN

21 PATIENTS WITH STABLE CAD*

Method Index Pre-PCI Post-PCI p-value

2-D echocardiography

LVEF (%) 47 ± 7.7 48.4 ± 9.2 0.10

WMSI 1.41 ± 0.35 1.39 ± 0.39 0.26

M-mode echocardiography

TAPSE (mm) 23 ± 2.7 23.2 ± 3.2 0.64

Doppler echocardiography

Tei index 0.4 ± 1.1 0.4 ± 1.1 0.33

Tissue Doppler Imaging (cm/sec)

Sa – septal 7.10 ± 1.37 7.29 ± 1.42 0.58

Sa – lateral 8.52 ± 2.25 8.19 ± 2.36 0.44

Sa – inferior 8.38 ± 1.91 8 ± 1.30 0.29

Sa – anterior 7.48 ± 2.14 7.2 ± 1.47 0.46

Sa – posterior 8.19 ± 1.72 8.24 ± 1.58 0.92

TA-Sa 11.8 ± 2 12.2 ± 2 0.282

*Means ± standard deviation. PCI: percutaneous coronary interven-tion; CAD: coronary artery disease; LVEF: left ventricular ejection fraction; WMSI: wall motion abnormality score index; Sa: peak systolic velocity of mitral annulus; TA-Sa: peak systolic velocity of tricuspid annulus.

TABLE 3. EARLY ECHOCARDIOGRAPHIC INDICES OF VENTRICULAR DIASTOLIC FUNCTION BEFORE AND AFTER SUCCESSFUL PCI IN

21 PATIENTS WITH STABLE CAD*

Method Index Pre-PCI Post-PCI p-value

Doppler echocardiography

E (m/s) 0.7 ± 0.2 0.7 ± 0.2 0.52

A (m/s) 0.7 ± 0.2 0.7 ± 0.2 0.83

E/A 1 ± 0.4 0.9 ± 0.2 0.27

DT (m sec) 214.1 ± 50 204.7 ± 57.8 0.48

IVRT (m sec) 93.6 ± 18.7 96.3 ± 18.5 0.53

Vp (cm/sec) 42.9 ± 10.8 51.8 ± 10.7 0.008

PVs (cm/sec) 55.2 ± 11 56.9 ± 11.7 0.41

PVd (cm/sec) 44 ± 10.4 42 ± 2.3 0.46

Tissue Doppler imaging (cm/sec)

Septal Ea 6.6 ± 1.7 7.3 ± 2.2 0.08

Aa 8.8 ± 1.7 8.8 ± 1.7 1.00

Lateral Ea 9 ± 2.8 8.5 ± 2.6 0.29

Aa 8.2 ± 2.4 8.4 ± 1.9 0.79

Inferior Em 7.6 ± 2.9 7 ± 1.5 0.32

Aa 7.6 ± 1.5 7.8 ± 2.1 0.72

Anterior Ea 8 ± 2.8 7.3 ± 2.6 0.14

Aa 10 ± 2.4 9.8 ± 2 0.75

Posterior Ea 8.5 ± 3.1 8.5 ± 2.8 0.94

Aa 9.4 ± 3.3 8.2 ± 2.3 0.08

*Means ± standard deviation. TAPSE: tricuspid annular plane systolic excursion; E: peak early diastolic velocity; A: peak late diastolic velocity; DT: deceleration time; IVRT: isovolumic relaxation time; Vp: mitral inflow propagation velocity; PVs: pulmonary vein systolic flow velocity; PVd: pulmonary vein diastolic flow velocity; Ea: early diastolic velocitiy of mitral annulus; Aa: late diastolic velocitiy of mitral annulus.


cial effects on cardiac function.23 It has been shown, however, that myocardial performance improves gradually after PCI,24 so we are hopeful that further improvements in myocardial function will be achieved over time following successful PCI.

A limitation to the current study could have been the rela-tively small number of patients evaluated. Moreover, since functional improvement following PCI may increase over time,24 early assessment of myocardial performance could be another limitation of this study. The final shortcoming may have been the fact that we did not consider clinical improvement along with echocardiographic parameters. To our knowledge, this study is, however, the first to cover a wide range of echocardiographic indices for post-PCI functional assessment in patients with stable CAD.

ConclusionUnlike studies that showed an improvement in TDI parameters of systolic and diastolic function in patients with stable CAD after successful PCI, in our population only the colour M-mode Doppler parameter improved 48 hours after successful elective PCI in patients with stable CAD. More studies should be done to corroborate the results presented here.

References1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke

statistics – 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69–171.

2. Bucher HC, Hengstler P, Schindler C, et al. Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomised controlled trials. Br Med J 2000; 321: 73–77.

3. Curtis JP, Krumholz HM: Keeping the patient in view: defining the appropriateness of percutaneous coronary interventions. Circulation 2004; 110: 3746–3748.

4. Sutherland GR, Stewart MJ, Groundstroem KW, et al. Color Doppler myocardial imaging: a new technique for the assessment of myocardial function. J Am Soc Echocardiogr 1994; 7: 441–458.

5. Çaylý Murat, Usal Ayhan, Demir Mesut, et al. The effect of successful elective percutaneous coronary intervention on left ventricular func-tions assessed with tissue Doppler imaging method. Türk Giriþimsel Kard Der 2007; 11: 146–150.

6. Tumuklu M, Kayikcioglu M, Aliyev E, et al. Evaluation of early alterations in transmitral diastolic flow and tissue Doppler findings of the Basal segments of both ventricles in early period after coronary angioplasty. Anadolu Kardiyol Derg 2003; 3: 16–23, AXVII–AXVIII.

7. Gasior Z, Drzewiecki J, Wita K, et al. Left ventricular systolic function after PTCA – recent and late assessment by exercise echocardiography. Pol Arch Med Wewn 1994; 92: 307–312.

8. Leung WH, Lau CP. Correlation of quantitative angiographic param-eters with changes in left ventricular diastolic function after angioplasty of the left anterior descending coronary artery. Am J Cardiol 1991; 67: 1061–1066.

9. Ricou F, Lerch R, Meier B, et al. Abnormal left ventricular filling pattern in patients with single vessel coronary artery disease: effect of angioplasty. Cardiology 1992; 80: 230–236.

10. Bach DS, Armstrong WF, Donovan CL, et al. Quantitative Doppler tissue imaging for assessment of regional myocardial velocities during transient ischemia and reperfusion. Am Heart J 1996; 132: 721–725.

11. Isaaz K. What are we actually measuring by Doppler tissue imaging? J Am Coll Cardiol 2000; 36: 897–899.

12. Ho CY, Solomon SD. A clinician’s guide to tissue Doppler imaging. Circulation 2006; 113: e396–398.

13. Smith SC, Feldman TE, Hirshfeld JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47: e1–121.

14. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440–1463.

15. Momtahen M, Abdi S, Ojaghi Z, et al. Global and regional left ventricu-lar function improvement following successful percutaneous coronary intervention in patients with ischemic left ventricular dysfunction. Arch Iran Med 2007; 10: 387–389.

16. Diller GP, Wasan BS, Thoma SA, et al. Evaluation of improved myocardial function in patients with chronic stable angina and apparent normalventricular function – a tissue Doppler study before and after percutaneous coronary intervention.J Am Soc Echocardiogr 2009; 22: 177–182

17. Labovitz AJ, Lewen MK, Kern M, et al. Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Coll Cardiol 1987; 10: 748–755.

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22. Dzavik V, Carere RG, Mancini GB, et al. Predictors of improvement in left ventricular function after percutaneous revascularization of occluded coronary arteries: a report from the Total Occlusion Study of Canada (TOSCA). Am Heart J 2001; 142: 301–308.

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health practitioners’ state of knowledge and challenges to effective management of hypertension at primary levelA PARKER, B NAGAR, G ThOMAS, M BADRI, NBA NTuSI

abstractBackground: Patient- and physician-related factors impact on the management and control of hypertension. Objectives: To systematically examine: (1) South African primary care doctors’ state of knowledge on the management of hypertension; (2) primary health practitioners’ knowledge on the South African hypertension guidelines; (3) current approaches to management of hypertensive patients; and (4) challenges to effective management of hypertension at primary level.Methods: A cross-sectional, observational study using a semi-structured questionnaire was carried out in two large community health centres (CHCs) in the Cape Town metro-pole. All 16 doctors employed at both CHCs were voluntar-ily enrolled, seven (43.7%) of whom were female, with 14 (87.5%) younger than 40 years of age. The majority (81.2%) of the doctors surveyed had been practicing for less than 10 years.Results: Ten (62.5%) of the doctors surveyed aimed to treat hypertension to target, and recommendations on lifestyle modifications were reportedly poorly done. While 11 (68.8%) of the doctors were aware of the South African hypertension guidelines, were (81.8%) of them were not conversant with the contents thereof. Doctors estimated that only 35% of their patients are treated to target. Poor patient adherence to prescribed treatment, language difficulty, heavy patient load, medical staff shortages, and patient loss to follow up were identified by the doctors as significant impediments to the effective management of hypertension at the primary level of care.Conclusion: Primary healthcare practitioners’ knowledge regarding hypertension and the South African hypertension guidelines is poor. Management of hypertension by these doctors is sub-optimal. There are significant challenges to effective management of hypertension at this level of care.

Keywords: hypertension, primary healthcare, South Africa, challenges to healthcare



DOI: 10.5830/CVJA–2010–066

Hypertension is common1 and it increases cardiovascular morbid-ity and mortality.2 In 2001, 54% of all strokes and 47% of all ischaemic heart disease were due to hypertension, with 80% of this blood pressure-attributable disease burden occurring in low- and middle-income countries. More than half occurred in people of working age (45 to 69 years of age).1 A recent Canadian study demonstrated that a simplified hypertension treatment algorithm administered to 45 general practices resulted in a significantly higher proportion of patients achieving their target blood pres-sure.3

Factors that impact on doctors’ ability to provide good management of hypertension have previously been investigated.4 Both patient- and physician-related factors have significant impact on blood pressure control in hypertensive patients.5 The South African Hypertension Society published guidelines, designed with expert consensus, to guide the management of hypertension in South Africa, to minimise the gap between the public and private sectors of healthcare, and to improve care of individuals with hypertension.6 Yet, the publication of these guidelines does not seem to have significantly impacted on the management practice of many doctors who treat hypertension.

There have been few studies in South Africa that have systemically examined doctors’ impressions of the phenomena that impede effective care of their hypertensive patients. Hence, the objectives of the study were to systematically examine: (1) South African primary care doctors’ state of knowledge on the management of hypertension; (2) primary health practitioners’ knowledge on the South African hypertension guidelines; (3) current approaches to management of hypertensive patients; and (4) challenges to effective management of hypertension at primary level.

MethodsDoctors working at two large community health centres (CHCs) with a predominantly black patient population in the Cape Town metropole were selected to participate in the study. The study was designed to be an observational study, with the data-collection tool in the form of a semi-structured questionnaire. The investigators conducted all interviews and assessments in English over a four-week period in 2008. Informed consent for inclusion in the study was obtained from all the doctors.

The data in this study were collected as part of a project for a fifth-year primary health block for the medical students enrolled at the University of Cape Town Faculty of Health Sciences. Permission for analysis of the data for the purpose of publication

department of Medicine, groote schuur hospital and the university of Cape town, south africaA PARKER, MB ChBB NAGAR, MB ChBG ThOMAS, MB ChBNBA NTuSI, FCP (SA), [email protected]

Clinical research support unit, department of Medicine, groote schuur hospital and the university of Cape town, south africaM BADRI, PhD


was obtained from the University of Cape Town Health Sciences Faculty Research Ethics Committee. Relevant statistical analysis using Microsoft Excel, SPSS and STATISTICA was performed. Normally distributed data were analysed using the Student’s t-test, and non-parametric data were analysed using either the Fisher’s exact test or Pearson chi-square test. All p-values were two-sided, and p < 0.05 were taken to indicate statistical signifi-cance.

resultsThere were 16 doctors employed at the two CHCs, all of whom were voluntarily enrolled into this study. Seven (43.7%) of the doctors were female, 14 (87.5%) were aged between 26 and 40 years, and 81.25% of the doctors surveyed had been practicing medicine for less than 10 years (Table 1).

Management of hypertension in generalAll the doctors (100%) felt that the management of hypertension was a significant part of their daily practice. Ten (62.5%) stated that they attempted to treat hypertension to target. All doctors thought that lifestyle modification was an important adjunct to the treatment of hypertension, yet recommendations on lifestyle modifications to patients were reportedly poorly done by all the doctors. Only 50% of doctors indicated that they even mentioned lifestyle modifications to some of their patients (Table 2).

Awareness of the South African hypertension guidelinesEleven (68.8%) of the doctors were aware of the recent South African hypertension guidelines. Of these 11, nine (81.8%) stated that they were not conversant with the content of the guidelines (this was reported in spite of the guidelines being prominently displayed in the corridors and some of the consult-ing rooms of both CHCs). Knowledge of the compelling indica-tions for treatment of hypertension, as stated in the hypertension guidelines, was poor, with the majority of doctors not knowing what these conditions are (Fig. 1).

Estimation of effective blood pressure controlOverall, the doctors estimated that 35% (range 5–60%) of their hypertensive patients were controlled on the antihypertensive treatment prescribed.

Preferred management approach to hypertensionDoctors were asked to list their preferred treatment for hyperten-sion. Eleven (68.8%) of the doctors stated that hydrochlorothi-azide was their preferred first-line antihypertensive agent, in the absence of compelling indications; with 11 (68.8%) indicating that enalapril was their preferred second-line agent. Ten (62.5) selected amlodipine as a preferred third-line agent. Four (25%) of the participants in the study indicated that β-blockers were their preferred fourth-line antihypertensive, with various other drugs listed as fourth-line options, in the absence of compelling indications (Table 2).

Doctors were also asked to choose from a list of four drugs (angiotensin converting enzyme inhibitor or angiotensin recep-tor blocker, calcium channel blocker, β-blocker or diuretic) and indicate their preferred choice of antihypertensive agent, when

TABLE 2. KNOWLEDGE ABOUT HYPERTENSION AND PREFERENCE FOR MANAGEMENT OF

HYPERTENSION AMONG DOCTORS SURVEYED

Proportion who felt that hypertension is an important aspect of their daily practice (%)

16 (100.0)

Proportion who attempt to treat hypertension to target (%) 10 (62.5)

Proportion who feel that lifestyle modification is an important aspect of management of hypertension (%)

16 (100.0)

Proportion who recommend lifestyle modification to their patients (%)

8 (50.0)

Proportion who are aware of the existence of the hypertension guidelines (%)

11 (68.8)

Proportion who are conversant with the contents of the hypertension guidelines (%)

2 (12.5)

Choice of drugs to treat hypertension, in the absence of compelling indications

11 (68.8)

First line: hydrochlorothiazide 11 (68.8)

Second line: enalapril 10 (62.5)

Third line: amlodipine 5 (31.25)

Fourth line: beta-blocker, hydralazine or other agent

TABLE 1. DEMOGRAPHIC DETAILS OF DOCTORS SURVEYED

Demographic details Doctors surveyed (n = 16)

Gender

male (%) 9 (56.3)

female (%) 7 (43.7)

Age (years)

< 25 (%) 1 (6.25)

26–30 (%) 7 (43.75)

31–40 (%) 7 (43.75)

over 60 (%) 1 (6.25)

Duration of practice (years)

0–5 (%) 8 (50.0)

6–10 (%) 5 (31.25)

11–15 (%) 1 (6.25)

16–20 (%) 1 (6.25)

> 35 (%) 1 (6.25)

Fig. 1. Compelling indications for the treatment of hyper-tension as given by the doctors surveyed. dM = diabetes mellitus, ihd = ischaemic heart disease; Pvd = periph-eral vascular disease, hC = hypercholesterolaemia, hF = heart failure, PMi = previous myocardial infarction, rd = renal disease, hiv = human immunodeficiency virus infection, Cva = cerebrovascular accident.

14121086420

dM ihd Pvd hC hF age Preg-nan-cy

PMi rd hiv Cva

doct

ors

(n)

indications for treatment of hypertension


the following compelling indications are present: ischaemic heart disease or angina, heart failure, diabetes mellitus, prior cerebrovascular accident, peripheral vascular disease, albumi-nuria, chronic kidney disease, left ventricular hypertrophy, and isolated systolic hypertension. Knowledge of the compelling indications for treatment of hypertension was poor, with the majority (62.5%) of doctors not knowing what the appropriate agent of choice for these conditions should be (Fig. 2).

Factors influencing optimal management of hypertensionThe main challenges to optimal treatment of hypertension in their settings, as reported by doctors in this study, included: (1) poor patient adherence to prescribed treatment (75%); (2) language difficulty (50%); (3) overwhelmingly heavy patient load (50%); (4) significant medical staff shortages (50%); and (4) patient loss to follow up (44%). Other factors that were mentioned included conditions of adverse poverty under which many patients live; poor patient literacy; intermittent shortage or lack of drugs; lack of functional equipment (including sphygmomanometers); and other systematic factors (Table 3).

discussionThe findings of this study suggest that the knowledge of South African primary healthcare practitioners regarding hypertension and its management is sub-optimal. Knowledge on the South African hypertension guidelines is poor. Doctors estimated that about two-thirds of their hypertensive patients have poor blood pressure control, and yet treatment for these patients is not routinely titrated upwards. Moreover, the doctors who participat-ed in this study identified significant challenges to their effective management of hypertension.

Various stakeholders in the healthcare sector will have to work together to address these challenges if we are to improve care of hypertensive patients in this country. Furthermore, ongo-ing education of doctors is crucial in order to increase knowledge on hypertension and awareness of the management guidelines

and to encourage them to overcome physician inertia. On a posi-tive note, it is interesting to observe that β-blockers were not considered as first-line treatment of hypertension, in the absence of compelling indications.

Despite hypertension being identified as an important aspect of the practice of doctors at the primary healthcare level, many doctors do not focus on lifestyle modifications. The reason for this phenomenon, as reported by the doctors surveyed, is the lack of adequate time at each consultation for explanation to patients about necessary lifestyle changes to complement their drug treatments.

The sixth report of the Joint National Committee on preven-tion, detection, evaluation and treatment of high blood pressure included evidence-based lifestyle modifications that have been shown to lower blood pressure in normotensive and hypertensive patients.7 These important lifestyle modifications include weight loss of 3 to 9%, moderation in alcohol use, smoking cessation, increased physical activity, reduced dietary salt intake, reduced intake of saturated fats and cholesterol, and adequate dietary intake of potassium, calcium and magnesium. Each of these lifestyle changes have the effect of lowering systolic blood pressure by 3 to 11 mmHg and the diastolic blood pressure by 2.5 to 5.5 mmHg.8-12

Therefore, as drugs fail to adequately control blood pressure in the majority of patients, these lifestyle changes are impor-tant adjuncts in the initial and comprehensive management of patients with an elevated blood pressure. These lifestyle altera-tions should be enforced at the primary level of care, rather than waiting for patients to develop complications and to receive these messages from secondary and tertiary hospitals, when they may be too late.

A disturbing finding was that a significant proportion (37.5%) of doctors surveyed did not aim to treat patients to target. Despondency on the part of overwhelmed healthcare practition-ers, including doctors in the primary level of care within the public sector in South Africa, in the management of hypertension has previously been documented by several authors.7,13,14 The net effect of these despondent attitudes towards patient care is further compromising an already crumbling management paradigm.

Almost 90% of doctors in this study were below the age of 40 years, with most having practiced as doctors for 10 years or less. This observation reflects the state of healthcare in South Africa, where fairly junior doctors are entrusted with enormous clinical responsibility. While these young doctors grow quickly in their trade and benefit from having to assume responsibility for the

TABLE 3. PROPORTION OF DOCTORS WHO IDENTIFIED FACTORS INFLUENCING OPTIMAL MANAGEMENT OF

HYPERTENSION

Poor patient treatment adherence 12 (75.0)

Language difficulty 8 (50.0)

Overwhelming patient load 8 (50.0)

Severe staff shortages 8 (50.0)

Patient loss to follow up 7 (43.75)

Poverty 4 (25.0)

Poor patient literacy 3 (18.75)

Lack of drugs 2 (12.5)

Lack of functional equipment 2 (12.5)

Systematic factors like financial constraints on tests 3 (18.75)

angina PMi hF dM Cva alb CKd lvh Jish

Fig. 2. Choice of preferred antihypertensive agent, when these compelling indications are present. angina = ischaemic heart disease or angina pectoris, PMi = previ-ous myocardial infarct, hF = heart failure, dM = diabetes mellitus, Cva = prior cerebrovascular accident, Pvd = peripheral vascular disease, alb = albuminuria, CKd = chronic kidney disease, lvh = left ventricular hypertro-phy, and Jish = just isolated systolic hypertension.

1009080706050403020100

unknown incorrect correctindications for treatment of hypertension

Choi

ce o

f tre

atm

ent (

%)


management of their patients, patient care is not always optimal. Availability of increased numbers of senior doctors and special-ists who provide outreach may go a long way in ameliorating some of these challenges.

Another disconcerting finding in this study was the obser-vation that most doctors were unable to name the compelling indications for hypertension treatment or failed to list the correct treatment when given a list of these conditions. This demon-strates that there is a need for ongoing education of doctors about management of conditions with important public health implications, such as hypertension. The publication of guidelines is an important way of developing minimum standards for coher-ence and uniformity in treatment of clinical entities. However, as demonstrated in this study, the prominent display of guidelines in hospital corridors and consulting rooms does not equate to physician knowledge.

An interesting question that arises from this study is: how can primary health practitioners who treat one of the most common conditions in their practice, hypertension, be unfamiliar with or ignorant of the latest guidelines? There is a perceived, and perhaps real disconnect between experts (who are mostly academics) who write guidelines, and primary healthcare doctors (who are expected to implement guidelines and improve health of the population), with limited opportunities for engagement between the two groups.

After publication of guidelines, dissemination of the message to the relevant doctors is of paramount importance. Publication in journals and posters is clearly not sufficient. Multi-pronged implementation and education programmes need to be devel-oped. Others have demonstrated that education alone is not enough to change physician behaviour, and that the process of change is more related to attitude.15,16

In other parts of the world, where there is also poor imple-mentation of hypertension guidelines by primary health doctors, authors have demonstrated that hypertension clinical guidelines are often regarded as optional rather than standards, and many doctors feel that the recommendations are not suitable for their patients.17 While it is not clear if such attitudes are also operation-al in our small sample of doctors, it is clear that multi-dimension-al risk stratification and intervention is too time-consuming for doctors who are already overwhelmed by the workload of patients.

An important aspect of this study was the examination of factors that impact on the ability of public-sector primary healthcare doctors to effectively treat hypertension. In the main, these challenges were related to reported poor adherence to treatment by patients, communication difficulties due to doctors not speaking the language of the patients, and heavy patient load in the context of significant shortage of both nurses and doctors. A further challenge elaborated on by the doctors is the fact that many patients regularly move between the Eastern Cape and Western Cape provinces, with the consequence of regular patient loss to follow up. High levels of poverty and illiteracy were also mentioned as factors that hamper effective care of patients. Drug shortages and lack of functional equipment are problems that also emerge, from time to time, to affect care of patients with hypertension and other chronic co-morbidities. Systematic factors, including financial restrictions on investiga-tion of patients at the primary level of care were also mentioned by some of the doctors.

Interestingly, in a different study by Steyn and colleagues,

conducted in a random sample of 18 CHCs in the Cape Town area, the authors similarly found that staff shortages, complex-ity of cases previously managed in tertiary hospitals and lack of financial resources for special investigations were reported by healthcare workers as significant impediments to their care of patients with chronic conditions.18

ConclusionThis study demonstrates that the majority of doctors treating hypertension in the primary health clinics are fairly junior, and significant gaps exist in their knowledge regarding management of hypertension. Awareness of the South African hypertension guidelines should be improved. Furthermore, an urgent, concert-ed, multi-sectorial effort to address the challenges to effective care of hypertensive patients at a primary level of care is needed.

The investigators thank the patients and staff based at Gugulethu Community Health Centre and Khayelitsha Site B Community Health Centre. The research reported in this study was not funded. Dr Ntusi receives funding from the Discovery Foundation and the Medical Research Council of South Africa.

References1. Lawes CMM, Vander Hoorn S, Rodgers A. Global burden of blood

pressure-related disease, 2001. Lancet 2008; 371: 151–1518.2. Norman R, Gaziano T, Laubscher R, et al. Estimating the burden of

disease attributable to high blood pressure in South Africa in 2000. S Afr Med J 2007; 97: 692–698.

3. Feldman RD, Zou GY, Vandervoort MK, et al. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension 2009; 53: 646–653.

4. Heagerty A. Optimising hypertension management in clinical practice. J Hum Hypertens 2006; 20: 841–849.

5. Dusing R. Overcoming barriers to effective blood pressure control in patients with hypertension. Curr Med Res Opin 2006; 22: 1545–1553.

6. Seedat YK, Croasdale MA, Milne FJ, et al. South African hypertension guideline 2006. S Afr Med J 2006; 96: 337–362.

7. Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National High Blood Pressure Education Program Coordinating Committee. 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: 2560–2572.

8. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: A meta-analysis of randomized, controlled trials. Ann Intern Med 2002; 136: 493–503.

9. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH collaborative research group. N Engl J Med 1997; 336: 1117–1124.

10. Mulrow CD, Chiquette E, Angel L, et al. Dieting to reduce body weight for controlling hypertension in adults. Cochrane Database Syst Rev 2000; (2): 000484.

11. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev 2004; (3): 004937.

12. Xin X, He J, Frontini MG, Ogden LG, Motsamai OI, Whelton PK. Effects of alcohol reduction on blood pressure: A meta-analysis of rand-omized controlled trials. Hypertension 2001; 38: 1112–1117.

13. Levitt NS, Bradshaw D, Zwarenstein MF, et al. Audit of public sector primary diabetes care in Cape Town, South Africa: high prevalence of complications, uncontrolled hyperglycaemia, and hypertension. Diabet Med 1997; 14: 1073–1077.

14. Lunt DWR, Edwards PR, Steyn K, Lombard CJ, Fehrsen GS.


William nelson ECg Quiz

QuestionThis is the ECG of a 60-year-old woman.What is significant?

The answer will be provided on page 196.

Hypertension care at a Cape Town community health centre. S Afr Med J 1998; 88: 544–548.


16. Lomas J, Anderson GM, Domnick-Pierre K, et al. Do practice guide-lines guide practice? The effect of a consensus statement on the practice of physicians. N Eng J Med 1989; 321: 1306–1311.

17. Woolf SH. Practice guidelines: a new reality in medicine. III. Impact on patient care. Arch Intern Med 1993; 153: 2646–2655.

18. Hetlevik I, Holmen J, Kruger O, et al. Implementing clinical guidelines in the treatment of hypertension in general practice. Blood Pressure 1998; 7: 270–276.



review article

the state of heart disease in sudanA SuLIMAN

abstractCardiovascular disease (CVD) is the leading cause of mortal-ity worldwide and an important cause of disability. In Africa, the burden of CVD is increasing rapidly and it is now a public health concern. Epidemiological data on diseases is scarce and fragmented on the continent.Aim: To review available data on the epidemiology and pattern of heart disease in Sudan.Methods: Data were obtained from the Sudan Household Survey (SHHS) 2006, annual health statistical reports of the Sudan Federal Ministry of Health, the STEPS survey of chronic disease risk factors in Sudan/Khartoum, and journal publications.Results: The SHHS reported a prevalence of 2.5% for heart disease. Hypertensive heart disease (HHD), rheumatic heart disease (RHD), ischaemic heart disease (IHD) and cardio-myopathy constitute more than 80% of CVD in Sudan. Hypertension (HTN) had a prevalence of 20.1 and 20.4% in the SHHS and STEPS survey, respectively. There were poor control rates and a high prevalence of target-organ damage in the local studies. RHD prevalence data were available only for Khartoum state and the incidence has dropped from 3/1 000 people in the 1980s to 0.3% in 2003. There were no data on any other states. The coronary event rates in 1989 were 112/100 000 people, with a total mortal-ity of 36/100 000. Prevalence rates of low physical activity, obesity, HTN, hypercholesterolaemia, diabetes and smoking were 86.8, 53.9, 23.6, 19.8, 19.2 and 12%, respectively, in the STEPS survey. Peripartum cardiomyopathy occurs at a rate of 1.5% of all deliveries. Congenital heart disease is prevalent in 0.2% of children.Conclusion: Heart diseases are an important cause of morbid-ity and mortality in Sudan. The tetrad of hypertension, RHD, IHD and cardiomyopathy constitute the bulk of CVD. Hypertension is prevalent, with poor control rates. A decline in rheumatic heart disease was seen in the capital state and no data were available on other parts of the country. No recent data on IHD were available. Peripartum cardiomyo-pathy and congenital heart disease occur at similar rates to those in other African countries.

Keywords: Sudan, prevalence, epidemiology, heart disease, pattern of heart disease, hypertensive heart disease, rheumatic heart disease, ischaemic heart disease, cardiomyopathy



DOI: 10.5830/CVJA–2010–054

Sudan is the largest country in Africa and the ninth largest in the world, with an area of about one million square miles. It has a population of more than 39 million people, comprising tribes that descended from African, Arab and Nubian origins.1,2 Sudan is geographically unique, lying in the north-east corner of the continent, extending from latitude 22° north to 3° south, with the northern part of the country in the Saharan belt and the central and southern parts in the sub-Saharan region.1

Worldwide, cardiovascular disease (CVD) is responsible for 30% of all deaths and 10% of DALYs (disability-adjusted life years).3 In Africa, the burden of cardiovascular disease is increasing rapidly and it is now a public health concern. It has a major socio-economic impact on individuals, families and socie-ties in terms of healthcare costs, work absenteeism and national productivity. The most important cardiovascular diseases in the African region are those related to hypertension, atherosclerosis, cardiomyopathies and rheumatic heart disease.4,5

In Sudan, like many other less-developed countries, particu-larly in sub-Saharan Africa, epidemiological data on diseases are scarce and fragmented.6 Most of the data on disease burden for sub-Saharan Africa come from extrapolations, as in the Global Burden of Disease Study (GBDS),7 which relies on cause-of-death models and expert opinion.

In this article, we aim to review available epidemiological data on the burden of cardiovascular disease and its pattern in Sudan, as well as the prevalence of individual cardiac diseases, namely hypertensive, rheumatic and atherosclerotic heart diseases and their risk factors, cardiomyopathies, particularly peripartum and dilated cardiomyopathy, and congenital heart diseases.

We reviewed data from annual health statistical reports8 issued by the Federal Ministry of Health, the Sudan Household Survey (SHHS) of 2006,9 World Health Organisation STEPS (STEPwise approach to Surveillance) data,10 published data using Medline search, with the terms ‘cardiovascular disease Sudan’, ‘heart disease Sudan’, ‘hypertensive heart disease Sudan’ and ‘cardio-myopathy Sudan’, and unpublished data on relevant topics. These were compared to similar data from other countries in the continent and worldwide, as well as estimates from the World Health Organisation (WHO) and the Global Burden of Disease Study.11

Burden of cardiovascular disease in sudanThe only epidemiological data on the prevalence of cardiovascu-lar disease in the community come from the SHHS.9 This survey

department of Medicine, Faculty of Medicine, university of Khartoum, Khartoum, sudanA SuLIMAN, MBBS, FACP, [email protected]; [email protected]


of 2006 was a questionnaire-based survey in all states of Sudan, organised by the Federal Ministry of Health and Ministry of Health of the Government of southern Sudan; 24 527 households and more than 55 000 Sudanese were surveyed. The self-report-ed prevalence of heart disease was 2.5%. This figure remains low compared to developed countries.12 Fig. 1 shows prevalence of cardiovascular disease compared to other non-communicable diseases in the SHHS.

The Federal Ministry of Health issues an annual health statis-tical report that includes data on causes of hospital mortality. Over the past decade, cardiovascular disease has been consist-ently reported in the top 10 causes of hospital mortality, with malaria and acute respiratory infections as the first two causes. Fig. 2 demonstrates the contribution of cardiovascular disease, malaria, respiratory tract infections, diabetes mellitus (DM) and hypertension to hospital mortality in Sudan from 1998 to 2008. Such a significant contribution of cardiovascular disease to mortality is also seen in other African countries.13,14

Pattern of heart disease in sudanIn 1937, an analysis was made of 100 consecutive cases of heart disease admitted to Khartoum Hospital: 80 had cardiovascular syphilis, followed by rheumatic heart disease. There was no

mention of ischaemic heart disease.In 1961 the same author, Dr Halim, analysed 958 consecutive

cardiac cases admitted to Khartoum Hospital. Hypertension and rheumatic heart disease (RHD) were the commonest two diag-noses at 44.4 and 25.4% of the sample, respectively. Ischaemic heart disease (IHD) was 12.6 % and syphilitic heart disease regressed to 6.0%.15 Table 1 summarises the result of that study.

Two other similar studies investigating the pattern of heart disease were conducted in the 1980s and 1990s. The first study conducted by Khalil et al. was in a community hospital in Khartoum North Hospital and included 539 patients from 1980 to 1983.16 The other was performed in 1992 in Al Shaab Hospital, which is a tertiary referral hospital, by Kurdufani et al. and included 1 000 patients. Unfortunately, the latter study was unpublished and data were obtained directly from the author.

Table 2 summarises the main findings from these two studies. They show that the tetrad of hypertensive heart disease, rheu-matic heart disease, ischaemic heart disease and cardiomyopathy are the main cardiovascular causes for hospital admission. These results are comparable to the recent Heart of Soweto study,17 which also showed that these four disease categories, together with pericardial disease, are the main cardiac causes for hospital presentation in Soweto, South Africa.

The contribution of HIV/AIDS to heart disease in Sudan, particularly cardiomyopathy and pericardial disease is unclear. However, this is expected to be less than what is seen in many parts of sub-Saharan Africa, as Sudan has one of the lowest HIV prevalence rates in this region. HIV prevalence rate for adults aged 15 to 49 in Sudan is 1.4% (1–2%),18 compared to 5.2% for sub-Saharan Africa in 2008.19

hypertensive heart diseaseHospital-based surveys in Sudan dating back from the middle of the last century have shown that hypertensive heart disease, particularly with its contribution to heart failure, is probably the commonest cause of cardiovascular disease.15,16 This can be explained by a number of factors, including high prevalence rates

TABLE 2. SUMMARY OF RECENT PATTERN OF HEART DISEASE STUDIES IN SUDAN16

Study (hospital, year)RHD (%)

HHD (%)

IHD (%)

Cardio-myopahty

(%)CHD (%)

Other (%)

Khalil et al. (Khartoum North Hospital, 1980–1983)

26.5 33.7 17.8 4.8 3.9 13.3

Kurdufani et al. (AlShaab Hospital, 1992)

30.0 12.0 32.0 6.0 2.0 18.0

RHD, rheumatic heart disease; HHD, hypertensive heart disease; IHD ishaemic heart disease; CHD, congenital heart disease.

TABLE 1. ANALYSIS OF 958 CARDIAC CASES INVESTIGATED IN KHARTOUM DURING THE YEARS 1957–196015

Cardiac disorder

Congen-ital SA HTN IHD PHD EMF RHD

Miscel-laneous

5 of total 3.7 6.0 44.4 12.6 2.0 3.2 25.4 2.7

SA, syphilitic aortitis; HTN, hypertension; IHD, ischaemic heart disease; PHD, pulmonary heart disease; EMF, endomyocardial fibrosis; RHD, rheumatic heart disease.

Fig. 1. Prevalence of cardiovascular diseases, hyperten-sion, diabetes mellitus, cancer, cataract and mental disor-ders in shhs.9 Cvd, cardiovascular disease; htn, hyper-tension; dM, diabetes mellitus; shhs, sudan household survey. available at http://www.ssccse.org/blog/surveys.

25

20

15

10

5

0htn dM Cataract Mental

disordersCvd Cancer

% o

f pop

ulat

ion

20.1

12.7

5.52.8 2.5

0.2

Fig. 2. hospital mortality of cardiovascular diseases, hypertension, diabetes mellitus, malaria and respiratory tract infections in sudan 1998–2008. Cvd, cardiovascular disease; htn, hypertension; dM, diabetes mellitus; rti, respiratory tract infection. adapted from annual health statistical reports of the Federal Minsitry of health.10 available at http://fmoh.gov.sd/indexar/php?id=6.

25

20

15

10

5

01998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

% o

f tot

al m

orta

lity

year

CvdMalariartihtndM


of hypertension, particularly in urban communities, poor control, and the larger contribution of hypertension to CVD in African patients. The SHHS and the STEPS survey have reported preva-lence rates of 20.1 and 20.4%, respectively for hypertension. Also, the control of blood pressure in hypertensive patients seems to be poor in Sudan.

Two outpatient surveys have been identified that assessed this issue, both using cut-off points of < 140/90 mmHg for good control. The first was conducted in eastern Sudan and showed control rates of 19.4%,20 and the other was in Khartoum state and showed a control rate of only 28.1%.21 Both surveys showed similar compliance rates with prescribed medication, of 59.6 and 59.4%, respectively. The commonest cause of non-compliance was inability to purchase medication.

The prevalence of target-organ damage, mainly cardiac and renal, in outpatient clinics in Sudan is relatively high, with at least one-fifth of the hypertensive population showing evidence of target-organ damage.22,23 Hypertension itself, as shown in the INTERHEART study, is a strong contributor to the hazards of CVD in black Africans, with an odds ratio (OR) of 7.0 versus 2.3–3.9 in other ethnic groups (p = 0.0002).24

This situation is not unique to Sudan and is seen throughout the continent, where hypertension is the leading cardiovascular disease and cause of heart failure.17,25,26 However, this condition is treatable and to some extent preventable.4

Prevalence of rheumatic heart diseases The highest prevalence of RHD is in sub-Saharan Africa, with a prevalence of 5.7 per 1 000 people, compared with 1.8 per 1 000 in North Africa, and 0.3 per 1 000 in economically developed countries with established market economies.27

The epidemiological data on rheumatic valvular heart disease in Sudan come from the WHO Global Rheumatic Fever/Rheumatic Heart Disease Prevention Program in Sudan. This project had two phases. Phase I was from 1986 to 1989, where more than 13 000 schoolchildren aged five to 15 years in Sahafa town were screened clinically. Sahafa was chosen because it had well-marked houses and streets and most of its inhabitants were low- and middle-income families that had moved to the capital from all districts of the country following the drought in the early 1980s. Prevalence of rheumatic heart disease in Sudan was found to be 3/1 000 population,28 as quoted by the World Health Organisation.29

Phase II of the programme was conducted from 1994 to 2003 in the state of Khartoum; 1 095 000 schoolchildren were screened in this phase. Prevalence was found to be 0.3/1 000 after implementation of a primary and secondary prevention programme. These data were presented by Dr N Kordofani at the 2006 World Congress of Cardiology in Barcelona, Spain. There are no data on other parts of the country. The 10-fold drop in RHD prevalence over less than two decades, seen in the capital state of Khartoum, due to screening and prevention is not expected in other states where no formal programme exists.

However, the recent work by Marijon et al., which demon-strated that the prevalence of RHD as detected by echocar-diographic screening is 10 times that of clinical screening.30 This raises a number of concerns for Sudan and the continent regarding the true prevalence of RHD and the feasibility and cost-effectiveness of echocardiographic screening.

atherosclerotic heart diseases and risk factorsIschaemic heart disease is the leading cause of death worldwide, both in high-income and low- and middle-income countries, except in sub-Saharan Africa where HIV/AIDS and infectious disease, mainly malaria, are the major causes of death. It is also responsible for 10% of DALYs lost in low- and middle-income countries and 18% in high-income countries.31,32 The incidence of ischaemic heart disease in Africa has risen greatly in the last decade and it has been estimated that it ranked eighth in the leading causes of death, and number one in those over 60 years of age.33-35

There has been only one population-based study in Sudan, conducted by Khalil et al., which addressed the issue of coro-nary event rates.36 All coronary events occurring in Khartoum, capital of Sudan, were registered during the calendar year 1989 using the diagnostic and classification criteria of the World Health Organisation Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project.37 The annual (1989) coronary event rate was 112/100 000 with a total mortality of 36/100 000. The highest event rate of 364/100 000 occurred in men aged 45 to 64 years. The event rates recorded in this study were low compared to most other MONICA centres, e.g. Spain (Catalonia) 187/100 000, Australia (Newcastle) 561/100 000 and Canada (Halifax) 605/100 000.38

However, these data are two decades old and it is believed that during this time, many third-world countries, and Sudan is no exception, have entered a period of epidemiological transition. Greater urbanisation and economic development has led to a shift in the major causes of death and disability, from infectious diseases to chronic non-communicable diseases such as cardio-vascular disease and cancer.39

The WHO 2002 estimates for IHD in Sudan,40 based on the Global Burden of Disease study,26 are an age-adjusted mortality rate of 205/100 000 and an age-adjusted DALYs of 1185/100 000 population. Such estimates need to be validated by local surveys. Table 3 presents age-standardised mortality rates for all-cause, non-communicable diseases, cardiovascular diseases, IHD and DALYs for IHD for Sudan and other African states from differ-ent regions of the continent.

TABLE 3. SHOWS MORTALITY RATES FOR ALL-CAUSE, CVD AND IHD AND YEARS OF LIFE LOST IN SUDAN

AND SELECTED AFRICAN COUNTRIES FROM DIFFERENT REGIONS OF THE CONTINENT

Country

Age- standardised

all-cause mortality rates per 100 000

Age- standardised

mortality rate for

NCD per 100 000

Age- standardised

mortality rate for

CVD per 100 000

Age- standardised

mortality rate for IHD per 100 000

Age- standardised

DALYs for IHD

per 100 000

Sudan 1495 902 499 204 1185

Egypt 1132 958 560 273 1781

Eritrea 1584 762 398 124 679

Ghana 1510 786 404 128 726

South Africa

2011 808 406 124 758

Source: World Health Organisation. Death and DALY estimates by cause, 2002. Available at http://www.who.int/entity/healthinfo/statistics/bodgbddeath-dalyestimates.xls (accessed 06 December 2009). NCD, non-communicable disease; CVD, cardiovascular disease; IHD, ischaemic heart disease; DALYs, disability-adjusted life years.


Several surveys and studies into the prevalence of risk factors of atherosclerotic disease in Sudan were conducted in recent years. The SHHS showed a self-reported prevalence of hyper-tension and DM of 20.4 and 12.7%, respectively. The STEPS survey41 of chronic risk factors for IHD, carried out in Khartoum state from December 2005 to January 2006 showed high preva-lence rates of these risk factors. Fig. 3 illustrates prevalence rates for hypertension, DM, obesity, hypercholesterolaemia, smoking and physical inactivity in the STEPS survey.

The high prevalence of these risk factors is alarming. The INTERHEART study showed that the nine risk factors (smoking, diabetes, hypertension, increased ratio of apolipoprotein B to apoliporotein A-1, increased weight-to-hip ratio, low consump-tion of fruits and vegetables, low physical activity, no alcohol intake and psychosocial stress) provided population-attributable risk (PAR) for developing a first-time myocardial infarction of 90.4% worldwide42 and 97.4% in Africa.24 Of these risk factors, only five (current/former tobacco smoking, self-reported diabe-tes and hypertension, abdominal obesity measured as waist-to-hip ratio, and elevated ApoB/ApoA-1 ratio) accounted for 78.4% of the PAR worldwide42 and 89.2% in the African participants.24

CardiomyopathiesIdiopathic dilated cardiomyopathy (DCM)Idiopathic DCM is a major cause of heart failure in Africa.43,44 However, there are no population-based data on the burden of the disease in Africa and most data come from hospital-based surveys.

Earlier hospital-based surveys show that cardiomyopathies constitute 4 to 6% of all cardiac admissions.16 In our cardiology unit at the Al Shaab Teaching Hospital in Khartoum, where the National Cardiothoracic Centre is located, 12% of all admis-sions in 2009 were due to idiopathic DCM. Many clinicians in Sudan believe that DCM is becoming more prevalent. Lack of epidemiological data that support such assumptions hinder the recognition of this disease as a major health issue.

Endomyocardial fibrosis (EMF)No epidemiological data are available on the prevalence of EMF in Sudan. Limited data are available from hospital-based surveys. In adults it seems to be a rare cause of heart disease.15

In the paediatric population, it appears to be a more important cause. Ali reviewed all paediatric patients with cardiac disease admitted at the Children’s Hospital, Khartoum from September 2007 to September 2008 and identified six patients with EMF, constituting 18% of all children with cardiomyopathy.45

Peripartum cardiomyopathy (PPCM)The only data on the incidence of PPCM come from unpublished work by Kineish et al. All deliveries in Khartoum Teaching Hospital from 1975 to 1979 were screened. Any woman who developed heart failure during the last trimester or during puer-perium was examined clinically, and evaluated by electrocardio-gram and chest X-ray. If no identifiable cause of heart failure was found, patients were labelled as having PPCM. Thirteen patients were identified out of 8 605 deliveries, with an incidence of 1.5 in 1 000 deliveries. This is similar to the incidence in the sub-Saharan region, except possibly in the Zaria province in northern Nigeria, which has the highest reported incidence rate of one in 100 deliveries.46,47

Congenital heart diseaseThe prevalence of congenital heart disease among schoolchildren aged five to 15 years was studied as part of phase 1 of the WHO Global Rheumatic Fever/Rheumatic Heart Disease Prevention Programme in Sudan. There were 27 cases of congenital heart disease found in a total of 13 322 children screened, giving a prevalence rate of 2.0 per 1 000 children. The rate is comparable to that of similar African countries but lower than European and North American rates.49-53

Among children admitted to hospital, congenital heart disease is the commonest cause of heart disease, followed by rheumatic heart disease and cardiomyopathy. Ventricular septal defect, atrial septal defect, tetralogy of Fallot, patent ductus arteriosus and pulmonary stenosis were the commonest diseases.54,55

ConclusionHeart disease is prevalent in Sudan, with at least 2.5% of the population affected, and it is one of the major causes of hospital mortality. The tetrad of hypertensive heart disease, ischaemic heart disease, rheumatic heart disease and cardiomyopathy constitute the bulk of heart disease.

Hypertension is prevalent, especially in urban communities, with poor control rates. Data on RHD are only available for the capital state of Khartoum, where a prevention programme succeeded in reducing prevalence 10-fold from 3/1 000 to 0.3/ 1 000 population. There are no recent epidemiological data on the prevalence of IHD. However, IHD risk factors are alarmingly prevalent in the community.

Prevalence of cardiomyopathies is not known, although it seems clinicians are recognising idiopathic dilated cardiomyo-pathy more frequently. EMF is rarely reported in adult patients in recent literature but is seen infrequently in paediatric popula-tion. Peripartum cardiomyopathy seems to occur at a similar incidence to that in other sub-Saharan countries. The prevalence rate of congenital heart disease is comparable to other African countries but lower than European and North American rates. Epidemiological data are scarce and fragmented.

The need for quality data cannot be overemphasised. However, Fig. 3. results of stEPs survey in sudan 2005/2006.

1009080706050403020100

% o

f tot

al p

opul

atio

n 86.8

53.9

23.6 19.8 19.212

source: World health organisation. available at http://www.emro.who.int/ncd/media/excel/sudan.xls

low physical activity

over-weight & obesity

hyper-tension

hyper-chole-sterol-aemia

diabetes smoking


there are enough existing data to warrant primary and secondary prevention programmes for risk factors for heart disease to go hand in hand with epidemiological surveys.

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Affairs website at http://www.sudan.gov.sd/en/ (accessed 10 December 2009).

2. Fifth Sudan Population and Housing Census – 2008 priority results. Available from Sudan Central Bureau of Statistics at http://www.cbs.gov.sd/RESULT/Priority%20English.xls (accessed 10 December 2009).

3. World Health Organization. The global burden of disease: 2004 update. Available at http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html (accessed 2 December 2009).

4. Opie LH, Mayosi BM. Cardiovascular disease in sub-Saharan Africa. Circulation 2005; 112: 3536–3540.

5. World Health Organization. Cardiovascular diseases in the African region: Current situation and perspectives. Report of the Director for the Regional office for Africa. August 2005. Available at afro.who.int/rc55/documents/afr_rc55_12_cardiovascular.pdf (accessed 2 December 2009).

6. Kaufman JS, Asuzu MC, Rotimi OO, Johnson OO, Owoaje EE, Cooper RS. The absence of adult mortality data for sub-Saharan Africa: a prac-tical solution. Bull Wld Hlth Org 1997; 75: 389–395.

7. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In: Lopez AD, Mathers CD, Ezzati M, et al., eds. Global Burden of Disease and Risk Factors. New York, Washington, DC: Oxford University Press & The World Bank, 2006: 45–240.

8. Sudan Federal Ministry of Health. Annual Health Statistical Reports. Available at http://fmoh.gov.sd/indexAr.php?id=16 (accessed 5 Decem-ber 2009).

9. Southern Sudan Commission for Census, Statistics and Evaluation. Sudan Household Survey 2006. Available at http://www.ssccse.org/blog/surveys (accessed 9 December 2006).

10. World Health Organization. STEPwise approach to surveillance (STEPS). Available at http://www.who.int/chp/steps/en/ (accessed 12 December 2009).

11. Mathers CD, Bernard C, Iburg K, Inoue M, Ma Fat D, Shibuya K, Stein C, Tomijima N. The Global Burden of Disease in 2002: data sources, methods and results. Geneva, World Health Organization.Available at http://www.who.int/evidence (accessed 12 December 2009).

12. Rosamond W, Flegal K, Friday G, et al. Heart Disease and Stroke Statistics – 2007 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: 69–171.

13. Bradshaw D, Groenewald P, Laubscher R, et al. Initial burden of disease estimates for South Africa, 2000. S Afr Med J 2003; 93: 682–88.

14. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009; 374: 934–947.

15. Halim AM, Jacques JE. Rheumatic heart disease in Sudan. Br Heart J 1961; 23: 383–385. Available at http://heart.bmj.com/cgi/reprint/23/4/383.(accessed 29/11/09).

16. Khalil S, El-Samani F, Dafalla G. Patterns of cardiovascular disease in Sudan: hospital load and recent Trends. Sudan Med J 1984; 20(4): 25–38.

17. Sliwa K, Wilkinson D, 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.

18. UNAIDS. Sudan country report. Available at http://www.unaids.org/en/CountryResponses/Countries/sudan.asp (accessed 15 January 2010).

19. UNAIDS/WHO. AIDS epidemic update 2009. Available at http://www.unaids.org/en/KnowledgeCentre/HIVData/EpiUpdate/EpiUpdArchive/2009/default.asp (accessed 15 January 2010).

20. Osman EM, Suleiman I, Elzubair AG. Patients’ knowledge of hyper-

tension and its control in Eastern Sudan. East Afr Med J 2007; 84(7): 324–328.

21. Abu-Aisha H, Elhassan EAM, Khamis AH, Abu-Elmaali A. Hyper-tension and obesity in police forces households in Khartoum, Sudan: A pilot report – part of the ‘Police Forces Hypertension, Diabetes, Renal Insufficiency, and Thyroid Derangements (HyDRIT) Study’, Sudan. Sudanese J Publ Hlth 2008: 3; 18–25.

22. Hussain AA, Elzubier AG, Ahmed ME. Target organ involvement in hypertensive patients in Eastern Sudan. J Hum Hypertens 1999; 13(1): 9–12.

23. Ahmed ME. The clinical presentation of hypertension in Sudan. Ethn Dis 1991; 1(3): 288–291.

24. Steyn K, Sliwa K, Hawken S, et al. Risk factors associated with myocardial infarction in Africa: the INTERHEART Africa study. Circulation 2005; 112: 3554–3561.

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

26. Ntusi NB, Mayosi BM. Epidemiology of heart failure in sub-Saharan Africa. Expert Rev Cardiovasc Ther 2009; 7(2):169–180.

27. Nkomo V. Epidemiology and prevention of valvular heart diseases and infective endocarditis in Africa. Heart 2007; 93:1510–1519.

28. Ibrahim-Khalil, et al. An epidemiological survey of rheumatic heart disease in sahafa town, Sudan. J Epidemiol Community health 1992; 46(5): 477–479.

29. World Health Organization. Current evidence for the burden of group A streptococcal diseases. 2005. Avilable at http://www.who.int/child_adolescent_health/documents/fch_cah_05_07/en/index. (accessed 1 December 2009).

30. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007; 2007: 357(5): 470–476.

31. Lopez AD, Mathers CD, Ezzati M, Jamison D, Murray CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747–1757.

32. World Health Organization. The atlas of heart disease and stroke. Available at http://www.who.int/cardiovascular_diseases/resources/atlas/en/ (accessed 13 December 2009).

33. Mensah GA. Ischaemic heart disease in Africa. Heart 2008; 94: 836–843.

34. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In: Lopez AD, Mathers CD, Ezzati M, et al., eds. Global Burden of Disease and Risk Factors. New York, Washington, DC: Oxford University Press & The World Bank, 2006: 45–240.

35. Rao C, Lopez AD, Hemed Y. Causes of death. In: Jamison DT, Feachem RG, Makgoba MW, et al., eds. Disease and Mortality in Sub-Saharan Africa. 2nd edn. Washington, DC: The World Bank, 2006: 67–82.

36. Khalil S, Ibrahim-Khalil M, El Hag M, et al. Coronary event rates in Khartoum, Sudan. J Clinic Epidemiol 1996; 9: 1013–1010.

37. Böthig S. WHO MONICA Project: objectives and design. Int J Epidemiol 1989; 18(3 Suppl 1): S29–37.

38. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Circulation 1994; 90; 583–612.

39. Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transi-tion, risk factors, and impact of urbanization. Circulation 2001; 104: 2746–2753.

40. World Health Organization. Death and DALY estimates by cause, 2002.41. Available at http://www.who.int/entity/healthinfo/statistics/bodgbd-

deathdalyestimates.xls (accessed 6 December 2009).42. World Health Organization. STEPwise approach to surveillance

(STEPS) Sudan. Available at http://www.emro.who.int/ncd/media/excel/sudan.xls.

43. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 1999; 364: 937–952.

44. Sliwa K, Albertino D, Bongani M. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005; 112(23): 3577–3583.


45. Mayosi B. Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa. Heart 2007; 93: 1176–1183.

46. Ali SK. Endomyocardial fibrosis: an under-diagnosed cause of cardio-myopathy in Sudanese children. J Trop Pediatr 2009; 55(5): 343–346.

47. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experience at King Edward Hospital, Durban, South Africa and a review of litera-ture. Trop Doct 1995; 25: 118–123.

48. Davidson NM, Parry EH. Peri-partum cardiac failure. Q J Med 1978; 47(188): 431–461.

49. Khalil S, Gharieb K, El Haj M, Khalil M, Hakiem S. Prevalence of congenital heart disease among schoolchildren of Sahafa Town, Sudan. Eastern Med Hlth J 1997; 3: 24–28.

50. Caddell JL, Connor DH. Congenital heart disease in Ugandan children

Br Heart J 1966; 28(6): 766–767. 51. Gupta B, Antia AU. Incidence of congenital heart disease in Nigerian

children. Br Heart J 1967; 29: 906–910. 52. Antia AU. Congenital heart disease in Nigeria. Arch Dis Childhood

1974; 49: 36–39. 53. Mitchell SC, Korones SB, Berendes HW. Congenital heart disease

in 56109 births: incidence and natural history. Circulation 1971; 43: 323–329.

54. Kenna AP, Smithells RW, Fielding DW. Congenital heart disease in Liverpool. Q J Med 1975; 44(173): 17–44.

55. El Hag AI. Pattern of congenital heart disease in Sudanese children. East Afr Med J 1994; 71(9): 580–586.

56. Sulafa KM, Karani Z. Diagnosis, management and outcome of heart disease in Sudanese patients. East Afr Med J 2007; 84(9): 434–440.

answer

William nelson ECg Quiz

This is a beautiful example of ‘concealed events’. Strip A: after four sinus beats, the P waves disappear, allowing the emergence of an escape ventricular focus after 1.76 sec.

This might simply be ‘sinus arrest’. A more romantic and attractive explanation is that there is ‘sino-atrial exit block’ and although ‘concealed’, the SA node continues to discharge, but the signal is unable to escape from the sinus node ‘island’. The measured pauses between the P waves represent reasonable multiples of the basic sinus cycle.

Strip B: sinus bradycardia of 40/min has developed. Due to the default of the sinus node, a junctional pacemaker awakens at 52/min to activate the heart. The dissociated P waves ‘leapfrog’ over the junctional complexes and have three fates: 1. When the interval due to the junctional discharge and the following P wave (R-P interval) is short (P waves 3 and 5), the atrial stimulus is blocked high in the AV junction. 2. When the R-P interval is longer (P waves 1 and 4), the stimulus is able to traverse the AV junction, but it is conducted with LBBB aberration.3. When the R-P interval is intermediate (P waves 2 and 6) the atrial stimulus penetrates lower into the AV junction. Although it is not transmitted to the ventricles, the signal reaches the site of the junctional pacemaker and resets it. This is an example of ‘anterograde concealed conduction’.


Case reports

Progressive human immunodeficiency virus-associated vasculopathy: time to revise antiretroviral therapy guidelines? NBA NTuSI, D TAyLOR, NG NAIDOO, M MENDELSON

abstractCardiovascular abnormalities were appreciated early in the epidemic of the acquired immunodeficiency syndrome (AIDS), even before the aetiological agent, human immuno-deficiency virus (HIV) was isolated and characterised. The aetiology and pathogenesis of cardiovascular disease in HIV infection is still the subject of intense speculation, and is likely multi-factorial. HIV affects every aspect of the cardiac axis, causing pericarditis, myocarditis, cardiomyopathy, coro-nary artery disease and microvascular dysfunction, valvu-lar heart disease, pulmonary vascular disease and pulmo-nary hypertension, stroke and peripheral vascular disease. HIV-associated vasculopathy is an increasingly recognised clinical entity, causing high morbidity and increasing mortal-ity in southern Africa, particularly from stroke and cardio-vascular disease. HIV causes disease of the vascular tree, either by a direct effect on vascular or perivascular tissue, or indirectly via immune complex-mediated mechanisms, asso-ciated opportunistic infections and malignancies. As a result, highly active antiretroviral therapy (HAART) may have an important role in controlling disease progression. We report a case of histologically defined primary HIV vasculopathy in which the chance to start HAART was initially missed and in which the patient progressed to require bilateral amputa-tions, but obtained disease quiescence upon commencement of HAART.

Keywords: human immunodeficiency virus, HIV-associated cardiovascular disease, HIV vasculopathy, highly active antiret-roviral therapy



DOI: 10.5830/CVJA–2010–048

Human immunodeficiency virus (HIV)-associated vasculopa-thy is an increasingly recognised, distinct clinico-pathological entity associated with significant morbidity and mortality in southern Africa. HIV itself causes vascular disease, either by a direct effect on vascular or perivascular tissue, or indirectly via immune complex-mediated mechanisms.1 As a result, highly active antiretroviral therapy (ART) may have an important role in controlling disease progression. We report on a case of histo-logically defined primary HIV-associated vasculopathy in which the opportunity to commence ART was missed and in which the patient progressed to bilateral lower limb amputations.

Case reportA 24-year-old woman was referred to the vascular surgical unit at Groote Schuur Hospital, with critical limb ischaemia (CLI) involving the left lower limb. She presented with a five-week history of ischaemic rest pain and early tissue necrosis involving the left first toe. Approximately six months previously, she had had a right below-the-knee amputation, performed at the refer-ring hospital for CLI, associated with major tissue necrosis, at which time the surgical specimen was not submitted for histo-logical assessment.

She had had pulmonary tuberculosis in childhood, subse-quently complicated by bronchiectasis and pulmonary hyperten-sion. She remained well until her pregnancy two years earlier, when she was diagnosed with HIV infection with a CD4 T-cell count of 529 cells/µl. She received a single dose of nevirapine at the onset of labour for prevention of mother-to-child transmis-sion of HIV. Her alcohol intake was 16 units/day on weekends, and she had smoked 15 to 30 cigarettes/day for six years.

Examination revealed absent pulses in the left lower limb, consistent with left femoro-popliteal disease. This was confirmed on duplex arteriography, which revealed occluded left distal superficial femoral artery, popliteal artery, popliteal trifurcation and all three crural arteries. Peripheral angiography demonstrat-ed similar findings with reconstitution of the left retromaleolar posterior tibial artery and tarsal arteries. An exhaustive search for alternative causes of vasculopathy, including autoimmune and infectious causes of vasculitis, hypercoagulable states and treatable causes of accelerated atherosclerosis were negative.

Cardiac Clinic, department of Medicine, groote schuur hospital and university of Cape town, south africaNBA NTuSI, FCP (SA), [email protected]

national health laboratory service, division of anatomical Pathology, groote schuur hospital and university of Cape town, south africaD TAyLOR, MMed

division of vascular surgery, department of surgery, groote schuur hospital and university of Cape town, south africaNG NAIDOO, FCS (SA)

division of infectious diseases and hiv Medicine, department of Medicine, groote schuur hospital and university of Cape town, south africaM MENDELSON, FRCP (uK), PhD


Fig. 1. a: low-power view showing a thickened vessel wall and prominent adventitial capillaries; B: high-power view of the previous section; C: a different specimen with Elastin van gieson stain showing reduplication of the lamina; d: specimen with alcian Blue stain showing mucopolysaccharide; E: higher power of previous section showing muco-polysaccharide in vessel wall; F: Elastin van gieson stain showing fragmented stromal collagen; g: showing inflam-mation of the capillaries of the adventitia; and h: another view of the inflamed adventitial capillaries.

a B

C d

E F

g h


Her CD4 T-cell count had declined to 331 cells/µl and HIV viral load was 60 000 copies/ml (log10 4.78).

We performed a left pedal artery bypass using a non-reversed, valve ablated, great saphenous vein and a first toeectomy. She was discharged 10 days post-operatively with a functioning graft and a viable left foot. Work-up for ART was begun in hospital, but she failed to return to clinic to start antiretrovirals.

She presented five months later with an occluded graft, secondary to sepsis involving the left leg, and an ischaemic left foot. There was no significant change in her CD4 T-cell count. Her HIV viral load had risen to log10 5.7. Causes of vasculopathy and pro-coagulant state other than HIV were again ruled out. A left above-the-knee amputation was performed, with an unevent-ful post-operative course. She was commenced on antiretroviral therapy as an inpatient without adverse effects.

Histological review of operative specimens showed no evidence of atherosclerosis, thrombosis or aneurysms. The small muscular arteries were thickened (Fig. 1A, B), with reduplication of the elastic lumina (Fig. 1C) and mucopolysaccharide deposi-tion in the adventitia (Fig. 1D, E). Some fragmentation of the tropocollagen was identified (Fig. 1F) and neovascularisation of the media was noted. There was no obvious vasculitis of the large vessels, but the adventitia revealed numerous capillaries (not slit-like) (Fig. 1G, H), and inflammation of the vaso vasorum, with abundant lymphocytes and plasma cells. These findings have previously been associated with HIV-associated vasculopathy.2

discussionThe clinical entity of HIV-associated vasculopathy encompasses a spectrum of conditions occurring in HIV-infected persons, including cardiovascular disease, cerebrovascular disease, arte-rial aneurysms, peripheral arterial occlusive disease, acute limb ischaemia, and deep-vein thrombosis. The initial description of this ‘distinctive arteriopathy’ by Joshi and colleagues in 1987, emanated from observations on histological specimens from children with advanced immunosuppression, showing vascu-lopathy with small and medium-size vessel involvement, intimal fibrosis, peri-vasculitis, fragmentation of elastic tissue and medial fibrosis and calcification.3

HIV-associated vasculopathy tends to affect young patients at an estimated prevalence of 0.19 to 23%.4,5 Its epidemiology remains largely unresolved, as the majority of studies are hospi-tal-based and therefore not reliably representative of prevalence and incidence in the general population. Any part of the vascular tree can be involved, but skin, central nervous system, skel-etal muscle, lung, kidney and peripheral nerves are commonly

affected.6 Clinical features are specific to the vascular territory involved, but typically manifest as either stroke, cardiomyopathy, pulmonary hypertension, HIV-associated nephropathy or periph-eral arterial disease in young patients, predominantly under 55 years of age.7

The aetiology and pathogenesis of HIV-associated vascu-lopathy is considered to be multi-factorial. Evidence for direct infection of the endothelium by HIV, and both humoral and cell-mediated immune injury to the vessels, leading to insidious or rapid damage to large elastic vessels has been proposed.2,8,9 HIV-associated vasculopathy involves an exclusively T-cell lymphocytic infiltrate with oligoclonal expansion of CD8

+ T cells that release super antigens, vascular adhesion molecules, immune complexes, growth factors and cytokines that mediate inflammation and vascular damage.10

Others have reported on the preponderance of CD3+ CD8

+ T cells in autopsy specimens of patients with HIV-associated vasculopathy, and have argued that it is the HIV-related immune aberration that leads to abundant CD3

+ CD8+ T cells that are large-

ly responsible for mediating HIV-associated vasculitis and vascu-lopathy through accelerated endothelial cell injury.11 Vascular injury caused by a prothrombotic state, malignant atrophic papulosis, thrombotic micro-angiopathy, systemic vasculitis or vasculopathy, and arteriolar para-amyloid deposition has also been identified.12

Histopathologically, large elastic arteries reveal multiple aneurysms, occlusions, and areas of stenosis, with no evidence of atherosclerosis. Microscopically, a leukocytoclastic vasculitis of the vasa vasora and peri-adventitial vessels has been demon-strated, with fragmentation of the tropocollagen, as was evident in our case. Interestingly, there is minimal inflammation of the media, but with a consistent finding of calcification of the inter-nal elastic lumina.2 Chetty was the first to describe the various histological sub-types of the vasculopathy associated with HIV infection (Table 1).2 A commonly utilised classification system for HIV vasculopathy and other rare HIV-associated vasculitides has been proposed by Johnson and colleagues (Table 2).13

TABLE 1. HISTOLOGICAL SUB-TYPES OF THE VASCULOPATHY ASSOCIATED WITH HIV

1. Specific infective agents (cytomegalovirus, tuberculosis, syphilis etc)

2. Polyarteritis nodosa-like necrotising vasculitis3. Hypersenstivity vasculitis (Henoch-Schonlein purpura, drugs,

cryoglobulins)4. Angiocentric immunoproliferative vasculitis (benign lymphocytic

angiitis, lymphoma)5. Granulomatous small-vessel vasculitis/primary CNS angiitis6. Large-vessel vasculitis/vasculopathy7. Non-specific vasculitidies

From Chetty R. Vasculitides associated with HIV infection. J Clin Pathol 2001; 54: 275–278 (with permission).

TABLE 2. A CLASSIFICATION SYSTEM FOR HIV-ASSOCIATED VASCULITIS/VASCULOPATHY

Group I Vasculitides that are well described in the non-HIV popu-lation and coincidentally occur in HIV-infected people (e.g. Takayasu’s arteritis, temporal arteritis, Behcet’s syndrome, Henoch-Schonlein purpura)

Group II Vasculitides related to adverse effects of drugs (including antiretroviral drugs and cotrimoxazole)

Group III Vasculitides related to known infectious agents that are more common in immunosuppression (e.g. cytomegalo-virus, Toxoplasma gondii, Pneumocystis jirovechii pneu-monia, hepatitis B)

Group IV Vasculitides that appear to have an association with HIV, have unusual clinical presentations that do not fit into previously described disease entities, where HIV pathogenesis probably facilitates development, and have diverse histopathological features that do not represent a single disease entity (e.g. erythema elevatum diutinum, microscopic polyangitis, Kawasaki-like syndromes, primary angiitis of the central nervous system, acute occlusion syndromes)

Adapted from Johnson RM, Barbarini G, Barbaro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV-infected patients. AIDS 2003; 17(Suppl 1): S7–S82 (with permission).


Management of HIV-associated vasculopathy requires a multi-disciplinary approach, with HIV physicians working hand in hand with vascular surgeons and rehabilitation specialists. Modification of vasculopathy risk is clearly important for secondary prophylaxis and includes administration of anti-plate-let therapy, angiotensin converting enzyme inhibition, and lipid-lowering therapy. There is no current evidence to support a role for corticosteroids or other immunosuppressants in the manage-ment of HIV-associated vasculopathy. A role for thrombolytic therapy in the acute setting has been proposed.14 Definitive surgi-cal management will depend on the manifest vascular pathology, and includes aneurysm repair, transcatheter embolisation, bypass procedures, endovascular procedures, thrombo-embolectomy, and/or amputation.

HIV-associated vasculopathy is not part of the WHO or CDC staging systems that are commonly used to define who is eligi-ble to receive ART. We believe that ART forms an essential part of therapy to prevent disease progression, irrespective of CD4 T-cell count, and propose that HIV vasculopathy be identified as a WHO stage IV diagnosis, in keeping with such entities as HIV-associated nephropathy and HIV-associated cardiomyopathy.

The choice of antiretroviral regimen for patients with vascu-lopathy should take into account the propensity for individual antiretrovirals to induce dyslipidaemia and insulin resistance. Nucleoside and non-nucleoside reverse transcriptase inhibitor protease inhibitors (PI) can cause increases in total cholesterol, LDL cholesterol and triglycerides.15 PIs as a group are commonly associated with dyslipidaemia and insulin resistance, both of which are risk factors for arteriosclerosis.16 If PI-based ART is required, a once-daily atazanavir-based regimen may be prefer-able in patients with HIV-associated vasculopathy, as it carries a lesser risk of dyslipidaemia than other PIs.17,18

ConclusionWe report on a histologically confirmed case of HIV-associated vasculopathy in which the option to start early ART and to alter disease progression was missed. Given the overwhelming burden of HIV infection in southern Africa, clinicians need to have a heightened index of suspicion for making the diagnosis of HIV-associated vasculopathy in young patients presenting with peripheral arterial disease. Early commencement of ART in the management of this condition may contribute to improved clini-cal outcomes in HIV-infected individuals with HIV-associated vasculopathy.

References1. Mandell BF, Calabrese LH. Infections and systemic vasculitis. Curr

Opin Rheumatol 1998; 10: 51–57.2. Chetty R. Vasculitides associated with HIV infection. J Clin Pathol

2001; 54: 275–278.3. Joshi VV, Pawell B, Connor E, et al. Arteriopathy in children with

acquired immune deficiency syndrome. Pediatr Pathol 1987; 7: 261–275.

4. Klein SK, Slim EJ, de Kruif MD, et al. Is chronic HIV infection associ-ated with venous thrombotic disease? A systematic review. Neth J Med 2005; 63: 129–136.

5. Gherardi R, Belec L, Mhiri C, et al. The spectrum of vasculitis in human immunodeficiency virus-infected patients. A clinicopathologi-cal evaluation. Arthritis Rheum 1993; 36: 1164–1174.

6. Naidoo NG, Beningfield SJ. Other manifestations of HIV vasculopathy. South Afr J Surg 2009; 47: 46–53.

7. Nair R, Robbs JV, Chetty R, et al. Occlusive arterial disease in HIV-infected patients: a preliminary report. Eur J Vasc Endovasc Surg 2000; 20: 235–240.

8. Cid MC. New developments in the pathogenesis of systemic vasculitis. Curr Opin Rheumatol 1996; 8: 1–11.

9. Potashner W, Buskila D, Patterson B, et al. Leukocytoclastic vasculitis with HIV infection. J Rheumatol 1990; 17: 1104–1107.

10. Barbaro G. Pathogenesis of HIV-associated heart disease. AIDS 2003; 17(Suppl 1): S12–S20.

11. Katsetos CD, Fincke JE, Legido A, et al. Angiocentric CD3+ T cell infiltrates in human immunodeficiency virus type-1 associated central nervous system disease in children. Clin Diagn Lab Immunol 1999; 6: 105–114.

12. Terada LS, Gu Y, Flores SC. AIDS vasculopathy. Am J Med Sci 2000; 320: 379–387.

13. Johnson RM, Barbarini G, Barbaro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV-infected patients. AIDS 2003; 17(Suppl 1): S77–S82.

14. Bush RL, Bianco CC, Bixler TJ, et al. Spontaneous arterial thrombosis in a patient with human immunodeficiency virus infection: successful treatment with pharmacomechanical thrombectomy. J Vasc Surg 2003; 38: 392–395.

15. Bedimo R. Body-fat abnormalities in patients with HIV: progress and challenges. J Int Assoc Physicians AIDS Care (Chic III) 2008; 7: 292–305.

16. Venter WDF, Sanne IM. The cardiovascular consequences of HIV and antiretroviral therapy. Cardiovasc J South Afr 2003; 14: 225–229

17. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE Study. J Acquir Immune Defic Syndr 2009 Dec 23. [Epub ahead of print]

18. Hammer SM. Management of newly diagnosed HIV infection. N Eng J Med 2005; 353: 1702–1710.


subclavian crush syndrome: a cause of pacemaker lead fractureF FEMENIA, JCL DIEZ, M ARCE, A BARANChuK

abstractA 48-year-old male with a symptomatic 2:1 atrio-ventric-ular block and a dual-chamber pacemaker, implanted one year previously, was admitted due to a syncopal episode. Pacemaker malfunction was identified as the cause of syncope. Subclavian crush syndrome was the cause of the pacemaker malfunction. Its incidence, consequences and management are discussed in this report.

Keywords: Subclavian crush syndrome, pacemaker lead, lead fracture



DOI: 10.5830/CVJA–2010–052

Various techniques for pacemaker implantation are universally used. A number of different methods for venous access are used for permanent pacemaker implantation, of which subclavian vein puncture using Seldinger’s technique is the most frequent.1 Subclavian crush syndrome is a well-described cause of pace-maker lead failure. It usually occurs after medial intrathoracic puncture of the subclavian vein and results in damage to the pacemaker lead body by entrapment within the costoclavicular ligament and/or the subclavian muscle.2

We present a case of a subclavian crush syndrome that occurred one year after dual-chamber pacemaker insertion using the subclavian puncture technique.

Case reportA 48-year-old male with a prior history of positive serology for Chagas’ disease, symptomatic 2:1 atrio-ventricular block and a dual-chamber pacemaker (Identity DR 5386, St Jude Medical, atrial lead: Tendril 1688 TC, ventricular lead: Isoflex 1646 T), implanted one year ago, was admitted due to a syncopal episode. Cardiac monitoring evidenced pacemaker dysfunction and fail-ure of capture (Fig. 1A).

Fluoroscopy revealed ventricular lead fracture below the clav-icle (Fig. 1B, white arrow). A venography ruled out subclavian vein obstruction (Fig. 1B). The fractured lead was abandoned and a new ventricular lead was implanted with no complications,

unidad de arritmias, departamento de Cardiología, hospital Español de Mendoza, argentinaF FEMENIA, MD, [email protected] ARCE, MD

arrhythmia service, Kingston general hospital, Queen’s university Kingston, ontario, CanadaJCL DIEZ, MD A BARANChuK, MD, FACC

using the same vein and puncturing more distally. The patient was discharged the following day.

discussionSubclavian vein puncture is usually performed for pacemaker implantation. Although this approach offers high success rates and low incidence of major complications, it has been associated with lead fracture (coil fracture or insulation damage) at stress points in the costoclavicular region.1 Subclavian crush syndrome is a well-described cause of lead fracture, resulting from lead (or leads) entrapment between the clavicle and the first rib following subclavian vein puncture.2-4 Its prevalence is up to 7% depending on the series.1 Injuries are more frequent if both leads are intro-duced via a single venous puncture. Cephalic vein dissection has been demonstrated to reduce the prevalence of complications associated with subclavian vein puncture.

Magney et al. have described a modification of the usual tech-nique in order to avoid entrapment of the leads in the subclavius muscle, the costocoracoid ligament, or the costoclavicular ligament (the catheters could be stressed with the movement of the ipsilateral upper extremity).5 This approach consists of introducing the lead or catheter into the subclavian vein near the lateral border of the first rib (extrathoracic segment). This type of placement avoids soft-tissue entrapment. Three years after this report, the same group reported a follow up on 461 patients who underwent pacemaker implantation using the described approach without having a single crush syndrome.6

In the presented case, there was not only compression of the electrodes between the clavicle and the rib, but also compression of the electrodes against each other, causing further erosion.

ConclusionSubclavian crush syndrome is a well-known cause of lead damage. Subclavian punctures performed too medially may increase the risk of this complication. Proper pacemaker follow up should be done in order to minimise the consequences of lead failure, particularly in the setting of pacemaker dependency.

References1. Gallik DM, Ben-Zur UM, Gross JN, Furman S. Lead fracture in

cephalic versus subclavian approach with transvenous implantable cardioverter defibrillator systems. Pacing Clin Electrophysiol 1996; 19: 1089–1094.

2. Erdoğan O, Aktoz M. Pacemaker lead failure due to crush injury. Anadolu Kardiyol Derg 2007; 7(4): 438–440.

3. Weiner S, Patel J, Jadonath RL, Goldner BG, Gross JN. Lead fail-ure due to the subclavian crush syndrome in a patient implanted with both standard and thin bipolar spiral wound leads. Pacing Clin Electrophysiol 1999; 22(6 Pt 1): 975–976.

4. Vyselaar JR, Michael KA, Nolan RL, Baranchuk A. Left subclavian vein occlusion after pacemaker insertion. Cardiovasc J Afr 2008; 19(3): 155.


5. Magney JE, Staplin DH, Flynn DM, Hunter DW. A new approach to percutaneous subclavian venipuncture to avoid lead fracture or central venous catheter occlusion. Pacing Clin Electrophysiol 1993; 16(11):

2133–2142.6. Magney JE, Alder S. New approach to subclavian venipuncture. Pacing

Clin Electrophysiol 1996; 19(5): 877.

Fig. 1. a. rhythm strip: appropriate atrial sensing and capture, failure of ventricular capture. B. Fluoroscopy (antero-posterior view): lead fracture (white arrow). the subclavian vein is patent.

B

a


diagnosis of a congenitally corrected transposition of the great arteries in a 50-year-old multiparous womanR JALALIAN, S MASOuMI, A GhAEMIAN

abstract Congenitally corrected transposition of the great arteries (cc-TGA) is a rare congenital heart disease. In the literature, few patients with this anomaly have been reported to be asymptomatic until after the fifth decade. We describe a 50- year-old female with five pregnancies and successful deliver-ies, who was unrecognised until late in her fifth decade.

Keywords: congenitally corrected transposition of great arteries, cc-TGA, congenital heart disease, pregnancy



DOI: 10.5830/CVJA–2010–053

Congenitally corrected transposition of the great arteries (cc-TGA) accounts for less than 1% of all congenital heart diseases.1 This anomaly is characterised by atrio-ventricular and ventriculo-arterial discordance.2 Associated anomalies occur in up to 95% of patients and consist of ventricular septal defect (VSD) (75%), pulmonary artery or subpulmonary artery stenosis (75%), and left-sided valve anomaly (> 75%) (tricuspid and often Ebstein like).

About 5% of patients with cc-TGA are born with a congenital heart block and acquire complete atrio-ventricular block at a rate of 2% per year.3 In addition, they may have an abnormality in the anatomy of their coronary artery, including a left coronary artery ostium over the commissure, a single left coronary artery from the right anterior sinus, the anterior descending artery coming off the right coronary artery, a circumflex ostium over the commissure, both ostia from the posterior sinus, an eccentric left coronary artery, a conal branch of the left coronary artery, or the conal artery near the left coronary artery.4

Although patients with no associated defects theoretically have a normal life span, few with this lesion survive 40 years because of associated congenital defects or the subsequent devel-opment of atrio-ventricular (AV) valvular insufficiency and/or heart block.5 Patients without any associated defects (< 5%) may be asymptomatic until late in adulthood. Dyspnoea and exercise intolerance resulting from systemic ventricular dysfunction and left-sided AV valve regurgitation most often appear from the fourth decade of life.

Case reportA 50-year-old woman with exertional dyspnoea and a history

of diabetes mellitus was referred to us to evaluate for coronary artery disease. She was married and had had five children with-out any major problems during her pregnancies. The patient was in NYHA class I to II and had not been on any medical treat-ment for her new symptoms. On physical examination, systolic murmurs (grade II/VI) were heard.

Electrocardiography (ECG) showed an initial Q wave in the right precordial leads without any Q wave in the left precordial leads. Also, our patient did not have any evidence of pre-exci-tation on surface ECG. An exercise tolerance test (ETT) was performed, but the patient had exertional dyspnoea in the early phase of stage II, so it was terminated before reaching the opti-mal heart rate (ETT with Bruce protocol, 4 METS).

With transthoracic echocardiography (TTE), prominent trabeculations and a moderate band in the left ventricle, with apical displacement of the left AV valve was seen (Figs 1, 2). The great vessels were in parallel and side by side. The aorta originat-ed from the left ventricle (morphological right ventricle), being left and anterior to the pulmonary artery (Fig. 3). The systemic ventricle (morphological right ventricle) had moderate dysfunc-tion and the left AV valve had mild-to-moderate regurgitation.

Transoesophagial echocardiography (TEE) was performed for optimal evaluation and showed drainage of all pulmonary veins into the left atrium (AV discordance) and ventriculo-arterial discordance. A 3-mm patent foramen ovale with right-to-left shunt was seen after injecting agitated saline via the right arm.

We also performed computed tomography (CT angiography) for assessment of the coronary arteries and to confirm the diag-nosis. Two separate right and left coronary arteries without any apparent lesions or anomalies and an anteriorly located aorta arising from a trabeculated ventricle were visualised (Figs 4, 5).

discussionLife expectancy of patients with cc-TGA without associated

Cardiovascular department, Mazandaran university of Medical sciences, sari, iranR JALALIAN, MDA GhAEMIAN, MD

Mazandaran university of Medical sciences, artesh Blvd, sari, iranS MASOuMI, MD, [email protected] Fig. 1. hypertrabeculated left ventricle (physiological

right ventricle) apically displaced, and left av valve.


anomalies depends on the systemic ventricular function.6 At an older age, the incidence of systemic ventricular dysfunction and clinical congestive heart failure increases, even in patients without concomitant anomalies. It has been reported that more than one-third of these patients will suffer from congestive heart failure by the fifth decade.7 In addition, the morphological right ventricle has an inherent vulnerability to developing failure and there is a complex relationship between systemic ventricu-lar dysfunction and the severity of AV valve regurgitation. Therefore, surgery should be considered for significant AV valve regurgitation before the appearance of irreversible ventricular dysfunction.8

With cc-TGA, coronary anomalies are occasionally present, so evaluation of these coronary anomalies (origin, course and distribution) is recommended.9 Since our patient had only mild symptoms and her AV valve regurgitation was also mild to moderate, we prefer to follow her up periodically.

References1. Webb GD, Mc Laughlin. PR, Gow RM, et al. Transposition complexes.

Cardiol Clin 1995; 11: 651–664. 2. Presbitero P, Somerville J, Rabajoli F, Stone S, Conte MR. Corrected

transposition of the great arteries without associated defects in adults patients: clinical profile and follow up. Br Heart J 1995; 74: 57–59.

3. Libby P, Bonow RO, Mann DL, Zieps DP. Braunwald’s Heart Disease.

8th edn. Philadelphia: Saunders, 2008: 1602.4. Ismat F, Baldwin H, Karl T, Weinberg P. Coronary artery in congenitally

corrected transposition of the great arteries. Int J Cardiol 2002; 86: 207–216.

5. Lieberson AD, Schumacher RR, Childress RH, Genovese PD. Corrected transposition of the great vessels in a 73-year-old man. Circulation 1969; 39: 96–100.

6. Carole A Warnes. Transposition of the great arteries. Circulation 2006; 114: 2699–2709.

7. Warnes CA. The adult with congenital heart disease: born to be bad? J Am Coll Cardiol 2005; 46: 1–8.

8. Graham TP (Jr), Parrish MD, Boucek RJ (Jr), Boerth RC, Breitweser JA, et al. Assessment of ventricular size and function in congeni-tally corrected transposition of great arteries. Am J Cardiol 1983; 51: 244–251.

9. Van Son JA, Danielson GK, Huhta JC, Warnes CA, Edwards WD, Schaff HU. Late results of systemic atrioventricular valve replacement in corrected TGA. J Thorac Ccardiovasc Surg 1995; 109: 642–652.

Fig. 3. Parallel great vessels with aorta anterior and on the left side.

Fig. 5. Ct angiography showing the aorta arising from the trabeculated right ventricle.

Fig. 4. Ct angiography showing anteriorly located aorta.

Fig. 2. hypertrabeculated left ventricle with moderate band (physiological right ventricle loop).


Cardiogenic shock due to dynamic left ventricular outflow tract obstruction of acute myocardial infarction: an under-diagnosed complicationCy KARABAy, G KOCABAy, A KALAyCI, h TANBOGA, M MERT, C KIRMA

abstractWe report on a patient who developed cardiogenic shock caused by dynamic left ventricular outflow tract (LVOT) obstruction following percutaneous coronary intervention for anteroseptal acute myocardial infarction.

Keywords: dynamic left ventricular outflow tract obstruction, myocardial infarction, shock, esmolol


Published online: 10/1/11


DOI: 10.5830/CVJA–2010–051

Acute dynamic left ventricular outflow tract (LVOT) obstruction has been reported as a complication of myocardial infarction.1 The incidence of this obstruction is unclear and it may well be under-diagnosed. This mechanical complication of myocardial infarction should be ruled out since the treatment of this condi-tion differs completely from that of acute coronary syndrome.

Case reportA 60-year-old male patient with no known disorder was admit-ted to the emergency deparment of our hospital for chest pain of three hours’ duration. He also complained of angina following effort over the last month. Physical examination showed that his blood pressure was 140/80 mmHg and pulse rate was rhythmical and 90 beats/minute. His other body systems were normal.

The ECG investigation showed anteroseptal myocardial infarction. He was taken to the catetherisation laboratory and angiography revealed that he had 100% obstruction in the proximal portion of the left anterior descending artery (LAD). A 3.0 × 20-mm bare-metal stent was placed in the lesioned vessel following a 2.0 × 20-mm balloon application. Thrombolysis in myocardial ınfarction (TIMI) 3 flow was achieved.

The patient developed dyspnoea one hour after the stent was placed. He became pale and hypothermic; his blood pressure was 70/40 mmHg and pulse rate 130 beats/minute. His physical

Kartal Kosuyolu yuksek ihtisas heart Education and research hospital, department of Cardiology, istanbul, turkeyCy KARABAy, MDG KOCABAy, MD, [email protected] KALAyCI, MDh TANBOGA, MDC KIRMA, MD

Kayseri Educational and research hospital, department of Endocrinology and Metabolism, Kayseri, turkey.M MERT, MD

examination revealed a new holosystolic ejection murmur, grade 3/6 in the apical area, with radiation to the axillary artery.

Transthoracic echocardiography was performed to exclude possible mechanical complications. Echocardiography revealed anterior anteroseptal hypokinesia, systolic anterior motion of the anterior leaflet of the mitral valve and mild mitral regurgitation. The ejection fraction was 35%. Doppler examination revealed the LVOT gradient to be a maximum gradient of 51 mmHg (Fig. 1).

Under close monitoring, intravenous fluids and esmolol were initiated. With reduction of the heart rate to below 70 beats/min, the murmur and other symptoms disappeared. After two hours, echocardiography was repeated and showed no LVOT obstruction. The patient was subsequently discharged in a stable condition.

discussionThe reason for a dynamic LVOT obstruction in the presence of acute coronary syndrome is usually due to compensated hyper-dynamic basal wall motion in patients with antero-apical infarc-tion. Hyperdynamic basal wall motion causes decreased LVOT cross-sectional area.3

The treatment of this situation is different from that for myocardial infarction. The use of vasodilators (nitrates), inotrop-ic agents (dopamine, epinephrine, dobutamine), intra-aortic balloon pump and volume depletion are contraindicated. Utilising alpha-agonists, beta-blockers and intravenous fluids reduces the gradient.1 Beta-blockers may help by decreasing hyperkinesis of the basal segments and decreasing the left ventricular gradi-ent and hypotension.4 In the present case, since the patient was hypotensive, we administered esmolol because of its rapid onset and very short duration of action.

Fig. 1. doppler examination showed the lvot gradient to be a maximum of 51 mmhg.


ConclusionDynamic LVOT obstruction may be encountered as a severe complication during acute coronary syndromes. In the case of extensive anterior ischaemia, even if mechanical reperfusion is performed, a Doppler echocardiogram should be obtained for the outflow tract velocity if the clinical status is deteriorating or not improving. If Doppler investigation determines the presence of a dynamic LVOT obstruction, the beta-blocker esmolol can be used.

References1. García Quintana A, Ortega Trujillo JR, Padrón Mújica A, et al.

Cardiogenic shock due to dynamic left ventricular outflow tract obstruction as a mechanical complication of acute myocardial infarc-tion. Rev Esp Cardiol 2002; 55:1324–1327.

2. Bartunek J, Vanderheyden M, de Bruyne B. Dynamic left ventricu-lar outflow tract obstruction after anterior myocardial infarction. A potential mechanism of myocardial rupture. Eur Heart J 1995; 16: 1439–1442.

3. Hrovatin E, Piazza R, Pavan D, et al. Dynamic left ventricular outflow tract obstruction in the setting of acute anterior myocardial infarction: a serious and potentially fatal complication? Echocardiography 2002; 19: 449–455.

4. Haley JH, Sinak LJ, Tajik AJ, et al. Dynamic left ventricular outflow tract obstruction in acute coronary syndromes: an important cause of new systolic murmur and cardiogenic shock. Mayo Clin Proc 1999; 74: 901–906.

snake-like thrombus in the right atrium causing pulmonary embolismCY KARABAY, G KOCABAY, A KALAYCİ, R ZEHİR, M MERT, C KİRMA

abstractIn this report, we present a case of an 84-year-old woman treated with a low-dose prolonged infusion of tissue plas-minogen activator (tPA) for a free-floating thrombus in the right atrium.

Keywords: thrombus, thrombolysis, echocardiography


Published online: 10/12/10


DOI: 10.5830/CVJA–2010–060

Free-floating right-heart thrombi can be seen in four to 18% of patients presenting with acute pulmonary embolism.1 Most are found in the right atrium and half have a mobile worm- or snake-like structure.2 Although right atrial thrombo-embolism is rare, it should be considered a cardiological emergency that could cause death by massive pulmonary or paradoxical embolism.3 The presence of a right-heart thrombus increases the risk of mortal-

Kartal Kosuyolu yuksek ihtisas heart Education and research hospital, department of Cardiology, istanbul, turkeyCy KARABAy, MDG KOCABAy, MD, [email protected] KALAYCİ, MDR ZEHİR, MDC KİRMA, MD

Kayseri Educational and research hospital, department of Endocrinology and Metabolism, Kayseri, turkeyM MERT, MD

ity compared to the presence of a pulmonary thrombo-embolus alone. Despite this, the optimal management of right-heart thrombo-emboli remains unclear.4

Case reportAn 84-year-old woman with chronic obstructive lung disease and chronic atrial fibrillation was admitted to our hospital for new-onset dyspnoea and palpitations. On physical examination, she had an irregular pulse of 110 beats/min and her blood pressure was 120/75 mmHg. She was dyspnoeic with a respiratory rate of 25 breaths per minute. Her temperature was 36.5°C. She had normal heart sounds except for a 3/6 pansystolic murmur in the tricuspid area, and her lung fields were clear. There was clinical evidence such as swelling and pain, indicating right deep-venous thrombosis.

The electrocardiogram showed atrial fibrillation. The plasma D-dimer level was > 5 000 ng/ml (normal < 500 ng/ml) and the BNP level was 990 ng/ml (normal < 150 ng/ml). Arterial blood gas measurement drawn in room air showed oxygen saturation of 92%, pH 7.40, partial pressure of carbon dioxide 35 mmHg and of oxygen 60 mmHg. A Doppler ultrasonography revealed right femoral deep-vein thrombosis.

We performed transthoracic echocardiography, which showed enlargement of the right atrium and a snake-like mobile mass, moving during systole and diastole into the right ventricle and atrium. The main pulmonary artery and its branches were clear. Doppler examination showed moderate tricuspid regurgitation and pulmonary artery hypertension (pulmonary artery systolic pressure of 50 mmHg) (Fig. 1).

The laboratory findings and her clinical situation were consist-ent with a diagnosis of acute pulmonary embolism. Although she was not hypotensive, and transthoracic echocardiography did not


show any thrombus in the main pulmonary artery or its branches, we decided to initiate thrombolytic therapy because of the high risk of the massive embolus. We administered a prolonged low-dose of recombinant tissue plasminogen activator (tPA) because of her advanced age.

After six hours of 50-mg tPA infusion, control echocardi-ography showed the thrombus was completely resolved, with clinical and haemodynamic improvement (Fig. 2). There after we administered a heparin infusion, followed by warfarin therapy. On the third day, she was discharged on warfarin treatment with sufficient INR levels.

discussionIn this report, we present an elderly patient with mobile, snake-like right atrial thrombus leading to pulmonary embolism. Snake-like thrombus is extremely mobile and patients with this shaped thrombus have a very poor prognosis, with a 45% mortal-ity rate.5

There is no generally accepted therapeutic choice. Although embolectomy is a frequently proposed treatment, Pierre-Justin et al.6 showed in a prospective study that thrombolytic therapy with tPA appeared to be rapidly effective in most patients, result-ing in complete resolution of the thrombus. Thrombolysis is also advantageous for intra-cavity thrombus, for the pulmonary pole and for deep-vein thrombosis. There is no consensus on the thrombolytic dose or the protocol of the therapy, but the

most common dose administered is 100 mg tPA over a two-hour infusion.5,7 Pierre-Justin et al.6 administered lower-dose tPA with more prolonged infusions.

In this case, we used low-dose tPA in a prolonged infusion because of the patient’s advanced age. With echocardiographic visualisation of the right atrial thrombus, we could monitor it and stop the thrombolytic therapy when the thrombus had resolved. With this strategy we could avoid complications caused by the thrombolytics.

References1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clin-

ical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–1389.

2. Lasing E, Weber T, Auer J, et al. Uncommon electrocardiogram in a patient with right atrial thrombus and pulmonary embolism. Int J Cardiol 2005; 103: 345–347.

3. Colletta M, Paoloni P, Ciliberti D, et al. Right atrial thrombosis and pulmonary embolism: role of echocardiography. Minerva Cardioangiol 1997; 45: 439–442.

4. Janssens U, Klues HG, Hanrath P. Successful thrombolysis of right atrial and ventricle thrombi in a patient with peripartum cardiomyopa-thy and extensive thromboembolism. Heart 1997; 78: 515–516.

5. Peláez JB, de Miguel EM, Moreno RS, et al. Right-atrial floating thrombus attached to the interatrial septum with massive pulmonary embo-lism diagnosed by echocardiography. Int J Cardiol 2008; 131: 125–127.

6. Pierre-Justin G, Pierard LA. Management of mobile right heart throm-bi: A prospective series. Int J Cardiol 2005; 99: 381–388.

7. Rose PS, Punjabi NM, Pearse DB. Treatment of right heart thromboem-boli. Chest 2002; 121: 806–814.

Fig. 2. resolution of the free-floating thrombus. ra: right atrium, rv: right ventricle, ao: aorta.

Fig. 1. apical four-chamber views of a snake-like throm-bus floating in the right atrium. ra: right atrium, rv: right ventricle, la: left atrium, lv: left ventricle. the thrombus is indicated with an arrow.


short Communication

the sensitivity of waist-to-height ratio in identifying children with high blood pressureBS MOTSWAGOLE, hS KRuGER, M FABER, JM VAN ROOyEN, Jh DE RIDDER

abstractWe determined the sensitivity of waist-to-height ratio (WHtR) as a marker for high blood pressure in children aged nine to 15 years (n = 1 131), from schools in the North West province, South Africa. Anthropometric and blood pressure measurements were taken. The sensitivity and specificity of the WHtR to identify children with high blood pressure were evaluated. At a cut-off value of 0.5, 7.9% of the girls and 3.4% of the boys had central adiposity. Thirteen per cent of the children were hypertensive. The optimal WHtR cut-off value to identify children with hypertension was 0.41 in both boys and girls. Positive correlations were observed between anthropometric indices. Using linear regression analyses, age and body mass index were significant predictors of high blood pressure in boys, while for girls it was height and weight. Results suggest that adopting a WHtR cut-off value < 0.5 could enhance the use of WHtR as a marker for high blood pressure in children.

Keywords: waist-to-height ratio, blood pressure, children, South Africa



DOI: 10.5830/CVJA–2010–062

Studies in both adults1,2 and children3-5 have suggested that waist-to-height ratio (WHtR) is more strongly associated with cardiovascular (CV) risk factors than body mass index (BMI). Several clinically relevant properties of the waist-to-height ratio have been pointed out, including its sensitivity as an early warn-ing of health risk and its simplicity for calculation. Also, it has been suggested that the same cut-off value may be used for both genders.6 Hence, it has been proposed as an alternative measure

for assessing central fatness in children on the basis that it is relatively age independent and that in normalising for growth, it might preclude the need for age-related reference charts.3,4,7 This index, however, is yet to be validated within the paediatric population.8

Previously, Ashwell and colleagues (1996)9 proposed an age-independent universal cut-off value of 0.5 for predicting CV risk. However, this value is yet to be tested to predict CV risk in children (Sung et al. 2008).10 This study was aimed at assessing the diagnostic accuracy of WHtR as a marker for future cardio-vascular events, such as high blood pressure in South African children, and whether WHtR could be used as a marker for high blood pressure.

MethodsThe study population consisted of 919 black South African children aged nine to 15 years, drawn from the THUSA BANA (Transition and Health during Urbanisation of South Africans; BANA, children) study, conducted between May 2000 and June 2001. All anthropometric measurements were taken according to standard methods11 by qualified anthropometrists using cali-brated apparatus.

Weight was measured to the nearest 0.1 kg on a calibrated electronic scale (Precision Health Scale) and height was meas-ured to the nearest 0.1 cm with a stadiometer calibrated using a steel measuring tape. Waist circumference (WC) was measured to the nearest 0.1 cm, half way between the superior ridge of the ilium and the lower border of the lowest floating rib, with a flexible Lufkin anthropometric steel tape.12 BMI was calculated by weight divided by height (m)2 and waist-to-height ratio was derived by dividing waist circumference (cm) by height (cm). The triceps and subscapular skinfolds were measured on the right side following standard techniques13 (Lohman, 1988), and were used to calculate percentage body fat using Boileau et al. (1985)14 formulae below:

Six to 11 years: (constant: boys = 3.4, girls = 1.4)% body fat = 1.35 (sum of triceps + subscapular skinfold) – 0.012 (sum of triceps + subscapular skinfold)2 – constant

12 to 14 years: (constant: boys = 4.4, girls 12–13 years = 2.4)% body fat = 1.35 (sum of triceps + subscapular skinfold) – 0.012 (sum of triceps + subscapular skinfold)2 – constant

15 to 18 years: (constant: boys = 5.4, girls 14–15 years = 3.4)% body fat = 1.35 (sum of triceps + subscapular skinfold) – 0.012 (sum of triceps + subscapular skinfold)2 – constant

Centre of Excellence for nutrition, north-West university, Potchefstroom, south africaBS MOTSWAGOLE, MSc, hS KRuGER, PhD, [email protected]

nutritional intervention research unit, Medical research Council, tygerberg, south africaM FABER, PhD

Faculty of health sciences, north-West university, hypertension in africa research team (hart), Potchefstroom, south africaJM VAN ROOyEN, DSc Jh DE RIDDER, PhD


Blood pressure was taken by connecting subjects to the Finapres (finger arterial pressure) apparatus.15 Details of how this procedure was conducted are described elsewhere.16 High blood pressure was defined according to the definition from the National High Blood Pressure Education Program work-ing group on high blood pressure in children and adolescents (2004),17 i.e. an average systolic or diastolic blood pressure > 95th percentile for gender, age and height.

SAS statistical package version 9.0 (2003)18 was used for data analysis. Descriptive statistics were computed by gender for age, height, weight, BMI, WC, WHtR, systolic blood pressure (SBP), diastolic blood pressure (DBP) and percentage body fat (% BF), expressed as mean and standard deviation (SD). Differences among means were investigated by analysis of variance.

Diagnostic accuracy of WHtR to predict high blood pressure was expressed in the following ways: sensitivity and specific-ity, odds ratio and confidence interval, positive predictive value (PPV) and negative predictive value (NPV). Sensitivity meas-ures are the proportion of actual positives which are correctly identified as such, and specificity measures are the proportion of negatives which are correctly identified. The optimal cut-off value was denoted by the value that had the largest overlap of sensitivity and specificity.19 The odds ratio compares the prob-ability of a certain event for two groups. The PPV of a test is the probability that a patient has a positive outcome given that they have a positive test result. This is in contrast to sensitivity, which is the probability that a patient has a positive test result

given that they have a positive outcome. Similarly, the NPV is the probability that a patient has a negative outcome given that they have a negative test result, in contrast to specificity, which is the probability that a patient has a negative test result given that they have a negative outcome.20

results and discussionCharacteristics of the children are presented in Table 1. Girls had statistically significantly greater values for all variables except for age, weight and WHtR. The prevalence of abdominal adipos-ity using a WHtR cut-off value of 0.5 identified 7.9% of the girls and 3.4% boys as having excess central adiposity. Overall, the prevalence of hypertension in these children was 13%.

Table 2 shows the comparison between the South African children in this study and a sample of children aged six to 14 years from a Japanese study, which was aimed at determining the best predictor for the presence of cardiovascular disease risk factors among anthropometric indices.4 The average value of WHtR in these children was between 0.41 and 0.44. Based on the results obtained, the authors proposed that WHtR could be used for detecting cardiovascular risk in children.

Tables 3 and 4 show different frequencies of children in each category of true positives, false positives, false negatives and true negatives which were used in the calculation of positive and negative predictive values for WHtR as a predictor of high blood pressure. The results obtained for different diagnostic measures

TABLE 1. MEAN AND STANDARD DEVIATION FOR THE CHARACTERISTICS OF THE CHILDREN

Variable Boys Girls p-value

Age (years) 12 (1.7) 12 (1.7) 0.91

Height (cm) 147.8 (13.0) 148.8 (11.1) < 0.01

Weight (kg) 38.0 (11.6) 41.0 (11.7) 0.18

Body mass index (kg/m2) 17.0 (3.1) 18.2 (3.5) < 0.01

Waist circumference (cm) 60.7 (7.4) 61.7 (7.8) 0.03

Waist-height ratio 0.41 (0.04) 0.41 (0.04) 0.13

Systolic blood pressure (mmHg) 99.21 (14.0) 104.3 (14.2) < 0.01

Diastolic blood pressure (mmHg) 63.8 (9.7) 65.5 (9.5) < 0.01

% body fat 14.4 (6.2) 22.8 (6.9) < 0.01

TABLE 2. MEAN AND STANDARD DEVIATION FOR THE CHARACTERISTICS OF JAPANESE

AND SOUTH AFRICAN CHILDREN

Variable

South African Japanese

Boys Girls Boys Girls

Age (years) 12.0 (1.7) 12.0 (1.7) 10.9 (0.5) 10.9 (0.5)

Height (cm) 147.8 (13.0) 148.8 (11.1) 145.2 (7.2) 144.4 (6.4)

Weight (kg) 38.0 (11.6) 41.0 (11.7) 39.2 (8.9) 38.3 (7.3)

Body mass index (kg/m2)

17.0 (3.1) 18.2 (3.5) 18.4 (3.0) 18.0 (3.2)

Waist circum-ference (cm)

60.7 (7.4) 61.7 (7.8) 61.2 (7.9) 58.1 (6.4)

Waist-height ratio 0.41 (0.04) 0.41 (0.04) 0.43 (0.05) 0.40 (0.04)

Systolic blood pressure (mmHg)

99.21 (14.0) 104.3 (14.2) 113.8 (11.2) 99.2 (14.0)

Diastolic blood pressure (mmHg)

63.8 (9.7) 65.5 (9.5) 60.4 (7.6) 61.5 (7.3)

% body fat 14.4 (6.2) 22.8 (6.9) 20.0 (8.0) 24.0 (7.0)

TABLE 5. DIAGNOSTIC ACCURACY MEASURES FOR WHTR AS A PREDICTOR OF BLOOD PRESSURE FOR BOYS AND

GIRLS AT 0.41 AND 0.5 WC CUT-OFF VALUES

Diagnostic accuracy measures

Waist circumference cut-off values

Boys Girls

0.41 0.5 0.41 0.5

Sensitivity (%) 61.9 4.8 62.0 7.6

Specificity (%) 53.6 98.6 51.4 93.9

Positive predictive value

0.53 0.99 0.51 0.97

Negative predictive value

0.38 0.95 0.39 0.92

Odds ratio 1.88 3.45 1.63 3.09

95% confidence interval

0.97; 3.67 0.61; 19.37 0.97; 2.74 1.04; 9.20

TABLE 3. 2 × 2 TABLE FOR BOYS AT 0.41 AND 0.5 WAIST CIRCUMFERENCE CUT-OFF VALUES

WHtR ≤ 0.41

WHtR ≥ 0.41 Total

WHtR ≤ 0.5

WHtR ≥ 0.5 Total

Non-hypertensive 150 129 279 276 4 280

Hypertensive 16 26 42 40 2 42

Total 166 155 321 316 6 322

TABLE 4. 2 × 2 TABLE FOR GIRLS AT 0.41 AND 0.5 WAIST CIRCUMFERENCE CUT-OFF VALUES

WHtR ≤ 0.41

WHtR ≥ 0.41 Total

WHtR ≤ 0.5

WHtR ≥ 0.5 Total

Non-hypertensive 148 144 292 284 8 292

Hypertensive 29 46 75 69 6 75

Total 177 190 367 353 14 367


are shown in Table 5. The optimal WHtR cut-off value with the highest sum of sensitivity and specificity values was the same in both boys and girls, namely 0.41. For this reason, diagnostic accuracy measures were computed for 0.41 and 0.5 WHtR cut-off values.

The level of sensitivity of a WHtR cut-off point of 0.5 was very low for both boys and girls (4.8 and 7.6%, respectively). The cut-off value of 0.41, which corresponds to a sensitivity of 61.9% and a specificity of 53.6% in boys seems to be the most appropriate and the same cut-off value was found for girls, but with a sensitivity of 62% and a specificity of 51%. The fact that the cut-off value obtained for both boys and girls was the same concurs with the fact that in adults, there is a known advantage to setting up a unisex cut-off point when using the WHtR as a predictor of cardiovascular disease risk.9

Hara et al.4 postulated that since WHtR takes into account children’s height, a single cut-off point can likely be set for the ratio, without age and gender difference bias.4 The observed cut-off value of 0.41 for WHtR from the current study is similar to what was observed for Japanese children.4 It is possible that this is because the children included in the two studies had similar anthropometric characteristics, and in particular, they were more or less the same height and had similar WC (Table 2).

On the contrary, results for odds ratio, PPV and NPV show that the WHtR cut-off value of 0.5 proved to be a better predic-tor for high blood pressure in children, as shown in Table 5. The reason for the conflicting results might be due to the fact that sensitivity and specificity are characteristics of a test and are not affected by the prevalence of the disease. However, although the PPV and NPV give a direct assessment of the usefulness of a test, they are affected by the prevalence of the disease. Bewick and colleagues20 stated that ‘the decision to use a diagnostic test depends not only on the diagnostic accuracy measures but also on the ultimate benefit to the patient. The prevalence of the outcome, which is the pre-test probability, must also be known. Generally, there is a trade-off between sensitivity and specificity, and the practitioner must make a decision based on their relative importance’.20

One potential limitation of our study is that the sample of children was from only one of nine provinces in South Africa. Although the children in this study were from both rural, infor-mal settlements and urban areas, the distribution was not even. This makes it difficult to suggest the 0.41 cut off for South African children and adolescents in general. Therefore a nation-ally representative sample is required to give a more valid cut-off value.

Another limitation might be the fact that blood pressure was measured on only one occasion, even though there were 10-minute intervals between the readings. In establishing the type of hypertension, blood pressure should be measured on three or more separate occasions.15 However, the procedure adopted in this study (vascular unloading technique of Penaz together with physical criteria of Wesseling) provides reliable, non-evasive and continuous estimates of blood pressure.16

ConclusionResults of the present study indicate that adopting a WHtR cut-off value lower than 0.5 for South African children may enhance sensitivity in identifying children at risk for hypertension.

However, a nationally representative cohort study is needed to confirm or determine a precise cut-off value for accurate predic-tion of the presence of hypertension. It is important to establish the diagnostic accuracy of WHtR and hence justify its use in predicting high blood pressure in the paediatric population. Identification of children with high blood pressure is important in controlling the impact of the condition because it allows for the diagnosis and counselling of persons and facilitates the implementation of both treatment and management strategies.

This study was supported in part by the South African Sugar Association grant. Special thanks go to Prof HS Steyn and Dr SM Ellis whose statistical consultation is gratefully acknowledged.

References1. Hsieh SD, Muto T. The superiority of waist-to-height ratio as an anthro-

pometric index to evaluate clustering of coronary risk factors among non-obese men and women. Prev Med 2005; 40: 216–220.

2. Bosy-Westphal A, Geisler C, Onur S, Korth O, Selberg O, Schrezenmeir J, et al. Value of body fat mass vs. anthropometric obesity indices in the assessment of metabolic risk factors. Int J Obes 2006; 30: 475–483.

3. Savva SC, Tornaritis M, Savva ME, Kourides Y, Panagi A, Silikiotou N, et al. Waist circumference and waist-to-height ratio are better predictors of cardiovascular disease risk factors in children than body mass index. Int J Obes Relat Metab Disord 2000; 24(11): 1453–1458.

4. Hara M, Saitou E, Iwata F, Ikada T, Harada K. Waist-to-height ratio is the best predictor of cardiovascular disease risk factors in Japanese schoolchildren. J Atheroscler Thromb 2002; 9: 127–132.

5. Kahn HS, Imperatore G, Cheng YJ. A population-based comparison of BMI percentiles and waist-to-height ratio for identifying cardiovascular risk in youth. J Pediatr 2005; 146: 482–488.

6. Guntsche Z, Guntsche EM, Saraví FD, Gonzalez LM, Avellaneda CL, Ayub E, et al. Umbilical waist-to-height ratio and trunk fat mass index (DXA) as markers of central adiposity and insulin resistance in Argentinean children with a family history of metabolic syndrome. J Pediatr Endocrinol Metab 2010; 23(3): 245–256.

7. Ashwell M. Waist to height ratio and the Ashwell shape chart could predict the health risks of obesity in adults and children in all ethnic groups. Nutr Food Science 2005; 35: 359–364.

8. Nambiar S, Truby H, Abbott RA, Davies PSW. Validating the waist-to-height ratio and developing centiles for use amongst children and adolescents. Acta Paediatric 2008; 98(1): 148–152.

9. Ashwell M, Lejeune S, McPherson K. Ratio of waist circumference to height may be better indicator of need for weight management. Br Med J 1996; 312: 377.

10. Sung RYT, So H-K, Choi K-C, Nelson EAS, Li AM, Yin JAT, et al. Waist circumference and waist-to height ratio of Hong Kong Chinese children. BMC Pub Hlth 2008; 8: 324–338.

11. Kruger R, Kruger HS, Macintyre UE. The determinants of overweight and obesity among 10–15-year-old schoolchildren in the North West Province, South Africa – the THUSA BANA (Transition and Health during Urbanisation of South Africans; BANA, children) study. Publ Hlth Nutr 2006; 9: 351–358.

12. Mukuddem-Petersen J, Kruger HS. Association between stunting and overweight among 10–15-year-old children in the North West Province of South Africa: the THUSA BANA study. Int J Obes 2004; 28: 842–851.

13. Lohman TG. Anthropometry and body composition. In: Lohman TG, Martorell R, eds. Anthropometric Standardization Manual, 1988. Champaign, IL: Human Kinetics Books.

14. Boileau RA, Lohman TG, Slaughter MH. Exercise and body composi-tion of children and youth. Scand Med Sci Sports 1985; 7(1): 17–27.

15. Schutte AE, Van Rooyen JM, Kruger HS, Malan NT, De Ridder JH. Dietary risk markers that contribute to the aetiology of hypertension in black South African children: the THUSA BANA study. J Hum Hypertens 2003; 17: 29–35.


16. Silke B, McAuley D. Accuracy and precision of blood pressure deter-mination with the Finapres: an overview using re-sampling statistics. J Hum Hypertens 1998; 12: 403–409.

17. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (supplement article): National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Pediatrics 2004:

114(2): 555–576.18. SAS Institute Inc, 2003. SAS Institute Inc, SAS OnlineDoc, Version

9.1, Cary, NC.19. Campbell MJ, Machin D. Medical Statistics: A Common Sense

Approach, 3rd edn. West Sussex, England: John Wiley and Sons, 2000.20. Bewick V, Cheek L, Ball J. Statistics review 13: Receiver operating

characteristics curves. Crit Care 2004; 8(6): 508–512.

international society of Cardiovascular disease Epidemiology and Prevention

44th 10-day international teaching seminar on Cardiovascular disease

Epidemiology and Prevention

15–27 January 2012

Cape town, south africa

The International Society of Cardiovascular Disease Epidemiology and Prevention announces the 44th 10-day international teaching seminar on cardiovascular disease epidemiology and prevention to be held 15–27 January 2012 in Cape Town, South Africa in conjunction with the South African Medical Research Council and the University of Cape Town.

Approximately 36 fellows can be accepted. The Society’s seminar committee will make the final selection. Nominees should ideally be at the postgraduate level with residency training or its equivalent, and be interested in cardiovascular disease epidemiology.

Normally, preference is given to younger candidates, with little or no formal training in epidemiology. Tuition, board and accommodation are provided without cost to fellows. Fellows and their sponsors are responsible for their own travel costs to the seminar. Should any accepted fellow be unable to attend, no substitute not reviewed by the seminar committee may be sent as an alternate by the institution.

FluEnCy in English is an aBsolutE EssEntial

Applications, including (1) a letter of nomination by the chief of department or institution, or other relevant sponsor, (2) a personal letter of application from the nominee, and (3) the applicant’s curriculum vitae, should be received before 15 September 2011 by the seminar coordinator, address below. Applications can be sent by e-mail but a signed hard copy should follow in the post.

Professor Kay-Tee Khaw,Clinical Gerontology Unit, PO Box 251University of Cambridge School of Clinical Medicine,Addenbrooke’s Hospital,Cambridge CB2 2QQ,England

Fax: +44-1223-336928Tel: +44-1223-217292e-mail: [email protected]


images in Cardiology

Malignant convulsive vasovagal syncopeB AMASyALI

abstractA patient was referred for evaluation of repeated episodes of syncope with loss of consciousness and convulsions. A dual-chamber pacemaker with rate-drop feature was implanted.

Keyword: syncope


Cardiovasc J Afr 2011; 22: 212 www.cvja.co.za

DOI: 10.5830/CVJA–2010–089

A 37-year-old man was referred for evaluation of repeated episodes of syncope. The episodes had always occurred in the upright position, without any prodromal symptoms. Although he had had a history of hyperthyroidism for six months, he was euthyroid during evaluation for the syncope. His laboratory tests were within normal limits. Cardiological examination, echocar-diography and 24-hour Holter monitoring were normal.

A tilt table test was obtained as part of the syncope evalua-tion. He had an asystolic pause at the 20th minute of the test. The asystolic pause continued despite the administration of 1 mg intravenous atropine sulphate at the 10th second. It lasted

24.340 seconds until the first junctional escape beat and 38.460 seconds until the first conducted sinus beat (Fig. 1), with loss of consciousness and convulsions.

On the basis of these results, a dual-chamber pacemaker with rate-drop feature was implanted. At nine months of follow-up, the patient reported no more episodes of syncope.

gulhane Military Medical academy, department of Cardiology, ankara, turkeyB AMASyALI, MD, [email protected]

Fig. 1. the rhythm strip during tilt-table testing, showing the malignant asystolic pause. asterisk: first junctional escape beat; arrow: first conducted sinus beat.


Cardio news

PasCar meeting in Kampala, ugandaA successful three-day meeting was held recently in Kampala to celebrate 30 years of this organisation.

Boehringer-ingelheim’s hospitality suite was a favoured place in the shade, drawing delegates to its well-staffed stand.

PasCar delegates with denk Pharma (germany) repre-sentatives, regina tischtau (second from left) and stephan huber.

south african members of the sa heart association, and the southern representative of PasCar attended the meeting. From left to right: dr naomi rapeport, Prof Brian rayner, Johan van der Merwe (Boehringer-ingelheim) and dr Colin schamroth.

dr ao Falase, nigeria, founding president of PasCar (right) gave a keynote address from his personal view on the history of PasCar. With him are two PasCar delegates.

industry representation was not as extensive as the south african experience, but companies with renewed interest in africa supported the meeting. omron, a netherlands-based company gave prizes. dr Jane nakibuuka, Mulago hospital (iCu), uganda was pleased with her digital blood pressure meter.

Bayer’s adalat featured on lake victoria in a CME even-ing, addressed by Prof Elijah n ogola, cardiologist from nairobi and PasCar vice-president (East africa). he emphasised the extent of hypertension in africa and the need to favour the use of long-acting, once-a-day nifedi-pine, to ensure protection against the morning surge of blood pressure and reduce Mi, stroke and other cardio-vascular events.


drug trends in Cardiology

the evolution of heart rate: past, present and futureProf Prakash Deedwania, Chief of Cardiology Division, uCSF, Fresno, CA

‘Heart rate is simple – and simple is not “sexy”. This has led to the mistaken impression that heart rate is not impor-tant. But, in fact, nothing is more impor-tant than heart rate.’ This is the viewpoint of Prof Prakash Deedwania, who was in South Africa recently as a guest of Servier.

Prof Deedwania cited a study that evaluated variables in heart failure. ‘Heart rate was shown to be the most powerful predictor of outcome’, he said. ‘Increments in heart rate are essential in causing ischaemia.’ He pointed out that animals with the slowest heart rates have the longest life spans. Tortoises, at six beats per minute (bpm), live an average 177 years, while mice, at 600 bpm, live a mere two years.

The first evidence of the prognostic importance of heart rate was published in the Journal of the American Medical Association as long ago as 1945. The study in question showed that even tran-sient tachycardia was associated with negative effects and, in the years since, many other studies have produced similar results, notably that a heart rate above 80 bpm is associated with higher cardiovas-cular and absolute mortality risk.

Prof Deedwania highlighted the following. The Paris Prospective study, published in 2005, showed that risk of sudden death increased progressively with resting heart rate in the general population. In the National FINRISK study published last year, elevated resting heart rate was found to be an independent risk factor for total mortality in healthy men and women.

The 1999 French Cohort study showed that resting heart rate indepen-dently predicted both cardiovascular and total mortality in both genders, while the Framingham study found that all-cause mortality increased progressively with resting heart rate in men with hyperten-sion. ONTARGET and TRANSCEND found that increased heart rate was asso-ciated with an increased risk of major

cardiovascular events in stable coronary artery disease (CAD) patients.

‘When we look at myocardial infarc-tion (MI), left ventricular ejection frac-tion (LVEF) is a powerful predictor, but no more so than heart rate’, he contin-ued. ‘This was shown in GISSI-3, which looked at in-hospital mortality and six-month mortality in MI survivors.’

‘The more heart rate increases, the more the ischaemia. Heart rate is there-fore a very powerful predictor of ischae-mia. Without increased heart rate, it is difficult to produce ischaemia.’

The place of ivabradine in CAD managementProf Deedwania feels that ivabradine is a useful addition to the beta-blocker category of drugs as it offers pure heart rate reduction without negative effects on other aspects of cardiac function-ing. ‘It improves coronary perfusion and maintains cardiac performance better than alternative drug therapy, with no effect on blood pressure, ventricular relaxa-tion and contractile force’, he said. ‘The Primary Efficacy study, published in 2003, showed that it reduced heart rate at rest and also proportionally, during exer-cise. However, it is important to ensure a therapeutic dose to achieve an optimal response.’

While dose for dose relative to ateno-lol, ivabradine offers similar heart rate reduction and comparable anti-anginal efficacy in respect of resting heart rate, it also improves exercise tolerance, something beta-blockers do not do. In the ASSOCIATE study, which evalu-ated ivabradine versus atenolol in well-controlled patients, ivabradine further reduced heart rate in patients already on beta-blockers, with an associated benefit in most exercise parameters. ‘Adding ivabradine to beta-blockers is therefore beneficial’, said Prof Deedwania. ‘It’s also a very good choice in the approxi-mately 30% of patients who are intolerant

of beta-blockers.’Relative to amlodipine, ivabradine

has also been shown to be non-inferi-or in respect of anti-anginal and anti-ischaemic efficacy. ‘It has been shown to work as monotherapy and to further enhance the benefits of beta-blockers and calcium channel blockers’, observed Prof Deedwania.

The BEAUTIFUL study evaluated high-risk patients with chronic stable CAD and a LVEF below 40%. ‘The lesson learned from the trial’s placebo arm was that a heart rate ≥ 70 bpm was associated with a significant increase in mortality. Ivabradine reduced coronary risk in these patients, and the benefits were particular-ly apparent in those who had both stable CAD and angina. Ivabradine is the only anti-anginal agent that actually reduces cardiovascular events in angina patients.’

Heart rate as a risk factor in chronic heart failureWorldwide, heart failure is increasing rapidly and is a major factor in healthcare expenditure. The EPHESUS trial showed that heart rate is a powerful predictor of outcome in heart failure, responsible for a significant increase in all-cause and cardiovascular mortality as well as combined cardiovascular mortality and hospitalisation – and this despite patients receiving optimal therapy.

The SHIfT trial’s primary objective was to ascertain whether ivabradine improves cardiovascular outcomes in moderate to severe chronic heart failure. Participants had heart rates ≥ 70 bpm and LVEFs ≤ 35% and were receiving recom-mended therapy.

‘We learned that heart rate is a risk factor in these patients, and that on aver-age ivabradine reduced heart rate from 80 to 64 bpm, something that was sustained through two-and-a-half years of follow up. Cardiovascular death/hospitalisation declined by a significant 18%, heart fail-ure hospitalisation was reduced by an

For full prescribing information, refer to package insert approved by medicines regulatory authority.

S3 CORALAN® 5 mg Tablets. Ivabradine 5 mg. Reg. No. A39/7.1.4/0410S3 CORALAN® 7,5 mg Tablets. Ivabradine 7,5 mg. Reg. No. A39/7.1.4/4011NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. TEL: +27 (0) 861 700 900. FAX: +27(0)11 233 6099.

References: 1. Vilaine JP et al. J Cardiovasc Pharmacol 2003;42:688-696. 2. Camm A et al. Drugs R&D 2003;4:83-89. 3. Borer J et al. Circulation 2003;107:817-823. 4. Swedberg K et al. Lancet 2010;376:875 -885.10

11/2

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OD

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S L O WTHE BEAT

Improve the outcome

Coralan® specifi cally reducesheart rate without affecting cardiac contraction 1, conduction 2 or blood pressure 3

Coralan® has powerful anti-anginal and anti-ischaemic effi cacy 3

Coralan® improves outcomes in heart failure patients with a heart rate above 70bpm - SHIFT 4

www.servier.com


even more significant 26%, and heart fail-ure death by 26%. These extremely posi-tive findings across all different endpoints were major news at the European Society of Cardiology meeting in 2010.’

Those patients who achieved a heart rate of less than 60 bpm showed the best reduction in primary outcomes. ‘Because beta-blockers do not necessarily achieve this and often cannot be titrated,

ivabradine is a valuable new choice in this context’, Prof Deedwania noted. ‘It achieves the lowest rate of heart failure mortality and its adverse events are not significant. It’s also cost effective, with the number-needed-to-treat (NNT) per year to prevent one primary endpoint being 26. The NNT to prevent one heart failure hospitalisation is 27.

Summing up, Prof Deedwania said

that reducing heart rate has clear cardio-protective effects and that, when used appropriately, ivabradine adds value over and above current standard therapy. ‘The results of the ongoing SIGNIFY study should confirm this even further’, he concluded.

Peter Wagenaar, Gauteng correspondent

new data support ivabradine use in chronic heart failureThe results of the SHIfT study on ivabra-dine in chronic heart failure support the benefits of this selective rate-lowering drug in lowering mortality and morbidity in this difficult-to-treat category of patients.1

Now, new data released at the 2011 European Society of Cardiology congress on heart failure held in Gothenburg, Sweden has provided further support for ivabradine’s use in terms of overall safety, use with beta-blockers and health-related quality-of-life determinants.2-4

Improvements in quality of lifeThe aspect of quality of life is particularly important, as this is greatly impaired in patients with congestive heart failure.

Prof Karl Swedberg from the University

of Gothenburg, who is particularly known for the first use of beta-blockade in the 1980s to treat heart failure due to dilated cardiomyopathy, has been closely involved in the SHIfT trial. Commenting on the SHIfT Quality Of Life trial, Prof Swedberg noted that improved survival and alleviation of patient suffering is a major goal in the management of heart failure patients.

‘However, currently prescribed heart failure treatments that prolong life, such as beta-blockers, only modestly improve quality of life for heart failure patients, if at all, whereas therapies such as diuretics that significantly improve quality of life have no demonstrable effect on survival. We need new therapies such as ivabradine that improve quality of life and survival’.2

Safety of ivabradine shown in the pre-specified ECG Holter study of patients participating in the SHIfT studyBlinded ECG Holter readings performed both at baseline and after eight months in 501 SHIfT participants (Table 1) show heart rate was significantly reduced over 24 hours, by 9.5 ± 10.1 bpm with ivabradine versus 1.2 ± 8.9 bpm in the placebo group. Heart rate reduction tended to be greater during the waking hours than at night.

Importantly, while some patients (one in five) experienced periods when the rate went below 40 bpm, no episodes of heart rate lowering below 30 bpm or any unex-pected abnormalities were observed with ivabradine (Table 2).

TABLE 1. BASE-LINE CHARACTERISTICS IN THE HOLTER SUB-STUDY AND THE MAIN SHIFT STUDY

Ivabradine (n = 298)

Placebo (n = 304)

Entire population (n = 6 505)

Age (years) 60 59 60

Gender (% male) 81 82 76

Heart rate (bpm) 79 79 80

LVEF (%) 28 28 29

NYHA class II (%) 46 45 49

NYHA class III–IV (%) 54 55 50

Ischaemic cause of heart failure (%) 68 66 68

History of AF (%) 7 6 8

Receiving beta-blockers (%) 93 92 90

Receiving ACEI/ARBs (%) 93 92 91

bpm: beats per minute, LVEF: left ventricular ejection fraction, NYHA: New York Heart Association, AF: atrial fibrillation, ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker.

TABLE 2. RESULTS FROM AMBULATORY 24-HOUR ELECTROCARDIOGRAPHIC HOLTER MONITORING

AFTER EIGHT MONTHS OF TREATMENT

Number of patientsIvabradine (n = 254)

Placebo (n = 247)

≥ 1 episode heart rate < 30 bpm 0 0

≥ 1 episode heart rate < 40 bpm 54 (21%) 21 (8.5%)

RR interval > 2.5 sec 3 (1.2%) 4 (1.6%)

RR interval > 3 sec 0 1 (0.4%)

Atrial fibrillation 6 (2.4%) 5 (2%)

Atrial flutter 0 0

Atrioventricular block II or high-degree block 4 (1.6%) 9 (3.6%)

Atrioventricular block III 0 0

Non-sustained ventricular tachycardia 71 (28%) 81 (33%)

Sustained ventricular tachycardia 0 0


letter to the Editor

Use with β-blockersResults from the CARVIVA-HF trial using carvedilol as the β-blocker and ivabradine have shown that ivabradine alone or in combination with beta-block-ers is safe and effective for improving exercise capacity and quality of life in patients.4

The interesting design of CARVIVA-HF investigated the therapeutic strategy of up-titrating ACE inhibitors and reducing heart rate by using three different strate-gies: carvedilol, ivabradine or a combina-

tion of both drugs. Prior to randomisation of the 123 patients, beta-blocker therapy was discontinued for eight weeks to allow up-titration of ACEI therapy.

Results analysed after 12 weeks showed improved exercise tolerance, exercise capacity, quality of life and heart function with ivabradine alone or when used in combination with carvedilol, over baseline and carvedilol-only therapy.

J Aalbers, Special Assignments Editor

1. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart disease (SHIfT): a randomised placebo-controlled study. Lancet 2010; 376: 875–885

2. ESC heart failure congress, 2011. Oral presentation: Inger Ekman, et al. Ivabradine is associated with improved health-related quality of life in patients with heart failure.

3. ESC heart failure congress, 2011. Poster. J Camm and associates.

4. ESC heart failure congress, 2011. Abstract 694. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure.

torsades de pointes

Torsades de pointes means twisting of the points. It is a French term and was first described by Dessertenne in 1966.1 It refers to a specific variety of ventricular tachycardia and is characterised by a twist of the QRS complex around the isoelectric baseline. The blood pressure drops and ventricular fibrillation can result in sudden death.

Torsades de pointes is associated with a long QT interval and it predisposes the patient to an R-on-T phenomenon. Here, the R wave representing ventricular depolarisation occurs simultane-ously with the relative refractory period at the end of repolarisa-tion. An R-on-T phenomenon can initite torsades de pointes.

During torsades de pointes, the heart rotates on its electri-cal axis at least 180 degrees. There is a long QT syndrome and prolonged Q-T interval, with long and short R-R intervals and early premature ventricular contraction.

The causes include diarrhoea, hypomagnesaemia and hypoka-laemia, anti-arrythmic drugs, hypoxia, acidosis, heart failure, left ventricular hypertrophy, bradycardia, female gender, hypother-mia and subarachnoid haemorrhage.

Treatment is to withdraw the offending drug, if any, infuse magnesium sulphate, and electrical therapy, e.g. an implantable cardioverter defibrillator.2,3

hD Solomons highlands North, Johannesburg, South Africa

References1. Dessertenne F. La tachycardia ventriclaire a deux foyers opposes vari-

ables. Arch Mal Coeur Vaiss 1966; 59(2): 263–272. PMID 4956181. (http;//www.ncbi.nlm.nih.gov/pubmed/4956181.)

2. Hoshinko K, Ogawa K, Hishitani T, Isobe T, Eto Y. Optimal administra-tion dosage of magnesium sulphate for torsades de pointes in children with long QT syndrome. J Am Coll Nutr 2004; 23(5): 497S–500S. PMID 15466950.

3. Hoshiko K, Ogawa K, Hishitani T,Isobe T, Etoh Y. Successful uses of magnesium sulphate for torsades de pointes in children with long QT syndrome. Paediatr Int 2006; 48(2); 112–117. PMID 16635167. doi; 10.1111/j.1442-200X.2006.02177x(http;//dx.doi.org/10.1111%2Fj.1442-200X.2006.02177.x).


Fda approves rivaroxaban for prevention of deep-vein thrombosis in surgeryRivaroxaban has just become the first factor Xa inhibitor and so far the only oral anticoagulant to be approved in the United States for orthopaedic surgery.1,2 The press release issued by Bayer/Johnson and Johnson notes that the FDA approval is based entirely on rivaroxa-ban’s performance in the three RECORD trials: 1, 2 and 3, suggesting that no further data were submitted to the FDA.3

The data from the RECORD trials showed significantly greater efficacy of rivaroxaban, both in head-to-head comparison with enoxaparin and when comparing extended-duration (five weeks) of rivaroxaban with short-dura-tion enoxaparin (two weeks), followed by placebo. In these trials, rivaroxaban and enoxaparin demonstrated similar safety profiles, including low rates of major bleeding.

The recommended dose of rivaroxa-ban is 10 mg taken orally once daily. The initial dose should be taken at least six to 10 hours after hip-replacement surgery, once homeostasis has been established. The recommended duration of treatment is 35 days, and for knee replacement it is 12 days.

As in South Africa, the FDA prescrib-ing information notes a contra-indication on rivaroxaban in cases of active major

bleeding, and a cautionary use in patients with severe renal impairment (creatinine clearance < 30 ml/min). Because of limit-ed clinical experience on this aspect, the FDA has requested a clinical trial to evaluate the effect of renal impairment (mild, moderate, severe), plus the concur-rent use of P-glycoprotein and moderate inhibitors of CYP3A4 on the pharmacoki-netics, pharmacodynamics and safety of rivaroxaban in volunteers, so that appro-priate dosing recommendations can be developed in these populations.

Usage of this agent should be avoid-ed in patients with moderate or severe impairment of liver function or in any patients with any degree of hepatic disease associated with coagulopathy.

Dabigatran etexilate, a direct thrombin inhibitor is not approved in the United States for prevention of deep-vein throm-bosis (DVT) in knee and hip replacements.

Dr PJ Erasmus, Stellenbosch Medi-clinic commentsMy current experience with rivaroxaban is based on experience of over 18 months. I have routinely used rivaroxaban for all my knee-replacement patients over this period, during which I have done more the 500 knee replacements.

My regimen is to use a long-acting subcutaneous heparin, nadroparin calci-um (Fraxiparine) during the intra- and peri-operative period. The reason being that we have had, over a long period, very few problems with postoperative bleeding on this regime. We use spinal anaesthesia and also prefer to start with anticoagulant therapy the evening before the operation.

Rivaroxaban should not be used with spinal anaesthesia and it should be start-ed only after surgery. (Special instruc-tions should be followed if the clinician decides to use rivaroxaban with spinal anaesthesia.)

On discharge, on the third or fourth postoperative day, we start the patients on rivaroxaban for 10 days. With this regime we have had no adverse bleeding episodes, DVTs or pulmonary embolisms for the past 18 months.


1. Stiles S. FDA approves oral anticoagulant rivaroxaban for DVT prevention at surgery. Heartwire, 1 July 2011.

2. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails

3. Janssen Pharmaceuticals. FDA approves Xarelto to help prevent DVT in patients undergoing knee or hip replacement surgery. 2 July 2011.

1 | Insert the test strip into the device (insertion automatically switches the device on).

1 2

2 | Prick your fingertip with the CoaguChek® Softclix lancing device to get a drop of blood.

3

3 | Apply the first drop of blood within 15 seconds. Side- or top-dosing on the test strip makes dosing very easy.

4

4 | Get your INR result within one minute.


south africa’s poor warfarin control raises questions of benefit above other anticoagulant therapies in atrial fibrillationSouth African patients entered into the ACTIVE-W trial were outside the ideal INR targets of 2–3 for 60% of the time while on warfarin therapy. This poor control of warfarin reduces benefit and raises the question as to whether other newer anticoagulant therapies should be used for stroke prevention in atrial fibril-lation. New management strategies are also needed to improve warfarin control.

Poor control of warfarin was a very significant feature of the South African-entered patients and, in fact, South Africa as a country was at the bottom of the log of achieved time in therapeutic range (TTR) (See Table 1, amended from refer-ence 1). Furthermore, no South African patients were in the upper quartiles of TTR control.

South Africa entered patients with atrial fibrillation into the ACTIVE-W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) trial, in which patients were randomised to receive dual antiplatelet therapy (clopidogrel 75 mg/day plus aspi-rin 75–100 mg/day or oral anticoagula-tion). In South Africa, the vitamin K antag-onist used was warfarin. Ninety-eight South African patients were randomised to warfarin therapy and included in the post hoc study on the influence of INR control on ACTIVE-W results.

The overall outcome (stroke, myocar-dial infarction, systemic embolism or vascular death) was found to be increased with clopidogrel plus aspirin, compared to oral anticoagulation. The mean TTR for all patients in ACTIVE-W was 63.4%

(median 65%).While there are differences between

centres within a particular country, South African centre-specific data were not disclosed. However, the authors noted that in the three countries with the lowest mean TTRs (South Africa, Brazil and Russia), 86% of patients had TTRs below the mean. In South Africa’s case, 86% of patients therefore had mean TTRs even lower than 46.3. Overwhelmingly, these data point to very poor warfarin control-to-target INRs in South Africa.

Effect of TTRs on treatment effect of warfarinThe effect of TTRs on treatment benefit of warfarin was evaluated in terms of TTR achieved at a particular centre. This was also adjusted for the patients’ charac-teristics and then evaluated in terms of the patients’ CHADS2 score (≥ 2 vs < 2), and finally, in a population-averaged model reflecting a country-level response.

Under all four criteria, patients in the lowest quartile of TTR in terms of their centres did not benefit and were at greater risk on their warfarin therapy then they would have been on anti-platelet therapy: clopidogrel plus aspirin. Across all these factors, the observed effect of the TTR quartile on warfarin or alternative oral treatment was robust and determined the level of benefit for individual patients.

Using these data in a population-aver-aged model, this study was able to esti-mate the minimum TTR needed to have at least some benefit from oral antico-

agulation. This level was determined to be above 58%, a countrywide objective that South Africa did not reach.

The role of self-monitoring could be helpful in the South African situation, as can the newer anticoagulants such as dabi-gatran, which is registered in the United States for stroke prevention in atrial fibril-lation. In the RE-LY trial and further eval-uation of dabigatran’s efficacy and safety, the advantages of dabigatran remained, irrespective of the centres’ quality of INR control. In fact, for all vascular events, non-haemorrhagic events were greater at sites with poor INR control than at those with good INR control.2


1. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, et al. on behalf of the ACTIVE-W investigators. Benefit of oral anticoagulation over antiplatelet thera-py in atrial fibrillation depends on the quality of international normalized ratio control achieved by centres and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029–2037. DOI: 10.1161/CIRCULATIONAHA.107.750000

2. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Grazia Franzosi M, Pais P, et al. on behalf of the RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of interna-tional normalized ratio control for stroke prevention in atrial fibrillation: an analy-sis of the RE-LY trial. Lancet, published online Aug 29 2010. DOI: 10.1016/S0140-6736(10)61194-4.

TABLE 1. TTR AND TIME TO RISK OF STROKE, MYOCARDIAL INFARCTION, SYSTEMIC EMBOLISM, VASCULAR DEATH, OR MAJOR HAEMORRHAGE FOR SOME OF THE 15 COUNTRIES PARTICIPATING IN ACTIVE-W

Patients per TTR quartile (low to high) (n) Mean

TTR

Clopidogrel + aspirin OAC Clopidogrel + ASA vs OAC

Country 1 2 3 4 Events %/y Events %/y RR 95% CI p

South Africa 55 43 0 0 46.3 5 8.42 8 14.94 0.57 0.19–1.75 0.33

Brazil 188 25 25 8 47.1 13 9.38 14 9.43 1.01 0.47–2.15 0.98

Russia 188 28 0 41 53.4 13 7.92 7 4.16 1.88 0.75–4.70 0.18

United States 135 460 363 116 62.9 59 8.02 48 6.6 1.25 0.85–1.83 0.26

Netherlands 65 98 163 49 64.0 15 6.65 7 3.17 2.12 0.86–5.20 0.10

Australia 5 12 54 145 74.5 18 12.92 5 3.76 3.60 1.34–9.71 0.01

United Kingdom 2 34 59 199 74.8 12 7.03 7 3.97 1.79 0.71–4.55 0.22

ASA: acetylsalicyclic acid; OAC: oral anticoagulation; RR: relative risk, rows are ordered by mean TTR.

THINGS ARE ABOUT TO CHANGE IN

ANTICOAGULATION THERAPY

Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg.

Tel: +27 (011) 348 2400 • Fax: +27 (011) 787 3766 • Company Reg. No. 1966/008618/07.

BI Ref No. 254/2010 (Nov 10)

EVERY DAY IN SOUTH AFRICA

44** PATIENTS WILL HAVE AN AF* RELATED STROKE1, 2, 3

22** OF THEM WILL DIE WITHIN A YEAR (50 %)4

90 % OF STROKE PATIENTS WITH KNOWN AF WERE NOT THERAPEUTICALLY ANTICOAGULATED4

*AF – Atrial Fibrillation** Best Estimate

REFERENCES: 1. Stats South-Africa. Stats-Online. P0302 - Mid-year population

estimates. Updated 20 July 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03022010.pdf

2. Connor M. Stroke Management in South Africa – Who is responsible? S Afr Psychiatry Rev 2005; 8: 125-126.

3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fi brillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.

4. Gladstone DJ, Bui E,Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40;235-240.

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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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81mgThe ORIGINAL low dose aspirinfor optimum cardio-protection


obesity and platelet reactivity: the relationship remains uncertainTwo recent studies on obesity have sought to provide clarity to the hypothesis that increasing BMI could be associated with high on-treatment platelet reactivity. These studies were undertaken in differ-ent populations.

The first study was undertaken in 251 patients undergoing elective PCI who were given dual antiplatelet therapy (clopidogrel and aspirin). Their platelet reactivity was measured six to 24 hours after PCI and any relationship with obesi-ty was examined.1

The second study was undertaken as part of the Genetic STudy of Aspirin Responsiveness (GeneSTAR), which was designed to examine the genetic determi-nants of platelet responsiveness to low-dose aspirin.2 This latter population of healthy at-risk-by-family-history cohort included 2 014 participants who were given low-dose aspirin (81-mg aspirin tablet) for 14 days. Platelet-function tests were performed at baseline and after 14 days.

The PCI study undertaken at the Washington Hospital Centre found no association between BMI and platelet reactivity, as quantified by a variety of platelet-function tests (LTA: light trans-mission aggregometry, VASP: vasodila-tor-stimulated phosphoprotein phospho-rylation, P2y12 and Verify now aspirin assays).

The baseline characteristics of the obese patients in this study were generally similar to those of the non-obese patients. Obese patients’ BMI was defined as above 30 kg/m2. Patients were mainly male and 25% were African-American.

All patients received a 600-mg loading dose of clopidogrel six hours before plate-let-reactivity testing or a 75-mg mainte-nance dose for more than five days before testing. Aspirin therapy was 325 mg six to 24 hours before platelet-reactivity testing.

The results show that all five platelet-reactivity tests were not normally distrib-uted, but using Spearman co-efficient and scatter plots, there was a very poor correlation between BMI and platelet reactivity. Using definitions specific to

each test, there was still no statistically significant association with BMI. Only chronic renal insufficiency was associat-ed with high on-treatment platelet reactiv-ity. The authors concluded that their study does not support an approach that would modify antiplatelet therapy of clopidogrel and aspirin in obese patients.

In the population of higher-risk but healthy family members of whom docu-mented CAD events occurred in close family members before 60 years of age, the baseline characteristics of the obese and non-obese groups were different. Obese individuals were older, female and black, and less likely to smoke cigarettes.

Platelet-function tests were performed at baseline and after 14 days of regu-lar non-enteric aspirin therapy (81 mg). Platelet reactivity was determined by platelet count, aggregometry (same test as in the first study) and plasma fibrino-gen. Aspirin assays were not performed as the tests of inhibition of the COX-1 path-way (AA aggregation and Tx-M: urinary excretion of 11-dehydro-thromboxane B2) were performed.

The study found that obese individu-als demonstrated greater ex vivo platelet activation in response to all agonists, including collagen, ADP and AA. In vivo platelet activation measured by Tx-M was also greater in the obese participants. Most measures were statistically signifi-cant or near significant between the obese and non-obese groups.

Platelet reactivity following aspirinIn assays directly related to the COX-1 pathway (e.g. AA aggregation and Tx-M), obese individuals consistently showed greater residual platelet reactivity (meas-ured in ohms) than non-obese individuals after aspirin. Similarly, a significantly larger fraction of obese individuals had any residual platelet reactivity to AA (measured in percentage non-zero aggre-gation) after aspirin than non-obese indi-viduals. Tx-M was suppressed in both groups with aspirin, but obese individu-als demonstrated greater in vivo platelet

reactivity after aspirin compared with non-obese individuals. A higher percent-age of obese individuals met the Tx-M criteria (upper quartile) for aspirin resist-ance following aspirin.

Similar to the direct COX-1 pathway, indirect COX-1 pathways (i.e. aggrega-tion to collagen and ADP) also showed significantly greater residual platelet reactivity after aspirin in obese than in non-obese individuals. For collagen and Tx-M, the absolute change in platelet activation was the same or greater in obese persons compared with the non-obese, while for ADP-induced platelet aggregation, there was a small increase.

A BMI cut off of 30 kg/m2 was chosen because there was a non-linear relation-ship between BMI and platelet reactivity that appeared at a BMI of 29.8 kg/m2. Similar results were obtained using waist circumference instead of BMI, but the relationship was not as strong.

In a very small sub-group (106 patients), a further aspirin dose of 325 mg/day was given for an additional 14 days, followed by platelet-function tests. The larger aspirin dose did not result in any further decrease in platelet activation.

The authors concluded that obese individuals had greater baseline plate-let function than non-obese patients, which suggests that while obese patients obtained a similar effect with low-dose aspirin, it may not have been sufficient to overcome their higher levels of native platelet activation. Further studies are needed to determine the clinical conse-quences of these observations in both epidemiological and clinical settings.


1. Gaglia MA, Torguson R, Pakala R, Xue Z, Sardi G, Mahmoudi M, et al. Relation of body mass index to on-treatment (clopidog-rel + aspirin) platelet reactivity. Am J Cardiol 2011. DOI: 10.1016/j.amjcard.2011.04.029

2. Bordeax BC, Qayyum R, Yanek LR, Vaiya D, Becker LC, Faraday N, et al. Effect of obesity on platelet reactivity and response to low-dose aspirin. Clinical study. Prevent Cardiol 2009. DOI: 10.1111/j.1751-7141.2009.00058.x.


arBs for cardiovascular and renal protection in high-risk patientsThe contribution of recent trials such as the extensive ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) ‘a thorough, double-blind, prospec-tive, randomised trial, which documents the equal-outcome efficacy of an ARB (telmisartan) and an ACE inhibitor in a high-risk population’ is noted in a recent meta-analysis of ARBs.1

Among ARBs, telmisartan is further differentiated by both its pharmacokinetic and pharmacodynamic properties.2 It has a longer half-life and higher lipophilicity than other agents in the class.

Focus on ONTARGET: cardio-vascular protection in high-risk patients without heart failureThe findings from the ONTARGET study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing the risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross-section of high-risk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.3

The ONTARGET study was designed to measure the effects of ramipril, telmisartan or a combination of the two drugs in patients over the age of 55 years. It recruited and randomised 25 620 patients over 18 months at 733 centres in 40 countries, including South Africa. These patients all had coronary, periph-eral or cerebrovascular disease or diabetes with end-organ damage.

Characteristics of the patients were similar in the three groups, which includ-ed 27% women, 75% of patients had coronary artery disease, 69% had hyper-tension, 38% had diabetes and 21% had stroke or transient ischaemic attack. The mean age was 66.4 years. Interestingly, while the majority of patients (70%) were Caucasian/European, there was a good representation of patients of Asian (15%), Latin (9%) and black African (2%) origins.

Prof Yusuf, professor of Medicine and director of the Population Health Research Institute at McMaster University, Ontario, Canada, pointed out when the ONTARGET results were announced, that this comparative head-to-head trial of telmisartan 80 mg and ramipril 10 mg

was designed to establish equivalence firstly (in statistical terms referred to as non-inferiority), and to provide clinically relevant data by choosing the usual dose of telmisartan and the proven dose of ramipril, based on the HOPE study. In addition, ONTARGET sought to answer the provocative question of whether the combination of an ACE inhibitor and an angiotensin receptor blocker would work for these high-risk patients and provide further benefit, as it does for patients with heart failure.

Comparison of telmisartan and ramiprilThe ONTARGET results showed that telmisartan (Micardis) therapy was as effective as ramipril in each component of the composite outcome, which included death from cardiovascular causes, myocar-dial infarction, stroke or hospitalisation for heart failure. The composite outcome occurred in 1 412 (16.5%) patients in the ramipril-alone treated group compared to 1 423 (16.7%) patients in the telmisartan-alone treated group.

There was no significant difference in the total number of deaths between the ramipril and telmisartan groups; 1 014 and 989 deaths, respectively. ‘Telmisartan was clearly non-inferior, as the confi-dence interval for the relative risk of the primary outcome was well below the prior established upper boundary of equiva-lence’, Prof Yusuf stressed. With regard to secondary outcomes, there were also no significant differences in the telmisartan-alone compared to the ramipril group.

Telmisartan therapy did, however, result in slightly improved blood pressure control, with somewhat lower blood pres-sure levels than those achieved in the rami-pril-alone group. Before the run-in period, the mean blood pressure was 141.8/82.1 mmHg. At six weeks, the mean blood pressure was reduced by 6.4/4.3 mmHg in the ramipril-alone group, compared to 6.9/5.2 mmHg in the telmisartan-alone group. Although the blood pressures in the telmisartan group remained slightly lower throughout the study, the differ-ence was not significant, and adjust-ment for this did not affect outcomes.

‘This study is of significant clini-cal importance because it demonstrates that telmisartan is an effective and safe alternative to ramipril. This means both

patients and physicians have choices and can use telmisartan where appropriate with a high degree of confidence. While we cannot be sure what we will see with other ARBs, with telmisartan, clinicians now know its efficacy and its tolerability’, Prof Yusuf concluded.

Renal protectionThe evidence supporting RAS blockade, and especially the use of ARBs in patients with type 2 diabetes and incipient and overt nephropathy continues to grow.

The IncipieNT to Overt Angiotensin II receptor blocker, Telmisartan, Investi-gation On type 2 diabetic Nephropathy (INNOVATION)4 study has shown that telmisartan delayed the transition from incipient to overt nephropathy in Japanese type 2 diabetes subjects, an effect that was only partly related to blood pressure control.

A clinical study conducted in patients with type 2 diabetes and overt protein-uria compared the renoprotective effect of telmisartan with that of losartan on a background of antihypertensive inter-vention as required to ensure similar blood pressure control [A trial to compare telmisartan 40 mg titrated to 80 mg versus losartan 100 mg in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO)].5 In this one-year, prospec-tive, double-blind study, telmisartan provided greater reduction in proteinuria compared with losartan.

Prof George Bakris of the Department of Medicine, Rush University Centre, Illinois, USA, pointed out that the ulti-mate test of the benefit of an antihyper-tensive agent is its ability to reduce renal and cardiovascular endpoints.6

J Aalbers, Specialist Assignments Editor

1. Bangalore S, Kumar S, Wetterslev J, Messerli FH. Br Med J 2011; 342: d2234. DOI: 10.1136/bmj.d2234.

2. Munger MA. Pharmacy Therapeut 2011; 36(1): 22–40.

3. ONTARGET proves telmisartan efficacy compared to ramipril in cardiovascular protection of patients at high risk and with-out heart failure. Cardiovasc J Afr 2008; 19(2): 108–109.

4. The Innovation Study Group. Diabetes Care 2007; 30(60): 1–2.

5. Bakris G, et al. Kidney Internal May 2008. DOI: 10.1038//ki.2008.204.

6. Cardiovasc J Afr 2007; 18: 337–340.

• In control of your prescription

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TELMISARTAN 80 MG TELMISARTAN + HCTZ

PRITOR® 40 mg. Each tablet contains telmisartan 40 mg. Reg. No. 33/7.1.3/0022.PRITOR® 80 mg. Each tablet contains telmisartan 80 mg. Reg. No. 33/7.1.3/0023.CO-PRITOR® 40/12,5 mg. Each tablet contains telmisartan 40 mg and hydrochlorothiazide 12,5 mg. Reg. No. 35/7.1.3/0347.CO-PRITOR® 80/12,5 mg. Each tablet contains telmisartan 80 mg and hydrochlorothiazide 12,5 mg. Reg. No. 35/7.1.3/0348.Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Fax: +27 (011) 787-3766. Cpy. Reg. No. 1966/008618/07.For full prescribing information refer to the package insert approved by the medicines regulatory authority. BI Ref 50/2010 (MAR 10)

S3

S3


safe use of ezetimibe plus simvastatin in high-risk vascular patients (with chronic kidney disease and Pad)The use of ezetimibe together with a statin to reduce LDL cholesterol in high-risk patients in whom raising the statin dose is not desirable has been shown to be safe in the SHARP trial and in a trial on a small group of peripheral arterial disease (PAD) patients.1,2

The SHARP study (9 270 patients) has shown that patients with chronic kidney disease who take simvastatin (20 mg) plus ezetimibe (10 mg) would typically reduce their risk of non-fatal atherosclerotic events by about a quarter (17%, CI: 0.74–0.94). This study provides new evidence for this group of patients as they are typi-cally excluded from statin and cardiovas-cular outcome trials. Importantly, there was no increase in cancer rates or myopa-thy in the ezetimibe-treated patients followed for a mean period of 4.9 years.

This independent UK trial was under-taken in patients with chronic kidney disease (with one previous measure-ment of serum/plasma creatine of at least 150 mmol/l in men and 130 mmol/l in women), whether on dialysis or not, and with no known history of myocardial infarction or coronary revascularisation.

Initially, patients entered into the trial were randomised in three ways: simvas-tatin only (20 mg), simvastatin (20 mg) and ezetimibe (10 mg) daily, or placebo, so as to test for any safety concerns with ezetimibe in the first year. No concerns were evident, so then the simvastatin group were further randomised to the placebo or the simvastatin–ezetimibe group. Patients were seen at two, six and 12 months, and every six months thereaf-ter, for at least four years in total.

LDL cholesterol levels were lowered by 0.80 mmol/l in patients not on dialysis and 0.60 mmol/l in dialysis patients. A third (33%) of the patients recruited were on dialysis (maintenance, haemodialysis and peritoneal) at randomisation, and a further third went onto dialysis during the trial, i.e. 60% of patients at the end of the study were on dialysis.

Some 30% of patients discontinued therapy with no excess of discontinua-tion in the simvastatin–ezetimibe arm. Because of non-study statin uptake in the placebo arm during the study, the average difference in proportion of those taking simvastatin plus ezetimibe versus non-

study statin was 61%.During the scheduled treatment peri-

od, there were 526 (11.3%) occurrences of a first major atherosclerotic event (non-fatal MI or coronary death, non-haemorrhage stroke or any arterial revas-cularisation) in the simvastatin–ezetimibe arm compared to 619 (13.4%) in those allocated to placebo.

Allocation to simvastatin–ezetimibe was associated non-significantly with fewer non-fatal MIs but no difference in coronary mortality. There was however a significant reduction in the risk of any type of stroke and of the need for revas-cularisation.

This trial’s outcome of beneficial advantage to patients with chronic kidney disease (without coronary heart disease) should provide the basis for wider use of cholesterol-lowering agents in patients with chronic kidney disease, and also those with coronary heart disease, who are likely to benefit even more than the SHARP cohort.

Comment to the Cardiovascular Journal of AfricaProf Brian Rayner, University of Cape TownChronic kidney disease (CKD) is now recognised as an independent risk for cardiovascular disease (CVD) and is the most important cause of death in patients with CKD. Statin therapy prevents adverse cardiovascular outcomes in patients with-out CKD, and post hoc analysis of cardio-vascular studies suggests a benefit of statin therapy in patients with reduced glomerular filtration rate.

In patients receiving haemodialysis, two trials (AURORA and 4D) showed no benefit from statins on a composite cardi-ovascular endpoint. However, CVD in patients receiving chronic haemodialysis is more complex, and whether the results of AURORA and 4D can be generalised to patients with CKD not receiving dialy-sis, is questionable.

In the SHARP study, 4 650 patients were assigned to receive simvastatin plus ezetimibe and 4 620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/l during a median follow up

of 4.9 years and produced a 17% propor-tional reduction in major atherosclerotic events with simvastatin plus ezetimibe (526, 11.3%) vs placebo (619, 13.4%) (RR = 0.83, p = 0.0021).

Non-significantly fewer patients allo-cated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (RR = 0.92, p = 0.37). There were significant reductions in non-haemorrhagic stroke (RR = 0.75, p = 0.01) and arterial revascularisation procedures (RR = 0.79, p = 0.0036). Risk reduction was similar between dialysis and non-dialysis patients. There was no excess risk of myopathy, hepatitis, gall-stones, cancer or non-vascular death.

This study definitively establishes the safety and efficacy of LDL-C lower-ing with simvastatin plus ezetimide in patients with CKD, whether they are receiving dialysis treatment or not.

The reasons for the difference between AURORA and the 4D study is not estab-lished, and may be due to differences in power or definition of cardiovascular events. However, until evidence is provid-ed of the beneficial effects of statins in randomised clinical trials in patients with CKD, cardiologists and nephrologists should prefer the combination therapy with simvastatin and ezetimide, based on the evidence. It is hoped that funders will support this approach in this very high-risk population, who require intensive cardiovascular protection.

It's theshell that

makes

safer.

R

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

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


letter to the Editor

Ezetimibe in PAD The small-group study of peripheral arte-rial disease (PAD) patients2 was a magnetic resonance imaging (MRI) study of plaque regression and did not show additional benefit with the addition of ezetimibe to patients already on statins whose LDL cholesterol was above the target of 80 mg/dl. However, tolerability was excellent; only one patient discontinued simvas-tatin therapy, while no discontinuations occurred in the ezetimibe treatment arms.

The PAD study was a surrogate-outcomes trial of 67 patients using MRI to evaluate atherosclerosis in the super-ficial femoral artery. Results showed no significant progression of atherosclerosis in the statin-naïve patients who were randomised to simvastatin 40 mg, or in those randomised to simvastatin plus

ezetimibe (10 mg).Patients previously on a statin who

had ezetimibe added at study enrolment, demonstrated plaque progression despite the significant reduction in LDL-C. It should be noted that this part of the trial had no control arm for comparison.

Prof Derick Raal, University of the WitwatersrandProf Raal noted that the PAD study has major efficacy limitations. ‘Numbers were small and the reproducibility of the technique used is still questionable. In my view, if ezetimibe is so “ineffec-tive or valueless”, there should also have been progression in the statin-naïve group who received the simvastatin/ezetimibe combination, which did not happen. In fact this group had the biggest regression

in plaque volume.’ ‘Surrogate endpoint trials can be very

misleading, as shown by the ARBITER 6 study, which, following discontinuation of the AIM-High study, must be seriously questioned. Finally, we need to await the results of the large outcome trial with ezetimibe (Improve-It).’


1. Baigent C, et al. (on behalf of the SHARP investigators). The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease. Lancet 9 June 2011. DOI: 10:1016/50140-6736(11)60739-3.

2. West AM, Anderson JD, Meyer CH, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use baseline. Atherosclerosis 2011; DOI: 10.1016/j.atherosclerosis.2011.04.005.

Torulopsis glabrata endocarditis in a retro-positive individualI present an unusual case of Torulopsis glabrata endocarditis in a retro-positive patient.

An HIV-positive patient presented with symptoms of endocarditis. He showed all the usual features of endocarditis, namely roth spots, splenomegaly, chang-ing murmurs, slinter haemorrhages, etc.

Initially, a dignosis of either acute or sub-acute bacterial endocarditis was enter-tained. However, fungal cultures showed the patient to have a Torulopsis glabratea endocarditis. The most common fungal culture found in vegetations on the heart valves is Candida albicans but Torulopsis glabrata has also been described.

These vegetations may be detected with transoesophageal echocardiography and generally the vegetations in fungal endocarditis are larger than those seen in acute or sub-acute bacterial endocarditis.1

The patient responded to antiretroviral treatment, intravenous amphoteracin B and intravenous fluconazole.

With the increase in prevalence of HIV/AIDS, diabetes and patients on immunosuppressive treatment for organ transplantation, there has been an increase in fungal endocarditis. Rheumatic heart disease is still rife in South Africa and many patients therefore have damaged heart valves, particularly mitral valves.

hD Solomons highlands North, Johannesburg, South Africa

Reference1. Sharpe DN. Torulopsis glabrata endocarditis

complicating aortic homograft. 26 March 1975. (WWW.NCBI Govpubmed/1055952.)

It's theshell that

makes

safer.

R

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

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

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 mild to moderate (1,3)

• Low discontinuation rate comparable to placebo (3)

• No monthly liver function testing required (3)

For full prescribing information, refer to the package insertReferences: 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.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. 23/REV/11/10/JA

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“THE CURRENT AHA DIETARY GUIDELINES

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OF APPROXIMATELY 1000 mg/DAY IN PATIENTS

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Vol. 54,No. 7 2009, August 11, 2009 585– 594

TRIMEGA™

* HIGH STRENGTH EPA & DHA 300 MG EPA AND

200 MG DHA IN A SINGLE CAPSULE

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(PTY) LTD Reg. No. 1993/003911/07

AFRICA

JULY / AUGUST 2011VOL 22 NO 4

CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

Cardiovascular Journal of A

frica . Vol 22, No 4, July/A

ugust 2011

• Management of hypertension at primary level

• Mitochondrial proteins in a mouse model

• Colour M-mode evaluation of myocardial performance

• Health practitioners’ management of hypertension

• Heart disease in Sudan

• Time to revise antiretroviral therapy guidelines

• Subclavian crush syndrome

• Left ventricular outflow tract obstruction of acute myocardial infarction

• Waist-to-height ratio in children with high blood pressure

• The evolution of heart rate Pr

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CVJA Volume 22, Issue 4

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Transcript of CVJA Volume 22, Issue 4