CVJA Volume 24, Issue 9 & 10 by Clinics Cardive Publishing

OCTOBER/NOVEMBER 2013 VOL 24 NO 9/10

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Prevalence and risk factors for hypertension in Nigeria • Coronary anomalies on routine coronary CT scans • Endothelial NOS levels and exercise in slow coronary flow • Vitamin E and antioxidant activity in slow coronary flow • Basilic vein transposition in haemodialysis patients

Cardiovascular Journal of Africa . Vol 24, No 9/10, October/November 2013

Printed by Tandym Printers

• Determinants of obesity in black South African women • ADVANCE cardiovascular risk model in people with diabetes

PUBLISHED ONLINE: • Left ventricular rupture after double valve replacement

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

Vol 24, No 9/10, OCTOBER/NOVEMBER 2013

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial

343 Reflections on a range of cardiovascular issues PA Brink

Cardiovascular Topics

344 Prevalence and risk factors for hypertension and association with ethnicity in Nigeria: results from a national survey GVVS Murthy • S Fox • S Sivasubramaniam • CE Gilbert • AM Mahdi • AU Imam • G Entekume • on behalf of the Nigeria National Blindness and Visual Impairment study group 351 The incidence of coronary anomalies on routine coronary computed tomography scans KO Karabay • A Yildiz • G Geceer • E Uysal • B Bagirtan 355

Endothelial nitric oxide synthase levels and their response to exercise in patients with slow coronary flow H Taşolar • F Eyyüpkoca • E Aktürk • Y Karakuş • M Cansel • J Yağmur • F Özyalın • B Altun • H Pekdemir

360 Vitamin E and antioxidant activity; its role in slow coronary flow VK Celik • İE Eken • G Yildiz • MB Yilmaz • A Gurlek • H Aydin 364

Comparison of one- and two-stage basilic vein transposition for arterio-venous fistula formation in haemodialysis patients: preliminary results S Ozcan • AK Gür • AÜ Yener • D Odabaşi

363

ASSAf recognises top South African scientists

Industry news

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)

Review Articles

369 Socio-cultural, environmental and behavioural determinants of obesity in black South African women LK Micklesfield • EV Lambert • DJ Hume • S Chantler • PR Pienaar • K Dickie • T Puoane • JH Goedecke

Vol 24, No 9/10, OCTOBER/NOVEMBER 2013

CONTENTS

376 The ADVANCE cardiovascular risk model and current strategies for cardiovascular disease risk evaluation in people with diabetes AP Kengne

Case Report

382

Ebstein’s anomaly and Down’s syndrome L Pepeta • S-A Clur

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

e1 Left ventricular rupture after double valve replacement in a patient with myocarditis due to myasthenia gravis M Argiriou • V Patris • N Lama • S Katsaridis • O Argiriou • C Charitos e4

Mini-sternotomy approach for aortic valve replacement in a patient with osteogenesis imperfecta G Dimitrakakis • J Rathod • UO von Oppell • A Pericleous • S Hutchison

e8 Antiphospholipid syndrome in a young Nigerian girl presenting with gangrenous toes RC Anakwue • C Chijioke • A Mbah • A Onuh • C Okwara e12

Kounis syndrome leads to cardiogenic shock K-L Chang • J Chen • J Yu • X-L Dou

managing editor

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

financial & production co-ordinator ELSABÉ BURMEISTER Tel: 021 976 8129 Fax: 086 664 4202 Cell: 082 775 6808 e-mail: elsabe@clinicscardive.com

Production Editor

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CONTENT MANAGER

Michael Meadon (Design Connection) Tel: 021 976 8129 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

GAUTENG CONTRIBUTOR

PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month. Copyright: Clinics Cardive Publishing (Pty) Ltd. Layout: Martingraphix

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343

Editorial Reflections on a range of cardiovascular issues Articles in this issue range from epidemiology and determinants of risk factors for non-communicable diseases, namely, the prevalence of hypertension in Nigeria (Murthy et al., page 344), to obesity in South African woman (Micklesfield et al., page 369) and risk determination of cardiovascular events in persons with diabetes mellitus (Kengne, page 376). Interesting cardiac perfusion abnormalities are addressed in three articles (Tasolar et al., Celik et al. and Chang et al., pages 355, 357, e12), which are complimented by an article on congenital coronary anomalies (Karabay et al., page 351) as detected by CT-scanning. Furthermore, two ways of creating a shunt for renal dialysis purposes using the basilica vein is discussed by Ozcan et al. (page 364). Murthy et al. in a well-designed survey of blindness and visual impairment in Nigeria, piggy-backed hypertension onto the study. They found a prevalence of hypertension of 44.9% in persons over 40 years, which varied across ‘ethnic’ groups, the Kanuri group having the highest prevalence of 77.5%. This begs the question of ethnicity, culture and race, the latter being historically of significant concern in South Africa, and brought to the fore by Micklesfield et al. in a review on factors determining obesity in black South African women. These concepts overlap, however, and there do not appear to be clear definitions. The South Africa government classifies four racial groups, namely, black, white, coloured (mixed ancestry) and Indian. Nevertheless, black African women in South Africa have an obesity prevalence of 31.8%, which is the highest in sub-Saharan Africa. Micklesfield and co-workers discuss the role of various factors, such as socio-cultural, behavioural, maternal and early life, socio-economic status, education, physical activity (or lack thereof), gender, urbanisation, eating behaviour and body image. Genetics, so fashionable currently, certainly does not appear to be a major determinant of obesity.

Kengne grapples with risk prediction in diabetes mellitus (DM); risk prediction that will be valid globally. He describes the ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) study, with which he was intimately involved. Diabetes mellitus is not just another risk factor to be added to other cardiovascular risk factors for cardiovascular disease (CVD), but is, rather, a condition with a gradient of influences. Therefore, a need for DM-specific risk determination is necessary. The ADVANCE study was a multi-centre study of persons with DM and therefore CVD risk, which led to a prediction model that has been both internally and externally validated. Formulae, such as those derived from the Framingham project, tend to overestimate risk in persons with DM. A calculator for calculating CVD risk in DM is available online (http://www. advanceriskengine.com/). Two groups from Turkey (Tasolar et al. and Celik et al.) address the phenomenon of slow coronary flow, an angiographic finding characterised by delayed distal vessel opacification in the absence of significant epicardial coronary disease. One article is about the role of endothelial nitric oxide synthase levels and the response to exercise, while the other is on the role of vitamin E and antioxidant activity in this phenomenon. The case study of Chang et al., published online, is about Kounis syndrome, defined by either cardiogenic shock or an acute coronary syndrome due to vaso-activity triggered by the release of inflammatory mediators following an allergic insult. So, overall, this edition of the journal has an interesting mix of articles with which to conclude 2013. Best wishes for the year to come. PAUL A BRINK, MB ChB, PhD, paul@clinicscardive.com

Department of Internal Medicine, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg

Thank you The Director of Clinics Cardive Publishing, Prof Paul Brink and the editorial team thank the authors, reviewers and all others who contributed to our journal during 2013. May peace, joy, hope and happiness be yours this holiday season and throughout the new year.

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Cardiovascular Topics Prevalence and risk factors for hypertension and association with ethnicity in Nigeria: results from a national survey GUDLAVALLETI VS MURTHY, SAMANTHA FOX, SELVARAJ SIVASUBRAMANIAM, CLARE E GILBERT, ABDULL M MAHDI, ABDULLAHI U IMAM, GABRIEL ENTEKUME, on behalf of the Nigeria National Blindness and Visual Impairment study group

Abstract Background: Non-communicable diseases are now a global priority. We report on the prevalence of hypertension and its risk factors, including ethnicity, in a nationally representative sample of Nigerian adults recruited to a survey of visual impairment. Indian Institute of Public Health, Public Health Foundation of India, Hyderabad, Andhra Pradesh, India

GUDLAVALLETI VS MURTHY, MD, MSc, gvsmurthy1956@gmail.com

International Centre for Eye Health, Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK SAMANTHA FOX, MD, MPH SELVARAJ SIVASUBRAMANIAM, MSc CLARE E GILBERT, MD, MSc, FRCOphth

Methods: A multi-stage, stratified, cluster random sample with probability proportional to size procedures was used to obtain a nationally representative sample of 13 591 subjects aged ≥ 40 years. Of these, 13 504 (99.4%) had a blood pressure measurement. Results: The prevalence of hypertension was 44.9% [95% confidence interval (CI): 43.5–46.3%]. Increasing age, gender, urban residence and body mass index were independent risk factors (p < 0.001). The Kanuri ethnic group had the highest prevalence of hypertension (77.5%, 95% CI: 71.0–84.0%). Conclusions: The high prevalence of hypertension in Nigeria is a cause for concern and suggests that it is inevitable that the impact of hypertension-related ill health is imminent, with the accompanying financial and societal costs to families and the state of Nigeria. Keywords: hypertension, ethnicity, Nigeria, survey

Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria

Submitted 31/1/13, accepted 14/8/13

Ministry of Health, Minna, Niger State, Nigeria

Cardiovasc J Afr 2013; 24: 344–350

ABDULL M MAHDI, FMCOphth, MSc ABDULLAHI U IMAM, DO, MSc

Vision Health Services, Ikeja, Lagos State, Nigeria GABRIEL ENTEKUME, OD

Nigeria National Blindness and Visual Impairment study group: International Agency for Prevention of Blindness, Africa region, Ibadan, Nigeria ABIOSE ADENIKE

Ophthalmology Department, Lions Eye Centre, Isolo General Hospital, Lagos Sate, Nigeria OLUFUNMILAYO O BANKOLE

Ministry of Health Awka, Anambra State, Nigeria C EZELUM

National Eye Centre, Kaduna, Nigeria FATIMA KYARI MANSUR M RABIU

Sight Savers West Africa Regional Office, Accra, Ghana HANNAH FAAL

Institute of Ophthalmology, University College London, London, UK PAK SANG LEE

Ministry of Health, Dutse, Jigawa State Nigeria ABUBAKAR TAFIDA

Published online 11/9/13 www.cvja.co.za

DOI: 10.5830/CVJA-2013-058

Hypertension is increasingly being recognised as an important public health problem in sub-Saharan Africa, with 26.9% of men and 28.4% of women in 2000 being estimated to have hypertension.1 Although lower than the prevalence in highincome countries (37.4% in men and 37.2% in women), in terms of numbers of people affected, the burden of hypertension in low- and middle-income countries is greater due to the large population.1 Hypertension has been recognised as a strong independent risk factor for heart disease and stroke and a predictor of premature death and disability from cardiovascular complications.2 It has been reported that 13.5% of deaths and 6% of disabilityadjusted life years (DALYs) were attributed to hypertension globally, and for low- and middle income people, these figures were 12.9 and 5.6%, respectively over the period 1990 to 2001.3 Although infectious diseases remain the leading cause of mortality and morbidity in sub-Saharan Africa, the prevalence of cardiovascular disease and hypertension is rising rapidly.4 It has been emphasised that urbanisation is a key reason for the increasing rates of hypertension, as evidenced by the higher

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prevalence of hypertension in urban areas.4-6 Urban lifestyles, characterised by sedentary living, increased salt intake, obesity and stress contribute to these differences.5 With the urban population in sub-Saharan Africa projected to increase, a greater risk of hypertension is anticipated. Studies on the association between ethnicity and hypertension in high-income countries have documented a higher prevalence of hypertension in black ethnic groups compared to white ethnic groups.7-9 Reasons for this association are complex, unclear and much debated, reflecting genetic and biochemical mechanisms, and environmental and socio-economic factors.10,11 There is limited evidence regarding differences in the prevalence of hypertension between ethnic groups within the broader classification of black ethnicity.6,12,13 Studies in Nigeria and sub-Saharan Africa have mainly involved specific geographical areas or have focused on sub-groups of the population.5,14 Surveys from Nigeria report prevalence estimates ranging from 20.2 to 36.6%, but all have involved participants with different age ranges.15-18 To plan services for hypertension in Nigeria, it is essential to have accurate prevalence estimates for the whole population and to identify populations at risk. Nigeria, which is the most populous country in sub-Saharan Africa, is home to over 250 different ethnic groups. Nigeria is experiencing rapid urbanisation of the population, which is likely to increase the population at risk for hypertension.19 The present study is one of the largest population-based surveys in the region and is able to provide a nationally representative estimate of hypertension for Nigeria.

Methods As part of the Nigerian national blindness and visual impairment survey of adults aged 40 years and older, data were collected on blood pressure. A detailed description of the sampling, enumeration, visual acuity and ocular examination procedures has been published previously.20 Nigeria is divided into six administrative zones, which are called geo-political zones (GPZ), 36 states and the federal capital territory of Abuja. Each state is subdivided into local government authorities (LGA), which are the smallest administrative unit. There are 774 LGAs in the country. A nationally representative sample was achieved through a multi-stage, stratified (by urban/rural location and GPZ), cluster random sampling with probability proportional to size procedures. A total of 310 clusters were identified, 226 were in rural areas and 84 in urban populations. The sample covered all 36 states. Fifty adults aged 40 years or older, who were normal residents (defined as being continually resident for at least the last three months) were randomly identified in each cluster. These people were identified by the enumeration team who, having found the centre of the cluster, spun a bottle and approached the first household in the direction the bottle pointed. The team, using an established protocol, travelled from house to house to identify eligible adults, until the quota was achieved. If fewer than 50 were identified, the search continued into the next village. Five clusters were not included due to civil unrest or refusal to participate. Basic demographic data and informed consent were taken from each person who agreed to take part. Respondents were invited to attend a clinical station which

345

was set up in each cluster. Enumerated individuals not reporting to the clinical station were followed up three times and offered an examination at their house. If they still did not take part they were deemed non-respondents and were not replaced. At the clinical station, individuals were interviewed to collect data on socio-demographic variables, including ethnic group, and history of disease and medication. All had anthropometric measures taken and their blood pressure was measured prior to ophthalmic examination. Each of the two survey teams had two qualified ophthalmologists and two ophthalmic nurses, who were recruited from each GPZ, so that they would know the main local languages. Hypertension was measured by a qualified ophthalmic nurse trained in the procedure, using an Omron wrist instrument (UB322, Omron Healthcare Ltd, Milton Keynes, England), with the occluding cuff being placed around the volar surface of the wrist. The instrument was calibrated every morning. A total of three readings were taken by a trained nurse, at least five minutes apart after at least 10 minutes’ rest in a sitting position. The nurses’ performance was regularly monitored by the senior investigators. The mean of the three readings was calculated as the individual’s blood pressure. Initial training was undertaken over two weeks and training sessions were repeated for each GPZ (two weeks each). A pilot study was conducted before the field work started in each GPZ. Inter-observer agreement studies were conducted periodically throughout the study for the ophthalmic nurses and the ophthalmologists. Data were collected over a 30-month period from January 2005 to July 2007. Height and weight were measured using a Tanita measurement scale (Model 1536, Tanita Corporation, Tokyo, Japan). The weight measure was calibrated every morning and checked for error using a standard weight. The World Health Organisation’s (WHO) classification of hypertension was used. Hypertension is defined as diastolic blood pressure (DBP) of 90 mmHg or greater, or a systolic blood pressure (SBP) of 140 mmHg or greater. The WHO grading system of hypertension to profile risk was also used. This defines grade 1 hypertension as SBP 140–159 mmHg or DBP 90–99 mmHg; grade 2 as SBP 160–179 mmHg or DBP 100–109 mmHg; and grade 3 as SBP ≥ 180 or DBP ≥110 mm Hg. These grades are used to assess the risk in individuals for a cardiac event in the context of other additional risk factors.21 Body mass index (BMI) was calculated from weight (kg) divided by height (m) squared. World Health Organisation categories of BMI were used in the analysis.22 Socio-economic status (SES) was calculated by assigning one of eight occupational categories, ranging from 0 (not in gainful employment) to 7 (professional), and a grade for the highest level of school attended, from 0 (no schooling) to 4 (university) for each person. The sum of the scores was calculated, with a higher score signifying a more affluent socio-economic status. The ranked SES scores were then divided into tertiles. Data on ethnic group were categorised such that groups with more than 100 participants were analysed separately, with all other ethnic groups combined into an ‘other’ group. Ethnic groups were classified based on the father’s ethnic status. Ethical approval for the study was provided by the London School of Hygiene and Tropical Medicine and the Federal Government of Nigeria. The study adhered to the tenets of the

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Declaration of Helsinki. Written informed consent was obtained from participants after an explanation of the nature of the study.

Statistical analysis A customised database was created in Microsoft Access and two trained data-entry clerks entered the data. Data entered by one operator were checked by the second operator and corrections were made when necessary. Quality assurance procedures included a random verification of filled forms completed in the field and at the project office. The data were cleaned and analysed using a statistical package (Stata 11; StataCorp, College Station, TX). Prevalence estimates together with 95% confidence intervals (CI) for hypertension are presented. Multiple logistic regression analysis was performed to identify risk factors for hypertension and to estimate adjusted odds ratios (OR). All the analyses accounted for clustering (design effect) due to the cluster sampling design adopted for the study. Missing values were excluded from all the analyses; p-values < 0.05 were considered statistically significant.

Results A total of 13 591 people took part in the study, 13 504 (99.4%) of whom had a valid blood pressure measurement. The mean TABLE 1. DEMOGRAPHIC CHARACTERISTICS AND MEAN BLOOD PRESSURE OF THE STUDY POPULATION Parameters surveyed

Frequency (n)

Percent Mean systolic Mean diastolic (%) BP (mmHg) (SD) BP (mm Hg) (SD)

13 504

138.2 (25.9)

age of participants was 55.9 years (± 12.4) (men: 56.8; women: 55.2 years). The mean age of respondents in the south-east geo-political zone was the highest (58.6 ± 12.8 years) and it was the lowest in the north-east zone (53.8 ± 11.6 years). The mean age in the north-west was 54.2 years (± 11.8), in north-central it was 55.8 years (± 12.7), in south-south it was 56 years (± 12.2) and in south-west, 57.8 years (± 11.8). Over 60% of those surveyed were under the age of 60 years. There were more females in the sample (54.1%) than males, and rural respondents constituted 77.6% of the sample (Table 1). Over 50% of the study population belonged to the four most populous ethnic groups in Nigeria: Hausa, Igbo, Yoruba and Fulani. The overall prevalence of hypertension was 44.9% (95% CI: 43.5–46.3%). The prevalence of grade 3 hypertension (the TABLE 2. PREVALENCE OF HYPERTENSION AND ASSOCIATION WITH SOCIO-DEMOGRAPHIC FACTORS Hypertension Hypertension Any grade 2 and 3 grade 3 hypertension SBP ≥ 140, SBP ≥ 160, SBP ≥ 180, DBP ≥ 90 mmHg DBP ≥ 100 mmHg DBP ≥ 110 mmHg %

95% CI

44.7 43.5–46.3 22.0 20.9–23.2

9.9

9.2–10.6

40–49 (4 858)

32.1 30.2–33.9 12.8 11.6–14.1

5.4

4.6–6.2

50–59 (3 554)

47.1 44.9–49.2 23.4 21.5–25.2 10.3

9.1-11.4

60–69 (2 758)

54.2 52.1–56.3 28.4 26.6–30.3 12.8 11.5–14.1

70–79 (1 643)

57.1 54.2–59.9 31.2 28.7–33.6 14.9 13.0–16.8

≥ 80 (691)

58.2 54.4–61.9 32.9 29.4–36.3 15.9 13.1–18.7

Parameters (n) All ages (13 504)

95% CI

Age group (years)

83.9 (15.3)

Age groups (years)

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p < 0.0001

Gender

40–49

4 858

36.0

130.2 (21.8)

81.9 (14.2)

Male (6 203)

42.6 40.9–44.4 19.2 17.8–20.5

50–59

3 554

26.3

139.3 (26.0)

85.1 (15.4)

Female (7 301)

46.8 45.3–48.4 24.5 23.1–25.9 11.1 10.1–12.0

60–69

2 758

20.4

144.0 (27.0)

85.2 (15.8)

70–79

1 643

12.2

146 (27.6)

84.4 (16.3)

691

5.1

146.3 (28.6)

84.4 (16.6)

≥ 80 Gender Male

6 203

45.9

136.8 (24.6)

83.4 (15.0)

Female

7 301

54.1

139.3 (27.0)

84.2 (15.6)

Rural

10 478

77.6

137.2 (25.5)

83.1 (15.0)

Urban

3 026

22.4

141.6 (27.1)

86.6 (16.1)

Residence

Literacy Literate

5 891

43.6

136.4 (25.1)

83.7 (15.3)

Illiterate

7 613

56.4

139.5 (26.5)

84.0 (15.3)

Geo-political zone

p < 0.0001

8.5

7.7–9.3

p < 0.0001

Residence Rural

43.0 41.3–44.6 20.5 19.2–21.8

Urban

51.6 48.4–54.9 27.3 24.5–30.2 12.8 10.9–14.8 p < 0.0001

p < 0.0001

9.1

8.3–9.8

p < 0.0002

Literacy Literate (5 891)

42.0 40.0–43.9 19.9 18.4–22.2

8.9

7.9–9.8

Illiterate (7 613)

47.2 45.5–48.9 23.6 22.2–25.1 10.7

9.8–11.6

p < 0.0001

p < 0.001

Geopolitical zone North-east (1 707)

60.5 55.1–65.8 33.5 28.7–38.2 16.5 13.1–20.0

South-east (1 657)

41.0 38.0–44.0 20.7 18.4–23.0

9.9

South-south (1 845)

34.2 31.2–37.2 17.0 14.6–19.4

7.0

5.4–8.7

North-west (3 577)

51.5 48.7–54.2 24.2 21.6–26.8 10.1

8.5–11.6

South-west (2 708)

40.1 37.1–43.2 19.7 17.4–22.0

9.2

7.9–10.5

North-central (2 010)

39.5 35.7–43.3 17.4 14.8–19.9

7.6

6.2–8.9

8.3–11.5

North-east

1 707

12.6

144.4 (27.7)

90.4 (16.5)

South-east

1 657

12.3

138.4 (28.0)

79.0 (14.8)

South-south

1 845

13.7

133.1 (25.9)

77.9 (14.8)

North-west

3 577

26.5

140.3 (24.3)

87.5 (13.7)

South-west

2 708

20.1

137.1 (26.4)

81.9 (15.0)

North-central

2 010

14.9

135.0 (23.4)

83.9 (14.5)

39.2 37.4–41.0 18.0 16.7–19.3

7.7

6.8–8.6

4 383

32.5

135.2 (24.5)

82.5 (14.7)

Moderately affluent (4 676) 43.5 41.4–45.5 20.0 18.5–21.6

8.8

7.8–9.8

Least affluent (4 445)

Moderately affluent

4 676

34.6

137.2 (25.4)

82.9 (14.9)

Least affluent

4 445

32.9

142.1 (27.4)

86.3 (16.1)

p < 0.0001

Socio-economic status Affluent (4 383)

Socio-economic status Most affluent

p < 0.0001

52.1 49.9–54.2 28.1 26.1–30.1 13.3 11.8–14.7 p < 0.0001

p < 0.0001

Body mass index (13 352)

Body mass index Underweight

1 495

11.1

134.3 (25.9)

81.2 (15.8)

Underweight (1 495)

39.6 36.6–42.6 18.7 16.5–21.0

8.5

6.9–10.1

Normal

8 156

60.4

136.1 (25.1)

82.7 (14.9)

Normal (8 156)

41.7 40.1–43.2 19.5 18.3–20.7

8.5

7.7–9.3

Overweight

2 588

19.2

142.3 (26.1)

86.4 (15.2)

Overweight (2 588)

50.9 48.7–53.2 26.0 24.0–28.0 11.9 10.5–13.3

Obese

1 113

8.2

147.9 (27.5)

89.8 (15.4)

Obese (1 113)

59.8 56.3–63.2 34.2 31.1–37.4 16.2 13.9–18.4

152

1.1

Missing data

p < 0.0001

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TABLE 3. ASSOCIATION BETWEEN HYPERTENSION AND SPECIFIC RISK FACTORS (UNIVARIATE ANALYSIS) Any hypertension SBP ≥ 140, DBP ≥ 90 mmHg Parameters OR

Grade 2 and 3 hypertension SBP ≥ 160, DBP ≥ 100 mmHg

95% CI p-value OR

95% CI

TABLE 4. ASSOCIATION BETWEEN HYPERTENSION AND SPECIFIC RISK FACTORS IN MULTIVARIATE ANALYSIS*

Grade 3 hypertension SBP ≥ 180, DBP ≥ 110 mmHg

p-value OR

95% CI

347

p-value

Age group (years)

Any hypertension SBP ≥ 140, DBP ≥ 90 mmHg Parameters OR

Grade 2 and 3 hypertension SBP ≥ 160, DBP ≥ 100mmHg

Grade 3 hypertension SBP ≥ 180, DBP ≥ 110 mmHg

95% CI p-value OR

1.00

0.001 1.00

95% CI

p-value

Age groups (years) 1.00

1.00

< 0.001

40–49

1.00

40–49

1.00

50–59

1.88 1.71–2.07 < 0.001 2.08 1.84–2.34 < 0.001 1.99 1.67–2.38 < 0.001

50–59

2.07 1.88–2.29 < 0.001 2.24 1.99–2.54 < 0.001 2.08 1.73–2.49 < 0.001

60–69

2.51 2.27–2.77 < 0.001 2.70 2.39–3.06 < 0.001 2.55 2.13–3.06 < 0.001

60–69

3.24 2.93–3.58 < 0.001 3.39 2.99–3.84 < 0.001 2.99 2.48–3.61 < 0.001

70–79

2.82 2.47–3.22 < 0.001 3.08 2.65–3.59 < 0.001 3.05 2.50–3.72 < 0.001

70–79

3.91 3.41–4.49 < 0.001 4.10 3.51–4.80 < 0.001 3.80 3.06–4.72 < 0.001

≥ 80

2.95 2.49–3.49 < 0.001 3.33 2.79–3.98 < 0.001 3.29 2.60–4.18 < 0.001

≥ 80

4.24 3.51–5.13 < 0.001 4.63 3.79–5.65

4.20 3.24–5.44

Male

1.00

Female

1.26 1.16–1.37 < 0.001 1.44 1.31–1.58 < 0.001 1.36 1.18–1.56 < 0.001

Gender

Male

1.00

Female

1.19 1.10–1.27 < 0.001 1.37 1.26–1.49 < 0.001 1.33 1.18–1.50 < 0.001

1.00

Residence

Rural

1.00

Urban

1.42 1.21–1.66 < 0.001 1.46 1.23–1.73 < 0.001 1.48 1.20–1.82 < 0.001

1.00

Literacy

1.00

Urban

1.31 1.14–1.49 < 0.001 1.32 1.12–1.54 < 0.001 1.33 1.10–1.6 < 0.003

1.00

North-east 3.81 2.94–4.92 < 0.001 3.14 2.40–4.1 < 0.001 3.16 2.24–4.45 < 0.001

1.00

Illiterate

1.23 1.13–1.35 < 0.001 1.24 1.12–1.38 < 0.001 1.23 1.09–1.40 < 0.001

1.00

Geo-political zones North-east 2.94 2.27–3.81 < 0.001 2.46 1.87–3.24 < 0.001 2.61 1.84–3.71 < 0.001 South-east 1.34 1.11–1.60

0.002 1.28 1.03–1.59 1.00

0.029 1.45 1.07–1.96

0.017

outhS south

1.00

Northwest

2.04 1.72–2.42 < 0.001 1.56 1.25–1.95 < 0.001 1.48 1.10–2.0

0.011

Southwest

1.29 1.07–1.55

0.006 1.20 0.96–1.51

0.108 1.33 0.99–1.78

0.056

Northcentral

1.26 1.02–1.54

0.03 1.03 0.80–1.32

0.824 1.08 0.79–1.48

0.635

1.00

Socio-economic status 1.00

1.00

oderate- 1.19 1.08–1.32 < 0.001 1.14 1.02–1.28 M ly affluent east L affluent

Rural

Geo-political zones

Literate

Affluent

1.00

1.00 0.025 1.15 0.98–1.35

0.084

1.69 1.52–1.87 < 0.001 1.78 1.58–2.01 < 0.001 1.83 1.55–2.15 < 0.001

Body mass index (13 352) nderU weight

0.92 0.81–1.04

Normal

1.00

0.163 0.95 0.83-1.10 1.00

0.489 1.00 0.82-1.22

0.998

1.00

verO weight

1.45 1.32–1.6 < 0.001 1.45 1.30–1.62 < 0.001 1.45 1.27–1.66 < 0.001

Obese

2.08 1.78–2.43 < 0.001 2.15 1.85–2.50 < 0.001 2.08 1.73–2.50 < 0.001

most severe grade) was 9.9% (95% CI: 9.2–10.6%) (Table 2). Among the 6 064 respondents who were diagnosed as having any hypertension, only 14.1% (854) knew previously that they were hypertensive. Among the 2 975 respondents who were observed to have grade 2 or 3 hypertension, 19.8% (588) were aware of their hypertension status. The prevalence of hypertension increased with age, ranging from 32.1% in 40–49 year olds to 58.2% in those aged ≥ 80 years (Table 3). The prevalence was higher in females (46.8%) and in urban participants (51.6%). The prevalence was also higher among illiterate respondents (47.2%). There was a wide variation in prevalence according to GPZ, the lowest being in the southsouth GPZ (34.2%), and highest in the north-east GPZ (60.5%). The prevalence of hypertension increased from the most affluent (39.2%) to the least affluent (52.1%). The prevalence of hypertension also increased with BMI category; 39.6% of those who were underweight had hypertension compared with 59.8%

South-east 1.27 1.06–1.53

0.012 1.21 0.97–1.5 1.00

0.094 1.35 1.00–1.82

0.053

Southsouth

1.00

Northwest

2.53 2.14–2.98 < 0.001 1.89 1.52–2.36

0.001 1.74 1.29–2.34 < 0.001

outhS west

1.16 0.98–1.38

0.090 1.07 0.86–1.33

0.536 1.20 0.90–1.59

0.208

Northcentral

1.29 1.05–1.58

0.016 1.04 0.81–1.03

0.766 1.07 0.79–1.46

0.644

Socio-economic status Affluent

1.00

Moderate- 0.97 0.88–1.06 ly affluent

0.473 0.91 0.81–1.03

0.130 0.94 0.80–1.11

0.467

Least affluent

0.128 1.14 1.00–1.29

0.056 1.17 0.99–1.39

0.063

Underweight

0.68 0.60–0.77 < 0.001 0.69 0.60–0.8 < 0.001 0.74 0.61–0.9

0.003

Normal

1.00

Overweight

1.69 1.53–1.86 < 0.001 1.63 1.46–1.82 < 0.001 1.59 1.39–1.82 < 0.001

Obese

2.61 2.23–3.05 < 0.001 2.53 2.16–2.97 < 0.001 2.35 1.92–2.87 < 0.001

1.09 0.97–1.22

Body mass index (13 352)

1.00

*Literacy was excluded from the multivariate model as it was associated with socioeconomic status.

in those who were obese. The same trends were noted with grades 2 and 3, and grade 3 hypertension. With univariate analysis, age, female gender, living in an urban area and being illiterate were strongly associated with all grades of hypertension (p < 0.001) (Table 3). Using the southsouth GPZ as the baseline, associations with GPZ were more variable. Socio-economic status was inversely associated with hypertension (p < 0.001); the odds ratio of hypertension were inversely associated with affluence. Compared with those with a normal BMI, being overweight, obese or underweight were all associated with hypertension. Multivariate analysis was undertaken using the same set of variables, excluding literacy due to its correlation with the measure of SES (Table 4). In this analysis, older age, female gender, urban area of residence and high and low BMI were independently associated with hypertension at the p < 0.001 level, with the same trends within categories as in the univariate analysis. Findings with regard to GPZ showed that in relation to the south-south,

348

participants living in all other GPZs had a significantly higher odds ratio of hypertension, apart from those in the south-west. Ethnicity data were missing for 58 participants and they were excluded from this analysis. The prevalence of hypertension varied by ethnic group, with the highest prevalence being in the Kanuri group (77.5%) and lowest in the Gbagyi group (25.9%) (Table 5). Adjusting for age, gender, place of residence and socio-economic status, the Kanuri, Nupe, Tiv, Fulani, Anang, Hausa and Edo ethnic groups had statistically significantly greater odds ratios of hypertension than the ‘other’ group. The Yoruba group had statistically significantly lower odds ratios of hypertension than the ‘other’ group.

Discussion The prevalence of hypertension reported in this survey was higher than in other smaller studies carried out in Nigeria, where the prevalence ranged from 20.2 to 36.6%.15,23-26 However the age range of respondents as well as definitions and methods used differed between studies. A systematic review of published data from 43 studies in Nigeria found that the prevalence of hypertension ranged between 8 and 46.4% depending on the study population and definitions used.16 A number of recent large surveys in sub-Saharan Africa reported the prevalence of hypertension to range from 19 to 50.1%,6,12,27-34 and a recent systematic review of surveys from the region confirms the wide variation in prevalence estimates.5 Prevalence of hypertension reported from different studies in Africa shows that Nigeria has a high prevalence rate for hypertension (Table 6). Some of the variation can be explained by methodological differences (e.g. some have focused on only rural populations) but variation in the age groups studied is likely to be a major factor. A limitation of our study was the non-availability of data on the use of anti-hypertensive medication in the present study. However, studies in Nigeria and other sub-Saharan African countries report that use of hypertensive medication was very TABLE 5. ALL GRADES OF HYPERTENSION AMONG THOSE AGED ≥ 40 YEARS IN NIGERIA, BY ETHNIC GROUP

Ethnic group

PrevaMean age ± lence SD (years) (%)

95% CI

Adjusted OR

95% CI

p-value

2 024 54.7 ± 12.1

41.5

37.5–45.5

Kanuri

333 54.4 ± 11.7

77.5

71.0–84.0

3.51

2.33–5.29 < 0.001

Nupe

208 53.9 ± 10.8

50.5

43.9–57.1

1.85

1.14–3.0

Other group

0.01

Tiv

342 55.9 ± 13.7

44.4

37.7–51.2

1.65

1.14–2.38

0.01

Igebe

143 54.8 ± 12.1

37.8

24.8–50.7

1.64

0.97–2.77

0.06

Fulani

832 54.1 ± 11.3

54.6

49.4–59.7

1.47

1.11–1.95

0.01

Ibibio

210 52.6 ± 11.5

38.6

30.1–47.0

1.45

0.99–2.13

0.06

Anang

132 54.2 ± 11.1

34.1

27.5–40.6

1.45

1.06–1.98

0.02

Hausa

3 361 54.4 ± 11.9

52.4

49.5–55.2

1.42

1.14–1.76 < 0.001

183 55.6 ± 12.9

41.5

33.5–49.6

1.38

0.83–2.30

Igala

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 9/10, October/November 2013

0.22

Edo

218 56.6 ± 12.4

39.0

35.8–42.2

1.32

1.01–1.72

0.05

Igbirra

163 56.7 ± 13.9

42.3

36.4–48.2

1.22

0.83–1.8

0.30

Ijaw

251 58.3 ± 12.9

39.4

28.8–50.1

1.07

0.69–1.67

0.75

Igbo

2 017 57.5 ± 12.7

40.4

37.6–43.1

1.04

0.77–1.40

0.78

Ekoi

103 57.3 ± 11.0

31.1

27.1–35.0

1.04

0.79–1.36

0.80 0.81

Urhobo

266 57.9 ± 13.4

36.1

27.1–45.0

0.94

0.58–1.53

Yoruba

2 525 58.5 ± 12.4

39.3

36.4–42.1

0.79

0.63–0.99

0.04

Gbagyi

135 54.8 ± 14.3

25.9

18.3–33.6

0.73

0.42–1.26

0.26

*Adjusted for age, gender, place of residence and socio-economic status.

low,5,13,23,27,32 and so this is unlikely to have significantly impacted on our prevalence estimate or the findings of association in the present study. If there was any bias, our estimate would be an under-estimate. We observed that women had a higher prevalence of hypertension than men in Nigeria. This corroborates the findings of many,4,5,24,27,35 but not all studies in Africa.28,32,34 A unique feature of the present study is that it provides estimates of the prevalence of hypertension among indigenously resident ethnic groups at a national level. Only one other study examined the association of ethnicity with hypertension in Nigeria but it was limited to one region of the country.15 Some evidence of ethnic variation has been reported in Kenya where statistically significant differences between ethnic groups were reported after adjusting for socio-demographic and TABLE 6. ESTIMATES OF HYPERTENSION FROM POPULATION-BASED STUDIES IN SUB-SAHARAN AFRICA

Author (year) Place of study

Age Sample range size (years)

Present study

Nigeria, nationwide

13 504

Isezuo et al.18 (2011)

Nigeria (rural and urban)

Oladapo et al.19 (2010)

Prevalence Prevalence (definition 1) (definition 2) (%) (%)

40+

45.9*

782 15–65

24.5

Nigeria (rural)

2 000 18–64

20.8

Adedoyin et al.20 (2008)

Nigeria (semi-urban)

2 097

20+

36.6*

Omuemu et al.21 (2007)

Nigeria (rural)

590

15+

20.2*

Olatunbosun et al.29 (2000)

Nigeria, (urban)

998 16–70

Cooper et al.13 (1997)

Nigeria (rural and urban)

1 171

25+

Andy et al.15 (2012)

Nigeria (rural)

3 869

15+

23.6

Ogah et al.18 (2013)

Nigeria (rural)

2 999

18+

31.8

Ekpenyong et al.38 (2010)

Nigeria (rural)

2 780

18-60

Maher et al.25 (2011)

Uganda (rural)

6 678

All

22.5*

De Ramirez et Malawi, Rwanda, Tanzania (rural) al.12 (2010)

1 485

18+

Mathenge et al.6 (2010)

Kenya (rural and urban)

4 396

50+

50.1

Damasceno et al.23 (2009)

Mozambique (rural and urban)

3 323 25–64

33.1

3 173 25–64

1 015

25+

30.3

2 559

15+

20.8

13 802

15+

23.9

5 369

15+

70+

69.9

Tesfaye et al.26 Ethiopia (urban) (2009) Addo et al.27 (2008)

Ghana (urban)

Kengne et al.28 Cameroon (urban) (2007) Steyn et al.24 (2001)

South Africa, nationwide

Gambia Van der Sande22 (2000) Dewhurst et al.39 (2011)

Tanzania (rural Hai)

2 223

Houinato et al.40 (2008)

Benin

6 853 25–64

Nigeria, Kenya Hendriks et al.41 (2009–11) (rural), Tanzania, Namibia (urban)

7 568

18+

24.3*

10.4 14.5*

27.9 Nigeria: 19.3 Kenya: 21.4 Tanzania: 23.7 Namibia: 38

*Medication details not available Definition 1: Diastolic BP 140 mmHg ≥ or SBP ≥ 90 mmHg Definition 2: Diastolic BP 160 mmHg ≥ or SBP ≥ 95 mmHg

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 9/10, October/November 2013

other cardiovascular risk factors,6 but a study from Nigeria and Cameroon did not find any association of hypertension with ethnicity.13 A review of existing studies to estimate the prevalence of hypertension in 11 sub-Saharan African countries found clear differences by country, which the authors suggested may be partly explained by ethnicity and other socio-demographic factors.14 The very high prevalence of hypertension among some ethnic groups such as the Kanuri in Nigeria needs further investigation as this ethnic group is concentrated in one localised region of the country. Our results show that the prevalence of hypertension in Nigeria is similar to that in high-income countries and is therefore a public health challenge. A review of published studies from Nigeria observed that the pooled prevalence of hypertension increased from 8.6% over the period 1970–1979 to 22.5% over the period 2000–2011.16 A national survey on non-communicable diseases in Nigeria documented that the prevalence of hypertension using a cut-off value of 160/95 mmHg was 11.2% (age-adjusted prevalence was 9.3%).36 The observed trend shows that Nigeria is at high risk of a significant increase in rates of hypertension in the near future. Recent evidence documents that hypertension is the commonest condition seen at medical centres in Nigeria.37 This has implications on mortality of people during the productive years of their lives. A study by Ekpenyong et al. estimated that five million Nigerians would die of non-communicable diseases (NCDs) in Nigeria alone.38 A significant proportion of these deaths may be contributed to by hypertension.

Conclusion The increase in NCDs in sub-Saharan Africa will mean that additional resources will be required for the detection and control of NCDs, which would compete with the resources being allocated for the control of communicable diseases, such as the neglected tropical diseases, malaria and HIV. Strategies and interventions will also be required to improve adherence to life-long medication. It is inevitable that hypertension and its consequences will lead to financial and societal costs to families and the states in sub-Saharan Africa and governments will need to respond to this emerging challenge. The authors thank the Federal Ministry of Health, state governments and the local government authorities in Nigeria for providing accommodation to the survey teams and other administrative and logistical support during the survey. We also thank Dr Brendan Dineen for his epidemiological input, members of the technical advisory group, Mrs Oye Quaye for managing the finances, Auwal Shehu and Dania Charles for data entry, the teams of ophthalmologists, ophthalmic nurses, enumerators, interviewers, liaison officers, drivers and cooks, Mr Pak Sang Lee for technical support, and the staff in the Sightsavers country office for their financial, managerial and administrative support, without which this survey could not have been undertaken. Financial support was provided by Sightsavers International, UK (http:// www.sightsavers.org/), Velux Stiftung, Germany (http://www.veluxstiftung. ch/home/index.php) and CBM, Germany (http://www.cbm.org/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The grant code of the London School of Hygiene and Tropical Medicine was ITCRBY61 (The grant closed in 2010).

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Birthday wishes The newly appointed director of Clinics Cardive Publishing, Prof Paul Brink, celebrated his 60th birthday in October. This milestone was celebrated with a

The Brink family

theme party ‘a trip down memory lane’. The guests dressed up for the occasion and much fun was had by all. While enjoying the fruits of his labours

so far, at this turning point in his life, we also wish Prof Brink great success for the future in his new endeavours. The editorial team

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The incidence of coronary anomalies on routine coronary computed tomography scans KANBER OCAL KARABAY, ABDULMELIK YILDIZ, GURKAN GECEER, ENDER UYSAL, BAYRAM BAGIRTAN

Abstract Objective: This study aimed to assess the incidence of coronary anomalies using 64-multi-slice coronary computed tomography (MSCT). Methods: The diagnostic MSCT scans of 745 consecutive patients were reviewed. Results: The incidence of coronary anomalies was 4.96%. The detected coronary anomalies included the conus artery originating separately from the right coronary sinus (RCS) (n = 8, 1.07%), absence of the left main artery (n = 7, 0.93%), a superior right coronary artery (RCA) (n = 7, 0.93%), the circumflex artery (CFX) arising from the RCS (n = 4, 0.53%), the CFX originating from the RCA (n = 2, 0.26%), a posterior RCA (n = 1, 0.13%), a coronary fistula from the left anterior descending artery and RCA to the pulmonary artery (n = 1, 0.13%), and a coronary aneurysm (n = 1, 0.13%). Conclusions: This study indicated that MSCT can be used to detect common coronary anomalies, and shows it has the potential to aid cardiologists and cardiac surgeons by revealing the origin and course of the coronary vessels. Keywords: coronary artery anomaly, coronary CT angiography, coronary artery fistula, coronary aneurysm, myocardial bridging Submitted 2/4/13, accepted 4/9/13 Published online 11/9/13 Cardiovasc J Afr 2013; 24: 351–354

www.cvja.co.za

DOI: 10.5830/CVJA-2013-066

The incidence of coronary anomalies (CCAs) in a typical angiographic study was 1.3%.1 Studies have been conducted on CCAs using conventional invasive coronary angiography in highly selected groups of patients but these studies may not reflect the true incidence of CCAs. Although the majority of CCAs are benign and incidentally detected during conventional angiography, certain CCAs may cause syncope, heart failure or sudden death, especially among young athletes.2,3 The US National Registry of Sudden Death in Department of Cardiology, Kadikoy Florence Nightingale Hospital, Istanbul, Turkey KANBER OCAL KARABAY, MD, ocalkarabay@hotmail.com

Department of Cardiology, Avrupa Safak Hospital, Istanbul, Turkey ABDULMELIK YILDIZ, MD BAYRAM BAGIRTAN, MD

Department of Radiology, Kadikoy Florence Nightingale Hospital, Istanbul, Turkey GURKAN GECEER, MD

Department of Radiology, Sisli Etfal Research and Training Hospital, Istanbul, Turkey ENDER UYSAL, MD

Athletes at the Minneapolis Heart Institute Registry found that CCAs were the second most common cause of sudden cardiac death (out of 17% of the population who died of cardiac-related causes).4 Although conventional invasive coronary angiography is considered the gold standard for the diagnosis of CCAs, transthoracic two-dimensional echocardiography, transoesophageal echocardiography, magnetic resonance imaging and multi-slice computed tomography (MSCT) can all identify for diagnosis, CCAs in certain groups of patients.5-10 Transthoracic twodimensional echocardiography may depict the origin of the coronary arteries, especially the left main artery, but successful detection of coronary anomalies depends on the age and size of the patient.5,6 Transoesophageal echocardiography has an increased success rate of identifying coronary anomalies in comparison with two-dimensional echocardiography. Nevertheless, the position of the transducer, cardiac motion, and the curvilinear course of the vessel all affect visualisation of coronary anomalies. Moreover, transoesophageal echocardiography is a semi-invasive method and is time consuming.6,7 Magnetic resonance (MR) imaging provides an accurate assessment of the course of anomalous coronary arteries.8,9 However, this technique cannot be performed in patients with pacemakers, certain types of arrhythmias or defibrillating devices, and it may be difficult to perform in claustrophobic patients. Furthermore, the spatial resolution of MR imaging is substantially inferior to that of the newest generation of CT scanners.10 Myocardial bridging (MB) is defined as the compression of a coronary artery during systole while it is normal in diastole. MB has been linked to serious cardiac events.11 The incidence of myocardial bridging in the population varies substantially according to invasive coronary angiography (13%) and autopsy (15–85%).12,13 The reported incidence of MB has increased up to 44% when using 64-MSCT.14 Because of its ability to cause serious cardiac events, diagnosing MB is clinically important. MSCT is a minimally invasive method that provides excellent temporal and spatial resolution of the coronary arteries. There have been a limited number of studies evaluating CCAs and MB with 64-MSCT. The aim of this study was to assess the incidence of CCAs and MB using 64-MSCT in a relatively large population.

Methods Our institutional ethics committee approved the study protocol. Two experienced radiologists and three invasive cardiologists who were familiar with CCA retrospectively interpreted 745 diagnostic scans of 745 consecutive patients taken between July 2007 and December 2011 at Istanbul Kadikoy Florence Nightingale Hospital. Previous reports were not used.

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Exclusion criteria were severe arrhythmia, previous serious allergic reaction to the contrast medium, pregnancy, and renal and respiratory failure. None of the patients had repeat CT scans. The indications for MSCT scans included the presence of chest pain, abnormal stress testing, the presence of ischaemia on non-invasive tests, coronary artery disease screenings and the determination of patency of bypass grafts or stents. Patients received a 50- to 100-mg oral dose of metoprolol one hour prior to the scan, with additional intravenous (IV) metoprolol administered immediately prior to the scan if necessary. The target heart rate (HR) was less than 70 beats per minute, under close cardiac monitoring for heart rate and blood pressure. If necessary, oral alprazolam (0.5–1 mg) was administered 60 min prior to the procedure. All patients received sublingual isosorbide dinitrate immediately prior to starting the scan protocol. Computed tomography coronary angiography was carried out using a 64-MSCT scanner (General Electric Light Speed VCT scanner, Waukesha, WI, USA) after IV injection of 80 ml of non-ionic contrast medium (Iopamiro 370; Bracco, Milan, Italy) as a bolus dose at a rate of 6 ml/s with retrospective ECG gating. The scan field was extended from the proximal aorta to the cardiac apex. The imaging parameters were as follows: detector collimation of 64 × 0.625 mm, tube voltage 120 kV, current 500–800 mA, gantry rotation time 350 ms, pitch 0.20, and slice thickness 0.625 mm. Retrospective ECG-gated images were obtained during one held breath. These images were evaluated with multiplanar reconstruction, maximum-intensity projection and threedimensional volume-rendering methods. The 75% phase during diastole was found to be optimal for the analysis of anomalies of the left coronary arteries. The right coronary artery (RCA) was evaluated at either the 45 or 75% phase of the cardiac cycle, depending on which phase presented the least amount of motion.

Results Of the 745 patients, 276 were female and 449 were male. The mean age was 54.9 ± 11.3 years. The indications for MSCT scans included the presence of chest pain (n = 250, 33.5%), or ischaemia on non-invasive tests (ECG, treadmill stress test or myocardial perfusion scintigraphy) (n = 153, 20.5%), coronary artery disease screenings (n = 220, 29.5%), and the determination of patency of bypass grafts (n = 76, 10.2%) or stents (n = 46, 6.1%). The incidence of diabetes, hypertension, hyperlipidaemia, family history and smoking were 14.7, 34.4, 34.7, 9.3 and 23.2%, respectively. The patients’ characteristics are shown in Table 1. Six patients with CCAs, and 16 with MB had atypical chest TABLE 1. PATIENTS’ CHARACTERISTICS* Characteristics Number Female 276 Male 449 Hypertension 257 Hyperlipidaemia 258 Diabetes 110 Smoking 173 Prior stenting 46 Prior bypass 76 *Median age ± SS = 54.9 ± 11.3 years.

% 37 60.2 34.4 34.6 14.7 23.2 6.1 10.2

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pain and dyspnoea. None of the patients with CCAs or MB suffered from syncope. Right dominance was observed in 563 patients (75.5%), balanced dominance in 110 (14.7%), and left dominance in 72 patients (9.6%). We identified 176 patients who had evidence of either a coronary anomaly (4.42%, n = 33) or myocardial bridging (19.1%, n = 143) (Table 2). The majority of patients with coronary anomalies were male (63.63%, n = 21). The patients with detected coronary anomalies included eight with the conus artery originating separately from the right coronary sinus (RCS) (1.07%), seven with absence of the left main artery (0.93%), seven with a superior right coronary artery (RCA) (0.93%), four with the circumflex artery (CFX) arising from the RCS (0.53%), two with the CFX originating from the RCA (0.26%), one with a posterior origin of the RCA (0.13%), one with a coronary fistula from the left anterior descending artery and RCA to the pulmonary artery (0.13%), and one with a coronary artery aneurysm (0.13%). Atherosclerosis was observed in four patients with an anomalous CFX arising from the RCA and five with a superior RCA. The other patients with coronary anomalies did not have any atherosclerosis. Of the six patients with anomalous origins of the CFX from either the RCA or RCS, three patients had mild atherosclerosis in all the coronary arteries including the anomalous CFX, one had atherosclerosis in only the anomalous CFX, and one had atherosclerosis in the other vessels but not in the anomalous CFX. One patient with an anomalous CFX did not have any atherosclerosis in any coronary artery. Four patients with a superior RCA had atherosclerosis in the anomalous and normal vessels, and one had atherosclerosis in only the superior RCA. One patient with a superior RCA origin had atherosclerosis in the normal originating coronary arteries but not in the anomalous RCA. One patient had no atherosclerosis in any of the vessels. One patient with a superior origin had a history of stenting, both in the superior RCA and the left anterior descending (LAD) artery. One patient with a posterior RCA had no atherosclerosis in the anomalous or normal vessels or the coronary arteries. Myocardial bridging was mostly observed in the LAD (93.7%, n = 134), intermediate artery (1.39%, n = 2), obtuse margin artery (1.39%, n = 2), first diagonal artery (0.6%, n = 1), second diagonal artery (0.6%, n = 1) and RCA (0.6%, n = 1). In total, myocardial bridging was observed in 19.1% of the patients (n = 143) (Table 3).

TABLE 2. CORONARY ANOMALIES Number Incidence (%) Anomalies (%) Benign anomalies CA from RCS 8 1.07 24.24 Absence of LMA 7 0.93 21.21 Posterior RCA 1 0.13 3.03 Potentially clinically significant anomalies Superior RCA 7 0.93 21.21 CFX from RCS 4 0.53 12.12 CFX from RCA 2 0.26 6.06 Coronary fistula 1 0.13 3.03 Coronary aneurysm 1 0.13 3.03 CA: conus artery; RCS: right coronary sinus; LM: left main artery; RCA: right coronary artery.

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TABLE 3. MYOCARDIAL BRIDGING Number Incidence (%) Anomalies (%) LAD 134 17.98 93.70 IM 2 0.26 1.39 OM1 2 0.26 1.39 OM2 1 0.13 0.69 D1 1 0.13 0.69 D2 1 0.13 0.69 RCA 1 0.13 0.69 LAD: left anterior descending artery; IM: intermediary artery; OM1: first obtuse margin artery; OM2: second obtuse margin artery; D1: first diagonal artery; D2: second diagonal artery; RCA: right coronary artery sinus; MB: myocardial bridging.

Discussion In this study, the CCAs identified were mostly benign and mostly found in asymptomatic patients. Coronary anomalies are the second most common cause of sudden death in young adults.4 Determination of the incidence and presentation of high-risk CCAs is important. Most of our knowledge on the incidence and presentation of CCAs comes from a highly selected and biased population of patients undergoing invasive coronary angiography. Although conventional coronary angiography is the gold standard for diagnosing CCA, its invasive nature, the difficulty in selective intubation of anomalous coronary arteries, and understanding the complex nature of the anomalous vessels during the procedure15-17 prevent its common usage to diagnose CCAs, especially in asymptomatic patients. Therefore conventional angiography may not be a true reflection of CCA incidence and presentation. MSCT, on the other hand, is minimally invasive, provides excellent temporal and spatial resolution, and has therefore recently become increasingly attractive for the diagnosis of CCAs. MSCT studies, including our study, have reported higher incidence rates compared with conventional invasive angiography studies (1.3%) (Table 4). This may be related to increased diagnosis of CCA with MSCT compared with conventional angiography,18,19 or it may be due to the study groups used. For example, when compared with conventional angiography, MSCT studies include more asymptomatic patients. A study by Cademartiri et al. included 49.7% asymptomatic patients.19 In a study by Girzades et al., 21.4% of patients with CCA and MB were asymptomatic.20 Similarly, our study included more asymptomatic (69.92%) than symptomatic patients. Recruiting asymptomatic patients in MSCT studies could be responsible for the apparent increased incidence of CCA. In previous studies, right dominance has been the most common dominance. Similarly, the results of our study indicated

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right dominance in the majority of our patients (75.5%), but balanced dominance (14.1%) in our study was slightly higher than reported in previous studies (4.2–7%).19,21 Lack of consensus on the definition of a co-dominant coronary artery system may explain this discrepancy. We defined co-dominance as origination of the posterior descending artery from the RCA and the posterior left descending branch from the CFX, which is similar to most other studies.22 However, some authors describe co-dominance with regard to the artery supplying the inferolateral portion of the posterior septum. These authors state that if both arteries supply this portion of the septum, the system should be referred to as co-dominant.23 In our patient group, the detected CCAs accepted as benign, as in previous studies,19-21,24,25 were as follows: the conus artery separately arising from the RCS, an absence of the left main, superior RCA, posterior RCA and CFX, arising either from the RCS or RCA.26 It is important to diagnose a CFX originating from the RCS or RCA before valve surgery so as to avoid damage during cardiac surgery.27 In addition, although a superior RCA has generally been accepted as a benign anomaly, some cardiac events caused by this anomaly have previously been reported.28 A coronary artery aneurysm is a localised dilatation of the coronary artery exceeding the diameter of the adjacent normal segment by 50%,29 and is generally caused by atherosclerosis. With MSCT, Adreini et al. found 30 aneurysms among 2 757 patients.21 Individual aneurysms were observed in 19 of the 30 aneurysms, and the other 11 aneurysms were in the same patient. In our study, we found one aneurysm in the right ventricular branch of the right coronary artery, most likely caused by atherosclerosis, which was found in all the coronary arteries. The size of the aneurysm was small so medical therapy was chosen. Erol et al. reported seven cases with fistulae (0.33% incidence).25 The fistulae were between the coronary and pulmonary artery (four cases), between the sino-atrial node artery and the left atrium (two cases) and between the right ventricular branch artery and the left ventricle (one case). When the Qp/Qs ratio is ≥ 2.0, surgical correction should be considered for coronary artery fistulae.30 Our patient had severe atherosclerosis in all the coronary vessels, which appeared to be the cause of the fistula. In this patient, the feeder vessels originated from both the LAD and RCA, and the ratio of total pulmonary blood flow to total systemic blood flow (Qp/Qs) was approximately 1. Therefore, medical therapy was chosen. Myocardial bridging is when a segment of a coronary artery is covered by a bridge of myocardium. The reported incidence is between 28.7 and 58%.31,32 In our study, the incidence of MB was 19.1% and was mostly observed in the LAD artery (93.7%, n = 134). In most patients, myocardial bridging has an

TABLE 4. STUDIES EVALUATING CORONARY ANOMALIES USING 64-MSCT No. Incidence Absence CFX from Fistula Aneurysm Conus from Right domipatients (%) LMA (%) RCS/RCA (%) MB (%) (%) (%) aorta (%) nancy (%) 543 18.4 3.3 0.55 10.9 0.5 1.6 11.6 86.6 Cademartiri et al.19 700 3.9 0.4 0.1 37 NA NA 22 76 Kosar et al.24 446 1.8 0.7 0.4 6.9 NA 0.4 NA NA Girzadas et al.20 2757 13.8 1.3 0.54 9.8 0.25 1.1 10.6 85 Andreini et al.21 2096 1.96 0.43 0.43 3.18 0.33 0.74 NA NA Erol et al.25 Karabay et al. (this study) 745 4.96 0.93 0.79 19.1 0.13 0.13 1.07 75.5 LM: left main artery; CFX: circumflex artery; RCA: right coronary artery; RCS: right coronary sinus; MB: myocardial bridging.

Superior RCA (%) NA 0.1 NA 0.29 0.38 0.93

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excellent survival rate of 97% at five years.33 Nevertheless, there have been reported associations with adverse cardiac events.34 None of the patients with MB had a history of cardiac events, and only 11.18% of our patients had symptoms of chest pain and dyspnoea during exercise. Beta-blocker therapy had been administered to those patients. There were a few limitations to this study. It was a retrospective study that included only a single centre. The number of patients with CCAs was low in comparison with conventional angiography studies. The study population included patients who required a cardiac CT scan, therefore the incidence of coronary anomalies among the general population has not been answered by this study.

15.

16.

17.

18.

19.

Conclusions Coronary anomalies and myocardial bridging were found to be common among patients undergoing cardiac CT scans at our institution, with an incidence of 23.6%. Most patients with CCA and MB who underwent MSCT were asymptomatic, and 77% of the patients with either CCA or MB were symptomatic.

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Yamanaka O, Hobbs RE. Coronary artery anomalies in 126,595 patients undergoing coronary arteriography. Catheter Cardiovasc Diagn 1990; 21: 28–40. Maron BJ, Epstein SE, Roberts WC. Sudden death in young competitive athletes. J Am Coll Cardiol 1986; 7: 204–214. Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden in young competitive athletes. J Am Coll Cardiol 2000; 35: 1493–1501. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980−2006. Circulation 2009; 119: 1085–1092. Douglas PS, Fiolkosti J, Berko B, Reichek N. Echocardiographic visualization of coronary artery anatomy in the adult. J Am Coll Cardiol 1988; 11: 565–571. Gaither NS, Rogan KM, Stajduhar K, et al. Anomalous origin and course of coronary arteries in adults: identification and improved imaging utilizing transesophageal echocardiography. Am Heart J 1991; 122(1 Pt  1): 69–75. Giannoccaro PJ, Sochowski RA, Morton BC, Chan KL. Complementary role of transoesophageal echocardiography to coronary angiography in the assessment of coronary artery anomalies. Br Heart J 1993; 70: 70–74. Post JC, van Rossum AC, Bronzwaer JG, et al. Magnetic resonance angiography of anomalous coronary arteries: a new gold standard for delineating proximal course? Circulation 1995; 92: 3163–3171. White CS, Laskey WK, Stafford JL, Ness-Aiver M. Coronary MRA: use in assessing anomalies of coronary artery origin. J Comput Assist Tomogr 1999; 23: 203–207. Datta J, White CS, Gilkeson RC, Meyer CA, Kansal S, Jani ML, et al. Anomalous coronary arteries in adults: depiction at multi-detector row CT angiography. Radiology 2005; 235: 812–818. Erdogan HI, Gul EE, Gok H. Relationship between myocardial bridges and arrhythmic complications. J Invasive Cardiol 2012; 24: E300–302. Angelini P, Trivellato M, Donis J, Leachman RD. Myocardial bridges: a review. Prog Cardiovasc Dis 1983; 26: 75–88. Geirnger E. The mural coronary. Am Heart J 1951; 41: 359–368. Lubarsky L, Gupta MP, Hecht HS. Evaluation of myocardial bridging

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Endothelial nitric oxide synthase levels and their response to exercise in patients with slow coronary flow HAKAN TAŞOLAR, FERHAT EYYÜPKOCA, ERDAL AKTÜRK, YASİN KARAKUŞ, MEHMET CANSEL, JÜLİDE YAĞMUR, FATMA ÖZYALIN, BURAK ALTUN, HASAN PEKDEMİR

Abstract Background: Endothelial dysfunction plays a key role in the aetiopathogenesis of slow coronary flow (SCF) even if there is no obstructive epicardial lesion. Reduced plasma levels of endothelial nitric oxide synthase (eNOS) are an important indicator of endothelial dysfunction. We aimed to determine plasma levels of eNOS and their relationship with exercise in patients with SCF. Methods: Twenty-two patients with SCF in at least one coronary artery and 17 healthy individuals were included in this study. The TIMI frame count method was used to determine SCF. Plasma levels of eNOS before and after effort were determined in the patient and control groups. Results: Basal eNOS levels in the patient group were lower than in the control group (p = 0.040), and plasma eNOS levels after exercise decreased more significantly in the patient group compared to the control group (p = 0.002). Median decreases of eNOS in response to exercise were higher in the SCF group than in the control group (p < 0.001), and the decrease observed in the control group was not statistically significant (p = 0.35). There were significantly negative correlations between TIMI frame count and plasma levels of eNOS at baseline and after exercise (r = –0.51, p = 0.015, r = –0.58, p = 0.005, respectively). Moreover, there was also a positive correlation between the rate–pressure product and plasma levels of eNOS after exercise in patients with SCF (r = 0.494, p = 0.019). Conclusion: Our findings indicate an important pathophysiological relationship between the severity of SCF in which endothelial dysfunction plays a role in its pathogenesis and the level of circulating plasma levels of eNOS. Department of Cardiology, Adiyaman University, Training and Research Hospital, Adiyaman, Turkey HAKAN TAŞOLAR, MD, hakantasolar@gmail.com ERDAL AKTÜRK, MD

Department of Cardiology, Faculty of Medicine, Inonu University, Malatya, Turkey FERHAT EYYÜPKOCA, MD MEHMET CANSEL, MD JÜLİDE YAĞMUR, MD HASAN PEKDEMİR, MD

Malatya State Hospital, Malatya, Turkey YASİN KARAKUŞ, MD

Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey FATMA ÖZYALIN, PhD

Department of Cardiology, Faculty of Medicine, Mart University, Canakkale, Turkey BURAK ALTUN, MD

Keywords: endothelial nitric oxide synthase, slow coronary flow, endothelial dysfunction, exercise, rate–pressure product Submitted 12/6/13, accepted 18/9/13 Cardiovasc J Afr 2013; 24: 355–359

www.cvja.co.za

DOI: 10.5830/CVJA-2013-072

Slow coronary flow (SCF), described for the first time by Tambe and his colleagues in 1972, is an angiographic diagnosis characterised by a low rate of flow of contrast agent in the epicardial coronary arteries, together with typical angina pectoris and normal coronary arteries.1 Even though micro- and macrovascular disease findings have been identified, such as myofibrillar hypertrophy, myofibrillar degeneration, hyperplastic fibromuscular thickening, luminal narrowing, endothelial degeneration, endothelial dysfunction and diffuse atherosclerosis, which may lead to reduced coronary flow reserve, uncertainties still exist in the aetiopathogenesis.2,3 Coronary blood flow and oxygen transport to the myocardium are increased by autoregulatory mechanisms for the increased metabolic needs associated with effort. The amount of oxygen extracted from the blood also increases, which leads to a decrease in the concentration of oxygen in the blood. Mitochondrial metabolism is altered by coronary endothelium-derived nitric oxide (NO) in an attempt to reduce the growing energy requirements.4,5 Vascular endothelium exhibits a number of haemostatic functions in normal blood vessels. NO is a key molecule for normal autoregulatory mechanisms, such as modulating the vasodilator response to tachycardia and exercise,6 and it has also been found to be essential for flow-mediated dilatation of large human arteries in vivo.7 Endothelial nitric oxide synthase (eNOS) is an enzyme involved in the synthesis of NO.8 Decreased plasma eNOS level is an important indicator of endothelial dysfunction.9 To our knowledge, there has been no study evaluating plasma eNOS levels and their response to exercise in SCF patients. Therefore we aimed to investigate the plasma levels of eNOS before and after exercise in patients with SCF.

Methods

Twenty-two patients (19 men, three women, mean age 48.5 ± 10.9 years) with angiographically proven SCF in at least one coronary artery but normal epicardial coronary arteries were enrolled in this study. Seventeen age- and gender-matched patients (12 men, five women, mean age 48.7 ± 9.6 years) who had undergone coronary angiography because of typical and quasi-typical symptoms of angina, with normal coronary arteries and normal coronary flow on coronary angiography comprised the control group. All control subjects had no history of cardiovascular disease, and normal echocardiographic and exercise studies. Because diet affects plasma eNOS levels,10,11

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none of the participants were provided any dietary programme. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Research Committee of Inonu University Faculty of Medicine. Informed consents were obtained from all the participants. Exclusion criteria for the study were defined as the presence of occlusive coronary artery disease in at least one coronary artery, valvular heart disease, blood pressure above 140/90 mmHg, cardiac arrhythmia, atrio-ventricular conduction abnormalities, congestive heart failure or cardiomyopathy, usage of any medication (e.g. statins, aspirin, beta-blockers, digoxine, non-steroidal anti-inflammatory drugs, warfarin, antidepressant medication, corticosteroids, insulin, oral antidiabetic drugs), chronic liver and renal disease, obesity, diabetes mellitus, chronic obstructive pulmonary disease, peripheral artery disease, congenital heart disease and an additional systemic disease. A standard coronary angiography procedure was performed on all participants through the femoral and radial artery with a Philips Integris 5000, Netherlands, coronary angiography device. Results of the coronary angiography were assessed by two blinded observers unaware of the patients’ plasma eNOS levels. The TIMI frame count method was used for the detection of SCF and measurement of opaque material.12 The time required for contrast to reach the distal decisive points of a coronary artery was expressed as frame count. The starting point was the moment when the contrast agent began to move forward contacting both sides of the artery. The end points were: for the left anterior descending artery (LAD), when the contrast agent had reached the branch point of the artery, called the mustache; for the right coronary artery (RCA), the point where the posterolateral artery has its first side branch; and for the circumflex artery (Cx), the point where the longest branch has a distal bifurcation. Because the LAD has a longer course than the other arteries, the calculated value was standardised by dividing it by 1.7. SCF was defined as the patients having frame count values above the standard deviations for at least one coronary artery: 36.2 ± 2.6 for the LAD, 22.2 ± 4.1 and for the Cx, and 20.4 ± 3.0 for the RCA.12 Sub-maximal exercise stress tests (EST) using the Bruce protocol (200 or until the maximal heart rate minus 15%) were performed on both groups after coronary angiography was completed. All medications taken by the patient and control groups were stopped for at least five half-lives before the test. Strength applied during the EST protocol was automatically calculated via an installed computer program according to the formula: maximal heart rate = 220 – age (years), depending on the participant’s maximal heart rate. Achievement of maximal heart rate, declaring of intolerable workload during the test and formation of any clinical indications (e.g. onset of typical chest pain, ≥ 0.1 mV horizontal or down-sloping ST-segment depression) were considered reasons for termination of the EST. Blood pressure was measured every other minute with a manual sphygmomanometer (Erka series, Dusseldorf, Germany). All readings for blood pressure and heart rate were taken by experienced technicians. Total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride, leukocyte, glucose, blood urea nitrogen and creatinine values of the patient and control samples were measured with biochemical analyses.

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Blood samples were obtained at rest and one minute after the exercise testing, using a 19-gauge needle by direct venipuncture, and drawn into 10-ml vacutainer tubes at room temperature containing K3-EDTA at rest and one minute after exercise testing. Sampling time was determined according to the study by Foote et al.13 The vacutainer tube was filled to capacity and gently inverted five times to ensure complete mixing of the anticoagulant. Then the sample was centrifuged at 1 000 rpm for 15 minutes. The resulting platelet-poor plasma was collected in 1.5-ml Eppendorf tubes and frozen at –40°C for biomarker assays. All samples were drawn and analysed by blinded technicians on the day of the study. After collecting all the samples, plasma levels of eNOS were determined using a commercially available sandwich enzyme immunoassay kit (Uscn Life Science Inc, Wuhan, China, E90868Hu, L101129537). The minimum detectable dose of NOS3 for this assay is less than 5.5 pg/ml. The measurable range of the eNOS assay was 15.6 to 1 000 pg/ml. Each sample was measured in duplicate, and the overall intraassay coefficient of variation was calculated. The intra-assay coefficients of variation were 3.6%.

Statistical analysis Data analyses were performed using SPSS statistical software version 17.0 (SPSS Inc., Chicago, IL, USA). Variable values were expressed as ± standard deviation and categorical values were expressed as percentage. Categorical variables between the two groups were compared by chi-square test and continuous variables were compared by independent Student’s t-test. Paired t-test was used for comparison of plasma eNOS levels and exercise parameters and their response to exercise in the study population. Correlations of continuous variables were evaluated using Pearson’s correlation test. A p-value < 0.05 was considered significant.

Results Clinical and demographic characteristics of patient and control groups are given in Table 1. There was no significant difference between the groups in terms of mean age, gender, systolic and diastolic blood pressure, total cholesterol levels, smoking, family history, and coronary artery disease history. Because of chest pain and more than 2-mm ST-segment depression, the EST was terminated in seven SCF patients. Three had both chest pain and ST-segment depression, and four had only chest pain. During the EST as well as during the angiographic process, no chest pain was experienced in the control group. Baseline heart rate, peak exercise heart rate, peak exercise systolic blood pressure and rate–pressure product at baseline and after exercise were evaluated in both groups and are given in Table 2. Baseline and post-exercise plasma levels of eNOS in the patient and control groups are given in Table 3. Basal eNOS levels in the patient group were lower than in the control group (p = 0.040), and plasma eNOS levels after exercise were more significantly decreased in the patient group compared to the control group (p = 0.002). Median decreases in eNOS level in response to exercise were higher in the SCF group than in the control group (p < 0.001), and the decrease observed in the control group was not statistically significant (p = 0.35) (Fig. 1).

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TABLE 1. CLINICAL CHARACTERISTICS OF PATIENT AND CONTROL GROUPS Clinical characteristics

TABLE 2. EXERCISE PARAMETERS OF STUDY POPULATION

SCF (n = 22)

Control (n = 17)

p-value

48.5 ± 10.9

48.7 ± 9.6

Age (year)

Controls (n = 17)

SCF (n = 22)

70.1 ± 2.8

69.0 ± 3.6

Peak exercise heart rate (bpm)

185.9 ± 10.8

159.5 ± 10.3

< 0.001

193.6 ± 10.8

179.9 ± 9.3

< 0.001

81.6 ± 5.6

80.6 ± 5.3

360.3 ± 32.4

287.2 ± 26.5

< 0.001

Exercise parameters Baseline heart rate (bpm)

p-value

Male gender, n (%)

19 (86.4)

12 (70.6)

23.4 ± 1.7

23.2 ± 1.6

Peak systolic blood pressure (mmHg)

BMI (kg/m2)

Systolic blood pressure (mmHg)

116.5 ± 7.2

117.0 ± 6.8

Baseline rate–pressure product

Diastolic blood pressure (mmHg)

76.2 ± 4.9

73.4 ± 5.2

Peak exercise rate–pressure product

Angina, n (%)

–

4 (18)

−

Smoking, n (%)

14 (63.6)

11 (58.8)

ST segment depression, n (%)

–

7 (32)

–

Family history, n (%)

13 (54.2)

9 (60.0)

87.3 ± 9.2

–

3 (14)

–

Fasting blood glucose (mg/dl)

87.0 ± 7.5

Both angina and ST depression, n (%)

SCF: slow coronary flow, NS: not significant.

Total cholesterol (mg/dl)

174.1 ± 24.1

180.6 ± 30.0

LDL cholesterol (mg/dl)

117.8 ± 36.8

121.0 ± 31.7

HDL cholesterol (mg/dl)

40.8 ± 8.4

36.3 ± 8.0

Triglyceride (mg/dl)

99.0 ± 27.6

111.5 ± 31.5

Ejection fraction (%)

61.1 ± 3.8

61.1 ± 3.9

TIMI frame count

49.4 ± 11.7

19.9 ± 5.9

< 0.001

SCF: slow coronary flow, LDL: low-density lipoprotein, HDL: high-density lipoprotein, TIMI: thrombolysis in myocardial infarction, NS: not significant.

There were significantly negative correlations between the TIMI frame count and plasma levels of eNOS at baseline and after exercise (r = –0.51, p = 0.015, r = –0.58, p = 0.005, respectively) (Figs 2, 3). Moreover, there was a positive correlation between the rate–pressure product and plasma levels of eNOS after exercise in patients with SCF (r = 0.494, p = 0.019) (Fig. 4).

Discussion The main objective of our study was to assess plasma eNOS levels and their response to exercise in patients with SCF. The main findings of our study were: (1) plasma levels of eNOS were lower in SCF patients than in control subjects, (2) the differences in eNOS levels between the two groups became greater after the exercise treadmill test, as a result of a significant decrease in plasma eNOS levels in patients with SCF, (3) there were significantly negative correlations between TIMI frame count and plasma levels of eNOS at baseline and after exercise, and (4) there was a positive correlation between the rate–pressure product and plasma levels of eNOS after exercise in SCF patients. SCF is a pathology that causes typical angina pectoris and decreases the flow velocity of contrast agents in the coronary arteries of patients with normal coronary angiography.1 Despite

TABLE 3. BASAL AND POST-EXERTION PLASMA BNP, CRP AND ENOS LEVELS eNOS (pg/ml)*

SCF (n = 22)

Control (n = 17)

p-value

Basal

32.58 ± 21.36

48.16 ± 24.35

0.040

Post-exertion

25.02 ± 17.69

44.13 ± 17.39

0.002

SCF: slow coronary flow, eNOS: endothelial nitric oxide synthase, NS: not significant. *p < 0.001 (baseline and after exercise in patients with SCF).

well-defined angiographic characteristics of SCF, knowledge on its clinical significance and aetiopathogenesis are insufficient. Occlusive disease of the small vessels, microvascular and/ or endothelial dysfunction have been over-emphasised in the aetiology of this disease. It was shown in previous studies that the pathophysiology of SCF was at the microvascular level and the disease has a dynamic character.1,2,14 A microcirculatory disorder of SCF was also clearly demonstrated in the results of these studies.3,15 The effects of exercise on the coronary microvascular tone are controversial. Sympathetic activation increases coronary flow, with both increasing heart rate and myocardial contractility,16 and endothelium-mediated vasodilation.17 Besides, increased sympathetic stimulation may also cause abnormal microvascular constriction in endothelial dysfunction.18 Essentially, the net effect of exercise is related to the pathophysiological state of the small coronary arteries. The endothelium normally displays a vasodilatory feature against various systemic, neurohumoral and mechanical stimuli, and regulates vasomotor tension, thrombosis, fibrinolysis, vascular cell growth, and leukocyte and platelet adhesion by secreting growth factors and inhibitors such as NO.19 NO is a key molecule in normal autoregulatory mechanisms such as 100.00

45 40 35 30 25 20 15

p = 0.35 p < 0.001

10 5 0

SCF Basal

Control

After exertion

Fig. 1. Plasma eNOS levels at baseline and after exercise in the study population.

Plasma levels of eNOS at baseline (pg/ml)

Endothelial nitric oxide synthase levels (pg/ml)

r = –0.51, p = 0.015

80.00 60.00 40.00 20.00 0.00

30.00

40.00

50.00

60.00

TIMI frame count

70.00

Fig. 2. Relationship between TIMI frame count and plasma levels of eNOS at baseline.

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Rate–pressure product

Plasma levels of eNOS after exercise (pg/ml)

60.00 40.00 20.00 0.00

400.00

r = –0.58, p = 0.005

80.00

30.00

40.00

50.00

60.00

TIMI frame count

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r = 0.494, p = 0.019

375.00 350.00 325.00 300.00 275.00 0.00

70.00

20.00

40.00

60.00

Plasma levels of eNOS (pg/ml)

80.00

Fig. 3. Relationship between TIMI frame count and basal plasma levels of eNOS after exercise.

Fig. 4. Relationship between rate–pressure product and plasma levels of eNOS.

modulating the vasodilator response to tachycardia and exercise.6 NO formed via eNOS plays a crucial role in the regulation of coronary blood flow, resulting in reduction of vascular resistance by vasodilation and in the inhibition of platelet aggregation and adhesion.20 It has also been shown that decreased plasma eNOS levels are an important indicator of endothelial dysfunction.9,21 There are many studies indicating endothelial function is impaired in patients with SCF. Sezgin et al. found that endothelial function was impaired in people with SCF, and the TIMI frame count was correlated with endothelial dysfunction.14 Pekdemir et al. showed that endothelin-1 (ET-1) was higher and NO concentration was lower in patients with SCF than in a matched group of control subjects, and it was suggested that this situation was due to endothelial dysfunction.22 The plasma levels of NO were also found to be lower in patients with SCF than in normal subjects.23,24 In another study, plasma NO levels were found to be lower in patients with SCF than in controls, and negatively correlated with TIMI frame count.25 Likewise, we found in our study that plasma levels of eNOS were lower and inversely correlated with TIMI frame count in SCF patients than in control subjects. These findings support the notion that endothelial function is impaired in SCF patients. Çamsari et al. found that baseline and peak exercise ET-1 and NO concentrations were impaired in patients with SCF and suggested that endothelial dysfunction may play an active role in the pathophysiology of SCF.26 In our study, we found that plasma levels of eNOS involved in the synthesis of NO were significantly lower in patients with SCF than in control subjects. In addition, this decline became even more pronounced after exercise. These findings appear to support the previous studies. Rate–pressure product (heart rate × systolic blood pressure) is well correlated with myocardial oxygen consumption. Therefore, failure of the oxygen supply to the myocardium when demand is high may result in severe cardiovascular events. In SCF patients, a negative correlation was previously reported between rate–-pressure product and post-exercise NT-proBNP levels, and a positive correlations was reported for post-exercise NO concentrations and maximal heart rate as well as exercise duration.26,27 On the basis of these concepts, the severity of ischaemia caused by exercise is generally considered to be closely related to increased ventricular wall stress or damage.27 In our study, we found a positive correlation between rate–pressure product

and plasma levels of eNOS after exercise in SCF patients. We believe that our results are consistent with previous studies,22,26 in which lower NO levels have been found due to the response of endothelial dysfunction to increased myocardial oxygen consumption in patients with SCF. Some limitations of this study should be considered. The design of our study was cross-sectional, and the sample size of the study population may not have been quite adequate.

Conclusion Our findings indicate that an important pathophysiological relationship exists between the severity of SCF in which endothelial dysfunction plays a role in the pathogenesis and level of circulating plasma levels of eNOS. To the best of our knowledge, this is the first study on this issue reported in the literature, and we believe that it will direct future large-scale studies.

References 1.

Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow velocity of dye in coronary arteries, a new angiografic finding. Am Heart J 1972; 84: 66–71. Arıi H, Arı S, Erdoğan E, Tiryakioğlu O, Huysal K, Koca V, et al. The effects of endothelial dysfunction and inflammation on slow coronary flow. Turk Kardiyol Dern Ars. 2010; 38(5): 327–3-33. Mangieri E, Macchiarelli G, Ciavolella M, Barillà F, Avella A, Martinotti A, et al. Slow coronary flow: Clinical and histopathological features in patients with otherwise normal epicardial coronary arteries. Cathet Cardiovasc Diagn 1996; 37: 375–381. Elsherbiny IA. Left ventricular function and exercise capacity in patients with slow coronary flow. Echocardiography 2012; 29(2): 158–164. Newcomer SC, Thijssen DH, Green DJ. Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exerciseinduced hemodynamics. J Appl Physiol 2011; 111(1): 311–320. Egashira K, Katsuda Y, Mohri M, Kuga T, Tagawa T, Kubota T, et al. Role of endothelium-derived nitric oxide in coronary vasodilatation induced by pacing tachycardia in humans. Circ Res 1996; 79: 331–335. Kooijman M, Thijssen DH, de Groot PC, Bleeker MW, van Kuppevelt HJ, Green DJ, et al. Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans. J Physiol. 2008 Feb 15; 586(4): 1137–11-45. Shimokawa H, Tsutsui M. Nitric oxide synthases in the pathogenesis of cardiovascular disease: lessons from genetically modified mice. Pflugers Arch 2010; 459(6): 959–967. Atochin DN, Huang PL. Endothelial nitric oxide synthase trans-

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genic models of endothelial dysfunction. Pflugers Arch 2010; 460(6): 965–974. Cook S, Hugli O, Egli M, Ménard B, Thalmann S, Sartori C, et al. Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes 2004; 53(8): 2067–2072. Schreihofer DA, Deutsch C, Lovekamp-Swan T, Sullivan JC, Dorrance AM. Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat. Vascul Pharmacol 2010; 52(5–6): 236–242. Albayrak S, Ordu S, Yuksel H, Ozhan H, Yazgan O, Yazici M. Efficacy of nebivolol on flow-mediated dilation in patients with slow coronary flow. Int Heart J. 2009 Sep; 50(5): 545–5-53. Foote RS, Pearlman JD, Siegel AH, Yeo KT. Detection of ExerciseInduced Ischemia by Changes in B-type natriuretic peptides. J Am Coll Cardiol 2004; 44(10): 1980–1987. Sezgin AT, Sigirci M, Barutcu I. Vascular endothelial function in patients with slow coronary flow. Coron Artery Dis 2003; 14: 155–161. Beltrame JF , Turner SP, Leslie SL, Solomon P, Friedman SB, Horowitz JD. The angiographic benefits of mibefradil in the coronary slow flow phenomenon. J Am Coll Cardiol 2004; 44(1): 57–62. Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol. 2012 Jan 1; 302(1): H10–-23. Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercise. Physiol Rev. 2008 Jul; 88(3): 1009–10-86. Tune JD, Gorman MW, Feigl EO. Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol 2004; 97(1): 404–415. Marsden PA. The vascular endothelium: a wonderful network: introduction. Semin Nephrol 2012; 32(2): 143–144.

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20. Toda N, Toda H. Coronary hemodynamic regulation by nitric oxide in experimental animals: recent advances. Eur J Pharmacol 2011; 667(1–3): 41–49. 21. Shin WS, Berkowitz DE, Ryoo SW. Increased arginase II activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice. Exp Mol Med 2012; 44(10): 594–602. 22. Pekdemir H, Polat G, Cin VG, Camsari A, Cicek D, Akkus MN, et al. Elevated plasma endothelin-1 levels in coronary sinus during rapid right atrial pacing in patients with slow coronary flow. Int J Cardiol 2004; 97(1): 35–41. 23. Yucel H, Ozaydin M, Dogan A, Erdogan D, Turker Y, Ceyhan BM, et al. Plasma concentrations of asymmetric dimethylarginine, nitric oxide and homocysteine in patients with slow coronary flow. Scand J Clin Lab Invest 2012; 72(6): 495–500. 24. Pekdemir H, Cicek D, Camsari A, Akkus MN, Cin VG, Doven O, Parmaksiz HT, Katircibasi MT, Ozcan ITet al. The relationship between plasma endothelin-1, nitric oxide levels, and heart rate variability in patients with coronary slow flow. Ann Noninvasive Electrocardiol 2004 Jan; 9(1): 24–33. 25. Sezgin N, Barutcu I, Sezgin AT, Gullu H, Turkmen M, Esen AM, et al. Plasma nitric oxide level and its role in slow coronary flow phenomenon. Int Heart J 2005; 46(3): 373–382. 26. Camsari A, Pekdemir H, Cicek D, Polat G, Akkus MN, Döven O, et al. Endothelin -1 and nitric oxide concentrations and their response to exercise in patients with slow coronary flow. Circulation 2003; 67: 1022–1028. 27. Yurtdaş M, Ozcan IT, Camsar A, Ciçek D, Tamer L, Cin VG, et al. NT-Pro-BNP levels and their response to exercise in patients with slow coronary flow. Arq Bras Cardiol 2012; 99(6): 1115–1122.

Cardiovascular congress diary 2014 DATE

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Vitamin E and antioxidant activity; its role in slow coronary flow VEYSEL KENAN CELIK, İMGE EZGI EKEN, GÜRSEL YILDIZ, MEHMET BIRHAN YILMAZ, AHMET GURLEK, HÜSEYIN AYDIN

Abstract

VEYSEL KENAN CELIK, PhD İMGE EZGI EKEN, PhD HÜSEYIN AYDIN, PhD

preventing the production of free radicals and for repairing oxidative damage.1-4 A free radical contains an unpaired electron in an atomic orbital. In this state, no molecular species is stable for long. A free radical will attract other molecules and either give or receive an electron to make itself thermodynamically stable.5 The most important free radicals in many disease states are oxygen derivatives such as hydrogen peroxide, superoxide and particularly, hydroxyl radical, which is the most harmful for tissues.1 Transition metals contain one or more unpaired electrons and are therefore also radicals when in the elemental state. However, their key property from the point of view of free radical biology is their variable valency, which allows them to undergo reactions involving the transfer of a single electron. The most important transition metals in human disease are iron and copper.6 These elements play a key role in the production of hydroxyl radicals in vivo.7 Hydrogen peroxide and superoxide can be detoxified enzymatically in the mammalian system by catalase and superoxide dismutase, respectively. However there is no enzymatic system that converts or detoxifies hydroxyl radicals. A hydroxyl radical can be detoxified by non-enzymatic systems. One of these is the tocopherols (α, β, γ and δ), which have a chromanol ring and a phenyl tail, and differ in the number and position of the methyl groups on the ring. The most important lipid-phase antioxidant is probably vitamin E.8-10 The coronary slow-flow phenomenon was first described in 1972 by Tambe et al.11 The phenomenon is an angiographic finding characterised by delayed distal vessel opacification in the absence of significant epicardial coronary disease. However, since that time, only a limited number of studies have focused on the aetiology of this unique angiographic phenomenon. Histopathological studies have revealed the loss of luminary diameter, and capillary and endothelial damage in these patients.12 Although the pathophysiological mechanisms of slow coronary flow phenomenon remain uncertain, there are several hypotheses that have been suggested, including endothelial activation and inflammation.13 However, the phenomenon is not well studied and deserves further investigation. In the present study, we investigated plasma vitamin E levels and antioxidant activity in patients with slow coronary flow (SCF) and compared them with those with normal coronary flow (NCF).

Clinic of Nephrology, Atatürk State Hospital, Zonguldak, Turkey

Methods

Aim: Oxidative stress, which is widely recognised as an important feature of many diseases, can be defined as an increased formation of reactive oxygen species or decreased antioxidant defense. In this study we measured plasma vitamin E levels and total antioxidant activity (AOA) in patients with slow coronary flow (SCF). Methods: The plasma vitamin E levels and AOA were measured in 40 patients with angiographically diagnosed SCF. Forty subjects with normal coronary flow (NCF) served as the control group. SCF and NCF were analysed, and blood samples were taken for plasma vitamin E levels and AOA. Plasma vitamin E levels and AOA in patients with SCF were evaluated and compared to those of patients with NCF. Results: There was no significant difference between the two groups in terms of plasma AOA, lipid profile and C-reactive protein (CRP) levels but there was a significant difference in vitamin E levels between the two groups (p = 0.001). Conclusion: Vitamin E levels were found to be lowered in patients with SCF compared to the NCF group. The association between smoking and vitamin E levels is worth further investigating in larger samples. Keywords: vitamin E, antioxidant activity, slow coronary flow Submitted 24/5/2013, accepted 25/10/2013 Cardiovasc J Afr 2013; 24: 360–363

www.cvja.co.za

DOI: 10.5830/CVJA-2013-076

The ability of antioxidant defense to scavenge reactive oxygen species (ROS) is important to protect tissues from oxidative damage. Cells and biological fluids have an array of protective antioxidant mechanisms, enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic, referred to as chain-breaking antioxidants (tocopherols, ubiquinol, carotenoids and flavonoids as lipid phase, and ascorbate, urate, glutathione and other thiols as aqueous phase), both for

Department of Biochemistry, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey

GÜRSEL YILDIZ, MD, drgursel@yahoo.com

Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey MEHMET BIRHAN YILMAZ, MD AHMET GURLEK, MD

Forty consecutive patients with angiographically diagnosed SCF in all three epicardial coronary arteries, and 40 subjects with normal coronary flow as a control group were enrolled in our study after obtaining informed consent. All patients underwent selective coronary angiography via the Judkins technique.

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Coronary flow of both groups was documented by the thrombolysis in myocardial infarction (TIMI) frame count (TFC). The TIMI frame count method is a simple, reproducible and quantitative index of coronary flow.14 To obtain corrected TFC for the left anterior descending (LAD) coronary artery, the TIMI frame count was divided by 1.7. The mean TFC for both groups was calculated by adding the TFC for the LAD, left circumflex artery (LCx) and right coronary artery (RCA), and then dividing the obtained value by three. The TFC in the LAD and the LCx were assessed in a right anterior oblique projection with caudal angulation (right anterior oblique caudal view) and TFC in the RCA was assessed in a left anterior oblique projection with cranial angulation (left anterior oblique cranial view). All angiograms were filmed at 30 frames/ sec. The TFC, a quantitative method of assessing coronary artery flow, was evaluated on the three main coronary branches (LAD, LCX and RCA), using the protocol described by Gibson et al.14 Patients with a corrected TFC greater than two standard deviations from the normal published range (36.2 ± 2.6 frames for LAD, 22.2 ± 1.4 for LCx and 20.4 ± 3 for RCA) for the particular vessel were considered as having slow coronary flow, while those whose corrected TFC fell within two standard deviations (cut-off value for the LAD > 38 frames, for the LCx > 28 frames, for the RCA > 26 frames) of the published normal range were labelled as having normal coronary flow.14 Patients with a history of coronary artery disease, recent myocardial infarction or an acute coronary syndrome (within the last two months), coronary vasospasm, coronary ectasia, left ventricular dysfunction, echocardiographically proven left ventricular hypertrophy, uncontrolled hypertension, renal dysfunction and connective tissue disease were excluded from the study. Additionally, patients in both groups who had taken any vitamin supplements within the previous eight weeks were also excluded from the study. All subjects were informed about the study and written consent was obtained from each. Venous blood samples were collected into tubes containing ethylenediamine tetraacetic acid (EDTA) after an eight-hour fast and immediately stored on ice at 4°C. The plasma was then separated from the cells by centrifugation at 3 000 rpm for 10 min and stored in several aliquots at –80°C until assayed. TABLE 1. CLINICAL AND LABORATORY CHARACTERISTICS OF THE GROUPS Variables

SCF group (n = 40)

NCF group (n = 40)

Age (year)

51 ± 12

48 ± 10

p-value NS*

Gender: female/male, n (%) 13 (32.5)/27 (67.5) 21 (52.5)/19 (47.5)

NS**

Hypertension, n (%)

37 (92.5)

25 (62.5)

NS**

3 (7.5)

2 (5)

NS**

Smoking, n (%)

27 (67.5)

12 (30)

0.001**

Triglycerides (mg/dl)

175 ± 112

169 ± 103

NS*

Total cholesterol (mg/dl)

187 ± 28

179 ± 29

NS*

HDL cholesterol (mg/dl)

38 ± 9

42 ± 15

NS*

LDL cholesterol (mg/dl)

107 ± 24

104 ± 25

NS*

6 ± 3.1

5.9 ± 2.6

NS*

Diabetes mellitus, n (%)

CRP (mg/l)

Data expressed as mean ± standard deviation. *Independent samples t-test, **Chi-square test. CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NCF, normal coronary flow; NS, not significant; SCF, slow coronary flow.

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Chemicals 2-thiobarbituric acid (TBA), α-tocoferol, and 2.4.6-tris (2-pyridyl)-s-triazine (TPTZ) were supplied by Sigma-Aldrich (Steinheim, Germany). All other chemicals used were obtained from Merck Darmstadt (Germany) and were of analytical grade. Plasma AOA was measured using a method defined as AOA by Koracevic.15 In this method, the hydroxyl radical, the most potent biological radical, is produced in a standardised solution of Fe-EDTA complex reacted with hydrogen peroxide by a Fenton-type reaction. These reactive oxygen species degrade benzoate, resulting in the release of thiobarbituric acid reactive substances (TBARS).16,17 Antioxidants from the added sample of human fluid cause suppression of the production of TBARS. The inhibition of colour development is defined as AOA. Plasma vitamin E levels were measured using a spectrophotometric method developed by Martinek.18 The assay results are expressed in μmol/l.

Statistical analysis Parametric data were expressed as mean ± standard deviation, and categorical data as percentages. SPSS 16.0 (SPSS, Inc, Chicago, Illinois) was used to perform statistical procedures. Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test. Parametric data were evaluated by independent samples t-test, non-parametric data were evaluated by Mann-Whitney U-test, and categorical data via chi-square test. A p-value ≤ 0.05 was accepted as significant.

Results Clinical and laboratory characteristics of the subjects are summarised in Table 1. Since mean TFC was higher in the study group as it was an enrolment criterion, it is not discussed in detail in the text. There were no significant differences in age, gender, hypertension, lipid profile, CRP levels and diabetes, except for smoking, between patients with SCF and controls. There were no significant differences in AOA levels between the two groups. However, plasma vitamin E levels in the SCF group were significantly lower than in the NCF group (Table 2). Among the non-smokers in both groups, vitamin E levels were lower in those with SCF compared to the control group (Table 3). However, among smokers in both groups, there was no significant difference in vitamin E levels. There was no significant difference in antioxidant activity between the groups and within each group in smokers and non-smokers with normal coronary flow and slow coronary flow (Table 4).

Discussion Slow coronary flow phenomenon is an important clinical entity because it may be the cause of angina at rest or during exercise, TABLE 2. ANTIOXIDANT ACTIVITY AND VITAMIN E LEVELS IN THE STUDY GROUPS Variables

NCF group (n = 40)

SCF group (n = 40)

p-value*

Vitamin E (μmol/l)

109.5 ± 31.6

85.6 ± 28.5

0.001

2.5 ± 0.6

2.7 ± 0.5

0.139

Antioxidant activity (μmol/l)

*Independent samples t-test. NCF, normal coronary flow; SCF, slow coronary flow.

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TABLE 3. VITAMIN E LEVELS WITHIN GROUPS AND BETWEEN GROUPS Smokers

Non-smokers

NCF group

95.4 ± 25.4

115.5 ± 32.4

0.082

Variables

SCF group

84.4 ± 28.6

88.2 ± 29.2

0.665

NCF group

2.4 ± 0.5

p-value*

0.248

Vitamin E (μmol/l)

Smokers Antioxidant activity (μmol/l)

Variables

Vitamin E (μmol/l)

TABLE 4. ANTIOXIDANT ACTIVITY LEVELS WITHIN GROUPS AND BETWEEN GROUPS p-value*

0.015

*Mann-Whitney U-test

n 28

2.7 ± 0.6

SCF group p-value*

Non-smokers

0. 072

Antioxidant activity (μmol/l) p-value* 2.7 ± 0.7

0.070

2.7 ± 0.3

0.938

0.752

*Mann-Whitney U-test.

acute myocardial infarction and hypertension. There have been several hypotheses suggested for slow coronary flow phenomenon since first described in 1972 by Tambe et al.11 In this theory, endothelial activation and inflammation, which have been reported to be a major contributing factor to many cardiovascular events and demonstrated to be associated with different clinical settings of coronary artery disease, are the most acceptable hypotheses for SCF.13, 21-23 The biological oxidative effects of free radicals on cells, DNA, proteins and lipids are controlled by a spectrum of exogenous dietary and endogenous antioxidants.24,25 Oxidative stress occurs when there is an imbalance between free radical production and antioxidant capacity. This may be due to increased free radical generation and/or loss of normal antioxidant defense. In the vascular wall, decreases in antioxidant defense are thought to alter several important physiological functions. Regulation of blood flow, inhibition of platelet aggregation, inhibition of leukocyte adhesion and control of cellular growth are influenced by oxidant stress. These phenomena ultimately modulate vessel diameter, remodelling and lesion formation.26,27 Within the lipid interior of membranes, lipophilic radicals are formed that are different from those seen in the intracellular aqueous milieu. Lipophilic radicals require different types of antioxidants such as vitamin E, β-carotene, co-enzyme Q10 and membrane structural organisation (phospholipids: cholesterol, different types of phospholipids and fatty acids important for membrane integrity) for their removal. Vitamin E has a unique biochemical role with both a chainbreaking property and lipoprotein antioxidant. In fact, vitamin E is a poor antioxidant outside the membrane bilayer, but very effective when incorporated into the membrane. Therefore, it can protect cell membranes from oxidative damage and this explains why vitamin E is the most important biological antioxidant but also one of the least important plasma antioxidants.28 Oxidative stress has been implicated in over a hundred disorders, including cardiovascular diseases,1,6,27,29 but there have been only a few investigations on oxidative stress or antioxidant status in patients with SCF.23 Furthermore, to the best of our knowledge, there is no study about vitamin E levels in patients with SCF in the literature. In the present study, we investigated AOA producing hydroxyl radicals in vitro using the Fenton reaction to observe antioxidant defense potential in patients with SCF, and measured vitamin E levels as a component of the antioxidant systems. We observed no difference between the two groups with regard to plasma antioxidant activity, but there was a significant difference in vitamin E levels between the two groups (p = 0.001). These results suggest that decreased vitamin E levels as a component of the antioxidant systems can be inadequate to protect endothelial cells from oxidative damage at the tissue level, which is less associated with total plasma activity of 19,20

hydrophilic compartments. Concerning the lack of significant difference among smokers in both groups, we have no explanation other than the potentially negative influence of smoking on vitamin E levels. Since we did not evaluate the TIMI frame counts individually, it would have been interesting to see how smoking and its frequency could affect coronary flow in smokers, even if they were within the normal range of TIMI frame counts. Since we did not include TIMI frame counts individually, our study was limited in terms of correlative association between the coronary flow rate and vitamin E levels. This could be investigated in another study. There may also be other confounding factors that were not considered in the current study. However, given the lack of information on the pathophysiology of slow coronary flow, this can be regarded as an initial study. The negative influence of smoking on vitamin E levels is interesting. Smoking, in addition to its many hazardous effects on the whole body, appears to render the endothelial membrane weak and exposed to the harmful influences of lipophilic radical attacks by having a negative effect on vitamin E levels.

Conclusion Our study has shown that levels of vitamin E, a membrane protector against oxidative stress, were decreased in patients with slow coronary flow. There also appeared to be a clear negative influence of smoking on vitamin E levels. The association between smoking and vitamin E levels is worth further investigation in larger samples.

References 1.

Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol 2001; 54: 176–186. 2. Change B, Sies H, Baveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 1979; 59: 527–605. 3. Yu BP. Cellular defenses from damage from reactive oxygen species. Physiol Rev 1994; 74: 139–162. 4. Reiter RJ. Oxidative processes and antioxidative defense mechanism. FASEB J 1995; 9: 526–533. 5. Halliwell B, Gutteridge JM. Free Radical in Biology and Medicine, 2nd edn. Oxford: Claendon Pres, 1989. 6. Halliwell B, Gutteridge JMC. Role of free radical and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186: 1–85. 7. Lloyd RV, Hana PM, Mason RP. The origin of the hydroxyl radical oxygen in the Fenton reaction. Free Radic Biol Med 1997; 262: 647–650. 8. Halliwell B. How to characterize an antioxidant: an update. Biochem Soc Symp 1995; 61: 73–101. 9. Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G. Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr 1991; 53: 314–321. 10. Horwitt MH. Data supporting supplementation of humans with vitamin E. J Nutr 1991; 121(3): 424–429.

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11. Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow velocity of dye in coronary arteries a new angiographic finding. Am Heart J 1972; 84: 66–71. 12. Mangieri E, Macchiarelli G, Ciavolella M, Barilla F, Avella A, Martinotti A, et al. Slow coronary flow: clinical and histopathological features in patients with otherwise normal epicardial coronary arteries. Cathet Cardiovasc Diagn 1996; 37: 375–381. 13. Jian-Jun L, Bo X, Zi-Cheng L, Jie Q, Bing-Qi W. Is slow coronary flow associated with inflammation? Med Hyp 2006; 66: 504–508. 14. Gibson CM, Cannon CP, Daley WL, Dodge JT, Alexander B, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93(5): 879–888. 15. Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 2001; 54: 356–361. 16. Gutteridge JMC, Maidt L, Poyer L. Superoxide dismutase and Fenton chemistry. Biochem J 1990; 269: 169–174. 17. Winterbourn CC. Comparison of superoxide with other reducing agents in biological production oh hydroxyl radicals. Biochem J 1979; 182: 625–628. 18. Martinek RG. Method for the determination of vitamin E (total tocopherols) in serum. Clin Chem 1964; 10(12): 1078–1086. 19. Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to “slow-flow phenomenon” in nonatherosclerotic coronary arteries: a case report. Angiology 1986; 37: 751–761. 20. Burchartt BA, Mukeriji V, Alpert MA. Coronary artery slow flow asso-

21. 22. 23.

24.

25. 26. 27.

28.

29.

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ciated with angina pectoris and hypertension: a case report. Angiology 1998; 49: 483–487. Shah PK. Inflammation, neointimal hyperplasia, and restenosis: as the leukocytes roll, the arteries thicken. Circulation 2003; 107: 2175–2177. Li JJ. Inflammation: an important mechanism for different clinical entities of coronary artery disease. Chin Med J 2005; 118: 1761–1768. Turhan H, Saydam GS, Erbay AR, Ayaz S, Yasar AS, Aksoy Y, et al. Increased plasma soluble adhesion molecules: ICAM-1, VCAM-1 and E-selectin levels in patients with slow coronary flow. Int J Cardiol 2006; 108: 224–230. Demirbag R, Yılmaz R, Gur M, Kunt A.S, Kocyigit A, Celik H, et al. DNA damage and plasma total antioxidant capacity in patients with slow coronary artery flow. Arch Turk Soc Cardiol 2006; 34(2): 89–93. Gutteridge JM. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1995; 41(12): 1819–1828. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997; 100(9): 2153–2157. Alexander RW. Hypertension and the pathogenesis of atherosclerosis: Oxidative stress and the mediation of arterial inflammatory response: A new perspective. Hypertension 1995; 25: 155–161. Burton GW, Joyce A, Ingold KV. First proof that vitamin E is a major lipid soluble, chain-breaking antioxidant in human blood plasma. Lancet 1982; ii: 327–328. Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999; 43: 562–571.

Industry News ASSAf recognises top South African scientists The Academy of Science of South Africa (ASSAf) recognised top South African scientists at its prestigious annual awards ceremony in Pretoria on 23 October 2013. ASSAf annually awards up to two ASSAf Science-for-Society gold medals for outstanding achievement in scientific thinking to the benefit of society. This year, Prof Olive Shisana was recognised for her contributions in the campaign to understand and contain HIV/AIDS in South Africa. Shisana is the chief executive officer of the Human Sciences Research Council (HSRC), honorary professor at the University of Cape Town and immediate past-president of the International Social Science Council. Prior to this, she served as the HSRC’s executive director of Social Aspects of HIV/AIDS and Health, and was previously the executive director of Family and Community Health, World Health Organisation, Geneva, Switzerland. Shisana is an authority in HIV surveillance, having been a principal investigator for several second-generation surveillance systems for HIV. She was one of the founders of the South African National Health and Nutrition

Examination Survey, as well as the Maternal and Child Mortality Surveillance. Her recurrent national household surveys on HIV/ AIDS prevalence, practices and attitudes have greatly influenced the HIV/AIDS campaign in our region. She has served on many national and international scientific committees and advisory boards, such the Ministerial Advisory Committee on National Health Insurance, the US Institute of Medicine’s Committee on Methodological Challenges in HIV Prevention Trials, the Emory University Global Health Institute Advisory Board, the South African National AIDS Council and the chair of the Nelson Mandela’s 46664 Board. She has recently been appointed to head the South Africa’s BRICS think tank and is chair of the Council of BRICS think tanks as well as the AIDS 2016 global conference South African co-chair. Two young scientists were also recognised for the prestigious AU-TWAS Young Scientists’ National Awards. These awards aim to recognise and reward the scientific achievements of young researchers working in Africa. The prize in the category Life

and Earth Sciences was awarded to Prof Landon Myer from the University of Cape Town. Prof Cornie Scheffer from Stellenbosch University received the prize in the category Basic Sciences, Technology and Innovation. The AU-TWAS Prize for Young Scientists in South Africa is managed by the Academy of Science of South Africa (ASSAf), on behalf of its partners, the African Union (AU), The World Academy of Sciences (TWAS) and the South African Department of Science and Technology (DST). Through this award, the AU and TWAS jointly recognise and reward an outstanding scientist in South Africa. The recipient should be under the age of 40, living and working in South Africa, and have a record of research publications in internationally recognised science journals. The award pertains to the scientific fields of life and Earth sciences; and basic sciences, technology and innovation. Myer is an associate professor in the Division of Epidemiology and Biostatistics of the School of Public Health and Family continued on page 368…

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Comparison of one- and two-stage basilic vein transposition for arterio-venous fistula formation in haemodialysis patients: preliminary results SEDAT OZCAN, ALİ KEMAL GÜR, ALİ ÜMİT YENER, DOLUNAY ODABAŞI

Abstract Objective: This study aimed to compare the results of oneand two-stage basilic vein transposition (BVT) in haemodialysis patients. Methods: This was a non-randomised, retrospective study between January 2007 and January 2012 on 96 patients who were diagnosed with end-stage renal failure (ESRF) (54 males, 42 females; mean age 43.6 ± 14 years) and underwent one- or two-stage BVT in our clinic. All patients who were not eligible for a native radio-cephalic or brachio-cephalic arterio-venous fistula (AVF) were scheduled for one- or twostage BVT after arterial (brachial, radial and ulnar) and venous (basilic and cephalic) Doppler ultrasonography. Patients were retrospectively divided into two groups: group 1, basilic vein diameter > 3 mm and patients who underwent one-stage BVT; and group 2, basilic vein diameter < 3 mm and patients who underwent two-stage BVT. In group 1, the basilic vein with a single incision was anastomosed to the brachial artery, followed by superficialisation. In group 2, the basilic vein was anastomosed to the brachial artery and they underwent the superficialisation procedure one month postoperatively. Fistula maturation and postoperative complications were assessed. Results: The mean diameter of the basilic vein was statistically significantly higher in group 1 (3.46 ± 0.2 mm) than in group 2 (2.79 ± 0.1 mm) (p < 0.05). In terms of postoperative complications, thrombosis, haemorrhage and haematoma were significantly higher in group 1 (34, 36 and 17%, respectively) than in group 2 (23, 14 and 6%, respectively) (p < 0.05). The rate of fistula maturation was significantly lower in group 1 (66%), compared to group 2 (77%) (p < 0.05). Time to fistula maturation was significantly shorter in group 1 (mean 41 ± 14 days), compared to group 2 (mean 64 ± 28 days) (p < 0.05). Conclusion: Two-stage BVT was superior to one-stage BVT due to its lower rate of postoperative complications and higher fistula maturation, despite its disadvantage of late fistula use. Although the diameter of the basilic vein was larger in patients who underwent one-stage BVT, we observed that one-stage BVT was disadvantageous in terms of postoperative complications and fistula maturation. Department of Cardiovascular Surgery, Çanakkale Onsekiz Mart University, Çanakkale, Turkey SEDAT OZCAN, MD, sedatozcan78@hotmail.com ALİ ÜMİT YENER, MD

Department of Cardiovascular Surgery, Yuzuncu Yil University, Van, Turkey ALİ KEMAL GÜR, MD DOLUNAY ODABAŞI, MD

Keywords: renal dialysis, arterio-venous fistula, basilic vein transposition, complication Submitted 11/6/13, accepted 25/10/13 Cardiovasc J Afr 2013; 24: 364–368

www.cvja.co.za

DOI: 10.5830/CVJA-2013-077

In recent years, the number of patients requiring haemodialysis (HD) has been rapidly increasing globally, including Turkey. Arterio-venous fistula (AVF) is the most frequently used method in patients with end-stage renal failure (ESRF) for HD.1 The Kidney Disease Outcome Quality Initiative (KDOQI) recommends autologous radio-cephalic or brachio-cephalic AVF as a primary method of choice in HD patients, and basilic vein transposition (BVT) as a secondary option.2,3 In 1976, Dagher et al.4 first described the technique of BVT for HD. In later years, several techniques were used.5-11 This study aimed to compare the patency and complication rates of AVF formed by one-stage and two-stage BVT.

Methods Between January 2007 and January 2012, 96 patients (54 males, mean age 43.6 ± 14 years) who were not eligible for radio-cephalic and brachio-cephalic AVF via native veins and who underwent BVT were included in this retrospective study. Patients were selected according to basilica vein diameter, which was evaluated with vascular Doppler. Group 1 consisted of patients with a basilic vein diameter > 3 mm and who underwent one-stage BVT (47 patients, 28 males; mean age 42.8 ± 14.5 years), and group 2 contained patients with a basilic vein diameter < 3 mm and who underwent two-stage BVT (59 patients, 36 males; mean age 44.5 ± 13.5 years). In group 1, the incision was performed through the basilic vein located in the medial condyle of the humerus and axillary area. The vein was carried over the fascia by tying the lateral branches during release of the basilic vein, while the nervus cutaneus medialis of the forearm was preserved. The basilic vein in the antecubital fossa was anastomosed to the brachial artery end to side, using 6-0 or 7-0 polypropylene continuous sutures. Following evaluation of the presence of thrill, the fascia and other layers were closed, lifting the vein and protecting the nerve. One month was allowed for the anastomosed graft to heal before the possible trauma of HD injection. In group 2 patients, the incision was made through the basilic vein located in the medial and lateral condyle of the humerus and was it anastomosed to the brachial artery laterally using 6-0 or 7-0 polypropylene continuous suture. The incisions were closed in the anatomical layers, after the presence of thrill was evaluated. In the next stage at one month, an incision was made through the basilic vein located in the medial condyle of the humerus and

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the axillary area. The vein was carried over the fascia by tying the lateral branches during the release of the basilic vein, while the nervus cutaneus medialis of the forearm was preserved. Following the evaluation of the presence of thrill, the fascia and others were closed in anatomical layers, lifting the vein and protecting the nerve. Patients whose wounds had healed after a month underwent HD. Postoperative complications of one- and two-stage BVT, including primary and secondary patency rates, thrombosis, haemorrhage, haematoma, infection and venous aneurysm were retrospectively analysed.

Statistical analysis was performed using Windows SPSS 14.0 (SPSS Inc, Chicago, IL, USA). Normally distributed data, which were expressed as mean ± standard deviation, were assessed using the t-test. The Kolmogorov-Smirnov test was used to analyse normal distribution of the numerical data. Categorical data were examined by Fischer’s exact test. The dual logistic regression test was used to assess the effects of clinical parameters such as haematoma or fistula maturation. A p-value of < 0.05 was considered statistically significant.

Results While 28 (59%) patients were male and 19 (41%) were female in group 1, 36 (61%) were male and 23 (39%) were female in group 2. The mean follow up was 36 months. The means of age, duration of ESRF, number of AVFs, patency duration, co-morbidities and diameter of the basilic vein and brachial artery are shown in Table 1. The diameter of the operated basilic vein was significantly higher in group 1 (3.46 ± 0.2 mm), than in group 2 (2.79 ± 0.1 mm) (p < 0.05). There was no significant difference in the diameter of the brachial artery between the groups. Bleeding– clotting times of the groups are shown in Table 2 and there was no significant difference. TABLE 1. DEMOGRAPHICS OF THE PATIENTS

Variables

Group 2 two-stage BVT (n = 59)

p-value

Gender (M/F)

M = 28 (59%)

M = 36 (61%)

F = 19 (41%)

F = 23 (39%)

M = 43.1 (± 16) M = 44.9 (± 14)

F = 42.5 (± 13)

F = 44.1 (± 13)

M = 63.1 (± 17) M = 61.7 (± 20)

F = 64.5 (± 18)

F = 63.3 (± 21)

M = 5 (± 1.6)

M = 5.2 (± 1.7)

F = 5.45 (± 1.7)

F =5.0 (± 1.6)

Hypertension

Diabetes mellitus

Previously opened AVF

Variables

Group 1 one-stage BVT (n = 47)

Group 2 two-stage BVT (n = 59)

PT (sec)

17 ± 4

16 ± 4

APTT (sec)

38 ± 7

41 ± 7

INR

1.3 ± 0.5

1.5 ± 0.7

Platelet count (103/ml)

385 ± 70

367 ± 67

Bleeding time (min)

6.1 ± 1.3

5.7 ± 1.2

Clotting time (min)

7.1 ± 2.3

7.3 ± 2.1

Protein C (%)

89 ± 28

92 ± 31

D-dimer (ng/dl)

275 ± 73

321 ± 67

Fibrinogen (g/l)

3.2 ± 0.7

2.8 ± 0.5

The ratio of fistula maturation, as well as postoperative mortality and morbidity rates are shown in Table 3. There was no significant difference in mortality rate, whereas a significant difference was found in morbidity between the groups (p < 0.05). The rate of fistula maturation was significantly lower in group 1 (66%) compared to group 2 (77%) (p < 0.05). The mean time to fistula maturation was 41 ± 14 days in group 1, while it was 64 ± 28 days in group 2, indicating a significant difference between the groups (p < 0.05). With regard to auxiliary interventions, the rate of intervention for early (≤ 10 days) fistula thrombosis was significantly higher in group 1 (21%) compared to group 2 (12%). However, there was no significant difference in rate of intervention for late (≥ 10 days) fistula thrombosis between the groups (20% in group 1; 22% in group 2). The number of auxiliary interventions to manage haemorrhage and haematoma following fistula formation was significantly higher in group 1 (17%, 10%) than in group 2 (6%, 2%) (p < 0.05). Auxiliary surgical interventions are summarised in Table 4. Primary and secondary patency rates in both groups are shown in Tables 5 to 8. Statistical comparisons of primary/ secondary patency rates between the groups are shown in Figs 1 and 2.

Discussion

Group 1 one-stage BVT (n = 47)

ESRF duration (months)

TABLE 2. BLEEDING–CLOTTING TIMES OF THE GROUPS

PT: prothrombin time, APTT: active partial thromboplastin time, INR: international normalised ratio.

Statistical analysis

Mean age (years)

365

Heart disease

Peripheral vascular disease

Smoking

Mean LDL-C (mmol/l)

157 ± 26

145 ± 21

Mean basilic vein diameter (mm)

3.46 ± 0.2

2.79 ± 0.1

< 0.05

Mean brachial artery diameter (mm)

3.71 ± 1.4

3.63 ± 1.5

BVT: basilic vein transposition, AVF: arteio-venous fistula, NS: non-significant, LDL-C: low-density lipoprotein cholesterol, ESRF: end-stage renal failure, M = male, F = female.

Patients with ESRF must receive HD to survive, until they undergo renal transplantation. AVF surgery to supply extracorporeal blood flow has been performed for many years during HD.12 The TABLE 3. COMPLICATIONS

Variables

Group 1 one-stage BVT (n = 47)

Group 2 two-stage BVT (n = 59)

Mortality

3 (6%)

2 (4%)

31 (66%)

45 (77%)

< 0.05

Maturation rate

p-value

Infection

6 (12%)

5 (10%)

Thrombosis

16 (34%)

11 (23%)

< 0.05

Bleeding

17 (36%)

7 (14%)

< 0.05

Haematoma

8 (17%)

3 (6%)

< 0.05

Pseudo-aneurysm

2 (4%)

3 (6%)

Steal syndrome

4 (8%)

3 (6%)

Oedema

5 (10%)

6 (10%)

Mean fistula maturation time (day)

41 ± 14

64 ± 28

< 0.05

Mean fistula flow rate (ml/min)

280 ± 23

300 ± 31

NS: non-significant.

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optimal flow rate is ≥ 200 ml/min with an easy-to-use device, providing sufficient supply in a durable and safe procedure.13,14 For this purpose, arteries and veins of the upper limbs are mostly used. Alternative methods can be applied for patients without suitable veins.15,16 In compliance with the KDOQI recommendations, BVT is the most preferred method for fistula formation in our clinic when autologous veins are not suitable to construct radio-cephalic and brachio-cephalic AVF.2,3 In our study, fistulae formed by one- and two-stage BVT were examined in terms of patency and complication rates. No significant difference was found between the groups in terms of age, gender, ESRF and the number of fistulae previously formed. In addition, there was no significant difference in co-morbidity or the mean diameter of the brachial artery. The diameter of the basilic vein was significantly larger in group 1

(3.46 ± 0.2 mm) compared to group 2 (2.79 ± 0.1 mm) (p < 0.05). There was no significant difference in mortality rate between the groups (6% in group 1; 4% in group 2) or mean flow rate of BVT. Time to fistula maturation was significantly shorter in group 1 (mean 41 ± 14 days) compared to group 2 (mean 64 ± 28 days) (p < 0.05). The rates of postoperative complications, including infection (12% in group 1; 10% in group 2), pseudoaneurysm (4% in group 1; 6% in group 2), steal syndrome (8% in group 1; 6% in group 2), and oedema (10% in group 1; 10% in group 2) were similar, indicating no significant difference between the groups. However, there was a significant difference between the groups in respect of thrombosis (34% in group 1; 23% in group 2), haemorrhage (36% in group 1; 14% in group 2) and haematoma (17% in group 1; 6% in group 2) (p < 0.05). A review of the literature revealed that infection rate was 7% in a study conducted by Dilege et al.17 and 14% in a study carried out by Veeramanive et al.18 In our study, the infection rate was 12 and 13% in groups 1 and 2, respectively. Rivers et al.19 found the rate of pseudoaneurysm to be 3%. In our study, the rate of pseudoaneurysm was 4 and 5% in group 1 and group 2, respectively. The rate of steal syndrome was 3.2–6.5% in published studies.21-23 We found that 8% of the patients in group 1 and 11% of those in group 2 had steal syndrome, indicating a higher rate compared to the literature. A total of 4% of the patients in group 1 and 6% of those in group 2 underwent secondary corrective surgery due to steal syndrome, which is a limb-threatening

TABLE 5. SECONDARY PATENCY RATES OF GROUP 1

TABLE 7. SECONDARY PATENCY RATES OF GROUP 2

TABLE 4. ASSISTED INTERVENTIONAL SURGERY RATES Group 1 one-stage BVT (n = 47)

Group 2 two-stage BVT (n = 59)

p-value

Early (≤ 10 day) thrombosis

10 (21%)

6 (12%)

< 0.05

Bleeding

8 (17%)

3 (6%)

< 0.05

Haematoma

5 (10%)

1 (2%)

< 0.05 NS

Variables

Late (≥ 10 day) thrombosis

9 (20%)

11 (22%)

Pseudo-aneurysm

2 (4%)

3 (6%)

Steal syndrome

2 (4%)

3 (6%)

NS: non-significant.

Month

n = 47

Function loss

Function loss rate

Patency rate

Cumulative patency rate

Month

Function loss

Function loss rate

Patency rate

Cumulative patency rate

0.15

0.85

85.00

0.06

0.94

94.00

0.10

0.90

76.00

0.04

0.96

90.00

0.02

0.98

74.00

0.07

0.93

84.00

0.02

0.98

72.00

0.02

0.98

82.00

0.02

0.98

70.00

0.02

0.98

80.00

0.06

0.94

66.00

0.02

0.98

77.00

TABLE 6. PRIMARY PATENCY RATES OF GROUP 1 Month

n = 47

Function loss

Function loss rate

Patency rate

TABLE 8. PRIMARY PATENCY RATES OF GROUP 2

Cumulative patency rate

Month

n = 59

Function loss

Function loss rate

Patency rate

Cumulative patency rate

0.17

0.83

83.00

0.12

0.88

88.00

0.15

0.85

70.00

0.04

0.96

84.00

0.03

0.97

68.00

0.05

0.95

80.00

0.06

0.94

64.00

0.07

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100 80

Patency rate

n = 59

60 40 20 0

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36th month

Fig. 1. Secondary patency rates of the two groups.

90 80 70 60 50 40 30 20 10 0

18th month Group 1

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Group 2

Fig. 2. Primary patency rates of the two groups.

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disease. The incidence of corrective surgery due to steal syndrome was up to 6.5% in the literature.22,24,25 Our results for surgery due to steal syndrome were consistent with that in the literature. In our study, the rate of fistula maturation was 66% in group 1 and 77% in group 2, indicating a higher rate in group 2, whereas the rate of thrombosis was 34% in group 1 and 23% in group 2, indicating a higher rate in group 1 (p < 0.05). Review of the literature revealed that the rate of fistula maturation following BVT was 62–97%.24,26-29 In our study, the mean diameter of the operated basilic vein was significantly higher in group 1 (3.46 ± 0.2 mm) than in group 2 (2.79 ± 0.1 mm) (p < 0.05). However, the rate of fistula maturation was higher in group 2, suggesting that the basilic vein that was arterialised using two-stage BVT may have adopted the changes seen in the venous configuration, although this is a controversial issue in the literature. The rate of patency at 36 months reported by Cantelmo et al.30 was 57%, while it was 52% at 30 months as reported by Rivers et al.19 In the literature, the rate of thrombosis was 3–38% with a wide range.23,24,26-29 There are few studies in the literature comparing different techniques for BVT.5,8,31 Kakkos et al.31 compared one-stage and modified two-stage BVT and found that fistula maturation was 85.5% in group 1 and 81.6% in group 2. The authors concluded that there was no significant difference between the groups. In our study, the rate of fistula maturation was higher in group 2 than in group 1, although the mean diameter of the basilic vein was larger in group 1. This is the most important aspect of our study. The mean diameter of the basilic vein that underwent BVT was not predetermined and it is well known that many factors influence fistula maturation.1,24,26,28,29,32,33 In addition, the most important limitation of our study compared to that of Kakkos et al.31 was the non-randomised design. With the study limitations, we discuss the possible effects of two complications, haemorrhage and haematoma, on thrombosis and fistula maturation. In our study, a significant difference was observed in terms of haemorrhage (36% in group 1; 17% in group 2) and haematoma (14% in group 1; 6% in group 2) between the groups (p < 0.05). Considering an equivalent heparin dose was administered to both groups, the higher rate of haemorrhage and haematoma may have resulted from wider surgical incisions in group 1. However, randomised clinical studies are required to draw a firm conclusion. Review of the literature revealed that the rate of haematoma was 3.6–11% in other studies.10,11,34 In our study, we found the rate of haematoma to be higher in group 1(17%) than in group 2 (8%). The rate of haematoma in group 2 was therefore consistent with the literature. With regard to possible factors affecting fistula maturation following BVT, postoperative haematoma and venous hypertension may be more important than the diameter of the basilic vein. This finding is also consistent with data published in the literature.21-23,24,25,31 With regard to auxiliary interventions, the rate of intervention for early (≤ 10 days) fistula thrombosis was significantly higher in group 1 (21%) than in group 2 (12%). The number of surgeries due to haemorrhage and haematoma was 17 and 10%, respectively in group 1, and 6 and 2%, respectively in group 2 (p < 0.05). These findings support the assumption that haemorrhage and haematoma are the most important factors in

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fistula maturation and thrombosis. There was no statistically significant difference in auxiliary interventions due to late (≥ 10 days) fistula thrombosis (20, 22%), pseudo-aneurysm (4, 6%) and steal syndrome (4, 6%) between the groups.

Conclusion AVF formation using BVT is a compelling procedure for the surgeon in order to avoid possible complications, including loss of function, infection, distal ischaemia and venous oedema. Two-stage BVT is superior to one-stage BVT due to its lower rate of postoperative complications, despite the disadvantage of late fistula use. Although the diameter of the basilic vein was higher in our patients who underwent one-stage BVT, we found one-stage BVT was disadvantageous in terms of postoperative complications and fistula maturation. However, we believe the method to be applied should be individually designed until further studies can be performed to establish the superiority of either of these techniques.

References 1. 2.

3. 4.

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16.

Quinton WE, Dillard D, Scribner BH. Cannulation of blood vessels for prolonged hemodialysis. Tr Am Soc Artif Int Organs 1960; 6: 104–113. Foundation NK. KDOQI clinical practice guidelines and clinical practice recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis adequacy and vascular access. Am J Kidney Dis 2006; 48(Suppl 1): 1–322. Foundation NK. KDOQI clinical practice guidelines for vascular access, 2000. Am J Kidney Dis 2001; 37(Suppl 1): 137–181. Dagher FJ, Gelber RL, Ramos EJ, Sadler JH. Basilic vein to brachial artery fistula: a new access for chronic hemodialysis. Sthn Med J 1976; 69: 1438–1440. El Mallah S. Staged basilic vein transposition for dialysis angioaccess. Int Angiol 1998; 17: 65–68. Zielinski CM, Mittal SK, Anderson P, Cummings J, Fenton S, ReilandSmith J, et al. Delayed superficialization of brachiobasilic fistula: technique and initial experience. Arch Surg 2001; 136: 929–932. Kapala A, Szmytkowski J, Stankiewicz W, Dabrowiecki S. A modified technique of delayed basilic transposition – initial results. Eur J Vasc Endovasc Surg 2006; 32: 316–317. Hossny A. Brachiobasilic arteriovenous fistula: different surgical techniques and their effects on fistula patency and dialysis related complications. J Vasc Surg 2003; 37: 821–826. Hill BB, Chan AK, Faruqi RM, Arko FR, Zarins CK, Fogarty TJ. Keyhole technique for autologous brachiobasilic transposition arteriovenous fistula. J Vasc Surg 2005; 42: 945–50. Martinez BD, LeSar CJ, Fogarty TJ, Zarins CK, Hermann G. Transposition of the basilic vein for arteriovenous fistula: an endoscopic approach. J Am Coll Surg 2001; 192: 233-6. Weyde W, Krajewska M, Letachowicz W, Kusztal M, Penar J, Klinger M. A new technique for autogenous brachiobasilic upper arm transposition for vascular access for hemodialysis. J Vasc Access 2006; 7: 74–76. Gelabert HA, Freischlag JA. Hemodialysis access. In: Rutherford RB ed. Vascular Surgery. Philadelphia: WB Saunders, 2000: 1466–1477. Turkish Society of Nephrology. Registry of the Nephrology, Dialysis and Transplantation in Turkey. Registry 2004. Omega CRO. İstanbul, Turkey: Turkish Society of Nephrology; 2005 June. Madran H, Ozgur B, Kursad S, Sakarya A, Erhan Y, Aydede H. Vascular interventions in chronic hemodialysis. Türkiye Klinikleri Kalp Damar Cer Derg 2001; 2: 38–47. Saritas B, Okyay K, Yilmazturk H. Perforating vein – brachial artery anastomosis as an alternative to conventional arterio-venous fistulae for hemodialysis: mid-term follow-up results. Türkiye Klinikleri J Cardiovasc Sci 2010; 22(2): 200–205. Basel H, Odabasi D, Akbayrak H. A-V fistula management between

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ulnar artery and brachiocephalic vein with saphenous vein graft ınterposition: a renal hemodialysis dependent patient. Turkish J Vasc Surg 2007; 16(3): 49–54. Dilege S, Baktiroglu S, Basar Y, Genc FA, Ozgür M. Basilic vein transposition as vascular access for hemodialysis. GKD Cer Derg 1995; 3: 140–142. Veeramani M, Vyas J, Sabnis R, Desai M. Small incision basilic vein transposition technique: A good alternative to standard method. Indian J Urol 2010; 26: 145–147. Rivers SP, Scher LA, Sheehan E, Lynn R, Veith FJ. Basilic vein transposition: an underused autologous alternative to prosthetic dialysis angioaccess. J Vasc Surg 1993; 18: 391–397. Davoudi M, Tayebi P, Baheshtian A. Primary patency time of basilic vein transposition versus prosthetic brachioaxillary access grafts in hemodialysis patients. J Vasc Access 2012; e-publ. Doi:10.5301/ jva.5000109. Woo K, Farber A, Doros G, Killeen K, Kohanzadeh S. Evaluation of the efficacy of the transposed upper arm arteriovenous fistula: a single institutional review of 190 basilic and cephalic vein transposition procedures. J Vasc Surg 2007; 46: 94–100. Harper SJF, Goncalves I, Doughman T, Nicholson ML. Arteriovenous fistula formation using transposed basilic vein: extensive single centre experience. Eur J Vasc Endovasc Surg 2008; 36: 237–241. Ascher E, Hingoran A, Gunduz Y, Yorkovich Y, Ward M, Miranda J, et al. The value and limitations of the arm cephalic and basilic vein for arteriovenous access. Ann Vasc Surg 2001; 15: 89–97. Wolford HY, Hsu J, Rhodes JM, Shortell CK, Davies MG, Bakhru A, et al. Outcome after autogenous brachial-basilic upper arm transpositions in the post-National Kidney Foundation Dialysis Outcomes Quality Initiative era. J Vasc Surg 2005; 42: 951–956. Butterworth PC, Doughman TM, Wheatley TJ, Nicholson ML.

… continued from page 363 Medicine at the University of Cape Town. He is also adjunct associate professor in the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA. His specific research focus is on reducing the impact of HIV/ AIDS on women’s, maternal and child health, particularly in the areas of prevention of mother-to-child HIV transmission and contraception for HIV-infected women. He has published more than 150 peerreviewed scientific publications and also serves on a number of national and international scientific committees. He has been an active proponent of open-access scientific publishing as part of a broader commitment to increasing the availability and uptake of research across Africa. Linked to this, he is the editor of the South African Journal of HIV Medicine and helped move the journal to an openaccess platform with international indexing. His research has been recognised through a number of prestigious awards, including the British Association Award (silver medal) from the Southern African Association for the Advancement of Science (2012) and the International Leadership Award from the

26.

27.

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34.

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Arteriovenous fistula using transposed basilic vein. Br J Surg 1998; 85: 653–654. Choi HM, Lal BK, Cerveira JJ, Padberg FT Jr, Silva MB Jr, Hobson RW 2nd, et al. Durability and cumulative functional patency of transposed and nontransposed arteriovenous fistulas. J Vasc Surg 2003; 38: 1206–1212. Murphy GJ, White SA, Knight AJ, Doughman T, Nicholson ML. Longterm results of arteriovenous fistulas using transposed autologous basilic vein. Br J Surg 2000; 87: 819–823. Rao RK, Azin GD, Hood DB, Rowe VL, Kohl RD, Katz SG, et al. Basilic vein transposition fistula: a good option for maintaining hemodialysis access site options? J Vasc Surg 2004; 39: 1043–1047. Fitzgerald JT, Schanzer A, Chin AI, McVicar JP, Perez RV, Troppmann C. Outcomes of upper arm arteriovenous fistulas for maintenance hemodialysis access. Arch Surg 2004; 139: 201–208. Cantelmo NL, LoGerfo FW, Menzoian JO. Brachiobasilic and brachiocephalic fistulas as secondary angioaccess routes. Surg Gynecol Obstet 1982; 155: 545–548. Kakkos SK, Haddad GK, Weaver MR, Haddad RK, Scully MM. Basilic vein transposition: What is the optimal technique? Eur J Vasc Endovasc Surg 2010; 39: 612–619. Patel ST, Hughes J, Mills JL Sr. Failure of arteriovenous fistula maturation: an unintended consequence of exceeding dialysis outcome quality initiative guidelines for hemodialysis Access. J Vasc Surg 2003; 38(3): 439–445. Berman SS, Gentile AT. Impact of secondary procedures in autogenous arteriovenous fistula maturation and maintenance. J Vasc Surg 2001; 34: 866–871. Sunil S, Sinha S, Sharma AK. Provision of long-term vascular access for haemodialysis in a patient with exhausted superficial arm veins. Br J Surg 2002; 89: 122–123.

Elizabeth Glaser Paediatric AIDS Foundation (2011–2014). Scheffer is the founder of the Biomedical Engineering Research Group (BERG) at Stellenbosch University. BERG is currently one of the leading groups in South Africa for research in the field of biomedical engineering. He has co-authored more than 100 scientific articles and supervised a vast number of postgraduate students. Some of his previous prizes and awards include, ‘Upcoming researcher of the year’, Faculty of Engineering, University of Stellenbosch, 2005; Winner in the DTI Technology Awards 2008 for best SMME development; Joint winner of the Baumgarten-Wagon award (Germany) in 2009 for outstanding contributions to engineering education, and the Rector’s award for excellent research 2010 and 2012. At the same event, the Sydney Brenner Fellowship, administered by the Academy and supported by the Oppenheimer Memorial Trust, was awarded for postdoctoral studies in the molecular and cellular biosciences conducted at an advanced level in South Africa. This award was established when Dr Sydney Brenner donated a portion of his 2002 Nobel Prize to ASSAf to permit ASSAf (in partnership with the Oppenheimer Memorial

Trust) to offer a prestigious postdoctoral Fellowship for research in molecular biology to be undertaken in South Africa over two years by an outstanding young scientist. The emphasis in the selection is on the excellence of the academic track record, evidence of unusual creativity and ingenuity in addressing scientific problems, both the novelty and feasibility of the proposed approach, and the quality, adequacy and appropriateness of the host environment. The 2014/15 Fellowship was awarded to Dr Anna Coussens, a postdoctoral research fellow at the University of Cape Town. She received her PhD from Queensland University of Technology, Australia, in developmental molecular biology. Thereafter she volunteered in Uganda with a medical students’ organisation, running health surveys in remote communities. This experience shaped her desire to become an infectious disease immunologist. She then moved to London where she contributed significantly to a programme of work on vitamin D regulation of the immune response to tuberculosis. Now in Cape Town, she is defining how seasonal UVB patterns affect vitamin D levels in healthy young adults and how this impacts on their immune response to HIV-1 infection.

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Review Articles Socio-cultural, environmental and behavioural determinants of obesity in black South African women LISA K MICKLESFIELD, ESTELLE V LAMBERT, DAVID JOHN HUME, SARAH CHANTLER, PAULA R PIENAAR, KASHA DICKIE, THANDI PUOANE, JULIA H GOEDECKE

Abstract

Prevalence of obesity

South Africa (SA) is undergoing a rapid epidemiological transition and has the highest prevalence of obesity in subSaharan Africa (SSA), with black women being the most affected (obesity prevalence 31.8%). Although genetic factors are important, socio-cultural, environmental and behavioural factors, as well as the influence of socio-economic status, more likely explain the high prevalence of obesity in black SA women. This review examines these determinants in black SA women, and compares them to their white counterparts, black SA men, and where appropriate, to women from SSA. Specifically this review focuses on environmental factors influencing obesity, the influence of urbanisation, as well as the interaction with socio-cultural and socio-economic factors. In addition, the role of maternal and early life factors and cultural aspects relating to body image are discussed. This information can be used to guide public health interventions aimed at reducing obesity in black SA women.

According to the World Health Organisation (WHO), obesity is a global epidemic that affects 500 million people worldwide, and is predicted to increase to one billion people by 2030.1 The rising prevalence of obesity is associated with an increased risk of non-communicable diseases (NCDs), such as cardiovascular disease, type 2 diabetes and several types of cancer.2 Until recently, Africa has been spared from this epidemic as it grappled with under-nutrition, as well as infectious diseases such as HIV and tuberculosis. However, over the last century the continent has seen a rapid rise in the prevalence of overweight and obesity, and their associated co-morbidities.3-5 This dual burden of disease in Africa is particularly devastating as it is compounded by the metabolic consequences of the roll out of anti-retroviral medications in certain countries.6,7 Within sub-Saharan Africa (SSA), the prevalence of obesity differs widely from as low as 1% in Ethiopia8 to as high as 27% in South Africa (SA).9 Only three other countries in SSA report a national obesity prevalence of over 20%, including Mauritania (23.3%),10 Swaziland (23.1%)11 and Gabon (21.5%).10 In SA, statistics from the 1998 National Demographic and Health survey (SADHS) reported an obesity prevalence of 30% in all women over the age of 15 years, which is more than three times higher than the prevalence in men (7.5%).12 Those most affected were black women, with a prevalence of 31.8%, compared to 6% in black men, 22.7% in white women, 21.1% in Indian women and 26.3% in women of mixed ancestry. The most recent SADHS undertaken in 20039 reported that the prevalence of obesity remains high in black women (28.5%). Of concern is the large increase in the prevalence of obesity among black SA adolescent girls,13 who will soon be entering adulthood and will therefore be at increased risk for future NCDs. For the purposes of this review, we attempted to outline the socio-cultural, environmental and behavioural determinants of obesity in black SA women, and compare them to their white counterparts, black SA men, and where appropriate, to women from SSA. The literature included in this review was selected from the available literature to highlight the magnitude and complexity of the determinants of obesity in this population (Fig. 1).

Keywords: South Africa, obesity, food security, diet, physical activity, body image, socio-economic status Submitted 12/6/13, accepted 12/9/13 Published online 19/9/13 Cardiovasc J Afr 2013; 24: 369â&#x20AC;&#x201C;375

www.cvja.co.za

DOI: 10.5830/CVJA-2013-069

MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa LISA K MICKLESFIELD, PhD, lisa.micklesfield@uct.ac.za

UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, UCT School of Health Sciences, University of Cape Town, South Africa LISA K MICKLESFIELD, PhD ESTELLE V LAMBERT, PhD DAVID JOHN HUME, BSc (Med) (Hons) SARAH CHANTLER, BSc (Med) (Hons) PAULA R PIENAAR, BSc (Med) (Hons) KASHA DICKIE, MSc (Med) JULIA H GOEDECKE

School of Public Health, University of the Western Cape, South Africa THANDI PUOANE, PhD

South African Medical Research Council, Parow, South Africa JULIA H GOEDECKE, PhD

Definitions of race, ethnicity and culture To contextualise this review, it is necessary to consider our definitions of race, ethnicity and culture, and the potential interactions between these constructs, particularly within the

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Soc ioec on

Ge n

r de

tus sta ic

Physical activity

ni ba Ur

Maternal and early life factors

sa tio n

Body image Diet and eating behaviour

at io n

Obesity

uc Ed

Fig. 1. A schematic representation of the inter-relationships between the socio-cultural, behavioural and environmental determinants of obesity in black South African women discussed in this review.

SA context where there are the potentially confounding effects of socio-economic status. Race has been defined by Williams et al.14 as ‘a complex multidimensional construct reflecting the confluence of biological factors and geographical origins, culture, economic, political, and legal factors, as well as racism’. In a recent commentary,15 it was suggested that race and ethnicity share a similar definition, however, the difference between the two constructs lies in the fact that ethnicity is usually defined by the group itself, whereas race is typically defined by others outside ‘the group’. Culture, on the other hand, has been defined as ‘the learned and shared beliefs, values, and life ways of a designated or particular group which are generally transmitted inter-generationally and influences one’s thinking and action modes’.15 For demographic and restitution purposes, the Government currently classifies race into black (ethnic Africans), white (Europeans, Jews and Middle Easterners), coloured or mixed ancestry (mixed race) and Indian (South Asian).

Socio-economic status and education Historically, black South Africans have been compromised in terms of education, access to healthcare and earning capacity under apartheid laws. This is still currently reflected in the 2008/2009 South African Living Conditions of Household Survey (LCS),16 in which it was demonstrated that 25% of black households fell within the lowest quintile of annual household consumption expenditure compared to 0.7% of white households, whereas 81% of white households fell within the highest quintile compared to 8.2% of black households. Differences in obesity and disease prevalence between these ethnic groups may be partly attributed to or mediated by these social inequalities.17 Studies in developed countries have shown an inverse relationship between socio-economic status and obesity,18,19 however studies in SA,12,20-22 as well as other SSA countries23-26 show a consistent positive association between obesity and socio-economic status. In these studies, obesity was positively associated with access to clean water and electricity,21,25 reduced housing density,22,25 as well as more money spent on food,27 higher energy intake,25 commuting by taxi/vehicle28 and reduced

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physical activity or increased sedentary behaviour,22,28-31 factors representing a transition towards a more Western lifestyle. In addition, in many black African communities, obesity or overweight may still be considered a sign of good health and beauty, as well as affluence,32,33 further impacting on the relationship between socio-economic status and obesity. On the other hand, level of education, although highly related to socio-economic status has been shown to be independently associated with obesity in SA and other SSA countries. Studies in many SSA countries,23,24,27 as well as regions in SA with lower socio-economic status,21 have shown a positive association between level of education and obesity. By contrast, results from the SADHS suggest that the relationship between education and obesity is not linear, as women with no education and women with a tertiary education had a lower body mass index (BMI) than those with some schooling.12 This may reflect the wider distribution of both education and socio-economic status in SA, which has recently been re-classified as a middle-income country,1 and which has one of the highest GINI coefficients in the world, suggesting extreme inequality with regard to poverty and wealth.34

Gender Studies in SA12,20,21,35 and other SSA countries23,25,26,28,29 have consistently reported that the prevalence of obesity is greater in women than men. Case and Menendez,20 using data collected from an informal urban settlement in SA, identified two factors to explain the gender difference in obesity rates in their study: (1) being nutritionally deprived as children; and (2) having a higher socio-economic status. These factors were associated with obesity in women, but not in men. Traditionally, black SA households are strongly patriarchal, with men holding a dominant position. For this reason, boys have been better cared for and nourished as babies and infants, so they do not necessarily experience the same level of nutritional deprivation at a young age as girls.36 However, due to migrant labour and high death rates related to HIV/AIDS among young adults, nearly half of all households in SA are headed by women.37 These households are among the poorest and most marginalised.16 In 2009, more than 20% of female-headed households reported experiencing hunger (skipping meals or running out of money) compared to only 15% of male-headed households.38

Urbanisation Rural and urban black SA communities have historically faced very different public health challenges, with infectious diseases associated with under-nutrition prevalent in rural communities, and a rising prevalence of NCDs associated with over-nutrition in urban-dwelling communities.30 This rural–urban gradient is still present in most SSA countries,30 but in SA, the disparities between rural and urban settings are attenuated. The 2003 SADHS reported a 21% prevalence of obesity in rural black SA women compared to 31% in urban black SA women. Urbanisation is accompanied by the adoption of a Westernised lifestyle, however in SA many cultural beliefs around lifestyle behaviours and body image are retained.36 Differences in diet have been identified as one of the possible causes of urban– rural differences in obesity prevalence,39 and the term ‘nutrition

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transition’ is now commonly used to refer to changes in the diet that occur with urbanisation. Recent data also suggest however that the nutrition transition is occurring within rural areas, possibly explaining the increasing prevalence of obesity in less developed settings.40-42 Another major contributing factor to the high prevalence of obesity in urban versus rural communities in SA and SSA is the increase in physical inactivity and the adoption of a more sedentary lifestyle with urbanisation.30,31,43

Maternal and early life factors Nutrient deprivation and the timing thereof during the intrauterine period leads to foetal programming, resulting in genetic and epigenetic adaptations.44,45 These biological adaptations predispose an individual to obesity when exposed later in life to an environment abundant with energy-dense and/or high-fat foods, as is currently experienced in middle-income countries such as SA.46 The prevalence of low birth weight (< 2.5 kg), very often the consequence of nutrient deprivation in utero, is 15% in SA, which is marginally higher than the overall prevalence of 13% in SSA.47 The COHORTS initiative, a study of birth cohorts in five low- or middle-income countries including SA, has shown that size at birth is linked to major features of the metabolic syndrome in adulthood, including obesity.48,49 However the relationship between pre-natal exposure and obesity in later life has been shown to fit a U-shaped curve. More specifically, low birth weight has been associated with increased levels of adult abdominal adiposity, while high birth weight was associated with overall adult adiposity.50,51 High birth weight has been shown to be a result of excessive maternal body weight or excessive weight gain during pregnancy.52,53 This is of concern in SA, given the high prevalence of obesity in SA adolescents and adult women. It is compounded further by healthcare inequalities, associated perceptions of the healthcare system, and the periodic lack of adequate resources that have led to late or poor attendance rates at antenatal clinics.54,55 Under-nutrition during the first six months of life increases the risk of stunting. Global statistics indicate that in SSA, the prevalence of stunting under the age of five years is 39%, with stunting rates ranging from 27% in Ghana to 55% in Niger, and SA reporting a stunting prevalence of 24%.47 In transitional societies of SSA, stunting and adolescent obesity may co-exist in the same geographic population.56 A cross-sectional growth survey conducted in rural SA children and adolescents aged one to 20 years showed that an estimated one in five children aged one to four years was stunted. Concurrently, the prevalence of combined overweight/ obesity was 20–25% among girls in late adolescence.56 Steyn et al. showed that stunting in children under the age of nine years resulted in a 1.8-fold increased risk of obesity.57 Moreover, other evidence suggests that individuals who were stunted as children were more likely to be overweight as adults.58 Furthermore, excessive weight gain during childhood was associated with adult body composition.59

Physical activity Physical activity may be defined as any bodily movement produced by skeletal muscle that requires energy expenditure.60

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Prior to the early 2000s, the evidence base for physical activity and health in SSA was limited, fragmented and localised, with few nationally representative samples. Self-report physical activity questionnaires were not standardised, often not validated in the populations in which they were being applied, and the focus was primarily on energy balance and seasonal agriculturerelated physical activity and under-nutrition. Recent WHO Stepwise surveillance initiatives, using a common instrument called the Global Physical Activity Questionnaire (GPAQ), have yielded a growing body of evidence on the global trends in physical activity and inactivity.61 The physical activity recommendations for health in adults are defined as engaging in at least 150 minutes of moderate-intensity activity per week, or 75 minutes of vigorous-intensity activity per week, or an equivalent combination of moderate- and vigorous-intensity activity.62 Physical inactivity has been defined as ‘doing no or very little at work, at home, for transport or during discretionary time’.63 In the African region, estimates of the prevalence of inactivity are widely varying, ranging from as low as 3.8 and 1.5% in women and men in the Comoros, to 15 and 9% in Ghanaian women and men, and 48 and 45% in SA women and men, respectively.61,63,64 The highest reported prevalences of inactivity in this region are similar in magnitude to those seen in North America, and higher than those reported in South America, Western Pacific or Asia.10 It appears that the inactivity gradient and obesity seem to be related to development within the region and within the country. An ecological evaluation of inactivity in women and men in 13 SSA countries demonstrated a significant correlation between gross national income (per capita) and prevalence of selfreported inactivity.65 Sobngwi et al.66 studied over 1 600 Cameroonian adults living in either rural or urban settings and found that lowered the odds for overweight and obesity in a dose-dependent manner, and that the odds for overweight and obesity, as well as impaired glucose tolerance, were significantly increased with increased lifetime exposure to an urban environment (percentage of life in a city). Conversely, in SA, results from the THUSA study showed that among a group of black adult women, physical inactivity was a stronger correlate of obesity than socio-economic status and dietary factors.31 As physical activity has been identified as playing a key role in influencing health outcomes, even in communities undergoing epidemiological transition, trends in physical activity behaviour have implications for public health and the emerging burden of NCDs in the region. Armstrong and Bull67 highlighted that in developing countries, ‘occupational-, domestic- and transport-related activities may contribute more to overall energy expenditure than leisure-time or recreational activity’, and therefore a multi-domain approach to the measurement of physical activity is essential. A recent study including data from 22 African countries showed a higher proportion of adult men compared to women (84 vs 76%) meeting the global physical activity recommendations.64 Although levels of physical activity varied greatly across these countries and population sub-groups, the study found that leisure time activity (5%) was consistently low, irrespective of gender, whereas work activity (moderate and vigorous combined) contributed the most (49%) to total physical activity time, followed by transportrelated activity (46%).64

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In SA, 25–37% of adults are sufficiently active,63 and data from the 2003 SADHS has shown that half the population are insufficiently active.9 Moreover, the SA survey shows a rural-to-urban gradient, with reduced physical activity levels with increasing urbanisation. Moreover, increasing education is associated with reduced occupational physical activity and increased leisure activity. These findings are corroborated by objective measurement in smaller regional studies in SSA, which demonstrate similar physical activity trends, with adult men being more physically active compared to adult women in both urban and rural settings, and education level affecting the domain of activity.68-70 Traditional methods for collecting physical activity by selfreport may over- or under-estimate actual levels.71 Moreover, ‘light activity’ is overlooked entirely. This is despite the fact that urban-dwelling persons in low- or middle-income countries such as SA are likely to spend a relatively large portion of their day in at least light activity, as opposed to being entirely sedentary (Kroff, pers commun, 2012). Importantly, work by Cook et al.43 has demonstrated that even light activity (accumulated steps per day) is associated with a reduced risk for obesity in a dosedependent manner. Adjusting for age, motor vehicle access, education, tobacco use and co-morbidities, and BMI was 1.4 kg/ m2 lower per 5 000 steps/day, and compared to being sedentary, the risk of obesity (BMI ≥ 30 kg/m2) was 52% lower for 10 000 steps/day. In countries such as SA, factors such as culture, socioeconomic status and the built environment may act as barriers to physical activity. For example, in a convenience sample of largely urban-dwelling South Africans, self-reported leisuretime moderate to vigorous physical activity was significantly higher in those persons living in neighbourhoods in which crime was not perceived to be a problem. These results are supported by recent work from Nigeria where they showed that perceived safety, aesthetics and cleanliness were inversely associated with obesity and positively associated with physical activity.72 However, in SA communities, walking for transport has still been shown to be higher in persons from communities in which there are no pavements (Lambert, Tshabangu and Naidoo, pers commun, 2012), suggesting that many behaviours are outside of an individuals own volition. Cultural barriers to physical activity in black SA women include the acceptability of wearing tight-fitting clothing when participating in sport, as well as the perception that participating in leisure-time physical activity takes time away from household chores.73

Diet and eating behaviour Dietary intake and quality have been shown to be associated with the prevalence and risk of obesity.74 Obesogenic dietary behaviours include a high-energy intake, high dietary fat and sugar intake, low-fibre fruit and vegetable intake, or a combination of the above. Several of these dietary habits and behaviours are associated with the adoption of a more Western lifestyle and represent the nutrition transition in developing countries. When compared to other SSA countries, SA is considered to be further along the nutrition transition, characterised by higher intakes of dietary energy (600 kCal above the mean for 39 other SSA countries) and fat intake (24.5% vs sample mean of 18.9%), as well as higher levels of obesity than other countries.46 In a

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study of Kenyan and SA women, Steyn et al.75 showed that the rural environment differed between countries, with more than 60% of rural Kenyan women having access to land, which was associated with a higher nutrient mean adequacy ratio, dietary diversity score and food variety score than rural SA women. This finding highlights the difference in the effect of the rural– urban environment of different populations along the nutrition transition. In SA, data from the 2003 SADHS showed an increase in dietary quality with urbanisation, as characterised by an improvement in micronutrient intake (micronutrient score based on tertiles of the RDA).9 In contrast, Oldewage-Theron et al.76 reported that nutrient quality was poor in peri-urban black SA women, with low food variety and diversity scores attributed to low household food security and availability. Consistent within all of these SA studies, including the THUSA study,39 urbanisation was associated with an increase in dietary fat intake, which corresponded to the increased prevalence of obesity in urban compared to rural women. Most black South Africans who urbanise do so into informal settlements that may not be situated close to any of the large food chains that offer a greater variety and quality of food. The most convenient place to purchase food is from informal vendors who sell inexpensive and less varied foods of poor quality. Indeed, data from a study in SA children showed that the lack of grocerystyle shops and many accessible tuck shops and street vendors is shaping new buying habits of children that include a higher intake of less nutritious foods.77 For example, a study of adolescents in the same cohort reported the frequent purchase of the ‘quarter’, a combination of white bread, polony, fried chips and cheese, as a meal.78 The ‘quarter’ is of good economical value based on the cost/kCal, but is low in fibre and micronutrient quality. Temple et al. have shown that a healthy diet is more expensive than a less healthy diet, and therefore is not affordable for the majority of South Africans.79 Socio-economic status is another important factor that influences dietary quality and food choices. Increased wealth and disposable income contribute to food choices and are associated with the aspiration to consume more meat products, bigger portion sizes, and a more frequent intake of fast foods.73 Conversely, low household food security is associated with poor dietary quality, characterised by low food variety and diversity scores.80 Household food security may be described as a continuum, from food secure, food insufficiency (some concern regarding having enough funds to buy food for the month, without changing diet), low food security (typically reducing the quality of the diet), to food insecure (where there is a reduced food intake and skipping meals).81 Notably, mothers who are food insecure are more likely to be overweight or obese than men and women without children, and food-insecure fathers. Martin and Lippert81 showed that this is not as a result of biological changes that occur with pregnancy, but rather may be the adoption of strategies, albeit unhealthy, to protect their children when faced with food insecurity. Furthermore, single mothers appear to be at greater risk for food insecurity and obesity, compared to women with partners. However, once households are truly food insecure, women are more likely to be underweight.

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In low-income countries in SSA, children of overweight mothers are often underweight,82 which differs from the situation in SA in which children of overweight mothers are more likely to be overweight.83 The notion that food insecurity is implicated in adult obesity is paradoxical, but may be explained by the consumption of energy-dense foods of low nutritional value.

Body image Cross-sectional studies have revealed that, unlike the vast majority of women who favour the lean, Westernised archetype, there is a preference for a larger body size among black SA women.32 This ideal stems from a cluster of culture-bound beliefs, which promote lifestyle behaviours commonly associated with obesity. International research has consistently shown that, after controlling for age, education, socio-economic status and body weight, men, irrespective of ethnicity, and black women display the lowest degrees of body size dissatisfaction compared to other ethnic groups.84-87 Furthermore, results from the SADHS confirm that black women were more likely to under-estimate their body size compared to women of other ethnic groups.12 In addition to black SA families showing a greater tolerance for increased body size,33 strong mother–daughter resemblances have been identified for numerous body image constructs, including body size ideals and perceptions of body size dissatisfaction.88 Socialisation moulds the body image of these women throughout all life stages, and may explain why this ideal is so well maintained from early childhood into adulthood. For instance, young girls are encouraged to be plump, with weight gain prior to marriage indicative of fertility and the ability to bear children.89 In addition, while men are socialised to do hard labour, girls are expected to perform light labour, which may provide limited motivation for a leaner body since activities of this nature do not necessitate high levels of physical aptitude.90 Similarly, low physical activity is due to the belief that physical activity is associated with weight loss, as well as sub-optimal environmental conditions such as a high crime rate and overcrowding.12,32 Notably, similar attitudes toward weight control have been found among black women in rural areas, where it was shown that most overweight and obese women did not desire weight loss.91 Ethnic body size preferences have been shown to govern how individuals respond to insults such as disease and sexual abuse. For example, a widely held belief among black SA women is that large people are happy and healthy, whereas those who are slender are perceived to experience personal problems and that they may have diseases such as HIV/AIDS.92 Furthermore, Goedecke et al.93 demonstrated that ethnicity altered the relationship between childhood sexual abuse and obesity. In this small study, white women who were sexually abused as children were more likely to be obese as adults. As obesity is viewed as less attractive, this has been suggested to protect against future sexual advances/abuses. By contrast, black women who were sexually abused as children were more likely to be lean, which was suggested as a means of protecting themselves from further abuse. Furthermore, other studies have reported that large women are respected, dignified and cannot be pushed around.32,94 The influence of family and community also alters body size and satisfaction. For example, once a woman marries, she

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is encouraged to gain weight as this signifies her husband’s ability to support her financially.32 In addition, the mother of the household is expected to be an authoritative figure capable of commanding respect from her children.36 This, combined with the expectation by black SA communities that people in positions of power should be big, promotes the adoption of higher degrees of tolerance for an increased body size. Puoane et al.32 conducted a study on SA community health workers, who are respected and important members of the community and who play an important role in assisting with the communication between the community and the formal health sector, and found that 95% were overweight or obese. Given that media influences extend further into disadvantaged areas as the economy improves, black SA women are increasingly exposed to conflicting body size ideals. Future studies should therefore monitor the effect of such influences on body size preferences.

Conclusion There is compelling evidence that the prevalence of obesity is increasing in SSA, and that this increase is linked to urbanisation, economic development and concomitant lifestyle risk factors, such as physical inactivity and poor dietary practices. In addition, there are a number of paradoxes that have emerged, including the positive association between food insecurity and obesity, the non-linear association between education and obesity, as well as the distinct differences between patterns and determinants of obesity in men and women in the region. Although this was not a systematic review, which may be considered a limitation, this review highlights the complexity of various socio-cultural, environmental and behavioural factors associated with obesity in black SA women. Public health interventions targeted at individual behavioural risk factors, although important, may have limited success in reducing obesity if other contributing factors such as culture, environment and socio-economic status are not considered.

Key messages • The prevalence of obesity is increasing in SSA, and is linked to urbanisation, economic development, and concomitant lifestyle risk factors, such as physical inactivity and poor dietary practices. • Socio-cultural, environmental and behavioural factors, as well as the influence of socio-economic status, contribute significantly to the high prevalence of obesity in black SA women. • Barriers to physical activity in black SA women include culture, socio-economic status and the built environment. • Food insecurity and dietary quality contribute to the prevalence of obesity in SA.

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The ADVANCE cardiovascular risk model and current strategies for cardiovascular disease risk evaluation in people with diabetes Andre Pascal Kengne

Abstract Purpose: To critically examine existing approaches to cardiovascular disease (CVD) risk evaluation in people with diabetes, and discuss the use of accurate and validated absolute CVD risk tools as an appropriate basis for CVD prevention in people with diabetes. Methods: This was a narrative review using evidence from the ADVANCE study and all relevant publications identified via PubMed MEDLINE. Results: There is sufficient evidence that diabetes does not confer a CVD risk equivalent to that in non-diabetic people with existing CVD in all circumstances. In people with diabetes, CVD risk follows a gradient. Reliably capturing this gradient depends on an adequate combination of several risk factors. Many global CVD risk tools applicable to people with diabetes have been developed. Those derived from older cohorts are less accurate in contemporary populations and many newer tools have not been tested. The ADVANCE risk engine, recently developed from the large multinational ADVANCE study, showed acceptable performance on the ADVANCE population and largely outperformed the popular Framingham risk equation when tested on the multinational DIAB-HYCAR cohort of people with type 2 diabetes. Conclusions: The high-risk status conferred by diabetes does not preclude estimation of absolute CVD risk using tools such as the ADVANCE risk engine and its use as the basis for initiating and intensifying CVD preventative measures. Adopting such an accurate and validated tool will likely improve prescriptions and outcomes of diabetes care. Keywords: diabetes mellitus, cardiovascular disease, risk evaluation, ADVANCE, absolute risk Submitted 6/5/13, accepted 10/6/13 Cardiovasc J Afr 2013; 24: 376–381

www.cvja.co.za

DOI: 10.5830/CVJA-2013-078

Cardiovascular disease (CVD), the leading global killer, is multifactorial by nature. No single risk factor taken alone is able to distinguish people who will go on to develop a cardiovascular event from those who will not. This consideration forms the basis of the contemporary multifactorial approaches to CVD risk evaluation and reduction. A key aim of CVD risk evaluation is to identify those in the population who’s health outcomes can be modified by performing more medical tests, starting treatments to reduce the South African Medical Research Council, Tygerberg, Cape Town, South Africa ANDRE PASCAL KENGNE, andre.kengne@mrc.ac.za

level of risk factors or increasing the doses of prescribed riskreducing therapies.1,2 Estimated risks are also used to educate patients about their chances of experiencing a cardiovascular event within a given time period (for example, five or 10 years). Equipped with this knowledge, patients are more likely to be motivated to adopt healthy lifestyle measures and/or to observe prescribed risk-modifying treatments. These patients are also more likely to regularly report back to their healthcare provider for monitoring and adaptation of treatments, to lower and maintain their risk factors at optimal levels. Concerning CVD in people with diabetes, healthcare providers who see these patients on a routine basis are interested in gauging the chances of their patients developing any major CVD event over a reasonable period of time (often five to 10 years), and not just specific components such as stroke or myocardial infarction. These busy healthcare providers are also interested in assessing the CVD risk of their patients using accurate and validated global CVD risk-evaluation tools.3-5 In the general population, efforts to develop reliable tools for evaluating CVD risk based on a combination of several risk factors have paralleled efforts to improve our understanding of the determinants of CVD and more efficient ways to control them.6 These efforts were initially led by the Framingham investigators, and more recently by investigators from other parts of the world.6,7 The first attempts to develop such tools from the Framingham study date back to the year 1967.8 These first tools, however, did not account for diabetes status or for any other indicator of chronic hyperglycaemia. Although many subsequent Framingham tools took diabetes status into consideration, the uptake of the Framingham tools in people with diabetes around the world has remained very limited, resulting in the adoption of multivariable CVD tools in people with diabetes to lag behind the general population. One reason was the lack of trust among researchers on the validity of the Framingham tools in people with diabetes, due to the relatively small number of people with diabetes in the Framingham cohort, and the non-inclusion of other indicators of exposure to chronic hyperglycaemia in the Framingham tools.9 Another major reason was the publication in the late 1990s of a study from Finland suggesting that people with diabetes but no history of cardiovascular disease had a future risk of CVD similar to the risk of non-diabetic people who have survived a CVD event in the past.10 This study inspired the concept of diabetes as a ‘CVD risk equivalent’, based on which people with diabetes should be treated with cardiovascular risk-reducing therapies such as statins or aspirin, without taking into consideration their absolute CVD risk levels. However, the concept of diabetes as a CVD risk equivalent has been losing ground in recent years, with the accumulating evidence challenging its validity in all circumstances,11 and supporting the

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importance of absolute risk estimation in people with diabetes as the appropriate basis for CVD risk-factor modification. Such an approach is further supported by the gradual shift in the management of diabetes mellitus from a glucocentric focus to an intensive multifactorial strategy targeting reduction in the risk of both macro- and microvascular complications of diabetes.12,13 The growing recognition of the importance of global CVD risk in people with diabetes has generated interest among researchers to develop tools with improved performance to estimate absolute risk in people with diabetes, or to establish the validity of the existing ones and refine their performance.7 The following development is a discussion on the rationale and strategies for global CVD risk estimation in people with diabetes, with emphasis on the specificities and limitations of these strategies. The discussion is largely inspired by new knowledge gained from CVD risk modelling in the ADVANCE study.3,14

Overview of global cardiovascular risk assessment Global cardiovascular risk assessment is based on the combination of predictive information from several cardiovascular risk factors using mathematical equations (also called models). In those models, the coefficient of each included risk factor indicates its relative contribution to the overall (global) CVD risk.2,15 A model can be used to estimate the risk that a disease is present (diagnostic model) or to estimate the risk that a particular disease or health event will occur within a given time period (prognostic models). The focus of the current article is on prognostic models. Once developed, a cardiovascular risk model normally requires a validation in both the sample population that was used to develop the model (internal validation) and in independent populations (external validation). Validation consists of testing whether the prognostic model accurately estimates the risk of future events in one or several populations.2,15 The performance of absolute cardiovascular risk models in validation studies is commonly assessed in terms of discrimination, calibration and, more recently, reclassification.2,15 Discrimination is the ability of the model to distinguish people who go on to develop a cardiovascular event and those who remain event free.2,15 For example, for two individuals with diabetes with one developing a cardiovascular event after 10 years of follow up and the other remaining CVD free within that same time period, a discriminating model will systematically assign, at the start of the follow up, a higher absolute risk to the first subject compared to the second. Discrimination is commonly assessed using the C-statistic, which ranges from 0.5 (lack of discrimination) to 1.0 (perfect discrimination).1,2,15 In general, a C-statistic of 0.7 or greater is considered acceptable. Calibration describes the agreement between estimated and observed risks. It is assessed by comparing absolute risk estimates from the model with the actual event rates in the test population.1,2,15 For illustration, a 10-year estimated absolute risk of CVD of 20% for a patient indicates that, in a given group of patients with similar characteristics, 20% will experience a cardiovascular event within a 10-year period of follow up. The most commonly reported measure of calibration is the Hosmer-Lemeshow statistic. Estimates of calibration are sensitive to differences in background levels of risk across

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populations. For example, if a given CVD risk model is developed in a high-risk population but tested in a low-risk population, the estimated absolute risks will be unreliably high. Recalibration of the risk model by adjusting the baseline risk estimates to fit the target population may help correcting the over- or underestimation of risk.1,15

Global cardiovascular risk estimation in people with diabetes Global CVD risk has been estimated in people with diabetes using essentially three main approaches.16 In the ‘CVD riskequivalent’ approach described above, the presence of diabetes mellitus is considered to confer a 10-year absolute CVD risk of 20% or more, which is approximately the 10-year CVD event rate observed in non-diabetic individuals with a prior history of CVD. Such an approach appears to be counter-intuitive as the CVD risk is not uniformly distributed among people with diabetes. This is further supported by many studies showing multivariable risk estimation to be significantly better than classification of diabetes as a cardiovascular risk equivalent.17,18 In the second approach, also termed ‘step approach’, unifying CVD risk-estimation models are developed for both people with diabetes and those without the condition. This approach assumes that major risk factors for CVD are related to future occurrence of CVD in a similar way, regardless of the status for diabetes mellitus. Stated otherwise, everything else being equal, an individual with diabetes will always have a higher risk of CVD (by a constant amount) than the non-diabetic subject with the same level of other risk factors (e.g. blood pressure or lipid levels). This has been the basis for models such as the popular Framingham cardiovascular absolute-risk models.16 In the last approach, also known as the ‘interaction approach’, CVD risk models are constructed separately for people with and without diabetes. This approach suggests that risk factors are related to future CVD risk in different ways in people with and without diabetes. This approach in people with diabetes was initially used by the UKPDS investigators.9,19 Available studies largely suggest that classical cardiovascular risk factors (including smoking, blood pressure and lipid variables) and even some novel risk factors,16,20-23 affect the risk of CVD in similar ways in people with and without diabetes with no evidence of interaction. Some risk factors or characteristics are likely to be more frequent in people with diabetes and may justify separate cardiovascular risk models for people with diabetes. These diabetes-specific characteristics include prescriptions of cardiovascular risk-reducing therapies, which may differ in people with and without diabetes. Additional specific factors are haemoglobin A1c (HbA1c) levels, urinary albumin excretion rate and markers of microvascular complications of diabetes in general (especially retinopathy). These have been demonstrated to be associated with CVD risk and can contribute useful information to predictions.24-29

Performance of popular CVD risk models and the ADVANCE study At the time the ADVANCE study was conducted, CVD riskprediction models in the general population were dominated by models developed from the Framingham Heart study, which

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for many could also be used in people with diabetes.7 CVD risk models specific to people with diabetes were also available, particularly those from the UKPDS study.7 However, the clinical utility and comparative performance of these popular CVD risk models in contemporary populations with diabetes in diverse settings were still to be established. Therefore, one of the major initial steps was to conduct extensive validation studies of the Framingham and UKPDS CVD risk models, using the unique features of the ADVANCE cohort.3 These validation studies revealed that, in the cohort of ADVANCE participants who had no known history of CVD at their enrolment in the trial, the four-year absolute risk of cardiovascular events and components was largely overestimated by the Framingham–Anderson,30 Framingham–D’Agostino31 and UKPDS risk models.9,19 This overestimation was also observed in men and women, Caucasians and non-Caucasians, and the double-placebo cohort (i.e. those assigned to the placebo group in the blood pressure-lowering arm and the standard-care group of the blood glucose control arm).3 Discrimination of the Framingham and UKPDS risk models in predicting CVD events in ADVANCE was poor for stroke, and modest to acceptable for coronary heart disease and total CVD. Recalibration substantially attenuated the magnitude of risk overestimation by the Framingham and UKPDS risk models in ADVANCE. Discrimination was unaffected as expected, indicating the need for new CVD risk models with improved predictive accuracy for people with diabetes, particularly those who are receiving many contemporary cardiovascular riskreducing therapies.

Development of the ADVANCE cardiovascular risk model In developing a new model for risk prediction, it is critical to account for the limitations of existing ones in order to improve performance. The inclusion in ADVANCE of participants from many countries provided the opportunity to account for the substantial variation in the care of diabetes and CVD around the world. Available models so far had been derived from homogenous populations. The ADVANCE model targets total CVD and therefore captures the interrelation between components of CVD such as CHD or stroke, unlike many existing models that have focused specifically on these components. The complexity of the relationship between chronic hyperglycaemia and cardiovascular risk has been less fully addressed in existing models. Some improvement was achieved in the ADVANCE model through integration of risk factors to capture both the exposure to chronic hyperglycaemia prior to and after the clinical diagnosis of diabetes. Statistical method is an important component of model development. Trusted statistical methods were used to select the potential risk factors and test their suitability for inclusion in the ADVANCE risk model.14 Risk factors considered for inclusion in the ADVANCE model were: age at clinical diagnosis of diabetes, duration of diagnosed diabetes, gender, blood pressure (BP) indices [systolic BP, diastolic BP, mean arterial (MAP) and pulse (PP) pressures], lipid variables [total, high-density lipoprotein (HDL) and non-HDL cholesterol, ratio of total:HDL cholesterol and triglycerides], body mass index (BMI), waist circumference, waist-to-hip ratio, BP-lowering medication (i.e. treated hypertension), statin use,

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current smoking, retinopathy, atrial fibrillation (past or present), urinary albumin:creatinine ratio (ACR), serum creatinine (Scr), HbA1c and fasting blood glucose levels, and randomised treatments (BP lowering and glucose control regimens). Ten of these candidate risk factors were included in the final ADVANCE risk model. Age at diabetes diagnosis and known duration of diabetes were preferred to age at baseline to improve the applicability of the ADVANCE risk model to other populations. The beta coefficients and accompanying standard error for risk factors in the ADVANCE risk model are shown in Table 1.14

Performance of the ADVANCE risk model The applicability of the ADVANCE risk model14 was tested on the same population used to develop the model (i.e. internal validation) and on an independent external sample for which the DIAB-HYCAR cohort32 was used. In both internal and external validations, the discrimination of the ADVANCE model was acceptable. In comparison with existing total CVD models, the ADVANCE model largely outperformed the Framingham– Anderson and Framingham–D’Agostino models. The calibration of the ADVANCE model was excellent in internal validation and good in external validation, with only a modest risk underestimation. This is likely explained by the difference in the levels of preventive therapies between ADVANCE and DIABHYCAR population. TABLE 1. BETA COEFFICIENTS (95% CONFIDENCE INTERVAL) AND STANDARD ERRORS FOR PREDICTORS IN THE ADVANCE CVD PREDICTION MODEL14 Parameter estimate (standard error) p-value*

Variable

0.062 (0.008)

< 0.001

–0.474 (0.098)

< 0.001

Known duration of diabetes (per 1-year increase)

0.083 (0.010)

< 0.001

Pulse pressure (per 1-mmHg increase)

0.007 (0.003)

0.016

Retinopathy (yes vs no)

0.383 (0.101)

< 0.001

Atrial fibrillation (present vs absent)

0.601 (0.154)

< 0.001

HbA1c (per 1% increase)

0.099 (0.027)

< 0.001

Log of urinary albumin/creatinine ratio (per 1-log mg/g increase)

0.193 (0.033)

< 0.001

Non-HDL cholesterol (per 1-mmol/l increase)

0.126 (0.034)

< 0.001

Treated hypertension (yes vs no)

0.242 (0.106)

0.022

Age at diagnosis (per 1-year increase) Gender (women vs men)

*Mutually adjusted. Baseline survival probability at four years: S0(4) = 0.951044.     Based on the Cox model, the probability P  ˆ  of an event at t years of follow up is defined by the following formula:

exp (Σ   ˆ  = 1 – S0 (t) P

p i=1

βi χi – Σpi= 1 βi     –χ    i)

where S0(t) is the baseline survival at t years; βi is the estimated regression coef    ficient, χi is the value of the predictor; χ  – i is the corresponding mean for continuous predictors (to account for the fact that the value of S0(t) is estimated at the mean level of predictors in the study population); and p denotes the number of predictors. Consider for example, a man diagnosed with diabetes at the age of 50, with a known duration of diabetes of three years, a pulse pressure of 50 mmHg and treated for hypertension, a urinary albumin/creatinine ratio of 50 mg/g, an HbA1c level of 7%, a non-HDL cholesterol level of 3.3 mmol/l, who has retinopathy and atrial fibrillation. The estimated risk based on the ADVANCE model is: p

Σ βiχi = 0.062*50 + 0.083*3 + 0.007*50 + 0.242*1 + 0.193*log(50) + 0.099*7 + 0.126*3.3 + 0.383*1 + 0.601*1 – 0.474*0 = 6.78882

i=1 p

Σ βiχi = 0.062*57.94 + 0.083*7.90 + 0.007*64.59 + 0.242*0.644 + 0.193*2.83 + 0.099*7.54 + 0.126*4 + 0.383*0.239 + 0.601*0.054 – 0.474*0.464 = 6.55666     exp (Σ β χ – Σ β     –χ    )  Pˆ  = 1 – S0 (t) = 1 − 0 .951044exp = 0.0613, or approximately 6.1%.

i=1

p i=1

(6.78882−6.55666)

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Interestingly, the agreement between predictions by the ADVANCE models and the observed CVD events was consistent across different cut-off points or predicted risk for CVD. For comparison, the two Framingham equations overestimated the risk of CVD in the DIAB-HYCAR cohort by 65% (Anderson equation) and 99% (D’Agostino equation). Using a cut-off point for four-year predicted risk of ≥ 8% (which is approximately equivalent to a 10-year predicted risk of 20% and above), the ADVANCE model would reliably identify 22% of the ADVANCE participants and 39% of the DIAB-HYCAR participants in whom 48% and 66% of CVD events, respectively, occurred during follow up. Further intensifying treatment in such groups on top of any baseline therapy could achieve significant gain in terms of CVD risk reduction.

Dissemination of the ADVANCE risk model To facilitate the uptake of the ADVANCE model in clinical practice, a hand-held calculator and a risk-scoring chart (Fig. 1) have been developed.14 Other tools from this model, including Step 1 Age at diagnosis (years) Points 29–34 0 35–39 1 40–44 2 45–50 3 51–56 4 57–62 5 63–68 6 69–74 7 75–80 8 81–86 9 Step 2 Known

duration (years) Points 0 0 1–5 1 6–10 2 11–15 3 16–20 4 21–25 5 26–30 6 31–35 7 36+ 8 Step 3

Gender Points Men 0 Women –1 Step 4 Atrial fibrillation Points No 0 Old or present 2

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an online calculator, are available on the website of the model to improve its uptake.33 Extensive validations have been conducted to assure that these tools provide estimates similar to those from the full ADVANCE risk equation.

Performance of existing global risk tools for cardiovascular risk estimation in diabetics Two systematic reviews have examined the performance of CVD risk-evaluation models applicable to people with diabetes.7,34 The most recent and comprehensive review identified 45 CVD risk models applicable to people with diabetes.7 Of these, 12 were specifically developed for people with type 2 diabetes (including the ADVANCE model) and 33 were developed in the general population, accounting for diabetes as a risk factor. These models vary greatly in their quality and the methodology used to develop them. Only about a third of the existing CVD risk tools applicable to people with diabetes have been externally validated in a population with diabetes. The discriminative ability of both

Step 5

Step 11

Retinopathy Points No 0 Yes 1

Sum-up points from steps 1 to 10 Look up predicted four-year risk of major CVD in the table

Step 6 Treated hypertension Points No 0 Yes 1 Step 7 Pulse pressure, mmHg Points < 50 0 50–110 1 111 + 2

Predicted four-year risk of major CVD

Step 8 HbA1c (%) Points < 6 0 6 – < 9 1 9 + 2 Step 9 Albuminuria Points Normoalbuminuria 0 Microalbuminuria 2 Macroalbuminuria 3 Step 10

Non HDL-C (mmol/l) Points < 3 0 3 – < 6 1 6 – < 9 2 9 + 5

Total points 5 or less 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Four-year risk (%) < 0.5 0.5 0.7 1.0 1.4 2.1 3.0 4.3 6.2 8.9 12.6 17.8 24.7 33.7 41.9 57.8 71.4 Above 83

As an illustration of the use of the risk-scoring chart, a male subject, diagnosed with diabetes three years previously at the age of 50 years, who has a pulse pressure of 50 mmHg and is currently treated for hypertension, also has retinopathy, atrial fibrillation and microalbuminuria, an HbA1c level of 7% and a non-HDL cholesterol level of 3.3 mmol/l, will receive a total score of 13 points: 0 for gender, 3 for age at diagnosis, 1 for known duration, 1 for pulse pressure, 1 for treated hypertension, 1 for retinopathy, 2 for atrial fibrillation, 2 for microabuminuria, and 1 for HbA1c and non-HDL cholesterol level each. A score of 13 points is equivalent to a four-year estimated risk of 6.2%, which is similar to the risk estimated for the same patient using the full equation.

Fig. 1. Major cardiovascular disease points and four-year predicted risk by the ADVANCE model equation.14

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diabetes-specific CVD prediction models and general population prediction models that use diabetes status as a predictor was generally acceptable to good (i.e. C-statistic ≥ 0.70). The discrimination of prediction models designed for the general population was moderate (C-statistic: 0.59–0.80) and their calibration generally poor. The most commonly validated models were the general population-based Framingham cardiovascular risk equations and the diabetes-specific UKPDS risk engines. The Framingham prediction models also showed a low-to-acceptable discrimination and a poor calibration. Although the discriminative power of UKPDS engines was acceptable, it had a poor calibration and a tendency toward systematic overestimation of risk, particularly in recent cohorts. The models with best external validity were more contemporary but these had been validated in other patient populations only once.7

Conclusion The quest for the appropriate approaches to assess cardiovascular risk and thus prevent vascular complications in individuals with diabetes is a continuing pursuit. Diabetes mellitus is not a cardiovascular risk equivalent in all circumstances. The CVD risk is not uniformly distributed in individuals with diabetes, but rather follows a gradient. Adequately capturing this gradient depends on the combination of individual risk factors. Global risk assessment appears to be the way forward for managing CVD risk among people with diabetes. Both the ADVANCE and subsequent studies have provided evidence that existing popular models derived from older cohorts were less accurate for cardiovascular risk evaluation in contemporary population with diabetes.7 The recognition of this non-optimal performance and other limitations of existing models have stimulated efforts to develop new cardiovascular risk models (including the ADVANCE model14) with improved predictive accuracy for people with diabetes. The ADVANCE model continues to enjoy the unique property that it was developed from a contemporary multinational cohort of people with diabetes, and has been successfully validated in another recent multinational cohort of individuals with diabetes. Inclusion of participants from developing countries in the ADVANCE cohort highlights the potential of the ADVANCE risk model for assisting cardiovascular risk-stratification efforts in many settings around the world.

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Moons K, Kengne AP, Grobbee DE, Royston P, Vergouwe Y, Altman D, et al. Risk prediction models: II. External validation, model updating, and impact assessment. Heart 2012: doi:10.1136/heartjnl-2011-301247. Moons K, Kengne AP, Woodward M, Royston P, Vergouwe Y, Altman D, et al. Risk prediction models: I. Development, internal validation, and assessing the incremental value of a new (bio)marker. Heart 2012; doi:10.1136/heartjnl-2011-301246. Kengne AP, Patel A, Colagiuri S, Heller S, Hamet P, Marre M, et al. The Framingham and UKPDS risk equations do not reliably estimate the probability of cardiovascular events in a large ethnically diverse sample of patients with diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study. Diabetologia 2010; 53: 821–831. Echouffo-Tcheugui JB, Kengne AP, Sobngwi E. Cardiovascular risk evaluation tools specific to population with diabetes. Arch Intern Med 2012; 172(6): 523–524.

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25. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141: 421–431. 26. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts coronary heart disease events in NIDDM patients. Diabetes Care 1996; 19: 1445–1448. 27. Van Hecke MV, Dekker JM, Stehouwer CD, Polak BC, Fuller JH, Sjolie AK, et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care 2005; 28: 1383–1389. 28. Targher G, Bertolini L, Tessari R, Zenari L, Arcaro G. Retinopathy predicts future cardiovascular events among type 2 diabetic patients: The Valpolicella Heart Diabetes Study. Diabetes Care 2006; 29: 1178. 29. Juutilainen A, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 2007; 30: 292–299.

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CardioVascular Journal of Africa

PROGRAMME LEADERS Dr Landi Lombard

Professor James Ker

Specialist endocrinologist and editor, South African Journal of Diabetes & Vascular Disease

Emeritus professor and professor in charge of education programmes at the University of Pretoria

A UNIQUE E-LEARNING OPPORTUNITY Learning objectives To enable participants to review and understand recent evidence demonstrating the residual risk of macro- and microvascular events that exists in patients with type 2 diabetes, even when their blood pressure is controlled and low-density lipoprotein cholesterol (LDL-C) targets are achieved; and to realise that additional therapeutic interventions are required to address this issue, particularly in those with atherogenic dyslipidaemia (low high-density lipoprotein cholesterol, and raised triglyceride and small, dense LDL-C particle levels).

Needs analysis Patients with type 2 diabetes have a two- to three-fold increased risk of cardiovascular disease compared with non-diabetics at any age. Indeed, about 65% of people with diabetes die as a result of a stroke or other cardiovascular event, such as a myocardial infarction. Microvascular disease is also common in this population and type 2 diabetes is a major cause of blindness, end-stage renal disease and non-traumatic limb amputation. The risk of these events remains high despite effective interventions to control blood pressure and lower LDL-C levels with statin therapy. Recent research has shown that many people with type 2 diabetes have atherogenic dyslipidaemia, which includes low levels of HDL-C as well as raised levels of triglycerides and atherogenic small, dense LDL-C particles. Statins have only limited effects on these elements of dyslipidaemia. However, when the statin is combined with a fibrate, cardiovascular risk can be significantly reduced. Additional fibrate therapy significantly reduces microvascular events, and prevents the risk of blindness, renal disease and peripheral vascular disease, resulting in limb amputation. Clinical trials have confirmed the clinical benefits of this treatment strategy in patients with type 2 diabetes.

ABOUT THIS PROGRAMME This modular and fully accredited education programme offers you opportunities to: • evaluate the importance of residual macro- and microvascular risk in your patients with type 2 diabetes • review discussions on the clinical issues with a distinguished international panel of experts • consider the clinical evidence for enhancing your current treatment strategies in patients with dyslipidaemia and type 2 diabetes. The programme will be available until 1 May 2014 and includes five interrelated modules, which provide an easily accessible but comprehensive review of this important clinical issue.

Each module offers: • a brief educational summary of key learning points • a 10-minute expert discussion (video) • 10 questions for you to obtain three CPD points per module.

website: http://www.cvja.co.za/dream/dream-landing.php

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Case Report Ebstein’s anomaly and Down’s syndrome LUNGILE PEPETA, SALLY-ANN CLUR

Abstract We report on two cases presenting with a rare combination of Ebstein’s anomaly and Down’s syndrome. The first patient presented with respiratory distress, mild cyanosis and right heart failure immediately after delivery. The symptoms improved with heart failure medication. The patient remained asymptomatic on follow up. The second patient was diagnosed antenatally with marked apical displacement of the tricuspid valve and a very small functional right ventricle compared to the left ventricle. At birth, the patient presented with an extreme form of Ebstein’s anomaly with severe cyanosis, marked right heart failure and ductal-dependent pulmonary blood flow. The patient died within days of birth. Keywords: Ebstein’s anomaly, Down’s syndrome, prenatal and postnatal diagnosis, right heart failure Submitted 21/8/11, accepted 14/8/13 Published online 5/9/13 Cardiovasc J Afr 2013; 24: 382–384

www.cvja.co.za

DOI: 10.5830/CVJA-2013-054

Ebstein’s anomaly was first described by Wilhelm Ebstein in 1866, in an autopsy report of a 19-year-old patient who had presented with cyanosis and right heart failure.1,2 Ebstein’s anomaly is characterised by significant apical displacement of the tricuspid valve. It is very rare, with an incidence of 1:20 000 live births, and accounts for less than 1% of all congenital heart defects.3 The time of clinical presentation may range from foetal life to late adulthood, depending on the extent of the tricuspid valve displacement, size and function of the right ventricle, right atrial size and degree of right-to-left shunting.4 By contrast, Down’s syndrome, first described by Seguin and Down in 1846 and 1866, respectively,5 is fairly common. Congenital cardiac lesions occur in 40 to 50% of these patients and include atrioventricular septal defects, atrial septal defects, ventricular septal defects, patent ductus arteriosus and tetralogy of Fallot.6 We present two cases of a very rare combination of Ebstein’s anomaly and Down’s syndrome.

Case reports Case 1 The patient was a female infant delivered at 33 weeks’ gestation, with a birth weight of 1 980 g and Apgar scores of 6 at one minute, 9 at five minutes and 9 at 10 minutes. She had the phenotypic features of Down’s syndrome and had respiratory distress with cyanosis. The oxygen saturations were 85% on room air and 98% on nasal prongs oxygen at 2 l/min. Her temperature was 38.8°C. The pulse rate was 170 beats per min (bpm). The blood pressure was normal. A 3/6 holosystolic murmur over the left lower parasternal boarder was noted. The liver was enlarged at 4 cm below the costal margin. The chest X-ray showed cardiomegaly with a cardiothoracic ratio of 65%, oligemic lung fields, features of right atrial and right ventricular enlargement, left aortic arch and situs solitus. The ECG showed a sinus rhythm with a rate of 165 bpm, PR interval of 100 ms and QRS axis of –40 degrees. There were tall R waves in V1 of 15 mm and deep Q waves in aVR, V1 and V2, features which were suggestive of right ventricular hypertrophy with strain. Echocardiography revealed a dilated right side of the heart (Fig. 1). The septal leaflet of the tricuspid valve was apically displaced at 7.8 mm below the anterior leaflet of the mitral valve and was redundant. This displacement when indexed for body surface area was significant at 49 mm/m2. Moderate tricuspid regurgitation was seen on colour flow Doppler. However, no tricuspid valve stenosis or right ventricular outflow tract obstruction was seen. The foramen ovale and ductus arteriosus were closed. No other cardiac abnormalities were detectable.

Dora Nginza Hospital, Port Elizabeth Hospital Complex, Port Elizabeth, South Africa LUNGILE PEPETA, FCPaed (SA), Cert.Cardiology (SA), MMed (Wits), Lungile.Pepeta@gmail.com

Department of Paediatric Cardiology, Emma Children’s Hospital, Academic Medical Centre (AMC) and Centre for Congenital Heart Anomalies Amsterdam-Leiden (CAHAL), The Netherlands SALLY-ANN CLUR, MB BCh, MSc (Med), FCP (SA) (Paed), PhD

Fig. 1. Two-dimensional echocardiogram in the fourchamber view of case 1, showing Ebstein’s anomaly with right atrial dilatation (RA) and apical displacement of the septal leaflet of the tricuspid valve (arrow), leading to atrialisation of the right ventricle (aRV). RV, right ventricle; LA, left atrium; LV, left ventricle.

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Fig. 2. Roentgenogram of case 2 showing a ‘wall-to-wall’ heart due to right atrial dilatation.

Chromosomal analysis confirmed Down’s syndrome (47, XX, +21). Elevated C-reactive protein suggested possible neonatal sepsis that was later confirmed on blood culture, as this was positive for Acinetobacter baumannii species, which was sensitive to Carbapenems. Sepsis was successfully treated with Meropenem following unsuccessful empirical antibiotic therapy. Heart failure therapy (digoxin, furosemide) and potassium supplements were added. C-reactive protein levels later normalised, she was weaned off oxygen and the heart failure treatment was stopped on follow up at the age of six months. She was thriving well off anti-failure medication with just mild tricuspid regurgitation at the last follow up at three years of age.

Case 2 A 38-year-old female, gravida 11, para 4, presented at the prenatal diagnosis unit 17 + 3 weeks pregnant. She had two live babies but had also suffered two ectopic pregnancies, two spontaneous miscarriages, two pregnancy terminations before 16 weeks’ gestation and two intrauterine deaths. An amniocentesis revealed a male foetus with Down’s syndrome (47, XY, +21). In view of her poor obstetric history and strong wish for another child, the couple decided to continue with the pregnancy.

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A foetal echocardiogram performed at 32 weeks’ gestation showed situs solitus, levocardia with atrioventricular concordance, and normal pulmonary and systemic venous return. The right atrium was dilated and the right ventricle was smaller than the left ventricle due to a very apically displaced coaption point of an abnormal tricuspid valve, consistent with Ebstein’s anomaly. There was severe tricuspid regurgitation with a velocity of 3.4 m/s, giving an estimated right ventricular pressure of 46 mmHg + right atrial pressure. A male infant was born by normal vaginal delivery at gestational age of 36 + 6 weeks. His birth weight was 2 840 g and Apgar scores were recorded as 8 at one minute and 9 at five minutes. The baby was cyanotic on room air with oxygen saturations of 60% that went up to 75% with the administration of 100% oxygen. Further examination revealed features of Down’s syndrome and severe respiratory distress. There were scattered pulmonary rhonchi and a 4/6 holosystolic murmur was heard in the 4th intercostal space, left parasternal border. The chest X-ray showed a ‘wall-to-wall’ heart such that it was not possible to comment on pulmonary vascularity (Fig. 2). The ECG revealed sinus rhythm with a rate of 126 bpm, QRS axis of +120, P axis of +45, PR interval of 120 ms, P pulmonale, incomplete right bundle branch block and QTc of 455 ms (Fig. 3). The echocardiogram showed severe Ebstein’s anomaly with functional pulmonary atresia, large right-to-left shunting at the atrial level and ductal-dependent pulmonary circulation. In light of the baby’s poor prognosis it was decided after consultation with the parents to withdraw further active management and the baby died 38 hours after birth.

Discussion We present two cases of Ebstein’s anomaly in babies with Down’s syndrome, which illustrate a less severe and an extreme form of this cardiac defect, respectively. Ebstein’s anomaly is defined as more than 0.8 cm/m2 apical displacement of the septal leaflet of the tricuspid valve.7 This may be associated with adherence of both the septal and posterior leaflets of the tricuspid valve to the myocardium, downward displacement of the functional annulus, dilatation of the ‘atrialised’ right ventricle, redundancy, fenestrations, tethering of the anterior leaflet, and dilatation of the true tricuspid valve annulus.8 In Ebstein’s anomaly, there is a failure of delamination of the inner layers of the inlet zone of the ventricles, the mechanism of which is not well understood.9 The clinical presentation varies

Fig. 3. ECG of case 2 showing the P pulmonale of right atrial enlargement and incomplete right bundle branch block, often seen in Ebstein’s anomaly.

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TABLE 1. SUMMARY OF KNOWN CASES OF DOWN’S SYNDROME WITH EBSTEIN’S ANOMALY Case number

Diagnosis

Presentation

Karyotype

1. Bauk, et al.5

Cardiac examination

20 years old, syncope

Clinical diagnosis

2. Johnson, et al.11

Autopsy

Fatal pneumonia

Not specified

Conclusion We report on two very rare cases of Ebstein’s anomaly with Down’s syndrome. It is possible that patients with Ebstein’s anomaly and Down’s syndrome have extreme endocardial cushion abnormalities, so that some of them die in utero. There is a need for routine screening for cardiac lesions, followed by foetal echocardiography for early detection of such abnormalities so that appropriate therapy can be commenced, as indicated.

3. Venturini, et al.12 Routine cardiac 55 years old, examination asymptomatic

Clinical diagnosis

4. Silvia, et al.13

Foetal echocardiography

After amniocentesis

Clinical diagnosis

5. Leite, et al.14

Foetal echocardiography

Suspected cardiac defect Not specified (hypoplastic left ventricle)

References

6. Cyrus, et al.15

Cardiac examination

Dysmorphic 8-month-old with failure to thrive

+21; 21

Newborn with cardiomegaly

Clinical diagnosis

7. Upadhyay, et al.16 Cardiac examination 8. This article

Postnatal echo- Cyanotic newborn with cardiography respiratory distress

47, XX, +21

9. This article

Foetal echocardiography

47, XY, +21

Suspected cardiac defect

from cyanosis, right-sided heart failure, arrhythmias and sudden cardiac death, to a completely asymptomatic presentation.3,4 Neonates might present with cyanosis mainly due to rightto-left shunting across an atrial septal defect or patent foramen ovale,4 as in the second case. The neonatal presentation may be associated with right heart failure as demonstrated by the two cases. The ECG may reveal features of right atrial enlargement as seen in case 2: prolongation of the PR interval, pre-excitation syndrome, and atrial and ventricular tachyarrhythmias.3 Chest roentgenogram may vary from a normal cardiac silhouette to a globular ‘wall-to-wall’ heart as in case 2, with or without oligemic lung fields.3 Medical treatment includes the standard heart failure medication such as digoxin and diuretics, as was given to the first patient. In cases with right ventricular outflow tract obstruction the pulmonary flow may be ductal-dependent, requiring prostaglandin therapy to maintain adequate oxygenation. The predictors of death in Ebstein’s anomaly include the grade of severity at presentation, foetal presentation, and right ventricular outflow tract obstruction (as evident in case 2).4 Ebstein’s anomaly is seldom associated with chromosomal syndromes. It has been reported in a case of Williams-Beuren syndrome,10 and seven cases of Down’s syndrome.5,11-16 These seven cases and our two cases are summarised in Table 1. It has been reported that there is a strong association between tricuspid regurgitation at 11 to 14 weeks’ gestation, Down’s syndrome and congenital cardiac defects.17,18 Foetal demise may occur spontaneously in both Ebstein’s anomaly and Down’s syndrome. It is possible therefore that a combination of Ebstein’s anomaly and Down’s syndrome might lead to early foetal demise, with resultant under-reporting of these cases. Postmortem examination and early foetal echocardiogram are not widely performed, such that the true incidence of Ebstein’s anomaly in these young Down’s syndrome foetuses remains unknown.

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6. 7.

8. 9.

10. 11.

12.

13.

14.

15.

16. 17.

18.

Mann RJ, Lie JT. The life story of Wilhelm Ebstein (1836 –1912) and his almost overlooked description of a congenital heart disease. Mayo Clin Proc 1979; 54: 197–204. Van Son JA, Konstantinov IE, Zimmermann V. Wilhelm Ebstein and Ebstein’s malformation. Eur J Cardiothorac Surg 2001; 20: 1082–1085. Attenhofer Jost CA, Connolly HM, Dearani JA, Edwards WD, Danielson GK. Ebstein’s anomaly. Circulation 2007; 115: 277–285. Giuliani ER, Fuster V, Brandenburg RO, Mair DD. Ebstein’s anomaly: the clinical features and natural history of Ebstein’s anomaly of the tricuspid valve. Mayo Clin Proc 1979; 54: 163–173. Bauk L, Espinola-Zavaleta N, Munoz-Castellanos L. Ebstein’s malformation in the setting of Down’s syndrome. Cardiol Young 2003; 13: 370–372 Liu MC, Corlett K. A study of congenital heart defects in mongolism. Arch Dis Child 1959; 34: 410–419. Shiina A, Seward JB, Edwards WD, Hagler DJ, Tajik AJ. Two dimensional echocardiographic spectrum of Ebstein’s anomaly: detailed anatomic assessment. J Am Coll Cardiol 1984; 3: 356 –370. Edwards WD. Embryology and pathologic features of Ebstein’s anomaly. Prog Pediatr Cardiol 1993; 2: 5–15. Anderson KR, Zuberbuhler JR, Anderson RH, Becker AE, Lie JT. Morphologic spectrum of Ebstein’s anomaly of the heart: a review. Mayo Clin Proc 1979; 54: 174–180. Williams DA, Cook AL. An Infant with Williams-Beuren syndrome. Cardiol Young 2010; 20: 445–447. Johnson CD, Ortiz-Celom PM, Sainz de la Pefia H, Barroso E. Ebstein’s anomaly in a patient with Down’s syndrome. Bol Assoc Med PR 1989; 81: 221–222. Venturini E, Musaio L, Strazzeri R, Baroni F. Ebstein’s tricuspid anomaly and Down’s syndrome. A clinical case report. Recenti Prog Med 1992; 83: 556–558. Silvia SR, Bruner JP, Moore CA. Prenatal diagnosis of Down’s syndrome in the presence of isolated Ebstein’s anomaly. Fetal Diagn Ther 1999; 14: 149–151. Leite MF, Gianisella RB, Zielinsky P. Intrauterine detection of Ebstein’s anomaly and Down’s syndrome. Prenatal Diagnosis of a rare combination. Arq Bras Cardiol 2004; 82: 390–395. Cyrus C, Cyril E, Cherian KM, Kulkarni S, Nallathambi C. Down syndrome with tandem 21;21 rearrangement and Ebstein’s anomaly – a case report. Int J Cardiol 2007; 115: E58–60. Upadhyay S, Law S, Kholwadwala D. A newborn with cardiomegaly. J Emerg Trauma Shock 2010; 3(3): 298. Huggon IC, DeFigueiredo DB, Allan LD. Tricuspid regurgitation in the diagnosis of chromosomal anomalies in the fetus at 10-14 weeks of gestation. Heart 2003; 89:1071–1073. Faiola S, Tsoi E, Huggon IC, Allan LD, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with tricuspid regurgitation at the 11 to 13+6-week scan. Ultrasound Obstet Gynecol 2005; 26: 22–27.

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Case Report Left ventricular rupture after double valve replacement in a patient with myocarditis due to myasthenia gravis MIHALIS ARGIRIOU, VASILIS PATRIS, NIKI LAMA, SOTIRIOS KATSARIDIS, ORESTIS ARGIRIOU, CHRISTOS CHARITOS

Abstract Myasthenia gravis is an autoimmune disease characterised by weakness of the skeletal muscles, with remissions and exacerbations due to antibodies acting on the acetylcholine receptors. This leads to the characteristic defect transmission in the neuromuscular junction. Treatment includes anticholinesterase agents, thymectomy, and immunosuppression. Surgical thymectomy can induce remission or improvement, allowing for reduction in the immunosuppressive treatment. The case of an 84-year-old female patient with myasthenia gravis, aortic valve stenosis, mitral valve regurgitation and myocarditis is described. The development of myocarditis was related to inflammatory cell infiltration, and progressive and additive focal cellular necrosis associated with reactive myocardial fibrosis. After replacement of the mitral valve, complications arose when a rupture of the left ventricular posterior wall occurred, which caused massive bleeding and sudden death on the operating table. Keywords: left ventricular rupture, double valve replacement, myasthenia gravis, thymectomy, myocarditis Submitted 6/1/13, accepted 14/8/13 Published online 5/9/13 Cardiovasc J Afr 2013; 24: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2013-056

Myasthenia gravis (MG) is an acquired autoimmune disease with remissions and exacerbations due to antibodies acting on the acetylcholine receptors (AChR). This leads to the characteristic defect transmission in the neuromuscular junction,1 usually resulting from a decreased number of active acetylcholine receptors (AChR) at the neuromuscular junction. It is characterised by weakness of the voluntary skeletal muscles.2 MG patients have been suggested to have a higher-than-normal prevalence of heart disease. Antibodies against β-adrenergic receptors in patients with MG bind to both β1- and β2-adrenergic Cardiac Surgery Department, Evaggelismos General Hospital, Athens, Greece MIHALIS ARGIRIOU, MD VASILIS PATRIS, MD, vaspatris@gmail.com NIKI LAMA, MD SOTIRIOS KATSARIDIS, MD ORESTIS ARGIRIOU, MD CHRISTOS CHARITOS, MD

receptors and this may be implicated in the few patients with MG who have heart disease.3 It is speculated that the heart and skeletal muscles are also autoimmune targets in MG.4 However, inflammatory myopathies, autoimmune-mediated myocarditis and/or myositis have developed in a few patients with MG, especially thymoma-associated MG.4 Treasure et al.5 classified the complications on the basis of the location of the tear: ruptures located in the posterior atrioventricular groove are type I, ruptures in the posterior wall of the left ventricle at the base of the papillary muscles are type II, and ruptures posterior to the atrio-ventricular area are type III. The ruptures have also been classified by time of presentation: early, delayed and late rupture. This report presents a rare case of early left ventricular rupture after mitral–aortic valve replacement in a patient with MG and myocarditis. The exact rupture could not be classified on the basis of the location because it was not possible to determine its precise location. However, it is postulated that the rupture may be classified as a type III in accordance with Sersar et al.6

Case report An 84-year-old female patient with a history of MG who was on medication for over two years was admitted to our department with an echocardiographic diagnosis of severe aortic valve stenosis (max Gr 84 and AVA 0.65–0.7 cm2), mitral valve regurgitation (3+), the ECG showed T-wave abnormality, atrioventricular dissociation, arrhythmias [chronic atrial fibrillation (AF)], and wide QRS complex. It is important to note that the patient was not treated with Cox-Maze IV (ablation) due to her chronic AF. The patient’s clinical status was classified as NYHA class III and her MG status was Osserman IIB, so her symptoms were not further investigated considering her severe double valvular disease. She was scheduled for an elective aortic–mitral valve repair with simultaneous thymectomy. Initially, a trans-sternal thymectomy was carried out and the hyperplastic thymus tissues were completely removed and sent for histological analysis. The ascending aorta and both venae cavae were cannulated, and cardiopulmonary bypass was instituted. After aortic cross-clamping, myocardial protection was achieved with antegrade and retrograde intermittent cold blood cardioplegia. A longitudinal left atrial incision parallel to the atrial septum was performed to expose the mitral valve. The valve leaflets were fragile and myxomatous, and the chordal structures of the anterior leaflet were ruptured. After excision

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infiltration by lymphocytes (Fig. 1). Immunohistochemistry showed that the lymphocytes were mostly CD3+ T cells (Fig. 2) and T-lymphocytes under the endocardium immune-expressing cytotoxic TIA-1 enzyme (Fig. 3).

Discussion

Fig. 1. Infiltration of cardiac muscle fibres by small lymphocytes; a focal aggregation consisting of approximately 25 lymphocytes (H-E stain, × 400).

of the anterior mitral leaflet, interrupted everting sutures were placed in the annulus and passed through the preserved posterior leaflet. The mitral valve was replaced with a 25-mm Sorin bileaflet (Sorin Group®) mechanical prosthesis. All interrupted sutures used for valve replacement were reinforced with Teflon (Bard®) felt pledgets to prevent dehiscence of the prosthesis. The aortic valve was replaced with a 19-mm Sorin (Sorin Group®) mechanical prosthesis. The atrial wall and aorta were sutured and the aortic cross-clamp was released. The procedure was straightforward, but after separation from cardiopulmonary bypass, the pericardium suddenly filled with blood and, on lifting the heart, bleeding was identified from the atrio-ventricular groove with swelling and haematoma in the posterior wall of the left ventricle. The patient was placed back onto bypass and cooled, and the heart was again perfused with cold blood cardioplegia. Teflon (Bard®) felt-buttressed interrupted sutures were placed, but considerable bleeding continued. We used BioGlue (Cryolife®) to stick a Teflon (Bard®) felt patch approximately 5–6 cm over the area involved, but the bleeding was not stopped, and the condition of the patient deteriorated. All external repair methods were tried, but the sutures themselves also caused additional damage to the friable heart tissue. The patient died on the operating table. Due to the patients’ background we sent heart tissue for biopsy. The biopsy showed diffuse myocardial necrosis with

Fig. 2. Detection of T-lymphocytes by CD3 immunohistochemical staining (× 200).

Rupture of the left ventricular posterior wall, although infrequent, is one of the most life-threatening sequelae of prosthetic replacement of the mitral valve.7 Its cause is controversial. Female gender, advanced age, intrinsic myocardial disease, mitral stenosis, small body size, and a small left ventricle have been considered as predisposing risk factors.8 A large number of intra-operative factors that initiate the primary tear and cause the transmural left ventricular rupture have been considered:9 • resection of excessive tissue during removal of the mitral valve and consequent injury of the annulus • inaccurate sizing of the annulus and insertion of an oversized prosthesis • entrance of deeply placed sutures into the ventricular myocardium • apical venting of the left ventricle with dislocation of the heart and consequent distortion of the left ventricular posterior wall when a rigid mitral prosthesis is in place • forceful traction on the mitral annulus • mechanical injury to the ventricular endocardium caused by such devices as metal vents and cardiotomy suckers, scissors used during valve excision and retractors used to expose the chordae tendineae • forceful compression of the ventricle against the prosthesis during manual massage • positioning the strut of a bioprosthesis against the posterior left ventricular wall. In most cases it is difficult to define the causes of left ventricular rupture. All the above intra-operative events have been linked to left ventricular rupture, but none of these occurred in the present case. In patients with a fragile and myxomatous

Fig. 3. T-lymphocytes under the endocardium immunoexpressing cytotoxic TIA-1 enzyme (× 200).

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valve, to reduce the risk of rupture of the left ventricular posterior wall after mitral valve replacement, the posterior mitral leaflet with attached chordae is preserved. An MG patient is often the subject of cardiac disease, as was the case with our patient. According to Hofstad et al.,10 16% of patients with MG have signs of cardiac disease, which is a much higher frequency than that found in the general population. This strongly indicates that these otherwise unexplained signs of heart disease are related to or caused by MG. Such findings are more frequent among thymoma patients (50%) than among non-thymoma patients (12%). The histological changes in the striated muscle found in MG are muscle fibre atrophy and varying degrees of inflammation.10 The inflammatory lesions range from discrete accumulations of lymphocytes without tissue destruction to extensive myonecrosis with heavy inflammatory cell infiltration and signs of regeneration. Hearts microscopically examined by Hofstad et al. had inflammatory infiltrates in the myocardium, with varying degrees of muscle fibre degeneration or necrosis.10 The cardiac findings may be caused by mechanisms specific to MG or they may represent non-specific myocardial damage. The focal, spotty localisation of the myocardial changes indicates that the heart pathology has a causal relationship with MG. Moreover, clinical evaluation usually represents the first diagnostic step for a patient with suspected MG. The evaluation of MG-related symptoms could be difficult as the cardiac disease may mask them. In our case, the pre-operative clinical status was not correctly addressed as the cardiac symptoms were predominant. Hence, the diagnosis of myocarditis in this patient was guided by the intra-operative and histological findings, which led to revaluation of the pre-operative clinical conditions.

Conclusion A dynamic hypothesis concerning the correlation between myocarditis due to myasthenia gravis and left ventricular rupture after mitral valve replacement is presented. Additionally, we believe that endomyocardial biopsy should be considered in this group of patients.

References Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330(25): 1797–1810. 2. Vincent A, Palace J, Hilton-Jones D: Myasthenia gravis. Lancet 2001; 357: 2122–2128. 3. Xu BY, Pirskanen R, Lefvert AK. Antibodies against beta1 and beta2 adrenergic receptors in myasthenia gravis. J Neuroimmunol 1998; 91: 82–88. 4. Zamecnik J, Vesely D, Jakubicka B, et al. Muscle lymphocytic infiltrates in thymoma associated myasthenia gravis are phenotypically different from those in polymyositis. Neuromuscul Disord 2007; 17(11–12): 935–942. 5. Treasure RL, Rainer WG, Strevey TE, Sadler TR. Intraoperative left ventricular rupture associated with mitral valve replacement. Chest 1974; 66: 511–514. 6. Sersar SI, Jamjoom AA. Left ventricular rupture post mitral valve replacement. Clin Med Cardiol 2009; 3: 101–113. 7. Karlson KJ, Ashraf MM, Berger RL. Rupture of left ventricle following mitral valve replacement. Ann Thorac Surg 1988; 46: 590–597. 8. Otaki M, Kitamura N. Left ventricular rupture following mitral valve replacement. Chest 1993; 104: 1431–1435. 9. Reardon MJ, Letsou GV, Reardon PR, Baldwin JC. Left ventricular rupture following mitral valve replacement. J Heart Valve Dis 1996; 5: 10–15. 10. Hofstad H, Ohm OJ, Mørk SJ, Aarli JA. Heart disease in myasthenia gravis. Acta Neurol Scand 1984: 70: 176–184. 1.

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Case Report Mini-sternotomy approach for aortic valve replacement in a patient with osteogenesis imperfecta GEORGIOS DIMITRAKAKIS, JITENDRAKUMAR RATHOD, ULRICH OTTO VON OPPELL, AGAMEMNON PERICLEOUS, STEPHEN HUTCHISON

Abstract Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue. Cardiovascular involvement is rare, related mainly to aortic valve regurgitation. Open-heart surgery in these patients is associated with increased morbidity and mortality rates as a result of tissue friability and bone brittleness as well as platelet dysfunction. We present a patient with OI who underwent successful aortic valve replacement with a mini-sternotomy approach.

in childhood. She had also had a previous sternal fracture, which had resulted in a pectus carinatum-type deformity as well as kyphoscoliosis and she was wheelchair bound (Figs 1, 2). In A

Keywords: osteogenesis imperfecta, cardiac surgery, aortic valve replacement, mini-sternotomy Submitted 24/4/13, accepted 18/9/13 Cardiovasc J Afr 2013; 24: e4â&#x20AC;&#x201C;e7

www.cvja.co.za

DOI: 10.5830/CVJA-2013-070

Osteogenesis imperfecta (OI) is a heritable disorder of collagen biosynthesis, which is transmitted in an autosomal dominant fashion. OI is characterised mainly by osseous fragility and even though its primary clinical manifestations include skeletal, cutaneous, ocular, dental and otological abnormalities, serious pathological conditions of the cardiovascular system have also been reported sporadically. The reported incidence is 1:20 000 to 1:50 000 patients in the general population, with a predominance in females. Cardiovascular involvement in OI is rare compared with that of other connective tissue disorders. Morbidity and mortality rates in OI patients who undergo cardiac surgery have been shown to be high.1

Case report A 34-year-old female was referred to our department for surgical intervention because of severe aortic valve regurgitation. The patient had been diagnosed with OI during childhood. Her past medical history included multiple limb fractures plus spinal compression fractures and various tendon-lengthening operations

Department of Cardiothoracic Surgery, University Hospital of Wales, Heath Park, Cardiff, United Kingdom

GEORGIOS DIMITRAKAKIS, MD, MSc, gdimitrakakis@yahoo.com JITENDRAKUMAR RATHOD, MSMch ULRICH OTTO VON OPPELL, MBBCh, PhD AGAMEMNON PERICLEOUS, BSc STEPHEN HUTCHISON, MD

Fig. 1. A: pre-operative chest X-ray. B: postoperative chest X-ray.

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Fig. 2. Postoperative radioisotope bone scan. There is increased uptake in the upper part of the sternum, however, there is no evidence of recent rib fracture.

addition, she had malaligned dentition and right-ear hearing loss as part of the OI syndrome. The patient presented with progressively increasing dyspnoea (NYHA III) over the previous 12 months and transthoracic echocardiography confirmed severe aortic valve regurgitation (Fig. 3). A CT coronary arteriogram showed no coronary artery disease and her predictive operative mortality (logistic EuroSCORE) was 4.7%. We elected to use a mini-sternotomy approach with an inverted T incision in order to maintain chest cage integrity. Cardiopulmonary bypass was established with cannulation of the ascending aorta using an aortic cannula (Seldinger’s technique) along with a single venous cannula. A hockey stick aortotomy was used and direct cold blood cardioplegia was given through the coronary ostia. An aortic valve replacement (Medtronic-Mosaic 25 mm) with pledgeted, supported and non-everted sutures was done uneventfully (cross-clamp time 62 min; perfusion time 81 min). All these manoeuvres were performed to minimise surgical trauma during the procedure. BioGlue was used to reinforce the aortotomy suture line and cannulation sites. Two units of platelets plus four units of fresh, frozen plasma were transfused after weaning from extra-corporeal circulation. The patient made an uneventful recovery and was discharged on the eighth postoperative day. At 36 months’ follow up, the patient was doing well. Histological sections of the aortic valve demonstrated myxoid degeneration and the morphology of the aortic wall was normal.

Discussion The first report of the term OI was by Olaus Jakob Ekman in a doctoral thesis for the University of Uppsala in 1788. He described a family where three generations of people had a condition that he termed ‘osteomalacia congenita’.2

Fig. 3. A: pre-operative echocardiography. B: postoperative echocardiography.

The severity of the disease is proportional to the quality of the mutation and the extent of the abnormal type I collagen. The percentage of OI patients requiring cardiac surgical treatment

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is uncertain. McKusick reported in his review of more than 100 patients with OI that only two patients were found to have severe aortic valve regurgitation.1 The severity of the skeletal manifestations does not correlate with the extent of cardiovascular involvement, which appears to be limited mainly to aortic and mitral valve regurgitation.1 The clinical presentation, diagnosis and indications for surgical treatment are similar to those for acquired cardiac diseases. Since 1965, when Criscitiello et al. first attempted aortic valve repair in a patient with OI, only approximately 45 cases have been reported in the English-language literature, and its review highlights the importance of surgical considerations.1 Surgical considerations are the friability and weakness of the tissues due to underlying connective tissue disorder, specifically in terms of suture lines and the secure implantation of the prosthetic valve. Dehiscence of the prosthetic valve or paravalvular leak has been reported and these potential complications must be kept in mind during the monitoring of the patient, not only postoperatively but also in the long-term follow-up period.1 In terms of assessment of the coronary arteries, it is better to avoid coronary angiography because of the friability of the vessels, and rather perform a CT angiogram or MRI. Eskola et al. reported in 2002 on right coronary artery dissection during the pre-operative assessment for cardiac catheterisation of an 18-year-old male patient suffering from aortic valve regurgitation and OI, leading to emergency coronary artery bypass grafting surgery plus aortic valve replacement for the primary disease.3 A further surgical consideration is the high risk of bleeding complications despite normal pre-operative coagulation status. These complications may be related to tissue friability as well as capillary fragility and platelet dysfunction, and may be in the form of epistaxis, melena, haematomas and surgical bleeding.1 As a result of the high risk of surgical bleeding, haemostatic glues, antifibrinolytic agents and blood products along with recombinant factor VIIa should be available to OI patients undergoing cardiac surgery. This risk of haemorrhagic complications is significantly increased if lifelong anticoagulation therapy is considered necessary following mechanical valve replacement. For this reason, it is essential to consider very carefully the type of operation and valve that will be used. The mini-sternotomy approach involves limited sternal split and manages the integrity of the lower rib cage. In OI patients, this approach not only limits rib fractures and postoperative pain but also improves mobilisation and recovery. Furthermore, if deemed necessary, the conversion to a median sternotomy approach is relatively easy to perform. This is, to our knowledge, the first reported case with a mini-sternotomy approach, using the inverted T incision to the lower part of sternum in a patient with OI. There was only one previous case report by Izzat et al., describing aortic valve replacement through a mini-sternotomy approach where an upper J incision was utilised.4 Kypson and Glower reported in 2002 on port-access approach for combined aortic and mitral valve replacement.5 During recent years, transcatheter aortic valve implantation (TAVI) for high-risk patients with symptomatic aortic valve disease has become an attractive method of surgical intervention for patients deemed unfit for conventional surgery.6 Furthermore,

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TAVI procedures provide significant improvement in terms of clinical outcome and subjective health-related quality of life in very elderly patients with symptomatic aortic valve stenosis.7 In intermediate surgical-risk elderly patients with aortic stenosis, TAVI and AVR were associated with similar mortality rates during follow up but with a different spectrum of peri-procedural complications.8 In our case, the patient was unsuitable for TAVI due to her young age, severe aortic valve regurgitation, combined with large aortic annulus. Moreover, due to the friability and weakness of the tissues because of OI syndrome and a higher risk of paravalvular leak, even with conventional surgery, we felt that the choice of mini-sternotomy approach was superior to TAVI. There are a few types of mini-sternotomy approaches that have been suggested as alternatives to conventional median sternotomy in cardiac surgery. These types include mainly the upper reversed-T and the upper J-shape mini-sternotomies. Both types give good exposure of the ascending aorta and root and allow safe arterial and venous cannulation. As a result, cardiac operations can be safely performed.9 Perrotta and Lentini, in their recent meta-analysis of the mini-sternomy approach for surgery of the aortic root and ascending aorta, reported extensively on the advantages and disadvantages of the method.9 The main advantages include a reduction in postoperative pain as well as blood loss and transfusion requirements. Furthermore, the smaller incision may be associated with a reduced risk of postoperative sternal dehiscence, infections and mediastinitis. The minimal exposure of the heart, which consequently leads to a reduced incidence of adhesions, may also prove advantageous in cases where a redo operation is required. Additional advantages include improvement in postoperative respiratory function, early extubation of the patient and shorter hospital stay. Finally, better cosmetic outcomes associated with a mini-sternotomy incision may be a preferable option, especially in younger patients.9 On the other hand, potential disadvantages of this approach are the difficulties in dealing with major intra-operative complications and the need for an urgent conversion to a full sternotomy, the requirement of a high level of dexterity by the surgeon, or side effects such as sacrifice of the internal mammary arteries and intercostal neurovascular bundles, and the occasional use of specific sternal wiring.9

Conclusion We believe that the mini-sternotomy approach for aortic valve operations in patients with OI is advantageous compared to median sternotomy. As a result, the mini-sternotomy approach should be in the armament of surgical treatment along with other methods such as port-access, transfemoral or transapical approaches, and each patient should be assessed on an individual basis.

References 1. 2. 3.

Wong RS, Follis FM, Shively BK, Wernly JA. Osteogenesis imperfecta and cardiovascular disease. Ann Thorac Surg 1995; 60: 1439–1443. Olaus Jacob Ekman. Dissertatio medica descriptionem et casus aliquot osteomalaciæ sistens. Upsaliæ, J. Edman, 1788. Eskola MJ, Niemelä KO, Kuusinen PR, Tarkka MR. Coronary artery dissection, combined aortic valve replacement and coronary bypass

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5. 6.

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grafting in osteogenesis imperfecta. Interact Cardiovasc Thorac Surg 2002; 1(2): 83–85. Izzat MB, Wan S, Wan IY, Khaw KS, Yim AP. Ministernotomy for aortic valve replacement in a patient with osteogenesis imperfecta. Ann Thorac Surg 1999; 67(4): 1171–1173. Kypson AP, Glower DD. Port-access approach for combined aortic and mitral valve surgery. Ann Thorac Surg 2002; 73(5): 1657–1658. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, et al. PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363(17): 1597–1607.

Grimaldi A, Figini F, Maisano F, Montofano M, Chieffo A, et al. Clinical outcome and quality of life in octogenarians following transcatheter aortic valve implantation (TAVI) for symptomatic aortic stenosis. Int J Cardiol 2012; S0167–5273(12): 1185–1190. Latib A, Maisano F, Bertoldi L, Giacomini A, Shannon J, et al. Transcatheter vs surgical aortic valve replacement in intermediatesurgical-risk patients with aortic stenosis: A propensity score-matched case-control study. Am Heart J 2012; 164(6): 910–917. Perrotta S and Lentini S. Ministernotomy approach for surgery of the aortic root and ascending aorta. Interact Cardiovasc Thorac Surg 2009; 9(5): 849–858.

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Case Report Antiphospholipid syndrome in a young Nigerian girl presenting with gangrenous toes RAPHAEL CHINEDU ANAKWUE, CHIOLI CHIJIOKE, ANTHONY MBAH, AUGUSTINE ONUH, CHRISTIAN OKWARA

Abstract We report on a 21-year-old Nigerian girl with toe gangrene, which is one of the most unlikely forms of presentation of antiphospholipid syndrome among Africans. The essence of this case report is to raise awareness that, although antiphospholipid syndrome typically presents in Africans in association with a pregnancy-related event or a neuropathology, it should be considered as a differential diagnosis in all African patients with unexplained vasculitis. A high index of suspicion and early treatment will prevent toe amputations and reduce mortality rates. Keywords: antiphospholipid syndrome, gangrenous toes, young Nigerian girl Submitted 28/4/13, accepted 26/9/13 Cardiovasc J Afr 2013; 24: e8–e11

www.cvja.co.za

DOI: 10.5830/CVJA-2013-073

Antiphospholipid syndrome is an auto-immune disorder in which the body mounts antibodies against proteins involved in the coagulation cascade, leading to thrombosis in the arteries and veins, and complications in pregnancy, such as abortions and stillbirths. The pathogenic antibodies assessed in APLS are the lupus anticoagulant (LA), anticardiolipin, and anti-β2-glycoprotein I. Lupus anticoagulant antibodies are identified by coagulation assays, in which they prolong clotting times. By contrast, anticardiolipin antibodies and anti-β2-glycoprotein I antibodies are detected by immunoassays that measure immunologic reactivity to a phospholipid or a phospholipid-binding protein (cardiolipin and β2-glycoprotein I, respectively).1 There are also three different antibodies that can be assessed: immunoglobulins G, M and A. The pathogenesis of APLS is controversial and there are three theories that seek to explain the pathogenesis of antiphospholipid syndrome. The first theory suggests that endothelial cells are College of Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria RAPHAEL CHINEDU ANAKWUE, MBBS, MSc, MWACP, FWACP, dranakwue@yahoo.com CHIOLI CHIJIOKE MBBS, MSc, FWACP, MD ANTHONY MBAH, MD, FMCP AUGUSTINE ONUH, MBBS, FWACP CHRISTIAN OKWARA MBBS, FWACP

activated following the binding of antiphospholipid antibodies. This sets off a cascade of reactions that culminates in thrombus formation. The antiphospholipid antibodies also recognise β2-glycoprotein I bound to resting endothelial cells.1,2 The second theory proposes that antiphospholipid antibodies interfere with or modulate the function of phospholipidbinding proteins involved in the regulation of coagulation. Antiphospholipid antibodies are also thought to interfere with the functions of β2-glycoprotein I, prothrombin, protein C, annexin V and tissue factor.3-5 The third theory recognises that oxidised low-density lipoprotein-induced oxidant-mediated injury to the vascular endothelium sets up a chain of reaction, including recognition of oxidised phospholipids and or phospholipid-binding proteins by the anticardiolipin antibody.6-8 The first and second theories may actually reflect the true pathogenesis of antiphospholipid syndrome. This is in keeping with the current findings, which confirm that the anticardiolipin antibodies detect antibodies to β2-glycoprotein I (β2GPI), and lupus anticoagulant tests are sensitive to antibodies to β2GPI (anti-β2GPI) and also antibodies to prothrombin.9 There are many mechanisms that could explain thrombosis in APLS.10 These are: increased expression of tissue factor on monocytes and endothelial cells, interference in the protein C anticoagulant pathway, inhibition of fibrinolysis, and inhibition of annexin V binding to phospholipids. More recently, the following have been implicated: the binding of anti-β2GPI to receptors (Toll-like receptors 2 and 4, annexin A2, glycoprotein 1b-alpha, and LRP8 in the LDL receptor family) and to different cell types (endothelial cells, platelets, monocytes and trophoblasts). All these lead to triggering of intracellular signalling and inflammatory responses.10 The thrombosis that defines APLS may be arterial or venous. The most frequent site of arterial thrombosis is in the cerebral vasculature, causing cerebral ischaemia/stroke, and in the heart, resulting in myocardial ischaemia, as well as in the arteries of the leg, arm, kidney and mesentery. Venous thrombosis could lead to deep-vein thrombosis and/or pulmonary thrombosis, and may also involve the portal, renal, mesenteric, intracranial and superficial (superficial thrombophlebitis) veins. Microvascular thrombosis could involve the lungs, brain, kidneys and other organs, causing multi-organ failure, the so-called catastrophic antiphospholipid syndrome (CAPLS).10 Diagnosis of antiphospholipid syndrome is based on the International Consensus statement of one clinical criterion or laboratory criterion.1,11 The clinical criterion includes one or more

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clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ, confirmed by findings from imaging studies, Doppler studies, or histopathology and/or pregnancy mortality, premature births, spontaneous abortions and stillbirth. The laboratory criterion outlines that patients must have (1) medium to high levels of immunoglobulin G (IgG) or immunoglobulin M (IgM), anticardiolipin (aCL), anti-beta-2 glycoprotein I, or LA on at least two occasions at least 12 weeks apart. Other criteria include cardiac valve vegetations (LibmanSachs endocarditis), valvular insufficiency, livedo reticularis, leg ulcers, migraine headaches, and a variety of neurological complications, including chorea and transverse myelopathy.1 The antiphospholipid syndrome can be primary or secondary depending on the presence or absence of autoimmune diseases, viral infections, cancer, but more commonly systemic lupus erythematosis. Epidemiological studies have shown that antiphospholipid antibodies are found among young, apparently healthy control subjects at a prevalence of 1–5% for both anticardiolipin antibodies and lupus anticoagulant antibodies.12 The prevalence of antiphospholipid antibodies increases with age, especially among elderly patients with coexisting chronic diseases.12 Many patients have laboratory evidence of antiphospholipid antibodies without clinical consequences. In apparently healthy control subjects, there are insufficient data to determine what percentage of those with antiphospholipid antibodies will eventually have a thrombotic event or a complication of pregnancy consistent with the antiphospholipid syndrome. In contrast, the antiphospholipid syndrome may develop in 50–70% of patients with both systemic lupus erythematosus and antiphospholipid antibodies after 20 years of follow up.12,13 The modality of treatment depends on the pattern of presentation. Aspirin and hydroxychloroquine are used in prophylaxis, warfarin is prescribed for prevention of further thromboses of large vessels and a combination of anticoagulants and steroids plus either plasmapheresis or intravenous immune globulin are effective in acute thrombotic microangiopathy. Currently, heparin administered to pregnant women with antiphospholipid syndrome after ultrasonographic demonstration of a live embryo is the treatment of choice.11

Fig. 1. Gangrene of the toes in a young Nigerian girl with antiphospholipid syndrome.

Case report A 21-year-old female Nigerian of Igbo ethnicity presented at the medical outpatient department of the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, with highgrade intermittent fever for seven weeks and symmetrical polyarthralgia for 10 days. The fever had resolved by the time she was evaluated in our centre. The patient was unmarried and her gyneco-obstetrical history was uneventful, with regular menstruation. She was not on oral contraceptives and does not smoke. She is not a known diabetes mellitus patient. She noted some numbness and discoloration of the toes. There was also associated weight loss, malaise and myalgia. On examination she was afebrile, very pale and normotensive (110/60 mmHg). The dorsalis pedis and posterior tibial artery pulsations were palpable bilaterally and synchronously but the intensity appeared equally reduced on both sides. There was black discoloration and demarcation of her toes, with a stockingpattern loss of sensation and vasculitis on her feet (Figs 1, 2). The rest of the clinical examination, which included a detailed assessment of the cardiovascular system, was unremarkable. Doppler studies showed reduced distal flow in the digital arteries supplying her toes. Foot radiographs were normal. An initial working diagnosis of autoimmune vasculitis with gangrene was made. The differential diagnoses considered were: systemic lupus erythematosis, antiphospholipid syndrome and any of the overlap syndromes. Her laboratory results showed anaemia (haemoglobin 7.8 g/ dl), renal impairment (serum urea 17.7 mmol/l, creatinine 224 µmol/l, estimated GFR 42.9 ml/min/1.73m2), proteinuria 3+,

Fig. 2. Vasculitis in the same patient.

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raised liver enzymes (alanine transaminase 61 units/ml, aspartate transaminase 32 units/ml, alkaline phosphatase 129 units/ml) and ESR (> 150 mm/h). Her HIV antibody screening test, lipid profile, fasting blood sugar, serum electrolytes and urinalysis were normal. Pregnancy was ruled out with a serum HCG test and pelvic ultrasound. Echocardiography showed normal cardiac chamber sizes, normal heart valves, no valvular stenosis or regurgitation, no intracardiac clots, vegetations or mass; normal diastolic and systolic function and normal pericardium. The serum anticardiolipin antibodies were elevated (IgM 17.08 units/ml and IgG 100.68 units/ml: normal for both < 10 units/ml). The anti-beta-2 glycoprotein IgM and IgG antibodies were increased: 50 units/ml and 182 units/ml, respectively (normal < 20 units/ml). Anti-nuclear antigen (ANA) was positive (1:1 280-speckled pattern). The anti-double-stranded DNA was positive (OD ratio 1.201). Rheumatoid factor was negative. From these results, a definitive diagnosis of antiphospholipid syndrome secondary to systemic lupus erythematosis was made and the patient’s further management was along that line. The patient was managed with a daily dose of subcutaneous enoxaparin 40 mg, tablet aspirin 75 mg, prednisolone 40 mg, vitamin C 400 mg tds, tramadol 50 mg tds, ranitidine 150 mg nocte. She was transfused with three units of blood on account of anaemia. She was reviewed by plastic surgeons and orthopaedic surgeons who decided that amputation of the 10 toes (toe disarticulation) was indicated due to the gangrene. She has been stable since amputation but was subsequently lost to follow up.

Discussion Very few cases of antiphospholipid syndrome (APLS) have been reported from sub-Saharan Africa. Apart from a low case incidence, other reasons could be a low index of suspicion, or a lack of investigative tools, and poverty. The patient’s illiteracy and poverty, made worse by the absence of an adequate health insurance scheme, was contributory to the inability of the authors to fully investigate and manage the index case presented here. The patient opted for surgery outright instead of allowing repeat assessment of the antiphospholipid antibodies. Only one set of antiphospholipid antibodies was also reported from western Nigeria, perhaps for similar reasons. From Nigeria, one of the two cases reported was that by Adelowo and Oguntona who documented five cases of secondary APLS in which association with pregnancy was the most common presentation; the rest being due to neurological manifestations.14 We realise that a single documentation of antiphospholipid antibodies in this case report does not fully satisfy the criteria for diagnosis of APLS, which requires that these antibodies should be found in medium to high levels on at least two occasions, at least 12 weeks apart. Studies among different ethnic groups have indicated that IgG antibodies are indeed the most common antibody associated with thrombosis in African-Americans.15,16 In other words, the high level of IgG found in this index case, together with the degree of toe gangrene morbidity, is strongly supportive of the diagnosis of APLS. Furthermore, the British committee for standards in haematology has stated in the 2012 guideline that the diagnostic

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criteria should be used with care. The final diagnosis of APLS should depend on a thorough assessment of the clinical history, consideration of alternative causes of thrombosis or pregnancy morbidity, and review of the laboratory data in light of knowledge of the limitations of the assays.10 APLS with toe gangrene is also infrequently reported in African-Americans. In a series of eight cases, the majority was secondary to systemic lupus erythematosis and mixed connective tissue disease and the most common presentation was neurological.17 It does appear that APLS associated with toe gangrene is rare in Africans and African-Americans and that toe gangrene is one of the most unlikely forms of presentation. Toe gangrene has been reported as a presentation of APLS in Caucasians.18 To the best of our knowledge, however, this is the first report of such a presentation in Africans or African-Americans. Livedo reticularis supports the diagnosis of APLS and signifies increased risk of arterial thrombosis.19 Fig. 2 shows vasculopathy in our index patient. The occurrence of gangrene as a potential complication in Africans emphasises the importance of considering APLS as a differential diagnosis in patients with toe gangrene. The renal impairment seen in the index case raises a question as to whether there was associated catastrophic antiphospholipid syndrome. However, venous or arterial thrombosis of the large vessels is less common in patients with catastrophic antiphospholipid syndrome, who tend to present with an acute thrombotic microangiopathy affecting the small vessels of multiple organs.20 In catastrophic antiphospholipid syndrome (CAPLS), there is clinical involvement of at least three different organ systems over a period of days or weeks, with histopathological evidence of multiple occlusions of the large or small vessels.20 The kidney is the organ most commonly affected (in 78% of patients: renal thrombotic microangiopathy), followed by the lungs (66%: adult respiratory distress syndrome), the central nervous system (56%; cerebral microthrombi and micro-infarction), the heart (50%: myocardial microthrombi), and the skin (50%). Disseminated intravascular coagulation, which does not occur in primary or secondary APLS, occurs in approximately 25% of patients with CAPLS. The abnormal liver function tests in our index patient may have been part of the clinical syndrome. Most patients with renal involvement have hypertension, often malignant, and approximately 25% require dialysis. The mortality rate in CAPLS is 50%, and death is usually due to multi-organ failure.20 It is unlikely that our patient had CAPLS given the clinical presentation. It will be necessary to make extra efforts to trace this patient. Mere amputation and healing of the wound will not cure her. Without adequate follow up and treatment, she is likely to come back with another thrombotic episode.

Conclusion The essence of this case report is to raise the awareness that, although antiphospholipid syndrome typically presents in Africans in association with a pregnancy-related event or a neuropathology, it should be considered as a differential diagnosis in all African patients with unexplained vasculitis. This is because early diagnosis and initiation of appropriate therapy will reduce morbidity and mortality rates.

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References 1.

Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752–763. 2. Meroni PL, Raschi E, Camera M, et al. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J Autoimmun 2000; 15: 237–240. 3. Meroni PL, Del Papa N, Raschi E, et al. β2-Glycoprotein I as a ‘cofactor’ for anti-phospholipid reactivity with endothelial cells. Lupus 1998; 7: Suppl 2: S44–S47. 4. Kandiah DA, Krilis SA. Beta2-glycoprotein I. Lupus 1994; 3: 207–212. 5. Roubey RAS. Tissue factor pathway and the antiphospholipid syndrome. J Autoimmun 2000; 15: 217–220. 6. Rand JH, Wu X-X, Andree HAM, et al. Pregnancy loss in the antiphospholipid-antibody syndrome – a possible thrombogenic mechanism. N Engl J Med 1997; 337:154–160 [Erratum: N Engl J Med 1997; 337: 1327.] 7. Ames PRJ. Antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: a unifying ‘membrane stress syndrome’ hypothesis. Lupus 1994; 3: 371–377. 8. Vaarala O, Alfthan G, Jauhiainen M , et al. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 341: 923–925. 9. Horkko S, Miller E, Dudl E, et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 1996; 98: 815–825. 10. Keeling D, Mackie I, Moore G, et al. Guidelines on investigation and management of APS. Br J Hematol 2012; 157: 47–58.

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11. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of classification criteria for definite APS. J Thromb Haemostasis 2005; vol?: 295–306. 12. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000; 15: 145–151. 13. Alarcon-Segovia D, Perez-Vazquez ME, Villa AR, Drenkard C, Cabiedes J. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Semin Arthritis Rheum 1992; 21: 275–286. 14. Adelowo OO, Oguntona S. Antiphospholipid syndrome in Nigeria: Report of five cases. East Afr Med J 2009; 86(2): 94–96. 15. Wilson WA, Perez MC, Michalski JP, Armatis PE. Cardiolipin antibodies and null alleles of C4 in black Americans with systemic lupus erythematosus. J Rheumatol 1988; 15: 1768–1772. 16. Uthman I, Khamashta M. Ethnic and geographical variation in antiphospholipid (Hughes’) syndrome. Ann Rheum Dis 2005; 64: 1671–1676. doi: 10.1136/ard.2005.038448. 17. Diri E, Cucurull E, Gharavi AE, et al. Antiphospholipid (Hughes’) syndrome in African-Americans: IgA aCL and abeta2 glycoprotein-I is the most frequent isotype. Lupus 1999; 8(4): 263–268. 18. Gonzalez ME, Kahn P, Prize HN, et al. Retiform purpura and digital gangrene secondary to antiphospholipid syndrome successfully treated with sildenafil. Arch Dermatol 2011; 147(2): 164–167. 19. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010; 76(9751): 1498–1509. 20. Asherson RA, Cervera R, Piette J-C, et al. Catastrophic antiphospholipid syndrome: clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998; 77: 195–207.

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Case Report Kounis syndrome leads to cardiogenic shock KUAI-LE CHANG, JIU CHEN, JUN YU, XIAO-LIANG DOU

Abstract Kounis syndrome has been defined as an acute coronary syndrome that manifests as unstable vasospastic or nonvasospastic angina, and even as acute myocardial infarction. It is triggered by the release of inflammatory mediators following an allergic insult or patient ill health, drug intake or environmental exposure. We report on a patient who was admitted to our hospital and diagnosed with unstable angina or acute myocardial infarction – according to analytical parameters, electrocardiographic abnormalities, and/or coronary angiography – in the context of progesterone as inducing factor. The results of a laboratory study revealed electrocardiogram changes, and increased myocardial enzymes, IgE antibodies and eosinophils. The patient experienced recurring chest pain, acute myocardial infarction, and cardiogenic shock after taking progesterone capsules; her medication history of progesterone clearly correlated with the onset of chest pain, which suggested that the cause of the vasospasm may have been related to progesterone use. We did not include patients with a history of bronchial asthma or allergic constitution. Nevertheless, the case suggests there is a correlation between Kounis syndrome and progesterone as inducing factor. Keywords: Kounis syndrome, cardiogenic shock, anaphylaxis, acute myocardial infarction, coronary vasospasm, progesterone Submitted 26/4/13, accepted 25/10/13 Cardiovasc J Afr 2013; 24: e12–e16

www.cvja.co.za

DOI: 10.5830/CVJA-2013-075

Kounis syndrome, also known as allergic angina syndrome, was described in 1991 by Kounis and Zafras1 as ‘the coincidental occurrence of chest pain and allergic reactions accompanied by clinical and laboratory findings of classic angina pectoris caused by inflammatory mediators released during the allergic insult’. They named the progression from chest pain to acute myocardial infarction ‘allergic myocardial infarction’.2,3 Department of Cardiology, 3rd Hospital of the Chinese People’s Liberation Army, 45 Dongfeng Road, Baoji, Shaanxi Province, China KUAI-LE CHANG, MD, academicchen@163.com JUN YU, MD

Centre for Mental Disease Control and Prevention, 3rd Hospital of the Chinese People’s Liberation Army, Baoji, Shaanxi Province, China JIU CHEN, MD XIAO-LIANG DOU, MD

This heart condition occurs in a considerable number of patients during episodes of anaphylaxis,4 and frequently in patients with prior coronary artery disease, although it has also been observed in patients with healthy coronary vessels. Vasospasm of the coronary arteries has been suggested to be the main pathophysiological mechanism.5 Knowing more about the pathogenesis of Kounis syndrome will provide a detailed understanding of such patients and may help to establish rehabilitation procedures along those lines. We report on a patient with Kounis syndrome due to taking progesterone medication.

Case report A 37-year-old woman was admitted to the hospital for paroxysmal retrosternal chest pain that had persisted for six months and had intensified over the previous five hours. The patient was a civil servant and had a body mass index of 18 kg/m2. She had experienced recurring retrosternal chest pain over the previous six months without any obvious cause. The painful episodes lasted approximately five to 10 minutes and typically occurred in the afternoon or at night, never in the morning. The pain could be relieved with rest. The patient had visited other hospitals for the symptoms but no abnormality was found on electrocardiography (ECG) (Fig. 1), echocardiography or chest X-ray. The patient was diagnosed with reflux oesophagitis but the intermittent use of entericcoated omeprazole tablets did not alleviate the pain. One month prior to admission, the chest pain became aggravated and began to occur more frequently, two to three times per week. The episodes of pain occurred between 16:00 and 23:00 and lasted from several minutes to half an hour before remitting. The pain was not correlated with physical activities or accompanied by referred pain. If the pain affected sleeping at night, the use of omeprazole tablets relieved the pain and promoted sleep. Three days prior to admission, the chest pain occurred frequently after excessive labour and was accompanied by cold sweating. The pain occurred two to three times a day, and each episode lasted between 10 minutes and one hour, primarily after dinner or before bedtime. Five hours prior to admission, the chest pain became aggravated and was accompanied by dizziness, cold sweats, chest tightness and shortness of breath. The patient was admitted to the emergency room and hospitalised. The patient had no medical or family history of hypertension, diabetes or coronary heart disease, and she had no history of smoking or alcohol abuse. She had a history of bronchial asthma that had persisted for more than 10 years, but the condition had been well controlled for four years by inhaling salmeterol xinafoate and fluticasone propionate powder (one puff/day). When the patient experienced an irregular menstrual cycle and reduced menstrual flow six months earlier, she began

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Fig. 1. An ECG six months prior to admission. Indication: sinus rhythm, normal ECG.

taking progesterone capsules (100 mg/pill) twice a day for five consecutive days, from the 20th day of the cycle, and the menstrual cycle and flow had returned to normal. Eight days prior to admission, the patient had taken progesterone capsules for five consecutive days. A physical examination on admission revealed a temperature of 36.8°C, a pulse of 78 beats/min, respiration of 20/min and

blood pressure of 110/70 mmHg. The lungs were clear to auscultation bilaterally. There was no expanding heart border or murmur at the valve auscultation areas, and the heart sounds were blunt. On admission, an electrocardiogram (ECG) displayed a sinus rhythm of 67 beats/min, ST-segment elevation in leads V1– V3, and inverted symmetric T waves in leads V4–V6 (Fig. 2). The laboratory tests showed the following: serum troponin I, 11.62

Fig. 2. The ECG at the time of admission. Indication: sinus rhythm, acute anterior myocardial infarction, inverted T wave in leads V4–V6.

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Fig. 3. An ECG during chest pain. Indication: sinus rhythm, old anterior myocardial infarction, hyper-acute T wave in leads V4–V6.

ng/l; creatine kinase MB, 210 mmol/l; myoglobin, 124 mmol/l; BNP 1 046 ng/ml; and no abnormalities in renal function, electrolyte parameters or routine blood and urine tests. A diagnosis of acute anterior myocardial infarction was established. The patient and her family declined an emergency coronary angiography test and treatment. She was given oxygen, ECG monitoring, oral enteric-coated aspirin tablets (300 mg), clopidogrel (300 mg), rosuvastatin calcium (10 mg) and a subcutaneous injection of low-molecular weight heparin calcium (5 000 U). Intravenous thrombolytic therapy with urokinase (200 U) was immediately performed. However, there were no significant changes in the ECG after 30 minutes or one hour, and after 1.5 hours, the patient became irritable, her face became pale grey, and she began sweating. The patient’s blood pressure dropped to 70/30 mmHg, and she presented with sinus bradycardia, third-degree atrio-ventricular block, a ventricular rate of 33 beats/min and unconsciousness. Atropine was applied through intravenous injection, which was immediately followed by ventricular tachycardia and ventricular fibrillation. After three defibrillation attempts (200 J), sinus rhythm was restored, and the heart rate was 130–160 beats/min. After one hour, the patient regained consciousness and reported chest tightness and shortness of breath, and exhibited a pale grey face and cold limbs. Dopamine (3 120 mg), norepinephrine (2 mg), metaraminol (160 mg) and dobutamine (1 640 mg) were administered; however, even with continuous high-dose intravenous infusion of blood pressure-raising drugs, the patient had recurring low blood pressure. Ten hours after resuscitation, the blood pressure was maintained at 90–100/60–70 mmHg, and small doses of dopamine (200 mg) and dobutamine (100 mg) were continuously administered by a micro-pump. Twelve hours after resuscitation, the patient’s blood pressure remained stable. Fourteen hours after resuscitation, she developed acute left ventricular failure and pink foamy sputum; the patient was given medication for heart failure, including furosemide dieresis and sodium nitroprusside. Three days later, her vital signs gradually became stable. Chest radiographs demonstrated increased and blurred lung markings on both sides, a small shadow in the lung and no abnormalities in the size, shape and position of the heart. The ECG results demonstrated a small amount of pericardial effusion, reduced left ventricular wall motion, mild mitral and tricuspid regurgitation and an ejection fraction (EF) of 51%. One week after hospitalisation, the patient experienced paroxysmal chest pain three times, and each occurrence lasted for five to 10 minutes. The pain was relieved with sublingual nitroglycerin. An ECG during paroxysmal chest pain showed a QS pattern in leads V1–V3; in leads V4–V6, an inverted T wave

became upright during the pain and returned to inverted when the pain was relieved (Fig. 3). For treatment, aspirin, clopidogrel, isosorbide mononitrate, rosuvastatin and trimetazidine were administered. Two weeks later, the patient’s condition stabilised. A coronary angiograph displayed no significant abnormalities in the left main, left anterior descending or circumflex arteries (Fig. 4), but a right coronary spasm was visible (Fig. 4). Routine blood testing prior to admission showed eosinophils at 0.52 × 109/l, and this value increased to 5.1 × 109/l during hospitalisation and then dropped to 0.53 × 109/l prior to discharge. The patient’s immunoglobulin E (IgE) was higher than 200 IU/ml, which indicated an increased titre. However, no significant abnormalities were identified by auto-antibody, anti-nuclear antibody, anti-dsDNA antibody or anti-mitochondrial antibody tests. The high-sensitivity C-reactive protein and immunoglobulin levels were normal. The patient’s oestrogen and progesterone levels were within normal ranges. Based on the previous medication plan, clopidogrel was stopped, and diltiazem and trimetazidine were administered instead. The patient was advised to stop taking progesterone capsules. The discharge diagnosis was Kounis syndrome with acute anterior myocardial infarction and cardiogenic shock (Killip class IV). After discharge, the patient received longterm medication to control the disease and remained in a stable condition without paroxysmal chest pain. At the three-month follow up, the patient’s menstrual cycle was regular and had a reasonable amount of flow.

Discussion Acute myocardial infarction primarily affects older men and postmenopausal women; it is rare in young women. The patient in this study was a slim young woman with no history of smoking, alcohol abuse or other risk factors for coronary heart disease, such as obesity, hyperlipidaemia, diabetes or high blood pressure. There was no family history of coronary artery disease. The patient had taken progesterone capsules every month prior to the onset of chest pain and later developed recurrent chest pain; therefore, we suspected that the unstable angina pectoris was related to progesterone use. Myocardial infarction in female patients has been correlated with hormone levels,6 and chest pain has been correlated with progesterone drugs.7 The cause of the present patient’s cardiogenic shock was acute myocardial infarction. Coronary angiography confirmed that the cause of the acute anterior myocardial infarction was coronary artery spasm and indicated a right coronary artery spasm and normal left coronary and descending arteries.7 However, the presence of a left and right coronary spasm, which may have led

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Fig. 4. A. Coronary angiograph of the left coronary artery. No significant stenosis was present in the left anterior descending or circumflex coronary arteries. B. First coronary angiography of the right coronary artery. Multiple severe stenoses were found in segments one to three of the right coronary artery, narrowing to 85%. C. Second coronary angiography of the right coronary artery. Multiple moderate stenoses were found in segments one to three of the right coronary artery, narrowing to 50%. D. Third coronary angiography of the right coronary artery. No significant stenosis was present in the right coronary artery.

to the cardiogenic episode, cannot be ruled out in this patient’s case. Asano et al.8,9 studied drug provocation tests in patients with vasospastic angina and found that more than 25% of the patients had multi-vessel spasms. Although prognosis is good for vasospastic angina patients, sudden cardiac death is not uncommon. Multi-vessel spasm can result in a large area of ischaemic myocardium, and vasospasm occurs frequently in the affected vessels, which can easily induce major cardiovascular accidents, including malignant arrhythmias and sudden death.

The patient described here had a history of bronchial asthma and allergies for many years. Laboratory tests after admission showed normal values of high-sensitivity C-reactive protein and immunoglobulin, but the patient’s eosinophils and IgE titres were significantly increased. In combination with the characteristics of chest pain and the coronary angiogram, Kounis syndrome was diagnosed. Kounis syndrome is an allergy-related acute coronary syndrome (ACS) associated with ST-segment elevation, including allergic angina and myocardial infarction.10 Characteristics of

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Kounis syndrome are similar to ACS cases that are caused by concurrent thrombosis during plaque rupture or erosion. In addition, coronary angiography can show coronary artery spasm, most commonly in the right coronary artery. Kounis syndrome11 is related to drug or food allergies and can induce severe coronary spasm that leads to myocardial infarction and sudden death. Pathogenesis of Kounis syndrome may be the result of mast cell activation by allergic reactions and the subsequent release of inflammatory mediators, which leads to coronary artery spasm or plaque rupture. Angiography confirmed coronary artery spasm in the present patient’s case. The cause of the vasospasm may have been related to the fact that the patient was prone to allergies that can induce Kounis syndrome. Six months prior to admission, the patient had experienced recurring chest pain after taking progesterone capsules; her medication history of progesterone clearly correlated with onset of chest pain, which suggested that the cause of the vasospasm might be related to progesterone use. However, a cautionary remark is necessary, as we could not exclude the possibility that pathogenesis of Kounis syndrome may have been the result of the interaction of progesterone use and an allergic constitution.

Conclusion Kounis syndrome is uncommon and is rarely reported domestically or internationally; the pathogenesis is poorly understood and requires further study. Therefore, for young female patients with angina or chest tightness who are prone to allergies or who have a clinical history of allergies, more attention should be given to Kounis syndrome. Attention should also be given to special pathological changes to the coronary artery, such as vasospasm, which can cause angina, myocardial infarction or sudden death. A weakness of this case report is the lack of an intravascular ultrasound or optical coherence tomography examination. Also we only found and reported on one case. If specific

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characteristics of Kounis syndrome can be identified, they may be useful potential pathogenic factors for Kounis syndrome. In the future, specific prevention and therapeutic strategies could then be implemented. We acknowledge with thanks the assistance of 3rd Hospital of the Chinese People’s Liberation Army Pathology Imaging Core for digital whole-slide imaging of this case.

References 1.

Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991; 45: 121–128. 2. Kounis NG, Zavras GM. Allergic angina and allergic myocardial infarction. Circulation 1996; 94: 1789. 3. Kounis NG, Grapsas GM, Goudevenos JA. Unstable angina, allergic angina and allergic myocardial infarction. Circulation 1999; 100: e156. 4. Moneret-Vautrin DA, Morisset M, Flabbee J, Beaudouin E, Kanny G. Epidemiology of life-threatening and lethal anaphylaxis: a review. Allergy 2005; 60: 443–451. 5. Brener Z, Zhuravenko I, Bergman M. Acute myocardial injury following penicillin-associated anaphylactic reaction in a patient with normal coronary arteries. Am J Med Sci 2007; 334: 305–307. 6. Ablewska U, Jankowski K, Rzewuska E, Liszewska-Pfejfer D, Hryniewiecki TA. Levels of endogenous gonadal hormones and their relationship with selected coronary artery disease risk factors among young women post myocardial infarction. Acta Biochim Polon 2011; 58: 385–389. 7. Chen LF, Guo P. Muscle injection of progesterone, a case study and literature review. Contemp Med 2011; 17: 79. 8. Asano T, Kobayashi Y, Ohno M, Nakayama T, Kuroda N, Komuro I. Multivessel coronary artery spasm refractory to intensive medical treatment. Angiology 2007; 58: 636–639. 9. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version. Circ J 2010; 74: 1745–1762. 10. Feuerstein G, Rabinovici R, Leor J, Winkler JD, Vonhof S. Plateletactivating factor and cardiac diseases: therapeutic potential for PAF inhibitors. J Lipid Cell Signal 1997; 15: 255–284. 11. Gázquez V, Dalmau G, Gaig P, Gomez C, Navarro S, Merce J. Kounis syndrome: report of 5 cases. J Investig Allergol Clin Immunol 2010; 20: 162–165.

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