CVJA Volume 25, Issue 1 by Clinics Cardive Publishing

JANUARY/FEBRUARY 2014 VOL 25 NO 1

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Multiple thrombophilic gene profiles in coronary slow flow • Atrial electromechanical coupling intervals in pregnancy • Real-world cost-effectiveness of TAVI • Metabolic syndrome and optimal cut-off values in Angola • Echocardiography of LV filling pressures with mitral valve stenosis

Cardiovascular Journal of Africa . Vol 25, No 1, January/February 2014

Printed by Tandym Printers

PUBLISHED ONLINE: • Chronic dissecting aneurysm of the ascending aorta • PCI in a centenarian patient with acute MI

Our B IG 3 A compelling choice for many patients at moderate cv risk who doctors see ever y d a y – “A S C O T d e m o n s t r a t e s t h a t t h e r i s k of hear t attacks can be more than halved in these patients” 1

Perindopril Erbumine 4 mg / 8 mg

Amlodipine Besylate 5 mg / 10 mg

Atorvastatin

10 mg, 20 mg, 40 mg, 80 mg

SEP R27 ,84

team

(excl. VAT)

Trusted

Affordable Evidence based Med icine

References 1. Sever PS, Dahlof B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

S3 Reg. No. 41/7.1.3/0671, 72 S3 Reg. No. 39/7.1/0117, 0120 S4 Reg. No. 42/7.5/0552, 0553, 0554, 0555

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

Vol 25, No 1, JANUARY/FEBRUARY 2014

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial

From the economics of TAVI and the pathophysiology of heart and vessel disease to metabolic disease in Africa and the developing world PA Brink

Vascular calcification is not associated with increased ambulatory central aortic systolic pressure in prevalent dialysis patients RJ Freercks • CR Swanepoel • KL Turest-Swartz • HRO Carrara • SEI Moosa • AS Lachman • BL Rayner

Endothelial function and germ-line ACE I/D, eNOS and PAI-1 gene profiles in patients with coronary slow flow in the Canakkale population: multiple thrombophilic gene profiles in coronary slow flow E Gazi • A Temız • B Altun • A Barutcu • F Silan • Y Colkesen • O Ozdemir

Cardiovascular Topics

15 Atrial electromechanical coupling intervals in pregnant subjects B Altun • H Tasolar • E Gazi • AC Gungor • A Uysal • A Temiz • A Barutcu • G Acar • Y Colkesen • U Ozturk • M Akkoyun 21 An analysis of real-world cost-effectiveness of TAVI in South Africa TA Mabin • P Candolfi 27 Prevalence of the metabolic syndrome and determination of optimal cut-off values of waist circumference in university employees from Angola P Magalhães • DP Capingana • JG Mill 34

Echocardiographic estimation of left ventricular filling pressures in patients with mitral valve stenosis R Sattarzadeh • A Tavoosi • P Tajik

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

Editors

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

Heart Failure Dr g visagie

PROF R DELPORT Chemical Pathology

Paediatric dr s brown

PROF BM MAYOSI Chronic Rheumatic Heart Disease

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular 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

Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne

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)

CONTENTS Vol 25, No 1, JANUARY/FEBRUARY 2014

Letters to the Editor

Non-compaction is not a simple genetic disorder J Finsterer • S Zarrouk-Mahjoub

B-type natriuretic peptide for the prediction of left ventricular remodelling C Bauters • M Fertin • F Pinet

Industry News

40 AstraZeneca Pharmaceuticals enables scientific innovation

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

Chronic dissecting aneurysm of the ascending aorta developed in a patient who had rejected surgical treatment for type II acute ascending aortic dissection three years earlier B Erkut • O Dag • MA Kaygin • HK Limandal • A Aydin • ES Calik

Case Reports

e5 Tachycardia-induced cardiomyopathy due to repetitive monomorphic ventricular ectopy in association with isolated left ventricular non-compaction D Osmonov • KS Özcan • A Ekmekçi • B Güngör • AT Alper • K Gürkam e8 Successful primary percutaneous coronary intervention in a centenarian patient with acute myocardial infarction S Aksoy • Y Velibey • B Koroglu • M Cagdas • O Guzelburc • N Cam • M Eren

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

Production Editor

SHAUNA GERMISHUIZEN Tel: 021 785 7178 Fax: 086 628 1197 e-mail: shauna@clinicscardive.com

Marketing & Advertising

MARIA PHILIPPOU Cell: 082 335 5444 e-mail: mariap1@updategpjournal.co.za

CONTENT MANAGER

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

GAUTENG CONTRIBUTOR

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

Printer: Durbanville Commercial Printers/ Tandym Print ONLINE SERVICES: Design Connection All submissions to CVJA are to be made online via www.cvja.co.za Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances. Postal address: PO Box 1013, Durbanville, RSA, 7551 Tel: 021 976 8129 Fax: 0866 644 202 Int.: +27 21 976 8129 e-mail: info@clinicscardive.com Electronic abstracts available on Pubmed Audited circulation

Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact elsabe@clinicscardive.com Subscriptions for 10 issues: To subscribe to the journal or change your postal address, e-mail elsabe@clinicscardive.com South Africa: R650 (excl VAT) Overseas: R1306 Online subscription: R200 The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Editorial From the economics of TAVI and the pathophysiology of heart and vessel disease to metabolic disease in Africa and the developing world The editor and staff of the journal welcome you, our readers, back in 2014. We trust that you enjoy the spread before your eyes. Hailing from Angola, Magalhães et al. (page 27) looked at the prevalence of the metabolic syndrome in employees of a university, and emphasise the importance of waist circumference (WC) cut-off values that are appropriate for a specific ethnic group. The investigators used the clinical chemistry data obtained to derive WC values for this group. One should keep in mind that in Africa over the longer term, what we need is epidemiological studies to determine the extent to which the metabolic syndrome, in whatever way we define it, predicts cardiovascular events such as myocardial infarction, stroke and other events. In one of two South African studies, health economics feature prominently. Mabin and Candolfi (page 21) compare costing of the relatively new intervention, transcatheter aortic valve implantation (TAVI), with conventional surgical aortic valve replacement (cAVR). Data were derived from these interventions in a private hospital group, a group where TAVI has been pioneered in South Africa, albeit with a major input from clinicians from university-associated public hospitals (Weich et al.1, Weich et al.2). The second article (Freercks et al., page 4) estimated central aortic systolic pressure (CASP) using a peripheral wrist-watchlike device BPro (HealthStats, Singapore). They found that CASP did not correlate with the degree of vascular calcification (VC), which is a risk factor for mortality in dialysis patients. Authors from Iran and the Netherlands (Sattarzad et al., page 34) tackled one of the holy grails in cardiac medicine using tissue Doppler, namely, an often-asked question: Is it the heart, the valves or the lungs that are responsible for a patient’s symptoms? In this instance they developed a Doppler-derived prediction

model of left ventricular end-diastolic pressure (LVEDP) in the presence of known mitral valve stenosis. Two articles emanate from Turkey. Gazi and fellow workers (page 9) examined endothelial function and dysfunction, and the association with polymorphisms in genes involved in endothelial function in patients with coronary slow flow (CSF). CSF is an angiographic phenomenon of delayed passage of contrast along the coronary arteries in the absence of stenosis in the epicardial arteries. As a proxy for endothelial function they used flowmediated dilatation (FMD) of the brachial artery. Altun et al. (page 15) worked from the premise that an increased risk of atrial fibrillation may be related to cardiac changes during pregnancy. They showed that P-wave dispersion and certain tissue Doppler-derived parameters of electromechanical coupling were different from those in the controls. The issue is complemented by online publication of three case reports. All in all a nice little feast with which to start the year. PAUL A BRINK, MB ChB, PhD, paul@clinicscardive.com Department of Internal Medicine, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg

References 1.

Weich H, Janson J, van Wyk J, Herbst P, le Roux P, Doubell A. Transjugular tricuspid valve-in-valve replacement. Circulation 2011; 124(5): e157–e160. Weich H, Ackermann C, Viljoen H, van Wyk J, Mabin T, Doubell AF. Transcatheter aortic valve replacement in a patient with an anomalous origin of the right coronary artery. Cathet Cardiovasc Intervent 2011; 78(7): 1013–1016.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

Cardiovascular Topics Vascular calcification is not associated with increased ambulatory central aortic systolic pressure in prevalent dialysis patients Robert J Freercks, Charles R Swanepoel, Kristy L Turest-Swartz, Henri RO Carrara, Sulaiman EI Moosa, Anthony S Lachman, Brian L Rayner Abstract

Introduction: Central aortic systolic pressure (CASP) strongly predicts cardiovascular outcomes. We undertook to measure ambulatory CASP in 74 prevalent dialysis patients using the BPro (HealthStats, Singapore) device. We also determined whether coronary or abdominal aortic calcification was associated with changes in CASP and whether interdialytic CASP predicted ambulatory measurement. Methods: All patients underwent computed tomography for coronary calcium score, lateral abdominal radiography for aortic calcium score, echocardiography for left ventricular mass index and ambulatory blood pressure measurement using BPro calibrated to brachial blood pressure. HealthStats was able to convert standard BPro SOFT® data into ambulatory CASP. Results: Ambulatory CASP was not different in those without and with coronary (137.6 vs 141.8 mmHg, respectively, p = 0.6) or aortic (136.6 vs 145.6 mmHg, respectively, p = 0.2) calcification. Furthermore, when expressed as a percentage of brachial systolic blood pressure to control for peripheral blood pressure, any difference in CASP was abolished: CASP: brachial systolic blood pressure ratio = 0.9 across all categories regardless of the presence of coronary or aortic calcification (p = 0.2 and 0.4, respectively). Supporting this finding, left ventricular mass index was also not different in those with or without vascular calcification (p = 0.7 and 0.8

Renal Unit, Groote Schuur Hospital, University of Cape Town, South Africa Robert J Freercks, FCP (SA), Cert Neph, MPhil (UCT), freercks@gmail.com Charles R Swanepoel, FRCP (Edin) Kristy L Turest-Swartz, MPH (UCT) Brian L Rayner, FCP, MMed

School of Public Health and Family Medicine, University of Cape Town, South Africa Henri RO Carrara, MPH (UMEA)

Radiologist, 2-Military Hospital, Cape Town

Sulaiman EI Moosa, MPhil, BSc (Hon), FCRad (Diag)

Cardiologist, 2-Military Hospital, Cape Town Anthony S Lachman, FCP (SA), FACC, FACP

for coronary and aortic calcification). Inter-dialytic office blood pressure and CASP correlated excellently with ambulatory measurements (r = 0.9 for both). Conclusion: Vascular calcification was not associated with changes in ambulatory central aortic systolic pressure in this cohort of prevalent dialysis patients. Inter-dialytic blood pressure and CASP correlated very well with ambulatory measurement. Keywords: vascular calcification, central blood pressure, dialysis, ambulatory blood pressure monitoring Submitted 4/4/13, accepted 14/11/13 Cardiovasc J Afr 2014; 25: 4–8

www.cvja.co.za

DOI: 10.5830/CVJA-2013-081

Vascular calcification (VC) is a novel vascular risk factor strongly associated with mortality in dialysis patients.1,2 Although various explanations exist for this association, one mechanism is through alterations in pulse-wave velocity (PWV). Vascular calcification is associated with increased aortic PWV,3 which in turn is associated with raised central aortic systolic pressure (CASP) and reduced coronary perfusion.4,5 As a result, brachial pressure may significantly under- or over-estimate central pressure.6 Not surprisingly therefore, central blood pressure parameters have been shown to predict hard cardiovascular endpoints (including mortality) better than concomitant brachial measurements.7-10 Whether vascular calcification is directly linked to central pressures is, however, unknown since there are many determinants of aortic stiffening other than calcification. Furthermore, a primarily damaged and stiff aorta may be the target for secondary deposition of calcium.11 CASP can be calculated using applanation tonometry-derived peripheral pulse waveforms and associated software.12 This avoids the obvious disadvantages of invasive central pressure determination. The major disadvantage of standard techniques, however, is the one-dimensional static measurement that is obtained, with no information on ambulatory values or nocturnal dipping status. Loss of normal nocturnal systolic blood pressure dipping is prevalent in chronic kidney disease (CKD) and likely contributes

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

to cardiovascular disease.13 Dipping, which can only be assessed using ambulatory monitoring techniques, correlates better with left ventricular mass index (LVMI) in end-stage renal disease than office-based blood pressure measurement.14,15 There have been calls for the routine use of ambulatory blood pressure monitoring (ABPM) in clinical studies of CKD13,16 and indeed, for investigations into the utility of ambulatory CASP in clinical practice.17,18 Combining both ambulatory and central pressure measurements is an attractive strategy, but until recently has not been technically possible. A non-invasive wrist watch-like device, BPro with A-Pulse CASP software (HealthStats, Singapore) was recently approved by the US Food and Drug Administration (FDA: K072593) for the measurement of CASP as well as ambulatory blood pressure. It is a small, wrist watch-like, cuffless monitor which obtains radial pressure waveforms by applanation tonometry. BPro has the ability to measure ambulatory CASP and although not yet commercially available, the manufacturer is able to convert data into ambulatory CASP using the same software. As part of a recently published study on vascular calcification,19 we sought to prospectively evaluate whether the presence of vascular calcification had any relationship with ambulatory CASP in our young CKD-5D cohort using the BPro® radial pulse-wave acquisition device. We also sought to determine the utility of inter-dialytic office brachial and central blood pressure measurements in predicting ambulatory parameters.

Methods The study was approved by the Research Ethics Committee of the University of Cape Town, South Africa. The full methodology has been published elsewhere,19 but briefly, cases were selected if they were on maintenance dialysis of three months or longer duration and were able to sign informed consent. Seventy-five prevalent dialysis patients 18 years or older were enrolled from Groote Schuur Hospital, Cape Town. Patients were excluded if they were pregnant or planning a pregnancy, had sustained arrhythmias or prior coronary stenting or bypass. One patient was excluded due to loss to follow up so the final case sample was 74 participants. Clinical and demographic data were collected and ethnicity was self-reported. Ambulatory and office blood pressure monitoring: the BPro® radial pulse wave acquisition device and A-pulse CASP® software (HealthStats, Singapore) system uses an N-point moving-average method to non-invasively derive CASP from the radial arterial pressure waveform. It has been validated against a generalised transfer function method using CAFE study data as well as central aortic pressures recorded in vivo at the aortic root, using a Millar’s SPC–454D tonometer (Millar’s instruments, Texas USA).20 The device also recently compared favourably to the widely used non-invasive SphygmoCor system (AtCor Medical, Sydney, New South Wales, Australia), with good agreement compared to invasively determined CASP.17 For blood pressure determination, the BPro™ has been validated against the Association for the Advancement of Medical Instrumentation and European Society of Hypertension (ESH) protocols and passed both validations.21 The BPro™ records pressure wave forms calibrated to the brachial blood pressure and samples up to 96 × 10-second blocks of time over 24 hours. This provides a 24-hour profile and summary of an

individual’s systolic, diastolic and mean arterial pressures via the use of BPro SOFT® software. Practically, the device was applied on the non-dominant arm or that which did not contain an AVF on the inter-dialytic day for haemodialysis patients or at a routine visit for prevalent dialysis patients. The device was then calibrated to office blood pressure – brachial blood pressure obtained via use of the MC3000 oscillometric device (HealthStats) according to the recommended ESH protocol.22 The manufacturer was able to convert the ABPM data into ambulatory CASP readings since the data are acquired in the same way for both. Cardiac CT and coronary calcium score: images were acquired using the Philips Brilliance 64-slice MDCT scanner. A standard protocol was used as follows: tube voltage, 120 kV; tube current, 55 mAs; detector collimation, 40 × 0.625 mm; gantry rotation, 400 ms. CT data were transferred to the Philips Extended Brilliance Workstation Version 4.0.2.145 for analysis and coronary calcium score was calculated with the Agatston algorithm.23 All scans were evaluated by a single experienced radiologist (SM) and the intra-reader variability was tested and was below 10%. Abdominal X-ray and abdominal aortic calcium score: a standard technique of exposing the lateral lumbar spine in the standing position (with 100-cm film distance, 94 KVP, and 33–200 mAs) was used. Calcific deposits in the abdominal aorta were scored as described by Kaupilla,24 by a single experienced clinician (RF) blinded to clinical data and coronary calcium score. Echocardiography: assessment of the left ventricular mass was done via use of M-mode echocardiography and this was calculated using the Penn convention.25 Left ventricular hypertrophy was defined as > 125 g/m2 in males and > 110 g/m2 in females as per ESH guidelines.26 All scans were obtained and evaluated by a single experienced cardiologist (AL).

Statistical analysis Normality was determined with the Shapiro–Wilk test. Continuous variables are expressed as mean ± SD or median and inter-quartile range (IQR) and compared with the two-tailed independent Student’s t-test and Mann–Whitney test as appropriate. Dichotomous data are presented as percentages and compared with chi-square tests. All analyses were conducted using Stata 12.0 statistical software (College Station, TX, USA).

Results Table 1 shows the baseline characteristics of all patients. Overall, only 27 patients (38.6%) in the cohort had a coronary calcium score ≥ 1, and 26 (35.6%) had an abdominal aortic calcium score ≥ 1. The median coronary calcium score in those with coronary calcification was 141 (IQR = 55–619) and in those with abdominal aortic calcification, the median abdominal aortic calcium score was 6 (IQR = 1–10). Table 2 shows the baseline characteristics for all subjects with and without coronary and/or abdominal aortic calcification. Both coronary and aortic calcium presence failed to show any association with CASP (p = 0.2 and 0.4, respectively). There was no difference when the ratio was compared in those with the highest versus lowest quartiles of coronary and aortic

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Table 1. Baseline characteristics of patients (n = 74 unless otherwise indicated) Range Characteristic Value (SD/IQR) Age, mean (years) 41.8 10.5 Women (%) 56.8 Months on dialysis, median 32.0 43.6 Diabetes (%) 13.5 Tobacco use (%) 41.9 History of cardiovascular disease (%) 4.0 Office systolic BP (mmHg) 146.8 28.0 Office diastolic BP (mmHg) 95.2 17.6 147.4 33.1 ABPM systolic BPa (mmHg) 97.6 21.7 ABPM diastolic BPa (mmHg) 49.8 15.4 ABPM peripheral pulse pressurea (mmHg) 139.2 31.3 ABPM central aortic systolic pressurea (mmHg) 5.3 5.5 ABPM dipping statusa (%) 180.4 97.4 LVMI (g/m2) LVH By ECHO 86.4 By ECG 70.3 Number of antihypertensives used, mean 2.3 1.4 SD, standard deviation; IQR, interquartile range; ABPM, ambulatory blood pressure monitoring; BP, blood pressure; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy. an = 72.

calcification (p = 0.2). Furthermore, there was no difference in the absolute difference between ambulatory systolic blood pressure and CASP values between those with and without coronary calcification (difference = 8.27 and 8.16, respectively, p = 0.8). Fig. 1 shows the correlation of office with ambulatory systolic blood pressure. Office systolic blood pressure and CASP correlated well with their ambulatory measurement (both r = 0.90).

Ambulatory systolic blood pressure

AFRICA

250

200

150

100

50 50

100 150 200 Office systolic blood pressure

250

Fig. 1. C orrelation between office and ambulatory systolic blood pressures.

Discussion This was an observational study of 75 consecutive patients undergoing dialysis in a South African public sector unit. The cohort was young with a low level of co-morbidity due to stringent criteria for the selection of dialysis patients. A key finding in this study was that both coronary and abdominal aortic calcification was not associated with a higher CASP relative to the brachial systolic blood pressure. This ratio was used to control for systolic blood pressure, which would otherwise make comparison between groups difficult. Since the study had an 80% power to detect a difference of > 3% in CASP, it was unlikely that there would be a clinically meaningful difference between CASP values with and without calcification. The reasons for these findings are unclear but may be that

Table 2. Baseline characteristics by presence of vascular calcification Coronary calcification Abdominal aortic calcification n CAC++ p-value n AAC– n AAC++ p-value Variable n CAC– Age (median) 43 38.3 27 46.0 < 0.01 47 39.3 26 46.0 < 0.01 Gender, m:f ratio 43 1.1 27 0.5 0.1 47 1.0 26 0.4 0.1 Tobacco use (ever) (%) 43 37.2 27 51.9 0.2 47 34.0 26 57.7 0.1 Prior cardiovascular events (%) 43 2.3 27 7.4 0.3 47 4.3 26 3.9 0.9 Presence of diabetes (%) 43 7.0 27 25.9 < 0.05 47 4.3 26 30.8 < 0.01 Office systolic BP (mmHg) 43 145.5 26 149.0 0.6 46 144.1 25 152.8 0.2 Office diastolic BP (mmHg) 43 95.4 26 94.8 0.9 46 94.5 25 96.5 0.7 Office central aortic systolic pressure (mmHg) 43 132.8 26 134.9 0.7 46 131.4 25 138.2 0.3 ABPM systolic BP (mmHg) 43 145.8 26 150.1 0.6 46 144.4 25 154.2 0.2 ABPM diastolic BP, mmHg 43 97.7 26 97.3 0.9 46 96.7 25 99.6 0.5 ABPM peripheral pulse pressure (mmHg) 43 48.0 26 52.8 0.2 46 39.7 25 46.0 0.1 ABPM central aortic systolic pressure (mmHg) 43 137.6 26 141.8 0.6 46 136.3 25 145.6 0.2 ABPM central aortic systolic/systolic pressure ratio 43 0.9 26 0.9 0.2 46 0.9 25 0.9 0.4 Nocturnal systolic dipping (%) 37 6.2 25 4.0 0.1 40 5.8 24 4.5 0.3 42 179.7 26 187.1 0.7 45 188.0 25 198.0 0.8 Left ventricular mass index (g/m2) LVH on echocardiography (%) 43 81.4 27 92.6 0.2 47 85.1 26 88.5 0.7 CAC–, coronary artery calcium score = 0; CAC++, coronary artery calcium score = ≥1; AAC–, abdominal aortic calcium score = 0; AAC++, abdominal aortic calcium score = ≥1; m:f = male:female; ABPM, ambulatory blood pressure monitoring; BP, blood pressure.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

vascular calcification is not directly responsible for aortic stiffening and the association of calcification with PWV is not causative. There are many other factors such as elastin fragmentation, endothelial dysfunction and advanced glycation that affect aortic stiffness other than calcification.11 Alternatively, since vascular micro-calcifications may be present in uraemic subjects without radiologically visible calcium,27 it is possible that vascular stiffening occurs earlier on and obscures any differences in CASP. Unfortunately, we were unable to measure PWV. As left ventricular mass index is strongly determined by CASP,8,28 the lack of association with vascular calcification supports our controversial findings. Non-dipping was particularly prevalent, as in other studies of CKD,29 and although it has been associated with vascular calcification,30 it was not different in those with and without vascular calcification in this cohort. However, the very poor dipping status overall may have obscured any clinically meaningful difference between the two groups. Both inter-dialytic office blood pressure and CASP correlated well with ambulatory blood pressure measurements. This has important implications since the FDA has called for the inclusion of CASP into clinical studies of blood pressure.4 Office CASP could therefore also represent ambulatory CASP well in other CKD-5D populations, although this requires further study. Our observations support findings by other groups where interdialytic measurement of blood pressure was superior to office blood pressure in predicting ambulatory measurements for CKD-5D patients.31,32 There were several limitations to our study. First, the patients in our cohort were young and one cannot be certain whether these findings would be reproduced in an older cohort. Second, we were not able to measure PWV in our study and it would have been useful to do this in attempting to reconcile the lack of effect of vascular calcification on central aortic pressures. It remains to be determined in this cohort whether vascular calcification occurs independently of changes in pulse-wave velocity. Third, CASP was indirectly measured, although a recent publication showed excellent correlation of BPro with direct measurement of CASP.17

References 1.

9. 10.

11. 12. 13.

Conclusion Coronary and abdominal aortic calcification was not associated with changes in central aortic systolic pressure or dipping status in young South African dialysis patients. Inter-dialytic office blood pressure and central aortic systolic pressure, when measured according to ESH standards, correlated very well with ambulatory measurements.

14.

15.

16. We are indebted to the staff at Groote Schuur Renal Unit as well as the 2-Military Hospital Radiology Department for their willing assistance. We thank Genzyme Corporation (Cambridge, MA) and Discovery Health (South Africa) for unrestricted research grants that made this possible. RF is grateful to National Renal Care (South Africa) for salary funding. Genzyme Corporation provided statistical advice during protocol design but was at no stage involved in the collection, analysis, interpretation and reporting of data herein. The authors declare no conflict of interest.

17.

18. 19.

London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18(9): 1731–1740. Matsuoka M, Iseki K, Tamashiro M, Fujimoto N, Higa N, Touma T, et al. Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol 2004; 8(1): 54–58. Raggi P, Bellasi A, Ferramosca E, Islam T, Muntner P, Block GA. Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 2007; 71(8): 802–807. Townsend RR, Roman MJ, Najjar SS, Cockcroft JR, Feig PU, Stockbridge NL. Central blood pressure measurements – an opportunity for efficacy and safety in drug development? J Am Soc Hypertens 2010; 4(5): 211–214. Leung MC, Meredith IT, Cameron JD. Aortic stiffness affects the coronary blood flow response to percutaneous coronary intervention. Am J Physiol Heart Circ Physiol 2006; 290(2): H624–630. McEniery CM, Yasmin, McDonnell B, Munnery M, Wallace SM, Rowe CV, et al. Central pressure: variability and impact of cardiovascular risk factors: the Anglo-Cardiff Collaborative Trial II. Hypertension 2008; 51(6): 1476–1482. Roman MJ, Devereux RB, Kizer JR, Okin PM, Lee ET, Wang W, et al. High central pulse pressure is independently associated with adverse cardiovascular outcome the strong heart study. J Am Coll Cardiol 2009; 54(18): 1730–1734. Wang KL, Cheng HM, Chuang SY, Spurgeon HA, Ting CT, Lakatta EG, et al. Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality? J Hypertens 2009; 27(3): 461–467. Williams B, Lacy PS. Central aortic pressure and clinical outcomes. J Hypertens 2009; 27(6): 1123–1125. Huang CM, Wang KL, Cheng HM, Chuang SY, Sung SH, Yu WC, et al. Central versus ambulatory blood pressure in the prediction of all-cause and cardiovascular mortalities. J Hypertens 2011; 29(3): 454–459. Williams B. The aorta and resistant hypertension. J Am Coll Cardiol 2009; 53(5): 452–454. London GM, Pannier B. Arterial functions: how to interpret the complex physiology. Nephrol Dial Transplant 2010; 25(12): 3815–3823. Thompson AM, Pickering TG. The role of ambulatory blood pressure monitoring in chronic and end-stage renal disease. Kidney Int 2006; 70(6): 1000–1007. Rahman M, Griffin V, Heyka R, Hoit B. Diurnal variation of blood pressure; reproducibility and association with left ventricular hypertrophy in hemodialysis patients. Blood Press Monit 2005; 10(1): 23–32. Wang AY, Lam CW, Chan IH, Wang M, Lui SF, Sanderson JE. Sudden cardiac death in end-stage renal disease patients: a 5-year prospective analysis. Hypertension 2010; 56(2): 210–216. Agarwal R. Home and ambulatory blood pressure monitoring in chronic kidney disease. Curr Opin Nephrol Hypertens 2009; 18(6): 507–512. Ott C. Comparison of two noninvasive devices for measurement of central systolic blood pressure with invasive measurement during cardiac catheterization. J Clin Hypertens 2012; 14(9): 575–579 Schillaci G, Pucci G. Central and 24-h blood pressure: dwarfs standing upon the shoulders of giants? J Hypertens 2011; 29(3): 430–433. Freercks R, Swanepoel C, Carrara H, Moosa S, Lachman A, Rayner B. Vascular calcification in South African dialysis patients: Ethnic variation, prevalence, detection and haemodynamic correlates. Nephrology (Carlton) 2012; 17(7): 607–615.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

20. Williams B, Lacy PS, Yan P, Hwee CN, Liang C, Ting CM. Development and validation of a novel method to derive central aortic systolic pressure from the radial pressure waveform using an N-point moving average method. J Am Coll Cardiol 2011; 57(8): 951–961. 21. Nair D, Tan SY, Gan HW, Lim SF, Tan J, Zhu M, et al. The use of ambulatory tonometric radial arterial wave capture to measure ambulatory blood pressure: the validation of a novel wrist-bound device in adults. J Hum Hypertens 2008; 22(3): 220–222. 22. Mansia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-ESC Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press 2007; 16(3): 135–232. 23. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15(4): 827–832. 24. Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PW. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis 1997; 132(2): 245–250. 25. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57(6): 450–458.

AFRICA

26. European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25(6): 1105–1187. 27. Schlieper G, Aretz A, Verberckmoes SC, Kruger T, Behets GJ, Ghadimi R, et al. Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol 2010; 21(4): 689–696. 28. Roman MJ, Okin PM, Kizer JR, Lee ET, Howard BV, Devereux RB. Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study. J Hypertens 2010; 28(2): 384–388. 29. Minutolo R, Agarwal R, Borrelli S, Chiodini P, Bellizzi V, Nappi F, et al. Prognostic role of ambulatory blood pressure measurement in patients with nondialysis chronic kidney disease. Arch Intern Med 2011; 171(12): 1090–1098. 30. Covic A, Goldsmith DJ. Ambulatory blood pressure monitoring in nephrology: focus on BP variability. J Nephrol; 12(4): 220–229. 31. Agarwal R, Andersen MJ, Bishu K, Saha C. Home blood pressure monitoring improves the diagnosis of hypertension in hemodialysis patients. Kidney Int 2006; 69(5): 900–906. 32. Agarwal R, Peixoto AJ, Santos SF, Zoccali C. Out-of-office blood pressure monitoring in chronic kidney disease. Blood Press Monit 2009; 14(1): 2–11.

Letter to the Editor Non-compaction is not a simple genetic disorder Dear Sir We read with interest the article by Osmonov et al. about an asymptomatic 16-year-old boy with left ventricular hypertrabeculation/non-compaction (LVHT) who was incidentally investigated cardiologically for repetitive monomorphic couplets/ triplets of premature ventricular ectopic beats with left bundle branch block morphology and inferior QRS axis.1 We have the following comments and concerns. We do not agree with the definition of LVHT as a genetic disorder. Although frequently associated with genetic disease, a clear-cut genotype/phenotype correlation has never been established for any of the mutated genes so far described in association with LVHT. An argument against a causal relationship is that in the majority of hereditary neuromuscular disorders (NMDs) associated with LVHT, LVHT is absent.2 Since the exact cause and pathomechanism of LVHT remains elusive, it is not justified to classify LVHT as a genetic disease.

The authors reported that systolic function improved after ablation. Did the patient also receive angiotensin converting enzyme inhibitors, angiotensin 2 blockers, beta-blockers or diuretics, or do the authors attribute improvement of systolic dysfunction within two months after the procedure exclusively to the ablation? The authors mentioned that the boy was scheduled for plastic surgery. Which operation was the patient intended to undergo? Did the patient present with dysmorphism, any skin problems, or bone abnormalities, which are occasionally found in patients with LVHT?3 LVHT has not only been misdiagnosed as distal heterotrophic cardiomyopathy, dilated cardiomyopathy, or left ventricular apical thrombus, but has also been mixed up with aberrant bands, papillary muscles, apical type of hypertrophic cardiomyopathy, myocardial abscess and toxoplasmosis.4 continued on page 20…

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Endothelial function and germ-line ACE I/D, eNOS and PAI-1 gene profiles in patients with coronary slow flow in the Canakkale population: multiple thrombophilic gene profiles in coronary slow flow Emine Gazi, Ahmet Temiz, Burak Altun, Ahmet Barutcu, Fatma Silan, Yucel Colkesen, Ozturk Ozdemir Abstract

Background: We examined the effects of ACE, PAI-1 and eNOS gene polymorphisms on endothelial function. The genes are related to atherosclerosis and endothelial dysfunction in coronary slow flow (CSF). Methods: Thirty-three patients with angiographically proven CSF and 48 subjects with normal coronary flow were enrolled in this study. Coronary flow patterns were determined by the thrombolysis in myocardial infarction (TIMI) frame count method. Endothelial function was assessed in the brachial artery by endothelium-dependent flow-mediated dilatation (FMD). PAI-1 4G/5G, eNOS T-786C and ACE I/D polymorphisms were determined by polymerase chain reaction (PCR) amplification. Results: No difference was found between the groups regarding age, heart rate and blood pressure. Males were more prevalent among patients with CSF than control subjects (58.8 vs 29.8%, p = 0.009). Mean TIMI frame counts were significantly higher in CSF patients (24.2 ± 4.0 vs 13.1 ± 2.5 fpm, p = 0.001). FMD was significantly lower in CSF patients than in the controls (4.9 ± 6.6 vs 7.9 ± 5.6%, p = 0.029). TIMI frame count and FMD were found to be negatively correlated in a correlation analysis (r = –0.269, p = 0.015). PAI-1 4G/5G, eNOS T-786C and ACE I/D polymorphisms were similar in the two groups. Conclusions: This study showed that endothelial function was impaired in patients with CSF. PAI-1, ACE and eNOS polymorphisms were not related to CSF in our study population. Keywords: thrombophilic genes, SNP, PAI-1 4G/5G, eNOS T-786C, ACE I/D, coronary slow flow Submitted 26/7/13, accepted 22/11/13 Published online 16/1/14 Cardiovasc J Afr 2014; 25: 9–14

www.cvja.co.za

DOI: 10.5830/CVJA-2013-083

Department of Cardiology, Faculty of Medicine, Canakkale Onsekiz mart University, Canakkale, Turkey Emine Gazi, MD, eordulu@hotmail.com Ahmet Temiz, MD Burak Altun, MD Ahmet Barutcu, MD Yucel Colkesen, MD

Department of Medical Genetics, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey Fatma Silan, MD Ozturk Ozdemir, MD

Coronary slow flow (CSF) was first reported in 1972 as an angiographic phenomenon, described as delayed passage of angiographic contrast agent along the coronary arteries in the absence of stenosis in the epicardial vessels.1 CSF is relatively rare, more frequently seen in young men and smokers with recurrent chest pain. Some cases of sudden cardiac death have been reported in patients with CSF.2 It was thought to be due to coronary microvascular endothelial dysfunction and diffuse atherosclerosis, although the aetiopathogenesis is unclear.3,4 Flowmediated dilatation (FMD) is a simple, non-invasive, repetitive method for assessment of endothelial function.5 Impaired FMD has been reported in CSF patients.6 The angiotensin converting enzyme (ACE) is part of the renin– angiotensin system and plays an important role in haemostasis of the vascular wall.7 Regulation of the activity of ACE in both the circulation and tissues is under the control of the ACE gene located on chromosome 17q23. The ACE gene has an insertion/ deletion (I/D) polymorphism in the non-coding region of the gene.8 Serum ACE activity is higher in subjects with deletion/ deletion (D/D) alleles than in subjects with I and D alleles and is related to hypertension and cardiovascular disease.8,9 The frequency of the DD genotype and D allele was reported to be higher in SCF patients.10,11 Nitric oxide (NO) is synthesised from L-arginine by nitric oxide synthase and has an effect on endothelial relaxation.12 NO plays a protective role in atherogenesis, and deficiency in NO activity causes coronary spasms.13 A polymorphism of endothelial NO synthase (eNOS) is located on chromosome 7q35-56 and influences NO production. Nakayama et al. originally reported a mutation of thymidine, being replaced by cytosine at the nucleotide -786 (T-786C) gene.14 This polymorphism, which results in a significant reduction in eNOS gene promoter activity, is associated with hypertension, acute coronary syndrome and coronary vasospasm.15-19 Tissue plasminogen activator inhibitor 1 (PAI-1) plays an important role in endogenous fibrinolytic activity. Recent studies demonstrated that elevated PAI-1 activity was related to atherosclerosis, and was an independent predictor of coronary artery disease and myocardial infarction.20,21 The PAI-1 gene is located on 7q21.3-22 and polymorphism of the 4G/5G gene is located in the PAI-1 gene promoter region. The fifth guanine (G) base is inserted or deleted in the 4G sequence in the 675th base of the initial transcription point upstream. The PAI-1 gene has three genotypes, namely, 4G/4G, 4G/5G and 5G/5G. 4G/4G allele carriers always have higher plasma PAI-1 activity than 4G/5G and 5G/5G carriers.22 The aim of this study was to investigate the association between ACE I/D, eNOS and PAI-1 gene polymorphisms and endothelial function, evaluated by FMD, in patients with CSF.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Methods

A total of 33 patients with CSF (mean age 55.8 ± 10.3 years) and 48 controls (mean age 53.9 ± 11.8 years) with normal coronary arteries were enrolled in this study. Coronary angiography was performed in the cardiology clinic between January 2010 and June 2012 on patients who had an indication for elective coronary angiography due to ischaemia detected on a treadmill test and/or myocardial perfusion scintigraphy. A complete history, findings of the physical examination, risk factors for atherosclerotic heart disease and medications were recorded. Patients who had been treated with antihypertensive drugs or those whose baseline blood pressure exceeded 140/90 mmHg were diagnosed with hypertension (HT). Diabetes mellitus (DM) was defined as fasting blood glucose levels > 126 mg/dl or the use of anti-diabetic medication. Hyperlipidaemia was defined as a total cholesterol level > 200 mg/dl and/or low-density cholesterol level > 160 mg/dl. Patients with known atherosclerotic disease, visualised coronary artery plaque in coronary angiography, peripheral artery disease, malignancy, renal and hepatic insufficiency, and chronic inflammatory disease were excluded from the study. All subjects agreed to participate in the research and the consent of the local ethics committee was obtained. Coronary angiography was performed with a femoral approach using Judkins catheters and the contrast agent iopramide (Ultravist-370, Bayer Schering Pharma, Germany) with angiographic equipment (GE Medical Systems, Innova 2100, USA). The thrombolysis and myocardial infarction (TIMI) frame rate was 30 frames per second (fps) and angiograms were recorded on a compact disc in DICOM format. Coronary blood flow was measured quantitatively using TIMI frame count, which was determined for each major coronary artery of each subject included in the study, according to the method first described by Gibson et al.23 The left anterior descending coronary artery (LAD) is usually longer than the other major coronary arteries and for that reason the TIMI frame count of this vessel is often higher. Therefore, to obtain the corrected TIMI frame count of the LAD, the TIMI frame count was divided by 1.7.23 TIMI frame counts in the LAD and left circumflex (LCx) arteries were assessed in the right anterior oblique projection, and the right coronary artery (RCA) in the left anterior oblique projection. The mean TIMI frame count for each subject was calculated by adding the TIMI frame counts for the LAD/1.7, LCx and RCA and then dividing the value obtained by 3. The corrected cut-off values due to the length of normal visualisation of the coronary arteries were 36.2 ± 2.6 frames for the LAD, 22.2 ± 4.1 frames for the LCx, and 20.4 ± 3 frames for the RCA. Any values obtained above these thresholds were considered CSF. Peripheral blood samples from CSF patients and healthy controls were used for genotyping for point mutations of PAI-1, MTHFR and ACE genes and are compared in the results. Three thrombophilic marker genes, plasminogen activator inhibitor-1 (PAI-1, rs1799889); two polymorphic regions for MTHRF (C677T, rs1801133 and A1298C, rs1801131), and ACE I/D (rs1799983) genes were analysed in the results.

Genotyping Peripheral blood samples containing EDTA were collected from

AFRICA

the patients and volunteer controls after a 12-hour overnight fast. All routine biochemical tests were carried out on an autoanalyser with the Cobas 6 000 Integra (Roche Diagnostics, IN, USA) auto-analyser device using the chemiluminescence method. Venous blood was collected in 6-ml EDTA tubes for isolation of the genomic DNA and stored at –20°C. A total of 81 DNA samples from patients with CSF and controls were genotyped by real-time polymerase chain reaction (PCR) analysis. The total genomic DNA was extracted by the MagnaPure Compact (Roche) and Invitek kit extraction techniques (Invitek®; Invisorb spin blood, Berlin, Germany). Target genes were amplified by real-time PCR, LightCycler 2.0 methods (Roche) for the CSF cohort and healthy controls. Briefly, LightCycler FastStart DNA Master HybProbes, master mix (water, PCR-grade, MgCl2, stock solution, primer mix, HtbProbe mix) and template DNA from patients and controls were used for real-time amplification for each target gene. The amplification protocol for MTHFR 677C>T consisted of a denaturation step of 10 minutes at 95°C. The amplification conditions for 45 cycles were: denaturation at 95°C for five seconds, annealing at 55°C for 10 seconds, extension at 72°C for 15 seconds, melting curve step with denaturation at 95°C for 20 seconds, annealing at 40°C for 20 seconds, melting at 85°C for two seconds and the cooling step at 40°C for 30 seconds. A software program (LightCycler 2.0, Roche) was used for detection of the mutated (channel 640 at 54.5°C) and wild genotype (channel 640 at 63°C) profiles for target 677 C>T SNP analysis. The amplification protocol for MTHFR 1298A>C consisted of a denaturation step of 10 minutes at 95°C. The amplification conditions for 40 cycles were: denaturation at 95°C for five seconds, annealing at 62°C for 10 seconds, extension at 72°C for six seconds, melting curve step with denaturation at 72°C for 30 seconds, annealing at 95°C for 20 seconds, melting at 40°C for one second and the cooling step at 40°C for 30 seconds. A software program (LightCycler 2.0, Roche) was used for detection of the mutated (channel 640 at 59°C) and wild genotype (channel 640 at 65°C) profiles for target 1298A>C SNP analysis. The amplification protocol for PAI-1 5G/4G consisted of a denaturation step of 10 minutes at 95°C. The amplification conditions for 40 cycles were: denaturation at 95°C for three seconds, annealing at 60°C for 10 seconds, extension at 72°C for 13 seconds, melting curve step with denaturation at 95°C for 30 seconds, annealing at 40°C for one minute, melting at 85°C for two seconds and the cooling step at 40°C for 30 seconds. A software program (LightCycler 2.0, Roche) was used for detection of the mutated (4G) (channel 640 at 54°C) and wild genotype (5G) (channel 640 at 61°C) profiles for target PAI-1 5G/4G analysis. The amplification protocol for ACE I/D consisted of a denaturation step of 10 minutes at 95°C. The amplification conditions for 45 cycles were: denaturation at 95°C for three seconds, annealing at 60°C for 10 seconds, extension at 72°C for 10 seconds, melting curve step with denaturation at 95°C for 30 seconds, annealing at 40°C for one minute, melting at 85°C for 10 seconds and the cooling step at 40°C for 30 seconds. A software program (LightCycler 2.0, Roche) was used for detection of the mutated (D, del) (channel 640 at 85°C) and wild genotype (I, Ins) (channel 640 at 93°C) profiles for target ACE I/D analysis.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Echocardiography Two-dimensional, M-mode, pulsed and colour-flow Doppler echocardiographic examinations were performed on all patients by one cardiologist with a Vivid 7 Pro echocardiography system (GE, Horten, Norway, 2–4 MHz phased-array transducer). During echocardiography, a single-lead electrocardiogram was recorded simultaneously. Data were recorded from the average of three cardiac cycles. M-mode and Doppler measurements were performed, adhering to the American Society of Echocardiography guidelines.24 A 10-MHz linear transducer was used for the brachial artery examination. Endothelial function of all subjects was assessed by a single ultrasonographer blinded to the coronary flow groups. Measurements were performed in a temperature-controlled room (22°C) in the morning and after eight to 12 hours of a fasting period. Ingestion of substances that might have affected measurements, such as caffeine, high-fat foods and vitamin C was not allowed for 12 hours before the study. Any vasoactive medication was discontinued at least five serum half-lives before the brachial studies. The right brachial artery was imaged above the antecubital fossa in the longitudinal plane. Upon acquiring an appropriate image, the surface of the skin was marked. The arm and the ultrasound probe were kept at the same position by the ultrasonographer during the entire study. The diameter of the brachial artery was measured from longitudinal images in which the lumen–intima interface was visualised on the anterior and posterior walls at end-diastole (onset of the R wave on the electrocardiogram), and the mean of the three highest measurements from five consecutive cardiac cycles was taken. After the basal lumen diameter and blood flow were noted at rest, a sphygmomanometer cuff was placed on the forearm and the cuff was inflated to 250 mmHg for arterial occlusion. After five minutes, the cuff was deflated and the lumen diameter was recorded one minute later, to assess endothelium-dependent flow-mediated dilatation (FMD) This was defined as both the maximum absolute change and maximum percentage change in vessel diameter during reactive hyperaemia: (diameter of reactive hyperaemia – diameter of baseline)

_____________________________________       × 100 FMD =       diameter of baseline

Statistical analysis All continuous variables were expressed as mean ± standard deviation and median (interquartile range). All measurements were evaluated with the Kolmogorov–Smirnov test, and the Shapiro–Wilk test was used to determine normal distribution. Comparisons of parametric and non-parametric values between the two groups were performed by means of Mann–Whitney U- or student t-tests. Categorical variables (risk factors and polymorphisms) were analysed using the chi-square test. Spearman’s correlation test was used for correlation between TIMI frame count and endothelial function. All statistical studies were carried out with the program SPPS (version 15.0, SPSS, Chicago, Illinois, USA); p-values < 0.05 were accepted as statistically significant. Risk estimations for the association of SCF with the polymorphisms were calculated using odds ratios (OR) and 95% confidence intervals (CI) by comparing the genotypic combinations.

Results

Clinical and laboratory findings of the subjects are shown in Table 1. Mean age and systolic blood pressure were similar between the two groups and all subjects were in sinus rhythm (55.8 ± 10.3 vs 53.9 ± 11.8 years, p = 0.456 and 126.4 ± 127.4 vs 127.4 ± 127.4 mmHg, p = 0.712, respectively). The TIMI frame counts for each epicardial artery were higher in patients with CSF than control subjects. Mean TIMI frame count was also significantly higher in CSF patients (24.2 ± 4.0 vs. 13.1 ± 2.5 fpm, p = 0.001). Echocardiographic and FMD measurements of the subjects are summarised in Table 2. Left ventricular ejection fraction (LVEF) was significantly lower in patients with CSF [59 (27–76) vs 64% (28–76), I = 0.019). FMD was significantly lower in CSF patients than controls (4.9 ± 6.6 vs 7.9 ± 5.6%, p = 0.029). TIMI frame count and FMD were negatively correlated in the correlation analysis (r = –0.269, p = 0.015). Genotype properties and allele frequencies were similar in the two groups. The PAI-1 5G allele was found to be marginally associated with the possibility of CSF, however it was not statistically significant (p = 0.06, OR: 2.82, 95% CI: 0.94–8.45) (Table 3).

Discussion This study showed that ACE, PAI and eNOS gene polymorphisms were not related to CSF in our population. Brachial artery FMD was impaired in patients with CSF, and the TIMI frame count was negatively correlated with FMD. ACE plays an important role in vascular wall haemostasis and endothelial function. The ACE D/D allele genotype was Table 1. Clinical characteristics and laboratory parameters of csf patients and healthy controls CSF (n = 33)

Controls (n = 48)

p-value

55.8 ± 10.3

53.9 ± 11.8

0.456

69 ± 11

69 ± 8

0.989

Fasting glucose (mg/dl)

99 (79–281)

91 (72–188)

0.048

LDL cholesterol (mg/dl)

113 ± 35

120 ± 29

0.350

HDL cholesterol (mg/dl)

44 ± 13

46 ± 10

Charactheristics Age (years, mean ± SD) Heart rate (bpm)

BSA (m2) Male, n (%)

1.87 (1.61–2.19) 1.79 (1.47–2.28)

0.447 0.231

20 (58.8)

14 (29.8)

0.009

Hypertension, n (%)

17 (50)

25 (53.2)

0.777

Diabetes mellitus, n (%)

9 (26.5)

7 (14.9)

0.197

Cigarette smoking, n (%)

9 (26.5)

12 (25.5)

0.924

ACE inhibitor

12 (35.3)

12 (25.5)

0.656

Beta-blocker

6 (17.6)

8 (17)

0.941

Statins

11 (32.4)

4 (8.5)

0.006

Acetyl salicylic acid

21 (61.8)

12 (25.5)

0.001

RCA

28 (16–38)

14 (4–22)

0.001

LCx

22 (11–40)

13 (8–21)

0.001

LAD

39.5 (22-56)

18 (10-34)

0.001

24.2 ± 4

13.1 ± 2.5

0.001

Medications, n (%)

TIMI frame count

Mean TIMI frame count

CSF, coronary slow flow; LDL, low-density lipoprotein; HDL, high-density lipoprotein; BSA, body surface area; TIMI, thrombolysis in myocardial infarction; RCA, right coronary artery; LCx, left circumflex artery; LAD, left anterior descending artery; bpm, beats per minute.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Table 2. Echocardiographic characteristics and flow-mediated dilatation in csf patients

Table 3. The polymorphic snps and genotype and allele frequencies of ace i/d, enos and pai-1 genes in csf patients and control group

CSF (n = 33)

Controls (n = 48)

p-value

LVEDD (mm)

48 (32–63)

47 (39–69)

0.755

LVESD (mm)

31 (23–48)

28 (20–60)

0.019

LVEF (%)

59 (27–76)

64 (28–76)

0.003

LA (mm)

38 (27–49)

36 (26–56)

0.059

E wave (cm/s)

66.3 ± 16.5

72.3 ± 17.5

0.127

IVRT (ms)

101.7 ± 22.7

96.9 ± 16.8

0.277

Clinical parameters

E/A ratio E/E′ ratio

1.06 (0.59–2.49) 1.12 (0.61–2.86) 7 (3.8–15.4)

0.973

8 (3.6–19.17)

0.097

Peak S (cm/s)

8 (5–11)

8 (6–13)

0.077

FMD (%)

4.9 ± 6.6

7.9 ± 5.6

0.029

CSF, coronary slow flow; LVDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; LA, left atrium; IVRT, isovolumetric relaxation time, FMD, flowmediated dilatation.

associated with higher serum ACE activity. Several studies have reported a relationship between the D allele and cardiovascular disease,25-28 and atherosclerosis.29,30 Kurtoglu et al. reported that concentrations of plasma endothelin-1 were increased and NOS were decreased in patients with CSF, as a result of microvascular vasomotor dysfunction, which may be important in this phenomenon.31 Pekdemir et al. demonstrated, with intravascular ultrasonography, decreasing fractional flow reserve in the coronary arteries in patients with CSF due to diffuse atherosclerosis.4 Tanriverdi et al. reported that the ACE I/D polymorphism correlated with carotid intima–media thickness, which is a sign of subclinical atherosclerosis.11 These findings suggest that endothelial dysfunction and diffuse atherosclerosis may play a role in the pathogenesis of CSF. Yalcin et al. reported that the frequency of the DD genotype and D allele were higher in patients with CSF, and DD genotypes were related to a possibility of CSF.32 In our study we found that the D allele was not related to the presence of CSF (Fig. 1). PAI-1 is a key regulator of the fibrinolytic process and is related to the PAI-1 promoter 4G/5G polymorphism, although it is regulated by several factors, including cytokines, growth factor and insulin.33-35 PAI-1 activity is to reduce plasma fibrinolytic activity, and poor fibrinolytic activity is related to cardiovascular events.36 The 4G/5G polymorphism in the promoter region of the PAI-1 gene is associated and correlated with plasma levels of PAI-1 or the response of PAI-1 to a regulator.37 There are few and conflicting results regarding the association of 4G allele carriers and coronary events. Some studies suggested that PAI-1 may play a role in atherogenesis due to increased PAI-1 expression, which has been demonstrated in atherosclerotic plaques.38 Lima et al. reported that plasma PAI-1 activity was higher in carriers of the 4G/4G genotype and this was correlated with atherosclerotic heart disease, as determined by coronary angiography.39 By contrast, Onalan et al. reported that the PAI-1 4G/4G genotype was related to a lower risk of the development of stable coronary artery disease because of the inhibitory effects of PAI on cellular migration.40 Likewise, some studies suggested that higher plasma levels of PAI were associated with the 4G/4G genotype, which could have been the cause of reduced plaque

Gene/genotypes

CSF (n = 33) n (%)

Controls (n = 48) n (%)

p-value

Odds ratio

95% CI

ACE I/D Ins/Ins

7 (21.22)

8 (16.6)

Ins/Del

15 (45.45)

23 (47.9)

Del/Del

11 (33.33)

17 (35.5)

Alleles I

0.44

0.40

–

0.56

0.60

0.593

0.74

0.24–2.21

eNOS T/T

18 (54)

25 (52)

T/C

13 (40)

19 (39.5)

C/C

2 (6)

4 (8.5)

Alleles T

0.74

0.71

–

0.26

0.29

0.759

0.87

0.37–2.06

0.06

2.82

0.94–8.45

PAI-1 5G/5G

10 (30.4)

11 (22.9)

5G/4G

18 (54.5)

21 (43.75)

4G/4G

5 (15.1)

16 (33.35)

Alleles 5G

0.58

0.45

0.42

0.55

growth.41,42 There is no study investigating the relationship between CSF and PAI-1 polymorphism in the literature. Our study, surprisingly, showed that PAI-1 4G allele carriers had a protective effect on CSF and the 5G allele was related to increasing risk for CSF. eNOS is a regulator enzyme in the cardiovascular system for functions such as vasodilatation, inhibition of leucocyte adhesion to the endothelium, vascular small muscle cell migration and proliferation, and platelet aggregation. Reduced endothelial NO concentration is an important cause of endothelial dysfunction.12,13,43,44 The T-786C variation of the eNOS gene is associated with reduction in gene promoter activity and the resulting reduction in NO levels, increasing the risk for coronary spasm.14 Some studies have shown reduced plasma NO levels in patients with CSF.3,45 Sezgin et al. reported that FMD of the brachial artery was impaired and decreased plasma NO levels in patients with CSF. They concluded that endothelial dysfunction might be a cause of CSF.46 Nurkalem et al. reported an association between CSF and T-786C polymorphism of the eNOS gene, and a positive correlation between TIMI frame count and the C allele.47 In our study, T-786C genotypes were not different between CSF patients and control subjects. Our study population included only a small number of patients, which could have been the cause of the different results. Several mechanisms, including endothelial dysfunction, diffuse atherosclerosis and small-vessel disease have been proposed as a cause of CSF.3,4 The relationship between endothelial dysfunction and atherosclerosis have been reported in previous studies.48,49 FMD is a factor in endothelial function and is correlated with carotid intima–media thickness and coronary flow reserve.5 Ari et al. reported impaired FMD of the brachial artery in patients with CSF

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

A 0.431

Conclusion

Melting peaks

This study shows that brachial artery FMD was impaired and the 4G allele of the PAI-1 4G/5G polymorphism was less prevalent among CSF patients. However, large-scale genetic studies need to be undertaken in CSF populations in order to understand the underlying mechanisms of aetiopathogenesis.

Fluorescence

0.331 0.231 0.131

I/I

References

0.031

0.411

75 80 85 Temperature (°C)

Melting peaks

Fluorescence

0.311

0.211 5.

0.111

D/D

0.011 6. 60

0.214

75 80 85 Temperature (°C)

95 7.

Melting peaks

Fluorescence

0.164

0.114 I/D

0.064

0.014 10. 60

75 80 85 Temperature (°C)

Fig. 1. M elting peak profiles of real-time PCR for wild (A) and mutated genotype (B: heterozygous and C: homozygous) profiles for the ACE gene in the controls and cases with coronary slow flow.

and a negative correlation between TIMI frame count and FMD.6 In our study, FMD was impaired in patients with CSF, and negatively correlated with TIMI frame count. We found no correlation between genotyping and FMD in this study. These results suggest that endothelial dysfunction is an important process in CSF. The most significant limitations of the present study include the small sample size; the control group was not a normal population of subjects, for ethical reasons; we could not measure inflammatory markers such as C-reactive protein, interleukins, NO and PAI-1 levels; and we could not perform intravascular ultrasonography on the patients for the determination of intimal thickening and calcification.

11.

12. 13.

14.

15.

16.

17.

Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow velocity of dye in coronary arteries, a new angiographic finding. Am Heart J 1972; 84: 66–71. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon – a new coronary microvascular disorder. Cardiology 2002; 97: 197–202. Sezgin AT, Sigirci A, Barutcu I, et al. Vascular endothelial function in patients with slow coronary flow. Coron Artery Dis 2003; 14: 155–161. Pekdemir H, Cin VG, Cicek D, et al. Slow coronary flow may be a sign of diffuse atherosclerosis. Contribution of FFR and IVUS. Acta Cardiol 2004; 59: 127–133. Gullu H, Erdoğan D, Calişkan M, et al. Interrelationship between noninvasive predictors of atherosclerosis: transthoracic coronary flow reserve, flow mediated dilation, carotid intima-media thickness, aortic stiffness, aortic distensibility, elastic modulus, and brachial artery diameter. Echocardiography 2006; 23: 835–842. Ari H, Ari S, Erdogan E, Tiryakioglu KH, Koca V, Bozat T. The effects of endothelial dysfunction and inflammation on slow coronary flow. Arch Turk Soc Cardiol 2010; 38: 327–333. Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res 1991; 68: 450–456. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–1346. Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995; 92: 1387–1388. Yalcın AA, Kalay N, Caglayan AO, et al. The relationship between slow coronary flow and angiotensin converting enzyme and ATIIR1 gene polymorphisms. J Natl Med Assoc 2009; 101: 40–45. Tanriverdi H, Evrengul H, Mergen H, et al. Early sign of atherosclerosis in slow coronary flow and relationship with angiotensin-converting enzyme I/D polymorphism. Heart Vessels 2007; 22: 1–8. Moncada S, Higgs A. The L-arginine–nitric oxide pathway. N Engl J Med 1993; 329: 2002–2012. Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 1996; 94: 266–271. Nakayama M, Yasue H, Yoshimura M, et al. T-786C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99: 2864–2870. Hibi K, Ishigami T, Tamura K, et al. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 1998; 32: 521–526. Hingorani AD, Liang CF, Fatibene J, et al. A common variant of the endothelial nitric oxide synthase (Glu298Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999; 100: 1515–1520. Colombo MG, Paradossi U, Andreassi MG, et al. Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

disease. Clin Chem 2003; 49: 389–395. 18. Tangurek B, Ozer N, Sayar N, et al. The relationship between endothelial nitric oxide synthase gene polymorphism (T-786C) and coronary artery disease in the Turkish population. Heart Vessels 2006; 21: 285–290. 19. Nakayama M, Yasue H, Yoshimura M, et al. T-786C mutation in the 5′ flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. Am J Cardiol 2000; 86: 628–634. 20. Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557–1563. 21. Held C, Hjemdahl P, Rehnqvist N, et al. Haemostatic markers, inflammatory parameters and lipids in male and female patients in the Angina Prognosis Study in Stockholm (APSIS). A comparison with healthy controls. J Intern Med 1997; 241: 59–69. 22. Eriksson P, Kallin B, van’t Hooft FM, Ba’venholm P, Hamsten A. Allele specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851–1855. 23. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93: 879–888. 24. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. 25. Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51: 197–205. 26. Raynolds MV, Bristow MR, Bush EW, et al. Perryman MB. Angiotensinconverting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet 1993; 342: 1073–1075. 27. Harn HJ, Chang CY, Ho LI, et al. Evidence that polymorphism of the angiotensin converting enzyme gene may be related to idiopathic dilated cardiomyopathy in the Chinese population. Biochem Mol Biol Int 1995; 35: 1175–1181. 28. Iwai N, Ohmichi N, Nakamura Y, Kinoshita M. DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy. Circulation 1994; 90: 2622–2628. 29. Castellano M, Muiesan ML, Rizzoni D, et al. Angiotensin converting enzyme I/D polymorphism and arterial wall thickness in a general population: the Vobarno Study. Circulation 1995; 91: 2721–2724. 30. Hosoi M, Nishizawa Y, Kogawa K, et al. Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients. Circulation 1996; 94: 704–707. 31. Kurtoglu N, Akcay A, Dindar I. Usefulness of oral dipyridamole therapy for angiographic slow coronary artery flow. Am J Cardiol 2001; 87: 777–779. 32. Yalcin AA, Kalay N, Caglayan AO, Kayaalti F, Duran M, Ozdogru I, et al. The relationship between slow coronary flow and angiotensin converting enzyme and ATIIR1 gene polymorphisms. J Natl Med Assoc 2009; 101: 40–45.

AFRICA

33. Van Hinsbergh VW, Kooistra T, van den Berg EA, Princen HM, Fiers W, Emeis JJ. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1998; 72: 1467–1473. 34. Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2. Thromb Haemost 1998; 60: 491–494. 35. Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739–10745. 36. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076– 1079. 37. Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost 2005; 93: 631–640. 38. Schneiderman J, Sawdey MS, Keeton MR, et al. Increase type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci 1992; 89: 6998–7002. 39. Lima LM, Carvalho MD, Fonseca Neto CP, Garcia JC, Sousa MO. PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease. Arq Bras Cardiol 2011; 97: 462–389. 40. Onalan O, Balta G, Oto A, et al. Plasminogen activator inhibitor-1 4G4G genotype is associated with myocardial infarction but not with stable coronary artery disease. J Thromb Thrombol 2008; 26: 211–217. 41. Schneider DJ, Hayes M, Wadsworth M, et al. Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type 1 (PAI-1). J Histochem Cytochem 2004; 52: 1091–1099. 42. Redmond EM, Cullen JP, Cahill PA, et al. Endothelial cells inhibit flow induced smooth muscle cell migration: role of plasminogen activator inhibitor-1. Circulation 2001; 103: 597–603. 43. Quyyumi AA, Dakak N, Andrews NP, et al. Nitric oxide activity in the human coronary circulation. J Clin Invest 1995; 95: 1747–1755. 44. Ohashi Y, Kawashima S, Hirata KI, et al. Hypotension and reduced nitric-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998; 2: 2061–2071. 45. Camsari A, Pekdemir H, Cicek D, et al. Endothelin-1 and nitric oxide concentrations and their response to exercise in patients with slow coronary flow. Circ J 2003; 67: 1022–1028. 46. Sezgin N, Barutcu I, Sezgin AT, et al. Plasmanitric oxide levels and its role in slow coronary flow phenomenon. Int Heart J 2005; 46: 373–382. 47. Nurkalem Z, Tangurek B, Zencirci E, et al. Endothelial nitric oxide synthase gene (T-786C) polymorphism in patients with slow coronary flow. Coron Artery Dis 2008; 19: 85–88. 48. Yan RT, Anderson TJ, Charbonneau F, Title L, Verma S, Lonn E. Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in middle-aged healthy men. J Am Coll Cardiol 2005; 45: 1980–1986. 49. Korkmaz H, Akbulut M, Ozbay Y, Koc M. The relation of intima-media thickness with endothelial function and left ventricular mass index. Anadolu Kardiyol Derg 2010; 10: 220–225.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Atrial electromechanical coupling intervals in pregnant subjects Burak Altun, Hakan Tasolar, Emi̇ne Gazi̇, Aysenur Cakir Gungor, Ahmet Uysal, Ahmet Temi̇z, Ahmet Barutcu, Gurkan Acar, Yucel Colkesen, Ufuk Ozturk, Murat Akkoy Abstract

Objective: The aim of this study was to evaluate atrial conduction abnormalities obtained by tissue Doppler imaging (TDI) and electrocardiogram analysis in pregnant subjects. Methods: A total of 30 pregnant subjects (28 ± 4 years) and 30 controls (28 ± 3 years) were included. Systolic and diastolic left ventricular (LV) function was measured using conventional echocardiography and TDI. Inter-atrial, intraatrial and intra-left atrial electromechanical coupling (PA) intervals were measured with TDI. P-wave dispersion (PD) was calculated from a 12-lead electrocardiogram. Results: Atrial electromechanical coupling at the septal and left lateral mitral annulus (PA septal, PA lateral) was significantly prolonged in pregnant subjects (62.1 ± 2.7 vs 55.3 ± 3.2 ms, p < 0.001; 45.7 ± 2.5 vs 43.1 ± 2.7 ms, p < 0.001, respectively). Inter-atrial (PA lateral – PA tricuspid), intra-atrial (PA septum – PA tricuspid) and intra-left atrial (PA lateral – PA septum) electromechanical coupling intervals, maximum P-wave (Pmax) duration and PD were significantly longer in the pregnant subjects (26.4 ± 4.0 vs 20.2 ± 3.6 ms, p < 0.001; 10.0 ± 2.0 vs 8.0 ± 2.6 ms, p = 0.002; 16.4 ± 3.3 vs 12.2 ± 3.0 ms, p < 0.001; 103.1 ± 5.4 vs 96.8 ± 7.4 ms, p < 0.001; 50.7 ± 6.8 vs 41.6 ± 5.5 ms, p < 0.001, respectively). We found a significant positive correlation between inter-atrial and intraleft atrial electromechanical coupling intervals and Pmax (r = 0.282, p = 0.029, r = 0.378, p = 0.003, respectively). Conclusion: This study showed that atrial electromechanical coupling intervals and PD, which are predictors of AF, were longer in pregnant subjects and this may cause an increased risk of AF in pregnancy. Department of Cardiology, Canakkale Onsekiz Mart University, Canakkale, Turkey Burak Altun, MD, drburakaltun@yahoo.com.tr Emi̇ne Gaz, MD Ahmet Temi̇, MD Ahmet Barutcu, MD Yucel Colkesen, MD Ufuk Ozturk, MD

Department of Cardiology, Adiyaman University Training and Research Hospital, Adiyaman, Turkey Hakan Tasolar, MD

Department of Obstetrics and Gynecology, Canakkale Onsekiz Mart University, Canakkale, Turkey Aysenur Cakir Gungor, MD Ahmet Uysal, MD

Department of Cardiology, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey Gurkan Acar, MD Murat Akkoyun, MD

Keywords: atrial electromechanical coupling, pregnancy, tissue Doppler imaging Submitted 11/6/13, accepted 29/11/13 Cardiovasc J Afr 2014; 25: 15–20

www.cvja.co.za

DOI: 10.5830/CVJA-2013-085

Atrial fibrillation (AF), which is the most common cardiac arrhythmia, may cause serious symptoms and impair quality of life.1 The development of AF is associated with many risk factors, including age, male gender, hypertension, heart failure, valvular disease, diabetes mellitus (DM) and left atrial (LA) enlargement.2-4 Electrical and/or mechanical remodelling of the atria is thought to be a pathophysiological characteristic of AF.5 The pregnant state may be pro-dysrhythmic. This is related to the cardiovascular, hormonal, haemodynamic and autonomic changes during healthy pregnancy. Levels of oestrogen and β-human chorionic gonadotropin increase dramatically. Haemodynamic changes include an increase in circulating blood volume, which increases cardiac output. This results in myocardial stretch and an increase in cardiac end-diastolic volume. High plasma catecholamine concentrations and adrenergic receptor sensitivity increase sympathetic tone. All these changes in pregnant women may make them more prone to dysrhythmogenesis.6 Most pregnant women complain of palpitations, dizziness and even syncope, but these symptoms are rarely associated with cardiac dysrhythmias. AF is the most common clinically significant cardiac arrhythmia in the general population but it is rarely seen in pregnant women. When it occurs, it can represent a benign, self-limited lone episode of AF or may be secondary to congenital or rheumatic valvular disease, hypertrophic cardiomyopathy, thyroid disease, or pre-excitation syndrome. Two simple electrocardiogram (ECG) markers, namely maximum P-wave duration (Pmax) and P-wave dispersion (PD), have been used to evaluate intra- and inter-atrial conduction times and the inhomogeneous propagation of sinus impulses, which are well-known electrophysiological characteristics of the atrium prone to fibrillation.7,8 Prolonged Pmax and PD have been reported to represent an increased risk for AF in patients with no underlying heart disease.7,8 Besides, evidence from laboratory and epidemiological research suggests that systemic inflammation may play a role in AF aetiology.9 It has also been demonstrated that atrial electromechanical coupling, measured by tissue Doppler imaging (TDI), as significantly longer in patients with paroxysmal AF than in control groups.10,11 To our knowledge, no study evaluating PD and atrial electromechanical coupling has been investigated in pregnant subjects without additional systemic disease. Therefore, in this

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

study we aimed to examine atrial electromechanical coupling and PD, reflecting inter-atrial conduction times in pregnant subjects.

Methods We consecutively studied 40 pregnant subjects. Eight were excluded from the study, because of thyroid dysfunction in three subjects, DM in three, unclearly identifiable P waves in two, and bundle branch block in two. The study population was composed of 30 pregnant subjects (mean age 28 ± 4 years) and 30 age-matched controls (mean age 28 ± 3 years). All the pregnant women were in the second trimester between 18 and 23 weeks. Physical examination, medical history of the patients and blood biochemistry were evaluated in both groups to exclude systemic diseases. Subjects with coronary artery disease, heart failure, rheumatic valve disease, primary cardiomyopathy, DM, hypertension, thyroid dysfunction, any previous arrhythmia, anaemia, electrolyte imbalance, chronic lung disease, and bundle branch block and atrio-ventricular conduction abnormalities on ECG were excluded from the study. Also, ECGs without clearly identifiable P waves were excluded from the PD analysis using standard 12-lead surface ECGs. All of the patients were in sinus rhythm and none was taking medications such as anti-arrhythmics, tricyclic antidepressants, antihistamines and antipsychotics. All patients signed informed consent form. The local ethics committee approved the study. Two-dimensional, M-mode, pulsed and colour-flow Doppler echocardiographic examinations of all subjects were performed by the same examiner with a commercially available machine (Vivid 7 pro, GE, Horten, Norway, 2–4 mHz phased array transducer). During the echocardiography, a one-lead electrocardiogram was recorded continuously. M-mode measurements were performed according to the criteria of the American Society of Echocardiography.12 LA diameter, and LV end-systolic and end-diastolic diameters were measured. LV ejection fraction (EF) was estimated using Simpson’s rule. LV mass was calculated with the Devereux formula.13 Conventional Doppler echocardiography was performed and pulsed-wave mitral flow velocities were measured from the apical four-chamber view by inserting a sample volume to the mitral leaflet tips. Mitral early diastolic velocity (E, cm/s), late diastolic velocity (A, cm/s), E/A ratio (E/A), E deceleration time (DT, ms), and isovolumetric relaxation time (IVRT, ms) were determined. Each representative value was obtained from the average of three measurements. The operator was blinded to the clinical details and results of the other investigations of each pregnant subject and control. Tissue Doppler imaging echocardiography was performed with transducer frequencies of 3.5–4.0 MHz, adjusting the spectral pulsed Doppler signal filters until a Nyquist limit of 15–20 cm/s was reached and using the minimal optimal gain. The monitor sweep speed was set at 50–100 mm/s to optimise the spectral display of myocardial velocities. Myocardial peak systolic (Sm, cm/s), and early (Em, cm/s) and late (Am, cm/s) diastolic velocities, Em/Am ratio, isovolumetric contraction time (ICT, ms), isovolumetric relaxation time (IRT, ms) and ejection time (ET, ms) were obtained by placing a tissue

AFRICA

Doppler sample volume in the basal segments of the anterior, inferior, lateral, and septal wall.14 The tricuspid annular motion was recorded at the right ventricular (RV) free wall. Myocardial performance index (MPI) was calculated using the (ICT + IRT)/ ET formula.15 By calculating the arithmetical mean value of the segmentary values, mean LV Sm, Em, mean Am, mean MPI, and Em/Am values were obtained. Tissue Doppler velocities therefore represent an average of the basal segments of the anterior, inferior, lateral and septal walls. Also, the E/Em ratio, an important non-invasive marker of pulmonary capillary wedge pressure and LV filling pressure, was calculated. Diastolic dysfunction was defined according to the guidelines of the European Association of Echocardiography/ American Society of Echocardiography as the presence of septal Em < 8 cm/s, lateral Em < 10 cm/s and LA volume ≥ 34 ml/m2.16 Atrial electromechanical coupling was determined as follows. In an apical four-chamber view, the pulsed Doppler sample volume was placed at the level of the LV lateral mitral annulus, septal mitral annulus, and RV tricuspid annulus. The time interval from the onset of the P wave on a surface ECG to the beginning of the late diastolic wave (Am), which is termed PA, was obtained from the lateral mitral annulus (PA lateral), septal mitral annulus (PA septal), and RV tricuspid annulus (PA tricuspid) (Fig. 1). The difference between PA lateral and PA tricuspid (PA lateral – PA tricuspid) was defined as the interatrial electromechanical coupling interval; PA septum and PA tricuspid (PA septum – PA tricuspid) was defined as intra-atrial electromechanical coupling interval; and the difference between PA septal and PA lateral (PA septal – PA lateral ) was defined as intra-left atrial electromechanical coupling interval.18 P-wave dispersion was measured on 12-lead ECGs. All standard 12-lead ECGs were obtained simultaneously using a recorder (Hewlett Packard, Pagewriter) set at a 50-mm/s paper speed and 1-mV/cm standardisation. ECG measurements were evaluated on the same day, in a one-month period in our routine practice. A single cardiologist, who was blinded to the clinical status of the subjects, measured ECG intervals. To decrease the error measurements, P-wave analysis was done with calipers and magnifying glass.

Fig. 1. M easurement of the time interval from the onset of the P wave on a surface ECG to the beginning of the A-wave (PA) interval using tissue Doppler echocardiography.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

The beginning of the P wave was defined as the point where the initial deflection of the P wave crossed the isoelectric line, and the end of the P wave was defined as the point where the final deflection of the P wave crossed the isoelectric line. ECGs with measurable P waves in less than 10 leads were also excluded from the analysis. In all patients, derivations were excluded if the beginning or ending of the P wave could not be clearly identified. PD was calculated by subtracting the minimum P-wave duration (Pmin) from the Pmax.

Statistical analysis Statistical analyses were performed using SPPS software (version 15.0, SPSS, Chicago, Illinois, USA). An assessment of the normality was done initially with Kolmogorov–Smirnov. All numerical data were expressed as mean ± standard deviation or median (interquartile range). Groups were compared by Mann–Whitney U- or student t-tests. The relationship between parameters was calculated using Pearson correlation analysis. The intra-observer variability for the detection of atrial electromechanical coupling was evaluated by Spearman’s correlation; p-values < 0.05 were considered significant.

Results The laboratory and clinical characteristics of the subjects are presented in Table 1. Mean age, heart rate, systolic and diastolic BP, and glucose levels were similar in both groups. However, haemoglobin levels were significantly lower in the pregnant subjects (12.6 ± 1.3 vs 13.3 ± 1.1 mg/dl, p = 0.046) and body mass index was higher in the pregnant subjects (26.8 ± 2.4 vs 24.4 ± 3.8 kg/m2, p = 0.006) Echocardiographic results are listed in Table 2. The LV end-diastolic and end-systolic dimensions, inter-ventricular septum thickness, LV posterior wall thickness, LV ejection fraction, LA diameter, and E velocity were similar in both groups. However, the A velocity and DT were significantly higher (81.3 ± 17.5 vs 65.0 ± 12.5 ms, p < 0.0001; 204.8 ± 20.8 vs 193.5 ± 15.9 ms, p = 0.007, respectively) in the pregnant subjects than the controls. There were no significant differences between the two groups with regard to Sm, Em, Am, IRT, ICT, ET and MPI values (Table 2). Intra-observer variability was assessed in 20 selected subjects at random from the patient study group by repeating the measurements under the same baseline conditions. Intra-observer coefficients of variation for echocardiographic measurements were found to be < 5% and non-significant. Table 1. Clinical and laboratory characteristics of the subjects Pregnant subjects Controls p-value Age (years) 28 ± 4 28 ± 3 0.817 Heart rate (bpm) 83.0 ± 10.8 80.2 ± 9.5 0.293 26.8 ± 2.4 24.4 ± 3.8 0.006 BMI (kg/m2) Glucose (mg/dl) 89.9 ± 10.0 90.9 ± 10.9 0.706 Hgb (mg/dl) 12.6 ± 1.3 13.3 ± 1.1 0.046 SBP (mmHg) 116.5 ± 12.3 116.5 ± 10.5 0.991 DBP (mmHg) 74.6 ± 7.1 74.2 ± 7.0 0.828 BMI: body mass index, Hgb: haemoglobin, SBP: systolic blood pressure, DBP: diastolic blood pressure.

The atrial electromechanical coupling parameters of different sites measured by TDI and P-wave measurements are shown in Table 3. The PA lateral and PA septum were significantly higher in the pregnant subjects compared with the controls (62.1 ± 2.7 vs 55.3 ± 3.2 ms, 45.7 ± 2.5 vs 43.1 ± 2.7 ms, p < 0.001). The PA tricuspid did not differ significantly between the groups (p > 0.05). Furthermore, inter-atrial, intra-atrial and intra-left atrial electromechanical coupling intervals were also prolonged in the pregnant subjects compared the controls (26.4 ± 4.0 vs 20.2 ± 3.6 ms, p < 0.001; 10.0 ± 2.0 vs 8.0 ± 2.6 ms, p = 0.002; 16.4 ± 3.3 vs 12.2 ± 3.0 ms, p < 0.001, respectively). P-wave measurements are given in Table 3. Both the Pmax and the PD were significantly longer in the pregnant subjects (103.1 ± 5.4 vs 96.8 ± 7.4 ms, p < 0.001; 50.7 ± 6.8 vs 41.6 ± 5.5 ms, p < 0.001, respectively). In addition, a significant positive correlation was found between inter-atrial and intra-left atrial electromechanical coupling interval and Pmax (r = 0.282, p = 0.029, r = 0.378, p = 0.003, respectively). In correlation analysis, no relationship was detected between the atrial electromechanical coupling parameters and clinical data such as age, heart rate, systolic and diastolic BP. However, there were significant correlations between the inter-atrial and intra-left atrial electromechanical coupling interval and the A velocity (r = 0.459, p < 0.001, r = 0.448, p < 0.001, respectively) (Fig. 2).

Table 2. Echocardiographic and tissue Doppler echocardiographic parameters Pregnant Parameters subjects Controls p-value Echocardiographic parameters LVEDD (mm) 45.4 ± 3.2 45.9 ± 4.0 0.579 LVESD (mm) 27.7 ± 3.1 28.9 ± 3.2 0.170 IVS thickness (mm) 9.8 ± 0.6 9.6 ± 1.1 0.427 PW thickness (mm) 8.6 ± 0.6 8.6 ± 1.2 0.900 LV mass 181.8 ± 43.8 160.5 ± 36.9 0.047 LV EF (%) 68.8 ± 6.4 66.7 ± 6.3 0.208 Left atrium dimension (mm) 33.0 ± 4.0 32.6 ± 4.9 0.753 Mitral E velocity (cm/s) 83.4 ± 18.3 79.9 ± 14.8 0.416 Mitral A velocity (cm/s) 81.3 ± 17.5 65.0 ± 12.5 < 0.001 DT (ms) 204.8 ± 20.8 193.5 ± 15.9 0.007 IVRT (ms) 90.1 ± 12.3 86.2 ± 5.4 0.223 Tissue Doppler parameters Sm (cm/s) 11.1 ± 2.4 10.6 ± 1.7 0.395 Em (cm/s) 12.8 ± 4.0 13.6 ± 3.3 0.371 Am (cm/s) 12.1 ± 2.4 10.8 ± 2.7 0.070 E/Em 6.9 ± 1.9 6.0 ± 1.3 0.046 ICT (ms) 69.8 ± 19.2 72.5 ± 14.7 0.545 IRT (ms) 64.1 ± 10.2 67.0 ± 11.6 0.321 ET (ms) 267.1 ± 31.2 281.8 ± 29.2 0.065 MPI 50.4 ± 9.2 49.8 ± 7.8 0.785 LV: left ventricular; LVEDD: LV end-diastolic dimension; LVESD: LV end-systolic dimension; IVS: interventricular septum; PW: posterior wall; EF: ejection fraction; DT: mitral E-wave deceleration time; IRT: isovolumetric relaxation time; Sm: mean LV systolic myocardial velocity; Em: mean LV myocardial early diastolic velocity; Am: mean LV myocardial late diastolic velocity; ICT: mean LV isovolumetric contraction time; IRT: mean LV isovolumetric relaxation time; ET: mean LV ejection time; MPI: myocardial performance index.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Discussion

There were three major findings of this study. The intra- and inter-atrial, and intra-left atrial electromechanical coupling intervals were significantly higher in the pregnant subjects. The Pmax and PD were also significantly higher in the pregnant subjects and there was a significant correlation between the inter-atrial and the intra-left atrial electromechanical coupling interval Pmax. Clapp et al. reported a progressive increase in all cardiac chamber dimensions in pregnancy.,19 However, Katz et al. found no statistically significant differences between left atrial diameter and left ventricular internal diastolic diameter (LVIDD) in pregnant subjects in the second trimester and at 12 weeks postpartum.,20 In our study, there were no differences between the LA diameter and LVIDD in pregnant subjects compared to the controls, which is in line with the previous study. Increases in maternal blood volume, cardiac output and heart rate are seen during pregnancy. These mechanisms affect the refractory period and conduction velocity. Schwartz and Priori found that stress and anxiety also caused arrhythmogenic effects by acting on the sympathetic nervous system.,21 Hormonal changes also seem to play an important role in arrhythmias during pregnancy. Gleicher et al. found that oestrogens increased the excitability and frequency of action potentials in uterine muscle tissue during pregnancy.,22 This increased adrenergic sensitivity may play a role in the genesis of arrhythmias by modifying the refractory period and conduction velocity in the re-entrant circuit. When left ventricular diastolic dysfunction occurs, emptying of the left atrium is also impaired. Following impaired left ventricular diastolic relaxation, there is increased atrial contribution to the mitral flow in the left ventricular diastolic flow, thus leading to myocardial overstretching and enlargement.,23 In our study, DT and A velocity were significantly higher in the pregnant subjects, but IVRT, IRT and ET were similar to the controls. The left atrium diameter is known to be correlated with cardiovascular events and a risk factor for AF.,24 These volumetric changes also constitute a high risk for AF. There are conflicting results on this topic. In our study, the diameters of the pregnant subjects were similar to those of the Table 3. Comparison of the electrocardiographic and electromechanical coupling parameters Pregnant subjects Controls p-value Maximum P-wave duration (ms) 103.1 ± 5.4 96.8 ± 7.4 < 0.001 Minimum P-wave duration (ms) 52.4 ± 6.3 55.1 ± 5.7 0.090 P-wave dispersion (ms) 50.7 ± 6.8 41.6 ± 5.5 < 0.001 PA lateral (ms) 62.1 ± 2.7 55.3 ± 3.2 < 0.001 PA septal (ms) 45.7 ± 2.5 43.1 ± 2.7 < 0.001 PA tricuspid (ms) 35.7 ± 2.7 35.1 ± 3.2 0.440 PA lateral – PA tricuspid* 26.4 ± 4.0 20.2 ± 3.6 < 0.001 PA septal – PA tricuspid** 10.0 ± 2.0 8.0 ± 2.6 0.002 PA lateral – PA septal*** 16.4 ± 3.3 12.2 ± 3.0 < 0.001 PA: time interval from the onset of the P wave on the surface ECG to the beginning of the A-wave interval with tissue Doppler imaging. *Inter-atrial electromechanical coupling interval, **Intra-atrial electromechanical coupling interval, ***Intra-left atrial electromechanical coupling interval.

AFRICA

controls, in line with our previous studies,24-26 whereas some studies found increased LA dimension in patients with diastolic dysfunction and increased coupling parameters.27,28 We believe there is a need for large-scale studies to shed light on this discrepancy. PD is related to non-homogenous and interrupted conduction of sinus impulses intra- and inter-atrially. Currently, prolonged Pmax, increased PD and atrial conduction disorders are associated with a higher risk of paroxysmal atrial tachyarrhythmias.7,8 Therefore, it has been suggested that PD can be used in the diagnosis of patients with a high risk of AF.7,8 It was moreover shown that PD was prolonged in chronic, inflammatory and rheumatic diseases, such as rheumatoid arthritis and Behcet’s disease.29,30 In another study, PD was increased in pregnancy due to shortening of the minimum P-wave length and it reached its longest length in the third trimester. Pregnancy also had no effect on Pmax.31 In our study, Pmax and PD were longer in pregnant subjects than in the controls, and this increased PD was related to prolonged Pmax. There are several ways to measure total atrial conduction time; one is signal-averaged ECG, which is the gold-standard technique, but it requires special hardware and is a longer technique. For this reason, measurement of total atrial conduction time by signal-averaged ECG is not often used in clinical practice. Mercadier et al. have shown PA TDI to be an easy, fast and reliable method to measure total atrial electrical activation time.,23 PA TDI duration is a readily available echocardiographic tool to estimate total atrial conduction time and it can easily be measured by all cardiologists. This novel echocardiographic tool has been validated by the P-wave duration on signal-averaged electrocardiography.32 Atrial conduction time can be measured by both invasive and non-invasive methods.33 Prolongation of atrial conduction time, as measured by TDI, is an independent predictor of new-onset or recurrent AF.34,3 Several studies have found that atrial conduction time measured by TDI increases in patients with various diseases, such as type 1DM,25 dilated cardiomyopathy,36 and ankylosing spondilitis.26 120

100

A velocity (ms)

r = 0.459 R 2 linear = 0.21

40 10.00

15.00 20.00 25.00 30.00 35.00 Inter-atrial electromechnical interval (ms)

Fig. 2. P ositive correlation between inter-atrial electromechanical intervals and mitral A-wave velocity.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Hormonal action may play a role in atrial conduction and depolarisation. Increased oestradiol levels in pregrant women may contribute to a longer PD. There are no data comparing PD in men and women. In our study, we demonstrated that atrial electromechanical coupling intervals, Pmax and PD, which is a non-invasive technique providing estimated risk of AF in sinus rhythm, were significantly more prolonged in pregnant subjects than in the controls. Our study is the first of its kind to investigate the relationship of atrial electromechanical coupling with pregnancy. We consider that prolonged PD may be related to volume overload secondary to pregnancy. We also believe that larger studies are needed to clarify this issue. This study had several limitations. It was a cross-sectional study and the population size was relatively small. Intra-observer variability of measurement of PA interval was not investigated. Patients could not be followed up prospectively in terms of detection of long-term cardiac arrhythmia. Other limitations were the use of manual ECG measurements, absence of Holter monitoring, and lack of electrophysiological evaluation. The absence of strain rate parameters was another potential limitation of our study.

Conclusion This study demonstrated that atrial electromechanical coupling intervals and PD, which are predictors of AF, were prolonged in the pregnant subjects. These results suggest that longer atrial electromechanical coupling intervals may cause an increased risk of AF in pregnancy.

References 1.

6. 7.

Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001; 37: 371–378. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba follow-up Study. Am J Med 1995; 98: 476–484. Diker E, Aydogdu S, Ozdemir M, Kural T, Polat K, Cehreli S, et al. Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol 1996; 77(1): 96–98. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. J Am Med Assoc 1994; 271(11): 840–844. Tang M, Zhang S, Sun Q, Huang C. Alterations in electrophysiology and tissue structure of the left atrial posterior wall in a canine model of atrial fibrillation caused by chronic atrial dilatation. Circ J 2007; 71: 1636–1642. Burkart TA, Conti JB. Arrhythmias in the pregnant patient: evaluation and management. Am Coll Cardiol Curr J Rev 1999; 8: 41–44. Dogan A, Kahraman H, Ozturk M, et al. P wave dispersion and left atrial appendage function for predicting recurrence after conversion of atrial fibrillation and relation of P wave dispersion to appendage function. Echocardiography 2004; 21: 523–530. Dilaveris PE, Gialafos JE. P-wave dispersion: A novel predictor of paroxysmal atrial fibrillation. Ann Noninvasive Electrocardiol 2001; 6: 159–165. Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatory

disorder? Eur Heart J 2006; 27: 136–149. 10. Omi W, Nagai H, Takamura M, et al. Doppler tissue analysis of atrial electromechanical coupling in paroxysmal atrial fibrillation. J Am Soc Echocardiogr 2005; 18: 39–44. 11. Cui QQ, Zhang W,Wang H, et al. Assessment of atrial electromechanical coupling and influential factors in nonrheumatic paroxysmal atrial fibrillation. Clin Cardiol 2008; 31: 74–78. 12. Quinones MA, Otto CM, Stoddard M, et al. Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. 13. Devereux RB, Reiche N. Echocardiographic determination of left ventricular mass in man: Anatomic validation of the method. Circulation 1977; 55: 613–618. 14. Birdane A, Korkmaz C, Ata N, et al. Tissue Doppler imaging in the evaluation of the left and right ventricular diastolic functions in rheumatoid arthritis. Echocardiography 2007; 24: 485–493. 15. Tei C, Ling LH, Hodge DO, et al. New index of combined systolic and diastolic myocardial performance: A simple and reproducible measure of cardiac function – a study in normals and dilated cardiomyopathy. J Cardiol 1995; 26: 357–366. 16. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22(2): 107–133. 17. Ozer N, Yavuz B, Can I, et al. Doppler tissue evaluation of intra-atrial and interatrial electromechanical delay and comparison with P-wave dispersion in patients with mitral stenosis. J Am Soc Echocardiogr 2005; 18: 945–948. 18. Valzania C, Rocchi G, Biffi M, et al. Left ventricular versus biventricular pacing: A randomized comparative study evaluatingmid-term electromechanical and clinical effects. Echocardiography 2008; 25(2): 141–148. 19. Clapp JF III, Capeless E. Cardiovascular function before, during and after the first and subsequent pregnancies. Am J Cardiol 1997; 80(11): 1469–1473. 20. Katz R, Karliner JS, Resnik R. Effects of a naturalvolumeoverload state (pregnancy) on left ventricular performance in normal human subjects. Circulation 1978; 58(3): 434–441. 21. Schwartz JP, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes PD, Jalife J (eds). Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: WB Saunders Co, 1990: 330–343. 22. Gleicher N, Meller J, Sandler RZ, Sullum S. Wolff-Parkinson-White syndrome in pregnancy. Obsret Gynecol 1961; 58: 748–52. 23. Mercadier JJ, de la Bastie D, Menasche P, N’Guyen Van Cao A, Bouveret P, Lorente P, et al. Alpha myosin heavy chain isoform and atrial size in patients with various types of mitral valve ventricular dysfunction: a quantitative study. J Am Coll Cardiol 1987; 9: 1024–1030. 24. Benjamin EJ, D’Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995; 92: 835–841. 25. Acar G, Akcay A, Sökmen A, Özkaya M, Güler E, Sökmen G, et al. Assessment of atrial electromechanical delay, diastolic functions, and left atrial mechanical functions in patients with type 1 diabetes mellitus. J Am Soc Echocardiogr 2009; 22: 732–738. 26. Acar G, Sayarlioglu M, Akcay A, et al. Assessment of atrial electromechanical coupling characteristics in patients with ankylosing spondylitis. Echocardiography 2009; 26: 549–557. 27. Weijs B, de Vos CB, Tieleman RG, et al. Clinical and echocardiographic correlates of intra-atrial conduction delay. Europace 2011; 13:

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

1681–1687. 28. Pytkowski M, Jankowska A, Maciag A, et al. Paroxysmal atrial fibrillation is associated with increased intra-atrial conduction delay. Europace 2008; 10(12): 1415–1420. 29. Yavuzkir M, Ozturk A, Dagli N, et al. Effect of ongoing inflammation in rheumatoid arthritis on P-wave dispersion. J Int Med Res 2007; 35: 796–802. 30. Dogan SM, Aydin M, Gursurer M, et al. The increase in P-wave dispersion is associated with the duration of disease in patientswith Behcet’s disease. Int J Cardiol 2008; 124: 407–410. 31. Ozmen N, Cebeci BS, Yiginer O, Muhcu M, Kardesoglu E, Dincturk M. P-wave dispersion is increased in pregnancy due to shortening of minimum duration of P: does this have clinical significance. J Int Med Res 2006; 34(5): 468–474. 32. Merckx KL, De Vos CB, Palmans A, Habets J, Cheriex EC, Crijns HJ, et al. Atrial activation time determined by transthoracic Doppler tissue imaging can be used as an estimate of the total duration of atrial electri-

cal activation. J Am Soc Echocardiogr 2005; 18(9): 940–944. 33. Daubert JC, Pavin D, Jauvert G, Mabo P. Intra and interatrial conduction delay: Implications for cardiac pacing. Pacing Clin Electrophysiol 2004; 27: 507–525. 34. De Vos CB, Weijs B, Crijns HJ, Cheriex EC, Palmans A, Habets J, et al. Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation. Heart 2009; 95: 835–840. 35. Park S M, Kim YH, Choi JI, Pak HN, Kim YH, Shim WJ. Left atrial electromechanical conduction time can predict six-month maintenance of sinus rhythm after electrical cardioversion in persistent atrial fibrillation by Doppler tissueechocardiography. J Am Soc Echocardiogr 2010; 23: 309–314. 36. Pala S, Tigen K, Karaahmet T, Dundar C, Kilicgedik A, Güler A, et al. Assessment of atrial electromechanical delay by tissue Doppler echocardiography in patients with nonischemic dilated cardiomyopathy. J Electrocardiol 2010; 43: 344–350.

… continued from page 8

applied therapeutic measures truly had a long-term effect in this particular patient without developing arrhythmias other than ventricular ectopic beats or heart failure since then.

LVHT frequently occurs familiarly.5 Were any other firstdegree relatives investigated for LVHT? Did any of the firstdegree relatives present with clinical cardiac disease? Was the family history positive for syncope, severe arrhythmias or sudden cardiac death? LVHT is frequently associated with chromosomal aberrations or NMDs. Did the boy undergo cytogenetic investigations to confirm a chromosomal defect or was he ever investigated by a myologist to confirm or rule out NMD? When examining the patient cardiologically, did he present with myopathic face, weakness of the limb, axial or respiratory muscles, wasting, or with fasciculations? What was the level of serum creatine kinase and serum lactate? We do not agree with the view that LVHT may develop into cardiomyopathy (discussion). LVHT is per se classified as an unclassified cardiomyopathy by the European and American Cardiological Society. A follow up of two months is very short. It would be interesting to know about any long-term results. Did ventricular arrhythmias recur? Did left ventricular dysfunction or dilatation of the cardiac cavities re-emerge? Overall, it would be helpful to receive more detailed information about the affected patient and his relatives to assess whether LVHT was associated with hereditary disease or not. Long-term data would help to assess whether the

Josef Finsterer, MD, PhD, fifigs1@yahoo.de Krankenanstalt Rudolfstiftung, Vienna, Austria Sinda Zarrouk-Mahjoub, PhD Laboratory of Biochemistry, UR Human Nutrition and Metabolic Disorders, Faculty of Medicine, Monastir, Tunisia

References 1.

3. 4. 5.

Osmonov D, Ozcan KS, Ekmekçi A, Güngör B, Alper AT, Gürkan K. Tachycardia-induced cardiomyopathy due to repetitive monomorphic ventricular ectopy in association with isolated left ventricular noncompaction. Cardiovasc J Afr 2013; 24: 1–3. Finsterer J, Stöllberger C, Fazio G. Neuromuscular disorders in left ventricular hypertrabeculation/noncompaction. Curr Pharm Des 2010; 16: 2895–2904. Patil MB, Patil SM. Left-ventricular noncompaction in an infant with trisomy 21. Pediatr Cardiol 2013; 34: 722–724. Finsterer J, Stöllberger C. Toxoplasmosis or left ventricular hypertrabeculation/non-compaction. J Med Life 2012; 5: 258–259. Finsterer J, Stöllberger C, Blazek G, Sehnal E. Familal left ventricular hypertrabeculation (noncompaction) is myopathic. Int J Cardiol 2013; 164: 312–317.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

An analysis of real-world cost-effectiveness of TAVI in South Africa Thomas A Mabin, Pascal Candolfi Abstract Objectives: Transcatheter aortic valve implantation (TAVI) has become the standard of care for inoperable patients with severe aortic stenosis and is an alternative to conventional surgery for high-risk aortic valve replacement (AVR) patients. There is a positive correlation between severity of pre-operative patients and hospital costs. The aim of this study was to compare empirically derived costs of the two therapies in South Africa. Methods: The cost-comparison analysis was performed with a MediClinic database including 239 conventional isolated AVR (cAVR) and 75 TAVI cases. All costs are given in 2011 ZAR. The subset of cAVR patients were derived from the relevant and available information in the database and their costs were compared with TAVI costs. Results: From the 75 available subjects, mean TAVI costs were ZAR 335.5k ± 47.9k, (median ZAR 326.5k) with a mean (median) ICU and hospital length of stay (LoS) of 2.7 (2.0) and 7.6 (6.5) days, respectively. The mean cAVR cost was lower at ZAR 213.9 ± 87.5k (median ZAR 193.6k) but this included the entire population costs (i.e. low to high surgical risk). When estimating cAVR costs, defined by LoS of more than six and 13 days in the ICU and hospital, respectively, and being over 75 years of age, the estimate increased to ZAR 337.9k, which was above the TAVI mean costs. In-hospital mortality was 5.3 and 7.9% for TAVI and the entire cAVR group, respectively. When considering the subset of cAVR patients most likely to be high risk, it increased to 21.4%. Conclusions: Within the context of limited clinical data we performed the first attempt at cost-effective analysis of TAVI vs cAVR in South Africa. Treatment of aortic stenosis with cAVR in a post hoc defined high-risk patient segment was more expensive than TAVI in South African centres. Despite common perceptions on costs, adoption of TAVI as an alternative, less-invasive therapy that has been clinically proven and recommended by an FDA advisory panel (Partner A) to be at least as effective as cAVR, has a viable economic argument in appropriate patients. Keywords: TAVI, cost effectiveness, interventional cardiology, cardiac surgery, aortic stenosis, aortic valve Submitted 3/3/13, accepted 9/12/13 Cardiovasc J Afr 2014; 25: 21–26

www.cvja.co.za

DOI: 10.5830/CVJA-2013-090

MediClinic Vergelegen, Somerset West, South Africa THOMAS A MABIN, FACC, FESC FRCP

Edwards Lifesciences SA, Nyon, Switzerland

PASCAL CANDOLFI, PhD, pascal_candolfi@edwards.com

Surgical replacement of defective aortic valves has become almost commonplace in recent years with good outcomes expected.1-3 A substantial number of patients suffering from severe aortic stenosis are considered inoperable due to existing co-morbidities not allowing a conventional surgical aortic valve replacement (cAVR) intervention. In the latest Euro Heart survey, the estimated prevalence of inoperable patients with severe aortic stenosis was 31.8%.4 The Partner Cohort B trial5,6 randomly assigned patients considered unsuitable candidates for surgery into two groups: standard therapy (including balloon aortic valvuloplasty) or a transcatheter aortic valve implantation (TAVI) via the transfemoral approach. The difference in rate of death from any cause was considerable, with an absolute 20 and 24.7% difference favouring TAVI at one and two years, respectively. TAVI has subsequently emerged as a new standard of care for these patients and is considered one of the most innovative breakthroughs in medicine in recent years. The Partner Cohort A trial7,8 randomly assigned high-risk patients and aimed to compare conventional surgery with TAVI (via a transfemoral or transapical approach). Non-inferiority was met and TAVI showed similar clinical benefit – absolute reduction of death from any cause of 2.5% (p = 0.45) and 1.1% (p = 0.78) at one and two years, respectively. The clinical trade off appeared to be between major vascular complications (more frequent with TAVI) and major bleeding (more frequent surgically). Myocardial infarction at two years, haemodynamics (mean gradient and EOA), anaesthesia and procedure time, recovery (assessed by ICU and hospital length of stay: LoS) were secondary endpoints that also improved with TAVI. Only limited cost-effectiveness studies with TAVI have been published so far. Reynolds et al.9 and Watt et al.10 looked at the cost-effectiveness of TAVI versus medical management for patients ineligible for cAVR, based on the Partner Cohort B trial, from the perspective of the US and UK environments, respectively. The incremental cost-effectiveness ratio (ICER) for TAVI in the US study was estimated at $50 200 per year of life gained or $61 889 per quality-adjusted life years (QALY) gained, and in the UK study at £16 100 in the base case. Both were well within the acceptable threshold. Gada et al.11 used a Markov model, also based on the Partner trial and derived the outcomes and costs from 10 000 simulations. They found TAVI and cAVR cost effective when compared with medical management, with incremental cost-effectiveness ratios (ICERs) of $39 964/QALYs and $39 280/QALYs, respectively. TAVI was associated with a QALY gain of 0.06 compared with cAVR but with a greater cost ($59 503 vs $56 339), yielding an ICER of $52 773/QALYs. We attempted to assess a cost-effective analysis of TAVI versus cAVR in South Africa. TAVI has not yet been fully embraced in the South African market, largely because of concerns on the initial cost of the device, without considering the potential cost

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

savings that may be realised by lowered complication rates and length of hospital stay. The available MediClinic administrative database has limited clinical outcomes but sufficient information to allow for the identification of high-risk cAVR patients who potentially could have been TAVI candidates, and to compare data with the patients who did undergo TAVI. TAVI has been introduced into clinical practice and is reimbursed in many European countries since its commercial availability in 2007. In the US, FDA approval arrived in November 2011 for inoperable patients and was overwhelmingly (11-0) recommended by an FDA advisory panel in June 2012 for patients at high risk for conventional surgery. The aim of this study was to compare outcomes between TAVI and cAVR in South Africa in order to evaluate the costs and benefits of both treatment options.

Methods An initial dataset was obtained from MediClinic, one of the largest South African private hospital groups, and contained billing records on 394 patients who had undergone conventional aortic valve replacement (cAVR) during the period 2009 to 2011 at eight cardiac hospitals, MediClinics Bloemfontein, Heart Hospital, Morningside, Nelspruit, Panorama, Vereeniging, Verglegen and Witwatersrand University Donald Gordon Medical Centre. From procedural coding we were able to exclude all patients who had undergone concomitant procedures with cAVR (e.g. CABG, ascending aorta) in order to compare more appropriately with TAVI patients who would not electively undergo these additional procedures. This produced a final dataset of 239 isolated cAVR patients. Over the same period the records of 75 TAVI patients were also available. The dataset included the total costs per patient to the healthcare provider (insurer) without professional fees and no breakdown of cost components was available. Professional fees vary from centre to centre and in order to avoid adding uncertainty to the analyses by including estimates, these were not included. Overall, costs were standardised to 2011 South African Rand (ZAR) using the South African consumer price index (CPI) published on the governmental statistics department website.12 For ease of interpretation and at the time of writing, 10 ZAR was approximately equal to € 1 or US$ 1.25. The database did not provide clinical risk scores, so to compare cAVR with TAVI we excluded the results of those patients who would not be considered for TAVI. Age ≥ 75 years provided the single predictive variable and we used ICU and hospital LoS as surrogates or proxies for indicators of ‘high-risk’ patients.

Statistical analysis Quantitative continuous variables are described with means ± standard deviation, and quantitative discrete variables with absolutes and relatives frequencies. Inference statistics comparing continuous variables were made using the t-test or Wilcoxon rank sum test as appropriate. To compare discrete variables, Pearson’s chi-squared test with Yate’s continuity correction or Fisher’s Exact test (when count data ≤ 5) were applied. Two-sided tests were used and a type I error significance level of 0.05 was considered. Distributions of quantitative continuous variables are

AFRICA

presented graphically with normalised histograms; the y-axis is given with densities, ensuring the total area equals one. When representing the distributions between groups, box-andwhisker plots (boxplots) were chosen. Relationship and linear correlation between quantitative continuous variables were populated and tested with Pearson’s product moment correlation coefficient. Linear models were fitted by ordinary least-square regression estimates and by robust regression using an M estimator (package MASS).13 Coefficient estimates are given with standard errors. All analyses were performed with the use of R software, version 2.13.1.14

Results We obtained a total sample of 75 TAVI and 239 isolated cAVR patients from the period 2009–2011. Descriptive and inference statistics for both TAVI and cAVR groups are presented in Table 1. The mean age for each group was 79.4 ± 7.3 versus 62.3 ± 15.2 years for TAVI and cAVR, respectively. This difference was highly statistically significant (p < 0.001). Male gender was more frequent in the cAVR group (59.8%) but less in the TAVI group (44.0%) and this difference was also statistically significant (p = 0.023). Due to limitations in the available clinical data, we were unable to make direct comparisons between groups and it is impossible to draw strong inferences. Surprisingly, in-hospital mortality rates were numerically higher for cAVR than TAVI. Out of the 75 TAVI patients, four (5.3%) died before discharge, compared to 19 (7.9%) for cAVR, although this difference was not statistically significant (p = 0.613). Much less surprisingly, TAVI, a less-invasive procedure, clearly demonstrated faster post-operative recovery. Indeed, the ICU LoS and the hospital LoS were reduced on average by 47.1% (2.7 ± 2.8 vs 5.1 ± 6.1 days, p < 0.001) and 44.1% (7.6 ± 4.9 vs 13.6 ± 9.2 days, p < 0.001), respectively. These reductions were also robust and were not impacted on by outliers; indeed, when considering the median ICU and hospital LoS, the corresponding reductions were 59.1% (2.0 vs 3.5) and 40.9% (6.5 vs 11.0), respectively. From an absolute perspective, the number of ICU days saved per patient with TAVI was between 1.5 (from medians) and 2.4 (from sample means). Similarly, we could expect a reduction in per-patient hospital LoS of between 4.5 (from medians) and six days (from sample means). The overall average cost per patient to the healthcare provider was ZAR 335.5k ± 47.9k for TAVI and ZAR 213.9k ± 87.4k for cAVR (p < 0.001). As we can see from Fig. 1, the cAVR distribution is highly skewed, indicating a presumably heterogeneous population with a wide range of what may be low- to high-risk patients (certainly heterogeneous post-operative outcomes). This seems not to be the case in the TAVI group Table 1. Descriptive table for tavi and cavr groups Variable Age (years) Male sex, n (%) ICU LoS (days) Hospital LoS (days) Total costs (ZAR) In-hospital mortality, n (%)

TAVI (n = 75) 79.4 ± 7.3 33 (44.0) 2.7 ± 2.8 7.6 ± 4.9 335.5k ± 47.9k 4 (5.3)

cAVR (n = 239) 62.3 ± 15.2 143 (59.8) 5.1 ± 6.1 13.6 ± 9.2 213.9k ± 87.4k 19 (7.9)

p-value < 0.001 0.023 < 0.001 < 0.001 < 0.001 0.613

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

900k

Slope OLS = 12.6

Total costs (ZAR)

Slope robust = 12.4

357k 327k 300k 229k

Linear correlation = 0.879

700k

500k 400k 300k

194k 167k

200k 100k 0

TAVI (n = 75)

Fig. 1. D istribution of total costs for TAVI and cAVR.

where the distribution is more symmetrical with fewer outliers. It seems safe to assume that these groups were not comparable in term of pre-operative severity or risk factors (the average age confirms this to an extent). This is also likely to be the case as TAVI is typically indicated only for inoperable and so-called ‘high-risk’ patients diagnosed with symptomatic severe aortic stenosis. However, cAVR is typically only avoided in patients where the operative risk is considered too high in comparison with the benefits gained, or in those patients determined as inoperable for anatomical reasons. Comparing the cost distributions, we see that the upper 21st percentile of the cAVR sample equals the same average costs as the entire TAVI group, that is, the most costly 50 patients undergoing cAVR generated the same average costs as the 75 TAVI patients (Fig. 2). We could then state that on average, one patient out of five could be treated with a less-invasive therapy associated with lower in-hospital mortality and faster recovery at an equal cost. In our sample, ICU and hospital LoS were also heavily positively correlated with cost and highly statistically significant

n: 239 Mean (sd): 213.9 (87.4) Median [IQ]: 193.6 [166.5–228.6] Range: 103.8–879.6

0.006

Mean of 21st upper percentile = mean TAVI

Density

20 30 40 ICU LoS (days)

Fig. 3. Correlation of ICU LoS with total costs of cAVR.

0.004

in both cases (p < 0.001). Figs 3 and 4 illustrate the linear relationship with linear regression models fitted. Each additional ICU and hospital day increased the total costs by ZAR 12.6k (0.44) and ZAR 7.9k (0.34), respectively. By contrast, age and gender, our only two pre-operative variables available, were not predictors of cost. The linear correlation between age and total costs was statistically significant (p < 0.001) but the coefficient, also positive, was low in comparison with the previous one of 0.226 (Fig. 5). The total cost distributions were similar for both sexes (Fig. 6).

Stratifying patient groups In order to make a comparison of costs between procedures, we attempted to use the available data to select those cAVR patients most likely to have also been eligible for a TAVI (assuming typical selection criteria). Although we had very few predictive risk factors, we examined the literature for data on LoS to use as proxies for defining a more ‘high-risk’ subgroup of cAVR patients. 900k

Slope OLS = 7.89 Slope robust = 7.08

Total costs (ZAR)

Isolated cAVR (n = 239)

Linear correlation = 0.83

700k

500k 400k 300k

0.002

200k 100k

0.000 100k

239k

400k 600k Cost of AVR (ZAR)

Fig. 2. Total cost distribution for cAVR.

900k

20 30 40 50 Hospital LoS (days)

Fig. 4. Correlation of hospital LoS with total costs of cAVR.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

900k

Slope OLS = 1.31

AFRICA

p-value = 0.696

Linear correlation = 0.226

700k

Total costs (ZAR)

Slope robust = 0.931

500k 400k 300k 200k

500k

230k 192k 166k

100k 20

Age

Fig. 5. Correlation of age with total costs of cAVR.

As a baseline for LoS with both TAVI and cAVR we have data from cohort A of the Partner trial,7,8,15 which gives values for ICU and hospital LoS. The means (medians) for the high-risk cAVR patients were 8.4 (5.0) ICU days and 16.7 (12.0) hospital days. Additionally, Thourani16 described the outcomes in surgical cohorts undergoing AVR who would meet the qualifications for transcatheter valve therapies and was able to retrieve data on 159 patients from January 2002 to December 2007 at four US academic institutions. Here the mean ICU and hospital LoS were 6.9 ± 10.6 and 12.6 ± 11.1 days, respectively; very similar to the Partner trial results. In a study from Switzerland, Wenaweser17 determined that a group of cAVR patients, who were younger and had lower predicted peri-operative risks (logistic EuroSCORE 12.5 ± 8.2%) compared with two other groups (TAVI or medical management), had a mean hospital LoS of 15.0 ± 20.2 days. The French Ministry of Health (MoH) records all procedures in the administrative PMSI database. The database is mandatory for each centre in order to be reimbursed. With the corresponding DRGs and specific procedure codes, we were able to select and retreive basic information from all isolated cardiac surgery procedures in France in 2010. This analysis gave us a real-life picture of the French cardiac surgery environment. Clinical data were limited, as was to be expected, but in-hospital mortality, hospital LoS and procedure costs were available. Specific risk scores, such as the logistic EuroSCORE or the STS score were not available, but we were able to populate the Charlson score, an administrative score calculated from the ICD codes. This score has been validated in different publications 18,19 and is used as a risk factor in various areas such as oncology,20 acute myocardial infarction,21 ischaemic stroke22 and infection.23 By using the score we gained an idea of the average pre-operative risk score for each of the four severity levels derived post surgery, leading to a specific reimbursement DRG. In the France 2 TAVI registry, including all TAVI procedures between 2010 and 2011,24 the Charlson score was calculated for 2 568 patients (unpublished data) in an intermediate report sent to the HAS (Haute Autorité de Santé or French National Authority for Health) to evaluate the technology, and the sample mean was 2.6 ± 2.2 (median = 2.0).

Female (n = 96)

Male (n = 143)

Fig. 6. Total costs of cAVR by gender.

Table 2 illustrates the strong correlation between the Charlson score, in-hospital mortality, hospital LoS, procedure costs and severity level defined postoperatively. From this table, it seems reasonable to assume that the majority of TAVI candidates would have been severity level 3 and 4. Therefore we could assume that around 15% of the entire cAVR population could have been considered high risk and would fit the TAVI indications. For these patients the ‘real-life’ clinical outcomes were far from what can be found in the literature, with average hospital LoS above 20 days and the in-hospital mortality rate up to 20%. Surprisingly, age did not seem to have a strong impact on hospital LoS, in-hospital mortality rate or procedure costs. To produce the most conservative estimate of the cAVR group comparable with TAVI, if we take our sample with the proxy thresholds defined above, i.e. ICU and hospital LoS above six and 13 days, respectively, patients ≥ 75 years, we derive our subset of high-risk patients. Table 3 shows the number of patients, in-hospital mortality rate and average costs for each criterion considered. When combining all three parameters, 14 patients (5.9%) were found, which is not surprising, as we could expect that some of these patients were treated with TAVI. The average costs estimate for our high-risk patients was ZAR 337.9k ± 80.9k, marginally higher than the average TAVI costs (ZAR 335.5k). However, very strikingly, the clinical outcome was much worse, with an in-hospital mortality rate of 21.4%, more than four times that of TAVI [RR = 0.25 (0.06–0.99), p = 0.075]. Table 2. Cardiac surgery (cavr) from the French moh database Patients

Severity Level 1 Level 2 Level 3 Level 4 Total

Age Charln % (years) son 2 537 20.3 69.2 1.02 5 805 46.4 73.0 1.74 2 733 21.8 73.6 2.47 1 437 11.5 71.9 2.84 12 512 100.0 72.3 1.88

Hospital Hospital mortalLoS ity (%) (days) 1.66 10.7 2.48 12.5 8.89 16.8 21.85 27.9 5.94 14.8

Total costs (ZAR) 14 365 16 304 22 196 32 250 19 029

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Table 3. Total cost and in-hospital mortality rate for our three proxies Patients Proxy ICU LoS > 6 days Hospital LoS > 13 days Age > 75 years All proxies combined

n 47 85 49 14

% 19.7 35.6 20.5 5.9

Hospital mortality Total costs (%) (ZAR) 19.1 320.2k ± 136.9k 9.4 276.9k ± 116.3k 10.2 236.2k ± 88.7k 21.4 337.9k ± 80.9k

Overall, with limited available data, and by using proxies to derive a subset of high-risk patients, we concluded that TAVI is likely to be cost-effective versus cAVR. Using the most conservative estimates, we predict a small number of patients who could benefit from TAVI versus cAVR, with a lower mortality rate at, on average, lower costs.

Discussion In our sample of TAVI and cAVR hospital records from an administrative database, we found that TAVI patients were on average older, had reduced ICU and hospital LoS, non-statistically significantly reduced mortality rates and higher costs than cAVR patients. However, by trying to identify those cAVR subjects who would most likely have been candidates for TAVI, we projected that a small group would have clinically benefitted from TAVI (lower mortality rate) at a reduced cost to the funder. The sample’s mean TAVI costs were higher than those of cAVR, but the latter group was more heterogeneous and presumably included a wide range of patients in terms of pre-operative severity levels, which means a direct comparison between the two groups is difficult. In-hospital mortality rate was lower in the TAVI group, which was not expected, as cAVR has a much broader utility and would be expected to be used in lower-risk patients. The average of the upper 21st percentile cAVR cost distribution was equal to the average TAVI cost, so from a purely economic perspective, we could assign one patient out of five with a novel, less-invasive treatment, ensuring faster recovery with a reduction of over 40% in ICU and hospital LoS at no additional cost. This substantial reduction was expected despite the difference in age between the two groups and reflects the more rapid and typically less-invasive nature of the procedure. It is also supported by numerous clinical data, although it may be confounded by local guidelines and operational practice, depending on the vagaries of the healthcare system (e.g. reimbursement practices, discharge to alternative local facilities). When estimating the high-risk cAVR costs, defined by patients staying more than six and 13 days in ICU and hospital, respectively (as was found in the Partner Cohort A trial), and being over 75 years of age, the estimate increased just above the TAVI mean cost, and the in-hospital mortality rate increased to 21.4%, a four-fold increase compared with the TAVI group, and a rate similar to that of the French MoH level 4 severity group. Our findings are not dissimilar to others in the literature. For example, Arnaoutakis25 studied the relationship between STS score and hospital charges. In their analysis the authors showed that the median hospital charges for patients with risk scores above and below 10% were US$ 88 241 and US$ 42 785,

respectively, a relative difference above 100%. In a multivariate regression model they found that each 1% increase in STS risk score was associated with an additional US$ 3 000. Additionally, Toumpoulis26 found a significant correlation between additive EuroSCORE and hospital LoS, as to be expected, whereby a higher-risk score leads to higher costs and extended LoS. There were several limitations with this work, most notably, the restricted clinical data available to us from an administrative database. The task of making any comparison between patients according to typical clinical criteria was therefore more difficult, but also post hoc matching of records has its own limitations. Of enormous benefit and in contrast to most economic analyses, we had access to precise billing data. Typically, other analyses use proxy cost data from other studies to estimate the total cost of a procedure, but here we had the total cost from admission to discharge, albeit without details of professional fees. It should be noted that the omission of professional fees favours cAVR, as these fees are likely to be higher than for TAVI. An additional limitation is that we do not have any data on re-admission after discharge. No differences are expected between the groups but additional analyses would help to quantify this important outcome. The transferability of the conclusions from this study are also limited, in common with those from any economic evaluation. We acquired our data from a South African administrative database and the clinical practice underpinning the costs derived may differ from other settings. However, this also provided a major strength of the study in that the data we had was derived from South African clinical practice and the results were not confounded by the use of unrelated data. The adoption of any new technology is challenging and especially if it is a ground-breaking intervention that challenges treatment paradigms. However, the data on TAVI from South Africa show that TAVI costs are much more predictable than cAVR, which should greatly aid planning and implementation. At best it would appear that TAVI could reduce costs to funders and improve outcomes in appropriately selected individuals.

Conclusion Within the context of limited clinical data, we performed the first attempt at cost-effective analysis of TAVI versus cAVR in South Africa. Treatment of aortic stenosis with cAVR in a post hoc defined high-risk patient segment is more expensive than TAVI in South African centres. Despite common perceptions on costs, adoption of TAVI as an alternative, less-invasive therapy that has been proven clinically and recommended by an FDA advisory panel (Partner A) to be at least as effective as cAVR has a viable economic argument in appropriate patients.

We thank the MediClinic Southern Africa private hospital group and particularly Mr Roly Buys, Ms Wanda de Beer and Mr Ryan Wedlake. Their administrative database was valuable and they advised us wisely and spent a consistent and generous amount of time making sure it was used accurately. Without their help this research could never have been performed. We also thank Hox-Com Analytic, particularly Mr Gilbert Caranhac, who provided the French MoH PMSI database. His valuable time ensured the accuracy of our findings on real-world cAVR clinical and economical outcomes in France.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

References 1.

2. 3.

10.

11.

12. 13.

Schwarz F, Baumann P, Manthey J, Hoffmann M, Schuler G, Mehmel HC, et al. The effect of aortic valve replacement on survival. Circulation 1982; 6: 1105–1110. Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009; 373: 956e66. Grunkemeier GL, Jin R, Starr A. Prosthetic heart valves: objective performance criteria versus randomized clinical trial. Ann Thorac Surg 2006; 82: 776–780. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro heart survey on valvular heart disease. Eur Heart J 2003; 24: 1231–1243. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363: 1597–1607. Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012; 366: 1696–1704. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter and surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011; 364: 2187–2198. Kodali SK , Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012; 366: 1686–1695. Reynolds MR, Magnuson EA, Wang K, Lei Y, Vilain K, Walczak J, et al. Cost Effectiveness of transcatheter aortic valve replacement compared with standard care among inoperable patients with severe aortic stenosis: Results from the PARTNER trial (Cohort B). Circulation 2012; 125: 1076–1077. Watt M, Mealing S, Eaton J, Piazza N, Moat N, Brasseur P, et al. Cost-effectiveness of transcatheter aortic valve replacement in patients ineligible for conventional aortic valve replacement. Heart (Br Med J) 2011; 98(5): 370–376. Gada H, Kapadia SR, Tuzcu EM, Svensson LG, Marwick TH. Markov model for selection of aortic valve replacement versus transcatheter aortic valve implantation (without replacement) in high-risk patients. Am J Cardiol 2012; 109(9): 1326–1333. South African consumer price index. Governmental Statistics Department. http://www.statssa.gov.za/keyindicators/CPI/CPIHistory.pdf. Venables WN, Ripley BD. Modern Applied Statistics, 4th edn. New York: Springer, 2002. ISBN 0-387-95457-0.

AFRICA

14. R Development core team. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing, 2008. ISBN 3-900051-07-0, URL http://www.R-project.org. 15. Miller DG, Blackstone EH, Mack MJ, Svensson LG, Kodali SK, Kapadia S, et al. TAVR vs. sAVR: Occurrence, hazard, risk factors, and consequences of neurological events in the PARTNER trial. IEEE TSC J 2012; 832-843.e13. 16. Thourani VH, Ailawadi G, Szeto WY, Dewey TM, Guyton RA, Mack MJ, et al. Outcomes of surgical aortic valve replacement in high-risk patients: a multi-institutional study. Ann Thorac Surg 2011; 91: 49–56. 17. Wenaweser P, Pilgrim T, Kadner A, Huber C, Stortecky S, Buellesfeld L, et al. Clinical outcomes of patients with severe aortic stenosis at increased surgical risk according to treatment modality. J Am Coll Cardiol 2011; 58(21): 2151–2162. 18. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994; 47: 1245–1251. 19. Li B, Evans D, Faris P, Dean S, Quan H. Risk adjustment performance of Charlson and Elixhauser comorbidities in ICD9 and ICD10 administrative databases. BMC Health Serv Res 2008; 8: 12. 20. Birim O, Kappetein AP, Bogers AJ. Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer. Eur J Cardiothorac Surg 2003; 28: 759–762. 21. Nunez JE, Nunez E, Facila L, Bertomeu V, Llacer A, Bodi V, et al. Prognostic value of Charlson comorbidity index at 30 days and 1 year after acute myocardial infarction. Rev Esp Cardiol 2004; 57: 842–849. 22. Goldstein LB, Samsa GP, Matchar DB, Horner RD. (2004). Charlson index comorbidity adjustment for ischemic stroke outcome studies. Stroke 2004; 35: 1941–1945. 23. Murray SB, Bates DW, Ngo L, Ufberg JW, Shapiro NI. Charlson index is associated with one-year mortality in emergency department patients with suspected infection. Acad Emerg Med 2006; 13(5): 530–536. Epub 2006 Mar 21. 24. Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreuil K, Fajadet J, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012; 366: 1705–1715. 25. Arnoutakis GJ, George TJ, Alejo DE, Merlo CA, Baumgartner WA, Cameron D, et al. STS risk score predicts hospital charges and resource use after AVR. J Thorac Cardiovasc Surg 2011; 142: 650–655. 26. Toumpoulis IK, Anagnostopoulos CE. Does EuroScore predict length of stay and specific postoperative complications after cardiac surgery? E J Computer Sci 2005; 27(1): 128–133.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Prevalence of the metabolic syndrome and determination of optimal cut-off values of waist circumference in university employees from Angola Pedro Magalhães, Daniel P Capingana, José G Mill Abstract Background: Estimates of the prevalence of the metabolic syndrome in Africans may be inconsistent due to lack of African-specific cut-off values of waist circumference (WC). This study determined the prevalence of the metabolic syndrome and defined optimal values of WC in Africans. Methods: This cross-sectional study collected demographic, anthropometric and clinical data of 615 Universitary employees, in Luanda, Angola. The metabolic syndrome was defined using the third report of the National Cholesterol Education Program Adult Treatment Panel (ATPIII) and the Joint Interim Statement (JIS) criteria. Receiver operating characteristics curves were constructed to assess cut-off values of WC. Results: The crude prevalence of the metabolic syndrome was higher with the JIS definition (27.8%, age-standardised 14.1%) than with the ATP III definition (17.6%, age-standardised 8.7%). Optimal cut-off values of WC were 87.5 and 80.5 cm in men and women, respectively. Conclusions: There was a high prevalence of the metabolic syndrome among our African subjects. Our data suggest different WC cut-off values for Africans in relation to other populations. Keywords: metabolic syndrome, waist circumference, Africans, Angola Submitted 3/4/13, accepted 9/12/13 Cardiovasc J Afr 2014; 25: 27–33

www.cvja.co.za

DOI: 10.5830/CVJA-2013-086

The metabolic syndrome is characterised by the presence of multiple metabolic risk factors for cardiovascular (CV) disease1 and type 2 diabetes mellitus.2 In clinical practice, the metabolic syndrome is diagnosed by combinations of three or more of the following five risk factors: central obesity, elevated blood pressure, glucose intolerance, hypertriglyceridaemia and low high-density lipoprotein cholesterol (HDL-C).3-6

Department of Physiology, Faculty of Medicine, University Agostinho Neto, Luanda, Angola Pedro Magalhães, MD, PhD, pedromagalhaes24@hotmail.com Daniel P Capingana, MD, PhD

Department of Physiology, Federal University of Espírito Santo, Vitoria, Brazil José G Mill, MD, PhD

Worldwide the prevalence of the metabolic syndrome is increasing and becoming a pandemic, and this increase has been mainly attributed to sedentary lifestyle and obesity.7 However, levels of prevalence may vary greatly according to cut-off points of diagnostic criteria and the ethnic group studied.8 In sub-Saharan Africa, the majority of countries are experiencing a rapid demographic and epidemiological transition.9,10 Available information from studies in African populations reported a prevalence of the metabolic syndrome ranging from 0% to as high as about 50% or more, depending on the population setting.11 These data however, are limited to some countries,12-21 since there are no available data for the majority of African countries. Angola is a country in sub-Saharan Africa, which in the last few years has undergone significant political changes, accompanied by a rapid economic growth and increased urbanisation. These changes may imply an increasing prevalence of factors contributing to the metabolic syndrome, such as obesity, insufficient physical activity, dyslipidaemia, high blood pressure and glucose intolerance. However, the prevalence of the metabolic syndrome and which factors contribution more to its occurrence in the Angolan population remain unknown. Despite the efforts of several organisations to regulate the algorithm for a definition of the metabolic syndrome,3-5 there is inconsistency on cut-off levels of waist circumference (WC) for defining the metabolic syndrome in several populations. The International Diabetes Federation (IDF)5 recommended the use of ethnic or country-specific cut-off values of WC for the majority of populations, a recommendation reinforced in the Joint Interim Statement (JIS),7 which tried to define different criteria for a definition of the metabolic syndrome. These cut-off values were defined using different methods. For example, Western countries derived their cut-off values of WC from a correlation with body mass index (BMI),4,22 whereas Asian groups tried to define WC cut-off values yielded by receiver operating characteristics (ROC) curve analyses.23 Due to a lack of specific data from African populations, cut-off points of WC derived from the European population have been recommended,5,7 although emerging data suggest that Africanspecific cut-off values would be different from the European cut-off points currently recommended by the IDF.18,24,25 Therefore, definition of a more reliable cut-off point for WC is needed to build a consistent tool for diagnosis of the metabolic syndrome in sub-Saharan African populations. The aim of this study was to determine the prevalence of the metabolic syndrome in a sample of Africans from Angola, using either the third report of the National Cholesterol Education Program Adult Treatment Panel (ATP III)4 or the JIS7 criteria. Additionally, this study tried to identify threshold WC levels that best predict other components of the metabolic syndrome.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Methods

This was a cross-sectional study on cardiovascular (CV) risk factors, conducted from 2009 to 2010 in employees of a public university in Luanda, Angola. Participants aged 20 years and older (n = 625) visited the Department of Physiology, Faculty of Medicine of Agostinho Neto University, Luanda, Angola to be submitted to clinical and laboratorial examinations to identify cardiovascular risk. A total of 615 subjects with complete data were included in this study. Details of the study design are described elsewhere.26,27 The study was conducted according to the tenets of the Declaration of Helsinki and participants signed an informed consent form approved by the Ethics Committee of the Faculty of Medicine, Agostinho Neto University. Clinical examinations were performed between 08:00 and noon in temperature-controlled rooms (22–23°C) after a 12-hour fast. Participants were asked to refrain from smoking, physical exercise and caffeinated beverages for at least 12 hours before the visit. Venous blood samples were obtained from the forearm by standard techniques and processed immediately using commercially available kits (BioSystems SA, Costa Brava 30, Barcelona, Spain) for determination of levels of serum triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), glucose, creatinine and uric acid. Biochemical parameters were analysed using enzymatic methods on a spectrophotometer (BioSystems BTS-310, Barcelona, Spain). In subjects with triglyceride levels < 400 mg/ dl (4.52 mmol/l), low-density lipoprotein cholesterol (LDL-C) was calculated according to Friedewald’s formula,28 and very low-density lipoprotein cholesterol (VLDL-C) was calculated as previously described.4 Diabetes was defined as a fasting glucose level ≥ 126 mg/dl (6.99 mmol/l) or the use of antidiabetic drugs.29 Dyslipidaemia was defined as the presence of one or more of the following: total cholesterol ≥ 200 mg/dl (5.18 mmol/l), triglycerides ≥ 150 mg/ dl (1.70 mmol/l), LDL-C ≥ 160 mg/dl (4.14 mmol/l), or HDL-C < 40 mg/dl (1.04 mmol/l) (men), < 50 mg/dl (1.30 mmol/l) (women).4 Demographics including socio-economic level, educational data and medical history were collected using a structured questionnaire. Participants were classified as non-smokers (never and ex-smokers) and current smokers (daily and occasional smokers). Anthropometric measures included weight, height, WC and hip circumference (HC), obtained from individuals wearing underwear and no shoes. Weight was measured to the nearest 0.1 kg using a previously calibrated mechanical scale (SECA GmbH & Co, Germany) with a maximum capacity of 220 kg. Height was measured with a precision of 0.5 cm using a stadiometer fixed to the SECA scale. WC and HC were each measured twice using an inextensible, 1-cm-wide tape measure. The WC was measured at the end of normal expiration, at the midpoint between the lower border of the rib cage and the top of the iliac crest,30 and recorded nearest to the 0.1 cm. The waist:hip ratio (WHR) was calculated from the WC and HC. BMI was calculated from the weight divided by the square of the height (kg/m2). According to BMI values, individuals were classified as normal (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (≥ 30.0 kg/m2).31 Socio-economic status was classified into quartiles according

AFRICA

to average monthly household income;27 first quartile (low socioeconomic class), second quartile (middle class), third quartile (upper middle class), and fourth quartile (upper class). Education was classified into three levels based on the number of years of education: low (≤ four years of education), middle (five to 12 years of education), and high (≥ 13 years of education).27 Blood pressure and heart rate were measured in triplicate in the non-dominant arm after five minutes of resting in a seated position with the arm at the level of the heart. These parameters were measured using a validated, automated digital oscillometric sphygmomanometer (Omron 705CP, Tokyo, Japan). The readings were repeated at three-minute intervals. The mean of the last two readings was recorded. The pulse pressure (PP) was computed as the difference between basal systolic blood pressure (SBP) and diastolic blood pressure (DBP). Mean blood pressure (MBP) was computed as the DBP + (PP/3). Hypertension was defined as SBP ≥ 140 mmHg, and/or DBP ≥ 90 mmHg, and/or the use of antihypertensive drugs. Both the ATP III4 and JIS7 criteria were used to define the metabolic syndrome. The ATP III definition was based on the presence of three or more of the following components: WC > 102 cm (men), 88 cm (women); SBP ≥ 130 mmHg and/ or DBP ≥ 85 mmHg and/or BP-lowering treatment; fasting triglyceride levels ≥ 150 mg/dl (1.70 mmol/l) or treatment for hypertriglyceridaemia; HDL-C < 40 mg/dl (1.04 mmol/l) (men), 50 mg/dl (1.30 mmol/l) (women), or treatment for dyslipidaemia; fasting glucose level ≥ 110 mg/dl or on antidiabetic medication. The JIS definition was based on the presence of three or more of the following components: WC ≥ 94 cm (men), 80 cm (women); SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg and/or BP-lowering treatment; fasting triglyceride levels ≥ 150 mg/dl (1.70 mmol/l) or treatment for hypertriglyceridaemia; HDL-C < 40 mg/dl (1.04 mmol/l) (men), 50 mg/dl (1.30 mmol/l) (women) or treatment for dyslipidaemia; fasting glucose level ≥ 100 mg/ dl (5.55 mmol/l) or on antidiabetic medication.

Statistical analysis Data were analysed using SPSS software, version 13.0 (SPSS Inc, Chicago, IL). Continuous variables are reported as mean ± standard deviation, and compared by gender using the independent-samples t-test. Categorical variables were expressed as proportions and compared using the chi-square test or Fisher’s exact test if appropriate. Prevalence of the metabolic syndrome was age-standardised by direct method using as reference the world population distribution as projected by the WHO for 2000 to 2025.32 Age-specific prevalence of the metabolic syndrome was estimated per age decades (< 30, 30–39, 40–49, 50–59 and ≥ 60 years). ROC curve analysis was performed to determine the appropriate cut-off points of WC for identifying subjects with two or more components of the metabolic syndrome (except for WC), as defined by the JIS criteria. For the purpose of this analysis, we considered the presence or absence of the metabolic syndrome as an outcome variable and WC as a testing variable. Optimal values of WC were obtained from the Youden index [maximum (sensitivity + specificity – 1)].33 Positive predictive values (PPV) and negative predictive values (NPV) were also presented. The kappa coefficient was used to assess the statistical

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

agreement between the ATP III and JIS criteria for identifying individuals with the metabolic syndrome. A p-value < 0.05 was considered statistically significant.

Results A complete data set was collected for 615 subjects (52.2% women). Compared with women (Table 1), men had higher mean values for height, WHR, creatinine and uric acid levels (all p < 0.001), and PP (p = 0.007). Women had higher mean values for HDL-C, WC, HC, BMI (all p < 0.001), and heart rate (p = 0.003). Age, weight, SBP, DBP, MBP, and glucose, total cholesterol, LDL-C, VLDL-C, and triglyceride levels were similar in both sexes. Table 2 shows distribution of risk factors, socio-economic and educational characteristics of the study population. Current smoking was higher in men (p = 0.035), whereas prevalence of overweight, obesity and low HDL-C levels were higher in women (all p < 0.001). However, prevalence of hypertension, diabetes, hypercholesterolaemia, hypertriglyceridaemia and high LDL-C levels were similar in both sexes (Table 2). The overall crude prevalence of the metabolic syndrome was 17.6% [age-standardised: 8.7%, 95% confidence interval (CI):

Table 1. Characteristics of the participants according to gender Characteristics All Men Women p-value Number (%) 615 (100) 294 (47.8) 321 (52.2) 0.392 Age (years) 44.5 ± 10.6 45.1 ± 11.1 44.0 ± 10.1 0.176 Weight (kg) 68.6 ± 15.3 68.0 ± 14.9 69.2 ± 15.7 0.349 Height (cm) 163.3 ± 7.9 167.4 ± 7.1 159.6 ± 6.6 < 0.001 WC (cm) 82.1 ± 13.3 80.1 ± 12.9 83.9 ± 13.5 < 0.001 HC (cm) 95.7 ± 11.3 91.5 ± 9.4 99.5 ± 11.4 < 0.001 WHR 0.86 ± 0.09 0.87 ± 0.08 0.84 ± 0.09 < 0.001 25.7 ± 5.4 24.1 ± 4.3 27.1 ± 5.8 < 0.001 BMI (kg/m2) SBP (mmHg) 134.7 ± 24.9 136.5 ± 22.7 133.0 ± 26.6 0.087 DBP (mmHg) 82.6 ± 14 82.7 ± 14.2 82.5 ± 13.8 0.862 PP (mmHg) 52.1 ± 14.9 53.8 ± 13.2 50.5 ± 16.2 0.007 MBP (mmHg) 100.0 ± 16.9 100.6 ± 16.4 99.4 ± 17.5 0.351 Heart rate (bpm) 68 ± 10 67 ± 10 69 ± 10 0.003 Glucose (mg/dl) 94.0 ± 21 94.9 ± 20 93.2 ± 21.8 (mmol/l) (5.22 ± 1.17) (5.27 ± 1.11) (5.17 ± 1.21) 0.313 Creatinine (mg/dl) 1.1 ± 0.2 1.2 ± 0.2 1.0 ± 0.2 (μmol/l) (97.24 ± 17.68) (106.08 ± 17.68) (88.40 ± 17.68) < 0.001 Uric acid (mg/dl) 5.4 ± 1.7 6.1 ± 1.7 4.8 ± 1.4 < 0.001 TC (mg/dl) 191.5 ± 38.9 189.5 ± 41.4 193.2 ± 36.5 (mmol/l) (4.96 ± 1.01) (4.91 ± 1.07) (5.0 ± 0.95) 0.239 HDL-C (mg/dl) 46.0 ± 10.9 44.1 ± 10.3 47.6 ± 11.2 (mmol/l) (1.19 ± 0.28) (1.14 ± .027) (1.23 ± 0.29) < 0.001 LDL-C (mg/dl) 125.5 ± 40.1 125.0 ± 41.8 125.9 ± 38.7 (mmol/l) (3.25 ± 1.04) (3.24 ± 1.08) (3.26 ± 1.0) 0.796 VLDL-C (mg/dl) 20.0 ± 8.0 20.4 ± 8.3 19.7 ± 7.7 (mmol/l) (0.52 ± 0.21) (0.53 ± 0.21) (0.51 ± 0.20) 0.339 TGL (mg/dl) 100.2 ± 40.0 101.8 ± 41.7 98.7 ± 38.4 (mmol/l) (1.13 ± 0.45) (1.15 ± 0.47) (1.12 ± 0.43) 0.339 Values are means ± standard deviation. WC, waist circumference; HC, hip circumference; WHR, waist-to-hip ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; MBP, mean blood pressure; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol; TGL, triglycerides.

Table 2. Risk factors, educational level and socio-economic class of the study population Characteristics All Men Women Hypertension, n (%) 278 (45.2) 136 (46.3) 142 (44.2) Current smokers, n (%) 39 (6.3) 25 (8.5) 14 (4.4) Diabetes, n (%) 35 (5.7) 16 (5.4) 19 (5.9) Overweight, n (%) 180 (29.3) 80 (27.2) 100 (31.2) Obesity, n (%) 120 (19.5) 27 (9.2) 93 (29.0) High TC, n (%) 68 (11.1) 31 (10.5) 37 (11.5) High TGL, n (%) 77 (12.5) 37 (12.6) 40 (12.5) High LDL-C, n (%) 121 (19.7) 61 (20.7) 60 (18.7) Low HDL-C, n (%) 308 (50.1) 108 (36.7) 200 (62.3) Education level Low, n (%) 213 (34.6) 110 (37.4) 103 (32.1) Medium, n (%) 150 (24.4) 69 (23.5) 81 (25.2) High, n (%) 252 (41.0) 115 (39.1) 137 (42.7) Socio-economic class Low, n (%) 154 (25.0) 81 (27.6) 73 (22.7) Middle, n (%) 156 (25.4) 77 (26.2) 79 (24.6) Upper middle, n (%) 152 (24.7) 66 (22.4) 86 (26.8) Upper, n (%) 153 (24.9) 70 (23.8) 83 (25.9) Values are number of subjects (n) and percentages (%).

p-value 0.615 0.035 0.799 < 0.001 < 0.001 0.698 0.963 0.522 < 0.001 0.926

0.392

6.8–11.3] for the ATP III criteria and 27.8% (age-standardised: 14.1.0%, 95% CI: 11.6–17.1) for the JIS criteria. As expected, the crude prevalence was higher in women than in men, irrespective of the criteria used (Table 3). In both sexes, the prevalence of the metabolic syndrome increased with age, however, women showed a higher prevalence in all age groups from 30 years and older (Table 3). Regarding socio-economic class and educational level (Table 4), there was no significant relationship of these factors with the metabolic syndrome in both sexes. Table 3. Crude and age-standardised prevalence of the metabolic syndrome in men and women according to atp iii and jis criteria Age group (years) n ATP III JIS Men (n = 294) < 30 40 2 (5.0) 3 (7.5) 30–39 52 2 (3.8) 4 (7.7) 40–49 89 8 (9.0) 15 (16.9) 50–59 90 10 (11.1) 23 (25.6) ≥ 60 23 3 (13.0) 5 (21.7) Total crude 294 25 (8.5) 50 (17.0) Age-standardised – 4.8 9.0 Women (n = 321) < 30 32 0 (0.0) 1 (3.1) 30–39 71 8 (11.3) 13 (18.3) 40–49 125 43 (34.4) 62 (49.6) 50–59 79 27 (34.2) 37 (46.8) ≥ 60 14 5 (35.7) 8 (57.1) Total crude 321 83 (25.9) 121 (37.7) Age-standardised (%) – 12.6 19.2 Overall (n = 615) Crude 615 108 (17.6) 171 (27.8) Age-standardised (%) – 8.7 14.1 Values are n (%). ATP III, National Cholesterol Education Program Third Adult Treatment Panel; JIS, Joint Interim Statement.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Table 4. Prevalence of the metabolic syndrome from jis criteria in men and women according to socio-economic class and educational level Number (%) Men Socio-economic class Low 8 (9.9) Middle 13 (16.9) Upper middle 11 (16.7) Upper 18 (25.7) Education level Low 15 (13.6) Medium 12 (17.4) High 23 (20.0) Women Socio-economic class Low 29 (39.7) Middle 28 (35.4) Upper middle 26 (30.2) Upper 38 (45.8) Education level Low 45 (43.7) Medium 27 (33.3) High 49 (35.8) Values are number of subjects (n) and percentages (%).

p-value 0.083

0.444

0.199

0.294

In individuals diagnosed with the metabolic syndrome from the JIS definition (n = 171), the most frequent components were elevated blood pressure: 52.5% (men 55.4% vs women 49.82%, p = 0.165), reduced HDL-C levels: 50.1% (men 36.7% vs women 62.3%, p < 0.001) and high WC: 39.8% (men 15.3% vs women 62.3%, p < 0.001). The less frequent components were elevated glucose levels: 23.4% (men 25.9% vs women 21.2%, Men

1.0

p = 0.172) and raised triglyceride levels: 10.7% (men 12.6% vs women 9.0%, p = 0.155). Although the prevalence of the metabolic syndrome diagnosed from the JIS criteria was higher than with the ATP III criteria, there was good agreement between the two classifications in the overall sample [kappa = 0.712, (p < 0.001; 95% CI: 0.648– 0.777)], as well as in men [kappa = 0.624 (p < 0.001; 95% CI: 0.493–0.755)] and in women [kappa = 0.731 (p < 0.001; 95% CI: 0.654–0.809)]. Fig. 1 shows results from the ROC curve analysis to identify subjects with two or more components of the metabolic syndrome using the JIS criteria. In men, the optimal cut-off value of WC to detect the metabolic syndrome with maximum sensitivity and specificity (Youden index = 0.563) was 87.5 cm (sensitivity 75.9%, 95% CI: 62.4–86.5; specificity 81.2%, 95% CI: 75.7–86; positive predictive value (PPV) 44.2%, 95% CI: 38.5–49.9 and negative predictive value (NPV) 94.2%, 95% CI: 91.5–96.9); whereas in women, the optimal cut-off value of WC (Youden index = 0.489) was 80.5 cm (sensitivity 88.4%, 95% CI: 81.3–93.5; specificity 60.5%, 95% CI: 53.4–67.3; PPV 57.5%, 95% CI: 52.1–62.9 and NPV 89.6%, 95% CI: 87.9–91.3). There was good accuracy (p < 0.001) of the cut-off values of the WC to predict other components of the metabolic syndrome, as suggested by values of the area under the ROC curve [men: 0.85 (95% CI: 0.80–0.89) and women: 0.79 (95% CI: 0.74–0.84)].

Discussion The main findings of this study were a high prevalence of the metabolic syndrome among our subjects and a different cut-off value for WC for the diagnosis of the metabolic syndrome from those recommended for Africans by other studies.5,7 To our knowledge, this is the first study reporting the prevalence of the metabolic syndrome in Angolans.

0.6

Sensitivity

0.8

Sensitivity

0.8

0.4

0.2

0.0

Women

1.0

0.2

0.0

0.2

0.4 0.6 Specificity

Diagonal segments are produced by ties.

0.8

1.0

0.0

0.2

0.4 0.6 Specificity

0.8

1.0

Diagonal segments are produced by ties.

Fig. 1. R eceiver operating characteristic (ROC) curves of waist circumference (WC) to detect the metabolic syndrome in men and women, according to the Joint Interim Statement definition. Area under the ROC curve: 0.85 in men and 0.79 in women. WC cut-off values in men: 87.5 cm (sensitivity 75.9%, specificity 81.2%) and 80.5 cm (sensitivity 88.4%, specificity 60.5%) in women.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Worldwide, the metabolic syndrome is increasingly becoming a pandemic,7 the level of prevalence being estimated to be 17–25% in the general population. However, estimates in sub-Saharan African populations are scarce and inaccurate.11 The crude prevalence in this study was in an intermediate point of the range (0–50%) reported for different African populations.11 The three most frequent components of the metabolic syndrome were elevated blood pressure, low HDL-C levels and elevated WC. A similar cluster of components was reported in an urban population in Kenya,20 and in a study including West Africans (Nigeria and Ghana) and African-Americans.34 Other studies reported a combination of high WC and low HDL-C levels as the most frequent components in Africans with high a prevalence of the metabolic syndrome.14,18,25 Although the underlying mechanisms are not fully understood, the increasing prevalence of the metabolic syndrome has been associated with a sedentary lifestyle and obesity.7 Also, it has been reported that in contrast to developed nations, in some African nations, a higher socio-economic status has been associated positively with increased obesity.35 In our study, distribution of the metabolic syndrome according to socio-economic class, defined by average household monthly income, was not significant. However, this study also showed a high prevalence of both obesity and overweight (47.8%) and hypertension (45.2%). The three most common components of the metabolic syndrome were elevated blood pressure, low HDL-C levels and high WC, suggesting a high risk for CV diseases in this occupational cohort. Therefore, considering the on-going socio-economic changes in Angola, the findings of this study may reflect the impact of the nutritional transition, behavioural and occupational changes, environmental risk factors and unhealthy lifestyle (mainly sedentary) with rapid weight gain, and the high consumption of salty and high caloric food. Although this study showed a good concordance between the two criteria, the crude prevalence estimated with the JIS definition was 10.2% higher than that estimated with ATP III. This difference was mainly attributed to the different cut-off point for WC, which is lower for JIS than for ATP III criteria. It is known that WC reflects both visceral and subcutaneous fat depots, but it has been used as a crude but relevant index of visceral adiposity. The role of visceral adiposity in the development of each metabolic syndrome component has been shown in non-African populations.36-39 In sub-Saharan African populations, a high WC was suggested as a key determinant for development of the metabolic syndrome.14 However, since country-specific cut-off values of WC still need to be defined for Africans, the cut-off values of WC derived from European population groups have been recommended for Africans.5,7 Emerging data suggested that African-specific cut-off values would be different from European cut-off values currently recommended by the IDF.18,24,25 In this study, the cut-off values for men were lower than that currently recommended for Africans (87.5 instead of 94 cm);5,7 whereas for women, these cut-off values were similar to those recommended for European and African women (80.5 vs 80 cm). A few studies have attempted to establish cut-off values of WC for African groups,18,24,25 and they found different cut-off values from those currently recommended. In our study, the value of 87.5 cm for men is similar to that reported in South African studies of African men (86 cm),18 but different for

women.18,25 However, our findings differed from those reported for men and women in another study of the same population (men: 90 cm, women: 98 cm).24 Discordant cut-off values of WC between different studies are to be expected since even in the same ethnic group, the WC may vary according to the country, as emphasised by the IDF5 and the JIS.7 Furthermore, it has been reported that variation in WC cut-off values obtained using the sensitivity and specificity approach were strongly correlated with mean levels of WC in the population.40,41 The cut-off values increased linearly with increasing population means, independent of WC measurement techniques and regardless of whether the health outcome was hypertension, dyslipidaemia, hyperglycaemia or a cluster of multiple outcomes.40 However, it remains to be clarified whether this variation was due to biological characteristics or the methodological approaches used to define the best cut-off point.40 In this study, women had higher mean values of WC than men (Table 1). It is known that the proportion of total fat in subcutaneous depots is higher in women than men.42 Therefore there is a potential risk of misclassification of women as having excessive visceral adiposity by using values of WC to predict other components of the metabolic syndrome. To minimise this difficulty in this study and ensure a correct classification for only women with strong evidence of two or more components of the metabolic syndrome, we selected the best cut-off values of WC, as suggested by the higher values of the Youden index. Therefore, this study reinforces the opinion that definition of cut-off values of WC should be country- and gender-specific. There was a potential limitation to this study. Because we studied a convenient sample consisting of staff of a public university, our findings may not apply to the Angolan population as a whole. As previously detailed,27 however, participants were recruited from all higher education institutions, which represented university staff in the whole country. When this study was designed in 2009, all university staff were invited to take part. The study group included all occupational and socio-economic classes, including teachers and non-teaching workers.26,27

Conclusion There was a high prevalence of the metabolic syndrome in this occupational cohort, with a higher prevalence among women. This study suggested that optimal cut-off values of WC of 87.5 and 80.5 cm would be appropriate for the diagnosis of the metabolic syndrome in men and women, respectively. This may imply that the prevalence would have been different from that reported in this study if these values had been used. Further investigation is therefore needed to confirm optimal cut-off values of WC in the general Angolan population, in order to consistently estimate the trends of cardiometabolic risk factors in African populations. This study was supported by grants from Fundação para Ciência e Desenvolvimento, Angola and CAPES, Brazil.

References 1.

Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovas-

6. 7.

8. 9.

10.

11. 12.

13.

14.

15.

16.

17.

18.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

cular mortality in middle-aged men. J Am Med Assoc 2002; 288(21): 2709–2716. Ford ES. Risks for all-cause mortality, cardiovascular, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005; 28(7): 1769–1778. Alberti KG MM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539–553. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Educational Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285(19): 2486–2497. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome: a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23: 469–480. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365(9468): 1415–1428. Alberti KG MM, 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 task force on epidemiology and prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640–1645. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008; 28: 629–636. World Health Organisation. Non-Communicable Diseases: A Strategy for the African Region. Harare, Zimbabwe: WHO Regional Office for Africa; 2000. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001; 104(22): 2746–2753. Okafor IC. The metabolic syndrome in Africa: Current trends. Indian J Endocrinol Metab 2012; 16(1): 56–66. Makuyana D, Gomo Z, Munyombwe T, Matenga JA, Hakim JG. Metabolic syndrome disorders in urban black Zimbabweans with type 2 Diabetes mellitus. Cent Afr J Med 2004; 50(3–4): 24–29. Ntyintyane LM, Panz VR, Raal FJ, Gill GV. Metabolic syndrome, undiagnosed diabetes mellitus and insulin resistance are highly prevalent in urbanised South African blacks with coronary artery disease. Cardiovasc J S Afr 2006; 17(2): 50–55. Fezeu L, Balkau B, Kengne AP, Sobngwi E, Mbanya J-C. Metabolic syndrome in a sub-Saharan African setting: central obesity may be the key determinant. Atherosclerosis 2007;193: 70–76. Ker JA, Rheeder P, Van Tonder R. Frequency of the metabolic syndrome in screened South African corporate executives. Cardiovasc J South Afr 2007; 18: 30–33. Ntandou G, Delisle H, Agueh V, Fayomi B. Abdominal obesity explains the positive rural-urban gradient in the prevalence of the metabolic syndrome in Benin, West Africa. Nutr Res 2009; 29: 180–189. Oladapo OO, Salako L, Sodiq O, Shoyinka K, Adedapo K, Falase AO. A prevalence of cardiometabolic risk factors among a rural Yoruba southwestern Nigerian population: a population-based survey. Cardiovasc J Afr 2010; 21(1): 26–31. Motala A, Esterhuizen T, Pirie FJ, Omar MAK. The prevalence of metabolic syndrome and determination of the optimal waist circumfer-

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30. 31.

32.

33. 34.

35.

AFRICA

ence cut-off points in a rural South African Community. Diabetes Care 2011; 34: 1032–1037. Akpalu J, Akpalu A, Ofei F. The metabolic syndrome among patients with cardiovascular disease in Accra, Ghana. Ghan Med J 2011; 45(4): 161–166. Kaduka LU, Kombe Y, Kenya E, Kuria E, Bore JK, Bukania ZN, Mwangi M. Prevalence of metabolic syndrome among an urban population in Kenya. Diabetes Care 2012; 35(4): 887–893. Kengne AP, Limen SN, Sobngwi E, Djouogo CFT, Nouedoui C. Metabolic syndrome in type 2 diabetes: comparative prevalence according to two sets of diagnostic criteria in sub-Saharan Africans. Diabet Metab Synd 2012; 4: 22. 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. Lin WY, Lee LT, Chen CY, Lo H, Hsia HH, Liu IL, Lin RS, Shau WY, Huang KC. Optimal cut-off values for obesity: using simple anthropometric indices to predict cardiovascular risk factors in Taiwan. In J Obes Relat Metab Disord 2002; 26: 1232– 1238. Prinsloo J, Malan L, de Ridder JH, Potgieter JC, Steyn HS. Determining the waist circumference cut-off which best predicts the metabolic syndrome components in urban Africans: The SABPA Study. Exp Clin Endocrinol Diabetes 2011; 119: 599–603 Crowther NJ, Norris SA. The current waist circumference cut point used for the diagnostic of metabolic syndrome in Sub-Saharan African women is not appropriate. PLOS One 2012; 7(11): 1–8. Magalhães P, Capingana DP, Silva ABT, Ferreira AVL, Sá Cunha R, Rodrigues SL, et al. Age- and gender-specific reference values of pulse wave velocity for African adults: Preliminary results. Age 2013; 35: 2345- 2355. Capingana DP, Magalhães P, Silva ABT, Gonçalves MAA, Baldo MP, Rodrigues SL, Simões CCF, Ferreira AVL, Mill JG. Prevalence of cardiovascular risk factors and socioeconomic level among publicsector workers in Angola. BMC Public Health 2013; 13: 732 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502. Pereira AC, Sposito AC, Mota GF, Cunha RS, Herkenhoff FL, Mill JG, et al. Endothelial nitric oxide synthase gene variant modulates the relationship between serum cholesterol levels and blood pressure in the general population: new evidence for a direct effect of lipids in arterial blood pressure. Atherosclerosis 2006; 184(1): 193–200. Lean MEJ, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. Br Med J 1995; 311: 158–161. World Health Organisation. Obesity: Preventing and managing the global epidemic: Report of a WHO Consultation on Obesity, Geneva, 3–5 June 1997. Geneva (CH): World Health Organisation, 1998. http:// whqlibdoc.who.int/hq/1998/WHO_NUT_NCD_98.1_(p1-158).pdf. Accessed 03 January 2013. Ahmad OB, Boschi-Pinto C, Lopez AD, Murray CJL, Lozano R, Inoue M. Age standardization of rates. A new WHO standard. EIP/GPE/EBD. GPE discussion paper Series. WHO 2001; 31: 1–14. Youden WJ. An index for rating diagnostic tests. Cancer 1950; 3: 32–35. Sumner AE, Zhou J, Doumatey A, Imoisili OE, Amoah A, Acheampong J, et al. Low HDL-cholesterol with normal triglycerides levels is the most common lipid pattern in West Africans and African Americans with metabolic syndrome: Implications for cardiovascular disease prevention. CVD Prev Control 2010; 5(3): 75–80. Fezeu L, Mincoulou E, Balkau B, Kengne AP, Awah P, Unwin N, et

AFRICA

36.

37.

38.

39.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

al. Association between socioeconomic status and obesity in urban Cameroon. Int J Epidemiol 2006; 35(1): 105–111. Boyko EJ, Leonetti DL, Bergstrom RW, Newell-Morris L, Fujimoto WY. Visceral adiposity, fasting plasma insulin, and lipid and lipoprotein levels in Japanese Americans. Int J Obes Relat Metab Disord 1996; 20: 801–808. Boyko EJ, Fujimoto WY, Leonetti DL, Newell-Morris L. Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans. Diabetes Care 2000; 23: 465–471. Hayashi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell-Morris L, Khan SE, et al. Visceral adiposity and the risk of impaired glucose tolerance: a prospective study among Japanese Americans. 2003; Diabetes Care 26: 650–655. Hayashi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell-Morris L,

Khan SE, et al. Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans. Ann Intern Med 2004; 140: 992–1000. 40. Wang Z, Ma J, Si D. Optimal cut-off values and population means of waist circumference in different populations. Nutr Res Rev 2010; 23: 191–199. 41. Takahara M, Katakami N, Kaneto H, Noguchi M, Shimomura I. Statistical reassessment of the association between waist circumference and clustering metabolic abnormalities in Japanese population. J Atheroscler Thromb 2012; 19: 767–778. 42. Hayashi T, Boyko EJ, Mc-Neely MJ, Leonetti DL, Khan SE, Fujimoto WY. Minimum waist and visceral fat values for identifying Japanese Americans at risk for the metabolic syndrome. Diabetes Care 2007; 30: 120–127.

Letter to the Editor B-type natriuretic peptide for the prediction of left ventricular remodelling Dear Sir We read with great interest the recent article by Choi et al.1 on the optimal time of B-type natriuretic peptide (BNP) sampling for the prediction of left ventricular (LV) remodelling after myocardial infarction (MI). Indeed, as underscored by Choi et al., LV remodelling remains a significant clinical problem in the modern era of MI management.2 In addition, BNP is currently the sole biomarker that has been convincingly associated with LV remodelling in multiple studies (reviewed in Fertin et al.3). It is therefore important to determine the best window of time for its determination in clinical practice. Using multivariate analysis in a cohort of 131 patients, the authors found that early levels (two to five days) of BNP were associated with LV remodelling in fully adjusted models, whereas late (three to four weeks) and long-term (six months) levels were not. We previously reported on the usefulness of serial (three to seven days, one, three and 12 months) assessment of BNP to predict LV remodelling after MI in a prospective study of 246 patients with a first anterior Q-wave MI.4 Our results, which were at variance from those of the study by Choi et al., demonstrated that BNP levels at any time point were associated with LV remodelling; the association was mild at baseline and stronger during follow up, particularly after three months. With multivariate analysis, BNP retained its predictive value at one, three and 12 months, but no longer at baseline. These

discrepancies between studies may be related to differences in study populations and/or therapeutic management. It is also important to know how missing values were handled when comparing models at different time points. From the data presented by Choi et al., it appears that BNP measurements at six months were lacking in more than 20% of the cases. This could theoretically have ‘disadvantaged’ BNP in late versus early models. At present, we believe that the optimal timing after MI for BNP determination in clinical practice remains an unsettled question. Christophe Bauters, MD, cbauters@chru-lille.fr Centre Hospitalier Régional et Universitaire de Lille, Lille; Inserm U744, Institut Pasteur de Lille, Université de Lille 2, Lille; Faculté de Médecine de Lille, Lille, France Marie Fertin, MD Florence Pinet, PhD Centre Hospitalier Régional et Universitaire de Lille, Lille; Inserm U744, Institut Pasteur de Lille, Université de Lille 2, Lille continued on page 39…

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

Echocardiographic estimation of left ventricular filling pressures in patients with mitral valve stenosis Roya Sattarzadeh, Anahita Tavoosi, Parvin Tajik Abstract Background: Estimation of left ventricular end-diastolic pressure (LVEDP) among patients with mitral valve disease may help to explain their symptoms. However, conventional Doppler measurements have limitations in predicting LVEDP in this group of patients. The aim of this study was to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves. Methods: Thirty-three patients with moderate to severe mitral stenosis (MS) who had indications for left heart catheterisation enrolled. Two-dimensional, M-mode, colour Doppler and tissue Doppler imaging indices, such as annular early diastolic velocity (Ea), isovolumic relaxation time (IVRT), pulmonary vein systolic and diastolic flow velocities, velocity propagation, left atrium area (LAA), interval between the onset of mitral E and annular Ea (TE–Ea), and Tei index were obtained. LVEDP was measured in all patients during left cardiac catheterisation. Linear correlation and multiple linear regressions were used for analysis. Results: The mean of LVEDP was 9.9 ± 5.3 mmHg. In univariate analysis, the only significant relationship was noted with LAA (p = 0.05, R2 = 0.11). However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP (p = 0.02, R2 = 0.26). For prediction of LVEDP ≥ 15 mmHg, the best model consisted of LAA, IVRT and Ea, and had a sensitivity of 85% and specificity of 85%. Conclusion: Our results provided evidence that, in patients with moderate to severe MS, LVEDP can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results. Keywords: Doppler echocardiography, tissue Doppler imaging, mitral stenosis, left ventricular end-diastolic pressure Submitted 12/5/13, accepted 9/12/13 Cardiovasc J Afr 2014; 25: 34–39

www.cvja.co.za

DOI: 10.5830/CVJA-2013-088

Cardiology Department of Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Roya Sattarzadeh, MD Anahita Tavoosi, MD, anahitatavoosi@gmail.com

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Parvin Tajik, MD, PhD

Mitral stenosis (MS) is prevalent in developing countries. By improving healthcare systems, it could be expected that the incidence of new cases would decrease and therefore the mean age of mitral stenosis patients would increase. This increase in age of MS patients is accompanied by the occurrence of other diseases, such as coronary artery disease, hypertension, diabetes mellitus and chronic obstructive pulmonary disease. In a number of patients with MS, the question arises of the impact of mitral valve disease (MVD) on the presenting symptom. For example, in patients presenting with dyspnea, with both significant MS and hypertension, increased left ventricular (LV) filling pressure due to hypertension could influence assessment of the severity of MS. In these patients, severity of MS could be underestimated because the increased diastolic pressure reduces the mitral valve gradient, and the increased LV stiffness shortens pressure half-time (PHT). Similarly, patients with both pulmonary disease and MS may have dyspnoea because of pulmonary rather than cardiac cause. It is therefore advantageous to assess LV filling pressure in these cases in an attempt to prove or refute a cardiac cause for dyspnoea. Using Doppler measurements to estimate LV filling pressures is desirable. However, conventional Doppler measurements have limitations in the prediction of left ventricular end-diastolic pressure (LVEDP) in this group of patients. For example, in patients with MS, the left atrium (LA) is enlarged to compensate for the increase in LA pressure. Similarly, mitral inflow peak early diastolic velocity (E) is highly dependent on LA pressure1 and also preload.2 Pulmonary venous (PV) flow also has a blunted pattern in most patients with MS.3 Therefore, in MS patients, LA size, mitral inflow pattern and pulmonary venous pattern are all altered, making these measurements unreliable for the estimation of LVEDP. However, other Doppler and tissue Doppler echocardiographic indices and time intervals, such as peak early diastolic velocity of mitral annulus (Ea), E/Ea ratio, mitral inflow propagation velocity (VP), E/VP, pulmonary vein velocities, Tei index and the ratio of isovolumic relaxation time (IVRT) to interval between the onset of mitral E and annular Ea (TE–Ea), which have shown promising values in the prediction of LV filling pressure in a variety of diseases,4-11 have not been assessed in the setting of mitral stenosis. The aim of this study was to analyse the components of mitral and pulmonary waves in patients with mitral stenosis and to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves.

Methods The study population comprised 33 consecutive patients with a mean age of 37 ± 9 years, and 23 were women. Inclusion

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 25, No 1, January/February 2014

criteria were patients with moderate to severe MS, defined by planimetry as mitral valve area (MVA) of less than 1.5 cm2, who were undergoing heart catheterisation, had no more than moderate mitral or aortic regurgitation, and the absence of aortic or tricuspid stenosis. To include these 33 patients, we screened 36 patients. Three were excluded; two had moderate to severe MR and one had moderate to severe AR. The reasons for undergoing heart catheterisation in patients with MS in our hospital are diagnostic coronary angiography before mitral valve surgery or performing percutaneous transvenous mitral commissurotemy. All patients were evaluated in the left lateral decubitus position by conventional (two-dimensional, M-mode and colour Doppler) and tissue Doppler echocardiography examinations, a maximum of three hours before cardiac catheterisation, by an experienced echocardiologist. The institutional review board of Imam Khomeini Hospital, which is a tertiary hospital, approved the study protocol. All A

participants gave written informed consent. This investigation was in accordance with the Declaration of Helsinki. All Doppler values represent the average of three and 10 beats in sinus and atrial fibrillation (AF) rhythm, respectively. Two-dimensional measurements were performed according to the recommendations of the American Society of Echocardiography.12 Mean diastolic transmitral pressure gradient, pressure half-time and mitral valve area by planimetry were calculated. Mitral inflow velocities were measured by pulsed-wave Doppler with the sample volume positioned between the tips of the mitral leaflets in the apical four-chamber view. Peak early diastolic velocity (E), peak late diastolic velocity (A), E/A ratio and deceleration time (DT) were obtained. Mitral inflow propagation velocity was measured as the maximum slope of the first aliasing velocity during early filling from the mitral valve plane to 4 cm distal to the LV cavity in the apical four-chamber view using colour M-mode Doppler. Pulmonary vein systolic flow velocity (PVs) and diastolic flow C

Fig. 1. D oppler signals from patients with mitral stenosis. A. Pulmonary vein flow velocities: S and D. B. IVRT is marked by two vertical lines between the end of aortic flow and the onset of mitral inflow. C. TEâ&#x20AC;&#x201C;Ea, which is the difference between two time intervals: the time interval between the peak of the R wave and the onset of mitral E velocity, as well as the time interval between the peak of the R wave and the onset of Ea.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

velocity (PVd) were measured from the apical four-chamber view by placing a sample volume in the right upper pulmonary vein using Doppler echocardiography (Fig. 1A). Isovolumic contraction time (IVCT), isovolumic relaxation time and ejection time (ET) were assessed by simultaneously measuring the flow into the LV outflow tract and mitral inflow using Doppler echocardiography (Fig. 1B). The index of myocardial performance (IMP or Tei index) was calculated by dividing the sum of IVRT and IVCT by ET. The pulsed-wave tissue Doppler imaging (TDI) was performed by activating the tissue Doppler function in the same echocardiographic machine. Mitral annulus velocities (myocardial diastolic velocities) were measured using a pulsedwave TDI technique by placing a 1–2-mm sample volume at the level of the septal and lateral annulus. Early diastolic and late diastolic (Aa) velocities of the mitral annulus were determined from the septal and lateral aspects, and the average was calculated. In addition, ratios such as E/Ea, E/Vp, IVRT/Tei, and PVs/ PVs + PVd were calculated. The time intervals between the peak of the R wave and the onset of the mitral E velocity, as well as the time interval between the peak of the R wave and the onset of Ea at the lateral mitral annulus were also measured (Fig. 1C). All Doppler measurements were obtained a maximum of three hours before cardiac catheterisation. Haemodynamic measurements were done by placing a 6-F fluid-filled catheter in the LV from the right femoral approach under fluoroscopic guidance. The fluid-filled pressure was balanced and calibrated with the external pressure transducer positioned at the mid-axillary level. All recordings were performed before the injection of contrast agent. LV end-diastolic pressure was measured at the nadir of the atrial contraction wave before the onset of rapid LV systolic pressure rise or at the peak of the R wave in a simultaneous ECG if the atrial contraction wave did not exist. Table 1. Summary of haemodynamic and echocardiographic measurements in patients with mitral stenosis Mean ± SD (n = 33) Heart rate (bpm) 83.4 ± 20.2 Mean arterial pressure (mmHg) 83.2 ± 10.1 Mean pulmonary pressure (mmHg) 44.3 ± 20.2 LVEF (%) 46.4 ± 7.7 28.4 ± 12.2 Left atrial area (cm2) Average annular Ea (cm/s) 5.5 ± 1.9 Average annular Aa (cm/s) 5.3 ± 1.5 Average E/Ea 38.0 ± 17.5 IVRT (ms) 55.1 ± 10.3 Tei index 0.3 ± 0.1 PVs/PVs + PVd 0.5 ± 0.1 TE–Ea (ms) 23.0 ± 53.0 Velocity propagation (cm/s) 61.0 ± 15.6 E/velocity propagation 0.1 ± 0.01 IVRT/TE–Ea 1.1 ± 4.8 SD, standard deviation; LVEF, left ventricular ejection fraction; Ea, peak early diastolic velocity of mitral annulus; Aa, peak late diastolic velocity of mitral annulus; E, mitral inflow peak early diastolic velocity; IVRT, isovolumic relaxation time; PVs, pulmonary vein systolic flow velocity; PVd, pulmonary vein diastolic flow velocity ; TE–Ea, interval between the onset of mitral E and annular Ea.

AFRICA

In MS patients undergoing percutaneous commissurotomy, the mean left atrial pressure (LAP) was also recorded. Haemodynamic data were collected at end-expiration by an investigator unaware of the echocardiographic measurements and represented the average of five and 10 cycles in sinus and AF rhythm, respectively.

Statistical analysis We described continuous variables as mean ± standard deviation (SD) and categorical data are expressed as frequencies and percentages. Two variables (right atrial area and LV diameter) had > 15% missing data and were omitted from further analysis. Missing values in other variables were imputed using a multiple imputation technique. The first set of imputations was used for further analyses. Due to the small sample size, we chose to perform a univariate pre-selection of clinically relevant predictors with a p-value threshold of 0.3. We then applied a backward selection procedure to develop the final prediction model using linear regression. Model performance was quantified with regard to discrimination [area under the receiver operating curve (AUC)]. The AUC ranges from 0.5 to 1.0 for sensible models. Statistical analyses were done with SPSS for Windows (SPSS Inc, Chicago, Ill), and R for Windows (Version 2.11.1).

Results All patients had moderate to severe MS, and 20 (58.8%) had severe MS (MVA ≤ 1 cm2). The mean MVA was 0.89 ± 0.19 cm2. Less than moderate AI and MR were seen in 60 and 66.7% of patients, respectively. Recording of PV flow was feasible in 30 out of 33 patients (90%). Echocardiographic and haemodynamic characteristics of the patient population are reported in Table 1. The mean LVEDP for the 33 patients was 9.9 ± 5.3 mmHg and ranged from 3–25 mmHg. The results of the univariate analyses are presented in Table 2. In univariate analysis, the only significant relationship was noted with left atrium area (LAA) Table 2. The results of univariate and multivariate linear regression for the prediction of lvedp Univariate model Multivariate model Coefficient Coefficient (SE) p-value Characteristic (SE) R2 p-value Intercept – – – –49.51 (6.31) 0.94 LAA 0.38 (0.19) 0.12 0.05 0.43 (0.18) 0.14 Ea –0.76 (0.50) 0.07 0.14 –0.89 (0.46) 0.02 Tei index 10.95 (8.9) 0.04 0.23 12.30 (8.08) 0.06 E/Ea 10.51 (6.32) 0.08 0.11 IVRT/TE–Ea 0.33 (0.28) 0.04 0.26 TE–Ea 0.02 (0.02) 0.03 0.30 VP 0.06 (0.07) 0.02 0.42 IVRT –0.07 (0.1) 0.02 0.46 E/VP 49.00 (115.34) 0.01 0.67 PVs/PVs + PVd –2.73 (13.36) 0.01 0.84 SE, standard error; LAA, left atrium area; Ea, peak early diastolic velocity of mitral annulus; E, mitral inflow peak early diastolic velocity; IVRT, isovolumic relaxation time; TE-Ea, interval between the onset of mitral E and annular Ea; VP, mitral inflow propagation velocity, PVs, pulmonary vein systolic flow velocity; PVd, pulmonary vein diastolic flow velocity.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Table 3. The results of univariate and multivariate logistic regression for predicting dichotomised lvedp (< 15 vs ≥15 mmHg)

Table 4. The results of univariate and multivariate analysis for prediction of the mean lap

Univariate model Multivariate model Characteristic Coefficient (SE) p-value Coefficient (SE) p-value Intercept – – 3.66 (6.25) 0.55 IVRT –0.09 (0.05) 0.05 –0.16 (0.10) 0.12 LAA 0.20 (0.11) 0.06 0.25 (0.13) 0.06 Ea –0.39 (0.27) 0.15 –0.62 (0.35) 0.07 Tei index 2.70 (3.88) 0.49 E/Ea 3.76 (2.60) 0.41 IVRT/TE–Ea 0.10 (0.14) 0.47 TE–Ea 0.01 (0.01) 0.41 VP 0.02 (0.03) 0.50 E/VP 31.67 (46.45) 0.50 PVs/PVs + PVd –4.06 (5.54) 0.46 SE, standard error; IVRT, isovolumic relaxation time; LAA, left atrium area; Ea, peak early diastolic velocity of mitral annulus; E, mitral inflow peak early diastolic velocity; TE–Ea, interval between the onset of mitral E and annular Ea; VP, mitral inflow propagation velocity, PVs, pulmonary vein systolic flow velocity; PVd, pulmonary vein diastolic flow velocity.

Univariate model Multivariate model Coefficient Coefficient (SE) p-value Characteristic (SE) R2 p-value Intercept – – – 20.77 (13.92) 0.14 E/Ea 26.40(8.78) 0.22 0.01 17.55 (8.60) 0.05 LAA 0.70 (0.50) 0.17 0.01 0.45 (0.25) 0.08 PVs/PVs + PVd –52.63 (17.92) 0.21 0.01 –32.57 (17.63) 0.07 Ea –0.87 (0.76) 0.03 0.25 IVRT/TE–Ea 0.15 (0.44) 0.01 0.73 TE–Ea 0.01 (0.03) 0.01 0.55 VP –0.02 (0.11) 0.01 0.79 IVRT –0.12 (0.15) 0.02 0.42 E/VP 364.07 (162.38) 0.14 0.03 Tei index –4.67 (13.36) 0.01 0.73 SE, standard error; E, mitral inflow peak early diastolic velocity; Ea, peak early diastolic velocity of mitral annulus; LAA, left atrium area; PVs, pulmonary vein systolic flow velocity; PVd, pulmonary vein diastolic flow velocity; IVRT, isovolumic relaxation time; TE–Ea, interval between the onset of mitral E and annular Ea; VP, mitral inflow propagation velocity.

(p = 0.05, R2 = 0.11). However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP (p = 0.02, R2 = 0.26). This model (Table 2) had an area under the ROC curve of 0.71 (95% CI: 0.61–0.80). We then dichotomised the LVEDP as below 15 and above 15 mmHg. In our series of patients, six had LVEDP ≥ 15 mmHg and the remaining 27 had values below 15 mmHg. The best model for predicting this variable consisted of LAA, IVRT and Ea. The results of univariate and multivariate logistic regression for predicting dichotomised LVEDP (< 15 vs ≥ 15 mmHg) are presented in Table 3. For prediction of a mean LVEDP ≥ 15 mmHg and with the

use of ROC curves, the model had a sensitivity of 85% and a specificity of 85% (Fig. 2). This sensitivity and specificity corresponded to the model value of –1.584. The area under the ROC curve was 0.86 (95% CI: 0.7–1; p < 0.001). The LAP for the 29 patients was 21.6 ± 8.9 mmHg and ranged from 8 to 50 mmHg. In univariate analysis, significant relationships were noted between E/Ea (p = 0.005, r2 = 0.22), E/VP (p = 0.032, r2 = 0.13), LAA (p = 0.013, r2 = 0.175) and PVs/PVs + PVd (p = 0.006, r2 = 0.21). In multivariate analysis E/Ea, LAA and PVs/PVs + PVd remained in the model to predict LAP (p = 0.001, r2 = 0.39). The results of the univariate and multivariate analyses are presented in Table 4.

Discussion

1.0

–1.584 (0.852, 0.857)

0.8

Sensitivity

0.6 AUC: 0.862

0.4

0.2

0.0 1.0

0.8

0.6 0.4 Specificity

0.2

0.0

Fig. 2. R eceiver operating characteristics (ROC) curve of the developed model for predicting mean LVEDP ≥ 15 mmHg. AUC: area under the curve.

The present study showed that conventional parameters of LV diastolic function are of limited value in patients with MS. However, it supported a model to estimate LVEDP in patients with significant MS. Interestingly, a number of patients with significant MS had a LVEDP > 15 mmHg, emphasising the importance of assessment of LVEDP in this patient population. Previous studies have reported on the estimation of mean pulmonary capillary wedge pressure (PCWP) by using mitral inflow in patients with MR,13,14 and in those with atrial fibrillation.4,15 In only one study,16 patients with MS were included. This study reported weak relationships between PCWP and mitral inflow velocities in patients with MVD, including patients with MS. In our study, in patients with MS (with and without AF), there were no associations between mitral inflow velocities (E, A, E/A, PHT) and LVEDP or mean LAP. This finding was expected, given the confounding effects of LV relaxation, LV stiffness, LAP and MVA on these measurements.17 Patients with MS have a prolonged DT despite an elevated LAP due to valvular stenosis, and DT (or PHT) itself can be used to grade the severity of MS.1 It is therefore not surprising that estimation of LV filling pressure from mitral peak diastolic velocities and DT in patients

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

with MVD was inaccurate in our study. Previous studies have shown that there is a correlation between pulmonary vein parameters and LAP in patients with mitral stenosis. In one study, among the variables of PV flow, the systolic fraction (i.e. the systolic velocity–time integral, expressed as a fraction of the sum of systolic and early diastolic velocity–time integral) correlated significantly with mean LAP (r = –0.71, p < 0.05) and mitral valve area (r = 0.64, p < 0.05). Peak velocity and the velocity–time integral in systole also significantly correlated with mean LAP (r = –0.66, r = –0.67 respectively, p < 0.05).18 In our study, the relationship of PVs/PVs + PVd with mean LAP reached the level of statistical significance. However, the relationship was weak. There was no relationship between this ratio and LVEDP. It is possible that because PVs/PVs + PVd relates best to mean LAP, we observed no correlations between this ratio and late diastolic LV pressures. With regard to TDI velocities, our observation was similar to previous studies.16,19 Ea velocity was reduced in patients with MS, despite a normal EF, and improved the predictive model of LVEDP. It also played a role in discriminate models to predict LVEDP > 15 mmHg. The accuracy of E/Ea for estimating LV filling pressure appeared to be better in patients with depressed LVEF (< 50%) than in patients with preserved LVEF (≥ 50%).6 This ratio (E/Ea) did not improve the prediction of LVEDP in our patients. This may have been because of the presence of a normal LVEF in most of our patients, and confirms an important limitation in using E/Ea in patients with significant MVD.16 IVRT has been used for decades in the clinical evaluation of patients with MS, being shorter in patients with more severe MS. LV relaxation also influences IVRT.16 All of these make the interpretation of the relationship between IVRT and LVEDP complicated. In our study, although there was no significant correlation between IVRT and LVEDP, this time interval could improve discriminate models to predict LVEDP > 15 mmHg. Although some previous studies showed strong relationships between the time interval TE–Ea and LV relaxation,11 and used this time interval in order to correct for the effect of LV relaxation on IVRT,16 we did not observe any relationship between IVRT/ TE–Ea ratio and LV filling pressure in patients with MS. Previous studies have established the value of left atrial size for the prediction of heart failure with both depressed5,20 and preserved left ventricular systolic function.21 In this study the LAA improved the prediction of LV filling pressure in patients with MS and also remained in the discriminate model to estimate LVEDP > 15 mmHg. There were several limitations to this study. First, there were few patients with MS and LV systolic dysfunction or a depressed EF. Also older patients and those with other cardiovascular diseases (coronary artery disease, hypertension and diabetes mellitus) were absent in our study. There were only six patients with AF in this study. Therefore, we were limited in extrapolating conclusions to these particular subgroups. Second, in order to obtain meaningful results, a strict and time-consuming methodology must be used, which may limit the everyday application of this method in a busy clinical practice. Therefore the results of our study could be applied in equivocal cases where conventional echocardiography is not matched with the patient’s symptoms.

AFRICA

Conclusion

Despite these limitations, our results provide evidence that, in patients with mitral stenosis, LV filling pressure can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results. Doppler echocardiography, a simple, readily available, non-invasive tool, may in future reduce the need for right heart catheterisation in patients with mitral stenosis and unexplained symptoms.

References 1.

Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s ‘Rosetta Stone.’ J Am Coll Cardiol 1997; 30: 8–18. 2. Stoddard MF, Pearson AC, Kern MJ, Ratcliff J, Mrosek DG, Labovitz AJ. Influence of alteration in preload on the pattern of left ventricular diastolic filling as assessed by Doppler echocardiography in humans. Circulation 1989; 79: 1226–1236. 3. Tabata T, Thomas JD, Klein AL. Pulmonary venous flow by Doppler echocardiography: revisited 12 years later. J Am Coll Cardiol 2003; 41: 1243–1250. 4. Traversi E, Cobelli F, Pozzoli M. Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure even when atrial fibrillation is present. Eur J Heart Fail 2001; 3: 173–181. 5. Arteaga RB, Hreybe H, Patel D, Landolfo C. Derivation and validation of a diagnostic model for the evaluation of left ventricular filling pressures and diastolic function using mitral annulus tissue Doppler imaging. Am Heart J 2008; 155: 924–929. 6. Dokainish H. Combining tissue Doppler echocardiography and B-type natriuretic peptide in the evaluation of left ventricular filling pressures: Review of the literature and clinical recommendations. Can J Cardiol 2007; 23: 983–989. 7. Yesildag O, Koprulu D, Yuksel S, Soylu K, Ozben B. Noninvasive assessment of left ventricular end-diastolic pressure with tissue Doppler imaging in patients with mitral regurgitation. Echocardiography 2011; 28: 633–640. 8. Su HM, Lin TH, Voon WC, Lai WT, Sheu SH. Combined Doppler index to track instantaneous changes in left ventricular filling pressure. Acta Cardiol 2005; 60: 421–425. 9. Su HM, Lin TH, Lee CS, Lin CT, Tang MH, Chin TT, et al. Usefulness of the ratio of transmitral E wave velocity to isovolumic relaxation flow propagation velocity for predicting left ventricular end-diastolic pressure. Ultrasound Med Biol 2008; 34: 1752–1757. 10. Abd-El-Rahim AR, Otsuji Y, Yuasa T, Zhang H, Takasaki K, Kumanohoso T, et al. Noninvasive differentiation of pseudonormal/ restrictive from normal mitral flow by Tei index: a simultaneous echocardiography-catheterization study in patients with acute anteroseptal myocardial infarction. J Am Soc Echocardiogr 2003; 16: 1231–1236. 11. Rivas-Gotz C, Khoury DS, Manolios M, Rao L, Kopelen HA, Nagueh SF. Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: a novel index of left ventricular relaxation: Experimental studies and clinical application. J Am Coll Cardiol 2003; 42: 1463–1470. 12. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA ,et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a

AFRICA

13.

14.

15.

16.

17.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440–1463. Pozzoli M, Capomolla S, Pinna G, Cobelli F, Tavazzi L. Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure with and without mitral regurgitation. J Am Coll Cardiol 1996; 27: 883–893. Rossi A, Cicoira M, Golia G, Anselmi M, Zardini P. Mitral regurgitation and left ventricular diastolic dysfunction similarly affect mitral and pulmonary vein flow Doppler parameters: the advantage of enddiastolic markers. J Am Soc Echocardiogr 2001; 14: 562–568. Temporelli PL, Scapellato F, Corra U, Eleuteri E, Imparato A, Giannuzzi P. Estimation of pulmonary wedge pressure by transmitral Doppler in patients with chronic heart failure and atrial fibrillation. Am J Cardiol 1999; 83: 724–727. Diwan A, McCulloch M, Lawrie GM, Reardon MJ, Nagueh SF. Doppler estimation of left ventricular filling pressures in patients with mitral valve disease. Circulation 2005; 111: 3281–3289. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. Recommendations for quantification of Doppler echocardiography: a

18.

19.

20.

21.

… continued from page 33

References 1.

Choi H, Yoo BS, Doh JH, Yoon HJ, Ahn MS, Kim JY, et al. The optimal time of B-type natriuretic peptide sampling associated with postmyocardial infarction remodelling after primary percutaneous coronary intervention. Cardiovasc J Afr 2013; 24: 165–170. Savoye C, Equine O, Tricot O, Nugue O, Segrestin B, Sautiere K, et al. Left ventricular remodeling after anterior wall acute myocardial infarc-

report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. Lee MM, Park SW, Kim CH, Sohn DW, Oh BH, Park YB, et al. Relation of pulmonary venous flow to mean left atrial pressure in mitral stenosis with sinus rhythm. Am Heart J 1993; 126: 1401–1407. Arat N,Yıldırm N,Guray U, Tufekcioglu O, Korkmaz S, Sabah I. Evaluation of the global systolic and diastolic function of the left ventricle by the total ejection isovolume index following percutaneous mitralballoon valvuloplasty: a tissue Doppler imaging study. Türk Kardiyol Dern Arş 2006; 34: 10–15. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993; 22: 1972–1982. Jaubert MP, Armero S, Bonello L, Nicoud A, Sbragia P, Paganelli F, et al. Predictors of B-type natriuretic peptide and left atrial volume index in patients with preserved left ventricular systolic function: an echocardiographic-catheterization study. Arch Cardiovasc Dis 2010; 103: 3–9.

tion in modern clinical practice (from the REmodelage VEntriculaire [REVE] study group). Am J Cardiol 2006; 98: 1144–1149 (17056315). Fertin M, Dubois E, Belliard A, Amouyel P, Pinet F, Bauters C. Usefulness of circulating biomarkers for the prediction of left ventricular remodeling after myocardial infarction. Am J Cardiol 2012; 110: 277–283 (22482862). Fertin M, Hennache B, Hamon M, Ennezat PV, Biausque F, Elkohen M, et al. Usefulness of serial assessment of B-type natriuretic peptide, troponin I, and C-reactive protein to predict left ventricular remodeling after acute myocardial infarction (from the REVE-2 study). Am J Cardiol 2010; 106: 1410–1416 (21059429).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

Industry News AstraZeneca Pharmaceuticals enables scientific innovation Critically aware of the need for funding that will develop research capacity and contribute to academic advancement in South Africa, ethical pharmaceutical company, AstraZeneca Pharmaceuticals, has set up a not-for-profit trust for the disbursement of medical research funding. The company will award R1.5 million a year for three years for academic research; high-level, non-interventional studies including doctoral and postdoctoral work that will generate significant data currently not available. The funding will be distributed to qualifying researchers through the AstraZeneca Research Trust, the independent body set up to administer the allocation of the funds. Managed by a scientific steering committee, six highly respected academics from various institutions around the country have been appointed to screen, review and ultimately, with full autonomy, decide on the apportionment of the grant funding. AstraZeneca will have no influence or participate in any decisions made regarding the fund allocation. This will be solely at the discretion of the academics administering the disbursements. Chairman of the AstraZeneca Research Trust, Prof Reid Ally says: ‘We have been

given carte blanche to decide which proposals will receive funding and we can look at non-communicable diseases… to document firstly how frequent the disease is, and then look at what we can do to change what is happening to us; whether this is diet related, environmental or genetic.’ AstraZeneca company president, South Africa and sub-Saharan Africa, Karl Friberg says, ‘Through the AstraZeneca Research Trust we will address the challenge of realising the full potential of Africa, while at the same time continuing to position AstraZeneca as a company that co-creates with local communities and academia, to meet the huge unmet need among African patients.’ As a global ethical company, AstraZeneca invests over US$4 billion each year in research and development and its focus is on the development of prescription medicines in seven therapeutic areas. According to Friberg, after several tough years, the company has a strong pipeline again, with over 12 new chemical entities in phase-three projects. ‘In the spirit of the project, and committed to unprejudiced research findings, we have made no attempt to limit the research to the therapeutic areas in which

we are operational. We are encouraging the generation of much-needed epidemiological data on non-communicable and other diseases, data we expect will come from high-level studies’, says Friberg. ‘The global healthcare landscape is changing at a rapid pace and in South Africa and the African continent we are sitting on a veritable non-communicable disease time bomb. Cardiovascular diseases, diabetes, obesity, metabolic syndrome and smokingrelated illnesses are becoming increasingly prevalent and are the scourge of Africa. The continent is ill equipped to fight these modern-day illnesses; it does not have the empirical data to properly manage and treat these potentially life-threatening diseases’, says Friberg. The pharmaceutical industry has not traditionally invested in this area of research, with funding customarily being allocated to the development of compounds and chemical entities. With extensive investment into research on HIV infection and TB, there has been little investment and focus on non-communicable diseases. ‘Without current, accurate data, we have no line of sight to the extent of the problem, or how to manage it. There are virtually no data on black females in even the most basic disease areas. We want to change this and be part of the data-generation process. Even if we cannot use it directly as a company, we want to be part of the solution’, says Friberg. ‘We hope our grants will help us meet a huge area of unmet need, ensuring the reprioritisation of healthcare initiatives and reshaping the landscape as we know it.’ Submissions for grant funding can be made during the course of 2014 but all applications for 2014 funding must be received by the Trust by the end of the first quarter of 2014. A six-week review period will be allocated for the scientific steering committee to make the necessary decisions. Grant awards will be announced and awarded in May 2014.

Karl Friberg, AstraZeneca company president, South Africa and sub-Saharan Africa.

Prof Adam Habib, vice chancellor, University of Witwatersrand.

This initiative is supported unconditionally by AstraZeneca. Further information can be found at: www.astrazenecatrust.co.za

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Case Report Chronic dissecting aneurysm of the ascending aorta developed in a patient who had rejected surgical treatment for type II acute ascending aortic dissection three years earlier Bi̇lgehan Erkut, Ozgur Dag, Mehmet Ali̇ Kaygi̇n, Husnu Kami̇l Li̇mandal, Ahmet Aydi̇n, Eyup Serhat Cali̇k Abstract

A 66-year-old male patient was admitted to our clinic because of shortness of breath and chest pain. A grade 4/6 diastolic murmur was heard on auscultation. Physical examination revealed signs of congestive heart failure and poor peripheral perfusion. There was a diagnosis of type II ascending aortic dissection in the history of the patient. He had refused emergency surgical intervention three years earlier. Computed tomography revealed that the ascending aorta was dilated to about 10 cm in diameter, and there was a chronic aortic type II dissection. The patient had second- to third-degree aortic insufficiency and he had a calcified bicuspid aortic valve on echocardiography. Two-vessel disease and a 90-mmHg aortic gradient were detected on angiography. Graft replacement of the ascending aorta, serape aortic valve replacement with a mechanical valve, and coronary arterial bypass grafting were performed successfully under cardiopulmonary bypass with an open aortic technique. The patient was discharged on the 10th postoperative day with no problems. Keywords: chronic aortic dissection, aortic graft replacement, aortic valve replacement, surgical treatment Submitted 27/9/12, accepted 8/11/13 Cardiovasc J Afr 2014; 25: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2013-079

Aortic dissection is considered chronic when the interval between the onset of the acute symptoms and surgery exceeds three weeks. This chronic form of dissection is rare because the

Department of Cardiovascular Surgery, Erzurum Regional Training and Research Hospital, Erzurum, Turkey Bi̇lgehan Erkut, MD, bilgehanerkut9@hotmail.com Ozgur Dag, MD Mehmet Ali̇ Kaygin, MD Husnu Kami̇l Li̇mandal, MD Ahmet Aydi̇n, MD Eyup Serhat Cali̇k, MD

spontaneous evolution of the acute form is death in the majority of cases. In cases not resulting in death and becoming chronic, usually there is aortic wall enlargement due to blood flow at the dissecting aortic section. This situation causes aneurysmal enlargement over time. The diameter of the ascending aorta continues to become larger until rupture occurs, or a diagnosis is made because of clinical symptoms in cases in which the aortic diameter broadens. Consequently, giant chronic dissecting, ascending aortic aneurysms occur. We present here one-stage repair for a patient with chronic type II aortic dissection, extensive enlargement of the ascending aorta, a calcified aortic valve, and coronary arterial disease.

Case report This concerns the case of a 66-year-old man who had previously been diagnosed with type II aortic dissection and who had refused surgical intervention. Three years later, the patient was hospitalised because of chest pain, shortness of breath, fatigue and dizziness. A grade 4/6 diastolic murmur was heard on auscultation. Chest X-rays showed a right pleural effusion. Computed tomography demonstrated a giant aneurysm of the ascending aorta, and it clearly disclosed a chronic Stanford type A aortic dissection compressing the native aorta (Fig. 1). Besides, there was an intimal flap, enlarged patent false lumen and true lumen with mural thrombus in the ascending aorta. The lesion was approximately 10 cm in diameter, the largest ever reported, and resulted from chronic aortic dissection. In transthoracic echocardiography, the patient had second- to third-degree aortic insufficiency and a calcified bicuspid aortic valve. Coronary and aortic root angiography was carried out to measure the aortic gradient and condition of the coronary artery. On angiography, two-vessel disease (left anterior descending and right coronary arterial disease), advanced aortic stenosis (90-mmHg gradient), and second-degree aortic insufficiency were detected. The patient was recommended for surgical treatment for advanced-stage aortic stenosis, chronic dissecting aortic aneurysm, and a coronary bypass. The patient consented to surgery and its risks and underwent surgery. After a sternotomy, the ascending aortic aneurysm was seen (Fig. 2). First, the femoral artery and right atrium were prepared for cardiopulmonary bypass, following systemic heparinisation

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 25, No 1, January/February 2014

Fig. 1. C omputed sequential tomographic images of a 66-year-old man diagnosed with acute type II aortic dissection three years previously. CT-scan illustrated dissection of the ascending aorta, dilatation of the ascending aorta and circulation in both the true (T) and false (F) lumens.

(300 units/kg). The femoral artery and two-stage venous cannulae were placed. The ascending aorta was pulled slightly proximally and, after the innominate artery was rotated and pended, it was explored. The diameter was approximately 11 mm. After the innominate artery was rotated with plastic tape, a purse suture was placed in it, and it was cannulated. The femoral arterial line was connected to the innominate arterial line (cerebral line) with the use of a Y-shaped connector, and cardiopulmonary bypass was initiated. The vent tube was inserted into the left ventricle via the right upper pulmonary vein. Myocardial protection was provided by systemic hypothermia at 30Â°C with antegrade administration of cardioplegia solution, and then by cold retrograde blood perfusion. After the pump flow rate was decreased to 10 ml/kg/ min, the femoral arterial line and proximal innominate artery were clamped. Then the femoral artery cardiopulmonary bypass was stopped and antegrade cerebral perfusion was provided using only the innominate artery cannula. Following this, a vertical incision was made in the aneurysm for an open aortic technique. The dilated ascending aorta was excised. A marked mural thrombus was present in the false lumen of the ascending aorta but the dissection did not extend to the coronary ostium (Fig. 3). A 30-mm tubular woven Dacron prosthesis (UB Shield GraftTM, Ube Medical Co. Ltd., Tokyo, Japan) was anastomosed, using 3-0 polypropylene and the open anastomosis technique, to the distal ascending aorta. After the distal stump was reinforced with a strip of polytetrafluoroethylene (ePTFE) felt on the outside of the aorta, a cross clamp was placed on the ascending aortic graft. Cardiopulmonary bypass was started with a normal flow rate using only the femoral artery, and the cannula in the innominate artery was removed. Later, the aortic valve was excised and an aortic valve replacement was performed with a number 21 mechanical

AFRICA

aortic valve. The ascending aortic graft was sutured to the proximal aorta. The aortic wall layers in the proximal stump were reinforced with 3-0 polypropylene, using a mattress-suture technique, with two expanded ePTFE felt strips, one on each side of the aorta. Thus, the procedures of a tubular ascending aortic graft and separated aortic valve replacement were completed (Fig. 4). De-airing of the left heart was carried out via the aortic root catheter, followed by declamping of the graft, and the patient was re-warmed. The heart spontaneously resumed beating into ventricular fibrillation, underwent cardioversion into a slow rhythm, and was then paced. About five minutes after declamping the aorta, the haemodynamics stabilised with good left ventricular contraction. During re-warming, a double coronary artery bypass to the right coronary artery (with saphenous vein) and the left coronary artery (with LIMA) was performed on the beating heart with a 6-0 and 7-0 running polypropylene suture. Then the saphenous vein was anastomosed to the right coronary artery with a side clamp, which was sutured to the ascending aortic graft. CPB was withdrawn uneventfully.

Fig. 2. I ntra-operative view of the chronic dissecting, ascending aortic aneurysm. The ascending aorta dilated to 10 cm in diameter.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

mortality and often have clinical findings different from those of acute dissections. Many patients with aortic dissection die before hospital admission. Mortality has been estimated at 1–2% per hour during the first two days. Early clinical recognition is crucial for emergency (usually surgical) management of these cases. However, in up to 38% of patients, the diagnosis is missed on initial clinical evaluation. In more than 20% of patients, the diagnosis is made only at autopsy, and few have been reported as chronic dissections. Meticulous diagnostic imaging and urgent surgical treatment are essential to improve survival.1,2 Aneurysms of the ascending aorta are generally caused by Marfan’s syndrome, post-stenotic dilatation in aortic valve disease, aortic arteriosclerosis, or chronic aortic dissection. The relationship between aortic aneurysm and chronic aortic dissection of the ascending aorta is one of a high rate of in-hospital mortality and poor long-term survival. Aneurysms caused by chronic aortic dissection are quite rare. The incidence of chronic ascending aortic dissection ranges from 21–31% in clinical and pathological series, and these include patients with previous cardiac surgery.

Fig. 3. I ntra-operative photo after the aortotomy illustrates the dissection with extensive involvement of the ascending aorta.

After sufficient haemostasis was achieved, the chest was closed. The hemispheric antegrade cerebral perfusion time was 35 minutes during the open aortic technique. The average aortic cross-clamp time was 63 minutes. The right radial artery pressure was maintained at 35 to 60 mmHg during the operation. On the first postoperative day, the patient regained consciousness, and the endotracheal tube was extubated on the second postoperative day. A postoperative enhanced CT showed no abnormal findings at the anastomotic site of the prosthesis, and no residual aortic dissection. The pathological diagnosis was aortic dissection without cystic medial necrosis. The patient was discharged on postoperative day 10 without any problems.

Discussion Diseases of the aorta are important contributory factors for morbidity and mortality, and are related to cardiovascular disease. One of these diseases is aortic dissection (AD), with a prevalence of five to 30 cases per million people per year. It is an exceptionally lethal condition. Almost three quarters of AD cases affect the ascending aorta and this, in the acute phase of the disease, carries a high risk of serious complications. Patients with aortic dissection may also present with acute aortic regurgitation, cardiac dysfunction, congestive heart failure, ischaemia to various organs, and neurological deficits. The few patients who survive the initial phase of an untreated type II aortic dissection have an extremely high long-term risk of

Fig. 4. P ostoperative view following ascending tubular graft replacement.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Our patient had not undergone either aortic or cardiac surgery before. He had been diagnosed with type II aortic dissection three years earlier and had rejected surgical intervention. The patient had not had any potentially life-threatening complications due to the ascending aortic dissection during the time following the initial diagnosis of the dissection. The dissecting aortic section had become chronic over the years and the aortic segment had become an aneurysmatic event. However, the patient had developed aortic calcification and the clinical picture became advanced-stage aortic stenosis because of a bicuspid aortic valve. Moreover, during his recent hospitalisation because of the chronic dissecting aortic aneurysm and calcified bicuspid aortic valve, coronary artery disease requiring surgical intervention was also identified. The surgical method is determined by the extent of the lesion. Bentall operations, total arch replacement, and ascending aortic replacement can be performed.3-5 During surgical intervention on the ascending aorta itself, its branches, or on aortic valves, cerebral protection can be achieved using techniques such as deep hypothermic circulatory arrest, retrograde cerebral perfusion, or antegrade selective cerebral perfusion, individually or in combination. In our patient, we ensured both systemic and cerebral perfusion using the open aortic technique under moderate hypothermia (30°C), performing direct innominate and femoral artery cannulation. During the open technique, the distal aortic graft was sutured, maintaining cerebral perfusion via the innominate artery only. Then the cross clamp was positioned over the sutured graft and cardiopulmonary bypass was continued through both innominate and femoral arterial routes. Both aortic valve replacement and proximal graft suturing were done and the cross clamp was removed. A coronary bypass procedure was then performed on the beating heart.

AFRICA

Conclusion

When our patient underwent a cardiopulmonary bypass, both innominate and femoral arterial perfusions were sufficient to sustain a systemic volume flow. Cerebral perfusion via the innominate artery only during the open aortic technique, and both innominate and femoral perfusions after cross-clamping sufficed to provide systemic protection and organ perfusion in our patient. The technique used for brain protection with normothermic direct innominate artery cannulation without circulatory arrest in the management of chronic aneurysmatic aortic dissection indicated that it is a safe and a suitable alternative to other procedures, such as DHTCA and/or antegrade or retrograde cerebral perfusion.

References 1.

Weymann A, Schmack B, Karck M, Szabó G. Giant Pseudoaneurysm of the Ascending Aorta Caused by Chronic Stanford Type A Aortic Dissection. Can J Cardiol 2011; 27: 871. Tsai TT, Trimarchi S, Nienaber CA. Acute aortic dissection: perspectives from the International Registry of Acute Aortic Dissection (IRAD). Eur J Vasc Endovasc Surg 2009; 37: 149–159. Maureira P, Vanhuyse F, Martin C, Lekehal M, Carteaux JP, Tran N, Villemot JP. Modified Bentall procedure using two short grafts for coronary reimplantation: long-term results. Ann Thorac Surg 2012; 93(2): 443–449. Shen K, Tang H, Jing R, Liu F, Zhou X. Application of triple-branched stent graft for Stanford type A aortic dissection: potential risks. Eur J Cardiothorac Surg 2012; 41(3): e12–17. Leontyev S, Borger MA, Legare JF, Merk D, Hahn J, Seeburger J, Lehmann S, Mohr FW. Iatrogenic type A aortic dissection during cardiac procedures: early and late outcome in 48 patients. Eur J Cardiothorac Surg 2012; 41(3): 641–646.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Case Report Tachycardia-induced cardiomyopathy due to repetitive monomorphic ventricular ectopy in association with isolated left ventricular non-compaction Damirbek Osmonov, Kazim Serhan Özcan, Ahmet Ekmekçi, Bariş Güngör, Ahmet Taha Alper, Kadir Gürkan Abstract Isolated left ventricular non-compaction is a rare genetic disorder manifesting mainly with heart failure, ventricular arrhythmias and systemic embolism. Isolated ventricular tachycardia originating from the right ventricular outflow tract is an arrhythmia that can be treated medically and/or by radiofrequency catheter ablation. Here, we report a case of an asymptomatic 16-year-old boy with a new diagnosis of dilated cardiomyopathy, left ventricular non-compaction and right ventricular outflow tract tachycardia. Electrophysiological studies and radiofrequency ablation of the right ventricular outflow tract tachycardia resulted in normalisation of left ventricular systolic function. This is the first case reporting left ventricular non-compaction in association with tachycardia-induced cardiomyopathy secondary to repetitive monomorphic right ventricular outflow tract tachycardia. Keywords: cardiomyopathy, dilated, left ventricular noncompaction, heart failure, ventricular premature complexes Submitted 21/4/12, accepted 8/11/13 Published online 2/12/13 Cardiovasc J Afr 2014; 25: e5–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2013-080

Isolated left ventricular non-compaction is a genetic disorder that develops secondary to arrest of the compaction process of the sponge-like embryonic myocardium to adult-type myocardium during the first trimester. Heart failure, ventricular Department of Cardiology, Almaty Sema Hospital, Almaty, Kazakhstan Damirbek Osmonov, MD

Department of Cardiology, Dr.Siyami Ersek Cardiovascular and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey Kazim Serhan Özcan, MD, serhandr@gmail.com Ahmet Ekmekçi, MD Bariş Güngör, MD Ahmet Taha Alper, MD Kadir Gürkan, MD

arrhythmias and systemic embolism are manifestations of the disease.1 We present a case of left ventricular non-compaction with tachycardia-induced cardiomyopathy related to repetitive monomorphic premature ventricular contractions originating from the right ventricular outflow tract.

Case report A 16-year-old boy was referred to our cardiology department because of repetitive premature ventricular contractions, which were diagnosed incidentally during pre-operative evaluation for plastic surgery. His history was unremarkable for any cardiac disease and he did not have any symptoms, including palpitation and dyspnoea, during assessment. An electrocardiogram revealed normal sinus rhythm with repetitive monomorphic couplets/triplets of premature ventricular contractions with left bundle branch block morphology and inferior QRS axis (Fig. 1). Twenty-four-hour rhythm Holter monitoring revealed that 70% of the total heart beats consisted of premature ventricular contractions. Transthoracic echocardiography showed left ventricular dilation and systolic dysfunction with an ejection fraction of 29%, and increase of the right ventricular outflow tract diameter. The apicolateral site of the left ventricle had excessively prominent trabeculations and deep inter-trabecular recesses with a non-compacted:compacted myocardium ratio higher than 2. Colour flow imaging revealed direct blood flow within the deep inter-trabecular recesses, which was compatible with left ventricular non-compaction. Cardiac magnetic resonance imaging confirmed the diagnosis of left ventricular non-compaction and left ventricular cardiomyopathy (Fig. 2). On electrophysiological study, the earliest ventricular activation site was on the anteroseptal portion of the superior right ventricular outflow tract. Pace mapping of this site revealed identical electrocardiographic morphology with the 12-lead electrocardiogram of the patient. The premature ventricular contractions disappeared after radiofrequency ablation applied to this site. The patient was discharged the day after the procedure. Control echocardiography performed two months later revealed normal left ventricular size and improved systolic function with an ejection fraction of 53%, but persistant excessively prominent trabeculations and deep inter-trabecular recesses with a non-compacted:compacted myocardium ratio higher than 2. On 24-hour rhythm Holter monitoring, the rhythm was sinus without any premature ventricular contractions.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

Fig. 1. T welve-lead electrocardiogram revealed repetitive monomorphic ventricular ectopy with the morphology of left bundle brunch block and inferiorly directed QRS axis.

Discussion Left ventricular non-compaction (LVNC) is a myocardial disease with a genetic basis that may result in heart failure, arrhythmia, thromboembolism and sudden death. The diagnosis based on the

Fig. 2. C ardiac magnetic resonance imaging revealed prominent trabeculations and deep inter-trabecular recesses in the left ventricular chamber long-axis view. LV: left ventricle RV: right ventricle.

ratio of the compacted to non-compacted ventricle at end-systole was defined by Jenni et al.2 and is confirmed with a ratio of non-compacted:compacted ≥ 2 in adults or ≥ 1.4 in children. We used the defined criteria for our patient. Paterick et al.3 suggested the ratio at end-diastole is also diagnostic but we did not use it for our case. Perhaps more so than any other cardiomyopathy, LVNC has been misdiagnosed as distal heterotrophic cardiomyopathy, dilated cardioyopathy or left ventricular apical thrombus.4 It was only with the advent of superior echocardiographic technology that discrimination of the two separate layers within the myocardium became possible. Malignant ventricular arrhythmias and sudden cardiac death are the leading causes of death in left ventricular non-compaction,5 whereas right ventricular outflow tract tachycardia is a relatively benign clinical entity and can be cured by medical therapy and radiofrequency ablation. Ventricular arrhythmias secondary to left ventricular non-compaction are usually resistant to antiarrhythmic drug therapy.6-8 The role of radiofrequency ablation in left ventricular non-compaction-related ventricular tachycardia has not been well defined and data in the literature are confined to case reports only.6-8 In two cases, the origin of ventricular tachycardia was the epicardial site of the non-compacted segment of the left ventricle, and in one case it was the interventricular septum. All cases had sustained ventricular tachycardia that was refractory to drug therapy. In our case the patient was free of symptoms. On electrophysiological study, the earliest ventricular activation site was sought by conventional techniques. In our laboratory we do this by simultaneously placing two ablation catheters on the

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

right ventricular outflow tract, and the earliest activation site is sought by competition. Using this technique, diagnosis of right ventricular outflow tract ventricular tachycardia was established. To the best of our knowledge, right ventricular outflow tract ventricular tachycardia in association with left ventricular non-compaction has never been reported. We could not determine whether the occurrence of both together was serendipitous or whether there was some relationship between the two. Right ventricular outflow tract ventricular tachycardia is a curable form of ventricular arrhythmia. Verapamil, beta-blockers and adenosine are used in acute and prophylactic treatment of this arrhythmia. Radiofrequency ablation is an alternative treatment modality with reported cure rates of 90%,9 which makes it a preferable option, given the young age of patients with right ventricular outflow tract ventricular tachycardia. In addition, normalisation of left ventricular systolic dysfunction has been reported after right ventricular outflow tract ventricular tachycardia ablation.10,11 In our case, the cardiomyopathy was also improved shortly after elimination of the repetitive premature ventricular contractions by radiofrequency ablation. Myocardial morphology of left ventricular non-compaction usually results in heart failure and patients may be prone to the development of cardiomyopathy in cases of tachycardia.5 Also, right ventricular outflow tract tachycardia may be induced from the remote cellular mechanism of the non-compacted segment,5,12 or it may induce heart failure in the potentially tachycardiasensitive myocardium of left ventricular non-compaction.5 Güvenç et al.12 reported a patient with exercise-induced ventricular tachycardia with left bundle branch block morphology, who had characteristics of idiopathic ventricular tachycardia, which was subsequently diagnosed as left ventricular non-compaction. Successful remission of the arrhythmia was ensured after the introduction of oral beta-blocker therapy.12 Oral beta-blockers are recommended as class Ia indication in patients with non-compaction but not in patients with RVOT ventricular tachycardia. Remission of RVOT ventricular tachycardia may be due to suppression of the arrhythmic trigger of the non-compacted segment by remote cellular mechanism.

Conclusion Although we could not establish a direct association between left ventricular non-compaction and right ventricular outflow tract ventricular tachycardia, this should be kept in mind in such cases. Curable forms of ventricular arrhythmias should be

carefully sought, even in patients with non-compaction and heart failure.

References 1.

Ritter M, Oechslin E, Sütsch G, Attenhofer C, Schneider J, Jenni R. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997; 72: 26–31. 2. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: A step towards classification as a distinct cardiomyopathy. Heart 2001; 86: 666– 671. 3. Paterick TE, Umland MM, Jan MF, Ammar KA, Kramer C, Khandheria BK, et al. Left ventricular noncompaction: A 25-year odyssey. J Am Soc Echocardiogr 2012; 25: 363–375. 4. Chung T, Yiannikas J, Lee LC, Lau GT, Kritharides L. Isolated noncompaction involving the left ventricular apex in adults. Am J Cardiol 2004; 94: 1214–1216. 5. Brescia ST, Rossano JW, Pignatelli R, Jefferies JL, Price JF, Decker JA, et al. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation 2013; 127(22): 2202–2208. 6. Lim HE, Pak HN, Shim WJ, Ro YM, Kim YH. Epicardial ablation of ventricular tachycardia associated with isolated ventricular noncompaction. Pacing Clin Electrophysiol 2006; 29(7): 797–799. 7. Fiala M, Januska J, Bulková V, Pleva M. Septal ventricular tachycardia with alternating LBBB-RBBB morphology in isolated ventricular noncompaction. J Cardiovasc Electrophysiol 2010; 21(6): 704–707. 8. Chinushi M, Iijima K, Furushima H, et al. Suppression of storms of ventricular tachycardia by epicardial ablation of isolated delayed potential in noncompaction cardiomyopathy. Pacing Clin Electrophysiol 2011 doi: 10.1111/j.1540-8159.2010.02999.x. 9. Lerman BB, Stein KM, Markowitz SM, Mittal S, Slotwiner DJ. Ventricular arrhythmias in normal hearts. Cardiol Clin 2000; 18: 265–291. 10. Grim W, Menz V, Hoffmann J, Maisch B. Reversal of tachycardiainduced cardiomyopathy following ablation of repetitive monomorphic right ventricular outflow tract tachycardia. Pacing Clin Electrophysiol 2001; 24(2): 166–171. 11. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patient with repetitive monomorphic ventricular ectopy originating from right ventricular outflow tract. Circulation 2005; 112(8): 1092–1097. 12. Güvenç TS, Ilhan E, Alper AT, Eren M. Exercise-induced right ventricular outflow tract tachycardia in a patient with isolated leftventricular noncompaction. ISRN Cardiol 2011; 2011: 729040.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

AFRICA

Case Report Successful primary percutaneous coronary intervention in a centenarian patient with acute myocardial infarction Sukru Aksoy, Yalci̇n Veli̇bey, Bayram Koroglu, Meti̇n Cagdas, Ozge Guzelburc, Nese Cam, Mehmet Eren Case report

Abstract A 104-year-old male patient was admitted to the emergency department with chest pain. An electrocardiogram showed ST-segment elevation in the anterior leads. He was immediately taken to the catheterisation laboratory for emergency angiography, which showed thrombotic stenosis at the proximal portion of the left anterior descending (LAD) artery. After intervention on the LAD lesion, successful balloon angioplasty with stenting was performed. Here, we report a case of successful primary percutaneous coronary intervention (PCI) in a centenarian patient with acute myocardial infarction. There are few clinical data on centenarian patients with acute myocardial infarction undergoing primary PCI. To the best of best our knowledge, this case is the first reported in the literature where primary PCI was performed on a centenarian patient. Keywords: centenarian patient, acute myocardial infarction, primary percutaneous coronary intervention Submitted 11/9/12, accepted 16/1/14 Cardiovasc J Afr 2014; 25: e8–e10

www.cvja.co.za

DOI: 10.5830/CVJA-2014-001

Primary percutaneous coronary intervention (PCI) is the best reperfusion therapy for patients with ST-segment elevation myocardial infarction (STMI).1,2 In the literature, there are only a few cases on centenarians with STMI undergoing primary PCI. In this report, we present a case of successful primary PCI in a 104-year-old patient with acute myocardial infarction.

Siyami Ersek Thoracic and Cardiovascular Surgery Centre, Training and Research Hospital, Department of Cardiology, Istanbul, Turkey Sukru Aksoy, MD Yalci̇n Veli̇bey, MD, dr_yalchin_dr@yahoo.com.tr Bayram Koroglu, MD Meti̇n Cagdas, MD Ozge Guzelburc, MD Nese Cam, MD, PhD Mehmet Eren, MD, PhD

A 104-year-old male with a past history of hypertension and type 2 diabetes mellitus presented to the emergency department with chest pain. His blood pressure and heart rate were 175/90 mmHg and 110 beats per minute, respectively. The electrocardiogram (ECG) showed anterior myocardial infarction with right bundle branch block (Fig. 1). With a diagnosis of acute anterior myocardial infarction and after a loading dose of clopidogrel (300 mg) and acetylsalicylic acid (300 mg), he was immediately taken to the catheterisation laboratory for emergency angiography using the transfemoral approach. Because of the potential decline in renal function in elderly patients, we used iso-osmolar contrast agent. Angiography demonstrated a 95% thrombotic stenosis at the proximal portion of the left anterior descending (LAD) artery (Fig. 1), and plaques in the circumflex (Cx) and right coronary (RCA) arteries without significant stenosis. We decided on primary intervention on the LAD lesion, and successful balloon angioplasty (Simpass 2 × 15 mm, 12 atm, AlviMedica, Istanbul, Turkey) with stenting (bare-metal stent, Ephesus 3 × 18 mm, 12 atm, Medtronic, Mineapolis, USA) was performed (Fig. 2). An ECG obtained 90 minutes after PCI showed complete ST-segment resolution (Fig. 3). No additional symptoms or PCI-related complications occurred during hospitalisation and the patient was discharged from hospital after six days without any symptoms. Transthoracic echocardiography after four days was normal except for concentric left ventricular hypertrophy and grade 1 diastolic dysfunction. He had a normal global ejection fraction (55%) without regional wall motion abnormalities.

Discussion PCI is currently the treatment of choice for patients presenting with ST-segment elevation myocardial infarction (STEMI). Studies on primary PCI of elderly patients show a low rate of procedure-related complications. Valente et al. suggested that primary PCI in very old patients (> 85 years) with STEMI was safe and effective in reducing the rate of PCI failure in the presence of a low Killip class on admission, whereas primary PCI was unable to affect the poor prognosis for very old patients with cardiogenic shock.3 In another study by Sakai et al., they showed that aggressive PCI in older patients improved the prognosis, and short door-toballoon time is an important parameter for a good prognosis.4 The TRIANA study also suggested that primary PCI may offer clinical advantages over fibrinolytic therapy, as manifested

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 25, No 1, January/February 2014

Fig. 1. T he ECG obtained at admission showed right bundle branch block and ST-segment elevation in the anterior derivations.

by the trend towards improvement in the combined endpoint of death, re-infarction and stroke at 30 days in the oldest (> 75 years) patients. There were no significant differences in complications, such as major haemorrhage, blood transfusion or renal failure.5 There are no studies on centenarian patients with acute myocardial infarction (AMI) undergoing PCI. In the literature there are only a few cases of patients older than 100 years with STEMI who had successful PCI.6,7 Because elderly patients may have more calcified or totally occluded lesions, poor left ventricular function and multiple co-morbid conditions, physicians may hesitate to perform primary PCI in centenarian A

patients. However each patient should be evaluated individually. Certain measures can be applied in order to reduce procedure-related complications in elderly patients who are candidates for primary PCI when co-morbid conditions are taken into consideration. Considering the increase in femoral arteriosclerosis due to old age, the percutaneous transradial approach can be selected because it may be less traumatic. Careful use of anticoagulant and anti-aggregant drugs has a very important role in reducing the risk of bleeding. Because of the potential decline in renal function, hypo- or iso-osmolar contrast agents should be used in centenarian patients with AMI undergoing primary PCI. C

Fig. 2. A . Selective left coronary angiogram obtained from the right anterior oblique cranial projection showing severe stenosis at the proximal portion of the left anterior descending artery. B and C. The same projection taken during and after stenting.

Fig. 3. An ECG obtained 90 minutes after PCI showing complete ST-segment resolution.

e10

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014

Conclusion

Primary PCI seems to be the best reperfusion therapy for STEMI, even in elderly patients. Although there are no studies on centenarians with STEMI undergoing primary PCI, some case reports show low procedure-related complication rates and that primary PCI is lifesaving.

References 1.

Van De Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008; 29: 2909–2945. William W, Philippe K, Nicolas D, et al. Myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010; 31: 41–44.

AFRICA

Valente S, Lazzeri C, Salvadori C, et al. Effectiveness and safety of routine primary angioplasty in patients aged ≥ 85 years with acute myocardial infarction. Circ J 2008; 72: 67–70. Sakai K, Nagayama S, Ihara K, et al. Primary percutaneous coronary intervention for acute myocardial infarction in the elderly aged ≥ 75 years. Catheter Cardiovasc Interv 2012; 79: 50–56. Bueno H, Betriu A, Heras M. Primary angioplasty vs. fibrinolysis in very old patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto Agudo de miocardio eN Ancianos) randomized trial and pooled analysis with previous studies. Eur Heart J 2011; 32: 51–60. Wang L, Zhang MZ, Yang G. Combined therapy with Chinese medicine and percutaneous transradial coronary intervention for a centenarian patient with acute myocardial infarction. Chin J Integr Med 2009;15: 233–235. Başar C, Bulur S, Aslantaş Y, Ekinozu I, Ozhan H. The oldest male patient in the literature who had undergone successful primary percutaneous intervention. Arch Turk Soc Cardiol 2011; Suppl 1: 316.

Perindopril Erbumine 4 mg / 8 mg

Amlodipine Besylate 5 mg / 10 mg

Atorvastatin

10 mg, 20 mg, 40 mg, 80 mg

SEP R27 ,84

team

(excl. VAT)

Trusted

Affordable Evidence based Med icine

References 1. Sever PS, Dahlof B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

S3 Reg. No. 41/7.1.3/0671, 72 S3 Reg. No. 39/7.1/0117, 0120 S4 Reg. No. 42/7.5/0552, 0553, 0554, 0555

JANUARY/FEBRUARY 2014 VOL 25 NO 1

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

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

Cardiovascular Journal of Africa . Vol 25, No 1, January/February 2014

Printed by Tandym Printers

• ADVANCE cardiovascular risk model in people with diabetes

PUBLISHED ONLINE: • Left ventricular rupture after double valve replacement