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Vol 28, No 2, MARCH/APRIL 2017

CONTENTS

Cardiovascular Journal of Africa 71

www.cvja.co.za

From the Editor’s Desk P Commerford

Cardiovascular Topics 72 Awareness of hypertension guidelines and the diagnosis and evaluation of hypertension by primary care physicians in Nigeria OK Ale • RW Braimoh 77 The role of genetics in coronary artery bypass surgery patients under 30 years of age S Sarikaya • E Aydin • Y Ozen • MB Rabus • O Altas • E Aksoy • T Ozer • K Kirali 81 The role of coronary artery collaterals in the preservation of left ventricular function: a study to address a long-standing controversy NO Ajayi • EA Vanker • KS Satyapal 86 Obesity in Botswana: time for new cut-off points for abdominal girth? CL Onen 92

Comparative analysis of anthropometric indices of obesity as correlates and potential predictors of risk for hypertension and prehypertension in a population in Nigeria CJ Ononamadu • CN Ezekwesili • OF Onyeukwu • UF Umeoguaju • OC Ezeigwe • GO Ihegboro

100

Chicken or the egg: ST elevation in lead aVR or SYNTAX score L Cerit

104 Relationship between Vitamin D and the development of atrial fibrillation after on-pump coronary artery bypass graft surgery L Cerit • H Kemal • K Gulsen • B Ozcem • Z Cerit • H Duygu 108

Factors associated with early mortality in haemodialysis patients undergoing coronary artery bypass surgery D Çevirme • T Adademir • M Aksüt • T Örki • KC Çakalağaoğlu • M Alp • K Kırali

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

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

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

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

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)

Vol 28, No 2, MARCH/APRIL 2017

CONTENTS

112 Presentation and mortality of patients hospitalised with acute heart failure in Botswana JC Mwita • MJ Dewhurst • MGMD Magafu • M Goepamang • B Omech • KL Majuta • M Gaenamong • TB Palai • M Mosepele • Y Mashalla 118 The effect of proximal anastomosis on the expansion rate of a dilated ascending aorta in coronary artery bypass surgery: a prospective study U Vural • AY Balcı • R Aksoy • MDF Özdemir • S Satılmış • M Kızılay • M Şenocak • H Şaşkın • İ Kayacıoğlu • İ Yekeler

Review Article 125 The integrated effect of moderate exercise on coronary heart disease MJ Mathews • EH Mathews • GE Mathews

Case Report 134 Pacemaker syndrome with sub-acute left ventricular systolic dysfunction in a patient with a dual-chamber pacemaker: consequence of lead switch at the header MR Khurwolah • BZ Vezi

PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed) Case Report

e1 Successful surgical treatment of a subtotal descending aortic occlusion M Puślecki • B Perek • S Stefaniak • A Siniawski • G Oszkinis • M Jemielity

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

From the Editor’s Desk The gap between clinical practice guidelines and usual clinical practice is acknowledged to exist worldwide, is seldom measured, but is considered to be important. In this issue, Ale and Braimoh (page 72) report on the knowledge of hypertension guidelines in a large sample of primary care physicians in Nigeria. Deficiencies in knowledge seemed to translate to deficiencies in diagnosis and management. In a cross-sectional study, Ononamadu and colleagues (page 92) compared the performance of eight anthropometric indices of obesity: body mass index (BMI), ponderal index, waist circumference (WC), hip circumference, waist–hip ratio, waist–height ratio, body adiposity index and conicity index as correlates and potential predictors of risk for hypertension and prehypertension in a Nigerian population, and also the possible effect of combining two or more indices in that regard. In a related but very different study, Onen (page 86) investigated anthropometric data from 215 male and 203 female patients seen in a specialist clinic in Gaborone, Botswana, between

2005 and 2015 to establish appropriate cut-off points for WC corresponding to a BMI of 30 kg/m2. Relative risks for cardiometabolic disorders were calculated for different BMIs and WCs. He proposes new cut-off values, which may be useful in studies in other sub-Saharan countries. The importance of studies such as those above is emphasised by the report from Mwita and co-authors (page 112) on the clinical characteristics and outcomes of patients admitted to hospital in Botswana with acute heart failure. The patients were younger than in similar series in other parts of the world and had a high short-term mortality rate. Components of the metabolic syndrome were considered to be important in causation. Attempts to curb the mortality associated with the metabolic syndrome require ongoing efforts to identify it and treat its components in Africa. Pat Commerford Editor-in-Chief

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

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Cardiovascular Topics Awareness of hypertension guidelines and the diagnosis and evaluation of hypertension by primary care physicians in Nigeria OK Ale, RW Braimoh

Abstract Background: The availability of numerous hypertension guidelines seems not to have impacted significantly on the burden of hypertension. We evaluated awareness of hypertension guidelines among primary-care physicians (PCPs) in Nigeria and its relationship to hypertension diagnosis and work up. Methods: Anonymous self-administered questionnaires were filled in by PCPs categorised into two groups: hypertension guideline aware (GA) and unaware (GU). Results: The 403 participating PCPs had a mean age and experience of 40 ± 11.34 and 14 ± 11.10 years, respectively, with 46.7% (n = 188) of them being GA. Out of the 19 questions assessed, GA and GU PCPs performed better in seven and two questions, respectively, while the two subgroups had a similar performance in 10 questions. The performance of the PCPs in government and private practice was similar. Conclusions: There is a gap between guideline recommendations and hypertension care in Nigeria that is further widened by PCPs’ unawareness of the guidelines. Popularising hypertension guidelines among PCPs may significantly improve hypertension care and reduce the burden of disease. Keywords: hypertension, guidelines, diagnosis, work up, primarycare physicians, Nigeria Submitted 26/6/15, accepted 5/4/16 Cardiovasc J Afr 2017; 28: 72–76

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DOI: 10.5830/CVJA-2016-048

Hypertension is a major public health challenge, with increasing prevalence worldwide.1 It is the leading cardiovascular (CV) risk factor for morbidity and mortality and the largest contributor to the global burden of disease.2,3 Approximately 40% of adults aged 25 years and older worldwide had hypertension in 2008, with Africa and the Americas having the highest (46%) and

Department of Medicine, Faculty of Clinical Sciences, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria OK Ale, MB BS, MPH, FMCP, gokeale@yahoo.com RW Braimoh, MB BS, FWACP

lowest (35%) prevalence, respectively.4 The estimated prevalence of hypertension in Nigeria is 29.5%.5 Undiagnosed, uncontrolled and inappropriately managed hypertension is associated with a high risk for morbidity and mortality from potentially preventable complications such as stroke, and kidney and heart diseases.2,3,6 However, evidence from clinical and epidemiological research has provided huge capabilities for lowering blood pressure in almost every person with hypertension.1 This evidence has been collated, evaluated and summarised into hypertension guidelines to assist physicians in selecting the best hypertension-management strategies, taking into account the impact on outcome, as well as the risk–beneﬁt ratio of particular diagnostic or therapeutic means. Few of these guidelines are indigenous to sub-Saharan Africa (SSA) despite the huge burden of hypertension in this region, and many of the available guidelines do not factor the peculiarities of SSA into their recommendations. Although it is important to consider the science of medicine for the treatment of hypertension, particular consideration should be given to cost-effectiveness and affordability because many countries in SSA have severe resource constraints.7 A good combination of science, cost-effectiveness and affordability is provided by the International Forum for Hypertension control and prevention in Africa (IFHA) recommendations for the prevention, diagnosis and management of hypertension and cardiovascular risk factors in sub-Saharan Africa.7 The presence of hypertension guidelines seems not to have significantly impacted on hypertension control in SSA, with the burden of hypertension increasing. Its epidemiology is generally characterised by low levels of awareness, poor treatment, poor blood pressure control and a high burden of hypertensionrelated complications.2,3,8 Hypertension is the commonest condition in the primary-care setting, and in many countries it is almost entirely managed by primary-care physicians (PCPs).5,9 It has been suggested that the detection and treatment of hypertension in the primary healthcare setting in SSA is poor.7 This is similar to the unsatisfactory management of hypertension and cardiovascular risk factors reported in various parts of the world.10-12 Limited knowledge of hypertension by healthcare professionals, among other factors, has been identified as being responsible for poor hypertension control in SSA.3 This makes it worthwhile to investigate the contribution of PCPs to the burden of undiagnosed and inadequately/inappropriately managed hypertension in Nigeria. Our aim was to evaluate awareness of hypertension

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

guidelines among PCPs in Lagos, Nigeria and its effect on their diagnostic approach to hypertension. We also sought to determine the relationship between the type of practice, namely private or government, and hypertension diagnosis and work up.

Methods Four hundred and three Lagos-based PCPs (general practitioners) attending continuing medical education programmes were categorised into two groups: hypertension guideline aware and guideline unaware. Hypertension guideline awareness status was defined by a ‘yes’ or ‘no’ answer to the question: ‘are you aware of hypertension guidelines?’ Physicians with speciality training in internal medicine were excluded from the study. Ethical clearance was obtained from the ethics and research committee of the Lagos University Teaching Hospital. Consent of each participant was obtained. Anonymous self-administered questionnaires consisting of 19 open-ended and closed questions on hypertension diagnosis and work up were used. The closed questions had either yes/ no or Likert-type scale responses. The study questionnaire was in four main domains: (1) type of practice – private versus government and number of patients seen; (2) hypertension detection – frequency of blood pressure checks in patients, resting before blood pressure measurement, number of blood pressure readings, blood pressure threshold levels; (3) clinical evaluation – personal history of diabetes mellitus, alcohol and tobacco habits, family history of diabetes and hypertension, evaluation for obesity, and blood pressure measurement; and (4) laboratory/ancillary evaluation – urinalysis, serum electrolytes and creatinine, blood glucose, lipogram, electrocardiogram and fundoscopy. An additional question on hypertension being a major public health problem was included.

Statistical analysis Likert-type scale responses were transformed into dichotomous responses of appropriate/yes (‘always done’ and ‘often or usually Table 1. Basic characteristics of the respondents according to their awareness of guidelines Awareness of guidelines All

Yes (GA)

No (GU)

n (%) mean ± SD

403 (100)

188 (46.7)

215 (53.3)

40.0 ± 11.3

38.5 ± 9.6

41.4 ± 12.6

Male

249 (61.8)

121 (64.4)

128 (59.5)

Female

154 (38.2)

67 (35.6)

87(40.3)

Years post registration (403)

14.3 ± 11.1

13.4 ± 9.9

15.1 ± 12.0

0.12

No of patients seen per day (403)

17.4 ± 14.3 17.5 ± 11.6 18.3 ± 16.2

0.58

Variable (n) No of physicians Age (397) Gender (403)

No of hypertensive patients seen per day (396)

4.1 ± 3.3

4.6 ± 3.6

Type of practice (403) Private (269)

269 (66.7)

137 (72.9)

132 (61.4)

134 (33.3)

51 (27.1)

83 (38.6)

369 (95.1)

164 (94.8)

205 (95.3)

Consider hypertension a public health challenge (388)

GA, guideline aware; GU, guideline unaware.

Data from 413 PCPs with a mean age of 40 ± 11.34 years and a mean post-registration experience of 14.30 ± 11.00 years were analysed. Guideline awareness among the cohort was 46.7% (n = 188). Tables 1 and 2 show the basic characteristics of the PCPs according to their awareness of hypertension guidelines and the type of practice, respectively. The guideline-aware (GA) physicians were younger than the guideline-unaware (GU) physicians (p < 0.05). The GA and GU physicians were similar in terms of gender, experience and patient load (p < 0.05). Hypertension was considered a major public health problem by 95.1% (n = 369) of the physicians. Table 3 shows hypertension knowledge, diagnosis and work up by the PCPs according to their awareness of hypertension guidelines. Out of the 19 questions asked, the GA PCPs performed better than the GU physicians in seven, the GU PCPs performed better than the GA physicians in two, and the two groups had a similar performance in the remaining 10 questions. The practice of routinely checking blood pressure of all adult patients in consultation was independent of whether or not the physicians considered hypertension a major public health challenge (χ2 = 0.07, p = 0.8). Table 2. Basic characteristics of the respondents according to the type of practice Type of practice

0.01 Variable (n) No of physicians Age (397)

0.21 5.95/0.015

Government (134)

Results

GA vs GU χ2/p-value

0.99/0.32

4.4 ± 3.5

done’) and inappropriate/no (‘sometimes done’, ‘occasionally done’ and ‘rarely or never done’) practice/behaviour. Another Likert-like scale (strongly agree, agree, neutral/undecided, disagree and strongly disagree) response to the statement ‘uncomplicated hypertension is usually asymptomatic’ was transformed into yes (strongly agree, agree) and no (neutral/undecided, disagree and strongly disagree). Definitions were adopted for binary outcomes based on the IFHA recommendations for prevention, diagnosis and management of hypertension and cardiovascular risk factors in sub-Saharan Africa. 7 All statistical data were analysed using the Statistical Package for Social Sciences (SPSS, version 16.0). Descriptive statistics were used to report the findings. Categorical and continuous variables were expressed as proportions and means ± SD respectively. The statistical significance of variables was tested using the chi-squared test for categorical variables and Student’s t-test for continuous variables. All tests were two-sided and values were considered statistically significant if p < 0.05.

0.06/0.80

Private vs n (%) n (%) n (%) government 2 mean ± SD mean ± SD mean ± SD χ /p-value All

Private

Government

403 (100)

269 (66.7)

134 (33.3)

40.0 ± 11.3 42.6 ± 11.9

35.0 ± 7.9

Gender (403)

< 0.001 20.47/ < 0.001

Male

249 (61.8)

187(69.5)

Female

154 (38.2)

82(30.5)

62(46.3) 72(53.7)

Years post registration (403)

14.3 ± 11.1

16.9 ±11.4

9.2 ± 8.5

< 0.001

No of patients seen per day (403)

17.4 ± 14.3 15.8 ± 10.8

22.2 ± 18.7

< 0.001

No of hypertensive patients seen per day (396)

4.4 ± 3.5

3.3 ± 2.3

6.5 ± 4.3

< 0.001

Awareness of guidelines (403)

188 (46.7)

137 (50.9)

51 (38.1)

5.95/0.015

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

Table 3. Hypertension knowledge, diagnosis and work up by the respondents according to their awareness of guidelines

Table 4. Hypertension knowledge, diagnosis and work up by the respondents according to their type of practice

Awareness of guidelines Variable (n)

All

Yes (GA)

No (GU)

n (%)

Type of practice GA vs GU χ2/p-value

Private vs Government government n (%) χ2/ p-value

All n (%)

Private n (%)

Correct BP threshold for hypertension diagnosis (403)

301 (74.7)

208 (77.3)

93 (69.4)

2.97/0.085

Routinely check BP in practice (392)

273 (69.6)

201 (76.4)

72 (55.8)

17.39/< 0.001

Allows short rest before measuring BP (390)

103 (26.4)

74 (28.4)

29 (22.5)

1.53/0.22

Variable (n)

Correct BP threshold for hypertension diagnosis (403)

301 (74.7)

158 (84)

143 (66.5)

76.3/ < 0.001

Routinely checked BP in practice (392)

273 (69.6)

144 (80.9)

129 (60.3)

19.5/ < 0.001

Allows short rest before measuring BP (390)

103 (26.4)

51 (28.3)

52 (24.8)

0.64/0.425

Take ≥ two BP readings before diagnosing hypertension (403)

264 (98.1)

134 (100)

0.175*

188 (100)

210 (97.7)

0.064*

Take ≥ two BP readings before diagnosing hypertension (403)

398 (98.8)

Measures BP in both arms during first visit (390)

63 (16.2)

36 (20)

27 (12.9)

3.65/0.056

Measures BP in both arms during first visit (390)

63 (16.2)

44 (16.7)

19 (15.1)

0.16/0.69

Agreed uncomplicated hypertension is asymptomatic (403)

177 (65.8)

104 (77.6)

5.9/0.015

111 (59)

170 (79)

< 0.001*

Agrees uncomplicated hypertension is asymptomatic (403)

281 (69.7)

FH of hypertension (398)

349 (87.7)

173 (92)

176 (83.8)

6.2/0.014

FH of hypertension (398)

349 (87.7)

229 (86.7)

120 (89.6)

0.65/0.42

< 0.001*

FH of DM ( 403)

305 (75.7)

212 (78.8)

93 (69.4)

4.30/0.04

PH of DM ( 400)

312 (78)

201 (75.6)

111 (82.8)

2.75/0.1

183 (45.8)

122 (45.4)

61 (45.5)

0.052/0.82

FH of DM ( 403)

305 (75.7)

163 (86.7)

142 (66.6)

312 (78)

161 (87)

151 (70)

< 0.001*

Obesity evaluation ( 400)

183 (45.8)

93 (50.3)

90 (41.9)

2.8/0.092

Alcohol history (403)

297 (73.7)

137 (72.9)

160 (74.4)

0.12/0.73

PH of DM ( 400)

Tobacco history (398)

297(74.6)

142 (75.5)

155 (73.8)

0.16/0.69

Physical activity evaluation (383)

251 (65.5)

128 (71.9)

123 (60)

6.0/0.014

297 (73.7)

201 (74.7)

96 (71.6)

0.44/0.51

297 (74.6)

211 (79.9)

86 (64.2)

11.64/0.001

Physical activity (383)

251 (65.5)

180 (70.9)

71 (53)

9.49/0.002

Urinalysis (403)

324 (80.4)

242 (90)

82 (61.2)

47/< 0.001 0.01/0.91

Blood glucose (398)

248 (62.3)

164 (62.1)

84 (62.7)

245 (61.4)

153 (57.7)

92 (68.7)

4.48/0.03

2.1/0.15

Lipogram (403)

166 (41.2)

104 (38.7)

62 (46.3)

2.14/0.14

93 (43.3)

0.8/0.37

Fundoscopy (400)

21 (9.8)

< 0.001*

Electrocardiography (398)

103 (49)

0.87/0.35

BP, blood pressure; FH, family history; PH, personal history; DM, diabetes mellitus; EUCr, serum electrolytes and creatinine; *Fisher’s exact test.

324 (80.4)

163 (86.7)

161 (74.9)

3.9/0.003

248 (62.3)

124 (66)

124 (59)

0.18*

EUCr (399)

245 (61.4)

120 (65.2)

125 (58.1)

Lipogram (403)

166 (41.2)

73 (38.8)

21 (5.3)

0 (0)

204 (51.3)

101 (53.7)

Electrocardiography (398)

Alcohol history (403) Tobacco history (398)

EUCr (399)

Urinalysis (403) Blood glucose (398)

Fundoscopy (400)

Obesity evaluation ( 400)

GA, guideline aware; GU, guideline unaware; BP, blood pressure; FH, family history; PH, personal history; DM, diabetes mellitus; EUCr, serum electrolytes and creatinine; *Fishers exact test.

Table 4 shows hypertension knowledge, diagnosis and work up by the PCPs according to the type of practice. One-third (n = 134) of respondents were in government practice. PCPs in private practice were older, more likely to be male, had more years of experience, saw fewer patients, and had a higher prevalence of hypertension guideline awareness (p < 0.05). Out of the 19 questions asked, physicians in private practice performed better in three, those in government practice also performed better in three, and the performance of the two groups in the remaining 13 questions was similar.

Discussion Identification of deficiencies in the approach of physicians to the prevention, diagnosis and management of hypertension is a prerequisite for planning interventions targeted towards hypertension control. Hypertension guidelines summarise evidence-based best practices aimed at improving hypertension diagnosis, evaluation, treatment and control. Knowledge of and adherence to guidelines by care givers is imperative for effective hypertension control. This will also help reduce the high risk of cardiovascular morbidity and mortality from the potentially preventable complications of hypertension, such as heart failure, kidney disease and stroke.13 Less than half of the respondents in this study (46.7%) were aware of the hypertension guidelines. This proportion is unsatisfactory but smaller than the 68.8% recorded for PCPs in South Africa.13 This suggests that hypertension management by

21 95.3)

17(6.3)

4 (3.1)

1.89/0.17

204 (51.3)

136 (51.5)

68 (50.7)

0.02/0.89

most of the PCPs in our study may not be evidence based. This is disquieting as it suggests that most hypertensive patients in Nigeria may not be benefiting from diagnostic and therapeutic advances in hypertension management since most individuals with hypertension are managed by PCPs.9 This survey finding represents a potential cause for concern as it may be responsible for the high burden of hypertension-related complications in Nigeria.2,8 However, the paucity of hypertension guidelines indigenous to SSA may be a reason for the above findings. Hypertension rarely causes symptoms in the early stages and in many people it goes undiagnosed.4 The fact that over two-thirds of hypertensive individuals in Nigeria are unaware of their hypertensive status makes proper surveillance for the detection of hypertensive individuals imperative for good hypertension control.2 This underlies the IFHA recommendation of blood pressure checks on all adult healthcare seekers at every encounter with healthcare providers.7 Two-thirds (69.9%) of the PCPs in this study routinely checked the blood pressure of patients in consultation. A similar proportion of the PCPs in this study (69.7%) also agreed that uncomplicated hypertension is usually asymptomatic. This however contrasts sharply with the high proportion (95.1%) of physicians who considered hypertension a major public health challenge. These findings suggest that the knowledge of the enormity of the challenge posed by hypertension may have been overridden by their inadequate knowledge of the symptomatology of hypertension. The effect of this is reflected in the lower proportion of PCPs who routinely checked the blood pressure of their adult clients in consultation.

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Running clinics that are very busy may also have contributed to the discordance between knowledge of the enormity of the hypertension burden and performing routine blood pressure checks on all adult patients. Our finding is however similar to that of an earlier survey by Ajuluchukwu et al.11 of general practitioners in Nigeria where 70% of the PCPs routinely checked the blood pressure of their patients in consultation. It is however lower than the 80.5 and 87% reported for Cameroon- and Australia-based PCPs.14,15 This practice may largely underlie the high burden of undiagnosed hypertension and hypertensive target-organ damage in Nigeria, although factors related to patient and healthcare systems such as poor health-seeking behaviour and the use of alternative medical practitioners may also be contributory.2,8 Symptoms of target-organ damage is what often brings patients with hypertension to healthcare facilities in Nigeria.2 The casual measurement of blood pressure varies widely, hence certain measures are recommended to improve its reliability.7,16 This includes making the patients sit comfortably for some minutes before blood pressure measurement is carried out, the measurement of blood pressure on both arms during the patient’s first visit, and subsequently choosing the arm with higher blood pressure as the reference.7,12 Only 26.4% of all respondents allowed a rest of 10 minutes or more, recommended by the IFHA guidelines.7 This recommended period appears to be too long for it to be practicable in routine clinical practice, hence the small proportion of respondents adhering to it. A shorter duration of rest, the five minutes recommended by the American JNC 7 guidelines,17 appears more practicable in day-to-day clinical practice considering the workload in primary healthcare facilities. The small proportion of respondents (16.2%) who measured blood pressure on both arms during a patient’s first visit may be due to high patient load or outright ignorance of this recommended practice. This contrasted sharply with the 55.1% of India-based PCPs who recorded blood pressure on both arms.18 PCPs may miss the clues for secondary hypertension by initial measurement of blood pressure on only one arm. Subjects with hypertension may be wrongly labelled as normotensive, and uncontrolled hypertension assessed as being controlled by the inadvertent use of the arm with a lower blood pressure value for evaluation. The practice of not identifying the arm with higher blood pressure and using it as the reference may also be contributory to the high burden of undiagnosed hypertension, uncontrolled hypertension and hypertensive target-organ damage in Nigeria.2,7,8 The above underscores a comment by Kaplan that the measurement of blood pressure is the clinical procedure of greatest importance that is performed in the sloppiest manner.19 Evaluation of the total cardiovascular risk of hypertensive individuals is recommended by the guidelines. Apart from assisting in prognostication, modification of some of these risk factors is associated with blood pressure reduction.7,17,20 On the other hand, failure to adhere to risk-factor modification, such as weight reduction for obese subjects, may result in resistant hypertension.7,17,20 A large majority of the PCPs clinically evaluated their patients for these risk factors, with the exception of obesity, which was performed by less than half of the PCPs. Not paying adequate attention to obesity in individuals with hypertension may be contributory to the high burden of uncontrolled hypertension reported globally.2,11,12 Another evaluation carried out routinely by a minority (41.2%)

of the PCPs was lipograms. This may be predicated on the belief that it is not an important investigation in sub-Saharan African blacks because of low levels of cholesterol.21 However recent studies have not only shown that lipid abnormalities are common in Nigerians newly presenting with hypertension, but also that these abnormalities worsen with the severity of hypertension.22,23 A very small proportion (5.3%) of respondents examined the optic fundus of their hypertensive patients. This is lower than the 18.9 and 56.6% reported for PCPs in Italy and Slovenia, respectively.24,25 It is however instructive to note that optic fundus examination was the least-frequently performed element of the minimal hypertension diagnostic procedures, not only in the current study, but also in the Italian and Slovenian studies.24,25 Likely reasons for this may include inadequate medical consultation time and dearth of skills and/or equipment for optic fundus examination. Though the approach of the practitioners in private and government practice to the evaluation of hypertension was heterogeneous, their overall performance was similar. Out of the 19 questions asked (excluding questions on awareness of guidelines) the PCPs in private practice performed better than those in government practice in their responses to three questions, and vice versa to three other questions. The performance of the two groups in the remaining 13 questions was similar. The reason for this similarity in the overall performance by these two groups is not apparent in this study, but we dared to postulate that it may have been due to the effect of PCPs in private practice having more time to read and adhere to guidelines being offset by the effect of better exposure to continuing professional education (practical and theoretical) by PCPs in government practice. As expected, the PCPs in the guideline-aware group performed better than those in the unaware group (seven out of 19 responses vs two out of 19 responses). This shows that hypertension guideline awareness is associated with better hypertension care and that awareness of these guidelines should be promoted among PCPs. In spite of these findings, the general performance of the guideline-aware PCPs was unsatisfactory. This may have been due to them not being conversant with the content of the hypertension guidelines despite being aware of the guidelines. This scenario was reported among South Africa-based PCPs by Parker et al. where 68.8% of the PCPs were aware of hypertension guidelines, but only 18.2% of the guideline-aware PCPs were conversant with the content thereof.13 A preference for the use of personal experience that is not evidenced based over evidence-based recommendations contained in guidelines has been documented among PCPs in Croatia. A similar scenario may have played out in our cohort of PCPs. Inadequate time for medical consultation may also be contributory to the suboptimal general performance of guideline-aware PCPs. Limitations of this study include the use of a self-administered questionnaire, which is limited by the varying abilities of the participants to recall. This study evaluated the knowledge of the PCPs, which may not represent their actual practices. Obtaining data from medical records would have given an excellent picture of what these PCPs actually do.

Conclusion Considering the enormity of issues related to hypertension in terms of the large segment of the population involved, the

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commonness of the condition in primary care (one in every four patients seen in this study), and the attendant morbidity and mortality rates, the performance of the cohort in in this study, irrespective of their guideline-awareness status, was unsatisfactory and poses significant challenges to hypertension care in Nigeria. The findings of this study suggest inadequate assessment of target-organ damage and patient risk stratification, with consequent poor global cardiovascular risk management, contrary to guideline recommendations.7,10,20 However, the fact that awareness of hypertension guidelines by PCPs is associated with improved hypertension care, as shown in this study, makes continuing professional education of general practitioners in evidence-based hypertension care, as expounded in hypertension guidelines, imperative in bridging the gap between the current reality and the desired in hypertension care.

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10. World Health Organization/International Society of Hypertension Writing Group 2003. World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11): 1983–1992. 11. Ajuluchukwu JNA, Jarikre AE, Inem VA. A survey of general medical practitioners’ knowledge of hypertension care: assessment of practice and choices influencing management. J Med and Medical Sci 1999; 1(2): 84–89. 12. Jafar TH, Jessani S, Jafary FH, Ishaq M, Orakzai R, Orakzai S, et al. General practitioners’ approach to hypertension in urban Pakistan – Disturbing trends in practice. Circulation 2005; 111: 1278–1283. 13. Parker A, Nagar B, Thomas G, Badri M, Ntusi NB. Health practitioners’ state of knowledge and challenges to effective management of hypertension at primary level. Cardiovasc J Afr 2011; 22(4): 186–190. 14. Noubiap JN, Jingi AM, Veigne SW, Onana AE, Yonta EW, Kingue S. Approach to hypertension among primary care physicians in the west

We thank all the participating physicians.

region of Cameroon: substantial room for improvement. Cardiovasc Diagn Ther 2014; 4(5): 357–364.

References 1.

Chobanian AV. The hypertension paradox – more uncontrolled disease despite improved therapy. N Engl J Med 2009; 361: 878–887.

Ogah OS, Okpechi I, Chukwuonye II, Akinyemi JO, Onwubere BJC, Falase AO, et al. Blood pressure, prevalence of hypertension and hypertension-related complications in Nigerian Africans: A review. World J

Awareness and approach towards hypertension management among

er, global public health crisis. Geneva, World Health Organization, 2013.

general practitioners of Western Vadodara. J Clin Diagn Res 2014; 8(8):

Adeloye D, Basquill C, Aderemi AV, Thompson JY, Obi FA. An esti-

MC05–8. 19. Kaplan NM. Commentary on the sixth report of the Joint National Committee (JNC-6). Am J Hypertens 1998; 11(1): 134–136.

James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb

20. ESH/ESC. 2003 European Society of Hypertension–European Society

C, Handler J, et al. 2014 evidence-based guideline for the manage-

of Cardiology guidelines for the management of arterial hypertension. J

appointed to the Eighth Joint National Committee (JNC 8). J Am Med Assoc 2014; 311(5): 507–520.

Hypertens 2003; 21: 1011–1053. 21. Seedat YK. Hypertension in black South Africans. J Hum Hypertens 1999; 13: 97–103.

Lemogoum D, Seedat YK, Mabadeje AFB, Mendis S, Bovet P,

22. Onwubuya EI, Anisiuba BC, Osuji CU, Ahaneku JE. Changes in lipids

Onwubere B, et al. on behalf of the IFHA. Recommendations for

and lipoprotein indices in relation to the severity of hypertension in

prevention diagnosis and management of hypertension and cardio-

newly diagnosed hypertensive Nigerians. ISRN Cardiol 2012; 2012:

vascular risk factors in sub-Saharan Africa. J Hypertens 2003; 21: 1993–2000. Salako BL, Ogah OS, Adebiyi AA, Adedapo KS, Bekibele CO, Oluleye

972341 23. Adamu UG, Okuku GA, Oladele CO, Abdullahi A, Oduh JI, Fasae AJ. Serum lipid profile and correlates in newly presenting Nigerians with

TS, et al. Unexpectedly high prevalence of target-organ damage in

arterial hypertension. Vasc Health Risk Manag 2013; 9: 763–768.

newly diagnosed Nigerians with hypertension. Cardiovasc J Afr 2007;

24. Cuspidi C, Michev I, Lonati L, Vaccarella A, Cristofari M, Garavelli

18(2): 77–83. 9.

Pressure: the JNC 7 report. J Am Med Assoc 2003; 289: 2560–2571. 18. Deshpande S, Patel N, Godbole E, Champaneri V, Singh N, Patel P.

World Health Organization. A global brief on hypertension: Silent kill-

ment of high blood pressure in adults: report from the panel members

151–183. 17. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, on Prevention, Detection, Evaluation, and Treatment of High Blood

and meta-analysis. J Hypertens 2015; 33(2): 230–242.

Guideline for the management of Hypertension. J Hypertens 1999; 17:

Izzo JL Jr, et al. The seventh report of the Joint National Committee

mate of the prevalence of hypertension in Nigeria: a systematic review 6.

Med J Aust 2009; 191(6): 324–329. 16. World Health Organisation – International Society of Hypertension

Ataklte F, Erqou S, Kaptoge S, Taye B, Echouffo-Tcheugui JB, Kengne systematic review and meta-analysis. Hypertension 2015; 65: 291–298.

cardiovascular disease risk management in Australian general practice.

Cardiol 2012; 4(12): 327–340. AP. Burden of undiagnosed hypertension in sub-Saharan Africa – A 4.

15. Webster RJ, Heeley EL, Peiris DP, Bayram C, Cass A, Patel AA. Gaps in

G, et al. Compliance to hypertension guidelines in clinical practice: a

Frijling BD, Spies TH, Lobo CM, Hulscher M, van Drenth BB,

multicentre pilot study in Italy. J Hum Hypertens 2002; 16(10): 699–703.

Braspenning JC, et al. Blood pressure control in treated hypertensive

25. Petek-Ster M, Kersnik J, Svab I. Compliance with hypertension guide-

patients: clinical performance of general practitioners. Br J Gen Pract

lines in general practice in Slovenia. Srp Arh Celok Lek 2007; 135:

2001; 51(462): 9–14.

191–196.

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The role of genetics in coronary artery bypass surgery patients under 30 years of age Sabit Sarikaya, Ebuzer Aydin, Yucel Ozen, Tanıl Ozer, Kaan Kirali, Murat Bulent Rabus

Abstract Aim: We undertook genetic assessment of coronary artery disease (CAD) in 20 patients aged 30 years or less undergoing coronary artery bypass grafting (CABG) surgery, to investigate the prognostic value of pre-defined genes. Methods: Twenty patients, who underwent CABG surgery between December 2001 and May 2013, were retrospectively analysed to find out the role their genetic make-up played in their disease. We used three genetic diagnostic tests, the plasminogen activator inhibitor (PAI)-1 gene, the A1/A2 polymorphism of glycoprotein IIIa (GpIIIa) gene, and common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene. Results: The mean age of patients was 26.35 ± 3.51 (19–30) years, and 90% were male (n = 18). One patient had diabetes, three had hypertension, 11 (55%) had dyslipidaemia and 16 (80%) were smokers. Eight of the patients (40%) had left ventricular ejection fraction (LVEF) < 50%, and functional capacity was poor in only two (10%) patients (NYHA III– IV). Follow up was completed in all patients (100%). We found five homozygous and 11 heterozygous mutations in the MTHFR gene, which predisposes individuals to coronary artery disease or deep-vein thrombosis. Eight patients were found to have a GpIIIa gene polymorphism, which is associated with increased risk of myocardial infarction (MI). Fifteen patients had a polymorphism in the promoter region of the PAI-1 gene, which is a major inhibitor of the fibrinolytic system. Conclusion: MTHFR C677T polymorphism, and GpIIIa and PAI-1 genes are risk factors for CAD. In young patients, genetic studies promise to revolutionise early diagnosis, treatment and prevention of CAD and MI. Keywords: coronary artery bypass graft (CABG), plasminogen activator inhibitor (PAI)-1, glycoprotein IIIa (GpIIIa), methylenetetrahydrofolate reductase (MTHFR), young patient Submitted 13/6/14, accepted 3/4/16 Published online 21/10/16 Cardiovasc J Afr 2017; 28: 77–80

www.cvja.co.za

DOI: 10.5830/CVJA-2016-042

Cardiovascular Surgery Department, Kartal Kosuyolu Research and Education Hospital, Istanbul, Turkey Sabit Sarikaya, MD Ebuzer Aydin, MD Yucel Ozen, MD Tanıl Ozer, MD Kaan Kirali, MD Murat Bulent Rabus, MD, muratrabus@yahoo.com

Although atherosclerotic cardiovascular disease is known as a disease of the elderly, an advanced stage of disease requiring intervention may be also encountered in younger people. Increased experience in interventional procedures and technological improvements enable us to treat young individuals who have the disease, thereby avoiding a deterioration in their quality of life. Although percutaneous interventional treatment is the first choice in appropriate cases, surgical treatment may also be selected as the first choice in young adult patients with advanced and multi-vessel disease, and is accompanied by early mobilisation and decreased duration of hospitalisation.1,2 When coronary artery bypass graft surgery (CABG) is indicated in young patients, the choice of operative technique, conduit selection and postoperative risk-factor modification should be carefully considered to prolong the graft patency and to avoid premature death.3 Although cardiovascular genetic studies lag behind genetic studies on other diseases, many advances have been made recently. Polymorphisms are gene variations that have only modest effects on the function of coded proteins or enzymes. However, they are common and can act as a risk factor together with the presence of environmental risk factors (cholesterol, stress, tobacco). Current advances in molecular biology make it possible to detect numerous polymorphisms that might have a detrimental effect on vascular pathology, hence the hypothesis that multiple polymorphisms in the presence of environmental factors could act synergistically in the pathogenesis of atherosclerosis and coronary artery disease (CAD), which are typically polygenic and multifactorial diseases. There are many genetic diagnostic tests and we selected three for this study, the plasminogen activator inhibitor (PAI)-1 gene, the A1/A2 polymorphism of glycoprotein IIIa (GpIIIa) gene, and a common polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, the thermolabile C677T.

Methods CABG was performed either isolated or concomitantly with other cardiac surgical interventions on 16 281 patients between December 2001 and May 2013 at our clinic. Twenty patients who were 30 years of age or older were included in this retrospective study. Pre-, intra- and post-operative characteristics of the patients were evaluated. The study protocol was approved by the Institutional Ethics Committee, and all patients gave consent to participate in the study. Medical data of the patients were reviewed, and patients were also called on to gather information about their recent health status. Cardiac operations were performed on a beating heart or by providing cardiac arrest under cardiopulmonary bypass. Various techniques were used for cardiac stabilisation in operations performed on a beating heart. Isothermic, hyperkalaemic blood cardioplegia was used via the antegrade route and/or retrogradely in order to provide cardiac arrest. Grafts were prepared perioperatively as autogenous grafts. The left (LIMA) and right

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internal mamarian artery (RIMA) and the radial artery were prepared as arterial grafts, whereas the great sapheneous vein was used as a venous graft. The total genomic DNA in the patients’ peripheral whole blood samples was isolated using GenXtract solution according to the manufacturer (Vienna-Lab Diagnostic GmbH). Afterwards, target DNA regions were amplified with multiflex polymerase chain reaction (PCR) using biotinylated primers, and amplified products were controlled with 3% agorose gel. After observing the amplicons belonging to the test strip containing immobilised allele-specific nucleotide probes on nitrocellulose membrane using CVD strip assay (Vienna-Lab Diagnostic GmbH), a hybridisation process was performed with profiblot T48 (Tecan) hybridisation instruments. Bound biotinylated sequences were detected using streptavidin-alkaline phosphatese and colour substrates.

Statistical analysis Statistical analysis was performed using SPSS software version 12.0 (SPSS Inc, Chicago, IL, USA). Numerical parameters are expressed as mean, median and standard deviations.

Results Mean age of the patients was 26.35 ± 3.51 (19–30) years, and 90% were male (n = 18) (Table 1). More than half of the patients had normal body mass index (BMI), and all had an urban lifestyle. Detailed medical information was gathered about familial and/ or sporadic diseases, personal history, habits and family history (Table 2). One patient had diabetes, three had hypertension, 11 (55%) had dyslipidaemia, and 16 (80%) were smokers. Eight of the patients (40%) had a left ventricular ejection fraction (LVEF) < 50%, and functional capacity was poor in only two (10%) patients (NYHA III–IV). The stents of the two patients who had coronary angioplasty and were operated on for stent re-stenosis, had been implanted one and five months earlier due to acute myocardial infarction. Isolated CABG was performed in 19 patients, whereas right CABG was performed concomittantly with aortoplasty in only one patient due to aortic stenosis (Table 3). Cardiac stabilisation without perfusion, using various techniques of cardiac arrest (off-pump CABG), was performed in seven out of 11 patients with single-vessel bypass surgery and two out of three patients with dual-vessel bypass surgery. Other patients were operated on under cardiopulmonary bypass (CPB). Table 1. Demographic characteristics of the patients Age (mean ± SD), years 26.35 ± 3.51 (19–30) Gender Male, n (%) 18 (90) Female, n (%) 2 (10) BMI, kg/m2, n (%) > 30 3 (15) 20–30 14 (70) 3 (15) < 20 Geographical region Rural, n (%) 0 (0) Urban, n (%) 20 (100) SD: standard deviation; BMI: body mass index.

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Table 2. Baseline characteristics of patients Patient characteristics Number of patients Percent Hypertension 3 15 Diabetes 1 5 Hyperlipidaemia 11 55 Familial 5 25 Vasculitis Takayasu arteritis 2 10 Carotid artery disease 2 10 Positive family history 7 35 Smoking 16 80 Alcohol use 3 15 Echocardiography LVEF > 50% 12 60 8 40 LVEF < 50% Valvular pathology 4 20 Coronary angiography Single-vessel disease 10 50 Dual-vessel disease 3 15 Multi-vessel disease 7 35 NYHA I–II 18 90 III–IV 2 10 Previous MI 6 30 Previous interventions CABG 0 0 PTCA/stent 2 10 Renal insufficiency 0 0 Chronic pulmonary diseases 1 5 LVEF: left ventricular ejection fraction; NYHA: NewYork Heart Association; MI: myocardial infarction; CABG: coranary artery bypass grafting; PTCA: percutaneous transluminal coranary angioplasty.

Isothermic hyperkalaemic blood cardioplegia was used for cardiac arrest. Mitral protection was provided by inducing moderate hypothermia and antegrade and/or the administration of blood cardioplegia. Bypass was performed with the LIMA flap to the left anterior descending artery (LAD) in all patients except three; two patients with peripheral artery disease due to vasculitis, and one who had right CABG surgery only. Bypass Table 3. Surgical information Surgery Number of patients Isolated CABG 19 Off-pump 9 On-pump 11 Total perfusion time (mean ± SD), min 65.6 ± 24.6 Aortic cross-clamp time (mean ± SD), min 42 ± 22.3 Number of vessels with bypass surgery Single 11 Double 3 Multiple 6 Graft type LIMA 17 RIMA 1 Radial artery 1 Saphaneous vein 19 CABG: coranary artery bypass grafting; SD: standard deviation; LIMA: left internal mammary artery; RIMA: right internal mammary artery.

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was performed with the RIMA on the right coronary artery (RCA) in one patient, and in another using a radial artery graft. All except two patients were operated on electively (these patients had coronary artery dissection at postpartum, and acute myocardial infarction, and they had emergency surgery). According to the EUROscore, two patients were evaluated as moderate risk, and the others were low risk. Two patients with low ventricular function were placed in the intensive care unit (ICU) under inotropic support. Patients were followed up routinely, and the extubation time was 7.4 ± 3.2 hours. Duration of ICU and hospital stay was 1.4 ± 0.9 and 5.6 ± 2.1 days, respectively. The medical treatment of two patients who were diagnosed with Takayasu’s arteritis and had severe extensive peripheral vasculopathy was continued as scheduled. Pre-operatively scheduled antihypertensive, antihyperlipidaemic and antidiabetic medical treatments were continued after surgery. Routine anticoagulant (acetylsalicyclic acid 150 mg/day) treatment was added on the first postoperative day. There were no hospital mortalities. All patients were contacted using the contact information in their medical files, and all of the contacted patients were alive. All except one patient reported that they had no limitations in physical activities, or socio-economic and emotional aspects, and their quality of life was no different from that of the normal population. One patient said he was not actively working because he had respiratory distress and low functional capacity. During control coronary angiography (CAG), one patient with dyspnoea, low functional capacity and moderate risk, who was operated on in April 2003, was diagnosed with obstructed saphenous vein grafts in December 2004, and it was observed that LIMA flow was slow and weak. Another patient, who had bypass surgery on the LAD and RCA in 2004, had coronary angiography performed in 2010 and a preliminary diagnosis of non-ST-segment MI. Angiography revealed that the grafts were patent, however there was critical stenosis in the circumflex artery (Cx), which had not undergone bypass surgery before. Angioplasty was performed on the Cx. In another patient, a stent was implanted in January 2006, and LAD bypass was performed in June 2006 after stent stenosis. In the control CAG in October 2006, we observed that the LIMA was open. Control CAG in 2009 of an unsymptomatic patient who had had triple-vessel bypass in 2003 revealed that the grafts were patent. Control CAG in 2007 of another patient with single-vessel bypass in 2003 revealed a patent graft. A patient with singlevessel bypass in 2004 also had a patent graft in 2009. Other patients who reported having no problems did not present to any hospital. Seven out of 20 followed-up patients said that they were still smoking the same number of cigarettes. We found five homozygous and 11 heterozygous mutations in MTHFR, which predisposes individuals to CAD or deep-vein thrombosis (DVT). Eight patients were found to have a GpIIIa gene polymorphism, which is associated with increased risk of MI. Fifteen patients had a polymorphism in the promoter region of the PAI-1 gene, which is a major inhibitor of the fibrinolytic system.

Discussion Coronary artery disease is generally defined as a disease of advanced age because of its prevalence in older individuals.

However it may also be encountered less frequently in younger people. Since they are active members of the national economy, it is clear that these young individuals should be treated in the most effective way. Successful treatment should involve uncomplicated and safe surgery, resulting in patient survival.4 Currently, criteria for successful treatment include not only patient survival but also duration of recovery and returning to an active life without any problems, as well the economic aspects of appropriate treatment options.4 Risk factors such as smoking and hyperlipidaemia are more commonly observed among young adults with severe coronary artery disease, whereas diseases such as hypertension and diabetes are more frequently observed in the elderly population.5,6 Cessation of smoking and improving dyslipidaemia may play a significant role in decreasing disease prevalence in early adulthood.5,6 CAD requiring CABG is common in middle-aged or elderly populations. In the current era, primary prevention includes identifying the genetic risk as well as optimising the modifiable risk factors. This is critical in this young population group before target-organ damage occurs.7 Selecting appropriate conduits for long-lasting graft patency is another important issue in these patients. The use of other arterial grafts such as the radial artery was proven to be superior to venous grafts for long-term patency, especially on the left coronary system.8 We observed some remarkably good early results in our series. Unfortunately, a more disappointing panorama can be observed when analysing their long-term evolution. Arteriosclerosis is a progressive disease and many patients in our series suffered its consequences during their follow up, as recurrent heart ischaemia, or major peripheral vascular complications, or both. Genetic studies of CAD and MI are lagging behind genetic studies of other cardiovascular disorders. The major reason for the limited success in this field of genetics is that CAD and MI are complex diseases, believed to be caused by many genetic and environmental factors, and the interaction between these factors.9 Appropriate treatment and prevention of these diseases is difficult because they are multifactorial. Many risk factors have been identified for CAD and MI, including smoking, advanced age, male gender, diabetes mellitus, high systolic blood pressure, personal history of angina pectoris, family history of CAD or MI, high-fat diet, infectious agents, obesity, increased plasma total and low-density lipoprotein (LDL) cholesterol levels, increased plasma triglyceride levels, and decreased plasma high-density lipoprotein (HDL) cholesterol levels.10-12 Among these factors, family history is one of the most significant independent risk factors for CAD and MI.13 This supports the hypothesis that genetic factors contribute to the development of CAD and MI, and we therefore used three genetic diagnostic tests to find a relationship between genetic make-up and heart disease. Rare genetic defects that cause extremely high plasma homocysteine levels also cause CAD.14,15 It was therefore hypothesised that, even within the normal range of plasma homocysteine concentrations, higher levels may appreciably increase CAD risk.15 The enzyme methylene tetrahydrofolate reductase, encoded by the MTHFR gene, uses folate to metabolise and thereby remove homocysteine.16 The MTHFR C677T polymorphism is common (T-allele frequency 15–45%) in many populations and reduces enzyme efficiency.

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We found five homozygous and 11 heterozygous mutations in the MTHFR gene and the others did not have mutations. Homozygosity for the C677T polymorphism of the MTHFR gene predisposes individuals to CAD or DVT. The A1/A2 polymorphism of the GpIIIa gene caused by a T-to-C nucleotide substitution at position 1565, which is associated with the occurrence of the amino acid Leu →Pro variant at residue 33 of the mature protein,17 has been widely studied in cardiovascular diseases.18 These studies have shown that possession of an A2 allele increases the risk for MI,19,20 CAD,21 and restenosis after stent placement.22 Eight patients had a GpIIIa gene polymorphism in our study. PAI-1 is a major inhibitor of the fibrinolytic system. This protein is under the control of the 4G/5G polymorphism of the PAI-1 gene, which is characterised by the presence of five guanine nucleotides in the promoter zone instead of four. Carriers of the 4G/5G allele would be more at risk for CAD.22-25 We had 15 patients who had this polymorphism. This study was limited by the small sample size and ethnicity differences. Further exploration would be useful in future studies, for which a larger sample size is needed.

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the young. Pathobiological determinants of atherosclerosis in youth research group. Am J Cardiol 1998; 82: 30T–36T. 8.

Malinowski M, Mrozek R, Twardowski R, Biernat J, Deja MA, Widenka K, et al. Left internal mammary artery improves 5-year survival in patients under 40 subjected to surgical revascularization. Heart Surg Forum 2006; 9: E493–497.

Marenberg ME, Risch N, Berkman LF, Floderus B,de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330: 1041–1046.

10. Shen G, Archacki SR, Wang Q. The molecular genetics of coronary artery disease and myocardial infarction. Acute Coron Syndrome 2004; 6: 129–141. 11. Slack J, Evans KA. The increased risk of death from ischaemic heart disease in first degree relatives of 121 men and 96 women with ischaemic heart disease. J Med Genet 1966; 2: 239–257. 12. Wang Q, Pyeritz RE. Molecular genetics of cardiovascular disease. In: Topol EJ (ed). Textbook of Cardiovascular Medicine. 1st edn. New York: Lippincott Williams & Wilkins, 2000: 1–12. 13. Schildkraut JM, Myers RH, Cupples LA, Kiely DK, Kannel WB. Coronary risk associated with age and sex of parental heart disease in the Framingham Study. Am J Cardiol 1989; 64: 555–559. 14. McCully KS Vascular pathology of homocysteinemia: implications for

Conclusion This study demonstrates that the MTHFR C677T polymorphism, and GpIIIa and PAI-1 genes are risk factors for CAD. Considering that individuals who have homozygous mutations in the MTHFR gene are prone to CAD in early adulthood, it is possible that altered enzyme efficiency contributes to this vulnerability. Genetic studies promise to revolutionise early diagnosis, treatment and prevention of CAD and MI. A unique advantage for the management of cardiovascular disease is that a significant number of cases are potentially preventable. Early diagnosis by genetic testing will force lifestyle modifications in individuals with genetic risk factors, which alone or in combination with other therapeutic options may delay the onset of CAD or prevent MI.

the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56: 111–128. 15. Clarke R, Daly L, Robinson K, Naughton E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149–1155. 16. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113. 17. Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest1989; 83: 1778–1781. 18. Reiner A, Siscovick DS, Rosendaal FR. Platelet glycoprotein polymorphisms and risk of thrombosis: facts and fancies. Rev Clin Exp Hematol 2001; 5: 262–287. 19. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, et

References 1.

20. Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the

et al. Middle and late-term results of coronary artery bypass surgery

platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrino21. Gardemann A, Humme J, Stricker J, Nguyen QD, Katz N, Philipp M, et

Zorlutuna Y. Coronary artery bypass surgery in young patients. Turkish

al. Association of the platelet glycoprotein IIIa PlA1/A2 gene polymor-

J Thorac Cardiovasc Surg 2002; 10: 1–4.

phism to coronary artery disease but not to nonfatal myocardial infarc-

Ng WK, Vedder M, Whitlock RM, Milsom FP, Smith WM, Kerr AR, Surg 1997; 11: 732–738.

vessel disease in males. Stroke 2004; 35(7): 1589–1593. Epub 2004 Jun 3. 23. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type I and coronary artery disease. N Engl J Med 2000; 343: 1792–1801. 24. Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, et al. The

Enar R, Sezgiç M, Çeliker C, Yazıcıoğlu N, Demiroğlu C. Acute

4G/5G genetic polymorphism in the promoter of the plasminogen acti-

myocardial infarction in young subjects. Arch Turk Soc Cardiol 1992;

vator inhibitor-1 (PAI-1) gene is associated with differences in plasma

20: 249–252.

PAI-1 activity but not with risk of myocardial infarction in the ECTIM

Köz C, Çelebi H, Yokuşoğlu M, Baysan O, Haşimi A, Serdaroğlu M, et al. The relation between coronary lesion distribution and risk factors in

et al. A2 alelle of GpIIIa gene is a risk factor for stroke caused by large-

Matera B, et al. Quality of life in young, professionally active men results. Kardiol Pol 2009; 67: 1078–1085.

tion in low risk patients. Thromb Haemost 1998; 80: 214–217. 22. Slowik A, Dziedzic T, Turaj W, Pera J, Glodzik-Sobanska L, Szermer P,

Tukasz JK, Woznica A, Pawlak A, Skarysz J, Eysymontt Z, Chromanskaundergoing coronary artery bypass grafting – short-term follow-up

gen. Circulation 1997; 96: 1424–1431.

Tokmakoğlu H, Kandemir Ö, Farsak B, Günaydın S, Yorgancıoğlu C,

et al. Coronary revascularization in young adults. Eur J Cardiothorac 4.

risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090–1094.

Demirkılıç U, Bolcal C, Küçükarslan N, Bingöl H, Öz BS, Kuralay E, in very young (20–29 years) patients. Anatol J Cardiol 2004; 4: 25–29.

al. A polymorphism of a platelet glycoprotein receptor as an inherited

study. Thromb Haemost 1995; 74: 837–841. 25. Iacoviello L, Burzotta F, Castelnuovo A, Zito F, Marchioli R, Donati

young adults. Anatol J Cardiol 2009; 9: 91–95.

MB. The AG/5G polymorphism of PAI-1 promoter gene and the risk of

McGill HC, McMahan CA. Determinants of artherosclerosis in

myocardial infarction: a metaanalysis.Thromb Haemost 1998; 79: 8–13.

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The role of coronary artery collaterals in the preservation of left ventricular function: a study to address a longstanding controversy NO Ajayi, EA Vanker, KS Satyapal

Abstract Introduction: The functional significance of coronary artery collateral (CAC) vasculature in humans has been debated for decades and this has been compounded by the lack of a standard, systematic, objective method of grading and documenting CAC flow in man. CACs serve as alternative conduits for blood in obstructive coronary artery disease. This study aimed to evaluate the impact of CACs on left ventricular function in the presence of total coronary arterial occlusion. Methods: The study group included the coronary angiographic records of 97 patients (mean age: 59 ± 8 years). CACs were graded from 0–3 based on the collateral connection between the donor and recipient arteries. Left ventricular function was computed from the ventriculogram and expressed as ejection fraction (EF). Results: The mean EF of the patients with grades 0, 1, 2 and 3 CACs were calculated as 50.4, 47, 60.5 and 70%, respectively. A significant difference was recorded in the mean EF calculated for the different CAC grades (p = 0.001). There was a significant positive correlation (p < 0.001; r = 0.478) between the mean EF and the CAC grades. Conclusion: The patients with better coronary collateral grades had a higher mean EF. Therefore, as the grade of CACs increased, there was an improvement in their ability to preserve left ventricular function. Keywords: coronary artery obstruction, coronary collateral artery, left ventricular function Submitted 29/5/15, accepted 16/4/16 Cardiovasc J Afr 2017; 28: 81–85

www.cvja.co.za

DOI: 10.5830/CVJA-2016-054

Controversy has existed for decades regarding the functional significance of coronary artery collaterals (CACs) in humans,1 and this has been compounded by the lack of a standard systematic method for determining CAC flow in man.2,3 These Department of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa NO Ajayi, MB BS, MMed Sc, PhD KS Satyapal, LRCP, LRCS, LM, MD, FICA (USA), FRCP (Irel), LLM (Medical Law), satyapalk@ukzn.ac.za

St Augustine’s Hospital, Chelmsford Medical Centre, Durban, South Africa EA Vanker, MB ChB, FRCS

CACs are reported to have a protective effect on myocardial perfusion and contractile function, and to prevent left ventricular (LV) aneurysm formation in the presence of severe coronary artery obstruction.4,5 The presence of collateral vessels may play a major role in determining whether the patient will develop symptoms of myocardial ischaemia and vulnerability of the myocardium to myocardial infarction.6 The use of coronary angiography allows correlation of the extent of development of CACs with the severity of coronary arterial disease.7,8 The presence of functional collateral vessels can be of important prognostic value and can also assist in determining the need for intervention and the type of interventional procedure to be performed.9,10 Indeed, the presence of well-developed coronary collateral vasculature and flow has been correlated with the absence of ischaemic symptoms in patients with established coronary artery disease (CAD).11 Meier and colleagues,12 in an analysis of previous studies on the effect of coronary collaterals on mortality, reported that well-developed collaterals reduced the mortality rate in the order of 35%. The presence of adequately developed collateral supply limits the degree of myocardial necrosis during myocardial infarction.8,13 The area at risk of myocardial infarction is inversely related to the collateral supply to that region, and therefore becomes zero in the presence of well-developed functional collaterals.14-16 In cases of unsuccessful intra-coronary thrombolytic therapy after the onset of symptoms in acute myocardial infarction, the improvement in LV function and wall motion in the infarct region have been associated with the presence of collateral flow to the region perfused by the obstructed vessel.5,17 However, some reports have cast doubt on the value of CACs. Banerjee reported that the presence of CACs had no protective role on the incidence of LV aneurysm formation following myocardial infarction.18 Ilia et al.19 also reported that there was no correlation between the characteristics of CACs and the presence or absence of LV systolic abnormality in patients with significant CAD. Furthermore, Turgut et al.20 stated that coronary collaterals did not have a protective role on preservation of LV function in the presence of severe left anterior descending artery stenosis. Meier et al. also reported that the development of good CACs increased the risk of restenosis after percutaneous coronary intervention.21 In view of these controversies, our study was undertaken to evaluate the effect of CACs on LV function in the setting of a totally occluded coronary artery demonstrated on angiogram.

Methods The study group was selected from the reviewed angiographic records of 2 029 consecutive patients (mean age: 59 ± 12

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years) who had had coronary catheterisation performed by interventional cardiologists for symptoms suggestive of CAD. In order to assess the effect of CACs on LV function in the presence of total occlusion of the coronary artery, only those coronary angiograms that had LV function assessed by ventriculography were selected for analysis. Ninety-seven such patients with total occlusion of a coronary artery and LV functional assessment were included in the analysed angiograms. The mean EF and the different grades of CACs in these patients were determined. The angiograms were obtained from the cardiac catheterisation laboratories of hospitals within the private sector in the eThekwini municipality region of KwaZulu-Natal, South Africa. Ethical approval (ethics number BE 196/13) for the study was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee. Coronary arteriography was performed via the percutaneous transfemoral approach by injecting a radio-opaque contrast agent into the coronary blood vessels, and the images were taken using X-ray fluoroscopy. These images were recorded on digital media in DICOM (Digital Imaging and Communication in Medicine) format and stored in the cardiac catheterisation laboratories. The relationship between the location of the atherosclerotic lesions and the CAC grades were examined in the angiograms that met the inclusion criteria. In addition, the relationship between the location of the atherosclerotic lesions and the mean EF was also evaluated. The location of atherosclerotic lesion was determined by dividing the coronary arteries into proximal, middle and distal regions. The Rentrop grading system22 is the most widely used grading system for coronary collaterals and is employed by many researchers. However, most patients are graded Rentrop 2 or 3 in chronic total coronary occlusion.23

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The grading of the coronary collaterals in the present study was based on the grading system used by Werner et al.,24 with the addition of a grade for absent CACs. This system centered on defining the collateral connection between the donor and the recipient arteries. Therefore, in this study, the coronary collaterals were graded as: grade 0 for absent collateralisation, where there were no demonstrable CACs to the distal region of the obstructed vessel (Fig. 1); grade 1 for poor collateralisation, where there were CACs showing no continuous connection between the donor and recipient arteries (Fig. 2); grade 2 for good collateralisation, where there were continuous threadlike connections between the donor and recipient arteries; and grade 3 for excellent collateralisation, where there were continuous prominent connections with side branches between the donor and recipient arteries (Fig. 3). Data were analysed with the Statistical Package for the Social Sciences (SPSS) version 21 for Windows (IBM SPSS, NY, USA). A p-value < 0.05 was considered statistically significant.

Results The mean age of the patients with coronary artery occlusion who had LV function assessed by ventriculography was 59 Âą 8 years. The patients consisted of 25.8% females and 74.2% males (Table 1). The grades of the CACs were as follows: absent (15.4%), poor (15.4%), good (36.9%) and excellent (32.3%). The morphological properties of the coronary arterial tree in the analysed angiograms are shown in Table 1. The grades of the collateral pathways with regard to the location of atherosclerotic obstruction were evaluated. They were recorded as 15.9, 9.1, 34.1 and 40.9% in the proximal region

LCA LCA

D LAD Cx

LAD

S R

S L

Fig. 1. C oronary angiogram in the right anterior oblique view (caudal angulation) showing obstruction of the diagonal branch of the left anterior descending (LAD) artery (red ring) without collateral vessels to the distal segment of the obstructed vessel. LCA, left coronary artery; D, diagonal; Cx, circumflex; OM, obtuse marginal artery.

L I

PDA

Fig. 2. Coronary angiogram in the right anterior oblique view showing the filling of the posterior descending artery of an obstructed right coronary artery (RCA) by grade 1 collateral vessel (red arrows) originating from the septal branch of the left anterior descending (LAD) artery. LCA, left coronary artery; Cx, circumflex; SB, septal branch; PDA, posterior descending artery.

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LCA LAD Cx

S R

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L I

Fig. 3. C oronary angiogram in the right anterior oblique view (caudal angulation) showing obstruction of the circumflex (Cx) branch (red ring) with the filling of the obtuse marginal (OM) branch by grade 3 collateral vessel (red arrows) originating from the diagonal branch of the left anterior descending (LAD) artery. D, diagonal.

of the coronary arteries for absent, poor, good and excellent CACs, respectively. The grades of the collateral pathways with obstruction of the middle region were recorded as 16.2, 16.2, 37.8 and 29.7% for absent, poor, good and excellent CACs, respectively. The grades of the collateral pathways with the obstruction of the distal region were recorded as 18.8, 18.8, 37.5 and 25% for absent, poor, good and excellent CACs, respectively. There was no significant difference in the grades of CACs between the different regions of obstruction (p = 0.87) (Table 2). Table 1. Parameters of patients who had left ventriculography performed Parameters Mean age, years (SD) Mean ejection fraction, % (SD) Gender (%) Female Male Coronary dominance (%) Co-dominance Left Right Location of obstruction (%) Proximal Middle Distal Grading of collateral (%) Absent Poor Good Excellent

Values (n = 97) 59.1 (8.8) 60.2 (18.1) 25.8 74.2 3.1 13.4 83.5 45.4 38.1 16.5 15.4 15.4 36.9 32.3

The mean EF of the patients with proximal, middle and distal location of atherosclerotic lesions was 63.3, 57.8 and 57.5%, respectively. This indicated that the best mean EF was recorded in the patients with proximally located atherosclerotic lesions. However, analysis of variance (ANOVA) showed that there was no significant difference in the mean EF calculated for the different locations of atherosclerotic lesions (p = 0.33) (Table 3). The mean EF of the patients with absent, poor, good and excellent CACs was calculated as 50.4, 47, 60.5 and 70%, respectively. ANOVA showed a significant difference in the mean EF calculated for the different CAC grades in the patients (p < 0.001) (Table 4). A post hoc test was performed to determine the significance of the differences in mean EF calculated for each grade of CAC. There were significant differences between the mean EF calculated for patients with absent and excellent CACs (p = 0.004), and between the mean EF for poor and excellent CACs (p < 0.001). In addition, there was also a significant difference between the mean EF calculated for patients with poor and good CACs (p < 0.05). The mean EF of the patients was also correlated with the CAC grades. In assessing the correlation between the mean EF and the CAC grades, a Spearmanâ&#x20AC;&#x2122;s correlation analysis was performed. This revealed a positive correlation coefficient (r = 0.478) that was significant (p < 0.001) between the mean EF of the patients and the CAC grades. This showed that the patients with better CAC grade had a higher mean EF.

Table 2. Grading of coronary collateral pathways in the obstruction of the different regions of the main coronary arteries in patients who had left ventriculography Obstructed coronary arterial region Proximal Middle Distal

Grades of collateral vessel (%) Absent Poor Good Excellent 15.9 9.1 34.1 40.9 16.2 16.2 37.8 29.7 18.8 18.8 37.5 25

p-value 0.87

Table 3. Mean ejection fraction of patients in the different locations of obstructive atherosclerotic lesions Lesion Sample Mean location size (n) (%) Proximal 44 63.3 Middle 37 57.8 Distal 16 57.5 Total 97 60.2 SD, standard deviation.

SD 16 19.8 19.5 18.1

Min (%) 29.4 18.7 19.2 18.7

Max (%) 86.5 85.9 88.4 88.4

p-value 0.33

Table 4. Mean ejection fraction of patients in the different coronary collateral grades Collateral Sample Mean grade size (n) (%) 16 50.4 Absent Poor 13 47 Good 35 60.5 Excellent 33 70 Total 97 60.2 SD, standard deviation.

SD 17.6 12 18.9 13.8 18.1

Min (%) 19.4 29.4 18.7 29.7 18.7

Max (%) 74.3 66.3 84.7 88.4 88.4

p-value < 0.001

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Discussion Coronary collateral arteries have their origin from the same embryonic precursor as the native coronary arteries during embryogenesis; therefore the foundation of these collateral arterial networks is laid down during embryonic life and is present in the newborn.9,25 The normal human heart contains interconnecting channels,26 hence, coronary collateral pathways are present in both normal and diseased hearts.21 These channels exist as microvessels whose function is not clear and is not demonstrable angiographically when coronary circulation is normal or mildly obstructed.11,26 Functional collaterals were suggested to have developed from hypertrophic evolution of the vessels present in the normal heart.6 This evolutionary process is triggered by myocardial ischaemia and/or an increase in the pressure gradient in the collateral network.8,25,27 Due to this pressure gradient, there is an increase in the volume of blood propelled through these channels. They progressively dilate and are eventually angiographically visible as coronary collateral channels.26 The pressure gradient also results in an increased fluid shear stress in the vessel.28 This fluid shear stress is a primary morphogenic physical factor that determines the size of the developing collateral vessel.25 In the present study, the best developed CACs were recorded in those patients who had proximally located lesions (40.9%). Excellent collaterals were found in 29.7 and 25% of middle and distally located lesions, respectively. The more proximally located the lesion, the higher the pressure gradient between the normal (collateral-donating) coronary artery and the obstructed (collateral-receiving) vessel. In addition, the more proximal the lesion was situated, the greater the mass of ‘at risk’ ischaemic myocardium.29 Therefore, the highest prevalence of excellent collaterals in patients with proximally located lesions in the present study may have resulted from the combination of these factors (increased pressure gradient and myocardial ischaemia). Consequently, this results in an increased stimulus for collateral vessel formation. It is apparent from the literature reviewed that there are no reports on the relationship between the situation of the lesion and LV function. In the present study, the mean EF calculated for the patients with proximally located lesions was the highest (63.3%) compared to mean EF for the middle (57.8%) and distally (57.5%) located lesions (Table 3). However, the current study did not find any significant difference in the prevalence of CACs with regard to the location of atherosclerotic lesion and the resultant preservation of LV function. There are conflicting reports with regard to the functional importance of coronary collateral arteries. Sheehan et al.30 examined global left ventricular ejection fraction (LVEF) in patients with acute myocardial infarction before treatment and at discharge. They reported that global LVEF increased in patients with CACs but was the same in patients without coronary collaterals. Habib et al.31 divided patients who failed to canalise at 90 minutes after administration of a thrombolytic agent, into two groups (with and without collaterals) and reported that global LVEF was significantly greater in patients with CACs at hospital discharge. On the contrary, Wackers et al.32 found no difference in the global LVEF in patients with and without CACs. There is yet another supposed negative effect of coronary collaterals, namely coronary ‘steal’. This occurs either when the pressure in the donor vessel is suddenly low or when there is

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higher resistance in the collateral pathway.33 Therefore, it results in the flow of blood from the region of the collateral-receiving vessel to the collateral-donating vessel. However, patients with poorly developed CACs are more prone to coronary steal than those with well-developed CACs.33 To our knowledge, this study is the first attempt at establishing a relationship between the different grades of CACs and LVEF in the presence of total coronary arterial obstruction. There was a significant difference (p < 0.001) in the mean EF calculated for the different grades of CACs. In addition, a post hoc test showed a significant difference in the mean EF between excellent and absent collaterals (p = 0.004) and excellent and poor collaterals (p < 0.001). Therefore the development of excellent collaterals has a significant supportive effect in the preservation of LV function compared to patients with absent or poor collateralisation. There was also a significant positive correlation between CAC grades and mean EF calculated for the different CAC grades. Our study corroborated the findings of Sheehan et al.30 and Habib et al.,31 that the presence of excellent and well-developed CACs had a significant role in the preservation of LV function. In addition, the present study showed that, as the grades of the CACs increased, there was an improvement in the ability of these collaterals to preserve LV function. Consequently, LV myocardial perfusion was greater in patients with well-developed CACs where the native artery was totally occluded, and resulted in better preservation of LV function even in the face of an acute coronary event.34 To date, the significance of collateral circulation in coronary bypass surgery has not yet been fully investigated. However, it has been reported that the collateral circulation is favourable for the successful construction of coronary artery bypass grafts.26 From the result of this study, it can therefore be seen that the presence of well-developed CACs should be considered in decision making in the management of patients with coronary arterial obstruction. In the presence of an adequately preserved LV function by coronary collaterals in asymptomatic patients, a strong case can be made for no intervention. Anecdotally, most cardiac practitioners would be aware of patients with total coronary arterial obstruction who have been leading a normal life, and even engaging in high-intensity sport without symptoms. Therefore, the significance of the coronary collateral arteries should not be underestimated, as identification of the CACs is relevant in clinical decision making.35 The limitations to the current study include the absence of clinical records, which made it impossible to determine the patients with risk factors and co-morbid conditions, such as diabetes mellitus and hypertension, which may also have influenced collateral vessel development. This would have enhanced the study; however, the aim of this study was to evaluate the functional importance of coronary collaterals on LV function, which was achieved by analysing the angiographic records.

Conclusion The location of atherosclerotic lesion had no significant effect on the prevalence of CAC grades and the resultant LV function. However, with the development of well-functioning coronary collaterals, there was a significant improvement in the ability of these collaterals to preserve LV function.

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References 1.

Traupe T, Gloekler S, de Marchi SF, Werner GS, Seiler C. Assessment of the human coronary collateral circulation. Circulation 2010; 122: 1210–1220.

Wainwright RJ, Maisey MN, Edwards AC, Sowton E. Functional

intervention: a meta-analysis. BMC Med 2012; 10: 62.

Baroldi G, Bigi R, Cortigiani L. Ultrasound imaging versus morphopa-

22. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collat-

thology in cardiovascular diseases. Coronary collateral circulation and

eral filling after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol 1985; 5: 587–592.

Heaps CL, Parker JL. Effects of exercise training on coronary collat-

23. Van der Hoeven NW, Teunissen PF, Werner GS, Delewi R, Schirmer

eralization and control of collateral resistance. J Appl Physiol 2011;

SH, Traupe T, et al. Clinical parameters associated with collateral devel-

111(2): 587–598.

opment in patients with chronic total coronary occlusion. Heart 2013;

Hirai T, Fujita M, Nakajima H, Asanoi H, Yamanishi K, Ohno A, et

99(15): 1100–1105.

al. Importance of collateral circulation for prevention of left ventricular

24. Werner GS, Ferrari M, Heinke S, Kuethe F, Surber R, Richartz BM,

aneurysm formation in acute myocardial infarction. Circulation 1989;

et al. Angiographic assessment of collateral connections in comparison

79: 791–796.

with invasively determined collateral function in chronic coronary occlu-

Koerselman J, van der Graaf Y, de Jaegere PP, Grobbee DE. Coronary

Gensini GG, Bruto da Costa BC. The coronary collateral circulation in living man. Am J Cardiol 1969; 24: 393–400. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation 1992; 85: 1197–1204.

cal implications. Int J Cardiol 2009; 137(3): 300–301. Coronary collaterals and risk for restenosis after percutaneous coronary

disease. Circulation 2003; 107: 2507–2511.

relevance of coronary collateral circulation: Clinical and epidemiologi-

evaluated by thallium-201 myocardial scintigraphy. Br Heart J 1980;

collaterals: An important and underexposed aspect of coronary artery 7.

1998; 63: 151–153. 20. Turgut O, Yilmaz MB, Yalta K, Tandogan I, Yilmaz A. Prognostic

21. Meier P, Indermuehle A, Pitt B, Traupe T, de Marchi SF, Crake1 T, et al.

atherosclerotic plaque. Cardiovasc Ultrasound 2005; 3: 6. 4.

with normal and impaired left ventricular systolic function. Int J Cardiol

significance of coronary collateral circulation during dynamic exercise 43: 47–55. 3.

Loukas M, Bilinsky S, Bilinsky E, Petru M, Anderson RH. The clinical anatomy of the coronary collateral circulation. Clin Anat 2009; 22: 146–160.

10. Levin DC, Kauff M, Baltaxe HA. Coronary collateral circulation. Am J Roentgenol Radium Ther Nuclear Med 1973; 119(3): 463–473. 11. Rockstroh J, Brown BG. Coronary collateral size, flow capacity, and growth: Estimates from the angiogram in patients with obstructive coronary disease. Circulation 2002; 105: 168–173. 12. Meier P, Schirmer SH, Lansky AJ, Timmis A, Pitt B, Seiler C. The collateral circulation of the heart. BMC Med 2013; 11: 143. 13. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation 1986; 74: 469–476.

sions. Circulation 2003; 107: 1972–1977. 25. Schaper W. Collateral circulation – Past and present. Basic Res Cardiol 2009; 104: 5–21. 26. Levin DC. Pathways and functional significance of the coronary collateral circulation. Circulation 1974; 50: 831–837. 27. Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M , Ohanyan V, et al. Coronary collateral growth – Back to the future. J Mol Cell Cardiol 2012; 52: 905–911. 28. Ladwiniec A, Hoye A. Coronary collaterals: a little give and take, and a few unanswered questions. J Clin Exp Cardiolog 2013; 4: 4. 29. Piek JJ, van Liebergen RA, Koch KT, Peters RJG, David GK. Clinical, angiographic and hemodynamic predictors of recruitable collateral flow assessed during balloon angioplasty coronary occlusion. J Am Coll Cardiol 1997; 9(2): 275–282. 30. Sheehan F, Braunwald E, Canner P, Dodge HT, Gore J, Natt PV, et al. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis In Myocardial Infarction (TIMI phase I) trial. Circulation 1987; 75: 817–829. 31. Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML,

14. De Marchi SF, Oswald P, Windecker S, Meier B, Seiler C. Reciprocal

et al. Influence of coronary collateral vessels on myocardial infarct size

relationship between left ventricular filling pressure and the recruitable

in humans: results of phase I Thrombolysis In Myocardial Infarction

human coronary collateral circulation. Eur Heart J 2005; 26: 558–566. 15. Gloekler S, Seiler C. Natural bypasses can save lives. Circulation 2007; 116: e340–e341

(TIMI) trial: the TIMI investigators. Circulation 1991; 83: 739–746. 32. Wackers J, Terrin ML, Kayden DS, Knatterud G, Forman S, Braunwald E, and the TIMI investigators. Quantitative radionuclide assessment

16. Choi JH, Chang SA, Choi JO, Song YB, Hahn JY, Choi SH, et al.

of regional ventricular function after thrombolytic therapy for acute

Frequency of myocardial infarction and its relationship to angiographic

myocardial infarction: results of phase I Thrombolysis In Myocardial

collateral flow in territories supplied by chronically occluded coronary arteries. Circulation 2013; 127(6): 703–709. 17. Schwartz H, Leiboff RL, Katz RJ, Wasserman AG, Bren GB, Varghese PJ, et al. Arteriographic predictors of spontaneous improvement in left ventricular function after myocardial infarction. Circulation 1985; 71: 466–472. 18. Banerjee AK, Madan Mohan SK, Ching GWK, Singh SP. Functional significance of coronary collateral vessels in patients with previous ‘Q’ wave infarction: relation to aneurysm, left ventricular end diastolic pressure and ejection fraction. Int J Cardiol 1993; 38: 263–271. 19. Ilia R, Carmel S, Cafri C, Gueron M. Coronary collaterals in patients

Infarction (TIMI) trial. J Am Coll Cardiol 1989; 13: 998–1005. 33. Liu K, Krone R. Evaluation of coronary steal in myocardium supplied by coronary collaterals: The role of speckle tracing analysis in rest and stress echocardiography. Echocardiography 2013; 30: 1111–1117. 34. Meier P, Gloekler S, Zbinden R, Beckh S, de Marchi SF, Zbinden S, et al. Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Circulation 2007; 116: 975–983. 35. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL. Noninvasive assessment of coronary collaterals in man by PET perfusion imaging. J NucI Med 1990; 31: 259–270.

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Obesity in Botswana: time for new cut-off points for abdominal girth? Churchill Lukwiya Onen

Abstract Introduction: Country-specific cut-off points for defining central obesity in black Africans are long overdue. Methods: Anthropometric data from 215 (51.4%) male and 203 (48.6%) female patients seen in Gaborone between 2005 and 2015 were analysed to establish appropriate cut-off points for waist circumference (WC) corresponding to a body mass index (BMI) of 30 kg/m2. Relative risks for cardiometabolic disorders were calculated for different BMI and WC categories using MedCalc®. The subjects’ mean age was 50.0 ± 10.8 years and 80.6% were Batswana. Results: Only 7.2% of patients had a BMI < 25 kg/m2, 27.3% were overweight and 65.5% were obese; mean BMI was 34.9 ± 6.5 kg/m2 in the women versus 31.0 ± 4.9 kg/m2 in the men (p < 0.0001). New cut-off points of 98 cm in men and 85 cm in women emerged. Different weight and WC categories appeared not to confer increased relative risk of hypertension, dysglycaemia or dyslipidaemia. Conclusion: The proposed WC cut-off values, if validated, should set the pace for larger studies across sub-Saharan Africa. Keywords: Botswana, obesity, waist circumference, cut-off points, modelling Submitted 31/12/15, accepted 8/5/16 Published online 4/7/16 Cardiovasc J Afr 2017; 28: 86–91

www.cvja.co.za

In 2012, HIV/AIDS accounted for a third of the causes of mortality (5 700 deaths), whereas stroke, ischaemic heart disease, diabetes mellitus and hypertensive heart disease together accounted for about 15% of deaths (2 900 deaths). Cardiovascular diseases and diabetes together constituted the third most common cause of disability-adjusted life years (DALYs). Since its description by Jean Vague8 nearly seven decades ago, abdominal obesity consistently features among criteria for the definition of the MetS, although the clustering of cardiovascular risk factors has greatly expanded. Obesity is also the bedrock in the International Diabetes Federation (IDF) definition of the MetS.9 The Joint Interim Statement (JIS) on the MetS recommended the use of population- and country-specific cut-off points to define an enlarged waist circumference.10 Accordingly, using non-validated cut-off points for waist circumference in the definition of obesity may falsify estimates of the MetS in the African setting. Inconsistent estimates of the MetS in sub-Saharan Africa have largely been due to lack of Africanspecific cut-off points for waist circumference.11-13 This study aimed firstly to determine the validity of current operational waist circumference cut-off points in Botswana; secondly, to determine the correlation between body mass index (BMI) and waist circumference (WC) in black African men and women, and in particular, the relationship between BMI of 30 kg/m2 and WC of 80 cm in women and 94 cm in men; and thirdly whether excessive body weight relates to cardiometabolic and other chronic medical disorders in the study population.

DOI: 10.5830/CVJA-2016-060

Methods

Several small observational studies in Botswana have produced inconsistencies in the prevalence of the metabolic syndrome (MetS), partly because of variations in methodological approaches to measurements of waist circumference and differences in study populations.1-3 Although Botswana was one of the poorest countries at independence, its diamond-dependent economy has propelled it to upper-middle income, with one of the fastestgrowing economies in the world, gross domestic product of $18 825 per capita in 2015, the fourth largest gross national income, and the highest human development index in sub-Saharan Africa.4,5 It is currently estimated that 57% of the population is urbanised. Overweight and obesity are therefore assuming epidemic proportions in the country. Life expectancy at birth is 63 and 65 years in men and women, respectively.6,7 This represents a 14-year increase for both genders between 2000 and 2012. The probability of dying between the ages of 15 and 60 years in men and women is 321 and 254 per thousand of the population, respectively.

Data from a heterogeneous group of adult patients seen over a 10-year period (2005–2015) at a specialised medical clinic I run in Gaborone city were extracted from conveniently sampled case notes, taking every sixth file from over 3 000 files accumulated in the filing room during a decade of private practice. Completeness of records was examined for the presence of weight (kg), height (cm), waist circumference (cm) and co-morbidities for each patient during the index visit. From the inception of the clinic at Gaborone Private Hospital, anthropometric measurements have been routinely performed whenever possible, using standard methods. Weight (kg) and height (cm) were measured in a similar manner to the method described by Dowse and Zimmet,14 using a well-calibrated scale. BMI was derived by dividing weight (kg) by the square of height (m2). Able-bodied participants were instructed to stand upright with the back against the stand, heels together and eyes directed forward so that the top of the tragus of the ear was horizontal with the inferior orbital margin, and the measuring plate was lowered on to the scalp to give the correct height. Waist circumference was measured with the individual standing upright with the side turned to the observer, who was often seated. A measuring tape attached to a spring, similar to

Centre for Chronic Diseases, Gaborone, Botswana Churchill Lukwiya Onen, MD, FRCP, onenkede@info.bw

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that used in the INTERHEART study,15 was placed snugly in a horizontal plane around the subject’s abdomen, mid-way between the rib cage and the iliac crest, and standard tension was applied. Demographic data, anthropometric measurements and co-morbidities for individual patients were entered into a database created using the Statistical Package for Social Sciences (IBM SPSS statistics 20®). Correlation plots were made for BMI (kg/m2) and WC (cm) in men and women, using 30 kg/m2 as the reference cut-off point for obesity, to determine corresponding mean WC (+ 95% CI) in both genders. Similar plots were made for BMI and WC using 94 cm in men and 80 cm in women as reference cut-off points for obesity to determine corresponding BMI (+ 95% CI) in both genders. Height (m) was also plotted against WC in both men and women. Patients were grouped into five WHO weight categories:16 normal weight (category 1; BMI 18.5–24.9 kg/m2), overweight (category 2; BMI 25.1–29.9 kg/m2), grade I obesity (category 3; BMI 30.0–34.9 kg/m2), grade II obesity (category 4; BMI 35.0–39.9 kg/m2), and grade III obesity (category 5; BMI ≥ 40.0 kg/m2). Women were arbitrarily grouped into three WC categories: category 1 (WC ≤ 80 cm), category 2 (WC 80.0–87.9 cm) and category 3 (WC ≥ 88 cm). Men were likewise grouped into three WC categories: category 1 (WC ≤ 94 cm), category 2 (WC 94.0–101.9 cm) and category 3 (WC ≥ 102 cm).

Statistical analyses With MedCalc® software,17 using category 1 BMI and category 1 WC as references, relative risks (+ 95% CI) for hypertension, dysglycaemia and dyslipidaemia were calculated for different BMI and WC categories. Sample means and standard deviations were calculated in the conventional way. Level of statistical significance was taken to be p < 0.05.

Results A total of 498 case notes were retrieved; 23 did not contain the required data. Of 475 case notes of patients with the required

anthropometric parameters, 20 naturalised non-black citizens of Botswana, 25 Asians and 12 Caucasians were excluded; the remaining 418 black African patients were analysed. This consisted of 215 men (51.4%) and 203 women (48.6%), mean age 50.0 ± 10.8 years, 80.6% of whom were Batswana and 19.4% were other black Africans. Only 7.2% had normal weight (BMI 18.5–24.9 kg/m2), 27.3% were overweight (BMI 25–29.9 kg/m2) and 65.5% were obese (BMI > 30 kg/m2). Significantly more women were obese (77.8%) compared to men (54.0%); mean BMI was 34.9 ± 6.5 versus 31.0 ± 4.9 kg/m2 (p < 0.0001). Hypertension affected 77.8% (325/418) and dysglycaemia 44.3% (185/418) of the patients. Lipid profiles were not estimated in a third of the sample group. Dyslipidaemia was documented in 67% of the remaining 279 patients. One man did not have a WC measurement and was excluded from the correlation plots. WC directly correlated with BMI in both genders (R2 linear = 0.774 in men; 0.644 in women) with new cut-off points of 98 cm (95% CI: 96.9–98.2 cm) in men and 85 cm (95% CI: 83.0–86.5 cm) in women, corresponding to BMI of 30 kg/m2. (Fig. 1A, B). The current operational WC of 94.0 cm in black African men corresponded to a BMI of 28.7 kg/m2, whereas in black women, the corresponding BMI was 28.0 kg/m2 for a WC of 80 cm (Fig. 2A, B). In both men and women, there was a poor correlation between height and WC (R2 linear = 0.036 in men; 0.005 in women) (Fig. 3A, 2B). There was no correlation between age and BMI among the 418 patients (R2 linear = 0.001). Table 1 shows the relative risks of hypertension, dysglycaemia and dyslipidaemia for different BMI categories versus normal weight (BMI < 25 kg/m2) among 418 patients. Table 2 shows the relative risks of any cardiovascular disease for different WC categories versus current reference WC (< 80 cm in women; < 94 cm in men). Both tables demonstrate no overall statistically significant risk relationship with hypertension, dysglycaemia and dyslipidaemia. Separate analysis showed that WC ≥ 102 cm in men was associated with 21% increased total co-morbidity, combining cardiometabolic and musculoskeletal disorders (RR 1.21; 95% CI: 1.03–1.42; p = 0.022).

B 50

R linear = 0.774

97.65

84.85 R2 linear = 0.644

BMI (kg/m2)

35 30

25 20

20 80

100

120 WC (cm)

140

100 120 WC (cm)

140

160

Fig. 1. C orrelation between BMI (kg/m2) and WC (cm) in (A) 214 men and (B) 203 women with BMI = 30 kg/m2 as cut-off point. BMI, body mass index; WC, waist circumference.

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B 50

R2 linear = 0.774

94.0

80.0 R2 linear = 0.644

BMI (kg/m2)

35 30

28.7

28.0

25 20

20 80

100

120

140

WC (cm)

100 120 WC (cm)

140

160

Fig. 2. C orrelation between BMI (kg/m2) and WC (cm) in (A) 214 men with WC = 94.0 cm and (B) 203 women with WC = 80 cm as cut-off point. BMI, body mass index; WC, waist circumference.

2.0

R2 linear = 0.036

1.8 1.7 Height (m)

Height (m)

1.9

R2 linear = 0.005

1.8 1.7

1.6 1.5

1.6

1.4

1.5 80

100

120

140

WC (cm)

100 120 WC (cm)

140

160

Fig. 3. P oor correlation between height and WC in (A) 214 men and (B) 203 women. WC, waist circumference.

Discussion There are strong indications for examining body size in the current context of affluence, social marketing and food consumption in Botswana. Anthropometric measurements are frequently used Table 1. Relative risks of hypertension, dysglycaemia and dyslipidaemia for different BMI categories versus normal weight (BMI < 25 kg/m2) among 418 patients (1) Hypertension, (2) dysglycaemia, (3) dyslipidaemia Relative risk

95% CI

p-value

Overweight (25–29.9)

(1) 0.99 (2) 0.94 (3) 1.24

(0.78–1.27) (0.61–1.45) (0.79–1.96)

0.95 0.78 0.36

Grade I (30–34.9)

(1) 1.09 (2) 0.88 (3) 1.24

(0.87–1.38) (0.57–1.36) (0.79–1.95)

0.45 0.57 0.36

Grade II (35–39.9)

(1) 1.12 (2) 1.01 (3) 1.07

(0.88–1.43) (0.65–1.59) (0.66–1.74)

0.45 0.95 0.77

(1) 1.06 (2) 1.02 (3) 1.23

(0.82–1.38) (0.64–1.62) (0.76–1.98)

0.64 0.94 0.40

WHO BMI category (kg/m2)

Grade III (> 40)

WHO, World Health Organisation; BMI, body mass index.

to determine parameters of overweight and obesity at most points in the healthcare system and during many ‘wellness’ programmes. Knowing that a person’s BMI exceeds 30 kg/m2 may be useful only in understanding the individual’s potential cardiometabolic risk and total burden of co-morbidity. After all, obesity may be an epiphenomenon for other cardiovascular disease risk factors. But failure to recognise obesity as a major health issue and its complex social and societal construct may Table 2. Relative risks of any cardiovascular disease for different waist circumference categories versus current reference waist circumferences (< 80 cm in women; < 94 cm in men) Any CVD relative risk Relative risk

95% CI

p-value

Men (94–101.9)

1.04

(0.91–1.18)

0.61

Women (80–87.9)

1.15

(0.84–1.59)

0.39

Men (> 102)

1.10

(0.99–1.22)

0.08

Women (> 88)

1.17

(0.86–1.58)

0.32

Waist circumference category (cm) Category 2

Category 3

CVD, cardiovascular disease refers to hypertension, dysglycaemia and dyslipidaemia.

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camouflage the problem and propagate inherent imperfections of the obesity-screening processes. Cataloguing BMI, WC and sometimes waist:hip ratios may not reflect their correlation to obesity-related sequelae. There are medically healthy obese individuals and metabolically obese normal-weight individuals, although the prevalence of these conditions in this community is unknown. National anthropometric data are scarce or unavailable. The growing prevalence of overweight and obesity sweeping southern Africa, with a national prevalence between 30 and 60% of populations over the age of 15 years, is largely due to dietary shift away from high-fibre, low-calorie diets rich in fruits and vegetables towards refined, energy-dense foods high in fat, calories, sweeteners and salt, and this affects females disproportionately.18,19 A paradoxical situation, in which poverty and high levels of overweight and obesity co-exist in urban settings, may be explained by reduced levels of physical activity in all groups. Coupled with rapid urbanisation, industrialisation and increased sedentary lifestyles, these nutritional and demographic transitions have ushered in the rapid emergence of non-communicable diseases, including hypertension, diabetes, stroke, heart disease and other cardiovascular diseases. Despite direct correlations between BMI and WC, findings from this situational analysis in Botswana suggest the need for new cut-off points for WC (98 cm in men; 85 cm in women) that correspond to a BMI of 30 kg/m2. Europid WC cut-off points (≥ 80 cm in women; ≥ 94 cm in men), as recommended by the IDF9 and currently used in sub-Saharan Africa to define central obesity do not appear to correlate with BMI ≥ 30 kg/m2 in Botswana. Elsewhere, there is a strong correlation between BMI of 25–34.9 kg/m2, WC ≥ 102 cm for men and ≥ 88 cm for women, and greater risk of hypertension, type 2 diabetes, dyslipidaemia and coronary heart disease.20 Western countries derived cut-off values of WC from correlation with BMI, whereas Asians tried to define WC cut-off values produced by receiver-operating characteristics (ROC) curve analysis.21,22 Measurements of skinfold thickness are less accurate, particularly in obese individuals and are therefore discouraged in routine screening exercises, except in epidemiological studies. Precise measurements of body fat using computed tomography (CT) or magnetic resonance imaging (MRI) scans or biochemical barometers such as adipokines are unlikely to be used outside research settings in Botswana. However, measurement of fasting insulin and glucose levels may help in the calculation of HOMA-IR in individuals with features of insulin resistance syndromes. In the Diabetes and Macrovascular Complications study of 258 adult diabetic patients in Botswana,1 the MetS defined using IDF criteria9 was more prevalent in diabetic women compared to diabetic men. Depending on which set of parameters in the IDF criteria was used for the definition, the prevalence of the MetS ranged from 41.7–83.7% in men, and 37.8–88.6% in women. Obesity, defined by waist:hip ratio (> 0.9 in men, > 0.85 in women) was present in 87.9% of diabetics, and by WC (> 94 cm men, > 80 cm in women) in 79.0% of diabetics, but prevalence of the MetS dropped to 38.3% using BMI (> 30 kg/m2). Large disparities in estimates of the MetS based on different parameters complicated its true prevalence estimates in that study. BMI was viewed as an insensitive indicator of the MetS, especially in diabetic women.

Garrido et al.2 conducted a small cross-sectional, observational study of 150 hospital workers at a peripheral facility in Botswana, representing nearly half of the hospital workforce, women comprising over 70% of the group. The investigators applied any three or more of the ATP III criteria for definition of the MetS.23 Low high-density lipoprotein (HDL) cholesterol affected 80% of the group, dysglycaemia 73.3%, hypertension 44%, central obesity 42% and hypertriglyceridaemia 14%. A third of the participants met the ATP III criteria for the MetS and 28.7% had a BMI > 30 kg/m2. That over 40% of hospital employees had central obesity, using higher cut-off points for WC raises the possibility of a high prevalence of abdominal obesity in the community. Another cross-sectional study by Malangu3 looked at 190 adult HIV-infected patients on highly active antiretroviral therapy (HAART) at Princess Marina Hospital in Gaborone in 2010. Their mean age was 42 ± 9.04 years and nearly threequarters of the group were women (74.2%). Using IDF criteria, the investigator showed an overall prevalence of the MetS in 11.1% of participants. Risk factors for the MetS included increased age, male gender and longer exposure to antiretroviral drugs, particularly protease inhibitors. Only 10% of participants had a BMI > 30 kg/m2, 13 of 141 women and eight of 49 men had abdominal obesity (WC ≥ 80 cm in women and ≥ 94 cm in men). The study design lacked comparator control groups (e.g. non-HIV-infected individuals or HIV-infected persons pre-HAART), making it difficult to determine the independent contribution of antiretroviral therapy to the MetS and this limits generalisability of the findings. However, it appears that obesity and the MetS were substantially lower in HIV-infected individuals, despite the use of different diagnostic criteria for the MetS. Studies from other parts of sub-Saharan Africa have generated wide variations in WC cut-off points. For example, central obesity defined by WC > 102 cm in men and > 88 cm in women was more common than generalised obesity (BMI > 30 kg/m2) in Cotonou, Benin.11 In South Africa, Motala et al.12 found that WC of > 86 cm in men and > 92 cm in women predicted the presence of at least two elements of the MetS in a cross-sectional, population-based study in a rural setting. That study was heavily gender biased, with 80% of the 947 participants being female. In 2014 Magalhães et al.,13 in another cross-sectional study of 615 university employees in Luanda, Angola, found overall prevalence of overweight to be 47.8%, and obesity in 45.2% of participants. Using JIS criteria, crude and age-standardised prevalence of the MetS were 27.8 and 14.1%, respectively. The crude and age-standardised prevalence of the MetS was 17.6 and 8.7% using ATP III criteria,23 which apply higher WC cut-off points (≥ 102 cm in men, ≥ 88 cm in women). Applying ROC curves of WC to detect the MetS, new cut-off points of this study were 87.5 cm in men (sensitivity 75.9%, specificity 81.2%) and 80.5 cm in women (sensitivity 88.4%, specificity 60.5%). The three most common criteria for the MetS were increased WC, hypertension and low serum HDL cholesterol levels. Women showed a higher prevalence in all age groups from the age of 30 years. The INTERHEART study, a case-controlled study of 27 000 participants from 52 countries, showed a graded and highly significant association between waist:hip ratios (WHR) and acute myocardial infarction worldwide.15 The association of WHR with acute myocardial infarction in the INTERHEART

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study addressed one of the most fundamental cardiovascular sequelae of excessive and disproportionate weight. Although the INTERHEART study investigators cast doubt on the use of BMI in the context of acute myocardial infarction, obesity, however defined, was associated with a myriad of conditions, including hypertension, diabetes mellitus, dyslipidaemia, obstructive sleep apnoea, gastro-oesophageal reflux, sudden death, stroke, certain types of cancer, infertility, degenerative joint disease and negative psychosocial impact. The Prospective Studies Collaboration addressed the association of BMI with cause-specific mortality in about 900 000 adults in 57 prospective studies.24 These authors concluded that other anthropometric measures such as WC and WHR could well add extra information to BMI, and BMI to them, but that BMI is in itself a strong predictor of overall mortality rate both above and below the apparent optimum of about 22.5 to 25 kg/m2. For screening purposes, it appears that measurements of WHR provide no advantage over WC alone, are cumbersome and may be fraught with errors in field situations. Furthermore, it may not be necessary to measure WC in persons with BMI > 35 kg/m2 since it adds little value in the predictive power of disease-risk classification.25 Inconsistencies in cut-off values for WC have potentially undesirable consequences for cardiovascular risk stratification, disease categorisation and prioritisation of preventative strategies for obesity. There is therefore a strong need for validation of these WC cut-off values for Botswana before they can be used for prediction of incident outcomes such as cardiovascular diseases or type 2 diabetes mellitus. Modelling may help to capture the scope and complexity of the obesity problem in Botswana. Applications of heterogeneous adaptive pieces of the puzzle that are affected by and/or influence the overall behaviour of individuals within society may lead to the development of empirically based public health models. Agent-based modelling (ABM) represents one such simplified example.26 Using the ABM approach, agents could represent individuals, their attributes, behaviours and relationships with other individuals in society. The environment could represent geographical locations, mobility, domestic settings, market forces and social networking. Systematic dynamic modelling (SDM) or perhaps more appropriately for Botswana, the MicroSimulation model, could be used to establish temporal and causal associations, if any, between obesity and related disorders, such as hypertension, diabetes, abnormal lipids, cardiovascular diseases, cancers, degenerative musculoskeletal disorders and psychological afflictions.27 The strategy focuses on ‘upstream’ preventive approaches rather than ‘downstream’ acute and chronic care. The goal is to enhance the number of safer, healthier people and prevent others from becoming vulnerable or being afflicted by obesity and its related complications. There are, however, several limitations of this study worth mentioning. Firstly, this was a retrospective analysis of case notes of a small number of patients seen at a specialised private medical practice. The finding may not therefore apply to the general population. Secondly, WC reflects both subcutaneous and visceral fat and at best represents a crude surrogate for visceral adiposity. Because women generally have more subcutaneous fat, there is a potential risk of misclassifying them as viscerally obese, thereby resulting in overestimation of the

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MetS in women. Thirdly, little is known about the full impact of the obesity epidemic on the health of the community, and failure to demonstrate statistically significant links between obesity and existing co-morbidities in this study should not be construed to suggest benigness of obesity in this population.

Conclusion This study reiterates the need for ethnic-specific WC cut-off points for defining central obesity and, by extension, for diagnosis of the MetS among black Africans. The proposed WC cut-off values, if validated, will set the pace for larger studies across sub-Saharan Africa. Variations in WC cut-off values illustrate the uniqueness of populations.

References 1.

Onen CL. Diabetes and macrovascular complications in adults in Botswana (DAMCAB). MD thesis 2010, Makerere University, Kampala, Uganda.

Garrido RA, Semeraro BM, Temesgen SM, Simi MR. Metabolic syndrome and obesity among workers at Kanye Seventh Day Adventist Hospital, Botswana. S Afr Med J 2009; 99: 331–334.

Malangu N. Factors associated with metabolic syndrome among HIV-positive patients at a health facility in Botswana. Br J Med Med Res 2014; 4(12): 2352–1361.

The World Factbook. Central Intelligence Agency. https://.cia.gov/ library/publications/the-world-factbook/geos/bc.html. (Accessed 19 July 2015).

http://www.nationsonline.org/oneworld/GNI_PPP_of_countries.htm (Accessed 19 July 2015).

http://www.who.int/gho/countries/bwa.pdf ?ua=1 (Accessed 19 July 2015).

http://www.who.int/countries/bwa/en/ (Accessed 19 July 2015).

Vague J. Sexual differentiation. A factor affecting the form of obesity. Presse Medicale 1947; 30: S39–S40.

Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005; 336: 1059–1062.

10. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Circulation 2009; 120: 1640–1645. 11. Fezeu L, Balkau B, Kengne A, Sobngwi E, Mbanya JC. Metabolic syndrome in a sub-Saharan African setting: Central obesity may be the key determinant. Atherosclerosis 2007; 193: 70–76. 12. Motala AA, Esterhuizen T, Pirie FJ, Omar MAK. The prevalence of the metabolic syndrome and determinants of the optimal waist circumference cut-off points in a rural South African community. Diabetes Care 2011; 34: 1032–1039. 13. Magalhães P, Capingana DP, Mill JG. Prevalence of the metabolic syndrome and determination of optimal cut-off values of waist circumference in university employees from Angola. Cardiov J Afr 2014; 25: 27–33. 14. Dowse GK, Zimmet P. A model protocol for diabetes and other noncommunicable disease field survey. Epidemiology and public health aspects of Diabetes. World Health Stat Q 1992; 45: 360–369. 15. Yusuf S, Hawken S, Ôunpuu S, Bautista L, Franzosi MG, et al,

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INTERHEART study investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case- control study. Lancet 2005; 366(9497): 1640–1649.

cardiovascular risk factors in Taiwan. In J Obes Relat Metab Disord 2002; 26: 1232–1238. 23. Expert panel on detection, evaluation, and treatment of high blood

16. Report of a WHO consultation. Obesity: prevalence and managing the

cholesterol in adults. Executive summary of the third report of the

global epidemic. World Health Org Tech Rep Ser 2000; 894: i–xii, 1–253).

National Cholesterol Education Program (NCEP) expert panel on

17. MedCalc® 1993–2015, Version 15.2.2 Altman DG. Practical Statistics for

detection, evaluation, and treatment of high blood cholesterol in adults

Medical Research. London: Chapman and Hall, 1991.

(Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2497.

18. Nnyepi MS, Gwisai N, Lekgoa M, Seru T. Evidence of nutrition transi-

24. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey

tion in Southern Africa. Proc Nutr Soc 2015; Feb 17: 1–9 Epub ahead

J, et al., prospective studies collaborators. Body mass index and cause-

of print.

specific mortality in 900,000 adults: collaborative analyses of 57

19. World Health Organization 2009. WHO Global InfoBase.

prospective studies. Lancet 2009; 373(9669): 1083–1096.

20. Jansen I, Katzmarzyk PT, Ross R. Body mass index, waist circumfer-

25. The Practical Guide: identification, evaluation, and treatment of

ence, and health risk: evidence in support of current National Institutes

overweight and obesity in adults. http://www.nhbli.nih.gov/guidelines/

of Health Guidelines. Arch Intern Med 2002; 162(18): 2074–2079. 21. Balkau B, Charles MA. Comment on the provisional report of WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999; 16: 442–443. 22. Lin WY, Lee LT, Chen CY, Lo H, Hsia HH, Liu IL, et al. Optimal cutoff values for obesity: using simple anthropometric indices to predict

obesity/prctgd_c.pdf (Accessed 06 November 2013). 26. Macal CM, North MJ. Tutorial on agent-based modeling and simulation. J Simulation 2010; 4: 151–162. doi:10.1057/jos.2010.3. 27. Homer JB, Hirsch GM. System dynamics modeling for public health: background and opportunities. Am J Public Health 2006; 96: 452–458. doi:10.2105/AJPH.2005.062059.

Conﬁdence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fi brillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015. S4 XARELTO ® 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia S2 : 12/8.2/0006; Botswana S2 : BOT1302296 S4 XARELTO ® 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112; Namibia S2 : 12/8.2/0007; Botswana S2 : BOT1302297 PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: +27 (0) 11 921 5044 Fax: +27 (0) 11 921 5041. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). L.ZA.MKT.GM.01.2016.1265 © Bayer January 2016 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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Comparative analysis of anthropometric indices of obesity as correlates and potential predictors of risk for hypertension and prehypertension in a population in Nigeria Chimaobi James Ononamadu, Chinwe Nonyelum Ezekwesili, Onyemaechi Faith Onyeukwu, Uchenna Francis Umeoguaju, Obiajulu Christian Ezeigwe, Godwin Okwudiri Ihegboro

Abstract Background: Obesity is a well-established independent risk factor for hypertension and other cardiometabolic disorders. However, the best anthropometric index of obesity that predicts or associates strongly with hypertension and related conditions remains controversial and inconclusive. Objective: This study compared the performance of eight anthropometric indices of obesity: body mass index (BMI), ponderal index (PI), waist circumference (WC), hip circumference (HC), waist–hip ratio (WHR), waist–height ratio (WHtR), body adiposity index (BAI) and conicity index (CI) as correlates and potential predictors of risk of hypertension and prehypertension in a Nigerian population, and also the possible effect of combining two or more indices in that regard. Methods: This church-based, cross-sectional study was conducted in Anambra state, south-eastern Nigeria from 2012 to 2013. A total of 912 persons (436 male and 476 female) drawn randomly from three major cities (Awka, Onitsha and Nnewi) in the state participated in the study. Information on demography, medical history and lifestyle were obtained using a well-structured and validated questionnaire. The systolic/diastolic blood pressure and anthropometric measurements were taken by well-trained personnel. The resulting data were analysed using descriptive statistics, logistic regression, Poisson regression and receiver operating characteristic curve analysis. Results: The mean values of all the anthropometric indices studied increased from normotension, through prehypertension to hypertension in both genders. BMI, WC, HC and CI were significantly higher (p < 0.05) in females than males. All the anthropometric indices studied were significantly (p < 0.001 except for CI) correlated with systolic and diastolic blood pressure. BMI, WHtR, WC and PI (with higher correlation coefficients for blood pressure) showed the best poten-

Department of Biochemistry and Forensic Science, Nigerian Police Academy, Wudil, Kano State, Nigeria Chimaobi James Ononamadu, PhD, ononamaducj0016@gmail.com Godwin Okwudiri Ihegboro, PhD

Department of Applied Biochemistry, Nnamdi Azikiwe University, Awka Anambra State, Nigeria Chinwe Nonyelum Ezekwesili, PhD Onyemaechi Faith Onyeukwu, MSc Uchenna Francis Umeoguaju, MSc Obiajulu Christian Ezeigwe, PhD

tial to predict hypertension and prehypertension in the study: BMI (cut-off = 24.49, AUC = 0.698; cut-off = 23.62, AUC = 0.659), WHtR (cut-off = 0.55, AUC = 0.682; cut-off = 0.5, AUC = 0.636), WC (cut-off = 91.44, AUC = 0.692; cut-off = 82.55, AUC = 0.645), PI (cut-off = 14.45, AUC = 0.670; cut-off = 13.69, AUC = 0.639), in males; and BMI (cut-off = 24.44, AUC = 0.622; cut-off = 28.01, AUC = 0.609), WHtR (cut-off = 0.51, AUC = 0.624; cut-off = 0.6, AUC = 0.572), WC (cut-off = 96.62, AUC = 0.616; cut-off = 96.52, AUC = 0.584), PI (cut-off = 16.38, AUC = 0.619; cut-off = 17.65, AUC = 0.599), in females for hypertension and prehypertension, respectively. In predicting hypertension risk, WC and WHtR did not significantly improve the performance of BMI in the models when included using our decision rule. Overall, CI had a very poor discriminatory power for both conditions in this study. Conclusion: BMI, WHtR, WC and PI emerged the best predictors of hypertension risk, and BMI, WC and PI of prehypertension risk in this study. The combination of high-performing anthropometric indices in a model did not improve their performance. Therefore we recommend the simultaneous but independent use of BMI and either WC or WHtR for predicting hypertension, and BMI and WC for prehypertension risk, bearing in mind that both types of index (abdominal and general obesity) account for different forms of obesity. Keywords: hypertension, prehypertension, obesity, anthropometric index, ROC curve Submitted 13/11/15, accepted 12/5/16 Published online 13/7/16 Cardiovasc J Afr 2017; 28: 92–99

www.cvja.co.za

DOI: 10.5830/CVJA-2016-061

The burden of the metabolic syndrome, which includes hypertension, is rising to epidemic proportions in Africa at present. According to the World Health Organisation (WHO) health report in 2001, cardiovascular diseases alone accounted for 9.2% of the total deaths in Africa, killing more people than even malaria.1 Hypertension and prehypertension are considered risk factors for cardiovascular and coronary heart disease. The prevalence and diagnosis of hypertension in children and adolescents appears to have increased in recent times.1 Prehypertension is considered a new category of hypertension and a major risk

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factor for developing clinical hypertension relative to those with normotension. It is characterised by blood pressure levels slightly higher than normal. Research in this area has suggested that exploration and modification of risk factors could help ameliorate this trend.1 Obesity is a disorder characterised by extensive fat accumulation, and the body fat is distributed in such a way that health and wellbeing are affected.2 The condition is an established risk factor for hypertension, hypercholesterolaemia, insulin resistance and diabetes.3,4 The close association of obesity with blood pressure has long been recognised in both genders and even in diverse racial/ethnic groups.5 Anthropometry is the most basic method for assessing body composition. It describes body mass, size, shape and level of fatness.6 It is an easy, economical and effective method that is used in the initial screening of obesity, hypertension and other metabolic disorders.7 Research efforts have developed many anthropometric indices to specifically describe obesity and fat distribution in humans. These include body mass index (BMI), ponderal index (PI), waist circumference (WC), hip circumference (HC), waist–hip ratio (WHR), waist–height ratio (WHtR), body adiposity index (BAI) and conicity index (CI). BMI is promulgated by the WHO as the most useful epidemiological measure of obesity, but its usefulness suffers from its inability to account for body fat distribution.8 BMI and PI are widely used to describe total or general obesity, while WC, WHR, WHtR and CI describe more visceral fat; abdominal or centralised obesity.9,10 Anthropometric indicators of abdominal obesity can provide estimates of the visceral adipose tissue, which in turn is associated with metabolic changes, hyperinsulinaemia, glucose intolerance, hypertriglyceridaemia and hypertension.11 The direct association between hypertension and anthropometric indices of obesity have been studied in many countries and ethnic groups,7 but results from different studies show that the best anthropometric index in predicting hypertension and other components of the metabolic syndrome remains inconclusive and controversial.7,12,13 Some studies reported that the best single indicator of the risk of hypertension in Japanese and Cuban populations was BMI.3,14 Other studies suggested WC was a better predictor in Greek,15 Taiwanese (women) and some Japanese men.7 WHtR has also been suggested as the best predictor of hypertension for elderly men in Barbados,14 Taiwanese men,16 and Korean men,17 whereas other studies demonstrated that WHR was the best predictor for Argentinian men and women,18 and indigenous Australian men and women.19 Lee and Kim,7 and Fuchs et al.13 suggested that combination of two or more indices could improve the predictive power of an index. Different studies have therefore posited that the predictive power of an anthropometric index may be population-dependent and vary across ethnic groups, age and gender.20,21 In Nigeria, studies that assessed the performance of anthropometric indices in predicting risk of some metabolic disorders such as hypertension are lacking. Okereke et al.22 evaluated the anthropometric indices for the diagnosis of obesity in pregnant women in Nigeria, and Okafor et al.23 compared the performance of WC and WHR. However, no study has comprehensively assessed the performance of anthropometric indices of obesity in predicting hypertension and prehypertension.

Based on this premise, our study intended to compare the performance of eight anthropometric measures of obesity: BMI, PI, WC, HC, WHR, WHtR, BAI and CI as indicators of risk for hypertension and prehypertension, and the effect (on the performance) of combining two or more of the best-performing indices.

Methods The study was a cross-sectional, church-based survey carried out in three major cities in Anambra state. The inclusion criteria were: age range 17–79 years, being a resident in the study areas Awka, Nnewi and Onitsha cities of Anambra state, being selected by the random sampling procedure explained below, providing informed consent/willingness to participate, and complying with the instructions of the study, for example, avoidance of alcohol, coffee, drugs and exercise at least 30 minutes before examination. Information on the prevalence of hypertension in the adult and paediatric population of Anambra state was lacking, but based on data in the literature, the prevalence in Nigeria ranges from 8–30%.24 Using the ‘stat calc’ function of Epi INFO (version 7) software, it was determined that a sample size of 900 was adequate to detect the prevalence of hypertension of 10–30% with 3% precision and 95% confidence. A total of 1 000 participants (we lost 88 to follow up on the day of testing and administration of the questionnaire) were randomly selected from 30 primary sampling units. A stratified random sampling technique was employed. In brief, the three major cities, Awka, Nnewi and Onitsha were selected for this study. The cities were stratified by location (rural versus urban areas) to ensure good representation. Since these populations are predominantly Christian, the survey was made church based. The churches constituted the primary units from which individuals or participants were randomly sampled; 10 churches from each city. Firstly, pre-visits to the three cities provided us with a list (dataset) of known churches in the communities within the cities. For each city, six and four churches were randomly selected from the urban and rural areas, respectively, using the ‘sample, count’ command of Stata statistical package. A total of 30 churches were selected from a total of 224 churches (Awka 71, Onitsha 90, Nnewi 63). The urban areas were more populated and therefore were sampled more. The selected churches were visited. A list of members who showed willingness to participate was made after explaining the objectives and nature of the study to the congregation, and 11 participants were randomly selected using the ‘sample, count’ command of Stata. Information on demography and lifestyle was obtained using a well-structured and validated questionnaire. Anthropometric data, which included weight, height, and waist and hip circumferences were obtained by well-trained personnel. Weight was measured to the nearest 0.5 kg using a weighing scale with the participant removing his/her footwear. Height was measured to the nearest 0.5 cm using a local stadiometer fixed to a wall. The waist circumference was measured at the level of the iliac crests,25 using a flexible tape and passing it along the umbilical level of the unclothed abdomen. The hip circumference was measured around the widest portion of the buttocks, with the tape parallel to the floor. Blood pressure was taken from the non-dominant arm after 15 minutes of rest, using appropriate cuff size and Accoson

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

Table 1. General characteristics of the study population No hypertension, n (%)

Variables

Hypertension, n (%)

Age (years) ≤ 20

92 (10.09)

7 (0.77)

21–25

279 (30.59)

29 (3.18)

26–40

245 (26.86)

90 (9.87)

88 (9.65)

82 (8.99)

≥ 41 City Awka

241 (26.43)

59 (6.47)

Onitsha

203 (22.26)

98 (10.75)

Nnewi

260 (28.51)

51 (5.59)

Gender Male

340 (37.28)

96 (10.53)

Female

364 (39.91)

112 (12.28)

Body mass index Underweight

13 (1.43)

3 (0.33)

Normal weight

394 (43.20)

64 (7.02)

Overweight

219 (24.01)

92 (10.09)

78 (8.55)

49 (5.37)

683 (75.64)

192 (21.26)

Yes

15 (1.66)

13 (1.44)

Obese Smoking

Physical activity Not active

25 (2.75)

31 (3.41)

Moderately active

385 (42.35)

136 (14.96)

Active

292 (32.12)

40 (4.40)

Not at all

314 (35.01)

89 (9.92)

≤ 1 per month

265 (29.54)

51 (5.69)

1–3 times per week

83 (9.25)

36 (4.01)

Every day

31 (3.46)

28 (3.12)

Alcohol consumption

brand of mercury sphygmomanometer. Systolic (SBP) and diastolic blood pressure (DBP) were the first and the fifth koroktoff sounds, respectively. Three consecutive measurements were made at an interval of five minutes after a 10-minute rest. The mean SBP and DBP determined from the second and third measurements were used for data analysis. Anthropometric indices were calculated as follows: BMI = weight (kg)/height2 (m); WHR = WC (cm)/HC (cm); WHtR = WC (cm)/height (cm); PI = weight (kg)/height3 (cm); WC (m)

BAI = HC (cm)/height1.5 (m) – 18; CI =  __________   weight  (kg)   0.109 ×  _______     height (cm)

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Hypertension was defined using the WHO/ISH criteria of SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg, or clinical diagnosis of hypertension, or prescription of any hypertensive drug. Prehypertension was defined as SBP ≥ 120 mmHg and/or DBP ≥ 80 mmHg. This study was conducted with adherence to ethical standards. Ethical approval was obtained from the ethics committee of Nnamadi Azikiwe Uiversity, Awka, Nigeria. The objectives and nature of the study were duly explained to the participants prior to the day of the test and interview. Informed consent in written form or by thumb print was obtained from all participants or parents. Strict confidentiality was maintained in accordance with standard medical practices.

Statistical analysis Comparison of means between the two groups was done using the independent t-test. Poisson regression models were used to examine the association between anthropometric indices and hypertension/prehypertension prevalence. The receiver operating characteristic (ROC) curve analysis was used to compare the performance of the anthropometric indices as potential predictors of the disease. The ROC curve is an analytical approach to define the highest combination of sensitivity and specificity of a screening test. The approach has been widely used to determine a cut-off point for decision making (e.g. having a disease or not) in both public health and clinical settings. Area under the curve (AUC) was used as a measure of predictive power. It is the most common measurement to quantify the performance of a screening test, and shows the ability of a test to correctly classify those with and without the disease. For example, an AUC of 0.75 indicates that 75% of the time, a randomly selected individual from the diseased group has a test value larger than that for a randomly selected individual from the non-diseased group. AUC values range from 0.5 (no prediction) to 1.0 (perfect prediction). AUC values are usually used as criteria to compare overall performance of different screening tests. In this study, AUCs for models were estimated using logistic regression models. To determine if the inclusion of WC, WHtR or PI improved the prediction of hypertension using BMI, we estimated the change in gender-specific prevalence ratio (from Poisson

Table 2. Mean (SEM) values of the anthropometric indices categorised by gender and hypertension status Male

Female

Normal (n = 142)

Prehypertensive (n = 198)

Hypertensive (n = 96)

Normal (n = 174)

Prehypertensive (n = 192)

Hypertensive (n = 112)

SBP, n (%)

104.44 ( 6.51)

121.29 (7.94)

145.13 (16.36)

104.44 (6.51)

121.54 (7.48)

145.68 (15.95)

0.749

DBP, n (%)

68.41 (6.02)

77.79 (5.39)

96.05 (8.98)

68.41 (6.02)

78.37 (5.94)

93.42 (11.32)

0.8795

Weight, n (%)

66.30 (9.10)

72.28 (11.13)

77.97 (14.09)

64.72 (11.11)

69.45 (11.86)

72.98 (15.55)

0.0000

Height, n (%)

169.11 (7.69)

169.74 (7.25)

170.58 (7.48)

162.20 (7.34)

162.50 (7.07)

162.65 (7.14)

0.0000

WC, n (%)

83.48 (8.03)

87.99 (8.16)

93.64 (11.86)

86.32 (10.66)

90.39 (12.71)

93.40 (11.86)

0.0117

HC, n (%)

93.56 (9.12)

97.58 (8.70)

101.73 (12.73)

98.08 (12.76)

101.09 (12.89)

103.58 (13.23)

0.0000

WHR, n (%)

0.89 (0.067)

0.90 (0.04)

0.92 (0.04)

0.88 (0.07)

0.90 (0.06)

0.90 (0.05)

0.0028

WHtR, n (%)

0.49 (0.044)

0.55 (0.067)

0.22 (0.03)

0.21 (0.03)

0.22 (0 .03)

0.23 (0.03)

0.0000

PI, n (%)

13.75 (1.96)

14.85 (2.49)

15.69 (2.37)

15.17 (2.33)

16.28 (3.07)

16.94 (3.28)

0.0000

BAI, n (%)

24.57 (3.91)

26.24 (4.56)

27.68 (5.33)

29.54 (5.96)

30.96 (6.97)

31.99 (6.19)

0.0000

BMI, n (%)

23.18 ( 2.90)

25.12 (3.78)

26.72 (3.95)

24.55 (3.57)

26.34 (4.43)

27.51 (5.22)

0.0001

1.23 (0.11)

1.24 (0.09)

1.28 (0.13)

1.25 (0.10)

1.27 (0.13)

1.29 (0.10)

0.0007

CI, n (%)

p-value

SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; HC, hip circumference; WHR, waist–hip ratio; WHtR, waist–height ratio; PI, ponderal index; BAI, body adiposity index; BMI, body mass index; CI, conicity index.

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Table 3. Correlation between blood pressure, age and anthropometric variables SBP (r)

p-value

DBP (r)

p-value

0.18

0.03

0.0000

0.12

0.01

0.0004

BAI BMI

0.33

0.11

0.0000

0.29

0.08

0.0000

WHtR

0.25

0.06

0.0000

0.21

0.04

0.0000

WHR

0.15

0.02

0.0000

0.19

0.04

0.0000

0.27

0.07

0.0000

0.25

0.06

0.0000

0.27

0.07

0.0000

0.22

0.05

0.0000

0.24

0.06

0.0000

0.16

0.02

0.0000

0.105

0.01

0.0014

0.08

0.01

0.0410

SBP, systolic blood pressure; DBP, diastolic blood pressure; BAI, body adiposity index; BMI, body mass index; WHtR, waist–height ratio; WHR, waist–hip ratio; PI, ponderal index; WC, waist circumference; HC, hip circumference; CI, conicity index.

regression models) and gender-specific AUC (from logistic regression models) between a model with BMI + WC, BMI + PI or BMI + WHtR to a model with BMI alone, as described by Tuan et al.28 A change in prevalence ratio or AUC of ≥ 10% was used as the criterion for a significant contribution of WC, PI, or WHtR to the prediction of hypertension using BMI. This criterion of ≥ 10% was adopted as it is commonly used to determine a notable confounding factor.26 Data analysis was conducted using Stata and MedCalc statistical packages. Model 1 was crude while model 2 was adjusted for factors, such as age, smoking, alcohol consumption and physical activity.

Results A total of 912 individuals aged 17 years and older from the three major cities participated and provided informed consent for the study; 32.89% of the respondents were from Awka, 33% from Onitsha and 34.10% from Nnewi. The overall crude prevalence of hypertension and prehypertension in the study population was 22.81 and 42.54%, respectively. Tables 1 and 2 show the general characteristics of our study population. The mean values of all the anthropometric indices analysed were significantly higher in the women, with the exception of weight, height and WHR, when compared to the men. The mean values of all anthropometric indices studied also increased from normotensive participants, through prehypertensive subjects and peaked in the hypertensive participants in both male and female categories, with hypertension showing the highest mean values for all anthropometric indices studied. Table 3 presents the results of the correlation between the anthropometric indices with blood pressure. All anthropometric indices correlated significantly with systolic and diastolic blood pressure. BMI had the highest correlation coefficient, while CI had the lowest. Table 4 lists the results of the predictive potentials of each individual anthropometric index in discriminating between hypertension and normotension, and between prehypertension and normotension. For hypertension, BMI, WHtR and WC had the strongest/highest predictive potential in both the male and female categories (WHtR was slightly higher). BMI and WHtR also performed relatively well in all age categories except for age category 2 (21–25 years) for BMI, and age categories 1 and 2 (≤ 20 years and 21–25 years) for WHtR. PI also showed a strong predictive power (AUC) in this regard but was lower than that

Table 4. Analysis of the predictive power of each index for hypertension and prehypertension Anthropometric Hypertension Prehypertenmeasures AUC p-value sion AUC p-value BAI# Age category 1 0.535 0.8185 0.542 0.5523 2 0.534 0.5274 0.525 0.4775 3 0.583 0.0229 0.500 0.9964 4 0.626 0.0034* 0.613 0.0642 BAI# Gender Male 0.625 0.0002* 0.581 0.0009* Female 0.594 0.0019* 0.564 0.0329* BMI Age category 1 0.727 0.0001* 0.563 0.3575 2 0.542 0.4923 0.571 0.0399* 3 0.686 0.0001* 0.622 0.0008* 4 0.589 0.0434* 0.674 0.0133* BMI Gender Male 0.698 0.0001* 0.659 0.0001* Female 0.622 0.0001* 0.609 0.0002* WHtR Age category 1 0.511 0.9172 0.559 0.3915 2 0.556 0.2618 0.515 0.6764 3 0.631 0.0002* 0.560 0.1080 4 0.601 0.0209* 0.615 0.1408 WHtR Gender Male 0.682 0.0001* 0.636 0.0001* Female 0.624 0.0001* 0.572 0.0163* WHR# Age category 1 0.623 0.3645 0.614 0.0839 2 0.502 0.9693 0.501 0.9817 3 0.643 0.0001* 0.619 0.0012* 4 0.525 0.5685 0.662 0.0876* WHR# Gender Male 0.645 0.0001* 0.562 0.0531* Female 0.570 0.0208* 0.554 0.0753* WC Age category 1 0.508 0.9433 0.591 0.1634 2 0.550 0.3858 0.556 0.1038 3 0.607 0.0031* 0.551 0.1645 4 0.542 0.3421 0.580 0.3115 WC Gender Male 0.692 0.0001* 0.645 0.0001* Female 0.616 0.0001* 0.584 0.0046* PI# Age category 1 0.680 0.0008* 0.652 0.0223* 2 0.525 0.6617 0.547 0.1818 3 0.679 0.0001* 0.607 0.0043* 4 0.642 0.0008* 0.670 0.0132* PI# Gender Male 0.670 0.0001* 0.639 0.0001* Female 0.619 0.0001* 0.599 0.0008* HC# Age category 1 0.530 0.8371 0.649 0.0193* 2 0.552 0.3242 0.543 0.2095 3 0.565 0.0866 0.507 0.8576 4 0.535 0.4372 0.567 0.3003 HC# Gender Male 0.646 0.0001* 0.602 0.0008* Female 0.592 0.0036* 0.584 0.005* CI# Age category 1 0.618 0.2350 0.556 0.3980 2 0.503 0.950 0.520 0.5602 3 0.527 0.4571 0.520 0.5915 4 0.539 0.3878 0.541 0.6106 CI# Gender Male 0.592 0.0082* 0.541 0.2032 Female 0.558 0.0528 0.533 0.2773 *Statistically significant at p < 0.05; #AUC significantly different from that of BMI. Age category 1 = ≤ 20 years, 2 = 21–25 years, 3 = 26–40 years, 4 = ≥ 41 years. BAI, body adiposity index; BMI, body mass index; WHtR, waist–height ratio; WHR, waist–hip ratio; WC, waist circumference; PI, ponderal index; HC, hip circumference; CI, conicity index.

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Table 7. Gender-specific prevalence ratios and AUCs of BMI for hypertension

Table 5. Prevalence ratios corresponding to one standard deviation increase in anthropometric measures Anthropometric index

Hypertension

Prehypertension

95% CI

p-value

95% CI

p-value

1.44

1.3–1.56

0.000

1.15

1.08–1.22

0.000

Model 1 WHtR

Male

95% CI

% PR p-value change

AUC

% AUC change p-value

Model 1 BMI

1.10

1.07–1.14

0.000

–

0.6978

–

1.0–1.10

0.206

6.56

0.7103

1.78

0.0011

1.41

1.28–1.56

0.000

1.2

1.13–1.27

0.000

BMI + WHtR 1.03

BMI

1.35

1.24–1.47

0.000

1.21

1.15–1.27

0.000

BMI + WC

1.02

0.97–1.08

0.341

7.55

0.7104

1.79

0.0000

1.32

1.21–1.44

0.000

1.17

1.11–1.23

0.000

BMI + PI

1.26

1.09–1.45

0.002

13.58

0.6963

0.22

0.0258

Model 2

Model 2 WHtR

1.15

1.01–1.30

0.030

1.04

0.97–1.11

0.258

1.06

1.02–1.10

0.002

0.8301

0.00

1.15

1.03–1.29

0.017

1.11

1.03–1.19

0.002

BMI + WHtR 1.04

0.99–1.09

0.142

1.90

0.8319

0.22

0.1850

BMI

1.14

1.01–1.27

0.028

1.11

1.04–1.10

0.001

BMI + WC

1.03

0.98–1.08

0.302

2.87

0.8373

0.86

0.0206

1.12

0.99–1.27

0.063

1.067 1.00–1.14

0.038

BMI + PI

1.17

1.01–1.36

0.037

9.87

0.8399

1.17

0.0381

PR, prevalence ratio; WHtR, waist–height ratio; WC, waist circumference; BMI, body mass index; PI, ponderal index. Model 1 was crude while model 2 was adjusted for factors such as age, smoking, alcohol consumption and physical activity.

of BMI (p < 0.05), WHtR and WC. There was no significant difference between the AUC of BMI and that of WHtR and WC. The predictive powers of the four indices were higher in male than female participants. For prehypertension, BMI, WC, PI and WHtR had higher predictive potentials for both genders, with BMI showing slightly higher power among the four indices. BMI and PI seemed to perform better in virtually all age groups than the other two indices. Table 5 examined the possible linear relationship between the four best anthropometric indices and hypertension and prehypertension prevalence (risk). The anthropometric indices were considered as continuous variables to calculate prevalence ratios corresponding to one standard deviation change. The hypertension prevalence ratio increased by 15% (WHtR), 15% (WC), 14% (BMI) and 12% (PI) with one standard Table 6. Cut-off points for anthropometric indices in predicting hypertension and prehypertension Hypertension Male

Female

Prehypertension Male

Female

BMI Cut-off point

24.49

24.44

23.62

28.01

Sensitivity

72.92

74.11

64.65

31.05

Specificity

48.9

64.79

58.51

0.29

0.20

Youden index J

0.33

0.20

WHtR 0.50

0.60

Sensitivity

Cut-off point

48.96

81.25

58.59

25.79

Specificity

40.38

61.97

93.68

0.22

0.21

0.2

Youden index J

0.55

0.33

0.508

WC Cut-off point

91.44

96.52

82.55

96.52

Sensitivity

53.13

40.18

71.21

32.11

Specificity

81.47

76.65

50.7

86.21

0.35

0.17

Youden index J

0.22

0.18

PI Cut-off point

14.45

16.38

13.69

17.65

Sensitivity

70.83

57.65

71.21

28.42

Specificity

57.65

67.3

57.75

87.36

0.30

0.16

Youden index J

0.28

0.24

BMI, body mass index; WHtR, waist–height ratio; WC, waist circumference; PI, ponderal index.

BMI

Female Model 1 BMI

1.07

1.04–1.10

0.000

BMI + WHtR 1.05

1.01–1.10

0.023

1.89

0.6221 0.6238

0.27

0.4532

BMI + WC

1.06

1.0–1.09

0.034

0.94

0.6245

0.39

0.2316

BMI + PI

1.14

1.01–1.29

0.027

6.34

0.6202

0.31

0.2527

Model 2 1.01

0.98–1.05

0.400

BMI + WHtR 1.02

BMI

0.98–1.07

0.359

0.99

0.7468 0.7477

0.12

0.6346

BMI + WC

1.02

0.97–1.06

0.450

0.99

0.7465

0.04

0.8587

BMI + PI

1.04

0.94–1.16

0.437

2.93

0.7474

0.08

0.5754

PR, prevalence ratio; BMI, body mass index; WHtR, waist–height ratio; WC, waist circumference; PI, ponderal index. Model 1 was crude while model 2 was adjusted for factors such as age, gender, smoking, alcohol consumption and physical activity. % change in PR = 100 × absolute [ln (PRBMI/PRtest variables)]; test variables were BMI + WC, BMI + WHtR, or BMI + PI.28 % change in AUC = 100 × absolute [ln (AUCBMI/AUCtest variables)]; test variables were BMI + WC, BMI + WHtR, or BMI + PI.28

deviation increase in the corresponding anthropometric index on adjusting for gender, age, alcohol intake and physical activity; the prehypertension prevalence ratio increased by 4% (WHtR), 11% (WC),11% (BMI) and 6.7% (PI). Table 6 lists the cut-off points and Youden index J for the four best anthropometric indices in predicting hypertension and prehypertension. The best Youden index J was recorded in BMI and WHtR for all categories but this was not strikingly distinct. The effect of other anthropometric indices on BMI prevalence ratio, as well as its hypertension predictive power is shown in Table 7. On average, each unit increase in BMI was associated with a 26 and 14% increase in prevalence ratio for hypertension in the male and female categories, respectively (model 1 p > 0.05 in most cases). There was about a 17 and 4% increase in prevalence ratio associated with one unit increase in BMI in model 2 in males (p < 0.05) and females (p > 0.05), respectively. The combination of WC, WHtR and PI did not change the prevalence ratio beyond 10%, except for PI, which gave percentage changes of 13.58 and 9.87% for model 1 and 2, respectively in males. The changes due to the addition of WC and WHtR were generally decremental, while that of PI was incremental. On average, the changes in PR were higher in model 1 compared to model 2. There was an increase in model fit (AUC) when WC, WHtR or PI were used in model 1 and 2, except for PI in model 1, which resulted in a slight decrease in AUC when compared with BMI only. However, none of the percentage changes in the AUCs of each model was < 2% (p < 0.05 in almost all models for males and > 0.05 in all models for females.)

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Discussion To our knowledge, this study is the first to comprehensively compare the performance of a large set of anthropometric indices as correlates and potential predictors of risk for hypertension and prehypertension in a typical Nigerian (West African) population. We analysed the performance of some anthropometric indices of obesity as potential predictors of hypertension and prehypertension. The mean values of the following anthropometric measures, BMI, WC, HC, CI and BAI were significantly higher in women. This could have been attributed to the general inactivity of women in this population. The mean values of all the anthropometric indices studied were higher in the prehypertensive and highest in the hypertensive participants relative to the normotensive participants. This is an indication that participants with a higher obesity index tend to have high blood pressure values. This finding is consistent with reports from previous studies.5,8,26 The correlation analysis showed that all the studied anthroprometric indices were correlated with SBP and DBP. BMI, WC, PI and WHtR had correlation coefficients greater than 0.25, while BAI and CI correlated poorly with blood pressure. Our results also showed BMI, WC, WHtR and PI performed best as potential predictors of the risk for hypertension on comparing respective AUCs from ROC curve analysis. The prevalence ratios for general obesity index were lower than that of central obesity in both the crude and adjusted models, however these differences were not large enough to suggest that central obesity index (WC or WhtR) outperformed general obesity index (BMI) in this study. There was no significant difference between the performances of BMI, WC and WHtR in predicting risk for hypertension. A similar finding was reported previously by Lee and co-workers.10 BAI and HC showed a fair performance in predicting hypertension and prehypertension risk. CI had a poor predictive power for hypertension and totally lacked the capacity to distinguish prehypertensive cases from normotensive cases. The results of the ROC and correlation analyses were consistent and showed similar trends. Anthropometric indices (BMI, WC, WHtR and PI), which had higher correlation coefficients with blood pressure (SBP and DBP), had very high AUCs that were statistically significant (p < 0.05). The reverse was true for poorly correlated anthropometric indices such as BAI, WHR and CI. CI was the poorest correlate of hypertension and prehypertension (AUC = 0.5, p > 0.05). BMI, WHtR and WC emerged the best predictors of hypertension and prehypertension in this study. These findings conform with and confirm the findings of Silva et al.27 in Brazillian women and men, Sanchez-Viveros et al.28 in Mexican women and men, and Uhernik et al.29 in Croatian men and women. They differ from those of Feldstein et al.18 in Argentina and Li et al.19 in Australia where none of BMI, WC or WHtR emerged as the best predictors of hypertension or prehypertension. These results also provide evidence to support the findings that suggested the superiority of WC and BMI over BAI.30 As mentioned above, epidemiological studies on the predictive potentials of anthropometric indices for hypertension and cardiovascular-related diseases are limited in Nigeria. Okafor et al.23 reported WC was a better predictor of obesity and hypertension than WHR in a population with similar characteristics to

our study population, while Sonuyi and co-workers31 reported normative values of selected anthropometric variables in Lagos, Nigeria. Both findings were consistent with our results. The differences in the results of some of the previous studies mentioned could have been attributed to differences in the characteristics of the populations. Evidence of racial/ethnic, gender and age variations in anthropometry is well established.32 Sakurai et al.3 reported that the percentage body fat in Asians, as measured by dual-energy X-ray absorptiometry is greater than in African Americans and whites with a similar BMI. Variations in the level of leptin (the product of the gene largely responsible for obesity) across different ethnic groups and races is also well established.33 Human body composition is evidently a result of complex multifactorial interactions between lifestyle, culture, environmental and genetic differences,33 which vary from place to place and impact differently on the results of studies in different populations. Secondly, rigours, technicalities and lack of universally accepted standards in measuring some anthropometric measures could account for some of the reported differences in different studies.34 Our study also provided evidence to suggest that the predictive potential of anthropometric indices may vary with age. BMI, PI and WHtR performed well in predicting risk for hypertension and prehypertension in three age categories (≤ 20, 26–40 and ≥ 40 years), while BAI was better in one age category (≥ 40 years). HC and CI were not particularly outstanding in any of the age categories. This differential performance in different age categories could also account for the variations in the results from different studies. Our predicted cut-off points for some of the anthropometric predictors of hypertension were somewhat similar to that proposed by the WHO and other studies8,10,11,35 in Korean, Brazilian and Pakistani populations, respectively. However, the cut-off points for WC and WHtR were higher in our study when compared to the WHO cut-off value. This could be attributed to the higher WC and lower height of females in the population. Africans and Westerners have quite distinct anthropometry occasioned by differences in culture, environment, genetics, nutrition as well as economy. Most of the recommended cut-off points are more representative of Western populations. The cut-off points for the anthropometric indices in our study differed markedly in women for prehypertension; the predicted cut-off points were higher in women and lower in men. The performance of the anthropometric indices in predicting both conditions differed by gender in this study. All the indices studied tended to predict risk for hypertension and prehypertension better in males than in females. These differences have also been corroborated by previous independent studies.3,7,36 There is evidence that fat distribution in men and women differs. Visceral fat is more dominant in men and subcutaneous fat in women. This may provide an explanation for the existence of gender differences in the performance of anthropometric indices. Visceral fat has a stronger association with metabolic abnormalities than subcutaneous fat,3 and this could also explain why we found a higher risk for hypertension with regard to obesity in males than females in this study. Our study presents evidence that the relationship between obesity and the two conditions, hypertension and prehypertension, differed in terms of the performance of anthropometric indices. This is to be expected as prehypertension has been described by JNC-7 as a new category of hypertension with high risk for the

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development of clinical hypertension.37 Most physicians describe it as a pre-sign to clinical hypertension. However, it has also been established that it presents a high risk for cardiovascular and coronary heart disease, even without the development of clinical hypertension and should be given adequate interventional attention by promoting early lifestyle modification to prevent progression to blood pressure or other related chronic diseases. Prehypertension, unlike hypertension, is most often without symptoms, but both conditions have been shown to share similar risk factors, such as age, overweight, obesity and hyperlipidaemia, but to different extents. The odds of the risk factors are usually higher in hypertension than in prehypertension. The association of higher cardiac and haemodynamic characteristics with hypertension and prehypertension has also shown similar trends.38 These minor differences may explain the differences in predictive potentials of some anthropometric indices for hypertension and prehypertension. Lee and Kim in their studies suggested the use of combined anthropometric indices in models to improve the predictive potential for hypertension or related diseases. Our study shows WC and WHtR added to the prediction of hypertension using BMI when included in a model, however, this contribution was not statistically significant using our decision rule. The association of WHtR, WC and BMI with hypertension prevalence rate was statistically significant and similar in magnitude on adjusting for age, gender, physical activity and alcohol intake, but differed for prehypertension. WC and BMI had a stronger (significant p < 0.05) association with prehypertension relative to PI and WHtR (p > 0.05). This was consistent with the ROC curve analysis result. This reinforces the fact that BMI, WHtR and WC were equally good indicators of hypertension in this population; none significantly outperformed the other. Overall, the mechanism of association of general obesity (BMI and PI) with hypertension may differ from that of central obesity (WHtR and WC) with hypertension. As mentioned, the changes due to the addition of WC and WHtR were generally decremental, while that of PI was incremental when WC, WHtR or PI was included in a model with BMI. This is to be expected as WC and WHtR were strongly correlated (τ = 0.95; p < 0.0001) and BMI and PI were also correlated (τ = 0.98; p < 0.0001). The correlation between BMI, WC and WHtR (τ = 0.60, τ = 0.64 respectively) was equally strong. The normalisation of BMI by a factor of 1/height (m) to give PI did not improve the predictive power of BMI, as traditional BMI outperformed PI in this study.

Despite these limitations, the study has some strengths. The study population was large and typical of an African population, where there has been dearth of data of this sort. The anthropometric and blood pressure measures were standardised.

Conclusion This study showed BMI, WC, WHtR and PI were strongly associated with blood pressure and were better potential predictors of risk for hypertension and prehypertension than the other indices tested. They performed well independently and there was no evidence to show that WC, WHtR or PI outperformed or statistically added to the prediction power of BMI. Their prediction potentials were better in the male gender and in predicting risk for hypertension than for prehypertension. In practice, these anthropometric measures are surrogate measures of body fat and are cost free, practical and easy to interpret for healthcare providers and lay people.39 In the context of developing countries, indices of obesity (both general and abdominal) could be used simultaneously but independently to predict risk for both conditions, since they both performed well and possibly define different mechanisms of the association of obesity with hypertension and other cardiovascular disorders.

References 1.

Ekwunife OI., Udeogaranya, PO, Nwatu IL. Prevalence, awareness, treatment and control of hypertension in a Nigerian population. Health 2010; 2: 731–735.

Mohammad NAA. Anthropometric measurements are simple predictors for metabolic syndrome. E-Int Sci Res J 2011; 3(4): 320–325.

Sakurai M, Miura K, Takamura T, Ota T, Ishizaki M, Morikawa Y, et al. Gender differences in the association between anthropometric indices of obesity and blood pressure in Japanese Hypertens Res 2006; 29(2): 75–80.

Ishikawa-Takata K, Ohta T, Moritaki K, Gotou T, Inoue S. Obesity, weight change and risk for hypertension, diabetes and hypercholesterolemia in Japanese men. Eur J Clin Nutr 2002; 56(7): 601–607.

Cassani RSL, Nobre F, Filho AP, Schmidt A. Relationship Between blood pressure and Anthropometry in a cohort of Brazilian man: A cross-sectional study. Am J Hypertens 2009; 22(9): 1–5.

Duren DL, Sherwood RJ, Czerwinski SA, Lee M, Choh AC, Srervogel RM, et al. Body composition methods: comparisons and interpretation. J Diabetes Sci Technol 2008; 2(6): 1139–1146

Lee ZB, Kim ZY. A comparison of the predictive power of anthropometric indices for hypertensive and hypotension risk. PLOS One 2014;

Limitations The limitations of the present study include: firstly, the cross sectional nature of the study precludes conclusion about a cause–effect relationship. A longitudinal study in this regard is required; secondly, our study population was drawn from a particular religious group in a state in south-eastern Nigeria. This may not be a true representation of the Anambra state population and therefore limits the application of our findings to other populations. However, it is noteworthy that the population not captured represented a negligible proportion of the major population. Thirdly, our overall sample size was large but on categorisation by age group, some age groups had small sample sizes, which may have limited our statistical power to detect better performance in some age categories.

AFRICA

9(1): 1–11. 8.

Kashyap K. Comparative evaluation and correlation of different anthropometric indices with blood pressure in adult populations. Int J Basic Appl Physiol 2012; 1(1): 36–41.

Chuang Y-C, Wang M-H, Huang D-H, Yang C-H, Lin J-D. To construct a forecasting model of the anthropometric chronic disease risk factor score. Chang Gung Med J 2006; 29(2): 135–142.

10. Lee J-W, Lim N-K, Back T-H, Park S-H, Park H-Y. Anthropometric indices as predictors of hypertension among men and women aged 40–69 years in the Korean population: the Korean Genome and Epidemiology Study BMC Public Health 2015; 15: 140–146. 11. Tostade Almeida R, Guimaraes de Almerda MM, Araujo TM. Abdominal obesity and cardiovascular risk: performance of anthropometric indexes in women. Arq Bras Cardiol 2009; 2(5): 345–350.

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12. Xu F, Wang YF, Lu LG, Liang Y, Wang ZY, Hong X, et al. Comparison of anthropometric indices of obesity in predicting subsequent risk of hyperglycemia among Chinese men and women in mainland China. Asia Pac J Clin Nutr 2010; 19(4): 586–593. 13. Fuchs FD, Gus M, Morera LB, Moraes RS, Wiehe M, Pereira GM, et al. Anthropometric indices and the incidence of hypertension: A comparative analysis. Obesity Res 2005; 13(9): 1515–1517. 14. Rodrigues Barbosa A, Balduino Munaretti D, Da Silva Coqueiro R, Ferreti Borgatto A. Anthropometric indexes of obesity and hypertension in elderly from Cuba and Barbados. J Nutr Health Aging 2011; 15: 17–21. 15. Panagiotakos DB, Chrysohoou C, Pitsavos C, Skoumas J, Lentzas Y, et al. Hierarchical analysis of anthropometric indices in the prediction of 5-year incidence of hypertension in apparently healthy adults: the ATTICA study. Atherosclerosis 2009; 209: 314–320. 16. Tseng CH, Chong CK, Chan TT, Bai CH, You SL, et al. Optimal

25. Aronne LJ. Classification of obesity and assessment of obesity related health risks. Obesity Res 2002; 10(2): 1055–1155. 26. Tuan NT, Adair LS, Stevens J, Popkin BM. Prediction of hypertension by different anthropometric indices in adults: The change in estimate approach. Public Health Nutr 2010; 13(5): 639–646. 27. Silva DA, Petroski EL, Peres MA. Accuracy and measures of association of anthropometric indexes of obesity to identify the presence of hypertension in adults: a population-based study in southern Brazil. Eur J Nutr 2013; 52: 237–246. 28. Sanchez-Viveros S, Barquera S, Medina-Solis CE, Velzquez-Alva MC, Valdez R. Association between diabetes mellitus and hypertension with anthropometric indicators in older adults: results of the Mexican Health Survey, 2000. J Nutr Health Aging 2008; 12: 327–333. 29. Uhernik AI, Milanovic SM. Anthropometric indices of obesity and hypertension in different age and gender groups of Croatian population. Coll Antropol 2009; 33: 75–80.

anthropometric factor cutoffs for hyperglycemia, hypertension and

30. Yu Y, Wang L, Liu H, Zhang S, Walker SO, Bartell T, et al. Body mass

dyslipidemia for the Taiwanese population. Atherosclerosis 2010; 210:

index and waist circumference rather than body adiposity are surrogates

585–589.

for body adiposity in a Chinese population. Nutr Clin Pract 2015; 30(2):

17. Park SH, Choi SJ, Lee KS, Park HY. Waist circumference and waistto-height ratio as predictors of cardiovascular disease risk in Korean adults. Circ J 2009; 73: 1643–1650. 18. Feldstein CA, Akopian M, Olivieri AO, Kramer AP, Nasi M, et al. A

274–282 31. Sonuyi AO, Akinpelu AO, Odole AC, Akinbo SRA. Normative values of selected anthropometric variables in Lagos Nigerian population. Orthop Muscul Syst 2013; 2(3): 1–4.

comparison of body mass index and waist-to-hip ratio as indicators of

32. Lutsey PL, Pereira MA, Bertoni AG, Kandula NR, Jacobs DR.

hypertension risk in an urban Argentine population: a hospital-based

Interactions between race/ethnicity and anthropometry in risk of inci-

study. Nutr Metab Cardiovasc Dis 2005; 15: 310–315. 19. Li M, McDermott RA. Using anthropometric indices to predict cardiometabolic risk factors in Australian indigenous populations. Diabetes Res Clin Pract 2010; 87: 401–406. 20. Perissinotto E, Pisent C, Sergi G, Grigoletto F. Anthropometric measurements in the elderly: age and gender differences. Br J Nutr 2002; 87: 177–186. 21. Kotian GB, Kedilaya PH. BMI is the best index to predict cardiovascular disease risk in young adult females. Int J Pharm Sci Rev Res 2013; 22(1): 188–191 22. Okereke CE, Anyaehie UB, Dim CC, Iyare EE, Nwagha UI. Evaluation of some anthropometric indices for the diagnosis of obesity in pregnancy in Nigeria: A cross sectional study. Afr Health Sci 2013; 13(4): 1034–1040.

dent diabetes. Am J Epidemiol 2010; 172: 197–204. 33. Wanger DR, Heyward VH. Measures of body composition in blacks and whites: a comparative review. Am J Clin Nutr 2000; 71: 1392–1402. 34. Goh LGH, Dhaliwal SS, Welborn TA, Lee AH, Della PR. Ethnicity and association between anthropometric indices of obesity and cardiovascular risk in women: a cross sectional study. Br Med J Open 2014; 4: 1–8. 35. Nadeem A, Naveed AK, Hussain MM, Raza SI. Cut-off values of anthropometric indices to determine insulin resistance in Pakistani adults. J Pak Med Assoc 2013; 63: 1220–1225. 36. Lee BJ, Kim ZY. Identification of the best anthropometric predictors of serum high- and low-density lipoproteins using machine learning. IEEE J Biomed Health Inf 2015; 19(5): 1747–1756. 37. Yadav S, Boddula R, Genitta G, Bhatia V, Bansal B, Kongara S, et al. Prevalence and risk factors of prehypertension and hypertension in an

23. Okafor CI, Fasanmade O, Ofoegbu E, Ohwovoriole AE. Comparison of

affluent north Indian population. Indian J Med Res 2008; 128: 712–720.

the performance of two measures of central adiposity among apparently

38. Drukteinis JS, Roman MJ, Fabsitz RR, Lee ET, Best LG, Russel M, et

healthy Nigerians using the receiver operating characteristic analysis.

al. Cardiac and systemic haemodynamic characteristics of hypertension

Indian J Endocrinol Metab 2011; 15(4): 320–326.

and prehypertension in adolescent and young adults: The Strong Heart

24. Ogah OS, Okechi I, Chukwuonye I, Akinyemi JO, Onwubere BJ, Falase

Study. Circulation 2007; 115: 221–227.

AO, et al. Blood pressure, prevalence of hypertension and hypertension

39. Can AS. Body mass index, waist-to-height ratio, cardiometabolic risk

related complications in Nigerian Africans: A review. World J Cardiol

factors and diseases in a new obesity classification proposal. Open

2012; 4(12): 327–346.

Obesity J 2011; 3: 56–61.

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Chicken or the egg: ST elevation in lead aVR or SYNTAX score Levent Cerit

Abstract Background: ST-segment elevation in lead aVR (STEaVR) anticipates left main and/or three-vessel disease (LM/3VD) in patients with acute coronary syndromes. STEaVR is generally reciprocal to and accompanied by ST-segment depression (STD) in the precordial leads. SYNTAX score (SS) is an angiographic scoring system and is widely used to evaluate the severity and complexity of coronary artery disease. The purpose of our study was to assess the relationship between STEaVR and SS. Methods: We performed a retrospective analysis of 117 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Electrocardiograms at presentation were reviewed, especially for ST-segment elevation of ≥ 0.05 mV in lead aVR and STD of ≥ 0.05 mV in more than two contiguous leads. All lesions causing ≥ 50% stenosis in a coronary artery with a diameter of ≥ 1.5 mm were included in the SS calculation. SS was divided into two groups: ≥ 23: high, < 23: low. Results: Among the 117 patients, 80 (68.4%) had STEaVR and 37 (31.6%) did not. Patients with STEaVR had a higher SS and higher rate of LM/3VD (85 vs 67.6%, p < 0.001; 86.2 vs 72.9%, p = 0.03, respectively) than those without STEaVR. On multivariate analysis, STEaVR [odds ratio (OR) 1.85; 95% confidence interval (CI): 1.20–3.97, p = 0.03] and STD in leads V1–V4 (OR 2.14; 95% CI: 1.46–4.23, p = 0.002) were independent predictors of a high SS. Conclusion: This study demonstrated that STEaVR was an independent predictor of a high SS. Keywords: SYNTAX score, electrocardiography, lead aVR Submitted 18/3/16, accepted 12/5/16 Published online 8/6/16 Cardiovasc J Afr 2017; 28: 100–103

www.cvja.co.za

DOI: 10.5830/CVJA-2016-062

Previous studies have shown the independent predictive value of ST-segment elevation in lead aVR (STEaVR) for left main and/ or three-vessel disease (LM/3VD) in non-ST-segment elevation acute coronary syndrome (NSTEACS).1,2 STEaVR is generally reciprocal to and accompanied by ST-segment depression (STD) in the precordial leads. Patients with acute coronary syndrome resulting from LM/3VD are at high risk of short- and long-term adverse cardiovascular events.3-5 Previous studies have assessed

Near East University Hospital, Nicosia, Cyprus Levent Cerit, MD, drcerit@hotmail.com

the independent predictive value of STEaVR for LM/3VD in NSTEACS and have reported conflicting results.1,2 SYNTAX score (SS) is a recently developed angiographic grading tool to evaluate the complexity of coronary artery disease. It is widely used for determining the optimal revascularisation strategy. It is also a powerful stratification mechanism, allowing uniform, standardised assessment of the extent and severity of coronary artery disease.6 The purpose of this study was to assess the relationship between STEaVR and SS in patients with NSTEACS.

Methods A retrospective analysis was performed on all patients who had undergone coronary angiography and coronary artery bypass grafting (CABG) between January 2013 and January 2016 at the Near East University Hospital. Myocardial infarction (MI) was diagnosed according to the criteria of the European Society of Cardiology and American College of Cardiology.7 Inclusion criteria for the study were troponin level greater than the 99th percentile reference value before cardiac catheterisation, chest pain or ischaemic changes on the electrocardiogram (ECG), including horizontal or down-sloping STD (≥ 0.05 mV), and absence of ST-segment elevation on the ECG. Exclusion criteria were previous CABG, bundle branch block or ventricular pace rhythm, severe aortic stenosis, hypertrophic cardiomyopathy, cardiac arrest on presentation, ventricular tachycardia, supraventricular tachycardia with heart rate greater than 160 beats per min, implantable cardioverter defibrillator shock, subsequent documented diagnosis of Takotsubo cardiomyopathy, myocarditis or pulmonary embolism. The study was approved by the local ethics committee. Patients’ demographic data and risk factors, including current smoking, diabetes mellitus (DM), hypertension (HT), hyperlipidaemia, previous MI, and previous percutaneous coronary intervention were obtained from medical records. Cardiac troponin T (cTnT) levels were measured using the electrochemiluminescence immunoassay method (Roche Cobas E601). The upper limit of normal for cTnT was 0.014 ng/ml, which represented the 99th percentile reference value. cTnT was measured serially at intervals of approximately four hours, both before and after catheterisation as clinically indicated, with the highest level noted as the peak cTnT. Two independent, blinded physicians reviewed ECGs obtained at presentation. In the event of an interpretative discrepancy, a consensus between reviewers was reached through discussion. ST-segment shifts were measured at the J point for ST-segment elevation and depression. STD of ≥ 0.05 mV in more than two contiguous leads was recorded. A cut-off value of ≥ 0.05 mV for STD was chosen, in line with the current universal definition of MI.8 The location of STD was recorded as the anterior (V1–

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V4), lateral (I, aVL, V5 and V6) and inferior (II, III and aVF) region. STEaVR of ≥ 0.05 mV was recorded. Transthoracic echocardiography was performed in a standard manner during hospitalisation, and left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson’s method. All patients underwent cardiac catheterisation within five days of presentation with NSTEACS. All patients underwent CABG within two weeks of presentation with NSTEACS. An independent cardiologist blinded to the clinical data reviewed all coronary angiography results for the purposes of comparative assessment with the primary treating cardiologist.

Coronary angiography and SYNTAX score analysis Coronary angiography was performed by the Judkins technique. All lesions causing ≥ 50% stenosis in a coronary artery with a diameter of ≥ 1.5 mm were included in the SS calculation. For calculation, the website software (http://www.SYNTAXcore. com) was used. The score was calculated for each patient with regard to the following parameters: coronary dominance, number of lesions, segments included per lesion, the presence of total occlusion, bifurcation, trifurcation, aorto-osteal lesion, severe tortuosity, calcification, thrombus, diffuse/small-vessel disease, and lesion length > 20 mm. SS was calculated separately by two interventional cardiologists blinded to the study protocol and patient characteristics. In the case of a contradiction between two results, the opinion of a senior interventional cardiologist was applied and a common consensus was obtained. SS was divided into two groups: ≥ 23: high, < 23: low.

Statistical analysis Statistical analysis was performed using the SPSS (version 20.0, SPSS Inc, Chicago, Illinois) software package. Continuous variables are expressed as mean ± standard deviation (mean ± SD) and categorical variables are expressed as percentage (%). The Kolmogorov–Smirnov test was used to evaluate the distribution of variables. Student’s t-test was used to evaluate continuous variables showing a normal distribution, and the Mann–Whitney U-test was used to evaluate variables that did

101

Table 2. Univariate analysis of predictors for a high SYNTAX score OR (95% CI)

p-value

Age

2.723 (1.534–4.842)

< 0.001

Diabetes mellitus

1.246 (0.827–1.543)

0.54

Hypertension

1.14 (0.784–1.457)

0.37

Inferior ST-segment depression

1.924 (1.465–3.147)

< 0.001

Lateral ST-segment depression

2.416 (1.354–4.249)

< 0.001

Anterior ST-segment depression

2.160 (1.527–3.895)

< 0.001

ST-elevation in lead aVR

3.012 (1.974–4.243)

< 0.001

Predictor variables

not show a normal distribution. A p-value < 0.05 was considered statistically significant. To identify predictors of increased SS, the following variables were initially assessed in a univariate model: age, hypertension, diabetes, STD in anterior, lateral and inferior leads, and STEaVR. Significant variables in univariate analysis were then entered into a multivariate logistic regression analysis using backward stepwise selection.

Results A total of 117 patients who underwent coronary angiography within five days and CABG within two weeks of presentation with the diagnosis of NSTEACS were included in the analysis. Among the 117 patients, 80 (68.4%) had a STEaVR of ≥ 0.05 mV. The patients’ characteristics are summarised and presented in Table 1. Patients with STEaVR were older, with a higher peak cTnT value (Table 1). With regard to ECG findings, patients with a STEaVR were more likely to have concomitant STD. Among 80 patients with STEaVR, 68 presented with concomitant STD, comprising anterior (56 patients), lateral (62 patients) and inferior (45 patients) STD (Table 1). Patients with STaVR had a significantly higher rate of LM/3VD and higher SS than those without STEaVR (86.2 vs 72.9%, p = 0.03; 85 vs 67.6%, p < 0.001, respectively) (Table 1). The results of univariate analysis are presented in Table 2. On univariate analysis, age, HT, DM, ST-segment elevation in lead aVR and STD in the anterior, lateral and inferior leads were associated with a high SS (Table 2). On multivariate analysis STEaVR and STD in the anterior leads were independent predictors for a high SS (OR 2.12; 95% CI: 1.34–4.13, p < 0.001; OR 1.64; 95% CI: 1.24–2.86, p = 0.02, respectively) (Table 3).

Discussion

Table 1. General characteristics of the patients ST elevation in lead aVR

Patient characteristics

+ (n = 80) (68.4%)

– (n = 37) (31.6%)

p-value

Age, years

63.3 ± 7.4

59.4 ± 8.1

0.027

Male gender, n (%)

27 (73.0)

62 (77.5)

0.485

Hypertension, n (%)

24 (64.8)

51(63.7)

0.352

Our study showed that STEaVR and STD in the anterior leads were independently associated with a high SS and higher rates of LM/3VD in patients with NSTEACS. To our knowledge, this is the first study to evaluate STEaVR in patients with NSTEACS who underwent coronary angiography followed by CABG surgery.

Diabetes mellitus, n (%)

38 (47.5)

13 (35.1)

< 0.001

Current smoking, n (%)

33 (41.2)

14 (37.9)

0.754

SYNTAX score

27.4 ± 4.9

23.1 ± 5.4

0.002

High SYNTAX score ratio, n (%)

68 (86)

25 (67.6)

< 0.001

Inferior ST-segment depression, n (%)

45 (56.2)

12 (32.4)

< 0.001

Predictor variables

OR (95% CI)

p-value

Lateral ST-segment depression, n (%)

62 (77)

14 (37.8)

< 0.001

Age

1.23 (0.652–1.524)

0.42

Anterior ST-segment depression, n (%)

56 (70)

14 (37.8)

< 0.001

Inferior ST-segment depression

1.324 (0.465–2.862)

0.39

Left ventricular ejection fraction (%)

58.5 ± 4.2

61.7 ± 5.6

0.652

Lateral ST-segment depression

2.351 (1.524–4.243)

< 0.001

Left main/three-vessel disease, n (%)

69 (86.2)

27 (72.9)

0.03

Anterior ST-segment depression

1.214 (0.527–1.253)

0.48

Peak troponin T (ng/ml)

1.8 ± 0.5

0.36 ± 0.12

0.002

ST elevation in lead aVR

2.827 (1.873–4.368)

< 0.001

Table 3. Multivariate analysis of predictors for high SYNTAX score

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Previous studies have reported the independent predictive value of STEaVR for LM/3VD in NSTEACS. Barbares et al.9 reported that patients with STEaVR had a higher prevalence of LM/3VD and increased risk of in-hospital death. Kosuge et al.1 showed that STEaVR (≥ 0.05mV) was independently associated with LM/3VD, and STEaVR and increased cTnT level were independent predictors of death or MI only in patients with NSTEMI. Rostoff et al.10 evaluated the prognostic role of STEaVR in 134 patients with NSTEACS and reported that left main coronary artery disease was independently associated with STEaVR. Atie et al.8 evaluated ECG changes in patients with left main disease and showed that the most frequently observed ECG finding was STD in leads V3, V4 and V5. In addition to the predictive value for LM/3VD, STD carries a significant prognostic value in patients with NSTEMI.11,12 Furthermore, STD in leads V4–V6 has been reported to be an independent predictor for short-term mortality in patients with inferior ST-elevation myocardial infarction (STEMI).13 In the present study, STD in the anterior leads was another independent predictor for a high SS. Janata et al.14 has shown the prognostic value of STEaVR in patients with acute pulmonary embolism. In our study pulmonary embolism was excluded by echocardiographic and biochemical findings. One of the most common causes of STEaVR is left ventricular hypertrophy (LVH), which may represent repolarisation abnormalities.15 In our study LVH was excluded by echocardiographic evaluation. Although major STEaVR (> 0.1 mV) remained an independent predictor of LM/3VD, minor (0.05–0.1 mV) and major STEaVR were not independent predictors of in-hospital or six-month death, after adjusting for other validated prognosticators in the GRACE risk model.2 Taglieri et al.16 investigated the prognostic significance of STEaVR in patients with NSTEMI. They reported that STD plus STEaVR were associated with highrisk coronary lesions and predicted in-hospital and one-year cardiovascular death. Several studies have reported a close relationship between STEaVR and in-hospital or one-year cardiovascular death.1,9,16 In this study, we could not evaluate the relationship with mortality due to lack of data. SS, which is used in the evaluation of angiographic severity and extent of coronary lesions, has been shown to predict mortality in addition to its role in the decision-making process of interventional procedure.6,17 SS predicted short- and longterm adverse events following revascularisation in a study by Valgimigli and co-workers.18 In our study, STEaVR was an independent predictor of increased SS. It is well known that SS predicts mortality after a revascularisation procedure. Nabati et al.19 reported that STEaVR was independently associated with severity of coronary artery atherosclerosis and decreased LVEF in patients with NSTEACS. Although we found a significant relationship between STEaVR and severity and extent of coronary artery disease, there was no difference regarding LVEF. Additionally, they have shown that this ECG pattern had been associated with markers of myocardial necrosis and high-risk coronary lesions, including multi- or three-vessel coronary artery disease.19 Similarly, in our study, there was a significant difference with regard to peak cTnT value in patients with STEaVR. Several studies have shown a different ratio of STEaVR in

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patients with NSTEACS; Barrabés et al.9 reported 32.2%, Kosuge et al.5 reported 27.4%, Taglieri et al.16 reported 15.7%, Misumida et al.20 reported 26%, and Nabati et al.21 reported 40.3%. In our study, the ratio of STEaVAR was 68.4%. Misumida et al.20 reported that patients with STEaVR had a significantly higher rate of LM/3VD than those without STEaVR (39 vs 18%, respectively, p < 0.001). Nabati et al.21 reported that patients with STEaVR had a significantly higher rate of three- or multi-vessel disease than those without STEaVR (53.8 vs 31.2%, respectively, p = 0.01). In our study, patients with STEaVR had a significantly higher rate of LM/3VD than those without STEaVR (86.2 vs 72.9%, respectively, p = 0.03). High rates of STEaVR and LM/3VD in our study are thought to have resulted from the inclusion of CABG patients into the study. There are several limitations in this study. First, our study was a retrospective, observational study. Second, the sample size was small. Third, we did not exclude patients with posterior infarction presenting with STD in V1–V4, which is equivalent of STEMI. Therefore, our study group may have included patients with posterior STEMI. Fourth, we could not access death records in our country, therefore we could not evaluate mortality rates in this study.

Conclusion This study demonstrates that STEaVR and STD in the anterior leads were independent predictors of a higher SS and higher rate of LM/3VD in patients with NSTEACS.

References 1.

Kosuge M, Kimura K, Ishikawa T, Ebina T, Shimizu T, Hibi K, et al. Predictors of left main or three-vessel disease in patients who have acute coronary syndromes with non-ST-segment elevation. Am J Cardiol 2005; 95: 1366–1369.

Yan AT, Yan RT, Kennelly BM, Anderson FA Jr, Budaj A, LópezSendón J, et al; GRACE investigators. Relationship of ST elevation in lead aVR with angiographic findings and outcome in non-ST elevation acute coronary syndromes. Am Heart J 2007; 154: 71–78.

Figueras J, Lidón RM. Coronary reserve, extent of coronary disease, recurrent angina and ECG changes during pain in the in-hospital prognosis of acute coronary syndromes. Eur Heart J 1993; 14: 185–194.

Figueras J, Domingo E, Hermosilla E. Long-term prognosis of clinical variables, coronary reserve and extent of coronary disease in patients with a first episode of unstable angina. Int J Cardiol 2005; 98: 27–34.

Kosuge M, Ebina T, Hibi K, Morita S, Endo M, Maejima N, et al. An early and simple predictor of severe left main and/or three-vessel disease in patients with non-ST-segment elevation acute coronary syndrome. Am J Cardiol 2011; 107: 495–500.

Yadav M, Palmerini T, Caixeta A, Madhavan MV, Sanidas E, Kirtane AJ, et al. Prediction of coronary risk by SYNTAX and derived scores: synergy between percutaneous coronary intervention with taxus and cardiac surgery. J Am Coll Cardiol 2013; 62: 1219–1230.

Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581–1598.

Atie J, Brugada P, Brugada J, Smeets JL, Cruz FE, Roukens MP, et al. Clinical presentation and prognosis of left main coronary artery disease in the 1980s. Eur Heart J 1991; 12: 495–502.

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Barrabés JA, Figueras J, Moure C, Cortadellas J, Soler-Soler J. Prognostic value of lead aVR in patients with a first non-ST-segment elevation acute myocardial infarction. Circulation 2003; 108: 814–819.

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15. Zhao Y, Wang J, Huang G, Ding C. Significance of ST-segment elevation in lead aVR. Chin Med J (Engl) 2014; 127(16): 3034. 16. Taglieri N, Marzocchi A, Saia F, Marrozzini C, Palmerini T, Ortolani

10. Rostoff P, Piwowarska W. ST segment elevation in lead aVR and coro-

Pet al. Short- and long-term prognostic significance of ST-segment

nary artery lesions in patients with acute coronary syndrome. Kardiol

elevation in lead aVR in patients with non-ST-segment elevation acute

Pol 2006; 64: 8–14.

coronary syndrome. Am J Cardiol 2011; 108: 21–28.

11. Schechtman KB, Capone RJ, Kleiger RE, Gibson RS, Schwartz DJ,

17. Crijns HJ, van Gelder IC, van Gilst WH, Hillege H, Gosselink AM, Lie

Roberts R, et al. Risk stratification of patients with non-Q-wave

KI. Serial antiarrhythmic drug treatment to maintain sinus rhythm after

myocardial infarction. The critical role of ST segment depression. The

electrical cardioversion for chronic atrial fibrillation or atrial flutter. Am

Diltiazem Reinfarction Study Research Group. Circulation 1989; 80: 1148–1158.

J Cardiol 1991; 68: 335–341. 18. Valgimigli M, Serruys PW, Tsuchida K, Vaina S, Morel MA, van den

12. Cannon CP, McCabe CH, Stone PH, Rogers WJ, Schactman M,

Brand MJ, et al; ARTS II. Cyphering the complexity of coronary artery

Thompson BW, et al. The electrocardiogram predicts one-year outcome

disease using the SYNTAX score to predict clinical outcome in patients

of patients with unstable angina and non-Q wave myocardial infarction:

with three-vessel lumen obstruction undergoing percutaneous coronary

results of the TIMI III Registry ECG Ancillary Study. Thrombolysis in Myocardial Ischemia. J Am Coll Cardiol 1997; 30: 133–140.

intervention. Am J Cardiol 2007; 99: 1072–1081. 19. Nabati M, Emadi M, Mollaalipour M, Bagheri B, Nouraei M.

13. Hasdai D, Sclarovsky S, Solodky A, Sulkes J, Strasberg B, Birnbaum Y.

ST-segment elevation in lead aVR in the setting of acute coro-

Prognostic significance of maximal precordial ST-segment depression in

nary syndrome. Acta Cardiol 2016; 71(1): 47–54. doi: 10.2143/

right (V1 to V3) versus left (V4 to V6) leads in patients with inferior wall acute myocardial infarction. Am J Cardiol 1994; 74: 1081–1084.

AC.71.1.3132097. 20. Misumida N, Kobayashi A, Fox JT, Hanon S, Schweitzer P, Kanei Y.

14. Pride YB, Tung P, Mohanavelu S, Zorkun C, Wiviott SD, Antman

Predictive value of ST-segment elevation in lead aVR for left main and/

EM, et al; TIMI Study Group. Angiographic and clinical outcomes

or three-vessel disease in non-ST-segment elevation myocardial infarc-

among patients with acute coronary syndromes presenting with isolat-

tion. Ann Noninvasive Electrocardiol 2016; 21: 91–97. doi: 10.1111/

ed anterior ST-segment depression: a TRITON-TIMI 38 (Trial to

anec.12272.

Assess Improvement in Therapeutic Outcomes by Optimizing Platelet

21. Nabati M, Emadi M, Mollaalipour M, Bagheri B, Nouraei M.

Inhibition With Prasugrel) substudy. J Am Coll Cardiol Cardiovasc

ST-segment elevation in lead aVR in the setting of acute coronary

Interv 2010; 3: 806–811.

syndrome. Acta Cardiol 2016; 71: 47–54. doi: 10.2143/AC.71.1.3132097.

Matie cardiologist receives prestigious fellowship FMHS Marketing & Communication/FGGW Bemarking & Kommunikasie A senior registrar from the Division of Cardiology, Dr Marshall Heradien, was awarded the prestigious Hamilton Naki Clinical Scholarship for 2016. He was one of two researchers to receive the award last year. Dr Shrish Budree, a paediatric gastroenterologist currently studying at Harvard University, is the other recipient. “This scholarship initiative, in which Netcare has joined hands with the medical schools of South African universities, creates opportunities for deserving South African medical practitioners to further their studies and research in their respective fields of specialisation, before returning to South Africa to continue to contribute towards the advancement of South African academic medicine,” Dr Richard Friedland, chief executive of Netcare said at the awards ceremony according to a statement by Netcare. The award is named after Hamilton Naki, a self-taught surgeon who assisted in the experimental work that preceded the first human heart transplant. Naki was recognised by the legendary Prof Christiaan Barnard as a man of extraordinary natural surgical ability, but who, due to the policies of apartheid, was denied any formal medical training, despite his remarkable aptitude. “In this way, we honour the legacy of Hamilton Naki and numerous other South Africans who were denied the chance to fulfil their potential in the field of medicine during apartheid

and ensure the continued progress of medicine in our country,” said Friedland. Dr Bonginkosi Chiliza, who until recently was an associate professor at the Department of Psychiatry, is the only other Matie to receive the award in the almost 10 years of its existence. Published with permission by the University of Stellenbosch: Faculty of Medicine & Health Sciences Marketing & Communication

Prof Bongani Mayosi, Dean of the Faculty of Health Sciences of the University of Cape Town, Dr Marshall Heradien, a cardiologist and specialist physician at Stellenbosch University who is one of the recipients of the 2016 Hamilton Naki Clinical Scholarship, and Dr Richard Friedland, chief executive officer of Netcare.

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Relationship between Vitamin D and the development of atrial fibrillation after on-pump coronary artery bypass graft surgery Levent Cerit, Hatice Kemal, Kamil Gulsen, Barcin Ozcem, Zeynep Cerit, Hamza Duygu

Abstract Background: Vitamin D deficiency is associated with many diverse cardiovascular disorders, such as hypertension, heart failure, stroke, coronary artery disease and atrial fibrillation. The relationship between Vitamin D and the development of atrial fibrillation after coronary artery bypass surgery (CABG) has not been studied. Therefore, we assessed the relationship between Vitamin D and the development of postoperative atrial fibrillation (POAF) after CABG. Methods: Medical records of consecutive patients who underwent CABG surgery were retrospectively reviewed for the development of atrial fibrillation in the postoperative period. Vitamin D, other biochemical parameters, and clinical and echocardiographic parameters were evaluated in all patients. The independent variables for the development of postoperative atrial fibrillation were defined and their predictive values were measured. Results: The study group consisted of 128 patients, of whom 41 (32%) developed POAF. Age, diabetes mellitus, chronic obstructive pulmonary disease, history of transient ischaemic attack/stroke, heart failure, left atrial diameter, platelet:largecell ratio, and creatinine, urea, uric acid, calcium and potassium levels were identified as important variables for the development of POAF. However, with logistic regression analysis, chronic obstructive pulmonary disease (OR: 28.737, 95% CI: 0.836–16.118, p < 0.001), heart failure (OR: 15.430, 95% CI: 0.989–7.649, p = 0.006), diabetes mellitus (OR: 11.486, 95% CI: 0.734–11.060, p = 0.001) and left atrial diameter (OR: 1.245, 95% CI: 0.086–6.431, p = 0.011) appeared as independent variables predicting the development of POAF. Conclusion: In our study, although there was a significant negative correlation between Vitamin D and left atrial diameter, Vitamin D level was not an independent predictor for POAF. Keywords: atrial fibrillation, Vitamin D, coronary artery bypass graft surgery Submitted 24/3/16, accepted 18/5/16 Published online 2/8/16 Cardiovasc J Afr 2017; 28: 104–107 DOI: 10.5830/CVJA-2016-064

Near East University, Nicosia, Cyprus Levent Cerit, MD, drcerit@hotmail.com Hatice Kemal, MD Kamil Gulsen, MD Barcin Ozcem, MD Zeynep Cerit, MD Hamza Duygu, MD

www.cvja.co.za

Atrial fibrillation (AF) is the most common arrhythmia occurring after coronary artery bypass graft (CABG) surgery and is seen in approximately 15 to 30% of patients. The occurence of postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality rates, longer hospital stay and a two- to three-fold increase in incidence of postoperative stroke. Older age, obesity, hypertension (HT), prior AF and cognestive heart failure are associated with a higher risk for POAF.1 Vitamin D is transformed in the liver and kidneys to calcidiol and calcitriol, respectively, and affects specific target tissues via Vitamin D receptors (VDRs). Calcitriol, the active form of Vitamin D, binds to VDRs in the intestines, bones and kidneys to increase calcium absorption from the intestines, promoting calcium deposition in the bones. VDRs are found in other tissues, including the brain, cardiomyocytes, vascular smooth muscle cells, endothelial cells, pancreatic beta-cells, skeletal muscle, the prostate, colon, macrophages and skin, exerting several pleiotropic effects. Vitamin D utilises a direct effect relating to atherosclerosis, such as modulating endothelial function and influencing vascular smooth muscle proliferation and migration.2,3 To our knowledge, the relationship between Vitamin D and POAF has not been studied before. Therefore, we assessed the relationship between Vitamin D and the development of POAF.

Methods The study group consisted of 128 consecutive patients who underwent on-pump CABG surgery. The data of the patients were retrospectively analysed for AF in the postoperative period until discharge. The study was approved by the local ethics committee. The patients were monitored using a heart-rhythm monitor in the intensive care unit. In addition, daily electrocardiographic recordings were obtained during the hospital stay, both in the intensive care unit and the regular ward. New-onset postoperative AF (as classified by the Society of Thoracic Surgeons) was defined as AF or atrial flutter occurring in the postoperative period and requiring medical treatment (beta-blocker, calcium channel blocker, amiodarone, anticoagulants and cardioversion). Patients who developed AF in the postoperative period up to discharge were included in the POAF group. Patients’ data, including age, gender, history of HT, chronic kidney disease, diabetes mellitus (DM), heart failure (HF), chronic obstructive pulmonary disease (COPD), congenital heart disease, valvular heart disease, liver disease, stroke, thyroid disease, pre-operative drug use (beta-blockers and statins), and echocardiographic variables such as ejection fraction (EF), left atrial diameter, and presence of valvular disease were retrospectively retrieved from the medical charts and included in the analysis.

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All patients underwent transthoracic echocardiography using a Vivid S5 (GE Healthcare) echocardiography device and Mass S5 probe (2–4 MHz). Standard two-dimensional and colour-flow Doppler evaluations were acquired according to the guidelines of the American and European Societies of Echocardiography.4 The EF was measured according to Simpson’s method. Left atrial diameter was measured in parasternal long-axis view using two-dimensional echocardiography at the end-systole of left ventricular systole. Study exclusion criteria were patients with paroxysmal or persistent AF, being on anti-arrhythmia medication, patients who underwent pharmacological or electrical cardioversion before CABG surgery due to reasons other than AF, patients who underwent other cardiac procedures in addition to CABG or who were planned to undergo emergency surgery, and patients who had significant valvular disease or prosthetic valvular disease. Levels of 25-hydroxy (OH) Vitamin D, calcium and other biochemical and haematological parameters were measured following a fasting period of eight hours. Serum 25-(OH) Vitamin D levels were measured by chemiluminescence immunoassay using a Lıaıson analyser (DiaSorin Inc). Vitamin D deficiency was defined as serum levels of 25-(OH) Vitamin D < 20 ng/ml and Vitamin D insufficiency was defined as a level of 20–29 ng/ ml. Plasma levels of 25-(OH) Vitamin D > 30 ng/ml were defined as normal.

Statistical analysis Statistical analysis was performed using the SPSS (version 20.0, SPSS Inc, Chicago, Illinois) software package. Continuous variables are expressed as mean ± standard deviation (mean ± SD) and categorical variables as percentage (%). The Kolmogorov–Smirnov test was used to evaluate the distribution of variables. The Student’s t-test was used to evaluate continuous variables showing a normal distribution, and the Mann–Whitney U-test was used to evaluate variables that did not show a normal distribution. A p-value < 0.05 was considered statistically significant.

Results This study included 128 consecutive patients, of whom 41 (32%) developed POAF. The main characteristics of patients who developed POAF and those who did not are presented in Table 1. All patients were on beta-blocker and statin therapy, and 93.7% were on angiotensin converting enzym inhibitor/angiotensin receptor blocker therapy. Comparisons of different laboratory and echocardiographic parameters are presented in Table 2. Univariate analysis identified age, DM, history of transcient ischaemic attack/stroke, COPD, heart failure, left atrial diameter, EF, and urea, creatinine, uric acid, potassium, calcium and 25-(OH) Vitamin D levels as significant factors for the development of POAF. Multivariate regression models revealed that COPD, DM, HF and left atrial diameter increased the probability of POAF independent of confounding factors (OR: 28.737, 95% CI: 0.836–16.118, p < 0.001 for COPD; OR: 11.486, 95% CI: 0.734–11.060, p = 0.001 for DM; OR: 15.430, 95% CI: 0.989–7.649, p = 0.006 for HF; OR: 1.245, 95% CI: 0.086–6.431, p = 0.011 for left atrial diameter).

Table 1. Patient characteristics POAF Patient characteristics

p-value

Present

Absent

Age (mean ± SD)

67.6 ± 8.6

63.9 ± 9.8

0.047

Body mass index (mean ± SD) (median)

27.2 ± 3.7 (25.8)

26.9 ± 4.1 26.7

0.755

Gender, n (%)

35 (85.4)

77 (88.5)

0.616

6 (14.6)

10 (11.5)

40 (97.6)

77 (88.5)

–

1 (2.4)

10 (11.5)

31 (75.6)

26 (29.9)

–

10 (24.4)

61 (70.1)

Male Female

Hypertension, n (%) Diabetes mellitus, n (%) TIA/stroke, n (%) COPD, n (%) Heart failure, n (%)

5 (12.2)

1 (4.7)

–

36 (87.8)

86 (98.9)

15 (36.6)

5 (5.7)

–

5 (5.7)

82 (94.3)

12 (29.3)

3 (3.4)

–

29 (70.7)

84 (96.6)

0.104 < 0.001 0.013 < 0.001 < 0.001

POAF, postoperative atrial fibrillation, TIA, transient ischaemic attack, COPD, chronic obstructive pulmonary disease.

Discussion AF is a growing global health concern and is linked to a wide range of medical complications, including heart failure, ischaemic stroke and death. It is estimated that AF may account for 10 to 15% of all strokes, with an associated increased mortality rate of up to 1.9-fold higher than without AF.5 COPD, HF, DM and left atrial diameter were found to be independent variables predicting the development of POAF. In previous studies, advanced age, male gender, chronic heart failure, pre-operative AF attacks, COPD, chronic renal disease, DM and the metabolic syndrome were reported to be pre-operative clinical parameters predicting the development of POAF.6 COPD is an independent risk factor for arrhythmias, especially AF and cardiovascular morbidity and mortality.7 COPD was found to be an important variable predicting the development of postoperative AF in this study. We believe that the relationship between COPD and POAF depends on hypoxia, hypercapnia, acidosis and inflammation. AF is one of the most common co-morbidities in patients with HF, while HF is also common in AF patients. Previous studies reported that the prevalence of AF in patients with chronic HF ranged from 15 to 50%.8 HF was found to be an important variable predicting the development of postoperative AF in our study. Aksakal and co-workers found DM increased the risk of developing AF.9 In our study, DM was found to be an important variable predicting the development of postoperative AF. The Framingham Offspring study found that individuals with 25-(OH) Vitamin D < 37.5 nmol/l had a hazard ratio of 1.62 for the development of cardiovascular disease compared to those with a level of ≥ 37 nmol/l.10 Furthermore, Vitamin D insufficiency was associated with endothelial dysfunction and subclinical atherosclerosis.11 Another study pointed out that 25-(OH) Vitamin D levels were significantly lower in patients with coronary artery disease than in those without.12 VDRs are found in myocytes and fibroblasts in the heart.13 A number of animal studies have confirmed that VDRs play an important role in cardiac hypertrophy.14 The risk of new-onset AF is significantly higher with increased left atrial diameter and left atrial volume.15 In our study, left atrial

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Table 2. Laboratory and echocardiograpic parameters POAF Present mean ± SD (median)

Absent mean ± SD (median)

13.5 ± 1.7 (13.1)

13.7 ± 1.5 (13.7)

0.316

218.9 ± 59.7 (212)

234.1 ± 66.6 (230)

0.68

White blood cells (103 cells/µl)

7.8 ± 2.3 (7.6)

7.6 ± 2.2 (7.5)

0.647

Mean platelet volume (fl)

10.5 ± 1.1 (10.5)

10.4 ± 0.9 (10.4)

0.303

Neutrophils (103 cells/µl)

4.7 ± 2.1 (4.6)

4.3 ± 1.2 (4.2)

0.384

Lymphocytes (103 cells/µl)

1.9 ± 0.8 (1.9)

2.3 ± 1.5 (1.9)

0.072

Neutrophils:lympocytes

2.9 ± 2.0 (2.5)

2.1 ± 0.8 (1.9)

0.136

Platelet:large cell ratio

33.6 ± 16.2 (29.4)

27.5 ± 6.7 (27)

0.006

Sedimentation (mm/h)

27.4 ± 23.2 (23.5)

24.9 ± 20.4 (19)

0.758

Urea (mg/dl)

46.8 ± 22.2 (41)

36.7 ± 4.3 (32)

0.012

1.07 ± 0.29 (1) (94.59 ± 25.64) (88.4)

0.94 ± 0.24 (0.8) (83.10 ± 21.22) (70.72)

0.013

136.7 ± 52.2 (110) (7.59 ± 2.90) (6.11)

120.3 ± 40.3 (106) (6.68 ± 2.24) (5.88)

0.340

C-reactive protein (mg/dl)

1.6 ± 2.5 (0.5)

0.8 ± 1.2 (0.3)

0.053

Total cholesterol (mg/dl)

179.2 ± 45.1 (178) (4.64 ± 1.17) (4.61)

183.8 ± 53.3 (179) (4.76 ± 1.38) (4.64)

0.680

High-density lipoprotein cholesterol (mg/dl) (mmol/l)

39 ± 8.3 (37) (1.01 ± 0.21) (0.96)

39.3 ± 11.6 (37) (1.02 ± 0.30) (0.96)

0.760

Low-density lipoprotein cholesterol (mg/dl) (mmol/l)

112.6 ± 38.5 (111.5) (2.92 ± 1.00) (2.89)

114.9 ± 46.9 (101) (2.98 ± 1.21) (2.62)

0.920

Trigylicerides (mg/dl)

180.1 ± 95.1 (168) (2.04 ± 1.07) (1.90)

150.1 ± 60.9 (140.5) (1.70 ± 0.69) (1.59)

0.231

25-hydroxy Vitamin D (ng/ml)

19.9 ± 6.1 (19.5)

26 ± 8.2 (26.4)

< 0.001

Calcium (mg/dl)

9.2 ± 0.5 (9.1)

9.4 ± 0.4 (9.4)

0.034

Magnesium (mg/dl)

2.1 ± 0.3 (2)

2.1 ± 0.4 (2.1)

0.086

4 ± 0.4 (4.1)

4.2 ± 0.3 (4.1)

0.163

Potassium (mmol/l)

4.1 ± 0.5 (4.1)

4.3 ± 0.3 (4.3)

<0.001

Uric acid (mg/dl)

6.4 ± 1.5 (6.19

5.5 ± 1.2 (5.4)

0.004

Left atrium (mm)

41.2 ± 4.3 (41)

37.8 ± 3.9 (38)

< 0.001

Ejection fraction (%)

51.3 ± 9.1 (55)

55.2 ± 6.7 (55)

0.043

Laboratory and echocardiographic parameters Haemoglobin (g/dl) Platelets (103/µl)

Creatinine (mg/dl) (mmol/l) Fasting plasma glucose (mg/dl) (mmol/l)

(mmol/l)

Albumin (g/dl)

p-value

POAF, postoperative atrial fibrillation.

diameter was found to be an important variable predicting the development of postoperative AF. The role of Vitamin D deficiency in the onset of AF was suggested because of several potential mechanisms described

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previously.16 Vitamin D regulates inflammatory responses and up-regulates the expression of anti-inflammatory cytokines, such as IL-10, according to in vitro experiments.17 Also, Vitamin D regulates activity of the renin–angiotensin–aldosterone system (RAAS). Activated RAAS can lead to oxidative stress and inflammation, both of which could culminate in AF.18 It is assumed that tissue angiotensin II may induce apoptosis of the cardiomyocytes and contribute to changes in atrial structure.19 There were conflicting results regarding low 25-(OH) Vitamin D levels and AF. On one hand, several studies demonstrated a close association between Vitamin D deficiency and AF, such as Demir et al.,20 who found a strong relationship between Vitamin D deficiency and non-valvular AF. Chen and co-workers found that serum 25-(OH) Vitamin D level correlated with high-sensitivity C-reactive protein and left atrial diameter, and was significantly associated with AF in Chinese patients with non-valvular persistent AF.21 Hanafy et al.22 revealed the direct electromechanical effects on the left atrium after Vitamin D administration, and found that Vitamin D could effectively prevent or terminate AF. On the other hand, no association was found between 25-(OH) Vitamin D levels and ischaemic heart disease, stroke or acute myocardial infarction, despite previous studies showing Vitamin D deficiency to be associated with increased incidence of these conditions.23-25 Rienstra et al.26 evaluated 2 930 participants of the Framingham Heart study during a follow-up period of 9.9 years and found no relationship between Vitamin D status and incident AF, concluding that Vitamin D deficiency does not promote the development of AF. Additionally, Qayyum et al.27 showed that there was no association between Vitamin D deficiency and type of AF or complications of AF. Another prospective cohort study based on the Rotterdam study did not support the hypothesis that Vitamin D level is associated with AF.28 Our study was the first to evaluate the predictive value of 25-(OH) Vitamin D level in the development of POAF. In recent studies, there has been a paradox between Vitamin D levels and AF, and a negative correlation between Vitamin D and left atrial diameter.15 In our study, although there was a significant negative correlation between Vitamin D and left atrial diameter, Vitamin D level was not an independent predictor for the development of POAF. We believe that the paradoxical results between Vitamin D and AF could be related to the activation of the RAAS caused by Vitamin D insuffiency, increased levels of reactive oxygen radicals, and individual differences in receptor activity. Also, because of the negative correlation between Vitamin D level and left atial diameter, it could be hypothesised that Vitamin D insuffiency could lead to atrial dilatation, causing AF. Further randomised clinical studies are needed in this field. Our study has some limitations. First, it was a retrospective study design. Second, AF was diagnosed by ECG monitoring in a hospital setting without performing a follow up after discharge. Third, the small sample size of this study was problematic. Fourth, measurement of Vitamin D levels occurred at a single point in time. Fifth, we did not determine parathyroid hormone levels.

Conclusion To the best or our knowledge, this study is the first to evaluate the relationship between POAF and 25-(OH) Vitamin D levels.

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Our study does not support the hypothesis that Vitamin D levels play a role in the aetiology of POAF. Further prospective, randomised studies with a larger number of patients are required to confirm our results.

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14. Chen S, Law CS, Grigsby CL, et al. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 2011: 124; 1838–1847. 15. Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women.

References 1.

Mayo Clin Proc 2001; 76: 467–475. 16. Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin–angiotensin

Filardo G, Hamilton C, Hebeler RF Jr, Hamman B, Grayburn P.

systems. Am J Physiol Endocrinol Metab 2005: 288; 125–132.

New-onset postoperative atrial fibrillation after isolated coronary artery bypass graft surgery and long-term survival. Circ Cardiovasc Qual 2.

17. Canning MO, Grotenhuis K, de Wit H, Ruwhof C, Drexhage HA.

Outcomes 2009; 2: 164–169.

1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the matu-

Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal

ration of fully active immature dendritic cells from monocytes. Eur J Endocrinol 2001; 145: 351–357.

Physiol 2005; 289: 8–28. 3.

MacDonald HM, Mavroeidi A, Fraser WD, et al. Sunlight and dietary

18. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A.

contributions to the seasonal Vitamin D status of cohorts of healthy

Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96: 1180–1184.

postmenopausal women living at northerly latitudes: a major cause for concern? Osteoporosis Int 2011; 22: 2461–2472. 4. 5.

19. Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S.

Lang RM, Bierig M, Devereux RB, et al. Recommendations for cham-

Evolution of the atrial fibrillation substrate in experimental conges-

ber quantification. Eur J Echocardiogr 2006; 7: 79–108.

tive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res 2003: 2; 315–325.

Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors and prognosis in

20. Demir M, Uyan U, Melek M. The effects of vitamin D deficiency on atrial fibrillation. Clin Appl Thromb Hemost 2014: 20; 98–103.

the Manito ba Follow-Up Study. Am J Med 1995; 98: 476–484. 6.

Banach M, Rysz J, Drozdz JA, et al. Risk factors of atrial fibrillation

21. Chen WR, Liu ZY, Shi Y, et al. Relation of low vitamin D to nonval-

following coronary artery bypass grafting: A preliminary report. Circ J

vular persistent atrial fibrillation in Chinese patients. Ann Noninvasive Electrocardiol 2014: 19; 166–173.

2006; 70: 438–441. 7.

Li J, Agarwal SK, Alonso A, et al. Airflow obstruction, lung function, and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2014; 129: 971–980.

Hanafy DA, Chang SL, Lu YY, et al. Electromechanical effects of 1,25-dihydroxyvitamin D with antiatrial fibrillation activities. J Cardiovasc Electrophysiol 2014: 3; 317–323.

Yamauchi T, Sakata Y, Miura M, et al.; CHART-2 investigators.

23. Forman J.P, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvi-

Prognostic impact of new-onset atrial fibrillation in patients with

tamin D levels and risk of incident hypertension. Hypertension 2007:

chronic heart failure – A report from the CHART-2 study. Circ J 2015; 80: 157–167. 9.

22.

5; 1063–1069. 24. Brondum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG.

Aksakal E, Tanboğa IH, Kurt M. Predictors of coronary lesions

25-hydroxyvitamin D levels and risk of ischemic heart disease, myocar-

complexity in patients with stable coronary artery disease. Angiology

dial infarction, and early death: population-based study and meta-

2013; 64: 304–309.

analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol 2012; 11:

10. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008; 117: 503–511. 11. Oz F, Cizgici A. Y, Oflaz H, et al. Impact of Vitamin D insufficiency on the epicardial coronary flow velocity and endothelial function. Coron Art Dis 2013; 24: 392–397. 12. Liew JY, Sasha SR, Ngu PJ, et al. Circulating Vitamin D levels are asso-

2794–2800. 25. Poole KE, Loveridge N, Barker PJ, et al. Reduced vitamin D in acute stroke. Stroke 2006: 1; 243–245. 26. Rienstra M, Cheng S, Larson MG, et al. Vitamin D status is not related to development of atrial fibrillation in the community. Am Heart J 2011; 3: 538–541.

ciated with the presence and severity of coronary artery disease but not

27. Qayyum F, Landex NL, Agner BR, Rasmussen M, Jøns C, Dixen U.

peripheral arterial disease in patients undergoing coronary angiography.

Vitamin D deficiency is unrelated to type of atrial fibrillation and its

Nutr Metab Cardiovasc Dis 2015; 25: 274–279. 13. Gardner DG, Chen S, Glenn DJ. Vitamin D and the heart. Am J Physiol Regul Integr Comp Physiol 2013: 305; 969–977.

complications. Dan Med J 2012; 59: 4505. 28. Vitezova A, Cartolano NS, Heeringa J, et al. Vitamin D and the risk of atrial fibrillation. The Rotterdam Study. PLoS One 2015; 10: e0125161.

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Factors associated with early mortality in haemodialysis patients undergoing coronary artery bypass surgery Deniz Çevirme, Taylan Adademir, Mehmet Aksüt, Tülay Örki, Kamil Cantürk Çakalağaoğlu, Mete Alp, Kaan Kırali

Abstract Introduction: Coronary artery bypass grafting (CABG) results in higher morbidity and mortality rates in end-stage renal disease (ESRD) patient populations than in patients with normal renal function. This study aimed to identify the early results of CABG performed on ESRD patients, and the factors that affected the mortality rates of those patients. Methods: A retrospective evaluation of our hospital database revealed 84 haemodialysis-receiving patients who underwent CABG during the years 2006 to 2012. Mortality was observed in 21 patients (group 1), and this group was compared with the remaining patients (group 2) for peri-operative parameters such as age, EuroSCORE, functional capacity, myocardial infarction, use of inotropes and completeness of revascularisation. Results: The study included 60 male (71.4%) and 24 female patients (28.6%); the participants’ mean age was 59.50 ± 9.93 years. The pre-operative additive EuroSCORE was 7.96 ± 2.88 (range: 2–18). Pre-operative functional capacity was impaired in 35.7% of the patients [New York Heart Association (NYHA) classes III–IV]. Mean age and preoperative EuroSCORE values of group 1 were significantly higher than those of group 2. Impaired functional capacity (NHYA classes III–IV) was also associated with mortality (OR: 3.333; 95% CI: 1.199–9.268). Fifty-four patients (64.3%) underwent on-pump CABG procedures, and 30 (35.7%) underwent off-pump CABG procedures. The study found no statistically significant difference in mortality rates between these two techniques. Mortality occurred in 12 patients (22.2%) in the on-pump group and in nine (30%) in the off-pump group. Complete revascularisation was performed on 46 patients (85.2%) in the on-pump group and seven (23.3%) in the off-pump group (p < 0.001). Conclusion: Advanced age, impaired NYHA functional capacity and pre-operative hypertension were determinative for early-term surgical mortality. An on-pump surgical technique is recommended to ensure completeness of revascularisation.

Keywords: coronary artery bypass surgery, chronic renal failure, haemodialysis, off-pump, on-pump Submitted 7/12/15, accepted 29/5/16 Published online 22/7/16 Cardiovasc J Afr 2017; 28: 108–111

www.cvja.co.za

DOI: 10.5830/CVJA-2016-066

The mortality rate of end-stage renal disease (ESRD) patients undergoing haemodialysis is high and over half of the deaths are due to cardiovascular problems.1,2 Coronary artery disease, heart failure and sudden death are the most common causes of morbidity.3 Coronary artery disease (CAD) is seen five to 20 times more frequently in uraemic patients than in the normal population. Because the lesions are widespread and complex, clinical prognoses worsen rapidly.4 Myocardial ischaemia is present because of some triggering situations in the absence of severe CAD.5 Heart failure occurs frequently in ESRD patients and is an independent predictor of mortality. Forty per cent of haemodialysis patients experience heart failure symptoms at the beginning of the procedure, and 25% of asymptomatic patients will develop heart failure within 3.5 years.6,7 The pre-, intra- and postoperative periods of coronary artery bypass graft (CABG) surgery must be treated more cautiously in this population. Factors affecting the morbidity and mortality rates of these patients must be well known to ensure that careful and appropriate follow up takes place. On-pump versus off-pump techniques, bleeding complications, and duration of postoperative intensive care period are among the main concerns with regard to this surgery. The aim of this study was to identify the factors affecting the mortality rate of ESRD patients who were receiving haemodialysis and had undergone CABG procedures.

Methods

Department of Cardiovascular Surgery, Kartal Koşuyolu Heart and Research Hospital, Istanbul, Turkey Deniz Çevirme, MD Taylan Adademir, MD, taylanadademir@gmail.com Mehmet Aksüt, MD Kamil Cantürk Çakalağaoğlu, MD Mete Alp, MD Kaan Kırali, MD

Department of Anesthesiology, Kartal Koşuyolu Heart and Research Hospital, Istanbul, Turkey Tülay Örki, MD

Eighty-four chronic renal failure patients who were receiving haemodialysis and underwent CABG operations during the period 2006 to 2012 were assessed in this retrospective study. Data collection was approved by the institutional review board of our hospital and was performed in accordance with the board’s regulations. All the patients underwent haemodialysis three times per week during the pre-operative period, and routine CABG procedures were administered to all of them. Haemodialysis was routinely performed the day before and the day after the operation. Narcotic anaesthesia was administered intravenously to all patients. Full median sternotomy was performed on all patients; the left internal mammarian artery and the saphenous vein were

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used as grafts. An aortic arterial and unicaval two-stage venous cannulation was performed on patients in the on-pump CABG group; an antegrade cardioplegia cannula and a venting cannula were placed into the aortic root, and a retrograde cardioplegia cannula was placed into the coronary sinus via the right atrium. Myocardial contraction was stopped in the diastolic phase using isothermic hyperkalaemic blood cardioplegia via an antegrade cannula, and myocardial protection was achieved using isothermic hyperkalaemic blood cardioplegia via a retrograde cannula, with the effect of systemic hypothermia. Haemodynamic monitoring was continued in the intensive care unit (ICU) and the patients underwent haemodialysis. Patients with early mortality (group 1) were compared with surviving patients (group 2) for peri-operative parameters (Table 1).

Table 2. Assessments for pre-operative mortality Mortality Yes, Mean ± SD

No, Mean ± SD

p-value

9.28 ± 3.39 (9)

7.52 ± 2.58 (8)

0.040*

48.33 ± 12.28 (50)

53.33 ± 10.85 (55)

0.103

0 (0.0)

16 (25.4)

9 (42.9)

29 (46.0)

10 (47.6)

18 (28.6)

2 (9.5)

0 (0.0)

EuroSCORE Ejection fraction (%) NYHA class, n (%)

0.004**

Canada class, n (%) 1

0 (0.0)

1 (1.6)

11 (52.4)

30 (47.6)

9 (42.9)

31 (49.2)

1 (4.8)

1 (1.6)

18 (85.7)

63 (100.0)

3 (14.3)

0 (0.0)

Smoker, n (%)

7 (33.3)

34 (54.0)

0.101

Diabetes, n (%)

11 (52.4)

37 (58.7)

0.611

6 (28.6)

19 (30.2)

0.890

13 (61.9)

54 (85.7)

0.019*

PAD, n (%)

3 (14.3)

16 (25.4)

0.292

COPD, n (%)

7 (33.3)

18 (28.6)

0.679

0.751

Surgery, n (%) Elective

Statistical analysis

Emergency

The Statistical Package for Social Sciences (SPSS) for Windows 15.0 was used to evaluate the findings of the study, and the Kolmogorov–Smirnov test was used to evaluate the coherence of the normal distribution of the study parameters. Descriptive statistical methods (standard deviation, frequency and mean) were used. The quantitative parameters were evaluated in two parts. The Student’s t-test was used for normally distributed parameters, and the Mann–Whitney U-test was performed for non-normally distributed parameters. The Wilcoxon test was used to compare the parameters in both groups. The chi-squared, Fisher’s exact and McNemar’s tests were used to compare qualitative parameters; p < 0.05 was accepted as significant. Univariate and multivariate analysis were used to determine independent risk factors.

Results Pre-operative findings were analysed according to demographic characteristics. The mean age of the patients who died was statistically significantly higher in the pre-operative evaluation (p < 0.05), as were the mean age and EuroSCORE (p < 0.05). The New York Heart Association (NYHA) functional capacity of the patients was found to be highly significantly correlated with mortality rate of patients (p < 0.01). Significantly more of the patients who died were in NYHA class III–IV (OR: 3.333; 95% CI: 1.199–9.268). There was a statistically significant difference with regard to mortality rate between the types of surgery (p < 0.05). Significantly more patients who received emergency surgery died (OR: 10.333; 95% CI: 1.012–105.487). There was also a statistically significant difference in the incidence of hypertension (p < 0.05) between the patients who died and those who survived. The incidence of hypertension in patients who died was significantly higher than in those who survived (Table 2).

Hypercholesterolaemia, n (%) Hypertension, n (%)

Mann-Whitney U-test for euroSCORE and ejection fraction; chi-squared test for the other variables. PAD: peripheral arterial disease, COPD: chronic obstructive pulmonary disease.

The ICU length of stay and extubation time of patients who died were statistically significantly longer than those of surviving patients (p < 0.01).The incidence of pneumonia in patients who died was statistically significantly higher than in those who survived (p < 0.01; Table 3).There was also a significant difference in pre- and postoperative values of creatinine kinase-MB (CK-MB) and troponin between living and dying patients (Table 4). The myocardial infarction (MI) rate in the pre-operative period was statistically significantly higher in patients who died than in surviving patients (p < 0.05; OR: 3.400; 95% CI: 1.027–11.257). The MI rate in the postoperative period was also statistically significantly higher in deceased cases than in the surviving patients (p < 0.01; OR: 8.800; 95% CI: 2.753–28.134). Table 3. Assessments for intra-operative mortality Mortality

Mortality

p-value

Yes, Mean ± SD

No, Mean ± SD

2.30 ± 1.62

1.79 ± 1.24

66.90 ± 110.99

15.03 ± 8.87

ACC (min)

77.00 ± 35.37

61.24 ± 22.23

TPT (min)

119.17 ± 45.30

99.90 ± 26.38

30.87 ± 2.19

30.98 ± 1.72

911.90 ± 580.06

652.38 ± 386.61

11.57 ± 9.08

3.93 ± 2.92

4.56 ± 2.26

5.48 ± 2.13

Transfusion (units) Extubation time (min)

Hypothermia (°C) Chest tube drainage (ml) ICU stay (day) Postoperative creatinine (mg/dl) (μmol/l) Redo surgery, n (%)

Table 1. Evaluation of mortality by demographic characteristics

0.014*

0.160

0.001** 0.166 0.183 0.861 0.067 0.001** 0.097

(403.10 ± 199.78) (484.43 ± 188.29) 1 (4.8)

1 (1.6)

Postoperative dialysis

19 (90.5)

57 (90.5)

Complete revascularisation, n (%)

12 (57.1)

41 (65.1)

10 (47.6)

2 (3.2)

0.440 1.000 0.514

Yes, Mean ± SD

No, Mean ± SD

p-value

Pneumonia, n (%)

63.47 ± 9.89

58.17 ± 9.66

0.033*

Female, n (%)

7 (33.3)

17 (27.0)

0.577

Male, n (%)

14 (66.7)

46 (73.0)

ACC: aortic cross clamp time, TPT: total perfusion time; ACC, TPT and hypothermia related to on-pump group (54 patients). + Student’s t-test for chest tube drainage and postoperative creatinine levels; Mann–Whitney U-test for other variables; ++Chi-squared test and/or Fisher’s exact test; **p < 0.01.

Age

Student’s t-test for age; chi-squared test for gender; *p < 0.05.

0.001**

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Table 4. Enzyme levels

Table 6. Surgical technical results

Mortality Yes, Mean ± SD

No, Mean ± SD

p-value

Blood transfusion (units)

CK-MB (U/I) Pre-op Postop p-value

On-pump Mean ± SD

Off-pump Mean ± SD

1.81 ± 1.31

2.10 ± 1.42

+ +

p-value 0.225

51.90 ± 153.75

20.55 ± 16.36

0.478

Extubation time (min)

29.77 ± 67.07

24.80 ± 43.44

135.95 ± 140.39

44.62 ± 50.56

0.006**

ACC (min)

64.74 ± 26.18

–

0.003**

0.001**

TPT (min)

104.18 ± 32.08

–

30.95 ± 1.81

–

694.44 ± 447.91

758.33 ± 467.76

Hypothermia (°C)

Troponin (ng/ml)

0.110

– 0.539

Pre-op

27.15 ± 123.57

0.15 ± 0.38

0.379

Chest tube drainage (ml)

Postop

33.14 ± 72.52

9.29 ± 10.61

0.019*

ICU stay (days)

5.98 ± 5.99

5.66 ± 6.47

0.001**

Postoperative creatinine (mg/dl)

5.10 ± 2.23

5.52 ± 2.12

p-value

(μmol/l)

Mann–Whitney U-test; ++Wilcoxon sign test; *p < 0.05; **p < 0.01.

Redo surgery, n (%)

There was no statistically significant difference with regard to the rate of use of intra-aortic balloon pump (IABP) in the pre-operative period (p > 0.05) between the two groups. The rate of use of IABP in the postoperative period was significantly higher in the deceased cases (p < 0.01; OR: 61.000; 95% CI: 11.422–325.788) than in the survivors. There was no statistically significant difference with regard to mortality rate in terms of use of inotropic medicines pre-operatively between the two groups (p > 0.05). The rate of use of inotropic medicines in the postoperative period was statistically significantly higher in the patients who died than in surviving patients (p < 0.01; OR: 6.400; 95% CI: 2.181–18.784; Table 5). Patients who had undergone emergency operations and were administered inotropic medications had statistically significantly higher mortality rates. Although complete revascularisation was not significantly related to mortality rate in both groups, the results were different when analysed with regard to the on- and off-pump group distribution (Table 6). Complete revascularisation was more frequently performed on patients in the on-pump group. The complete revascularisation rate was 23.3% in the off-pump and 85.2% in the on-pump group, and this difference was statistically significant (p < 0.01). A comparison of the mortality rates of the two groups, however, revealed no statistically significant difference (p > 0.05). Table 5. Pre-operative vs postoperative assessments in exitus patients Mortality p-value

Yes, n (%)

No, n (%)

Pre-op

17 (81.0)

35 (55.6)

0.038*

Postop

11 (52.4)

7 (11.1)

0.001**

0.070

0.001**

Pre-op

2 (9.5)

7 (11.1)

0.839

Postop

2 (9.5)

1 (1.6)

0.153

MI, n (%)

p-value

CVA, n (%)

p-value

1.000

0.031*

IABP, n (%) Pre-op

2 (9.5)

0 (0)

Postop

14 (66.7)

2 (3.2)

p-value

0.001**

0.060 0.001**

0.500

Inotrope, n (%) Pre-op

2 (9.5)

0 (0)

Postop

14 (66.7)

15 (23.8)

0.001**

p-value

0.060 0.001**

Chi-squared and/or Fisher’s exact test; ++McNemar test; *p < 0.05; **p < 0.01. MI: myocardial infarction, CVA: cerebrovascular accident, IABP: intra-aortic balloon pump.

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0.712 0.404

(450.84 ± 197.13) (487.97 ± 187.41) 1.000

1 (1.9)

1 (3.3)

Postoperative dialysis, n (%)

49 (90.7)

27 (90.0)

Complete revascularisation, n (%)

46 (85.2)

7 (23.3)

9 (16.7)

3 (10.0)

12 (22.2)

9 (30.0)

Pneumonia, n (%) Exitus, n (%)

0.912 0.001** 0.403 0.430

Student’s t-test for drainage and postoperative creatinine levels; Mann–Whitney U-test for other variables; ++Chi-squared test and/or Fisher’s exact test; **p < 0.01. ACC: aortic cross clamp time, TPT: total perfusion time. +

Discussion The mortality rate associated with cardiovascular surgical procedures is higher for patients experiencing chronic renal failure than for patients with normal renal function.8,9 A restricted tolerance to decreased blood pressure, bleeding complications due to coagulatory problems, insufficient excretion of toxic metabolites, and sensitivity to infection may play a significant role in cases of uraemic patients. A maturity series of 296 cases reported by Ko et al. revealed a mortality rate of 9%; the study showed that mortality occurred in patients with high NYHA functional class, left main coronary artery disease, accompanying cerebrovascular disease, or emergent surgical procedures.8 Krishnaswami et al. reported survival rates as follows: first 30 days: 91–92%; first year: 77–78%.10 Nwiloh et al. found a 20.8% mortality rate as a result of subgroup analyses in isolated CABG with ESRD patients.11 In Kaul and co-workers’ series of 35 cases published in 1994, the surgical mortality rate was 11.4%. They observed that congestive heart failure and a high NYHA class were determinants of mortality and that left main coronary artery disease did not affect mortality rates.12 Most surgeons prefer the off-pump technique because it obviates the complications of cardiopulmonary bypass (CPB) and reduces in-hospital length of stay and associated costs; however, the patient’s clinical status and risk factors limit this procedure’s applicability. In research conducted by Chu et al., the authors examined all data and follow-up results relating to patients on whom off- and on-pump techniques were performed. The findings revealed that in-hospital mortality rates of patients in whom the on- and off-pump techniques were used were similar (3 and 3.2%, respectively). Moreover, no difference was found between the two groups with regard to postoperative stroke development in patients who were discharged.13 Despite this, extended hospitalisation and increased costs were observed for the off-pump group. The physiological and anatomical features of the coronary arteries also limit the benefits of the off-pump technique. Factors that limit the success of a distal anastomosis are as follows: difficulty in reaching the coronary artery, intra-myocardial coronary artery, poor quality of the artery and arterial plaque formation, and extent of the surgeon’s experience. The results obtained from

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our research indicate that there was no statistically significant difference between pre-operative risk factors and postoperative parameters of patients with kidney failure who were operated on with the use of off- and on-pump techniques. The results of the mortality evaluations were likewise statistically insignificant. Generally, complete revascularisation is the preferred approach in CABG surgery, and one of the important goals is to provide patients with good long-term NYHA functional status.14,15 Incomplete revascularisation is applied in certain cases. In a study performed by Caputo et al., the results of incomplete and complete revascularisation with the use of off-pump techniques were compared, and a two-year follow up determined that the risk of mortality for the patients with incomplete revascularisation exhibited a statistically significant increase, compared to that of the other group.16 In-hospital mortality and peri-operative myocardial infarction rates were also observed to be considerably higher for the group of patients on whom incomplete revascularisation was performed. According to the data obtained from patients with chronic renal failure, incomplete revascularisation was performed on 23 patients (76.7%) in the off-pump group and four (14.8%) in the on-pump group. Complete revascularisation was found to be more prominent in the on-pump group of 46 patients (85.2%). Two studies showed reduced platelet counts and platelet dysfunction (reduced platelet adhesiveness) due to uraemia, and an abnormal von Willebrand factor led to bleeding in chronic renal failure patients receiving haemodialysis.17,18 Nakatsu and colleagues noted the risk of haemorrhagic complications associated with heart valve surgery in ESRD patients. They found similar risk rates in bioprosthesis and mechanical heart valve patients.19 Prolonged extubation time and ICU stay are interrelated parameters. Pneumonia complications are due these extended times. This cohort study had several limitations. Because it was a typical retrospective study, it suffered from lack of randomisation. The patient population was relatively small, which may have reduced our ability to detect statistically significant differences.

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all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18(9):1731–1740. 2.

Yamauchi T, Miyata H, Sakaguchi T, et al. Coronary artery bypass grafting in hemodialysis-dependent patients. Circ J 2012; 76(5): 1115–1120.

Leier CV, Boudolulas H. Renal disorders and heart disease. In: Braunwald E, Zipes DP, Libby P (eds). Heart Disease. 5th edn. Philadelphia: WB Saunders, 1997: 1914–1938.

Gradaus F, Ivens K, Peters AJ, et al. Angiographic progression of coronary artery disease in patients with end-stage renal disease. Nephrol Dial Transplant 2001; 16(6): 1198–1202.

Logar CM, Herzog CA, Beddhu S. Diagnosis and therapy of coronary artery disease in renal failure, end-stage renal disease, and renal transplant populations. Am J Med Sci 2003; 325(4): 214–222.

Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int 1995; 47(3): 884–890.

Churchill DN, Taylor DW, Cook RJ, et al. Canadian Hemodialysis Morbidity Study. Am J Kidney Dis1992; 19: 214–234.

8. Ko W, Kreiger KH, İsom OW. Cardiopulmonary bypass procedures in dialysis patients. Ann Thorac Surg l993; 55(3): 677–684.

Bhattacharyya N, Cheung AH, Dang CR, et al. Open heart surgery in patients with end stage renal disease. Ann J Nephrol 1997; 17(5): 435–439.

10. Krishnaswami A, Leong TK, Hlatky MA, Chang TI, Go AS. Temporal trends in mortality after coronary artery revascularization in patients with end-stage renal disease. Perm J 2014; 18(3): 11–16. 11. Nwiloh JO, Obialo CI. Heart surgery in end-stage renal disease: is outcome worse for African American patients? Open J Cardiovasc Surg 2013; 6: 21–26. 12. Kaul TK, Fields BL, Reddy MA, Kahn DR. Cardiac operations in patient with end-stage renal disease. Ann Thorac Surg 1994; 57(3): 691–696. 13. Chu D, Bakaeen FG, Dao TK, LeMaire SA, Coselli JS, Huh J. On-pump versus off-pump coronary artery bypass grafting in a cohort of 63,000 patients. Ann Thorac Surg 2009; 87(6): 1820–1827. 14. Horai T, Fukui T, Tabata M, Takanashi S. Early and mid-term results of off-pump coronary artery bypass grafting in patients with end stage renal disease: surgical outcomes after achievement of complete revascu-

Conclusion Coronary artery bypass surgery is a highly risky approach for patients suffering from ESRD. On-pump surgery is preferred for the best surgical results, especially in elderly and high-risk patients. Peri-operative MI and an increased CK-MB level are predictive factors for mortality. However, uncontrolled hypertension and low functional capacity (NYHA) are independent determinants of mortality for this patient group.

larization. Interact Cardiovasc Thorac Surg 2008; 7(2): 218–221. 15. Kleisli T, Cheng W, Jacobs MJ, et al. In the current era, complete revascularization improves survival after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2005; 129(6): 1283–1291. 16. Caputo M, Reeves BC, Rajkaruna C, Awair H, Angelini GD. Incomplete revascularization during OPCAB surgery is associated with reduced mid-term event-free survival. Ann Thorac Surg 2005; 80(6): 2141–2147. 17. Remuzzi G. Bleeding in renal failure. Lancet 1988; 331(8596): 1205–1208. 18. Rabelink AJ, Zwaginga JJ, Koomans HA, Sixma JJ. Thrombosis and hemostasis in renal disease. Kidney Int 1994; 46(2): 287–296.

References 1.

London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on

19. Nakatsu T, Tamura N, Yanagi S, Kyo S, Koshiji T, Sakata R. Hemorrhage as a life-threatening complication after valve replacement in end-stage renal disease patients. Gen Thorac Cardiovasc Surg 2015; 63(7): 386–394.

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Presentation and mortality of patients hospitalised with acute heart failure in Botswana Julius Chacha Mwita, Matthew J Dewhurst, Mgaywa GMD Magafu, Monkgogi Goepamang, Bernard Omech, Koketso Lister Majuta, Marea Gaenamong, Tommy Baboloki Palai, Mosepele Mosepele, Yohana Mashalla

Abstract Introduction: Heart failure is a common cause of hospitalisation and therefore contributes to in-hospital outcomes such as mortality. In this study we describe patient characteristics and outcomes of acute heart failure (AHF) in Botswana. Methods: Socio-demographic, clinical and laboratory data were collected from 193 consecutive patients admitted with AHF at Princess Marina Hospital in Gaborone between February 2014 and February 2015. The length of hospital stay and 30-, 90- and 180-day in-hospital mortality rates were assessed. Results: The mean age was 54 ± 17.1 years, and 53.9% of the patients were male. All patients were symptomatic (77.5% in NYHA functional class III or IV) and the majority (64.8%) presented with significant left ventricular dysfunction. The most common concomitant medical conditions were hypertension (54.9%), human immuno-deficiency virus (HIV) (33.9%), anaemia (23.3%) and prior diabetes mellitus (15.5%). Moderate to severe renal dysfunction was detected in 60 (31.1%) patients. Peripartum cardiomyopathy was one of the important causes of heart failure in female patients. The most commonly used treatment included furosemide (86%), beta-blockers (72.1%), angiotensin converting enzyme inhibitors (67.4%), spironolactone (59.9%), digoxin (22.1%),

Department of Internal Medicine, University of Botswana, Gaborone, Botswana Julius Chacha Mwita, MD, MMed, MSc, jmwita@gmail.com Bernard Omech, MB ChB, MMed Koketso Lister Majuta, MB BS Marea Gaenamong, MB BS Tommy Baboloki Palai, MB BS Mosepele Mosepele, MD, MSc

Department of Cardiology, North Tees and Hartlepool NHS Foundation Trust, UK Matthew J Dewhurst, MD, MRCP

Department of Family Medicine and Public Health, University of Botswana, Gaborone, Botswana Mgaywa GMD Magafu, MD, MPH, PhD

Department of Internal medicine, Princess Marina Hospital, Gaborone,Botswana Julius Chacha Mwita, MD, MMed, MSc, Monkgogi Goepamang, MB ChB, MRCPI Bernard Omech, MB ChB, MMed Tommy Baboloki Palai, MB BS Mosepele Mosepele, MD, MSc

Department of Biomedical Sciences, University of Botswana, Gaborone, Botswana Yohana Mashalla, MD, PhD

angiotensin receptor blockers (5.8%), nitrates (4.7%) and hydralazine (1.7%). The median length of stay was nine days, and the in-hospital mortality rate was 10.9%. Thirty-, 90- and 180-day case fatality rates were 14.7, 25.8 and 30.8%, respectively. Mortality at 180 days was significantly associated with increasing age, lower haemoglobin level, lower glomerular filtration rate, hyponatraemia, higher N-terminal pro-brain natriuretic peptide levels, and prolonged hospital stay. Conclusions: AHF is a major public health problem in Botswana, with high in-hospital and post-discharge mortality rates and prolonged hospital stays. Late and symptomatic presentation is common, and the most common aetiologies are preventable and/or treatable co-morbidities, including hypertension, diabetes mellitus, renal failure and HIV. Keywords: acute heart failure, in-hospital mortality, length of hospital stay, outcomes, Botswana Submitted 31/3/16, accepted 19/6/16 Published online 24/8/16 Cardiovasc J Afr 2017; 28: 112–117

www.cvja.co.za

DOI: 10.5830/CVJA-2016-067

The prevalence of heart failure (HF) is increasing in Africa, adding to the already existing burden of infectious diseases and making HF a common cause of hospitalisation on the continent.1,2 HF is one of the primary reasons for regular hospital visits and admissions, accounting for about three to 7% of admissions in Africa.3 In spite of advances in treatment, patients admitted with acute heart failure (AHF) have outcomes that are worse than many types of cancer.4,5 In Africa, where the majority of patients are likely to present late and with severe symptoms, the in-hospital mortality rate of AHF ranges from nine to 12.5%, which is considerably higher than in developed countries.6 Even after hospital discharge, case fatality rates for HF remain high, with mortality rates of more than 25, 40 and 75% at three months, one year and five years after diagnosis, respectively.7-9 Although HF management has advanced in the Western world, in many developing countries, including Botswana, the benefits may not be evident for several reasons, including insufficient human resources, lack of appropriate medications and discontinuity of care. This study aimed to describe clinical profiles and outcomes in patients with AHF admitted at Princess Marina Hospital (PMH) in Gaborone, Botswana.

Methods This was an observational study conducted at PMH, Botswana’s major tertiary and referral hospital, with a catchment population

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of 231 592 in Gaborone, plus patients referred from other areas of the country.10 The study was granted ethical clearance by the University of Botswana and PMH institutional review boards, and permission to carry out the study was obtained from the Ministry of Health. Written informed consent was obtained before data collection from all participants, or their relatives, in cases where the patient was unable to consent. Consecutive AHF patients aged 18 years of age or older admitted to the hospital between February 2014 and February 2015 were enrolled in the study. HF was defined according to the criteria of the European Society of Cardiology (ESC), and both decompensated HF in patients with a previous HF diagnosis and new-onset AHF were included.11 Patients were excluded if they had other diseases with a short-term prognosis, such as malignancy or World Health Organisation stage 4 HIV infection. From the enrolled patients, symptoms and signs of HF were ascertained, and the admission functional status was assessed using the New York Heart Association (NYHA) classification.12 Any pre-hospital medical history of atrial fibrillation, valvular heart disease, diabetes mellitus, hypertension, HIV infection and cerebrovascular disease was also recorded. On the day of enrolment, three blood pressure measurements were obtained and averaged.13 The blood pressure measurement made on admission was also recorded. A patient was considered hypertensive on the basis of a self-reported history of hypertension and/or the use of blood pressure-lowering medications or a sustained blood pressure ≥ 140/90 mmHg during the course of the admission.14 Complete blood counts, serum electrolytes, urea, creatinine, uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP) analyses were performed on all enrolled patients. Moderate to severe renal failure was diagnosed by an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 at admission and/or by patients being on dialysis.1 Patients whose haemoglobin values were less than 10 g/dl were classified as having anaemia.7,1 Testing for HIV was done for patients whose sero-status was unknown. Echocardiography using a Vivid S™ S6 machine (GE Healthcare view, USA) was performed on all patients by two cardiologists (JM and MG) according to the American Society of Echocardiography guidelines.16 Two-dimensional M-mode measurements of left ventricular (LV) internal dimension, interventricular septal thickness and posterior wall thickness were made at end-diastole and end-systole.16,17 M-mode measurements for the left atrial diameters were obtained at end-systole. Left ventricular ejection fraction (LVEF) was calculated from left ventricular volumes obtained at end-diastole and end-systole using the modified biplane Simpson’s rule in the apical four- and two-chamber views.16 LVEF < 45% was used to define significant LV systolic dysfunction, whereas patients with LVEF > 45% were assessed as having HF with preserved ejection fraction. Right ventricular dysfunction was assessed by a tricuspid annular plane systolic excursion (TAPSE) < 16 cm.17 Available clinical and echocardiographic data were used to assign a likely primary aetiology to each patient based on the ESC guidelines and the Heart of Soweto study definitions.11,18 Ischaemic HF was determined by the presence of LV systolic dysfunction, regional wall-motion abnormality, electrocardiographic abnormalities, and angiographically confirmed diagnosis of coronary artery disease.18 Patients with LV systolic dysfunction

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and dilated left ventricle (LVEDD > 55 mm) of indeterminate cause were classified as having idiopathic dilated cardiomyopathy.18 Peripartum cardiomyopathy was diagnosed in patients with echocardiographic features of dilated cardiomyopathy without a demonstrable cause, and if disease presented for the first time within the last trimester of pregnancy or in the first five months postpartum.19 Other causes of HF included pericardial disease, congenital heart disease, amyloidosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, thyroid heart disease and HIV infection.20 Hospital length of stay (LOS) and in-hospital mortality were assessed for each participant. LOS was defined as the number of days from hospital admission to discharge. After discharge, patients were followed up at the PMH out-patient cardiac clinic for clinical evaluation and medication adjustment or titration. HF medications at discharge or at end-of-study follow up were documented, and patients were contacted whenever they missed their scheduled out-patient appointments, to reschedule for another appointment. In the event that participants were not contactable, the next of kin/nominated contacts were contacted. For participants who relocated to other health facilities, their information was retrieved from the nationwide electronic medical records (EMR) database, which contains clinical notes, laboratory results, pharmacy data and information on dates of patient clinic and hospital visits. Information on mortality was collected at 30, 90 and 180 days by telephone contact with their next of kin/nominated contacts and/or from the EMR. Participants who could not be contacted or traced through the EMR after discharge were declared as lost to follow up. Other patients were censored at the last available contact or clinic visit.

Statistical analysis All data were analysed using SPSS version 23.0 for Windows (SPSS Inc, Chicago, IL, USA), and summary statistics were calculated for all patient variables. Continuous variables are presented as means ± one standard deviation (SD) or medians. For non-continuous variables, absolute and relative frequencies (%) were used. Comparisons between normally distributed continuous variables were performed using the Student’s t-test or Kruskal–Wallis test. Associations between categorical variables were tested with contingency tables and Pearson’s chi-squared test; p-values less than 0.05 were considered statistically significant.

Results From the 202 patients admitted with HF during the study period, 193 (95.5%) were enrolled. Nine patients were excluded from the study because they failed to meet the inclusion criteria, four were unwilling to participate, two died and one was transferred to another hospital before enrolment. More than half of the enrolled patients (56%) were referrals from health facilities outside Gaborone. Table 1 shows the clinical and demographic characteristics of the study population. Most patients were black Africans (98.4%). Cigarette and alcohol use was found in 13 and 15%, respectively. The mean age of the patients [± standard deviation (SD)] was 54.2 ± 17.1 years, ranging from 20 to 89 years. Smoking was significantly more common in the men (18.3%)

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than in women (6.7%). All patients were symptomatic, and the majority (77.5%) presented with dyspnoea (NYHA functional class III or IV), peripheral oedema, orthopnoea, palpitations and basal crepitations. Overall, the median (IQR) systolic and diastolic blood pressures were 120.0 (103.8–133.5) and 74 (67–81.5) mmHg, respectively. Because of cost limitations, the NT-proBNP level was determined in only 107 patients, with a median value (IQR) of 3 314 (1 360–6 506) pg/ml. More than one-half (54.9%) of the patients were hypertensive. Hypertension was more commonly reported in the women than the men (64.0 vs 47.1%, p < 0.05). A prior diagnosis of diabetes mellitus was present in 30 (15.5%) patients and often coexisted Table 1. Clinical and demographic characteristics of patients admitted with heart failure Characteristics

n = 193

Mean age (years) (SD)

54.2 ± 17.1

Male gender, n (%)

104 (53.9)

Medical history, n (%) Hypertension

106 (54.9)

Prior type 2 diabetes

30 (15.5)

Renal failure

28 (15.0)

Rheumatic heart disease

21 (10.9)

Ischaemic heart disease

11 (5.7)

Stroke

19 (9.8)

Atrial fibrillation

19 (9.8)

HIV positive

61 (33.9)

Symptoms, n (%) Shortness of breath

178 (92.2)

NYHA II

40 (22.5)

NYHA III

94 (52.8)

NYHA IV

44 (24.7)

Orthopnoea

151 (78.2)

Peripheral oedema

148 (76.7)

Paroxysmal nocturnal dyspnoea

152 (78.8)

Physical findings Mean heart rate (bpm) (SD)

95.1 ± 21.2

Median systolic blood pressure (mmHg) (Q1–Q3)

120.0 (103.8–133.5)

Median diastolic blood pressure (mmHg) (Q1–Q3)

74 (67–81.5)

Murmur, n (%) Cyanosis, n (%)

76 (39.4) 7 (3.6)

Pedal oedema, n (%)

132 (68.4)

Elevated jugular venous pressure, n (%)

127 (65.8)

S3 gallop, n (%)

72 (37.3)

Basal crepitation, n (%)

126 (65.3)

Hepatomegaly, n (%)

100 (52.6)

Ascites, n (%)

43 (23.8)

Pleural effusion, n (%)

31 (16.1)

Laboratory tests Mean haemoglobin (g/dl) (SD) Creatinine (µmol/l) median (Q1–Q3) Urea (mmol/l) median (Q1–Q3) Mean sodium (mmol/l) (SD) Mean potassium (mmol/l) (SD) eGFR (ml/min/1.73 m2) median (Q1–Q3)

12.0 ± 2.96 98.0 (70–137.5) 8.3 (4.9–13.7) 134.1 ± 6.8 4.4 ± 0.9 75.9 (52.5–112.4)

Echocardiography Mean LVEF (%) (SD) Mean LA (mm) (SD) Mean IVSD (mm) (SD)

41.8 ± 20.0 43 ± 9 12.9 ± 4.1

LVEF, left ventricular ejection fraction; eGFR, glomerular filtration rate; IQR, interquartile range; SD, standard deviation; Q, quartile; NYHA, New York Heart Association functional class; LVEF, left ventricular ejection fraction, LA, left atrium; IVSD, interventricular septum diameter.

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with hypertension. Moderate to severe renal dysfunction was detected in 60 (31.1%) patients. Forty-five (23.3%) patients had a haemoglobin level < 10 g/dl, a finding that was commonly seen among those with chronic kidney disease. Overall, anaemia was more common in the women than men. HIV results were available for 180 (93.3%), and about a third (33.9%) of these patients were HIV positive. The mean LVEF was 41.7%, and about two-thirds (64.8%) of the patients had HF with significant systolic dysfunction (LVEF < 45%). Seventy-three (37.8%) patients presented with severely depressed LV function (LVEF < 30%), which was more common in men than women (44.2 vs 30.3%, p < 0.05). Left atrial diameter was enlarged to a mean value of 43 mm, and moderate to severe mitral and tricuspid regurgitation was common (31.6 and 40.4%, respectively). Other less common valvular disorders found were mitral stenosis, aortic regurgitation and aortic stenosis. The commonest causes of HF were hypertensive heart disease (40.4%), dilated cardiomyopathy (19.6%), cor pulmonale (9.8%), valvular heart disease (9.3%) and pericardial disease (6.2%). Overall, right ventricular dysfunction was common, present in 86 (44.6%) patients, and often coexisted with left ventricular systolic dysfunction. Pericardial disease, dilated cardiomyopathy and right HF were more common in men while hypertensive and valvular HF were more common in women. Although peripartum cardiomyopathy only accounted for 4.1% of all cases of HF, it turned out to be the third commonest cause of HF among female patients, occurring in eight (9%) of all female patients. The mean age of patients with peripartum cardiomyopathy was significantly lower than the other female patients (32 ± 7.3 vs 57 ± 16.8 years, p < 0.01). Patients with pericardial disease were more likely to be HIV positive than those with other types of HF. Ischaemic heart disease was found in 5.7% of the patients and was more common in women and patients with hypertension and diabetes. Other causes of HF in the cohort included amyloidosis, hypertrophic cardiomyopathy, thyroid heart disease and congenital heart disease. Table 2 shows patient outcomes in the wards, discharge medications, and outcomes over the six months of postdischarge follow up. Overall, diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, and spironolactone were often prescribed to patients at discharge. The most commonly used medications were carvedilol, bisprolol, enalapril, telmisartan and furosemide. In-hospital mortality rate of HF patients was 10.9%, and was associated with hyponatraemia (p = 0.023), elevated NT-proBNP (p = 0.001) and urea levels (p = 0.013), and hyperuricaemia (p = 0.036). The median length of stay was nine days (IQR 5–15). The LOS was similar regardless of the NYHA functional status of HF after hospital discharge. After 30 days, three (1.6%) patients could not be traced telephonically and were declared lost to follow up. Seven patients (4.1%) died within 30 days of discharge from hospital. Overall, 28/190 (14.7%) patients died within 30 days of admission. By the 90th day after admission, 10 (5.2%) patients were lost to follow up, and of the rest, 47/183 (25.7%) were deceased. A total of 11 (5.7%) were lost to follow up by six months of admission, and the 180-day case fatalities from HF were 30.8%. Mortality at 180 days was significantly associated with increasing age, lower haemoglobin level, lower eGFR, hyponatraemia, higher NT-proBNP levels, and prolonged hospital stay (Table 3).

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Table 2. Outcomes and discharge medications of patients admitted with acute heart failure at Princess Marina Hospital Discharge medication

Number (%)

Diuretics

148 (86)

Beta-blockers

124 (72.1)

ACE inhibitors

116 (67.40

Angiotensin receptor blockers

10 (5.8)

Spironolactone

103 (59.9)

Digoxin

38 (22.1)

Nitrate

8 (4.7)

Hydralazine

3 (1.7)

Outcome Median length of hospital stay (IQR)

9 (5–15)

In-hospital mortality (n = 193)

21 (10.9)

30-day mortality

(n = 190)

28 (14.7)

90-day mortality (n = 182)

47 (25.8)

180-day mortality (n = 181)

56 (30.9)

Discussion This is the first observational study of acute HF in Botswana, and it confirms the findings of previous studies that are unique to the African setting. Contrary to the situation in developed countries, where HF patients present at a much older age, with most cases recorded around the seventh and eighth decades of life, our cohort comprised relatively young patients (mean age 54 years).21 Similar to previous studies of AHF patients in Africa, our data have shown that HF affects young and middle-aged Africans in their most productive period of life.7,18,22-25 Table 3. Associations between demographic and medical characteristics of the patients and mortality outcome at the end of the follow-up period (six months post-admission) Outcome Characteristic Age (years) mean (SD) Male gender, n (%)

Died (n = 56)

Survived (n = 125)

p-value

59.8 (16.5)

51.93 (16.547)

0.004†

32 (57.1)

65 (52)

0.60*

Medical history, n (%) Hypertension

27 (48.2)

72 (57.6)

0.200*

Diabetes

7 (12.5)

21 (16.8)

0.515* 1.00*

Rheumatic heart disease

4 (7.1)

10 (7.9)

Ischaemic heart disease

3 (5.4)

15 (12)

0.281*

Stroke/TIA

4 (7.1)

13 (10.4)

0.591*

Atrial fibrillation

7 (12.5)

11 (8.8)

0.431*

HIV positive

16 (28.6)

41 (32.8)

0.306*

Median SAP (mmHg)

120.5 (108–131.4)

120.0 (101.5–141.3)

0.887‡

Mean DAP (mmHg)

75.3 (67–79.9)

74 (66.0– 85.3)

0.878‡

LVEF (%)

41.9 ± 20.7

41.8 ± 20.2

0.975†

Haemoglobin (g/dl)

11.2 ± 3.1

12.4 ± 2.7

0.010†

MCV (%)

87.9 ± 9.5

89.3 ± 10.9

0.337†

70.95 (41.7–95.6)

84.8 (55.9–113.6)

0.043‡

Clinical history

eGFR (ml/min/1.73 m2), median (IQR) Sodium (mEq/l) LOS (days), median (IQR) Creatinine (µmol/l), median (IQR) Urea (mmol/l), median (IQR) NT-proBNP (pg/ml), median (IQR)

132.0 ± 8.0

135.1 ± 6.1

0.010†

11 (6.0–19.8 )

7 (5–12.3)

0.005‡

116.5 (80.5–149.0)

96.0 (66.8–130.8)

0.041‡

11.4 (6.6–18.9)

7.1 (4.7–12.0)

0.002‡

6597 (4340.0–18810.3) 2739.0 (998.5–4656.0) < 0.001‡

* Chi- squared; ‡Kruskal–Wallis, †Student’s t-test. TIA, transient ischaemic attack; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; LVEF, left ventricular ejection fraction; MCV, mean corpuscular volume; eGFR, estimated glomerular filtration rate; LOS, length of stay; NT-proBNP, N-terminal pro-brain natriuretic peptide.

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The young age at presentation is not surprising because of the predominance of non-ischaemic causes of HF among black Africans, such as hypertension, which often occur early in life and remain undetected, or if detected are inadequately treated. In our cohort, ischaemic HF was found in only 5.7% of the patients. As expected, a significant proportion of our patients was symptomatic, with left ventricular systolic dysfunction, and was predominantly men.7,22,23 More than three-quarters (77.5%) presented in NYHA functional class III or IV, a finding which is in agreement with previous reports.6 One of the most striking features of this cohort was the relatively high prevalence of HIV-seropositive patients. The prevalence of HIV seropositivity (33.9%) reported in this study is far higher than in the previous largest HF study among HIV-poitive patients in South Africa.20 The observed high prevalence of HIV in our cohort may partly be explained by a relatively higher prevalence of HIV in Botswana than in South Africa.26 Botswana has the world’s third-highest HIV infection rate in the world after Swaziland and Lesotho, with an adult prevalence rate of about 24.4% in 2012.26 This high prevalence of HIV infection in our cohort provides additional evidence of the confluence of non-communicable and infectious diseases as co-morbidities among HF patients in Africa. HIV-associated cardiomyopathy, pulmonary hypertension, pericardial disease and accelerated atherosclerosis are known to occur frequently in HIV-positive patients.27 Our data reaffirm that hypertension, diabetes, renal failure and anaemia are still common and contribute significantly to the aetiological burden of HF in Africa. These co-morbidities are not only the likely aetiologies of HF, but are also factors that affect the clinical course of the disease, and should be concurrently addressed at the time of admission.28 Consistent with previous reports from sub-Saharan Africa, hypertensive heart disease, dilated cardiomyopathy, cor pulmonale (right heart disease), peripartum cardiomyopathy, pericardial disease and valvular heart disease were the common causes of HF in our cohort.6,7,18,20,22,23,25,27 Ischaemic HF, however, was uncommon in our cohort, and patients with pericardial disease were more likely to be HIV positive than those with other types of HF. In our study, peripartum cardiomyopathy was the third commonest aetiology of HF among females. Although the mean age of patients with peripartum cardiomyopathy was similar to previous studies in Africa, the reported prevalence (9%) was lower than that reported in other African studies, where 13 to 60% of admissions for HF in females were related to peripartum cardiomyopathy.25,29,30 Nevertheless, consistent with the above studies, it is clear that peripartum cardiomyopathy is one of the important causes of HF among female patients in Africa. The present study demonstrates that patients with HF are at risk for adverse clinical outcomes, which ranks HF among the major causes of death of cardiovascular origin in Africa.6 The in-hospital mortality rate (10.9%) in our cohort is similar to the nine to 12.5% case fatality rates reported elsewhere in Africa, but was higher than reports from high-income countries.6,21,24,31 Generally, African-Americans have been reported to have a lower in-hospital mortality rate compared to Caucasians, and the same results could be expected among HF patients in Africa if the quality of care was similar.31 However, in resourcepoor settings such as ours, there is inconsistent availability of HF medications, limited access to intensive care services,

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and non-availability of advanced HF treatments such as cardiac resynchronisation therapy and assist devices, which are commonly used in the developed world. The high mortality rates in the current study and other African studies should therefore be taken as a call for improvement in the care of patients with HF in sub-Saharan Africa. The LOS is another measure of quality of in-hospital care of HF and is directly related to cost.32 The median LOS of nine days in our cohort is similar to previous studies in Africa and Europe, but more than twice that reported in North America.7,21,24,31 The LOS found in our study and probably other African studies may be explained by multiple factors that include a significant coexistence of other acute or chronic medical conditions, occasional interruption of treatment due to unavailability of medication at hospitals, non-compliance, low rates of intensive care admission, and patients’ non-medical problems requiring intervention. Being a tertiary hospital in Botswana, PMH receives patients with severe forms of HF, including patients referred from distant hospitals, whose hospital stays may be prolonged by lack of timely transport back to their referring hospitals or residence. After discharge, case fatality rates among those with HF are reported to be high, with up to 40% of those with severe HF dying within one year.7,8 In our study, about a third (30.9%) of patients died within six months of admission, a rate that is significantly higher than the 180-day mortality rate of 17.8% reported in the large THESUS-HF study.5 The difference in mortality rates may partly be explained by the fact that the THESUS-HF study was performed in different settings with variable patient presentations and mortality rates.7 Several co-morbidities that were prevalent among our patients, and are known to independently increase the risk of mortality among HF patients were hypertension, diabetes, renal failure and anaemia.28 Overall, our study showed that in-hospital and post-discharge mortality rates were higher in patients who had longer lengths of hospital stay, hyponatraemia, older age, lower haemoglobin level, higher NT-proBNP level, and lower eGFR. These poor prognostic factors have also been reported in other studies.28 This study was undertaken in a small town and hence is limited by the relatively small number of patients. However it provides useful findings, opening new avenues for future studies on HF. Because our cohort was selected from a tertiary hospital, it is likely to over-represent those with severe HF. For various reasons, we could not follow up all our patients at our clinic after discharge, and it was not possible to gather information on their treatment. Therefore, the influence of the differences in out-patient care on patients’ outcomes could not be assessed. All deaths were assumed to be attributable to HF, which is also likely to be an overestimation because of other significant medical co-morbidities that were prevalent in our patients.

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both on an in-patient basis and in the community following discharge, in order to help improve prognosis. We thank the patients and their relatives for their cooperation. We acknowledge the nursing staff at the medical wards and cardiac clinic for their assistance with the study. Lastly, we thank Dr Daniel Baxter for his critical comments on the manuscript. This study was supported by a grant from the University of Botswana; Round 25.

References 1.

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

Onwuchekwa AC, Asekomeh GE. Pattern of heart failure in a Nigerian teaching hospital. Vasc Health Risk Management 2009; 5: 745.

Damasceno A, Cotter G, Dzudie A, Sliwa K, Mayosi BM. Heart failure in sub-Saharan Africa: time for action. J Am Coll Cardiol 2007; 50(17): 1688–1693.

Varela-Roman A, Gonzalez-Juanatey J, Basante P, Trillo R, GarcíaSeara J, Martinez-Sande J, et al. Clinical characteristics and prognosis of hospitalised inpatients with heart failure and preserved or reduced left ventricular ejection fraction. Heart 2002; 88(3): 249–254.

McMurray J, Stewart S. The burden of heart failure. Eur Heart J (Suppl) 2002; 4: D50.

Kengne AP, Dzudie A, Sobngwi E. Heart failure in sub-Saharan Africa: a literature review with emphasis on individuals with diabetes. Vasc Health Risk Management 2008; 4(1): p. 123.

Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries: results of the sub-Saharan Africa Survey of Heart Failure. Arch Int Med 2012; 172(18): 1386–1394.

McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart 2000. 83(5): 596–602.

Ho K, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993; 88(1): 107–115.

10. Population

and Housing Census 2011/National Statistical Tables

Report [Internet]. Statistics Botswana. 2011 [cited 2016 Jul 20]. Available from: http://www.cso.gov.bw/images/national_statisticsreport.pdf. 11. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur J Heart Failure 2012; 14(8): 803–869. 12. Fisher JD. New York Heart Association Classification. Arch Int Med 1972; 129(5): 836–836. 13. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for blood pressure measurement in humans and experimental animals part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005; 45(1): 142–161. 14. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb

Conclusion

C, Handler J, et al. 2014 evidence-based guideline for the manage-

This study has demonstrated high morbidity and mortality rates among patients admitted to a tertiary hospital in Botswana for AHF. Both non-communicable (hypertension) and infectious diseases (HIV) are common among HF patients and often coexist. As mortality rates among HF patient remain high after admission, efforts should be made to improve HF management,

appointed to the Eighth Joint National Committee (JNC 8). J Am Aed

ment of high blood pressure in adults: report from the panel members Assoc 2014; 311(5): 507–520. 15. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Int Med 1999; 130(6): 461–470.

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16. Picard MH., Adams D, Bierig SM, Dent JM, Douglas PS, Gillam LD, et

hospitalized for heart failure in the United States: rationale, design,

al. American Society of Echocardiography recommendations for quality

and preliminary observations from the first 100,000 cases in the Acute

echocardiography laboratory operations. J Am Soc Echocardiogr 2011;

Decompensated Heart Failure National Registry (ADHERE). Am

24(1): 1–10.

Heart J 2005; 149(2): 209–216.

17. Masani N, Allen J, Chambers J. Echocardiography: Guidelines for

25. Karaye KM, Sani MU. Factors associated with poor prognosis among

Chamber Quantification. London: British Society of Echocardiography,

patients admitted with heart failure in a Nigerian tertiary medical

2010.

centre: a cross-sectional study. BMC Cardiovasc Disord 2008; 8(1): 1.

18. Stewart S, Wilkinson D, Hansen C, Vaghela V, Mvungi R, McMurray

26. World Health Organization, UNAIDS, Global HIV/AIDS response:

J, et al. Predominance of heart failure in the Heart of Soweto Study

epidemic update and health sector progress towards universal access:

cohort emerging challenges for urban African communities. Circulation

progress report 2011 [Internet]. Geneva: WHO; 2011; 233: 2012 [cited

2008; 118(23): 2360–2367.

2012 Oct 29].

19. Hibbard JU, Lindheimer M, Lang RM. A modified definition for

27. Ntsekhe M, Mayosi BM. Cardiac manifestations of HIV infection:

peripartum cardiomyopathy and prognosis based on echocardiography.

an African perspective. Nature Clin Prac Cardiovasc Med 2009; 6(2):

Obstet Gynecol 1999; 94(2): 311–316.

120–127.

20. Sliwa K, Carrington MJ, Becker A, Thienemann F, Ntsekhe M, Stewart

28. Van Deursen VM, Urso R, Laroche C, Damman K, Dahlström U,

S. Contribution of the human immunodeficiency virus/acquired immu-

Tavazzi L, et al. Co‐morbidities in patients with heart failure: an analysis

nodeficiency syndrome epidemic to de novo presentations of heart

of the European Heart Failure Pilot Survey. Eur J Heart Failure 2014;

disease in the Heart of Soweto Study cohort. Eur Heart J 2012; 33(7): 866–874.

16(1): 103–111. 29. Sliwa K, Förster O, Libhaber E, Fett JD, Sundstrom JB, Hilfiker-

21. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola

Kleiner D, et al. Peripartum cardiomyopathy: inflammatory markers as

V-P, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospital-

predictors of outcome in 100 prospectively studied patients. Eur Heart

ized acute heart failure patients: description of population. Eur Heart J 2006; 27(22): 2725–2736.

J 2006; 27(4): 441–446. 30. Isezuo SA, Abubakar SA. Epidemiologic profile of peripartum cardio-

22. Ogah OS, Stewart S, Falase AO, Akinyemi JO, Adegbite GD, Alabi AA,

myopathy in a tertiary care hospital. Ethnicity Dis 2006; 17(2): 228–233.

et al. Contemporary profile of acute heart failure in southern Nigeria:

31. Kamath SA, Drazner MH, Wynne J, Fonarow GC, Yancy CW.

Data from the Abeokuta heart failure clinical registry. J Am Coll

Characteristics and outcomes in African American patients with decom-

Cardiol: Heart Failure 2014; 2(3): 250–259.

pensated heart failure. Arch Int Med 2008; 168(11): 1152–1158.

23. Makubi A, Hage C, Lwakatare J, Kisenge P, Makani J, Rydén L, et

32. Krumholz HM, Keenan PS, Brush JE, Bufalino VJ, Chernew ME,

al. Contemporary aetiology, clinical characteristics and prognosis of

Epstein AJ, et al. Standards for measures used for public reporting of

adults with heart failure observed in a tertiary hospital in Tanzania:

efficiency in health care: a scientific statement from the American Heart

the prospective Tanzania Heart Failure (TaHeF) study. Heart 2014:

Association Interdisciplinary Council on Quality of Care and Outcomes

heartjnl-2014-305599.

Research and the American College of Cardiology Foundation. J Am

24. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients

Coll Cardiol 2008; 52(18): 1518–1526.

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The effect of proximal anastomosis on the expansion rate of a dilated ascending aorta in coronary artery bypass surgery: a prospective study Ahmet Yavuz Balcı, Unsal Vural, Rezan Aksoy, MD Fatih Özdemir, Seçkin Satılmış, Mehmet Kızılay, Mutlu Şenocak, Huseyin Şaşkın, İlyas Kayacıoğlu, İbrahim Yekeler

Abstract Background: This study was designed to determine the short- and long-term effects of proximal aortic anastomosis, performed during isolated coronary artery bypass grafting (CABG) in patients with dilatation of the ascending aorta who did not require surgical intervention. Methods: The study was performed on 192 (38 female and 160 male patients; mean age, 62.1 ± 9.2 years; range, 42–80 years) patients with dilatation of the ascending aorta who underwent CABG surgery between 1 June 2006 and 31 May 2014. In group 1 (n = 114), the saphenous vein and left internal mammarian artery grafts were used, and proximal anastomosis was performed on the ascending aorta. In group 2 (n = 78), left and right internal mammarian artery grafts were used, and proximal aortic anastomosis was not performed. Pre-operatively and in the first and third years postoperatively, the ascending aortic diameter was measured and recorded using transthoracic echocardiography at four different regions (annulus, sinus of Valsalva, sinotubular junction and tubular aorta). Results: A statistically significant difference was found between the groups for the number of grafts used and the duration of aortic cross-clamping and cardiopulmonary bypass. No significant intergroup difference was seen for the mean diameter of the ascending aorta (p > 0.05). Annual changes in the aortic diameter were found to be extremely significantly different in both groups (p = 0.0001). Mean values of the aortic diameter at the level of the sinotubular

Department of Cardiovascular Surgery, Dr Siyami Ersek Cardiovascular Surgery and Thoracic Hospital, Istanbul, Turkey Ahmet Yavuz Balcı, MD Unsal Vural, MD, unsalvural@gmail.com MD Fatih Özdemir MD Mehmet Kızılay MD Mutlu Şenocak MD İlyas Kayacıoğlu MD, PhD İbrahim Yekeler, MD

Department of Cardiovascular Surgery, Koşuyolu Training and Research Hospital, Istanbul, Turkey Rezan Aksoy, MD

Department of Cardiology, Acibadem University, Istanbul, Turkey Seçkin Satılmış, MD

Department of Cardiovascular Surgery, Derince Training and Research Hospital, Istanbul, Turkey Huseyin Şaşkın, MD

junction and tubular ascending aorta, mean aortic diameters (p = 0.002 and p = 0.0001, respectively), annual increase in diameter (p = 0.0001 and p = 0.0001, respectively), and mean annual difference in diameter (p = 0.0001 and p = 0.0001, respectively) at one and three years postoperatively were statistically significantly different between the groups. Conclusion: In patients with ascending aortic dilatation who did not require surgical intervention and who had proximal anastomosis of the ascending aorta and underwent only CABG, we detected statistically significant increases in the diameter of the sinotubular junction and tubular aorta up to three years postoperatively.

Keywords: coronary artery bypass grafting, aortic dilatation, proximal anastomosis Submitted 23/11/15, accepted 10/7/16 Published online 22/8/16 Cardiovasc J Afr 2017; 28: 118–124

www.cvja.co.za

DOI: 10.5830/CVJA-2016-071

Aortic dilatation is a clinical entity with many aetiological factors, which can be seen singly or in association with other cardiac pathologies. Generally, anuloaortic ectasia, Marfan syndrome, atherosclerotic aortic degeneration, aortic dissection and bicuspid aortic valve disease accompany aortic dilatation.1 Despite novel approaches in surgical and endovascular treatment procedures for aneurysms, the same degree of advancement has not been achieved with regard to the molecular and cellular mechanisms that trigger its pathogenesis and progression. Genetic factors and inflammatory responses are recognised as important aspects in the development of aneurysms. Fedak et al. reported the fundamental role of matrix metalloproteinases (MMP) in the structural integrity of the aorta.2 In some studies, loss of elastin and collagen of the aortic wall has been demonstrated to induce the development of aneurysms. Loss of elastin and collagen is caused by an increase in the activity of matrix proteinases (elastase and collagenase) or a decrease in the activity of anti-proteases [mellaproteinase tissue inhibitor (TIMP)] and alpha-1-antitrypsin.2 Increase in the levels of intercellular adhesion molecules induces migration of macrophages to this region, with the resultant increase in the production of MMP2 and MMP9, fragmentation of elastin and triggering of aneurysm formation. Macrophages degrade elastin by activating tumour necrosis factor and interleukin-1. The production of elastin and collagen may also be impaired

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due to genetic causes, as seen in Marfan syndrome and Ehlers Danlos type 4.2 Knowing the aetiological factors causing aneurysms may contribute to slowing down the pathogenic process and determination of a treatment modality. Aortic valve pathologies, hypertension, smoking, alcoholic beverages, diabetes mellitus, cross-clamping, cannulation site, aortic suture lines, and proximal anastomosis of coronary artery grafts have been held responsible for the development of aortic aneurysms. Formulae suggested to estimate the growth rate of aortic aneurysms demonstrate differences based on aetiological, regional and geographic conditions.3 This study was designed to determine the short- and longterm effects of proximal aortic anastomosis performed during isolated coronary artery bypass grafting (CABG) in patients with dilatation of the ascending aorta who did not require surgical intervention.

Methods The study, to be performed on patients with dilatation of the ascending aorta who would undergo CABG surgery in the clinics of Dr Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital between 1 June 2006 and 31 May 2014, was initiated after approval of the local ethics committee was obtained. The objective of the study was explained to all patients and their written approval was obtained. The study was completed with 192 patients (38 female and 160 male; mean age 62.1 ± 9.2 years; range 42–80 years) who had to undergo isolated CABG surgery. Patients with a diagnosis of connective tissue disease, those who had undergone additional cardiac surgery, re-operation, cases with aneurysms at various regions of the aorta or peripheral arteries, individuals with extremely calcified aortae and congenital or acquired aortic valve pathologies, and patients lost to postoperative follow up were excluded from the study. Patients who had cardiopulmonary bypass (CPB) and isolated CABG and those whose ascending aortic diameter was 40–45 mm (mean: 42.1 ± 1.8 mm) at its widest region, determined using transthoracic echocardiography (TTE), were included in the study. The patients were divided into two groups. In group 1 (n = 114, 59.4%), saphenous vein and left internal mammarian artery (LIMA) grafts were used, and proximal anastomosis was performed on the ascending aorta. In group 2 (n = 78, 40.6%), LIMA and right internal mammarian artery (RIMA) grafts were used, and proximal aortic anastomosis was not performed. Clinical and demographic data of the patients related to age and gender, left ventricular ejection fraction (LVEF), hypertension (HT), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic renal failure (CRF), previous myocardial infarction (MI), hyperlipidaemia, peripheral artery disease (PAD), stroke, smoking status and alcohol use were recorded. Pre-operatively and in the first and third years postoperatively, the ascending aorta was measured and recorded using TTE diameters at four different regions (annulus, sinus of Valsalva, sinotubular junction and tubular aorta). Postoperative monitoring of the patients was achieved via communication with patients by telephone. Under routine intra-operative anaesthesia, a median sternotomy was performed on all patients. The bypass grafts

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(LIMA, RIMA, saphenous vein) were prepared. Following heparinisation (3 mg/kg IV), an arterial cannula was inserted into the ascending aorta and a two-stage cannula was implanted into the right atrium. Using a roller pump and membrane oxygenator, we proceeded with CPB. During CPB, activated coagulation time was maintained over 400 seconds. Moderate levels of systemic hypothermia (28–30°C) were used. Pump flow rate and perfusion pressure were held at 2.2–2.4 l/min/m2 and 50–85 mmHg, respectively. Following crossclamping of the aorta, cold blood cardioplegia was performed in the antegrade direction to achieve cardiac arrest. After completion of the distal anastomosis, cardioplegic solution was delivered through the saphenous vein graft and myocardial protection was maintained. After placement of the side clamps, proximal anastomosis was performed on a beating heart. The patients were extubated in the intensive care unit within three to six hours of the operation. As criteria for extubation, the patient had to be wide awake, haemodynamically stable, and the amount of hourly drainage had to have dropped to acceptable amounts. During the postoperative period, patients who did not develop major complications were followed up in the ward. All patients were discharged after an average of seven to nine days. As a control, TTE was performed at one and four weeks postoperatively and no pathological evidence was found. TTE was repeated at one and three years postoperatively. The TTE procedure was performed by a cardiologist blinded to the grouping of patients. Before the procedure, the patients were informed about the procedure and their approvals were obtained. Measurements were made at four different regions of the ascending aorta. During TTE, ventricular and valvular dysfunction (if any) were also determined. Left ventricular end-diastolic (LVEDD) and end-systolic diameters (LVESD), LVEF, and systolic and diastolic volumes were also determined. In our study we chose TTE rather than CT angiography as TTE provides information on ventricular and valvular function and evaluates the aortic annulus and sinotubular junction more effectively, in addition to its lower cost and non-toxicity.

Statistical analysis For statistical evaluations, the SPSS statistical program (SPSS for Windows, version 11.0, SPSS Inc, Chicago) was used. If all measured data demonstrated a normal distribution, they were expressed as mean ± standard deviation; if not, they were indicated as median (minimum–maximum) values. Numerical data were presented as percentages (%). For data obtained with measurements, normality of distribution was evaluated using histograms or the Kolmogorov– Smirnov test and their homogeneity were assessed with Levene’s test for equality of variance. For data with normal and homogenous distribution, intergroup difference was evaluated using the Student’s t-test, while data with non-normal and non-homogenous distributions were evaluated using the Mann– Whitney U-test. Intergroup differences among the numerical data were evaluated with parametric or non-parametric Pearson’s chi-squared and Fisher’s exact test, based on the parametric or non-parametric distribution of data, respectively. In comparisons of mean values of dependent groups, Friedman’s S-test was used. Data with a p-value < 0.05 was accepted as statistically significant.

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Results Demographic characteristics and clinical features of the patients with aortic dilatation who underwent CPB and isolated CABG surgery are summarised in Table 1. No statistically significant differences were found between the groups for demographic and clinical characteristics (p > 0.05). The mean number of grafts used in the CABG operation was calculated for group 1 [3.6 ± 0.9 (median: 4; range: 1–6)] and group 2 [1.5 ± 0.5; (median: 1; range: 1–2)]. A statistically significant intergroup difference was found (p = 0.0001). Mean aortic cross-clamping durations were 54.9 ± 11.5 min (median: 65.5, range: 23–76) in group 1 and 26.7 ± 6.4 min (median: 25, range: 18–35) in group 2. A statistically significant intergroup difference was found between the groups (p = 0.0001). Mean CPB durations were 82.8 ± 14.3 min (median: 84, range: 39–109) in group 1 and 46.7 ± 6.3 min (median: 46, range: 35–58) in group 2 (p = 0.0001). Total mean intubation times were 5.6 ± 1.9 hours (median: 5, range: 3–14) in group 1 and 5.5 ± 1.2 hours (median: 5, range: 4–12) in group 2. Mean duration of stay in the postoperative intensive care unit was 29.3 ± 17.1 hours (median: 21, range: 17–88) in group 1 and 29.7 ± 15.3 hours (median: 22, range: 17–71) in group 2, with no significant intergroup differences (p = 0.53). Mean hospital stay of the patients was 6.1 ± 1.6 days (median: 5, range: 5–12) in group 1 and 5.8 ± 1.1 days (median: 5, range: 5–9) in group 2 with no significant intergroup differences (p = 0.83). In group 1, 48 (42.2%) and in group 2, 35 (44.9%) patients required transfusion of blood and blood products during the postoperative period, with no statistically significant difference between the groups (p = 0.70). The mean total amount of postoperative drainage was 348 ± 169 ml (median: 300, range: 150–1100) in group 1 and 335 ± 125 ml (median: 300, range: 150–700) in group 2, with no statistically significant intergroup difference (p = 0.93). Changes in the aortic root and ascending aortic diameter over three years and analysis of this change are shown in Table 2. No statistically significant intergroup difference was seen at the level

of the aortic annulus (Fig. 1) (p = 0.22, p = 0.25 and p = 0.13, respectively). Annual changes in aortic diameter were found to be extremely significantly different in both groups (p = 0.0001). However, when mean differences in diameters were analysed by year, no statistically significant intergroup difference was detected (p = 0.21 and p = 0.37, respectively). Mean values of aortic diameter at the level of the sinus of Valsalva were not significantly different between the groups (Fig. 2) (p = 0.53, p = 0.37 and p = 0.30, respectively). However, annual increases in diameter were found to be extremely significantly different in both groups (p = 0.0001 and p = 0.0001, respectively). The mean difference in diameter one year postoperatively Table 2. Comparison of transthoracic echocardiography measurements and annual differences Group 1 (n = 114) Presence of proximal anastomosis

Group 2 (n = 78) Absence of proximal anastomosis

Pre-operative annulus diameter (mm) (median, range)

24.2 ± 2.8 (24, 19–29)

23.7 ± 3.1 (24, 18–31)

0.22a

1st year annulus diameter (mm) (median, range)

24.6 ± 2.7 (25, 20–30)

24.2 ± 2.9 (24, 19–31)

0.25a

3rd year annulus diameter (mm) (median, range)

25.6 ± 2.8 (26, 21–31)

25.0 ± 2.8 (25, 20–32)

0.13a

Group 1 Group 2 (n = 114) (n = 78) Presence of proxi- Absence of proximal anastomosis mal anastomosis Mean age (years) (median, range) Male, n (%) Female, n (%)

p-value

63.0 ± 9.2 (63, 42–80)

61.0 ± 9.3 (61, 42–80)

0.12**

93 (60.4)

61 (39.6)

0.56*

21 (55.3)

17 (44.7)

0.45*

Ejection fraction (%) (median, range)

53.5 ± 10.2 (55, 30–70)

53.7 ± 10.5 (55, 30–70)

0.91**

Hypertension, n (%)

28 (24.6)

27 (34.6)

0.13*

Diabetes mellitus, n (%)

43 (37.7)

37 (47.4)

0.18*

Smoking status, n (%)

34 (29.8)

19 (24.4)

0.41*

Hyperlipidemia, n (%)

44 (38.6)

34 (43.6)

0.49*

COPD, n (%)

11 (9.6)

5 (6.4)

0.43*

Pre-operative CRF, n (%)

6 (3.3)

2 (2.6)

0.48***

Peripheral artery disease, n (%)

8 (7.0)

3 (3.8)

0.53***

History of stroke, n (%)

7 (6.1)

2 (2.6)

0.32***

Previous myocardial infarction, n (%)

30 (26.3)

23 (29.5)

0.63*

Alcohol use, n (%)

15 (13.2)

8 (8.3)

0.54*

*Pearson’s chi-squared test; **Mann–Whitney U-test; ***Fisher’s exact test. COPD = chronic obstructive pulmonary disease; CRF = chronic renal failure.

p-value

0.0001b

1st year annulus diameter difference (mm) (median, range)

0.37 ± 0.50 (0, 0–2)

0.46 ± 0.53 (0, 0–2)

0.21a

3rd year annulus diameter difference (mm) (median, range)

1.37 ± 0.55 (1, 1–3)

1.27 ± 0.70 (1, 0–3)

0.37a

p-value

0.0001b

Pre-operative sinus of Valsalva diameter (mm) (median, range)

37.2 ± 1.6 (37, 34–40)

37.1 ± 1.6 (37, 34–41)

0.53a

1st year sinus valsalva diameter (mm) (median, range)

38.0 ± 1.7 (38, 35–41)

37.8 ± 1.6 (38, 35–42)

0.37a

3rd year sinus of Valsalva diameter (mm) (median, range)

38.8 ± 1.6 (39, 36–42)

38.5 ± 1.7 (39, 35–42)

0.30a

p-value

0.0001b

1st year sinus of Valsalva diameter difference (mm) (median, range)

0.79 ± 0.43 (1, 0–2)

0.76 ± 0.49 (1, 0–2)

0.57a

3rd year sinus of Valsalva diameter difference (mm) (median, range)

1.63 ± 0.49 (2, 1–2)

1.45 ± 0.53 (1, 1–3)

0.01a

p-value

0.0001b

Pre-operative STJ diameter (mm) (median, range)

39.1 ± 1.1 (39, 33–41)

38.9 ± 1.6 (39, 36–42)

0.08a

1st year STJ diameter (mm) (median, range)

40.3 ± 1.1 (40, 37–42)

39.7 ± 1.6 (39.5, 36–43)

0.002a

3rd year STJ diameter (mm) (median, range)

41.4 ± 1.2 (41.5, 38–44)

40.3±1.7 (40, 37–45)

0.0001a

p-value Table 1. Demographic and clinical characteristics of the patients

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0.0001b

1st year STJ diameter difference (mm) (median, range)

0.99 ± 0.36 (1, 0–2)

0.76 ± 0.49 (1, 0–2)

0.0001a

3rd year STJ diameter difference (mm) (median, range)

2.21 ± 0.66 (2, 0–3)

1.35 ± 0.88 (1, 0–3)

0.0001a

p-value

0.0001b

Pre-operative ascending aorta diameter (mm) (median, range)

41.5 ± 1.3 (41, 40–45)

41.6 ± 1.6 (41, 40–45)

0.79a

1st year ascending aorta diameter (mm) (median, range)

43.0 ± 1.5 (43, 40–48)

42.1 ± 1.5 (42, 40–45)

0.0001a

3rd year ascending aorta diameter (mm) (median, range)

44.3 ± 1.6 (44, 42–49)

42.9 ± 1.6 (43, 40–46)

0.0001a

p-value

0.0001b

1st year ascending aorta diameter difference (mm) (median, range)

1.51 ± 0.76 (2, 0–3)

0.58 ± 0.57 (1, 0–2)

0.0001a

3rd year ascending aorta diameter difference (mm) (median, range)

2.77 ± 0.95 (3, 1–5)

1.32 ± 0.57 (1, 0–3)

0.0001a

0.0001b

p-value

Mann–Whitney U-test; bFriedman S-test; STJ = sinotubular junction.

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Diameter (mm)

26 24 22

Aortotomy absent

Aortotomy present

Pre-operative aortic annulus diameter

Pre-operative SJT diameter

Post-operative first year aortic annulus diameter

Post-operative first year SJT diameter

Post-operative third year aortic annulus diameter

Post-operative third year SJT diameter

was not statistically significantly different between the groups (p = 0.57), while at three years, the intergroup difference was statistically significantly different (p = 0.01). Pre-operatively at the level of the sinotubular junction, the mean aortic diameters were not significantly different between the groups (Fig. 3) (p = 0.08), while the mean aortic diameters at one and three years postoperatively were statistically significantly different between the groups (p = 0.002 and p = 0.0001, respectively). Annual increase in diameter was extremely significantly different between the groups (p = 0.0001 and p = 0.0001, respectively). Mean annual difference in diameter was found to be extremely significantly different between the groups (p = 0.0001 and p = 0.0001, respectively). Pre-operatively, mean aortic diameters measured at the level of the tubular ascending aorta were not significantly different between the groups (Fig. 4) (p = 0.79). However, mean aortic diameters measured one and three years postoperatively were extremely significantly different between the groups (p = 0.0001 and p = 0.0001, respectively). The increase in diameter of the ascending aorta was extremely significantly different in both groups (p = 0.0001 and p = 0.0001, respectively). Intergroup differences in mean value of the diameter of the ascending aorta at one and three years postoperatively were extremely significantly different (p = 0.0001 and p = 0.0001, respectively).

Fig. 3. Measurements of the sinotubular junction.

Discussion Since proximal anastomosis of the coronary artery graft to the ascending aorta requires aortotomy, aortic integrity is disrupted during this procedure. Besides, coronary artery grafts in their new position will increase the haemodynamic workload of the ascending aorta and, theoretically, they can be seen as a cause of aortic dilatation. However, no clinical or experimental study in the literature has held coronary artery grafts responsible for aortic dilatation. We could also not find any study in the literature evaluating the relationship between mid- and long-term increase in aortic diameter and proximal anastomosis performed on the ascending aorta in patients with aortic dilatation who did not require surgical intervention but underwent CPB and isolated CABG. We searched for the words ‘aortic dilatation’, ‘proximal anastomosis’ and ‘coronary artery bypass grafting’ in the English literature of PubMed, but could not find any article related to this topic. No study could be found in the literature referring to aortic dilatation caused by aortic side clamping. Therefore no assessment was done in our study on the effects of aortic side clamping versus aortotomy. New studies are needed to determine whether there is a difference. We rarely undertake proximal anastomosis to the aorta using the aortic cross-clamp, we prefer the aortic side-clamp.

50 48

Diameter (mm)

Aortotomy present

Fig. 1. Measurements of the aortic annulus.

38 36 34

20 18

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46 44 42

Aortotomy absent

Aortotomy present

Aortotomy absent

Aortotomy present

Pre-operative sinus valsalva diameter

Pre-operative ascending aortic diameter

Post-operative first year sinus valsalva diameter

Post-operative first year ascending aortic diameter

Post-operative third year sinus valsalva diameter

Post-operative third year ascending aortic diameter

Fig. 2. Measurements of the sinus of Valsalva.

Fig. 4. Measurements of the ascending aorta.

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In this study, we tried to determine whether proximal anastomosis performed on the ascending aorta in patients who had undergone CPB and isolated CABG surgery had any effect on the mean increase in aortic diameter during the early and mid-term postoperative period. Arteriotomy on dilated aortae for proximal anastomosis of saphenous vein grafts to the aorta leads to disruption of the elastic structure and connective tissue integrity of the aorta. How this affects the dilatation of the aorta is unknown. This study aimed at answering that question. In our study, we found that annual increases in all segments of the aorta were statistically significantly different in both groups. In patients who had undergone proximal anastomosis of the ascending aorta, increases in the diameter of the sinotubular junction and ascending aorta at one and three years postoperatively were significantly greater than in patients who had not undergone a proximal anastomosis. We believe that this strengthens our hypothesis, which asserted that surgical manipulation on a dilated ascending aorta increases the speed of aortic expansion. An aortic diameter exceeding normal limits, based on the patient’s age and body surface area, is termed aortic dilatation, and if it increases more than 50% of normal, it is termed aortic aneurysm.4 Aneurysm of the ascending aorta is a frequently seen clinical condition. Haemodynamic force, degradation of the configured extracellular matrix, familial predisposition and transmural inflammation have been demonstrated as aetiological factors for this disease.5 Aortic wall strain acts in direct proportion with aortic diameter and pressure, while it is in inverse proportion with aortic wall thickness, in compliance with Laplace’s law [wall strain = pressure × radius (r)/2 × wall thickness (h)].6 The wall of the enlarged aorta has a risk of rupture. Recent studies have reported that aneurysms with a diameter less than 50 mm have a 2% annual risk of rupture.6 However, as reported in various studies, for aneurysms with a diameter of 60 mm, annual risk of rupture and mortality increases up to 11.8 and 6.9%, respectively. The probability of their combined risk has been reported at 14.1%.7 In patients with aneurysms of the ascending aorta who will undergo valvular surgery, dilatations of less than 50 cm, unexplained dilatations of ≥ 55 mm, patients with Marfan syndrome and bicuspid aortic dilatations of ≥ 50 mm, and for smaller dilatations with an annual growth rate of 10 mm, surgery is recommended.8 In our patients, the aortic diameter was 40–45 mm (mean 41.5 ± 1.4 mm) without any connective tissue disease as aetiological factor, so we did not consider any indication for surgery in our patients. Postoperative dilatation rate is important because of the risks of dilatation and rupture. Expansion rate of the ascending aorta with a diameter of 40 mm following aortic valve surgery has been reported as 0.5–2.4 mm/year (mean 0.45 mm/year).9,10 However Andrus et al. found an expansion rate after aortic valve replacement (AVR) of –0.1 mm/year. This suggests that AVR changes the natural course of aortic dilatation.11 Keane et al. reported that ascending aortae of patients with bicuspid valves are more frequently prone to dilatation.9 In their series of 14 cases, Yasuda et al. followed their patients for 10 years and reported an annual aortic expansion rate of 0.08 mm/year. In their studies using CT angiography and echocardiography for evaluation, they indicated that an increase in the aortic diameter

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of 0.2–0.3 mm within 10 years was not statistically significant. In our study, postoperative (group 2) dilatation in cases with tricuspid aortic valves had an annual dilatation rate of 1 mm/ year (Table 2). We believe that this dilatation rate was related to risk factors independent of surgery and valvular pathology. Natsuaki et al. reported that patients who underwent mechanical valve implantation carried a higher risk of aortic dissection and rupture when compared with those who had received biological valves.12 This contradicts the belief that biological valves leave behind greater residual gradient and undergo faster degeneration in sepsis and infection as endocarditis. In our patients during the three years of follow up, we did not observe aortic dissection and rapid development of aneurysmatic dilatation (Fig. 1). However, cases with post-CABG dissection have occasionally been reported in the literature.13 Mortality rates in cases of surgery of the ascending aorta have been reported to range between 1.7 and 17.1% and in re-operated cases, between 6 and 32%.14,15 The surgical procedures used and aetiological factors are known determinants of mortality.13 In their series, Atik et al. detected aortic dilatations in three (17%) patients following coronary artery surgery.14 Songur et al. reported aortic dilatation in 50 cases within nine years of cardiac surgery; eleven (22%) of these cases with aortic dilatation developed after CABG. In these cases, average diameter of the ascending aorta after the first and second operation was indicated as 4.1 and 5.5 cm, respectively.16 Aortic manipulation (proximal anastomosis line, cannulation, suture lines, crossclamping injury) and aortic valve pathologies have been held responsible for the development of these dilatations. No case– control studies where aortic valves were evaluated following proximal anastomosis have been performed. In our cases, we detected a dilatation rate of 3.04 mm over three years (7.1%) at the level of the tubular segment of the ascending aorta. In the patients who underwent proximal anastomosis, aortic dilatation was more severe (median 3.7 mm per three years; 8.7%) but the intergroup difference was not statistically significantly different (p = 0.059). In the first postoperative year, the intergroup difference was significantly different at the level of the tubular aorta (p = 0.02). Dilatation of all segments of the ascending aorta over time was statistically significantly different in both groups (p = 0.001; Table 2). Intergroup difference in the tubular ascending aorta in the first year could have been related to the proximal anastomosis. However when the magnitude of standard deviation and width of confidence intervals are taken into consideration, a confounding effect of aetiological factors (connective tissue disease) should not be overlooked (Fig. 1). The causative effects of risk factors such as diabetes mellitus, hypercholesterolaemia, age, hypertension, smoking and alcohol abuse on atherosclerosis are well recognised.17 Narrowings or occlusions occur in the vasa vasorum of the atherosclerotic aorta, which result in an increase in the levels of elastase enzyme, a decrease in the levels of anti-protease enzyme and degradation of the elastin. Consequently, aneurysmatic dilatations develop on the weakened vascular wall.18,19 Matsuyama et al. detected a higher number of patients with PAD, TIA, stroke, current and past smoking history and COPD among those who had developed aortic dilatation following AVR.20 However, they reported a lower incidence of aortic dilatation in patients who used beta-blockers and those with calcified aortae.21 In our patients, the presence of COPD, smoking, stroke and

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beta-blocker use did not differ between the groups (p > 0.05) (Table 3). However, during the three years of follow up, only a minimal contribution of COPD to aortic dilatation at the level of the sinus of Valsalva was detected (Table 3). In patients with diabetes, the expansion velocity was observed to be 0.4 mm/year, being most marked at the level of the sinotubular junction. Hypertension is known to be an independent risk factor for aortic dilatation. In various studies, annual increases in the diameter of the ascending aorta have been reported at 1.25 mm in normotensive and 2.8 mm in hypertensive patients.21 However, since these patients are continually on drug therapy, it is difficult to investigate the effects of uncontrolled hypertension on annual expansion rates. In the presence of controlled hypertension and diabetes, dilatation of the sinotubular junction and tubular segments of the aorta was more frequently observed. In tractable hypertension, annual dilatation rate at the level of the tubular aorta was found to be 2.2 mm.21 In our study, age demonstrated a significant correlation with dilatation rates in both groups for all segments of the aorta, excluding the aortic ring. Other risk factors made minimal contributions to dilatation rates, with no statistically significant differences (p > 0.05) (Table 3). Various formulae have been developed to predict the expansion rate of aortic aneurysms, but no correlation between the determined and estimated size of the aneurysm could be demonstrated.22 Bonser et al. followed up the natural course of aneurysms in their series and reported an annual aortic expansion rate of 3.3 mm for 44-mm-dilated aneurysms associated with thrombi, but without any evidence of stroke and TIA. The annual expansion rate was 1.9 mm without the concurrent presence of thrombi. In this series, decreased growth rates were reported for larger aneurysms.22 Similarly, segments proximal and distal to the aneuryms were tracked in patients who had previously undergone aortic surgery, and a decrease in expansion rate of the aneurysms to 1.18–1.59 mm/year was reported.19 In our cases, annual expansion rates differed in various aortic regions, while the tubular (mid-) segment of the ascending aorta was the most dilated portion. Irrespective of aetiological factors, the mean expansion rate of this segment was 1.2 ± 0.9 mm/year, which was similar to the dilatation rate following AVR. On TTE, measurements of the aortic diameter may demonstrate individual differences. CT angiography has a higher sensitivity and specificity for the ascending aorta. However, in multi-slice sections, it is difficult to evaluate the sinotubular junction and annulus. In addition to the higher cost of CT angiography, the contrast material used carries risks of anaphylaxis and renal toxicity. Therefore, we deemed it appropriate to analyse our cases using TTE, which allows evaluation of ventricular and valvular function.

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the opinion that in long-term follow-up studies (five to 10 years), more significant and precise results would be obtained. Genetic investigations were not done in our cases or in other studies on this subject. When undertaking genetic investigations, if patients with connective tissue disorders are grouped separately, then the number of extreme values would decrease and these groups would demonstrate a more homogenous distribution, with similar effects on the outcomes.

Conclusion In our three-year follow-up study on patients with ascending aortic dilatation that did not require surgical intervention, who underwent proximal anastomosis of the ascending aorta and only CABG surgery, we detected significant increases in diameters of the sinotubular junction and tubular aorta. Since our study population was homogenous as far as the demographic and clinical characteristics were concerned, and their hypertension was under control, we believe that this statistically significant postoperative increase in expansion rate of dilated aorta was induced by the surgical interventions performed on the aorta. However, since clinical progression of these cases is unpredictable, periodic echocardiographic or CT angiographic monitoring of these patients is required, with regard to the development of aortic dissection and aneurysm.

References 1.

Kızıltan HT, Baltalı M, Kayaselçuk F, Korkmaz ME, Müderrisoğlu H, Taşdelen, et al. Histopathological changes associated with ascending aortic dilatation. Turkish J Thorac Cardiovasc Surg 2002; 10: 206–210.

Fedak PW, de Sa MP, Verma S, Nili N, Kazemian P, Butany J Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg 2003; 126(3): 797–806. Doi: http://dx.doi.org/10.1016/ S0022-5223(03)00398-2.

Hirose Y1, Hamada S, Takamiya M, Imakita S, Naito H, Nishimura T. Aortic aneurysms: growth rates measured with CT. Radiology 1992; 185: 249–252. Doi: http://dx.doi.org/10.1148/radiology. 185.1.1523317.

Ergin MA, Spielvogel D, Apaydin A, Lansman SL, McCullough JN, Galla JD, Griepp RB. Surgical treatment of the dilated ascending aorta: When and how? Ann Thorac Surg 1999; 67: 1834–1839.

Kaya A, Kaya Y, Gunaydin ZY, Enginyurt O, Polat YK, Topcu S, et al. Relationship between serum gamma-glutamyl transferase levels with ascending aortic dilatation. Eurasian J Med 2014; 46(2): 89–95.

Davies RR, Goldstein LJ, Coady MA, Tittle SL, Rizzo JA, Kopf GS, et al. Yearly rupture or dissection rates for thoracic aortic aneurysms: Simple prediction based on size. Ann Thorac Surg 2002; 73: 17–27; Discussion 27–28. PMID:11834007.

Lung B, Gohlke-Bärwolf C, Tornos P, Tribouilloy C, Hall R, Butchart E, Vahanian A. Recommendations on the management of the asymptomatic patient with valvular heart disease. Eur Heart J 2002; 23(16):

Limitations Pre-operatively, the aortic diameters of our patients ranged between 40 and 45 mm. Since it is known that the expansion rate decreases in proportion to the increase in aortic diameter, we believe that comparative regression analysis between groups of aortae with varying diameters would reveal a correlation. Although our follow-up period was only three years, we obtained values close to those cited in the literature. However, we are of

1253–1266. PMID: 12698958. 8.

ESC guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J 2014; 35: 2873–2926

Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation 2000; 102(19 Suppl 3): III35–39. Doi: 10.1161/01.CIR. 102.suppl_3.III-35.

10. Kawachi Y, Nakashima A, Kosuga T, Tomoeda H, Toshima Y, Nishimura Y. Comparative study of the natural history and operative

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outcome in patients 75 years and older with thoracic aortic aneurysm. Circ J 2003; 67: 592–596. Doi: http://dx.doi.org/ 10.1253/circj.67.592.

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7934112. 17. Fedakar A, Fındık O, Buğra O, Kalender M, Konukoğlu O, Balkanay

11. Andrus BW, O’Rourke DJ, Dacey LJ, Palac RT. Stability of ascending

M, et al. Evaluation of coronary artery disease and other risk factors in

aortic dilatation following aortic valve replacement. Circulation 2003;

patients with abdominal aortic aneurysm. Türk Göğüs Kalp Damar Cer

108(Suppl 1): II295–299. Doi: 10.1161/01.cir.0000087385.63569.79.

Derg 2011; 19(4): 545–550. Doi: 10.5606/tgkdc.dergisi.2011.085.

12. Natsuaki M, Itoh T, Rikitake K, Okazaki Y, Naitoh K. Aortic compli-

18. Xu C, Zarins CK, Glagov S. Aneurysmal and occlusive atherosclerosis

cations after aortic valve replacement in patients with dilated ascending

of the human abdominal aorta. J Vasc Surg 2001; 33: 91–96. Doi: http://

aorta and aortic regurgitation. J Heart Valve Dis 1998; 7: 504–509.

dx.doi.org/ 10.1067/mva.2001.109744. 19. Ghosh A, Pechota A, Coleman D, Upchurch GR Jr, Eliason JL.

PMID: 9793846. 13. Songur CM, Erdolu B, Rabuş MB, Aydın C, Yılmaz E, Ulus T. Aortic

Cigarette smoke-induced MMP2 and MMP9 secretion from aortic

pathologies after cardiac surgery. Türk Göğüs Kalp Damar Cer Derg

vascular smooth cells is mediated via the Jak/Stat pathway. Hum

2013; 21(1): 21–25. Doi: 10.5606/tgkdc.dergisi.2013.6897.

Pathol 2015; 46(2): 284–294. Doi: http://dx.doi.org/10.1016/j. humpath.

14. Atik FA, Navia JL, Svensson LG, Vega PR, Feng J, Brizzio ME, et al.

2014.11.003.

Surgical treatment of pseudoaneurysm of the thoracic aorta. J Thorac

20. Matsuyama K, Usui A, Akita T, Yoshikawa M, Murayama M, Yano

Cardiovasc Surg 2006; 132(2): 379–385. Doi: http://dx.doi.org/10.1016/j.

T, et al. Natural history of a dilated ascending aorta after aortic valve

jtcvs.2006.03.052.

replacement. Circ J 2005; 69: 392–396. Doi: http://dx.doi.org/10.1253/

15. Stowe CL, Baertlein MA, Wierman MD, Rucker M, Ebra G. Surgical

circj.69.392.

management of ascending and aortic arch disease: refined techniques

21. Kuralay E, Demirkilic U, Ozal E, Oz BS, Cingoz F, Gunay C, et al.

with improved results. Ann Thorac Surg 1998; 66(2): 388–395. Doi:

Surgical approach to ascending aorta in bicuspid aortic valve. J Card Surg 2003; 18: 173–180. Doi: 10.1046/j.1540-8191.2003.02025.x.

http://dx.doi.org/10.1016/S0003-4975(98)00535-9. 16. Jault F, Nataf P, Rama A, Fontanel M, Vaissier E, Pavie A, et al.

22. Bonser CR, Pagano D, Lewis ME, Rooney SJ, Guest P, Davies P, et al.

Chronic disease of the ascending aorta. Surgical treatment and long-

Clinical and patho-anatomical factors affecting expansion of thoracic

term results. J Thorac Cardiovasc Surg 1994; 108(4): 747–754. PMID:

aortic aneurysms. Heart 2000; 84: 277–283. Doi: 10.1136/heart. 84.3.277.

CSI AFRICA 2017 CATHETER INTERVENTIONS IN CONGENITAL, STRUCTURAL AND VALVAR HEART DISEASE DECEMBER 1 – 2, 2017 | NAIROBI | KENYA

SAVE THE DATE CSI Africa 2017 will take place on December 1 – 2, 2017 in Nairobi, Kenya. Please join us for an overview of catheter interventions in congenital, structural and valvar heart disease in children and adults. CSI Africa will provide a forum for physicians from Central Africa, with an opportunity to exchange ideas and learn from each other. Read more on the congress website.

THE PROGRAM The program will include lectures, debates and recorded cases from local and international faculty and is designed to address issues and topics specific to Central Africa. Topics will include: • • • • •

Paravalvar leak closure Left atrial apendage closure Pulmonary valve replacement Echo evaluation of ASDs and VSDs Coarctation stenting

• • • • •

ASD closure VSD closure Transseptal puncture PDA closure Pulmonary valvuloplasty

• Mitral valvuloplasty • How to develop structural, congenital and valvar interventions in Africa • Challenging cases, problems & complications

WHO SHOULD ATTEND? The meeting is designed for adult and pediatric interventional cardiologists, cardiothoracic surgeons, anaesthetists, imaging specialists & colleagues of other disciplines, such as nursing staff, who wish to know more about this field.

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Review Article The integrated effect of moderate exercise on coronary heart disease Marc J Mathews, Edward H Mathews, George E Mathews

Abstract Background: Moderate exercise is associated with a lower risk for coronary heart disease (CHD). A suitable integrated model of the CHD pathogenetic pathways relevant to moderate exercise may help to elucidate this association. Such a model is currently not available in the literature. Methods: An integrated model of CHD was developed and used to investigate pathogenetic pathways of importance between exercise and CHD. Using biomarker relative-risk data, the pathogenetic effects are representable as measurable effects based on changes in biomarkers. Results: The integrated model provides insight into higherorder interactions underlying the associations between CHD and moderate exercise. A novel ‘connection graph’ was developed, which simplifies these interactions. It quantitatively illustrates the relationship between moderate exercise and various serological biomarkers of CHD. The connection graph of moderate exercise elucidates all the possible integrated actions through which risk reduction may occur. Conclusion: An integrated model of CHD provides a summary of the effects of moderate exercise on CHD. It also shows the importance of each CHD pathway that moderate exercise influences. The CHD risk-reducing effects of exercise appear to be primarily driven by decreased inflammation and altered metabolism. Keywords: moderate exercise, biomarkers, integrated model Submitted 11/9/15, accepted 5/5/16 Published online 12/12/16 Cardiovasc J Afr 2017; 28: 125–133

www.cvja.co.za

DOI: 10.5830/CVJA-2016-058

Coronary heart disease (CHD) is known to be the major cause of death globally.1 However, it is well documented that regular moderate physical exercise is associated with fewer CHD events in symptomatic2 and asymptomatic3,4 subjects. The precise mechanisms underlying this inverse association

Centre for Research and Continued Engineering Development, North-West University, Potchefstroom, South Africa Marc J Mathews, PhD Edward H Mathews, PhD George E Mathews, 20270046@nwu.ac.za

are unclear. However, it is apparent that CHD risk may be substantially mediated, through moderate exercise, by changes in blood pressure, insulin resistance and glucose intolerance, systemic inflammation, triglyceride concentrations, low highdensity lipoprotein (HDL) levels and obesity.4,5 It may therefore prove beneficial to quantify and elucidate the underlying pathogenetic effect of moderate exercise on the pathogenesis of CHD. Using a previously described integrated model of CHD,6,7 we investigated the interconnectivity of moderate exercise and the pathogenesis and pathophysiological attributed to CHD.

Methods An integrated model was developed as part of a larger research project.6 This project has partially been described in previous articles dealing with certain subsets of the research.7-9 Briefly, a systematic review of the literature post-1998 and including highly cited articles was conducted for CHD pathogenesis, health factors, biomarkers and pharmacotherapeutics. This research was combined to develop the integrated model of CHD. During the systematic literature review, PubMed, Science Direct, Ebsco Host and Google Scholar were searched for publications with ‘coronary heart disease’ or ‘coronary artery disease’ or ‘cardiovascular disease’ or ‘CHD’ as a keyword and combinations with ‘lifestyle effects’, ‘relative risk prediction’, ‘network analysis’, ‘pathway analysis’, ‘interconnections’, ‘systems biology’, ‘pathogenesis’, ‘biomarkers’, ‘conventional biomarkers’, ‘drugs’, ‘therapeutics’, ‘pharmacotherapeutics’, ‘hypercoagulability’, ‘hypercholesterolaemia’, ‘hyperglycaemia’, ‘hyperinsulinaemia’, ‘inflammation’ and ‘hypertension’ in the title of the study. Also searched were all major relevant speciality journals in the areas of cardiology, alcohol consumption, nutrition, cigarette smoking, physical exercise, oral health, psychological stress, depression, sleep disorders, endocrinology, psychoneuroendocrinology, systems biology, physiology, periodontology, CHD, the metabolic syndrome and diabetes. The health factors in the integrated model were considered as lifestyle effects or co-morbid health disorders that have been associated with statistically significant increases or decreases in CHD risk. This resulted in nine health factors being considered in the model, namely alcohol, food, exercise, smoking, oral health, stress, depression, insomnia and sleep apnoea. The biomarkers considered for the integrated model were mainly those whose measurement has been associated with statistically significant increases or decreases in CHD risk.

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This resulted in 23 biomarkers being considered in the model, namely triglycerides, low-density lipoprotein (LDL), HDL, apolipoprotein-B (Apo B), leptin, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), growth-differentiation factor-15 (GDF15), osteoprotegerin (OPG), myeloperoxidase (MPO), B-type natriuretic peptide (BNP), homocysteine, fibrinogen, troponins, urinary albumin-to-creatinine ratio (ACR), glycosylated haemoglobin (HbA1c), insulin-like growth factor-1 (IGF-1), adiponectin, cortisol, brain-derived neurotrophic factor (BDNF) and insulin resistance. In brief, the systematic review of the literature revealed the pathological effects of various health factors on the pathogenesis of CHD. This information was combined to form a visual representation of the pathogenesis of CHD as it is affected by these health factors. The biomarkers were included in the visual representation to show functionally measurable aspects of the pathogenesis.6,7 This visual representation presents an integrated model of CHD. This integrated model of CHD schematically illustrates the complexity of CHD and shows all theoretical pathogenetic pathways between health factors and CHD. The model has been previously used to describe the effects of high-carbohydrate diets on CHD,7 and the possible mechanisms through which antidepressants9 and moderate alcohol consumption8 may reduce CHD risk. In this study the integrated model was used to describe the integrated effects of exercise on the pathogenesis of CHD. Furthermore, the effect of exercise on CHD was investigated by analysing the effect that exercise has been shown to have on measurable and quantifiable biomarkers.

Statistical analysis It must be noted that some of the relative risk (RR) values in this article differ from convention. The need for this comes as a result of the visual scaling of the traditional RR. Traditionally, if one plots an RR = 3 and RR = 0.33, respectively, one does not ‘look’ three times worse and the other three times better than the normal RR = 1. The reason is that the scales for the positive and negative effects are not numerically similar. A graph of ‘good’ and ‘bad’ RR can therefore be deceptive for the untrained person, for example a patient. This article rather uses the method that the conventional RR = 3 is three times worse than the normal RR = 1, while the conventional RR = 0.33 means that the patient’s position is three times better than the normal RR = 1. Therefore, in summary, a conventional RR = 3 is presented as per normal, as a three-fold increase in risk and a conventional RR = 0.33 is presented as a three-fold decrease in risk (1/0.33 = 3).

Results Integrated model of coronary heart disease The integrated model of CHD that was developed in previous studies is presented in Fig. 1. The pathways (pathogenesis of CHD) within the integrated model can be tracked from where a chosen health factor influences the relevant tissue, to the end state of CHD. The pathways are therefore a visual representation of previously published knowledge. Salient serological biomarkers

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) and pharmacotherapeutics (shown in Fig. (shown in Fig. 1 as ) that act on the pathways are further indicated in Fig. 1. 1 as The focus of this review is on using the integrated model to describe the interconnections of moderate exercise on the pathogenesis of CHD. Therefore a more detailed discussion of Fig. 1, relevant to exercise, is given in the next section. This review therefore attempts to quantify the CHD effect of moderate exercise by the connection of these to an array of biomarkers that represent increasing or decreasing CHD risk.

Pathogenetic effects of physical exercise In order to appraise the CHD effects of moderate exercise, the relevant pathogenetic pathways need to be considered. While Fig. 1 also indicates other health factors, only the pathways activated by moderate exercise are summarised in Table 1. It is however important to note that not all the pathways will be relevant to every patient and that all the pathways may not be active simultaneously, or occur in the same patient. Fig. 1 (pathway: 3a-53-55-hyperglycaemia) shows the pathways involved in a lack of physical exercise (and decreased daily energy expenditure) and how this affects carbohydrate metabolism through changes in muscle glucose transporter Table 1. Putative effects of moderate exercise and salient CHD pathogenetic pathways Pathways, and pathway numbers corresponding to those in Fig. 1 References 38, 39 a. 3a-53-↓ blood glucose-55-↓ hyperglycaemia 40–47 b. 3a-53-↓ blood glucose-54-↓ PI3K:MAPK-69-↓ insulin resistance-72-↓ platelet factors-73-↓ hypercoagulability 38, 40, c. 3a-53-↓ blood glucose-54-↓ PI3K:MAPK-69-↓ insulin 45–48 resistance-72-↓ ROS 49 d. 3a-53-↓ blood glucose-54-28-101-↓ insulin resistance-72↑ vasodilation e. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin 29, 30, 38, 45, 48 II-89-↓ hypertension-100-↓ ROS-85-↓ COX1/2-85-↓ inflammatory state 50 f. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin II-89-↓ SMC proliferation 51–54 g. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin II-89-↑ IGF1-84-↓ SMC proliferation 29 h. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin II-89-↓ VCAM1/MCP1-73-↓ hypercoagulation 38, 55, 56 i. 3c-↓ visceral adipose tissue-↓ ectopic fat 38, 56, 57 j. 3c-19-↑ adiponectin-38-↓ TNFα/IL6-56-Liver-12-↓ LDL-33-↓ oxLDL-51-↓ hypercholesterolaemia 58 k. 3c-19-↑ adiponectin-39-↓ insulin resistance 55 l. 3c-19-↑ adiponectin-39-↓ SMC proliferation 5, 32, m. 3c-21-↓ TNFα/IL6-56-Liver-12-↓ LDL-33-↓ 59–62 oxLDL-51-↓ hypercholesterolaemia 5, 32, n. 3c-21-↓ TNFα/IL6-41-↓ P. gingivalis-43-↓ periodonti59–62 tis-64-↓ platelet factors-73-↓ hypercoagulability 5, 32, 38, o. 3c-18-↓ FFA-37-↓ plasma lipids-34-Liver-12-↓ LDL-3356, 59–62 ↓ oxLDL-51-↓ hypercholesterolaemia ↑, up regulation/increase; ↓, down regulation/decrease; x-y-z indicates pathway connecting x to y to z. FFA, free fatty acids; IGF 1, insulinlike growth factor-1; IL6, interleukin-6; LDL, low-density lipoprotein; MAPK, mitogen-activated protein (MAP) kinase; MCP 1, monocyte chemo-attractant protein-1; NO, nitric oxide; oxLDL, oxidised LDL; P gingivalis, Porphyromonas gingivalis; PI3K, phosphatidylinositol 3-kinase; PI3K:MAPK, ratio of PI3K to MAPK; ROS, reactive oxygen species; SMC, smooth muscle cell; TNFα, tumour necrosis factor-α; VCAM 1, vascular cell adhesion molecule-1.

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Fig. 1. C onceptual model of general health factors, salient CHD pathogenetic pathways and CHD hallmarks. (From: M Mathews, L Liebenberg, E Mathews. How do high glycemic load diets influence coronary heart disease? Nutr Metab 2015; 12(1): 6.7) The affective pathway of pharmacotherapeutics (blue boxes) is shown in Fig. 1, and salient serological biomarkers are indicated by the tags ( ). The blunted arrows denote antagonise or inhibit, and pointed arrows denote up-regulate or facilitate. ACE, angiotensin converting enzyme; BDNF, brain-derived neurotrophic factor; β-blocker, beta-adrenergic antagonists; BNP, B-type natriuretic peptide; COX, cyclooxygenase; CRP, C-reactive protein; D-dimer, fibrin degradation product D; FFA, free fatty acids; GCF, gingival crevicular fluid; HbA1c, glycosylated haemoglobin A1c; HDL, high-density lipoprotein; Hs, homocysteine; ICAM, intracellular adhesion molecule; IGF-1, insulin-like growth factor-1; IL, interleukin; LDL, low-density lipoprotein; MAPK, mitogen-activated protein (MAP) kinase; MCP, monocyte chemo-attractant protein; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; MPO, myeloperoxidase; NFκβ, nuclear factor-κβ; NLRP3, Inflammasome responsible for activation of inflammatory processes as well as epithelial cell regeneration and microflora; NO, nitric oxide; NO-NSAIDs, combinational NO-non-steroidal anti-inflammatory drug; OPG, osteoprotegerin; oxLDL, oxidised LDL; PAI, plasminogen activator inhibitor; PDGF, platelet-derived growth factor; P gingivalis, Porphyromonas gingivalis; PI3K, phosphatidylinositol 3-kinase; RANKL, receptor activator of nuclear factor kappa-beta ligand; ROS, reactive oxygen species; SCD-40, recombinant human sCD40 ligand; SMC, smooth muscle cell; SSRI, serotonin reuptake inhibitors; TF, tissue factor; TMAO, an oxidation product of trimethylamine (TMA); TNF-α , tumour necrosis factor-α; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor.

(GLUT) protein content. Denervation of skeletal muscle results in rapid decreases in both muscle GLUT-4 contents and insulinstimulated glucose uptake, therefore resulting in hyperglycaemia and concomitant hyperinsulinaemia (both CHD hallmarks) in non-diabetic patients.10

Lack of physical exercise may also contribute to the accumulation of visceral fat, reduced lipoprotein lipase activity and reduced clearance of triglycerides, leading to increased LDL levels, decreased HDL levels, and increased LDL-to-HDL ratios, and eventually to hypercholesterolaemia.11 This state

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subsequently activates the oxidative stress/inflammation cascade. This in turn underlies insulin resistance and the evolution of micro- and macrovascular complications (Fig. 1, pathways: 3a-53-blood glucose-54-PI3K:MAPK-69-insulin resistance-72ROS). Hyperinsulinaemia, by itself, contributes significantly to atherogenecity, leading to CHD.12 An increase in plasma free fatty acid (FFA) concentrations plays a key role in the pathogenesis of insulin resistance through actions that block insulin signal transduction. An increase in FFA levels results in induction of oxidative stress, low-grade systemic inflammation, and subnormal vascular reactivity, in addition to causing insulin resistance.5 As insulin resistance also results in the relative non-suppression of adipocyte hormone-sensitive lipase,13 there is further enhancement in lipolysis, increased FFA and insulin resistance. As insulin suppresses pro-inflammatory transcription factors, such as nuclear factor-κβ (NF-κβ), and also suppresses reactive oxygen species (ROS) generation, insulin resistance therefore also has a comprehensive pro-inflammatory effect (Fig. 1, pathways: 3c-18-FFA-37-plasma lipids-34-12LDL-33-oxLDL-51-hypercholesterolaemia). Fig. 1 therefore shows why an insulin-resistant state may be pro-inflammatory. The origin of the insulin resistance may be traced back to the pro-inflammatory cytokine TNF-α, which is expressed by adipose tissue.14 Adipose tissue has been shown to express not only TNF-α, but also other pro-inflammatory mediators, including CRP. Macrophages residing in the adipose tissue may also be a source of pro-inflammatory factors and they can also modulate the secretory activities of adipocytes15 (Fig. 1, pathway: 3c-21-TNFα/IL6). During regular moderate exercise, IL-6 is produced by skeletal muscle fibres via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of anti-inflammatory cytokines, which inhibit the production of pro-inflammatory TNF-α.16 Additionally, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. Regular physical exercise therefore induces suppression of TNF-α and thereby offers protection against TNF-α-induced insulin resistance.16 Low-grade systemic inflammation therefore appears to be aetiologically linked to the pathogenesis of CHD,17 countered by moderate exercise with its anti-inflammatory effects5 (Fig. 1, pathway: 3a-53-blood glucose-54-69-insulin resistance-71). The adipokine adiponectin is anti-inflammatory and potentially anti-atherogenic.5 Low adiponectin levels act as a marker for CHD and are associated with overweight subjects.18 Regular physical exercise (and an energy-controlled diet) reduces visceral fat mass, with a subsequent increased release of antiinflammatory adiponectin, therefore resulting in reduced risk of CHD19 (Fig. 1, pathway: 3c-19-39-insulin resistance). Lack of physical exercise may lead to hypertension, another CHD hallmark, through increased vascular and sympathetic tone created by reduced bioavailability of nitrous oxide (NO) and activation of the renin–angiotensin system20, 21 (Fig. 1, pathway: 3a-53-blood glucose-54-60-72-vasodilation). Hypertension is directly correlated with visceral fat mass, which may be decreased by moderate exercise.22 The lower blood glucose levels that result from moderate exercise lead to a reduction in the phosphatidylinositol 3-kinase (PI3K) to mitogen-activated protein kinase (MAPK) ratio, which in turn decreases insulin resistance23 (Fig. 1, pathway: 3a-53-blood glucose-54-69-72-73-hypercoagulabilty). Increased

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insulin sensitivity decreases serum levels of platelet factors and thus reduces the potential for hypercoagulability.24,25 Moderate exercise also increases coronary blood flow,26 which increases the release of prostaglandins.27 This is important in heart microvasculature, in which prostaglandins are substantially involved in flow-mediated vasodilation.27 Moderate exercise acts on the central nervous system by decreasing serum cortisol levels.28 This in turn reduces insulin resistance, which decreases angiotensin II levels and results in reduced hypertension. Reactive oxygen species (ROS) and cyclooxygenase (COX) 1/2 levels reduce concomitantly, which lead to a lower inflammatory state20 (Fig. 1, pathway: insulin resistance-85-inflammatory state). It is apparent that moderate exercise directly and indirectly affects a plethora of interconnected pathogenetic mechanisms. Each CHD hallmark and pathogenetic trait can amplify the Table 2. Association between biomarkers and prediction of CHD relative risk Size of studies Prediction of CHD relative (N = number of trials, ReferBiomarker (class and salient examples) risk (95% CI) n = number of patients) ences Lipid-related markers Triglycerides 0.99 (0.94–1.05) (N = 68, n = 302 430) 63 LDL 1.25 (1.18–1.33) (N = 15, n = 233 455) 64 HDL Apo B Leptin Inflammatory markers hsCRP IL-6

0.78 (0.74–0.82) (N = 68, n = 302 430) 1.43 (1.35–1.51) (N = 15, n = 233 455) 1.04 (0.92–1.17) (n = 1 832)

1.20 (1.18–1.22) (N = 38, n = 166 596) 1.25 (1.19–1.32) (N = 25, n = 42 123)

64 65

TNF-α GDF-15

1.17 (1.09–1.25)

(N = 7, n = 6 107)

1.40 (1.10–1.80)

(n = 1 740)

OPG

1.41 (1.33–1.57)

(n = 5 863)

Marker of oxidative stress MPO

1.17 (1.06–1.30) (n = 2 861) Marker of vascular function and neurohormonal activity BNP 1.42 (1.24–1.63) (N = 40, n = 87 474) Homocysteine

1.15 (1.09–1.22)

(N = 20, n = 22 652)

70 71 72, 73

Coagulation marker Fibrinogen

1.15 (1.13–1.17) (N = 40, n = 185 892)

Necrosis marker Troponins

1.15 (1.04–1.27)

(n = 3 265)

Renal function marker Urinary ACR

1.57 (1.26–1.95)

(n = 626)

Metabolic markers HbA1c

1.42 (1.16–1.74)

(N = 2, n = 2 442)

IGF-1

0.76 (0.56–1.04)

(n = 3 967)

Adiponectin

0.97 (0.86–1.09)

(N = 14, n = 21 272)

Cortisol

1.10 (0.97–1.25)

(n = 2 512) ?

78, 79

BDNF ? 80–82 Insulin resistance 1.46 (1.26–1.69) (N = 17, n = 51 161) 83 (HOMA) From: M Mathews, L Liebenberg, E Mathews. How do high glycemic load diets influence coronary heart disease? Nutr Metab 2015; 12(1): 6.7 n , number of participants; N, number of trials; CI, confidence interval; ACR, albumin-to-creatinine ratio; Apo B, apolipoprotein-B; BDNF, brain-derived neurotrophic factor; BNP, B-type natriuretic peptide; GDF-15, growthdifferentiation factor-15; HbA1c, glycated haemoglobin A1c; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; hsCRP, high-sensitivity C-reactive protein; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LDL, low-density lipoprotein; MPO, myeloperoxidase; OPG, osteoprotegerin; TNF-α, tumour necrosis factor-α.

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Fig. 2. N ormalised relative risks (fold-change) of salient current biomarkers or of potential serological biomarkers for CHD. (From: M Mathews, L Liebenberg, E Mathews. How do high glycemic load diets influence coronary heart disease? Nutr Metab 2015; 12(1): 6.7) Increased IGF-1 and HDL levels are associated with a moderately decreased CHD risk. (IGF-1 and HDL levels are significantly inversely correlated to relative risk for CHD.) N indicates number of trials; I, 95% confidence interval; ACR, albumin-to-creatinine ratio; Adipo, adiponectin; ApoB, apolipoprotein-B; BDNF, brain-derived neurotrophic factor; BNP, B-type natriuretic peptide; Cort, cortisol; CRP, C-reactive protein; cysteine, homocysteine; fibrin, fibrinogen; GDF-15, growth-differentiation factor-15; HbA1c, glycosylated haemoglobin A1c; HDL, high-density lipoprotein; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LDL, low-density lipoprotein; MPO, myeloperoxidase; OPG, osteoprotegerin; TNF-α, tumour necrosis factor-α; Trigl, triglycerides; Trop, troponins.

patient’s risk of CHD, therefore necessitating an integrated, multi-faceted therapeutic approach. In this section, the pathogenetic pathways activated by moderate exercise are described, but the effects of these pathways have not been quantified. The next interrogation was therefore whether biomarkers could quantify the CHD effect of moderate exercise. This was accomplished by using connection graphs, which link the relative effect of a health or pathogenic factor to the individual biomarkers through the pathways that are shown in Fig. 1.

Biomarkers of coronary heart disease The integrated model that was developed is a high-level conceptual model, from which the interconnectedness of CHD is immediately apparent (Fig. 1). The model is however complicated. Biomarkers can be used as indicators of an underlying disorder and the measurement of specific biomarkers enables prediction of the RR for CHD associated with the biomarker.29-31 The relevant biomarkers and their association with CHD risk per one standard deviation increase in said biomarker are given in Table 2. This can allow for the quantification of the effects of moderate exercise on the pathogenesis of CHD. To simplify the integrated model, serological biomarkers (which can easily be measured) are used to link the effect of exercise to the corresponding RR of CHD. Fig. 2 presents a comparison of the RR associated with an array of serological biomarkers per one standard deviation increase in the biomarker.7

Effects of moderate exercise Using the integrated model in Fig. 1, it is possible to account for the impact that moderate exercise would have on the serological biomarkers of CHD. This enables a simplification of the integrated model into a connection graph, which shows all the connections between moderate exercise and the measurable serological biomarkers. The connection graph presented in Fig. 3 does not neglect any of the underlying complexity of CHD. To more clearly determine the effect of exercise on different biomarkers in Fig. 3, the biomarkers previously shown in Fig. 2 were divided into eight classes, namely vascular function and neurohormonal activity, renal function, necrosis, coagulation, oxidative stress, lipids, and metabolic and inflammatory markers. The pathogenetic pathways (from Fig. 1) are superimposed on the connecting lines in Fig. 3. Increasing line thickness indicates a connection with possible greater pathogenetic effect (as quantified by biomarker relative-risk prediction of CHD). For example, the risk of CHD is relatively low when considering leptin, therefore the connection line between exercise and leptin is thinner than for others (e.g. Apo B). It is intriguing to see that moderate exercise has a connection to all the serological biomarkers. This further highlights the inverse correlation between CHD risk and moderate exercise. From the connection graph in Fig. 3, it can be noted that the potential risk reduction effect of moderate exercise may be greatly influenced by changes in inflammatory, metabolic and lipid markers, which provide a considerable increased risk for CHD.2-4

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Fig. 3. Interconnection of relative risk effects of moderate exercise and serological biomarkers for CHD. ACR, albumin-to-creatinine ratio; Adipo, adiponectin; Apo B, apolipoprotein-B; BDNF, brain-derived neurotrophic factor; BNP, B-type natriuretic peptide; Cort, cortisol; CRP, C-reactive protein; cysteine, homocysteine; fibrin, fibrinogen; GDF-15, growth-differentiation factor-15; HbA1c, glycosylated haemoglobin A1c; HDL, high-density lipoprotein; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LDL, low-density lipoprotein; MPO, myeloperoxidase; OPG, osteoprotegerin; TNF-α, tumour necrosis factor-α; Trigl, triglycerides; Trop, troponins.

Mora and co-workers determined the mechanisms of the reduced risk of CHD associated with exercise in women.2 They found that a reduction in inflammatory biomarkers were the largest contributors to lowered risk. These were followed, in order, by blood pressure, lipid levels, body mass index (BMI) and haemoglobin level. In the study, the combination of different individual risk factors quantified only 35.5% of the total risk reduction due to physical exercise on CHD.2 It is therefore clear that the risk factors used by Mora and co-workers, in terms of serological biomarkers, did not fully quantify the risks associated with CHD. In their study, LDL, HDL and Apo B serum levels were recorded to monitor lipid levels, but only hsCRP serum levels were used for deducing inflammatory levels.2 It may therefore be possible that with the addition of the other biomarkers indicated in Fig. 3, the effect of moderate exercise may be better quantified. In Fig. 3, it is clear from the risk associated with inflammation that reduction in inflammation would prove beneficial to CHD risk. The full extent of the relationship between exercise and inflammation has not been determined but it has been proven that chronic moderate exercise has a systemic anti-inflammatory effect.5,16,32 It has further been shown that the anti-inflammatory effect of exercise provides the largest individual risk-reduction component of moderate exercise in women.2

Naturally there is a strong link to the metabolic process that is manifested in the connection to the metabolic biomarkers, specifically insulin resistance and glycated haemoglobin level.33,34 This connection may be largely mediated by the increased expenditure of energy, which produces favourable effects on CHD pathogenesis.10, 23 Moderate exercise is also related to changes in lipid factors such as increases in HDL cholesterol and decreases in LDL cholesterol and Apo B levels.33,34

Discussion It is clear that there are a wide variety of effects of exercise on the pathogenesis of CHD, which can be described by the changes in biomarkers. However, from the connection graph in Fig. 3, it is not immediately clear what the overall effect of moderate exercise is on CHD. This effect has been quantified in the RR reduction for CHD, which is observed in those who engage in moderate exercise. Moderate-intensity physical exercise of 1 100 kcal/week is associated with an average RR of 0.75 (0.71–0.79), based on a large meta-analysis.35 The RR of 0.75 would correlate to a RR reduction of 1.33-fold using the method previously described in the Methods section. The data from Fig. 3 show that inflammation and metabolic

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dysregulation may be key aspects in the pathogenesis of CHD.5,10,16,23,32-34 These aspects decrease during exercise and may therefore play a part in the 1.33-fold decreased risk for CHD. Based on the evidence, it is believed that the CHD benefit associated with exercise is substantial and should garner a similar level of public interest as do other risk factors such as smoking, high cholesterol levels and treatments such as statin therapy. However, while exercise is frequently advised for healthy living,36 it is unfortunate that only 48.9% of Americans meet the physical activity guidelines. It follows from this that 51.1% of Americans do not meet the minimum physical activity guidelines, which results in 162.8 million Americans at a greater risk of CHD due to physical inactivity.37 The individual studies selected unfortunately represent only the risk associated with the cohort studied and cannot accurately be extrapolated to other populations without further research.

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Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 2011; 11(9): 607–615.

Mathews MJ. A systems engineering approach to coronary heart disease [PhD dissertation]. Potchefstroom: North-West University, 2016.

Mathews MJ, Liebenberg L, Mathews EH. How do high glycemic load diets influence coronary heart disease? Nutr Metab 2015; 12(1): 6.

Mathews MJ, Liebenberg L, Mathews EH. The mechanism by which moderate alcohol consumption influences coronary heart disease. Nutr J. 2015; 14(1): 33.

Mathews MJ, Mathews EH, Liebenberg L. The mechanisms by which antidepressants may reduce coronary heart disease risk. BMC Cardiovasc Disord 2015; 15(1): 82.

10. Strasser B. Physical activity in obesity and metabolic syndrome. Ann NY Acad Sci 2013; 1281(1): 141–159. 11. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activ-

Conclusion Although it is well known that moderate exercise is associated with a lower risk of CHD, all the positive effects on CHD pathogenesis were not available in a detailed integrated model. Such a model would help provide further insight. A high-level conceptual model was therefore developed, which links moderate exercise with the pathogenesis, hallmarks and biomarkers of CHD. The novel connection graph developed from this model shows, at a glance, the positive effect of moderate exercise on certain important aspects of the pathogenesis of CHD. It helps to graphically explain why moderate exercise is associated with lower CHD risk. From this it is apparent that exercise has a wideranging impact on the pathogenesis of CHD, with these effects notable in changes in CHD biomarkers. The integrated high-level CHD model and simplified connection graph provide a summary of evidence for a causal relationship between CHD risk and moderate exercise. We acknowledge the fact that the integrated view is relevant to other lifestyle issues and for full comprehension will have to be replicated in other articles describing these factors.

ity: the evidence. Can Med Assoc J 2006; 174(6): 801–809. 12. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37(12): 1595–1607. 13. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005; 111(11): 1448– 1454. 14. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87–91. 15. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesityrelated insulin resistance. J Clin Invest 2003; 112(12): 1821–1830. 16. Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005; 98(4): 1154–1162. 17. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32(9): 2045–2051. 18. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. J Am Med Assoc 2004; 291(14): 1730–1737. 19. Pedersen BK, Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports 2006; 16(S1): 3–63. 20. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE.

The angel investor was Dr Arnold van Dyk and the research was later selffunded. Prof Leon Liebenberg was involved in the initial research.

Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998; 32(6): 965–971. 21. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,

References 1.

Mathers CD, Boerma T, Fat DM. Global and regional causes of death. Br Med Bull 2009; 92(1): 7–32.

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42(6): 1206–1252. 22. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, et al.

Mora S, Cook N, Buring JE, Ridker PM, Lee I-M. Physical activity and

Clinical implications of obesity with specific focus on cardiovascu-

reduced risk of cardiovascular events potential mediating mechanisms.

lar disease. A statement for professionals from the American Heart

Circulation 2007; 116(19): 2110–2118.

Association Council on Nutrition, Physical Activity, and Metabolism:

Green DJ, Spence A, Halliwill JR, Cable NT, Thijssen DH. Exercise

endorsed by the American College of Cardiology Foundation.

and vascular adaptation in asymptomatic humans. Exp Physiol 2011; 96(2): 57–70. 4.

Izzo JL, et al. Seventh report of the joint National Committee on

Thompson PD, Buchner D, Piña IL, Balady GJ, Williams MA, Marcus

Circulation 2004; 110(18): 2952–2967. 23. Rose AJ, Richter EA. Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology 2005; 20(4): 260–270.

BH, et al. Exercise and physical activity in the prevention and treatment

24. Cimenti C, Schlagenhauf A, Leschnik B, Schretter M, Tschakert

of atherosclerotic cardiovascular disease: A statement from the Council

G, Gröschl W, et al. Low endogenous thrombin potential in trained

on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation,

subjects. Thromb Res 2013; 131(6): e281–e285.

and Prevention) and the Council on Nutrition, Physical Activity, and

25. Rauramaa R, Salonen JT, Seppänen K, Salonen R, Venäläinen J,

Metabolism (Subcommittee on Physical Activity). Circulation 2003;

Ihanainen M, et al. Inhibition of platelet aggregability by moderate-

107(24): 3109–3116.

intensity physical exercise: a randomized clinical trial in overweight men.

132

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

Circulation 1986; 74(5): 939–944. 26. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342(7): 454–460. 27. Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998; 98(24): 2709–2715. 28. Raastad T, Bjøro T, Hallen J. Hormonal responses to high-and moderate-intensity strength exercise. Eur J Appl Physiol 2000; 82(1–2): 121–128. 29. Libby P. Inflammation in atherosclerosis Nature 2002; 420: 868–874.

AFRICA

acute exercise-induced cortisol on CCR2 expression on human monocytes. Brain Behav Immun 2008; 22(7): 1066–1071. 48. Teixeira de Lemos E, Oliveira J, Páscoa Pinheiro J, Reis F. Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev 2012; 2012: 15. 49. Wang JC, Bennett M. Aging and atherosclerosis mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 2012; 111(2): 245–259. 50. Epstein FH, Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340(2): 115–126. 51. von der Thüsen JH, Borensztajn KS, Moimas S, van Heiningen S,

30. Packard RR, Libby P. Inflammation in atherosclerosis: from vascular

Teeling P, van Berkel TJ, et al. IGF-1 has plaque-stabilizing effects in

biology to biomarker discovery and risk prediction. Clin Chem 2008;

atherosclerosis by altering vascular smooth muscle cell phenotype. Am J

54(1): 24–38. 31. Vasan RS. Biomarkers of cardiovascular disease molecular basis and practical considerations. Circulation 2006; 113(19): 2335–2362. 32. Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta 2010; 411(11): 785–793.

Pathol 2011; 178(2): 924–934. 52. Shai S-Y, Sukhanov S, Higashi Y, Vaughn C, Rosen CJ, Delafontaine P. Low circulating insulin-like growth factor I increases atherosclerosis in ApoE-deficient mice. Am J Physiol Heart Circ Physiol 2011; 300(5): H1898.

33. Jorge MLMP, de Oliveira VN, Resende NM, Paraiso LF, Calixto A,

53. Ruidavets J, Luc G, Machez E, Genoux A, Kee F, Arveiler D, et al.

Diniz ALD, et al. The effects of aerobic, resistance, and combined

Effects of insulin-like growth factor 1 in preventing acute coronary

exercise on metabolic control, inflammatory markers, adipocytokines, and muscle insulin signaling in patients with type 2 diabetes mellitus. Metabolism 2011; 60(9): 1244–1252. 34. Kelley GA, Kelley KS. Efficacy of aerobic exercise on coronary heart disease risk factors. Prev Cardiol 2008; 11(2): 71–75. 35. Sattelmair J, Pertman J, Ding EL, Kohl HW, Haskell W, Lee I-M. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation 2011; 124(7): 789–795.

syndromes: The PRIME study. Atherosclerosis 2011; 218(2): 464–469. 54. Higashi Y, Sukhanov S, Anwar A, Shai S-Y, Delafontaine P. Aging, atherosclerosis, and IGF-1. J Gerontol A Biol Sci Med Sci 2012; 67(6): 626–639. 55. Van Gaal LF, Mertens IL, Christophe E. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444(7121): 875–880. 56. Mougios V. Exercise Biochemistry. Champaign, IL: Human Kinetics, 2006.

36. Committee PAGA. Physical activity guidelines for Americans.

57. Yu Z, Ye X, Wang J, Qi Q, Franco OH, Rennie KL, et al. Associations of

Washington, DC: US Department of Health and Human Services, 2008.

physical activity with inflammatory factors, adipocytokines, and meta-

37. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB,

bolic syndrome in middle-aged and older chinese people. Circulation

et al. Heart disease and stroke statistics – 2013 update: a report from the American Heart Association. Circulation 2013; 127(1): e6–e245. 38. Golbidi S, Laher I. Exercise and the cardiovascular system. Cardiol Res Pract 2012; 2012: e210852. 39. Chan D, Ng LL. Biomarkers in acute myocardial infarction. BMC Med 2010; 8(1): 34. 40. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev 2007; 28(5): 463–491.

2009; 119(23): 2969–2977. 58. Wang TJ, Wollert KC, Larson MG, Coglianese E, McCabe EL, Cheng S, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation 2012; 126(13): 1596–1604. 59. Autenrieth C, Schneider A, Doering A, Meisinger C, Herder C, Koenig W, et al. Association between different domains of physical activity and markers of inflammation. Med Sci Sports Exerc 2009; 41(9): 1706–1713. 60. Lira FS, Rosa JC, Pimentel GD, Souza HA, Caperuto EC, Carnevali

41. Myers J, Kaykha A, George S, Abella J, Zaheer N, Lear S, et al. Fitness

LC, et al. Endotoxin levels correlate positively with a sedentary lifestyle

versus physical activity patterns in predicting mortality in men. Am J

and negatively with highly trained subjects. Lipids Health Dis 2010;

Med 2004; 117(12): 912–918.

9(1): 82.

42. Green DJ, O’Driscoll G, Joyner MJ, Cable NT. Exercise and cardiovas-

61. Shanely R, Nieman D, Henson D, Jin F, Knab A, Sha W. Inflammation

cular risk reduction: time to update the rationale for exercise? J Appl

and oxidative stress are lower in physically fit and active adults. Scand J

Physiol 2008; 105(2): 766–768. 43. Jenkins NT, Martin JS, Laughlin MH, Padilla J. Exercise-induced signals for vascular endothelial adaptations: implications for cardiovascular disease. Curr Cardiovasc Risk Rep 2012; 6(4): 331–346. 44. Høstmark AT, Ekeland GS, Beckstrøm AC, Meen HD. Postprandial light physical activity blunts the blood glucose increase. Prev Med 2006; 42(5): 369–371.

Med Sci Sports 2011: 215–223. 62. Pedersen BK. The diseasome of physical inactivity–and the role of myokines in muscle–fat cross talk. J Physiol. 2009;587(23):5559-68. 63. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. J Am Med Assoc 2009; 302(18): 1993–2000. 64. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ,

45. Boulé NG, Weisnagel SJ, Lakka TA, Tremblay A, Bergman RN,

de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol,

Rankinen T, et al. Effects of exercise training on glucose homeostasis:

non-high-density lipoprotein cholesterol, and apolipoprotein B as mark-

The HERITAGE Family study. Diabetes Care 2005; 28(1): 108–114.

ers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011; 4(3):

46. Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leonhardt W,

337–345.

Fuecker K, Hanefeld M. Postchallenge plasma glucose and glycemic

65. Luc G, Empana J, Morange P, Juhan-Vague I, Arveiler D, Ferrieres J,

spikes are more strongly associated with atherosclerosis than fasting

et al. Adipocytokines and the risk of coronary heart disease in healthy

glucose or HbA1c level. Diabetes Care 2000; 23(12): 1830–1834. 47. Okutsu M, Suzuki K, Ishijima T, Peake J, Higuchi M. The effects of

middle aged men: the PRIME study. Int J Obes 2009; 34(1): 118–126. 66. Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR,

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

Gao P, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367(14): 1310–1320. 67. Kaptoge S, Seshasai SRK, Gao P, Freitag DF, Butterworth AS,

133

urinary albumin levels as predictors of mortality and cardiovascular events in older adults. J Am Med Assoc 2005; 293(13): 1609–1616. 75. Pai JK, Cahill LE, Hu FB, Rexrode KM, Manson JE, Rimm EB.

Borglykke A, et al. Inflammatory cytokines and risk of coronary heart

Hemoglobin A1c is associated with increased risk of incident coronary

disease: new prospective study and updated meta-analysis. Eur Heart J

heart disease among apparently healthy, nondiabetic men and women. J

2014; 35(9): 578–589.

Am Heart Assoc 2013; 2(2): e000077.

68. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E.

76. Schneider HJ, Wallaschofski H, Volzke H, Markus MR, Doerr M, Felix

Growth-differentiation factor-15 is a robust, independent predictor of

SB, et al. Incremental effects of endocrine and metabolic biomarkers

11-year mortality risk in community-dwelling older adults: the Rancho

and abdominal obesity on cardiovascular mortality prediction. PloS

Bernardo study. Circulation 2011; 123(19): 2101–2110.

One 2012; 7(3): e33084.

69. Mogelvang R, Pedersen SH, Flyvbjerg A, Bjerre M, Iversen AZ,

77. Kanhai D, Kranendonk M, Uiterwaal C, Graaf Y, Kappelle L, Visseren

Galatius S, et al. Comparison of osteoprotegerin to traditional athero-

F. Adiponectin and incident coronary heart disease and stroke. A

sclerotic risk factors and high-sensitivity C-reactive protein for diagnosis

systematic review and meta‐analysis of prospective studies. Obes Rev

of atherosclerosis. Am J Cardiol 2012; 109(4): 515–520.

2013; 14(7): 555–567.

70. Rana JS, Arsenault BJ, Després J-P, Côté M, Talmud PJ, Ninio E, et al.

78. Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P.

Inflammatory biomarkers, physical activity, waist circumference, and

Cortisol, testosterone, and coronary heart disease: prospective evidence

risk of future coronary heart disease in healthy men and women. Eur Heart J 2009; 32(3): 336–344. 71. Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin R,

from the Caerphilly study. Circulation 2005; 112(3): 332–340. 79. Hamer M, Endrighi R, Venuraju SM, Lahiri A, Steptoe A. Cortisol responses to mental stress and the progression of coronary artery calci-

Saleheen D, et al. B-type natriuretic peptides and cardiovascular

fication in healthy men and women. PloS One. 2012; 7(2): e31356.

risk systematic review and meta-analysis of 40 prospective studies.

80. Noble EE, Billington CJ, Kotz CM, Wang C. The lighter side of BDNF.

Circulation 2009; 120(22): 2177–2187. 72. Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc 2008; 83(11): 1203–1212. 73. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc 2002; 288(16): 2015–2022. 74. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and

Am J Physiol Regul Integr Comp Physiol 2011; 300(5): R1053. 81. Karatsoreos IN, McEwen BS. Psychobiological allostasis: resistance, resilience and vulnerability. Trends Cogn Sci 2011; 15(12): 576–584. 82. Calabrese F, Molteni R, Racagni G, Riva MA. Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology 2009; 34: S208-S216. 83. Gast KB, Tjeerdema N, Stijnen T, Smit JW, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PloS One 2012; 7(12): e52036.

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Case Report Pacemaker syndrome with sub-acute left ventricular systolic dysfunction in a patient with a dual-chamber pacemaker: consequence of lead switch at the header Mohammad Reeaze Khurwolah, Brian Zwelethini Vezi

Abstract In the daily practice of pacemaker insertion, the occurrence of atrial and ventricular lead switch at the pacemaker box header is a rare and unintentional phenomenon, with less than five cases reported in the literature. The lead switch may have dire consequences, depending on the indication for the pacemaker. One of these consequences is pacemaker syndrome, in which the normal sequence of atrial and ventricular activation is impaired, leading to sub-optimal ventricular filling and cardiac output. It is important for the attending physician to recognise any worsening of symptoms in a patient who has recently had a permanent pacemaker inserted. In the case of a dual-chamber pacemaker, switching of the atrial and ventricular leads at the pacemaker box header should be strongly suspected. We present an unusual case of pacemaker syndrome and right ventricular-only pacinginduced left ventricular systolic dysfunction in a patient with a dual-chamber pacemaker.

Keywords: permanent pacemaker, lead switch, pacemaker syndrome, right ventricular-only pacing-induced left ventricular systolic dysfunction Submitted 27/5/14, accepted 14/9/16 Cardiovasc J Afr 2017; 28: 134–136

www.cvja.co.za

DOI: 10.5830/CVJA-2016-081

Patients may present with a variety of symptoms, depending on the underlying rhythm, pacing rate and percentage of the paced beats. The symptoms of pacemaker syndrome are usually non-specific but often include dizzy spells, shortness of breath, fatigue, near-syncope, syncope or frank heart failure. The occurrence of right ventricular-only pacing-induced left ventricular systolic dysfunction has been well documented.2-4

Case report A 40-year-old man presented with symptoms of undue fatigue and shortness of breath with minimal exertion. His resting heart rate was noted to reach 28 beats per minute (bpm) during waking hours. He was diagnosed with sick sinus syndrome and had a dual-chamber permanent pacemaker inserted. Subsequently, he reported feeling more ill and complained of dizziness, nearsyncope and syncope, worsening of shortness of breath, more fatigue, and what he described as a ‘strange heartbeat with fluttering’. Prior to the dual-chamber pacemaker insertion, he had undergone coronary angiography and left ventriculography, which showed normal epicardial coronary arteries and a left ventricular ejection fraction (LVEF) of 74%. On physical examination post pacemaker insertion, his blood pressure was 106/76 mmHg, with a heart rate (HR) of 76 bpm. The jugular venous pressure was elevated up to the angle of the jaw and cannon waves were present. His heart sounds were otherwise normal with no murmurs elicited, and there were no signs of heart failure. His chest was clear. The electrocardiogram

In the daily practice of pacemaker insertion, the occurrence of atrial and ventricular lead switch at the pacemaker box header is a rare and unintentional phenomenon, with less than five cases reported in the literature.1 The diagnosis of lead switch at the header is usually straightforward and is noticed quite early. If not, the possibility of this important complication should be considered in any patient presenting with ill-defined symptoms during pacemaker follow up. Inkosi Albert Luthuli Central Hospital, Durban, KwaZuluNatal, South Africa Mohammad Reeaze Khurwolah, MB ChB (UCT), nush.11426@ hotmail.com Brian Zwelethini Vezi, FCP (SA)

Fig. 1. Paced QRS with sensed P wave at the end of the QRS, indicative of atrioventricular dyssynchrony.

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135

Fig. 2. E lectrogram showing typical right ventricular pacing, compatible with VVI mode despite AAIR–DDDR programming at the pacemaker. This shows ventricular pacing when in fact pacing is from the right atrial lead. There is ‘atrial sensing’ from the ventricular lead.

(ECG) showed paced QRS with P wave at the end of the QRS complex, indicative of atrioventricular dyssynchrony (Fig. 1). These clinical findings, together with the ECG, raised the suspicion of pacemaker syndrome. Pacemaker interrogation showed that his pacemaker was programmed to AAIR–DDDR mode with a base rate of 70 bpm; the battery power was fine. The ECG showed typical right ventricular pacing compatible with VVIR mode despite AAIR– DDDR programming. Moreover, an atrial electrogram (EGM) showed ventricular pacing and a ventricular EGM showed sensed atrial depolarisation (Fig. 2). These findings were highly suggestive of atrial/ventricular lead switch at the pacemaker header. The underlying rhythm was sinus with an intrinsic rate of 45 bpm. Chest X-ray and fluoroscopy showed that the atrial and ventricular leads were situated in the correct positions in the respective chambers. The patient subsequently underwent a corrective procedure (lead repositioning) without temporary pacing cover. During the procedure, it was confirmed that the leads were switched, with the ventricular lead connected to the atrial port, and the atrial lead connected to the ventricular port. Both the atrial and ventricular leads were disconnected and tested, after which they were reconnected to the appropriate ports at the pacemaker header. Atrial pace and ventricular sense were achieved through the AAIR–DDDR pacing mode (Fig. 3). It was noteworthy that prior to correction, the blood pressure was 108/62 mmHg, with a HR of 45 bpm. Post correction, the blood pressure immediately rose to 141/77 mmHg, with a HR of 72 bpm (AP–VS). An echocardiogram done later the same day showed that

the LVEF had dropped from 74 to 49% post pacemaker insertion. This high LVEF was thought to have been due to right ventricular-only pacing-induced left ventricular systolic dysfunction. The differential diagnosis for pacemaker syndrome includes: acute coronary syndromes, hyperthyroidism, hypothyroidism, pacemaker failure, pacemaker-mediated tachycardia and cardiogenic pulmonary oedema, among others.5 In our case, the rise in systolic blood pressure of > 20 mmHg post correction of the leads confirmed the diagnosis of pacemaker syndrome. The above differential diagnoses were ruled out as follows: the cardiac biomarkers were negative with no ST changes on the ECG, which ruled out an acute coronary syndrome. The patient was biochemically euthyroid with no clinical features of hyper- or hypothyroidism. The pacemaker was functional, ruling out the possibility of pacemaker failure. The resting heart rate was less than 100 bpm and this excluded the possibility of pacemaker syndrome in this case being due to pacemakermedicated tachycardia. The patient was clinically not in left ventricular failure, with clear lung fields on chest radiography and on auscultation, and therefore cardiogenic pulmonary oedema was an unlikely cause of his symptoms. Pulmonary embolism was also ruled out based on a negative D-dimer laboratory result.

Discussion Pacemaker syndrome is defined as intolerance to ventricularbased (VVIR) pacing due to loss of atrioventricular (AV) synchrony.6 It is an iatrogenic disorder that results from the

Fig. 3. T welve-lead ECG post lead repositioning showing proper atrial and ventricular pacing in AAIR–DDDR pacing mode.

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haemodynamic sequelae of right ventricular-only pacing. Symptoms range from fatigability to syncope and occur during ventricular pacing. Postulated mechanisms include loss of AV synchrony, vasodepressor reflexes, and retrograde atrial activation. One of the ways to avoid pacemaker syndrome is maintenance of AV synchrony with a dual-chamber pacemaker with atrial tracking. The overall incidence of pacemaker syndrome is unclear, with different studies reporting different results. In the Mode Selection Trial (MOST), pacemaker syndrome incidence was approximately 18%.6 According to Ausubel and Furman, the estimated incidence of pacemaker syndrome ranged from seven to 20%.7 The aetiology of pacemaker syndrome is poorly understood, but several risk factors are associated with its development: • Low intrinsic rate and high ventricular pacing rate, as noted in our patient, results in high percentage of ventricular pacing, therefore more AV dyssynchrony, and this may also explain the development of left ventricular systolic dysfunction. • Intact ventricular–atrial (VA) conduction poses a greater risk for the development of pacemaker syndrome. • Patients with non-compliant ventricles, such as in diastolic dysfunction, heart failure, hypertrophic cardiomyopathy, among others, are particularly sensitive to loss of atrial contribution to ventricular filling.8 • Ventricular pacing leads to decreased cardiac output, with the resultant increase in left atrial pressure and left ventricular filling pressure.5 A major cause of AV dyssynchrony is VA conduction. Retrograde conduction leads to non-physiological timing of atrial contraction in relation to ventricular contraction. It should, however, be noted that many conditions other than VA conduction promote AV dyssynchrony. Conventional non-physiological right ventricular pacing has deleterious effects on left ventricular systolic function.2 Yu et al. reported that conventional right ventricular apical pacing resulted in adverse left ventricular remodelling and therefore a reduction in LVEF in patients with normal systolic function.3 From the MOST and DAVID trials,4 it has become clear that a high amount of right ventricular apical pacing may be associated with a worse clinical outcome, including worsening left ventricular systolic function, new-onset congestive cardiac

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failure, as well as tachyarrhythmias, such as atrial fibrillation. Unfortunately, it remains unclear as to the exact amount of right ventricular apical pacing that negatively affects cardiac function.

Conclusion This case demonstrated that switching of atrial and ventricular leads at the pacemaker header resulted in pacemaker syndrome in a patient with a dual-chamber permanent pacemaker. The syndrome was due to incorrectly connected leads, resulting in ventricular paced atrial sensed (VP-AS), essentially producing the VVI pacing with retrograde conduction and loss of AV synchrony. This case also illustrates the possibility of right ventricular pacing-induced left ventricular dysfunction and highlights the need to maintain a high level of concentration during device implantation.

References 1.

Hamdi A, Jastrzebski M, Hawas JM. A dual chamber pacemaker leads switch at the header – An electrocardiographical and clinical picture, a case report. J Sulaimani Med Coll 2013; 3(2): 131.

Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony: implications for therapy. J Am Coll Cardiol 2009; 54(9): 764–776.

Yu C-M, Chen JY-S, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009; 361: 2123–2134.

Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. J Am Med Assoc 2002; 288: 3115–3123.

Pacemaker syndrome, Medscape Reference. http://emedicine.medscape. com/article/159706-overview.

Link MS, Hellkamp AS, Estes NAM, et al. High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST). J Am Coll Cardiol 2004; 43(11): 2066–2071.

Ausubel K, Furman A. The pacemaker syndrome. Ann Intern Med 1985; 103(3): 420–429.

Pacemaker syndrome, Cardiology. http://cardiologyheartt.blogspot. com/2014/01/pacemaker-syndrome.html.

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Case Report Successful surgical treatment of a subtotal descending aortic occlusion Mateusz Puślecki, Bartłomiej Perek, Sebastian Stefaniak, Andrzej Siniawski, Grzegorz Oszkinis, Marek Jemielity Case report

Abstract We present the case of a 33-year-old man with middle aortic syndrome. The final diagnosis was established with magnetic resonance imaging. He underwent a successful aorto-aortic bypass. Two-year follow-up imaging showed the new graft was patent, with no abnormalities at the anastomosis sites. At the last follow-up examination he was asymptomatic with no neurological dysfunction. Keywords: surgical treatment, subtotal aorta occlusion, descending aorta Submitted 15/11/15, accepted 17/2/16 Cardiovasc J Afr 2017; 28: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2016-012

Middle aortic syndrome is a rare vascular anomaly, with a long segment of stenotic descending thoracic and abdominal aorta.1-3 Its aetiology is not commonly known although in some cases, chronic inflammation with mononuclear cell infiltration is considered to be of importance, as in Takayashu disease. The rarity of this entity encouraged us to share our experience. We therefore present the case of a young man with middle aortic syndrome who underwent successful surgery with a good late outcome.

Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, Poznan, Poland Mateusz Puślecki, PhD, MD Bartłomiej Perek, PhD, MD Sebastian Stefaniak, PhD, MD, seb.kos@gmail.com Marek Jemielity, MD

Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland Andrzej Siniawski, PhD, MD

Department of Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland Grzegorz Oszkinis, MD

A 33-year-old man was examined because of hypertension and easy fatigability of the lower extremities. The femoral pulses were poorly present. His blood pressure, measured indirectly at admission, was 180/120 mmHg at the brachial artery and 90/70 mmHg in the thigh. His medical history included isolated, poorly controlled arterial hypertension despite aggressive pharmacotherapy (amlodipine, ramipril, nebivolol and methyldopum). The resuts of routine laboratory examinations were normal, including C-reactive protein and procalcytonin. On admission, transthoracic echocardiography showed a left ventricle with preserved systolic performance (left ventricular ejection fraction 56%) and aortic valve with correct morphology and function. Due to a slight dilatation of the ascending aorta on routine examination (chest X-ray, echocardiography), he was referred for magnetic resonance (MRI) imaging of the aorta. On MRI, the ascending aorta and aortic arch were normal. Approximately 25 mm distal to the left subclavian artery orifice, a severely stenotic segment of the descending aorta was visualised. Critical (3–4 mm) aortic coarctation was diagnosed. It confined not only the thoracic aorta, but also the abdominal aorta up to the coeliac trunk (total lesion length 180 mm) (Fig. 1). Moreover, the supradiaphragmatic descending aorta was completely occluded. The aortic arch branches and coeliac and renal arteries were normal without any changes compromising flow. The collateral circulation was excessively developed, predominantly through the intercostal branches and markedly dilated left and right thoracic arteries (Fig. 1). In the narrowed aortic wall, signal enhancement was noted in the short time inversion recovery (STIR) MRI window, which suggested an underlying chronic inflammatory process, or aortitis. Surgery was performed through a left thoracotomy and abdominal retroperitoneal approach by cardiac and vascular surgeons. First, the descending aorta was side-clamped distal to the left subclavian artery and a 22-mm-diameter prosthetic vascular graft was anastomosed in an end-to-side fashion. Then it was passed through a small incision in the left lateral portion of the diaphragm. Eventually, distal anastomosis was performed 15 mm below the renal arteries to a macroscopically normal aortic wall. During surgery, specimens from the anastomosis sites were taken for histological examination. The patient’s postoperative course was complicated by transient paresis of the brachial plexus. Aggressive postoperative rehabilitation at both the cardiac surgery department and rehabilitation centre enabled complete functional recovery. After surgery, there was no need for hypertensive agents and his arterial

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017

Fig. 1. P re-operative MRI. The 180-mm-long narrowing of the descending aorta with a critical (3–4 mm) coarctation. The excessively developed collateral circulation, mainly through intercostal branches and dilated left and right mammary arteries.

pressure was well controlled (brachial blood pressure of 110/70 mmHg and femoral pressure of 100/65 mmHg). Prednisone was added as oral therapy. Histopatological examination of the aortic specimens showed a chronic inflammatory process and eventually the final diagnosis of chronic aortitis was established. Two-year follow-up MRI angiography and computed tomographic (CT) examinations showed the new graft was patent, with no abnormalities at the anastomosis sites (Fig. 2). At the last follow up, he was asymptomatic with no neurological dysfunction.

Discussion Obstructive lesions or hypoplasia of the descending aorta is a rare vascular anomaly.1,2,4 The term middle aortic syndrome (MAS) describes the clinico-anatomical entity of the aorta, irrespective of its aetiology and pathogenesis. This rare pathology involves the descending thoracic aorta, abdominal aorta or both.3 Despite it rarity, MAS is still the subject of clinical research, and the aetiology of this vascular disease remains unclear. Among other factors, non-specific aortic narrowing may be caused by congenital influences, inflammation, developmental

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Fig. 2. Postoperative MRI of the aorto-aortic bypass showing a patent graft accompanied by a completely occluded native descending aorta.

disorders or infection.2,3 MAS may be congenital or acquired postnatally. Congenital coarctation is thought to be due to incomplete fusion or overfusion of the embryonic dorsal aortae. Another hypothesis implicates intra-uterine injury or infection, particularly by Rubella virus, as a risk factor that may precipitate aortic hypoplasia. Acquired MAS is associated with neurofibromatosis, William’s syndrome, Alagille syndrome, fibromuscular dysplasia, retroperitoneal fibrosis (Ormond disease), mucopolysaccharidosis, foetal alcohol syndrome and Takayasu arteritis.1-4 In our case, MAS was most likely acquired and caused by chronic inflammatory disease. The poorly controlled hypertension diagnosed before surgery was successfully resolved by the surgery. At the last follow up, the patient did not need any antihypertensive drugs to control his arterial pressure. Therefore the duration of malignant hypertension was relatively short and did not cause any irreversible complications. On the other hand, severe stenosis of the thoracic and abdominal aorta is an unusual cause of arterial hypertension in the upper extremities, independent of the aetiology of aortic coarctation. Symptoms typically occur within the first three decades of life and include hypertension, lower extremity claudication and mesenteric ischaemia. Therefore symptomatic MAS should be considered a life-threatening condition (possible

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fatal hypertension-related events). All cases with medically resistant hypertension should undergo imaging of both the descending thoracic and abdominal aortae to reveal any potentially curable vascular pathologies. In cases with MAS-induced poorly controlled hypertension, early surgical treatment is recommended.1-4 This strategy may prevent the development of irreversible organ dysfunction. Several surgical techniques have been described.1-4 One is endarterectomy, which should be avoided due to poor long-term clinical results. Nowadays the most widely used surgical method is aorto-aortic bypass with the use of prosthetic grafts. Besides surgical approaches, the endovascular approach has been developed recently, with some case reports in the literature. It is based on the rapid evolution of thoracic endovascular aortic repair (TEVAR) procedures in aortic coarctation, which could become significant in the near future. Before surgery, our patient was disqualified from the endovascular approach, based on the opinion of the vascular team in our hospital (interventional radiologist, vascular surgeon and cardiac surgeon). Total occlusion of the supradiaphragmatic aorta is a contraindication for the endovascular approach. The effect of aortic reconstruction with aorto-aortic bypass is usually permanent, irrespective of the aetiology. It should also be recommended in view of the complexity of the aortic lesions causing MAS, including diffuse pathology of the aortic wall and adjacent tissues. Our case supports earlier reports describing successful use of aorto-aortic bypass. In our patient, a left thoraco-abdominal retroperitoneal approach to the normal aorta above and below the lesions and lateral clamping of the

aorta were used. It enabled a good overview of the descending aorta and facilitated proper selection of the sites of side-to-end anastomoses.

Conclusion This elective operation with a Dacron prosthesis was relatively safe and it was confirmed as an effective method of treatment, with marked postoperative reduction in arterial blood pressure. However, this method required strict cooperation between radiologist, and cardiac and vascular surgeons. We stress that a multidisciplinary approach should be recommended in treatment of this rare but complex aortic wall pathology.

References 1.

Petrunic M,Tonkovic I, Grabic D, Popovic L, Radanovic B, Kruzic Z. Middle aortic syndrome: some diagnostic and therapeutic considerations. Eur J Endovasc Surg 1999; 18: 83–85.

Connolly JE, Wilson SE, Lawrence PL, Fujitani RM. Middle aortic syndrome: distal thoracic and abdominal coarctation, a disorder with multiple etiologies. J Am Coll Surg 2002; 194: 774–781.

Bobby JJ, Emami JM, Farmer RD, Newman CG. Operative survival and 40 year follow up of surgical repair of aortic coarctation. Br Heart J 1991; 65: 271–276.

Segers B, Derluy M, Barroy JP, Brunet AP. Isolated supradiaphragmatic descending thoracic aorta stenosis in a Takayasu’s disease: surgical cure. Eur J Cardiothorac Surg 2001; 20: 1243–1245.

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