CVJA Volume 24, Issue 3 by Clinics Cardive Publishing

APRIL 2013 VOL 24 NO 3

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CardioVascular Journal of Africa (official journal for PASCAR)

• Non-communicable diseases in Uganda • Selective inhibition of angiotensin II type 1 receptors • Hypertension and associated factors in older adults • Neonatal circulatory failure due to hypertensive crisis • Decreased vascular contractility induced by hemin • Cardiovascular complications in RHD patients

Cardiovascular Journal of Africa . Vol 24, No 3, April 2013

Printed by Tandym Printers

• Management of acute ischaemic stroke

Five decades of global cardiovascular heritage

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CardioVascular Journal of Africa (official journal for PASCAR)

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VOL 24, NO 3. APRIL 2013

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EditoriaL

51 Acute ischaemic stroke: highlighting the need for early intervention G Modi

Cardiovascular Topics

52 The prevalence and distribution of non-communicable diseases and their risk factors in Kasese district, Uganda CK Mondo • MA Otim • G Akol • R Musoke • J Orem 58

Modulation of haemodynamics, endogeneous antioxidant enzymes, and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressure-overload rats G Moinuddin • MN Inamdar • KS Kulkarni • C Kulkarni

Hypertension and associated factors in older adults in South Africa K Peltzer • N Phaswana-Mafuya

Neonatal circulatory failure due to acute hypertensive crisis: clinical and echocardiographic clues J Louw • S Brown • L Thewissen • A Smits • B Eyskens • R Heying • B Cools • E Levtchenko • K Allegaert • M Gewillig

76 Decreased vascular contractility induced by hemin is associated with a reduced rho-kinase activity B Awede • M-C Lemaire • P Bonnet • V Eder 80

Cardiovascular complications in newly diagnosed rheumatic heart disease patients at Mulago Hospital, Uganda E Okello • Z Wanzhu • C Musoke • A Twalib • B Kakande • P Lwabi • NB Wilson • CK Mondo • R Odoi-Adome • J Freers

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

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie

Heart Failure Dr g visagie Paediatric dr s brown Renal Hypertension dr brian rayner

Regional Editor (Kenya) Dr F Bukachi

Surgical dr f aziz

Regional Editor (South Africa) PROF R DELPORT

Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

Letter to the Editor

Cardiomyopathies and myocardial disorders in Africa: present status and the way forward BM Mayosi

Management of ischaemic stroke in the acute setting: review of the current status K Jivan • K Ranchod • G Modi

Review Article

VOL 24, NO 3. APRIL 2013

CONTENTS

Cardio News

93 Successes, failures, challenges and ground-breaking research: messages from the 6th World Congress of Paediatric Cardiology and Cardiac Surgery L Zühlke

Drug Trends in Cardiology

95 South African studies in the international literature G Hardy 97

Higher statin doses linked to acute kidney injury: South African experts comment on clinical implications J Aalbers

98 Treating hypertension in the elderly, even white-coat hypertension, is essential J Aalbers 100 Use new antiplatelet therapies consistently in clinical practice J Aalbers

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

Case Reports

Left ventricular non-compaction in pregnancy ID Kilic • H Tanriverdi • H Evrengul • S Uslu • MA Sungur

e3 Unusual variant of scimitar syndrome associated with an absent right pulmonary artery, stenosis of the inferior vena cava, hemi-azygous continuation and the VACTERL association FF Takawira • F Omar e7

Candida parapsilosis endocarditis on a prosthetic aortic valve with unclear echocardiographic features CM Mvondo • F d’Auria • P Sordillo • A Pellegrino • M Adreoni • L Chiariello

e9 Robotically assisted ventricular tachycardia substrate modification ablation with the novel Lynx TM integrated sheath and RF ablation catheter F Lorgat • E Pudney • H van Deventer e12 Unexpected preserved brain perfusion imaging despite severe and diffuse atherosclerosis of supra-aortic trunks G Gargiulo • F Tortora • M Cirillo • C Perrino • GG Schiattarella • B Trimarco • G Esposito managing editor

GLENDA HARDY Tel: 021 976 8129 Cell: 071 819 6425 e-mail: glenda@clinicscardive.com

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

Editorial Acute ischaemic stroke: highlighting the need for early intervention If only the brain was like the heart where losing a ‘bit’ from ischaemia and infarction would have little effect on its function, the treatment of stroke in the acute setting would not be such a public health issue. The effects of stroke on an individual and the burden its leaves on families and society are enormous and costly. Stroke remains the third leading cause of death worldwide. The annual death toll on stroke is reported as being approximately 7.8 million.1 Despite current treatment options and interventions, this number is projected to rise and reach almost eight million in the next 15 years. In developed countries the cost of stroke treatment ranges from $500–150 000.2 This wide range is presumably related to the greater use of mechanical interventions in some countries as opposed to predominantly pharmaceutical interventions in others. Unfortunately, in developing countries, cost estimates are not readily available. The only reported data comes from Togo where a cost of EUR400 is estimated.3 Definitive treatment that would completely reverse an ischaemic event to the brain remains the holy grail of neurology. In the review by Drs Jivan, Ranchod and Modi, a PUBMED search and analysis of data on the management of acute ischaemic stroke (AIS) from 1995 to 2012 is presented. The interventions described include intravenous recombinant tissue plasminogen activator (IV r-tPA)-induced thrombolysis, intraarterial (IA) thrombolysis and the controversial aspects of clotremoval treatments. The conclusions are simple in that the gold standard for treating AIS remains IV r-tPA. The important facts in this regard are that the other intravenously administered agents, including streptokinase, reteplase, urokinase, anistreplase and staphylokinase, show no benefit and should be avoided in routine clinical practice.4 The data on IV r-tPA from the ECASS 3 trial indicated that for every 100 patients treated in the 3–4.5-hour window period, 16.4 will have a better outcome and 2.7 will have a worse outcome.5 The risk of intracranial haemorrhage was 27 vs 17.6% for placebo.5 The mortality between the treated and placebo groups were not significantly different. The data therefore indicate that the treatment modality is not ideal and is limited by the 3–4.5-hour window period but we have nothing better. IA thrombolysis should theoretically be the better treatment option but strangely, the suggestion in the literature is that IA thrombolysis in not significantly better than IV thrombolysis.6 A conclusive study in this regard is lacking. With regard to mechanical clot retrieval, the simple answer is that this is becoming ‘much ado with nothing significantly

attained’. The theoretical concept is appealing and the technical expertise is available. The results, however, and in particular with the popular MERCI device, have been disappointing. The investment in mechanical clot retrieval continues and newer devices are developing, including a penumbra system, which disrupts and aspirates the thrombus. This is undergoing evaluation and is apparently promising. Stent-based therapy and endovascular angioplasty are also used with varying degrees of success. The problem with these devices is that the endpoint of recanalisation is readily achieved but is not associated with clinically significant outcomes. The future of this therapeutic approach therefore remains to be determined. The conclusions are that for patients with AIS, early intervention within 4.5 hours with IV r-tPA is the only option for reversal at present. This needs to become widely used in the emergency departments of all public and private hospitals nationally. We must review and recharge the national drive for public stroke awareness to facilitate this. GIRISH MODI, MB BCh (Wits), MSc (Lond), PhD (Lond), FCP (SA), FRCP (Lond)

Department of Neurosciences, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

References 1. 2.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

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Cardiovascular Topics The prevalence and distribution of non-communicable diseases and their risk factors in Kasese district, Uganda CHARLES KIIZA MONDO, MARCEL ANDREW OTIM, GEORGE AKOL, ROBERT MUSOKE, JACKSON OREM

Abstract Background: To date there has been no population-based survey of the major risk factors for non-communicable diseases (NCD) in Uganda. Hospital-based data from urban centres report an increasing burden of NCDs in Uganda. This population-based survey aimed to describe the prevalence of risk factors for NCDs in a rural Ugandan district. Methods: The survey was conducted using the WHO STEPwise approach to surveillance of non-communicable diseases (STEPS) methodology. Participants (n = 611) were residents of the Kasese district selected in a one-step, complete survey of a rural district. Standardised international protocols were used to record history of disease, and measure behavioural risk factors (smoking, alcohol consumption, fruit and vegetable consumption, physical activity), physical characteristics [weight, height, waist and hip circumferences, blood pressure (BP)], fasting blood glucose (BG) and total cholesterol (TC) levels. Data were analysed using simple descriptive analysis. Results: In this sample, the prevalence of hypertension (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) was 22.1% for men and 20.5% for women. Fifteen per cent of men and 16.8% of women were overweight [body mass index (BMI) ≥ 25 kg/m2] and 4.9% of men and 9.0% of women were obese (BMI ≥ 30 kg/m2). Nine per cent of participants were diabetic, 7.2% ate five or more combined servings of fruit per day while only 1.2% ate five or more combined servings of vegetables per day. Fifty-one per cent of the population were physically inactive and 9.6% were daily smokers. Thirty-one per cent of females had fasting blood sugar levels (FBS) ≥ 6.1 mmol/l while 10% of males had FBS > 6.1 mmol/l. Conclusion: This study presents evidence on the magnitude of NCDs, their risk factors and gender distribution in a rural population in Uganda, a poor country in east-central Africa. Department of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda

CHARLES KIIZA MONDO, MB ChB, MMed, PhD, charlesmondo2011@gmail.com MARCEL ANDREW OTIM, MB ChB, MMed, MD ROBERT MUSOKE, MB ChB, MSc

Alcomed Specialist Diagnostic Service, Kasese, Uganda GEORGE AKOL, MB ChB, MMed, MRCP

Uganda Cancer Institute and Department of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda JACKSON OREM, MB ChB, MMed

These data, when combined with urban population data, could be useful in the formulation and advocacy of NCD policy and plans of action in Uganda. Keywords: non-communicable diseases, WHO STEPs, smoking, obesity, physical activity Submitted 24/4/12, accepted 28/11/12 Cardiovasc J Afr 2013; 24: 52–57

www.cvja.co.za

DOI: 10.5830/CVJA-2012-081

Non-communicable diseases (NCDs) are currently responsible for 35% of all deaths in low- and middle-income countries,1 and this alarming figure is predicted to rise in the near future. The World Health Organisation projects that the burden of disease due to NCDs will increase rapidly in the years ahead. From a projected total of 58 million deaths from all causes in 2005, it was estimated that NCDs would account for 35 million deaths, which was double the number of deaths from all communicable diseases (including HIV/AIDS, tuberculosis and malaria), maternal and perinatal conditions and nutritional deficiencies combined.1 This epidemiological transition in global health from infectious diseases to NCDs is posing not only a threat to the health of those affected but also places an enormous burden on the health systems of nations, particularly those of the least-developed countries, as they must now address a double burden of acute and chronic diseases amidst scarce resources.2-4 Furthermore, this epidemiological transition is adversely impacting on socio-economic development of nations, as NCDs tend to be more prevalent in young working class people.2 As a more sophisticated workforce becomes a highly valued and harder-toreplace economic investment, the increasing prevalence of NCD risk factors in developing countries, particularly sub-Saharan Africa (SSA), becomes a real threat to economic progress, adversely impacting on all the previous gains made in combating HIV, malaria, tuberculosis and other infectious diseases.5 In Uganda, while acute infectious communicable diseases still contribute the major (75%) disease burden, with malaria, acute respiratory infections and HIV/AIDS among the top 10 causes of illness and death,6 the burden of NCDs is increasingly posing a threat of dual epidemics of communicable and non-communicable diseases. The International Diabetes Federation put estimates of incidence of diabetes mellitus in Uganda at 50 000 affected individuals in the year 2003, and projected a 10-fold increase in the cases of diabetes by 2025 if no interventions are initiated.7 Estimates suggest that as many as 8%

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

of people living in Kampala may have type 2 diabetes (T2D),8 while deaths attributed to NCDs in Uganda were estimated at 31 700 in 2002.9 Estimates of age-standardised mortality from NCDs suggest that countries in SSA, including Uganda, might have a more than three-fold higher mortality rate than several European countries, including the UK.9 However, these estimates are based on limited data and statistical models derived from child mortality rates and cause-specific rates from external sources. Several publications have highlighted the need for local high-quality epidemiological data on the burden of NCDs and their risk factors, particularly in SSA where such data are scarce.10,11-14 To date, there has been no systematic population-based study on NCD risk factors conducted in Uganda. Accordingly, between December 2011 and February 2012, we conducted a cross-sectional survey using the WHO NCD STEPS survey tools to determine the magnitude of NCDs and their risk factors in Kasese district, Uganda to serve as a pilot study for the nationwide survey of NCD risk factors.

Methods Ethical approval was granted by the Uganda National Council for Science and Technology’s Human Research and Ethics Committee, and the President’s Office Research Secretariat. Written informed consent was obtained before participants were enrolled in the study, using the WHO NCD STEPS survey consent form. This study was a community population-based, cross-sectional survey designed according to a WHO STEPwise approach to chronic disease risk-factor surveillance.15 Data were collected in three steps; step 1 used a questionnaire to collect demographic and lifestyle data; step 2 involved measurements of height, weight, blood pressure (BP), waist and hip circumference; and step 3 used laboratory (biochemistry) investigations. Kasese district is divided into two counties, Bukonzuo (10 sub-counties) and Busongora (12 sub-counties). One sub-county was selected from each county. Bugoye sub-county from Busongora is predominantly rural, whereas Mpondwe sub-county from Bukonzuo is peri-urban. The two sub-counties selected are the most populous in each county. Both sub-counties comprise 14 parishes, 61 villages with a total of 11 986 households. Using the cluster sampling method, seven households were randomly selected from each village. Finally, at least one adult in the selected households was invited to participate. Where a household had no consenting adults, the neighbouring household was approached. The survey was conducted using the WHO recommended STEPwise approach.16 Step 1, the survey questionnaire, was administered by the field staff. It consisted of core (age, gender, education in years, current exposure to tobacco and alcohol, diet and physical activity), expanded (rural/urban setting, occupation, average household income) and optional (marital status, medical and health history, past history of smoking and alcohol consumption) variables. The medical and health history component included questions on medication, cigarette use, diabetes mellitus and hypertension. Step 2 involved physical body measurements, including BP, height, weight, and waist and hip circumference measurements. BP measurements were taken using battery-powered digital BP

machines (Omron M3-I). The participant was asked to sit on the chair and rest quietly for 15 minutes with his/her legs uncrossed. The left arm of the participant was then placed on the table with the palm facing upward. Three readings, three to five minutes apart, were then taken on the left arm. During the analysis the average of the last two readings was the final BP reading used. Height was measured with the participant standing upright against a wall on which a height mark was made. Measurements were taken with the participant barefoot, standing with the back against the wall and head in the Frankfort position, with heels together. The participant was asked to stretch to the fullest. After being appropriately positioned, the participant was asked to exhale and a mark was made with a white chalk to mark the height. The height was then measured to the nearest 0.1 cm from the mark to the floor using a tape measure. Weight measurements were taken on a pre-calibrated weighing scale (Seca scale). Participants were weighed dressed in light clothing and barefoot. Measurements were taken to the nearest 0.1 kg. Step 3 involved laboratory tests. Consenting participants were asked not to consume any food, only water from after supper that day until the survey team collected the blood samples the next day (eight-hour fast). People converged at the agreed place in their community. Those who had complied with the overnight fast were eligible for finger-prick blood sample collection. Total cholesterol (TC) and triglyceride (TG) levels were measured using Reflotron-Plus machines manufactured by Roche. Fasting blood glucose (FBG) level was measured on two machines, the Accu-Chek Active glucometer from Roche and the Soft-Style glucometer from Chem-labs. Hypertension was defined as a diastolic BP of 90 mmHg or more, or a systolic BP of 140 mmHg or more, or currently on medication for hypertension (documented in the health booklet). Diastolic BP ≥ 110 mmHg or systolic ≥ 180 mmHg was considered to be severe hypertension. Raised fasting blood glucose was defined as a blood glucose level ≥ 7.0 mmol/l or currently on medication for diabetes mellitus (documented in the health booklet). Raised total cholesterol was defined as cholesterol level ≥ 5.0 mmol/l. Overweight was defined as body mass index (BMI) ≥ 25.0 kg/m2 and obesity as BMI ≥ 30.0 kg/ m2. Excessive or harmful use of alcohol was defined as the consumption of five or more for men, four or more for women, standard units per day for three or more days per week. Physical activity was measured using questions on four different aspects: physical activity at the workplace, physical activity during recreation time, physical activity while travelling, and physical resting time. A heavy smoker is, according to the recommendations of the World Health Organisation (WHO), a smoker with a daily consumption of more than 20 cigarettes.

Statistical analysis Data were collected manually using case record forms (CRFs), captured into epi-data and later transferred to STATA version 10 for analysis. Values are expressed as percentages of total respondents. Simple bivariate analysis was used to analyse the data. Priority was given to practical benefit and clinical significance in interpreting statistically significant data. Statistical significance was set at p < 0.05.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

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Number of eligible participants selected 611 No. refused to take part in the survey (93, 15.22%) Number of participants interviewed (518, 100%)

Number of participants with body mass index measured (513, 99.03%)

No. consented to take part in the survery (518, 84.78%)

Number of participants with blood pressure measured (518, 100%)

Number of participants with blood glucose measured (499, 96.33%)

Fasting blood glucose (128, 25.65%)

Number of participants with blood cholesterol measured (518, 100%)

Non-fasting blood glucose (371, 74.35%)

Fig. 1. Flow diagram.

Results A total of 611 eligible adults were selected and approached to participate in the survey. Of these, 93 (15.22%) refused while 518 (84.87%) consented to take part in the survey. Of the 518 participants who took part, 56% were female and 29% had no formal education, while 41% had primary school education. BP, and fasting blood sugar and total cholesterol levels were measured in 100, 25.7 and 27.8%, respectively of the 518 participants (Fig. 1, Table 1). Sixteen per cent of females and 11% of males were told by the doctor that they had hypertension, while only 8% of females and 7% of males with diagnosed hypertension were currently on medication for hypertension (Fig. 2). Twenty per cent of females

had SBP ≥ 140 mmHg and 20% had DBP ≥ 90 mmHg; while 22% of males had SBP ≥ 140 mmHg and 17% had DBP ≥ 90 mmHg (Fig. 3). There was no statistical difference between the genders (SBP, p = 0.758; DBP, p = 0.503). Ten per cent of males had fasting blood sugar levels > 6.0 mmol/l compared to 33% of females, while 12.5% of male had a positive family history of diabetes mellitus (DM) and 3.5% were on treatment for DM. Sixteen per cent of females had a positive family history of DM and 2.2% were on treatment for DM (Figs 4, 5). 18 16 14 12

Total 528

n 297

% 45.5

Female n % 231 54.5

Gender* Age (years) 25–34 179 98 34.0 81 35.1 35–44 118 63 21.9 55 23.9 45–54 104 57 19.9 47 20.2 55–64 57 36 12.8 21 9.3 > 64 60 33 11.5 27 11.5 Education None 112 41 14.1 71 30.9 Primary school 243 129 45.1 114 49.7 Secondary school (O level) 113 82 28.3 31 13.5 Secondary school (A level) 27 18 6.4 9 3.9 University/college 23 17 6.1 6 2.0 Occupation Peasant 326 159 55.6 167 72.2 Trader 20 11 3.7 9 3.9 Teacher 28 22 7.4 6 2.5 Housewife/homemaker 10 0 0 10 4.49 Other 80 66 23.3 14 6.2 None 54 29 10.1 25 10.7 Marital status Married 411 244 84.9 167 71.9 Separated 38 17 6.1 21 9.3 Widowed 39 8 2.4 31 13.5 Never married 30 18 6.7 12 5.3 *Percentage is by column for gender only. The rest of the variables are by rows.

10 8 6 4 2 0

Male

History of hypertension

Told by Dr.

on Treat

Fig. 2. History of hypertension (HT) and treatment status; 11% of males knew of their hypertension, 7% were on treatment; 16% of females knew of their hypertension, 8% were on treatment. 90 80 70 60 %

Male

TABLE 1. CHARACTERISTICS OF THE STUDY PARTICIPANTS

50 40 30 20 10 0

< 140 ≥ 140 < 90 ≥ 90 Diastolic BP Systolic BP Blood pressure Male Female M+F

Fig. 3. Systolic and diastolic BP; 21% of the population had SBP ≥ 140 mmHg; 18% had DBP ≥ 90 mmHg.

10 8

30 20

2 Male

Female Diabetes category Family History

Male

Diabetic

The prevalence of underweight, overweight and obesity were more frequent in women than men (35.9 vs 20.2%, 16.7 vs 14.7% and 9.0 vs 4.9%) (Fig. 6). Raised total cholesterol was more frequent in women than men (16 vs 11%). Ten per cent of the population had elevated total cholesterol levels while 21% had elevated triglyceride levels (Fig. 7). Nine per cent of males and 5.7% females ate five or more servings of fruit per day; 1.2% of males and 1.1% of females ate five or more servings of vegetables per day. Tobacco smoking, alcohol drinking (any amount) and excessive alcohol drinking were more common in men than women (22.5 vs 15.5%, 23.9 vs 10.3%, 4.1 vs 1.2%, respectively). There was no significant difference between the genders with regard to physical activity (52% male, 50% female, p = 0.703) (Figs 8–11).

Discussion This is the first population-based survey using internationally standardised protocols to report the prevalence of risk factors for NCDs in the Kasese district of Uganda. This study demonstrated that chronic non-communicable diseases and their risk factors constitute a public health problem in the Kasese district, with at least one in five men smoking tobacco, one in five with B

100

F M F+M

Under wt (%)

Over wt (%)

Obese (%)

35.9 20.2 29.9

16.7 14.7 15.6

9.0 4.9 6.7

hypertension, one in 10 with a positive family history of DM, one in five being pre-diabetic and therefore a candidate for the metabolic syndrome, and one in five overweight/obese. The first major finding of this study was the high prevalence of hypertension, both self-reported and point-measured BP during the survey. The majority of people with hypertension did not know they had this medical problem, which is consistent with findings from other studies in sub-Saharan Africa.17 Hypertension is the leading cause of stroke in Africa. A further finding that only 3.7% were on treatment reflects the low level of knowledge of the dangers of untreated hypertension in the population. A striking finding was that there was no difference in the prevalence of hypertension between the genders. Factors not measured in this survey, and which may explain the observed risk among women, were hormonal status, saturated fat consumption and salt intake. Also, further studies should be done to document the proportion of those on treatment whose BP is under control, as well as the presence of hypertensive heart disease among those with hypertension. The second major finding was that the risk profile of this predominantly rural population of Kasese was markedly different from that reported previously for the urban and peri100

25 %

40 30

< 6.1 6.1–6.9 ≥ 7.0 Fasting glucose, n = 128 Male

6 4

Male Female FBS, n ≥ 6.1

Female

Fig. 5. Fasting blood sugar (FBS) levels. (a) 19% had FBS of 6.1–6.9 mmol/l; 9% ≥ 7.0 mmol/l. (b) 31% of females had FBS ≥ 6.1 mmol/l, 10% of males ≥ 6.1 mmol/l.

50 40

≥ 30

Female

26–29

BMI

Fig. 6. Body mass index; 29.9% were underweight, 15.6% were overweight, and 6.7% were obese.

19–25

M+F

Fig. 4. Family history of DM and on treatment for DM; 13.9% of the total study population had a family history of DM; 2.9% were diabetic.

< 19

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

% of total population

AFRICA

≥ 5.2 < 5.2 Total Cholesterol Male

≥ 1.7 < 1.7 Triglycerides Female

Male Female High Cholesterol + Triglycerides

Fig. 7. Cholesterol and triglycerides; 14% of males had elevated lipid levels, 18% of females had elevated lipid levels.

20 15 10 5 0

Male

M+F Female Smoking habits Tobacco smoking Daily smokers

50.5 50

49.5 49

48.5 48

47.5 Male

Female Physical activity

M+F

Fig. 9. Physical activity; 51% of the population were physically inactive.

30 25 20 15 10 0

Male

Female Alcohol drinking habits

Ever Drunk

Last 1 yr

M+F

â&#x2030;Ľ 5 days per wk

Fig. 10. Alcohol consumption; 41.6% had never drunk alcohol in their life; 34.1% had drunk in the past 12 months; 5.3% of the active drinkers drank â&#x2030;Ľ five days/ week (average number of drinks per day was three for men and two for women).

population. A key strength of this study was the use of a representative sample, with analysis taking into account the complex survey design. The relatively high response level minimises the likelihood of selection bias, and the range of factors that were measured should be a good reflection of those factors in the Kasese population. The use of WHO standardised protocols, intensive training of data-collection staff, pre-study testing of procedures, and the close supervision of staff during data collection all highlight the attention that was paid to minimising avoidable sources of measurement error. Limitations of this study need to be borne in mind. The STEPS methodology is designed to provide standardised information on key modifiable risk factors that can be measured in populationbased surveys without resorting to high-technology instruments. It is not designed to measure total energy intake, dietary fat, dietary sodium, body fatness or physical activity by objective methods, such as accelerometry and pedometry. Information on these factors would have provided a more comprehensive picture of the relationships we studied. In addition, these crosssectional data do not allow age-related differences in BP, blood glucose and total cholesterol levels to be attributed to ageing, independent of cohort effects. Assessment of risk factors by age group as well as fasting blood sugar level for different BMIs would have provided more insight. Finally, due to lack of power, we were not able to assess the relationship between underweight and diabetes. % of total population

% of total population

urban settings.10-12 The prevalence of raised blood glucose levels (defined as capillary whole BG of at least 6.1 mmol/l) in 31% of females and 10% of males, DM (13.9% had a family history of DM, 2.9% were diabetic), raised BMI (15.6% were overweight, 6.7% were obese), and tobacco smoking (24% had history of smoking with 9.6% heavy smokers) were markedly higher than previously speculated. The level of physical activity was surprisingly lower than expected in this predominantly hilly area, although different definitions of physical activity could have led to this response. These findings support the need for regular screening of individuals for NCDs and their risk factors. There was a high prevalence of underweight people (29.9%). When taken together with the observed rates of DM and glucose intolerance, questions arise with regard to the possibility of a connection between under-nutrition and DM. In general, this study highlights the need to undertake population-based studies in all districts in the country to quantify the magnitude of NCDs at a national level. It is evident that there is variation among ethnic groups and locations, as various factors contribute to the development of disease and other factors contribute to the perpetuation of diseases. In order to institute a cost-effective intervention, the specific factors at play in a given population must be identified. It may not be appropriate to generalise these findings to refer to the Karamoja population. These results though are useful in guiding intervention and preventative measures for the Kasese population, and should be well received by policy makers in the local government of Kasese, as well as the ministry headquarters. For example, vegetables and fruits are grown in large quantities in Kasese, but consumption is low. Most are sold to the cities. The population is not aware of the benefits to their health of eating fruit and vegetables. Mass education to encourage increased consumption of fruits and vegetables will benefit the

Fig. 8. Smoking habits; 24% had a history of smoking; 9.6% were daily smokers (average number of cigarettes per day was six for males and three for females).

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% of Population

% of total population

10 8 6 4 2 0

M+F Male Female Fruit and vegetables consumption

Fruits

Vegetables

Fig. 11. Fruit and vegetable intake; 7.2% of the total population ate five or more servings of fruit per week; 1.2% of the total population ate five or more servings of vegetables per week.

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Conclusion This study provides the first NCD risk-factor profile of people in the Kasese district, Uganda, using internationally standardised methodology. Our findings for this predominantly rural sample provide evidence for health policy-makers as well as district authorities on lifestyle problems in the population studied. The burden of more diseases is to be expected if an effective prevention strategy is not undertaken. Although even short-term educational programmes have been shown to be effective in improving lifestyle, a durable education strategy and cost-saving policies supported by sustained largescale media education and school-based educational programmes could be the starting point for a possible national programme on controlling NCDs in Uganda. A national NCD risk-factor survey should however be undertaken to avoid biased generalisation of results, as Kasese is not a representative population of Uganda.

5. 6.

7. 8.

9. 10.

11.

12. We thank DANIDA through the Danish NCD Alliance – Uganda NCD Alliance partnership for financial support for the data collection. We also thank Dr Bahendeka Silver for his contribution during the initial design of the study protocol. Ms Susanne Vilquarzt of the Danish NCD Alliance was helpful in writing the grant application to DANIDA. Ms Wandera Rebecca was helpful in data capture and analysis. We thank the entire field staff in Kasese for the data collection. We are grateful to Dr Hassan Sebina, the management and staff at Kagando Hospital and Alcomed Clinics for their invaluable input.

References 1.

3. 4.

Lopez D, Mathers C, Ezzati M Jamison T, Murray C, eds. Global Burden of Disease and Risk Factors. New York: Oxford University, 2006. Kengne AP, Amoah AGB, Mbanya JC. Cardiovascular complications of diabetes mellitus in sub-Saharan Africa. Circulation 2005; 112: 3592–3601. Greenberg H, Raymond SU, Leeder SR. Cardiovascular disease and global health: threat and opportunity. Health Affairs 2005; 24: 31–41. Strong K, Mathers C, Leeder S, Beaglehole R. Preventing chronic diseases: how many lives can we save? Lancet 2005; 366: 1578–1582.

13.

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16. 17.

Greenberg H, Raymond SU, Leeder SR. Cardiovascular disease and global health: threat and opportunity. Health Affairs 2005; 24: 31–41. Hyder AA, Liu L, Morrow RH, Ghaffer A; Global Forum for Health Research. Application of Burden of Disease Analyses in Developing Countries, 2006. International Diabetes Federation. Diabetes Atlas. 2nd edn. Brussels, 2003. Lasky D, Becerra E, Boto W, Otim M, Ntambi J. Obesity and gender differences in the risk of type 2 diabetes mellitus in Uganda. Nutrition 2002; 18: 417–421. WHO. Disease burden estimates. http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html. 2009. Maher D, Smeeth L, Sekajugo J. Health transition in Africa: practical policy proposals for primary care. Bull World Health Org 2010; 88: 943–948. doi: 10.2471/BLT.10.077891. Maher D, Harries AD, Zachariah R, Enarson D. A global framework for action to improve the primary care response to chronic non-communicable diseases: a solution to a neglected problem. BMC Public Health 2009; 9: 355. doi: 10.1186/1471–2458-9-355. Lins NE, Jones CM, Nilson JR. New frontiers for the sustainable prevention and control of non-communicable diseases (NCDs): a view from sub-Saharan Africa. Glob Health Promot 2010; 17: 27–30. doi: 10.1177/1757975910363927. McCarthy M, Maher D, Ly A, Ndip A. Developing the agenda for European Union collaboration on non-communicable diseases research in Sub-Saharan Africa. Health Res Policy Syst 2010; 8: 13. doi: 10.1186/1478-4505-8-13. Unwin N, Setel P, Rashid S, Mugusi F, Mbanya JC, et al. Noncommunicable diseases in sub-Saharan Africa: where do they feature in the health research agenda? Bull World Health Org 2001; 79: 947–953. World Health Organisation Regional Office for South-East Asia. Research priorities in noncommunicable diseases. Kathmandu, Nepal. 2009. Available: http://www.searo.who.int/LinkFiles/Non_ Communicable_Diseases_Research_priorities. pdf. Accessed 29 Nov 2010. Mensah GA. Epidemiology of stroke and high BP in Africa. Heart 2008; 94: 697–705. doi: 10.1136/hrt.2007.127753. World Health Organization. Noncommunicable Diseases and Mental Health Cluster. WHO STEPS Surveillance Manual: The WHO STEPwise Approach to Chronic Disease Risk Factor Surveillance. Geneva: World Health Organization, 2005.

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Modulation of haemodynamics, endogeneous antioxidant enzymes, and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressureoverload rats GHULAM MOINUDDIN, MOHAMMED NASEERUDDIN INAMDAR, KALA S KULKARNI, CHANDA KULKARNI

Abstract

Submitted 17/6/10, accepted 28/11/12

Background: Constriction of the thoracic or abdominal aorta provides an experimental model of pressure-overload cardiac hypertrophy. Blockade of AT1 receptors is beneficial in preventing target-organ damage in hypertension. Objective: To examine the effect of angiotensin II receptor antagonists on blood pressure, endogenous antioxidant enzyme and histopathological changes in pressure-overload rats. Methods: Pressure overload was produced by abdominal aortic banding (AAB) using a blunt 22-guage needle in male rats as a model of cardiac hypertrophy. After surgery, the AAB-induced hypertension (AABIH) rats were treated with losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbesartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of surgery, the rats were observed for general characteristics and mortality, and we determined non-invasive blood pressure (NIBP), endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activities, and histology of the target organs. Results: In the AABIH group, significant increase in systolic blood pressure was observed from weeks 3 to 16 compared with the control group, along with reduced serum catalase and SOD activities. The treated groups showed significant reduction in systolic BP and increase in serum SOD and catalase activities. The histological changes induced in the target organs, namely heart, liver, kidneys and thoracic aorta in the AABIH rats were attenuated in the treated rats. Conclusion: Blockade of the AT1 receptor caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress in the hypertensive rats, which was evidenced by the protection observed in the treatment groups.

Cardiovasc J Afr 2013; 24: 58–65

Keywords: abdominal aortic banding, cardiac hypertrophy, hypertension, RAS, AT1 receptor blockers Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India

GHULAM MOINUDDIN, MPharm, PhD (Pharmacol), ghulam. moinuddin5@gmail.com MOHAMMED NASEERUDDIN INAMDAR, MPharm, PhD (Pharmacol)

Clinical Pharmacy, School of Pharmacy and Technology Management, Mumbai, India KALA S KULKARNI, MD

Department of Pharmacology, St John’s Medical College, Bangalore, India CHANDA KULKARNI, MB BS, MD, PhD

www.cvja.co.za

DOI: 10.5830/CVJA-2012-080

Angiotensin II (Ang-II), the most active component of the renin– angiotensin system (RAS), is a multifunctional hormone that plays an important role in cardiovascular physiology and pathology.1 Ang-II production in proximity to its receptors on the target cells constitutes the local RAS, which regulates cardiovascular functions in both autocrine and paracrine systems. Ang-II, a potent mediator of the RAS, plays a pivotal physiological role in cardiovascular homeostasis. Ang-II is a strong vasoconstrictor of the peripheral vasculature and induces hypertrophy, hyperplasia or both in resistance arteries, vascular smooth muscle cells (VSMCs), endothelial cells and cardiomyocytes.2-5 Due to these actions, Ang-II is thought to be an important mediator in the development and maintenance of hypertension, atherosclerosis, diabetes, and cardiac and renal failure.6 The actions of Ang-II are primarily mediated by two receptors, Ang-II type 1 (AT1) and type 2 (AT2). The activation of the AT1 receptor mediates vasoconstriction, proliferation of vascular smooth muscle cells, and production of extracellular matrix proteins by vascular smooth muscle cells. By contrast, the AT2 receptor has been considered to mediate vasodilation, antiproliferation, and pro-apoptosis in the vasculature, presumably mediated by the activation of the nitric oxide (NO) system via bradykinin production.1 The elevation of systemic blood pressure (BP) associated with hypertension is a risk factor for cardiovascular disease and renal failure. Often it is the pathophysiological alterations and impairments associated with hypertension that lessen life expectancy. Pharmacological intervention has been relatively successful in normalising the elevation in BP. However, the assumption that reduction in BP will totally reverse hypertensioninduced pathophysiological changes remains unclear.7-10 Cardiac hypertrophy is an increase in the mass of the contractile and ancillary proteins of the heart above that which is normal for the given stage of its maturational growth.11 In its initial stages, the hypertrophied ventricle is able to compensate in the face of an increased workload, but in later stages, the diastolic and eventually the systolic properties of the left ventricle become impaired, causing decompensation, which this leads to heart failure. The commonest cause of cardiac hypertrophy is hypertension. Hypertrophy is an independent risk factor for sudden death of unknown origin and also increases the risk of myocardial ischaemia and ventricular arrhythmias.11 A role for the RAS in the development of hypertension is well established in both human and animal models, such

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as the spontaneously hypertensive rat. Interruption of the RAS pathway, either by preventing the formation of Ang-II (i.e. angiotensin-converting enzyme inhibitor) or by blocking its actions at the level of the peptide receptor (AT1 receptor antagonists), has been shown to reduced BP and protect against target-organ injury.12-15 However, the attenuation or delay of non-haemodynamic pathophysiological impairments with these agents does not reduce the risk in hypertensive patients.9-10 In addition, chronic administration of traditional therapies is necessary for long-term antihypertensive benefits. Constriction of the thoracic or abdominal aorta provides an experimental model of what has previously been described as pressure-overload cardiac hypertrophy. The increased blood pressure proximal to the constriction has been postulated to provide a stimulus for the development of cardiac hypertrophy.16 This study was designed to examine the effects of AT1 receptor antagonists on the non-invasive (indirect) tail-cuff method, using an automated cuff inflator pulse-detection system to estimate the endogenous antioxidant enzyme [serum catalase and superoxide dismutase (SOD)] activity. Histopathological changes in the target organs (heart, liver, kidneys and thoracic aorta) were analysed to compare the histopathological changes induced in untreated abdominal aortic banding-induced hypertension (AABIH) and cardiac hypertrophy in rats.

Drug treatment was started on the animals recovering from surgery, with losartan, candesartan and irbesartan administered daily for 16 weeks. The three drugs were formulated freshly using 1% carboxy methyl cellulose (CMC) in distilled water and were administered orally in a dose volume of 2 ml/kg body weight; 1% CMC solution was used as vehicle. After the surgery the animals were placed in their cages and were observed for general characteristics and mortality. Non-invasive (indirect) blood pressure (NIBP) was determined by the tail-cuff method using an automated cuff inflator pulse-detection system (AD Instruments, NIBP measurement apparatus). Non-anaesthetised rats were placed in a restraining holder from which the tail protruded. Vasodilatation was achieved by local warming of the tail with an infrared bulb. The cuff and transducer were placed around the tail, and the cuff was inflated until the pulse disappeared. When the cuff was deflated, the point of reappearance of the pulse indicated the value of systolic blood pressure. The reported values are from a minimum of three recordings performed on each animal by the same investigator. The NIBP was measured during weeks 1, 3 and 16. The patency of the hypertension induced by AAB was ascertained during week 3.

Endogenous anti-oxidant enzyme activity Methods Healthy adult male albino Wistar rats weighing between 150 and 210 g were selected. Animals were maintained under standard laboratory conditions at 28 ± 2°C, relative humidity of 50 ± 15% and normal photo-period (12-h dark and 12-h light). Commercial pellet diet (Amruth Ltd, India) and water were provided ad libitum. The experimental protocol was approved by the Institutional Animal Ethics Committee and by the animal regulatory body of the government (Al-Ameen College of Pharmacy, India. Reg. No. 83/1999/CPCSEA). The test drugs losartan, candesartan and irbesartan were procured from Micro Labs Private Ltd and Biocon Ltd, India, respectively. Animals were randomly divided into different groups, each with eight male Wistar rats and they were treated as follows: control (normotensive) sham-operated rats; untreated AABIH rats; AABIH rats treated with losartan (40 mg/kg/day p.o.); candesartan (10 mg/kg/day p.o.); and irbesartan (10 mg/kg/ day p.o.), respectively. Pressure overload was produced by abdominal aortic banding (AAB), which has primarily been used as a model of cardiac hypertrophy.17 Briefly, animals were anesthetised using a combination of ketamine (70 mg/kg, i.p) and xylazine (10 mg/kg, i.p.) and the aorta was exposed through a midline abdominal incision. For the banding model, a blunt 22-gauge needle was placed adjacent to the abdominal aorta between the renal arties just below the renal bifurcations, and a ligature was tightened around the aorta and adjacent needle. The sham procedure for the control rats included injection of the same dose of combination anesthesia, an incision of approximately the same size, and the placement of a loosely tied ligature at the same position on the abdominal aorta.18 The muscular layer was sutured, followed by the abdominal skin, and the animals were isolated in a cage for recovery. The dead animals were removed from the cage.

After the NIBP measurement, the rats were anaesthetised with ether and blood was collected in 2-ml Eppendorff tubes from the retro-orbital plexus, with the help of heparinised capillary tubes, for the estimation of anti-oxidant enzyme activity. The collected blood was centrifuged for 15 min at 7 000 rpm and the supernatant (serum) was used for the estimation of biochemical parameters, namely catalase and SOD activity. The catalase activity was determined spectrophotometrically according to standard protocol as per the Clariborne method.19 Briefly, to 1.95 ml of 10 mM H2O2 in 60 mM phosphate buffer (pH 7.0), 0.05 ml of the plasma/serum was added and degradation of H2O2 was followed at 240 nm per min. The rate of decomposition of H2O2 was calculated using the formula k = 2.303/Δt × log (A1/A2) S-1, followed by calculation of catalase in terms of U/mg of protein. A unit of catalase is defined as the quantity that decomposes 1.0 μmole of H2O2 per min at pH 7.0 and 25°C, while this H2O2 concentration falls from 10.3 to 9.2 mM. SOD activity was determined based on the ability of SOD to inhibit the auto-oxidation of epinephrine to adrenochrome at alkaline pH as per the method of Misra and Fridovich.20 Briefly, 25 μl of the supernatant obtained from the centrifuged blood was added to the mixture of 0.1 mM adrenaline in carbonate buffer (pH 10.2) in a total volume of 1 ml, and the formation of adrenochrome was measured at 295 nm. The SOD activity (U/ mg of protein) was calculated using a standard plot.

Histopathological evaluation of target organs At the end of 16 weeks, after the NIBP measurement, rats from each group were anaesthetised with ether and the target organs (heart, liver, kidneys and thoracic aorta) were collected and placed in the separate containers containing 10% neutral buffered formalin, pH 6.8–7.0 (10 ml 40% formaldehyde, 0.35 g anhydrous sodium dihydrogen phosphate, 0.65 g anhydrous

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disodium hydrogen phosphate, 90 ml distilled water). The samples were sectioned, stained and processed for histopathological evaluation. The organs were processed, sectioned at 5-μm thickness and stained with standard haematoxylin and eosin. The slides were mounted and evaluated under a microscope by a qualified pathologist. The histological evaluation was performed to compare the changes induced in untreated and treated AABIH rats with AT1 receptor blockers in comparison with the control, sham-operated rat organs (heart, liver, kidneys and thoracic aorta).

Statistical analysis The values are expressed as mean ± SEM. Data were analysed by analysis of variance (ANOVA) followed by Tukey’s multiplecomparison test to compare the treatment groups with the control group using a GraphPad Prism.

Results The sham-operated control (normotensive) group, AABIH rats, and the groups treated with AT1 receptor antagonists (losartan, candesartan and irbesartan) were monitored periodically. In terms of general appearance and behaviour, nothing unusual was noted in any of the treatment groups. The body weight gain in both the treated and untreated groups was slightly lower than in their respective control groups, but the differences were not significant (p > 0.05). Mortality in the AAB animals during or immediately after surgery was about 20%. Another 15% of the animals died within 24 hours of surgery. In the AABIH group, there was a significant increase in systolic blood pressure from weeks 3 to 16 (p < 0.001) compared to the control, sham-operated group. Significant reduction in the systolic blood pressure was observed in the losartan-, candesartan- (p < 0.001) and irbesartan-treated (p < 0.05) groups, compared with the AABIH group (Table 1). In the AABIH group, there was a significant (p < 0.001)

TABLE 1. EFFECT OF AT1 RECEPTOR ANTAGONISTS ON SYSTOLIC BP OF AABIH AND CARDIAC HYPERTROPHY RATS Systolic BP Systolic BP % Increase in (mmHg) (mmHg) systolic BP week 1 week 16 week 16 Control 94.14 ± 0.589 105.9 ± 0.7004 12.96 ± 1.21 158.7 ± 2.194 39.37 ± 1.494 Hypertensive 114.5 ± 0.816 149.3 ± 0.821# Losartan 114.4 ± 0.9197 120.3 ± 4.113 6.144 ± 3.66*** Candesartan 104.8 ± 1.880 126.0 ± 2.481 14.04 ± 3.98*** Irbesartan 102.8 ± 0.427 126.7 ± 1.298 23.75 ± 0.895* AABIH = abdominal aortic banding-induced hypertension. Values are expressed in mean ± SEM, n = 8. Statistical analysis: one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test. *Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.05). **Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.01). ***Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.001). # Systolic blood pressure during week 3. The patency of the hypertension induced by abdominal aortic banding was ascertained during week 3.

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decrease in catalase activity compared to the control, shamoperated group. In the groups treated with losartan (p < 0.001) and irbesartan (p < 0.05), there was a significant increase in the level of catalase activity compared with the AABIH group. However, there was no significant increase in catalase activity in the candesartan group (p > 0.05) (Table 2). In the AABIH group, there was a significant reduction in SOD activity when compared to the control, sham-operated group. A significant increase (p < 0.001) in serum SOD activity was observed in the losartan-, candesartan- and irbesartantreated groups, compared to the AABIH group (Table 2).

Histopathological evaluation Histological sections from the normal control, sham-operated rat hearts showed normal structure and architecture. Heart sections of the untreated AABIH rats showed mild to moderate degrees of haemorrhage (accumulation of red blood corpuscles in between the cardiac fibres), mild perivascular fibrosis (fibrous tissue proliferation around the blood vessels), defragmentation of cardiac fibres (loss of striations), congestion (accumulation of red blood cells in the blood vessels in the parenchyma), oedema (separation of cardiac fibres), and mild vacuolations and focal areas of necrosis in one or two areas. The tissue also showed mild lymphocytic infiltration (Fig. 1A, B). Compared to the untreated AABIH group, the losartan-treated group showed a mild degree of haemorrhage, mild perivascular fibrosis, defragmentation of the cardiac fibres, congestion, oedema and mild vacuolations. The tissue also showed mild lymphocytic infiltration. The candesartan-treated group showed a mild-to-moderate degree of haemorrhage, mild perivascular fibrosis, and defragmentation of cardiac fibres, congestion, oedema, moderate vacuolations and focal areas of necrosis in one or two areas. The irbesartan-treated group showed mild-tomoderate degrees of haemorrhage, mild-to-moderate oedema, and separation of cardiac fibres and congestion (Fig. 1C–E) The sections of normal control, sham-operated rat livers showed normal structure and architecture. Liver sections of the untreated AABIH rats showed congestion, multifocal areas of necrosis, and dilation of the central vein. There was also a severe degree of degeneration and vacuolations restricted to the border

Treatment

TABLE 2. EFFECT OF AT1 RECEPTOR ANTAGONISTS ON SERUM SOD AND CATALASE LEVELS IN THE PRESSUREOVERLOAD AABIH AND CARDIAC HYPERTROPHY RATS Treatment SOD (units /ml) Catalase (units /ml) Control 19.61 ± 0.4095 160.0 ± 5.768 Hypertensive 12.92 ± 0.4601 144.7 ± 2.204 Losartan 35.55 ± 1.622*** 202.0 ± 3.539*** Candesartan 25.72 ± 1.586*** 146.6 ± 1.997 Irbesartan 27.74 ± 0.7738*** 176.2 ± 4.043* AABIH = abdominal aortic banding-induced hypertension. Values are expressed in mean ± SEM, n = 8. Statistical analysis: one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test. *Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.05) **Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.01) ***Statistically significant decrease in systolic BP compared with hypertensive group (p < 0.001).

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Liver

Kidneys

Thoracic aorta

Normal

Heart

Normal

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Losartan Candesartan

Fig. 1. Heart and liver tissue sections of normal control, hypertensive and AT1 receptor blocker-treated groups. A: Section of normal control hearts showing normal structure and architecture (40×); B: hypertensive heart showing moderate inflammatory cell infiltration (10×); C: Losartantreated heart showing very minimal vacuolations (40×); D: Candesartan-treated heart showing moderate oedema (40×); E: Irbesartan-treated heart showing moderate oedema (40×), F: Normal liver; G: Hypertensive liver showing severe vacuolar degeneration characterised by the formation of vacuoles in the hepatocytes, clear cells and perivascular cuffing (10×); H: Losartan-treated liver showing minimal vacuolar changes just below the capsular region (4×); I: Candesartan-treated liver showing a moderate degree of vacuolar degeneration, oedema, congestion and mild perivascular cuffing (4×); J: Irbesartan-treated liver showing minimal vacuolar degeneration (4×).

Irbesartan

Candesartan

Losartan

Hypertensive

Fig. 2: Kidney and thoracic aorta sections of normal, hypertensive and AT1 receptor blocker-treated groups. A: Normal kidney section (4×) B: Hypertensive kidneys showing severe oedema, characterised by dilatation of the tubules and haemorrhage in the glomeruli and tubules (10×); C: Losartan-treated kidneys showing minimal vacuolations (4×); D: Candesartan-treated kidneys showing moderate oedema and haemorrhage, and hypertrophy of the tubules (10×); E: Irbesartan-treated kidneys showing moderate oedema, haemorrhage and hypertrophy of the tubules (10×); F: Normal thoracic aorta sections (4×) G: Hypertensive aorta showing minimal foam cell formation in between the fibres (4×); H: Losartan-treated aorta showing no changes (4×); I: Candesartan-treated aorta showing one or two foam cells (4×); J: Irbesartan-treated aorta showing no changes (4×).

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areas below the hepatic capsule, indicating the initial stages of ischaemia (lack of blood supply). Compared to the untreated AABIH group, the losartan-treated group showed congestion, and dilation of the central vein. There was also a moderate degree of vacuolations in the hepatic parenchyma. The candesartan-treated group showed congestion, multifocal areas of necrosis, and dilation of the central vein. There was also a moderate degree of degeneration and vacuolations in the hepatic parenchyma (hydropic degeneration), indicating a moderate degree of ischaemia. The tissue also showed a mildto-moderate degree of neutrophil and lymphocytic infiltration. The irbesartan-treated group showed congestion, dilation of the central vein, mild haemorrhage and moderate vacuolations in the borders of the hepatic parenchyma, indicating limited ischaemia (Fig. 1F–J). The sections of normal control, sham-operated rat kidneys showed normal structure and architecture. The kidney section of the untreated AABIH rats showed oedema, vacuolations in the tubules, moderate to severe haemorrhage and congested vessels. Compared to the untreated AABIH group, the kidney sections of the losartan-treated group showed oedema, vacuolations in the tubules, a moderate degree of haemorrhage, congested blood vessels, and dilatation of vessels and hypertrophy of the tubules. The sections of the candesartan-treated group showed mild oedema, vacuolations in the tubules, a mild-to-moderate degree of haemorrhage, and congested blood vessels. The sections of the irbesartan-treated group showed mild oedema, vacuolations in the tubules, a mild-to-moderate degree of haemorrhage, and congested blood vessels (Fig. 2A–E). The sections of normal control, sham-operated rat thoracic aorta showed normal structure and architecture. The thoracic aorta section of the untreated AABIH rats showed mild accumulation of foam cells in between the fibres. Compared to the untreated AABIH group, the sections of the losartan-treated group showed no changes. The sections of the candesartantreated group showed one to two foam cells. The sections of the irbesartan-treated group showed no changes (Fig. 2F–J). From the results of the histopathological evaluation, it is evident that angiotensin receptor antagonists significantly reduced the histological changes in the target organs such as heart, liver, kidneys and thoracic aorta, compared to the untreated AABIH group. Therefore the AT1 receptor blockers have the potential to protect end organs. They were shown in this study to have beneficial effects in the treatment of hypertension, both by decreasing blood pressure and protecting the target organs.

Discussion The results of this study demonstrate that blockade of AT1 receptors with AT1 antagonists reduced the systolic BP significantly, caused an improvement in the myocardial antioxidant reserve (serum catalase and SOD enzyme activity), decreased oxidative stress and reduced the histopathological changes induced in the pressure-overload rat model of AABIH and cardiac hypertrophy. In our study, abdominal aortic banding was found to have increased systolic BP in a consistent manner, which was sustainable throughout the study period. Constriction of the thoracic or abdominal aorta provides an experimental model of what has been previously described as pressure-overload

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cardiac hypertrophy. The increased blood pressure proximal to the constriction has been postulated to provide a stimulus for the development of cardiac hypertrophy.16 Bardy and co-workers21 reported that increased transmural pressure in the aorta might be causing the local generation of Ang-II, which acts synergistically with the transmural pressure to enhance vascular fibronectin expression via the AT1 receptor. Furthermore, Bonnet and co-workers22 later demonstrated that the AT2 receptor mRNA was up-regulated in rat mesenteric arteries after a pressure dose of Ang-II infusion for two weeks, suggesting the involvement of AT1 receptor mediation in this Ang-II effect, because AT1 receptor antagonists inhibited the Ang-II-induced up-regulation of the AT2 receptor. In the aortic banding model, the decreased blood pressure distal to the banding stimulates the kidney to release renin, resulting in increased circulating levels of Ang-II. However, as shown by investigators,17,23 the fact that the elevation of plasma renin is observed only within a few days of aortic banding does not account for the increased levels of AT2 receptor mRNA over three weeks. Because Ang-II binds to the AT1 and AT2 receptor subtypes with similar affinity,24 the contractile response of the aorta to Ang-II seems to be dependent on the relative expression level and/or responsiveness of both receptors. Therefore it seems that the decreased response to Ang-II in the pressure-overloaded aorta is likely to depend on, at least in part, the up-regulation of the AT2 receptor. AT1 receptor antagonists dose-dependently attenuated the pressor response to intravenous angiotensin-II25-30 and reduced blood pressure in animal models of hypertension. They also reduced cardiac hypertrophy and improved haemodynamics in animal models of heart failure.25,31-33 They increased sodium excretion and diuresis, lowered blood pressure and proteinuria, and reduced glomerulosclerosis in rats with chronic renal failure.34,35 Ang-II receptor antagonists have been thoroughly evaluated for their efficacy in mild, moderate and severe hypertension, and lower BP more effectively than placebo without affecting heart rate.25,27-31 They do so regardless of gender, race or age. Longterm studies have demonstrated that angiotensin II antagonists have comparable efficacy in terms of blood pressure reduction at trough.28,36-40 In the present study, we observed a reduction in systolic BP in the AABIH rats treated with an AT1 receptor antagonist, which is in agreement with previously reported studies. Free radical-scavenging antioxidants such as SOD and catalase are the first line of cellular defense against oxidative injury.41 The observed decrease in levels of these antioxidants in the heart following ischaemia–reperfusion in our study confirms the excessive generation of reactive oxygen species, such as superoxide and hydrogen peroxide, which in turns leads to consumption of these endogenous antioxidants. It has been well documented that AABIH causes increased oxidative stress in rats, as evidenced by reduction in serum SOD and catalase activities.42,43 In the present study, we observed that the decreased activities of SOD and catalase in AABIH in the rats were significantly ameliorated by treatment with AT1 receptor antagonists. These finding are in accordance with studies reporting that telmisartan had an antioxidant effect in a mouse model of atherosclerosis.44 The increase in endogenous antioxidant activities is an indication of structural integrity and

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protection of the myocardium, which was achieved by treatment with AT1 receptor antagonists. In our studies, we observed significant improvement in endogenous antioxidant activity, as evidenced by the elevation in serum SOD and catalase activity. This is in concurrence with that reported by Khafer and Singal who also showed that treatment with losartan reduced oxidative stress, as indicated by an increase in the redox ratio and decreased lipid hydroperoxide content in the myocardial infarction.45 Numerous studies have demonstrated reversal of left ventricular hypertrophy, reduced fibrosis, and improvement in coronary flow and cardiac function following losartan treatment.46,47 Myocardial antioxidants are dynamic in nature and have been reported to change in various physiological and pathological conditions, including hypertrophy,48 exercise49 and adriamycininduced cardiomyopathy.50 It is also known that different enzymatic and non-enzymatic antioxidants respond uniquely in a variety of oxidative stress conditions. For example, hypoxia resulted in a reduction in MnSOD and glutathione peroxidase (GPx) activities with no change in catalase activity.51 In the pressure overload-induced model of heart failure, only SOD activity was significantly less, with no changes in the GPx and catalase activities.52 Studies have reported unique regional differences in non-enzymatic antioxidants in hearts subjected to ischaemia– reperfusion.53 The exact stimulus for the altered activity of these enzymes is not known; however, increased free radical formation and/or lipid peroxidation during stress conditions may act as a signal.54 Using the rat coronary artery ligation model, studies have reported depressed myocardial endogenous antioxidant reserve and increased oxidative stress associated with poor cardiac function.55-57 It is important to protect target organs from damage induced by hypertension. This study demonstrates the histological damage caused by hypertension induced by AAB in rats. Mild perivascular fibrosis, oedema and mild lymphocytic infiltration observed in the hypertensive rats concurs with that reported by Chen et al.,58 along with defragmentation of cardiac fibres, mild-to-moderate degrees of haemorrhage, congestion, mild vacuolations and focal areas of necrosis in one or two areas. All these changes indicate the extent of damage to the heart due to hypertension in this model. As described in the results, treatment with AT1 receptor antagonists reduced the intensity of cardiac damage, as shown by the mild degree of haemorrhage, mild perivascular fibrosis, defragmentation of cardiac fibres, congestion, oedema and mild vacuolations. Studies by Kumiko and co-workers demonstrated that early and transient treatment with AT1 receptor antagonists were effective in the prevention of hypertension-induced end-organ damage.59 Sections of liver in the untreated AABIH group showed congestion, multifocal areas of necrosis, and dilation of the central vein. There was also a moderate degree of degeneration and vacuolations restricted to the border areas below the hepatic capsule, indicating early stages of ischaemia. Histological changes following inhibition of the AT1 receptors were mild haemorrhage and moderate vacuolations in the borders of the hepatic parenchyma, indicating a decrease in the extent of liver damage or limited ischaemia. Suppression of D-galactosamine-induced liver injury by

the AT1 receptor blocker losartan, reported by Chan and co-workers, suggests the protective effect of the AT1 receptor blocker.60 This is in line with our results, as there were mildto-moderate degrees of vacuolation and degeneration in the hepatic parenchyma, indicating a moderate degree of ischaemia. Therefore treatment with AT1 receptor blockers has therapeutic potential in preventing the histopathological changes observed in target organs of the hypertensive group. Sections of the kidneys in the untreated AABIH group showed oedema, vacuolations in the tubules, moderate to severe haemorrhage and congested vessels, all of which are signs of renal damage, which is in agreement with an earlier study.61 As described in the results, treatment with AT1 receptor antagonists reduced the intensity of damage to the renal tissue, indicated by mild vacuolations in the tubules, a moderate degree of haemorrhage, and congested blood vessels. Endothelial dysfunction is one of the most important mechanisms involved in the development of atherosclerosis and is present in patients with various cardiovascular risk factors, including hypertension, hypercholesterolaemia and type 2 diabetes, as well as in patients with coronary artery disease. Endothelial dysfunction has important prognostic implications in these groups of patients.62,63 Blocking the RAS with AT1 receptor antagonists clearly ameliorates endothelial dysfunction, an effect that is not totally dependent on BP reduction. In an elegant study,64 resistance arteries obtained from subcutaneous gluteus muscle biopsies from a small group of hypertensive patients and normotensive controls were studied by measuring the endothelium-dependent and independent responses and the cross-sectional area.64 Histological sections of the thoracic aorta in the untreated AABIH group showed mild accumulation of foam cells in between the fibres. Treatment with AT1 receptor antagonists resulted in protection from this, which may be attributed to the protective effect on vascular endothelium seen in hypertension-induced damage to the vasculature.

Conclusion Our study demonstrates that inhibition of the AT1 receptor with AT1 antagonists caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress, and prevented pathophysiological alterations associated with hypertension in rats, which was evident in the protection of histological changes observed in the treatment groups. The study also emphasises that modulation of the RAS by AT1 receptor blockade is beneficial in preventing target-organ damage in hypertension. The authors thank the Al-Ameen College of Pharmacy for funding, supporting and providing the facilities needed.

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Letter to the Editor Cardiomyopathies and myocardial disorders in Africa: present status and the way forward AO Falase and OS Ogah. Cardiovasc J Afr 2012; 23: 552–562

Dear Sir I read with great interest the review by Falase and Ogah on cardiomyopathies and myocardial disorders in Africa.1 It is a timely contribution to the ongoing discourse on the contemporary status of heart muscle disease in Africa.2,3 There are however several issues that need to be addressed by the authors of the review. The first relates to the statement by the authors that ‘there are no reports of left ventricular non-compaction from Africa, possibly because African cardiologists are not yet familiar with its echocardiographic changes’. This statement is contrary to the published literature. Over the past six years, there have been several reports from different countries of African patients with left ventricular non-compaction, including Djibouti, South Africa and Sudan.4-8 The second issue relates to the following statement in the abstract and text of the review: ‘there are no reports of … ion channelopathies in Africa’. I would like to draw the authors to the discovery of impaired endocytosis of the ion channel TRPM4 as

a cause of human progressive familial heart block type I in South Africans.9 This work by colleagues and their collaborators from Stellenbosch University represents one of the most significant contributions of African scientists to the understanding of the pathogenesis of cardiac disease in recent times. The third issue is one of clarification. The authors refer to genotyping the ‘Hb’ gene in patients with cardiomyopathy. It is not clear what the ‘Hb’ gene is, or the rationale for postulating a linkage with cardiomyopathy. Information on the locus on the gene map and laboratory conditions used for typing the gene would assist other investigators in verifying the findings of the authors. The fourth issue from the review relates to the discussion of the classification of cardiomyopathies. The authors propose a new classification that is based on the proposal of the American Heart Association.10 It is curious that the authors have omitted any continued on page 71…

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Hypertension and associated factors in older adults in South Africa KARL PELTZER, NANCY PHASWANA-MAFUYA

Abstract Background: Older adults are disproportionately affected by hypertension, which is an established risk factor for cardiovascular disease. Little attention has been focused on hypertension and associated factors among older adults in Africa. Therefore, this study aimed to investigate the prevalence and associated factors of hypertension in a national sample of older South Africans who participated in the Study of Global Ageing and Adults’ Health (SAGE) in 2008. Methods: In 2008 we conducted a national, population-based, cross-sectional study of a sample of 3 840 subjects aged 50 years or older in South Africa. The questionnaire included socio-demographic characteristics, health variables, and anthropometric and blood pressure measurements. Results: The prevalence of hypertension in the sample population was 77.3% (male 74.4%, female 79.6%). The rates of awareness, treatment and control among the hypertensive participants were 38.1, 32.7 and 17.1%, respectively. The results of multivariate logistic regression analysis revealed that the prevalence of hypertension was associated with being in the Coloured population group, having had a stroke, being overweight or obese and having had five or more out-patients care visits in the past 12 months. Hypertension was inversely associated with current alcohol use. Conclusion: This study revealed high rates of hypertension among older adults (50 years and more) in South Africa, which puts them at risk for cardiovascular disease. The percentages of hypertensive subjects who were aware, treated and controlled were very low. These data underscore the urgent need to strengthen the public health education and blood pressure-monitoring systems to better manage hypertension among older adults in South Africa. Keywords: hypertension, risk factors, older adults, South Africa Submitted 7/4/12, accepted 11/1/13 Cardiovasc J Afr 2013; 24: 67–72

www.cvja.co.za

DOI: 10.5830/CVJA-2013-002

HIV/AIDS/SIT and TB (HAST), Human Sciences Research Council, Pretoria, South Africa KARL PELTZER, PhD, KPeltzer@hsrc.ac.za NANCY PHASWANA-MAFUYA, PhD

Department of Psychology, University of Limpopo, Turfloop, South Africa and ASEAN Institute for Health Development, Mahidol University, Salaya, Thailand KARL PELTZER, PhD

Office of the Vice Chancellor, Nelson Mandela Metropolitan University, Port Elizabeth, South Africa NANCY PHASWANA-MAFUYA, PhD

High blood pressure in South Africa is estimated to have caused 46 888 deaths and 390 860 disability-adjusted life years in 2000.1 Hypertension alone is the leading reason for attending primary care and is the most common diagnosis (13.1%) in South Africa.2 In population-based surveys, high rates of hypertension were found among older adults in South Africa, 44.0–52.0% among men and 51.6–60.4% among women in 1998.3 In other countries, in Dakar, Senegal, 65.4% of subjects had hypertension,4 in urban Zimbabwe 72%.5 In Malawi, Rwanda and Tanzania, hypertension was found in 41.0% of men and 36.6% of women.6 In Costa Rica, 65% were hypertensive,7 and 42.4% of women in Accra, Ghana had hypertension.8 In Brazil, self-reported hypertension was 55%,9 in rural China it was 57–64.9%,10 and in another study in China it was 24.2–43.8%.11 In Turkey 71.2–82.2% of subjects had hypertension,12 and in Taiwan 31.1–38.0%.13 Various factors have been found to be associated with hypertension, including socio-demographics (older age, female gender, lower education level, lower household income),13-16 geolocality (urban residence),17 other risk factors or behaviour, including stroke,18 diabetes,19,20 higher body mass index (BMI),5,10,13,14 physical inactivity,16,22,23 insufficient fruit and vegetable intake,13,23-25 smoking and drinking,10,16,22 greater limitations on activities of daily living (ADLs) and instrumental activities of daily living (IADLs),26 higher frequency of doctor visits,4 and less social cohesion.27 In general, it is estimated that in South Africa only 26% of men and 51% of women are aware of their hypertension.1 Among older adults in Senegal, half of those suffering from high blood pressure were aware of their problem, and among the latter, 70% said they were on treatment. However, of these, only 17% had controlled arterial blood pressure.4 Among rural older adults in China, the rates of awareness, treatment and control were very low (overall 35.2, 28.7 and 1.0%, respectively).10 Few studies exist investigating hypertension among older adults in low- and middle-income countries. Yet, research studies ‘demonstrate a clear evolution in the prevalence, awareness, treatment and control of hypertension during the ageing process’.4 Therefore, this study aimed to investigate the prevalence and associated factors of hypertension in a national sample of older South Africans who participated in the Study of Global Ageing and Adults’ Health (SAGE) in 2008.

Methods We conducted a national, population-based, cross-sectional study with a sample of 3 840 subjects aged 50 years or older in South Africa in 2008. The SAGE sample design entailed a two-stage probability sample that yielded national and sub-national estimates to an acceptable precision at provincial level, by locality type (urban and rural) and population group (including black, Coloured, Indian or Asian, and white). The overall response rate among those aged 50 years or older was 60%.

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The Global Study on Ageing (SAGE) survey was carried out in South Africa in partnership with the World Health Organisation (WHO), the National Department of Health, and the Human Sciences Research Council (HSRC). The study was approved by the Human Sciences Research Council Research Ethics Committee and the national Department of Health. Blood pressure (systolic and diastolic) was measured three times on the right arm/wrist of the seated respondent using an automated recording device (OMRON R6 Wrist Blood Pressure Monitor, HEM-6000-E, Omron Healthcare Europe, BV, Hoofddorp and The Netherlands). Out of three measurements, the average of the last two readings was used. In accordance with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, individuals with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/or who reported the current use of antihypertensive medication were considered to be suffering from high blood pressure.28 Awareness was defined as history of hypertension based on diagnosis by a healthcare provider. Treatment was defined as taking any medication or other treatment for hypertension in the last two weeks prior to the survey, and control was defined as blood pressure < 140 and < 90 mmHg at the time of the survey. Lifetime tobacco users were asked ‘Do you currently use (smoke, sniff or chew) any tobacco products such as cigarettes, cigars, pipes, chewing tobacco or snuff?’ The response options were ‘Yes, daily’, ‘Yes, but not daily’ and ‘No, not at all’. Daily tobacco use was coded = 1, and not daily and not at all = 0.29 Lifetime alcohol users were asked about current (past month) alcohol use. Past month alcohol use was coded = 1 and no past month alcohol use = 0. Height and weight were measured. Body mass index (BMI) was used as an indicator of obesity (≥ 30 kg/m2), calculated as weight in kg divided by height in metres squared. Overweight and/or obesity were defined as BMI ≥ 25 kg/m2 and underweight as < 18.5 kg/m2. Social cohesion was measured with nine items, starting with the introduction ‘How often in the last 12 months have you… e.g. attended any group, club, society, union or organisational meeting?’ All nine items were summed to get a social cohesion index. Response options ranged from never = 1 to daily = 5. Cronbach alpha for the social cohesion index in this sample was 0.73. Physical activity was measured using the General Physical Activity Questionnaire (GPAQ). The instrument gathers information on physical activity in three domains (activity at work, travel to and from places, and recreational activities), as well as time spent sitting. The questionnaire also assesses vigorous and moderate activities performed at work and for recreational activities. Information on the number of days a week spent on different activities, and time spent in a typical day for each activity was also recorded.30 Cronbach alpha for the GPAQ in this sample was 0.77. For physical activity, in addition to the total minutes of activity, the activity volume was also computed by weighting each type of activity by its energy requirement in metabolic equivalents (METs). One MET was defined as the energy cost of sitting quietly, and was equivalent to a caloric consumption of 1 kcal/kg/h. A MET-minute showed the total activity volume on a weekly basis, and was calculated by multiplying the time spent on each activity during a week by the MET-values of each

level of activity. MET-values for different levels of activities were set as 4 MET for moderate intensity physical activity, 8 MET for vigorous physical activity, and 4 MET for transport-related walking or cycling. The total physical activity for GPAQ2 was calculated as the sum of the total moderate, vigorous, and transport-related activities per week. The number of days and total physical activity MET-minutes per week were used to classify respondents into three categories of low, moderate and high level of physical activities. Less than 600 MET-minutes per week was classified as low physical activity.30 Fruit and vegetable consumption was assessed with the questions ‘How many servings of fruit do you eat on a typical day?’ and ‘How many servings of vegetables do you eat on a typical day?’ Insufficient fruit and vegetable consumption was defined as less than five servings of fruits and/or vegetables a day. Overall self-rated health status was based on respondents’ assessment of their current health status on a five-point scale in response to the question: ‘In general, how would you rate your health today?’ Response categories were: very good, good, moderate, bad and very bad. Very good and good were grouped together and coded = 1, moderate = 2 and bad and very bad were grouped together and coded = 3. Activity limitation (difficulty an individual may have in executing task or actions) was assessed with one item ‘Overall in the last 30 days, how much difficulty did you have with work or household activities?’ Response options ranged from 1 = none to 5 = extreme/cannot do. None were coded = 1, mild = 2, moderate = 3 and severe and extreme were grouped together and coded = 4. Finally, participants were asked about a list of chronic and other conditions they had been diagnosed with, including diabetes, hypertension, stroke, angina and arthritis. Of participants who responded to having been diagnosed with hypertension, the question was asked, ‘Have you been taking any medication or other treatment for it during the last two weeks?’ Other treatment might include a weight-loss programme or change in eating habits. Attendance at out-patient care was assessed with the question, ‘Over the last 12 months, did you receive ant healthcare not including an overnight stay in hospital or long-term care facility?’ Of those who indicated ‘yes’ they had to report the number of times they had received healthcare or consultation in the last 12 months. Frequency of attendance at out-patient care was grouped into none = 0, one to four = 2, five or more = 3. To estimate economic or wealth status, a random-effects probit model was used to identify indicator-specific thresholds that represent the point on the wealth scale above which a household is more likely to own a particular asset than not. This enabled an estimation of an asset ladder. These estimates of thresholds, combined with actual assets observed to be owned for any given household, were used to produce an estimate of household-level wealth status. This was used to create wealth quintiles.31 Lowest and second-lowest wealth quintiles were grouped together as low = 1, the middle wealth quintile was medium = 2 and the fourth and highest wealth quintiles were grouped together as high = 3.

Statistical analysis The data were entered using CSPro and analysed using STATA Version 10. The data were weighted using post-stratified

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individual probability weights based on the selection probability at each stage of selection. Individual weights were post-stratified by province, gender and age groups according to the 2009 medium mid-year population estimates from Statistics South Africa, available at: http://www.statssa.gov.za/publications/ P0302/P03022009.pdf. Computed estimates and odds ratios were reported with 95% confidence intervals and a two-tailed p-value of 0.05 was used as the cut-off point for statistical significance. Associations between key outcomes of hypertension, and socio-demographic and health variables were evaluated calculating odds ratios (OR). Multivariate logistic regression was used for evaluation of the impact of explanatory variables for key outcome of hypertension (binary dependent variable). All variables statistically significant at p < 0.05 in bivariate analyses were included in the multivariable models. In the analysis, weighted percentages were reported.

older) in South Africa. These rates seemed to be higher than in a previous survey in South Africa (men 44.0–52.0% and women 51.6–60.4%) in 1998,3 and similar to other studies such as in urban Senegal (65.4%),4 urban Zimbabwe (72%),5 and Turkey (71.2–82.2%).12 The rates were higher than in a number of other countries including rural Malawi, Rwanda and Tanzania (36.6– 41.0%),6 Brazil (55%),9 China (24.2–64.9%),10,11 and Taiwan (31.1–38.0%).13 The study further found that regarding socio-demographics, with multivariate analysis, being in the Coloured population group was associated with higher rates of hypertension. This

Results

All Age (years) 50–59 60–69 70 and over

1695 (49.9) 520 (71.3) 682 (77.9) 1202 (74.9) 1233 (30.6) 391 (79.4) 563 (81.6) 954 (80.6) 912 (19.5) 248 (75.1) 438 (80.5) 686 (78.4)

Population group African black White Coloured Indian or Asian

2053 (74.0) 269 (9.3) 655 (12.8) 307 (3.8)

575 (73.1) 92 (75.6) 195 (88.1) 97 (74.1)

975 (80.0) 101 (83.0) 350 (83.1) 117 (78.5)

1550 (77.3) 193 (79.6) 545 (85.0) 214 (76.8)

Marital status Single Married Separated/divorced Widow

512 (14.3) 2007 (55.9) 230 (5.9) 1020 (23.9)

97 (71.5) 870 (74.2) 60 (66.0) 120 (84.8)

292 (83.1) 571 (74.2) 116 (82.3) 667 (82.6)

389 (80.1) 1441 (74.2) 176 (77.7) 787 (82.9)

Educational level No schooling Less than primary Primary Secondary

854 (25.2) 803 (24.0) 779 (22.4) 923 (28.3)

231 (78.3) 227 (69.4) 232 (79.2) 261 (74.9)

422 (81.2) 404 (85.6) 364 (79.3) 337 (76.5)

653 (80.2) 631 (78.9) 596 (79.2) 598 (75.8)

Wealth Low Medium High

1482 (40.6) 429 (71.1) 646 (78.7) 1075 (75.4) 731 (18.2) 197 (74.7) 377 (79.9) 574 (78.3) 1608 (41.2) 525 (77.1) 651 (80.2) 1176 (78.6)

Geolocality Rural Urban

1276 (35.1) 392 (75.9) 524 (78.7) 916 (77.5) 2561 (64.9) 766 (73.7) 1157 (80.1) 1923 (77.2)

The total sample included 3 840 South African subjects 50 years or older, 44.1% were men and 55.9% were women. The most prevalent population group was black Africans (74%), and almost half (49.9%) were between 50 and 59 years old. The educational level of most participants (71.6%) was lower than secondary school education and almost two-thirds (64.9%) lived in an urban area. A large group (72.4%) of older adults were overweight or obese, 20.4% were daily tobacco users, 4.0% had had a stroke, and 9.2% had diabetes. More than half (52.2%) engaged in low physical activity, two-thirds (67.7%) ate insufficient fruit and vegetables, and a small proportion (13.7%) were current alcohol users. A sizeable proportion (17.5%) rated their health status as bad or very bad, 10.7% reported severe or extreme activity limitation and 28.1% were out-patients five times or more. The prevalence rates of hypertension were 77.3% (male 74.4%, female 79.6%) (Table 1). The results of the multivariate logistic regression analysis revealed that the prevalence of hypertension was associated with being in the Coloured population group, having had a stroke, being overweight and having had five or more out-patients care visits in the past 12 months. Prevalence of hypertension was inversely associated with current alcohol use (Table 2). Overall, 30.3% of older hypertensive people were aware of their diagnosis, 24.8% of older hypertensives were taking treatment in the past two weeks to lower their blood pressure, and 48.8% of those who were taking antihypertensive treatment had their blood pressure controlled. Women, older age and more frequent out-patient visits in the past 12 months were associated with awareness of their hypertensive status and were taking treatment to lower their blood pressure in the past two weeks. However, there were no statistical differences in gender, age and out-patient visits among those who were taking antihypertensive treatment and had their blood pressure controlled. Of the total 2 841 hypertensive participants, 1 081 (38.1%) were aware of their hypertension, 985 (32.7%) were being treated, and 486 (17.1%) had their hypertension under controll (Table 3).

Discussion The study found significant rates of hypertension of 77.3% (male 74.4%, female 79.6%) among older adults (50 years and

TABLE 1. SAMPLE CHARACTERISTICS AND PREVALENCE RATE OF HYPERTENSION AMONG OLDER SOUTH AFRICANS Prevalence rate of hypertension Total sample 3840

Other conditions 139 (4.0) Stroke 219 (5.2) Angina 360 (9.2) Diabetes 2505 (72.4) Overweight (BMI ≥ 25 kg/m2) Underweight (BMI < 18.5 kg/m2) 184 (4.3) Arthritis 851 (24.7)

Male Female (n = 1638) (n = 2202)

Total

1159 (74.4) 1683 (79.6) 2842 (77.3)

48 (88.2) 62 (76.2) 107 (88.4) 745 (77.3) 51 (64.4) 198 (81.8)

71 (91.5) 114 (76.2) 202 (90.2) 1253 (82.8) 63 (66.8) 472 (83.0)

119 (90.0) 176 (76.2) 309 (89.6) 1998 (80.5) 114 (65.5) 670 (82.6)

Daily tobacco use

810 (20.4) 295 (74.6) 315 (76.3) 610 (75.4)

Alcohol use (past month)

557 (13.7) 248 (66.6) 151 (77.5) 399 (70.3)

Physical activity Low Moderate High

2100 (52.2) 567 (73.2) 940 (79.0) 1507 (76.6) 692 (16.6) 233 (79.6) 302 (76.9) 535 (78.1) 1044 (31.2) 357 (73.4) 440 (82.1) 797 (78.1)

Insufficient fruit and vegetables

2817 (67.7) 834 (77.3) 1245 (77.0) 2079 (77.1)

Subjective health status Very/good Moderate Bad/very bad

1469 (37.9) 486 (71.3) 565 (75.4) 1051 (73.4) 1681 (44.9) 495 (78.2) 834 (80.9) 1329 (79.8) 617 (17.5) 177 (73.9) 281 (84.4) 458 (79.9)

Activity limitation None Mild Moderate Severe/extreme

1465 (38.5) 625 (16.7) 1275 (34.2) 370 (10.7)

487 (73.6) 191 (71.6) 369 (75.9) 103 (78.5)

566 (74.8) 297 (80.5) 628 (81.0) 178 (89.6)

1053 (74.2) 488 (76.5) 997 (78.9) 281 (85.8)

22.1 (6.5)

21.9 (6.2)

21.4 (6.1)

21.6 (6.1)

Social cohesion index (range 9–72); mean (SD)

Outpatient visits in past 12 months 0 1176 (38.2) 372 (72.2) 464 (74.5) 836 (73.3) 1–4 908 (33.7) 271 (76.2) 414 (79.2) 685 (77.9) 5 or more 941 (28.1) 282 (80.4) 513 (86.4) 795 (84.2)

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TABLE 2. MULTIPLE LOGISTIC REGRESSION OF HYPERTENSION PREVALENCE IN OLDER SOUTH AFRICANS Gender Female Male

UOR (95% CI)

AOR (95% CI)

1.00 0.75 (0.57–0.98)*

1.00 0.85 (0.80–1.63)

Age (years) 50–59 60–69 70 and over

1.00 1.40 (1.12–1.75)** 1.22 (0.87–1.70)

1.00 1.30 (0.94–1.79) 1.19 (0.80–1.78)

Population group African black White Coloured Indian or Asian

1.00 1.14 (0.64–2.05) 1.66 (1.07–2.59)* 0.97 (0.59–1.60)

1.00 1.23 (0.66–2.30) 1.89 (1.04–3.44)* 0.82 (0.47–1.42)

Marital status Single Married Separated/divorced Widow

1.00 0.71 (0.43–1.18) 0.86 (0.43–1.72) 1.20 (0.66–2.19)

Educational level No schooling Less than primary Primary Secondary

1.00 1.15 (0.74–1.81) 1.18 (0.86–1.60) 0.97 (0.71–1.31)

Wealth Low Medium High

1.00 1.18 (0.78–1.77) 1.20 (0.80–1.80)

Geolocality Rural Urban

1.00 0.98 (0.59–1.65)

Other conditions Stroke Angina Diabetes Overweight(BMI ≥ 25 kg/m2) Underweight (BMI < 18.5 kg/m2) Arthritis Daily tobacco use Alcohol use (past month)

2.67 (1.10–6.47)* 4.48 (1.48–13.59)** 0.92 (0.56–1.51) 2.65 (1.86–3.78)*** 1.30 (0.86–1.98) 1.67 (1.41–1.98)*** 1.52 (1.15–2.01)** 0.53 (0.30–0.97)* 0.77 (0.36–1.64) 1.49 (1.06–2.11)* 1.13 (0.75–1.69) 0.85 (0.56–1.30) 0.64 (0.47–0.85)**

Physical activity Low Moderate High

1.00 1.01 (0.70–1.45) 0.92 (0.66–1.27)

Insufficient fruit and vegetables

0.96 (0.65–1.43)

0.64 (0.49–0.84)**

Subjective health status Very/good Moderate Bad/very bad

1.00 1.43 (1.12–1.83)** 1.44 (0.77–2.68)

1.00 1.41 (0.95–2.10) 1.27 (0.62–2.58)

Activity limitation None Mild Moderate Severe/extreme

1.00 1.13 (0.84–1.52) 1.30 (0.90–1.88) 2.10 (1.12–3.93)*

1.00 0.92 (0.59–1.45) 0.92 (0.58–1.48) 1.60 (0.70–3.64)

Social cohesion index (range 9–72); mean (SD) Outpatient visits in past 12 months 0 1–4 5 or more

1.01 (0.9-1.03)

1.00 1.00 1.28 (0.84–1.96) 1.14 (0.80–1.63) 1.94 (1.34–2.81)*** 1.93 (1.48–2.51)***

***p < 0.001; **p < 0.01; *p < 0.5.

confirms previous studies in women.3 Further initiatives are required to address the high rate of hypertension in this population group. Unlike in other studies,13-15,17 this study did not find any effect of gender, age, level of education and geolocality on hypertensive status. In terms of health variables, this study was in agreement with other studies,4,10,13,14,18,31 that having had a stroke, being overweight and having had more out-patients care visits in the past 12 months were associated with hypertension. Unlike some other studies,10,13,21,23-25,33 this study did not find insufficient fruit and

TABLE 3. MULTIVARIATE LOGISTIC REGRESSION OF AWARENESS, TREATMENT AND CONTROL RATES OF HYPERTENSION AMONG OLDER ADULTS IN SOUTH AFRICA Awareness (30.3%)

Treatment (24.8%)

Control of treated (48.8%)

AOR (95% CI)

Gender Female Male

1.00 1.00 1.00 0.68 (0.51–0.90)** 0.67 (0.50–0.88)** 1.09 (0.81–1.46)

Age 50-59 60-69 70 and over

1.00 1.00 1.00 1.70 (1.16–2.48)** 1.89 (1.38–2.58)*** 0.73 (0.55–0.95) 1.77 (1.22–2.59)** 2.15 (1.40–3.30)*** 0.73 (0.50–1.06)

Population group African black White Coloured Indian or Asian

1.00 0.81 (0.40–1.62) 1.00 (0.65–1.52) 1.08 (0.56–2.07)

1.00 0.97 (0.52–1.83) 1.09 (0.73–1.63) 1.45 (0.73–2.91)

1.00 0.89 (0.44–1.80) 0.80 (0.58–1.10) 1.25 (0.64–2.45)

Marital status Single Married Separated/divorced Widow

1.00 1.38 (0.83–2.29) 1.17 (0.69–1.97) 1.67 (0.96–2.92)

1.00 1.50 (0.85–2.66) 1.11 (0.62–1.99) 1.45 (0.81–2.62)

1.00 1.44 (0.90–2.29) 1.11 (0.65–2.45) 1.51 (0.93–2.46)

Educational level No schooling Less than primary Primary Secondary

1.00 0.96 (0.65–1.52) 1.10 (0.72–1.68) 0.94 (0.65–1.38)

1.00 1.03 (0.67–1.58) 1.03 (0.65–1.61) 1.09 (0.75–1.59)

1.00 0.99 (0.64–1.54) 1.04 (0.73–1.49) 1.54 (1.04–2.27)*

Wealth Low Medium High

1.00 1.43 (0.98–2.08) 1.55 (1.00–2.40)*

1.00 1.36 (0.84–2.20) 1.34 (0.75–2.40)

1.00 0.75 (0.49–1.15) 0.93 (0.64–1.33)

Geolocality Rural Urban

1.00 1.27 (0.95–1.71)

1.00 1.30 (0.84–2.01)

1.00 1.17 (0.87–1.58)

Outpatient visits in past 12 months 0 1–4 5 or more

1.00 1.00 1.00 1.85 (1.10–3.11)* 1.94 (1.20–3.12)** 0.85 (0.61–1.17) 4.49 (3.02–6.66)*** 5.95 (3.96–8.95)*** 0.87 (0.63–1.19)

***p < 0.001; **p < 0.01; *p < 0.5.

vegetable intake, smoking, being physically inactive and having more limitations in activities of daily living to be associated with hypertension. The finding that current alcohol use was protective for hypertension in this study may be in line with some previous studies where light-to-moderate alcohol consumption decreased hypertension risk in women and increased the risk in men.21 The rates of awareness, treatment and control among the hypertensive participants in the present study (38.1, 32.7 and 17.1%, respectively) were as low as in some studies in rural China (35.2, 28.7 and 1.0%),10 Senegal (49.5, 37.0 and 5.7%),4 and Italy (65.6, 59.5 and 10.5%).18 They were however lower than in studies in Costa Rica (74.9% aware and more than half controlled)7 and in the USA (74% aware and 51.6% controlled among men and 37% controlled among women).34 As found in some other studies, in this study, women were more frequently aware of their hypertension and more frequently treated.7,35 They were not significantly more frequently controlled than men, though, as found in other studies.7,36 In the group of individuals who were unaware of their hypertension, it may have been because of multiple factors, such as never having been screened for hypertension, having been previously diagnosed but had forgotten the diagnosis, the medical provider had not considered their blood pressure levels to be sufficiently elevated to warrant the diagnosis, or had had inadequate health education and limited access to healthcare services.9,35 Therefore, more efforts, such as public health education and a blood pressuremonitoring system should be included for the older age group,

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particularly men, to improve their unsatisfactory awareness, treatment and control of hypertension.10

Limitations of the study This study had several limitations. Firstly, the self-report of health variables such as tobacco or alcohol use should be interpreted with caution; it is possible that respondents under-reported, especially females. As in many studies, arterial blood pressure was measured three times during a single session (two hours), which may have led to an overestimation of the prevalence of hypertension. In addition, the awareness and treatment rate of hypertension was solely assessed by individual self-report. Furthermore, this study was based on data collected in a crosssectional survey. We cannot, therefore, ascribe causality to any of the associated factors in the study.

Conclusion This study revealed high rates of hypertension among older adults (50 years and more) in South Africa, which put them at risk for cardiovascular disease. The percentages of hypertensives who were aware of, treated for and controlled were very low. These data underscore the urgent need to strengthen the public health education and blood pressure-monitoring systems to better manage hypertension among older adults in South Africa. Community healthcare workers in their new role in South Africa could screen for hypertension among older adults using a primary care ‘high-risk’ approach once every two years. This screening process would enable the health system to identify and cater for the needs of this vulnerable population group.37 Funding was provided predominantly from the National Department of Health with additional funding provided by the United States National Institute on Aging through an interagency agreement with the World Health Organisation, and the Human Sciences Research Council, South Africa.

References 1. 2. 3.

Rayner B. Hypertension: detection and management in South Africa. Nephron Clin Pract 2010; 116(4): c269–273. Mash B, Fairall L, Adejayan O, et al. A morbidity survey of South African primary care. PLoS One 2012; 7(3): e32358. Steyn K, Gaziano TA, Bradshaw D, et al. Hypertension in South African adults: results from the Demographic and Health Survey, 1998. J Hypertens 2001; 19(10): 1717–1725. Macia E, Duboz P, Gueye L. Prevalence, awareness, treatment and control of hypertension among adults 50 years and older in Dakar, Senegal. Cardiovasc J Afr 2011; 22: 1–5. Mufunda J, Scott LJ, Chifamba J, et al. Correlates of blood pressure in an urban Zimbabwean population and comparison to other populations of African origin. J Hum Hypertens 2000; 14(1): 65–73. Negin J, Cumming R, de Ramirez SS, et al. Risk factors for noncommunicable diseases among older adults in rural Africa. Trop Med Intern Health 2011; 16(5): 640–646. Méndez-Chacón E, Santamaría-Ulloa C, Rosero-Bixby L. Factors associated with hypertension prevalence, unawareness and treatment among Costa Rican elderly. BMC Public Health 2008; 8: 275. Duda RB, Anarfi JK, Adanu RM, et al. The health of the ‘older women’ in Accra, Ghana: results of the Women’s Health Study of Accra. J Cross Cult Gerontol 2011; 26(3): 299–314. Lima e Costa MF, Peixoto SV, et al. Health behaviors among older adults with hypertension, Brazil, 2006. Rev Saude Publica 2009; 43(Suppl 2): 18–26.

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10. Pang W, Li Z, Sun Z, et al. Prevalence of hypertension and associated factors among older rural adults: results from Liaoning Province, China. Med Princ Pract 2010; 19(1): 22–27. 11. Ruixing Y, Jiaqiang D, Dezhai Y, et al. Effects of demographic characteristics, health-related behaviors and lifestyle factors on the prevalence of hypertension for the middle-aged and elderly in the Guangxi Hei Yi Zhuang and Han populations. Kidney Blood Press Res 2006; 29(5): 312–320. 12. Erem C, Hacihasanoglu A, Kocak M, et al. Prevalence of prehypertension and hypertension and associated risk factors among Turkish adults: Trabzon Hypertension Study. J Public Health (Oxf) 2009; 31(1): 47–58. 13. Tsai AC, Liou JC, Chang MC. Interview to study the determinants of hypertension in older adults in Taiwan: a population based crosssectional survey. Asia Pac J Clin Nutr 2007; 16(2): 338–345. 14. Hendriks ME, Wit FW, Roos MT, et al. Hypertension in sub-Saharan Africa: cross-sectional surveys in four rural and urban communities. PLoS One 2012; 7(3): e32638. 15. Kaplan MS, Huguet N, Feeny DH, McFarland BH. Self-reported hypertension prevalence and income among older adults in Canada and the United States. Soc Sci Med 2010; 70(6): 844–849. 16. Teo GS, Idris MN. Prevalence of hypertension among Chinese elderly and its relationship to behavioural and nutritional factors. Med J Malaysia 1996; 51(1): 33–40. 17. Agyemang C. Rural and urban differences in blood pressure and hypertension in Ghana, West Africa. Public Health 2006; 120(6): 525–533. 18. Ngoungou EB, Aboyans V, Kouna P, et al. Prevalence of cardiovascular disease in Gabon: A population study. Arch Cardiovasc Dis 2012; 105(2): 77–83. 19. Prencipe M, Casini AR, Santini M, et al. Prevalence, awareness, treatment and control of hypertension in the elderly: results from a population survey. J Hum Hypertens 2000; 14(12): 825–830. 20. Long AN, Dagogo-Jack S. Comorbidities of diabetes and hypertension: mechanisms and approach to target organ protection. J Clin Hypertens (Greenwich) 2011; 13(4): 244–251. 21. Giday A, Tadesse B. Prevalence and determinants of hypertension in rural and urban areas of southern Ethiopia. Ethiop Med J 2011; 49(2): 139–147. 22. De Ramirez SS, Enquobahrie DA, Nyadzi G, et al. Prevalence and correlates of hypertension: a cross-sectional study among rural populations in sub-Saharan Africa. J Hum Hypertens 2010; 24(12): 786–795. 23. Wang L, Manson JE, Gaziano JM, et al. Fruit and vegetable intake and the risk of hypertension in middle-aged and older women. Am J Hypertens 2012; 25(2): 180–189. 24. Zhao D, Qi Y, Zheng Z, et al. Dietary factors associated with hypertension. Nat Rev Cardiol 2011; 8(8): 456–465. 25. Caskie GI, Sutton MC, Margrett JA.The relation of hypertension to changes in ADL/IADL limitations of Mexican american older adults. J Gerontol B Psychol Sci Soc Sci 2010; 65B(3): 296–305. 26. Mujahid MS, Diez Roux AV, Morenoff JD, et al. Neighborhood characteristics and hypertension. Epidemiology 2008; 19(4): 590–598. 27. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252. 28. World Health Organisation (WHO). Guidelines for controlling and monitoring the tobacco epidemic. Geneva, Switzerland: WHO, 1998. 29. World Health Organisation (WHO). Global Physical Activity Surveillance. (http://www.who.int/chp/steps/GPAQ/en/index.html, accessed 2 December 2010), 2009. 30. Chatterji S, Kowal P, Mathers C, et al. The health of aging populations in China and India. Health Aff (Millwood) 2008; 27(4): 1052–1063. 31. Mufunda J, Mebrahtu G, Usman A, et al. The prevalence of hypertension and its relationship with obesity: results from a national blood pressure survey in Eritrea. J Hum Hypertens 2006; 20(1): 59–65. 32. Banda JA, Clouston K, Sui X, et al. Protective health factors and incident hypertension in men. Am J Hypertens 2010; 23(6): 599–605. 33. Sesso HD, Cook NR, Buring JE, et al. Alcohol consumption and the risk of hypertension in women and men. Hypertension 2008; 51(4): 1080–1087. 34. Ostchega Y, Dillon CF, Hughes JP, et al. Trends in hypertension preva-

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lence, awareness, treatment, and control in older US adults: data from the National Health and Nutrition Examination Survey 1988 to 2004. J Am Geriatr Soc 2007; 55(7): 1056–1065. 35. Brindel P, Hanon O, Dartigues JF, et al. Prevalence, awareness, treatment, and control of hypertension in the elderly: the Three City study. J Hypertens 2006; 24(1): 51–58.

36. Satish S, Markides KS, Zhang D, Goodwin JS. Factors influencing unawareness of hypertension among Older Mexican Americans. Preventive Med 1997; 26: 645–650. 37. John J, Muliyil J, Balraj V. Screening for hypertension among older adults: a primary care ‘high risk’ approach. Indian J Community Med 2010; 35(1): 67–69.

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reference to the alternative classification scheme of the European Society of Cardiology.11 In the latter scheme, cardiomyopathy is regarded as a structural and functional abnormality of the myocardium that is not due to hypertension, coronary artery disease, valvular heart disease, pericardial disease, or congenital heart disease. Furthermore, cardiomyopathy is sub-classified into familial/genetic or non-familial/non-genetic types. I have found that the European Society of Cardiology classification lends itself well to the clinical evaluation of patients with unexplained heart failure in the African setting.12,13 It would be of interest to know the opinion of the authors and that of the Pan-African Society of Cardiology (as suggested by the authors) on the utility of the European classification of cardiomyopathy compared to the version of the American Heart Association in the African environment. Finally, the authors make a case for a new and unique classification of myocardial disorders for Africa. It is not clear why Africans should be an exception to other populations of the world. We have shown previously that while the burden of disease may be higher for certain forms of cardiomyopathy in Africa, the pathophysiological features of the cardiomyopathies are likely to be the same in all continental populations.13,14 Therefore, the aspiration of the Pan-African Society of Cardiology should probably be to contribute to the development of a universal classification of cardiomyopathy for all people in the world, possibly under the auspices of the World Health Organisation or the World Heart Federation.

BONGANI M MAYOSI, DPhil, FCP (SA), bongani.mayosi@ uct.ac.za Department of Medicine, Old Groote Schuur Hospital, Cape Town, South Africa

References 1.

Falase AO, Ogah OS. Cardiomyopathies and myocardial disorders in Africa: present status and the way forward. Cardiovasc J Afr 2012; 23: 552–562.

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Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005; 112(23): 3577–3583. Mayosi BM. Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa. Heart 2007; 93(10): 1176–1183. Ker J, Van Der Merwe C. Isolated left ventricular non-compaction as a cause of thrombo-embolic stroke: a case report and review. Cardiovasc J S Afr 2006; 17: 146–147. Ali SK. Unique features of non-compaction of the ventricular myocardium in Arab and African patients. Cardiovasc J Afr 2008; 19: 241–245. Massoure PL, Lamblin G, Bertani A, Eve O, Kaiser E. Rare cause of heart failure in an elderly woman in Djibouti: left ventricular non compaction. Med Trop (Mars) 2011; 71: 505–507. Peters F, Dos Santos C, Essop R. Isolated left ventricular non-compaction with normal ejection fraction. Cardiovasc J Afr 2011; 22: 90–93. Peters F, Khandheria BK, dos Santos C, Matioda H, Mogogane MT, Essop MR. Isolated left ventricular noncompaction in identical twins. Am J Cardiol 2012; 110(8): 1175–1179. Kruse M, Schulze-Bahr E, Corfield V, et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest 2009; 119(9): 2737–2744. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary working groups; and Council on Epidemiology and Prevention. Circulation 2006; 113(14): 1807–1816. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial diseases. Eur Heart J 2008; 29: 270–276. Ntusi NBA, Badri M, Gumedze F, Wonkam A, Mayosi BM. Clinical characteristics and outcomes of familial and idiopathic dilated cardiomyopathy in Cape Town: A comparative study of 120 cases followed up over 14 years. S Afr Med J 2011; 101(6): 399–404. Ntusi NBA, Wonkam A, Shaboodien G, Badri M, Mayosi BM. Frequency and clinical genetics of familial dilated cardiomyopathy in Cape Town: Implications for the evaluation of patients with unexplained cardiomyopathy. S Afr Med J 2011; 101(6): 394–398. Watkins DA, Hendricks N, Shaboodien G, et al. Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the Arrhythmogenic Right Ventricular Cardiomyopathy Registry of South Africa. Heart Rhythm 2009; 6(11, Supplement 1): S10–S7.

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Neonatal circulatory failure due to acute hypertensive crisis: clinical and echocardiographic clues JACOBA LOUW, STEPHEN BROWN, LIESBETH THEWISSEN, ANNE SMITS, BENEDICTE EYSKENS, RUTH HEYING, BJORN COOLS, ELENA LEVTCHENKO, KAREL ALLEGAERT, MARC GEWILLIG

Abstract Objective: Circulatory failure due to acute arterial hypertension in the neonatal period is rare. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute neonatal hypertensive crisis. Methods: Neonatal and cardiology databases from 2007 to 2010 were reviewed. An established diagnosis of circulatory failure due to neonatal hypertension before the age of 14 days was required for inclusion. Six patients were identified. Results: Five patients presented with circulatory failure due to an acute hypertensive crisis. The median age at presentation was 8.5 days (range: 6.0–11.0) with a median body weight of 3.58 kg (range: 0.86–4.70). Echocardiography demonstrated mild left ventricular dysfunction [median shortening fraction (SF) 25%, range 10–30) and mild aortic regurgitation in 83% (5/6) of patients. One patient with left ventricular dysfunction (SF = 17%) had a large apical thrombus. Two patients were hypotensive, and hypertension only became evident after restoration of cardiac output. Administration of intravenous milrinone was successful, with rapid improvement of the clinical condition. Left ventricular function normalised in all survivors. Conclusion: Early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life-threatening condition. At presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis being the cause of circulatory failure. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in a structurally normal heart should alert the physician to the presence of underlying hypertension.

Keywords: neonatal, shock, hypertension, crisis, echocardiography Submitted 5/5/12, accepted 11/1/13 Cardiovasc J Afr 2013; 24: 73–77

www.cvja.co.za

DOI: 10.5830/CVJA-2013-003

Circulatory failure is frequently the forerunner of a serious underlying condition in the neonate. It requires rapid detection of origin to differentiate non-cardiac (e.g. sepsis, metabolic derangements) from cardiac causes. Echocardiography is requested as an early diagnostic test, primarily with the intention to exclude potentially lethal structural heart disease, for example coarctation of the aorta, critical aortic stenosis, or hypoplastic left heart. When left ventricular dysfunction is observed, the focus shifts to myocardial disease. Acute episodes of systemic hypertension are rarely, if ever, considered in the differential diagnosis. Very little is known about the incidence of acute hypertensive crisis in newborn infants. Acute systemic hypertensive episodes during this period are most likely under-recognised and underdiagnosed. It is a rare but potentially life-threatening condition. Systemic hypertension in neonates has a reported incidence varying from 0.2 to 2.6%.1-4 Cardiomegaly, hypocontractility, overt cardiac failure and even death related to neonatal hypertension have been described but consist mostly of a few case reports.2,3,5-10 Successful management relies on early and prompt recognition and treatment. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute hypertensive events.

Methods Paediatric Cardiology, University Hospitals Leuven, Leuven, Belgium JACOBA LOUW, MD STEPHEN BROWN, MMed, FCPaed, DCH BENEDICTE EYSKENS, MD, PhD RUTH HEYING, MD, PhD BJORN COOLS, MD MARC GEWILLIG, MD PhD, marc.gewillig@uzleuven.be

University of the Free State, Bloemfontein, South Africa STEPHEN BROWN, MMed, FCPaed, DCH

Neonatology, University Hospitals Leuven, Leuven, Belgium LIESBETH THEWISSEN, MD KAREL ALLEGAERT, MD, PhD

Paediatric Nephrology, University Hospitals Leuven, Leuven, Belgium ANNE SMITS, MD ELENA LEVTCHENKO, MD PhD

This was a retrospective review. To be considered for inclusion, an established diagnosis of circulatory failure associated with a blood pressure more than the 95th percentile for gestational age and weight during the course of admission in the neonatal intensive care unit before the age of 14 days was essential.3 Neonatal and cardiology databases of a tertiary referral centre from 2007 to 2010, consisting of 2 632 admissions to the neonatal intensive care unit, were reviewed. Six patients with circulatory collapse and documented systemic hypertension, as defined, were identified. Standard descriptive and demographic data were obtained from patient records. Patient charts were reviewed for clinical course, laboratory results and outcome. In order to eliminate inter-observer bias, echocardiograms performed during the initial presentation were digitally reviewed by a single paediatric cardiologist and recalculated. The averages of previous and recalculated measurements were used.

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TABLE 1. CLINICAL CHARACTERISTICS AT PRESENTATION

1 2 3 4

Weight (g) 3210 4700 3650 3520

5 3680 6 860

BP (mmHg) – 160/110 – 140/110

Lactate (mmol/l) 2.5 1.4 3.2 2

100/70 –

11 1.7

Associated symptoms shock, respiratory distress RF shock feeding intolerance, electrolyte disturbances distended abdomen poor circulation

Echocardiography RegurgiCentral line tation SF % – AR, MR 10 umbillical, venous AR, MR 30 umbillical, arterial and venous AR, MR 17 femoral, venous MR 25

Anti-HT Rx follow Findings up – yes – no vascular insult right kidney no – no

femoral, venous AR, MR umbillical, arterial and venous AR, MR

25 dysplastic right kidney yes poor* thrombus occlusion died descending aorta BP: blood pressure at initial presentation, SF: shortening fraction at initial presentation, R: respiratory failure, AR: aortic regurgitation, MR: mitral regurgitation, R: right, anti-HT Rx: antihypertensive medication. *Extremely poor contractility on visual inspection, measurements not possible (initial echocardiogram).

Left ventricular systolic function, end-diastolic dimension and wall thickness were measured by means of standard M-mode and two-dimensional views. Using previously published normal values, z-scores were calculated.11,12 Mitral and aortic regurgitation were classified according to width and length of colour Doppler jet as mild (jet < 25%), moderate (jet 25–50%) or severe (jet > 50%). Approval by the local medical ethics committee was obtained. Data were analysed using standard statistical software (SPSS for windows®, Chicago, Illinois, USA, version 18). Data are presented as medians with minimum and maximum values where appropriate.

Results The median age at presentation was 8.5 days (range: 6.0–11.0) with a median body weight of 3.58 kg (range: 0.86–4.70). All infants were full term, except one 28 weeks premature infant with a birth weight of 860 g. All patients had circulatory failure and required admission to the intensive care unit for cardiopulmonary support. At initial presentation, three infants had hypertension while two patients were hypotensive and one normotensive. Hypertension in the latter only became evident after resuscitation and restoration of cardiac output. Common symptoms included lethargy, feeding intolerance or poor feeding. Patient characteristics are depicted in Table 1. Umbilical arterial lines had been inserted in two children prior to the episodes of hypertension. None of the mothers were diabetic and maternal health was good except in one where a history of herpes infection and pre-eclampsia was present. There was no history of ingestion of drugs associated with hypertension. Lactate levels were elevated in most infants on admission (Table 1), with a median of 2.6 mmol/l (range: 1.4–11). Troponin levels were measured in three patients and were elevated in patients 1 and 5: 0.16 and 2.01 µg/l, respectively (normal: < 0.13 µg/l). Both plasma renin activity (PRA) and aldosterone levels were markedly elevated in five patients, with medians of 32.6 µg/l/h (range 10.5–> 37) (local laboratory neonatal reference value: < 16.6 µg/l/h) and 2 396 ng/l (range: 763–24 920) (local laboratory neonatal reference value: 7–184), respectively. In one patient aldosterone levels were within the normal range, but PRA was elevated (37.4 µg/l/h). Urine catecholamines were normal in all patients. Plasma PRA and aldosterone levels gradually decreased and normalised in all patients after a median of eight

days (range: 7–13) and antihypertensive treatment could be diminished or discontinued. Systolic cardiac function was considerably impaired in three patients and mildly impaired in two, with a median SF of 25% for the group as a whole (range: 10–30%, Table 1), while left ventricular end-diastolic dimensions were within normal reference ranges (Table 2). Left ventricular posterior wall thickness was increased in three and interventricular septal thickness in four patients, respectively (Table 2). In one patient with considerable hypocontractility, a thrombus of 5 × 9 mm was observed in the apex of the left ventricle (Fig. 1). Mild to moderate aortic regurgitation was seen in five of the six patients (Fig. 2) and mild to moderate mitral regurgitation (MR) in all (Table 1). All aortic and mitral valves were morphologically normal. Interestingly, the coronary arteries were reported to be more prominent than usual in four patients on visual inspection of the echocardiograms (Fig. 3). Milrinone was used in five patients to treat circulatory failure. All patients improved rapidly with normalisation of left ventricular systolic function. The majority of patients required at least two antihypertensive drugs to control the blood pressure in the intensive care unit once they were stabilised. Underlying causes of hypertension were found in three patients. One patient had a vascular insult of the right kidney and one a dysplastic right kidney. Thrombosis of the abdominal aorta was seen in the 860-g neonate who did not survive. Both this patient as well as the infant with vascular damage of the kidney had umbilical arterial lines prior to presentation. No demonstrable underlying cause could be identified in the other three patients. TABLE 2. ECHOCARDIOGRAPHIC FINDINGS LVEDD IVS LVPW Measurement (mm) median 19 5 5 minimum 16 4 4 maximum 21 10 5 z-score median 1.1 4.2 2.5 minimum –0.6 0.8 0.2 maximum 2 5.9 2.5 LVEDD: left ventricular end-diastolic diameter, IVS: interventricular septum, LVPW: left ventricular posterior wall.

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Fig. 1. Aortic regurgitation. Mild aortic regurgitation in four-chamber view (A), and long-axial plane (B). LV, left ventricle.

Four patients are currently being followed up, with ages of 0.7, 1.0, 3.0 and 3.7 years, respectively. In three of these, permanent renal sequelae are present, namely renal atrophy, dysplastic kidneys, asymmetric renal function and proteinuria. In one of these, cortical atrophy with dysfunction of the kidney only became apparent during follow up. Two still require antihypertensive medication, but all have a normal shortening fraction.

Discussion Over a four-year period in a busy neonatal unit in a referral centre, only six patients with circulatory failure due to acute hypertensive crisis were identified, indicating how rare this condition is. These patients are usually critically ill and may die if not diagnosed and treated promptly. All our patients presented within two weeks of birth. This, remarkably, resembles findings in the only other previously published series where the median age at presentation was 7.2 days.13 Similar to our findings, they also observed that the initial clinical symptoms were mostly non-specific and related to feeding and respiratory difficulties. It is of clinical significance that all our patients presented with some form of circulatory failure. Although most were hypertensive (n = 3), two patients presented with hypotension and shock and one was normotensive (Table 1). Hypertension due to

increased systemic vascular resistance only became apparent after they were stabilised and resuscitated. The hypotension was most likely caused by impaired left ventricular systolic performance as confirmed by reduced fractional shortening. In most of our patients, hypertrophy of the interventricular septum and/or left ventricular posterior wall was evident. This increase in left ventricular mass had also been reported by Peterson.13 Hypertension in our patients was most likely of recent postnatal onset. We postulate that antenatal onset of hypertension is unlikely, since one then would have expected significant biventricular hypertrophy with significant pulmonary hypertension, Such patients present with cyanosis due to atrial right-to-left shunt.14 The differential diagnosis of neonatal hypertension has been extensively reviewed.3 An important question to be answered is what triggers these postnatal arterial hypertensive events? Could it be related to the postnatal haemodynamic and humoral changes which â&#x20AC;&#x2DC;relaxâ&#x20AC;&#x2122; the homeostatic vasomotor tone and elicit an acute biochemical response? Alternatively, is it due to mostly intrinsic renal abnormalities which then become manifest, or are these events triggered by iatrogenic factors such as thrombi from umbilical lines? Thromboembolic events related to umbilical lines are acknowledged as the most common cause of clinical hypertension in neonates. In this study, renal causes were identified in two infants and thrombus in one. More studies are needed to answer these questions. Echocardiography is usually requested once an infant with circulatory failure is admitted to the neonatal intensive care unit. Faced with this clinical presentation, the demonstration of hypocontractility would inevitably lead the cardiologist to consider a differential diagnosis of myocarditis, cardiomyopathy, coarctation of the aorta or coronary artery anomalies. Left ventricular hypocontractility in the absence of hypertension will be misleading in this case. However, careful analysis of the abovementioned echocardiographic findings associated with mild aortic regurgitation should alert the physician to consider systemic hypertension as the probable underlying cause. Mitral regurgitation is not unexpected in the presence of left ventricular dysfunction and is frequently observed in association with cardiomyopathy. However, aortic regurgitation is very unusual in a supposedly normal heart, provided the valve is structurally normal. Although the left heart was not dilated, central aortic and mitral valve regurgitation were seen in the majority of patients. We did not measure aortic diameter in this study but Peterson and coworkers reported mild dilation in their study, which they ascribed to the increased aortic distensability A

Fig. 2. Thrombus in the left ventricular apex. Apical fourchamber view demonstrating thrombus in the left ventricular apex (arrow). LV, left ventricle; RV, right ventricle.

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Fig. 3. Prominent coronary arteries. Short-axis image with arrow indicating prominent right coronary artery (A), and left coronary artery (B).

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in neonates.13,15 This could possibly provide an explanation for the mild to moderate AR observed in our patients. Left ventricular hypocontractility was observed in a significant number of our patients. Acute decompensation can be explained on the basis of normal neonatal cardiac physiology. The neonatal heart has, by way of its structure, function and unique changes in loading conditions, limited cardiac reserves and therefore also less compensatory ability. After birth, volume load on the left heart increases sharply, from less than 35% of the total output to 50% of combined ventricular output. Afterload also increases due to marked increase in the systemic vascular resistance. If an additional insult such as the acute pressure load of arterial hypertension is added to an ‘untrained’, adapting left ventricle, acute left ventricular failure becomes a realistic scenario. The dilated coronary arteries in two-thirds of our patients are intriguing. Adult studies have shown coronary arteries to proportionately increase in diameter in association with left ventricular hypertrophy.16,17 Furthermore, coronary arteries rapidly dilate in response to increased myocardial demand.18 Taken as a constellation of findings, one can therefore deduce that the combination of all these echocardiographic findings would indicate acute cardiac overload of recent onset. Cardiac failure was treated using milrinone, which in our clinical judgment gave a beneficial response in all our patients and improved cardiac function. Milrinone is a treatment of choice under these circumstances since the phosphodiesterase inhibitors decrease systemic and pulmonary vascular resistances and increase cardiac contractility.19 It should be noted that the reference ranges for plasma renin activity show marked variation and vary from laboratory to laboratory. Although transient elevation of PRA or/and plasma aldosterone levels, with subsequent normalisation after control of hypertension, was observed in all patients, underlying renal causes could only be demonstrated in two patients during admission. Whether this renin–angiotensin–aldosterone system activation was part of a reactive stress response or a causative event remains unclear.18,20,21 Nevertheless, outcome in general was good, with gradual disappearance of hypertension and the normalisation of PRA and aldosterone levels in all patients.

to the possibility of underlying hypertension. Clinicians and echocardiographers should be aware that at presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis and failure to consider the diagnosis may lead to death. Long-term cardiac outcome in survivors appears good. Grant sponsors: Rotary Tienen Foundation and Eddy Merckx Research Foundation. RH was supported by a grant of the Research Foundation Flanders (FWO, Klinische Doctoraatsbeurs), Belgium.

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Limitations The study was limited by the small number of patients and its retrospective nature. In order to reduce observer bias and variability, all echocardiograms were independently re-examined by a single cardiologist. As a consequence of the small sample of patients, the true incidence of hypertension cannot be determined. Only patients with circulatory failure were included, therefore patients with milder forms of disease may not have been detected. Diastolic functional assessments were not carried out at admission and are therefore not available. Further studies are required to elucidate the underlying pathophysiology.

15.

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Conclusion Findings of this study are based on a limited number of patients. However, early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life-threatening condition. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in an otherwise structurally normal heart should alert the physician

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Decreased vascular contractility induced by hemin is associated with a reduced rho-kinase activity BONAVENTURE AWEDE, MARIE-CHRISTINE LEMAIRE, PIERRE BONNET, VERONIQUE EDER

Abstract Objectives: In this study, the role of rho-kinase activity in the modulation of vascular contractility induced by hemin, a heme oxygenase inducer, was investigated. Methods: Aortic rings from Wistar rats were incubated in physiological saline solution (PSS) containing hemin at 10-4 M for six hours then contracted with phenylephrine, and a dose-response curve was established. The effect of Y-27632, a rho-kinase inhibitor, on the relaxation of the pre-contracted aortic rings was then studied. Results: Incubation of the aortic rings in hemin induced an increased expression of heme oxygenase 1 (HO-1). A reduction in the contractile force of aortic rings incubated in hemin was observed in response to phenylephrine. Y-27632 at a concentration of 10-6 M induced a 36% relaxation of the control aortic rings but only a 20% relaxation in aortic rings treated with hemin. Conclusion: These data suggest that the decreased vascular contractility induced by hemin could, in part, result from an inhibition of rho-kinase activity. Keywords: haeme oxygenase, vascular contractility, rho-kinase Submitted 31/12/09, accepted 18/1/13 Cardiovasc J Afr 2013; 24: 78–81

www.cvja.co.za

DOI: 10.5830/CVJA-2013-005

Carbon monoxide (CO), like nitric oxide (NO), has been shown to decrease vascular contractility. This gas is endogenously produced by the breakdown of heme into biliverdin, iron and CO, and the reaction is catalysed by heme oxygenase. Heme oxygenase (HO) exists in three isoforms: an inductive form, HO-1, and two constitutive forms, HO-2 and HO-3.1 Hemin is one of the components that induces expression of HO-1 in vascular tissues both in vitro and in vivo. Hemin is also a substrate of heme oxygenase. In vitro induction of HO-1, which results in CO production, decreased both animal and human arterial contractility.2,3 Longterm in vivo administration of hemin to spontaneous hypertensive rats (SHR) has been shown to normalise arterial pressure.4 If smooth muscle contraction is regulated by the cytosolic calcium concentration, which induces activation of myosin LAB.P.ART.-EA3852, Faculty of Medicine, University of Tours, 10 bis Boulevard Tonnellé, Tours, France BONAVENTURE AWEDE, MD, PhD MARIE-CHRISTINE LEMAIRE, MD, PhD PIERRE BONNET, MD, PhD VERONIQUE EDER, MD, PhD

Unité de Physiologie, Faculté des Sciences de la Santé, Université d’Abomey-Calavi, Bénin BONAVENTURE AWEDE, MD, PhD, Bonawed@yahoo.com

light-chain kinase and then phosphorylation of the regulatory myosin light chain, it is also regulated by the calcium sensitivity of myofilaments. This mechanism is partly achieved by the inhibition of myosin light-chain phosphatase, and the small GTPase rho and its target rho-associated kinase participate in this inhibition.5,6 Increased activity of rho-kinase has been observed in many models of arterial hypertension, and administration of inhibitors of rho-kinase activity has been shown to lower blood pressure.7-10 Activation of rho-kinase is also involved in many other cardiovascular disorders.11-13 Previous studies have shown that the effects of carbon monoxide or heme oxygenase 1 induction on vascular contractility or blood pressure occur via activation of soluble guanylate cyclase, which results in the production of cyclic GMP and via activation of the potassium current.3,4,14-16 The possible involvement of rho-kinase has never been investigated in vitro. In this study, we hypothetised that induction of heme oxygenase could result in decreased activation of rho-kinase. Therefore the effect of inhibition of rho-kinase on the relaxation of pre-contracted aortic rings was investigated following incubation in hemin.

Methods All animal experimental protocols were performed with the approval of the regional ethics committee (CREEA no CL2007013). Twelve-week-old rats used in this study were housed at 21°C with 12-hour light/dark cycles. They were fed with standard laboratory food and had unlimited access to drinking water. Hemin solution was prepared by dissolving hemin (Fluka, France) in a phosphate buffer solution (PBS) pH 12 and adjusted to pH 7.4. Animals were anesthetised by an intraperitoneal injection of sodium pentobarbital (100 mg/kg of body weight).

Contraction of isolated artery rings The rats were euthanised and the thoracic aorta was dissected. Transverse ring sections were isolated and the endothelium was destroyed by rubbing the intimal surface with forceps. The rings were then suspended between two wires connected to the bottom of an organ bath and to an isometric force transducer that allowed the recording of the tension developed by each ring. In all experiments, the rings were stretched against a 3-g pre-load in the organ bath, which was filled with physiological saline solution (PSS) at 37°C, containing (in mM): NaCl 138.6; KCl 5.4; CaCl2 1.8; MgCl2 1.2; NaH2PO4 0.33; HEPES 10 and glucose 11. The pH was adjusted to 7.4 using NaOH. After one hour of rest (equilibrium), the rings were pre-contracted with a PSS solution containing 80 mM K+ (K80) in order to provide maximal contractile amplitude of tone. This was used as a reference and to check tissue viability. A relaxation response to acetylcholine was used to confirm the absence of endothelium.

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The vascular rings were then contracted with a cumulative dose of phenylephrine (10-9 to 10-6 M). After washing the rings to suppress the effects of phenylephrine, the rings were incubated in PSS containing hemin at a concentration of 10-4 M. After six hours of incubation, the rings were contracted again with a cumulative dose of phenylephrine.

Relaxation effect of Y-27632 Relaxation induced by Y-27632 [(R)-(+)-trans-N-(4-pyridyl)4-(1-aminoethyl)-cyclohexanecarboxamide] (Tocris, France), a rho-kinase inhibitor, was tested on either the control rings or rings incubated in hemin following contraction induced by phenylephrine at 10-6 M. Y-27632 was used at a concentration of 3 × 10-7 M. Results were expressed as a percentage of the magnitude of contraction with 10-6 M of phenylephrine. All the data were collected with a computerised dataacquisition system using Genie software (Adventech, USA). All the analyses were carried out using Origin 6 software (Microcal Software, Northampton, MA, USA).

Immunohistochemistry Aortic rings incubated in either PSS or PSS with hemin at 10 M were embedded in ‘optimal cutting temperature compound’ (Tissue-TekR OCT compound, Sakura Finetek, France) and then frozen in liquid nitrogen. Transverse sections of 7 µm were made using a cryostat and mounted on a microscope slide. Immunohistochemical analysis of HO-1 was performed. Sections were first incubated with a rabbit polyclonal anti-rat HO-1 antibody at room temperature for four hours. The antigen– antibody reaction was detected using a molecular probe Alexa fluor dye goat anti-rabbit secondary antibody (Interchim, France). The positive reaction was visualised under confocal microscopy. -4

Statistical analysis

120 100

Cumulative concentrations of phenylephrine induced a concentration-dependent increase in the contraction of aortic rings. As shown in Fig. 1, incubation of aortic rings in hemin solution induced a decrease of the contractile force of the aortic rings at all concentrations of phenylephrine from 3 × 10-8 to 10-6 M. The application of Y-27632, a specific and potent rho-kinase inhibitor, induced a relaxation in the isolated aortic rings. In the control aortic rings, the magnitude of the relaxation at 3 × 10-7 M of Y-27632 was 36% of the contraction induced by 10-6 M of phenylephrine. In aortic rings treated with hemin, the relaxation induced by Y-27632 was reduced to 20% of the contraction induced by phenylephrine (Fig. 2). Immunohistochemical study showed expression of HO-1 in both control and hemin-treated aortic rings. As shown in Fig. 3, six-hour incubation of aortic rings in hemin resulted in an increased expression of HO-1.

Discussion The main findings of this study were that the decreased contractility of the aortic rings induced by hemin was associated with a reduced effect of Y-27632, a rho-kinase inhibitor, on the relaxation of aortic rings pre-contracted with phenylephrine. The reduced vascular smooth muscle contractile force induced by hemin found in this study was associated with an increased expression of heme oxygenase HO-1. This is in agreement with data previously published on rat and human vessels.3 The change in contractile force produced was observed after six hours of incubation in hemin, not after four hours, as was observed in human vessels. The four-hour duration in our study was without significant effect on the phenylephrine-induced contraction of aortic rings. The hemin effect on vascular contractility occurs via mechanisms involving heme oxygenase, as it has been shown that these effects were suppressed by inhibition of HO-1 activity.3,4,15 Moreover, it has been shown that vascular effects of heme oxygenase and CO are mediated by activation of soluble guanylate cyclase, with increased production of cyclic GMP and activation of potassium channels.3,4,15

* *

80 *

60 40

Results

Control, n = 9 Hemin, n = 7

1,00E–09 1,00E–08 3,00E–08 1,00E–07 3,00E–07 1,00E–06 Phenylephrine concentration (mol/l)

Fig. 1. Cumulative dose effect of phenylephrine on the contraction of control aortic rings (triangle) and aortic rings incubated in hemin solution 10-4 M for six hours (square). Values are expressed as percentage of magnitude of contraction induced by 10-6 M of phenylephrine (PE) before the six-hour incubation. * Significantly different from control (p < 0.05.)

Relaxation (% of contraction with phenyleprhine)

Force (% maximal contraction with PE)

Results are expressed as means ± SEM. Differences between control and hemin groups were compared using Student’s t-test and the level of statistical significance was set at p < 0.05.

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50 40 30

20 10 0

Control, n = 12

Hemin, n = 10

Fig. 2. Relaxation effect of Y-27632, a rhoA-kinase inhibitor, on aortic ring contraction induced by phenylephrine at 10-6 M. The clear column represents control aortic rings and shaded column aortic rings incubated in hemin. Values are expressed as percentage of the magnitude of contraction induced by 10-6 M of phenylephrine. ** Significantly different from control (p < 0.01.)

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Control

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Hemin

Fig. 3. Expression of heme oxygenase (HO-1) in aortic rings. Images represent 7-μm-thick transverse sections of aortic rings in which expression of heme oxygenase 1 (HO-1) was detected by immunofluorescence using an Alexa fluo-labelled secondary antibody after incubation with an anti-HO-1 antibody. On the left, a section of control aortic ring and on the right, a section of aortic ring incubated for six hours in physiological saline solution containing hemin at 10-4 M. Increased expression of HO-1 (light fluorescence) is observed in the hemin aortic ring compared to that in the control ring.

Here we found that decreased vascular contractility induced by hemin incubation was associated with a reduction in the relaxation effect of Y-27632. Since Y-27632 is a specific inhibitor of rho-kinase activity,7 this effect suggests that following incubation in hemin, the activity of rho-kinase in aortic smooth muscle was partially inhibited. As rho-kinase is involved with calcium sensitivity in vascular smooth muscle, this reduced activity of rho-kinase could explain in part the reduced contractile force developed by aortic rings in response to phenylephrine. Previously, we have shown that the relaxation effect of Y-27632 was greater in aortic rings from hypertensive rats than in those from normotensive Wistar rats. Moreover, 21 days’ administration of hemin resulted in a reduction in the relaxation effect of Y-27632 on aortic rings from hypertensive rats but was without significant effect on the relaxation of aortic rings induced by Y-27632.17 Therefore, although six-hour incubation of aortic rings in hemin resulted in a reduction of the relaxation effect of Y-27632, suggesting a decrease of rho-kinase activity, 21 days’ administration of hemin did not alter the rho-kinase activity in the aortas of Wistar normotensive rat. However, this long-term administration of hemin decreased the rho-kinase activity in vessels from spontaneously hypertensive rats where this activity was higher than in normotensive rats. To explain the absence of effect on Wistar rat blood pressure during long-term administration of hemin, some mechanisms could have occurred to prevent the reduction of rho-kinase activity and maintain vascular contractility.

Conclusion Six-hour incubation of aortic rings in hemin solution resulted in increased heme oxygenase 1 expression and decreased aortic contractility associated with a partial inhibition of rho-kinase activity. The mechanism of this hemin-induced inhibition of rho-kinase activity remains to be elucidated.

References 1.

2. 3.

10.

11. 12. 13.

Maines MD, Gibbs PEM. 30 some years of heme oxygenase: from a ‘molecular wrecking ball’ to a ‘mesmerizing’ trigger of cellular events. Biochem Biophys Res Commun 2005; 338: 568–577. Wang R, Wang Z, Wu L. Carbon monoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol 1997; 121: 927–934. Achouh P, Simonet S, Badier-Commander C, Chardigny C, VayssettesCourchay C, Zegdi R, et al. The induction of heme oxygenase 1 decreases contractility in human internal thoracic artery and radial artery grafts. J Thorac Cardiovasc Surg 2005; 130: 1573–1580. Wang R, Shamloul R, Wang X, Meng Q, Wu L. Sustained normalization of high blood pressure in spontaneously hypertensensive rats by implanted hemin pump. Hypertension 2006; 48: 685–692. Somlyo AP, Somlyo AV. Calcium sensitivity of smooth muscle and nonmuscle myosine II: Modulated by G proteins, kinases and myosin phosphatase. Physiol Rev 2003; 83: 1325–1358. Hirano K, Hirano M, Kanaide H. Regulation of myosin phosphorylation and myofilament calcium sensitivity in vascular smooth muscle. J Smooth Muscle Res 2004; 40: 219–236. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Yamagami K, et al. Calcium sensitization of smooth muscle mediated by rho-associated protein kinase in hypertension. Nature 1997; 990–994. Chrissobolis S, Sobey CG. Evidence that rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension. Cir Res 2001; 88: 774–779. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J, et al. Involvement of rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J 2001; doi:10.1096/ fj00-073fje. Seko T, Ito M, Okamoto R, Moriki N, Onishi K, Isaka N, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res 2003; 92: 411–418. Loirand G, Guérin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006; 98: 332–334. Noma K, Oyama N, Liao JK. Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol 2006; 290: C661–C668. Calo LA, Pessina AC. RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. J

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Hypertens 2007; 25: 259–264. 14. Wang R, Wu L, Wang Z. The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells. Pflügers Arch-Eur J Physiol 1997; 434: 285–291. 15. Sammut IA, Foresti R, Clark JE, Exon DJ, Vesely MJJ, Sarathchandra P, et al. Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1. Br J Pharmacol 1998; 125: 1437–1444.

16. Ndisang JF, Wu L, Zhao W, Wang R. Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats. Blood 2003; 101: 3893–3900. 17. Awede B, Lemaire MC, Hyvelin JM, Halimi JM, Bonnet P, Eder V. Hemin, a carbon monoxide donor, improves aortic elasticity by inhibiting RhoA-Rho kinase pathway in spontaneous hypertensive rat. Eur J Pharmacol 2010; 626: 256–261.

DAKAR

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

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

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Cardiovascular complications in newly diagnosed rheumatic heart disease patients at Mulago Hospital, Uganda EMMY OKELLO, ZHANG WANZHU, CHARLES MUSOKE, ALIKU TWALIB, BARBARA KAKANDE, PETER LWABI, NYAKOOJO B WILSON, CHARLES K MONDO, R ODOI-ADOME, JUERGEN FREERS

Abstract Background: Complications of rheumatic heart disease are associated with severe morbidity and mortality in developing countries where the disease prevalence remains high. Due to lack of screening services, many patients present late, with severe valve disease. In Uganda, the disease and its complications are still not well studied. Objective: To profile and describe cardiovascular complications in newly diagnosed rheumatic heart disease patients attending the Mulago National Referral Hospital in Uganda. Methods: This was a cross-sectional study where consecutive, newly diagnosed rheumatic heart disease patients were assessed and followed up for complications, such as heart failure, pulmonary hypertension, atrial fibrillation, recurrence of acute rheumatic fever, and stroke. Results: A total of 309 (115 males and 196 females) definite rheumatic heart disease patients aged 15–60 years were enrolled in the study and analysed. Complications occurred in 49% (152/309) of the newly diagnosed rheumatic heart disease cases, with heart failure (46.9%) the most common complication, followed by pulmonary arterial hypertension (32.7%), atrial fibrillation (13.9%), recurrence of acute rheumatic fever (11.4%), infective endocarditis (4.5%) and stroke (1.3%). Atrial fibrillation and acute rheumatic fever were the most common complications associated with heart failure. Conclusion: In this study we found that about 50% of newly diagnosed rheumatic heart disease patients in Uganda presented with complications. Heart failure and pulmonary arterial hypertension were the most commonly observed complications.

Department of Medicine, Division of Cardiology, College of Health Sciences, Makerere University, Uganda EMMY OKELLO, MB ChB, MMed, emmkol@hotmail.com ZHANG WANZHU, MB ChB CHARLES MUSOKE, MB ChB BARBARA KAKANDE, MB ChB, MMed CHARLES K MONDO, MB ChB, MMed, PhD JUERGEN FREERS, MB ChB, MMed

Uganda Heart Institute, Mulago National Referral Hospital, Makerere University, Uganda EMMY OKELLO, MB ChB, MMed ALIKU TWALIB, MB ChB, MMed BARBARA KAKANDE, MB ChB, MMed, PETER LWABI, MB ChB, MMed, NYAKOOJO B WILSON, MD, PhD CHARLES K MONDO, MB ChB, MMed, PhD

School of Pharmacy, Makerere University, Uganda R ODOI-ADOME, MB ChB, MSc, PhD

Keywords: rheumatic heart disease, complications, newly diagnosed patients Submitted 18/5/12, accepted 18/1/13 Cardiovasc J Afr 2013; 24: 82–87

www.cvja.co.za

DOI: 10.5830/CVJA-2013-004

Worldwide, rheumatic heart disease (RHD) and its complications result in about 233 000 deaths annually. The World Health Organisation (WHO) estimates that approximately 16 million people are currently affected by the disease.1 The majority of RHD cases occur in Africa where prevalence rates are as high as one in 10 people in some communities.1-3 Acute rheumatic fever is the result of a hyper-immune response to Group A streptococcal infection in the susceptible host. The resulting valvular damage, or RHD, is the only longterm consequence of acute rheumatic fever. Lack of primary prevention (treatment of group A streptococcal infections), and lack of screening programmes to detect early RHD, results in late disease presentation, with most patients only seeking medical care due to symptoms related to complications of the disease. Consequently, patients present with various long-term structural and haemodynamic complications, such as heart failure, atrial fibrillation and stroke.4-6 The situation is worsened by low clinician knowledge in the diagnosis and treatment of the disease and some of its complications.7 Late presentation denies patients an opportunity for early intervention in the management the disease, including early medical treatment and institution of benzathine penicillin prophylaxis, which has been shown to prevent recurrence of acute rheumatic fever.8 Apart from a prevalence survey in primary schools, no systemic study has documented the complications of RHD in newly diagnosed patients in Uganda, making it difficult to design guidelines for prevention, diagnosis and treatment. The awareness, surveillance, advocacy and prevention (ASAP) programme was developed to increase awareness and surveillance of RHD in most affected countries.9,10 The strategy aims at raising awareness among the general public and healthcare workers about RHD, and improving the quality of information regarding RHD. The objective of the present study was to describe complications as found in newly diagnosed RHD patients attending Mulago National Referral Hospital in Uganda.

Methods The study was approved by the Institutional Review Board (IRB) of the School of Medicine, Makerere University College of Health Sciences and the Uganda National Council for Science and Technology (UNCST).

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Consecutive patients with a diagnosis of RHD were enrolled in this cross-sectional study between June 2010 and January 2012. We report on complication rates at presentation in those who were newly diagnosed with definite RHD. The study was conducted at Mulago Hospital, Uganda’s main national referral hospital and teaching hospital for the Makerere University College of Health Sciences. Annually, Mulago Hospital admits approximately 60 000 patients and diagnoses approximately 240 new cases of rheumatic heart disease. For the purposes of this study, we were exclusively interested in patients newly diagnosed with RHD. To be included in this analysis, the patient was required to be between the ages of 15 and 60 years, to have definite RHD (2006 WHO/NIH criteria) confirmed by echocardiography, and to be willing to sign informed consent. Exclusion criteria included prior diagnosis of RHD, age < 15 or > 60 years, and/or presence of congenital heart disease. Furthermore, patients found to have atrial fibrillation in addition to abnormal electrolyte levels or abnormal thyroid function tests were also excluded. Medical doctors from the Mulago Hospital complex as well as other regional hospitals were invited to participate in the study by referring all patients aged 15 to 60 years with suspected RHD to the study site. Patients who were referred for evaluation underwent a comprehensive screening evaluation to determine the presence or absence of rheumatic heart disease. A medical history was obtained, including history of acute rheumatic fever (ARF): recent sore throat, joint pain, tremors or skin rash. A comprehensive physical examination including auscultation of the chest was carried out. A specific search for known complications of RHD such as heart failure, pulmonary hypertension, atrial fibrillation, infective endocarditis, stroke and recurrence of acute rheumatic fever was carried out during the physical examination and was later confirmed by specific tests. Standard transthoracic echocardiography (GE, Vivid 8, Chicago, USA) was preformed according to the American Society of Cardiology guidelines.11 Patients found to have congenital heart disease were referred to the Paediatric Cardiology Division for further evaluation. For the remainder of the patients, the 2006 WHO/NIH Joint Consensus Statement on Echocardiographic Diagnosis of RHD was used to classify patients as ‘definite’, ‘probable’, or ‘possible’ RHD, or as ‘no disease’.12 Cases confirmed to have definite RHD were asked to sign informed consent. Study participants then completed a detailed demographic profile and clinical questionnaire. They also underwent a chest X-ray and standard 12-lead electrocardiography (Cardiopac, Germany). Finally, 6 ml of venous blood was obtained through peripheral venipuncture, and complete blood counts, anti-streptolysin O (ASO) titres, erythrocyte sedimentation rate and C-reactive protein were determined.

Echocardiographic definitions Echocardiographic images were obtained from the parasternal long-axis, parasternal short-axis, apical four- and five-chamber and sub-costal views. Morphological abnormalities of the mitral valve, including thickening or calcification of the leaflets, and fusion, shortening, fibrosis, and /or calcification of the mitral chordae were recorded.

Mitral stenosis was labelled as significant if there was evidence of flow acceleration across the mitral valve with a mean pressure gradient > 4 m/s.12 Severity of mitral stenosis was determined by planimetry and pressure half-time methods, as mild (MVA > 1.5 cm2), moderate (MVA = 1.1–1.5 cm2) and severe (MVA < 1.0 cm2). Mitral regurgitation was labelled as significant if it was seen in two views by colour Doppler, was > 2 cm from the coaptation point of the valve leaflets, was high velocity, and persisted throughout systole.12 Mitral regurgitation was classified as severe if there was systolic flow reversal in the pulmonary veins. Morphological abnormalities of the aortic valve, including commissural fusion of the aortic leaflets, increased echogenicity along the leaflet edges, and systolic doming of the aortic leaflets was noted. Aortic stenosis was graded based on valve area as well as using flow velocity and mean pressure gradient across the valve (mild if valve area > 1.5 cm, moderate if valve area was 1.1–1.5 cm and severe if valve area < 1 cm). Aortic regurgitation was labelled as significant if it was seen in two planes, was at least 1 cm from the coaptation point of the valve leaflets, and was high velocity.12

Complications of rheumatic heart disease Following a pre-study survey of common complications presenting on our wards, a consensus was made to profile the following complications as they occurred: • Heart failure, which was defined according to the Framingham criteria,13 and New York Heart Association functional status. • Acute rheumatic fever was defined according to the 199214 and 2003 WHO modified Jones criteria for diagnosis of ARF recurrence in patients with RHD.15 • Infective endocarditis was diagnosed according to standard criteria as previously published.16 • Atrial fibrillation was diagnosed using the blinded Minnesota code.17 • Stroke was diagnosed during history and clinical examination, and confirmed on brain computer tomography scan (CT scan). • Pulmonary hypertension (PAH) was diagnosed based on clinical examination (findings of a loud second heart sound, murmur of tricuspid regurgitation, dilated pulmonary arteries on a chest X-ray) and confirmed using echocardiography. Doppler interrogation of tricuspid valve regurgitation was used to quantify the pulmonary arterial pressure. Pulmonary arterial systolic pressure (PASP) over 36 mmHg was defined as pulmonary hypertension.18

Statistical analysis Data were double entered and stored in EPI data version 3.0 (EpiData Association, Odense M, Denmark). Analysis was done using STATA 10.0 statistical package (Stata Corporation,College Station, TX, USA). Categorical variables were analysed using the Chi-square test, while continuous variables were analysed using the independent-samples two-tailed Student’s t-tests. Results are expressed as means ± standard deviation. In all statistical tests, p < 0.05 was regarded as significant.

Results Three-hundred and eighty patients with suspected RHD were referred for study enrollment. Congenital heart disease was

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found in seven patients, who were excluded from the analysis. RHD was found in 373 patients and 350 of these met the criteria for definite RHD. Of these 350 patients, 41 had a previous diagnosis of RHD and were excluded from the analysis. The remaining 309 patients, newly diagnosed as definite RHD, comprised this analysis (Fig. 1). Demographic information for the study population can be found in Table 1. The median age in males and females was 30 years, with an interquartile range of 20. Most cases were of low socio-economic status with little or no education and unemployed. Cardiovascular symptoms, including palpitations, fatigue, chest pain, oedema and syncope were found in 85.1% of the study enrolments. Palpitations were by far the most common complaint, being found in 84.5% of the total population, with equal distribution between males and females (Table 2). Complications were found in 49% (152/309) of the newly diagnosed RHD cases. Heart failure (46.9%) was the commonest complication, followed by pulmonary hypertension (32.7%), atrial fibrillation (13.9%), acute recurrence of rheumatic fever (11.4%), infective endocarditis (4.5%) and stroke (1.3%) (Table 2). Pulmonary hypertension was observed in about 33% of cases with no difference between male and female respondents. The mitral (70%) and aortic valves (30%) were the most affected valves in those with infective endocarditis. Mitral regurgitation (MR) was the most common valvular lesion, followed by mixed mitral and aortic regurgitation, mitral stenosis and mixed-valve disease (Table 3). The average left ventricular end-diastolic diameter (LVEDD), average left ventricular end-systolic diameter (LVESD) and average ejection fraction (LVEF) for cases with MR was 65 mm (normal range 35–55 mm), 50 mm (normal range 25–40 mm) and 54% (normal range 40–70%), respectively, with 52% of the cases presenting with severe MR. Those with aortic regurgitation (AR) had average LVEDD, LVESD and LVEF of 58 mm, 44 mm and 56%, respectively, with 46% presenting with severe AR; 49% of the mitral stenosis cases were graded as severe (Table 3). An analysis of factors associated with congestive heart failure was performed. Atrial fibrillation was the commonest complication associated with congestive heart failure (81.4% Referred for suspected RHD (n = 380) Congenital Heart Disease (n = 7) ASD (n = 4) VSD (n = 1) PAVSD (n = 1) PS (n = 1)

Possible RHD (n = 9)

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TABLE 1. DEMOGRAPHIC PROFILE OF RHD CASES n = 309 (%)

Patient characteristics Age (years), median (IQR)

30 (20)

Gender Male

113 (36.6)

Female

196 (63.5)

Education None

23 (7.4)

Primary

142 (45.9)

Secondary

99 (32.0)

Tertiary (college/university)

45 (14.6)

Occupation Peasant farmer

147 (49.1)

Civil servant

44 (14.7)

Small business owner

33 (11.4)

Student/pupil

73 (24.58)

Medication after diagnosis Diuretics

299 (98.4)

Benzathine penicillin

268 (97.1)

Beta-adrenergic blockers

223 (77.2)

Digoxin

212 (74.6)

Angiotensin converting enzyme inhibitors

43 (16.5)

Warfarin

48 (18)

Antiplatelates

9 (3.4)

Beta-adrenergic blockers

223 (77.2)

Calcium channel blockers

3 (1.2)

Diuretics

299 (98.4)

Ace inhibitors

43 (16.5)

Height (cm), median (IQR)

162 (12)

Weight (kg), mean (SD)

55.2 (13.8)

Pulse rate (beats/min), median (IQR)

90 (33)

IQR = inter-quartile range; SD = standard deviation.

CHF vs 18.6% no CHF, p < 0.05), followed by acute rheumatic fever recurrence (71.4% CHF vs 28.6% no CHF, p = 0.002), and infective endocarditis (78.6% CHF vs 21.4% no CHF, p = 0.015) (Table 4). In addition, 50% of cases with stroke presented in atrial fibrillation. The rest had mitral stenosis in sinus rhythm; 35 cases presented with recurrence of ARF. Average ASO titre and TABLE 2. CLINICAL PRESENTATION AND COMPLICATIONS Complication

RHD (n = 373)

Total cases

Total n (%) 309 (100)

Males n (%)

Females n (%)

113 (36.6) 196 (63.5)

Symptoms

Probable RHD (n = 14)

Definate RHD (n = 350) Pre-existing diagnosis (n = 41) New diagnosis (n = 309)

Fig. 1. Flow chart of study participants’ enrollment.

Palpitations

263 (85.1) 117 (44.4) 146 (56.6)

Fatigue

261 (84.5) 138 (52.8) 123 (47.2)

Chest pain

138 (44.7)

59 (42.7)

79 (57.3)

Oedema

112 (36.2)

36 (32.1)

76 (67.9)

Syncope

20 (6.4)

13 (65)

7 (35)

Congestive heart failure

145 (46.9)

56 (49.5)

89 (45.4)

Acute rheumatic fever

35 (11.4)

16 (14.3)

19 (9.7)

4 (1.3)

1 (0.9)

3 (1.5)

Clinically symptomatic peripheral embolism

Major bleeding

Infective endocarditis

14 (4.5)

7 (6.2)

7 (3.6)

Atrial fibrillation

43 (13.9)

16 (14.2)

27 (13.8)

Pulmonary hypertension

98 (32.7)

37 (32.7)

61 (31.1)

Complications

Stroke

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C-reactive protein levels were 526.7 mg/l (normal range 0.00– 200.0) and 97.4I U/ml (normal range 0.0–5.0), respectively. In addition to the carditis, joint pain and chorea were the only extracardiac manifestations of acute rheumatic fever observed. All cases of recurrence of ARF presented in heart failure.

Discussion Rheumatic heart disease remains a common cause of heart failure in developing countries and ranks among systemic hypertension and idiopathic dilated cardiomyopathy as the leading causes of heart failure in these nations.19,20 Rheumatic heart disease is one of the most common cardiac diagnoses seen in Uganda.21 Among our cohort of patients newly presenting with RHD, almost 90% reported cardiovascular symptoms and almost 50% had already developed related complications. This is the first study to profile the presentation of rheumatic heart disease in Uganda and highlights the tendency for late disease presentation and high rates of associated complications. Demographic information obtained from this study agrees with previous studies that RHD is a disease of low socioeconomic status and low educational level, as the majority of the respondents had either primary-level or no education.22,23 Our data continue to highlight that RHD is a disease of poverty, low productivity, poor quality of life and early mortality.19,20 In our cohort, mitral regurgitation was the commonest valve lesion, with the majority presenting in heart failure, and about half presenting with severe mitral valve regurgitation, with average LVEDD, LVESD and LVEF of 65 mm, 50 mm and 54%, respectively This is severe valve disease and recent studies have showed that an average LVESD of 50 mm or more is associated with rapid decline in cardiac function.24 In addition, it has been shown that delayed surgery is associated with a poor TABLE 3. VALVE LESIONS VERSUS COMPLICATIONS

Total n (%) Total cases Age, median (IQR)

Mitral stenosis n (%)

Mitral regurgitation n (%)

Aortic stenosis n (%)

Aortic Regurgitation n (%)

309 (100)

104 (33.6)

280 (90.6)

8 (2.6)

128 (41.4)

30 (20)

33 (15)

30 (14)

29 (19)

Gender Male

113 (36.6) 31 (27.4) 102 (90.3)

4 (3.5)

45 (39.8)

Female

196 (63.5

73 (37.2) 178 (90.8)

4 (2.0)

83 (42.4)

Heart failure

145 (46.9) 54 (37.2) 131 (90.3)

1 (0.7)

58 (40.0)

ARF

35 (11.4)

10 (28.6)

Complications 9 (25.7)

33 (94.3)

Stroke

4 (1.3)

2 (50)

4 (100)

2 (50)

Infective endocarditis

14 (4.5)

5 (35.7)

13 (92.9)

6 (42.8)

Atrial fibrillation

43 (13.9)

25 (58.1)

35 (81.4)

14 (32.6)

postoperative prognosis.24,25 Furthermore, Sliwa et al. in a study of the clinical characteristics of newly diagnosed RHD as seen in the Heart of Soweto study, South Africa,5 found the prevalence of newly diagnosed RHD to be 36% among patients diagnosed with any valvular heart disease, out of an overall total of 4 005 cases. Mitral regurgitation was the commonest valve lesion. Only 25% of cases had average LVDD > 55 mm, lower than that in our study where 52% of cases with mitral regurgitation had average LVEDD > 55 mm. This indicates that the cases in their study probably presented or were picked out earlier. Cardiovascular symptoms typically manifest when valvular regurgitation or stenosis (regardless of valve) becomes severe.26 This was demonstrated in our population, where 52% of patients had severe mitral regurgitation with average LVESD > 55 mm, and 80% of these patients reported symptoms. Among our cohort, the complication rate at presentation was almost 50%. This is slightly higher than reported by Sani et al., who studied the prevalence and pattern of RHD in the Nigerian savanah. In their echocardiography-based study, 32% had left ventricular dysfunction, among other complications, at the time of initial diagnosis.6 This is slightly lower than our reported rate of 49%. In our population, pulmonary hypertension was the second most common complication, affecting almost one-third of patients at the time of presentation. Males and females were affected equally. Pulmonary hypertension commonly develops as a complication of mitral and aortic valve disease.27 Development of pulmonary hypertension decreases quality of life and shortens life expectancy.27,28 Recurrent ARF was found in 11% of patients at the time of the initial diagnosis. Most of these cases did not fulfill the classical Jones criteria.14,29 Joint pains, chorea and evidence of Group A streptococcal infection, as shown by raised ASO titres were the only criteria met. These findings support the use of the 2003 WHO modification of the Jones criteria29 for the diagnosis of recurrence of ARF in established RHD. The tendency of patients to present during an episode of recurrent ARF has been previously described. Ravisha and colleagues reported data on 550 cases of newly diagnosed RHD in India.19 In their study, almost 40% of newly diagnosed patients were presenting with recurrence of ARF, and the rate of heart failure in these patients was 36%. We report that 100% of those presenting with ARF met the criteria for heart failure, which is most likely what brought them to our attention. It is not completely understood whether the heart failure that

TABLE 4. BIVARIATE ANALYSIS OF HEART FAILURE PREDICTORS Congestive heart failure

Dimensions 48 ± 9

65 ± 13

50 ± 9

58 ± 14

265 (85.7)

9 (8.7)

219 (78.2)

3 (37.5)

56 (43.8)

40 ± 11

33 ± 11

50 ± 13

37 ± 18

44 ± 15

LVESD > 45 mm

148 (47.8)

5 (4.8)

193 (68.9)

3 (37.5)

29 (22.5)

Mean LAD (mm)

Mean LVEDD (mm) LVEDD > 55 mm Mean LVESD (mm)

Mean LVEF (%)

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58 ± 17

59.7

59.5

56.3

Systolic dysfunction

101.9 (33)

9 (9)

126 (45)

3 (12)

38 (30)

Severity of valve lesion (%)

mild: moderate: severe

23:28:49

20:28:52

24:53:23 13:41:46

Male Female

Yes, n (%)

No, n (%)

56 (49.6)

57 (50.4 )

p-value

89 (45.4)

107 (54.6)

0.225

Systolic blood pressure, mean ± SD

117 ± 1.76

124 ± 1.82

0.006

Diastolic blood pressure, median (IQR)

70 (60–82)

71 (63–84)

0.614

25 (71.4)

10 (28.6)

0.002

1 (50)

2 (50)

0.906

Infective endocarditis

11 (78.6)

3 (21.4)

0.015

Atrial fibrillation

35 (81.4)

8 (18.6)

< 0.05

Other complications of RHD Acute rheumatic fever Stroke

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occurs in ARF is due to myocarditis or severe valve damage. Essop et al.30 suggested that the heart failure observed during ARF is probably secondary to volume overload from the valve lesion, not primary myocardial dysfunction. Our data suggest that myocardial dysfunction contributes to the heart failure seen, as patients with ARF had decreased left ventricular ejection fraction (mean 44%). Whether the myocardial dysfunction is attributable to acute myocarditis or secondary to acute on chronic volume overload remains unknown. In the future, myocardial biopsy might provide this answer and help direct therapy. Silwa and collegues5 report a different experience with recurrent ARF. In their study, there were no cases of ARF at the time of the initial RHD diagnosis. This difference is likely attributable to the notifiable nature of ARF in South Africa. Among countries in sub-Saharan Africa, active surveillance for new ARF cases is unique to South Africa. As we are reporting only new diagnoses, no patient in our cohort was receiving benzathine penicillin. Benzathine penicillin prophylaxis reduces recurrence of ARF to less than 20% in those who achieve at least 80% adherence.8 Two to three weekly benzathine penicillin injections are now thought to offer better protection than the older recommendation of injections every four weeks.31,32 Atrial fibrillation was found in almost 14% of our patients, and was the third most common complication. Worldwide, atrial fibrillation is the most common sustained arrhythmia and is associated with complications such as heart failure, stroke and other embolic phenomena.33 In our cohort, atrial fibrillation had the strongest association with heart failure; 81.4% of our patients with atrial fibrillation had heart failure. This was not surprising given that the average left atrial diameter was 5.5 cm in the cases with atrial fibrillation. Previous studies have showed that patients with dilated atria over 5.0 cm are less likely to remain in sinus rhythm even after attempted cardioversion or ablation.34 Patients with atrial fibrillation are also at increased risk of cardio-embolic phenomena, secondary to stasis of blood and clot formation.35,36 In the present study, four patients presented with stroke, all of whom had concurrent atrial fibrillation. No patients were on anticoagulant medication at presentation. The best strategy for medical management of this population in the developing world is debatable. Fearing side effects, clinicians often hesitate to prescribe anticoagulation in settings where reliable dosing and monitoring of INR levels is difficult. Yet, this can have dire consequences for the patient.37,38 Evidence is clear from developed nations that patients with atrial fibrillation have decreased stroke when properly anticoagulated.39,40 It is our practice to concomitantly begin low-molecular weight heparin and coumadin at the time of anti-arrythmia initiation (for either rate or rhythm control).41 The main limitation to this study was that it was conducted at the national referral hospital where severe cases are typically referred for treatment. This may have under-represented the number of patients with milder forms of the disease, who are seen at lower levels of the healthcare system.

Conclusion We describe the first report of RHD presentation in Uganda. We have compiled a profile of symptoms and complications in 309 patients, including symptoms and complications at the time of

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presentation. Almost all (88%) patients were symptomatic, and half had already developed complications from RHD. Patients presented late in the disease course, suggesting there may be opportunity for earlier intervention. In 2012, the World Heart Federation published the first evidence-based guidelines for echocardiographic screening in RHD.42 Implementation of a screening programme using these guidelines may be an effective way to detected cases early, when patients have the most to gain from secondary prophylaxis. We also noted that recurrence of acute rheumatic fever was high in our study. This underscores the urgent need to improve patients’ and healthcare providers’ knowledge of the diagnosis and treatment of streptococcal infections, as well as delivery and adherence to secondary prophylaxis. It is clear that there is much work to be done to prevent RHD and to ensure patients who develop RHD are diagnosed before symptoms and complications develop. Raising awareness of the burden of RHD, as well as the development of local guidelines for screening, diagnosis and management could begin to lessen the devastation of this all too-common disease. We thank the staff of the Division of Cardiology, Makerere University and the Uganda Heart Institute for their support of the study. The study (grant number R24TW008861) was supported by the office of the United States Global Aids Coordinator, National Institutes of Health and Health Resources and Services Administration, and the Millennium Science Initiative. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

References 1.

Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5: 685–694. 2. Longo-Mbenza B, Bayekula M, Ngiyulu R, Kintoki VE, Bikangi NF, et al. Survey of rheumatic heart disease in school children of Kinshasa town. Int J Cardiol 1998; 63: 287–294. 3. Ibrahim-Khalil S, Elhag M, Ali E, et al. An epidemiological survey of rheumatic fever and rheumatic heart disease in Sahafa town, Sudan. J Epidemiol Commun Health1992; 5: 477–479. 4. Jovanović DR, Beslać-Bumbasirević L, Raicević R, et al. Etiology of ischemic stroke among young adults of Serbia (Abstract). Vojnosanit Pregl 2008; 65: 803–809. 5. Sliwa K, Carrington M, Bongani MM, Zigiriadis E, Mvungi R, et al. Incidence and characteristics of newly diagnosed rheumatic heart disease in Urban African adults: insights from the Heart of Soweto Study. Eur Heart J 2010; 31: 719–727. 6. Sani M, Karaye KM, Borodo MM. Prevalence and pattern of rheumatic heart disease in the Nigerian savannah: an echocardiographic study. Cardiovasc J Afr 2007; 18: 295–299. 7. Kakkar N, Kaur R. Knowledge base of clinicians regarding oral anticoagulant therapy in a teaching institution – a questionnaire survey. J Assoc Physicians India 2004; 52: 868–872. 8. Manyemba J, Mayosi BM. Penicillin for secondary prevention of rheumatic fever. Cochrane Database Syst Rev 2002; 3: CD002227. 9. Mayosi BM. A proposal for the eradication of rheumatic fever in our lifetime. S Afr Med J 2006; 96: 229–230. 10. Mayosi BM, Robertson K, Volmink, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006; 96: 246. 11. Sahn DJ, DeMaria A, Kisslo J, Weyman A. The committee on M-mode standardization of the American Society of Echocardiography. Recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083. 12. Carapetis J, Paar J, Cherian T. Standardization of epidemiologic proto-

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cols for surveillance of post-streptococcal sequelae: acute rheumatic fever, rheumatic heart disease and acute post-streptococcal glomerulonephritis. National Institutes of Allergy and Infectious Disease, 2006. http://www.niaid.nih.gov/topics/strepThroat/Documents/groupasequelae.pdf. McKee PA, Castelli WE, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. New Engl J Med 1971; 285: 1441–1446. Special writing group of the committee on rheumatic fever. Guidelines for the diagnosis of acute rheumatic fever: Jones criteria. J Am Med Assoc 1992; 268: 2068–2073. Rheumatic fever and rheumatic heart disease: report of a WHO expert consultation, Geneva, 29 October – 1 November 2001. Geneva: World Health Organization, 2004. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001; 345: 1318–1330. Prineas RJ, Rischard SC, Blackburn H. The Minnesota Code Manual of Eelectrocardiographic Findings: Standards and Procedures for Measurement and Classification. Boston, MA: John Wright, 1982. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43(Suppl): 40S–47S. Muna WFT. Cardiovascular disorders in Africa. World Health Stat Q 1993; 46: 125–126. Ravisha MS, Tullu MS, Kamat JR. Rheumatic fever and rheumatic heart disease: clinical profile of 550 cases in India. Arch Med Res 2003; 34: 382–387. Kayima J, Mungoma M, Mondo C, Freers J. The changing pattern of cardiac disease in Africa: the Ugandan experience. Cardiovasc J Afr 2011; 22: S9. Kumar R. Controlling rheumatic heart disease in developing countries. World Health Forum 1995; 16: 47–51. Jaine R, Baker M, Venugopal K. Acute rheumatic fever associated with household crowding in a developed country. Pediatr Infect Dis J 2011; 30: 315–319. Vahanian M, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007; 28: 230. Tornos P, Sambola A, Permanyer-Miralda G, et al. Long-term outcome of surgically treated aortic regurgitation: Influence of guideline adherence toward early surgery. J Am Coll Cardiol 2006; 47: 1012. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, et al. Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society

of Thoracic Surgeons. Circulation 2008; 118: e523–661. 27. Harikrishnan S, Kartha CC. Pulmonary hypertension in rheumatic heart disease. Pulmon Vasc Res Inst Rev 2009; 1: 13–19. 28. Bahl V, Chandra S, Talwar K, Kaul U, Sharma S, et al. Balloon mitral valvotomy in patients with systemic and suprasystemic pulmonary artery pressures. Catheter Cardiovasc Diagn 1995; 36: 211–215. 29. Jones T. Diagnosis of rheumatic fever. J Am Med Assoc 1944; 126: 481–484. 30. Essop MR, Wisenbaugh T, Sareli P. Evidence against a myocardial factor as a cause of ventricular dilatation in active rheumatic carditis. J Am Coll Cardiol 1993; 22: 826–829. 31. Kassem AS, Zaher SR, Abou Shleib H, el-Kholy AG, Madkour AA, et al. Rheumatic fever prophylaxis using benzathine penicillin G (BPG): two week versus four-week regimens: comparison of two brands of BPG. Pediatrics 1996; 97: 992–995. 32. Lue HC, Wu MH, Wang JK, Wu FF, Wu YN. Three- versus four-week administration of benzathine penicillin G: effects on incidence of streptococcal infections and recurrences of rheumatic fever. Pediatrics 1996; 97: 984–988. 33. Wolf P, Abbott R, Kannel W. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–988. 34. Schopka S, Christof S, Andreas K, Kortner A, Tafelmeier A, et al. Ablation of atrial fibrillation with the Epicor system: a prospective observational trial to evaluate safety and efficacy and predictors of success. J Cardiothorac Surg 2010; 5: 34. 35. Jørgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Copenhagen Stroke study. Stroke 1996; 27: 1765–1769. 36. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995; 155: 469–473. 37. Kakkar N, Kaur R. Knowledge base of clinicians regarding oral anticoagulant therapy in a teaching institution – a questionnaire survey. J Assoc Physicians India 2004; 52: 868–872. 38. You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderateintensity anticoagulation? Br J Clin Pharmacol 2005; 59: 582–587. 39. Roy D, Marchand E, Gagné P, Chabot M, Cartier R. Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation. Am Heart J 1986; 112: 1039–1043. 40. Kakkar N, Kaur R, John M. Outpatient oral anticoagulant management – an audit of 82 patients. J Assoc Physicians India 2005; 53: 847–852. 41. Wyse DG, Waldo AL, DiMarco JP, et al. Atrial Fibrillation Followup Investigation of Rhythm Management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825–1833. 42. Reményi B, Wilson N, Steer A, Ferreria B, Kado J, Kumar K, et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease – an evidence-based guideline. Nat Rev Cardiol 2012; 5: 297–309.

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Review Article Management of ischaemic stroke in the acute setting: review of the current status KALPESH JIVAN, KAUSHIK RANCHOD, GIRISH MODI

Abstract Acute ischaemic stroke can be treated by clot busting and clot removal. Thrombolysis using intravenous recombinanttissue plasminogen activator (IV r-TPA) is the current gold standard for the treatment of acute ischaemic stroke (AIS). The main failure of this type of treatment is the short time interval from stroke onset within which it has to be used for any benefit. The evidence is that IV r-TPA has to be used within 4.5 hours. Other modalities of treatment are not as effective and need more scrutiny and examination. The available modalities are intra-arterial thrombolysis and clot-retrieval devices. Not unexpectedly, recanalisation treatments have flourished at a rapid rate. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques. Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable intravenous r-tPA treatment within the 4.5-hour period following onset of stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of ‘stroke attack’ should be revisited, especially in the resource-limited context. This approach at present will halt to some extent the stroke pandemic that we are facing. Keywords: stroke, intravenous r-tPA, recanalisation treatments Submitted 5/3/12, accepted 11/1/13 Cardiovasc J Afr 2013; 24: 88–94

www.cvja.co.za

in 2015 and to 7.8 million in 2030. The global focus on stroke treatment is based on these figures and reflects the impact stroke has on society. In a recent review, taking into account 120 cost studies in developed countries, the average costs of stroke ranged from $468 to $146 149.2 There is limited information regarding the cost of stroke in developing countries. The approximate cost of ischaemic stroke in Togo is EUR428.80.3 Currently there is inadequate information regarding the cost of stroke in South Africa.4 The main issue with regard to stroke is outcome. Clinical outcomes of stroke have been reviewed in 174 acute stroke trials.5 Death occurred in 76% of patients in the trials, impairment of body function and structure in 76%, disability (activity limitations) in 42%, and adverse social impact or restricted quality of life occurred in only 2% of patients. Functional outcomes are the main cause of stroke cost. Stroke is the eighth most significant cause of life lost due to illness and the ninth most important cause of disability in South Africa.4 The ultimate goal in stroke management is to reverse the stroke and leave no disability. This has however not been possible to date. From a pathophysiological point of view, in the acute setting, this could be achieved by improving perfusion in the ischaemic area. Current models of stroke pathology indicate the area of infarction following a stroke is surrounded by an ischaemic penumbra. Cerebral blood flow (CBF) of below 10–12 ml/100 g/min results in irreversible neuronal injury/infarction.6 Within an hour of hypoxic ischaemic insult, this core of infarction is surrounded by an oligaemic zone called the ischaemic penumbra where autoregulation is ineffective. The penumbra phase generally begins when CBF flow falls below 20 ml/100 g/min.6 Cellular integrity and function are preserved in this potentially salvageable penumbra for variable periods of time. Although little can be done to save the infarcted core, it is the penumbra that is the target of salvage therapies.

DOI: 10.5830/CVJA-2013-001

Stroke is the third leading cause of death worldwide, resulting in approximately 5.7 million deaths annually.1 With current treatment options, this number is projected to rise to 6.5 million Division of Neurology, Department of Neurosciences, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa KALPESH JIVAN, MB BCh (Wits), FC Neurol (SA) KAUSHIK RANCHOD, MB BCh (Wits), FC Neurol (SA) GIRISH MODI, MB BCh (Wits), MSc (Lond), PHD (Lond), FCP (SA), FRCP (Lond), gmodicns@mweb.co.za

Methods A PUBMED search was conducted using the keywords ‘acute stroke management’, ‘interventional devices for acute stroke’, ‘intravenous thrombolysis’, ‘intra-arterial thrombolysis’, ‘guidelines for stroke management’ and ‘prevention of strokes’ from 1995 to 2012.

Results Three types of treatment in the acute setting have emerged to salvage the penumbra, reduce the area of infarction and improve

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stroke outcome. These include clot busting, clot removal and prevention of recurrence of stroke.

Clot busting This is achieved by intravenous or intra-arterial thrombolysis.

Intravenous recombinant tissue plasminogen activator (IV r-tPA) IV r-tPA when used within three hours of stroke onset in select patients with acute ischaemic stroke (AIS) is the only US Food and Drug Administration (FDA)-approved thrombolytic treatment for stroke.7 South African guidelines recommend it should be administered at a hospital where rapid triage of stroke patients is possible, with established protocols for the use of r-tPA and where good post-treatment care is available.4 In 1995 the landmark NINDS trial randomised 624 patients with AIS to receive 0.9 mg/kg of IV r-tPA or placebo within three hours of stroke onset.8 Three months after treatment, 50% of patients in the treatment arm had minimal or no disability compared to 38% of patients in the placebo study arm: a 12% absolute improvement. Although 6.4% of patients treated with IV r-tPA developed symptomatic intracerebral haemorrhage (sICH) compared to 0.6% of patients given placebo, the death rate in the two treatment groups was similar at three months (17 vs 20%). This was the first time a treatment for stroke had improved or reduced disability significantly. In two other large, randomised, double-blinded phase 3 trials, the European Cooperative Acute Stroke study (ECASS) and ECASS-II, IV r-tPA was not more effective than placebo in improving neurological outcomes 90 days after stroke.7,9 A dose of 1.1 mg/kg of IV r-tPA was used in ECASS and a dose of 0.9 mg/kg was used in ECASS II. In both trials, patients were treated up to six hours after stroke. The ATLANTIS A and ATLANTIS B trials from North America, both placebo-controlled, doubleblinded, randomised trials, also did not support the use of IV r-tPA beyond three hours of ischaemic stroke onset.10,11 Taking into account the findings of all these studies, the 2007 American Heart Association/American Stroke Association (AHA) guidelines recommended the dosing regimen of 0.9 mg/ kg (maximum 90 mg) for selected patients who may be treated within three hours of onset of AIS (class I, level of evidence A).12 Ten per cent of the dose is given as an initial intravenous bolus and the rest is infused over one hour provided there are no contraindications for the treatment.12 However, this dose is not universally accepted, with most Japanese studies continuing to support the use of 0.6 mg/kg.13 Treatment benefit is time dependent and the number needed to treat (NNT) to get one more favourable outcome drops from four during the first 90 minutes to seven at three hours, and towards 14 between three and 4.5 hours.14,15 This implies that there is no potential benefit beyond three hours. In 2008 the ECASS III trial showed that IV r-tPA administered within three to 4.5 hours of stroke onset may offer a moderate benefit when applied to all patients with potentially disabling deficits.15 The incidence of intracranial haemorrhage was higher with IV r-tPA than with placebo in this study [27.0 vs 17.6% for any intracranial haemorrhage (p = 0.001) and 2.4 vs 0.2% for symptomatic intracranial hemorrhage (p = 0.008)], but mortality did not differ significantly between the two groups.

In the joint-outcome table analysis of the ECASS III trial, the number needed to treat to benefit (NNTB) was 6.1 and the number needed to treat to harm (NNTH) was 37.5, which indicates that for every 100 patients treated in the three- to 4.5-hour window, 16.4 will have a better outcome and 2.7 will have a worse outcome by â&#x2030;Ľ 1 level on the modified Rankin score (mRS) of global disability.16 In other words, among individuals matching the ECASS III cohort, as a result of treatment with IV rTPA in the three- to 4.5-hour window, approximately one in six patients have a better outcome and one in 35 have a worse outcome. Furthermore, in a study determining the NNTH following IV r-tPA, most patients who experienced sICH after IV r-tPA therapy had severe baseline insults and were destined for a poor outcome.17 In other words, the sICH may have caused temporary early worsening, but is unlikely to have altered the final functional outcome. Using a 15-variable prognostic model derived from the placebo group in NINDS 1 and 2, it was found that the NNTH ranged from 29.7 to 40.1.17 This implies that among individuals matching the NINDS cohort, for every 100 patients treated with IV r-tPA , only one will experience a severely disabled or fatal final outcome. Based on these findings, the AHA issued revised guidelines that expanded the window for IV r-tPA treatment from three to 4.5 hours in eligible patients.18 In a recent phase 2B trial comparing the use of alteplase to tenecteplase in eligible patients within six hours of onset of acute ischaemic stroke, tenecteplace was shown to be superior in terms of significantly better clinical improvement and reperfusion.19 A phase 3 trial is needed to confirm this. There is no evidence showing benefit with any other intravenously administered thrombolytic agents, including streptokinase, reteplase, urokinase, anistreplase and staphylokinase for use in acute stroke. These should be avoided in routine clinical practice outside the context of a clinical trial.4 Studies with desmoteplase and ancrod, a defibrogenating enzyme derived from snake venom, are underway. Risks and benefits of treatment with IV r-tPA for AIS should be discussed with the patient or family before administration.12 Written consent has been deemed as not necessary by health authorities.12 Adverse events of IV r-tPA include intracranial haemorrhage, anaphylactic reaction, angio-oedema and myocardial rupture.12 In a recent international, multicentre, randomised, open-treatment trial, assessing the benefits and harms of IV r-tPA given within six hours of AIS, deterioration due to swelling of the infarct and sICH in the first seven days was more significant in those patients who received IV r-tPA compared to those who did not.20 Patients receiving IV r-tPA also had significantly more non-fatal extracranial haemorrhages.20 Difficulties in administering IV r-tPA within 4.5 hours include early recognition of signs of stroke by the patient or family members, early evaluation of the patient by paramedics, rapid transport of patients to stroke centres, availability of radiological services, and appropriate evaluation by an experienced clinician as to the suitability of thrombolytic therapy. Indications and contraindications for IV r-TPA are described in Table 1.

Intra-arterial (IA) thrombolysis AHA guidelines recommend that IA thrombolysis can be considered an option for treatment of AIS due to occlusions of

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TABLE 1. USE OF IV THROMBOLYSIS IN AIS Indications for IV thrombolysis in AIS • Age > 18 and < 80 years.15 • Symptoms onset within 4.5 hours.15 • Measurable deficit on the National Institutes of Health Stroke Scale (NIHSS) examination.4 • CT scan does not show haemorrhage or non-stroke cause of deficit.4 Contraindications for IV thrombolysis in AIS • Rapidly improving or minor symptoms.12 • Stroke within past three months.12 • Previous intracerebral haemorrhage or vascular malformation.12 • Patient has symptoms suggestive of subarachnoid hemorrhage.12 • Bleeding diathesis.15 • Arterial puncture at non-compressible site or lumbar puncture within the last seven days.12 • Gastrointestinal or urinary tract bleeding in the last 21 days.12 • Invasive surgery or delivery in last two weeks.12 • Platelet count < 100 000 /µl.12 • On treatment with heparin with prolonged aPTT.12 • On treatment with oral anticoagulation with INR > 1.7.12 • Serious head trauma within the previous three months.15 • Systolic blood pressure > 185 mmHg, diastolic blood pressure > 110 mmHg.4 • No myocardial infarction in the previous three months.12 • Seizures at onset of stroke with postictal residual neurological impairments.12 • Blood glucose < 50 mg/dl (2.7 mmol/l).4,15 • Multilobar infarction (hypodensity > 1/3 of cerebral hemisphere).12

the MCA only if given within six hours of stroke onset in patients who are not otherwise candidates for IV r-tPA.12 This would include patients described in Table 1. Prolyse in Acute Cerebral Thromboembolism (PROACT) II, the only randomised study that has examined the safety and efficacy of IA thrombolysis in patients with AIS, compared outcomes of 121 patients in the treatment group treated with intra-arterial recombinant prourokinase (r-proUK) and heparin within six hours of stroke onset, with outcomes of 59 patients in the control group treated with heparin alone.21 In this study, the technique involved placing an infusion microcatheter under angiographic guidance into a proximally (M1 or M2 segment of the middle cerebral artery) occluding thrombus; 4.5 mg of r-proUK was infused at a rate of 30 ml/h into the thrombus. One hour later, a second angiogram was done through the microcatheter and the remaining 4.5 mg of r-proUK was infused over the next hour. Another diagnostic carotid angiogram was performed at two hours to assess final vessel patency. Theoretically, IA thrombolysis may offer a higher dose of thrombolytic drug delivery to the clot with fewer systemic complications and higher recanalisation rates.22 In the PROACT II treatment group, the recanalisation rate was 66% with 40% of patients reaching functional independence within 90 days.21 In the control group, the recanalisation rate was 18% with 25% of patients reaching functional independence. sICH occurred in 10% of treated patients compared to 2% of controls, but the increase in sICH did not affect mortality rates, which were 25 and 27%, respectively. These results cannot be compared to any of the IV r-TPA trials as the study methods and patient selections were different.

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Also, one has to factor in the need for greater skill and the risks of catheterisation when doing IA thrombolysis. There is no randomised controlled study comparing IV r-TPA versus IA r-TPA with/without heparin. In a recent meta-analysis, the outcomes of IV r-tPA from three randomised, controlled trials, namely, Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT), PROACT and PROACT II were pooled together and statistically averaged using odds ratios for 130 patients. This was then compared to the outcomes of IA thrombolysis by sensitivity analysis.23 Using these statistical methods, no benefit was shown from IA thrombolysis.23 However the obvious criticism of this meta-analysis is that data was obtained from three different trials in which the times to treatment were not uniform. In the PROACT and PROACT II studies, the authors could not obtain information of arrival time to hospital and treatment with IV r-tPA. Therefore while there is a suggestion in the literature that IA thrombolysis is not significantly better than IV r-tPA, robust studies using these two arms are still lacking.23 Despite this the results of this IA r-TPA trial were promising. Unfortunately, treatment with prourokinase + heparin was not approved by the FDA, which demanded a confirmatory study that was never performed.24 The availability of intra-arterial thrombolysis should generally not preclude the intravenous administration of r-tPA in otherwise eligible patients.12

Clot removal Mechanical clot retrieval Mechanical revascularisation for acute stroke may be considered in large-vessel occlusions. Recently, complex devices have been developed. These can be divided into two major groups: • Proximal devices, which apply force to the proximal base of the thrombus. • Distal devices, which approach the thrombus proximally but a guide wire and microcatheter is advanced distally and then unsheathed to apply force to the distal base of the thrombus. This group includes snare-like, basket-like or coil-like devices. Mechanical thrombectomy can also be performed in patients who have received IV r-tPA and in those who are not candidates for IV r-tPA. Results of multiple non-randomised trials have shown these devices to be safe for clot removal in acute ischaemic stroke patients presenting up to eight hours from onset of the event.22 It requires the knowledge and skills of trained neurointerventionalists with experience in the use of the devices. Two FDA-approved devices are available specifically for mechanical thrombectomy: the MERCI retriever and the penumbra system. The Mechanical Embolus Removal in Cerebral Ischaemia (MERCI) retriever is a cork-screw-shaped device consisting of a flexible nitinol wire in five helical loops. It allows for placement distally and then en bloc removal of the thrombus. The MERCI and Multi MERCI trials evaluated the safety and efficacy in the setting of stroke within eight hours of onset.25,26 The MERCI trial included 151 patients with anterior or posterior circulation stroke secondary to large-vessel occlusion.25 Primary outcomes were recanalisation defined as a thrombolysis in myocardial infarction (TIMI) score of 2–3 and safety.25 Secondary outcomes were modified Rankin score (mRS) and

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NIHSS scores at 30 and 90 days and death, myocardial infarction or second stroke within 30 days. A good neurological outcome was defined as MRS < 2 (i.e. either asymptomatic or no significant disability) or a NIHSS score improvement ≥ 10 points. Recanalisation (TIMI 2–3) was achieved in 46% of treated patients, with these patients having better neurological outcomes. The risk of stroke, MI or death at 30 days was 40% and mortality rates at 90 days were 43.5%. Increasing age and a higher admission NIHSS score were associated with higher mortality rates. Clinically significant procedural complications occurred in 7.1% of patients and sICH in 7.8% of patients. In the Multi MERCI trial, 160 patients were treated within eight hours of stroke onset.26 In this study, prior treatment with IV r-tPA, mechanical clot disruption, IA thrombolysis and other adjunctive therapies were allowed. IV r-tPA had been administered to 29% of the participants without recanalisation prior to the procedure. Recanalisation was achieved in 55% of patients with the retriever alone and in up to 68% when adjunctive therapies were used. At 90 days good neurological outcomes (mRS ≤ 2) were achieved in 36% of patients and NIHSS scores improved > 10 points in 26% of patients. Given that clot burden in the internal carotid artery terminus and basilar artery can be substantially higher and therefore less likely to be recanalised with thrombolytics, the data suggest that the device provides an advantage over IA thrombolytic therapy alone for all large-vessel occlusions.26 Treatment with IV r-tPA prior to MERCI device deployment did not increase the chance of sICH. Overall mortality at 90 days was 34%. Although the mortality rates were relatively high in both MERCI and Multi MERCI trials this most likely represents the overall stroke severity of the patients enrolled. The penumbra system works proximally to disrupt and aspirate the thrombus. It comprises a series of devices, primarily an aspiration catheter, with a distal wire to keep the catheter clear, and a grasping device designed to remove harder thrombus if the aspiration device fails to recanalise the vessel. A prospective multi-centre trial of the penumbra system enrolled 125 patients presenting within two hours of stroke.27 The primary endpoints were vessel revascularisation and device safety. Recanalisation rates were 81.6% and serious adverse rate was 3.2%. An NIHSS score showed improvement of > 4 points in 57.8% of patients and an mRS ≤ 2 at 90 days in 25% of patients. Mortality rates at 30 and 90 days were 26 and 32.8%, respectively. More recent studies with the device reported recanalisation rates of between 85 and 93%.24 A review of all studies to date with neurothrombectomy devices revealed widely varying rates of recanalisation (43–78% with MERCI retriever and 83–100% with the penumbra system). Rates of harm included symptomatic (0–10% with MERCI and 0–11% with penumbra system) or asymptomatic (28–43 and 1–30%, respectively) intracranial haemorrhage. Vessel perforation or dissection (0–7 and 0–5%, respectively) also varied by device.28 Predictors of poor outcome were age, history of stroke, and higher baseline severity scores. Successful recanalisation was the sole predictor of good outcomes.28 Despite the FDA approving the MERCI device in 2004 and the penumbra system in 2007 for use in acute ischaemic strokes, their clinical efficacy is yet to be fully established in a controlled outcomes trial.24 The data as published are enticing and one is already seeing an increase in the use of these devices. The main

problems remain patient selection, type and nature of stroke and clinical outcome. The studies have focused on recanalisation as the sole measure of outcome but, as in the IV r-TPA trials, it should really be clinical outcome.

Endovascular angioplasty and stenting Balloon angioplasty with or without stent placement, as is used in patients with acute myocardial infarction, has been used to recanalise cerebral arterial occlusions. Unlike cardiac arteries which have the firm muscular support of the myocardium, cerebral arteries are suspended in cerebrospinal fluid and are hence more prone to dissections and tears. Furthermore, the approach to cerebro-arterial occlusions is often tortuous, making navigation much more difficult. Reperfusion rates of approximately 80% with mortality of about 30% have been reported.24 However the AHA guidelines do not recommend this form of treatment.12

Stent-based thrombectomy Self-expanding stents for cerebral use have advantages over balloon angioplasty as they can be delivered to the target vessel with reduced barotrauma, thereby decreasing the risk of rupturing or dissecting the cerebral vessel.29 Moreover, they adapt much better to the shape and anatomy of the affected artery. The solitaire AB stent is a self-expanding microstent. The device is deployed at the level of occlusion and the clot is enmeshed in the stent and then removed proximally. Studies have shown successful revascularisation in patients presenting within eight hours of AIS.24A recent study suggest that recanalisation rates > 85% can be achieved with the Solitaire stent in anterior large-vessel occlusions, thereby substantially increasing the rate of good outcome for these patients with an otherwise poor prognosis.30 The above endovascular approaches for treatment of stroke are viable but costly. They require a dedicated stroke interventionalist with a support team of angiography technicians and nurses. The equipment needed to carry out these procedures is also expensive. Careful selection of patients is imperative in order to achieve maximum benefit. In South Africa, interventionalists are few, and hence this poses a greater difficulty in achieving the ultimate goal of early reperfusion.

Multimodal reperfusion therapy Faster and more complete recanalisation should translate into better patient outcomes. To achieve this, the trend in acute coronary syndromes has been to use multiple pharmacological agents and, increasingly, percutaneous coronary intervention. However, currently available data do not provide conclusive evidence for either the safety or efficacy of combinations of medications to improve cerebral perfusion. Data with regard to the usefulness of mechanical devices to augment the effects of pharmacological thrombolysis to treat AIS are also limited.

Prevention of recurrent stroke Antiplatelets Aspirin is widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) and ischaemic

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stroke of arterial origin because it is effective and inexpensive. Aspirin reduces recurrent strokes rather than limiting the neurological consequence of a stroke.12 Two large trials evaluated aspirin for the treatment of acute ischaemic stroke.31,32 The Chinese Acute Stroke trial (CAST) and the International Stroke trial (IST) randomised just over 40 000 patients with acute ischaemic stroke. In conjunction, these studies concluded that aspirin given within 48 hours of stroke produces a modest but definite benefit with about 10 fewer deaths or recurrent strokes per 1 000 in the first few weeks. Oral aspirin (150â&#x20AC;&#x201C;300 mg loading dose) given within 48 hours after ischaemic stroke is recommended. However, aspirin or other antithrombotic therapy should not be initiated within 24 hours if thrombolytic therapy is given.4 Dipyridamole plus aspirin, or clopidogrel alone, is more superior to aspirin alone in secondary prevention of strokes and other vascular events and their overall safety profiles are similar.33,34 However, a considerable proportion of patients discontinue dipyridamole therapy because of headache,35 and clopidogrel is more expensive than aspirin. Clopidogrel in conjunction with aspirin is not more effective than clopidogrel alone in preventing ischaemic strokes and other vascular events. Furthermore, this combination also increases the risk of major bleeding.36 Although the AHA guidelines do not recommend clopidogrel or dipyramidole either alone or in conjunction with aspirin for the treatment of acute ischaemic stroke, a recent systematic review, which assessed the clinical effectiveness and cost effectiveness of the above three agents, used either alone or in combination, concluded that for patients with ischaemic stroke or TIA, modified-release dipyridamole + aspirin, followed by aspirin alone, followed by clopidogrel, appears to be a cost-effective approach to the prevention of future occlusive vascular events.37 Intravenous glycoprotein IIb/IIIa inhibitors such as abciximab are currently not recommended for use in acute ischaemic stroke until more research is available.12 Newer antithrombotic agents that have shown efficacy in acute coronary syndromes, such as thienopyridine and prasugrel, and the non-thienopyridine, ticagrelor (a reversible ADP receptor antagonist) may be promising potential treatments for acute TIA and ischaemic stroke.28

Anticoagulants Data suggest that early anticoagulation with heparin or the low-molecular weight heparins/danaparoid does not lower the risk of early recurrent strokes nor does it halt neurological worsening. It also increases the risk of bleeding in the brain or other parts of the body. Hence it is not recommended for use in acute ischaemic strokes and should certainly not be given within 24 hours of thrombolytic therapy.12 Warfarin is universally used as an antithrombotic therapy for patients with TIA or ischaemic strokes of cardiac origin. Warfarin has been shown to reduce the risk of recurrent stroke or systemic embolism by about 61% in atrial fibrillation (AF) patients with recent TIA or ischaemic stroke.38 However warfarin does increase the risk of major extracranial haemorrhage. According to the South African stroke guidelines, dose-adjusted warfarin is recommended for patients with cardio-embolic ischaemic stroke or TIA associated with intermittent or persistent atrial fibrillation.4

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Newer oral anticoagulants such as dabigatran, apixabin and rivaroxaban have emerged and trials on these drugs in stroke prevention for patients in AF appear promising. Recently, three large phase III randomised, controlled trials, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), and the Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial have shown that dabigatran, rivaroxaban and apixabin are each more efficacious than warfarin for preventing strokes in patients with AF, with lower rates of intracranial bleeding.39-41 Other advantages of these anticoagulants over warfarin are that they can be used in fixed doses and regular monitoring of anticoagulation intensity is not necessary.42 The FDA has approved dabigatran and rivaroxaban for stroke reduction in people with non-valvular atrial fibrillation.43 FDA approval for apixabin is pending. Three studies have compared these three oral anticoagulants for stroke prevention in AF patients.44-46 Apixaban was shown to be as effective as dabigatran but rivaroxaban was less effective than dabigatran.44 Apixaban was associated with less major bleeding than dabigatran or rivaroxaban.44 Dabigatran is more cost effective than rivaroxaban in terms of acute care and long-term follow up costs, as well as accrual of quality-adjusted life years.45 Apixaban is associated with less major and gastrointestinal bleeding than dabigatran and rivaroxaban.46 Randomised trials comparing the three drugs are required to confirm these findings. Apixabin was also directly compared to aspirin in the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial and shown to be more effective in reducing strokes compared to aspirin in AF patients who have had previous strokes or TIAs and who are unsuitable for or unwilling to take a vitamin K agonist.47

Treatment of dyslipidaemia Dyslipidaemia is a major risk factor for coronary heart disease but its role in ischaemic stroke is not clear. It is however associated with atherosclerosis, which causes strokes.4 A meta-analysis of 90 000 patients suggested that larger low-density lipoprotein cholesterol (LDL-C) reductions better reduce the risk of stroke.48 In five placebo-controlled studies with more than 40 000 patients with coronary heart disease, HMG-CoA reductase inhibitors (statins) reduced the risk of stroke by 19â&#x20AC;&#x201C;50%.49 Of all the statins, atorvastatin is the most favourable.49 Simvastatin reduced major vascular event by 20%. AHA guidelines recommend using a statin to reduce the risk of recurrent stroke in patients with evidence of atherosclerosis, an LDL-C level > 100 mg/dl, and those who are without known coronary heart disease.50 Maximum benefit is attained with a reduction of the LDL-C level by at least 50% or below 70 mg/dl. Other medications used to treat dyslipidaemia include niacin, fibrates and cholesterol-absorption inhibitors. Niacin and gemfibrozil are recommended (class 2b) for use in patients with ischaemic stroke or TIA with low high-density lipoprotein cholesterol (HDL-C.) levels. Lipid-lowering therapy is associated with delayed cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolaemia.51

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Treatment of large-artery atherosclerosis Carotid revascularisation by carotid endarterectomy (CEA) or carotid angioplasty and stenosis (CAS) has been well documented in research to prevent strokes, provided there is appropriate case selection with the risk–benefit ratio being favourable for the patient. Current AHA guidelines advocate CEA for severe ipsilateral carotid artery stenosis (70–99%) in patients with recent TIA or ischaemic strokes, if the perioperative morbidity and mortality risk is less than 6%.50 CEA can be considered for moderate carotid stenosis (50–69%) depending on patient-specific factors such as age, gender and co-morbidities and again, if the peri-operative morbidity and mortality risk is less than 6%. With stenosis less than 50%, CEA or CAS is not recommended. When the diameter of the lumen of the internal carotid artery is reduced by 70% on non-invasive imaging or 50% on catheter angiography, CAS can be considered as an alternative to CEA for symptomatic patients at average or low risk of complications associated with endovascular intervention.

Conclusion There are many different ways of treating AIS. However the evidence points to IV r-tPA as the most effective and at present the gold standard of AIS treatment. Despite this, recanalisation treatments as described are flourishing at a rapid rate and more emphasis and interest are being directed at these areas. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques. Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable IV r-tPA treatment within the 4.5-hour period following onset of the stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of ‘stroke attack’ should be revisited, especially in the resource-limited context. Intensive public-awareness campaigns (television, radio, the internet, social networking, newspapers) about early recognition of stroke as well as the importance of time constraints for a favourable outcome should be devised. Education of emergency medical personnel as well as staff of smaller medical facilities is also crucial in enabling faster referral to a unit where thrombolysis can be done. This approach at present will halt to some extent the stroke pandemic that we are facing. Public profiling of stroke will strongly assist in dealing with risk factors and implementation of preventative strategies. A final point that needs to be made is that imaging modalities are being refined towards identifying with more accuracy patients who would fulfill the criteria for IV thrombolysis following ischaemic stroke. Currently multi-parametric MRI studies are gaining momentum in terms of identifying such patients. Specifically, diffusion–perfusion mismatch, gradient echo, MRA (MR angiogram) and FLAIR (Fluid Attenuated Inversion Recovery) sequences on MRI are being used. These have the advantage of providing more detailed information of the

ischaemic penumbra and the extent of infarction that cannot be determined on CT scanning techniques. This reduces the risks of intracranial haemorrhage following thrombolysis. The disadvantage is that patients who would have otherwise qualified by CT criteria are likely to be rejected on the MRI criteria. Further refinements in this area are likely to occur that will make thrombolysis more objective with better outcomes.

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tissue plasminogen activator therapy in the 3- to 4.5-hour window : joint outcome table analysis of the ECASS 3 trial. Stroke 2009; 40: 2433–2437. Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke 2007; 38: 2279–2283. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr; on behalf of the American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischaemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40: 2945–2948. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomised trial of tenecteplase versus alteplase for acute ischaemic stroke. N Engl J Med 2012; 366: 1099–1107. The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379: 2352–2363. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc 1999; 282(21): 2003–2011. Khalessi AA, Natarajan SK, Orion D, Binning MJ, Siddiqui A, Levy EI, Hopkins LN. Acute stroke intervention. J Am Col Cardiol Cardiovasc Interv 2011; 4(3): 261–269. Powers WJ. Thromobolysis for acute ischaemic stroke: is intraarterial better than intravenous? A treatment effects model. J Stroke Cerebrovasc Dis 2012; 21(5): 401–403. Cohen JE, Itshayek E, Moskovici S, Gomori JM, Fraifeld S, Eichel R, Leker RR. State-of-the-art reperfusion strategies for acute ischemic stroke. J Clin Neurosci 2011; 18(3): 319–323. Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, et al; MERCI Trial Investigators. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005; 36(7): 1432–1438. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, et al; Multi MERCI Investigators, Frei D, Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008; 39(4): 1205–1212. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Penumbra Pivotal Stroke Trial Investigators. Stroke 2009; 40(8): 2761–2768. Baker WL, Colby JA, Tongbram V, Talati R, Silverman IE, White CM, et al. Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence. Ann Intern Med 2011; 154(4): 243–252. Velat GJ, Hoh BL, Levy EI, Mocco J. Primary intracranial stenting in acute ischemic stroke. Curr Cardiol Rep 2010; 12(1): 14–19. Mpotsaris A, Bussmeyer M, Loehr C, Oelerich M, Buchner H, Weber W. Mechanical thrombectomy in severe acute stroke: preliminary results of the Solitaire stent. J Neurol Neurosurg Psychiatry 2012; 83(1): 117–118. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349(9066): 1641– 1649. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349(9065): 1569–1581. Halkes PH, Gray LJ, Bath PM, Diener HC, Guiraud-Chaumeil B, Yatsu FM, Algra A. Dipyridamole plus aspirin versus aspirin alone in secondary prevention after TIA or stroke: a meta-analysis by risk. J Neurol Neurosurg Psychiatry 2008; 79(11): 1218–1223. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329–1339.

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35. Halkes PHA, van Gijn, Kappelle LJ, Koudstaal PJ, Algra A, ESPRIT study group. Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry 2009; 80: 437–439 36. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364(9431): 331–337. 37. Greenhalgh J, Bagust A, Boland A, Martin Saborido C, Oyee J, Blundell M, et al. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis. Health Technol Assess 2011; 15(31): 1–178. 38. Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol 2010; 9(3): 273–284. 39. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al, RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): 1139–1151. 40. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10): 883–891. 41. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11): 981–992. 42. Potpara TS, Polovina MM, Licina MM, Stojanovic RM, Prostran MS, Lip GY. Novel oral anticoagulants for stroke prevention in atrial fibrillation: focus on apixaban. Adv Ther 2012; 29(6): 491–507. 43. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Metaanalysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012; 110(3): 453–460. 44. Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost 2012 Jun 28; 108(3). EPub ahead of print. 45. Kansal AR, Sharma M, Bradley-Kennedy C, Clemens A, Monz BU, Peng S, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada. Comparative efficacy and cost-effectiveness. Thromb Haemost 2012; 108(4). Epub ahead of print. 46. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012 Aug 21. Epub ahead of print. 47. Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, et al; AVERROES Steering Committee and Investigators. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 2012; 11(3): 225–231. 48. Amarenco P, Labreuche J, Lavallée P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-todate meta-analysis. Stroke 2004; 35(12): 2902–2909. 49. Gaspardone A, Arca M. Atorvastatin: its clinical role in cerebrovascular prevention. Drugs 2007; 67(Suppl 1): 55–62. 50. Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42(1): 227–276. 51. Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, Marais AD. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011; 124(20): 2202–2207.

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Cardio News Successes, failures, challenges and ground-breaking research: messages from the 6th World Congress of Paediatric Cardiology and Cardiac Surgery A remarkable cardiac event, the largest and most prestigious yet on African soil, took place in February this year. The 6th World Congress of Paediatric Cardiology and Cardiac Surgery was held in Cape Town, with over 3 000 registered delegates and over 2 500 scientific attendees. It was hosted by the South African Heart Association and organised by the Paediatric Cardiac Society of South Africa, a special-interest group of the South African Heart Association, whose major objective is to improve the quality of care of children with congenital and acquired heart disease. This was reflected in the vision for this conference: not only to host the very best faculty and research minds but to use the opportunity to raise awareness of heart disease in the world’s children and the glaring inadequacies in terms of access to essential care. This congress, the premier event in our speciality, would focus equally on the needs of children and adults with highly complex lesions and those with acquired preventable disease such as rheumatic heart disease, a scourge of poverty and inequality, and ultimately forge a new and invigorated agenda for children with heart disease. There were three key messages embedded within the fabric of the conference. Firstly, the premise is misleading that congenital heart disease is only the realm of paediatric cardiologists and paediatric cardiac surgeons. Firstly, the premise that congenital heart disease is only the realm of paediatric cardiac surgeons is misleading. Not only are the numbers of adults with congenital heart disease outstripping those born with cardiac disease in the developed world, with these numbers also continuing to grow in emerging economies,1 but it has become clear in recent decades that in fact the origins of non-communicable cardiac disease lie in childhood, with critical events occurring in the first 1 000 days of life.2 Secondly, the most crucial

element in caring for those with heart disease is teamwork, multisectorial and multidisciplinary collaboration.3 Finally, as a congress representing the world, the needs of the majority of the world’s children needed to be the central tenant throughout the congress. With these messages in mind, several unique elements were incorporated to achieve these important goals. Each day began with plenary lectures, which allowed the delegates to congregate as a team of healthcare providers and focus on messages affecting practice from the most outstanding leaders in the field. Each day concluded with a ‘lecture of your life’, attended by the entire audience, which included talks on climate change, the transcendence of injury in Olympic and Paralympic sport and a screening of an Oscar-nominated documentary called ‘Open Heart’. A fundamental addition to the congress was an entire track devoted to health systems – incorporating dialogue from a variety of sectors, discussions around infrastructure development, focusing on training and lessons to improve system inadequacies. Throughout the day, parallel sessions were presented with clear themes but always reflecting the ethos of the aforementioned messages. Rheumatic heart disease (RHD) is thought to affect at least 36 million people worldwide and is a predominant killer of children, adolescents and young adults.4 Largely eradicated in the developed world, it continues to wreak havoc in developing countries despite simple, cost-effective and cheap medicines being available for its prevention. Several key papers were presented during the five-day event, which reflects a renewed vigour in this arena by countries most affected by the disease. The announcement of a major investment in new vaccine research by the New Zealand and Australian government was made by Profs Jonathan Carapetis and Diana Lennon at a press conference during the conference. This trans-Tasman

funding will fast-track the development of a vaccine targeting acute rheumatic fever (ARF) and will attempt to bring about phase three vaccine studies within five years.5 Prof Bongani Mayosi refocused attention on primary prevention of RHD when he presented ground-breaking research emanating from the University of Cape Town, demonstrating the costeffectiveness of treating sore throat, using penicillin, to prevent ARF.6 The key to managing tertiary patients with RHD is employing a strategy of crucial evidenced-based interventions such as anticoagulation for those with mechanical valves. The rheumatic heart disease global registry (REMEDY) is a hospital-based registry aiming to describe contemporary patterns in the management of tertiary patients while identifying significant areas of concern and need.7 Thus far, over 3 000 patients have been enrolled in this study and already early data confirm that even those that are being treated are not receiving the care they need, for a variety of reasons. A key player in the fight against RHD has been the World Heart Federation, with several senior attendees. Dr Bo Remenyi presented their strategic plan to reduce RHD mortality by 25% in the under-25s by 2025, an ambitious but achievable goal.8 It is clear that efforts such as these highlighted at the conference are sorely needed to effect critical changes in this entirely preventable disease. Advocacy messages from patients and parents are often the most powerful. This was highlighted in several outstanding lectures within the plenary symposia and the two patient and parent summits. Ms Amy Verstappen, the president and CEO of the Adult Congenital Heart Association, spoke passionately about the need to plan for a lifetime with congenital heart disease. She stressed the fact that congenital heart disease is a lifelong chronic condition, and that all units with

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cardiac programmes needed to incorporate care plans into present management for the future of their patients.9 Integral to these plans is the involvement of patients and parents. Prof Gil Wernovsky reported on the fundamental shift from doctor-centred care to a patient-centred approach, ushering in a new era shared decision making. It has been predicted that by the year 2030, the prevalence of death from cardiovascular disease (CVD) will have increased significantly, with the largest increase occurring in Africa.10 Clearly, the perception that CVD is not relevant to developing countries is erroneous and needs to be urgently redressed. Several important plenaries highlighting new research on tobacco use, hypertension, obesity and atherosclerosis,11,12 and emphasising significant mechanisms in combating non-communicable diseases were presented.13 Paediatric cardiology has undergone dramatic advances in the past decade and several of these were showcased in live transmissions from units in South Africa and Europe.14 The possibility to perform highly technical procedures to repair conditions associated with diseases such as RHD and tuberculosis in developing countries, without the need for cardiac surgery, is extremely exciting. In the interventional track, a young patient with Takayasu’s arteritis (thought to be associated with tuberculosis) was given a new lease on life after a stent was placed in a coarcted segment of the aorta, while a Namibian boy had a trans-catheter pulmonary valve implanted. These cases represented not only a triumph for the patients, but also the congress and practitioners, as it was the first African congress to perform successful live interventions on paediatric cases. The need to perform medical procedures, especially those of high complexity, safely and accurately is paramount. Learning about efficiency and safety from other high-pressure industries such as Formula 1 racing and the commercial airline industry will aid hospitals to improve their outcomes, decrease errors and increase productivity. Prof Allan Goldman, convenor of the Risky Business conference series, delivered a lecture titled: ‘Heart surgery is a risky business: how to doing it better and safer for less’. He concluded that the new challenge in heart surgery was

enhanced quality of life, better long-term results and a change in the way we think and work in order to improve outcomes. The World Congress attempted throughout to reinforce the conviction that children with heart disease worldwide ought not to be denied the benefits of medical science. Sessions on emerging programmes in all regions of the world highlighted these inadequacies and discrepancies but also show-cased examples of successful units in among others, Angola, Fiji, Cameroon and Borneo. Humanitarian efforts were emphasised with talks from networks and organisations such as the Global Heart Network and Children’s Heartlink, which provide infrastructure, training and capacity building in order to support units to evolve into independent centres. Despite these reports, the failure to treat patients with congenital and non-communicable heart diseases in countries in Africa remains an extraordinary failure in the face of global resources to address these problems. Prof Gene Bukhman reminded his audience during his plenary ‘Starting a heart programme: lessons from Rwanda’ that extraordinary changes in the health of the poor were possible in a short period of time in countries where leadership, collaboration, equity and planning were harnessed to improve outcomes. The Minister of Health of Rwanda addressed the congress via videolink and reported that over the last decade, deaths in Rwanda from HIV, TB and malaria have dropped by 80%, maternal mortality by 60% and life expectancy has doubled, at an average healthcare cost of $55 per person per year. Innovations in such resource-poor regions have demonstrated that healthcare can be both equitable and affordable. It was the wish of the organisers that delegates enjoy not only a fruitful academic experience with colleagues and faculty but also an enriching cultural and social encounter within South Africa. This was most ably provided by excellent opening and gala ceremonies with music by Loyiso Bala, the Cape Town Youth orchestra and choir, and soloists, while the iconic Johnny Clegg entertained delegates at a picnic in Kirstenbosch Botanical Garden. In tune with the social responsibility facet of the congress, several crèches and playgroups in Cape Town benefited from the donation of the warm winter picnic blankets.

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The congress was the premier cardiac event on the continent of Africa to date, both in terms of numbers of delegates and faculty. The scientific content sought to emphasise current challenges in Africa and South Africa, thus including private, public and government sectors in the important dialogues around finding sustainable to health system deficiencies. It emphasised current challenges for paediatric cardiac care in Africa and South Africa,15 and included multiple sectors in discussing possible solutions to existing health system deficiencies. The Deputy Minister of Health opened the congress while the honourable Minister of Health of South Africa, Aaron Motsoaledi addressed the meeting as a faculty member, on his vision for school health. The Minister of Health of Rwanda lectured on ‘Uniting to address paediatric cardiac disease in Africa’ in addition to the lecture by the Minister of Health of Rwanda on uniting to address paediatric cardiac disease in Africa, the Honourable Minister of Health of South Africa, Dr Aaron Motsoaledi was a member of our faculty and delivered a lecture outlining his vision for school health in Africa. Throughout the meeting, the highest levels of achievements in research and technological development were balanced with provocative explorations relevant to equitable distribution of cardiac care to needy children everywhere. In this way, the congress remained true to its vision to represent the majority of the world’s children with heart disease, raise awareness, and ultimately contribute to improving care for children of all ages with congenital and acquired heart disease in all regions of the world. LIESL ZÜHLKE, MB ChB, DCH, FCPaeds, Cert Card MPH, Liesl.zuhlke@uct.ac.za

School of Adolescent and Child Health, Red Cross War Memorial Children’s Hospital; Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa; President of the Paediatric Cardiac Society of South Africa, President of the 2013 World Congress Company and member of the local organising committee of the World Congress

References 1.

Van der Bom T, Bouma BJ, Meijboom FJ, Zwinderman AH, Mulder BJ. The prevalence of adult congenital heart disease, results from a systematic review and evidence based calculation. Am Heart J

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2012; 164(4): 568–575. Roy A, Prabhakaran D. Impact of current knowledge on CVD prevention. Indian Heart J 2008; 60(2 Suppl B): B23–28. Kugler JD, Beekman Iii RH, Rosenthal GL, Jenkins KJ, Klitzner TS, Martin GR, et al. Development of a pediatric cardiology quality improvement collaborative: from inception to implementation. From the Joint Council on Congenital Heart Disease Quality Improvement Task Force. Congenit Heart Dis 2009; 4(5): 318–328. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet 2012; 379(9819): 953–964. http://www.scoop.co.nz/stories/SC1302/ S00051/rheumatic-fever-investmentwelcomed-by-maurice-wilkins-centr.htm. [cited 2013 13 april 2013]. Irlam J MB, Engel M, Gaziano TA. Primary prevention of acute rheumatic fever and rheumatic heart disease with penicillin in

South African children with pharyngitis: A cost-effectiveness analysis. Circulation Cardiovasc Quality Outcomes 2013; in press. 7. Karthikeyan G, Zuhlke L, Engel M, Rangarajan S, Yusuf S, Teo K, et al. Rationale and design of a Global Rheumatic Heart Disease Registry: the REMEDY study. Am Heart J 2012; 163(4): 535–540 e1. 8. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease. Nat Rev Cardiol 2013 Apr 2. 9. Kovacs AH, Verstappen A. The whole adult congenital heart disease patient. Prog Cardiovasc Dis 2011; 53(4): 247–253. 10. Horton R. Non-communicable diseases: 2015 to 2025 [Comment]. Lancet 2013; 381(9866): 509–510. 11. Yach D. From Framingham to the

12.

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Framework Convention on Tobacco Control. Prog Cardiovasc Dis 2010; 53(1): 52–54. Skilton MR, Mikkila V, Wurtz P, Ala-Korpela M, Sim KA, Soininen P, et al. Fetal growth, omega-3 (n-3) fatty acids, and progression of subclinical atherosclerosis: preventing fetal origins of disease? The Cardiovascular Risk in Young Finns Study. Am J Clin Nutr 2013; 97(1): 58–65. Mensah GA, Mayosi BM. The 2011 United Nations high-level meeting on non-communicable diseases: the Africa agenda calls for a 5-by-5 approach. S Afr Med J 2013; 103(2): 77–79. Weisse AB. Cardiac surgery: a century of progress. Tex Heart Inst J 2011; 38(5): 486–490. Hoosen EG, Cilliers AM, Hugo-Hamman CT, Brown SC, Lawrenson JB, Zuhlke L, et al. Paediatric cardiac services in South Africa. S Afr Med J 2011; 101(2): 106–107.

Drug Trends in Cardiology South African studies in the international literature Considerations of ethnicity and gender in chronic diseases of lifestyle The current global attention directed at non-communicable diseases (NCDs) is being driven at the highest levels, with the World Health Assembly adopting the important new global target of a 25% reduction in preventable NCD deaths by 2025 (the 25 by 25 goal). South Africa, and indeed sub-Saharan Africa, is currently a melting pot of confounding factors affecting both risk and prevalence of chronic diseases of lifestyle, now reaching epidemic proportions in the developing world. Addressing social and economic inequalities among disadvantaged groups, regulation of the food, drink, alcohol and tobacco industries, and learning from the lessons of the HIV and TB epidemics are all vital to tackling NCDs on a national and international level. Further confounding factors in diagnosis and medical management of NCDs need to be considered in that sometimes profound differences in risk factors are evident based on ethnicity

and gender. Many guidelines developed by North American and European bodies are not necessarily appropriate for use in the developing world. South African publications in the international literature consider some of these concerns.

Urban black women at greater risk of chronic heart failure with a younger age of onset Changing dietary habits and consequent nutritional deficiencies are having a significant impact on the health status of individuals living with chronic heart failure (CHF) in Soweto. Interesting findings of Dr Pretorius’ study can be seen in the demographic profile of the Sowetan population living with heart failure.1 Contrary to European findings, in an urban cohort of black Africans, more women present with CHF than men. Furthermore, the mean age of onset for women is lower than for men in the Soweto study, as well as occurring at a younger age (5–10 years) than in European counterparts.

Pretorius S. The impact of dietary habits and nutritional deficiencies in urban African patients living with heart failure in Soweto, South Africa – A review. Endocrin Metab Immune Disord Drug Targets 2013: 13 (1). Jan 15 [Epub ahead of print].

Ethnic variations in the role of adipose tissue on insulin resistance in women Compared to their white counterparts, urban black women experience a disproportionately higher prevalence of type 2 diabetes (T2D), as well as higher levels of the major risk factors of obesity and insulin resistance. Numerous mechanisms have been postulated as to what underlies the increased risk of T2D. Julia Goedecke from the UCT/MRC Research Unit for Exercise Science and Sport Medicine, SAMRC and colleagues from the Department of Human Biology and Department of Medicine at UCT have published a review on the role of adipose tissue in insulin resistance in women of African ancestry.1 Centralisation of body fat, specifically increased visceral adipose tissue (VAT), is

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historically one of the major determinants of insulin resistance; whereas peripheral subcutaneous adipose tissue (VAT) has been shown to be ‘protective’ in predominantly white populations. However, numerous studies indicate that at the same level of body mass index (BMI) or waist circumference, black women are more insulin resistant than their white counterparts in spite of having less VAT and hepatic steatosis. In white women, VAT is the most significant determinant of insulin sensitivity, whereas in black women this is more closely associated with abdominal SAT. Gluteal SAT is negatively correlated with insulin sensitivity in black but not white women. The larger SAT adipocyte size in black women is associated with a reduced adipogenic capacity and a higher expression of inflammatory genes compared with their white counterparts. Questions raised include whether adipose tissue hypertrophy in black women is associated with increased hypoxia and/or oxidative stress in SAT and consequently insulin resistance. 1.

Goedecke JH, Levitt NS, Evans J, Ellman N, Hume DJ, Kotze L, et al. The role of adipose tissue in insulin resistance in women of African ancestry. J Obesity 2013, Article ID 952916. http://dx.doi. org/10.1155/2013/952916.

Population-specific cut-off points proposed for diagnosis of the metabolic syndrome in South Africa Nigel Crowther and Shane Norris of the Witwatersrand University’s Departments of Chemical Pathology and Paediatrics question the appropriateness of the European guidelines used for the diagnosis of the metabolic syndrome in sub-Saharan African women. Their study measured the prevalence of obesity and related metabolic disorders in an urban population of black women to determine the appropriate waist cut-off point for diagnosing metabolic syndrome.1 Of 1 251 African females from the Birth to Twenty cohort in Soweto, prevalence of obesity, T2D and the metabolic syndrome were 50.1, 14.3 and 42.1%, respectively. The appropriate waist cut-off point was found to be 91.5 cm (currently recommended levels are 80.0 cm) and was similar to the cut-off points obtained for detecting increased risk of insulin

resistance (89.0 cm), dyscglycaemia (88.4 cm), hypertension (90.1 cm), hypo-highdensity lipoproteinaemia (87.6 cm) and hyper-low-density lipoproteinaemia (90.5 cm). The similar waist cut-off points identified for the detection of the individual components of the metabolic syndrome and related cardiovascular risk factors demonstrates that the risk for different metabolic diseases increases at the same level of abdominal adiposity, suggesting a common aetiological pathway. Salome Kruger and colleagues from the Centre of Excellence for Nutrition at the North West University’s Potchefstroom campus propose a cut-off point of waist-toheight ratio (WHtR) of 0.41 for metabolic risk in African township adolescents.2 It has previously been proposed that a WHtR > 0.5 be the cut-off point for abdominal obesity in both genders and all ages. To date it is unknown if this cut-off point is appropriate for previously undernourished adolescents. Assessment of the cut-off value of WHtR associated with increased metabolic risk was performed in 178 black South African adolescents aged between 14 and 18 years. The WHtR cut-off points ranged from 0.40 to 0.41, with best diagnostic value at 0.41. A WHtR of 0.40 had 80% sensitivity and 38.5% specificity to classify fasting blood glucose > 5.6 mmol/l. A WHtR of 0.41 had 64% sensitivity and 58.5% specificity for a HOMA-IR > 3.4; 55% sensitivity and 55.6% specificity for a high-sensitivity C-reactive protein level > 1 mg/l; and a 64% sensitivity and 50.2% specificity for a blood pressure higher than the age-, gender-, and height-specific 90th percentiles. 1.

Crowther NJ and Norris SA. The current waist circumference cut point used for the diagnosis of metabolic syndrome in subSaharan African women is not appropriate. PLOS ONE 2012; 7(11): e48883. Kruger HS, Faber M, Schutte AE, Ellis SM. A proposed cutoff point of waist-to-height ratio for metabolic risk in African township adolescents. Nutrition 2013; 29(3): 502–507.

Geographic variation of hypertension in South Africa A study arising out of the Division of Health Sciences, University of Warwick Medical School, Coventry, UK, examines the geographic variation of hypertension in South Africa.1 Analysis of the South African Demographic and Health Survey

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of 13 596 individuals older than 15 years mapped the geographic distribution of hypertension at the provincial level, accounting for individual risk factors. Overall prevalence of hypertension (blood pressure ≥ 140/90 mmHg or selfreported diagnosis or on medication) was 30.4%. Higher prevalence of hypertension was significantly associated with current smoking, current drinking, self-reported sleep problems and the presence of cardiovascular comorbidities such as T2D. The North West, Free State and Northern Cape provinces had the highest prevalence of hypertension, with the lowest levels found in Limpopo. These geographic variations suggest the potential role of socio-economic, nutritional and environmental factors beyond individuallevel risk factors in the development of hypertension. 1.

Kandal NB, Tigbe W, Manda SO, Stranges S. Geographic variation of hypertension in subSaharan Africa: a case study of South Africa. Am J Hypertens 2012; 26(3): 382–391.

NCD risk factors in a highHIV-prevalence rural setting Abraham Malaza of the Africa Centre for Health and Population Studies, University of KwaZulu-Natal, and colleagues examined adult hypertension and obesity in a high-HIV-prevalence rural area.1 The prevalence of obesity in women was 6.5 times higher than in men, whereas prevalence of hypertension was 1.4 times higher than in men. Obesity was a bigger risk factor for hypertension in men and overweight was a risk factor for men only. The BMI of men and women on antiretroviral treatment (ART) was lower than that of their HIV-negative counterparts. The negative association of ART with BMI could be attributed to late presentation and initiation of individuals on ART and the associated weight loss with advanced HIV disease progression. It is also possible that HIV-infected persons are more in contact with healthcare services, so they may be more susceptible to adopting nutrition-related advice. 1.

Malaza A, Mossong J, Barnighausen T, Newell ML. Hypertension and Obesity in Adults Living in a High HIV Prevalence Rural Area in South Africa. PLOS ONE 2012; 7(10): e47761.

G Hardy

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Higher statin doses linked to acute kidney injury: South African experts comment on clinical implications A meta-analysis published recently in the British Medical Journal has linked higher doses of statins (resulting in at least a 45% reduction in low-density lipoprotein cholesterol) to a higher risk of acute kidney injury (AKI) in the first four months of therapy compared to lowerdose statins.1 The study was based on data from Canadian, UK and USA databases of some two million patients, where each index case of AKI was matched with 10 controls from the same database and also matched in terms of time of initiation of therapy. Patients were judged to be treated with higher statin doses if they were given ≥ 10 mg rosuvastatin, ≥ 20 mg atorvastatin and ≥ 40 mg simvastatin. The rate ratio of hospitalisation for AKI for users of high-potency versus low-potency statins was 1.34 (95% CI: 1.25–1.43) for those without a chronic kidney disease (CKD) history and a non-significant 1.10 (95% CI: 0.99–1.23) for those with a CKD history.

CVJAfrica asked two South African experts for their comments on the study: Prof Brian Rayner, hypertension and renal expert, University of Cape Town, and Dr Dirk Blom, lipid expert, University of Cape Town Prof Brian Rayner The risks of acute kidney injury were shown to be raised by 34% over the first four months. This sounds large, but translates to only one extra acute kidney injury event per 1 700 patients treated with the higher dose. The difficulties of interpreting metaanalyses of this kind are well known as they group together patients with different co-morbidities and perhaps different predispositions to AKI, although this study did try to match index cases to appropriate controls. There were important differences in demographics in the high-dose statin

group, with more heart failure and more use of ARBs and ACE inhibitors, factors well known to predispose to AKI. Additionally there are no data in the use of contrast between the groups, which is a major omission from the article. This could account for the higher incidence in the first 120 days, especially in patients treated for secondary prevention requiring coronary angiograms. For the clinician there are also no data on the causes and severity of AKI, which would be useful in determining causation in the high-dose group. Additionally AKI can range from a 25% increase in creatinine level to life-threatening renal failure requiring dialysis. Dr Dirk Blom Observational database studies rely on the accuracy and completeness of diagnostic coding; in this case the coding for acute kidney injury. Because this is a database study, we do not know the context in which higher statin doses were prescribed, e.g. were statin doses increased following an intervention (contrast administration) or cardiovascular event. We also do not know much about the severity of the kidney injuries observed. Observational studies are prone to confounding (e.g. sicker patients are prescribed more therapy) and although the authors adjusted their data by using propensity scoring, a residual risk of confounding remains. Patients on highdose statins had higher rates of congestive cardiac failure (not sufficiently different to account for the observed effect on AKI) and were more likely to use ACE inhibitors, ARBs, loop diuretics and betablockers. This study showed no statistically significant harm with the higher dose of statins given to patients with CKD. This is certainly at odds with expectations, as CKD patients would be more vulnerable to any potential renal effects of the ‘morepotent statins’. Our clinical recommendations for daily practice are:

• We would not change therapy at the moment, i.e. continue patients who are on high doses on their current therapy if indicated. • Be alert that there may be a small excess risk of AKI in those on highdose statin therapy and avoid nephrotoxic medications or interventions. • Clinical judgement is required when choosing a statin; the clinician needs to balance cardiovascular risk, lipid profile and potential statin side effects. • Statin therapy has known benefits and should not be withheld because of fears of AKI. The absolute risk of AKI remains very low • Clinicians should not lose sight of the fact that admission rates for AKI are markedly higher in those with CKD than those with no CKD (the difference varies by database but the rate is at least tenfold and often greater). The risk of AKI in those with CKD is therefore, a major concern and statins do not pose a specific threat here. Focus on good management of those with CKD to avoid precipitating acute kidney injury. This will likely be the intervention that has the largest benefit. The absolute risk increase for AKI from high-dose statins is very small in those without CKD when compared to the very high baseline risk of AKI in those with CKD. • There have been reports of proteinuria with high-dose statins (especially with very high doses, such as rosuvastatin 80 mg/day, which was subsequently not marketed). • Other observational studies have also shown an increased risk of AKI with statin therapy, but observational data are not well suited to causality analyses. J Aalbers 1.

Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, et al. Use of high potency statins and rates of admission for acute kidney injury: multicentre, retrospective observational analysis of administrative databases. Br Med J 2013; 346: 1880. doi:10.1136/bmj. f880 (published 20 March 2013).

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Treating hypertension in the elderly, even white-coat hypertension, is essential

7 6

p = 0.055

5 4 3 2 1 0

Follow up (year)

Placebo No. at Risk Placebo

1912

Indapamide SR 1933 ± perinodpril

30 p = 0.019

Indapamide SR ± perinodpril 1484 807 374 194 1557 873 417 229

Fig. 1. All stroke (30% reduction).

Follow up (year)

Placebo No. at Risk Placebo

1912

Indapamide SR 1933 ± perinodpril

finding that at study entry, CBP exceeded the morning ABP by 32/10 mmHg in the subgroup examined, indicating that 50% of participants fulfilled the established criteria for WCH. White-coat hypertension is said to be present when the CBP is above normal but the ABP is judged to be normal. It has also long been recognised that the CBP–ABP differences increase with age such that the ABP falls with age relative to CBP. In HYVET, with such a high number of patients with WCH, it is unlikely that the study would have produced such positive results if the WCH had been ignored, as is currently recommended by hypertension treatment guidelines. The observation that the presence of white-coat hypertension in the very elderly represents an ‘at-risk’ population warrants further investigation. 1.

No. of events per 100 patients

was less than 150/80 mmHg and this approach was associated with a 21% reduction in total mortality, a 30% reduction in stroke and a 34% reduction in any cardiovascular event. These results apply to the trial participants who were over 80 years of age with an untreated systolic clinic-measured blood pressure (CBP) of 160–199 mHg and a CBP difference of 15/6 mmHg between the placebo and the actively treated group after two years (Figs 1-3). The population of HYVET was quite healthy elderly people; only 12% had had previous coronary vascular disease and 7% had diabetes. However, more than 90% were known to be hypertensive, of which approximately one-third had not previously been treated. The evidence from the ambulatory study highlights the fact that the beneficial blood pressure-lowering action of the indapamide-based therapy with added perindopril was effective and safe over the 24-hour period. This ambulatory blood pressure (ABP) study has also provided valuable insights on the value of treating ‘white-coat hypertension’ in the very elderly, as it has shown that between 40 and 60% of eligible participants in the main study may have had white-coat hypertension. This is based on the ABP No. of events per 100 patients

No. of events per 100 patients

Hypertension treatment in the very elderly over the age of 80 years is beneficial and is associated with reduced risk of death from stroke, death from any cause and heart failure.1 The results from the extensive Hypertension in the Very Elderly Trial (HYVET) using indapamide sustained release 1.5 mg and either 2 or 4 mg perindopril daily provides tangible evidence for this approach. Recently, the Ambulatory Blood Pressure (ABP) results were published of a subgroup of 284 of the almost 4 000 patients who participated in the initial HYVET study by the investigators, headed by Prof Christopher Bulpitt, emeritus professor of Geriatric and Cardiovascular Medicine, Imperial College, London.2 HYVET was a pivotal study in the super-elderly and is still the only large, double-blind, randomised trial to address the dilemma of treating hypertension in the over-80-year-old patient. It was a very difficult trial to perform and took some 10 years to recruit and randomise 3 845 patients. However, the results were clear cut and resolved the clinical uncertainty of treating these very elderly patients. Further analysis of the extensive dataset now provides further clinical insights of importance. In HYVET, the goal blood pressure

Beckett NS, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358. Advance publication 10.1056/NejMoa0801369. Bulpitt CJ, Beckett N, Peters R, Staessen JA, et al. Does white coat hypertension require treatment over age 80?: Results of the Hypertension in the Very Elderly Trial Ambulatory Blood Pressure side project. Hypertension 2012 published online November 19, 2012. 5 4

p = 0.046

3 2 1 0

Indapamide SR ± perinodpril 1492 814 379 202 1565 877 420 231

Fig. 2. Total mortality (21% reduction).

Placebo No. at Risk Placebo

Follow up (year)

1912

Indapamide SR 1933 ± perinodpril

Indapamide SR ± perinodpril 1492 814 379 202 1565 877 420 231

Fig. 3. Fatal stroke (39% reduction).

Major Advances in Cardiology 2010

2005

SHIfT

PREAMI

2008

2005

2008

2003

Perindopril and Remodelling in Elderly with Acute Myocardial Infarction

BEAUTIf UL

H Y P E R T E N S I O N I N T H E V E R Y E L D E R LY T R I A L

2007

2001

ACTION IN DIABETES VASCULAR DISEASE: PRETERAX AND DIAMICRON MR CONTROLLED EVALUATION

ONCE DAILY

PREXUM PLUS COVERSYL ®

Perindopril 4 mg/Indapamide 1.25 mg

ONCE DAILY

PREXUM COVERSYL

4 - 10 mg

P e r i n d o p r i l

S3 PREXUM® PLUS Tablets. Perindopril 4 mg and Indapamide 1,25 mg. Reg. No. 38/7.1.3/0028. S3 COVERSYL® PLUS Tablets. Perindopril 4 mg and Indapamide 1.25 mg. Reg. No.: 33/7.1.3/0363. S3 PREXUM® 4 mg Tablets. Perindopril 4 mg. Reg. No. 36/7.1.3/0020. S3 PREXUM® 10 mg Tablets. Perindopril 10 mg. Reg. No. A39/7.1.3/0233. S3 COVERSYL® 4 mg Tablets. Perindopril 4 mg. Reg. No.: X/7.1.3/314. S3 COVERSYL® 10 mg Tablets. Perindopril 10 mg. Reg. No. A39/7.1.3/0236. S3 CORALAN® 7,5 mg Tablets. Ivabradine 7,5 mg. Reg. No. A39/7.1.4/4011. For full prescribing information, refer to package insert approved by medicines regulatory authority. NAME 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)11 525 3401. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: BIOGARAN SA (Pty) Ltd. Reg. No. 2001/011749/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27(0)11 525 3448. Fax: +27(0) 866 465 144. 143352

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Use new antiplatelet therapies consistently in clinical practice Optimising the benefits of new antiplatelet therapies in daily clinical practice should be based on selecting the particular agents that the responsible clinician would like to use in managing acute coronary syndrome (ACS) patients and then sticking to this selection. Speaking in Accra, Ghana to African cardiologists and physicians attending a special AstraZeneca-sponsored CME symposium, Prof Jean-Pierre Bassand, past president of the European Society of Cardiology and head of Cardiology at the University of Besancon, Franche-Comte, noted that ‘In my 35 years of experience in cardiology, physicians and nurses respond best when they have a simpler regimen of anti-coagulation and anti-platelet agents to use in the ACS setting.’ Aspirin’s position as a rather weak antiplatelet agent is now open to challenge by the newer agents, which offer greater and more consistent platelet inhibition, Prof Bassand said. ‘The use of clopidogrel with aspirin in dual anti-platelet therapy was based on the results of the CURE and Chinese CCS1 studies, which showed significant reductions in the traditional composite endpoints of cardiovascular death, myocardial infarction (MI) and stroke. These agents in combination became the first-line antiplatelet treatment in ACS to reduce events, and of course in interventional approaches, to reduce stent thrombosis.’ Over time and in response to the still significant mortality and morbidity that ACS patients are exposed to, new efforts in anti-platelet innovation focused mainly on the ADP receptors of platelets, now referred to as P2Y12 receptors. The first agent to be introduced in this class of P2 Y12 antagonists was prasugrel, which showed superiority to clopidogrel in combination with aspirin, with a 20% relative risk reduction (RRR) in death, MI and stroke in the TRITON study, but with an expected increase in major bleeding risk. The range of inhibition of platelets was much greater (75% inhibition) compared to the 35–40% achieved using clopidogrel. The benefits of prasugrel have been shown to be a faster onset of action with greater and more consistent platelet inhibition. ‘But the TRITON study used a niche approach in that prasugrel was administered in the catheterisation laboratory to ACS patients whose anatomy was known and who were also clopidogrel naïve. This has resulted naturally in a

more limited evidence-based guideline recommendation for prasugrel’s use internationally’, Prof Bassand said. The next agent (recently launched in both Ghana and Mauritius), ticagrelor, is a new chemical class of P2Y12 antagonist, a cyclopentyltriazolo-pyrimidine and not a thienopyridine pro-drug like clopidogrel and prasugrel. It does however have a similar profile to prasugrel with regard to its onset of action, and achieving greater inhibition of platelet function with an increased risk of bleeding. In the PLATO trial, a major phase III trial in over 18 000 ACS patients, tigacelor was compared to clopidogrel, both in combination with aspirin. The primary endpoint was time to first occurrence of death from vascular causes, MI or stroke. At 12 months, the primary endpoint had occurred in 9.8% of patients receiving ticagrelor compared to 11.7% of patients receiving clopidogrel. This treatment benefit was seen within 30 days and was maintained over the study period of 12 months. There was also a further 15% risk reduction in myocardial infarction rates in patients receiving ticagrelor over clopidogrel-treated patients. ‘However, what was completely new in the PLATO study was the statistically highly significant absolute risk reduction of 1.1% in cardiovascular mortality in the ticagrelor-treated patients’, Dr Bassand said. The explanation for the overall reduction in cardiovascular death is uncertain, but may be due to the blocking of adenosine uptake by cells. ‘Perhaps the better results are also due to a more consistent effect of ticagrelor over the wider base of patients treated in the PLATO study, which included all-comers in the ACS, reflecting the spectrum of patients seen in daily clinical practice.’ ‘PLATO also included all ACS patients whether they had been treated with clopidogrel or not, and also regardless of whether the clinician intended to manage the patient medically, using interventional or surgical procedures’, Prof Bassand stressed. Prof Bassand has been intimately involved with the development of ESC guidelines for STEMI (2012) and non-STEMI (2007 and 2011) management over the past decade. ‘These guidelines have incorporated the new agents but not in a hierarchical manner. The guidelines ‘We may in future have to recommend no aspirin for ACS patients’, he speculated.

Prof JP Bassand speaking at the African launch of ticagrelor

include the first-line use of ticagrelor based on the PLATO study results, noting its particular value in diabetic and renalfailure patients. For prasugrel patients, selection is needed, as those with a low body weight, a prior history of stroke and the elderly (above 75 years) do not derive benefit and are at higher risk for bleeding’. In addition, prasugrel should be given in the catheterisation laboratory only, in clopidogrel-naïve patients intended for PCI once their anatomy is known, except in patients with STEMI intended for primary PCI in whom prasugrel can be administered before their anatomy is known. In medically managed patients, no superior efficacy over clopidogrel was shown with prasugrel in the Trilogy trial. In patients who cannot be given ticagrelor or prasugrel, clopidogrel remains a valid option. Setting his sights on the future, Prof Bassand noted the need to recognise the weak anti-platelet action of aspirin and the developing data based on the WOEST trial, which has driven a first nail in the coffin of aspirin use in ACS. ‘While this study was in only 600 patients and looks at the use of clopidogrel with a vitamin K antagonist, compared to triple therapy with aspirin, clopidogrel and a vitamin K antagonist in patients with atrial fibrillation who are already on oral anticoagulation for thrombosis prevention and who then undergo PCI stenting, the results showed no benefit of triple over dual therapy but a higher risk of bleeding and death. This may have implications for aspirin therapy if this information were confirmed by larger trials in the future.’ J Aalbers

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Case Report Left ventricular non-compaction in pregnancy ISMAIL DOGU KILIC, HALIL TANRIVERDI, HARUN EVRENGUL, SUKRIYE USLU, MUSTAFA AZMI SUNGUR

Abstract

Case report

Left-ventricular non-compaction (LVNC) represents an arrest in the normal process of myocardial compaction, resulting in multiple, prominent, persistant trabeculations and deep inter-trabecular recesses communicating with the ventricular cavity. LVNC is a rarely encountered cardiomyopathy and few cases have been reported in pregnancy. In this case report we present a patient who referred to our clinic with symptoms of heart failure during pregnancy and whose echocardiographic examination revealed prominent trabeculations in the left ventricle.

A 19-year-old postpartum woman with dyspnoea was referred to our clinic for further evaluation. Although she had not experienced any cardiac symptoms during her pregnancy, she felt progressive dyspnoea and began coughing three weeks before her delivery. She had presented to an institution where she was hospitalised for a few days, before she was referred to our clinic. Her medical history was unremarkable and she had no family history of heart failure. On physical examination, her heart rate was 98 beats/min and her blood pressure was 100/70 mmHg. She had jugular venous distention, diffuse crepitation rales in both lungs, and an apical 2–3/6 pansystolic murmur. An electrocardiogram showed non-specific T-wave changes. Echocardiography revealed a dilated left ventricle (end-systolic diameter 49 mm) with an ejection fraction of 20%, severe mitral and tricuspid regurgitation, and mild aortic regurgitation. Pulmonary artery systolic pressure was estimated at 57 mmHg from tricuspid regurgitation. Two-dimensional echocardiography demonstrated prominent trabeculations of the left ventricle, with colour Doppler examination showing penetration of blood flow into the sinusoidal recesses formed by these trabeculations (Fig. 1). Since there is no specific therapy for the condition, the patient was treated with beta-blockers, angiotensin converting enzyme inhibitors, diuretics and acetyl salicylic acid. Neither prophylactic anti-arrhythmic therapy nor anticoagulant therapy was given. At her three-month follow-up examination, her ejection fraction and functional capacity had improved.

Keywords: pregnancy, non-compaction, heart failure Submitted 15/4/12, accepted 23/10/12 Cardiovasc J Afr 2013; 24: e1–e2

www.cvja.co.za

DOI: 10.5830/CVJA-2012-075

Left ventricular non-compaction (LVNC), also known as ‘spongy myocardium’, represents an arrest in the normal process of myocardial compaction, resulting in the persistence of multiple prominent trabeculations and deep inter-trabecular recesses communicating with the ventricular cavity.1,2 The presentation may follow a spectrum from no symptoms to poorly functioning dilated ventricles, a high incidence of ventricular arrhythmias, and systemic emboli.3 The diagnosis is usually made using echocardiography and, increasingly, magnetic resonance imaging (MRI), despite lacking universally accepted criteria.4 Multi-detector computed tomography (CT) may also help detect the abnormal architecture of the left ventricle.5 Left ventricular non-compaction is a rare cardiomyopathy that appears more often in children than adults, with only a few cases reported in pregnancy.6,7 In this report we present a patient who was referred to our clinic with symptoms of heart failure during pregnancy, and whose echocardiographic examination revealed prominent trabeculations in the left ventricle.

Discussion Left ventricular non-compaction is a rare congenital cardiomyopathy caused by an arrest in the normal process of endomyocardial morphogenesis. This disorder is characterised by multiple prominent trabeculations and deep inter-trabecular recesses communicating with the ventricular cavity.1,2 A

Department of Cardiology, Pamukkale University School of Medicine, Denizli, Istanbul, Turkey ISMAIL DOGU KILIC, MD, idogukilic@gmail.com HALIL TANRIVERDI, MD HARUN EVRENGUL, MD SUKRIYE USLU, MD

Pasabahce State Hospital, Istanbul, Turkey MUSTAFA AZMI SUNGUR, MD

Fig. 1. A: increased left ventricular trabeculation B: colour Doppler showing blood flow between the trabeculations.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013

Patients with LVNC may be asymptomatic or present with cardiac dysfunction, ventricular arrhythmias or systemic emboli.3 In this report we present a patient diagnosed with LVNC during pregnancy. Despite being congenital, the reason for this patient becoming symptomatic may be explained by the haemodynamic changes during the pregnancy. During pregnancy, blood volume and cardiac output increase, which may precipitate symptoms of heart failure.8 Although maximal haemodynamic changes occur earlier in pregnancy,7 the patient had attributed her symptoms solely to pregnancy, until she became frankly dyspnoeic. Indeed, symptoms of heart failure such as dyspnoea, dizziness, pedal oedema, and orthopnoea can occur even in normal pregnancies.8 Nevertheless, if the symptoms develop suddenly or become serious, as in this case, further evaluation is needed. Traditionally, left ventricular non-compaction is diagnosed by two-dimensional and colour Doppler echocardiography. A number of echocardiographic definitions for the diagnosis of LVNC are used. Commonly used criteria include the identification of excessive (more than three) prominent (more than 2 mm in diameter) trabeculae with inter-trabecular recesses that penetrate deeply into the myocardium, from which blood flows directly into and out of the ventricular cavity (which is demonstrated using colour Doppler imaging), in the absence of other structural heart disease.9 The method Jenni and colleagues proposed relies on the detection of two myocardial layers, compact and non-compact, in short-axis views of the left ventricle in end-systole. LVNC is diagnosed according to the ratio of these layers.4,10 Increasingly, MRI is being used and CT may be of value. In this case, the diagnosis of LVNC was made by echocardiography showing excessive prominent trabeculations, with colour Doppler echocardiography revealing blood flow between the trabeculations. Trabeculation was predominant in the apex and the lateral wall and this was consistent with previous work by Boyd et al.10 Computed tomography and MRI revealed similar trabeculations in this patient (Fig. 2). The differential diagnosis for this patient included peripartum cardiomyopathy, which is a form of idiopathic primary myocardial disease associated with pregnancy. The European Society of Cardiology recently defined peripartum cardiomyopathy as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within five months of delivery.11 However, in our case it was not possible to determine whether this clinical presentation was due to LVNC that became symptomatic with the haemodynamic changes of pregnancy, or A

Fig. 2. A: computed tomography. B: magnetic resonance imaging showing increased trabeculation.

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whether peripartum cardiomyopathy complicated this patient’s pregnancy. Conditions that may be falsely diagnosed as LVNC should also be included in the differential diagnosis. These conditions include false tendons, aberrant bands, thrombi, the apical type of hypertrophic cardiomyopathy, fibromas, obliterative processes of the left ventricular cavity, intra-myocardial haematomas, cardiac metastases, and intra-myocardial abscesses.12 However, both imaging modalities showed prominent trabeculations and the patient’s clinical course made these diagnoses unlikely.

Conclusion Dyspnoea is common during pregnancy. Development of dyspnoea in the pregnant woman leaves the clinician with the question of whether the dyspnoea comes from an underlying cardiac or pulmonary disease or it is due to the pregnancy itself. This case reminds us that although LVNC is rarely diagnosed in pregnancy, rare causes of heart failure should also be kept in mind during the evaluation of symptoms of heart failure.

References 1.

Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, et al. Report of the 1995 World Health Organization/ International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996; 93: 841–842. 2. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108(21): 2672–2678. 3. Murphy RT, Thaman R, Blanes JG, Thaman R, Blanes JG, et al. Natural history and familial characteristics of isolated left ventricular noncompaction. Eur Heart J 2005; 26: 187–192. 4. Kohli SK, Pantazis AA, Shah JS, Adeyemi B, Jackson G, McKenna WJ, et al. Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J 2008; 29(1): 89–95. 5. Bladt O, Vanhoenacker R, Bevernage C, Leyman P. Isolated noncompaction of ventricular myocardium. Diagnosis with multidetector computed tomography. JBR-BTR 2008; 91(4): 153–154. 6. Munehisa Y, Watanabe H, Kosaka T, Kimura A, Ito H. Successful outcome in a pregnant woman with isolated noncompaction of the left ventricular myocardium. Intern Med 2007; 46(6): 285–289. 7. Patel C, Shirali G, Pereira N. Left ventricular noncompaction mimicking peripartum cardiomyopathy. J Am Soc Echocardiogr 2007; 20(8): 1009.e9–12. 8. Ramaraj R, Sorrell VL.Peripartum cardiomyopathy: Causes, diagnosis, and treatment. Cleve Clin J Med 2009; 76(5): 289–96. 9. Ahmed I, Phan TT, Lipkin GW, Frenneaux M. Ventricular noncompaction in a female patient with nephropathic cystinosis: a case report. J Med Case Reports 2009; 29(3): 31. 10. Boyd MT, Seward JB, Tajik AJ, Edwards WD. Frequency and location of prominent left ventricular trabeculations at autopsy in 474 normal human hearts: implications for valuation of mural thrombi by twodimensional echocardiography. Am Coll Cardiol 1987; 9: J323–326. 11. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29(2): 270–276. 12. Stöllberger C, Finsterer J. Pitfalls in the diagnosis of left ventricular hypertrabeculation/non-compaction. Postgrad Med J 2006; 82(972): 679–683.

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Case Report Unusual variant of scimitar syndrome associated with an absent right pulmonary artery, stenosis of the inferior vena cava, hemi-azygous continuation and the VACTERL association FARIRAI F TAKAWIRA, FAREED OMAR

Abstract We report on a two-month-old infant with an unusual form of scimitar syndrome, associated with an absent right pulmonary artery, obstructed inferior vena cava, hemi-azygous continuation and the VACTERL association. The infant posed a major management problem and eventually died from a lower respiratory tract infection. Keywords: scimitar syndrome, absent pulmonary artery, hemiazygous, stenosis, inferior vena cava, VACTERL association Submitted 4/5/10, accepted 28/11/12 Cardiovasc J Afr 2013; 24: e3–e6

www.cvja.co.za

DOI: 10.5830/CVJA-2012-079

Scimitar syndrome is a rare and complex congenital anomaly that often involves hypoplasia of the right lung, partial anomalous pulmonary venous connection (PAPVC) of the right lung draining into the inferior vena cava (IVC) and a systemic collateral artery from the descending aorta supplying the right lower lobe (lobar sequestration). The right pulmonary artery (RPA) is often hypoplastic but may be completely absent.1-3 Scimitar syndrome may be associated with other congenital heart defects or occur in isolation. We describe a young infant with scimitar syndrome associated with an absent RPA, an obstructed IVC and the VACTERL association (Vertebral defects, Anal atresia, Cardiac anomalies, Tracheo-oEsophageal fistula, Renal abnormalities and Limb anomalies). These conditions have not previously been described together in the English literature. The infant posed a major management problem and eventually died from a lower respiratory tract infection.

She was transferred to our institution at two months of age for elective surgical repair of the fistula. She was noted to be tachypnoeic and on chest radiography was suspected to have ‘dextrocardia’. She was therefore referred to our cardiology service for evaluation. On clinical examination she weighed 3.3 kg and was not thriving. She was not cyanosed but had saturations of 90% on 2 l/ min of nasal oxygen. Her pulse was 160 beats/min and the blood pressure 75/44 mmHg. The trachea deviated to the right due to a right mediastinal shift. The apex beat was felt in the fourth right intercostal space/mid-clavicular line. The second heart sound was loud and a soft 2/6 ejection systolic murmur was audible along the upper sternal border. She was in congestive cardiac failure, as evidenced by tachypnoea, tachycardia, a gallop rhythm and hepatomegaly. There was dullness to percussion of the right hemithorax with decreased air entry.

Case report A female infant was noted soon after birth to have anal atresia, a recto-vaginal fistula and hypoplasia of the right thumb. She was the product of the first pregnancy of a 19-year-old mother. Steve Biko Academic Hospital and Department of Paediatric Cardiology, University of Pretoria, South Africa FARIRAI F TAKAWIRA, FCPaed (SA), fari.takawira@up.ac.za FAREED OMAR, MBCHB, FCPaed (SA)

Fig. 1. Chest radiography demonstrating dextroposition and right mediastinal shift. Hemivertabrae and scoliosis are also evident.

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Fig. 2. Electrocardiogram demonstrates tachycardia, extreme right-axis deviation, right atrial enlargement and right ventricular hypertrophy.

Chest radiography (Fig. 1) demonstrated hypoplasia of the right lung, with a right mediastinal shift. There were hemivertebrae and a mild scoliosis present. Electrocardiography (Fig. 2) demonstrated a heart rate of 170 beats/min, extreme right-axis deviation, right atrial enlargement and marked right ventricular hypertrophy. On echocardiography the heart was shifted over to the right hemithorax and standard views could be obtained by moving the probe towards the right chest. A

There was situs solitus and no atrial or ventricular inversion. The right atrium (RA), right ventricle (RV) and main pulmonary artery (MPA) segment were dilated. The dilated right heart compressed the left, with both the interventricular and interatrial septa deviated to the left. The estimated pulmonary pressure from the tricuspid regurgitation gradient was 70 mmHg. A small patent foramen ovale with bidirectional shunting was noted. The right pulmonary artery (RPA) could not be visualised. The left pulmonary veins drained normally into the left atrium, but the B

LPA LPA

Fig. 3. RV (A) and MPA (B) angiograms demonstrating RV hypertrophy and an absent RPA. Tracheal deviation to the right is also shown (arrows). (RV, right ventricle; MPA, main pulmonary artery; LPA, left pulmonary artery; RPA, right pulmonary artery).

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Fig. 4. Abnormal right pulmonary vein draining into the stenosed inferior vena cava (arrow).

right pulmonary vein was draining into a stenosed inferior vena cava, just before it entered the RA. A gradient of 15 mmHg at this junction was demonstrated. At cardiac catheterisation, there was a step-up in the high IVC A

saturation. Severe pulmonary hypertension of 80/22 mmHg was demonstrated. Angiography demonstrated a hypertrophied and dilated RV, a large MPA and an absent RPA (Fig. 3). PAPVC of the right pulmonary vein draining into the IVC was also noted (Fig. 4). The stenosed IVC was clearly demonstrated before its entry into the RA (Fig. 5). There was a hemi-azygous continuation which drained into the superior vena cava (SVC) and the RA (Fig. 5). A systemic collateral from the descending aorta supplying the lower lobe of the right lung was visible during the venous phase of the pulmonary angiogram. A diagnosis of scimitar syndrome with an absent RPA and an obstructed IVC was made. In view of the anal atresia, recto-vaginal fistula, hemi-vertebrae with scoliosis, right thumb hypoplasia and scimitar syndrome, the criteria for diagnosis of the VACTERL association were fulfilled. Due to the absent RPA and right lung hypoplasia, surgical repair of the PAPVC and re-routing of the anomalous right pulmonary vein into the left atrium (LA) were considered of little haemodynamic benefit. Right pneumonectomy was deemed the best surgical option, but could not be undertaken in early infancy. The patient initially improved with the administration of anti-failure treatment (furosemide and digoxin) and could be discharged from hospital. Unfortunately, she succumbed a few weeks later to a lower respiratory tract infection while at home and an autopsy could not be performed.

Discussion Scimitar syndrome is a rare form of PAPVC involving the right lung. There is associated hypoplasia of the right lung and RPA with a right mediastinal shift creating dextroposition of the heart. The RPA may be completely absent,3-5 as was the B

SVC HZ

IVC

Fig. 5. (A) Obstructed IVC with hemi-azygous continuation draining into the SVC. (B) Catheter advanced from the femoral vein into the hemi-azygous continuation, SVC, RA, and into the IVC (IVC, inferior vena cava; SVC, superior vena cava; HZ, hemi-zygous, RA, right atrium).

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case in our patient. The abnormal pulmonary vein draining into the IVC can often be seen as a classic curvilinear density on the right chest on plain radiography and is shaped like a Turkish sword or scimitar. This may not always be evident. It is also known as congenital pulmonary veno-lobar syndrome, hypogenic lung syndrome, mirror image lung syndrome, vena cava bronchovascular syndrome, epibronchial right pulmonary artery syndrome or Halasz’s syndrome.1-3 Halasz first used the term ‘scimitar’ in 1956,3 but Neill coined the term ‘scimitar syndrome’ in 1960.1-3,6 The aetiology remains unknown. It occurs more frequently in females and may be familial.1,6 It remains unclear why it predominantly involves the right lung, although there have been a few case reports involving the left lung.7 There are several associations described with the scimitar syndrome, including the horse-shoe lung and absence of the RPA. It has rarely been described with a hypoplastic or interrupted IVC. Agnoletti et al. described a similar case with scimitar syndrome, absent RPA and a persistent primitive hepatic venous plexus.8,9 The IVC was also stenosed in their case. The pathophysiology in scimitar syndrome resembles that of PAPVC or left-to-right shunting at atrial level with volume overload and dilatation of the RA, RV and pulmonary arteries. Pulmonary hypertension may develop, especially where there is associated obstruction of the scimitar vein. The systemic collateral supply from the aorta to the right lung also functions as a left-to-right shunt, increasing the flow through the scimitar vein and worsening the pulmonary hypertension. In our patient, the left lung received the whole cardiac output and this exacerbated the pulmonary hypertension. The abnormal systemic supply leads to sequestration of the left lung. This may lead to recurrent chest infections and bronchiectasis. There is a wide clinical spectrum in scimitar syndrome, ranging from severely ill infants to asymptomatic adults. The infantile type is the severe form and presents in the first three months of life with respiratory and cardiac failure and often has a poor long-term outcome.10,11 This group usually has other associated cardiac defects, commonly atrial septal and ventricular septal defects and tends to have severe pulmonary hypertension. The adult type is often asymptomatic, presenting later in life as an incidental finding on chest radiography and is usually benign. Treatment for symptomatic patients with scimitar syndrome consists of surgical repair of the PAPVC, with the anomalous scimitar vein being redirected to the LA and ligation or coil embolisation of the systemic collateral supply to the right lung.12-15 Obstruction by thrombosis and fibrosis of the redirected pulmonary vein is a common post-operative complication.12 Lobectomy, and in some cases, pneumonectomy of the affected lung has been performed.3,12 VACTERL association is an acronym used to describe a series of non-randomly associated birth defects (vertebral defects, anal

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atresia, cardiac anomalies, tracheo-esophageal fistula, renal abnormalities and limb anomalies). To our knowledge, this rare association of scimitar syndrome, absent RPA, stenosis of the IVC with hemi-azygous continuation and the VACTERL association has not been previously described in the English literature. Scimitar syndrome as the cardiac component of the VACTERL association is very uncommon. In their series of 32 patients with scimitar syndrome over 20 years, Najm and colleagues describe only one patient with the VACTERL association.16

References 1.

2. 3. 4.

10. 11.

12.

13. 14.

15. 16.

Grech V, Xuereb R, Xuereb M, Manche A, et al. Late presentation and successful treatment of classical scimitar syndrome. Images Paediatr Cardiol 2003; 16: 49–62. Muktachand L, Rokade RV, Devdas S, et al. Scimitar syndrome. Ind J Paediatr 2005; 72: 245–247 Patel AM, Joshi R, Vaghela D, et al. A face of scimitar syndrome. Ind J Radiol Imag 2004; 14: 401–404. Beitzke A, Zobel G, Rigler B, et al. Scimitar syndrome with absence of the right pulmonary artery: a case with volume-induced, reversible leftsided pulmonary hypertension. Paediatr Cardiol 1992; 13: 119–121. Saltik IL, Eroglu AG, Oztune F, Sarioglu A. Scimitar syndrome with absence of the right pulmonary artery: a case report. Turk J Paediatr 1999; 41: 399–402. Neill CA, Ferenca C, Sabiston DC. The familial occurrence of hypoplastic right lung with anomalous systemic arterial supply and venous return, ‘scimitar syndrome’. Bull Johns Hopkins Hospital 1960; 107: 1–21. Rutledge JM, Hiatt PW, Wesley VG 3rd, et al. A sword for the left hand: an unusual case of left sided scimitar syndrome. Paediatr Cardiol 2001; 22: 350–352. Mac Donald C, Mikhailian H, Yoo S, et al. Angiographic findings of persistent primitive hepatic venous plexus with underdevelopment of the infrahepatic inferior vena cava in paediatric patients. Am J Radiol 2000; 175: 1397–1401. Agnoletti G, Bonnet D, De Blic J. Scimitar syndrome associated with absence of the right pulmonary artery and a persistent primitive hepatic venous plexus. Cardiol Young 2005; 15: 216–218. Sehgal A, Loughran-Fowlds A. Scimitar syndrome. Indian J Paediatr 2005; 72: 249–251. Gikonyo DK, Tandon R, Lucas RV Jnr, et al. Scimitar syndrome in neonates: Report of 4 cases and review of the literature. Paediatr Cardiol 1986; 6: 193–197. Schramel FMNH, Westermann CJJ, Knaepen PJ, et al. The scimitar syndrome: Clinical spectrum and surgical treatment. Eur Resp J 1995; 8: 196–201. Desai PR, Babu M. Scimitar syndrome as a differential diagnosis in a child with recurrent wheeze. Arch Dis Child 2002; 87: 357. Oshima Y, Hashimoto I, Shimazu C, et al. Atypical infantile form of scimitar syndrome with bronchomalacia. Interact Cardiovasc Thorac Surg 2003; 2: 298–300. Mordue B. A case series of 5 infants with scimitar syndrome. Adv Neonat Cardiol 2003; 3: 121–132. Najm HK, Williams WG, Coles JG, et al. Scimitar syndrome: Twenty years’s experience and results of repair. J Thorac Cardiovasc Surg 1996; 112: 1161–1168.

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Case Report Candida parapsilosis endocarditis on a prosthetic aortic valve with unclear echocardiographic features CHARLES MVE MVONDO, FRANCESCA D’AURIA, PASQUALE SORDILLO, ANTONIO PELLEGRINO, MASSIMO ADREONI, LUIGI CHIARIELLO

Abstract Fungal endocarditis is rare in comparison with bacterial endocarditis and is associated with a poor prognosis. Despite the proven reliability of echocardiography, false negatives are not uncommon and may influence the therapeutic strategy, as some reports have supported the efficacy of antifungal treatment alone. We report on a case of bioprosthetic aortic valve Candida parapsilosis endocarditis without typical echocardiograhy findings, which we treated with both antifungal and surgical therapy. Keywords: Candida parapsilosis, prosthetic heart valve, endocarditis Submitted 16/5/12, accepted 24/1/13 Cardiovasc J Afr 2013; 24: e7–e8

www.cvja.co.za

DOI: 10.5830/CVJA-2013-006

Infective endocarditis is a high-risk condition that may affect native and prosthetic heart valves.1 Bacterial endocarditis is more common than fungal endocarditis (FE), with the latter predominantly caused by Candida species. Candida albicans represents the main cause of candidaemia, followed by Candida parapsilosis. FE is correlated with major embolic events and a poor prognosis.1 Its incidence has increased over the last two decades because of an increased use of intravenous drugs, invasive diagnostic methods and vascular implants, which are major predisposing factors. Therefore, patients with a prosthetic heart valve carry a significant risk of contracting FE. Clinical diagnosis of FE, as for bacterial endocarditis, is based on the reviewed Duke’s criteria, and echocardiography2,3 remains a reliable diagnostic tool in the management of FE. However, even with transoesophageal echocardiography, false

negatives are not uncommon and may influence the therapeutic strategy, especially when there is no evidence of vegetations or valve dysfunction. We describe a case of bioprosthetic aortic valve C parapsilosis FE, without typical echocardiography findings. Although several publications have reported successful FE treatment with antifungal therapy alone,4 we performed a combined surgical and medical approach as recommended by the guidelines.2

Case report A 44-year-old female patient with a history of smoking was admitted to our cardiac surgical unit at the Tor Vergata University Hospital in Rome. One year earlier she had complained of dysphonia. Chest computed tomography showed cardiomegaly, and transthoracic two-dimensional (2D) echocardiography revealed severe aortic valve stenosis. Four months later she underwent aortic valve replacement at our institution, with a bioprosthetic bovine pericardial valve (Sorin Mitroflow 21 mm), after a short period of medical treatment for acute pancreatitis and liver impairment in a medical care unit. Her postoperative course was uneventful and on the sixth post-operative day, she was transferred to a rehabilitation clinic. Six weeks later, she had fever (40°C) and odynophagia, associated with cough and chest pain. Echocardiography showed an absence of vegetations and normal function of the native valves and prosthesis. Empirical intravenous antibiotic treatment with vancomycin (15 mg/kg/ day), gentamicin (1 mg/kg, three times a day) and rifampicin (600 mg/day) was then started. Subsequent blood cultures revealed the presence of C parapsilosis, although both transthoracic and transoesophageal echocardiography (Fig. 1) had failed to detect typical lesions. A

Department of Cardiac Surgery, Policlinico Tor Vergata, Tor Vergata University of Rome, Rome, Italy CHARLES MVE MVONDO, MD, mmvondocarlo@yahoo.fr FRANCESCA D’AURIA, MD ANTONIO PELLEGRINO, MD LUIGI CHIARIELLO, MD

Department of Internal Medicine, Infectious Diseases Unit, Policlinico Tor Vergata, Tor Vergata University of Rome, Rome, Italy PASQUALE SORDILLO, MD MASSIMO ADREONI, MD

Fig. 1. Pre-operative 2D echocardiogram images; (a) transthoracic echocardiogram: long-axis left parasternal view; (b) transoesophageal modality: mid-oesophageal aortic valve short-axis view.

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Fig. 2. Bioprosthetic valve with diffuse vegetations inside the strut: (a) ventricular and (b) aortic views.

Antifungal therapy with caspofungin (70 mg intravenous loading dose, followed by 50 mg/day) was started according to the demonstrated antibiogram susceptibility (MIC 0.25 mg/l). After more positive blood cultures, despite antifungal therapy, the patient underwent surgery for prosthetic aortic valve replacement (Bioprothesis Sorin Mitroflow 21 mm) with aortic annular reinforcement using an autologous pericardial patch, since there was intra-operative evidence of aortic annulus involvement and diffused prosthetic valve vegetations (Fig. 2). On the sixth post operative day, the patient was moved to the Infectious Diseases Unit without fever. No neurological dysfunction occurred during the perioperative period. After one week, a new series of blood cultures was negative, and no episodes of fever occurred during the following 12 months. Currently, the patient is in good clinical condition, and she is still on antifungal therapy (oral fluconazole 200 mg/day), with diagnostic examinations performed every six months (transthoracic echocardiogram, blood cultures, complete blood count, and markers of inflammation, renal and liver function). In the absence of renal and liver dysfunction, we routinely recommend antifungal therapy for at least two years after surgery, to avoid recurrence of FE.

Discussion Fungal endocarditis is uncommon and predominantly caused by Candida species, and less frequently by Aspergillus species. C albicans is found in 46% of cases of FE, while C parapsilosis is found in 17%.1 FE is known to be a high-risk condition for septic embolism and is associated with a poorer prognosis compared with bacterial endocarditis. Moreover, recurrence of fungal infection occurs in almost 30% of patients even after completion of the appropriate therapy.5 Risk factors for FE include extensive surgery, prolonged hospitalisation and invasive medical procedures, although the most important predisposing factor appears to be the use of intravenous drugs. In the latter case, C parapsilosis is the most common aetiological agent, with a specific ability to generate a biofilm that tends to cover non-biological surfaces; this could explain its high association with the presence of intravascular devices.5 In the last 20 years, 72 cases of FE were caused by C parapsilosis, of which 26 on prosthetic heart valves have been reported.4 Half of the patients were treated with antifungal therapy alone. A surgical approach is advised depending on the patient’s clinical status and on the echocardiographic findings. Echocardiography is useful not only to confirm the diagnosis,

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but also for the decision-making process and for surgical timing. Sometimes, huge vegetations with a high embolic potential, or signs of significant valve dysfunction can be detected, thus leading to urgent or emergency surgery. The combination of antifungal chemotherapy and surgical removal of the diseased valve is the most accepted therapeutic strategy for patients with FE.2,5 However, in some instances, medical therapy alone with modern antifungal agents has been demonstrated to be sufficient to obtain complete healing of the prosthetic valve, unless friable vegetations are identified at echocardiography. Nonetheless, in our case, medical therapy failed to resolve the fungaemia, and no evidence of endocarditis was identified on echocardiography before the operation, while at surgery the prosthetic valve was found to be extensively covered by vegetations. False negatives at echocardiography appear to be relatively common and surgery should always be considered when dealing with FE on prosthetic heart valves, even in the absence of a clear demonstration of vegetations. A possible explanation could be that if the vegetations are present predominantly inside the struts, they are not mobile, and consequently are not easily visualised, as in the present case. Therefore, this possibility should be suspected and specifically addressed in the diagnostic process. The use of three-dimensional echocardiography should be considered for atypical cases of infective endocarditis, to improve the accuracy of the diagnostic evaluation.6,7

Conclusion We believe that diagnostic imaging may underestimate the entity of prosthetic valve involvement during FE. Given the limited evidence for the success of medical therapy alone, and the failure of 2D echocardiography to reveal the severity of disease in our patient, early surgical exploration should be considered when a prosthetic heart valve FE is diagnosed, to speed resolution of the disease and to prevent embolism from unidentified vegetations.

References 1.

Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer AW, et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998; 98: 2936–2948. Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Eur Heart J 2009; 30: 2369–2413 Donal E, Abgueguen P, Coisne D, Gouello J, McFadden E, Allal J, et al . Echocardiographic features of Candida species endocarditis: 12 cases and a review of published reports. Heart 2001; 86: 179–182. Garzoni C, Nobre VA, Garbino J. Candida parapsilosis endocarditis: a comparative review of the literature. Eur J Clin Microbiol Infect Dis 2007; 26: 915–926. Ellis ME, Al-Abdely H, Sandridge A, Greer W, Ventura W. Fungal endocarditis: evidence in the world literature, 1965–1995. Clin Infect Dis 2001; 32: 50–62. Pérez de Isla L, Zamorano J, Malangatana G, Almería C, Rodrigo JL, Cordeiro P, Macaya C. Usefulness of real-time 3-dimensional echocardiography in the assessment of infective endocarditis: initial experience. J Ultrasound Med 2005; 24: 231–233. Caselli S, Mazzesi G, Tritapepe L, Barretta A, Pandian NG, Agati L, Fedele F. 3D echocardiographic delineation of mitral–aortic intervalular fibrosa pseudoaneurysm caused by bicuspid aortic valve endocarditis. Echocardiography 2011; 28: E1–4.

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Case Report Robotically assisted ventricular tachycardia substrate modification ablation with the novel LynxTM integrated sheath and RF ablation catheter FAIZEL LORGAT, EVAN PUDNEY, HELENA VAN DEVENTER

Abstract Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically controlled catheter ablation reduces operator fatigue and exposure to X-rays, and provides greater precision and stability of the catheter. A new flexible, integrated robotic sheath and ablation catheter has recently been introduced (LynxTM) and used in atrial ablation procedures. We describe the first VT substrate modification ablation in the world with the LynxTM robotic radio frequency ablation catheter. Keywords: robotic ablation, ischaemic VT, remote navigation, LynxTM catheter Submitted 9/8/12, accepted 5/3/13 Cardiovasc J Afr 2013; 24: e9â&#x20AC;&#x201C;e11

www.cvja.co.za

DOI: 10.5830/CVJA-2013-008

Catheter ablation of ventricular tachycardia (VT) is usually a demanding and time-consuming procedure. Robotically controlled catheter ablation has the potential to reduce operator fatigue, with the added advantage of greater precision and Christiaan Barnard Memorial Hospital, Cape Town, South Africa FAIZEL LORGAT, MB Ch B, PhD, FCP (SA), florgat@iafrica.com EVAN PUDNEY, Clin Tech HELENA VAN DEVENTER, Clin Tech

stability of the catheter. Remote navigation also reduces operator exposure to X-rays. VT has been successfully ablated using first-generation robotic technology,1,2 which is still in its infancy. Improvements have the potential to further enhance outcomes. A new flexible, integrated robotic sheath and ablation catheter has recently been introduced (LynxTM, Hansen Medical, Mountain View, CA) and used in atrial ablation procedures.3 We describe the first VT substrate modification ablation in the world with the new LynxTM robotic radio frequency (RF) ablation catheter.

Case report The patient was a 78-year-old man with ischaemic heart disease, diabetes, hypertension and hypercholesterolaemia. In 1991 he underwent coronary artery bypass surgery. In 2007 he presented with sustained monomorphic VT which failed simultaneous treatment with bisoprolol and amiodarone. A cardiac electrophysiological study was performed. Ischaemic scar substrate was identified using voltage mapping. Manual catheter ablation was performed to the posterior lateral aspect of the mid left ventricle (LV) using the retrograde approach. Both bisoprolol and amiodarone were successfully discontinued post ablation. In early 2009, drug-eluting stents were placed in a vein graft to the right coronary artery and a diagonal branch of the left anterior descending (LAD) coronary artery. In July 2010 the left internal mammary artery occluded and a drug-eluting stent was placed in the native LAD.

Fig. 1. Admission ECG demonstrating broad-complex tachycardia with atypical right bundle branch morphology.

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In September 2010 the patient again presented with a sustained monomorphic VT. The morphology was different from that seen in 2007 (Fig. 1). A cardioversion was performed and maintenance amiodarone (200 mg daily) was commenced after intravenous loading. In October 2010 he was re-admitted in VT with the same morphology (Fig. 1). Urgent cardioversion was required due to severe hypotension. His course was complicated by acute tubular necrosis. Despite repeat loading with intravenous amiodarone 1.2 g daily for one week, he continued to have frequent paroxysms of VT. A cardiac electrophysiological study was performed under general anaesthesia via the right femoral vein. A quadripolar catheter was placed in the right ventricular apex. A Preface trans-septal sheath (Biosense Webster, Diamond Bar, CA) and a trans-septal needle (Bard Electrophysiology, Lowell, MA) were used to perform a trans-septal puncture. A 15–25 variable loop lasso catheter (Biosense Webster, Diamond Bar, CA) and the Ensite 3-D mapping system (St Jude Medical, Inc, St Paul, MN) were used to generate a map of the left ventricle. The lasso catheter and the Preface sheath were subsequently withdrawn. A guidewire was left behind to preserve trans-septal access. A LynxTM intergraded RF ablation catheter and robotic sheath (Fig. 2) was robotically guided across the inter-atrial septum adjacent to the guidewire and through the mitral valve into the LV. The guidewire was subsequently withdrawn. A detailed voltage map of the LV was constructed using the LynxTM catheter (Fig. 3). A large scar was noted on the posterior–inferior aspect of the mid LV. Anaesthesia suppressed the salvos of VT so pace mapping with the robotic ablation catheter was performed within the scar border zone. Twelve out of 12 pace matches were obtained for clinical VT on the posterior lateral aspect of the apex. Mid-diastolic potentials were noted in the sites where 12 out of 12 pace matches were obtained. Ablation was performed whenever 12 out of 12 pace matches were obtained. Accelerated ventricular rhythms identical to clinical VT were frequently induced during ablation. The procedure was terminated when accelerated ventricular rhythms were no longer inducible with RF energy delivery. Physician workstation, remote catheter manipulator and robotic sheath

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Due to poor LV function (ejection fraction 35%), borderline blood pressure under anaesthesia even in sinus rhythm and recent acute tubular necrosis, no attempt was made to induce VT either before or after ablation. Total procedure time was three hours 30 minutes, RF ablation time was 16 minutes and 45 seconds and fluoroscopy time (Siemens single-plane X-ray at seven frames per second) was 18 minutes (2 565.1 µg/m2). Post-ablation VT was not seen again. Amiodarone 200 mg daily was continued as maintenance treatment and weaned down to 100 mg daily after three months. At 21 months’ follow up the patient is well on amiodarone 50 mg, telmisartan 80 mg, simvastatin 20 mg, and aspirin 81 mg daily, and metformin 850 mg twice daily. There was no recurrence of VT and complete resolution of renal function.

Discussion This case report details the first successful RF ablation of a ventricular arrhythmia using a novel flexible robotic technology. The LynxTM catheter is a 12-French compatible integrated robotic sheath and open irrigated RF ablation catheter. The ablation catheter has seven irrigation holes and a flat tip. Previous robotic VT ablations have been performed using the 14-French compatible Artisan sheath (Fig. 2). The reduced profile of the LynxTM catheter enhances its flexibility and safety. This has significant advantages for the trans-septal and trans-mitral crossing and has the potential to reduce groin-related complications. Having completed more than 100 ablations with this catheter (mostly left atrial ablations), we have also found the set up time of the LynxTM robotic catheter to be significantly reduced since the ablation catheter is integrated into the robotic sheath, and the purging process has been simplified when compared to the Artisan sheath. We believe that the outcome of this procedure was favourably influenced by the robotic technology and particularly the new LynxTM catheter. The smaller profile and enhanced flexibility was of particular relevance in this case since the patient was elderly, ablation was required in the apex of the LV, and the relevant site was targeted using the trans-septal and trans-mitral approach. The enhanced catheter stability provided by the robotic sheath and the capacity to continuously measure contact via IntelliSense Fine Force technology also most likely improved the efficiency of both mapping and ablation. IntelliSense Fine Force technology uses contact-induced interference with catheter movement as a surrogate measure of

Lynx

Artisan

Lynx

Fig. 2. The Hansen robotic system with Artisan sheath and Lynx catheter (integrated robotic sheath and RF ablation catheter).

Fig. 3. Posterior view of the Ensite 3-D voltage map with ablation sites on the scar border zone in the apex of the left ventricle.

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contact force. This technology has also been used to improve safety by generating tactile feedback to the Instinctive motion controller used for remote navigation of the catheter. Intellisense Fine Force measurements are displayed graphically and above a set threshold transmitted as warning vibrations to the Instinctive motion controller used to remotely manipulate the LynxTM catheter. Despite the acute angulation of the robotic catheter inherent in the trans-septal trans-mitral approach, we found contact-force measurements to be useful, although frequent re-baselining was required to maintain stable measurements. This was not the case when the Artisan catheter was used in the ventricles.2 This may be because of the enhanced flexibility of the LynxTM catheter. The impact of robotic technology on the comfort of the operator cannot be underestimated. Reduced operator fatigue probably results in improved decision making and procedural efficiency and safety. Importantly, X-ray exposure to the operator was negligible since catheter manipulation was remotely performed. Two remote robotic catheter manipulation technologies are currently available, a robotically controlled sheath system (Hansen) and a magnetic navigation system (Stereotaxis). We opted for the Hansen system because of the ease of installation and the small footprint of the device. No additional alterations to the cardiac catheterisation facility are reqired. The magnetic system requires reinforcement of the floor due to the weight of the large magnets and the walls require shielding to limit the effects of the magnetic field. Furthermore, at the time when we opted to purchase a robotic system, there were unresolved technical issues with the cooling of the magnetic catheter. A second-generation cooled magnetic catheter has since been released. Our patient was clearly a candidate for an implantable

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cardioverter defibrillator (ICD) since he had significantly reduced LV ejection fraction and monomorphic haemodynamically significant VT. Resynchronisation therapy was not indicated as QRS duration was less than 150 ms in sinus rhythm. The role of device therapy in this setting with particular reference to the impact on mortality was discussed in considerable detail. The negative impact of shocks on quality of life was cited by the patient and family as an important reason to defer device implant. A son and daughter of the patient are medical doctors so they were well informed. It was agreed that an ICD would only be implanted if ablation failed to control symptoms, in which case the objective was to use anti-tachycardia pacing to terminate VT (with shock therapy as a last resort).

Conclusion We describe the first robotically assisted RF ablation of ischaemic VT in the world, using a novel integrated RF ablation catheter and robotic sheath with a reduced profile and enhanced flexibility.

References 1.

Koa-Wing M, Linton NWF, Kojodjojo P, O’ Neill MD, Peters NS, Davies W, Kanagaratnam P. Robotic catheter ablation of ventricular tachycardia in a patient with congenital heart disease and Rastelli repair. J Cardiovasc Electrophysiol 2009; 20(10): 1163–1166. Valderrábano M, Dave AS, Báez-Escudero JL, Rami T. Robotic catheter ablation of ventricular tachycardia: initial experience. Heart Rhythm 2011; 8: 1837–1846. Di Biase L, Gallinghouse J, Rajappan K, Schilling R, Kautzner J, Mohanty P, et al. Preliminary acute results of robotic catheter ablation of atrial fibrillation utilizing the Lynx robotic catheter system in humans: safety and feasibility. J Cardiovasc Electrophysiol 2011; 22(4): 496–497.

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Case Report Unexpected preserved brain perfusion imaging despite severe and diffuse atherosclerosis of supra-aortic trunks GIUSEPPE GARGIULO, FABIO TORTORA, MARIO CIRILLO, CINZIA PERRINO, GABRIELE GIACOMO SCHIATTARELLA, BRUNO TRIMARCO, GIOVANNI ESPOSITO

Abstract We report an unusual case of a patient whose whole cerebral circulation was supported by poor vicariate collaterals and a severely atherosclerotic right vertebral artery, with no brain perfusion abnormalities. Our belief is that despite the brain imaging and the absence of symptoms, because of his critical vascular disease and the paucity of data from large randomised clinical trials on vertebro-basilar revascularisation, the case required an extremely cautious approach regarding any kind of revascularisation. An accurate imaging analysis together with clinical features allowed us to decide on a strategy based on optimal medical therapy and careful clinical monitoring. Keywords: brain perfusion, atherosclerosis, supra-aortic trunks, imaging Submitted 17/11/12, accepted 5/3/13 Cardiovasc J Afr 2013; 24: e12–e14

www.cvja.co.za

DOI: 10.5830/CVJA-2013-009

Case report A 61-year-old man was admitted to our department for routine cardiological evaluation. He suffered from hypertension, dyslipidaemia, diffuse atherosclerosis with a history of coronary artery bypass graft in 2001 (saphenous vein grafts for a triple-vessel coronary artery disease), percutaneous transluminal coronary angioplasty (PTCA) with stent implantation in the right coronary artery and intermediate branch in 2006, and a history of symptomatic lower extremity arterial disease treated by PTA, with stent implantation on the left external iliac artery in 2009. He was also a heavy smoker.

Division of Cardiology, Department of Clinical Medicine, Cardiovascular Sciences and Immunology, Federico II University, Naples, Italy GIUSEPPE GARGIULO, MD CINZIA PERRINO, MD, PhD GABRIELE GIACOMO SCHIATTARELLA, MD BRUNO TRIMARCO, MD GIOVANNI ESPOSITO, MD, PhD, espogiov@unina.it

Division of Neuroradiology, Department of Neurological Sciences, Second University, Naples, Italy FABIO TORTORA, MD MARIO CIRILLO, MD

He had no severe clinical conditions, being asymptomatic for cerebrovascular symptoms and upper extremity claudication, and with normal blood parameters. Arterial blood pressure was 110/70 mmHg on the right arm and 90/60 mmHg on the left arm, suggesting a possible subclavian steal syndrome. Echo colour Doppler of the supra-aortic trunks (SATs) confirmed this hypothesis. SATs angiography and magnetic resonance angiography (MRA) were then performed, revealing: (1) a significant stenosis of the brachiocephalic artery (BA) at its origin, with a post-stenotic dilatation; (2) a significant stenosis of the right subclavian artery (SA) in its middle tract, beyond the origin of the vertebral artery (VA); (3) a significant stenosis of the right VA at its origin; (4) a proximal occlusion of the right internal carotid artery (ICA); (5) a significant ostial stenosis of the left common carotid artery (CCA); (6) a proximal occlusion of the left ICA; (7) a proximal occlusion of the left SA up to the VA origin; and (8) a sub-occlusive stenosis of the left VA at its origin, with a subclavian steal (Fig. 1A). Therefore, the only patent vessel for brain perfusion was the diseased right VA. A well-developed collateral circulation at the Willis circle was also demonstrated secondary to an arterial flow through the right vertebral artery and a hypertrophic compensation bilaterally of the external carotid artery (Fig. 1B). Surprisingly, cerebrovascular magnetic resonance imaging (MRI) demonstrated regular morphology and appearance of brain parenchyma (Fig. 2A), and regular perfusion with dynamic susceptibility contrast-enhanced MRI (DSCe-MRI) in both anterior and posterior circulation, despite the critical atherosclerotic involvement of the supra-aortic trunks (Fig. 2B). Importantly, coronary–subclavian steal syndrome and myocardial ischaemia1 did not occur in this patient because of the presence of three venous grafts in the coronary arteries rather than a left internal mammary artery anasthomosis. Based on the brain imaging results, the absence of symptoms, and the paucity of data from large randomised clinical trials on vertebro-basilar revascularisation, cerebrovascular revascularisation was excluded. Maximal medical therapy was indicated with aspirin, clopidogrel (we also checked the patient’s sensitivity to clopidogrel by light transmittance aggregometry, resulting in a positive response), rosuvastatin, ramipril and bisoprolol. Furthermore, smoking cessation was strongly suggested. Follow-up visits were performed focusing on accurate anamnesis and physical examinations to search for new signs and symptoms of ischaemia (such as fugax amaurosis, aphasia,

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Fig. 1. A: Volume-rendering reconstruction of contrast-enhanced MRA shows significant stenosis of the brachiocephalic trunk (o), occlusion of the left origin of the subclavian artery (*), thrombosis of the ICA bilaterally (→), and stenosis of both vertebral arteries at the origin of the subclavian artery (>). B: Volume-rendering reconstruction of TOF3D MRA shows regular vessel flow of the proximal and distal tract of the Willis circle, with hypertrophic compensatory posterior communicating arteries (pCoA) bilaterally. The intracavernous tract of the ICA is not visible bilaterally.

anesthesia, hypostenia and plegias, thoracic dolor, dyspnoea episodes, lower-limb claudication), and echo colour Doppler analysis of the SATs. At one-year follow up, the patient was still asymptomatic and in a satisfactory physical condition.

Discussion Atherosclerotic disease represents the leading cause of death and morbidity in industrialised nations. It is a chronic, systemic disease that may involve multiple vascular areas at the same time; not only the coronary arteries, but also the peripheral vessels, particularly the SATs, namely carotid and vertebral arteries in their extra-cranial portions, the lower limbs, renal, hypogastric and mesenteric arteries. The most important impact of atherosclerosis on mortality and morbidity after myocardial ischaemia is due to cerebrovascular disease. Stroke is the third cause of mortality and the leading cause of long-term disability in the Western world. In 80% of cases it is due to cerebral ischaemia, while the haemorrhagic type accounts

Fig. 2. A: Fast-spin echo T2w axial scan shows regular morphology and appearance of brain parenchyma. B: EPI FFE T2* perfusion map shows regular and symmetrical rCBV of the cerebral anterior and posterior circulation. The artifact in the frontal area is due to the patient’s oral prosthesis.

for only 15–20% of the total number of strokes.2,3 Extra-cranial atherosclerotic occlusions account for 15–20% of all ischaemic strokes, while atheromatous lesions of the intracranial vessels are rarely responsible for cerebral infarction. Carotid occlusions are more frequently responsible for the genesis of a stroke, however one-quarter of ischaemic strokes involve the posterior circulation, and stenosis of the VA may account for up to 20% of posterior circulation ischaemic strokes. For all these reasons, treatment of SATs atherosclerosis is crucial to prevent stroke. The mainstay of treatment is the optimisation of medical therapy for primary and secondary prevention of cardiovascular accidents and, if necessary, surgical or endovascular revascularisation. Non-invasive management includes removal and treatment of atherosclerosis risk factors such as smoking, hypertension, dyslipidaemia and diabetes. A significant reduction in mortality from stroke has been demonstrated with anti-hypertensive therapy to values below 140/90 mmHg, statin-based lipid-lowering therapy, and an adequate hypoglycaemia regimen.2-4 Another cornerstone of medical treatment is antiplatelet therapy with aspirin and, in high-risk patients, clopidogrel, dipyridamole and ticlodipine, not only as secondary prevention, but also in patients with evidence of an atherosclerotic occlusion of the carotid or vertebral circulation, with or without ischaemic symptoms. The purpose of this medical approach is to decrease global cardiovascular risk, not only the risk of a cerebrovascular accident. An invasive approach, on the other hand, acts on a specific lesion, restoring the patency of the vascular lumen and reducing the potential hazards due to the presence of an atheromatous plaque such as thrombosis, thrombo-embolism and intra-plaque haemorrhage. With regard to carotid stenosis, the gold standard has for many years been surgical treatment (carotid endarterectomy, CEA), however in the last two decades endovascular stenting of carotid lesions (CAS) has joined surgery as a valid therapeutic alternative, with specific benefits and unfavourable aspects. Recently, the equivalence of these two approaches has been clearly demonstrated in the CREST trial.5

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On the other hand, for the posterior circle, clinical evidence appears more fragmentary. Surgery may be performed, but it brings more difficulties than the ‘simple’ carotid endarterectomy, possibly requiring hard artefacts as extra-anatomical bypasses or the re-implantation of VAs over CCAs. Similarly, there are positive reports on endovascular treatment of these lesions.2,3,6 However, there are no randomised clinical trials reporting on surgery or stenting. With regard to the pathology of SATs, it is not rare to observe bilateral carotid stenosis or the co-existence of obstructions involving both the anterior and posterior circulation. These patients generally have an aggressive form of atherosclerotic disease, due to multiple, severe risk factors and individual predisposition; ischaemic cardiopathy and claudication intermittens are often associated. Management of these clinical patients is critical and is partly assisted by the guidelines. Decision making is complex, many aspects need to be considered (risk factors, feasibility, chance of success, problems and hazards of revascularisation, co-morbidity, life expectancy, patient’s compliance with antiplatelet therapy, etc) and each patient is assessed independently.

References

Conclusions

This was an unusual case of a patient whose cerebral circulation was supported by poor vicariate collaterals and a severe atherosclerotic right vertebral artery, with no brain perfusion abnormalities. We took an extremely cautious approach regarding revascularisation. An accurate imaging analysis together with clinical features allowed us to decide on a strategy based on optimal medical therapy and careful clinical monitoring.

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Karakulak UN, Kose IC, Evranos B, Okutucu S, Hazirolan T, Aytemir K, et al. Multimodality imaging of coronary-subclavian-vertebral steal syndrome. Circulation 2012; 125(2): e241–243. Epub 2012/01/18. Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/ SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Circulation 2011; 124(4): e54–130. Epub 2011/02/02. Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011; 32(22): 2851–906. Epub 2011/08/30. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-todate meta-analysis. Stroke 2004; 35(12): 2902–2909. Epub 2004/10/30. Brott TG, Hobson RW, 2nd, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363(1): 11–23. Epub 2010/05/28. Eberhardt O, Naegele T, Raygrotzki S, Weller M, Ernemann U. Stenting of vertebrobasilar arteries in symptomatic atherosclerotic disease and acute occlusion: case series and review of the literature. J Vasc Surg 2006; 43(6): 1145–1154. Epub 2006/06/13.

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• Management of acute ischaemic stroke