CVJA Volume 24, Issue 7 by Clinics Cardive Publishing

AUGUST 2013 VOL 24 NO 7

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Mortality in low-risk patients undergoing CABG • Re-operation in mechanical valve replacement surgery • Vitamins C and E in patients awaiting CABG • Prophylactic levosimendan in high-risk valve surgery • Homocysteinaemia, hyperglycaemia, dyslipidaemia, hypertension and obesity • CIMT and high hs-CRP levels predict unstable CAD • Sirolimus-eluting versus bare-metal stents in CAD patients with diabetes • Early repolarisation in a black African population

Cardiovascular Journal of Africa . Vol 24, No 7, August 2013

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• Diagnostic and prognostic values of BNP and NT-pro-BNP

PUBLISHED ONLINE: • Radiofrequency ablation of the great saphenous vein

CardioVascular Journal of Africa

PROGRAMME LEADERS Dr Landi Lombard

Professor James Ker

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

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

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

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

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

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

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

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

VOL 24, NO 7. AUGUST 2013

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Cardiovascular Topics

247 Analysis of mortality in low-risk patients undergoing coronary artery bypass grafting C Cakalagaoglu • C Koksal • T Adademir • M Yildiz • A Fedakar • M Şahin • Fi Kutlay • B Yigiter 251 A retrospective analysis of factors influencing re-operation in patients undergoing mechanical valve replacement E Aydin • F Yapici 255 Does vitamin C or its combination with vitamin E improve radial artery endotheliumdependent vasodilatation in patients awaiting coronary artery bypass surgery? A Uzun • U Yener • OF Cıcek • O Yener • A Yalcınkaya • A Dıken • T Ozkan • A Turkvatan • M Ulas 260

Effectiveness of prophylactic levosimendan in high-risk valve surgery patients O Ersoy • E Boysan • EU Unal • K Yay • U Yener • F Cicekcioglu • F Katircioglu

265 Association of homocysteinaemia with hyperglycaemia, dyslipidaemia, hypertension and obesity D Sengwayo • M Moraba • S Motaung 270 Increased carotid intima–media thickness associated with high hs-CRP levels is a predictor of unstable coronary artery disease SA Abdushi • FU Kryeziu • FD Nazreku 274

Efficacy and safety of sirolimus-eluting stents versus bare-metal stents in coronary artery disease patients with diabetes: a meta-analysis Y Qiao • Y Bian • X Yan • Z Liu • Y Chen

280 Prevalence and significance of early repolarisation in a black African population: data of 246 individuals with cardiovascular morbidity A Bonny • DN Noah • SN Amougou • C Saka

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

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

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

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

Regional Editor (Kenya) Dr F Bukachi

Surgical dr f aziz

Regional Editor (South Africa) PROF R DELPORT

Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

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

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

Review Article

286 Diagnostic and prognostic values of B-type natriuretic peptides (BNP) and N-terminal fragment brain natriuretic peptides (NT-pro-BNP) L Maries • I Manitiu

Drug Trends in Cardiology

291 Reports from the American Diabetes Association’s 73rd scientific sessions, 21–25 June 2013, Chicago, Illinois G Hardy

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

e1 Radiofrequency ablation of the great saphenous vein in an elderly patient with co-morbid disease AÜ Yener • Ö Yener • HS Gedik • K Korkmaz • T Özkan • A Lafçi • K Çağli

VOL 24, NO 7. AUGUST 2013

CONTENTS

290 Saxagliptin demonstrates no increased risk for cardiovascular death, heart attack or stroke in the SAVOR cardiovascular outcomes trial G Hardy

managing editor

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

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GAUTENG CONTRIBUTOR

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

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Cardiovascular Topics Analysis of mortality in low-risk patients undergoing coronary artery bypass grafting CANTURK CAKALAGAOGLU, CENGIZ KOKSAL, TAYLAN ADADEMIR, MUSTAFA YILDIZ, ALI FEDAKAR, MÜSLÜM ŞAHIN, FIKRI KUTLAY, BESIM YIGITER

Abstract Aim: The aims of this study were to determine the early mortality rate in low-risk coronary artery bypass graft (CABG) patients and examine the causes of death, to identify problems that could be avoided in future surgeries. Methods: All low-risk patients (EuroSCORE ≤ 2) who died after CABG were included. Their peri-operative information was meticulously studied by internal and independent external reviewers to identify causes of death, which were classified as: cardiac or non-cardiac; and a further division as: (1) non-preventable, (2) preventable (technical error), and (3) preventable (system error). Results: Early mortality was 0.93% (24/2 570). Eleven patients (45.8%) were classified as preventable deaths. In six of them the main problem was identified as graft thrombosis, which was secondary to a technical error of either the harvesting or anastomosis of the left internal mammarian artery. There were also five system errors identified as delays in the treatment of an identified and potentially reversible problem. Conclusions: Correction of technical and system errors, such as harvesting of the left internal mammarian artery, haemostasis during surgery, and establishing standard protocols for the transfer of patients from ward to intensive care units will eventually lead to improvement in both the quality of care and patient outcomes, even in low-risk groups. Cardiovascular Surgery Clinic, Kartal Kosuyolu Research and Training Hospital, Kartal, Istanbul, Turkey CANTURK CAKALAGAOGLU, MD CENGIZ KOKSAL, MD TAYLAN ADADEMIR, MD, adademir@gmail.com ALI FEDAKAR, MD

Department of Cardiology, Sakarya University, Sakarya, Turkey MUSTAFA YILDIZ, MD

Cardiology Clinic, Kartal Kosuyolu Research and Training Hospital, Kartal, Istanbul, Turkey MÜSLÜM ŞAHIN

Cardiovascular Surgery Clinic, Veni Vidi Hospital, Dagkapi, Diyarbakir, Turkey FIKRI KUTLAY, MD

Cardiovascular Surgery Clinic, Isvicre Hospital, Icerenkoy, Istanbul, Turkey BESIM YIGITER, MD

Keywords: coronary artery bypass grafting, myocardial infarction, risk assessment, low risk Submitted 6/6/13, accepted 24/5/13

www.cvja.co.za

Cardiovasc J Afr 2013; 24: 247–250 DOI: 10.5830/CVJA-2013-040

Scoring systems that predict the risk of operative mortality have been under development for more than a decade and one of the most frequently used systems, EuroSCORE, has been established.1,2 EuroSCORE divides patients into three risk groups, based on the score obtained during assessment: low-risk patients (value ≤ 2) have a predicted mortality of 1.27–1.29% and an observed mortality of 0.4–1.0%.2-7 Although the reasons for mortality have been extensively studied in high-risk patients,8,9 only a few reports have analysed the reasons for and possible preventive strategies of mortality in low-risk patients undergoing coronary artery bypass grafting (CABG).10,11 Drawing on the FIASCO study,10 we reviewed the mortality in our own low-risk CABG patient population in order to identify whether death could be considered preventable, and if so, whether it was due to a technical or system error.

Methods The study was approved by the local hospital ethics committee. All cardiac surgical patients were prospectively risk stratified using the additive and logistic EuroSCORE.12 The cardiac surgery unit recorded all patients’ characteristics, operation details and postoperative outcomes contemporaneously in a computer database. Patients with an additive EuroSCORE ≤ 2 who died in the early postoperative period (death from any cause within 30 days of the operation) were identified from the database. For the study, patient inclusion criteria were: women undergoing CABG with no other risk factors (one point) or with any risk factor adding one point (two points), and men undergoing CABG with one or two risk factors of one point or with one two-point risk factor. We exluded patients with moderate and high EuroSCOREs. All of the operations were performed on-pump; combined operations (CABG + heart vessel/carotid/aorta surgery/etc.) and emergencies surgeries were also excluded. The details of each case were reviewed and analysed by the cardiac surgery and anaesthetic teams. The details of the patients were also reviewed by an independent surgeon from

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another hospital, who has considerable experience in assessing patients’ hospital records. The cause of death of each patient was identified and a decision was made to define the death as cardiac or non-cardiac related. Also, as in the FIASCO study, deaths were further classified into three categories: (1) non-preventable, (2) preventable (technical error), and (3) preventable (system error), in order to determine the cause of death.10

Results Between 2002 and 2007, 3 729 patients underwent on-pump CABG surgery at our hospital and 2 570 (69%) of them were identified as having an additive EuroSCORE ≤ 2. They were categorised as a low-risk group according to the EuroSCORE definition.2,3 There were 24 early mortalities (defined as occurring within 30 days of the CABG operation) in the study group and therefore mortality was found to be 0.93% (24 out of 2 570). The deaths were further classified as cardiac and non-cardiac, and according to this division, nine (37.5%) of the deaths were found to have cardiac causes, whereas 15 (62.5%) were considered to have a non-cardiac cause. As in the FIASCO study, when deaths were classified into non-preventable, preventable (technical error) or preventable (system error),10 11 (45.8%) of the deaths were considered to be preventable and 13 (54.2%) were non-preventable, a

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categorisation which both internal and external reviewers agreed upon. The details of patient deaths are summarised in Table 1. All patients in this group received left internal mammary artery grafts for revascularisation of the left anterior descending artery. Other grafts were obtained from veins, and on average each patient received 2.9 ± 0.7 bypass grafts. Among those 13 patients (54.2%) who were categorised as suffering unpreventable deaths, seven patients were diagnosed with a stroke, two had sepsis due to mediastinitis, one had pulmonary emboli (PE) without prominent deep-vein thrombosis, and another had respiratory insufficiency postoperatively. One patient had sudden cardiac arrest after discharge, and the last patient died due to ischaemic heart disease and possible poor distal run-off, causing a hypotensive cardiopulmonary failure in the ward that was not responsive to cardiopulmonary resuscitation. This patient was weaned off bypass with the help of intra-aortic balloon pump (IABP), but unfortunately died on the sixth day after the operation. The patient who died of PE had been re-admitted to the intensive care unit (ICU) with sudden sharp chest pains and respiratory insufficiency six days after surgery. The sudden onset of symptoms and a chest X-ray suggested PE. The patient succumbed to respiratory failure 11 days after surgery. The other patient who died of respiratory failure had chronic obstructive pulmonary disease (COPD). After the operation, mechanical

TABLE 1. SUMMARY OF THE CAUSE OF DEATH AND POSSIBLE IDENTIFIED PROBLEMS IN LOW-RISK CABG OPERATIONS Cardiac No Age Gender Cause of death death Preventable Identified problem 1 56 Male Cardiac arrest in the ICU, peri-operative MI Yes Yes – technical Haematoma of LIMA, occlusion of graft 2 64 Male Cardiac arrest in the ICU, peri-operative MI Yes Yes – technical Dissection of LIMA, occlusion of graft 3 63 Male Cardiac arrest in the ward, peri-operative MI Yes Yes – technical Haematoma of LIMA, occlusion of graft 4 58 Male Cardiac arrest in the ICU, peri-operative MI Yes Yes – technical Dissection of LIMA, occlusion of graft 5 59 Female Cardiac arrest in the ICU, peri-operative MI Yes Yes – technical Haematoma of LIMA, occlusion of graft 6 54 Male Ventricular fibrillation after CABG × 3 in ICU, Yes Yes – technical Surgical technical error of anastomosis? 2 saphenous vein occlusions No Yes – system System error 7 57 Female Renal failure (excessive blood transfusion) 2 800 mm3 drainage, late revision surgery No Yes – system System error 8 61 Male Renal failure ( excessive blood transfusion) 3 650 mm3 drainage, no revision 9 53 Male Pneumothorax-related respiratory insufficiency in ward No Yes – system System error, unable to transfer to ICU on time 10 67 Male Development of LCOS in ICU stay Yes Yes – system System error, early discharge from ICU 11 65 Male Stroke, pre-operative normal sinus rhythm and No Yes – system System error, lack of cardioversion on time postoperative atrial fibrillation-related cerebral infarct and emboli due to intracardiac thrombi 12 55 Male Stroke No No 13 57 Male Stroke No No 14 46 Male Stroke No No 15 54 Male Stroke No No 16 53 Female Stroke No No 17 59 Female Stroke No No 18 68 Male Stroke No No 19 58 Male Mediastinitis No No 20 58 Female Mediastinitis No No 21 55 Male Pulmonary emboli No No 22 54 Male Respiratory failure, bullous lung disease No No 23 54 Male Ischaemic heart disease, poor distal run-off Yes No 24 61 Male Sudden cardiac death after discharge Yes No Possible late tamponade? CABG: coronary artery bypass grafting, MI: myocardial infarction, ICU: intensive care unit, LIMA: left internal mammarian artery, LCOS: low-cardiac output syndrome.

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ventilatory support was discontinued on postoperative day four, however, hypoxaemia, possibly due to atelectasis and a ventilation–perfusion mismatch, required re-intubation. Death occurred due to respiratory failure on postoperative day six. Eleven patients (45.8%) in the group of 24 deaths were found to have the cause of death categorised as preventable. Six were deemed technical errors and five system errors. Among the preventable deaths due to technical errors, all six patients suffered graft thrombosis. In five of the patients, graft thrombosis was encountered due to LIMA thrombosis. These patients developed low-cardiac output syndrome (LCOS) in the early postoperative period, requiring cardiopulmonary resuscitation and re-exploration, which showed dissection of the LIMA or haematoma at the LIMA wall. Although in two of these cases, the left anterior descending (LAD) coronary artery was bypassed with a saphenous vein graft for a second time, death was inevitable but secondary to peri-operative MI. In the sixth patient who had graft thrombosis, ventricular fibrillation occurred on the third day after surgery and was the cause of death. Emergency cardiopulmonary bypass (CPB) was initiated after cardiopulmonary resuscitation. During surgical exploration, two thrombosed saphenous vein grafts were detected. Five of the patients in the preventable death group were considered to have suffered a system error. The two patients who died of renal failure had excessive bleeding in the early postoperative period. Haemodialysis was initiated in both patients but they succumbed on the sixth and eighth days after surgery, respectively. One of the patients had atrial fibrillation (AF) but there was no attempt at cardioversion, possibly due to lack of communication between the consultant and the junior on-call doctor; the final cause of death was stroke. Another patient, diagnosed with bullous lung disease, had subcutaneous emphysema and after an episode of sudden respiratory insufficiency, died in the ward on day 19 after surgery. A further patient with hypotension was transferred to the ward by a junior surgeon on postoperative day three, without considering that the clinical status of the patient required continuous inotropic support. This system error led to low-cardiac output syndrome and subsequent cardiac arrest. The patient failed to respond to cardiopulmonary resuscitation in the ward.

Discussion During open-heart surgery, patients with a high risk for cardiac surgery are extensively studied and there is substantial documentation of successful surgical outcomes in this group of patients.8,9 However, there is not enough data on preventable deaths in low-risk groups of patients. The investigation of low-risk groups with a EuroSCORE ≤ 2 requires a larger group of patients to demonstrate accurate mortality rates and it is often more difficult to predict the possible risk factors that influence outcomes of mortality in a small group. In a study by Freed et al.,10 in a group of 4 294 patients with a logistic EuroSCORE ≤ 2, a total of 16 patients (0.37%) died. It has been claimed that over a third of the deaths studied were potentially preventable, suggesting that further improvement in outcomes is possible through modification of surgical technique or a change in the systematic delivery of cardiac surgical care and training. In our study group, of a total of nine patients (37.5%) with

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peri-operative myocardial infarction and cardiac-related death, seven (77.8%) were considered to be preventable, and in five patients, the main problem was identified as LIMA harvesting. LIMA–LAD bypass is the mainstay of coronary surgery.12,13 The LIMA is used extensively as a bypass graft, with excellent patency rates.13,14 However, careful technical preparation is needed to prevent occlusion. In other studies on isolated CABG, mainly CPB, cardioplegic solution, problems in myocardial protection, and the length of aortic cross-clamp were considered to be factors that may have increased cardiac-related mortality.10-14 Our study found that in five of the nine patients (55.6%) who suffered cardiac-related death, technical problems in LIMA harvesting was the most important cause of cardiac origin. Two patients also died of renal failure as a result of excessive blood transfusions. Meticulous haemostasis and early exploration for postoperative bleeding may help to prevent excessive blood transfusion and therefore the development of renal insufficiency that requires dialysis, which is well known to increase mortality.15 In one patient, stroke was the reason for death, due to postoperative atrial fibrillation. However, the cause of death was secondary to a miscommunication between the junior surgeon on the ward and the senior surgeon, which caused a preventable system error. Early cardioversion is crucial and potentially lifesaving in the face of acute rhythm disturbances, which require immediate intervention. Late detection in the ward, miscommunication between the surgical team, and inability to transfer the patient to the ICU on time are all system-related errors that need to be identified and solutions discussed in order to prevent further fatalities. In another patient who was still in the ward under medical supervision, underestimation of respiratory insufficiency due to pneumothorax was the cause of death. A further patient with clinical signs of deterioration of the haemodynamic status was transferred to the ward by a junior surgeon who underestimated the clinical status of the patient, leading to a system error and death. These system errors can be corrected by more established protocols and closer follow up of patients after surgery. Common to both the above cases, delay in the treatment of an identified and potentially reversible problem was recognised. The cause of this delay in taking appropriate action was the lack of or unclear communication between senior and junior surgeons. There are several similar studies but they differed from our study in several ways, as the current study was designed to understand the details of mortality in low-risk cardiac surgery patients. In both the FIASCO study10 and the Stockholm experience,11 all cardiac surgical procedures were included, whereas our study dealt with only CABG surgery. Another difference from the FIASCO study was that patients were included who died within 30 days of surgery. Previous studies have only included in-hospital mortality, similar to the study by Janiec et al.11 The Stockholm experience has revealed excellent results (0.38% mortality), even in patient groups with a EuroSCORE ≤ 3. However, the incidence of preventable deaths was only 13% (2/15) of all deaths. In the FIASCO study, the incidence of mortality was similar to that of the Stockholm study (0.37%) in a group of low-risk patients with a logistic EuroSCORE ≤ 2. The incidence of preventable causes of death was 43%, markedly higher than that of the Stockholm experience.10,11

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In our study, the mortality rate (0.93%) was higher than in both the above studies. Most importantly, the incidence of preventable death was found to have occurred in 11 patients (45.8%) in the group. Therefore we argue that reduction of technical surgical errors and system errors will improve the outcomes of this low-risk patient group. The main areas for improvement are seen as: (1) meticulous LIMA harvesting, (2) improvement in surgical technique for haemostasis during the surgical procedure, and (3) established protocols for patient care in the ICU and ward. There were two limitations of the study; one was that the number of deaths in this group (24/2 570) still constitutes a relatively small number of patients from which to determine the real risk factors influencing mortality. A larger patient group or the pooling of patients through collaboration between hospitals will yield valuable data on this subject. The second major limitation of our study was the lack of an objective definition of preventable and non-preventable causes of death. In order to categorise a death as preventable or non-preventable, we had to rely on consensus between the authors and an expert external to the study, while searching for similar studies in the literature.10,11

Conclusion This study was conducted because there is insufficient data on the causes of preventable deaths in the low-risk group of patients undergoing isolated CABG. A structured analysis of the events preceding an unexpected fatality in patients with no or minimal risk factors should reveal potentially correctable issues. Furthermore, the correction of technical and system errors, such as LIMA harvesting and haemostasis during surgery, as well as the establishment of protocols for transferring patients from the ward to the intensive care unit will eventually lead to improvement in the quality of care and surgical outcomes.

10.

11. 12.

13. 14.

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Geissler HJ, Hölzl P, Marohl S, et al. Risk stratification in heart surgery: comparison of six score system. Eur J Cardiothorac Surg 2000; 17: 400–406. Roques F, Nashef SAM, Michel P, et al. Risk factors and outcome

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in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999; 15: 816–823. Nashef SAM, Carey F, Charman S. The relationship between predicted and actual cardiac surgical mortality: impact of risk grouping and individual surgeons. Eur J Cardiothorac Surg 2001; 19: 817–820. Nashef SAM, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16: 9–13. Michel P, Roques F, Nashef SAM , et al. Logistic or additive EuroSCORE for high-risk patients? Eur J Cardiothorac Surg 2003; 23: 684–687. Kawachi Y, Nakashima A, Toshima Y, Arinaga K, Kawano H. Risk stratification analysis of operative mortality in heart and thoracic aorta surgery: comparison between Parsonnet and EuroSCORE additive model. Eur J Cardiothorac Surg 2001; 20: 961–966. Sergeant P, de Worm E, Meyns B. Single centre domain validation of the EuroSCORE on a consecutive sample of primary and repeat CABG. Eur J Cardiothorac Surg 2001; 20: 1176–1182. Ascione R, Narayan P, Rogers CA, Lim KH, Capoun R, Angelini GD. Early and midterm clinical outcome in patients with severe left ventricular dysfunction undergoing coronary artery surgery. Ann Thorac Surg 2003; 76: 793–799. Gaudino M, Glieca F, Alessandrini F, et al. High risk coronary artery bypass patients: Incidence, surgical strategies, and results. Ann Thorac Surg 2004; 77: 574–580. Freed DH, Drain AJ, Kitcat J, Jones MT, Nashef SAM. Death in low-risk cardiac surgery: the failure to achieve a satisfactory cardiac outcome (FIASCO) study. Interact Cardiovasc Thorac Surg 2009; 9: 623–625. Janiec M, Sartipy U. Death in low-risk cardiac surgery: Stockholm experience. Interact Cardiovasc Thorac Surg 2010; 11: 547–549. Parolari A, Alamanni F, Polvani G, et al. Meta analysis of randomized trials comparing off-pump with on-pump coronary artery bypass graft patency. Ann Thorac Surg 2005; 80: 2121–2125. Kitamura S. Physiological and metabolic effects of grafts in coronary artery bypass surgery. Circ J 2011; 75: 766–772. Hartman J, Meijboom B, Galema T, Takkenberg H, Schets AM, de Feyter P, et al. Ultrasonographic and DSCT scan analysis of single lima versus arterial T grafts 12 years after surgery. J Cardiovasc Surg (Torino) 2010; 51: 399–407. Ranucci M, Romitti F, Isgro G, et al. Oxygen delivery during cardiopulmonary bypass and acute renal failure after coronary operations. Ann Thorac Surg 2005; 80: 2213–2220.

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A retrospective analysis of factors influencing re-operation in patients undergoing mechanical valve replacement EBUZER AYDIN, FIKRI YAPICI

Abstract Background: We aimed to determine the possible factors leading to re-operation in patients undergoing mechanical valve replacement and to investigate the relationship between valvular thrombus formation and mean platelet volume. Methods: The medical records of 43 patients with mechanical valve implantation, who were admitted to the Department of Cardiovascular Surgery of Dr Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital between 2000 and 2005 were analysed retrospectively. Data recorded included demographic characteristics, valve type, size and location, implantation position, warfarin use, INR level, additional cardiac intervention, presence of left atrial thrombus, valvular thrombus, pannus formation, perivalvular leak, left atrial aneurysm, platelet count and mean platelet volume (MPV), bleeding after the primary surgery and/or revision of surgery due to other reasons, valve protection, aortic root expansion, presence of valve calcification and infective endocarditis, pre- and postoperative rhythm pattern, brand name of prosthesis, distance of the patient’s house from a cardiac surgery centre, and concomitant noncardiac systemic diseases. Results: Mean age was 49.3 years (range 19–78 years). Of the patients, 51% (n = 22) were males and 49% (n = 21) were females. The re-operation mortality was 11.6%. Age, gender, valve type, brand of valve prosthesis, and implantation position were not risk factors for re-operation. The MPV was higher and statistically significant in patients with valvular thrombus during re-operation (p < 0.001). MPV was determined to be an independent risk factor with 85% sensitivity and 87% specificity. Conclusion: MPV and INR levels should be closely monitored when designing individualised postoperative medical treatment for patients undergoing heart valve re-operation. Keywords: platelet dysfunction, re-operation, heart valve prosthesis implantation, risk factors, mortality, retrospective studies Submitted 13/3/13, accepted 7/6/13 Cardiovasc J Afr 2013; 24: 251–254

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DOI: 10.5830/CVJA-2013-044

Currently, cardiac valve diseases that require surgery are mainly due to stenosis, insufficiency, and fixed valves in stenosis accompanied by insufficiency. Acute rheumatic fever is the main cause of mitral insufficiency in developing populations.1 Department of Cardiovascular Surgery, Dr Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey EBUZER AYDIN, MD, ebuzermd@gmail.com FIKRI YAPICI, MD

Improved survival rate after the primary surgery has led to increased numbers of re-operations.2 Therefore, in recent years there has been a tendency towards increasing age of patients undergoing re-operations on heart valve prostheses.3 The major causes of re-operation include progression of postoperative native valve disease after non-valve surgery, and structural degeneration of bioprosthetic surgical valves. Re-operations are more complicated than the initial procedure due to adhesive processes around the heart, and the common association of pulmonary hypertension (PHT). In addition, replacement operations are often performed in functionally compromised patients who tolerate complications less well.4 In the past, re-operative valve surgery was associated with a higher mortality rate than with primary valve operations; however, mortality and morbidity rates have decreased recently.2,4,5 Although mechanical valves are long-lasting in young patients, there is an increased risk for thrombogenic, particularly thromboembolic, events and this requires longterm anticoagulation therapy. Such thromboembolic events are dependent on valve design, materials used and characteristics of the patient.6 Endocarditis, dehiscence, perivalvular leak and pannus formation are commonly encountered with mechanical and biological valves, while acute prosthetic valve thrombosis is the main complication of mechanical valves. In this study, we aimed to determine possible factors leading to re-operation in patients undergoing mechanical valve replacement and also to investigate the relationship between valvular thrombus formation and mean platelet volume (MPV).

Methods Between 2000 and 2005, 2 141 patients underwent heart valve surgery in the Department of Cardiovascular Surgery of Dr Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey. Of the patients, 1 615 had valve surgery, 370 had valve surgery with coronary artery bypass graft (CABG) surgery, and 156 had mitral valve repair. During the same time interval, the number of re-operations was 176. Retrospective analysis was performed on the medical data of 60 re-operated patients, but 17 were excluded from the study due to missing data. Therefore, the study group was made up of 43 patients who had undergone mechanical valve implantation. Patients who underwent bioprosthetic valve replacement during the primary surgery were also excluded from the study to achieve more homogenous results and to investigate whether each parameter, namely valvular thrombus formation, pannus formation and perivalvular leak, was an independent risk factor for valve dysfunction and re-operation. Data recorded included age, gender, valve type, valve size, valve location, implantation position, warfarin use, INR level, additional cardiac intervention, presence of left atrial thrombus, valvular thrombus, pannus formation, perivalvular leak, left atrial aneurysm, platelet count and MPV, bleeding after the primary

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surgery and/or revision surgery due to other reasons, valve protection, aortic root expansion, presence of valve calcification and infective endocarditis, pre-operative and postoperative rhythm pattern, brand name of prosthesis, distance of the patient’s house from a cardiac surgery centre, and concomitant non-cardiac systemic diseases. The factors potentially leading to re-operation included valvular thrombus formation, pannus formation and perivalvular leak. The study protocol was approved by the local ethics committee.

Statistical analysis This was performed using Windows SPSS v13.0 software. Data were expressed as percentage. A p-value of < 0.05 was considered significant. Categorical data were expressed as number and percentage, while numerical data were expressed as mean ± standard deviation. Pearson’s chi-square test and Fisher’s exact test were used for non-parametric variables, while the Mann-Whitney U-test was performed for parametric variables. A linear regression analysis was also performed for significant parameters. A ROC curve was drawn to determine the sensitivity and specificity of these parameters.

Results The mean age of patients was 49.3 years (range 19–78 years); 51% (n = 22) were males and 49% (n = 21) were females. Twenty-nine patients underwent mitral valve replacement, while 12 underwent aortic valve replacement. A tricuspid valve was implanted in two patients. There was no statistically significant difference in baseline demographic characteristics of the patients. Age and gender were not a determining factor for re-operation. Demographic characteristics of the patients and distribution of indications for re-operation are summarised in Tables 1 and 2, respectively. The incidence of thrombus formation in mechanical prosthetic valves was statistically significantly higher in patients with valve calcification (p < 0.05) and left atrial thrombus (p = 0.007) during the primary surgery. Pearson’s chi-square test revealed TABLE 1. DEMOGRAPHIC CHARACTERISTICS OF THE PATIENTS Variables Gender Male Female Valve replacement Mitral Aortic Tricuspid Implantation position Anatomical Extra-anatomical Additional cardiac intervention Concomitant non-cardiac disease Concomitant cardiac disease Infective endocarditis Perivalvular leak Valve calcification Pannus formation

Number (n)

Percentage (%)

22 21

51 49

29 12 2

67.4 27.9 4.6

33 10 10 3 3 13 23 17 19

76.7 23.2 23.2 6.9 6.9 30.2 53.4 39.5 44.1

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that the incidence of perivalvular leak was higher in patients with left atrial thrombus during the primary surgery (p < 0.05). The incidence of perivalvular leak was statistically higher in patients with valvular thrombus and pannus formation (p < 0.05). In addition, the incidence of perivalvular leak was higher in patients with infective endocarditis compared with those without the disease (p < 0.05). The re-operation mortality rate was 11.6%. A total of 67.4% (n = 29) of patients had mitral valve disease, while 27.9% (n = 12) had aortic valve disease. A mitral valve was implanted anatomically and extra-anatomically in 22 and seven patients, respectively. It was observed that valve type and implantation position were not risk factors for re-operation. A St Jude (St Jude Medical Inc, Minnesota, USA) prosthetic valve was implanted in 81.4% of patients, a Carbomedics valve (SuzerCarbomedics Inc, Austin, Texas, USA) was implanted in 7% of patients, and a Medtronic valve (Medtronic Inc, Minnesota, USA) was implanted in 7% of patients. The brand of valve prosthesis was not a risk factor for re-operation (Fig. 1). The mean platelet volume was higher and statistically significant in patients with valvular thrombus during re-operation (p < 0.001). A linear regression analysis was performed of parameters that were statistically significantly related to valvular thrombus, including left atrial thrombus, MPV, valve calcification, and perivalvular leak. It was observed that there was a statistically significant impact of these four parameters on valvular thrombus formation (R = 0.60). However, MPV was an independent risk factor (p < 0.001). A ROC curve showed a higher percentage of sensitivity (85%) and specificity (87%) (Fig. 2).

Discussion Although surgical modalities and myocardial protection techniques have been improved recently, the mortality rate of heart valve re-operation varies between 10 and 20%.7 This leads to increased cost of care and work load of surgical centres. Delay in re-operation also results in increased morbidity and mortality, particularly in developing countries. Such undesired outcomes may be prevented by defining the factors that lead to re-operation and designing a preventive healthcare policy. Overall complications observed with prosthetic heart valves are divided into six main categories: structural valvular deterioration, non-structural dysfunction, valve thrombosis, embolism, bleeding and endocarditis. While leaflet calcification and leaflet tearing are more commonly encountered with TABLE 2. DISTRIBUTION OF INDICATIONS FOR RE-OPERATION AMONG PATIENTS Indications* Number of patients Perivalvular leakage 23 Thrombus formation 21 Pannus formation 19 Valvular calcification 17 Infective endocarditis 13 Additional cardiac intervention 10 Left atrial thrombus 6 Accompanying cardiac disease 3 Left atrial aneurism 2 *There were patients with more than one indication for re-operation.

Thrombus (+) Thrombus (–) Leakage (+) Leakage (–) Pannus (+) Pannus (–)

16 14 12 10 8 6

1.0 0.8 0.6 0.4

4 2 0

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Sensitivity

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0.2 Mitral

Aorta Valves

Tricuspid

0.0 0.0

0.2

0.4

0.6

0.8

1.0

Fig. 1. Distribution of pathologies on the prosthetic valves.

Fig. 2. ROC curve.

bioprosthetic heart valve implantation, haemolysis, platelet activation and thromboembolic events resulting from clot formation are commonly encountered in mechanical heart valves.8 Biomedical engineering studies revealed that these complications might be related to non-physiological blood flow patterns in the vicinity of the heart valves. In fact, the potential of abnormal flow patterns to promote blood cell damage has long been recognised. Abnormal flow patterns cause thrombus formation by imposing forces on cell elements in high shearstress regions (so leading to haemolysis and platelet activation), and changing the frequency of contact (particularly activating platelets for thrombus formation). In addition, these abnormal flow patterns might induce leaflet calcification, and tearing in tissue and polymeric valves by high shear-force regions near the leaflet surfaces.8,9 For clinical interpretation, it has been reported in the literature that mechanical valve dehiscence and pannus formation were encountered with both bioprosthetic and mechanical valves. Acute prosthetic valve thrombosis was commonly seen with mechanical valves only.10 In line with the literature, our results demonstrated that thrombus and pannus formation were the leading indications for re-operation, whereas left atrial thrombus and valvular calcification were diagnosed in nearly one-quarter of the sample group. We believe that a high risk of thrombus formation in patients with left atrial thrombus and valvular calcification in the initial surgery might indicate a tendency to thrombosis and ongoing inflammatory processes. Correlated with this process, MPV may indicate increased risk of thrombosis and the inflammatory process. No or inadequate oral anticoagulation (INR < 2.5) or extreme fluctuations of INR values were also reported as strong risk factors in the aetiology of mechanical prosthetic valve thrombosis.11 In our study, no direct correlation was determined between valvular thrombus formation and anticoagulant use. Similarly, we did not observe any statistically significant relationship between warfarin use/INR levels and thrombosis (p > 0.05). The distance of the patient from a cardiac surgery centre was another major factor in the management of the condition. The postoperative life expectancy of patients undergoing prosthetic valve replacement was closely related to reversibility of myocardial or other organ damage. Therefore, the timing of the operation was critical.6 Bioprosthetic valves may be more useful for patients who live in rural areas.

Although there was a statistically significant relationship between the presence of calcification in the native valve and valvular thrombus during the primary surgery (p > 0.05), it was not significantly related to perivalvular leak (p > 0.5). However, the incidence of perivalvular leak was expected to be increased in patients with annular calcification. This may have been caused by the small sample size of the study. The aortic annulus is not only a circular structure that supports the leaflets of the heart valve, it also allows opening of the leaflets during the ventricular systole. The anatomical structure and shape of the aorta as well as the ventricular outflow tract are of utmost importance for maintaining blood flow. Considering these anatomical and physiological characteristics, non-conformity of the prosthetic valve and annulus may lead to perivalvular leak. In a study by Beghi et al., it was shown that perivalvular leak led to aortic valve replacement.12 The factors leading to perivalvular leak include prosthetic valve endocarditis, Marfan syndrome, bicuspid aorta and a highly calcific aortic annulus. The major site for perivalvular leak is the mid-zone of the non-coronary sinus and the right coronary sinus.13 In the present study, we suggest that the anatomical structure of the zone resulted in perivalvular leak. In addition, Thubrikar et al. demonstrated that non-conformity of the prosthetic valve and aortic annulus led to perivalvular leak in these zones.14 In another study investigating reasons for prosthetic mitral valve regurgitation, it was shown that 46% of the patients underwent re-operation due to structural degeneration of the valve.15 Structural degeneration was defined as valve stenosis or regurgitation secondary to calcification or ruptured leaflets, whereas non-structural degeneration was defined as valve stenosis or regurgitation secondary to trauma, pannus formation or surgery. In these patients, perivalvular leak was the leading cause of re-operation in 20%, non-structural degeneration in 10%, progression of primary valve disease in 8%, and infective endocarditis in 6%. Mitral valve re-operation did not increase the length of hospital stay, compared to the primary surgery. In addition, re-operation was shown not to be a risk factor for peri-operative mortality. Despite a higher incidence of perivalvular leak with mechanical valves, structural degeneration was more often seen with bioprosthetic valves. There was no difference in postoperative complications and mortality rate between the groups. The incidence of infective endocarditis was similar between the groups. A total of 30.2% of the patients had infective endocarditis

1 – Specificity

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in our study. We also defined a statistically significant relationship between infective endocarditis and perivalvular leak (p = 0.043). As anticipated, infection resulted in structural degeneration and eventually perivalvular leak. Infective endocarditis also increased the risk for valvular thrombus. This may have been due to the low sociocultural status of the patients, and impaired communication between the patient and treating physician to provide effective and suitable medical treatment. There are studies in the literature investigating the role of MPV in various conditions, such as coronary artery ectasia, outcome after myocardial infarction, unstable angina, coronary artery disease in haemodialysis patients, atherosclerosis and coronary heart diseases.16-21 MPV was reported to be an indicator of platelet activation, which resulted in development of thrombosis. It was found that large platelets contained denser, more active granules metabolically and enzymatically, with higher thrombotic potential. Therefore, they secreted more pro-thrombotic substances, pro-coagulatory surface proteins, thromboxane A2, serotonin and β-thromboglobulin. Taşoğlu et al.22 conducted a study on the predictive marker value of MPV in patients with mechanical valve thrombosis. They reported that MPV may be used effectively during follow up of these patients. Similarly, we determined that MPV values were higher in patients with valvular thrombus, compared to the controls. This indicated a statistically significant trend. Based on the ROC curve, MPV had more than 80% sensitivity and specificity. However, the small sample size, non-standardised MPV values before re-operation, absence of detailed genetic examination, and thrombogenic factors were critical limitations of our study. Many studies have been conducted using cheap but effective markers to identify the relationship between thrombosis and inflammation. As MPV is believed by some researchers to be a good candidate, it is being investigated in various cardiac diseases. MPV is therefore considered an acute-phase reactant and in recent years has been shown to be raised in inflammatory processes.23 Bansal et al.24 reported that the incidence of pulmonary embolism and PHT were higher in patients with chronic obstructive pulmonary disease and a higher level of MPV.

Conclusion Morbidity and mortality rates in heart valve re-operations can be decreased by the effective use of warfarin, the adoption of minimally invasive surgery, and the use of improved materials and advanced technology in artificial heart valve production. Moreover, MPV is an independent risk factor for valvular thrombus formation. Therefore, MPV values should be assessed and INR levels should be monitored more often when designing individualised postoperative medical treatment for patients undergoing heart valve re-operation.

10.

11.

12.

13.

14.

15.

16.

17. 18.

19.

20.

21.

22.

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Iung B, Vahanian A. Mitral stenosis. Ann Cardiol Angeiol 2003; 52(2): 117–124. Weerasinghe A, Edwards MB, Taylor KM. First redo heart valve replacement: a 10-year analysis. Circulation 1999; 99(5): 655–658. Fremes SE, Goldman BS, Ivanov J, Weisel RD, David TE, Salerno T. Valvular surgery in the elderly. Circulation 1989; 80(3 Pt 1): 177–190.

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Cohn LH, Aranki SF, Rizzo RJ, Adams DH, Coqswell KA, Kinchla NM, et al. Decrease in operative risk of reoperative valve surgery. Ann Thorac Surg 1993; 56(1): 15–20. Jones JM, O’kane H, Gladstone DJ, Sarsam MA, Campalani G, MacGowan SW, et al. Repeat heart valve surgery: risk factors for operative mortality. J Thorac Cardiovasc Surg 2001; 122(5): 913–918. Rizzoli G, Guglielmi C, Toscano G, Pistorio V, Vendramin I, Bottio T, et al. Reoperations for acute prosthetic thrombosis and pannus: an assessment of rates, relationship and risk. Eur J Cardiothorac Surg 1999; 16(1): 74–80. Toker ME, Eren E, Guler M, Kirali K, Yanartas M, Balkanay M, et al. Second and third cardiac valve reoperations: factors influencing death and long-term survival. Tex Heart Inst J 2009; 36(6): 557–562. Dasi LP, Simon HA, Sucosky P, Yoganathan AP. Fluid mechanics of artificial heart valves. Clin Exp Pharmacol Physiol 2009; 36(2): 225–237. Nobili M, Sheriff J, Morbiducci U, Redaelli A, Bluestein D. Platelet activation due to hemodynamic shear stresses: damage accumulation model and comparison to in vitro measurements. ASAIO J 2008; 54(1): 64–72. Sivasubramanian S, Vijayshankar CS, Krishnamurthy SM, Santhosham R, Dwaraknath V, Rajaram S. Surgical management of prosthetic valve obstruction with the Sorin tilting disk prosthesis. J Heart Valve Dis 1996; 5(5): 548–552. Bollag L, Attenhofer Jost CH, Vogt PR, Linka AZ, Rickli H, Oechslin E, et al. Symptomatic mechanical heart valve thrombosis: high morbidity and mortality despite successful treatment options. Swiss Med Wkly 2001; 131(9-10): 109–116. Beghi C, De Cicco G, Nicolini F, Ballore L, Reverberi C, Gherli T. Cardiac valve reoperations: analysis of operative risk factors in 154 patients. J Heart Valve Dis 2002; 11(2): 258–262. De Cicco F, Lorusso R, Colli A, Nicolini F, Fragnito C, Grimaldi T, Borrello B, et al. Aortic valve periprosthetic leakage: anatomic observations and surgical results. Ann Thorac Surg 2005; 79(5): 1480–1485. Thubrikar M, Nolan SP, Bosher LP, Deck JD. The cyclic changes and structure of the base of the aortic valve. Am Heart J 1980; 99(2): 217–224. Potter DD, Sundt TM 3rd, Zehr KJ, Dearani JA, Daly RC, Mullany CJ, et al. Risk of repeat mitral valve replacement for failed mitral valve prostheses. Ann Thorac Surg 2004; 78(1): 67–72. Sen N, Tavil Y, Yazici HU, Hizal F, Açikgöz SK, Abaci A, et al. Mean platelet volume in patients with coronary artery ectasia. Med Sci Monit 2007; 13: CR356–9. Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409–1411. Pizzulli L, Yang A, Martin JF, Lüderitz B. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998; 19: 80–84. Henning BF, Zidek W, Linder B, Tepel M. Mean platelet volume and coronary heart disease in hemodialysis patients. Kidney Blood Press Res 2002; 25: 103–108. Kario K, Matsuo T, Nakao K. Cigarette smoking increases the mean platelet volume in elderly patients with risk factors for atherosclerosis. Clin Lab Haematol 1992; 14: 281–287. Trowbridge EA, Martin JF. The platelet volume distribution: a signature of the prethrombotic state in coronary heart disease? Thromb Haemost 1987; 58: 714–717. Taşoğlu I, Yalçınkaya A, Ulaş MM, Lafçı G, Çiçek OF, Ulus AT, et al. Could mean platelet volume be a predictive marker for mechanical valve thrombosis? Turkish J Thorac Cardiovasc Surg 2011; 19(3): 301–304. Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des 2011; 17(1): 47–58. Bansal R, Gupta HL, Goel A, Yadav M. Association of increased platelet volume in patients of chronic obstructive pulmonary disease: Clinical implications J Ind Acad Clin Med 2002; 3(2): 169–172.

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Does vitamin C or its combination with vitamin E improve radial artery endothelium-dependent vasodilatation in patients awaiting coronary artery bypass surgery? ALPER UZUN, UMIT YENER, OMER FARUK CICEK, OZLEM YENER, ADNAN YALCINKAYA, ADEM DIKEN, TURGUT OZKAN, AYSEL TURKVATAN, MAHMUT ULAS

Abstract

Keywords: antioxidants, vitamin C, vitamin E, atherosclerosis

Background: We evaluated the vasodilatory effects of two antioxidants, vitamins C (ascorbic acid) and E (α-tocopherol), on radial artery and endothelium-dependent responses in patients awaiting coronary artery bypass surgery. Methods: The study was performed in three groups. The first group took 2 g of vitamin C orally (n = 31, vitamin C group), the second group took 2 g of vitamin C with 600 mg of vitamin E orally (n = 31, vitamins C + E group), and the third group took no medication (n = 31, control group). After baseline measurements were taken of the radial artery lumen diameter, flow volume and lumen area in the non-dominant radial artery, occlusion was maintained for five minutes with a pressure cuff placed around the arm. The measurements were taken again at the time of deflating the cuff, and 60 seconds later. The measurements were repeated after medication in two of the groups and after placebo in the third group. Results: We compared values of the vitamin C group with those of the vitamins C + E group, and found that the latter were higher than those of the vitamin C group but not statistically significant. In the control group, there was no statistical difference. Conclusion: Vitamin C or its combination with vitamin E significantly enhanced endothelium-dependent vasodilatation in the radial circulation of patients with coronary artery disease. Its combination with vitamin E was superior to vitamin C administration alone for endothelial enhancement but this difference was not statistically significant. We hypothesised that vitamin C or its combination with vitamin E may be used as antioxidants for arterial graft patency in patients undergoing coronary artery surgery.

Submitted 14/4/13, accepted 7/6/13 Cardiovasc J Afr 2013; 24: 255–259

www.cvja.co.za

DOI: 10.5830/CVJA-2013-046

ALPER UZUN, MD

In patients with atherosclerosis, there is biochemical evidence to suggest increased oxidative stress, which results from an altered balance of endogenous pro- and antioxidants. Vitamin C, the main water-soluble antioxidant in human plasma, has been shown to reverse endothelial dysfunction in patients with ischaemic heart disease in the same way as vitamin E.1 It effectively scavenges superoxide and other reactive oxygen species, and plays an important role in regulation of the intracellular redox state through its interaction with glutathione.2 The Health Professionals Follow-up study demonstrated an inverse relationship between vitamin E intake and coronary artery disease (CAD) events.3 In this study, risk for CAD events in subjects in the highest quintile of vitamin E intake (median 419.0 IU/day) was significantly reduced by 41%, compared with the subjects in the lowest quintile of vitamin E intake (median 6.4 IU/day).3,4 Other studies suggest that a high dietary intake of flavonoids (polyphenolic antioxidants) naturally present in vegetables, fruits, tea and vitamin E is associated with a decline in CAD events.5 Nonetheless, in a subgroup analysis of patients who had undergone previous coronary artery bypass surgery, coronary artery lesion progression was less in subjects with a supplementary vitamin E intake of 100 IU per day or more, compared with patients with a lower intake.6 Therefore, we hypothesised that vitamin C and E would improve abnormal endothelium-dependent vasomotor function in patients with atherosclerosis. We tested this hypothesis by examining endothelium-dependent, flow-mediated radial artery dilatation before and two hours after oral administration of vitamin C or vitamin C plus vitamin E in two groups of patients awaiting coronary artery bypass surgery, compared with the control group.

Department of Cardiovascular Surgery, Turkey Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey

Methods

Department of Cardiovascular Surgery, Ankara Education and Research Hospital, Ankara, Turkey

UMIT YENER, MD OMER FARUK CICEK, MD, farux@hotmail.com ADNAN YALCINKAYA, MD ADEM DIKEN, MD TURGUT OZKAN, MD MAHMUT ULAS, MD

Department of Radiology, Turkey Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey OZLEM YENER, MD AYSEL TURKVATAN, MD

A total of 93 patients were randomly divided into three groups: group 1, vitamin C group, n = 31; group 2, vitamins C + E group, n = 31; group 3, control group, n = 31. Patients referred to our clinic were screened for enrolment, and patients with significant coronary artery disease were eligible for the study. In all patients, the presence of coronary artery disease was confirmed angiographically (at least one coronary stenosis > 70%). All patients gave informed consent. The study was conducted in accordance with the policies and procedures of the Education

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and Planning Committee of our hospital. All vasoactive medications were withheld for at least 12 hours before the study, and all long-acting vasoactive medications were withheld for at least 24 hours. Alcohol and caffeine were prohibited within 12 hours of the study. Patients who had a smoking history refrained from smoking at least 48 hours before the study to prevent any relevant effect of smoking. Patients with unstable angina, severe cardiac failure, additional cardiac (valvular, congenital, etc) or peripheral vascular disease, renal and hepatic dysfunction, uncontrolled hypertension, or any other condition that would preclude withholding vasoactive medications, and patients taking antioxidant vitamin supplements, oestrogen replacement therapy or allopurinol were excluded from the study.

Study protocol and radial artery image with ultrasound studies The vasodilator response in the radial artery was determined from two-dimensional ultrasound images by an evaluator blinded to the study. The images were obtained with the use of a 7.0-MHz linear-array transducer (model SSA-770A Ultrasound System; Toshiba, Tokyo, Japan). Examination was performed with the patient resting supine for at least five minutes in a quiet setting. For each patient, radial artery images were obtained 2 and 5 cm above the radial styloid. This location was marked, and all subsequent images were obtained at the same location. Images were recorded on a super-VHS videocassette recorder and radial artery diameters were measured from the tape with ultrasonic calipers. Measurements of radial artery diameter were taken from the anterior to the posterior interface between the media and adventitia at end-diastole, incident with the R-wave, on a continuously recorded ECG. The measurements were performed by one observer who was blinded to the details. At the moment of measurement, arterial blood pressures were checked for the safety of the study and were found normal (120/80 mmHg) in all patients. In all patients, first, baseline Doppler ultrasound images were obtained (measurement 1: D1, FV1, A1). The radial artery of the non-dominant arm was scanned in transverse section and the lumen diameter (D1) was measured. Then, flow volume (FV1) and lumen area (A1) were measured in longitudinal section and all measurements were recorded. Second, a blood pressure cuff, placed at the proximal portion of the arm, was inflated to occlusive pressure (200 mmHg), and occlusion was maintained for five minutes to induce hyperaemia. The cuff was then rapidly deflated and pulsed Doppler signals and measurements were recorded at the moment of cuff deflation for 15 seconds (measurement 2: D2, FV2, A2). Finally, two-dimensional and pulsed-Doppler measurements were again obtained and recorded 60 seconds after cuff deflation (measurement 3: D3, FV3, A3). In group l, patients were then given 2 g oral vitamin C (Redoxon, Bayer, Germany, 1 000-mg tablets) and a repeat radial ultrasound study was performed two hours after oral administration to evaluate its effect on radial artery vasodilation in the first 31 patients. These measurements were accepted as study measurements for group 1 (measurements 4, 5, 6 for group 1: D4, 5, 6; FV4, 5, 6; A4, 5, 6). In group 2, the next 31 patients were given orally 2 g vitamin

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C and 600 IU vitamin E (Ephynal, Roche, France, 300 IU, oral capsules), and a repeat radial ultrasound study was performed two hours after oral administration to evaluate their effects on radial artery vasodilation. These measurements were accepted as study measurements for group 2 (measurement 4, 5, 6 for group 2: D4, 5, 6; FV4, 5, 6; A4, 5, 6). In group 3, patients took no medication and the measurements were repeated. Finally, the increasing values of D, FV and A of the two study groups were compared and the mean difference of their increasing values was measured (Table 1). In the control group, the results of the measurements were almost the same and there was no statistically significant difference between measurements (p > 0.05).

Statistical analysis Results were analysed using SPSS software (SPSS 18.0.1 for Windows; SPSS, Chicago, IL, USA). Comparisons of groups were performed with the Student’s t-test and non-parametric Mann-Whitney U-test for continuous variables and the Fisher exact test for discrete variables, as appropriate. Pre–post comparisons with paired observations were analysed using the Wilcoxon signed-ranks test. Linear regression models were built with least-squares methods using all variables and also with a backward elimination approach, starting with all variables that were significant (p < 0.05) in univariate relationships and eliminating variables with p-values greater than 0.05, in a stepwise fashion.

Results Ninety-three patients were included in the study from 1 February to 31 August 2008. Patient characteristics are summarised in Table 2. Median age, male/female gender, and left ventricular ejection fraction were similar in the three groups (p > 0.05). The presence of diabetes was similar in the study groups, but scarce in the control group. A history of smoking in the vitamin C group TABLE 1. INCREASING VALUES OF FLOW VOLUME, AREA AND DIAMETER Vitamin C Vitamin C+E (mean value) (mean value) p-value FV4–FV1 1.322 1.677 0.542 A4–A1 8.096 7.929 0.952 D4–D1 2.225 2.548 0.651 FV5–FV2 2.322 2.354 0.968 A5–A2 9.064 13.364 0.211 D5–D2 2.225 2.741 0.454 FV6–FV3 1.322 1.871 0.378 A6–A3 6.612 10.806 0.378 D6–D3 2.225 2.387 0.790 FV1, FV4, baseline flow volume before and after drug intake, respectively; FV2, FV5, flow volume at the moment of cuff deflation before and after drug intake, respectively; FV3, FV6, flow volume 60 seconds after cuff deflation before and after drug intake, respectively. A1, A4, baseline area before and after drug intake, respectively; A2, A5, area at the moment of cuff deflation before and after drug intake, respectively; A3, A6, area 60 seconds after cuff deflation before and after drug intake, respectively. D1, D4, baseline diameter before and after drug intake, respectively; D2, D5, diameter at the moment of cuff deflation before and after drug intake, respectively; D3, D6, diameter 60 seconds after cuff deflation before and after drug intake, respectively.

TABLE 2. SUMMARY OF THE KEY CHARACTERISTICS OF THE SUBJECTS

Age, median Ejection fraction Male/female History of smoking Diabetes mellitus Mild hypertension

Vitamin C group 56.32 ± 12.50 49.64 ± 12.57 24/7 16 7 15

Vitamin C + E group 55.74 ± 13.36 51.90 ± 9.83 25/6 11 7 10

Control group 56.20 ± 12.40 50.30 ± 10.47 26/5 10 4 10

(group 1) was higher than in the vitamins C + E group (group 2) and the control group. Also, a history of mild hypertension in the vitamin C group was higher than in the vitamins C + E and control groups but it was not statistically significant. Pre- and post-administration measurements of vitamin C in group 1 showed a statistically significant increase in the radial artery flow volume, lumen diameter and lumen area after two hours of vitamin C administration (Figs 1–3) (p < 0.001). Preand post-administration measurements of vitamins C + E in group 2 showed a statistically significant increase in the radial artery flow volume, lumen diameter and lumen area after two hours of vitamin C with vitamin E administration (Figs 4–6) (p < 0.001). Patients in both the vitamin C group (measurement 4, 5, 6 for group 1) and in the vitamins C + E group (measurement 4, 5, 6 for group 2) showed statistically significant increases in the radial artery flow volume, lumen diameter and lumen area when compared with the time of measurements 1, 2 and 3. Its combination with vitamin E was superior to vitamin C administration alone for endothelium-dependent vasodilatation but this difference was not statistically significant. This is shown in Table 2. Against the two groups, there was no statistical difference in the control group. The repeat measurements were not statistically 0.2

FV1

Flow volume (l/min)

0.18

FV4

0.16

FV2

0.14

FV5 FV3

0.12

FV6

0.1 0.08 0.06 0.04 0.02 0

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 1. Flow volume measurements on the radial artery before and after oral vitamin C administration. FV1, FV4, baseline flow volume before and after vitamin C, respectively; FV2, FV5, flow volume at the moment of cuff deflation before and after vitamin C, respectively; FV3, FV6, flow volume 60 seconds after cuff deflation before and after vitamin C, respectively.

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A1 A4 A2 A5 A3 A6

10 8 6 4 2 0

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 2. Radial artery area measurements before and after oral vitamin C administration. A1, A4, baseline area before and after vitamin C, respectively; A2, A5, area at the moment of cuff deflation before and after vitamin C, respectively; A3, A6, area 60 seconds after cuff deflation before and after vitamin C, respectively.

different from the first measurements and they were also not different from the baseline measurements of the two groups.

Discussion Antioxidants vitamins C and E improved defective endothelial function. This has been attributed to an enhancement in the synthesis or prevention of the breakdown of nitric oxide (NO).7 NO plays a major role in maintaining normal tonus in the artery. This study demonstrated that administration of vitamin C or its combination with vitamin E increased endothelium-dependent dilatation in patients awaiting coronary artery bypass surgery. The radial artery is increasingly being used as a conduit for coronary bypass grafting because of reports of long-term patency, accessibility and encouraging mid-term results.8-10 The choice of a potent vasodilator with minimal side effects appears to be an important parameter in ensuring the success of radial artery conduits. Also, imaging by Doppler ultrasound of radial artery dilatation after drug treatment is easy. Therefore we particularly used the radial artery for measurements. A history of smoking is an important parameter that can affect the results. Its vasoconstrictor effect on the endothelium has been shown in many studies. In our study, the vitamin C group 4 Radial artery diameter (mm)

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3.5 3 2.5 2 1.5

D1 D4 D2 D5 D3 D6

1 0.5 0

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 3. Radial artery diameter before and after oral vitamin C administration. D1, D4, baseline diameter before and after vitamin C, respectively; D2, D5, diameter at the moment of cuff deflation before and after vitamin C, respectively; D3, D6, diameter 60 seconds after cuff deflation before and after vitamin C, respectively.

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FV1 FV4

0.25

FV2 FV5

FV3 FV6

0.2 0.15 0.1 0.05 1

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 4. Flow volume measurements on the radial artery before and after oral vitamins C + E administration. FV1, FV4, baseline flow volume before and after vitamin C + E, respectively; FV2, FV5, flow volume at the moment of cuff deflation before and after vitamins C + E, respectively; FV3, FV6, flow volume 60 seconds after cuff deflation before and after vitamin C, respectively.

Radial artery area (mm2)

had more subjects with a history of smoking than the vitamins C + E and control groups, but this was not important because all smokers refrained from smoking for at least 48 hours before the study to prevent any significant effects of smoking. Several large epidemiological studies have suggested that dietary intake of vitamin C is inversely associated with the risk of ischaemic heart disease.11 In other studies, however, vasodilation was observed to increase over a period of only two hours.11,12 We repeated the measurements after two hours of administration because Levin et al. showed that plasma ascorbic acid levels reached a plateau after two hours and remained elevated five hours after ingestion.13 On the other hand, Westhuyzen et al. showed that α-tocopherol concentrations after oral intake had reached the same levels by the second hour and stayed at that level for almost five hours.14 We therefore did not measure the blood levels of vitamins C and E. Drossos et al. showed that vitamin C, like vitamin E, has a potent vasodilating effect on the radial artery.15 They examined the dilation of the lumen surface and colour Doppler images of the non-dominant radial artery just before and two hours after oral vitamin C administration. The results provided evidence that vitamin C was a potent vasodilator in healthy subjects, particularly in smokers. In addition, it was a superior acute vasodilating agent in vivo compared with diltiazem in ischaemic patients awaiting cardiac surgery.15 In our study, we used the same method to measure radial artery vasodilation. We took measurements at the time of cuff 20

A1 A4

A2 A5

A3 A6

10 5 0

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 5. Radial artery area measurements before and after oral vitamins C + E administration. A1, A4, baseline area before and after vitamins C + E, respectively; A2, A5, area at the moment of cuff deflation before and after vitamins C + E, respectively; A3, A6, area 60 seconds after cuff deflation before and after vitamins C + E, respectively.

deflation and 60 seconds later to observe the effect of vitamin C on the endothelium. Excessive vascular oxidative stress has been linked to impaired endothelium-dependent arterial relaxation in coronary artery disease. Keaney et al. showed in their study the beneficial effects of vitamin E on endothelial function.16 Vitamins C and E may favourably influence cardiovascular risk, but there are several important differences between these naturally occurring antioxidants. Vitamin C is water soluble, and is present in most body fluids. However, vitamin E is a lipidsoluble antioxidant. The primary antioxidant mechanisms of these antioxidants are also distinct. The important antioxidant properties of vitamin C are its abilities to scavenge superoxide anions and to preserve reduced intracellular glutathione concentrations. Also, vitamin C is required for the regeneration of vitamin E.17 Vitamin C may thus prevent low-density lipoprotein (LDL) oxidation, either through the recycling of vitamin E or by scavenging free radicals directly.18 We therefore observed the beneficial effects of vitamins C and E on endothelial function in our study. In a recent double-blind trial, Brown et al. studied simvastatin– niacin and antioxidant vitamin therapy, alone and together, for cardiovascular protection in patients with coronary disease and low plasma levels of high-density lipoprotein (HDL) cholesterol.19 The baseline levels of LDL cholesterol and triglycerides decreased when antioxidant vitamins were added to the simvastatin–niacin regimen. The HDL level increased by 18% in those treated with simvastatin–niacin and antioxidant vitamins. With simvastatin– niacin and antioxidant vitamin therapy, the levels of HDL2 and apolipoprotein A-I [Lp(A-I)] increased by 81%. The resistance of LDL to oxidation increased by 35%. In an another study, Behrendt et al. showed that vitamin C and E combinations reduced cardiac transplant-associated arteriosclerosis in patients with normal or abnormal endothelial function. The magnitude of benefit was larger in patients with endothelial dysfunction.20

Conclusion This study demonstrated that oral administration of the antioxidants vitamins C and E in physiological doses may enhance endothelium-dependent vasodilatation in the radial Radial artery diameter (mm)

Flow volume (l/min)

0.3

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D1 D4

D2 D5

D3 D6

4 3 2 1 0

9 11 13 15 17 19 21 23 25 27 29 31

Patients

Fig. 6. Radial artery diameter before and after oral vitamins C + E administration. D1, D4, baseline diameter before and after vitamins C + E, respectively; D2, D5, diameter at the moment of cuff deflation before and after vitamins C + E, respectively; D3, D6, diameter 60 seconds after cuff deflation before and after vitamins C + E, respectively.

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artery of patients with coronary artery disease. However, the combination was not more effective than vitamin C alone. This finding suggests that in this setting, increased oxidative stress may be an important mechanism for impaired endothelial function. Combination of vitamins C and E may show beneficial effects on graft patency due to improved vasomotor function of the endothelium (as on radial artery or internal mammarian artery conduits) in patients undergoing coronary artery surgery.

References 1.

3. 4.

8. 9.

Hamabe A, Takase B, Uehata A, et al. Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C. Am J Cardiol 2001; 87: 1154–1159. Winkler BS, Orselli SM, Rex TS. The redox couple between glutathione and ascorbic acid: a chemical and physiologic perspective. Free Radic Biol Med 1994; 17: 333–339. Hoffman RM, Garewal HS. Antioxidants and the prevention of coronary heart disease. Arch Intern Med 1995; 155: 241–246. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993; 328: 1450–1456. Jha P, Flather M, Lonn E, et al. The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic and clinical trial data. Ann Intern Med 1995; 123: 860–872. Hodis HN, Mack WG, LaBree L, et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. J Am Med Assoc 1995; 273: 1849–1854. Gokce N, Keaney JF Jr, Frei B, et al. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1999; 99: 3234–3240. Parolari A, Rubini P, Alamanni F, et al. The radial artery: Which place in coronary operation? Ann Thorac Surg 2000; 69: 1288–1294. Tatoulis J, Buxton BF, Fuller JA. Bilateral radial artery grafts in coronary reconstruction:technique and early results in 261 patients. Ann

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Thorac Surg 1998; 66: 714–719. 10. Weinschelbaum EE, Macchia A, Caramutti VM, et al. Myocardial revascularization with radial and mammary arteries: initial and midterm results. Ann Thorac Surg 2000; 70: 1378–1383. 11. Riemersma RA, Wood DA, Macintyre CCH, et al. Low plasma vitamin E and C and increased risk of angina in Scottish men. Ann NY Acad Sci 1989; 570: 291–295. 12. Simon BC, Haudenschild CC, Cohen RA. Preservation of endotheliumdependent relaxation in atherosclerotic rabbit aorta by probucol. J Cardiovasc Pharmacol 1993; 21: 893–901. 13. Levine GN, Frei B, Koulouris SN, et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996; 93: 1107–1113. 14. Westhuyzen J, Cochrane AD, Tesar PJ, et al. Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1997; 113: 942–948. 15. Drossos ED, Toumpoulis IK, Katritsis DG, et al. Is vitamin C superior to diltiazem for radial artery vasodilation in patients awaiting coronary artery bypass grafting? J Thorac Cardiovasc Surg 2003; 125: 330–335. 16. Keaney JF, Guo Y, Cunningham D, et al. Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation. J Clin Invest 1996; 98: 386–394. 17. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999; 69: 1086–1107. 18. Mullan BA, Young IS, Fee H, et al. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension 2002; 40: 804–809. 19. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345: 1583–1592. 20. Behrendt D, Beltrame J, Hikiti H, et al. Impact of coronary endothelial function on the progression of cardiac transplant-associated arteriosclerosis: effect of anti-oxidant vitamins C and E. J Heart Lung Transplant 2006; 25: 426–433.

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Effectiveness of prophylactic levosimendan in high-risk valve surgery patients OZGUR ERSOY, EMRE BOYSAN, ERTEKIN UTKU UNAL, KEREM YAY, UMIT YENER, FERIT CICEKCIOGLU, FEHMI KATIRCIOGLU

Abstract

Submitted 22/4/13, accepted 7/6/13

Background: Levosimendan has anti-ischaemic effects, improves myocardial contractility and increases systemic, pulmonary and coronary vasodilatation. These properties suggest potential advantages in high-risk cardiac valve surgery patients where cardioprotection would be valuable. The present study investigated the peri-operative haemodynamic effects of prophylactic levosimendan infusion in cardiac valve surgery patients with low ejection fraction and/ or severe pulmonary arterial hypertension. Methods: Between May 2006 and July 2007, 20 consecutive patients with severe pulmonary arterial hypertension (systolic pulmonary artery pressure ≥ 60 mmHg) and/or low ejection fraction (< 50%) who underwent valve surgery in our clinic were included in the study and randomised into two groups. Levosimendan was administered to 10 patients in group I and not to the 10 patients in the control group. Cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) were recorded for each patient preoperatively and for 24 hours following the operation. Results: CO and CI values were higher in the levosimendan group during the study period (p < 0.05). MPAP and PVR values were significantly lower in the levosimendan group for the 24-hour period (p < 0.05) and SVR values were significantly lower after 24 hours in both groups. When clinical results were considered, no difference in favour of levosimendan was detected regarding the mortality and morbidity rates between the groups. Conclusion: Levosimendan improved the haemodynamics in cardiac valve surgery patients with low ejection fraction and/ or severe pulmonary arterial hypertension, and facilitated weaning from cardiopulmonary bypass in such high-risk patients when started as a prophylactic agent.

Cardiovasc J Afr 2013; 24: 260–264

Keywords: cardiac valve, cardiac surgery, pulmonary hypertension, levosimendan, left ventricular dysfunction

Department of Cardiovascular Surgery, Turkey Yuksek Ihtisas Hospital, Ankara, Turkey OZGUR ERSOY, MD EMRE BOYSAN, MD ERTEKIN UTKU UNAL, MD, utkuunal@gmail.com KEREM YAY, MD UMIT YENER, MD FERIT CICEKCIOGLU, MD

Department of Cardiovascular Surgery, Ankara Hospital, Ankara, Turkey FEHMI KATIRCIOGLU, MD

www.cvja.co.za

DOI: 10.5830/CVJA-2013-047

Pulmonary arterial hypertension and low ejection fraction were among the key factors determining prognosis during the postoperative period in patients with cardiac valve disease who underwent cardiac surgery.1,2 Left ventricular dysfunction, which makes weaning from cardiopulmonary bypass (CPB) difficult and increases morbidity and mortality rates, may develop in the patient group that has either or both pulmonary arterial hypertension and low ejection fraction. Levosimendan is a recently introduced calcium sensitiser. It enhances myocardial contractility by sensitisation of troponin C to calcium, and provides systemic, pulmonary and coronary arterial and venous vasodilatation due to activation of the ATP-sensitive potassium channels in smooth muscle fibres.3 It has positive inotropic and anti-stunning effects.4,5 It has been reported that levosimendan facilitated weaning from CPB in high-risk patient groups by reducing pulmonary arterial pressure and increasing both right and left ventricular contractility, which means improved ejection fraction and cardiac output.6,7 In the present study, we documented haemodynamic changes caused by levosimendan infusion, instituted just after the induction of anaesthesia, as a measure in cardiac valve surgery patients with low ejection fraction and/or pulmonary arterial hypertension.

Methods Between May 2006 and July 2007, 20 consecutive patients with severe pulmonary arterial hypertension (systolic pulmonary artery pressure ≥ 60 mmHg) and low ejection fraction (< 50%) who underwent valve surgery in our clinic, were included in the study and randomised to two groups (levosimendan and control groups). The conventional definition of pulmonary arterial hypertension includes mean pulmonary arterial pressure of > 25 mmHg at rest as assessed by right heart catheterisation. Our study group of patients was selected as having severe pulmonary hypertension, which was defined in our clinical practice as systolic pulmonary artery pressure ≥ 60 mmHg. This study complied with the Declaration of Helsinki and ethical approval was granted by the local institutional review board. Informed consent was obtained from all patients. The anaesthetic and surgical management of all patients was the same in both groups. Induction and maintenance of general anaesthesia with endotracheal intubation was standardised in all the patients (sufentanil, midazolam, pancuronium or atracurium, and sevoflurane in oxygen with air). Invasive haemodynamic monitoring, including thermodilution catheterisation, was established, allowing for haemodynamic measurements at different time points.

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Myocardial protection was obtained by cold blood cardioplegic solution. Patients were cooled to 32°C applying alpha-stat acid– base management. Perfusion pressure was maintained in the range of 40 to 70 mmHg. Cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) were recorded for each patient. Levosimendan (Simdax; Orion Corporation, Finland) was administered to 10 patients following anaesthetic induction, with a loading dose of 12 μg/kg administered in 10 minutes, followed by a 24-hour infusion at a rate of 0.1 μl/kg/min (group I). Ten patients to whom levosimendan was not administered were regarded as the control group (group II). Measurements were performed using a 7F Multiflex thermodilution catheter (Abbot Laboratories, Hospital Products Division, USA). Cold normal saline was administered through the proximal end of the thermodilution catheter and sampling was performed from the distal end of the catheter. Five measurements were carried out for each parameter, minimum and maximum values were excluded, and averages of the remaining values were obtained. On the other hand, PVR and SVR values were calculated and recorded by the computer system. Following insertion of the thermodilution catheter after general anaesthesia, initial values were recorded for all the patients and these were regarded as baseline values (CO1, CI1, SVR1, PVR1, and MPAP1). The rest of the measurements in the levosimendan group were acquired following the administration of the loading dose (CO2, CI2, SVR2, PVR2, MPAP2), at the sixth hour of the levosimendan infusion (CO3, CI3, SVR3, PVR3, MPAP3), at the 12th hour of levosimendan infusion (CO4, CI4, SVR4, PVR4, MPAP4), and at 24th hour of the levosimendan infusion (CO5, CI5, SVR5, PVR5, MPAP5). Measurements for the control group were performed at equivalent periods.

Statistical analysis Normally distributed continuous variables were expressed as mean values ± standard deviation (SD). Categorical variables were expressed as numbers and percentages. Demographic characteristics, peri-operative variables and calculated values were compared using independent samples t-test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Within-group differences were evaluated with the paired-samples t-test. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed

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TABLE 2. SURGICAL PROCEDURES PERFORMED Group I Group II Surgery type (levosimendan) (control) MVR (redo) 2 2 MVR 2 4 AVR + MVR 3 2 Mitral repair 1 0 Mitral repair + CABG 2 0 AVR + MVR (redo AVR) 0 1 AVR + MVR (redo MVR) 0 1 MVR: mitral valve replacement, AVR: aortic valve replacement, CABG: coronary artery bypass graft.

using the SPSS statistical software (SPSS for Windows 12.0, Inc., Chicago, IL, USA).

Results Demographic data of patients in the levosimendan and control groups are shown in Table 1. There was no difference between the two groups apart from body surface area values. In addition, there was no difference between EuroSCORE values of groups I and II (p = 0.418). In group I, there were three patients with mitral regurgitation, four with mitral stenosis and three with combined aortic stenosis and mitral stenosis. On the other hand, in group II, there were six patients with mitral stenosis, two with combined aortic stenosis and mitral stenosis and two with prosthetic valve dysfunction. Surgical procedures performed on both groups are summarised in Table 2. Duration of cross-clamp, CPB and surgery, dosage of inotropic drugs, and the length of intensive care unit and hospital stay of both groups are documented in Table 3. There was no significant difference between cross-clamp, CPB and operation times. No difference was detected for length of intensive care unit stay, whereas it was found that the length of hospital stay for the study group was significantly longer (group I: 7.8 ± 2.4 days vs group II: 5.8 ± 1.5 days; p = 0.014). No marked adverse reaction to the drug was observed in group I. A statistically significant difference in favour of the levosimendan group was recorded regarding the statistical values of cardiac outputs and cardiac indexes between the two groups. For baseline values, CO1 values of group I were significantly TABLE 3. INTRA- AND POSTOPERATIVE DATA

TABLE 1. COMPARISON OF DEMOGRAPHIC DATA BETWEEN GROUPS Group I Group II (levosimendan) (control) Characteristics (n = 10) (n = 10) p-value Age (years) 49.6 ± 10.7 45.7 ± 7.9 0.125 Male/female 5/5 3/7 0.361 1.60 ± 0.22 1.67 ± 0.17 0.006 BSA (m2) Functional capacity (NYHA) 3.2 ± 0.6 3.4 ± 0.5 1.000 Pre-operative EF (%) 46.8 ± 10.9 49.0 ± 12.0 0.182 COPD (+/–) 3/7 2/7 0.695 Pre-operative sPAP (mmHg) 71.2 ± 23.6 72.8 ± 15.8 0.151 BSA: body surface area, COPD: chronic obstructive pulmonary disease, EF: ejection fraction, NYHA: New York Heart Association, sPAP: systolic pulmonary arterial pressure.

Features Group I Group II p-value XCL period (min) 88.7 ± 56.4 69.2 ± 26.8 0.779 CPB period (min) 115.4 ± 62.8 89.4 ± 33.2 0.884 Operation time (min) 219.5 ± 83.2 155.0 ± 49.4 0.424 Need for inotropic drug 5 2 0.160 Need for IABP 0 0 – Mortality 0 0 – Postoperative exploration 0 0 – Low cardiac output 0 0 – Acute renal failure 0 0 – Length of stay in ICU (days) 2.7 ± 2.1 1.4 ± 1.3 0.893 Length of stay at hospital (days) 7.8 ± 2.4 5.8 ± 1.5 0.012 XCL: cross-clamp, CPB: cardiopulmonary bypass; IABP: intra-aortic balloon counterpulsation, ICU: intensive care unit.

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Levosimendan

CO (l/min)

6 4 2 0 CO1

CO2

CI (l/min/m2)

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CO5

Control

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CI2

CI3 CI4 Study period Levosimendan

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Study period Levosimendan

Control

CI5 Control

50 40 30 20 10 0 MPAP1

D 500

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MPAP3 MPAP4 Study period

Levosimendan

MPAP5

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PVR (dyn/s/cm–5)

400 300 200 100 0 PVR1

2000

SVR (dyn/s/cm–5)

PVR2

PVR3 PVR4 Study period

Levosimendan

PVR5 Control

1500 1000 500 0 SVR1

SVR2

SVR3 SVR4 Study period

SVR5

Fig. 1. Course of measurements between the two groups over time. A. cardiac output, B. cardiac index, C. mean pulmonary artery pressure (MPAP), D. pulmonary vascular resistance (PVR), E. systemic vascular resistance (SVR).

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lower than those of group II (group I: 3.02 ± 0.36 l/min vs group II: 3.71 ± 0.92 l/min; p = 0.001) (Fig. 1A). Considering all measurements, CO3 and CO5 for group I were higher than those of the control group, whereas there was no difference for the other measurements [respectively for groups I and II; CO2: 4.39 ± 1.56 vs 4.18 ± 0.72 l/min (p = 0.804); CO3: 5.01 ± 0.57 vs 4.11 ± 1.00 l/ min (p = 0.024); CO4: 5.03 ± 1.01 vs 4.62 ± 0.61 l/min (p = 0.191); CO5: 5.94 ± 1.14 vs 4.87 ± 0.34 l/min (p = 0.049)] (Fig. 1A). When within-group CO increase was evaluated, CO in the levosimendan group showed a significant increase with time compared to baseline values (CO1: 3.02 ± 0.36 l/min vs CO5: 5.94 ± 1.14 l/min; p = 0.018). On the other hand, increase in the control group over time was not found to be significant (CO1: 3.71 ± 0.92 l/min vs CO5: 4.87 ± 0.34 l/min; p = 0.506). Statistically significant differences in favour of group I were recorded regarding the values of CI between the two groups. CI in group I increased significantly compared to the control group [respectively for groups I and II; CI2: 2.68 ± 0.83 vs 2.54 ± 0.47 l/min/m² (p = 0.273); CI3: 3.13 ± 0.37 vs 2.40 ± 0.54 l/min/m² (p = 0.229); CI4: 3.43 ± 0.66 vs 2.74 ± 0.31 l/min/m² (p = 0.006); CI5: 3.84 ± 0.81 vs 2.94 ± 0.29 l/min/m² (p = 0.001)] (Fig. 1B). When the within-group CI increase was evaluated, CI in group 1 showed a significant increase over time compared to baseline values (CI1: 1.89 ± 0.30 l/min/m² vs CI5: 3.84 ± 0.81 l/ min/m²; p = 0.014). Although the increase in group II over time was found to be significant (CI1: 2.60 ± 1.26 vs 2.94 ± 029 l/ min/m²; p = 0.048) this increase was more apparent in group I. Basal pulmonary arterial pressures were compared (PAP1) between groups. PAP1 in group I was higher compared to that in group II (respectively for groups I and II; PAP1: 51.25 ± 26.95 vs 47.00 ± 9.00 mmHg; p = 0.001). PAP1 was decreased significantly in group I over time (PAP1: 51.25 ± 26.95 mmHg vs PAP5: 36.00 ± 12.56 mmHg; p = 0.032). This decrease was not significant in the control group (PAP1: 47.00 ± 9.00 mmHg vs PAP5: 35.85 ± 8.29 mmHg; p = 0.595) (Fig. 1C). When basal pulmonary vascular resistance values (PVR1) were compared, values in group I were higher compared to those in group II (respectively for groups I and II; PVR1:432.4 ± 340.4 vs 164.2 ± 79.5 dyne/s/cm5; p = 0.027). The decrease in PVR over time was marked in group I (PVR1: 432.4 ± 340.4 dyne/s/cm5 vs PVR5: 218.7 ± 163.2 dyne/s/cm5; p = 0.009). This decrease was not significantly different with time in the control group (PVR1: 164.2 ± 79.5 dyne/s/cm5 vs PVR5: 116.1 ± 49.6 dyne/s/cm5; p = 0.445) (Fig. 1D). Baseline systemic vascular resistance values (SVR1) were compared between the groups. In group II, SVR1 was higher than that in group I (respectively for groups I and II; SVR1: 1681.2 ± 422.6 vs 1740.0 ± 698.5 dyne/s/cm5, p = 0.032). Decrease in SVR with time was significant in group I (SVR1: 1681.2 ± 422.6 dyne/s/cm5 vs SVR5: 1039.2 ± 354.2 dyne/s/cm5; p = 0.015). In the control group, SVR1 also showed a significant decrease (SVR1: 1740.0 ± 698.5 dyne/s/cm5 vs SVR5: 1272.2 ± 375.5 dyne/s/cm5; p = 0.036) (Fig. 1E).

Discussion Nowadays many patients indicated for cardiac surgery are at high peri-operative risk for increased risk of morbidity and mortality. Pulmonary arterial hypertension and low ejection fraction are among the key factors determining prognosis

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in the postoperative period in patients with valve diseases.1,2 Individually or combined, the presence of these risk factors may make the weaning from CPB difficult and may cause severe left and right ventricular failure after the CPB procedure. Treatment methods for patients who cannot be weaned from CPB or develop low cardiac output after CPB include use of inotropic agents, vasodilators, intra-aortic balloon pump, insertion of a balloon pump into the pulmonary artery, implementation of right ventricular assist devices and extracorporeal membrane oxygenisation. A newly developed agent, levosimendan, is now available. It exhibits positive inotropic activity by increasing the ionised calcium sensitivity of cardiac troponin C and facilitating calcium binding to the myofilaments. Additionally, it exhibits vasodilator effects on the decrease in intracellular calcium level by allowing the ATP-sensitive potassium channels to be opened.3 Levosimendan differs from other positive inotropic drugs with features such as increasing contractility without increasing myocardial oxygen consumption, improving coronary perfusion with its vasodilator activity, reducing preload and afterload by vasodilatation in the pulmonary, renal, splanchnic, cerebral and systemic arteries as well as in the saphenous, portal and systemic veins.8,9 There are many reported studies of levosimendan being used in cardiac surgery. In many of these studies, levosimendan was started after cardiac surgery or during CPB weaning.6 In only a few studies, levosimendan was started before CPB. Tritapepe et al. reported that a short infusion of levosimendan before coronary artery bypass grafting (CABG) protected the myocardium and improved postoperative haemodynamics. Levosimendan-treated patients had lower postoperative troponin I concentrations and a higher cardiac index, suggestive of a preconditioning effect.10 Leppikangas et al. administered levosimendan to patients who underwent combined aortic valve and coronary bypass surgery for 24 hours before surgery. They found that both CI and stroke volume were higher in the levosimendan group and concluded that in patients undergoing risky cardiac surgery, levosimendan improved haemodynamics compared with placebo.11 Brezina et al. showed that levosimendan infusion after the induction of general anaesthesia in high-risk cardiac surgery patients resulted in better outcomes for the length of hospital stay and 30-day mortality rate, compared with patients receiving dobutamine and milrinone.12 In another study by Tritapepe et al., intravenous bolus administration of levosimendan over a 10-minute period before initiation of bypass resulted in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support and a shorter length of intensive care unit stay, compared with placebo.13 In our work, a dose titration study showed that even at a minimal dosage of levosimendan, an increase of approximately 12 ml in stroke volume and an increase of 0.7 l/min/mÂ˛ in cardiac index were found. When compared with placebo, levosimendan caused a significantly higher positive haemodynamic response at the sixth hour (17% with placebo, 80% with levosimendan). Symptomatic improvement in patients has been found to be parallel to haemodynamic improvement. Folloth et al. demonstrated that positive haemodynamic responses continued for 24 hours following discontinuation of the infusion.14 In our study, cardiac output and cardiac index values in the levosimendan group were significantly lower compared

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to the control group. Cardiac output and cardiac index in the levosimendan group also showed remarkable increases compared to the control group. In patients receiving levosimendan, at the end of the 24th hour, an increase of approximately 2.9 l/min in cardiac output and an increase of approximately 2 l/min/m2 in cardiac index were found. In the control group, at the end of the 24th hour, this increase remained limited to approximately 0.7 l/min in cardiac output and 0.3 l/min/m2 in cardiac index. Correspondingly, Tachibana et al. showed that levosimendan improved left ventricular systolic and diastolic performance at rest and during exercise after heart failure.15 In our study, we also examined pulmonary arterial pressure, pulmonary vascular resistance and systemic vascular resistance in order to determine the vasodilatatory effect of levosimendan. When considered individually, initial values of mean pulmonary arterial pressure were found to be significantly higher in the levosimendan group. At the end of the 24th hour, a marked decrease in the pulmonary arterial pressure was observed in the levosimendan group, but the decrease in the control group was not significant. A marked decrease in pulmonary vascular resistance values was also recorded in favour of levosimendan at the end of the 24th hour. These results were consistent with those of Lilleberg et al., who found that levosimendan decreased pulmonary vascular resistance early after CABG.16 Systemic vascular resistance values showed marked decreases in both the levosimendan and control groups. Pre-operative cardiac output values in the levosimendan group were less than those of the control group, whereas pulmonary vascular resistance and pulmonary pressure values measured by thermodilution catheter were significantly higher compared to the control group. Despite these values, this patient group was easily weaned from CPB and the postoperative period went smoothly. This patient group was discharged with a full recovery. More significant results were obtained from the levosimendan group compared to the control group regarding increases in postoperative CO and CI, and decreases in PVR and PAP values. Based on the published literature mentioned above, we expected that greater preservation of cardiac function after CPB would result in a better recovery. Our results were consistent with these findings. This indicates that levosimendan was beneficial. However, when clinical results were considered, no difference in favour of levosimendan was determined regarding the mortality and morbidity rates between the groups. The most common adverse reactions with levosimendan include headache, dizziness, hypotension, ventricular tachycardia, atrial fibrillation, tachycardia, ventricular extrasystoles, cardiac failure, myocardial ischaemia, extrasystoles, nausea, vomiting, constipation, diarrhoea, insomnia, decreased haemoglobin and hypokalaemia. There was no significant adverse effect from the drug in our study group. When the groups were compared with regard to risk scoring (EuroSCORE), they were found to be similar. On the other hand, the pre-operative CO and CI values were lower and the PVR and PAP values were higher in the levosimendan group, but it will be noted that this was a more high-risk group. Despite this, this group could easily be weaned from CPB and discharged with a full recovery. In our study, patients in the levosimendan group were discharged later than the control group, contrary to results in

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the literature. We surmise this was because of their more risky profiles despite the fact that their EuroSCOREs were similar to those of the control group. Rates of mortality and morbidity were found to be similar in both groups, possibly due to the small number of patients in the study.

6. 7. 8.

Conclusion

Our study shows that pre-operative use of levosimendan in cardiac valve surgery patients with low ejection fractions and/or pulmonary arterial hypertension resulted in improved haemodynamic parameters, which may have provided better and faster recovery after CPB. In larger studies with more patients, the positive effects of levosimendan on clinical outcomes may be seen more clearly.

10.

References 1. 2.

3. 4.

Cevese PG, Gallucci V, Valfre C, et al. Pulmonary hypertension in mitral valve surgery. J Cardiovasc Surg (Torino) 1980; 21: 7–10. Vincens JJ, Temizer D, Post JR, et al. Long-term outcome of cardiac surgery in patients with mitral stenosis and severe pulmonary hypertension. Circulation 1995; 92: II137–142. Figgit DP, Gillies PS, Goa KL. Levosimendan. Drugs 2001; 61: 613–627. De Hert SG, Lorsomradee S, Cromheecke S, et al. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg 2007; 104: 766–773. Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilator

11.

12.

13.

14.

15.

16.

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agent. Anesthesiology 2006; 104: 556–569. Raja SG, Rayen BS. Levosimendan in cardiac surgery: current best available evidence. Ann Thorac Surg 2006; 81: 1536–1546. Mebazaa A, Barraud D, Welschbillig S. Randomized clinical trials with levosimendan. Am J Cardiol 2005; 96: 74G–79G. Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol 2005; 96: 68G–73G. McBride BF, White CM. Levosimendan: implications for clinicians. J Clin Pharmacol 2003; 43: 1071–1081. Tritapepe L, De Santis V, Vitale D, et al. Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study. Br J Anaesth 2006; 96: 694–700. Leppikangas H, Järvelä K, Sisto T, et al. Preoperative levosimendan infusion in combined aortic valve and coronary bypass surgery. Br J Anaesth 2011; 106: 298–304. Brezina A, Riha H, Pirk J. Prophylactic application of levosimendan in cardiac surgical patients with severe left ventricle dysfunction. Exp Clin Cardiol 2009; 14: e31–34. Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 2009; 102: 198–204. Follath F, Franco F, Cardoso JS. European experience on the practical use of levosimendan in patients with acute heart failure syndromes. Am J Cardiol 2005; 96: 80G–85G. Tachibana H, Cheng HJ, Ukai T, et al. Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure. Am J Physiol Heart Circ Physiol 2005; 288: H914–922. Lilleberg J, Nieminen MS, Akkila J, et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998; 19: 660–668.

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Association of homocysteinaemia with hyperglycaemia, dyslipidaemia, hypertension and obesity DUDU SENGWAYO, MPHO MORABA, SHIRLEY MOTAUNG

Abstract Aim: Hyperhomocysteinaemia and the metabolic syndrome are associated with increased cardiovascular risk. We investigated whether there is a link between the metabolic syndrome or its components and homocysteine levels in a population without cardiovascular disease. Methods: From the population sample of 382 participants (286 females and 96 males) we isolated those reflecting the metabolic syndrome and determined their homocysteine levels. We then evaluated the association of homocysteine with hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia, hypertension and obesity, using a significance level of p = 0.05. Enzymatic methods were used for all biochemical parameters. Results: We found the statistical relationship between homocysteine and the metabolic syndrome as follows: hyperglycaemia (p = 0.175), hypertriglyceridaemia (p = 0.442), hypercholesterolaemia (p = 0.480), obesity (p = 0.080); and hypertension: systolic pressure (p = 0.002) and diastolic pressure (p = 0.033). Conclusion: We found no statistically significant association between baseline plasma homocysteine levels and the metabolic syndrome, except for hypertension. Keywords: hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia, hypertension, obesity, homocysteine Submitted 17/4/13, accepted 14/8/13 Cardiovasc J Afr 2013; 24: 265–269

www.cvja.co.za

DOI: 10.5830/CVJA-2013-059

Diabetes mellitus is a group of metabolic diseases characterised by hyperglycaemia, resulting from defects in insulin secretion, insulin action or both. It is associated with several cardiovascular disorders, including angiopathy and platelet hyperactivity, which are major causes of morbidity and mortality in type 2 diabetes mellitus.1 Atherosclerosis is substantially more prevalent and progresses rapidly in diabetes mellitus.2 There are an estimated 23.6 million people in the USA (7.8% of the population) with diabetes.1 The vascular complication of diabetes mellitus, at its earliest stage, is manifested as endothelial dysfunction,3 decreasing the bioavailability of nitric Department of Medical Science, Health Public and Health Promotion, School of Health Sciences, Faculty of Health Sciences, University of Limpopo (Turfloop Campus), Sovenga, South Africa MPHO MORABA, DTech

Department of Biomedical Sciences, Faculty of Science, Tshwane University of Technology, Pretoria, South Africa DUDU SENGWAYO, MTech SHIRLEY MOTAUNG, DTech, motaungsckm@tut.ac.za

oxide, which protects blood vessels from endogenous injuries.4 Hyperglycaemia inhibits fibrinolysis by decreasing the activity of plasminogen activator and enhances coagulation by activating procoagulants into thrombosis.5 Homocysteine is an amino acid derived from methionine. The latter is an intermediate in the conversion of homocysteine to cysteine. Homocysteine is metabolised via two pathways: remethylation, in which homocysteine is converted into methionine, and transulphuration, in which homocysteine is converted into cysteine. In the former pathway, homocysteine acquires a methyl group, either from the conversion of 5-methyltetrahydrofolate into hydrofolate or from the conversion of betaine into the N′ N-dimethylglycine.6 Vitamins B12 and B6 are important in the conversion of 5-methyltetrahydrofolate into hydrofolate and therefore for the remethylation pathway and the metabolism of homocysteine into methionine.7 Epidemiological studies suggest hyperhomocysteinaemia to be an independent risk factor for developing atherothrombotic vascular disease.8 Mechanisms by which hyperhomocysteinaemia causes vascular disease include promotion of atherosclerosis by damaging the inner lining of arteries and promoting thrombosis through pathological collagen activation of the intrinsic pathway,9 impairment of thrombolysis, increased production of hydrogen peroxide, endothelial dysfunction, and increased oxidation of low-density lipoproteins.8 Some of the complications of arterial thrombosis following hyperhomocysteinaemia include coronary heart disease, myocardial infarction, stroke, peripheral vascular disease, miscarriage, pulmonary embolism, retinal embolism and neural tube defect (spina bifida).9 The homocysteine level may be increased in hypertensive, overweight and obese subjects.10 Homocysteine is thought to help regulate glucose metabolism and insulin absorption.11 Homocysteine has been suggested to contribute to the atherosclerotic process of diabetes mellitus. High homocysteine levels have been reported in diabetic patients,2,12 and elevated levels are a strong risk factor in these patients.1 The elevation occurs particularly in patients with type 2 diabetes, as well as in individuals in prediabetic states who exhibit insulin resistance.13 The levels of homocysteine in such individuals are also influenced by their insulin concentrations, and therapy with insulin and medications such as metformin and glitazones that can either raise or lower homocysteine levels.12 The effect of hyperhomocysteinaemia on diabetes and insulin resistance has been reported with unclear synergism.12 Homocysteine levels have been reported as either low or elevated compared to non-diabetic subjects, reflecting the potential role of homocysteine in the development of macro- and microvascular disease in diabetic patients.13,1 Shaikh et al. found that 58% of their diabetic participants had elevated homocysteine levels and males were predominant in this group.1 This finding is consistent with that of Schalinske’s study.14 These authors reported a strong association between atherosclerosis, hyperhomocysteinaemia and type 2

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diabetes in the Japanese population. They concluded that hyperhomocysteinaemia in diabetes mellitus may contribute to the development of chronic complications. Vayรก et al. established a borderline statistically significant association (p = 0.008) between hyperhomocysteinaemia and hyperglycaemia (p = 0.054).15 Hypertension is a condition where the artery walls are stiffer and present increased resistance to blood flow. This requires the heart to beat more forcefully and increases the pressure of blood leaving the heart. High blood pressure is often called the silent killer because in the initial stages it presents with no symptoms. It is only after an organ in the body has been irritated or damaged, that the consequences of high blood pressure are realised.16 Hypertension places stress on the target organs, including kidneys, eyes and heart, causing them to deteriorate over time. Hypertension contributes to 75% of all strokes and heart attacks.17 One in three African-Americans has hypertension. One African-American dies every hour from the disease, and more than 30% of African-Americans can count hypertension or its complications as the leading cause of death.17 The hypothesis that homocysteine may play a role in the pathogenesis of essential hypertension is based on the fact that homocysteine induces arteriolar constriction, renal dysfunction and increased sodium reabsorption, increasing arterial stiffness.18 Homocysteine increases oxidative stress, which causes oxidative injury to the vascular endothelium, diminishing vasodilation by nitric oxide, stimulating proliferation of vascular smooth muscle cells and altering the elastic properties of the vascular wall, leading to an increase in hypertension.18 These authors concluded that homocysteine may contribute to blood pressure elevation. Atif et al. observed that plasma homocysteine was raised in most patients with hypertension.19 The authors found in their study that 80% of their hypertensive subjects were hyperhomocysteinaemic. Karatela and Sainani found a high prevalence of hyperhomocysteinaemia associated with raised blood pressure, with raised systolic and diastolic pressures.10 Nabipour et al. reported significantly higher homocysteine levels in subjects with high blood pressure.20 Vayรก et al. however found no statistically significant association (p = 0.008) between hyperhomocysteinaemia and hypertension (p = 0.229).15 In large community-based studies, plasma homocysteine was found to be cross-sectionally associated with blood pressure, especially systolic pressure, unadjusted for gender and age.21,22 The authors however found that adjusted for gender and age, the relationship of plasma homocysteine to the incidence of hypertension was statistically non-significant. Experimental investigations evaluating the association of homocysteine and blood pressure have not yielded consistent results. Diet-induced hyperhomocysteinaemia has been demonstrated to elevate blood pressure in some investigations but to lower it in others.21 A positive association of total homocysteine with both systolic and diastolic blood pressure was reported in several clinical cross-sectional studies.21 These authors found no major relationship between baseline plasma homocysteine level and incidence of hypertension. Lipids are a group of organic compounds that include, among others, cholesterol, triglycerides, phospholipids, lipoprotein and sterols, which are insoluble in water but soluble in non-polar organic solvents.23 Fats (solid lipids) constitute approximately

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34% of the energy used in the human body.24-26 Of the lipids, triglycerides and cholesterols [very low-density lipoprotein (LDL), LDL and high-density lipoprotein (HDL) cholesterol] are the components that play a major role in atherosclerosis, the forerunner of arteriosclerosis.27 All body cells are capable of LDL cholesterol (LDL-C) synthesis. This favours deposition of cholesterol in the cells and blood vessels. LDL-C is therefore atherogenic. HDL transports cholesterol from the cells to the liver for degradation into bile salts (sodium taurocholate and deoxycholate).23 HDL-C is therefore anti-atherogenic and protective against the development of atherothrombosis. High triglyceride levels are significant risk factors for cardiovascular disease and are a marker for atherogenic remnant lipoprotein, such as very LDL-C. Even in the presence of tightly controlled LDL-C levels, evidence indicates that high triglyceride levels and low HDL-C levels are independent thrombosis and cardiovascular risk factors.28 About half of all deaths in developed countries are caused by homocysteinaemia and dyslipidaemia (hypercholesterolaemia and hypertriglyceridaemia).29 According to Rima and Wolfgang, there is an association between hyperhomocysteinaemia and dyslipidaemia, and diabetes mellitus is common to hyperhomocysteinaemia and hypercholesterolaemia.30 Vayรก et al. found no statistically significant association (p = 0.008) between hyperhomocysteinaemia and low HDL-C levels (p = 0.491) and hypertriglyceridaemia (p = 0.490).15 However, Nabipour et al. found subjects with lower HDL-C levels had higher homocysteine levels (p = 0.001).20 Obesity is characterised by excess body fat due to an imbalance between calorie intake and expenditure. Causes of obesity include high calorie intake, lack of exercise and genetic susceptibility or psychiatric illness.31 Obesity is defined as a body mass index (BMI) greater than 30 kg/m2.32 Two patterns of obesity are central (visceral) obesity and peripheral obesity. The former is more common in males and carries a higher risk of coronary heart disease, as well as various forms of metabolic derangement, including dyslipidaemia and impaired glucose tolerance. Peripheral obesity is when fat accumulates in the gluteo-femoral area. It is more common in women but less associated with cardiovascular risk, as a complication of arterial thrombosis.33 Obesity is an independent risk factor for the complications of atherosclerotic vascular disease, such as myocardial infarction and stroke and has been found to elicit and increase the risk of arterial thrombosis.6,34 Obesity affects about 1.3 billion people worldwide, and 3.0 to 20.4% of South African males and 25.9 to 54.3% of females.32,35 Karatela and Sainani observed an increased prevalence of hyperhomocysteinaemia in overweight and obese subjects.10 Nabipour et al. found no significant association between homocysteine level and BMI in a study of the relationship between the metabolic syndrome and homocysteine levels.20 However, Vayรก et al. found in four studies that increased homocysteine levels were related mostly to abdominal obesity.15 Sanlier and Yabanci found increased body weight to be associated with hyperhomocysteinaemia, but without gender differences.36 El-Sammak et al. also found hyperhomocysteinaemia to increase with age, possibly because of the presence of other factors that raise plasma total homocysteine levels with age, especially increased deterioration in other organ functions.37

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Methods

Results

The study was cross-sectional and prospective. Participants were recruited by trained field workers and consented voluntarily in writing. Ethical approval was obtained from the Tshwane University of Technology Ethics Committee (Ref: 2010/09/004). A standard informed consent form was signed by all participants. A questionnaire was used to obtain information on demographic characteristics, lifestyle, eating habits, health conditions such as surgical operations, diabetes mellitus, previous arterial thrombosis, previous pulmonary embolism, hyperlipidaemia, kidney problems, obesity/overweight and heart failure. Cardiovascular disease was one of the ailments that no participants reported to be suffering from. Fasting blood samples were collected from participants at the Nobody Clinic in Ga-Mothapo. Subjects who had not fasted for at least nine hours before sample collection and could not withdraw medication for that period were excluded from the study. Blood was collected by professional nurses. One 4.5-ml blood sample was collected from each participant in a sodium fluoride tube for glucose analysis, in a plain tube for triglycerides and cholesterol estimation, and in an EDTA-anticoagulated tube for homocysteine level assay. The body weight of the participants wearing light clothing without shoes was measured using a weight scale from Omron. The height was measured without shoes in an upright position using the Seca telescopic height-measuring rod. The BMI was calculated using the formula: BMI = weight in kg/(height in m)2. Blood pressure was measured using the Omron MI-5. Blood glucose, triglyceride and cholesterol levels were measured using the ILab 300 Plus Chemistry System from Beckman Coulter. Homocysteine was estimated using the Beckman Coulter Synchron system analyser. Enzymatic methods were used for all biochemical parameters. The diagnostic criteria used for the parameters were set as follows: hyperhomocysteinaemia = blood homocysteine > 15 µmol/l, hyperglycaemia = blood glucose > 7.0 mmol/l, hypercholesterolaemia = blood cholesterol > 5.7 mmo/l, hypertriglyceridaemia = blood triglyceride > 2.26 mmol/l, obesity = BMI > 30 kg/m2, systolic blood pressure > 140 mmHg = hypersystolic blood pressure, and diastolic blood pressure > 90 mmHg = hyperdiastolic. The collected data were analysed with Statistical Package for Social Science (SPSS) version 18. The results were expressed in percentages of p-values for association. A p-value of 0.05 was regarded as statistically significant.

The study consisted of 382 participants. The mean age of the study participants was 38.45 years. The mean values for the studied parameters were as follows: homocysteine 9.44 µmol/l, glucose 5.42 mmol/l, systolic blood pressure 125.65 mmHg, diastolic blood pressure 81.06 mmHg, cholesterol 4.18 mmol/l, triglycerides 1.22 mmol/l and BMI 26.80 kg/m2 (Table 1). The associations of hyperhomocysteinaemia with hyperglycaemia (p = 0.175), hypertriglyceridaemia (p = 0.442) and hypercholesterolaemia (p = 0.480) were statistically insignificant. The association of hyperhomocysteinaemia with obesity was found to be partially significant (p = 0.080). The associations of hyperhomocysteinaemia with hypersystolic (p = 0.002) and hyperdiastolic (p = 0.033) blood pressures were statistically significant. Of the 45 hyperglycaemic participants, three were also hyperhomocysteinaemic, constituting about 6.7%. Of the 39 hypertriglyceridaemic participants, three were also hyperhomocysteinaemic, constituting about 7.7%. Of the 38 hypercholesterolaemic participants, five were also hyperhomocysteinaemic, constituting about 13.1%. Of the 72 participants with high systolic blood pressure, 11 were also hyperhomocysteinaemic, constituting about 15.3%. Of the 84 participants with high diastolic blood pressure, 16 were also hyperhomocysteinaemic, constituting about 19.0%. Of the 95 obese participants, 10 were also hyperhomocysteinaemic, constituting about 10.5%.

Discussion We estimated homocysteine levels in 45 hyperglycaemic subjects for evaluation of association and found no statistical significance (p = 0.175) (Table 2). Three hyperglycaemic subjects (6.7%) were hyperhomocysteinaemic (Table 3). Different findings about the relationship have been reported above. Vayá et al., in their study of the relationship between homocysteine and hyperglycaemia, found a partial association.15 Elias and Eng, and Shaikh et al. reported that homocysteine levels can be low or elevated in diabetes mellitus.1,13 These findings and ours are contrary to the findings of Mishra et al.2 and Akali et al.12 who found high homocysteine levels in diabetic patients. They found high levels of homocysteine to be a strong risk factor in diabetic patients. This was supported by the findings of Shaikh et al. and Schalinske.1,14 Shaikh et al. found more than half of their diabetic participants had elevated homocysteine levels.1 The discrepancy with our results could have been attributable to the influence on homocysteine of insulin concentrations, therapy with insulin and

TABLE 1. CHARACTERISTICS OF THE PARTICIPANTS Variable Age (years) Homocysteine (µmol/l) Glucose (mmol/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Cholesterol (mmol/l) Triglycerides (mmol/l) Body mass index (kg/m2)

Mean ± SD 38.45 ± 17.283 9.44 ± 4.13 5.42 ± 2.555 125.65 ± 19.164 81.06 ± 11.351 4.18 ± 1.396 1.22 (0.83–1.68) 26.80 ± 6.20

TABLE 2. P-VALUES FOR SIGNIFICANCE OF ASSOCIATION Homocysteinaemia Metabolic disorder n = 45 Hyperglycaemia (n = 45) n = 39 Hypertriglyceridaemia (n = 39) n = 38 Hypercholesterolaemia (n = 38) n = 72 Systolic blood pressure (n = 72) n = 84 Diastolic blood pressure (n = 84) n = 95 Obesity (n = 95) 95% confidence interval and p = 0.05 level of significance.

p-value 0.175 0.442 0.480 0.002 0.033 0.080

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TABLE 3. PREVALENCE OF HYPERHOMOCYSTEINAEMIA WITH HYPERGLYCAEMIA, HYPERTRIGLYCERIDAEMIA, HYPERCHOLESTEROLAEMIA, HYPERTENSION AND OBESITY HyperhomocysteinPrevalence rate aemia Metabolic disorder (%) n=3 Hyperglycaemia (n = 45) 6.7 n=3 Hypertriglyceridaemia (n = 39) 7.7 n=5 Hypercholesterolaemia (n = 38) 13.1 n = 11 Systolic blood pressure (n = 72) 15.3 n = 16 Diastolic blood pressure (n = 84) 19.0 n = 10 Obesity (n = 95) 10.5 Prevalence of hyperhomocysteinaemia = number of hyperhomocysteinaemic subjects per number of subjects in the respective components of the metabolic syndrome.

medication.12 Control of these confounding factors in our study may have improved the level of association. We determined homocysteine levels in 39 hypertriglyceridaemic and 38 hypercholesterolaemic subjects. No statistically significant association was found between homocysteine and hypertriglyceridaemia (p = 0.442) and hypercholesterolaemia (p = 0.480) (Table 2). Three hypertriglyceridaemic subjects had hyperhomocysteinaemia (7.7%) while five hypercholesterolaemic subjects had hyperhomocysteinaemia (13.1%) (Table 3). The insignificant association was supported by the findings of Vayá et al.15 However, Nabipour et al. found significant associations between lower HDL cholesterol and high homocysteine levels.20 Homocysteine levels were estimated in 72 subjects with high systolic blood pressure and 84 subjects with high diastolic blood pressure, a total of 156 hypertensive subjects. Homocysteine was statistically significantly associated with both systolic (p = 0.002) and diastolic (p = 0.033) blood pressure (Table 2). Eleven hypersystolic subjects (15.3%) were hyperhomocysteinaemic while 16 hyperdiastolic subjects (19%) were hyperhomocysteinaemic (Table 3). These findings are supported by various researchers, who found hyperhomocysteinaemia to be significantly associated with hypertension.10,20-22 The association of homocysteine with hypertension may be due to the fact that homocysteine induces arteriolar constriction, renal dysfunction and increased sodium absorption, with increased arteriolar stiffness.18 It increases oxidative stress, which causes oxidative injury to the vascular endothelium, diminishing vasodilation by nitric oxide. It also stimulates the proliferation of vascular smooth muscle cells and alters the elastic properties of the vascular wall, leading to an increase in hypertension.18 On the basis of our findings, the large body of supporting evidence and the mechanisms of association, homocysteine levels can be used to track blood pressure. Hyperhomocysteinaemia reflects a causal effect rather than being concomitant to elevated blood pressure. In our present study we evaluated 95 obese subjects for homocysteine association with obesity. We found a borderline association (p = 0.080) (Table 2). Ten obese subjects were hyperhomocysteinaemic (Table 3). The association was partly supported by other researchers, who found increased prevalence of hyperhomocysteinaemia in obese subjects.10,15,36 Depending on age and the pattern of obesity, homocysteine may be significantly associated with obesity. This viewpoint is supported by the findings of Vayá et al.15 and El-Sammak et al.37

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Conclusion We found no statistically significant relationship between baseline plasma homocysteine levels and hyperglycaemia, dyslipidaemia and obesity. There was, however, a significant relationship between homocysteine levels and hypertension. According to our cross-sectional study, high baseline plasma homocysteine level is a major risk factor for hypertension and can be used in blood pressure tracking in a large, community-based sample. The study supported the hypothesis that plasma homocysteine is casually related to elevated blood pressure. Additional prospective investigations are recommended to confirm these findings. A study evaluating the association between plasma homocysteine levels and hyperglycaemia after a few days of treatment withdrawal would probably yield better and more reliable results. Unfortunately, withdrawing treatment from diabetic subjects may be risky, especially in those with high glucose levels. We plan in future to compare homomocysteine levels between participants with and without the metabolic syndrome. We thank the Tshwane University of Technology and the University of Limpopo (Turfloop campus) for financial assistance.

References 1.

6. 7.

9. 10.

11.

12.

13.

Shaikh MK, Devrajani BR, Shaikh A, Shah SZA, Shaikh S, Singh D. Plasma homocysteine level in patients with diabetes mellitus, World App Sc J 2012; 16(9): 1269–1273. Akalin A, Alatas O, Colak O. Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients. Eur J Endocrinol 2008; 158; 47–52. Babic N, Dervisevic A, Huskic J, Music, M. Coagulation factor VIII activity in diabetes. Med Glas Ljek Kamore Zenicko-doboj Kantona 2011; 8(1): 134–139. Creager MA, Luscher TF, Consentino F, Beckman JA. Diabetes and vascular disease: Pathophysiology, clinical consequences and medical therapy. J Am Heart Assoc 2003; 108: 1527–1532. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR. Explaining the disease in US death from coronary disease. New Engl J Med 2007; 356(23): 2388–2398. Lowe GDO. Venous and arterial thrombosis: Epidemiology and risk factors at various ages. Maturitas 2004; 47(4): 259–263. Ntaios G, Savopoulos C, Grekas D, Hatzitolios A. Homocysteine metabolism and causes of hyperhomocysteinaemia. Arch Cardio Dis 2009; 102(12): 847–854. Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD. Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. Can Med Assoc J 2005; 172(12): 1569–1573. Guilliams TG. Homocysteine – a risk factor for vascular diseases. J Am Neutraceut Assoc 2004; 7(1): 11–16. Karatela RA, Sainani GS. Plasma homocysteine in obese, overweight and hypertensive subjects in Mumbai. Indian Heart J 2009; 61(2): 156–159. Hajer GR, van der Graaf Y, Olijhoek JK, Verhaar MC, Visseren FJ. Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome. Heart 2007; 93(2): 216–220. Mishra PK, Tyagi N, Sen U, Joshua IG, Tyagi SC. Synergism in hyperhomocysteinemia and diabetes: RHle of PPAR gamma and tempol. Cardiovasc Diabetol 2010; 9(49): 1–8. Schalinske KL. Interrelationship between diabetes and homocysteine metabolism: Hormonal regulation of cystathionine beta-synthase. Nutr Rev 2003; 61(4): 136-138.

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14. Elias AN, Eng S. Homocysteine concentrations in patients with diabetes mellitus – relationship to microvascular and macrovascular disease. Diabetes Obesity Metab 2005; 117–121. 15. Vayá A, Carmona P, Badia N, Pérez R, Hernandez MA, Corella D. Homocysteine levels and the metabolic syndrome in a Mediterranean population. Clin Hemorheol Microcirc 2011; 47(1): 59–66. 16. Wedro BC. 2009 Blood pressure guidelines. Available at http://www. medicinenet.com/script/main/art.asp?articlekey=83068. [Accessed: 21/09/2011]. 17. Lim K, Steinberg G. Preeclampsia. 2010. Available from: http://emedicine.medscape.com/article/1476919-overview. [Accessed: 20/9/2011]. 18. Sen U, Tyagi SC. Homocysteine and hypertension in diabetes: Does PPARγ have a regulatory role? PPAR Res 2010, Article ID 806538, doi:10.1155/2010/806538. 19. Atif A, Rizvi MA, Tauheed S, Aamir I, Majeed F, Siddiqui K, et al. Serum homocysteine concentrations in patients with hypertension. Pak J Physiol 2008; 4(1): 21–22. 20. Nabipour I, Ebrahim A, Jafari SM, Vahdat K, Assadi M, Movahed A, et al. The metabolic syndrome is not associated with homocysteinemia: The Persian Gulf healthy heart study. J Endocrinol Invest 2009; 32(5): 406–410. 21. Sundström J, Sullivan L, D’Agostino RB, Jacques PF, Selhub J, Rosenberg IH, et al. Plasma homocysteine, hypertension incidence, and blood pressure tracking. The Framingham heart study. Hypertension 2003; 42: 1100–1105. 22. Stehouwer CD, van Guldener C. Does homocysteine cause hypertension? Clin Chem Lab Med 2003; 41(11): 1408–1411. 23. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, et al. Lipoprotein management in patients with cardio-metabolic risk. J Am Coll of Cardiol 2008; 31(4): 811–822. 24. Mahan LK, Escort-Stump S. Food, Nutrition and Diet Therapy, 11th edn. Philadelphia: Elsevier 2007: 41, 46. 25. Mahan LK, Escort-Stump S. Food, Nutrition and Diet Therapy, 11th

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edn. Philadelphia: Elsevier 2007: 864, 866, 872. 26. Nelson DL, Cox MM. Digestion, Mobilization, and Transport of Fats, 5th edn, New York: WH Freeman and Co 2008: 346–347. 27. Barter P, Gotto AM, Larosa JC, Maroni J, Szarek M. HDL cholesterol, very low levels of LDL cholesterol and cardiovascular events. N Engl J Med 2007; 357(13): 1301–1310. 28. Cziraky MJ, Watson KE, Talbert RL. Targeting low HDL-cholesterol to decrease residual cardiovascular risk in managed care setting. J Manag Care Pharm 2008; 14(8): S3–S28. 29. Fahy E, Subramaniam S, Brown HA. A comprehensive classification system for lipids. J Lipid Res 2005; 46(5): 839–862. 30. Obeid R, Herrmann W. Homocysteine and cholesterol: Guilt by association? Stroke 2009; 40(7): e516. 31. Rippey FF. Thrombosis and Embolism. General Pathology, 1st edn, Johannesburg: Witwatersrand University Press 2003: 103–109. 32. Malhotra R, Hoyo C, Ostbye T, Hughes G, Schwartz D, Tsolekile L, et al. Deteminants of obesity in an urban township of South Africa. S Afr J Clin Nutr 2008; 21(4): 315–320. 33. Darvall KA, Sam RC, Silverman SH, Bradbury AW, Adam DJ. Obesity and thrombosis. Eur J Vasc Endovasc Surg 2007; 33: 223–233. 34. Bodary PF, Randal J, Westrick BS, Wickenheiser KJ, Shen Y, Daniel T, et al. Effect of leptin on arterial thrombosis following vascular injury in mice. J Am Med Ass 2002; 287(13): 1706–1709. 35. Goedecke JH, Jennings CL, Lambert EV. Obesity in South Africa. Chronic diseases of lifestyle in South Africa since 1995–2005. Cape Town: South African Medical Research Council, 2006: 65–79. 36. Sanlier N, Yabanci N. 2007. Relationship between body mass index, lipids and homocysteine levels in university students. J Pak Med Assoc 2007; 57(10): 491–495. 37. EL Sammak M, Kandil M, EL-Hifni S, Hosni R, Ragab M. Elevated plasma homocysteine is positively associated with age independent of C677T mutation of the methylenetetrahydrofolate reductase gene in selected Egyptian subjects. Int J Med Sci 2004; 1: 181–192.

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Increased carotid intima–media thickness associated with high hs-CRP levels is a predictor of unstable coronary artery disease SEJRAN AHMET ABDUSHI, FADIL UKË KRYEZIU, FEIM DURAK NAZREKU

Abstract Increased values of carotid intima–media thickness (CIMT) and high-sensitivity C-reactive protein (hs-CRP) are predictors of acute coronary events. We analysed the link between CIMT and hs-CRP in cases with coronary artery disease (CAD). From 1 January to 30 June 2012, we evaluated 43 patients with acute coronary syndrome (group A), 50 patients with stable coronary artery disease (group B) and 50 healthy volunteers (group C). All were analysed for CIMT and hs-CRP levels. CIMT values were higher in groups A and B (0.94 ± 0.21 mm, 0.89 ± 0.19 mm, respectively) and lower in group C (0.64 ± 0.09 mm), and this was statistically significant (p < 0.0001). However the values of hs-CRP were higher in group A (1.87 ± 0.36 mg/l) and lower in groups B and C (1.07 ± 0.28 mg/l, 0.97 ± 0.45 mg/l, respectively) and this was also statistically significant (p < 0.0001). Keywords: CIMT, hs-CRP, atherosclerosis, stable coronary disease, unstable coronary disease Submitted 12/5/13, accepted 14/8/13 Cardiovasc J Afr 2013; 24: 270–273

www.cvja.co.za

DOI: 10.5830/CVJA-2013-061

More than half of acute myocardial infarctions originate from blood vessels with stenosis of less than 50%.1 Moreover, cholesterol level is a poor predictor of cardiovascular risk. This was documented by data from the Framingham Heart study, where more than a third of patients with coronary artery disease (CAD) had values of total cholesterol lower than 5.1 mmol/l.2 A method is therefore needed to improve prediction of cardiovascular risk. During the 1990s it became clear that many other factors besides conventional risk factors, such as homeostatic and thrombotic mechanisms, markers of inflammation and genetic risk factors may have an influence on cardiovascular risk.3-9 For pathogenesis of coronary artery disease, the presence of atherosclerotic plaques is significant.4 The structure of the coronary artery wall is not static. With increase in its external diameter, development of atherosclerotic plaques will be possible without significant narrowing of the lumen of the artery.10 Several necropsy studies have reported very strong correlations between atherosclerosis in the carotid and coronary arteries.11,12 Prim Dr Daut Mustafa Regional Hospital, Prizren, Republic of Kosovo SEJRAN AHMET ABDUSHI, MSc, sejran2003@yahoo.com FEIM DURAK NAZREKU, MSc

National Institute of Public Health, Prizren, Republic of Kosovo FADIL UKË KRYEZIU, MSc

Increase in carotid artery intima–media thickness (CIMT) is considered a marker for early atherosclerosis.13 Risk prediction for coronary artery disease may be improved by additional information on the increase in CIMT, together with traditional risk factors.14 Recently, inflammation has emerged as an important factor in the process of atherosclerosis,15 therefore hs-CRP has been included as a new risk factor for CAD.16 In a recent study it was concluded that both hs-CRP and conventional lipid parameters can be used to predict the risk for CAD.17 Exercise stress testing provides useful information on the prognosis of patients with stable CAD and stable patients after acute coronary syndrome.18 Myers et al. found that subjects with stable CAD who achieved < 5 METs (metabolic equivalents) in exercise stress tests had four times higher mortality rates than subjects who achieved > 10 METs.19 The aim of this study was to analyse the association between changes in CIMT and hs-CRP values in cases with stable and unstable coronary artery disease.

Methods Between 1 January and 30 June 2012, a total of 143 subjects were included in this prospective study. All subjects were placed in three groups: group A (patients with acute coronary syndrome) included 43 patients with acute coronary artery syndrome, 25 (58.14%) with acute myocardial infarction and 18 (41.86%) with unstable angina pectoris. Group B included 50 patients with stable coronary artery disease, 37 (74%) of them with stable angina pectoris and 13 (26%) with a stable condition after myocardial infarction, and all achieved ≥ 5 METs in exercise stress testing. Group C (control group) included 50 healthy volunteers with negative exercise stress testing. We excluded all subjects with acute infection, active chronic inflammatory diseases (inflammatory bowel disease, rheumatic diseases, upper and lower respiratory tract diseases, etc.), patients after a recent myocardial infarction (less than one month before the study onset), patients with recent trauma (surgery, burns) and those with malignancies. Adjustment was made for age and gender. All individuals were interviewed about risk factors and regularity of therapy. Routine biochemical analyses were performed, with special emphasis on fasting glucose levels and lipid profiles [total cholesterol, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol and triglycerides]. In group A, blood samples for hs-CRP were obtained on admission, and at a time interval shorter than six hours from the onset of symptoms, and stored at –70°C. We also took samples for cardiac (troponin I, myoglobin, CK-MB) enzymes. Carotid ultrasound was done by a single operator using an Aloka-Prosound SSD-4000SV system equipped with a 7.5-MHz

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TABLE 1. BASELINE CLINICAL CHARACTERISTICS OF THE STUDY POPULATIONS Age (years)

Group A

Group B

Group C

p-value

59.3 ± 4.5

57.3 ± 9.7

56.1 ± 7.3

0.129 NS*

Male, n (%)

29 (67.44)

32 (64)

23 (46)

0.072 NS**

Hypertension, n (%)

18 (41.86)

17 (34)

9 (18)

0.038 S**

Diabetes, n (%)

22 (51.16)

22 (44)

11 (22)

0.022 S**

BMI (kg/m2)

29.37 ± 2.7 28.12 ± 2.3

24.6 ± 3.1

0.0001 S*

Fasting glucose (mmol/l)

7.3 ± 2.15 6.94 ± 1.81 5.733 ± 2.29 0.001 S*

Total cholesterol (mmol/l) 6.45 ± 2.31 6.13 ± 2.10 5.13 ± 1.48 0.004 S*

Fig. 1. Measurement of CIMT. 1. Lumen–intima interface, 2. media–adventicia interface.

linear array probe. Measurements were carried out at the far wall (far wall from ultrasound probe) on the right and left common carotid artery, as recommended by the American Society of Echocardiography 2008,20 and the mean value was used in the study (Fig. 1). Diagnosis of acute coronary syndrome was established on the recommendations of the European Society of Cardiology 201121 and 2012.22 Bicycle exercise testing (Cardiax stress ECG, Germany) was performed to assess exercise functional capacity (expressed in METs) using the Bruce protocol.23 Exercise was continued until the heart rate reached 85% of the estimated maximum age-predicted target heart rate for each patient, or was symptom limited. We considered only patients who achieved ≥ 5 METs.

Statistical analyses All data are presented as the mean ± SD or frequency (%), unless otherwise stated. The baseline clinical characteristics of the groups were compared using one-way ANOVA for continuous variables and the chi-square test for non-continuous variables. Statistical significance was set at p < 0.05.

Results Baseline clinical characteristics of the study population are summarised in Table 1. CIMT values were higher in group A and B, and lower values were found in group C (0.94 ± 0.21 mm, 0.89 ± 0.19 mm, 0.64 ± 0.09 mm, respectively). Statistical analysis showed significant differences between groups A and C (p < 0.0001), and also between groups B and C (p < 0.0001), but no significant difference was found between groups A and B (p

CIMT (mm)

1.2

p < 0.0001 0.94

0.89

0.8

0.95 ± 0.32 1.05 ± 0.29 1.41 ± 0.34 0.0001 S*

Triglycerides (mmol/l)

3.27 ± 0.53 3.19 ± 1.01 2.014 ± 0.85 0.0001 S*

Smokers, n (%)

30 (69.77)

0.2

23 (46)

0.057 NS**

> 0.05) (Fig. 2). Values of hs-CRP were significantly higher in group A (1.87 ± 0.36 mg/l) than in group B (1.07 ± 0.28 mg/l) and group C (0.97 ± 0.45 mg/l) (p < 0.0001). There was no significant difference between hs-CRP levels in groups B and C (p > 0.1) (Fig. 3).

Discussion One of the most important results from this study was that CIMT could predict the presence of coronary artery disease, but it could not predict coronary events. These data are consistent with the findings of other authors. Using radionuclide myocardial perfusion imaging in asymptomatic diabetic subjects, Nair et al. found higher carotid IMT values to be highly predictive of ischaemia.24 Yoko et al. concluded from their study that the addition of max-IMT to conventional risk factors substantially improved the risk stratification for CAD.25 Baldassarre et al. found that a risk-stratification strategy based on CIMT as an adjunct to the Framingham risk score was a rational approach to prevention of cardiovascular disease.26 However, the results of our study did not support the above findings that CIMT is a good predictor of coronary events. Another important conclusion from our study was that elevated levels of hs-CRP seemed to coincide more with plaque destabilisation in cases of acute coronary syndrome, since hs-CRP levels did not differ significantly in cases with stable CAD from those of healthy individuals. These data are also not consistent with data from other authors. Saudi patients with stable chronic CAD had higher hs-CRP levels compared to healthy individuals.27 Khan et al. found that patients with chronic stable angina had elevated levels of hs-CRP.28 2

1.87

1.5

0.4

31 (62)

2.97 ± 1.11 0.0001 S*

BMI: body mass index; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol. *One-way ANOVA test; **Chi-square test.

2.5 0.64

0.6

4.53 ± 1.27 4.1 ± 1.01

HDL-C (mmol/l)

CRP (mg/l)

1.4

LDL-C (mmol/l)

p < 0.0001 1.07

p > 0.1

0.97

0.5

Group A

Group B

Fig. 2. Mean CIMT ± SD in the study groups.

Group C

Group A

Group B

Group C

Fig. 3. Mean hs-CRP ± SD in the study groups.

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Our results suggest that elevated levels of hs-CRP are manifestations of atherosclerotic plaque instability and a sign of increased risk of acute coronary events. In the study by Ghazala and Mansoor, they confirmed that inflammation can be implicated in the transformation of stable coronary plaque to unstable plaques, rupture and thrombus.29 Kadi et al. found in patients with stable coronary artery disease and insufficient coronary circulation, serum hs-CRP levels were higher than in patients with adequate coronary collateral circulation.30 Zhumin et al. found that the values of hs-CRP were higher in patients with unstable carotid atherosclerotic plaques than in patients with stable plaques or without plaques.31 According to Ridker et al., hs-CRP has been established as an independent risk factor for future cardiovascular events. It adds prognostic information to the Framingham risk score and at all levels of the metabolic syndrome.32 The findings of our study support this opinion. We believe that the presumed pathophysiological mechanism of atherosclerotic plaque destabilisation in patients with stable coronary artery disease could be via activation of the macrophages in plaques, which leads to secretion of metalloproteinases, cathepsins and collagenases. These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture and initiate plaque thrombosis. Pre-interventional intravascular ultrasound studies of patients with acute myocardial infarction have shown significantly more plaque rupture in patients with elevated hs-CRP levels, suggesting that this may reflect the inflammatory activity of a ruptured plaque and/or the plausible intensification of focal inflammatory processes that destabilise vulnerable plaques.33 Results from this study have shown that measurement of CIMT should be used as a tool to identify individuals with coronary atherosclerosis, but when these changes are associated with increased levels of hs-CRP (in the absence of other causes for the increase in hs-CRP levels) then destabilisation of stable CAD should be considered. The small sample size was a major limitation of this study. Larger epidemiological studies are needed to clarify the diagnostic value of CIMT to identify CAD, and the usefulness of hS-CRP for the prediction of acute coronary syndromes in cases with increased CIMT.

7. 8. 9. 10.

11.

12.

13.

14.

15.

16.

17. 18.

Conclusion Measurement of CIMT is a non-invasive predictor of CAD but it has little prognostic value in predicting CAD events. While hs-CRP is a good predictor of acute coronary events, normal values of hs-CRP do not exclude the presence of stable CAD. The determination of hs-CRP and CIMT together could help in the diagnosis of CAD, and for predicting coronary events. We support the consensual statements for the assessment of CIMT and hs-CRP in individuals who are traditionally considered to be at moderate cardiovascular risk.

References 1. 2. 3. 4.

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Efficacy and safety of sirolimus-eluting stents versus bare-metal stents in coronary artery disease patients with diabetes: a meta-analysis YANXIANG QIAO, YUAN BIAN, XIANLIANG YAN, ZHENFANG LIU, YUGUO CHEN

Abstract Objective: To compare by meta-analysis the efficacy and safety of sirolimus-eluting and bare-metal stents in coronary artery disease (CAD) patients with diabetes. Methods: PubMed, MEDLINE and EMBASE were searched from 1971 to 2012. Data on the efficacy and safety of sirolimus-eluting and bare-metal stents in patients with diabetes were collected. A meta-analysis was then performed on a total of 1 259 CAD patients with diabetes from six studies. The odds ratio (OR) was used for comparison. Subgroup analysis was performed according to the sample size, year of study, subjects’ geographic area and study method. Results: Compared with those in the bare-metal stent group (BMS), the subjects in the sirolimus-eluting stent (SES) group had a reduced risk for major cardiac events [OR 0.42, 95% confidence interval (CI): 024–0.74, p < 0.01] and target-lesion revascularisation (OR 0.26, 95% CI: 0.11–0.59, p < 0.01). There was no difference for myocardial infarction (OR 0.92, 95% CI: 0.61–1.40, p > 0.05) or mortality (OR 1.19, 95% CI: 0.74–1.92, p > 0.05). Subgroup analysis showed a significant difference for overall risk of major cardiac events between SES and BMS when the sample size was ≤ 90 (OR 0.28, 95% CI: 0.16–0.48, p < 0.01), when it was a randomised control trial (RCT) (OR 0.28, 95% CI: 0.19–0.42, p < 0.01), or when it was performed on European subjects (OR 0.45, 95% CI: 0.27–0.77, p < 0.01). The sensitivity was not different when one study was removed at a time. Conclusion: Our study confirmed that SES are safer and more effective than BMS in CAD patients with diabetes, as far as major cardiac events are concerned. Keywords: sirolimus-eluting stent, bare-metal stent, diabetes, meta-analysis, efficacy, safety Submitted 22/5/13, accepted 14/8/13 Cardiovasc J Afr 2013; 24: 274–279

www.cvja.co.za

DOI: 10.5830/CVJA-2013-062

According to Nodari et al., compared to patients without diabetes, those with diabetes mellitus (DM) had increased cardiovascular morbidity and mortality, and were more likely to develop congestive heart failure (CHF).1 Van Nunen used

Department of Emergency Medicine, Qilu Hospital, Shandong Univeristy, Shandong, China YANXIANG QIAO, MD YUAN BIAN, MD XIANLIANG YAN, MD ZHENFANG LIU, MD YUGUO CHEN, MD, PhD, dr.yuguo.chen@gmail.com

coronary stents for revascularisation in acute cardiac events and improved the prognosis, with a high success rate and favourable early outcome.2 The traditional bare-metal stent (BMS) was initially widely used, with considerable efficacy and safety. However, longterm outcome and restenosis rate has been very discouraging.3 Recently, sirolimus-eluting stents (SES) have been increasingly used for treating restenosis after having used BMS, as well as for treating the native coronary narrowing.4-7 For coronary arterial disease (CAD) patients with diabetes, the outcome, efficacy and safety of SES and BMS remain controversial,8-16 mainly due to small sample sizes or low statistical power. Meta-analysis, combining results of several studies and producing a single estimate of major events with enhanced precision, has been considered a powerful tool for summarising inconsistent results from different studies.17-20 Heterogeneity and publication bias can be detected with funnel plots and other methodologies.21-26 To clarify this controversy, in this study, we performed a meta-analysis and subgroup analysis, along with heterogeneity and publication-bias analysis, and compared the major cardiac events, target-lesion revascularisation, myocardial infarction and mortality rate in CAD patients with diabetes who were treated with SES or BMS.

Methods PubMed, MEDLINE, EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google scholar were searched. The following keywords were used, ‘sirolimus-eluting stents’, ‘baremetal stents’, ‘coronary arterial disease’, ‘diabetes’, ‘diabetic’, ‘safety’, ‘efficacy’, ‘study’ and ‘trial’. The time period was limited from 1 January 1971 to 31 December 2012. The language published in was limited to English only. References of the articles were also checked for additional studies. Studies included were randomised, controlled trials (RCT) and non-RCT conducted in coronary artery disease patients with diabetes treated with SES or BMS (studies with these two methods compared), regardless of the sample size. Excluded studies were those investigating patients with CAD or DM in only case reports or review articles, duplicated articles, and those with no comparison of SES and BMS. After the investigators were trained, the data-mining form was developed and modified. The data included study details such as first author, year of study, year of publication, geographical area of subjects, demographics of subjects, and events with follow up after being treated with SES or BMS. According to the standard protocol, two investigators (A and B) mined the data independently, which was reviewed by the third one (C). Discrepancies were resolved through internal and external discussions (with the original investigators).

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Statistical analysis Analysis was performed with software review manager 5.1 (Cochrane collaboration, http://ims.cochrane.org/revman) and comprehensive meta-analysis (Englewood, NJ); p < 0.05 was regarded as statistically significant. Meta-analysis was performed in fixed- or random-effect models. Odds ratios (OR) and 95% confidence intervals (CI) were estimated in each study. Pooled ORs were obtained using the Mantel-Haenszel method in a fixed-effect model, and the DerSimonian-Laid method in a random-effects model.24 The significance of pooled ORs was determined by the Z-test. Cochrane’s Q-statistic was used to assess within- and betweenstudies variations. A p < 0.10 on the Q-statistic was regarded as heterogeneity across the studies. I2 was also used to test heterogeneity with the formula:

3 658 potentially relevant reports identified and screened (Pubmed, 1103; MEDLINE, 765; Springer, 650; Elsevier Science Direct, 880 Cochrance Library, 50; Google Scholar 210)

323 potentially relevant reports after duplicates removed 323 excluded by review of abstract (65 reviews; 156 not diabetic patients; 55 not reported BMS data) 47 retrieved for detailed assessment 41 excluded by review of full text (25 for only reported EMS data but not for comparison; 16 due to not available data)

(Q − df)      × 100% I =   _______ 2

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where I2 < 25% means no heterogeneity; I2 = 25–50% means moderate heterogeneity; I2 > 50% means large or extreme heterogeneity.27 The random-effects model was also used for evaluating the possibility of heterogeneity of studies. Publication bias was evaluated with Egger’s test and funnel plots,28 which compensate for each other’s drawbacks. If there is evidence of publication bias, the funnel plot is noticeably asymmetric. For the Egger’s test the significance level was set at 0.05. Sensitivity analysis was also performed to test reliability of the results, by removing one study at a time and repeating the meta-analysis.

Results As shown in Fig. 1, among 3 658 articles potentially relevant to the search terms (PubMed: 1 103; MEDLINE: 765; Springer: 650; Elsevier Science Direct: 880; Cochrane Library: 50; Google Scholar: 210), 323 potentially relevant studies were selected after the duplicates were removed. When the abstracts were screened,

6 separate studies included in meta-analysis

Fig. 1. Flow chart of selection of the studies.

276 were excluded (65 were review articles, 156 were not diabetic patients, 55 did not report on BMS data). Among the remaining 47, another 41 were excluded (25 only reported on BMS data without comparisons, 16 were excluded due to unavailable data). Finally, six studies were included in this meta-analysis. The characteristics of the included studies are presented in Table 1. These six studies were conducted from 2002 to 2006 and published between 2005 and 2008, three in Europeans, two in Americans, and one in Asians and Americans. A total of 1 259 CAD subjects with diabetes (SES 614 and BMS 645) were included, with an average age of 65 years. The sample sizes ranged from 83 to 458, and the studies were RCTs and non-RCTs.

TABLE 1. CHARACTERISTICS OF STUDIES INCLUDED IN THE META-ANALYSIS

Study Aoki J, et al. Jimenez-Quevedo P, et al. Baumgart D, et al. Daemen J, et al. Chan C, et al. Maresta A, et al.

Study year 2002–2003 2003 2002–2004 2002–2003 2002–2004 2004–2006

Study Country Ethnicity method Netherlands European Non-RCT United States America RCT Germany European RCT United States America Non-RCT United States and Asia America and Asian RCT Italy European RCT

Follow up (years) 1 1 1 1 1 1

SES group BMS group Sample Sample size Age (years) size Age (years) 112 63 ± 10 118 64 ± 11 80 65.4 ± 8 80 67.9 ± 9 94 66 ± 9 96 66 ± 10 206 62.0 ± 10 252 62.7 ± 10 54 58.7 ± 9.7 29 62.5 ± 10.3 68 71 ± 9 70 69 ± 9

TABLE 2. POOLED ODDS RATIO FOR THE SES VERSUS THE BMS GROUP Subgroups Overall effects Sample size ≤ 90 Sample size > 90 RCT Non-RCT European American and Asian

No. of studies 6 3 3 4 2 3 3

Random model OR (95% CI) Z 0.42 (0.24–0.74) 3.00 0.28 (0.16–0.48) 4.60 0.61 (0.31–1.21) 1.42 0.28 (0.19–0.42) 6.14 0.87 (0.61–1.24) 0.76 0.45 (0.27–0.77) 2.95 0.37 (0.11–1.27) 1.58

p value < 0.01 < 0.01 0.15 < 0.01 0.446 < 0.01 0.115

Q 20.14 2.39 8.70 2.40 0.92 3.71 15.55

Test of heterogeneity p-value I2 (%) < 0.01 75.2 0.303 16.3 0.013 77.0 0.495 0.0 0.338 0.0 0.156 46.1 < 0.01 87.1

Egger’s test for publication bias t p-value –4.19 0.014 –3.66 0.62 –9.26 0.20 –2.36 0.531 –5.29 – –7.98 0.46 –5.92 0.23

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The efficacy of SES versus BMS is presented in Table 2. As shown, the pooled OR was 0.42 (95% CI: 0.24–0.74, p < 0.01) for SES versus BMS. This suggests that, after the data had been pooled, SES were more effective than BMS in CAD patients with diabetes. However, there was publication bias (t = –4.19, p < 0.05). As shown in Fig. 2A, the pooled OR was 0.42 (95% CI: 0.24–0.74, p < 0.01) for overall events, suggesting that SES had a better outcome compared with BMS, with a greater reduction in risk for major cardiac events. However, there were heterogeneities between the studies (Q2 = 20.14, I2 = 75.0%, p < 0.1) and publication bias, as shown in Fig. 2B (asymmetric funnel plot). This was further confirmed with Egger’s linear regression test, shown in Table 2 (t = –4.19, p < 0.05). As shown in Fig. 3, the pooled OR was 0.26 (95% CI: 0.11– 0.59, p < 0.01) for SES versus BMS, suggesting that SES had a better revascularisation rate for target lesions compared with BMS. However, there were heterogeneities between the studies A

M–H, random, (95% CI)

Aoki J, et al.

112

118

18.5

0.70 (0.39–1.24)

Baumgart D, et al.

17.2

0.29 (0.15–0.58)

0.2

12.8

0.25 (0.09–0.71)

206

252

20.1

1.00 (0.64–1.56)

15.0

0.18 (0.07–0.41)

16.4

0.42 (0.20–0.90)

100.0

0.42 (0.24–0.74)

Jimenez-Quevedo P, et al. Maresta A, et al. Total (95% CI) Total events

614

645

117

SE (log OR)

Total

Daemen J, et al.

BMS

Odds ratio

Events

Weight (%)

Odds ratio

Total

Chan C, et al.

SES

(Q2 = 24.44, I2 = 80.0%, p < 0.1) and publication bias (t = –6.44, p < 0.05). As shown in Fig. 4, the pooled OR was 0.92 (95% CI: 0.61– 1.40, p > 0.05) for SES versus BMS, suggesting that the overall risk for myocardial infarction was not significantly different between these two groups. There was no heterogeneity between the studies (Q2 = 4.37, I2 = 0%, p > 0.1) but there was publication bias (t = –3.44, p < 0.05). As shown in Fig. 5, the pooled OR was 1.19 (95% CI: 0.74–1.92, p > 0.05) for SES versus BMS, suggesting that the overall risk of mortality was not significantly different between the groups. There was no publication bias (t = –1.69, P > 0.05) or heterogeneities between the studies (Q2 = 3.88, I2 = 0.0%, p > 0.1). Subgroup analyses were stratified by sample size, subjects’ geographical area and study method. As shown in Table 2 and Figure 6A–C, the pooled OR was 0.28 (95% CI: 0.16–0.48, p < 0.01, Fig. 6A) for SES versus BMS in studies whose sample size

Events

Study or subgroup

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0.4 0.6 0.8

200

0.01 0.1 SES

Heterogeneity: Tau2 = 0.36; Chi2 = 20.14, df = 5 (p = 0.001); I2 = 75% Test for overall effect: Z = 3.00 (p = 0.003)

10 100 BMS

0.01 0.1

100

Fig. 2. A: Forest plots of studies with major adverse cardiac events in the SES group versus the BMS group. B: Funnel plots of studies with major adverse cardiac events in the SES group versus the BMS group. Odds ratio

Odds ratio

Events

SES Total

Events

Total

Weight (%)

M–H, random, (95% CI)

Aoki J, et al.

112

118

17.9

0.36 (0.16–0.82)

Baumgart D, et al.

14.6

0.10 (0.03–0.34)

Chan C, et al.

15.7

0.28 (0.09–0.85)

206

252

19.9

0.98 (0.57–1.67)

Jimenez-Quevedo P, et al.

16.4

0.12 (0.04–0.34)

Maresta A, et al.

15.5

0.15 (0.05–0.45)

100.0

0.26 (0.11–0.59)

Study or subgroup

Daemen J, et al.

Total (95% CI) Total events

BMS

614

645

141

0.01 0.1 SES

Heterogeneity: Tau2 = 0.83; Chi2 = 24.44, df = 5 (p = 0.0002); I2 = 80% Test for overall effect: Z = 3.22 (p = 0.001)

10 100 BMS

Fig. 3. Forest plots of studies with target-lesion revascularisation events in the SES group versus the BMS group. SES Study or subgroup Aoki J, et al. Baumgart D, et al. Chan C, et al. Daemen J, et al. Jimenez-Quevedo P, et al. Maresta A, et al.

Weight (%)

Odds ratio

M–H, random, (95% CI)

Total

Events

Total

112

118

25.1

1.42 (0.67–3.02)

10.4

0.81 (0.21–3.11)

5.6

0.25 (0.02–2.94)

206

252

20.7

1.12 (0.47–2.69)

12.8

0.32 (0.06–1.62)

25.4

0.77 (0.32–1.85)

100.0

0.92 (0.61–1.40)

Total (95% CI) Total events

BMS

Events

614 46

Heterogeneity: Chi2 = 4.37, df = 5 (p = 0.50); I2 = 0% Test for overall effect: Z = 0.37 (p = 0.71)

645 52

0.01 0.1 SES

Fig. 4. Forest plots of studies with myocardial infarction events in the SES group versus the BMS group.

10 100 BMS

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SES Study or subgroup Aoki J, et al.

Odds ratio

Events

Total

Events

BMS Total

Weight (%)

M–H, random, (95% CI)

112

118

22.2

1.81 (0.72–4.54)

Baumgart D, et al.

12.1

1.29 (0.34–4.97)

Chan C, et al.

10.3

0.10 (0.00–2.18)

206

252

43.0

1.16 (0.56–2.40)

Jimenez-Quevedo P, et al.

6.4

0.49 (0.04–5.56)

Maresta A, et al.

Daemen J, et al.

Total (95% CI) Total events

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614 37

70 645

6.1

1.57 (0.25–9.70)

100.0

1.19 (0.74–1.92)

Heterogeneity: Chi2 = 3.88, df = 5 (p = 0.57); I2 = 0% Test for overall effect: Z = 0.72 (p = 0.47)

Fig. 5. Forest plots of studies with mortality events in the SES group versus the BMS group.

was above 90, with heterogeneities between the studies (Q2 = 8.7, I2 = 77%, p < 0.1). The pooled OR was 0.61 (95% CI: 0.31–1.21, p > 0.05, Fig. 6A) in studies whose sample size was 90 or less, without heterogeneities between the studies (Q2 = 2.39, I2 = 16%, p > 0.1). The pooled OR was 0.45 (95% CI = 0.27–0.77, p < 0.01, Fig. 6B) in studies whose subjects were European, without heterogeneities between the studies (Q2 = 3.71, I2 = 46%, p > 0.1). The pooled OR was 0.37 (95% CI: 0.11–1.27, p > 0.05, Fig. 6B) in studies whose subjects were American and Asian, with heterogeneities between the studies (Q2 = 15.55, I2 = 87%, p < 0.1). The pooled OR was 0.28 (95% CI: 0.19–0.42, p < 0.01, Fig. 6C) in studies whose study method was RCT, without heterogeneities between the studies (Q2 = 2.4, I2 = 0%, p > 0.1). The pooled OR was 0.87 (95% CI: 0.61–1.24, p > 0.05, Fig. 6C) in studies whose method of study was non-RCT, without heterogeneities between the studies (Q2 = 0.92, I2 = 0%, p > 0.1). By removing one study at a time, a sensitivity analysis was performed and the model was rerun to determine the effect on each estimate. It showed that the above meta-analysis estimates did not change significantly after removal of each study, implying that these results were statistically reliable.

Discussion A growing number of studies has shown the efficacy and safety of SES versus BMS for treating CAD patients with diabetes,9,29 but the outcome has been controversial. In this analysis, we retrieved six studies, which included 1 259 CAD subjects with diabetes, and performed a meta-analysis. It showed that the SES group had a significant reduction in major adverse cardiac events, as well as target-lesion revascularisations, compared with the BMS group. There was no significant difference for myocardial infarction or mortality. These results are consistent with a recent study that suggested a significant reduction in target-vessel revascularisations with SES, but with similar mortality rates.9 Unlike this study, in which the incidence of myocardial infarction was higher, our analysis showed no difference for myocardial infarctions between the groups. Another recent study conducted in Europeans confirmed the efficacy of SES compared with BMS, along with comparable mortality rates and myocardial infarctions,11 which further proved the validity of our analysis. The efficacy and safety of SES have been receiving more and more supportive reports.30-33 The uniqueness of our analysis and findings is that it proved the efficacy and safety of SES in CAD patients with diabetes.

0.01 0.1 SES

10 100 BMS

Heterogeneity is one major concern with regard to the validity of meta-analyses.26,34 Non-homogeneous data can easily give misleading results. In our study, the Q and I2 statistics were performed to test heterogeneity. For all samples, there was significant heterogeneity for major adverse cardiac events in the SES and BMS groups. We further conducted subgroup analysis according to sample size, ethnicity and study method. It demonstrated that in the studies where sample size was ≤ 90, method was a RCT and population was European, the overall major cardiac events were significantly different between the SES and BMS groups. Heterogeneity between the studies was decreased after stratifying the samples. No significant heterogeneity was observed with RCTs, suggesting an RCT is important for good results. More high-quality RCTs are therefore warranted. Another concern for meta-analyses is publication bias, due to selection of the studies included. In this study, using funnel plots and Egger’s test,28,35,36 we found publication bias for overall major cardiac events, target-lesion revascularisations and myocardial infarction, but not for overall mortality. Furthermore, the sensitivity analysis confirmed there was no change if one study was removed at a time. Although more studies would have produced better results, overall, our results were statistically reliable.

Conclusion This meta-analysis suggested that, compared with BMS, SES are more effective and safer for reducing major cardiac events in CAD patients with diabetes. This may indicate the direction for future trials and clinical implementation.

References 1.

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Nodari S, Manerba A, Vaccari A, Milesi G, Carubelli V, Lazzarini V, et al. Six-year prognosis of diabetic patients with coronary artery disease. Eur J Clin Invest 2012; 42(4): 376–383. Van Nunen LX, Tonino PA. Recent insights into the treatment of stable CAD: FFR-guided PCI vs. medical therapy. Herz 2013. 2013 Apr 17. [Epub ahead of print]. Haase J, Jung T, Störger H, Hofmann M, Reinemer H, Schwarz CE, et al. Long-term outcome after implantation of bare metal stents for the treatment of coronary artery disease: rationale for the clinical use of antiproliferative stent coatings. J Interv Cardiol 2003; 16(6): 469–473. Lemos PA, Bienert I. The Supralimus® sirolimus-eluting stent. Expert Rev Med Devices 2013. 2013 Apr 18. [Epub ahead of print]. Hsieh IC, Chang SH, Wang CY, Lee CH, Lin FC, Chen CC. Acute and long-term outcomes of ostial stentings among bare-metal stents, sirolimus-eluting stents, and paclitaxel-eluting stents. Coron Artery Dis

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A SES BMS Study or subgroup Events Total Events Total 6.2.2 Both groups’ sample size > 90 Aoki J, et al. 27 112 37 118 Baumgart D, et al. 15 94 38 96 Daemen J, et al. 44 206 54 252 Subtotal (95% CI) 412 466 Total events 86 129 Heterogeneity: Tau2 = 0.28, Chi2 = 8.70, df = 2 (p = 0.01); I2 = 77% Test for overall effect: Z = 1.42 (p = 0.15) 6.2.3 Both groups’ sample size ≤ 90 Chan C, et al. 8 54 Jimenez-Quevedo P, et al. 8 80 Maresta A, et al. 15 68 Subtotal (95% CI) 202 Total events 31 Heterogeneity: Tau2 = 0.04, Chi2 = 2.39, df = 2 (p = 0.30); I2 = 16% Test for overall effect: Z = 4.60 (p < 0.00001)

Weight (%)

Odds ratio M–H, random, (95% CI)

18.5 17.2 20.1 55.8

0.71 (0.39–1.24) 0.29 (0.15–0.58) 1.00 (0.64–1.56) 0.61 (0.31–1.20)

179

12.8 15.0 16.4 44.2

0.25 (0.09–0.71) 0.18 (0.07–0.41) 0.42 (0.20–0.90) 0.28 (0.16–0.48)

645

100.0

0.42 (0.24–0.74)

12 31 28

29 80 70

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Odds ratio M–H, random, (95% CI)

Total (95% CI) 614 Total events 117 200 Heterogeneity: Tau2 = 0.36, Chi2 = 20.14, df = 5 (p = 0.001); I2 = 75% Test for overall effect: Z = 3.00 (p = 0.003) Test for subgroup differences: Chi2 = 3.12, df = 1 (p = 0.08); I2 = 68.0%

0.01 0.1 SES

B SES BMS Study or subgroup Events Total Events Total 1.1.1 European Subgroup Aoki J, et al. 27 112 37 118 Baumgart D, et al. 15 94 38 96 Maresta A, et al. 15 68 28 70 Subtotal (95% CI) 274 284 Total events 57 103 Heterogeneity: Tau2 = 0.10, Chi2 = 3.71, df = 2 (p = 0.16); I2 = 46% Test for overall effect: Z = 2.95 (p = 0.003) 1.1.2 American and Asian Chan C, et al. 8 54 12 Daemen J, et al. 44 206 54 Jimenez-Quevedo P, et al. 8 80 31 Subtotal (95% CI) 340 Total events 60 97 Heterogeneity: Tau2 = 1.02, Chi2 = 15.55, df = 2 (p = 0.0004); I2 = 87% Test for overall effect: Z = 1.58 (p = 0.11) Total (95% CI) 614 Total events 117 200 Heterogeneity: Tau2 = 0.36, Chi2 = 20.14, df = 5 (p = 0.001); I2 = 75% Test for overall effect: Z = 3.00 (p = 0.003) Test for subgroup differences: Chi2 = 0.09, df = 1 (p = 0.77); I2 = 0%

Weight (%)

Odds ratio M–H, random, (95% CI)

18.5 17.2 16.4 52.1

0.70 (0.39–1.24) 0.29 (0.15–0.58) 0.42 (0.20–0.90) 0.45 (0.27–0.77)

361

12.8 20.1 15.0 47.9

0.25 (0.09–0.71) 1.00 (0.64–1.56) 0.18 (0.07–0.41) 0.37 (0.11–1.27)

645

100.0

0.42 (0.24–0.74)

29 252 80

5.1.2 Non-RCT Aoki J, et al. 27 112 37 Daemen J, et al. 44 206 54 Subtotal (95% CI) 318 Total events 71 91 Heterogeneity: Tau2 = 0.00, Chi2 = 0.92, df = 1 (p = 0.34); I2 = 0% Test for overall effect: Z = 0.76 (p = 0.45)

118 252 370

Total (95% CI) 614 645 Total events 117 200 Heterogeneity: Tau2 = 0.36, Chi2 = 20.14, df = 5 (p = 0.001); I2 = 75% Test for overall effect: Z = 3.00 (p = 0.003) Test for subgroup differences: Chi2 = 16.81, df = 1 (p < 0.0010); I2 = 94.1%

Weight (%)

Odds ratio M–H, random, (95% CI)

17.2 12.8 15.0 16.4 61.4

0.29 (0.15–0.58) 0.25 (0.09–0.71) 0.18 (0.07–0.41) 0.42 (0.20–0.90) 0.28 (0.19–0.42)

18.5 20.1 38.6

0.70 (0.39–1.24) 1.00 (0.64–1.56) 0.87 (0.61–1.24)

100.0

0.42 (0.24–0.74)

10 100 BMS

Odds ratio M–H, random, (95% CI)

0.01 0.1 SES

C SES BMS Study or subgroup Events Total Events Total 5.1.1 RCT Baumgart D, et al. 15 94 38 96 Chan C, et al. 8 54 12 29 Jimenez-Quevedo P, et al. 8 80 31 80 Maresta A, et al. 15 68 28 70 Subtotal (95% CI) 296 275 Total events 46 109 Heterogeneity: Tau2 = 0.00, Chi2 = 2.40, df = 3 (p = 0.49); I2 = 0% Test for overall effect: Z = 6.14 (p = 0.00001)

10 100 BMS

Odds ratio M–H, random, (95% CI)

0.01 0.1 SES

10 100 BMS

Fig. 6. A: Forest plots of sample size subgroups. B: Forest plots of ethnicity subgroups. C: RCT or non-RCT subgroups.

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10.

11.

12.

13.

14.

15.

16.

17.

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18. DerSimonian R. Meta-analysis in the design and monitoring of clinical trials. Stat Med 1996 15(12): 1237–1248. 19. Klebanoff MA, Levine RJ, DerSimonian R. Large trials vs meta-analysis of smaller trials. J Am Med Assoc 1997; 277(5): 376–377. 20. Geller N, Freedman L, Lee YJ, DerSimonian R. Conference on metaanalysis in the design and monitoring of clinical trials. Stat Med 1999; 18(6): 753–754. 21. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097. 22. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. Br Med J 2011; 343: D4002. 23. DerSimonian R, Levine RJ.. Resolving discrepancies between a metaanalysis and a subsequent large controlled trial. J Am Med Assoc 1999; 282(7): 664–670. 24. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 2007; 28(2): 105–114. 25. Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects metaanalyses. Br Med J 2011; 342(d549). 26. Moreno SG, Sutton AJ, Thompson JR, Ades AE, Abrams KR, Cooper NJ. A generalized weighting regression-derived meta-analysis estimator robust to small-study effects and heterogeneity. Stat Med 2012; 31(14): 1407–1417. 27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11): 1539–1558. 28. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315(7109): 629–634. 29. Jiménez-Quevedo P, Hernando L, Gómez-Hospital JA, Iñiguez A, Sanroman A, Alfonso F, Hernández-Antolín R, et al. Sirolimus-eluting stent versus bare metal stent in diabetic patients: the final five-year follow-up of the DIABETES trial. EuroIntervention 2013; 2013 Mar 22. pii: 20120620-01. [Epub ahead of print]. 30. Galassi AR, Tomasello SD, Costanzo L, Campisano MB, Barrano G, Tamburino C. Long-term clinical and angiographic results of Sirolimus-Eluting Stent in Complex Coronary Chronic Total Occlusion Revascularization: the SECTOR registry. J Interv Cardiol 2011; 24(5): 426–436. 31. De Waha A, Dibra A, Kufner S, Baumgart D, Sabate M, Maresta A, Schömig A, Kastrati A. Long-term outcome after sirolimus-eluting stents versus bare metal stents in patients with diabetes mellitus: a patient-level meta-analysis of randomized trials. Clin Res Cardiol 2011; 100(7): 561–570. 32. Kandzari DE, Rao SV, Moses JW, Dzavik V, Strauss BH, Kutryk MJ, Simonton CA, et al; ACROSS/TOSCA-4 investigators. Clinical and angiographic outcomes with sirolimus-eluting stents in total coronary occlusions: the ACROSS/TOSCA-4 (Approaches to Chronic Occlusions With Sirolimus-Eluting Stents/Total Occlusion Study of Coronary Arteries-4) trial. J Am Coll Cardiol Cardiovasc Interv 2009; 2(2): 97–106. 33. Byrne RA, Kastrati A. Is there a preferable DES in diabetic patients? A critical appraisal of the evidence. Catheter Cardiovasc Interv 2008; 72(7): 944–949. 34. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002; 21(11): 1559–1573. 35. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 2001; 54(10): 1046–1055. 36. Zwahlen M, Renehan A, Egger M. Meta-analysis in medical research: potentials and limitations. Urol Oncol 2008; 26(3): 320–329.

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Prevalence and significance of early repolarisation in a black African population: data of 246 individuals with cardiovascular morbidity AIME BONNY, DOMINIQUE NOAH NOAH, SYLVIE NDONGO AMOUGOU, CECILE SAKA

Abstract Background: Early repolarisation (ER) is commonly seen on electrocardiograms (ECG). Recent reports have described the relationship between ER and sudden cardiac death (SCD). The prevalence and significance of ER have not been studied in black Africans. Methods: We matched clinical and ECG records of subjects over 18 years of age who consulted a cardiac unit in two medical centres of Douala, Cameroon. A questionnaire focusing on past history of syncope or family history of sudden unexplained death (SUD) was filled in by each subject. A 12-lead ECG was recorded by a trained nurse and analysed by two independent physicians. Results: Of the 752 ECGs recorded, we studied 246 index cases. The mean age of subjects was 45 ± 16 years and 53% were female. Almost 57% had hypertension, 41% had palpitations and 18% reported a history of syncope. ER pattern was found in 20% [slurring in three (3%), notching in 13% and both in three (7%)]. ER subjects were younger than those without (41 ± 16 vs 49 ± 16 years, p = 0.0048). Lead localisation was predominantly the laterals for the slurring pattern, whereas the inferior and lateral leads were equally involved for the notching pattern. Negative T waves in the infero-lateral leads were associated with ER (p = 0.00025). Among the subjects with syncope, 41% displayed ER and 13% did not have ER (p = 0.00014). The notching pattern seemed to be associated with syncope (p = 0.00011). Conclusion: Early repolarisation is frequent in black Africans, especially in the setting of cardiovascular morbidity. Early repolarisation may be associated with a past history of syncope, especially the notched pattern.

Early repolarisation (ER) is an electrocardiographic pattern that consists of early onset as well as an elevation of the transitional QRST–ST junction over 0.1 mV (J-point elevation or JPE) between the depolarisation end and the repolarisation onset of the ventricles.1,2 This electrophysiological phenomenon is recorded in a surface electrocardiogram (ECG) as J-point elevation, followed by ST-segment elevation and frequently T-wave inversion. The J-point elevation displays two types, including the notching and slurring patterns (Fig. 1). Interest in this ECG feature is on the increase since it seems not always to be a benign phenotype,3-5 as was previously thought.6-9 Indeed, there is growing interest in establishing a correlation between ER and adverse outcomes (Fig. 2).10-13 As the prevalence of ER is common in the general population and thought to occur more in blacks (Fig. 3),1 management of subjects with unexplained syncope and ER in their ECGs may be challenging, particularly in black populations. We aimed to assess the prevalence and significance of ER patterns in a black African population in the setting of tertiary hospitals in Cameroon.

Methods Over a two-week period, we matched ECG and clinical data from a sample of patients fulfilling the following inclusion

Keywords: early repolarisation, syncope, ethnicity, black Africans Submitted 30/11/12, accepted 15/8/13 Cardiovasc J Afr 2013; 24: 280–285

www.cvja.co.za

DOI: 10.5830/CVJA-2013-063

Faculty of Medicine and Phamaceutical Sciences, University Hospital of Douala, Douala, Cameroon AIME BONNY, MD, aimebonny@yahoo.fr

Department of Gastroenterology, Central Hospital of Yaoundé, Yaoundé, Cameroon DOMINIQUE NOAH NOAH, MD

Services de réanimation et de cardiologie, Centre HospitaloUniversitaire de Yaoundé, Yaoundé, Cameroon SYLVIE NDONGO AMOUGOU, MD

Laboratory of Electrocardiography, Hôpital Laquintinie, Douala, Cameroon CECILE SAKA, MSc

Fig. 1. Two distinct variants of early repolarisation in the lateral leads with the J-point elevation ≥ 1 mm. On the left, the ‘notch’ variant, which consists of a positive hump in the QRS–ST junction (a prominent J point resembling an Osborn wave). On the right, the ‘slur’ variant, which is a smooth deflection resembling a delta wave in the terminal portion of the descending part of an R wave.

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Fig. 2. The ECG of a 39-year-old African who experienced syncope during soccer. Detailed examination was normal. Slurring type early repolarisation variant in leads DI and V4‒V6 was the sole diagnostic finding. 1

Fig. 3. ECGs featuring early repolarisation in four black African subjects. 1. Slurring pattern in the inferior leads with a ventricular ectopic beat. 2. Notching pattern in leads V4‒V6 together with slurring pattern in DI. 3. J-point elevation in leads DIII and VF. 4. Intermittent (2/3) notching pattern in the VL lead.

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criteria: adult subjects (> 18 years); cardiovascular symptoms or conditions such as palpitations, chest pain, dyspnoea, syncope, hypertension; and ECG done during the study period. The exclusion criteria were: any other causes of transient loss of consciousness such as seizure (Table 1); subjects with low-amplitude ECG waves; subjects with a permanent pacemaker, as ventricular stimulation alters repolarisation; any drug that could potentially modify the QRS, Q-T and ST-T duration and morphology (Table 1); subjects who did not sign the consent form. Each subject filled in a questionnaire focusing on a past history of transient loss of consciousness (TLOC) or family history of sudden cardiac death (SCD). The diagnosis of syncope was based on the European Society of Cardiology (ESC) guidelines.10 Detailed physical evaluation was performed. The ethics committees of both hospitals approved the protocol. A trained nurse recorded the ECGs using a paper speed of 25 mm/s at 10 mm/mV. After a resting period of at least 5 min, the ECG was registered in the supine position using a numerical electrocardiograph with the capability to review and modify the value of the parameters. Resting 12-lead ECG for each subject was analysed independently by two trained physicians. A diagnosis of ER was retained if both examiners concluded that at least two consecutive leads displayed a slurring or notching pattern of the descending part of the R wave or a prominent J wave with ST-segment elevation ≥ 1 mm in the lateral or inferior leads. We also paid attention to variation of the J-T segment as ascending, descending or horizontal morphology. For a practical understanding, we attributed the term type 1 (t1) to the slurring variant of ER and type 2 (t2) to the notching variant. We divided our sample into four groups: ERt1 = early repolarisation type 1, ERt2 = early repolarisation type 2, ERt1t2 = mixed variant, and ER– = the normal pattern of repolarisation.

Statistical analysis Continuous variables are expressed as means ± SD and statistical significance was assessed using the unpaired Student’s t-test, TABLE 1. DIFFERENTIAL DIAGNOSIS BETWEEN SYNCOPE AND SEIZURE Mechanism

Syncope Global transient cerebral hypoperfusion

Age (years) at Over 45 if coronary first manifestation artery disease Mainly < 45 if other cardiac causes such as channelopathies Symptoms Before TLOC Nausea Vomiting Sweating and body cold During TLOC Brief clonic movement (< 15 sec) always secondary to LOC

Seizure Abnormal excessive or synchronous neuronal activity Less than 45 (often, apart from secondary seizure due to brain damage)

Aura (funny smell) Crying

Prolonged clonic movement at the beginning of LOC Automatism Blue face After TLOC Nausea Prolonged disorientation Pale face Post-event amnesia Normal orientation Weakness, courbature TLOC = transient loss of consciousness; LOC = loss of consciousness.

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or Mann-Whitney U-test where used to compare mean values between two groups of subjects with ER (ER+) and without (ER–). Categorical variables, were summarised as proportions, and compared using the χ2 test or Fischer’s exact test. ANOVA and the Kruskal-Wallis test were used to compare mean values between more than two subgroups (ERt1, ERt2, ERt1t2, ER–). The Bonferroni correction was used for adjustment in multiple comparisons. All tests with a two-tailed p-value < 0.05 were considered statistically significant. Statistical analysis was performed with SPSS version 11.0.1 software (SPSS Inc)

Results Over the two-week period, ECGs were performed in 752 subjects, among whom 248 had cardiac symptoms (palpitations, past history of syncope, chest pain or dyspnoea) or cardiovascular morbidity (hypertension, diabetes, heart failure). Two subjects had low-amplitude ECGs, which did not permit analysis of the repolarisation and they were excluded. In the remaining 246 subjects studied, the mean age was 45 ± 16 years and 53% were female. The group with ER was younger: 41 ± 16 years versus 49 ± 16 years in subjects without ER (p = 0.0048). Baseline characteristics of the sample are shown in Table 2. There were 184 ambulatory subjects (75%). Indications for an ECG were hypertension screening in 57% subjects, and palpitations or dizziness in 41%. Two of the in-patients were diagnosed with acute heart failure, and 35 subjects (14.5%) had diabetes. TLOC was reported by 45 (18%) subjects, 19 (41%) in the ER group and 26 (13%) in the group without ER (p = 0.00014). A family history of sudden unexpected death (SUD) was reported in three cases (6.5%) in the ER group and in 14 cases (8.5%) in the group with normal repolarisation (p = ns). Atrial fibrillation was found in four (1.7%) subjects. ER was observed in 20% of the population, with the following distribution: slurring pattern in 3.3%, notching pattern in 13%, and both in 3.7%. Among the ER ECGs, we ascertained ascending J-T morphology in eight, descending in five and horizontal in 16 patients. TABLE 2. DEMOGRAPHIC, CLINICAL AND ELECTROCARDIOGRAPHIC CHARACTERISTICS OF THE SAMPLE Aetiology – – – – – – unknown hypertension

ER+ ER– (n = 49) (n = 197) p-value 41 ± 16 49 ± 16 0.0048 53 47 ns 29 28 ns 34 (14) 103 (43) ns 12 (5) 24 (10) ns 19 (41) 65 (33) ns 19 (41) 26 (13) 0.00014 0 2 ns 3 (6.5) 14 (8.6) ns 14 (9) 2 (1) 0.00025

Age (years) Female (%) BMI (kg/m2) Hypertension, n (%) Diabetes, n (%) Palpitation, n (%) Syncope, n (%) Acute HF Family history of SUD, n (%) T(–) wave, n (%) Drug therapy Beta-blockers 0 0 Amiodarone 0 0 Other anti-arrhythmics 0 0 Psychotropic drugs 0 0 ER = early repolarisation; BMI = body mass index; HF = heart failure; SUD = sudden unexpected death; T(–) wave = negative T wave.

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The slurring pattern was more frequent in the lateral leads (DI = 12%, V6 = 6% and V5 = 4%). The notching pattern was uniformly distributed in the limb and left precordial leads (DI and DII = 20%, VF = 18%, VL = 16%, V5 and V6 = 14%; p > 0.05). The prevalence of negative T waves was 3.7% in this population. In subjects with ER, seven (14%) displayed negative T waves, whereas only two (1%) without ER had this abnormality (p = 0.00025). Subjects with ECGs displaying the ER pattern had a more frequent past history of syncope (p = 0.00014). This association was more pronounced in the subgroup of patients with the notching variant of ER pattern (p = 0.0001), as shown in Table 3. However, we did not find any correlation between the J-T-segment variations (ascending, descending or horizontal) of ER and syncope. A family history of SUD was not more frequent in subjects with ER features (p = ns)

Some studies have described the variation in J-T-segment characteristics after the ER waveforms, the so-called descending, ascending and horizontal morphology, as having prognostic significance.15,16 Indeed, a horizontal/descending J-T segment in the inferior leads was associated with a significant risk of arrhythmic death, whereas the ascending morphology seemed to have a benign outcome.16 In our study, neither ascending nor horizontal/descending patterns were associated with syncope. One potential explanation could be the small sample size. We also emphasise that the heterogeneity of syncope could be a concern. Arrhythmogenic syncope as a risk marker of SCD merits a prospective investigation in subjects with ER pattern. Our study attempted to put this issue into perspective and discuss the current knowledge on the prevalence and significance of early repolarisation.

Discussion

ER and cardiovascular outcomes

In this study, we observed a high prevalence of ER in patients with a high rate of cardiovascular morbidity. The frequency of ER pattern found was higher than that reported in the general population.1,4 ER and syncope seemed to be linked, especially the notching pattern. The higher rate of ER in this specific population of subjects at risk for cardiac diseases could indicate a possible risk marker, or an ‘innocent bystander’ of this ECG pattern. Patients with ER more frequently had negative T waves, suggesting a select population with a poorer prognosis. This finding in such a specific population with a poor prognosis may indicate overlapping of an ER phenotype in cardiovascular outcomes. This study, as with several others, highlights the question of the relationship between ER and syncope.11,12 Most studies reporting the clinical significance of ER dealt with the strongest clinical outcome, which is sudden cardiac death due to ventricular tachyarrhythmias. As syncope has a heterogeneity of mechanisms and causes, it is difficult to evaluate its link with ER. Not all syncopes (e.g. reflex syncope and cardiogenic syncope) have the same explanation in terms of electrophysiological properties of ion channel exchanges driving the formation of J-point elevation (JPE).13,14 We assumed that non-cardiogenic syncope was not associated with the JPE pattern.

TABLE 3. COMPARISON BETWEEN SUBGROUPS ACCORDING TO TYPES OF EARLY REPOLARISATION ER– ER+ t1 ER+ t2 ER+ t1t2 (n = 197) (n = 8) (n = 32) (n = 9) p-value Age (years) 49 ± 16 30 ± 16 45 ± 15 35 ± 14 0.0031 Female, n (%) 107 (54) 4 (50) 14 (44) 3 (33) ns Palpitations, n (%) 65 (33) 3 (37) 10 (31) 6 (67) ns Syncope, n (%) 26 (13) 3 (37) 15 (47) 1 (11) 0.0001 Family SUD, n (%) 14 (7) 2 (25) 1 (3) 0 ns T(–) wave, n (%) 2 (1) 1 (< 1) 4 (2) 2 (1) 0.0004 Bonferroni correction was used to calculate the p-value. ERV– = absence of early repolarisation; ERV+ = presence of early repolarisation variant; t1 = type 1 or slurring pattern; t2 = type 2 or notching pattern; t1t2 = both patterns; T(–) wave = negative T wave; TLOC = transient loss of consciousness; SUD = sudden unexpected death.

ER seems to be associated with a high risk of cardiac arrest.3,17-23 The present study was not designed to confirm this finding. In the absence of other known causes of syncope, it is difficult to confirm whether ER may be responsible for fainting. Nevertheless, ER has been found in individuals suffering from syncope. 11, 12,24 Indeed, we previously reported the case of exertion syncope with only ER in an apparently healthy young adult.12 Maury et al.24 documented a spontaneous VF by a loop recorder in a patient with an ECG pattern of ER in the inferior leads, who presented with syncope. The current population was highly specific for being at risk for cardiovascular morbidity, since we studied subjects referred to a cardiac unit for cardiovascular risk factors such as hypertension or diabetes as well as for cardiac-related symptoms (e.g. loss of consciousness). For this reason, the high rate of reported syncope may be explained by the pre-specified clinical behaviour of the sample. Several studies have reported the high prevalence of ER in young individuals,21 with disappearance of this pattern over time (10 years) in 62% of individuals in the Veterans Affairs Palo Alto cohort.25 Our findings confirm this result, as the group of subjects with ER was significantly younger than those without ER. We hypothesise that ER pattern, which is an electrocardiographic manifestation of mismatch between outward and inward trans-membrane ionic currents, is a juvenile phenotype, which progressively disappears with time. It would be of interest to establish the distribution of J-T-segment morphologies (ascending, horizontal/descending) according to age group. This information may add data to aid understanding of risk stratification of ER pattern, as the odds of arrhythmic outcomes follows the life expectancy of each index individual.

Prognostic markers of ER Recent studies suggest that ER is not as benign as was earlier believed. Therefore a careful evaluation of carriers, especially in those with syncope or ventricular arrhythmias and/or a family history of sudden cardiac death is justified.14 Many studies have attempted to identify markers of malignancy, helping to clarify the clinical significance of this syndrome.

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In individuals in whom ER was associated with a high rate of cardiac death, J-point elevation ≥ 0.2 mV was found to be a strong predictor.4 In the cohort studied by Tikkanen et al., inferior lead involvement was the sole risk marker of cardiac and sudden arrhythmia deaths, whereas a rapidly ascending ST segment after the J point seems to be a benign variant.4,16 The lateral leads were also incriminated in other studies.9,17 Therefore, given the definition of ER syndrome, which excludes the right precordial leads, lead localisations have marginal significance. Few trials have compared gender and origin of individuals exhibiting ER.26 In the ARIC study, whites and females were at higher risk of SCD.27 Two distinct patterns of J-point elevation are recognised. Patel et al. found the notching (a positive J-point deflection inscribed on the S wave) pattern seemed to be of great value in the risk stratification of individuals with ventricular vulnerability.28 Maury et al.29 found the same significance of the notching pattern, and in his cohort from the city of Toulouse (France), the long-term follow up of a general population has linked the notching variant of ER to cardiac mortality. Although the notched variant has been shown to have a malignant outcome, the slurred (a smooth transition from QRS to ST segment) variant of repolarisation may confer the same risk as reported by Haruta el al.17 Our study, although retrospective in design, clearly emphasised a strong association between the notching variant of ER and a history of syncope in index cases of individuals presenting to the tertiary medical centres for cardiac morbidity with a high prevalence of past history of syncope.

6. 7.

10.

Study limitations The strength of this study was that although ER is claimed to be more prevalent in black American individuals,1 to our knowledge, the prevalence and significance of ER pattern in a black African population has been understudied. However, some limitations merit consideration. First, the study population was a relatively small, select population of black African subjects with cardiovascular morbidity. Second, although the patient interrogation was blinded to the ECG results, the diagnosis of syncope was made retrospectively and based on only the patient’s interrogation. Therefore, it was difficult to distinguish cardiogenic syncope among all causes. Third, this was a crosssectional rather than a cohort evaluation of ER. Therefore, we could not test the relationship between ER and cardiovascular morbidity and mortality, as was done by several other studies.

Conclusion Early repolarisation is a common finding on ECGs of black African individuals presenting for cardiovascular morbidity. The notching rather than the slurring variant was significantly associated with a past history of syncope. J-T-segment morphology was not reported to be linked to syncope. The prognostic significance of ER needs to be established in a prospective fashion.

11.

12.

13. 14. 15.

16.

17.

18.

19.

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Boineau JP. The early repolarization variant-an ECG enigma with both QRS and J-STT anormalies. J Electrocardiol 2007; 40: 3.e1–3.e10. Riera AR, Uchida AH, Schapachnik E, Dubner S, Zhang L, Filho CF,

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et al. Early repolarization variant: epidemiological aspects, mechanism, and differential diagnosis. Cardiol J 2008; 15: 4–16. Haïssaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008 May 8; 358: 2016–2023. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009; 361: 2529–2537. Boineau JP. The early repolarization variant – normal or a marker of heart disease in certain subjects. J Electrocardiol 2007; 40: 3.e11–3. e16. Mehta M, Jain AC, Mehta A. Early repolarization. Clin Cardiol 1999; 22: 59–65. Perez MV, Uberoi A, Jain NA, Ashley E, Turakhia MP, Froelicher V. The prognostic value of early repolarization with ST-segment elevation in African Americans. Heart Rhythm 2011 Nov 15. [Epub ahead of print]. Uberoi A, Jain NA, Perez M, Weinkopff A, Ashley E, Hadley D, et al. Early repolarization in an ambulatory clinical population. Circulation 2011; 124: 2208–2214. Merchant FM, Noseworthy PA, Weiner RB, Singh SM, Ruskin JN, Reddy VY. Ability of terminal QRS notching to distinguish benign from malignant electrocardiographic forms of early repolarization. Am J Cardiol 2009; 104: 1402–1406. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M. Dahm JB, et al. Guidelines for the diagnosis and management of syncope. The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA), Heart Failure Association (HFA) and the Heart Rhythm Society (HRS). Endorsed by the following societies, European Society of Emergency Medicine (EuSEM), European Federation of Internal Medicine (EFIM), European Union Geriatric Medicine Society (EUGMS), American Geriatrics Society (AGS), European Neurological Society (ENS), European Federation of Autonomic Societies (EFAS), American Autonomic Society (AAS). Eur Heart J 2009; 30: 2631–2671. Efremidis M, Letsas KP, Weber R, Gavrielatos G, Filippatosm GS, Sideris A, et al. Recurrent syncope associated with a distinct ECG pattern consisting of short QT interval, early repolarization and atrioventricular block. Clin Res Cardiol 2009; 98: 807–810. Bonny A, Ditah I, Amara W, Hamdaoui B, Frank R, Le Heuzey JY. Early repolarization electrocardiography pattern with unexplained syncope during training in a young black African non-elite athlete: an accidental finding? Cardiol J 2009; 16: 259–263. Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ J 2012; 76: 1054–1065. Antzelevitch C, Yan GX. J-wave syndromes. From cell to bedside. J Electrocardiol 2011; 44: 656–661. Noseworthy PA, Tikkanen JT, Porthan K, Oikarinen L, Pietilä A, Harald K, et al. The early repolarization pattern in the general population: clinical correlates and heritability. J Am Coll Cardiol 2011; 57: 2284–2289. Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011; 123: 2666–2673. Haruta D, Matsuo K, Tsuneto A, Ichimaru S, Hida A, Sera N, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011; 123: 2931–2937. Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman MM, Zeltser D, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008; 52:1231–1238. Haïssaguerre M, Sacher F, Nogami A, Komiya N, Bernard A, Probst V, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol 2009; 53: 612–619. Stern S. Clinical aspects of the early repolarization syndrome: a 2011 update. Ann Noninvasive Electrocardiol 2011; 16:192–195. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003; 115: 171–177.

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22. Derval N, Simpson CS, Birnie DH, Healey JS, Chauhan V, Champagne J, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011; 58: 722–728. 23. Nunn LM, Bhar-Amato J, Lowe MD, Macfarlane PW, Rogers P, McKenna WJ, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011; 58: 286–290. 24. Maury P, Sacher F, Rollin A, Duparc A, Mondoly P, Probst V. Ventricular fibrillation in loop recorder memories in a patient with early repolarization syndrome. Europace 2012; 14: 148–149. 25. Junttila MJ, Sager SJ, Tikkanen JT, Anttonen O, Huikuri HV, Myerburg RJ. Clinical significance of variants of J-points and J-waves: early repolarization patterns and risk. Eur Heart J 2012. doi: 10.1093/eurheartj/ ehs110.

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26. Adhikarla C, Boga M, Wood AD, Froelicher VF. Natural history of the electrocardiographic pattern of early repolarization in ambulatory patients. Am J Cardiol 2011; 108:1831–1835. 27. Olson KA, Viera AJ, Soliman EZ, Crow RS, Rosamond WD. Longterm prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011; 32: 3098–3106. 28. Patel RB, Ng J, Reddy V, Chokshi M, Parikh K, Subacius H, et al. Early repolarization associated with ventricular arrhythmias in patients with chronic coronary artery disease. Circ Arrhythm Electrophysiol 2010; 3: 489–495. 29. Rollin A, Maury P, Bongard V, Sacher F, Delay M, Duparc A, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012; 110: 1302–1308.

Cardiovascular congress diary 2013/2014 DATE

CONFERENCE

PLACE

CONTACT DETAILS TO REGISTER

2012 ESC, European Society of Cardiology congress

Munich, Germany

www.escardio.org

Columbus, US

www.nationwidechildrens.org/ishac-home

AUGUST 2013 25–29 August

SEPTEMBER 2013 11–13 September 6th international symposium on hybrid approach to congenital heart disease 2012 OCTOBER 2013 10–12 October

Federation of Infectious Disease Society in South Africa (FIDSSA)

Drakensberg, SA

www.fidssa.co.za

13–16 October

10th international congress on coronary and artery disease from prevention to intervention (ICCAD)

Florence, Italy

www.kenes.com/iccad

Dallas, Texas, USA

http://my.americanheart.org/

www.criticalcare.org.za

NOVEMBER 2013 16–20 November 86th American Heart Association scientific sessions (AHA) Critical care refresher course 2013

21–24 November 5th international conference of fixed combination in the treatment of Bangkok, Thailand hypertension, dyslipidaemia and diabetes mellitus

www.fixedcombination.com/2013

FEBRUARY 2014 20–23 February

UCT Department of Medicine General Physicians Conference

Cape Town, SA

www.physicians2014.co.za

To advertise your conference/meeting, e-mail details and half-page high-resolution PDF advert to info@clinicscardive.com

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Review Article Diagnostic and prognostic values of B-type natriuretic peptides (BNP) and N-terminal fragment brain natriuretic peptides (NT-pro-BNP) LORENA MARIES, IOAN MANITIU

Abstract B-type natriuretic peptide (BNP) is a member of a fournatriuretic peptide family that shares a common 17-peptide ring structure. The N-terminal fragment (NT-pro-BNP) is biologically inert, but both are secreted in the plasma in equimolar quantities and both have been evaluated for use in the management of congestive heart failure. BNP and NT-pro-BNP are frequently used in the diagnosis of congestive heart failure and distinguishing between patients with dyspnoea of cardiac or pulmonary origin. Values of NT-proBNP are affected by age or the presence of one or several co-morbidities such as chronic renal failure, type 2 diabetes, and acute coronary syndrome. ‘Normal’ values of these peptides also vary depending on the type of test used. The performance characteristics of these tests vary depending on the patients on whom they are used and the manufacturer. For this reason, the determination of reference values for this peptide represents such a challenge. Keywords: natriuretic peptides, prognostic values, NT-pro-BNP Submitted 6/12/12, accepted 14/8/13 Cardiovasc J Afr 2013; 24: 286–289

www.cvja.co.za

DOI: 10.5830/CVJA-2013-055

BNP was initially discovered in the porcine brain, but the largest concentrations are found in the heart. It is a peptide with 32 amino acids, synthesised in the ventricles as a response to stretching of the myocytes and/or pressure overload. It is released as an active hormone and as an inactive N-terminal fragment (NT-pro-BNP).1 Once released in the blood flow, BNP has numerous physiological actions, their net effect being to reduce pre- and post-load. Specifically, BNP produces a decreased vascular tonus by relaxing the smooth muscles, leading to a decrease in post-load. In addition, it induces a movement of fluid into the interstitial space, thus leading to a decrease in pre-load. BNP reduces the proliferation of fibroblasts and smooth muscle cells, sympathetic nervous activity, water and salt retention, release of the antidiuresis hormone, and synthesis

Lucian Blaga University, Sibiu, Romania

LORENA MARIES, MD, PhD student, lorenamaries@yahoo.com IOAN MANITIU, MD, PhD

of aldosterone and its release from the adrenal glands. In the kidneys, BNP increases glomerular filtration rate and renal blood flow by increasing the outgoing arterial tonus and decreasing the ingoing one. In addition it decreases the release of renin and the reabsorption of sodium, leading to diuresis and natriuresis.2 The N-terminal fragment of BNP is derived from proteolysis of pro-BNP, which is composed of 108 amino acids. It consists of 76 amino acids and has recently caused great interest, due to its possible role in monitoring heart failure and distinguishing acute coronary syndromes. Its effects on diuresis and natriuresis in patients with congestive heart failure represent a compensatory mechanism for stress on the myocytes, which leads to ventricular dysfunction.1

Diagnostic and prognostic value of BNP and NT-pro-BNP Serum levels of natriuretic peptides are important, not just as indicators of numerous cardiovascular deficiencies but also as markers of their severity.1 For patients with acute coronary syndromes, the determination of BNP levels offers predictive information on the apportioning of risk, in the absence of elevation in the S-T interval. In addition, BNP and NT-pro-BNP have prognostic significance for acute pulmonary embolism.1 The diagnostic value was recently confirmed by Coutance et al.3 Even if high levels of BNP demonstrate a high sensitivity for detecting patients with risk of sudden death, the specificity of this neurohormone is decreased. A diverse analysis between mortality and levels of BNP was recently conducted by Nunez and his team, which demonstrated a positive linear correlation between the risk of death and BNP level.4 With regard to the prognostic value of NT-pro-BNP for chronic heart failure, the Val-HeFT study (Valsartan Heart Failure Trial) demonstrated the positive nature of advanced heart failure. Moreover, BNP concentrations appeared significantly increased in patients with dilated cardiomyopathy and cardiovascular disease in NYHA classes III or IV, but it could not predict mortality or the requirement for a heart transplant.1

Variability of BNP Despite the evidence that BNP is secreted in ventricular overload states, there is an individual and inter-individual variation in both healthy subjects and those with stable chronic heart failure, which makes the interpretation of BNP levels difficult. Multiple

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studies have shown that only changes in BNP level larger than approximately 113 to 130% and changes in NT-pro-BNP larger than 90 to 98% can be considered to have exceeded individual, inter-individual and analytical variations.2 There are several reasons for these variations. In healthy subjects, BNP level is connected to gender and age; its levels increase with age and are higher in women than in men. Despite increases with age, BNP and NT-pro-BNP proved effective in excluding congestive heart failure in an elderly population that presented with acute dyspnoea. Race also plays a role, with a higher variability being seen in African-Americans than Caucasians.2 Studies conducted in Africa found reference values higher than those recommended by the manufacturer.5 A recent study showed that the reference value for NT-pro-BNP depends on age over 50 years.6 Another study containing nonagenarian patients reported a link between values of NT-pro-BNP and echocardiographic anomalies.7 Levels of BNP are lower for obese patients compared to non-obese. In addition, it was observed that genetics plays a role in the variability of BNP levels. Along with age, gender, genetics and body mass index, there are other physiological reasons for the variability of BNP. Renal function also affects levels of BNP, significantly increased levels being recorded for those with renal dysfunction. Patients on haemodialysis showed significant rhythmic oscillations in BNP levels, compared to healthy subjects.2 In the Breathing Not Properly study, BNP predictors from ‘the grey area’ in the absence of heart failure included age, atrial fibrillation, lower body mass index and anaemia.2 The lack of a single set of normal values due to different idiopathic levels and the available commercial kits can lead to confusion in clinical application. While some researchers claim that values above 100 pg/ml indicate heart failure, others suggest a value above 200 pg/ml. The ADHERE study, which included over 48 000 patients, indicated as prognosticators of mortality values over 430 pg/ml.8 In all cited conditions, a careful clinical examination, accompanied by an echocardiographic examination that evaluates the systolic–diastolic function, should be complementary to BNP analysis for diagnostic strategy and implementation of treatment.9

Heart failure Chronic heart failure is an illness that is appearing with increasing frequency, especially in elderly patients. Nevertheless, classification is often difficult due to non-specific symptoms and the lack of a ‘gold standard’ protocol for a correct diagnosis.9 The European guidelines from 2008 highlight the role of natriuretic peptides as potential markers of heart failure.9 Measurement of plasma concentrations of BNP has proved to be a very efficient screening technique for the identification of patients with various heart diseases, regardless of aetiology and the degree of systolic dysfunction of the left ventricle, which has the potential to develop into manifested heart failure and has a high risk of producing a cardiovascular event. Recently, the Food and Drug Administration approved NT-pro-BNP for evaluation of the prognosis of patients with congestive heart failure and acute coronary syndromes. Determination of BNP level was also approved for risk segregation in acute coronary syndromes.10 Multiple studies have confirmed the efficiency of the

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determination of BNP concentrations in the plasma of patients with acute dyspnoea. The Breathing Not Properly study is an example, in which 1 586 patients participated.9 In addition, studies such as Val-HeFT11,12 and COPERNICUS13 indicated that chronic treatment with beta-blockers and blockers of the renin– angiotensin–aldosterone system led to a reduction in levels of natriuretic peptides in the plasma and improved the prognosis, which was possibly a reflection of the improvement in cardiac function secondary to treatment.2 Together with its role in acute decompensated heart failure, levels of BNP are also high for diastolic dysfunction. Increased BNP levels can be found with isolated diastolic dysfunction, hypertrophic cardiomyopathy, or associated with systolic dysfunction. Echocardiographic parameters correlated with BNP levels include mass index of the left ventricle, its end-diastolic volume and isometric relaxation time. The further the stage of diastolic dysfunction the higher the levels of BNP.2

Other heart diseases As with congestive heart failure, BNP level has a prognostic value for acute coronary syndromes. BNP is additive with, and independent of, the increases in troponin I for these syndromes.2 A sub-study of Breathing Not Properly showed that plasma levels of BNP were high for patients with atrial fibrillation that was not diagnosed with congestive heart failure, but its levels were not different in the presence of heart failure.2 In addition, levels of BNP were high with heart valve diseases and aortic stenosis, and were linearly related to the symptoms. Moreover, levels over 190 pg/ml foresaw a negative evolution, suggesting that BNP can be used for identification of subgroups of patients that would benefit from a replacement of the aortic valve. In addition, BNP level was increased with aortic insufficiency.2 For patients with mitral insufficiency, an increased BNP level was correlated with mortality and the onset of congestive heart failure, regardless of the degree of regurgitation present on echocardiography, suggesting that BNP is a reflection of its atrial and ventricular consequences.2 Finally, it was proven that NT-proBNP was correlated with symptoms and echocardiographic severity of mitral stenosis.2 In addition, the levels of BNP were increased in patients with pulmonary embolism and pulmonary hypertension.2 In unstable angina, NT-pro-BNP represents an effective marker of the damage produced by cardiac ischaemia. The severity of the coronary disease is shown by an increase in the levels of NT-pro-BNP. In addition, in the case of acute coronary syndromes, NT-pro-BNP had an immuno-modulating role and offered important information for the prognosis of patients.1 Castro et al.14 divided 87 patients with non-ST-segment elevation acute coronary syndrome into two groups: 37 (42.5%) with unstable angina and 50 (57.5%) with non-ST-segment elevation myocardial infarction. Left ventricular ejection fraction above 40% was found in 86.2% of the total sample. Serum levels of NT-proBNP were higher in patients with non-ST-segment elevation myocardial infarction than in those with unstable angina (p < 0.001).14 Increased levels of NT-pro-BNP were associated with increases in troponin I (rs = 0.425, p < 0.001), peak CK-MB (rs = 0.458, p < 0.001) and low left ventricular ejection fraction (rs = –0.345, p = 0.002); no correlation was found with the TIMI

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risk score (rs = 0.082, p = 0.44). Multivariate analysis revealed that left ventricular ejection fraction and troponin I levels were independently correlated with NT-pro-BNP levels (p = 0.017 and p = 0.002, respectively).14

Renal failure Renal failure complicates congestive heart failure so often that many have suggested a ‘cardio–renal’ syndrome, which influences survival, duration of hospitalisation and re-admission ratio.2 A sub-study of PRIDE15 showed a reduction in the sensitivity and specificity of NT-pro-BNP in the diagnosis of heart failure for persons with renal failure, and also showed that its concentration tends to be more affected by renal dysfunction than BNP levels.2 The levels of BNP are known to be significantly increased for patients on haemodialysis, and they are known to decrease after dialysis.2 In another study that involved 72 patients on haemodialysis, NT-pro-BNP level was not associated with heart failure, but was dependent on factors associated with an increase in post-load.16 An association between increased levels of NT-pro-BNP and chronic renal failure was also demonstrated in patients without left ventricular dysfunction.17,18

Diabetes mellitus In a study on 371 patients with heart failure, 81 of whom had diabetes, the levels of 10 neurohormones from the plasma (adrenaline, noradrenaline, dopamine, aldosterone, renin, endothelin, ANP, NT-pro-ANP, BNP and NT-pro-BNP) were measured. All patients were also part of the PRIME-II study that investigated the effects of ibopamine on the causes of mortality in patients with moderate or severe heart failure.19 Most of the neurohormones were similar between the two groups, but patients with diabetes had higher values of BNP and NT-pro-BNP. The patients were monitored for five years, and during this time, 195 died, of whom 51 had diabetes. For patients with diabetes, noradrenaline, ANP, NT-pro-ANP, BNP and NT-pro-BNP levels were significantly higher than in those who did not survive. Therefore BNP and NT-pro-BNP proved the strongest predictors of outcome for both groups of patients.19 The most likely explanation for the increase in BNP and NT-pro-BNP levels in these patients with diabetes was the presence of diastolic dysfunction.19 Another study showed normal values of NT-pro-BNP for women with gestational type 2 diabetes mellitus, and lower values for those with insulindependent gestational diabetes.20

Cirrhotic cardiomyopathy Cirrhotic cardiomyopathy is an under-diagnosed condition. This is most likely due to the fact that there is no single diagnostic test to identify these patients.21 Numerous recent studies demonstrated that patients with hepatic cirrhosis had increased plasma concentrations of BNP and NT-pro-BNP, representing markers of early ventricular dysfunction. Henriksen et al.22 showed that these markers were correlated with the severity of hepatic cirrhosis, and with heart dysfunction. BNP could therefore have prognostic value with regard to the evolution of cirrhosis. In addition NT-pro-BNP represents a useful marker to demonstrate the existence of

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diastolic dysfunction of the left ventricle caused by a chronic hepatic disease.23 A study conducted on 153 patients subjected to a liver transplant determined their BNP levels post-transplant and on days 1 and 7. It was observed that a BNP level higher than 391 pg/ml immediately after the liver transplant appeared to be an early marker for heart dysfunction related to the cirrhosis.24

Conclusion In patients with dyspnoea, overlapping or even conflicting history, physical and radiographic findings often hinder the differentiation between cardiac and non-cardiac aetiology. The primary value of BNP and NT-pro-BNP testing in the emergency department is its diagnostic value in the differential diagnosis of acute dyspnoea and possible congestive heart failure. Levels of natriuretic peptides may also assist the emergency physician in appropriately triaging the patient with congestive heart failure.25 Studies have shown that measurements of BNP or NT-pro-BNP in the emergency department can be used to establish the diagnosis of congestive heart failure when clinical presentation is ambiguous or when confounding co-morbidities are present.25 After multiple studies, the conclusion was reached that levels of BNP < 100 pg/ml and > 500 pg/ml have a positive and negative predictive value, respectively, of 90% for the diagnosis of congestive heart failure for patients presenting with acute dyspnoea. For values between 100 and 500 pg/ml, the physicians must consider underlying left ventricular dysfunction, the effects of renal failure, or right ventricular dysfunction secondary to chronic pulmonary disease or acute pulmonary embolism.25 The recommended thresholds of less than 100 pg/ml to rule out heart failure and more than 500 pg/ml to rule in heart failure have been estimated to have the following likelihood ratios (LRs): LR-negative = 0.13 and LR-positive = 8.1. These different cut-off values create an intermediate range of 100–500 pg/ml with an LR-positive of only 1.9 pg/ml. Therefore, an intermediate BNP result alone cannot be used to rule in or rule out heart failure.25 Research done on the POSDRU/6/1.5/S/26 project was co-financed by the European Social Funds by means of the Sectoral Operational Programme for the Development of the Human Resources 2007–2013.

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Cacciaputo F. Natriuretic Peptide System and Cardiovascular Disease. Heart Views 2010; 11(1): 10–15. Burke MA, Cotts WG. Interpretation of B-type natriuretic peptide in cardiac disease and other comorbid conditions. Heart Fail Rev 2007; 12: 23–36. Coutance G, La Page O, Lo T, Hamon M. Prognostic value of brain natriuretic peptide in acute pulmonary embolism. Critical Care 2008; 12: 1–7. Nunez J, Nunez E, Robies R, Bodi V, Sanchis J, Carratala A, Aprici M, Liacer A. Prognostic value of brain natiuretic peptide in acute heart failure: mortalità and hospital redmission. Rev Esp Cardiol 2008; 61:1332–1337. Ajuluchukwu J, Ekure E, Mbakwem A, et al. Reliability and accuracy of point-of-care amino-terminal probrain natriuretic peptide in congestive heart failure patients. Internet J Cardiol 2010; 9(2). Bernstein LH, Zions MY, Alam ME, et al. What is the best approximation of reference normal for NT-pro-BNP? Clinical levels for enhanced assessment of NT-pro-BNP (CLEAN). J Motor Learn Dev 2011; 2(2):

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16–21. Vaes B, Delgado V, Bax J, et al. Diagnostic accuracy of plasma NT-proBNP levels for excluding cardiac abnormalities in the very elderly. BMC Geriatrics 2010; 10: 85. Fonarow GC, Peacock WF, Phillips CO, Givertz MM, Lopatin M, ADHERE scientific advisory committee and investigators. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007; 49: 1943–1950. Palazzuoli A, Gallotta M, Quatrini I, Nuti R. Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure. Vasc Health Risk Manag 2010; 6: 411–418. Raizada A, Bhandari S, Khan MA, et al. Brain type natriuretic peptide (BNP) – a marker of new millennium in diagnosis of congestive heart failure. Indian J Clin Biochem 2007; 22(1): 4–9. Latini R, Masson S, Anand I, et al. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004; 25: 292–299. Masson S, Latini R, Arnand IS, Phil D, Barlera S, Angelici L, et al. for the Val-HeFT investigators. Prognostic value of changes in N-terminal proBNP in Val-HeFT. J Am Coll Cardiol 2008; 52: 997–1003. Hartmann F, Packer M, Coats A, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 2004; 110: 1780–1786. Castro LR, Alencar MC, Barbosa MM, Nunes Mdo C, Cardoso JR, Ribeiro AL. NT-proBNP levels in patients with non-ST-segment elevation acute coronary syndrome. Arq Bras Cardiol 2011; 97(6): 456–461. Januzzi J, Camargo C, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–954.

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16. Booth J, Pinney J, Davenport A. N-terminal pro-BNP – marker of cardiac dysfunction, fluid overload, or malnutrition in hemodialysis patients? Clin J Am Soc Nephrol 2010; 5: 1036–1040. 17. Baig JA, Alam JM, Ansari MA, et al. Evaluation of NT pro BNP of diagnostic significance in patients with chronic kidney diseases. Pak J Biochem Mol Biol 2010; 43(2): 99–104. 18. David S, Kumpers P, Seidler V, et al. Diagnostic value of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) for left ventricular dysfunction in patients with chronic kidney disease stage 5 on haemodialysis. Nephrol Dial Transplant 2008; 23: 1370–1377. 19. Van der Horst ICC, de Boer RA, Hillege HL, et al. Neurohormonal profile of patients with heart failure and diabetes. Netherlands Heart J 2010; 18(4): 190–196. 20. Andreas M, Zeisler H, Handisurya A, et al. N-terminal-pro-brain natriuretic peptide is decreased in insulin dependent gestational diabetes mellitus: a prospective cohort trial. Cardiovasc Diabetol 2011; 10: 28. 21. Wong F. Cirrhotic cardiomyopathy. Hepatol Int 2009; 3(1): 294–304. 22. Henriksen JH, Gotze JP, Fuglsang S, et al. Increased circulating probrain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease. Gut 2003; 52(10): 1511–1517. 23. Kneiseler G, Herzer K, Marggraf G, et al. Die Interaktion zwischen Leber und Herz. Z Herz-, Thorax- Gefäßchirurgie 2010; 24(6): 334–340. 24. Gallinat A, Neumann T, Kaiser G, et al. Brain natriuretic peptide (BNP): an early marker of cardiac dysfunction after liver transplantation? Liver Outcomes, Supplement to Transplantation 2010; 90(2S): 1739. 25. Schreiber D, Nix DA, Brown DFM et al. Natriuretic peptides in congestive heart failure. http://emedicine.medscape.com/article/761722-overview, updated: Jan 10, 2012 (accessed May 2012).

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Drug Trends in Cardiology Saxagliptin demonstrates no increased risk for cardiovascular death, heart attack or stroke in the SAVOR cardiovascular outcomes trial Results presented at the recent 2013 European Society of Cardiology congress in Amsterdam, The Netherlands, and published in the New England Journal of Medicine contribute to on-going questions concerning the safety of many diabetes treatments, particularly regarding the impact of their use on risk of cardiovascular death, heart attack or stroke. SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus) is the largest cardiovascular outcomes trial to study a diverse population of type 2 diabetes mellitus (T2DM) patients at high risk for cardiovascular events. SAVOR was a randomised, doubleblind, placebo-controlled trial of 16 492 patients in more than 700 sites worldwide, designed to evaluate the cardiovascular safety and efficacy of saxagliptin in adults with T2DM at risk for cardiovascular death, heart attack and stroke, compared to placebo. The median follow up was 2.1 years and maximum follow up was 2.9 years. Saxagliptin demonstrated no increased risk for the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal ischaemic stroke when added to a patient’s current standard of care (with or without

other anti-diabetic therapies), compared to placebo. Recruitment included patients with T2DM and baseline HbA1c levels of 6.5 to 12.0%, on any diabetes treatment including diet, insulin and/or oral therapy (excluding GLP-1 agonists and DPP-4 inhibitors) who were at elevated risk for cardiovascular events according to two categories: • patients ≥ 40 years of age with established cardiovascular disease, defined as ischaemic heart disease, peripheral vascular disease or ischaemic stroke • males ≥ 55 years of age and females ≥ 60 years with at least one of the following risk factors: dyslipidaemia, hypertension or current smoking, but without established cardiovascular disease. Further grouping was based on renal function, including patients with normal/ mild (eGFR > 50 ml/min), moderate (eGFR 30–50 ml/min) or severe (eGFR < 30 ml/min) renal impairment. The primary efficacy objective was to determine, as a superiority assessment, whether treatment with saxagliptin compared to placebo (when added to current background therapy) would result in a reduction in the composite endpoint of cardiovascular death, non-fatal MI or

non-fatal ischaemic stroke in patients with T2DM. Saxagliptin demonstrated no increased risk in the primary composite endpoint: 7.3% in the saxagliptin group versus 7.2% in the placebo group [hazard ratio (HR): 1.00; 95% confidence interval (CI): 0.89–1.12; non-inferiority p < 0.001; superiority p = 0.99). Saxagliptin did not meet the primary efficacy endpoint of superiority to placebo. Secondary efficacy objectives included a reduction in the primary composite endpoint together with hospitalisation for heart failure, coronary revascularisation or unstable angina pectoris, and reduction in all-cause mortality. Hospitalisation for heart failure, unstable angina or coronary revascularisation occurred in 12.8% of the saxagliptin group versus 12.4% in the placebo group (HR: 1.02; 95% CI: 0.94–1.11; p = 0.66). Hospitalisation for heart failure occurred at a greater rate in the saxagliptin group (3.5%) than in the placebo group (2.8%) (HR: 1.27; 95% CI: 1.07–1.51; p = 0.007). The pre-specified secondary endpoint of all-cause mortality occurred at 4.9% in the saxagliptin group versus 4.2% in the placebo group (HR: 1.11; 95% CI: 0.96–1.27; p = 0.15). G Hardy

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Reports from the American Diabetes Association’s 73rd scientific sessions, 21–25 June 2013, Chicago, Illinois Intensive HbA1c management in type 1 diabetes sees persistent benefit Preliminary results of the latest data from the Diabetes Control and Complications trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial were published as abstracts and presented at the recent ADA meeting. The 10-year DCCT, which began in 1983, demonstrated a consistent beneficial effect of intensive therapy on reducing complications compared with conventional therapy. The DCCT revealed that intensive therapy, lowering HbA1c levels to 7% rather than the 9%, which was standard practice at the time in patients with type 1 diabetes, diminished a range of complications by about 35 to 75%, establishing intensive therapy as the standard of care. Improved glucose control was achieved with frequent insulin injections or insulin pump therapy, guided by frequent selfmonitoring of blood glucose with fingerprick testing. The trial was extended into EDIC (now running for a total of 30 years); 95% of trial patients who are still alive continue to participate in the trial. While the initial DCCT results were dramatic, the effect of intensive therapy in reducing the longerterm consequences of complications, including kidney failure, loss of vision, amputations and heart disease, were unknown. Over 18 years, those patients who had intensive management and maintained an HbA1c target of 7% had a 46% lower risk of retinopathy, a 39% reduced risk of microalbuminuria, and a 61% lower risk of macroalbuminuria (p < 0.0001 for all). The long-term consequences of intensive therapy have shown a 50% reduction in risk for developing impaired kidney function. Intensive therapy also reduced the incidence of heart disease and stroke by almost 60%. Researchers also reported new data on musculoskeletal complications, particularly cheiroarthropathy, which presents with peri-articular skin thickening of the hands and limited joint mobility. Cheiroarthropathy typically results from the accumulation of advanced glycation

end-products in the collagen, and includes carpal tunnel syndrome, adhesive capsulitis, Dupuytren’s contracture, flexor tenosynovitis (or ‘trigger finger’), and prayer sign (or trouble holding the hands flat when palm-to-palm). Researchers found that a third of about 1 200 patients (33%) had at least one type of this complication, with the most common being adhesive capsulitis, followed by carpal tunnel and then prayer sign. Another 20% of patients had at least two complications, and a further 10% had at least three. About 3% had four or more complications. Risk factors for these conditions included older age, female gender, longer duration of disease, and higher HbA1c levels over time. http://www.medpagetoday.com/MeetingCoverage/ADA/40047 http://www.diabetes.org/for-media/2013/scisessions-dcct-edic.html

New therapeutic targets for type 2 diabetes Recent years have seen a dramatic expansion in the range of pharmacological therapy for type 2 diabetes. A range of new therapeutic targets were under discussion.

Beta-cells The beta-cell plays a crucial role in type 2 diabetes, with beta-cell pathways offering multiple potential drug targets. Free fatty acid receptor 1 (FFAR-1 or GPR40) is one of the most promising targets. Free fatty acids are both metabolic fuels and signalling pathways that are highly expressed in the beta-cells, the hypothalamus and the gut. The investigational compound TAK-875 has shown reductions in HbA1c levels similar to those with glimepiride; with significantly fewer incidents of hypoglycaemia and no effect on weight, insulin sensitivity, blood pressure or pulse. The compound has also shown no significant drug-related adverse events.

Insulin receptors The most important cause of insulin resistance is obesity and treating obesity is probably the most effective way to

treat insulin resistance. Other approaches include enhancing insulin receptor activity and modulating signalling downstream from the receptor. Enhancement and activation of insulin receptors has met with success in rodent models, but none of these compounds appear to be appropriate for human use. Other investigative agents potentiate insulin receptor activity to increase glucose uptake.

Targeting inflammation Reducing inflammation in adipose tissue and skeletal muscle with salsalate has positive metabolic consequences, including a decrease in numbers of white blood cells, neutrophils and lymphocytes, and HbA1c levels. Another target is the nuclear factor kappa-B, or NF-kB, a pathway that acts as a master regulator of inflammatory signalling in both adipose tissue and skeletal muscle. Pharmacological intervention in this pathway appears to have beneficial effects on the metabolism and inflammation.

Targeting glucose absorption and excretion One of the approaches to targeting glucose absorption and excretion is to enhance the activity of sodium glucose co-transporter 2 (SGLT-2) in order to boost renal glucose excretion. Dapagliflozin and canagliflozin have been approved for use by the Federal Drug Administration, and positive phase 3 data on empagliflozin were presented at the meeting. These agents can be used with other antiglycaemics but safety questions remain.

Look AHEAD: lifestyle intervention in type 2 diabetes offers microvascular benefit but does not lower risk of cardiovascular disease Look AHEAD (Action for Health in Diabetes) is the longest and largest randomised, controlled trial to examine the effects of an intensive lifestyleintervention programme in overweight and obese participants with type 2 diabetes. Investigators presented 11-year results of lifestyle interventions designed

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to achieve at least a 7% weight loss, and increase physical activity to 175 minutes per week, implemented through group and individual sessions. In terms of cardiovascular effects of intensive lifestyle interventions in type 2 diabetes, the trial was stopped for futility reasons after a median follow up of 9.6 years. The primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for angina during follow up. An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in the study population. However, it did show benefit of a 31% reduction in the risk of advanced kidney disease and a 14% reduction in the risk of diabetic retinopathy. Also of note was a 20% reduction in new incidence of depression in the intensive lifestyleintervention arm. Improvements in fitness levels saw improvements in other markers of metabolic risk, such as HbA1c levels and systolic blood pressure. LDL cholesterol levels were not improved with the intensive lifestyle-intervention programme. The Look AHEAD research group. Cardiovascular effects of intensive lifestyle intervention in type 2

diabetes. N Engl J Med 2013; 369: 145–154. http://www.medscape.com/viewarticle/806816? t=1

Exercise may be the best medicine for diabetes patients Dr Samuel Dagogo-Black, professor and director of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Centre, said ‘A preponderance of evidence mandates lifestyle change, principally exercise and diet, as the pre-eminent and primary consideration for any and all purposes where the goal is to improve insulin sensitivity, reduce obesity and prevent diabetes. The vast majority of overweight people who are insulin resistant will benefit greatly from a 5 to 10% weight loss.’ Dr Dagogo-Black is also of the opinion that there are very limited roles for drugs and surgery. ‘Pharmacotherapy can help a very select cohort of patients who fail to respond to exercise and dietary changes, whereas bariatric surgery is appropriate for an even smaller and targeted cohort’. Dr Barry Braun, associate professor of Kinesiology at the University of Massachusetts, stated that insulin sensitivity is improved dramatically by a single exercise session, and even more

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by a three-month training programme. Research into the effects of exercise and metformin in patients with pre-diabetes indicate that while exercise plus metformin is not better than exercise alone, the combination is better than metformin alone. Dr Paul Coen, assistant professor of Health and Physical Activity at the University of Pittsburgh, says that exercise provides additional benefits to cardiometabolic risk following bariatric surgery. Experts recommend 150 minutes of aerobic exercise a week; however any amount of exercise is better than none.

New perspectives on type 2 diabetes risk factors Epidemiological research continues to uncover a growing list of novel risk factors that include environmental elements. Metals, plasticisers and air pollution are not typically considered risk factors for type 2 diabetes; however recent research suggests they should be. Epidemiological data have implicated environmental exposure to arsenic and phthalates, both common compounds used as plasticisers across the globe, as risk factors for the development of type 2 diabetes. G Hardy

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Case Report Radiofrequency ablation of the great saphenous vein in an elderly patient with co-morbid disease ALİ ÜMİT YENER, ÖZLEM YENER, HIKMET SELÇUK GEDIK, KEMAL KORKMAZ, TURGUT ÖZKAN, AYŞE LAFÇI, KERIM ÇAĞLI

Abstract An 86-year-old male patient with hypertension, Parkinsonism, benign prostatic hyperplasia, cataract and chronic obstructive pulmonary disease had a history of coronary bypass surgery in two veins due to anterior myocardial infarction one year earlier. He presented with pain and feelings of paresthesia below the knee of his left leg, and had fallen twice. He had used compressions and venoprotective medication for two years and had also received physiotherapy but it had not alleviated the symptoms. He had varicose dilatations in the left leg and pigmentation and a recovered venous ulcer scar were present on the medial malleolus. The patient was classed as grade 4 according to the CEAP classification. Because there was no deficiency in the superficial femoral and popliteal veins, the patient was taken for endovenous ablation. He had no pain or sensation of heaviness in the legs on postoperative day 10, and the first, third and sixth months of check up. Endovenous ablation is a procedure that increases the quality of life and comfort in elderly patients, with minimal pain. Radiofrequency catheter procedures have proven to be more successful in patients of all age groups than procedures such as standard surgery and foam therapy. Keywords: catheter ablation, venous insufficiency Submitted 6/5/13, accepted 14/8/13 Cardiovasc J Afr 2013; 24: e1–e2

www.cvja.co.za

DOI: 10.5830/CVJA-2013-060

Department of Cardiovascular Surgery, Medical Faculty, Çanakkale Onsekiz Mart University, Kepez, Çanakkale, Turkey ALİ ÜMİT YENER, MD, yener@comu.edu.tr

Department of Radiology, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey ÖZLEM YENER, MD

Department of Cardiovascular Surgery, Ankara Numune Research and Education Hospital, Ankara, Turkey HIKMET SELÇUK GEDIK, MD KEMAL KORKMAZ, MD KERIM ÇAĞLI, MD

Department of Anaesthesiology, Ankara Numune Research and Education Hospital, Ankara, Turkey AYŞE LAFÇI, MD

Department of Cardiovascular Surgery, Ankara Yuksek İhtisas Hospital, Ankara, Turkey TURGUT ÖZKAN, MD

With chronic venous insufficiency, surgical indications are determined according to the symptoms of the patient, objective data based on varicosities, and complications. The aim of surgery is to eliminate the cause of venous hypertension, diminish the symptoms of patients, and prevent complications such as venous ulcers from occurring in the future.1 In elderly patients, remission of venectasia ulcers is difficult due to venous hypertension.2

Case report An 86-year-old male patient with hypertension, Parkinsonism, benign prostate hyperplasia, cataract (with no vision in the left eye) and chronic obstructive pulmonary disease had a history of coronary bypass surgery in two veins due to anterior myocardial infarction one year earlier. The patient was taking medication for these diseases. Presenting with pain and feelings of paresthesia below the knee of his left leg, the patient had also fallen twice due to sensations of heaviness in his legs. He had used compressions and venoprotective medication for two years and also received physiotherapy, but he presented to our clinic unable to alleviate the symptoms. The patient’s physical examination revealed varicose dilatations in the left leg. Pigmentation and a recovered venous ulcer scar were present in the medial malleolus of his left leg due to a saphenous vein graft that had been used for bypass surgery. Active cardiac symptoms were not present. No heart problem was found from the cardiac tests conducted in our clinic (normal left ventricular ejection fraction, no ischaemia on ECG). His clinical status was classified according to the CEAP (Clinical severity, aEtiology or cause, Anatomy, Pathophysiology) classification pre-operatively as grade 4. Along with high output reflux through the sinus of Valsalva in the sapheno-femoral junction, the saphenous diameter at the sapheno-femoral junction was measured as 8 mm, and the upper left knee saphenous diameter was 5.6 mm. Due to the fact that no deficiency was present in the superficial femoral and popliteal veins, the patient was taken for endovenous ablation. The patient was cannulated with a 16-g needle from the area under the left knee with accompanying local anaesthesia. A guide wire was moved forward through the needle and a sheath was inserted. Under the guidance of continuous-wave Doppler and duplex scanning ultrasonography, a radiofrequency ablation catheter was inserted so as to keep the superficial epigastric vein open up to 2 cm behind the sapheno-femoral junction. Tumescent anesthesia was administered throughout the saphenous vein trace to be ablated.

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A saphenous vein segment of 38 cm was ablated by applying 40-Watt power on each centimetre using a radiofrequency ablation catheter (ClosureFast®). Each 7-cm saphenous segment was ablated twice. Following the procedure, it was confirmed that the patient’s great saphenous vein was obliterated and that no flow was seen on colour Doppler ultrasonography. The patient was then sent to the ward with no complications. Mobilisation was done in the clinic and the tight bandages were removed four hours later. The patient wore class 2 (32 mmHg) compression pantyhose until the next evening. On the third day postoperatively, on continuous-wave Doppler and duplex scanning ultrasonography, the great saphenous vein segment was seen to be obliterated and no flow was seen. The patient had no pain or sensations of heaviness in his legs on the tenth day postoperatively, and the first, third and sixth months of check up.

Discussion Standard venous surgery may lead to unwanted outcomes such as continued pain in elderly patients. In a study by Weinmann et al., pain and swelling in the extremities following standard surgery was observed at a rate of 89% in a group of patients (mean age

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79 years). Complete recovery of patients was delayed up to about eight weeks and ulcers recurred in some patients.3

Conclusion Endovenous ablation is a procedure that increases the quality of life and comfort of elderly patients, with minimal pain, and they can return to active life immediately. Radiofrequency ablation procedures have proved to be more successful in patients of all age groups than procedures such as standard surgery and foam therapy.4

References 1. 2. 3.

O’Hare JL, Earnshaw JJ. Practical advice for the treatment of venous disease in the elderly. Phlebology 2008; 23: 101–102. Hansson C. Optimal treatment of venous (stasis) ulcers in elderly patients. Drugs Aging 1994; 5(5): 323–334. Weinmann EE, Poluksht N, Chayen D, Bass A. Surgery of the superficial venous system in elderly patients. Vasc Endovascular Surg 2003; 37(2): 111–115. Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011; 98(8): 1079–1087.

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