CVJA Volume 25, Issue 3 by Clinics Cardive Publishing

MAY/JUNE 2014 VOL 25 NO 3

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Topical rifamycin in diabetics undergoing CABG • Carbon monoxide poisoning and cardiac repolarisation • Platelet volume and myocardial perfusion defect in diabetics • Cardiac preconditioning in isolated perfused hearts • Quality of life in patients with atherosclerosis obliterans or Buerger ’s disease • Simultaneous CABG and carotid endarterectomy • Understanding the rise in CVD in Africa • Novel risk markers in women with ischaemic heart disease

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Cardiovascular Journal of Africa . Vol 25, No 3, May/June 2014

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Introducing the only RAASi/CCB combination with proven all-cause mortality benefits.2,3

Reference: 1. South African Hypertension Guideline 2011. YK Seedat, BL Rayner. S Afr Med J 2012;102:57-84 2. 2013 ESH/ESC Guidelines for the managment of arterial hypertension. Mancia G, Fagard R et al. Euro Heart J. Doi:10.1093/eurheart/eht151 3. Mourad JJ, Jeaune SL et al. Current Medical Research and Opinion. 2010;9:2263-2276 S3 Coveram速 5 mg /5 mg tablets: Perindopril arginine 5 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0933 S3 Coveram速 5 mg/10 mg tablets: Perindopril arginine 5 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0934 S3 Coveram速 10 mg/5 mg tablets: Perindopril arginine 10 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0935 S3 Coveram速 10 mg/10 mg tablets: Perindopril arginine 10 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0936 For full prescribing information, refer to the package insert approved by the medicines regulatory authority, Dec 2013. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27 (0)861 700 900. Fax: +27 (0)11 525 3401.

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

Vol 25, No 3, MAY/JUNE 2014

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

From the Editor’s Desk

The protective effect of topical rifamycin treatment against sternal wound infection in diabetic patients undergoing on-pump coronary artery bypass graft surgery F Aygun • A Kuzgun • S Ulucan • A Keser • M Akpek • MG Kaya

100

Assessment of the efficacy of Ankaferd blood stopper on the prevention of postoperative pericardial adhesions Y Nazli • N Colak • MF Alpay • H Haltas • ON Aksoy • IO Akkaya • O Cakir

106

Carbon monoxide poisoning increases T peak–Tend dispersion and QTc dispersion M Eroglu • O Uz • Z Isilak • M Yalcin • AO Yildirim • E Kardesoglu

110

Mean platelet volume is associated with myocardial perfusion defect in diabetic patients S Sarikaya • S Sahin • L Akyol • E Borekci • YK Yilmaz • F Altunkas • K Karaman • S Karacavus • AR Erbay

114

Is there a role for surgery in the management of isolated secundum atrial septal defect in adults? C Bolcal • G Arslan • M Kadan • S Doganci • C Barcin • A Iyisoy • V Yildirim • M Arslan

118

Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3 RF Kelly-Laubscher • JC King • D Hacking • S Somers • S Hastie • T Stewart • A Imamdin • G Maarman • S Pedretti • S Lecour

124

Comparison of quality of life in patients with peripheral arterial disease caused by atherosclerosis obliterans or Buerger’s disease R Karakoyun • C Köksoy • Z Şener • U Gündüz • B Karakaş • M Karakoyun

PA Brink

Cardiovascular Topics

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

Editors

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

Heart Failure Dr g visagie

PROF R DELPORT Chemical Pathology

Paediatric dr s brown

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

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

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

DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board

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

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

Vol 25, No 3, MAY/JUNE 2014

CONTENTS

130 Simultaneous coronary artery bypass grafting and carotid endarterectomy can be performed with low mortality rates E Aydin • Y Ozen • S Sarikaya • I Yukseltan 134 Understanding the rise in cardiovascular diseases in Africa: harmonising H3Africa genomic epidemiological teams and tools MO Owolabi • GA Mensah • P Kimmel • D Adu • M Ramsay • S Waddy • B Ovbiagele • C Rabadan-Diehl • R Rasooly • S Akarolo-Anthony • C Rotimi as members of the H3Africa Consortium

137

Review Article

Novel cardiovascular risk markers in women with ischaemic heart disease Dana Pop • Alexandra Dădârlat • D Zdrenghea

Industry News

142 AstraZeneca Pharmaceuticals launches in Zambia

Cardio News

144

Bridging the divide at the 2014 annual SA Heart Congress

PUBLISHED ONLINE (Available on www.cvja.co.za, PubMed and PubMed Central) Case ReportS

e1 Delayed embolisation of Amplatzer ASD closure device caused partial obstruction of left ventricular outflow tract S-H Kim • KH Kim • YM Lim • J-Y Moon • W-I Yang • IJ Kim • S-W Lim e4

Emergency endovascular aortic repair of a ruptured mycotic aorto-iliac aneurysm presenting with lumbar radiculopathy T-Y Lee • C-S Tsai • Y-T Tsai • C-Y Lin • Y-C Lin • P-S Hsu

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

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 3, May/June 2014

From the Editor’s Desk Alas, this is my last time writing ‘From the Editor’s Desk’. The CVJA has a new editor-in-chief, Prof Patrick Commerford. He succeeds Prof AJ Brink, a founder of this journal and editorin-chief until his death in October 2012. From the July/August issue, Prof Commerford will be responsible for overseeing the processing of articles through the editorial system, sourcing original articles where necessary, writing editorials, and maintaining the high standard of the journal. CVJA is now in its 25th year, a quarter of a century old, and this event is soon to be celebrated. However, we certainly had a rocky ride after the death of Prof AJ Brink at 89, which, although not untimely, created an unanticipated void. We are certain Prof Commerford will create a smoother ride for all at the journal offices. Prof Commerford is a well-respected clinician, educator, scientist, and an organiser and administrator. He has served on national medical and scientific bodies, even heading some. He has extensive experience in medical scientific writing and reviewing, and also, to the benefit of the journal, experience as an editor. I will remain intimately involved in the business side of the journal, maintaining it as a stable and financially viable venture. Prof Commerford has served on the editorial boards of a number of journals, including CVJA. He recently retired as professor and head of the cardiology unit at Groote Schuur Hospital, where he occupied the Helen and Morris Mauerberger chair. For this issue, we have as usual, reviews, original articles and case studies, the latter only available on the web. Scolch et al. touts the virtues of cardiac magnetic resonance (CMR) imaging. CMR is certainly impressive but one must remember that if the mountain cannot go to Mohamed, Mohamed must go to the mountain. In that regard, echocardiographic machines will not easily be replaced. They are cheaper and very mobile. You can take them to your patient in your rooms, the clinic, ward, ICU, theatre, and in distant places. As a review article, Pop et al. (page 137) addresses nonstandard markers of cardiovascular risk in women, teasing out from other studies factors pertaining to woman. Among the original studies, we have articles ranging from isolated perfused rat hearts and preconditioning in the basic science laboratory (Kelly-Laubscher et al., page 118) to platelet morphology and myocardial perfusion in patients with diabetes mellitus from the clinical laboratory (Sarikaya et al., page 110). From catastrophic carbon monoxide poisoning we learn of the

Prof Commerford, MB ChB, FCP (SA)

effects on cardiac repolarisation (Eroglu et al., page 106). For the surgically minded, the safety of simultaneous coronary artery bypass grafting and carotid endarterectomy is described (Aydin et al., page 130). There is an observational study on quality of life in patients with atherosclerosis obliterance versus those with Buerger’s disease (Karakoyun et al., page 124). We trust that you will enjoy this issue. PAUL A BRINK, MB ChB, PhD, paul@clinicscardive.com Department of Internal Medicine, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 25, No 3, May/June 2014

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Cardiovascular Topics The protective effect of topical rifamycin treatment against sternal wound infection in diabetic patients undergoing on-pump coronary artery bypass graft surgery Fatih Aygun, Ahmet Kuzgun, Seref Ulucan, Ahmet Keser, Mahmut Akpek, Mehmet G Kaya Abstract

Keywords: rifamycin, sternal wound infection, on-pump CABG

Objectives: The aim of this study was to investigate the protective effect of topical rifamycin SV treatment against sternal wound infection (SWI) in diabetic patients undergoing on-pump coronary artery bypass graft (CABG) surgery. Methods: One hundred and fifty-nine diabetic patients who were scheduled to undergo isolated on-pump CABG surgery were included. Eight were excluded for various reasons. Of the 151 patients, 51 were on insulin therapy and 100 were on oral anti-diabetics. The risk of mediastinitis was assessed using the American College of Cardiology/American Heart Association 2004 guideline update for CABG surgery. According to the risk scores, patients were divided into two comparable groups: the rifamycin group (n = 78) received topical rifamycin treatment after on-pump CABG surgery, and the control group (n = 73) received no topical treatment. Results: Deep sternal wound infection (mediastinitis) was not observed in either group (0/78 vs 0/73, p = 1.0). No superficial sternal wound infection was observed in the rifamycin group, however, it did occur in one patient in the control group (0/78 vs 1/73, p = 0.303). Wound culture was performed and coagulase-negative staphylococci were observed. The infection regressed on initiation of antibiotic therapy against isolated bacteria and the patient was discharged after a full recovery. Conclusion: Although the difference in rate of superficial sternal wound infection (SSWI) in the rifamycin and control groups was not statistically significant, locally applied rifamycin SV during closure of the sternum in the CABG operation may have had a protective affect against SWI.

Submitted 13/1/13, accepted 20/2/14 Cardiovasc J Afr 2014; 25: 96â&#x20AC;&#x201C;99

Department of Cardiovascular Surgery, School of Medicine, Mevlana University, Konya, Turkey Fatih Aygun, MD Ahmet Kuzgun, MD

Department of Cardiology, School of Medicine, Mevlana University, Konya, Turkey Seref Ulucan, MD, serefulucan@hotmail.com Ahmet Keser, MD

Department of Cardiology, School of Medicine, Erciyes University, Kayseri, Turkey Mahmut Akpek, MD Mehmet G Kaya, MD

www.cvja.co.za

DOI: 10.5830/CVJA-2014-008

Sternal wound infection (SWI) is a rare complication occurring after coronary artery bypass graft (CABG) surgery. Sternal wound infection occurs in one to 3% of patients and has a mortality rate of up to 40%. It is also associated with prolonged hospital stay and increased healthcare costs.1-4 According to the American College of Cardiology/American Heart Association (ACC/AHA) 2004 guideline update for CABG surgery, the risk of mediastinitis is evaluated before CABG surgery using factors, such as age of patient, the presence of obesity, diabetes or chronic obstructive pulmonary disease (COPD), the need for dialysis, an ejection fraction (EF) < 40%, and being scheduled for emergency surgery.5 In studies by Khanlari et al. and Kloos et al., patients with SWI were divided into two subgroups: superficial sternal wound infection (SSWI) and deep sternal wound infection (DSWI).6,7 While SSWI involves only subcutaneous tissue, DSWI is associated with sternal osteomyelitis and sometimes with infected retrosternal space (termed mediastinitis). These researchers reported that DSWI occurred in 0.25 to 2.3% of patients.6,7 Rifamycin SV is a relatively effective agent for the treatment of gram-positive bacteria, Mycobacterium tuberculosis and certain gram-negative bacteria. Rifampicin, derived from rifamycin SV, is readily absorbed after oral administration and possesses higher antimicrobial activity against Staphylococcus aureus, S epidermidis, Streptococcus viridans and Mycobacterium tuberculosis, even in very low doses. In only one study in the literature has the use of antibiotics containing rifampicin been suggested to improve outcomes in staphylococcal deep-wound infections.6 In the present study, we aimed to investigate the protective effects of topical rifamycin SV treatment on SWI after on-pump CABG surgery in diabetic patients.

Methods One hundred and fifty-nine diabetic patients who were scheduled

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 3, May/June 2014

to undergo isolated CABG surgery in the Department of Cardiovascular Surgery, Mevlana University between July 2008 and July 2011 were prospectively enrolled. Of these patients, eight were excluded due to use of the intra-operative beatingheart technique, a need for revision in the post-operative period, or death. In the remaining 151 patients, the risk of mediastinitis was assessed according to the ACC/AHA 2004 guideline update for CABG surgery.5 We grouped the patients according to their mediastinitis risk scores into two comparable groups: the rifamycin group consisted of 78 patients (52 male, mean age 62 ± 8 years) who received local antibiotic rifamycin SV i.m. (Rif® 250 mg/3-ml ampoule) on the sternal region after CABG surgery, and the control group consisted of 73 patients (45 male, mean age 61 ± 8 years). They did not receive a local antibiotic. The local ethics committee approved the study. Written informed consent was obtained from the patients. It was determined prior to the initiation of the study that patients developing SSWI would be treated by the administration of antibiotics alone. Patients developing DSWI would be treated by the administration of antibiotics plus surgery. During the pre-operative period, all patients were assessed for the risk of mediastinitis according to the ACC/AHA 2004 guideline for CABG surgery,5 using eight parameters including age, presence of obesity, diabetes or COPD, the need for dialysis, ejection fraction (EF) < 40%, and scheduled for emergency surgery. Baseline characteristics, parameters used to assess the risk of mediastinitis, and post- and intra-operative data of the patients are presented in Table 1. Skin cleansing was performed in all patients prior to surgery. Combined insulin therapy with regular human insulin (Humulin® R 100 U/ml) and insulin glargine (Lantus® 100 U/ml) was administered to control blood glucose levels below 200 mg/dl during pre-, intra- and postoperative periods. Insulin infusion was initiated in patients as required. The standard prophylactic antibiotic regimen used in our clinic was administered to patients, that is 1 g cefazolin sodium (Cefamezin-IM/IV®) 30 Table 1. Baseline clinical characteristics of the study groups. Group 1 Group 2 (n = 78) (n = 73) p-value Age (years) 62 ± 8 61 ± 8 0.605 Sex (F/M) 26/52 28/45 0.635 28.9 ± 4.6 29.1 ± 4.2 0.796 BMI (kg/m2) Mediastinitis risk score 0.7 ± 0.4 0.7 ± 0.4 0.570 Number of grafts (n) 3.2 ± 1.0 3.3 ± 1.0 0.557 CABG time (min) 104 ± 30 105 ± 27 0.896 Cross-clamp (min) 70 ± 21 71 ± 20 0.687 24-hour drainage (ml) 508 ± 200 549 ± 317 0.350 Total drainage (ml) 515 ± 202 587 ± 334 0.113 COPD 6 (7.7%) 4 (5.5%) 0.746 Dialysis 2 (2.6%) 3 (4.1%) 0.673 Ejection fraction (< 40%) 13 (16.7%) 12 (16.4%) 0.856 Urgent surgery 1 (1.3%) 3 (4.1%) 0.353 Emergency surgery 0 (0%) 0 (0%) 1.0 Sternal infection 0 (0%) 1 (1.4%) 0.303 Categorical variables are expressed as number (percentage) and continuous variables as mean = SD. BMI = body mass index; CABG = coronary artery bypass graft; COPD = chronic obstructive pulmonary disease.

minutes before surgery and 1 g every eight hours after surgery for 48 hours. Cardiopulmonary bypass (CPB) duration, cross-clamping times and number of grafts in both groups are shown in Table 1. Only left internal mammary artery grafts were used in all patients. Meticulous aseptic techniques were used during the operation and unnecessary use of electrocautery and excessive perfusion in CPB were avoided. All patients were kept in the intensive care unit for 24 hours and the patients were referred to a regular ward within the second 24 hours after drains and arterial catheters were removed. Central venous catheters were removed on the second postoperative day. The patients were discharged on postoperative day 6 ± 3. In the rifamycin group, mediastinum, sternum and suprasternal tissues were irrigated after surgery using rifamycin SV i.m. (Rif® 250 mg/3-ml ampoule) diluted with 10 ml isotonic solution. In the control group, irrigation was not performed. The two groups were compared with regard to risk for sternal infection.

Statistical analysis Statistical analysis was performed using statistical package for social sciences 13.0 (SPSS Inc, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to determine the distribution of numerical parameters. Continuous variables are presented as mean ± standard deviation. For comparison of independent continuous variables, the Student’s t-test or Mann–Whitney U-test was used where appropriate. Categorical data were compared using the Fisher’s exact test or chi-square test. For all statistics, a p-value < 0.05 was considered statistically significant.

Results There were no significant differences between the two groups in terms of baseline characteristics and mediastinitis risk percentages (Table 1). The patients were followed up for the development of SWI for 30 days after the surgery. In neither group did DSWI occur. While no SSWI was observed in the rifamycin group, it was observed in one patient in the control group (0/78 vs 1/73, p = 0.303). This patient, who used oral anti-diabetic medication, was 75 years old and had a serum creatinine level below 2.5 mg/ dl, had a low risk profile (total risk score: 3 and pre-operative mediastinitis risk percentage: 0.5%), according to the ACC/AHA 2004 guideline.5 Wound culture was performed and coagulase-negative staphylococci (CoNS) were observed. The patient was put on appropriate antibiotic therapy with sodium fusidate (Stafine® tablet 500 mg) three times daily and rifampicin (Rifcap® capsule 150 mg) twice daily. The infection regressed and the patient was discharged after a full recovery. The amount of drainage in the control group, particularly in four patients, was higher than in the patients in the rifamycin group, however, the difference was not statistically significant. This was attributed to the pre-operatively administered antiplatelet agents rather than to surgical reasons, and re-exploration was not required. However, none of the four patients developed sternal infection. None of the patients required re-exploration due to bleeding, tamponade or for other reasons.

Discussion

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 3, May/June 2014

Rifamycin was first isolated in 1957 from a fermentation culture of Nocardia mediterranei and used as a novel antibiotic compound. Rifamycin SV is a relatively effective agent for the treatment of gram-positive bacteria, Mycobacterium tuberculosis and certain gram-negative bacteria. Rifampicin, an orally active agent that possesses higher antimicrobial activity, is derived from rifamycin SV. It has lower antimicrobial activity compared to its orally active derivative of rifampicin; however, both are effective against gram-positive cocci, especially staphylococci. Moreover, they possess higher antimicrobial activity against Staphylococcus aureus, S epidermidis, Streptococcus viridans and Mycobacterium tuberculosis, even in very low doses. There is only one study reporting improved outcomes in DSWI with the use of rifampicin.6 CoNS are part of normal skin flora.7 They are omnipresent and cause infection in patients as well as in hospital staff.7,8 CoNS are multiple-drug-resistant pathogens that can infect deep surgical wounds and have the potential to threaten life.9 Stahle et al.10 reported the rate of CoNS in surgical wound infections as 14%. It is known that CoNS are also the predominant bacteria in DSWI.11 SWI are divided into two subgroups: superficial sternal wound infection (SSWI) and deep sternal wound infection (DSWI). While SSWI involves only subcutaneous tissue, DSWI is associated with sternal osteomyelitis and sometimes with infected retrosternal space (termed mediastinitis).12 Studies have reported that DSWI occurs in 0.25 to 2.3% of patients.13-17 While re-opening and debridement of the mediastinum is required in the treatment of DSWI, administration of antibiotics is generally sufficient to treat SSWI. In the present study, only one patient (1/151, 0.66%) in the control group developed SSWI and was treated with the administration of antibiotics. DSWI occurring after CABG operation has a multifactorial aetiology, with a potential risk of death and high hospital costs.18 Many studies have suggested the underlying aetiology of DSWI occurring after CABG to be obesity, advanced age, prolonged CPB duration, diabetes, high creatinine levels, use of bilateral internal mammary artery grafts, and unnecessary use of electrocautery.14,18-21 Recent studies have suggested that DSWI is associated with obesity and re-operation, and also indicated that use of bilateral internal mammary artery grafts, duration and complexity of the operation, and diabetes are other risk factors.22 It is well known that mobilisation of the internal mammary artery causes sternal devascularisation and the resultant ischaemia contributes to sternal dehiscence or infection.14,22 In the present study, according to the ACC/AHA 2004 guideline,5 the pre-operative mediastinitis risk percentage of one patient who developed SSWI was 0.5%, due to the risk factors, advanced age and the presence of diabetes. Although this patient was not a dialysis patient, he/she had a high creatinine level (2.5 mg/dl). In a 10-year retrospective study of 5 440 patients who underwent cardiac surgery, Khanlari et al.6 evaluated 100 patients with staphylococcal DSWI developing after cardiac surgery. They reported that a rifampicin-containing antibiotic regimen significantly improved the outcomes during a one-year follow-up period. Many factors have been implicated in the occurrence of DSWI after cardiac surgery. However, there is no consensus on which is the most important and best predictive factor.23

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On the other hand, diabetes has emerged as a significant risk factor of cardiovascular surgeons, for the development of DSWI after CABG operation. In terms of the pathophysiological consequences of diabetes, microvascular changes and elevated blood glucose levels impair the healing process of surgical wounds.24,25 The present study is distinctive in that it examined patients who were on oral anti-diabetic agents or insulin therapy.

Conclusion Although the difference in the rate of superficial sternal wound infection between the rifamycin and control groups was not statistically significant, locally applied rifamycin SV during closure of the sternum after CABG surgery may have had a protective affect against SWI. We thank Associate Prof Ismail Keskin of the Department of Biometry and Genetics, Selçuk University, Konya, Turkey for his contribution to evaluation of the results and statistical analysis.

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Farinas MC, Gald PF, Bernal JM, et al. Suppurative mediastinitis after open-heart surgery: a case-control study covering a seven-year period in Santander, Spain. Clin Infect Dis 1995; 20(2): 272–279. Toumpoulis IK, Anagnostopoulos CE, DeRose JJ. The impact of deep sternal wound infection on long-term survival after coronary artery bypass grafting. Chest 2005; 127(2): 464–471. Hollenbeak CS, Murphy DM, Koenig S, et al. The clinical and economic impact of deep chest surgical site infections following coronary artery baypas graft surgery. Chest 2000; 118(2): 397–402. Mossad SB, Serkey JM, Longworth DL, et al. Coagulase-negative staphylococcal sternal wound infections after open heart operations. Ann Thorac Surg 1997; 63(2): 395–401. ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery. Circulation 2004; 110; e340-e437. Khanlari B, Elzi L, Estermann L, Weisser M, Brett W, et al. A rifampicin-containing antibiotic treatment improves outcome of staphylococcal deep sternal wound infections. J Antimicrob Chemother 2010; 65(8): 1799–1806. Kloos WE, Musselwhite MS. Distribution and persistence of Staphylococcus and Micrococcus and other aerobic bacteria on human skin. Appl Microbiol 1975; 30(3): 381–385. Babb JR, Lyman P, Ayliffe GA. Risk of airborne transmission in an operating theatre containing four ultraclean units. J Hosp Infect 1995; 31(3): 159–168. Emori TG, Gaynes RP. An owerview of nosocomial infections, including the role for the microbiology laboratory. Clin Microbiol Rev 1993; 6(4): 428–442. Stahle E, Tammelin A, Bergstrom R, Hambreus A, Nystrom SO, Hansson HE. Sternal wound complications – incidence, microbiology and risk factors. Eur J Cardiothorac Surg 1997; 11(6): 1146–1153. Loop FD, Lytle BW, Cosgrove DM, et al. J. Maxwell Chamberlain memorial paper: sternal wound complications after isolated coronary artery bypass grafting: early and late mortality, morbidity, and cost of care. Ann Thorac Surg 1990; 49(2): 179–186. El Oakley RM, Wright JE. Postoperative mediastinitis: classification and management. Ann Thorac Surg 1996; 61(3): 1030–1036. Sarr MG, Gott VL, Townsend TR. Mediastinal infection after cardiac surgery. Ann Thorac Surg 1984; 38(4): 415–423.

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14. The Parisian mediastinitis study group. Risk factors for deep sternal wound infection after sternotomy: a prospective, multicenter study. J Thorac Cardiovasc Surg 1996; 111(6): 1200–1207. 15. Baskett RJ, MacDougall CE, Ross DB. Is mediastinitis a preventable complication? A 10-year review. Ann Thorac Surg 1999; 67(2): 462–465. 16. Ottino G, Paulis RD, Pansini S, et al. Major sternal wound infection after open-heart surgery: a multivariate analysis of risk factors in 2579 consecutive operative procedures. Ann Thorac Surg 1987; 44(2): 173–179. 17. Demmy TL, Park SB, Liebler GA, et al. Recent experience with major sternal wound complications. Ann Thorac Surg 1990; 49(3): 458–462. 18. Kirklin JW, Barratt-Boyes BG. Cardiac Surgery. 2nd edn. New York: Churchill Livingstone, 1993: 225–226. 19. Ivert T, Lindblom D, Sahni J, Eldh J. Management of deep sternal wound infection after cardiac surgery – Hanuman syndrome. Scand J Cardiovasc Surg 1991; 25(2): 111–117. 20. Loop FD, Lytle BW, Cosgrove DM, Mahfood S, et al. Sternal wound complications after isolated coronary artery by pass grafting: early

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and late mortality, morbidity, and cost of care. Ann Thorac Surg 1990; 49(2): 179–186. Grossi EA, Espisito R, Haris LJ, Crooke GA, et al. Sternal wound infections and use of internal mammary artery grafts. J Thorac Cardiovasc Surg 1991; 102(3): 342–347. Seyfer AE, Shriver CD, Miller TR, Graeber GM. Sternal blood flow after median sternotomy and mobilization of the internal arteries. Surgery 1988; 104(5): 899–904. Frriedman ND, Bull AL, Russo PL, Leder K, Reid C, Billah B, et al. An alternative scoring system to predict risk for surgical site infection complicating coronary artery bypass graft surgery. Infect Control Hosp Epidemiol 2007; 28(10): 1162–1168. Furnary AP, Zerr KJ, Grunkemier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999; 67(2): 352–360. Zerr KJ, Fyrnary AP, Grunkemier GL, Bookin S, Kanhere V, Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 1997; 63(2): 356–361.

15th ANNUAL SA HEART CONGRESS

REGISTRATION & ACCOMMODATION BOOKINGS OPEN SA Heart Congress 2014 will be held in Durban, from 16 – 19 October, with the central theme being ‘Bridging the Divide’. This is the divide that exists between current best practice – and the challenges encountered in implementing these ideals. All medical and allied professionals with an interest in cardiac health are warmly invited by the organising committee to attend.

For more information: EUROPA ORGANISATION AFRICA Tel +27 11 325 0020 Fax: +27 11 325 0028 or 0865 102 208 Email info@eoafrica.co.za

IN SOUTH AFRICA

at the SA Heart Association Congress

Bridging the Divide | 16 - 19 October 2014 International Convention Centre • Durban • South Africa

Website www.saheart.org/congress2014

WW00035 SAHEART ANN_1/2HA4.indd 1

07/03/2014 13:21

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Assessment of the efficacy of Ankaferd blood stopper on the prevention of postoperative pericardial adhesions Yunus Nazli, Necmettin Colak, Mehmet Fatih Alpay, Hacer Haltas, Omer Nuri Aksoy, Ismail Olgun Akkaya, Omer Cakir Abstract Objectives: Ankaferd has been used as a blood-stopping agent and it may also have an anti-inflammatory effect. We investigated the efficacy of Ankaferd in preventing postoperative pericardial adhesions in an experimental rabbit model. Methods: Sixteen New Zealand white rabbits were used and categorised into two groups: an Ankaferd and a control group. The Ankaferd group of rabbits was treated with a sponge impregnated with Ankaferd solution, which was applied over the abraded epicardium. A sponge impregnated with 0.9% isotonic NaCl solution was applied to the control group using the same protocol. Scores for adhesion and visibility of coronary vessels were graded by macroscopic examination, and pericardial tissues were analysed microscopically in terms of inflammation and fibrosis. Results: In the Ankaferd group, the adhesion scores were significantly higher than in the control group (p = 0.007). When the groups were compared according to the prevalence of fibrosis and degree of inflammation, the Ankaferd group was found to be statistically significantly different from the control group in terms of prevalence of fibrosis (p = 0.028). Conclusion: Topical application of Ankaferd to prevent postoperative pericardial adhesions increased adhesion and fibrosis scores. Keywords: cardiac operation, Ankaferd, pericardial adhesion Submitted 6/2/14, accepted 20/2/14 Cardiovasc J Afr 2014; 25: 100–105

www.cvja.co.za

Despite ongoing improvements during cardiac re-operation surgery, the presence of pericardial adhesions not only adds to the surgery time but also increases the risk of life-threatening injuries to the heart, great vessels or previously placed coronary bypass conduits by obscuring the true anatomy.1 Various methods and materials have been investigated to prevent or reduce the severity of postoperative adhesions in the retrosternal spaces and mediastinal structures. Fibrinolytic agents, histamine antagonists, anti-coagulants, anti-inflammatory drugs (corticosteroids, non-steroidal drugs), antibiotics, several natural physical barriers (heterologous pericardium, omentum, peritoneum, amnion, fibrin, gelatin, collagen and hyaluronic acid) and synthetic physical barriers (rubber, silicon-based materials, cellulose, polytetrafluoroethylene, polyvinyl alcohol and polyester derivatives) have been tried with variable success for such purposes.2-6 Unfortunately, despite continuous advances and research, to date there is no ideal method to prevent or reduce postoperative pericardial adhesion formation. Ankaferd blood stopper® (ABS) (Ankaferd Ilac Kozmetik AS, Istanbul, Turkey) is a folkloric medicinal plant extract. Ankaferd has been used as a blood-stopping agent against various types of bleeding. It has been approved by the Ministry of Health in Turkey for the management of bleeds due to external injury and dental surgery. It has also been used as a topical agent for the prevention of postoperative intra-abdominal fibrosis in experimental studies, and variable results have been obtained.7,8 To the best of our knowledge, there is no report on the effect of Ankaferd in preventing postoperative pericardial adhesions to date. The present experimental study was designed to investigate the effect of intrapericardially administered Ankaferd on reducing postoperative pericardial adhesion formation in the rabbit model.

DOI: 10.5830/CVJA-2014-011

Postoperative pericardial adhesion formation occurs frequently after cardiac surgery and is an important cause of morbidity and mortality at the time of re-operation. As the number of patients undergoing cardiac surgery continues to increase, the number of potential candidates for re-operation is increasing exponentially. Department of Cardiovascular Surgery, University of Turgut Ozal, Ankara, Turkey Yunus Nazli, MD, yunusnazli@gmail.com Necmettin Colak, MD Mehmet Fatih Alpay, MD Omer Nuri Aksoy, MD Ismail Olgun Akkaya, MD Omer Cakir, MD

Department of Pathology, University of Turgut Ozal, Ankara, Turkey Hacer Haltas, MD

Methods The study protocol was approved by the Ethics Committee for Animal Research, Ankara Education and Research Hospital, Ankara, Turkey. Sixteen New Zealand white rabbits weighing 2.5 to 3.0 kg were anesthetised with 35 mg/kg ketamine hydrocloride and 5 mg/kg xylazine administered intramuscularly.9,10 After disappearance of the pedal reflex in the hind limbs, the rabbits were placed in the supine position on a heated operating table and their temperature was maintained at 39°C by monitoring their rectal temperature.11,12 The pedal reflex was checked every five minutes throughout the surgical procedure. A venous line was established in the ear and a saline solution was infused at a rate of 3 mg/kg/h. Prophylactic antibiotic (cefazolin sodium 40 mg/kg) was given intravenously just before the operation. All had continuous two-lead electrocardiograph monitoring during the surgery. A paediatric facial mask in which oxygen gas flowed at a rate of 200 ml/min was placed on each rabbit.13

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The surgical procedure was performed sterilely. After a midline muscle and skin incision was made over the sternum, the xiphoid process was carefully detached from the sternal part of the diaphragm. A median sternotomy was then performed; the median incision went down from the xiphoid process towards the jugular notch of the sternum exactly along the midline of the sternum so that injury to the parietal pleura was avoided. Sternal retractors were used to spread the sternal edges and maintain surgical exposure. The epicardium and parietal pericardium related to the right ventricle atrium, and right and left ventricle were abraded with 10 vertically reciprocal movements of dry gauze in order to create local inflammation.13 The rabbits were divided into two groups: the Ankaferd group was treated with a sponge that had been soaked in a 2-ml concentration of ABS solution (Ankaferd blood stopper® ampoule, 2 ml, Istanbul, Turkey) and applied over the abraded epicardium for five minutes (n = 8). The sponge was then removed. The abraded areas of the epicardium were irrigated immediately with enough saline to dispose of the remaining ABS. In the control group, the sponge was soaked in a 0.9% isotonic NaCl solution (serum fizyolojik 0.9% NaCl, 5 ml/ampoule, Adeka, Turkey) and was applied to the surface of the abraded epicardium for five minutes (n = 8). The sponge was then removed. The investigators were blinded during the application of Ankaferd or saline. The sternum was closed with three interrupted sutures using 3-0 nylon and a needle with a tapered point. The muscle layers and skin were then closed with continuous sutures using 4-0 nylon and a cutting needle. The rabbits were allowed to recover. During the surgical procedure, all rabbits exhibited spontaneous respiration and loss of the pedal reflex. The rabbits were sacrificed two weeks after surgery with a lethal dose of pentobarbital (150 mg/kg) (Nembutol, IE Ulagay, Istanbul, Turkey). The heart and pericardium were removed en bloc. Specimens were fixed in 10% formaldehyde, embedded in paraffin and sectioned into 4-µm slices, which were stained with haematoxylin and eosin to assess the inflammatory reaction and degree of fibrosis, and to check for remnants of the pericardial substitute in the two groups.

Macroscopic examination The heart and pericardium were removed with the anterior chest wall en bloc. The severity of pericardial adhesions and visibility of coronary vessels were evaluated by the same two blinded observers and scored. The following qualitative grading system was used to evaluate the tenacity of the adhesions: 0 = no adhesions; 1 = mild adhesions (transparent filmy adhesions separable by lifting the pericardium from the myocardium without dissection); 2 = moderate adhesions (fibrous and easily separated by blunt dissection); 3 = severe adhesions (thick, requiring aggressive blunt dissection); 4 = very severe adhesions (multiple thick adhesions requiring aggressive dissection that damaged adherent tissue).14 In addition, another grading system was used to evaluate the visibility of the coronary arteries: 0 = clearly visible, 1 = blurred, 2 = completely obscured.6

Light microscopic examination After the macroscopic scoring, the paraffin-embedded heart tissues (segments of the pericardium and heart from the site of

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abrasion, which had been marked with a prolene stitch) were cut into 4-µm thick sections and stained with haematoxylin and eosin. Histopathological evaluation was performed by one pathologist who was blinded to the study groups. The severity of the inflammatory reaction was based on quantification of the inflammatory cells (i.e. neutrophils, plasma cells, lymphocytes) and inflammatory foci. The scoring schemes of Lu et al.15 were used to grade inflammation (0 = no cell infiltration; 1 = sparse, focal infiltration of lymphocytes and plasma cells; 2 = focal infiltration of neutrophils, plasma cells and lymphocytes; and 3 = diffuse infiltration of neutrophils, plasma cells and lymphocytes), and fibrosis (0 = no fibrous reaction; 1 = sparse, focal fibrous connective tissue, hyalinisation and fibrin deposition; 2 = a thin layer of focal fibrous connective tissue, hyalinisation and fibrin deposition; and 3 = a thick layer of focal fibrous connective tissue, hyalinisation and fibrin deposition).

Statistical analysis The sample size of our study was calculated with G*Power (G*Power Ver. 3.00.10, Franz Faul, Üniversität Kiel, Germany, http://www.psycho.uniduesseldorf. de/aap/projects/gpower/) statistical packages. The required sample size for 80% power, α = 0.05 type I error, β = 0.20 type II error, and f = 0.70 effect size was calculated as 16, including eight New Zealand white rabbits in each group. To protect the study from potential loss to follow up, one more rabbit was included in each group and the study was completed with a sample size of 18. Data coding and statistical analyses were conducted with SPSS (version 15; SPSS Inc, Chicago, IL, USA). Following the entering of the rabbits’ data into the computer, all the necessary diagnostic checks and corrections were performed. Conformity of the measured values to normal distribution was examined graphically and using a Shapiro-Wilks test. In presenting descriptive statistics, numbers and percentages were used for categorical variables, and medians and ranges were used for non-normally distributed variables. The Mann-Whitney U-test was used to compare the median values of the groups. The chi-square test was performed to evaluate the difference in the proportion of rabbits in the groups. Groups that were close to each other were combined and a 2 × 2 table chi-square test was created. The likelihood ratio test was used for the comparison of these groups. The two-tailed test of p ≤ 0.05 was considered statistically significant.

Results All animals tolerated the procedure with no apparent postoperative complications. Results were analysed in terms of macro- and microscopic findings.

Macroscopic findings A total of 16 rabbits were evaluated for grading of pericardial adhesions by macroscopic findings. In six cases in the control group and one case in the Ankaferd group, pericardial adhesions were split by blunt dissection (Fig. 1A). By contrast, seven of the Ankaferd group and two of the control group were associated with tight adherences to the sternum and the rest of the pericardium, requiring sharp dissection (Fig. 1B).

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There were statistically significant differences between the Ankaferd and control groups in terms of the adhesion score [Ankaferd vs control group: 3 (2–4) vs 2 (1–3), p = 0.007] (Fig. 2). There was no statistically significant difference between the Ankaferd and control group in terms of the visibility of coronary vessels score [Ankaferd vs control group: 1 (1–2) vs 1 (1–2), p = 0.105] (Table 1). When the prevalence of pericardial adhesion was compared, there was a positive trend in the odds ratio for severe to very severe adhesion in the Ankaferd group (Ankaferd vs control group: 87.5 vs 25%, respectively) (Table 2). When the groups were compared according to the degree of pericardial adhesions and the visibility of coronary vessels score, there were statistically significant differences between the Ankaferd and control group (p = 0.009, p = 0.033, respectively) (Table 2). In our study, there was no infection or delayed healing at the wound site. Results of the macro- and microscopic scores A

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Table 1. Results of macroscopic and microscopic scores between the control and Ankaferd groups. Ankaferd group (n = 8) Median (range)

Variables Macroscopic scores Pericardial adhesions 3 (2–4) Visibility of coronary vessels 2 (1–2) Microscopic scores Inflammation 2 (2–3) Fibrosis 3 (3–3) NS, not statistically significant (p > 0.05).

Control group (n = 8) Median (range)

2 (1–3) 1 (1–2)

2.680 0.007 2.000 0.105 (NS)

3 (1–3) 3 (1–3)

1.061 0.382 (NS) 1.852 0.234 (NS)

and distribution of the scores between the control and Ankaferd groups are shown in Tables 1 and 2.

Microscopic findings There were no statistically significant differences between the Ankaferd and control groups in terms of severity of fibrosis (p = 0.234) (Table 1). However, severe fibrosis was present in 100% of the Ankaferd group and 62.5% of the control group. When the groups were compared according to the prevalence of fibrosis and degree of inflammation, statistically significant differences between the groups were found in the Ankaferd group only in terms of the prevalence of fibrosis (p = 0.028) (Fig. 3A, B). There were no statistically significant differences between the Ankaferd and control group with regard to degree of inflammation (p = 0.220) (Fig. 4A, B) (Table 2).

Discussion B

One of the primary long-term postoperative concerns after a sternotomy is the formation of pericardial adhesions during the healing process. These adhesions are an important cause of morbidity and mortality in cardiac surgery.16 Pericardial adhesions may attach the heart to the undersurface of the sternum and neighboring structures, compromise right ventricular

Pericardial adhesion score

Fig. 1. A . Two weeks after the initial operation, adhesion formation in the control group was significantly lower between the epicardial and pericardial surfaces. This was determined as being more easily dissected. B. Severe pericardial adhesions, which were difficult to dissect out, were observed between the epicardium and mediastinal tissues in the Ankaferd group.

p = 0.007

0 Ankaferd

Groups

Control

Fig. 2. D ifferences in pericardial adhesion score between the two groups.

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Table 2. The distribution of the macroscopic and microscopic scores between the control and Ankaferd groups Ankaferd group n (%)

Variables Macroscopic scores Pericardial adhesions Mild – moderate (1+2) 1 (12.5) Severe – very severe (3+4) 7 (87.5) Visibility of coronary vessels Blurred (1) 1 (12.5) Completely obscured (2) 7 (87.5) Microscopic scores Inflammation None – mild (0+1) 0 (0.0) Moderate – severe (2+3) Fibrosis 8 (100) Mild – moderate (1+2) 0 (0.0) Severe (3) 8 (100) NS, not statistically significant (p > 0.05).

Control group n (%)

6 (75) 2 (25)

6.904

0.009

5 (62.5) 3 (37.5)

4.557

0.033

1 (12.5)

1.453 0.220 (NS)

7 (87.5) 3 (37.5) 5 (62.5)

4.857

0.028

Fig. 3. A. Histopathological section showing grade II fibrosis (**) in the control group (H&E ×200). B. Histopathological section showing severe fibrosis (**) around the myocardium (*) in the Ankaferd group (H&E ×200).

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contraction, and restrict left ventricular diastolic filling. They can also obscure the anatomy of the heart, coronary arteries and great vessels, and coronary grafts if present, immensely complicating the procedure for re-operation by prolonging surgery time, and potentially escalating serious mediastinal injury during re-entry.17,18 Adhesion formation occurs as a consequence of the inflammatory response to surgical trauma, which can start within a few hours of surgery, as routine surgical procedures consist of tissue handling, including abrasion, desiccation, ischaemia, haemorrhage, exposure to foreign material and overheating by lamps.18 Histological examination of pericardial tissues from animals undergoing cardiac surgical procedures indicates that damage to the mesothelium (especially by abrasion) is adhesiogenic.19,20 It is known that mesothelial cells are responsible for the fibrinolytic properties of coelomic cavities, and damage to these cells is the trigger for adhesion formation.5 According to several previous studies, although the mechanism of adhesion formation is not fully understood, fibroblast activity and inflammatory A

Fig. 4. M icroscopic pictures of the control (A) and Ankaferd (B) groups showing dense lymphocyte infiltration (**) near the myocardial tissue (*) (H&E ×200).

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responses are believed to be important in the pathogenesis of adhesion formation. The inflammatory response is a complex pathophysiological process including many chemical and cytokine mediators that cause extravascular plasma leakage (as a consequence of increased vascular permeability) and the formation of fibrin. This leads to the formation of serosanguineous exudate, which in turn initiates adhesion formation.16 Fibrin provides a framework for fibroblast proliferation, the synthesis of collagen and adhesion formation.18 Increase in reactive oxygen species (ROS) after endothelial tissue damage, which occurs during open surgery, may play a role in postoperative adhesion formation. Evidence has shown that ROS scavengers could reduce adhesion formation in animal models.16,21 Subsequently, if these initial adhesions are not lysed, they are organised into fibrous adhesions by activated fibroblasts. However, in a state of imbalance between fibrin deposition and dissolution, deposited fibrin may persist and fibrinous adhesions may develop.16,21 Unfortunately, despite continuous advances and research, an ideal method and material to decrease postoperative pericardial adhesion formation have not been found. A number of antiadhesive interventions have been developed and many have been tested clinically and experimentally in cardiac applications. Various methods and agents have been used with controversial results.22 Some studies have focused primarily on substitutes (autogenous, heterogenous and synthetic) providing a barrier between the epicardium and pericardium or overlying sternum, while other work has evaluated the ability of a variety of pharmacological agents to decrease or prevent pericardial adhesion formation after cardiac surgery.16,23-25 Anti-inflammatory drugs, antibiotics and topical application of fibrinolytic agents have also been shown to decrease pericardial adhesion formation.16,26,27 ABS is a herbal extract attained from five different plants: Thymus vulgaris (thyme), Glycyrrhiza glabra (licorice), Vitis vinifera (unriped grape), Alpinia officinarum (galangal) and Urtica dioica (stinging nettle). It has been folklorically used in traditional Turkish medicinal practice. ABS represents an alternative treatment modality for many kinds of bleeding that are resistant to conventional methods. Today, topical ABS is used and has provided positive results in spontaneous or secondary bleeding (gastrointestinal, orthopedic, nasal, dermal) due to body injuries, traumas, and minor or major surgical interventions and wound healing.28 Besides its homeostatic activity, Kocak et al.29 reported that Ankaferd might also have anti-inflammatory effects.7 Tests have demonstrated its safety, efficacy, sterility and non-toxicity for external usage.8,30 Al et al.7 showed that Ankaferd was not efficient in reducing postoperative intra-abdominal adhesions. Conversely, Cömert et al.8 reported that there was less intra-peritoneal adhesion formation in the Ankaferd than in the control group. However, the safety and non-toxicity of Ankaferd for intra-pericardial usage and the effects of Ankaferd on postoperative pericardial adhesion have yet to be assessed. In the present study, fibrosis score measurements showed no statistically significant difference between the Ankaferd and control groups (p = 0.234). However when the groups were compared according to the prevalence of fibrosis, there were statistically significant differences between the groups (p

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= 0.028), and fibrosis scores were significantly higher in the Ankaferd group. The results of our study showed that topical application of Ankaferd could increase pericardial adhesion after abrasive injury of the epicardial surface in a rabbit model. In addition to the pericardial adhesion and visibility of coronary vessels score, histological evaluation was used to evaluate the effect of Ankaferd on inflammation and fibrosis in the rabbit model. However, there were no statistically significant differences between the groups in terms of inflammatory scores and degree of inflammation (p = 0.382, p = 0.220, respectively). Hence, efficacy of Ankaferd on inflammation was not observed in the histological evaluation.

Conclusion We applied Ankaferd to try and reduce postoperative pericardial adhesion in an experimental rabbit model. The use of Ankaferd increased the adhesion and fibrosis scores. However, its efficacy on inflammation was not demonstrated. Further studies with Ankaferd are necessary to evaluate its efficacy in prevention of adhesion formation in cardiac surgery. This study was supported by the Scientific Research Fund of Fatih University.

References 1.

Loop FD, Cosgrove DM, Kramer JR. Late clinical and arteriographic results in 500 coronary artery reoperations. J Thorac Cardiovasc Surg 1981; 81: 675–684. 2. Diamond P, DeCherney AH. Pathogenesis of adhesion formation/ reformation: Application to reproductive pelvic surgery. Microsurgery 1987; 8: 103–107. 3. Edwards GA, Glattauer V, Nash TJ, et al. In vivo evaluation of a collagenous membrane as an absorbable adhesion barrier. J Biomed Mater Res 1997; 34: 291–297. 4. Matsuda S, Se N, Iwata H, Ikada Y. Evaluation of the antiadhesion potential of UV crosslinked gelatin films in a rat abdominal model. Biomaterials 2002; 23: 2901–2908. 5. Lopes JB, Dallan LA, Campana-Filho SP, et al. Keratinocyte growth factor: a new mesothelial targeted therapy to reduce postoperative pericardial adhesions. Eur J Cardiothorac Surg 2009; 35: 313–318. 6. Biçer M, Bayram AS, Gürbüz O, et al. Assessment of the efficacy of bio-absorbable oxidized regenerated cellulose for prevention of postoperative pericardial adhesion in the rabbit model. J Int Med Res 2008; 36: 1311–1318. 7. Al B, Kilic H, Zengin S, et al. Efficiency of Ankaferd Blood Stopper Used in Bleeding Control on Intraabdominal Adhesions Formed Postoperatively. Clin Appl Thromb Hemost 2013 Jan 2. [Epub ahead of print]. 8. Cömert M, Karakaya K, Barut F, et al. Does intraabdominal use of Ankaferd Blood Stopper cause increased intraperitoneal adhesions? Ulus Travma Acil Cerrahi Derg 2010; 16: 383–389. 9. White GL, Holmes DD: A comparison of ketamine and the combination ketaminexylazine for effective surgical anesthesia in the rabbit. Lab Anim Sci 1976; 26: 804–806. 10. Green CJ, Knight J, Precious S, Simpkin S. Ketamine alone and combined with diazepam or xylazine in laboratory animals: A 10 year experience. Lab Anim 1981; 15: 163–170. 11. Flecknell PA, John M, Mitchell M, Shurey C. Injectable anaesthetic techniques in 2 species of gerbil (Meriones libycus and Meriones

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unguiculatus). Lab Anim 1983; 17: 118–122. 12. Peeters ME, Gil D, Teske E, et al. Four methods for general anaesthesia in the rabbit: a comparative study. Lab Anim 1988; 22: 355–360. 13. Fujita M, Morimoto Y, Ishihara M, et al. A new rabbit model of myocardial infarction without endotracheal intubation. J Surg Res 2004; 116: 124–128. 14. Connors RC, Muir JJ, Liu Y, et al. Postoperative pericardial adhesion prevention using Carbylan-SX in a rabbit model. J Surg Res 2007; 140: 237–242. 15. Lu JH, Chang Y, Sung HW, et al. Heparinization on pericardial substitutes can reduce adhesion and epicardial inflammation in the dog. J Thorac Cardiovasc Surg 1998; 115: 1111–1120. 16. Saeidi M, Sobhani R, Movahedi M, Alsaeidi S, Samani RE: Effect of melatonin in the prevention of postoperative pericardial adhesion formation. Interact Cardiovasc Thorac Surg 2009; 9: 26–28. 17. Kuschel TJ, Gruszka A, Hermanns-Sachweh B, et al. Prevention of postoperative pericardial adhesions with TachoSil. Ann Thorac Surg 2013; 95: 183–188. 18. Alizzi AM, Summers P, Boon VH, et al. Reduction of post-surgical pericardial adhesions using a pig model. Heart Lung Circ 2012; 21: 22–29. 19. Burns JW, Skinner K, Colt J, et al. Prevention of tissue injury and postsurgical adhesions by precoating tissues with hyaluronic acid solutions. J Surg Res 1995; 59: 644–652. 20. Cliff WJ, Grobety J, Ryan GB. Postoperative pericardial adhesions: The role of mild serosal injury and spilled blood. J Thoracic Cardiovasc Surg 1973; 65: 744–750. 21. Binda MM, Molinas CR, Koninckx PR. Reactive oxygen species and

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adhesion formation: clinical implications in adhesion prevention. Hum Reprod 2003; 18: 2503–2507. Lopes JB, Dallan LA, Moreira LF, et al. Synergism between keratinocyte growth factor and carboxymethyl chitosan reduces pericardial adhesions. Ann Thorac Surg 2010; 90: 566–572. Nkere UU. Postoperative adhesion formation and the use of adhesion preventing techniques in cardiac and general surgery. ASAIO J 2000; 46: 654–656. Shapira N, Gordon CI, Lemole GM. Occlusion of aortocoronary vein grafts in association with bovine pericardium. Am J Cardiovasc Pathol 1990; 3: 87–90. Urschel HC, Jr, Razzuk MA, Gardner M. Coronary artery bypass occlusion second to postcardiotomy syndrome. Ann Thorac Surg 1976; 22: 528–531. Colak N, Nazli Y, Tasoglu I, et al. The effect of mitomycin-C in reducing pericardial adhesion after cardiac surgery in rabbits. Can J Cardiol 2013; 29: 712–717. Konertz WF, Kostelka M, Mohr FW, et al. Reducing the incidence and severity of pericardial adhesions with a sprayable polymeric matrix. Ann Thorac Surg 2003; 76: 1270–1274. Leblebisatan G, Bay A, Karakus SC, Kekilli M, Haznedaroglu IC. Topical Ankaferd hemostat application for the management of oral cavity bleedings in children with hemorrhagic diathesis. Blood Coagul Fibrinolysis 2012; 23: 494–497. Koçak E, Akbal E, Taş A, et al. Anti-inflammatory efficiency of Ankaferd blood stopper in experimental distal colitis model. Saudi J Gastroenterol 2013; 19: 126–130. www.ankaferd.com.

Cardiovascular congress diary 2014 DATE

CONFERENCE

LOCATION

CONTACT DETAILS TO REGISTER

11–12

RAAS satellite meeting 2014

Spier Wine Estate, Cape Town, SA

http://raassatellite2014.org

25–28

International Academy of Cardiology annual scientific sessions 2014, 19th World Congress on heart disease

Hyatt Regency, Boston, MA, USA

http://www.cardiologyonline.com/

ASSAF 8th annual meeting

Belmont Square Conference Centre, http://www.assaf.co.za/ Rondebosch, Cape Town, SA susan@assaf.org.za

Stroke and hypertension congress

Southern Sun Elangeni, Durban, SA www.strokeandhypertension2014.co.za

SA Paediatric Society/SA Society of Paediatric Surgeons

ICC, Cape Town, SA

www.sapacongress2014.co.za sonja@londocor.co.za

16–19

15th Annual SA Heart Congress 2014

ICC, Durban, SA

www.saheart.org

22–24

4th World Congress of Regional Anaesthesia and Pain Therapy

ICC, Cape Town, SA

AHA scientific session CME

Illiniois, Chicago, USA

JULY

AUGUST 22–24 SEPTEMBER 10–14 OCTOBER

NOVEMBER 15

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

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Carbon monoxide poisoning increases Tpeak–Tend dispersion and QTc dispersion Murat Eroglu, Omer Uz, Zafer Isilak, Murat Yalcin, Ali Osman Yildirim, Ejder Kardesoglu Abstract Objective: Carbon monoxide (CO) poisoning leads to cardiac dysrhythmia. Increased heterogeneity in ventricular repolarisation on electrocardiogram (ECG) shows an increased risk of arrhythmia. A number of parameters are used to evaluate ventricular repolarisation heterogeneity on ECG. The aim of our study is to investigate the effect of acute CO poisoning on indirect parameters of ventricular repolarisation on ECG. Methods: Sixty-seven patients were included in this case– control study. Thirty patients with acute CO poisoning were assigned to group 1 (19 females, mean age: 30.8 ± 11.3 years). A control group was formed with patients without known cardiac disease (group 2, n = 37; 25 females, mean age: 26.0 ± 5.2 years). Twelve-lead ECG and serum electrolyte levels were recorded in all patients. Also, carboxyhaemoglobin (COHb) levels were recorded in group 1. Tpeak–Tend (TpTe) interval, TpTe dispersion, TpTe/QT ratio, QT interval and QTd durations were measured as parameters of ventricular repolarisation. Corrected QT (QTc) and QTc dispersion (QTcd) intervals were determined with the Bazett’s formula. Results: The mean COHb level in group 1 was 27.6 ± 7.4% and mean duration of CO exposure was 163.5 ± 110.9 min. No statistically significant difference was found in age, gender, serum electrolytes or blood pressure levels between the groups. QRS, QT, QTc, TpTe interval and TpTe/QT ratio were similar between the groups (p > 0.05). QTcd (65.7 ± 64.4 vs 42.1 ± 14.2 ms, p = 0.003) and TpTe dispersion (40.5 ± 14.8 vs 33.2 ± 4.9 ms, p = 0.006) were significantly longer in group 1 than group 2. COHb level was moderately correlated with TpTe dispersion (r = 0.29; p = 0.01). Conclusion: To our knowledge, this is the first study to investigate TpTe interval and dispersion in CO poisoning. Our results showed that TpTe dispersion and QTc dispersion increased after CO poisoning. Keywods: carbon monoxide, electrocardiogram, dysrhythmia, ventricular repolarisation

Submitted 20/7/12, accepted 24/2/14 Cardiovasc J Afr 2014; 25: 106–109

www.cvja.co.za

DOI: 10.5830/CVJA-2014-012

Carbon monoxide (CO) poisoning may cause myocardial toxicity and life-threating cardiac arrhythmias.1-3 Acute coronary syndrome, myocardial injury, myocardial dysfunction, cardiac arrest and various types of arrhythmias have been reported in patients with acute CO poisoning.4 CO binds myocardial myoglobin and reduces myocardial oxygen reserve.5 Previous studies reported that episodes of atrial fibrillation, premature ventricular beats and sinusal tachycardia may be seen in patients with acute CO poisoning.6,7 Recent studies also suggested that risk of atrial and ventricular arrhythmia is increased in CO poisoning, due to prolonged QTc and QTc dispersion.2,3,8 Ventricular repolarisation can be evaluated by measuring QT interval, corrected QT interval, and QT dispersion. Among these parameters, QT dispersion represents the heterogeneity of ventricular repolarisation and was clearly shown to be associated with ventricular arrhythmia.9 Tpeak–Tend (TpTe) interval is defined as the interval between the peak point and endpoint of the T wave on surface electrocardiography and is a novel index of transmural dispersion of ventricular repolarisation.10 TpTe/QT ratio and TpTe/QTc ratio were used in previous studies as an electrocardiographic index in the evaluation of risk of ventricular arrhythmia.11,12 The effect of acute CO poisoning on QT intervals was investigated in a number of studies.2,3,8 However, to the best of our knowledge, TpTe interval, TpTe dispersion, TpTe/QT ratio and TpTe/ QTc ratio have not been investigated sufficiently in patients with CO poisoning. In this study, we aimed to investigate the effect of acute CO poisoning on electrocardiographic parameters, which indirectly show ventricular repolarisation heterogeneity. We also investigated the relationship between carboxyhaemoglobin (COHb) levels and these parameters.

Methods Department of Emergency Medicine, Haydarpasa Teaching Hospital, Gulhane Military Medical Academy, Istanbul, Turkey Murat Eroglu, MD, drmeroglu@yahoo.com Ali Osman Yildirim, MD

Department of Cardiology, Haydarpasa Teaching Hospital, Gulhane Military Medical Academy, Istanbul, Turkey Omer Uz, MD Zafer Isilak, MD Murat Yalcin, MD Ejder Kardesoglu, MD

The ethics committee of Gulhane Military Medical Academy Haydarpasa Teaching Hospital approved the study protocol. The control group was composed of 37 healthy medical staff or volunteers aged from 20 to 40 years (mean 26.0; SD = 5.2), comprising 25 women and 12 men. Patients who were treated with normobaric oxygen for CO poisoning at the Emergency Department of Gulhane Military Medical Academy between 1 October 2005 and 31 May 2006 comprised the study group. Diagnosis of CO poisoning was made based on medical history and a COHb level > 5% (10% in smokers). Patients excluded from the study were those with coronary artery disease or other known heart disease, such as valvular

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diseases or rhythm disorders, those taking drugs known to influence QT interval, patients with ECG abnormalities such as atrial fibrillation, conduction delay, bundle branch blocks, immeasurable T waves, and those with stroke, obstructive lung diseases, malignancies and those who received hyperbaric oxygen therapy. On admission to the emergency department, blood samples were obtained for blood gas analysis, total blood cell counts and biochemical parameters. COHb measurements were performed with Synthesis 45 (Italy). Baseline 12-lead ECGs were recorded with a paper speed of 25 mm/s and standardisation of 1.0 mV/cm in all patients. The QT intervals were measured from the onset of the QRS complex to the end of the T wave, defined as the return T-P baseline. When U waves were present, the QT intervals were measured to the nadir of the notch between the T and U waves. QTc interval was calculated using the Bazett’s formula. The QTc dispersion (QTcd) is the difference between minimum and maximum QTc intervals. TpTe interval was measured from the peak of the T wave to the end of the T wave. The end of the T wave was defined as the junction of the T wave with the isoelectric line. The difference between minimum and maximum TpTe intervals on ECG (TpTe.max–TpTe.min) was considered TpTe dispersion. TpTe/QT ratio and TpTe/QTc ratio were also calculated. Two experienced cardiologists (ZI and MY), who were unaware of the patient’s clinical condition, took two measurements of the QT and TpTe interval from each measurable lead.

Statistical analysis The data are presented as mean ± SD. The independentsamples t-test was used to compare continuous variables and the chi-square test was used for categorical variables. Pearson’s correlation coefficients were determined for the relationship of COHb levels with ECG parameters (QTc, QTcd, TpTe, TpTe dispersion and TpTe/QTc). A p-value < 0.05 was accepted as statistically significant. Statistical analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, IL).

Results A total of 67 patients (28.5 ± 9.0 years, 44 female) were included in the study. Eight (27%) among the CO-intoxicated

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patients were smokers. Clinical characteristics of the patients are presented in Table 1. Mean COHb level was 27.6 ± 7.4%. Mean duration of CO exposure was 164 ± 111 minutes and mean emergency department arrival time was 68 ± 123 minutes. We found a negative correlation between the time to emergency department arrival and COHb level (r = –0.568, p = 0.001). We also found a negative correlation between age and COHb level (r = –0.469, p = 0.01). Seven patients among the CO-intoxicated patients had sinus tachycardia on the ECG records taken at the emergency department. The mean heart rate of the CO-intoxicated patients was found to be mildly higher than that of the normal subjects. However, the difference was not statistically significant (p > 0.05) (Table 1). The QTcd durations of CO-intoxicated patients were significantly longer than that of normal subjects (63.1 ± 10.9 vs 42.1 ± 4.3 ms; p = 0.0001) (Table 2). The QTcd value was detected to be above 60 ms in 19 subjects of the CO-intoxicated patients (63%) and in none of the normal subjects (p < 0.001). The TpTe dispersion value of the CO-intoxicated patients was significantly higher than that of normal subjects (41.4 ± 13.0 vs 33.2 ± 4.9 ms; p = 0.001). TpTe/QTcd ratio was lower in the CO-intoxicated patients compared to the normal subjects (1.52 ± 0.29 vs 2.0 ± 0.34; p = 0.001). Pearson’s correlation analysis revealed that a moderately significant positive correlation was present only between TpTe dispersion and COHb levels (r = 0.39, p = 0.03) (Fig. 1). Correlations between electrocardiographic measurements and COHb levels of the patients are presented in Table 3.

Discussion Our results showed that Tpeak–Tend dispersion and QTc dispersion were higher in CO-intoxicated patients compared to normal subjects. TpTe/QTcd ratio was lower in CO-intoxicated patients compared to normal subjects. We found a positive correlation only between Tpeak–Tend dispersion and COHb level. Our results indicated that TpTe dispersion may be one of the reasons for arrhythmia caused by CO poisoning. CO may lead to persistent or reversible myocardial damage, mainly due to myocardial hypoxaemia and direct action of CO on the heart.13 Binding to myoglobin may reduce oxygen availability in the heart and cause arrhythmias and cardiac dysfunction.14 Cardiovascular effects of CO poisoning include tachycardia,

Table 1. Clinical characteristics of the study population. CO-intoxicated Normal subjects p* patients (n = 30) (n = 37) Age (years) 30.8 ± 11.3 26.0 ± 5.2 > 0.05 Gender (F/M) 19/11 25/12 > 0.05 23.1 ± 5.5 24.6 ± 6.9 > 0.05 BMI (kg/m2) Mean heart rate (beats/min) 92.5 ± 16.2 82.0 ± 13.0 > 0.05 SBP (mmHg) 118.7 ± 9.6 122.1 ± 8.7 > 0.05 DBP(mmHg) 78.2 ± 8.4 72.1 ± 7.5 > 0.05 CO exposure time (min) 163.5 ± 110.9 COHb (g/dl) 27.6 ± 7.4 Time to ED arrival (min) 68.3 ± 123.1 Smoker, n (%) 8 (27) 11 (30) > 0.05 BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ED, emergency department.

Table 2. Electrocardiographic measurements of the groups.

QT interval (ms) QTc interval (ms) TpTe /QTc time (ms) TpTe/QTd time (ms) TpTe/QTcd time (ms) TpTe dispersion (ms) TpTe/QT time (ms) QTd interval (ms) QTcd interval (ms) TpTe time (ms)

CO-intoxicated Normal subjects patients (n = 30) (n = 37) 355.7 ± 90.7 359.6 ± 26.4 382.1 ± 11.4 403.7 ± 19.7 0.26 ± 0.02 0.20 ± 0.02 1.78 ± 0.32 1.85 ± 0.27 1.52 ± 0.29 2.0 ± 0.34 41.4 ± 13.0 33.2 ± 4.9 0.26 ± 0.04 0.23 ± 0.02 57.2 ± 10.8 55.1 ± 3.7 63.1 ± 10.9 42.1 ± 4.3 87.5 ± 19.0 83.1 ± 8.3

p* 0.51 0.31 0.16 0.2 0.001 0.001 0.11 0.1 0.0001 0.21

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Table 3. Correlations between electrocardiographic measurements and COHb levels. R p* QT interval (ms) –0.12 0.52 –0.11 0.53 QTc interval (ms) 0.07 0.68 QTd interval (ms) 0.18 0.33 QTcd interval (ms) 0.19 0.33 TpTe time (ms) 0.39 0.03* TpTe dispersion (ms) 0.08 0.66 TpTe/QT time (ms) 0.17 0.35 TpTe /QTc (ms) 0.06 0.71 TpTe /QTd (ms) 0.07 0.69 TpTe /QTcd (ms)

40 R 2 linear = 0.039

20 10.00

hypotension, dysrhythmia, ischaemia, infarction, and, in some cases, cardiac arrest.15,16 Previous studies reported that episodes of atrial fibrillation, premature ventricular beats and sinus tachycardia developed in patients with acute CO poisoning.6,7 QT and QTc show ventricular repolarisation on ECG. A prolonged QT interval indicates impaired myocardial refractoriness. Prolonged QT and QTc intervals can cause a number of arrhythmias, including torsades de pointes, polymorphic ventricular tachycardia and ventricular fibrillation.17,18 A number of studies have investigated the effect of acute CO poisoning on QT and QTc intervals. These studies found that QTc but not QT interval was prolonged in CO-poisoned patients compared to control subjects.4,19 In our study, however, we found that neither QT nor QTc intervals was prolonged after CO poisoning. QT and QTc dispersion represent physiological variability of regional ventricular repolarisation. Increased QT and QTc dispersions are related to heterogeneity of regional ventricular repolarisation and are accepted as the markers of arrhythmias.17,20 Data concerning the effect of acute CO poisoning on QT and QTc dispersion is limited. However, it has been reported that CO poisoning increased QT and QTc dispersion.4,19 We found that the durations of QTcd were significantly prolonged in adult patients with acute CO poisoning. TpTe interval is used as an index of transmural dispersion of ventricular repolarisation.10 TpTe dispersion, TpTe/QT ratio and TpTe/QTc ratio are also used as an electrocardiographic index of ventricular arrhythmogenesis.12,21 Sicouri et al. found a relationship between ventricular arrhythmia and prolonged TpTe interval.22 Previous studies have demonstrated that prolongation of TpTe duration is associated with increased mortality in Brugada syndrome, long QT syndromes, hypertrophic cardiomyopathy, and in patients undergoing primary percutaneous coronary intervention for myocardial infarction.11 In our study, TpTe interval, TpTe/QT ratio and TpTe/QTc ratio did not change significantly after CO poisoning. However, we did find a correlation between TpTe dispersion and COHb levels. In our study we found that only QTc dispersion and TpTe dispersion increased in patients with CO poisoning. We concluded that these two parameters are more valuable among the ECG parameters to demonstrate risk of ventricular arrhythmia in patients with CO poisoning. The limitation of this study was the relatively small number of patients with CO poisoning. Therefore, a follow-up investigation with a larger sample size is warranted.

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Tpeak-Tend dispersion

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20.00 30.00 COHb, %

40.00

Fig. 1. A moderately significant positive relationship between TpTe dispersion and COHb levels.

Conclusion Our results showed that Tpeak–Tend dispersion and QTc dispersion increased after CO poisoning. We believe that CO poisoning impaired the homogeneity of ventricular repolarisation and may have caused increased Tpeak–Tend dispersion and QTc dispersion. Further studies are needed to evaluate the importance of electrocardiographic parameters in CO poisoning.

References 1.

Gandini C, Castoldi AF, Candura SM, Priori S, Locatelli C, Butera R, et al. Cardiac damage in pediatric carbon monoxide poisoning. J Toxicol Clin Toxicol 2001; 39: 45–51. 2. Gurkan Y, Canatay H, Toprak A, Oral E, Toker K. Carbon monoxide poisoning- a cause of increased QT dispersion. Acta Anesthesiol Scand 2002; 46: 180–183. 3. MacMillan CSA, Wildsmith JAW, Hamilton WFD. Reversible increase in QT dispersion during carbon monoxide poisoning. Acta Anesthesiol Scand 2001; 45: 396–397. 4. Hanci V, Ayoglu H, Yurtlu S, Yildirim N, Okyay D, Erdogan G, et al. Effects of acute carbon monoxide poisoning on the P-wave and QT interval dispersions. Anadolu Kardiyol Derg 2011; 11(1): 48–52. 5. Marius-Nunez AL. Myocardial infarction with normal coronary arteries after acute exposure CO. Chest 1990; 97: 491–494. 6. Carnevali R, Omboni E, Rossati M, Villa A, Checchini M. Electrocardiographic changes in acute carbon monoxide poisoning. Minerva Med 1987; 78: 175–178. 7. San Lorenzo IS, Chiesa M, Gamba P, Toniolo A. Cardiologic aspects of carbon monoxide poisoning. Cardiologia 1989; 34: 439–446. 8. Yelken B, Tanriverdi B, Cetinbas F, Memis D, Sut N. The assessment of QT intervals in acute carbon monoxide poisoning. Anadolu Kardiyol Derg 2009; 9: 397–400. 9. Higham PD, Campbell RW. QT dispersion. Br Heart J 1994; 71: 508–510. 10. Kors JA, Ritsema van Eck HJ, van Herpen G. The meaning of the Tp-Te interval and its diagnostic value. J Electrocardiol 2008; 41: 575–580. 11. Kilicaslan F, Tokatli A, Ozdag F, Uzun M, Uz O, Isilak Z, et al. Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleepapnea. Pacing Clin Electrophysiol 2012 Jun 5. doi: 10.1111/j.1540-8159.2012.03439.x.

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[Epub ahead of print]. 12. Gupta P, Patel C, Patel H, Narayanaswamy S, Malhotra B, Green JT, Yan GX. T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol 2008; 41: 567–574. 13. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med 1998; 339: 1603–1608. 14. Henz S, Maeder M. Prospective study of accidental carbon monoxide poisoning in 38 Swiss soldiers. Swiss Med Wkly 2005; 135(27–28): 398–408. 15. Hardy KR, Thom SR. Pathophysiology and treatment of carbon monoxide poisoning. J Toxicol Clin Toxicol 1994; 32: 613–629. 16. Myers RA. Carbon monoxide poisoning. J Emerg Med 1984; 1: 245–248. 17. Sari I, Zengin S, Ozer O, Davutoglu V, Yildirim C, Aksoy M. Chronic carbon monoxide exposure increases electrocardiographic P-wave and QT dispersion. Inhal Toxicol 2008; 20: 879–884.

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18. Hume-Smith HV, Sanatani S, Lim J, Chau A, Whyte SD. The effect of propofol concentration on dispersion of myocardial repolarization in children. Anesth Analg 2008; 107: 806–810. 19. Gurkan Y, Canatay H, Toprak A, Ural E, Toker K. Carbon monoxide poisoning – a cause of increased QT dispersion. Acta Anaesthesiol Scand 2002; 46: 180–183. 20. Shimizu H, Ohnishi Y, Inoue T, Yokoyama M. QT and JT dispersion in patients with monomorphic or polymorphic ventricular tachycardia/ ventricular fibrillation. J Electrocardiol 2001; 34: 119–125. 21. Dogan U, Yavas G, Tekinalp M, Yavas C, Ata OY, Ozdemir K. Evaluation of the acute effect of palonosetron on transmural dispersion of myocardial repolarization. Eur Rev Med Pharmacol Sci 2012; 16(4): 462–468. 22. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res 1991; 68: 1729–1741.

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ETES & DIAB

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Mean platelet volume is associated with myocardial perfusion defect in diabetic patients Savas Sarikaya, Safak Sahin, Lutfi Akyol, Elif Borekci, Yunus Keser Yilmaz, Fatih Altunkas, Kayihan Karaman, Seyhan Karacavus, Ali Riza Erbay Abstract Aim: Our aim was to evaluate whether there was a relationship between mean platelet volume and myocardial perfusion defect in diabetic patients using myocardial perfusion imaging. Method: Forty-four diabetic patients with myocardial perfusion defect (group 1) and 44 diabetic patients without myocardial perfusion defect (group 2), matched for age and gender, were retrospectively examined. Levels of mean platelet volume (MPV) in the two groups were assessed. Results: MPV was higher in group 1 than group 2 patients (8.76 ± 0.76 and 8.25 ± 0.78 fl), respectively, p = 0.003). Levels of glucose, triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, haemoglobin (Hb) and glycosylated haemoglobin (HbA1c), and body mass index (BMI) in the two groups were not statistically significantly different. Multivariate logistic regression analyses showed that MPV was the only variable independently associated with myocardial perfusion defects (OR: 2.401, 95% CI: 1.298–4.440, p = 0.013). Conclusion: This study showed that higher MPV was associated with myocardial perfusion defects. Higher MPV in diabetic patients was independently related to myocardial perfusion defects and may be an indicator of myocardial ischaemia.

Department of Cardiology, School of Medicine, Bozok University, Yozgat, Turkey Savas Sarikaya, MD Ali Riza Erbay, MD

Department of Internal Medicine, School of Medicine, Gaziosmanpaşa University, Tokat, Turkey Safak Sahin, MD, drsafaksahin@gmail.com

Department of Internal Medicine, School of Medicine, Bozok University, Yozgat, Turkey Lutfi Akyol, MD Elif Borekci, MD

Department of Cardiovascular Surgery, School of Medicine, Bozok University, Yozgat, Turkey Yunus Keser Yilmaz, MD

Department of Cardiology, School of Medicine, Gaziosmanpaşa University, Tokat, Turkey Fatih Altunkas, MD Kayihan Karaman, MD

Department of Nuclear Medicine, School of Medicine, Bozok University, Yozgat, Turkey Seyhan Karacavus, MD

Keywords: myocardial perfusion defect, mean platelet volume, diabetes mellitus Submitted 18/7/13, accepted 14/3/14 Cardiovasc J Afr 2014; 25: 110–113

www.cvja.co.za

DOI: 10.5830/CVJA-2014-013

Diabetes mellitus (DM) is considered a coronary artery risk equivalent.1 DM is associated with an increased risk of cardiovascular morbidity and mortality.2,3 DM may cause myocardial perfusion defects involving the main coronary artery and myocardial microvascular circulation. Myocardial perfusion imaging (MPI) is a useful non-invasive tool to determine whether there is a myocardial perfusion defect.4 Platelet volume is a marker of platelet activation and function and is measured as mean platelet volume (MPV).5 MPV has become a prognostic factor in coronary heart disease and may eventually be accepted as a parameter of platelet activity.6 MPV is emerging as a new risk factor for vascular complications of DM of which atherothrombosis plays a crucial role.7 However, to the best of our knowledge, there have been no reports in the literature to evaluate the relationship between MPV and myocardial perfusion defect using MPI in patients with diabetes. Our aim was to evaluate whether there was a relationship between myocardial perfusion defect using myocardial perfusion scintigraphy and MPV in selected diabetic patients.

Methods Eighty-eight patients with type 2 diabetes who had MPI between January and May 2013 in Bozok and Gaziosmanpaşa universities were retrospectively examined. Eighty-eight patients were enrolled in the study and divided into two groups, matched for age and gender: the myocardial perfusion defect group (group 1) and a group with no myocardial perfusion defect (group 2). Group 1 consisted of 44 subjects (14 men and 30 women, mean age: 61.75 ± 7.86 years). Group 2 consisted of 44 subjects (12 men and 32 women, mean age: 60.48 ± 9.28 years). Patients with a history of myocardial infarction, unstable angina pectoris, cardiac surgery, angiographically proven coronary artery disease, endocrine disorder without diabetes, systemic inflammatory disease, rhythm disorder, any medication that could affect the MPV, suspicious scintigraphy results due to breast attenuation, and aperture and fixed (scar) perfusion defects were excluded. The blood samples were withdrawn following a 12-hour fast. Glucose, creatinine and lipid profiles were determined using standard methods. For both groups, we measured the MPV from blood samples that were obtained following venipuncture. The

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blood was collected in tripotassium EDTA tubes. We analysed the blood samples using an automatic blood counter within one hour of drawing the blood. The patients underwent a two-day stress/rest single-photonemission tomography and gated GSPECT study using adenosine with a standard weight-based infusion protocol (140 μg/kg/min). The six-minute adenosine infusion was begun and 740 MBq (20 mCi) of MIBI was injected after three minutes. After a 45-minute delay, a stress set of images was acquired. At rest, before receiving technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI), the patients were given one to two tablets of sublingual nitroglycerin (0.4 mg), five minutes apart and they were injected with 740 MBq (20 mCi) of MIBI. A GSPECT study was performed 45 minutes later. GSPECT data were acquired in the supine position with the double-head SPECT-γ camera equipped with a high-resolution low-energy collimator. The obtained data were projected as myocardial tomographic slices in short-axis, vertical long-axis and horizontal long-axis views. Electrocardiogram gating was applied to the cardiac cycle with eight frames per cardiac cycle. The myocardium was divided into 17 segments following the American Society of Nuclear Cardiology/American College of Cardiology/American Heart Association guidelines.8 GSPECT dates were processed and analysed using 4D-MSPECT software, which determines the extent and severity of left ventricular perfusion defect size and the extent of reversible (ischaemia) or fixed (scar) perfusion defects.9 The programme assigned a score of 0 to 4 to each segment based on activity level: 0 = normal, 1 = equivocal, 2 = moderate, 3 = severe reduction of radioisotope uptake, and 4 = absence of detectable tracer uptake. Abnormal perfusion, motion and thickening were defined as a score of ≥ 2. The summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated based on the conventional 17-segment model. The summed difference score (SDS), indicating the extent of reversible perfusion defects, was obtained by calculating the differences between the SSS and SRS. Table 1. Baseline characteristic of the patients. Group 1 Group 2 p-value Age (years) 60.02 ± 9.28 60.81 ± 8.02 0.660 Women (%) 72.7 68.2 0.408 HT (%) 72.7 86.4 0.093 HL (%) 47.7 56.8 0.281 Aspirin (%) 34.1 29.5 0.410 31.41 ± 6.23 30.41 ± 5.7 0.446 BMI (kg/m2) Glucose (mg/dl) 131.79 ± 40.553 151.16 ± 54.213 0.070 TG (mg/dl) 192.36 ± 116.48 171.71 ± 87.321 0.600 TC (mg/dl) 190.04 ± 42.25 178.83 ± 46.73 0.258 HDL-C (mg/dl) 40.58 ± 5.911 38.68 ± 6.08 0.167 LDL-C (mg/dl) 118.77 ± 28.75 108.28 ± 33.82 0.133 Hb (g/dl) 13.16 ± 1.40 13.42 ± 1.46 0.399 MPV (fl) 8.76 ± 0.76 8.25 ± 0.78 0.003 8.67 ± 0.68 8.35 ± 0.86 0.094 HbA1c (%) HT: hypertension; HL: hyperlipidaemia TG: triglycerides; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: lowdensity lipoprotein cholesterol; Hb: haemoglobin; MPV: mean platelet volume; HbA1c: glycosylated haemoglobin.

Statistical analysis Statistical analyses were performed using SPSS 18.0 software. Parametric values are given as mean ± standard deviation and non-parametric values as a percentage. To compare parametric continuous variables, the Student’s t-test was used; to compare non-parametric continuous variables, the Mann–Whitney U-test was used. Categorical data were compared by chi-square distribution. Stepwise multivariate logistic regression models were created to determine independent variables for myocardial perfusion defect. For multivariate regression, variables with a p-value < 0.1 in univariate analysis were selected. Two-tailed p-values < 0.05 were considered to indicate statistical significance.

Results Baseline characteristic of the patients are given in Table 1. Levels of glucose, triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, haemoglobin (Hb) and glycosylated haemoglobin (HbA1c), and body mass index (BMI) in the two groups were not statistically significantly different. The MPV level was higher in group 1 than in group 2 patients (8.76 ± 0.78 and 8.25 ± 0.78 fl, respectively, p = 0.003). Levels of MPV in the two groups are shown in Fig. 1. Univariate analysis showed that MPV, and HbA1c and glucose levels were significantly involved in myocardial perfusion defects. Multivariate logistic regression analyses showed that MPV was the only variable independently associated with myocardial perfusion defect (OR: 2.401, 95% CI: 1.298–4.440, p = 0.013) (Table 2).

Discussion This study showed that there was a relationship between myocardial perfusion defect and MPV. MPV was higher in the group with myocardial perfusion defects, compared to the one without myocardial perfusion defects. Patients with diabetes develop vascular complications, including macrovascular complications [coronary artery disease (CAD), peripheral vascular disease and stroke] and microvascular complications [diabetic nephropathy (DN), diabetic retinopathy (DR) and 10.00

9.00 MPV

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8.00

7.00

6.00 MPD (–)

Groups

Fig. 1. MPV levels in the two groups.

MPD (+)

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Table 2. Univariate and multivariate regression analyses of independent variables for MPD. Variables MPV (fl) Glucose (mg/dl) HbA1c (%) Age (years) Gender HT (mg/dl) BMI (km/m2) TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) LDL (mg/dl) Hb (%)

OR 2.401 1.009 1.800 1.011 1.244 2.375 0.991 0.994 0.998 0.948 0.989 1.138

Univariate Multivariate 95% CI p-value OR 95% CI 1.298–4.440 0.005 2.484 1.215–5.081 0.999–1.029 0.072 1.008 0.997–1.019 0.993–3.474 0.08 1.984 0.980–4.018 0.963–1.061 0.664 0.497–3.16 0.641 0.801–7.043 0.119 0.92–1.067 0.820 0.984–1.004 0.256 0.994–1.002 0.360 0.878–1.023 0.167 0.975–1.003 0.134 0.845–1.534 0.395

p-value 0.013 0.178 0.064

peripheral neuropathy].10 Continuous hyperglycaemia may cause endothelial dysfunction and vascular lesions, resulting in diabetic vascular complications. 11,12 Type 2 diabetes is a substantial risk factor in atherosclerotic cardiovascular disease.13,14 Cardiovascular disease (CVD) is the leading cause of death in patients with type 2 DM.15 Asymptomatic CAD is common in patients with DM and is a strong predictor of future poor outcome of coronary vascular events, as well as early death.16,17 DM is associated with generalised endothelial dysfunction and small-vessel abnormalities.18,19 Perfusion defects are substantial predictors of coronary events in patients with known or suspected coronary heart disease (CHD).20 It is proposed that concomitant abnormalities of perfusion imaging scans in patients with diabetes with normal coronary angiograms may be caused by micro-angiopathy or endothelial dysfunction. Accordingly, it reflects an increased likelihood of future coronary events.21 The majority of studies on ischaemia have used SPECT MPI. An analysis of the diagnostic accuracy of pharmacologically induced stress MPI reported a mean sensitivity and specificity of 88 and 77%, respectively.22 Platelet volume is a marker of platelet activation and function, and is measured using MPV.5 Platelets that have dense granules are more active biochemically, functionally and metabolically. Large platelets secrete high levels of prothrombogenic thromboxane A2, serotonin, beta-thromboglobulin and procoagulant membrane proteins such as P-selectin and glycoprotein IIIa.5,23 Platelets secrete a large number of substances that are crucial mediators of coagulation, inflammation, thrombosis and atherosclerosis.24,25 It is also well known that large platelets are a risk factor for developing coronary thrombosis, leading to myocardial infarction.19,23,26,27 Measurement of platelet activation and/or aggregation may provide prognostic information in patients at risk for or following a cardiovascular event.28,29 Reports have revealed that there is a close relationship between MPV and cardiovascular risk factors, including impaired fasting glucose levels, diabetes mellitus, hypertension, hypercholesterolaemia, obesity and the metabolic syndrome.30-32 Increased platelet activity is reported to play a role in the development of vascular complications in diabetic patients.18 MPV was increased in patients with SCF complex and cardiac

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syndrome X, both being related to microvascular defects and endothelial dysfunction.33,34 In the present study, we showed that MPV was associated with myocardial perfusion defect, using MPI in diabetic patients. In our study, MPV was increased in the myocardial perfusion defect group compared to those without myocardial perfusion defects. DM not only involves the main coronary artery but also the microvascular circulation, leading to myocardial perfusion defects. Perfusion defects are significant predictors of coronary events in patients with known or suspected CHD.20 The main limitation of our study was the small sample size, which could result in low statistical power for equivalency testing, leading to false-negative results. Second, because of the retrospective nature of data collection, the angiographic results of the patients were not evaluated. MPI may reflect myocardial perfusion defects but it was not able to show the anatomical status of the coronary artery. We cannot extend our results to the general population due to our broad exclusion criteria.

Conclusion MPV levels were higher in the diabetic patients with myocardial perfusion defects than in those without myocardial perfusion defects. In diabetic patients, increased MPV may be an independent marker of myocardial perfusion defects, which are associated with adverse coronary events.

References 1.

Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent? results from 25 years of follow-up in the Renfrew and Paisley survey. Diabetes Care 2005; 28: 1588–1593. 2. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. J Am Med Assoc 1979; 241: 2035–2038. 3. Nathan DM, Meigs J, Singer DE. The epidemiology of cardiovascular disease in type 2 diabetes mellitus: how sweet it is ... or is it? Lancet 1997; 350(Suppl 1): SI4–9. 4. Misko J. Evaluation of myocardial perfusion and viability in coronary artery disease in view of the new revascularization guidelines. Nuclear Med Rev Central Eastern Eur 2012; 15: 46–51. 5. Martin JF, Shaw T, Heggie J, Penington DG. Measurement of the density of human platelets and its relationship to volume. Br J Haematol 1983; 54: 337–352. 6. Erhart S, Beer JH, Reinhart WH. Influence of aspirin on platelet count and volume in humans. Acta Haematol 1999; 101: 140–144. 7. Zuberi BF, Akhtar N, Afsar S. Comparison of mean platelet volume in patients with diabetes mellitus, impaired fasting glucose and nondiabetic subjects. Singapore Med J 2008; 49: 114–116. 8. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002; 105: 539–542. 9. Ficaro EP, Lee BC, Kritzman JN, Corbett JR. Corridor4DM: the Michigan method for quantitative nuclear cardiology. J Nucl Cardiol 2007; 14: 455–465. 10. Murea M, Ma L, Freedman BI. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Studies 2012; 9: 6–22.

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11. Bae SH, Lee J, Roh KH, Kim J. Platelet activation in patients with diabetic retinopathy. Korean J Ophthalmol 2003; 17: 140–144. 12. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813–820. 13. Kitada S, Otsuka Y, Kokubu N, et al. Post-load hyperglycemia as an important predictor of long-term adverse cardiac events after acute myocardial infarction: a scientific study. Cardiovasc Diabetol 2010; 9: 75. 14. Nishimura R, Nakagami T, Sone H, Ohashi Y, Tajima N. Relationship between hemoglobin A1c and cardiovascular disease in mild-to-moderate hypercholesterolemic Japanese individuals: subanalysis of a largescale randomized controlled trial. Cardiovasc Diabetol 2011; 10: 58. 15. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001; 44(Suppl 2): S14–21. 16. Koistinen MJ. Prevalence of asymptomatic myocardial ischaemia in diabetic subjects. Br Med J 1990; 301: 92–95. 17. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. Am J Cardiol 1997; 79: 134–139. 18. Demirtunc R, Duman D, Basar M, Bilgi M, Teomete M, Garip T. The relationship between glycemic control and platelet activity in type 2 diabetes mellitus. J Diabetes Complicat 2009; 23: 89–94. 19. Senaran H, Ileri M, Altinbas A, et al. Thrombopoietin and mean platelet volume in coronary artery disease. Clin Cardiol 2001; 24: 405–408. 20. Thomas GS, Miyamoto MI, Morello AP, 3rd, et al. Technetium 99m sestamibi myocardial perfusion imaging predicts clinical outcome in the community outpatient setting. The Nuclear Utility in the Community (NUC) Study. J Am Coll Cardiol 2004; 43: 213–223. 21. Nitenberg A, Ledoux S, Valensi P, Sachs R, Attali JR, Antony I. Impairment of coronary microvascular dilation in response to cold pressor-induced sympathetic stimulation in type 2 diabetic patients with abnormal stress thallium imaging. Diabetes 2001; 50: 1180–1185. 22. Djaberi R, Beishuizen ED, Pereira AM, et al. Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus. Diabetologia 2008; 51: 1581–1593.

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23. Endler G, Klimesch A, Sunder-Plassmann H, et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002; 117: 399–404. 24. Coppinger JA, Cagney G, Toomey S, et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 2004; 103: 2096–2104. 25. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Investigat 2005; 115: 3378–3384. 26. Rao AK, Goldberg RE, Walsh PN. Platelet coagulant activities in diabetes mellitus. Evidence for relationship between platelet coagulant hyperactivity and platelet volume. J Lab Clin Med 1984; 103: 82–92. 27. Jakubowski JA, Adler B, Thompson CB, Valeri CR, Deykin D. Influence of platelet volume on the ability of prostacyclin to inhibit platelet aggregation and the release reaction. J Lab Clin Med 1985; 105: 271–276. 28. Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1999; 33: 634–639. 29. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. New Engl J Med 1990; 322: 1549–1554. 30. Tavil Y, Sen N, Yazici HU, Hizal F, Abaci A, Cengel A. Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease. Thromb Res 2007; 120: 245–250. 31. Varol E, Akcay S, Ozaydin M, Erdogan D, Dogan A, Altinbas A. Mean platelet volume is associated with insulin resistance in non-obese, non-diabetic patients with coronary artery disease. J Cardiol 2010; 56: 154–158. 32. Coban E, Bostan F, Ozdogan M. The mean platelet volume in subjects with impaired fasting glucose. Platelets 2006; 17: 67–69. 33. Cay S, Biyikoglu F, Cihan G, Korkmaz S. Mean platelet volume in the patients with cardiac syndrome X. J Thromb thrombol 2005; 20: 175–178. 34. Gokce M, Kaplan S, Tekelioglu Y, Erdogan T, Kucukosmanoglu M. Platelet function disorder in patients with coronary slow flow. Clin Cardiol 2005; 28: 145–148.

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Is there a role for surgery in the management of isolated secundum atrial septal defect in adults? Cengiz Bolcal, Gokhan Arslan, Murat Kadan, Suat Doganci, Cem Barcin, Atilla Iyisoy, Vedat Yildirim, Mehmet Arslan Abstract Objectives: The aim of this retrospective study was to compare the short-term outcomes of surgical versus transcatheter closure of secundum atrial septal defect (ASD) in adults. Methods: From January 2008 to October 2012, 229 patients aged 18 years and older with significant isolated secundum ASDs were admitted to our hospital. We focused only on objective data obtained from their medical records. We collected and compared a total of 163 patients with isolated secundum ASD, who were treated with device occlusion or surgical closure, and had no missing data. Postoperative outcomes, rhythm disturbances, residual ASD, infection rates and length of hospital stay were compared. Results: Complete follow-up data were available for 42 (46%) patients in the device group and for 121 (87%) in the surgery group. Complete closure was observed in 41 of the 42 patients (97.6%) in the device group (p = 0.258) and in all 121 in the surgery group (100 %) (p > 0.05). There were no mortalities. The mean length of hospital stay in the device group was 1.92 ± 0.43 days and in the surgery group 7.14 ± 0.14 days (p < 0.01). Conclusions: The transcatheter approach for closure of ASDs is an effective and safe treatment option when performed for certain indications. Broadening the spectrum of indications may cause some adverse events. Surgical treatment remains a good alternative for all patients with ASDs and can be performed safely in order not to increase procedure-related complications. Keywords: atrial septal defect, device occluder, cardiac surgery, adult congenital heart disease

Department of Cardiovascular Surgery, Gulhane Military Academy of Medicine, Ankara, Turkey Cengiz Bolcal, MD, bolcalc@yahoo.com Gokhan Arslan, MD Murat Kadan, MD Suat Doganci, MD Mehmet Arslan, MD

Department of Cardiology, Gulhane Military Academy of Medicine, Ankara, Turkey Cem Barcin, MD Atilla Iyisoy, MD

Department of Anesthesiology, Gulhane Military Academy of Medicine, Ankara, Turkey Vedat Yildirim, MD

Submitted 26/2/14, accepted 14/3/14 Cardiovasc J Afr 2014; 25: 114–117

www.cvja.co.za

DOI: 10.5830/CVJA-2014-015

Isolated atrial septal defect (ASD) is the most common form of congenital heart abnormalities in adults and approximately 80% are located in the region of the fossa ovalis (ostium secundum ASD).1 Indications for closure are in cases where the ratio of pulmonary-to-systemic flow (Qp/Qs) is higher than 1.5, without significant elevation of pulmonary vascular resistance. Surgical closure of ASDs has been performed for over 60 years and techniques have steadily improved, using smaller incisions and minimally invasive techniques. On the other hand, in the last 20 years, various transcatheter ASD closure techniques and devices have been developed, among which, percutaneous treatment with a septal occluder device is the most popular.2,3 Despite increasing use of occluder devices and the fact that studies have been published internationally pointing out some of the advantages and disadvantages compared with surgery in adults, no formal comparison of efficacy, morbidity and complications has been published.2-4 We present a retrospective comparison of short-term (three months) results for transcatheter and surgical closure of 163 ostium secundum ASD patients in a university hospital.

Methods This was a retrospective analysis at a single centre, studying two groups of adult patients with isolated secundum ASDs who were treated by occlusion with a device, or with surgical closure. Postoperative outcomes, rhythm disturbances, residual ASD, infection rates and length of hospital stay of these two groups were compared. Between January 2008 and October 2012, 229 patients admitted to our centre, aged 18 years and older with significant isolated secundum ASDs, who had undergone surgical or transcatheter closure of the ASD and who had follow-up data, were assessed in this trial. Follow up was obtained from a chart review and routine three-month post-repair check-up records. We focused only on objective data obtained from the medical records and we compared 163 patients with complete data in two groups (device closure and surgery). As routine practice in our clinic, secundum ASD assessment is performed using transthoracic echocardiography (TTE) and transoesophageal echocardiography (TEE). Defect size is estimated by TTE and TEE, and also by balloon sizing. The patients are assigned to device treatment or surgical closure according to septum morphology, location of the defect, the presence of rims around the defect, and the patient’s choice.

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Our indications for device implantation are the presence of a secundum ASD (diameter ≤ 30 mm), left-to-right shunt with Qp/Qs ratio ≥ 1.5, presence of right ventricular volume overload, and symptoms associated with the defect (arrhythmias, transient ischaemic attack). On the other hand, indications for surgical repair are the presence of associated congenital cardiac anomalies requiring surgical repair (including primum ASD, sinus venosus ASD and multiple defects that would not be adequately covered by a device), pulmonary vascular resistance ≥ 7 Woods units, haemodynamic instability, intracardiac thrombi, contra-indications to antiplatelet agents, and insufficiency of the rims. The patients were fully informed on the treatment options and then decided with their cardiologists which option they would choose. Device implantation was performed under general anaesthesia and guidance with continuous TEE monitoring. Defect diameters were measured by TEE. The appropriate-sized device was then screwed on the cable and advanced inside the correct-sized sheath (6–14 F). The sheath is usually positioned over the guide wire inside the left upper pulmonary vein or in the middle of the left atrium. The Occlutech Figulla ASD occluder (Occlutech International, Sweden, 6–40 mm, 3-mm increments) was used in all patients. Under fluoroscopic and TEE guidance, both left and right discs were deployed in sequence across the defect. After deployment of the device, the geometry of the device and the presence of a residual shunt were evaluated. The configuration of the tissue adjacent to the device, including the ascending aorta, atrioventricular valves, pulmonary vein, superior vena cava, inferior vena cava and coronary sinus were observed. Before releasing the device, a gentle ‘Minnesota wiggle’ was performed to verify the stability of the device. Final examination by TEE was performed to verify the device location and any residual shunting. Unfractioned heparin was administered to keep the activated clotting time (ACT) at > 250 seconds during the entire procedure. We also used appropriate antibiotics before and after the procedure. Patients are usually observed overnight and discharged home the following day. All patients were instructed on prophylaxis for infective endocarditis for a total of six months after device placement. Aspirin 300 mg (for six months) and clopidogrel 75 mg (for three months) were initiated after closure. Before discharge, a chest X-ray, electrocardiography and echocardiography were performed. The patients undergoing surgical treatment were operated on under general anaesthesia using the standard approach. The right atrium was opened following median sternotomy and the ASD closed by primary suture or pericardial patch under cardiopulmonary bypass. The patients were then taken to the intensive care unit, and the following day to the postoperative ward for recovery, until their condition had stabilised, after which they were discharged. Post-procedure records up to discharge from the hospital and routine three-month results related to the end-points were compared. Three months after the procedure, all patients in the study underwent a physical examination, electrocardiogram, chest radiograph and transthoracic echocardiogram with colour Doppler. The primary end-point was rhythm disturbances, residual ASD, infection, or any cardiovascular procedure-related major or

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minor complications, excluding death. The secondary end-point was death related to both procedures. Patients were considered to have had successful ASD closure if they had no or < 2-mm-wide colour jet residual shunts as assessed by colour Doppler echocardiography. Early efficacy was successful closure of the defects by device or operation without moderate (2–4-mm-wide colour jet) or large (≥ 4-mm-wide colour jet) residual shunts, or major complications after discharge from hospital (cerebral embolism, cardiac perforation with tamponade, endocarditis, repeat operation, cardiac arrhythmias requiring permanent pacemaker placement or long-term antiarrhythmia medication, device embolisation requiring immediate surgical removal or death due to the procedure). Safety was defined as the absence of death or complications. Minor complications included device embolisation with percutaneous retrieval, pericardial effusion requiring medical management, evidence of device-associated thrombus formation without embolisation (with or without treatment), cardiac arrhythmia with treatment, phrenic nerve injury, accesssite haematoma, other vascular access-site complications, retroperitoneal haematoma, surgical wound complications or infection.

Statistical analysis All the available data were analysed by the SPSS program (Statistical Package for Social Sciences for Windows 17.0) (Chicago, IL, USA). Descriptive statistical methods (number, percentage, mean, standard deviation) were used on the data. Differences in variables were analysed using the independent samples t-test and chi-square tests as appropriate, and p-values < 0.05 were considered significant.

Results A total of 163 patients with complete medical records from the 229 patients who were treated for secundum ASDs were registered in the study. Table 1 summarises the baseline clinical and demographic characteristics of the two groups, together with the results obtained. Mean age for the device group was 24 ± 0.35 years, whereas it was 28.46 ± 0.7 years for the surgery group. In the device group, the median defect diameter assigned to percutaneous closure was 14.5 mm (range 4–28 mm), whereas it was 25 mm (range 3–46 mm) for surgical closure. The mean pulmonary and systemic blood flow (Qp/Qs) ratio in the device group was 1.82 ± 0.46 and in the surgery group Table 1. Demographic and baseline characteristics of the patients. Surgery Device p-value Patients (n) 121 42 0.258 Male, n (%) 105 (87) 42 (100) Female, n (%) 16 (13) 0 (0) Mean age (years) 24.46 ± 0.7 24 ± 0.35 0.554 Mean EF (%) 65 ± 0.36 63.9 ± 0.43 0.108 Mean Qp/Qs 2.2 ± 0.03 1.82 ± 0.46 < 0.05 Mean PAP (mmHg) 33.8 ± 0.89 28.2 ± 1.34 < 0.05 EF, ejection fraction; PAP, pulmonary artery pressure; Qp/Qs, pulmonary-to-systemic flow ratio.

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it was 2.2 ± 0.03 (p < 0.05). The pulmonary arterial pressure (PAP) ratio in the device group was 28.2 ± 1.34 mmHg and in the surgery group it was 33.8 ± 0.89 mmHg (p = 0.01). The mean length of hospital stay in the device group was 1.92 ± 0.43 days and in the surgery group, 7.14 ± 0.14 days (p < 0.05). Follow up was available for 42 (46%) patients in the device group and for 121 (87%) in the surgery group. During the follow-up period, complete closure was observed in 41 of 42 patients (97.6%) in the device group and in all 121 patients in the surgery group (100%) (p = 0.258). In one patient (3%), a small (< 2 mm wide) colour jet residual shunt as assessed by colour Doppler echocardiography in the device group and the patient was followed up without additional processing. Cardiac arrhythmias requiring pacemaker placement or longterm anti-arrhythmia medication were not observed. Minor cardiac arrhythmias not requiring medical treatment in hospital were observed in one patient in the device group (3%) (firstdegree AV block), and in three patients in the surgery group (2%) (two with sinus arrhythmia and one with first-degree AV block) (p = 0.72). During the three-month follow up, arrhythmias were not observed in either group (χ2 = 0.0, p = 0.0). The mean amount of mediastinal bleeding was 364 ± 19.6 ml, and moderate bleeding was observed in two patients (1.5%). These patients in the surgery group underwent revision surgery for bleeding. Pericardial effusion due to surgery was observed in four patients (3.3%) and treated with medical therapy. Infection of the surgical site was not observed, while pulmonary infections were observed in two patients (1.5%) in the surgery group. Haematoma in the femoral region was observed in four patients (9%) in the device group. None of the patients experienced worsening related to mitral or tricuspid valve regurgitation, and none developed left ventricular failure in either group. There were no cases of erosions, ischaemic stroke, cardiac perforation, late embolisation, thrombus formation, or malposition of the device after percutaneous closure of the ASD. Mortality was 0% for both groups. Complications and outcomes of the patients are given in Table 2.

Discussion Transcatheter closure of ASD with septal occluder devices has increasingly become a practical alternative to surgical techniques in patients with suitable ASDs. Its principal benefits include fewer complications, the absence of an incision scar, shorter Table 2. Complications and outcomes during follow up. Residual shunt, n (%) Moderate bleeding and revision, n (%) Pulmonary infection, n (%) Surgery site infection Arrhythmias in hospital, n (%) Arrhythmias during follow up Mean hospital stay (days) Mean mediastinal drainage (ml) Pericardial effusion, n (%) Femoral haematoma, n (%) *Independent samples t-test.

Device Surgery p-value 1 (2.4) 0 0.258 – 2 (1.7) 0 2 (1.7) – 0 1 (2.4) 3 (2.5) 0.726 0 0 1.92 ± 0.43 7.14 ± 0.14 < 0.001* – 364 ± 19.6 – 4 (3.3) 4 (9) –

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length of hospital stay and less discomfort for the patients. The efficacy of percutaneous device closure has been well reported from case series and comparative studies.2-5 Our study confirms previous findings that ASD closure is generally successful and involves low morbidity and mortality rates with both surgical and device closure.5-8 In some series,6,7 complete closure (with no residual shunt) was achieved less often by the percutaneous method. In our study, however, as in other series, the success rate was similar for both techniques. Complication rates with either treatment modalities were reported to be low.5-8 The most frequently reported complications after surgical closure were arrhythmia, pericardial effusion, mediastinal bleeding needing revision, and infection, together with the potential risks associated with blood transfusion. On the other hand, device closure may be accompanied by tamponade, embolisation of the device, symptomatic gaseous embolism, or unwanted problems related to femoral puncture.1,5,9 In the device group, femoral haematoma was observed in four patients in our study. There was no case of thrombus-related embolism or cardiac tamponade. However complications, although minor, occurred more frequently in the surgery group. There were four cases of pericardial effusions in this group. Length of hospital stay was significantly longer in the surgery group, which is in agreement with other comparative studies.5-8 Apart from the length of hospitalisation, the groups were comparable, with good cardiac outcomes. Another important consideration favouring device closure is the absence of a surgical scar. This is a notable advantage, particularly in female patients. Parallel with improvements in closure device technology, there have also been improvements in the surgical approach, such as using mini-sternotomy, thoracotomy, and endoscopic and robotic surgery.10-12 Although we usually use the minimally invasive approach, due to the patient numbers in our surgical group, we performed only a standard sternotomy. Our results are comparable with the device group, with good outcomes. There were some limitations to this study. It had a retrospective design and patient groups were non-randomised. Only 71% of patients had complete sets of data. In retrospective studies, managing to collect full sets of data is difficult. Additional studies and longer-term follow up of these or other randomised patient groups would be valuable for making recommendations about treatment modalities.

Conclusion There have recently been dramatic developments in both surgical and percutaneous methods of treatment of ASDs, together with the development of emerging technologies. New strategies are an improvement on older methods and device closure is replacing open-heart surgery, especially in suitable patients with isolated ASDs. The range of indications for device closure is frequently not well defined. Increasing the range of indications for device closure, however, may cause complications that would make surgical treatment a more attractive option. As is evident from this study, surgical treatment can be performed efficaciously with low complication and mortality rates. The surgical approach therefore maintains its position as an essential alternative method, particularly in patients who are unsuitable for device closure.

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This article has been accepted as an oral presentation at the 22nd annual meeting of the Asian Society for Cardiovascular and Thoracic Surgery in Istanbul, to be held from 3–6 April 2014.

References 1.

Rothman A. Management of atrial septal defect. In: Braunwald E, eds. Harrison’s Advances in Cardiology. New York: McGraw-Hill 2003, 303–210. Post MC, Suttorp MJ, Jaarsma W, Plokker HW. Comparison of outcome and complications using different types of devices for percutaneous closure of a secundum atrial septal defect in adults: a singlecenter experience. Catheter Cardiovasc Interv 2006; 67: 438–443. Butera G, Carminati M, Chessa M, Youssef R, Drago M, Giamberti A, et al. Percutaneous versus surgical closure of secundum atrial septal defect: comparison of early results and complications. Am Heart J 2006; 151: 228–234. Rosas M, Zabal C, Garcia-Montes J, Buendia A, Webb G, Attie F. Transcatheter versus surgical closure of secundum atrial septal defect in adults: impact of age at intervention. A concurrent matched comparative study. Congenit Heart Dis 2007; 2: 148–155. Berger F, Vogel M, Alexi-Meskishvili, Lange PE. Comparison of

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results and complications of surgical and Amplatzer device closure of atrial septal defects. J Thorac Cardiovasc Surg 1999; 118: 674–680. 6. Thomson JD, Aburawi EH, Watterson KG, Van Doorn C, Gibbs JL. Surgical and transcatheter (Amplatzer) closure of atrial septal defects: a prospective comparison of results and cost. Heart 2002; 87: 466–469. 7. Rao PS. Transcatheter closure of atrial septal defect: are we there yet? J Am Coll Cardiol 1998; 31: 1117–1119. 8. Du ZD, Hijazi ZM, Kleinman CS, Silverman NH, Larntz K. Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults. J Am Coll Cardiol 2002; 11: 1836–1844. 9. Meier B, Lock JE. Contemporary management of Patent Foramen Ovale. Circulation 2003; 107: 5–9. 10. Argenziano M, Oz MC, Kohmoto T, Morgan J, Dimitui J, Mongero L, et al. Totally endoscopic atrial septal defect repair with robotic assistance. Circulation. 2003; 108(Suppl 1): II191–1194. 11. Doll N, Walther T, Falk V, Binner C, Bucerius J, Borger MA, et al. Secundum ASD closure using a right lateral minithoracotomy: fiveyear experience in 122 patients. Ann Thorac Surg 2003; 75: 1527–1530. 12. Liu G, Qiao Y, Ma L, Ni L, Zeng S, Li Q. Totally thoracoscopic surgery for the treatment of atrial septal defect without of the robotic Da Vinci surgical system. J Cardiothorac Surg 2013; 8: 119.

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Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3 Roisin F Kelly-Laubscher, Jonathan C King, Damian Hacking, Sarin Somers, Samantha Hastie, Tessa Stewart, Aqeela Imamdin, Gerald Maarman, Sarah Pedretti, Sandrine Lecour Abstract Aims: Sphingosine-1-phosphate (S1P) is a cardioprotective agent. Signal transducer and activator of transcription 3 (STAT-3) is a key mediator of many cardioprotective agents. We aimed to explore whether STAT-3 is a key mediator in S1P-induced preconditioning. Methods: Langendorff-perfused hearts from Wistar rats and wild-type or cardiomyocyte-specific STAT-3 knockout mice were pre-treated with S1P (10 nmol/l), with or without the STAT-3 pathway inhibitor AG490, before an ischaemia– reperfusion insult. Triphenyltetrazolium chloride and Evans blue staining were used for the determination of infarct size. Western blot analysis was carried out on the S1P pre-treated hearts for detection of cytosolic, nuclear and mitochondrial phosphorylated and total STAT-3 proteins. Results: Pre-treatment with S1P decreased the infarct size in isolated rat (5 ± 3% vs control 26 ± 8%, p < 0.01) and wild-type mouse hearts (13 ± 1% vs control 33 ± 3%, p < 0.05). This protective effect was abolished in the rat hearts pre-treated with AG490 (30 ± 10%, p = ns vs control) and in the hearts from STAT-3 knockout mice (35 ± 4% vs control 30 ± 3%, p = ns). Levels of phosphorylated STAT-3 were significantly increased in both the nuclear (p < 0.05 vs control) and mitochondrial (p < 0.05 vs control) fractions in the S1P pre-treated hearts, but remained unchanged in the cytosolic fraction (p = ns vs control). Conclusion: These novel results demonstrate that pharmacological preconditioning with S1P in the isolated heart is mediated by activation of mitochondrial and nuclear STAT-3, therefore suggesting that S1P may be a novel therapeutic target to modulate mitochondrial and nuclear function in cardiovascular disease in order to protect the heart against ischaemia–reperfusion.

Hatter Institute for Cardiovascular Research in Africa, Chris Barnard Building, Medical School Campus, University of Cape Town, Cape Town, South Africa Roisin F Kelly-Laubscher, PhD, Roisin.Kelly@uct.ac.za Jonathan C King, MMed Damian Hacking Sarin Somers Samantha Hastie Tessa Stewart Aqeela Imamdin Gerald Maarman Sarah Pedretti Sandrine Lecour, PhD

Keywords: STAT-3, cardioprotection, preconditioning, sphingosine-1-phosphate, myocardial infarction Submitted 9/12/13, accepted 31/3/14 Cardiovasc J Afr 2014; 25: 118–123

www.cvja.co.za

DOI: 10.5830/CVJA-2014-016

Signal transducer and activator of transcription 3 (STAT-3) is a downstream mediator of many cardioprotective agents, most notably, of ischaemic pre- and postconditioning,1-5 i.e. protection brought about by repeated bouts of brief ischaemia before (preconditioning) and after (postconditioning) a prolonged period of ischaemia. Many pharmacological conditioning agents such as adenosine,6 opioids,7 erythropoietin,8 ethanolamine,9 melatonin,10 leptin,11 and tumour necrosis factor alpha (TNFα)4,12 also protect via the activation of STAT-3. These findings have led to the description of a novel pathway involved in both mechanical and pharmacological preconditioning: ‘survivor activating factor enhancement’ (SAFE).5,13 This study focused on the role of the SAFE pathway, more specifically STAT-3, in S1P-induced preconditioning. Sphingolipids and their metabolites are important signalling molecules in the heart. There is growing evidence that major components of the sphingolipid pathway, such as ceramide, sphingosine and sphingosine-1-phosphate (S1P) can protect the heart against an ischaemia–reperfusion insult, but the exact mechanism remains unclear.14-18 Signalling molecules such as protein kinase Cε,15 the pro-survival protein kinase-B/Akt18 and extracellular signal-regulated kinase 1/2, which are major components of the ‘reperfusion injury salvage kinase’ pathway (RISK),19,20 are implicated in S1P-induced preconditioning. Recent data have demonstrated that S1P upregulates STAT3 phosphorylation in other organ systems both in vitro21 and in vivo.22 It was also demonstrated that STAT-3 mediates S1P-induced protection against doxorubicin-induced toxicity in isolated ventricular cardiomyocytes.23 Similarly, pharmacological postconditioning with S1P protects isolated mouse hearts against a global ischaemia–reperfusion insult via STAT-3 activation in the mitochondrion and nucleus,24 therefore suggesting a link between S1P and STAT-3, and hence activation of the SAFE pathway by S1P. However whether the same mechanism of protection is involved in S1P-induced preconditioning remains unknown. In this study, we used cardiomyocyte-specific STAT-3 knockout mice and a STAT-3 pathway inhibitor to investigate the role of STAT-3 in the cardioprotective effect of pharmacological preconditioning with S1P against both global and regional ischaemia–reperfusion injury.

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Methods

All experimental procedures were performed with the approval of the Faculty of Health Sciences Animal Ethics Committee, University of Cape Town. All protocols were carried out in compliance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Council of Europe No 123, Strasbourg 1985). Male Wistar rats (250–300 g, n = 56), wild-type and cardiomyocyte-specific STAT-3 knockout mice (14–16 weeks, n = 31) were bred and obtained from the University of Cape Town Animal Unit as previously described.6

Isolated STAT-3 knockout heart model Cardiomyocyte-specific STAT-3 knockout mice (STAT-3 KO) and wild-type littermate control mice were anaesthetised (sodium pentobarbitone, 60 mg/kg i.p.) and heparinised (25 IU i.p.). Once an adequate level of anaesthesia was achieved, the chest was opened, the heart was rapidly removed and placed in ice cold (4oC) modified Krebs-Henseleit buffer, and the aorta was cannulated. The hearts were then perfused with Krebs-Henseleit buffer using the Langendorff system as previously described.25 A minimum of 1.5 ml/min and maximum of 5.0 ml/min of coronary flow rate, heart rate between 460 and 600 beats per minute (bpm) and developed force ≥ 4 g was deemed acceptable. No haemodynamic data were collected during the protocol. After a 20-minute stabilisation period, the hearts were subjected to 35 minutes of global ischaemia followed by 45 minutes of reperfusion. Hearts were pre-treated with S1P (10 nmol/l in DMSO) for seven minutes, followed by a 10-minute washout period before global ischaemia, as previously described.14 At the end of each experimental protocol, the infarct size was assessed by triphenyltetrazolium chloride (TTC) staining. The infarct size was determined with planimetry.25

For the measurement of infarct size, the coronary artery was re-occluded at the end of the reperfusion period and a solution of 2.5% Evans blue was perfused to delineate the area at risk (AAR). The hearts were then frozen and cut into slices, and incubated in sodium phosphate buffer containing 1% w/v TTC for 15 minutes to visualise the unstained infarct region. The infarct size and AAR were determined with planimetry and the infarct size was expressed as a percentage of the AAR.

Preparation of hearts for Western blots In the isolated rat hearts, the ventricular tissue from control and S1P pre-treated hearts was excised before the regional ischaemic insult (seven minutes after S1P treatment), freeze clamped using Wollenberger tongs in liquid nitrogen and stored at –80°C. The frozen hearts were wrapped in aluminium foil and pulverised under liquid nitrogen before being transferred to tubes for storage. For extraction of nuclear and cytosolic protein, pieces of the left ventricle were homogenised twice by Polytron using the homogenisation buffer described by Williams and Ford.27 The suspension was then centrifuged at 10 000 g (12 000 rpm) for five minutes at 4°C. The supernatant containing the cytosolic fraction was collected and transferred into a fresh tube. The pelleted fraction was resuspended in the same homogenisation buffer supplemented with 1% Triton X-100, as described previously.27 A Control

Stabilsation

Ischaemia

Reperfusion

S1P preconditioning Stabilsation

Ischaemia

Reperfusion

35 min

45 min

20 min

S1P

Isolated rat heart model

The rats were anaesthetised with sodium pentobarbital (50 mg/ kg i.p.) and heparinised (500 IU i.v.). The hearts were rapidly excised and perfused retrogradely by the Langendorff technique, as previously described.25 Rat hearts that did not comply with the following criteria were excluded: (1) left ventricular pressure greater than 80 mmHg, (2) coronary flow rate at a minimum of 8 ml/min and maximum of 16 ml/min, (3) heart rate at a minimum of 240 bpm and maximum of 400 bpm. After 30 minutes of stabilisation, all hearts were subjected to 30 minutes of regional standard ischaemia by occlusion of the left coronary artery and 120 minutes of reperfusion, as previously described.25 Hearts were pre-treated with S1P (10 nmol/l in DMSO) for seven minutes followed by a 10-minute washout period before the standard ischaemia. In half of the rats, the JAK-STAT-3 inhibitor, AG490 (100 nmol/l),26 was given for 15 minutes: three minutes before, seven minutes concomitantly with S1P (S1P + AG490 group) and five minutes after perfusion with S1P (Fig. 1). Haemodynamic parameters were assessed throughout the experiment and included heart rate, left ventricular developed pressure (LVDP) and coronary flow. Haemodynamic variables were statistically tested for intergroup and intragroup variation.

Control

Infarct size 7’

Stabilsation

S1P preconditioning Stabilsation S1P + AG490

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Reperfusion

Ischaemia

Reperfusion

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Fig. 1. P reconditioning protocols. (A) Schematic diagram of isolated mouse hearts undergoing a preconditioning protocol with and without S1P pre-treatment. (B) Schematic diagram of isolated mouse hearts undergoing a preconditioning protocol with and without S1P pre-treatment. These protocols were repeated in the presence of the STAT-3 inhibitor AG490.

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After centrifugation for 30 minutes at 10 000 g (12 000 rpm) at 4°C, the supernatant containing the nuclear fraction was carefully removed and transferred to a clean tube. For extraction of mitochondrial and cytosolic protein, the frozen rat hearts were finely minced with scissors in a lysis buffer, as described by Lewin et al.,28 and then transferred to a Dounce homogeniser. After homogenisation, the suspension was centrifuged at 600 g for five minutes at 4°C. The supernatant was transferred to a fresh micro-centrifuge tube and centrifuged at 10 300 g (11 500 rpm) for 10 minutes. The supernatant is now the cytosolic fraction and the pellet the mitochondrial fraction. The pellet was resuspended in 40 µl incubation buffer (250 mM sucrose, 25 mM Tris, 8.5 mM KH2PO4). The proteins were quantitated and an equal volume low-ionic strength sample buffer [10 % sodium dodecyl sulphate (SDS), glycerol, mercaptoethanol, Tris (pH 6.8), bromophenol blue) was added to each sample.

Western blot analysis Phosphorylated and total STAT-3 levels were analysed by SDS polyacrylamide gel electrophoresis with antibodies from Cell Signalling Technology. Proteins were revealed with enhanced chemiluminescence (ECL) Western blotting detection reagents (Amersham, UK) and the images were captured electronically using a GeneGnome HR (Syngene Bioimaging, UK). Levels of phosphorylated and total STAT-3 were determined in the same samples and under the same conditions but on separate membranes. Equal loading was verified with β-actin staining for the nuclear and cytoplasmic fractions and voltage-dependent anion channel (VDAC) for the mitochondrial fractions. Levels of phosphorylated proteins were normalised to their total protein levels. Relative densitometry was determined using Quantity One software (Biorad). The cytoplasmic fraction analysed in these

experiments came from a different group of hearts, however all hearts came from the same strain of rat of the same age and they were treated identically.

Statistical analysis Data are presented as mean ± SEM. Comparisons between multiple groups were performed by one-way ANOVA followed by the Dunnet’s post hoc test (Graph Pad Instat). A value of p < 0.05 was considered statistically significant.

Results S1P-induced preconditioning was inhibited in the STAT-3 knockout mice Control hearts subjected to 35 minutes of global ischaemia and 45 minutes of reperfusion had an infarct size of 33 ± 3%. Pre-treatment with S1P (10 nmol/l) resulted in a significant reduction in the infarct size to 13 ± 1% (Fig. 2) (p < 0.05 vs wild-type control hearts). Ischaemic control hearts from STAT-3 knockout mice had an infarct size of 30 ± 3 %. The infarctsparing effect observed with S1P pre-treatment in the wild-type hearts was absent in the knockout hearts (35 ± 4%, p = ns vs control hearts) (Fig 2). Of note, the present experiments were conducted concomitantly with our other experiments exploring the cardioprotective effect of S1P as a postconditioning agent. The infarct size for the control groups only [in both wild-type (n = 10) and knockout animals (n = 8)] contributed to data already reported.24

Inhibition of STAT-3 activation abrogated protection by S1P-induced preconditioning In the isolated rat heart model, the control hearts subjected to a regional ischaemia–reperfusion insult had an infarct size of 26 ± 8%. Pre-treatment with S1P (10 nmol/l) (Fig. 3) reduced the infarct size (5 ± 3% vs ischaemic control, p < 0.01, n = 6). 45

20 15

Infarct size (%)

10 5 0

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CTL

S1P

CTL

S1P

Fig. 2. T he cardioprotective effect of S1P was abolished in cardiomyocyte-specific STAT-3 knockout mice subjected to ischaemia–reperfusion. In isolated hearts from cardiac-specific STAT-3- knockout mice, S1P failed to protect against an ischaemia–reperfusion insult. (n ≥ 6 for all groups, *p < 0.05 vs wild-type control). WT = wild type, KO = knockout. STAT-3 = signal transducer and activator of transcription-3.

30 25 20 15 10

5 0

CTL

S1P

S1P + AG

Fig. 3. S 1P conferred protection via STAT-3 in the Langendorff-perfused rat heart. Co-incubation of the STAT-3 inhibitor AG490 (100 nmol/l) with S1P abolished the infarct-sparing effect of S1P in isolated rat hearts [n > 6 per group, *p < 0.01 vs control (CTL)].

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To investigate the role of STAT-3 in S1P-induced preconditioning, we administered the Jak/STAT-3 inhibitor, AG490 (Fig. 3). Perfusion of AG490 abolished the cardioprotective effect of S1P (30 ± 10% vs ischaemic control, p = ns, n = 6). There was no significant difference in the size of the area at risk between the four groups (data not shown). After 30 minutes of regional ischaemia and 120 minutes of reperfusion, the LVDP, heart rate and coronary flow were not significantly different between the four groups (Table 1). No significant differences in heart rate were found within any group at the different time points measured. As expected, all groups showed a significant decrease (p < 0.05) in LVDP by the end of the reperfusion period compared to pre-ischemic values. Interestingly, only groups treated with AG490 demonstrated a significant decrease in LVDP five minutes into reperfusion compared to baseline values (p < 0.05). All groups except the control group demonstrated a significantly decreased coronary flow rate by the end of reperfusion compared to baseline values (p < 0.05).

S1P induced an increase in phosphorylated STAT-3 in the nucleus and mitochondrion Western blot analysis of tissue extracted from isolated rat hearts revealed an increase in nuclear (control 1 vs S1P; 3.42 ± 0.83 arbitrary units, p < 0.05) and mitochondrial (control 1 vs S1P; 1.52 ± 0.10 arbitrary units, p < 0.05) phosphorylated/total STAT3 after S1P pre-treatment (Fig. 4B, C). S1P pre-treatment did not significantly alter the cytoplasmic phosphorylation of STAT-3 (control 1 vs S1P; 1.00 ± 0.27 arbitrary units, p = ns). There was no significant change in total STAT-3 in the cytosolic, nuclear or mitochondrial fractions.

Discussion Our present study demonstrates that pre-treatment with S1P protected against ischaemia–reperfusion injury via the activation of STAT-3. This was evidenced by several of our findings. Firstly, A

Cytoplasm

S1P-induced preconditioning was inhibited in STAT-3 knockout mice. Secondly, S1P-induced preconditioning was inhibited by the STAT-3 inhibitor, AG490. Thirdly, S1P upregulated the phosphorylation of both nuclear and mitochondrial STAT-3.

S1P can activate the JAK/ STAT-3 pathway S1P is now recognised as a cardioprotective agent both in vivo and ex vivo.17,18,29,30 S1P can induce cardioprotection as a pre- or postconditioning stimulus.14,17,18,31 Furthermore, S1P mediates the cardioprotective effects of other preconditioning agents, e.g. TNFα,4 and ethanolamine.9 In fact, TNFα and STAT-3 are both Table 1. Haemodynamic parameters of isolated rat hearts exposed to regional ischaemia and S1P-induced preconditioning PreIschaemia Reperfusion Reperfusion Parameters ischaemia (5 min) (5 min) (120 min) LVDP (mmHg) IC 86 ± 7 54 ± 10 69 ± 8 46 ± 8* S1P 83 ± 5 35 ± 12 71 ± 7 45 ± 7* S1P + AG 99 ± 3 65 ± 15 81 ± 3 67 ± 3* AG 92 ± 5 57 ± 17 75 ± 4 66 ± 4* Heart rate (bpm) IC 287 ± 18 263 ± 43 270 ± 14 293 ± 11 S1P 280 ± 20 250 ± 55 288 ± 42 268 ± 28 S1P + AG 273 ± 17 290 ± 60 297 ± 18 283 ± 21 AG 293 ± 18 270 ± 64 240 ± 15 257 ± 24 Coronary flow (ml/min) IC 10.8 ± 1.4 8±5 11.2 ± 1.7 7.8 ± 1.9 S1P 9.7 ± 0.9 4±1 9.8 ± 0.8 5.9 ± 0.8* S1P + AG 9.8 ± 1.0 5±1 8.4 ± 0.6 5.8 ± 0.7* AG 8.1 ± 0.3 5±1 8.2 ± 0.2 5.0 ± 0.2* Parameters measured prior to ischaemia (pre-ischaemia), at five minutes into ischaemia and at five minutes and 120 minutes after reperfusion, respectively. IC = ischaemic control, S1P = sphingosine-1-phosphate, AG = AG490, LVDP = left ventricular developed pressure, (n = 6 per group.*p < 0.05 reperfusion at 120 minutes vs pre-ischaemia).

Nucleus

Mitochondria

P-STAT-3 (ser)

Total STAT-3

4 3 2 1 0

Control

Beta actin

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Control

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Control

S1P

4 3 2

1 0

Control

S1P

Fig. 4. S 1P pre-treatment increased phosphorylation of nuclear and mitochondrial STAT-3. Representative Western blots demonstrating levels of phosphorylated-STAT-3/total STAT-3 in (A) the cytoplasm, (B) the nucleus, and (C) the mitochondria after seven minutes of S1P pre-treatment in isolated rat hearts (n = 4 per group, *p < 0.05 vs control).

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members of the cardioprotective SAFE pathway and S1P may act via TNFα to activate STAT-3.24 Using a cardiomyocyte-specific STAT-3 knockout mouse model and the STAT-3 inhibitor, we demonstrated the requirement of STAT-3 for S1P-induced preconditioning in a whole-organ model. Although STAT-3 in other cell types of the heart has also been implicated in ischaemic preconditioning, the current results suggest that cardiomyocyte STAT-3 is required for S1P-induced cardioprotection. This is supported by experiments looking at ischaemic preconditioning, which showed that part of the protective response mediated by endothelial STAT-3 was caused by upregulation of cardiomyocyte-specific STAT-3.32 Less evidence is available on the preconditioning role of STAT-3 in other cardiac cell types.

Cellular localisation of STAT-3 activation S1P pre-treatment significantly increased nuclear levels of phosphorylated STAT-3. Phosphorylation of STAT-3 is suggested to increase translocation of STAT-3 from the cytoplasm to the nucleus where it acts as a transcription factor. However, if STAT3 did translocate from the cytoplasm to the nucleus, one would expect a concomitant increase in total STAT-3 in the nucleus and possibly a decrease in total cytoplasmic STAT-3. Our results do not show an increase in total nuclear STAT-3 or a decrease in cytosolic STAT-3. This may suggest either that an increase in STAT-3 export from the nucleus to the cytoplasm compensates for the movement of the phosphorylated form of STAT-3 into the nucleus, and/or that phosphorylation occurs for STAT-3 already present in the nucleus. STAT-3 is best known as a transcription factor, however, the results of transcription are unlikely to produce the protective effects seen in these short-term experiments. This may suggest that phosphorylated STAT-3 also plays a non-transcriptional role in the nucleus, e.g. DNA repair in response to oxidative stress,33 or interaction with other signalling molecules within the nucleus.34 S1P pre-treatment also significantly increased mitochondrial levels of phosphorylated STAT-3. Recently, it has been suggested that rather than the cytosolic or nuclear pool of STAT-3 accounting for the protective effects of pre- and postconditioning, the mitochondrial pool of STAT-3 may also be important.35 The mechanism by which the mitochondrial STAT-3 acts remains unknown. However evidence from other studies suggests that it may affect cellular respiration and opening of the mitochondrial permeability transition pore. 23,35,36 The dual site activation of STAT-3 is in agreement with the findings of Somers et al.,24 who found that S1P-induced postconditioning caused an increase in STAT-3 activation in the nucleus and mitochondrion. Despite these similar findings, Somers et al.24 observed a concurrent decrease in cytosolic STAT3 activation, which was not seen in the present study. The main difference in the protocols used in these two studies was the time at which S1P was administered. In S1P-induced preconditioning, S1P was administered before ischaemia to a healthy heart under physiological conditions. In S1P-induced postconditioning, the stimulus was provided in a pathological (post-ischaemic) state. The reduction of infarct size seen in the current study was similar to that seen when S1P was given as a postconditioning agent. This may suggest that the levels of STAT-3 activation in the cytosolic fraction do not affect S1P-mediated protection but

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it is possible that they could affect long-term recovery from cardiovascular disease, such as remodelling. However, it should be noted that the changes in activation of STAT-3 seen in this study focused on phosphorylation levels seven minutes after S1P treatment, which may not be representative of the changes over time. Furthermore, the current study only looked at phosphorylation of the serine residue of STAT-3. Future studies should explore the changes in phosphorylation of STAT-3 on both the serine and tyrosine residues over time in response to S1P-induced pre- and postconditioning to confirm different patterns of activation. In humans with myocardial infarction, other cardiovascular risk factors are normally present, such as hypertension and diabetes. These may affect the ability of some pharmacological agents to protect the heart.37 The experiments described in this article were carried out on healthy animals. Therefore, it is imperative that S1P-induced preconditioning be confirmed in animal models that include these co-morbidities.

Conclusion Our data strongly suggest that the cardioprotective effects of S1P-induced preconditioning may be mediated by dual activation of STAT-3 in the nucleus and mitochondria. Our data provide a unique therapeutic opportunity to target survival against ischaemia–reperfusion injuries, especially since S1P and its sphingolipid pathway form part of the high-density lipoproteins (HDL). Addition of S1P to already existing synthetic HDL may be considered a therapeutic option in the prevention of cardiac damage associated with ischaemia–reperfusion. This work was supported in part by the National Research Foundation of South Africa, the Inter-University Cape Heart Group of the South African Medical Research Council and the Servier Heart Failure Project. Dr RF Kelly-Laubscher was supported by the Claude Leon Foundation and Prof S Lecour was partly supported by the Medical Research Council Career Award.

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Comparison of quality of life in patients with peripheral arterial disease caused by atherosclerosis obliterans or Buerger’s disease Rojbin Karakoyun, Cüneyt Köksoy, Zeynep Şener, Umut Gündüz, Bariş Karakaş, Mustafa Karakoyun Abstract Objective: Buerger’s disease and atherosclerosis obliterans (ASO) are two peripheral arterial diseases (PAD) that are frequently encountered. The aim of this study was to compare quality of life (QOL) in patients with Buerger’s disease and ASO. Methods: We prospectively followed 86 patients who were admitted to our hospital due to ASO or Buerger’s disease. Their ischaemia was evaluated according to the clinical category chronic limb ischaemia at the time of hospital admission and at six and 12 months. The QOL was measured at the time of hospital admission and at six and 12 months with the Short Form Health Status Survey (SF-36) and Vascular Quality of Life Questionnaire (VASCUQOL). Results: A total of 86 patients with ASO or Buerger’s disease (47 and 39, respectively) were included in the study. Pain parameters from both SF-36 and VASCUQOL scores were lower in patients with Buerger’s disease at the time of hospital admission and at six months. The impairment in QOL was found to be proportional to the extent of chronic limb ischaemia. Conversely, when patients with critical limb ischaemia were evaluated, no difference was observed between those with ASO or Buerger’s disease in terms of QOL. Amputations were found to have a negative effect on quality of life. Conclusion: Buerger’s disease had a more pronounced negative effect on QOL than ASO, particularly in terms of pain score. When critical limb ischaemia was considered, ASO and Buerger’s disease impaired quality of life at the same rate.

Submitted 17/7/13, accepted 1/4/14 Cardiovasc J Afr 2014; 25: 124–129

www.cvja.co.za

DOI: 10.5830/CVJA-2014-017

Rojbin Karakoyun, MD, drrojbin@hotmail.com Cüneyt Köksoy, MD Zeynep Şener, MD

Vascular diseases are well studied today because of the relationship between arterial age and human age, the close connection between aging and arterial diseases, and the fact that the majority of deaths result from diseases of the vascular system. Among vascular diseases, chronic occlusive arterial disease of the lower extremities is of great importance in terms of mortality and morbidity. An increase in the incidence of peripheral arterial diseases is also a consequence of the gradually increasing size of the elderly population.1 The treatment strategy for patients should not be intended only for the prevention of extremity loss in peripheral arterial diseases (PAD), but also for the determination and treatment of risk factors, thus resulting in increased quality of life. Nowadays, the objective determination of quality of life, and evaluation of the association between quality of life and treatment methods in PAD is of great importance.1-3 Buerger’s disease is a PAD that is frequently encountered and causes significant loss of the extremities. Generally, although its pathological characteristics are well described, there is inadequate information about its impact on daily life and general health levels of patients, and about the difference in terms of quality of life between patients with Buerger’s disease and atherosclerosis obliterans (ASO), which are the most significant causes of PAD. These two types of PAD show different aetiology, age of appearance and co-morbidity. These differences may influence the patient’s quality of life differently. Based on our clinical observations, we assumed the quality of life in patients with Buerger’s disease may be worse than that of patients with ASO. Although studies evaluating quality of life in PAD have been carried out, there is, to our knowledge, no study that evaluates quality of life in patients with Buerger’s disease, or a comparison of quality of life in patients with ASO and Buerger’s disease, which are the most significant chronic occlusive arterial diseases. The objective of our study was to compare the quality of life in patients with ASO and Buerger’s disease.

Department of Surgery, Antalya Training and Research Hospital, Antalya, Turkey

Methods

Department of Radiology, Veni-Vidi Hospital, Diyarbakir, Turkey

This prospective study included patients with ASO and Buerger’s disease who were admitted to the Department of Vascular Surgery, University of Ankara between 2008 and 2010. Those patients with chronic lower limb ischaemia due to ASO or Buerger’s disease were evaluated in terms of symptoms, risk

Keywords: Buerger’s disease, atherosclerosis obliterans, quality of life

Division of Vascular Surgery, Department of General Surgery, Faculty of Medicine, Ankara University, Ankara, Turkey

Umut Gündüz, MD Barış Karakaş, MD

Mustafa Karakoyun, MD

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factors and accompanying vascular or non-vascular diseases. An arterial examination of the lower extremity, and an ankle/ brachial pressure index (ABI) and arterial duplex examination of the patients were then performed. Patients with ASO who matched the criteria for inclusion in this study were those with atherosclerotic lower limb ischaemia at the time of admission, and patients with lower extremity involvement. Patients with Buerger’s disease who matched the criteria for inclusion in this study were those with lower extremity involvement, and patients with Buerger’s disease, diagnosed according to Shionoya’s criteria,4 at the time of admission. These criteria included smoking history; onset before the age of 50 years; infra-popliteal arterial occlusions; either upper limb involvement or phlebitis migrans; and absence of atherosclerotic risk factors other than smoking. Written informed consent was obtained from all study participants. At the time of hospital admission, the patients’ ischaemia was evaluated according to the clinical categories of chronic limb ischaemia (Rutherford classification5) by inviting patients back to the hospital at six and 12 months following the first admission. Patients’ quality of life was evaluated from the Short Form Health Status Survey (SF-36), which provides a measurement of change in physical components, including physical function, physical status, bodily pain and general health, as well as mental components, including mental health, emotional status, social function and vitality. The impact of PAD was also evaluated from the Vascular Quality-of-Life Questionnaire (VASCUQOL), which consists of pain, symptoms, activities, social well-being and emotional wellbeing domains.6 The questionnaries were applied by a research staff member who had no information on these patients. Following the measurement of quality of life, treatment modalities including surgery or medical therapy, where necessary and appropriate, were initiated. In general, endovascular and bypass procedures were preferred for ASO patients with critical ischaemia and unbearable claudication. Risk-factor reduction and medical treatments were used for all ASO patients. For Buerger’s disease patients with critical ischaemia, the target vessel was evaluated for distal bypass and smoking cessation was advised. Distal bypass was used for patients where appropriate. Table 1. Demographic characteristics, additional diseases and amputation rates of patients Atherosclerosis (n = 47) 60.28

Buerger’s disease (n = 39) 47.77

p-value Age (years) ns Gender Male (%) 80.9 94.9 ns Female (%) 19.1 5.1 ns Smoker (%) 59.6 94.9 0.002* Non-smoker (%) 40.4 5.1 ns Additional diseases Diabetes (%) 49.1 9.6 < 0.001* Hypertension (%) 49.9 7.6 < 0.001* Obesity (%) 4.4 5.4 ns ABI (mean) 0.42 0.40 ns Affected extremity (right–left) (%) 51–41 25–41 ns ABI = ankle/brachial pressure index. *Statistically significant value.

Sympathectomy, infusion of prostaglandin (PGE2), medical treatment and wound care were used for patients in whom distal bypass was inappropriate or in those who had failed bypass. In the presence of necrotic tissue, minor or major amputations were performed. All parameters evaluated at baseline were also repeated at six and 12 months post admission.

Statistical analysis Comparisons between groups were made using Pearson’s chi-square test for categorical variables and independent t-tests for continuous variables. A p-value less than 0.05 was accepted as statistically significant. Statistical analyses were carried out using SPSS for Windows 15.0 (SPSS Inc., Chicago, Illinois, USA).

Results A total of 86 patients, 47 with ASO and 39 with Buerger’s disease, were included in the study. Demographic characteristics and additional diseases at the time of admission of the patients are shown in Table 1. The rate of smoking was statistically significantly higher in Buerger’s disease patients than in those with ASO (p = 0.002). The frequency of diabetes and hypertension was significantly higher in ASO patients than in those with Buerger’s disease (p < 0.001, p < 0.001 respectively).

Vascular involvement at the time of admission In the ASO group, claudication was identified in 23 (48.9%) patients, pain at rest occurred in six (12.8%), and ischaemic wound symptoms were observed in 18 (38.3%) patients. In the Buerger’s disease group, claudication was identified in one (2.6%) patient, pain at rest occurred in six (15.4%), and ischaemic wound symptoms were observed in 32 (82%) patients at the time of admission to hospital. The rate of ischaemic wound symptoms in patients with Buerger’s disease was statistically significantly higher than in the ASO group (p = 0.001). There were statistically significant differences between the groups in anatomical localisation of ischaemic wounds, which were determined with invasive and non-invasive methods. In Buerger’s disease patients, the level of disease was observed to be mostly at the popliteo-crural level. In the ASO group, aortoiliac involvement was present in 18 (38.2%) patients, femoropopliteal involvement was found in 18 (38.2%), and popliteocrural involvement was present in 11 (23.4%) patients. In the Table 2. Comparison of the two groups in terms of chronic limb ischaemia criteria Atherosclerosis, n (%)

Buerger’s disease, n (%)

2 (4.3)

0 (0)

2 (2.3)

p-value ns

Category 2

9 (19.1)

0 (0)

9 (10.5)

Category 3

12 (25.5)

1 (2.6)

13 (15.1)

Category 4

6 (12.8)

6 (15.4)

12 (14)

Category Category 1

Category 5 Category 6

18 (38.3) 0 (0)

*Statistically significant value.

Total, n (%)

30 (76.9)

48 (55.8)

< 0.001*

2 (5.1)

2 (2.3)

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Table 3. Evaluation of SF-36 between the groups First evaluation 6-month follow up 12-month follow up Quality-of-life Atherosclerosis Buerger’s Atherosclerosis Buerger’s Atherosclerosis Buerger’s variables (n = 47) disease (n = 39) p-value (n = 33) disease (n = 33) p-value (n = 22) disease (n = 25) p-value Physical function 27.3 ± 3.6 26.9 ± 4.2 0.94 53.4 ± 6.0 47.9 ± 5.5 0.50 67.9 ± 7.3 56.9 ± 6.2 0.26 Physical status 9.5 ± 3.9 3.8 ± 2.6 0.25 60.6 ± 8.3 44.2 ± 7.7 0.15 70.4 ± 9.6 50.5 ± 9.3 0.14 Social function 34.7 ± 3.7 26.4 ± 4.0 0.12 58.7 ± 5.2 47.7 ± 5.6 0.15 75.5 ± 7.5 70.7 ± 6.8 0.63 Body pain 30.1 ± 3.4 19.9 ± 2.7 0.02* 68.5 ± 5.0 41.3 ± 5.8 0.001* 78.6 ± 6.9 64.3 ± 8.1 0.19 Mental health 52.9 ± 3.6 50.6 ± 3.6 0.65 60.7 ± 4.2 54.2 ± 4.4 0.28 72.1 ± 3.7 65.2 ± 3.9 0.21 Emotional status 18.6 ± 4.9 11.9 ± 4.6 0.33 60.5 ± 7.9 49.3 ± 7.7 0.31 74.2 ± 9.2 56.1 ± 9.2 0.17 Vitality 36.0 ± 3.2 36.2 ± 3.3 0.97 52.6 ± 4.1 47.5 ± 4.2 0.39 62.7 ± 5.2 56.0 ± 4.0 0.31 General health 43.2 ± 2.5 37.4 ± 2.4 0.10 55.7 ± 3.2 49.3 ± 3.0 0.15 64.1 ± 4.7 62.1 ± 4.1 0.74 Values are median ± SE. p-values are between-group comparisons. *Statistically significant value.

Buerger’s disease group, aorto-iliac involvement was present in two (5.1%) patients, femoro-popliteal involvement was found in 10 (25.6%), and popliteo-crural involvement was present in 27 (69.2%) patients (p < 0.001). According to chronic limb ischaemia criteria, Buerger’s disease patients were found to be in an advanced stage at the beginning of the study (Table 2). A total of 38.3% of patients in the ASO group and 76.9% of those in the Buerger’s disease group were in category 5 (p < 0.001). The two groups were compared in terms of number of operations performed at the time of hospital admission, and a statistically significantly higher number of vascular operations was observed in the ASO patients compared with the Buerger’s disease patients. Peripheral vascular surgery was performed in a total of 30 (63.8%) patients in the ASO group and nine (23.1%) in the Buerger’s disease group (p < 0.001). When early vascular complications related to vascular interventions were compared, no significant differences were observed between the two groups in terms of patency and thrombosis rates (data not presented). The rate of minor and major amputations undertaken in the contralateral leg was 4.2 and 4.2%, respectively in ASO patients. The corresponding rates in Buerger’s disease patients were 20.5 and 10.3%, respectively. The rate of both minor and major amputations in the contralateral leg was significantly higher in Buerger’s disease patients (p = 0.027, p = 0.027, respectively). The rate of minor amputations undertaken in the leg with a lesion was 4.2% in ASO patients and 35.9% in Buerger’s disease patients; this difference was statistically significant (p < 0.001). The rate of amputation within one year of hospital admission was found to be 23.4% in ASO patients and 48.7% in Buerger’s

disease patients (p < 0.05). There was no mortality in either group during the one-year follow-up period.

Results of SF-36 The two groups were evaluated using the SF-36 score measuring quality of life. A statistically significant difference was found between the two groups in terms of pain at the time of hospital admission and at six months post admission (p = 0.02, p = 0.001 respectively). Pain in Buerger’s disease patients was observed to be more pronounced; however, this difference disappeared at 12 months (Table 3). The SF-36 scores for patients with peripheral vascular disease (irrespective of group) were compared according to category of chronic limb ischaemia. The quality of life of patients whose level of chronic limb ischaemia was category 5 and over at the time of the first admission was worse in terms of pain, general health, social function, emotional status and mental health than that of patients with SF-36 scores less than category 5. These parameters were found to be statistically significant (p = 0.02, p = 0.02, p = 0.02, p = 0.03, p = 0.04, respectively) (Table 4). The difference in quality of life according to category of the SF-36 questionnaire disappeared at six and 12 months. Using the SF-36, when ASO and Buerger’s disease patients were divided into subgroups in terms of category of chronic limb ischaemia, no significant difference was determined for this parameter. However, when patients with advanced PAD in category 5 and over were compared with patients with chronic ischaemia of category 5 and over, there was no statistically significant difference between these groups (data not presented).

Table 4. Evaluation of SF-36 according to category level for independent groups First evaluation 6-month follow up Quality-of-life Category ≤ 4 Category ≥ 5 Category ≤ 4 Category ≥ 5 variables (n = 36) (n =50) p-value (n = 24) (n = 43) Physical function 28.3 ± 4.0 26.3 ± 3.7 0.71 58.7 ± 6.8 46.1 ± 4.9 Physical status 7.6 ± 4.3 6.5 ± 3.0 0.82 59.8 ± 9.4 48.1 ± 7.2 Pain 33.8 ± 3.6 19.6 ± 2.5 0.02* 63.9 ± 6.3 49.7 ± 5.4 General health 46.8 ± 2.7 36.0 ± 2.1 0.02* 57.0 ± 3.5 49.9 ± 2.8 Vitality 38.4 ± 3.5 34.4 ± 3.0 0.39 56.5 ± 4.0 46.4 ± 3.9 Social function 38.0 ± 4.4 25.7 ± 3.3 0.02* 62.8 ± 5.9 47.7 ± 4.9 Emotional status 24.3 ± 6.3 9.3 ± 3.5 0.03* 65.4 ± 8.3 48.9 ± 7.2 Mental health 58.0 ± 3.9 47.5 ± 3.3 0.04* 65.2 ± 4.6 53.0 ± 3.8 Values are median ± SE. p-values are between-group comparisons. *Statistically significant value.

p-value 0.61 0.72 0.55 0.81 0.77 0.54 0.56 0.78

12-month follow up Category ≤ 4 Category ≥ 5 (n = 22) (n = 25) 63.7 ± 8.6 61.1 ± 5.7 58.3 ± 8.6 60.7 ± 8.5 73.0 ± 7.7 69.7 ± 7.4 63.0 ± 5.1 63.0 ± 3.9 61.6 ± 5.5 57.6 ± 4.0 73.1 ± 8.3 72.8 ± 6.4 67.3 ± 9.5 62.9 ± 8.6 68.9 ± 4.7 68.1 ± 3.3

p-value 0.81 0.79 0.78 0.92 0.83 0.81 0.75 0.91

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Table 5. Evaluation of VASCUQOL between the groups. First evaluation 6-month follow up 12-month follow up Quality-of-life Atherosclerosis Buerger’s Atherosclerosis Buerger’s Atherosclerosis Buerger’s variables (n = 47) disease (n = 39) p-value (n = 33) disease (n = 33) p-value (n = 22) disease (n = 25) p-value Pain 2.6 ± 0.2 1.8 ± 0.1 0.008* 4.6 ± 0.3 3.7 ± 0.2 0.04* 5.2 ± 0.5 5.0 ± 0.4 0.74 Symptom 3.0 ± 0.2 2.5 ± 0.2 0.08 5.0 ± 0.2 4.0 ± 0.3 0.02* 5.5 ± 0.4 5.4 ± 0.3 0.82 Activity 2.2 ± 0.1 2.1 ± 0.2 0.81 4.5 ± 0.3 3.9 ± 0.3 0.20 5.3 ± 0.4 4.7 ± 0.4 0.36 Social status 3.0 ± 0.2 2.6 ± 0.2 0.17 4.6 ± 0.3 3.7 ± 0.2 0.02* 5.3 ± 0.4 4.6 ± 0.3 0.19 Emotional status 2.6 ± 0.2 2.4 ± 0.2 0.40 4.8 ± 0.3 3.9 ± 0.3 0.06 5.6 ± 0.4 4.7 ± 0.4 0.14 Values are median ± SE. p-values are between the groups comparisons. *Statistically significant value.

From these data, quality of life in patients with both ASO and Buerger’s disease was negatively affected after critical ischaemia developed in the leg.

Results of VASCUQOL Quality of life was evaluated with VASCUQOL at the time of hospital admission, and at six and 12 months’ follow up. Statistically significant differences were found between both groups in terms of pain at the time of hospital admission. Statistically significant differences were also found between both groups in terms of pain, symptom level and social status at six months (p = 0.008, p = 0.04, p = 0.02, p = 0.02, respectively). Pain was observed to be more explicit and social status more impaired in Buerger’s disease patients; however, this difference disappeared at 12 months (Table 5). VASCUQOL scores of patients with PAD (irrespective of group) were compared according to the clinical categories of chronic limb ischaemia (Rutherford classification4). Patients whose category level was 5 and over were observed to be significantly worse in terms of total VASCUQOL score, symptom level and social status at the time of the first admission, as well as symptom level and social status at six months (Table 6). In terms of total VASCUQOL score, when patients with advanced PAD in only category 5 and over were compared with patients with chronic ischaemia of category 5 and over, there were no statistically significant differences between the groups in at the time of hospital admission or at six and 12 months (p = 0.602, p = 0.347, p = 0.839, respectively) (data not presented).

Impact of amputation on quality of life The impact of limb amputations within one year of hospital admission on quality of life was evaluated. According to the SF-36 score, at admission, amputation negatively affected pain

in patients with both ASO and Buerger’s disease (p = 0.003). The amputation also negatively affected physical function, physical status, pain, general health, social functions and emotional status in these patients at six months (p = 0.002, p = 0.007, p = 0.001, p = 0.009, p = 0.005, p = 0.001, respectively) and at 12 months (p = 0.002, p = 0.007, p = 0.001, p = 0.009, p = 0.005, p = 0.001, respectively). Additionally, amputation was found to negatively affect mental status in the ASO patients at 12 months (p = 0.011). The total VASCUQOL scores were significantly lower in amputees with ASO and Buerger’s disease at six and 12 months (p = 0.039, p = 0.001, respectively) than the SF-36 scores. Difference in quality of life in ASO and Buerger’s disease patients who were not amputees was evaluated. The total VASCUQOL score was found to be lower in Buerger’s disease patients at the time of hospital admission and at six months (p = 0.032, p = 0.005, respectively) than in ASO patients. Difference in quality of life between amputees with Buerger’s disease and ASO was also evaluated. No significant differences in quality of life were observed at admission or at six and 12 months in these groups (p = 0.84, p = 0.48, p = 0.32, respectively). These results could have been related to the fact that the source of pain had been amputated in these ASO and Buerger’s disease patients, therefore no difference in quality of life would be expected. However, quality of life was observed to be significantly worse in non-amputee Buerger’s disease patients than ASO patients.

Discussion Peripheral arterial diseases are high-morbidity diseases that have a negative effect on quality of life.7-9 Although there are numerous studies on quality of life in patients with PAD, or comparing quality of life between patients with PAD and other cardiovascular diseases,10 to our knowledge, there is no study that compares quality of life between the different categories of PAD,

Table 6. Evaluation of VASCUQOL according to category level First evaluation Quality-of-life Category ≤ 4 Category ≥ 5 variables (n = 36) (n = 50) p-value Pain 2.5 ± 0.2 2.1 ± 0.1 0.13 Symptoms 3.3 ± 0.2 2.4 ± 0.1 0.02* Activity 2.2 ± 0.1 2.1 ± 0.1 0.73 Social status 3.3 ± 0.2 2.4 ± 0.1 0.003* Emotional status 2.8 ± 0.3 2.3 ± 0.2 0.17 Total VASCUQOL 2.9 ± 0.2 2.3 ± 0.1 0.006* Values are median ± SE. *Statistically significant value.

6-month follow up Category ≤ 4 Category ≥ 5 (n = 24) (n = 43) 4.2 ± 0.4 4.1 ± 0.3 5.0 ± 0.2 4.3 ± 0.2 4.6 ± 0.3 3.9 ± 0.2 4.7 ± 0.3 3.8 ± 0.2 4.8 ± 0.4 4.1 ± 0.3 4.7 ± 0.3 4.1 ± 0.2

p-value 0.79 0.04* 0.14 0.03* 0.12 0.13

12-month follow up Category ≤ 4 Category ≥ 5 (n = 22) (n = 25) 5.0 ± 0.5 5.2 ± 0.4 5.6 ± 0.4 5.4 ± 0.3 5.1 ± 0.5 4.9 ± 0.3 5.2 ± 0.4 4.7 ± 0.4 5.4 ± 0.5 4.9 ± 0.4 5.2 ± 0.4 5.0 ± 0.3

p-value 0.84 0.76 0.72 0.46 0.52 0.63

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namely ASO and Buerger’s disease. This study is therefore the first to undertake such a comparison. According to our study, in general, although Buerger’s disease had a more pronounced negative effect on quality of life, particularly in terms of pain score, both ASO and Buerger’s disease impaired quality of life to a similar degree when critical limb ischaemia was considered. A range of studies have examined the question of quality of life because it is unclear which questions best describe quality of life.11-15 To evaluate quality of life, we used the SF-36, which has a generic and general meaning, and the VASCUQOL, which is specific to PAD. The advantage of generic tests is that they can be used for a variety of diseases. However, their susceptibility is low, and their focus on specific effects related to the disease is not good.16 The VASCUQOL includes specific questions associated with PAD and better evaluates the effects after treatment.17,18 However, to date, no adequate comparative studies associated with generic or specific tests have been performed in patients with PAD. Comparative studies are needed. In the study performed by Morgan et al., these two scores complemented each other and were compatible.17 Generally, it follows that when ischaemic lesions become serious in PAD, quality of life is impaired. In our study, impairment in the pain component of quality of life in Buerger’s disease patients was demonstrated. Buerger’s disease patients were more affected in terms of pain in both the SF-36 and VASCUQOL than were ASO patients. In an intergroup comparison, a statistically significant difference was found between the two groups in terms of pain at the time of hospital admission and at six months. Pain was identified to be more pronounced in Buerger’s disease patients; however, this significant difference disappeared at 12 months. From an evaluation of all the heterogeneous patients included in this study, who had symptomatology varying from claudication to ischaemic gangrenes, Buerger’s disease generally impaired quality of life to a greater extent than ASO. Critical leg ischaemia was present in only half of the atherosclerotic patients whereas it was present in almost all of the Buerger’s disease patients. In order to reduce heterogeneity in the evaluation, quality of life was evaluated in patients with only critical ischaemia. The conclusion was reached that the patient groups were not very different. In other words, when evaluating criteria such as pain at rest, or presence of ischaemic wound or gangrene, these conditions affected quality of life negatively, irrespective of whether they arose from ASO or Buerger’s disease. Another parameter affecting quality of life was amputation. In many studies, amputations have been reported to seriously impair quality of life.19,20 In the study by Luther,20 144 patients with critical ischaemia were evaluated in terms of quality of life, determined by ankle/brachial index and pain. They also found that single or multiple amputations did not cause a difference in quality of life. Amputations were observed to affect morbidity and mortality rates however, particularly in the eighth and ninth decades.20 In our study, 23.4% of all patients with ASO and 48.7% of all patients with Buerger’s disease underwent amputation in the follow-up period of one year. Throughout the follow up, the quality of life in patients with amputations was significantly affected in terms of general health, pain, mental status, physical function, and emotional and social status in both ASO and Buerger’s disease patients.

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According to the SF-36 score, amputation was observed to negatively affect pain at the time of admission in both ASO and Buerger’s disease patients. The quality of life in amputee patients was evaluated again at the six- and 12-month follow up. Amputations affected physical function, physical status, pain, general health, social function and emotional status in both ASO and Buerger’s disease patients. When the difference in quality of life between amputee ASO and Buerger’s disease patients was evaluated with the VASCUQOL score, we observed no differences between the two groups, either at the time of hospital admission or at six or 12 months. The interpretation of this result is that because the source of the pain in patients who had undergone amputation due to either ASO or Buerger’s disease was removed, no difference in quality of life would be expected. However, quality of life was worse in Buerger’s disease patients without amputation compared with ASO patients. There are a few limitations to this study. According to our study, Buerger’s disease affected quality of life more negatively than ASO, particularly with regard to pain score. Depressive symptoms are high among patients with PAD. The presence of depression may be a helpful factor in assessing pain scales in patients with PAD.21-23 However, in our study, patients’ psychological conditions were not considered. Assessment of life of quality may be more effective in PAD patients after treatment of psychological or emotional disorders. Another limitation is that the effects of surgical and medical treatment on quality of life were not evaluated. Furthermore, as is commonly known, smoking is a highly significant risk factor for the progression of Buerger’s disease.24 However we did not compare quality of life between patients who had stopped smoking and those who continued to smoke. If the three parameters: determination of psychological situation, its treatment, and smoking had been taken into account, different results in terms of quality of life may have been observed.

Conclusion Buerger’s disease showed a more pronounced negative effect on quality of life than ASO, particularly in terms of pain score. However, when critical limb ischaemia was considered, both ASO and Buerger’s disease impaired the quality of life in patients to a similar degree. There is a need for further studies to reassess the quality of life after psychological assessment and treatment, where necessary, of patients.

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Simultaneous coronary artery bypass grafting and carotid endarterectomy can be performed with low mortality rates Ebuzer Aydin, Yucel Ozen, Sabit Sarikaya, Ismail Yukseltan Abstract Introduction: There is controversy over the best approach for patients with concomitant carotid and coronary artery disease. In this study, we report on our experience with simultaneous carotid endarterectomy (CEA) and coronary artery bypass graft (CABG) surgery in our clinic in the light of data in the literature. Methods: Between January 1996 and January 2009, a total of 110 patients (86 males, 24 females; mean age 65.11 ± 7.81 years; range 44–85 years), who were admitted to the cardiovascular surgery clinic at our hospital, were retrospectively analysed. All patients underwent simultaneous CEA and CABG. Demographic characteristics of the patients and a history of previous myocardial infarction (MI), hypertension, diabetes mellitus, hyperlipidaemia, peripheral arterial disease and smoking were recorded. Results: One patient (0.9%) with major stroke died due to ventricular fibrillation. Peri-operative neurological complications were observed in seven patients (6%). Complications were persistent in two patients. Four patients (3%) had postoperative major stroke, whereas three patients (2%) had transient hemiparesis. No peri-operative myocardial infarction was observed. Conclusion: Simultaneous CEA and CABG can be performed with low rates of mortality and morbidity. Keywords: coronary artery bypass grafting, carotid endarterectomy, carotid artery disease, coronary artery disease, cerebrovascular event Submitted 5/2/14, accepted 10/4/14 Cardiovasc J Afr 2014; 25: 130–133

www.cvja.co.za

DOI: 10.5830/CVJA-2014-018

There is controversy over the best approach for patients with concomitant carotid and coronary artery disease.1 Therapeutic strategies include isolated coronary artery bypass grafting (CABG), staged carotid endarterectomy (CEA) and CABG,

Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey Ebuzer Aydin, MD, ebuzermd@gmail.com Yucel Ozen, MD Sabit Sarikaya, MD

Taksim German Hospital, Istanbul, Turkey Ismail Yukseltan, MD

reversed staged CEA and CABG, and simultaneous procedures under single anaesthesia.2 Although reported experiences over three decades are available, combining CEA with CABG remains to be elucidated.3 Furthermore, risk of cerebrovascular accident (CVA), which is one of the major predictors of prognosis of CABG, has been reported to increase up to 14% in patients with severe carotid artery stenosis (> 80%).4-9 Peri-operative neurological events such as stroke after CABG are the major neurological complications, which increase with age.10 The incidence of peri-operative stroke has been well documented at approximately 2% of all cardiac surgeries.11 Despite reduced overall complication rates over the years after CABG, the incidence of stroke remains relatively unchanged.10 The aetiology of peri-operative stroke is multi-factorial including hypotension or hypoperfusion-induced reduced brain flow, atherosclerosis due to micro- or macro-embolisation, and intra- or extra-cranial vascular diseases.5 In addition, carotid artery disease is a critical factor; however, it is considered unlikely to be the only culprit for peri-operative strokes.12 Although no consensus on the optimal management of patients with concomitant carotid and coronary artery disease has been reached,13 simultaneous CEA and CABG surgery is often associated with low rates of mortality and morbidity.14-17 In this study, we report our experience with simultaneous CEA and CABG surgery in our clinic in the light of data in the literature.

Methods This retrospective study included a total of 110 patients admitted to the cardiovascular surgery clinic of the Universal Taksim German Hospital between January 1996 and January 2009. All patients underwent simultaneous CEA and CABG. Demographic characteristics of the patients as well as a history of previous myocardial infarction (MI), hypertension, diabetes mellitus, hyperlipidaemia, peripheral arterial disease and smoking were recorded. Carotid artery stenosis was examined using carotid Doppler ultrasound. Patients aged ≥ 65 years with peripheral artery disease, previous cerebrovascular disease or CEA, symptomatic disease and heart murmur were candidates for carotid Doppler ultrasound. Half of the patients underwent a shunting procedure. We performed CEA in patients with ≥ 80% carotid artery stenosis. All patients were on acetylsalicylic acid and clopidogrel postoperatively. CEA was performed under general anaesthesia before CABG. The operation was carried out without shunting in patients with unilateral lesions and with shunting in those with bilateral critical stenosis or 100% stenosis unilaterally. Patients with bilateral critical carotid lesions underwent surgery for unilateral carotid lesion three days prior to CEA.

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Table 1. Operative findings Findings Numerical values Number of distal anastomoses 296 Grafted patient rate (%) 2.69 CPB time (min) 51.72 ± 17.15 (23–95) ACC time (min) 24.39 ± 8.41 (11–46) Duration of carotid clamping (min) 18.56 ± 7.23 (9–42) Carotid closure technique [n, (%)] Primary 2 (1.8) Vein 50 (45.5) Hemashield 58 (52.7) CPB, cardiopulmonary bypass time; ACC, aortic cross-clamping time.

The remaining lesion was operated on during CABG. The arteriotomy was closed using a patch in 108 patients (98.2%), except for two patients (1.8%) who underwent primary closure. Bleeding control was achieved. The incision was left open. Following the median sternotomy, on-pump CABG was performed with systemic hypothermia maintained at 32°C using two-stage venous and aortic cannulae. Mean arterial pressure was maintained at 60 mmHg during cardiopulmonary bypass (CPB). Operative findings are presented in Table 1.

Statistical analysis Statistical analysis was performed using SPSS for Windows v 13.0 software (SPSS Inc, Chicago, IL, USA). Descriptive statistics were used to summarise both quantitative data including the mean, standard deviation, and maximum and minimum values, and categorical variables including frequency distribution and percentage. Kolmogorov–Smirnov and Shapiro–Wilks tests were used to analyse normally distributed variables. One-way analysis of variance (ANOVA) was performed to determine the significance of differences between the groups. The chi-square test was also used to identify possible correlations among the variables, while the Spearman test was carried out to calculate power and direction of the correlation. A 95% confidence interval (CI) was calculated. A p-value of < 0.05 was considered statistically significant.

Results A total of 86 patients (78.2%) were male and 24 (21.8%) were female. The mean age was 65.11 ± 7.81 years (range 44–85 years). Demographic characteristics and clinical data of the patients are shown in Table 2. Of these patients, 27 were symptomatic, while 83 were asymptomatic. All patients who were operated on had ipsilateral carotid artery disease. Only four patients had ≥ 80% contralateral carotid artery stenosis. One patient (0.9%) with a cerebrovascular accident died due to subsequent ventricular arrhythmia in the early phase. Four patients (3%) had postoperative major stroke, whereas three (2%) had transient hemiparesis. No perioperative MI was observed. Early postoperative complications are summarised in Table 3. Spearman’s correlation showed a positive correlation between the duration of cross-clamping and shunt usage (40%). The mean duration of cross-clamping was 15.9 and 21.1 min in patients

Table 2. Demographic and clinical characteristics Number of Characteristics patients (n) Gender Female 24 Male 86 Previous myocardial infarction 28 Neurological history Asymptomatic 82 Symptomatic 27 Hypertension 77 Smoking 38 Diabetes mellitus 39 Hyperlipidaemia 34 Peripheral artery disease 19 Mean age 65.11 ± 7.81 years, range 44–85

Percentage (%) 78.2 21.8 25.5 74.5 24.5 70 34.5 35.5 30.9 17.3

without and with shunts, respectively. It reached statistical significance (p < 0.049). Although shunt implantation prolonged the duration of cross-clamping, there was no statistically significant difference in neurological complication rate (p = 0.301). In addition, four patients had haematoma and neurological complications due to local bleeding. One patient required re-do CABG surgery. Another patient underwent revision surgery due to sternal dehiscence. Three patients underwent revision surgery due to bleeding following CABG.

Discussion Today individuals with concomitant carotid and coronary artery disease are still challenging patients for surgeons. With increasing age of patients and stenosis rate, it is obvious that this will become more significant in future years.7 The incidence of carotid stenosis has been estimated as 12% in patients with coronary artery disease.4,18 Nearly half of the patients with carotid artery disease also have concomitant coronary artery disease.19 Peri-operative prevention of myocardial and cerebral accidents is an ongoing debate. Several studies have demonstrated a mortality rate for simultaneous CEA and CABG of 0–8.9% and a stroke rate of 0–9%.4-9,19 Lower mean arterial pressures of cardiopulmonary bypass, systemic vasodilatory response and plaque embolism during aortic cross-clamping increase the risk of peri-operative stroke in CABG patients.20 In a randomised study, Roach et al.21 reported a neurological complication rate of 6.1% in patients who underwent elective CABG surgery, with serious complications in 3%. The authors

Table 3. Postoperative complications Complications Early mortality Persistent hemiplegia Transient hemiparesis Transient ischaemic attack Peri-operative myocardial infarction Ventricular arrhythmia Atrial fibrillation

Number 1 3 4 1 0 2 3

Percentage 0.9 2 3 0.9 0 1 2

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highlighted the critical role of examination of the carotid artery stenosis pre-operatively. There are also several studies showing a neurological accident rate of 7.4–20.3% with a mortality rate of 6.9–13.8% in patients with concomitant carotid artery disease undergoing CABG alone.5,22,23 In addition, as higher morbidity rates (7–8%), which were strongly associated with peri-operative MI were reported in patients requiring CABG with isolated CEA procedure,22 simultaneous CEA and CABG is currently usually recommended.24,25 Furthermore, there is controversy on the optimal treatment for patients with concomitant carotid and coronary artery disease. Surgeons should consider a number of clinical parameters when selecting the simultaneous or staged approach. To illustrate, postoperative MI was reported to be 7% in symptomatic patients and 1% in asymptomatic patients with coronary artery disease who underwent CEA followed by CABG.19,26 The incidence of peri-operative stroke, on the other hand, is markedly increased in patients with ≥ 80% carotid artery stenosis, suggesting a staged approach, including CABG followed by CEA.27 However, the incidence of cardiovascular accidents is mainly associated with embolism rather than low cardiac-output thrombosis rate in patients undergoing elective CABG surgery.28 Simultaneous intervention was first described in a singleanesthesia period.29 Trachiotis et al.30 and Akins et al.18 reported that the simultaneous approach was highly effective in reducing neurological and myocardial complications. Additionally, Takach et al.31 indicated that simultaneous intervention was as safe as the staged approach in high-risk patients, which was consistent with our study findings. In another single-centre study, the simultaneous approach to CEA and CABG was reported to be associated with equivalent mortality and stroke profiles, as well as lower overall complication rates and hospital charges.20 There are several studies reporting a shorter length of hospital stay, 26,32 lower costs26,33 and acceptable early mortality and morbidity rates.34-36 Similarly, we found the mortality and major stroke rates to be 0.9 and 2%, respectively. Nevertheless, despite an increased number of studies showing the merits of the simultaneous approach, national and international guidelines have provided no consensus yet due to the lack of prospective, randomised clinical trials. However, simultaneous CEA and CABG in asymptomatic patients with bilateral severe disease in particular, has been widely recommended.13 Moreover, carotid artery stenting (CAS), which is less invasive, with a lower rate of myocardial events, has been popular in recent years. However, deliberate action should be taken until its long-term results are documented, as there is currently limited evidence supporting the use of CAS.10

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Conclusion Our clinical experience indicated that simultaneous CEA and CABG can be performed safely. Furthermore, it increases patient comfort, since anaesthesia is given once, and two operations are carried out at a single session. Therefore, we recommend the simultaneous approach for patients with coronary and carotid artery disease. However, further large-scale, multicentred, randomised clinical studies are required to draw final conclusions.

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Baiou D, Karageorge A, Spyt T, Naylor AR. Patients undergoing cardiac surgery with asymptomatic unilateral carotid stenoses have a low risk of peri-operative stroke. Eur J Vasc Endovasc Surg 2009; 38: 556–559. Naylor AR, Mehta Z, Rothwell PM. A systematic review and metaanalysis of 30-day outcomes following staged carotid artery stenting and coronary bypass. Eur J Vasc Endovasc Surg 2009; 37: 379–387. Byrne J, Darling III RC, Roddy SP, Mehta M, Paty PSK, Kreienberg PB, et al. Combined carotid endarterectomy and coronary artery bypass grafting in patients with asymptomatic high-grade stenoses: An analysis of 758 procedures. J Vasc Surg 2006; 44: 67–72. Faggioli GL, Curl GR, Ricotta JJ. The role of carotid screening before coronary artery bypass. J Vasc Surg 1990; 12: 724–731. Hertzer NR, Loop FD, Taylor PC, Beven EG. Combined myocardial revascularization and carotid endarterectomy: Operative and late results in 331 patients. J Thorac Cardiovasc Surg 1983; 85: 577–589. Huh J, Wall M, Soltero E. Treatment of combined coronary and carotid artery disease. Curr Opin Cardiol 2003; 18: 447–453. Khaitan L, Sutter FP, Goldman SM, Chamogeorgakis T, Wertan MA, Priest BP, et al. Simultaneous carotid endarterectomy and coronary revascularization. Ann Thorac Surg 2000; 69: 421–424. John R, Choudhri AF, Weinberg AD, Ting W, Rose EA, Smith CR, et al. Multicenterreview of preoperative risk factors for stroke after coronary artery bypass grafting. Ann Thorac Surg 2000; 69: 30–35; discussion 35–36. Brener BS, Brief DK, Albert J, Goldenkraz RJ, Parsonnet V. The risk of stroke in patients with asymptomatic carotidstenosis undergoing cardiac surgery: a follow-up study. J Vasc Surg 1987; 5: 269–279. Kolh PH, Comte L, Tchana-Sato V, Honore C, Kerzmann A, Mauer M, Limet R. Concurrent coronary and carotid artery surgery: factors influencing perioperative outcome and long-term results. Eur Heart J 2006; 27: 49–56. Naylor AR, Mehta Z, Rothwell PM, Bell PRF. Stroke during Coronary artery bypass surgery: a critical review of the role of carotid artery disease. Eur J Vasc Endovasc Surg 2002; 23: 283e94. Van der Heyden J, Lans HW, van Werkum JW, Schepens M, Ackerstaff RG, Suttorp MJ. Will carotid angioplasty become the preferred alternative to staged or synchronous carotid endarterectomy in patients undergoing cardiac surgery? Eur J Vasc Endovasc Surg 2008; 36: 379–384. Naylor AR. Managing patients with symptomatic coronary and carotid artery disease. Perspect Vasc Surg Endovasc Ther 2010; 22: 70–76. Eren E, Balkanay M, Toker ME, Tunçer A, Anasiz H, Güler M, Daglar B, et al. Simultaneous carotid endarterectomy and coronary revascularization is safe using either on-pump or off-pump technique. Int Heart J 2005; 46: 783–793 Levy E, Yakubovitch D, Rudis E, Anner H, Landsberg G, Berlatzky Y, Elami A. The role of combined carotid endarterectomy and coronary artery bypass grafting in the era of carotid stenting in view of long-term results. Interact Cardiovasc Thorac Surg 2012; 15(6): 984–988. Ren S, Liu P, Ma G, Wang F, Qian S, Fan X. Long-term outcomes of synchronous carotid endarterectomy and coronary artery bypass grafting versus solely carotid endarterectomy. Ann Thorac Cardiovasc Surg 2012; 18(3): 228–235. Yuan SM, Wu HW, Jing H. Treatment strategy for combined carotid artery stenosis and coronary artery disease: staged or simultaneous surgical procedure? Tohoku J Exp Med 2009; 219: 243–250 Akins LW, Moncure AC, Daggett WM. Safety and efficiency of concomitant carotid and coronary artery operations. Ann Thorac Surg 1995; 60: 311–317. Ennix CL Jr, Lawrie GM, Morris GC Jr, Crawford ES, Howell JF,

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Reardon MJ, et al. Improved results of carotid endarterectomy in patients with symptomatic coronary disease: An analysis of 1546 consecutive carotid operations. Stroke 1979; 10: 122–125. Gopaldas RR, Chu D, Dao TK, Huh J, LeMaire SA, Lin P, et al. Staged versus synchronous carotid endarterectomy and coronary artery bypass grafting: analysis of 10-year nationwide outcomes. Ann Thorac Surg 2011; 91: 1323–1329. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter study of perioperative ischemia research group and the Ischemia Research and Education Foundation investigators. N Engl J Med 1996; 335: 1857–1863. Reul GJ, Morris GC, Howell JF, Crawford ES, Stelter WY. Current concepts in coronary artery surgery: A critical analysis of 1287 patients. Ann Thorac Surg 1972; 14: 243–259. Jones EL, Craver JM, Michalik RA, Murphy DA, Guyton RA, Bone DK, et al. Combined carotid and coronary operations: When are they necessary? J Thorac Cardiovasc Surg 1984; 87: 7–16. Minami K, Fukahara K, Boethig D, Bairaktaris A, Fritzsche D, Koerfer R. Long-term results of simultaneouscarotid endarterectomy and myocardial revascularization with cardiopulmonary bypass used for both procedures. J Thorac Cardiovasc Surg 2000; 119: 764–773. Hertzer NR, O’Hara PJ, Mascha EJ, Krajewski LP, Sullivan TM, Beven EG. Early outcome assessment for 2228 consecutive carotid endarterectomy procedures: The Cleveland Clinic experience from 1989 to 1995. J Vasc Surg 1997; 26: 1–10. Narcis H. Reduction in hospitalisation rates following simultaneous carotidendarterectomy and coronary artery bypass grafting; experience from a single centre. Interact Cardiovasc Thorac Surg 2006; 5: 367–372. Giangola G, Migaly J, Riles TS, Lamparello PJ, Adelman MA, Grossi

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E, et al. Perioperative morbidity and mortality in combined vs. staged approaches to carotid and coronary revascularization. Ann Vasc Surg 1996; 10: 138–142. Ropper AH, Wechsler LR, Wilson LS. Carotid bruit and the risk of stroke in elective surgery. N Engl J Med 1982: 307; 1388–1390. Akins CW. Combined carotid endarterectomy and coronary revascularization operation. Ann Thorac Surg 1998; 66: 483–484. Trachiotis GD, Pfister AJ. Management strategy for simultaneous carotid endarterectomy and coronary revascularization. Ann Thorac Surg 1997; 64: 1013–1018. Takach TJ, Reul GJ, Cooley DA, Duncan JM, Ott DA, Livesay JJ, et al. Is an integrated approach warranted for concomitant carotid and coronary disease? Ann Thorac Surg 1997; 64: 16–22. Brow TD, Kakkar VV, Pepper JR, Das SK. Toward a rational management of concomitant carotid and coronary artery disease. J Cardiovasc Surg (Torino) 1999; 40: 837–844. Daily PO, Freeman RK, Dembitsky WP, Adamson RM, Moreno-Cabral MJ, Marcus S, et al. Cost reduction by combined carotid endarterectomy and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996; 111: 1185–1192. Gaudino M, Glieca F, Alessandini F, Cellini C, Luciani N, Praqliola C, et al. Individualized surgical strategy for the reduction of stroke in patients undergoing CABG. Ann Thorac Surg 1999; 67: 1246–1253. Plestis KA, Ke S, Jiang ZD, Howell JF. Combined carotid endarterectomy and coronary artery bypass: Immediate and long-term results. Ann Vasc Surg 1999; 13: 84–92. Kaul TK, Fields BL, Riggins LS, Wyatt DA, Jones CR. Coexistent coronary and cerebrovascular disease: results of simultaneous surgical management in specific patient groups. Cardiovasc Surg 2000; 8: 355–365.

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Understanding the rise in cardiovascular diseases in Africa: harmonising H3Africa genomic epidemiological teams and tools Mayowa O Owolabi, George A Mensah, Paul L Kimmel, Dwomoa Adu, Michele Ramsay, Salina P Waddy, Bruce Ovbiagele, Cristina Rabadan-Diehl, Rebekah Rasooly, Sally N Akarolo-Anthony, Charles Rotimi as members of the H3Africa Consortium Abstract Cardiovascular diseases, principally ischaemic heart disease and stroke, are the leading causes of global mortality and morbidity. Together with other non-communicable diseases, they account for more than 60% of global deaths and pose major social, economic and developmental challenges worldwide. In Africa, there is now compelling evidence that the major cardiovascular disease (CVD) risk factors are on the rise, and so are the related fatal and non-fatal sequelae, which occur at significantly younger ages than seen in high-income countries. In order to tackle this rising burden of CVD, the H3Africa Cardiovascular Working Group will hold an inaugural workshop on 30 May 2014 in Cape Town, South Africa. The primary workshop objectives are to enhance our understanding of the genetic underpinnings of the common major CVDs in Africa and strengthen collaborations among the H3Africa teams and other researchers using novel genomic and epidemiological tools to contribute to reducing the burden of CVD on the continent. Keywords: cardiovascular diseases, H3Africa, Africa, genomics, epidemiology Submitted 23/3/14, accepted 13/5/14 Cardiovasc J Afr 2014; 25: 134â&#x20AC;&#x201C;136

www.cvja.co.za

DOI: 10.5830/CVJA-2014-030

Department of Medicine, University College Hospital, University of Ibadan, Ibadan, Nigeria Mayowa O Owolabi, Dr Med, mayowaowolabi@yahoo.com

Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA George A Mensah, MD, george.mesah@nih.gov Cristina Rabadan-Diehl, MD

Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA Paul L Kimmel, MD Rebekah Rasooly, MD

University of Ghana Medical School, Accra, Ghana Dwomoa Adu, MD

Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand; Division of Human

Non-communicable diseases (NCDs) are currently responsible for over 60% of global deaths. NCDs, which threaten the economic and social development of nations across the globe, are predicted to increase in the coming decades.1 Globally, non-communicable cardiovascular diseases (CVDs) are the leading cause of mortality, morbidity and rising healthcare costs.1-5 Although there are huge data gaps6,7 and time lags between original data gathering and publication on the current burden of CVD in Africa, recent evidence suggests that the burden of stroke and other CVDs is rising on the continent.3,8-12 Stroke is the second leading cause of death globally, with 70.9% of deaths due to stroke, and 77.7% of the disability-adjusted life years lost occurring in low- and middle-income countries, many of which are in Africa.8 Whereas ischaemic heart disease tops the list of CVDs in high-income countries, stroke predominates in African countries.3,10-13 This is possibly because most African countries are in stage two or three of their epidemiological transition.14 This epidemiological transition is due to a combination of lifestyle and dietary changes, urbanisation, and demographic transition (increasing life expectancy and population growth),7,14,15 against a background of unique patterns of genomic variation. Whereas from 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% in high-income countries due to the successful deployment of public health tools and interventions,8 it has increased in Africa.8,9 There is an urgent need to identify knowledge gaps and propose a synergistic Genetics, NHLS and School of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa

Michele Ramsay, PhD

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Salina P Waddy, MD

Department of Neurology, Medical University of South Carolina, Charleston, SC, USA Bruce Ovbiagele, MD

Department of Nutrition, Harvard School of Public Health, Boston, MA, USA Sally N Akarolo-Anthony, MD

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA Charles Rotimi, PhD

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research agenda to accurately determine the current burden and fully characterise and quantify the factors underlying this epidemic in Africa. The Cardiovascular Working Group of H3Africa therefore aims to explore this rising burden of CVDs using novel genomic and epidemiological tools to inform appropriate interventions for the continent. We seek to comprehensively characterise the genomic, sociocultural, economic and behavioural risk factors leading to the development of clinical risk factors (e.g. hypertension and diabetes) and sub-clinical disease (e.g. cardiac and cerebral vascular structural changes), which in turn result in multiple organ damage7,16 (e.g. stroke, and kidney and heart failure). To begin this work, the H3Africa Cardiovascular Working Group will hold an inaugural workshop on 30 May 2014 in Cape Town, South Africa, in conjunction with the fourth H3Africa consortium meeting (www.h3africa.org/9-news/125-fourthh3africa-consortium-meeting). The specific working group objectives are (1) to review the current burden of CVDs and their risk factors in Africa, identifying knowledge gaps; (2) to provide the research and surveillance pillar of the integrated CVDs quadrangle (the remaining three pillars are prevention, acute care and rehabilitation) aimed at reducing the rising burden of CVDs; (3) to develop, nurture and strengthen synergistic symbiotic collaboration among H3Africa teams exploring CVDs and their risk factors using novel genomic and epidemiological tools; (4) to enhance our understanding of the genetic underpinnings of the common major CVDs in Africa and across the globe; and (5) to facilitate an appreciation of the pathophysiological interrelationships between cardiometabolic diseases and certain infectious/inflammatory diseases (e.g. rheumatic heart disease, HIV), the heart, brain and kidneys.7,16-21 It is anticipated that refinement and harmonisation of phenotypic characteristics, consideration of environmental factors, and the recruitment of large numbers of well-characterised patients with diverse CVDs across the continent will result in a better understanding of the links between phenotype and genotype in this extremely important group of diseases. In understanding these complex interrelationships throughout the course of life, we will study important pathways, including endothelial dysfunction, indices of microvascular damage (e.g. albuminuria), oxidative stress, inflammatory processes, as well as endocrine and paracrine influences.22-24 Furthermore, we will explore how these indices inform the development of riskprediction models and integrated surveillance systems, as well as tailored (responsive) systems and individual-level preventive and therapeutic interventions within and beyond the continent. The H3Africa Cardiovascular Working Group welcomes the active participation of all interested scientists in the inaugural workshop on 30 May 2014 in Cape Town.

The Wellcome Trust <http://www.wellcome.ac.uk/> is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. See http://www. h3africa.org/consortium/projects for a complete list of grants. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of Health or the US Department of Health and Human Services.

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13. We thank the members of the H3Africa consortium and its international expert panel of advisors for building this remarkable resource. The H3Africa consortium is funded by the National Institutes of Health and the Wellcome Trust. The workshop is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Human Genome Research Institute, and the National Institutes of Health office of AIDS Research.

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factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2224–2260. Baumgartner-Parzer SM, Waldhausl WK. The endothelium as a metabolic and endocrine organ: its relation with insulin resistance. Exp Clin Endocrinol Diabetes 2001; 109(Suppl 2): S166–S179. Frohlich ED. Mechanisms contributing to high blood pressure. Ann Intern Med 1983; 98(5 Pt 2): 709–714. Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 2007; 65(12 Pt 2): S140–S146. Mensah GA. Endothelial Biomedicine: The Public Health Challenges and Opportunities. In: Aird WC (ed). Endothelial Biomedicine. Cambridge, UK: Cambridge University Press, 2007: 1807–1814.

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21. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107(3): 499–511. 22. Futrakul N, Sridama V, Futrakul P. Microalbuminuria – a biomarker of renal microvascular disease. Ren Fail 2009; 31(2): 140–143. 23. Ochodnicky P, Henning RH, van Dokkum RP, de Zeeuw D. Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol 2006; 47(Suppl 2): S151–S162. 24. Ovbiagele B. Microalbuminuria: risk factor and potential therapeutic target for stroke? J Neurol Sci 2008; 271(1–2): 21–28.

4 June 2014 Dear Catheter Laboratory Unit Manager Re: Complementary ISCAP cardiac catheterisation manual to cath labs in Africa! The Pan-African Society of Cardiology (PASCAR) is privileged to announce that the Interventional Society of Catheter Laboratory Allied Professionals (ISCAP), a working group of the South African Society of Cardiovascular Intervention (SASCI) has offered to donate a cardiac catheterisation training manual to each cath lab unit in Africa. ISCAP wishes to support educational partnerships with cath labs across Africa. This partnership will ultimately benefit the interventional cardiology patient in Africa and is a first step towards achieving this goal. This manual was compiled by experienced South African catheter laboratory professionals over a two-year period and is issued under the auspices of SASCI and ISCAP. It was launched at the recent AfricaPCR course in Cape Town, South Africa, and was well received by cardiologists and allied professionals alike. The printing of the manual was primarily supported by B Braun South African, and Medtronic Africa offered to hand-deliver each manual. PASCAR wishes to thank these partners for their unconditional contribution` to interventional cardiology education in Africa. ISCAP would appreciate your feedback/opinion. Please forward comments and your contact details to George Nel (george@medsoc.co.za), who will forward it to the respective societies. Visit www.pascar.co.za and www.sasci.co.za for more information. With appreciation, Professor Bongani M Mayosi, DPhil, FCP (SA) President, Pan-African Society of Cardiology

PASCAR Society Office – george@medsoc.co.za, T +27 83 458 5954, F +27 86 603 9885, www.pascar.co.za

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Review Article Novel cardiovascular risk markers in women with ischaemic heart disease Dana Pop, Alexandra Dădârlat, D Zdrenghea Abstract The incidence of coronary heart disease in premenopausal women is lower than in men because of their hormonal protection. Angina pectoris occurs in women about 10 years later than in men. However, mortality from ischaemic heart disease remains higher in women than in men. Current studies are focusing on novel cardiovascular risk biomarkers because it seems that traditional cardiovascular risk factors and their assessment scores underestimate the risk in females. Increased plasma levels of these newly established biomarkers of risk have been found to worsen endothelial dysfunction and inflammation, both of which play a key role in the pathogenesis of microvascular angina, which is very common in women. These novel cardiovascular risk markers can be classified into three categories: inflammatory markers, markers of haemostasis, and other biomarkers. Keywords: ischaemic heart disease, women, new cardiovascular risk factors Submitted 4/12/13, accepted 14/3/14 Cardiovasc J Afr 2014; 25: 137–141

www.cvja.co.za

DOI: 10.5830/CVJA-2014-014

Cardiovascular disease (CVD) represents the leading cause of death among women in Europe. About 53% of female deaths are due to CVD, particularly coronary heart disease and stroke.1-9 The incidence of coronary heart disease is significantly lower in premenopausal women, due to their hormonal protection, but there are reportedly more complex mechanisms involved. Angina pectoris and heart attack occur in women about 10 and 20 years, respectively, later than in men.5 There are significant gender-related differences concerning coronary heart disease. The particularities regarding women are: higher prevalence in women over 75 years, the first coronary event is 10 years later than in men, atypical symptoms,

University of Medicine and Pharmacy Iuliu Haţieganu, Cluj-Napoca, Romania Dana Pop, MD Alexandra Dădârlat, ale_dadarlat@yahoo.com D Zdrenghea, MD

high incidence of non-Q-wave myocardial infarction, and the prevalence of coronary arteries without angiographic findings is twice as common as in men.6 Since 2004, guidelines have been emphasising the importance of recognising cardiovascular risk factors in women and also to classify women at high, intermediate or ‘ideal’ cardiovascular risk.2-4 A high-risk status is given not only by the presence of coronary artery disease, cerebrovascular disease, chronic arterial occlusive disease, aortic aneurysm or a Framingham score over 10%, but also by the presence of chronic kidney disease or diabetes.2 Women who face the threat of cardiovascular disease present with one or more risk factors including: smoking, pro-atherogenic diet, obesity (especially central obesity), family history of cardiovascular disease at a young age, hypertension and dyslipidaemia. Furthermore, it seems that subclinical vascular disease (such as coronary calcification), the metabolic syndrome, a low effort capacity or an abnormal heart rate recovery after the exercise stress test creates a prominent cardiovascular risk among women.2 Latest studies show that women diagnosed with collagen disease (auto-immune disease), a history of pre-eclampsia, gestational diabetes or pregnancyinduced hypertension require strict medical management due to their high predictive ability for the development of cardiovascular disease.2 Ideal cardiovascular health status is gained by women with blood pressure below 120/80 mmHg, total cholesterol level below 200 mg/dl, fasting plasma glucose below 100 mg/dl (without specific treatment), body mass index (BMI) below 25 kg/m2 and, undoubtedly, by those who practice intense physical exercise at least 150 minutes per week, or moderate exercise for 75 minutes per week, and by non-smoking women.2 Review of the evidence reveals that compilation of traditional risk factors and cardiovascular risk scores underestimates the risk in women. Therefore, ongoing areas of research are focusing on novel markers of cardiovascular risk. These novel cardiovascular risk biomarkers have been selected because their increased plasma levels worsen endothelial dysfunction and inflammation, both being key players in the pathogenesis of microvascular angina, which is a common phenomenon in women.1 The Women’s Health Initiative hormone trials showed that at least 18 new biomarkers are useful in estimating cardiovascular risk in postmenopausal women. These are lipoprotein (a), homocysteine, insulin, C-reactive protein (CRP), E-selectin, interleukin-6, matrix metalloproteinase-9, fibrin D-dimer, factor VIII, plasminogen activator inhibitor-1 antigen, prothrombin fragment 1.2, plasmin–antiplasmin complex, thrombin-

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activatable fibrinolysis inhibitor, von Willebrand factor, fibrinogen, haematocrit, leukocyte and platelet counts.10 These novel biomarkers of cardiovascular risk are classified into three categories: inflammatory markers, haemostasis markers, and other biomarkers.

Inflammatory markers High-sensitivity C-reactive protein (hs-CRP) The latest European guidelines on CVD prevention in clinical practice (2012) recommend the determination of high-sensitivity CRP levels as part of the refined risk assessment in patients with an unusual or moderate CVD risk profile (class IIB, level B).11 Normal values for this inflammatory factor are below 2 mg/dl. CRP levels in women are higher than in men, especially during puberty.2 The JUPITER trial reported that an hs-CRP value over 2 mg/dl in association with a low-density lipoprotein (LDL) cholesterol value below 130 mg/dl in women without cardiovascular pathology increases the risk of cardiovascular events.12 Moreover, high levels of CRP in women without cardiovascular disease are important predictors for the development of fatal heart attack and stroke.13 The greater the number of cardiovascular risk factors that apply to a woman, the higher her hs-CRP level.13 Elevated CRP levels have been associated with the presence of the metabolic syndrome, diabetes and chronic heart failure. Furthermore, recent studies show that a high CRP value is correlated with an increased incidence and prevalence of auto-immune diseases in women, such as rheumatoid arthritis and lupus erythematosus.3-6 The Women’s Health study demonstrated that the addition of hs-CRP to the Framingham score improved the predictive accuracy of cardiovascular risk, especially in women with a 5–20% risk in 10 years.14 Evidence from the Women’s Ischemia Syndrome Evaluation, a prospective study, reported that high levels of amyloid serum A, IL-6, sICAM1 and CRP had the highest predictive accuracy in 27 347 postmenopausal women apparently without cardiovascular disease.15 The guidelines do not however recommend routine evaluation of this inflammatory biomarker, CRP.2,11

Fibrinogen High levels of fibrinogen are associated with an increased risk of cardiovascular disease in both men and women, but there are still substantial gender-specific differences.6,13 On one hand, plasma fibrinogen levels increase with menopause, but also during the use of oral contraceptives and pregnancy.16,17 On the other hand, hormone replacement therapy lowers serum levels of fibrinogen.16 The latest European guidelines on cardiovascular disease prevention in clinical practice recommend the determination of fibrinogen levels as part of a refined risk assessment in patients with an unusual or moderate CVD risk profile (class IIB, level B).11

Interleukin-6 (IL-6) IL-6 stimulates hepatic release of CRP and fibrinogen, both acute-phase reactants involved in the process of atherosclerosis and atherothrombosis. Unfortunately, there are contradictory

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data regarding the role of IL-6 in the development of coronary heart disease in women.10,17 Atherosclerosis reported from the British Women’s Heart and Health study that the level of this cytokine was not directly associated with the risk of coronary heart disease.18 Interestingly, the Women’s Health Initiative showed a direct correlation between high levels of IL-6 and ischaemic heart disease.10 Undoubtedly, cardiovascular risk was not assessed only by measuring the IL-6 plasma levels, but also by determining other cardiovascular risk factors.10

Matrix metalloproteinase-9 (MMP-9) MMP-9, along with CRP, IL-6 and increased levels of leukocytes may provide accuracy in the prediction of developing coronary heart disease in women.10,17,19

E-selectin Various studies impugn the relationship between E-selectin and cardiovascular risk.17,19 On the other hand, there is evidence to support the predictive value of E-selectin for cardiovascular events.17,19,20

Haemostasis markers There are sufficient data concerning the association of D-dimer, coagulation factor VII, von Willebrand factor and fibrinogen levels with the risk of coronary heart disease in women (after statistical adjustments for traditional risk factors).21 Studies demonstrated the presence of high levels of coagulation factor VII in women suffering from angina or other cardiovascular diseases.22-25 However, the most eloquent reports support the use of D-dimer in estimating prognosis of cardiovascular death and other events in women.26

Plasminogen activator inhibitor-1 (PAI-1) Recent studies identified lower PAI-1 levels in premenopausal than postmenopausal women.16,17 The concentration of PAI-1 was lower in women taking hormone replacement therapy, compared with non-users.6,16 Gene-specific differences and changes in PAI-1 values during the postmenopausal years may be related to PAI-1 gene polymorphism. The 4G/5G mutation was found more frequently among postmenopausal women with coronary heart disease than in premenopausal women.16

Lipoprotein (a) [Lp(a)] As is well known, elevated levels of Lp(a) increase the risk of ischaemic heart disease in both men and women. Investigators demonstrated a clear association between Lp(a), LDL cholesterol, hypertension, hyperhomocysteinaemia and hyperfibrinogenaemia in men. Also in women an increase in Lp(a) levels with age has been reported.6 Notably, Lp(a) is an emerging cardiovascular risk factor in both pre- and postmenopausal women as it contributes to the formation of atherosclerosis. Sometimes high levels of Lp(a) are correlated with high CRP levels.27

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High Lp(a) values together with abnormal blood lipid levels are risk factors for cardiovascular disease in women, even in those under 60 years.16 New research on women offers strong evidence that heart attack risk increased as Lp(a) levels rose.28

Lipoprotein-associated phospholipase A2 (Lp-PLA2) Recent data confirm the involvement of Lp-PLA2 in the development of atherosclerosis by modifying the affinity of LDL particles for extracellular matrix proteins.30-32 Moreover, Lp-PLA2 favours lipid accumulation in arterial walls, lipid peroxidation, and hydrolysis of lysophospholipids and free fatty acids.33,34 Lp-PLA2 may be identified as an independent risk factor for rupture of atheroma plaque and thrombo-embolic events.12 The latest European guidelines on cardiovascular disease prevention in clinical practice recommend the determination of Lp-PLA2 values as part of a refined risk assessment in patients at high risk of a recurrent acute atherothrombotic event (class IIB, level B).11 The 2010 ACCF/AHA Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults reported that calculation of Lp-PLA2 levels may be reasonable for cardiovascular risk assessment in intermediaterisk asymptomatic adults (class IIb level B).35 The recent Nurses’ Health study showed that levels of Lp-PLA2 were significantly associated with the incidence of ischaemic heart disease in women.36 According to some research results, women have higher levels of secretory phospholipase A2 (sPLA2) than men. It was reported that elevated sPLA2 levels were correlated with high CRP levels.27,37

Homocysteine In general, women present with lower homocysteine values than men, but elevation occurs during the menopausal years.16,38 Also, a number of studies suggested a relationship between serum homocysteine levels and the presence of coronary artery disease in women, but not in men.14 Therefore, it represents a stronger atherogenic factor in women than in men.16 Other studies however did not identify homocysteine as a significant factor in predicting statistical risk of coronary heart disease after adjustment for traditional risk factors, even though they found a positive correlation between this biomarker and ischaemic heart disease.38 Nevertheless, the latest European guideline on cardiovascular disease prevention in clinical practice states that homocysteine may be measured as part of a refined risk assessment in patients with an unusual or moderate CVD risk profile (class IIB, level B).11 The measurement of serum homocysteine levels is not part of the routine screening process for cardiovascular risk assessment.11

Other markers Natriuretic peptides The Framingham Offspring study showed that 10 elevated biomarkers, and high B-type natriuretic peptides (BNP) indicated cardiovascular risk.39 On the other hand, the Swedish Malmö diet and cancer cohort showed that only BNP and mid-region pro-adenomedulin levels were associated with a doubled cardiovascular risk.40

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The 2012 ESC guidelines for the management of heart failure revealed that BNP, N-terminal pro B-type natriuretic peptide (NT-proBNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels showed usefulness in detecting heart failure patients, a differential diagnosis of dyspneoa and risk stratification.41 The KORA study included 1 005 women and men aged between 25 and 75 years. The goal of this study was to determine the variation in the NT-proBNP and BNP levels in a 10-year period. They reported a strong correlation between gender, age and plasma levels of natriuretic peptides. Both NT-proBNP and BNP serum concentrations recorded an elevation during the follow-up period, especially in women.42 However, it has been shown that a BNP value that exceeds 500 pg/ml represents a stronger predictor of death in women than men with heart failure.43 Growth differentiation factor-15 (GDF-15) is a novel biomarker under investigation, which is synthesised in ischaemic myocytes. There is evidence that it strongly indicates an increased risk of cardiovascular death.44

Conclusion Despite the use of these novel cardiovascular risk factors, the presence of hypertension, diabetes, physical inactivity and inflammatory markers remain the most potent cardiovascular risk factors in women, regardless of age. Novel cardiovascular risk factors may play a decisive role in the early diagnosis of ischaemic heart disease, especially in women with suspected myocardial ischaemia, but without electrocardiographic, echocardiographic or angiographic findings. However, their routine measurement is difficult to implement. The guidelines regarding coronary artery disease in women could suggest the determination/evaluation of these novel cardiovascular risk factors when a differential diagnosis should be considered.

References 1.

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Newby LK, Douglas PS. Cardiovascular disease in women. In: Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th edn. Ed Saunders, 2011: 1757–1769. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women – 2011 update: a guideline from the American Heart Association. Circulation 2011; 123: 1243–1262. Alfonso F, Bermejo J, Segovia J. Cardiovascular disease in women. Why now? Rev Esp Cardiol 2006; 59: 259–263. Stramba-Badiale M, Fox KM, Priori SG, et al. Cardiovascular diseases in women: a statement from the policy conference of the European Society of Cardiology. Eur Heart J 2006; 27: 994–1005. Wenger NK, Shaw LJ, Vaccarino V. Coronary heart disease in women: update 2008. Clin Pharmacol Ther 2008; 83: 37–51. Pilote L, Dasgupta K, Guru V, et al. A comprehensive view of sexspecific issues related to cardiovascular disease. Can Med Assoc J 2007; 176: S1–S41. Andreotti F, Marchese N. Women and coronary heart disease. Heart 2008; 94: 108–116. Anand S, Islam S, Rosengren A, et al. Risk factors for myocardial infarction in women and men: insights from the INTERHEART study.

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Eur Heart J 2008; 29: 932–940. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe: epidemiological update. Eur Heart J 2013; 34: 3028–3034. Kim HC, Greenland P, Rossouw JE, et al. Multimarker prediction of coronary heart disease risk: The Women’s Health Initiative. J Am Coll Cardiol 2010; 55: 2080–2091. Perk J, De Backer G, Gohlke H, et. al. Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Prev Cardiol 2012; 19: 585–667. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and metaanalysis of women from primary prevention trials. Circulation 2010; 121: 1069–1077. Bermudez EA, Rifai N, Buring J, Manson JE, Ridker PM. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler Thromb Vasc Biol 2002; 22: 1668–1673. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006; 145: 21–29. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health – National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008; 93: 1276–1284. Stangl V, Baumann G, Stangl K. Coronary atherogenic risk factors in women. Eur Heart J 2002; 23:1738–1752. Mitu F, Pop D, Zdrenghea D. Particularităţi ale bolilor cardiovasculare la femei. Ed. Clusium. Cluj-Napoca, 2012. Fraser A, May M, Lowe G, et al. Interleukin-6 and incident coronary heart disease: results from the British Women’s Heart and Health Study. Atherosclerosis 2009; 202: 567–572. Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008; 5: 78. Lowe GD. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 2005; 3:1618–1627. Woodward M, Rumley A, Welsh P, MacMahon S, Lowe G. A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease. J Thromb Haemost 2007; 5:1795–1800. Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294:1799–1809. Rossouw JE, Cushman M, Greenland P, et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the Women’s Health Initiative trials of hormone therapy. Arch Intern Med 2008; 168: 2245–2253.

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24. Woodward M, Rumley A, Welsh P, MacMahon S, Lowe G. A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease. J Thromb Haemost 2007; 5:1795–1800. 25. Smith A, Patterson C, Yarnell J, Rumley A, Ben-Shlomo Y, Lowe G. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study. Circulation 2005; 112: 3080–3087. 26. Danesh J, Whincup P, Walker M, et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation 2001; 103: 2323–2327. 27. Rana JS, Cote M, Després JP, et al. Inflammatory biomarkers and the prediction of coronary events among people at intermediate risk: the EPIC-Norfolk prospective population study. Heart 2009; 95: 1682–1687. 28. Wassertheil-Smoller S, Kooperberg C, McGinn AP, et al. Lipoproteinassociated phospholipase A2, hormone use, and the risk of ischemic stroke in postmenopausal women. Hypertension 2008; 51: 1115–1122. 29. Hatoum IJ, Cook NR, Nelson JJ, Rexrode KM, Rimm EB. Lipoproteinassociated phospholipase A2 activity improves risk discrimination of incident coronary heart disease among women. Am Heart J 2011; 161: 516–522. 30. Camejo G, Hurt-Camejo E, Wiklund O, Bondjers G. Association of apo B lipoproteins with arterial proteoglycans: pathological significance and molecular basis. Atherosclerosis 1998; 139: 205–222. 31. Sartipy P, Camejo G, Svensson L, Hurt-Camejo E. Phospholipase A(2) modification of low density lipoproteins forms small high density particles with increased affinity for proteoglycans and glycosaminoglycans. J Biol Chem 1999; 274: 25913–25920. 32. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A(2) induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb Vasc Biol 2001; 21: 1053–1058. 33. Neuzil J, Upston JM, Witting PK, Scott KF, Stocker R. Secretory phospholipase A2 and lipoprotein lipase enhance 15-lipoxygenaseinduced enzymic and nonenzymic lipid peroxidation in low-density lipoproteins. Biochemistry 1998; 37: 9203–9210. 34. Oestvang J, Bonnefont-Rousselot D, Ninio E, Hakala JK, Johansen B, Anthonsen MW. Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity. J Lipid Res 2004; 45: 831–838. 35. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010; 56:50–103. 36. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol 1989; 129: 687–702. 37. Rosenson RS, Hurt-Camejo E. Novel therapeutic concepts: Phospholipase A2 enzymes and the risk of atherosclerosis. Eur Heart J 2012; 33: 2899–2909. 38. Burke AP, Farb A, Malcom GT, et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998; 97: 2110–2116. 39. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006; 355: 2631–2639. 40. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the

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community. J Am Med Assoc 2009; 302: 49–57. 41. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et. al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787–1847. 42. Luchner, A., Behrens, G., Stritzke J, et al. Long-term pattern of brain natriuretic peptide and N-terminal pro brain natriuretic peptide and its

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determinants in the general population: contribution of age, gender, and cardiac and extra-cardiac factors. Eur J Heart Fail 2013; 15: 859–867. 43. Christ M, Laule-Kilian K, Hochholzer W, et al. Gender-specific risk stratification with B-type natriuretic peptide levels in patients with acute dyspnea: insights from the B-type natriuretic peptide for acute shortness of breath evaluation study. J Am Coll Cardiol 2006; 48: 1808–1812. 44. Ge Y, Wang TJ. Identifying novel biomarkers for cardiovascular disease risk prediction. J Intern Med 2012; 272: 430–439.

The 8th Annual Meeting of the National Scholarly Editors’ Forum of South Africa Wednesday 30 July 2014 Venue: Belmont Square Conference Centre, Rondebosch, Cape Town We are pleased to announce that the 8th annual meeting of the National Scholarly Editors’ Forum of South Africa will be held at the Belmont Square Conference Centre, Rondebosch, Cape Town on Wednesday 30 July 2014 from 10:00–16:30. The annual meeting is an opportunity for journal editors to exchange information and knowledge in our field. It is also an exceptional occasion to meet not only our disciplinary peers, but other experts who share the same interests. The ad hoc organising committee will draft the preliminary agenda and if you have any agenda items for discussion, please submit such items to me, Gugulethu (Gugulethu@assaf.org.za). In addition, if there are specific articles, research or reports that you would like to share with editors at this meeting, please send them to me as well. Please note that there are limited travel grants available. Please submit a motivation to me on Gugulethu@assaf.org.za. If you seek clarity on any NSEF-related matter, please contact Mrs Susan Veldsman at ASSAf on susan@assaf.org.za or 012 349-6611.

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Industry News AstraZeneca Pharmaceuticals launches in Zambia After months of planning, we are pleased to announce that AstraZeneca Pharmaceuticals is now officially operational in Zambia. As a global biopharmaceutical company, AstraZeneca touches many people’s lives by providing innovative medicines for some of the world’s most serious diseases. We are inspired and optimistic that we now find ourselves in a position where we can bring our healthcare solutions to the people of Zambia; meaningful solutions that will help us deliver on our promise of ‘better health for all’. We recognise the magnitude of the healthcare problems we face as a continent – without doubt, non-communicable diseases (NCDs) are the scourge of Africa – and AstraZeneca is committed to finding ways to treat and prevent the spread of these serious illnesses. We believe our commitment to making a success of our entry into the Zambian market is an important step towards the realisation of this goal and in turn, the full potential of Africa. By partnering with local healthcare practitioners and the larger medical community, we hope to gain a deeper understanding of the medical challenges facing the country, and look forward to sharing and collaborating with Government in this process. The timing of AstraZeneca Pharmaceuticals’ launch into Zambia could not have been better: the African continent is sitting on a veritable NCD time bomb with cardiovascular diseases, diabetes,

obesity, oncology and smoking-related illnesses becoming increasingly prevalent. ‘There is a huge unmet medical need on the continent, and Zambia is no different. AstraZeneca has the right medical expertise and products to make a meaningful difference, particularly in the areas of non-communicable diseases’, reports Karl Friberg, AstraZeneca company president, South Africa and sub-Saharan Africa. AstraZeneca is one of only a handful of pure-play biopharmaceutical companies to span the entire value chain of a medicine from discovery, early- and late-stage development, to manufacturing and distribution, as well as the global commercialisation of primary-care and speciality-care medicines that transform lives. The company will initially be focusing on providing cardiovascular, respiratory and gastrointestinal drugs to the Zambian market and will keep expanding its product portfolio to cover diseases such as oncology and diabetes. As a global ethical company, AstraZeneca invests over US$4 billion in research and development each year in order to search for solutions to unmet medical needs. The company has a strong pipeline in place, particularly in respiratory medicine, infection, oncology and diabetes, with plans to launch five new diabetes brands plus a drug for acute coronary syndrome in the near future. Heading up the all-local team in Zambia is a highly experienced country leader (Tania Nyirongo). Future employment opportunities for Zambians are good,

World Health Organisation NCD key facts • NCDs kill more than 36 million people each year. Some 80% (29 million) of all NCD deaths occur in low- and middle-income countries. • More than nine million of all deaths attributed to NCDs occur before the age of 60; 90% of these ‘premature’ deaths occurred in low- and middleincome countries.

• Cardiovascular diseases account for most NCD deaths, or 17.3 million people annually, followed by cancers (7.6 million), respiratory diseases (4.2 million), and diabetes (1.3 million1). • These four groups of diseases account for around 80% of all NCD deaths. • They share four risk factors: tobacco use, physical inactivity, the harmful use of alcohol and unhealthy diets.

particularly as the business grows organically, at which point additional medical sales representatives will be required. ‘We are totally committed to the success of the business in Zambia’, says Friberg. ‘Our intention is to make a difference to the healthcare industry in Zambia and to this end we will be bringing in three international speakers to address the local medical community on the latest treatments in the areas of oncology, and gastrointestinal and respiratory diseases as part of our launch. We also intend to host regular symposiums and product launches and to ensure close communication with the medical community through our medical sales reps.’ The company is already operational in 11 sub-Saharan African countries, including Ghana, Nigeria, Kenya, Ethiopia, Uganda, Tanzania, Angola, Mozambique, Botswana, Namibia and Mauritius as well as South Africa. It plans to launch in Rwanda next. A scientific leader in its field, AstraZeneca manufactures in 16 countries and is committed to ensuring a reliable supply of medicines wherever they are needed. Operational in over 100 countries and employing more than 51 000 people, its medicines are used by millions of patients globally.

For further information or to set up interviews, contact Kedi Motshedi. Tel: (011) 465-9815, Cell: 072 979 785, e-mail: kedi@simonsayscom.co.za.

References 1.

Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 19902010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 2012; 380(9859):2224-2260.

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Cardio News Bridging the divide at the 2014 annual SA Heart Congress The 15th annual SA Heart Congress will focus on bridging the divide between best practice and the challenges faced in implementing these ideals. To be held at the International Convention Centre in Durban, from 16–19 October 2014, the congress will be hosting leading international faculty as well as local experts, and for the first time a dedicated team from the European Society of Cardiology (ESC). The ESC faculty will share some of the key clinical issues (hot topics) and late-breaking clinical trials from their recent 2014 congress. Although cardiovascular disease (CVD) has always been at the forefront of research and development, course director, Dr Sajidah Khan comments that innovation in the pharmacology domain has plateaued over the past decade. The opening plenary session will focus on novel approaches in CVD research, linking molecular science to clinical cardiology. Not forgetting the basics, Dr Khan says ‘Confusion has arisen in the ranks regarding basic entities, such as what constitutes high blood pressure and what the therapeutic targets should be for treating high lipid levels’. The differing

viewpoints will be discussed during one of the plenary sessions. In addition, she points out ‘Although cardiology is now very high tech on one hand, on the other hand there is also a divergence of opinion with regard to fundamentals, such as what constitutes optimal nutrition for good cardiovascular health’ – another congress topic. She hopes to generate healthy debate on the issue. The topical subject of nutriceuticals, and whether they have a role to play in cardiac health, is also earmarked for discussion. To get delegates up to speed with current technology, the international faculty will present on the latest innovations in bio-absorbable scaffolding and renal denervation, as well as aspects of pacing and electrophysiology. The current status quo with regard to heart transplantation in South Africa, in both the public and private health sectors, should also generate much discussion. In addition to the mainstream programme, pre-congress workshops on Thursday 16 October have been devoted to updates for non-cardiologists, particularly catering to the needs of general practitioners, as well as a comprehen-

sive echocardiography workshop by a prominent faculty from the Mayo Clinic. Parallel sessions will also be run for the individual cardiac societies, focusing on their areas of specific interest, which will include paediatric cardiology, cardiac arrhythmia, heart failure, cardiac imaging, cardiovascular research, cardiothoracic surgery, and the allied professionals associated with our discipline. The 2014 SA Heart Congress hopes to address a larger audience this year, with cardiac anaesthetists participating in a novel session titled ‘Let the team meet’. ‘Medical professionals with a special interest in cardiovascular disease cannot afford to miss this congress’, Dr Khan concludes. ‘The faculty line-up is outstanding and they have condensed the most up-to-date information into just 3.5 days. An added bonus is that Durban is one of the few cities in the world where you get a major urban metropolis located within a sub-tropical resort!’

For more information on the 2014 SA Heart Congress, visit www.saheart.org/congresss2014, or contact Europa Organisation Africa on (011) 325-0020, or email: info@eoafrica.co.za.

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Case Report Delayed embolisation of Amplatzer ASD closure device caused partial obstruction of left ventricular outflow tract Sang-Hoon Kim, Kyung Ho Kim, Yeong Min Lim, Jae-Youn Moon, Woo-In Yang, In Jai Kim, Sang-Wook Lim Abstract A 54-year-old male presented with symptoms of dyspnoea, and oedema of the lower extremities. Transthoracic echocardiography (TTE) revealed secondum-type atrial septal defect (ASD). He successfully received a 30-mm Amplatzer ASD closure device percutaneously. Echocardiography immediately after the procedure and the next day showed a wellpositioned device. He was discharged the next day on 100 mg aspirin daily and warfarinisation due to atrial fibrillation. A month later, he revisited the hospital due to recurrence of dyspnoea and a grade 2 systolic murmur was heard on the left parasternal border. A chest X-ray showed abnormal location of the closure device and TTE revealed re-appearance of the ASD and an embolised Amplatzer device in the left ventricular outflow tract (LVOT) with partial obstruction. He requested surgery to remove the Amplatzer device and received an ASD patch repair, tricuspid valve repair and modified Maze operation concurrently. He is now in routine follow up without any other complications. Keywords: atrial septal defect, closure device, embolisation Submitted 7/2/14, accepted 22/4/14 Cardiovasc J Afr 2014; 25: e1â&#x20AC;&#x201C;e3

www.cvja.co.za

DOI: 10.5830/CVJA-2014-019

Percutaneous atrial septal closure with a closure device has been proven safe and effective, and has become the standard treatment for secondum-type atrial septal defect (ASD). Transcatheter ASD closure is a relatively safe procedure with a low complication rate. However some complications can occur, such as device embolisation, erosion, pericardial effusion with tamponade, thrombus, stroke and endocarditis.1

Department of Cardiology, CHA Bundang Medical Centre, CHA University, Seongnam, Korea Sang-Hoon Kim, MD Kyung Ho Kim, MD Yeong Min Lim, MD Jae-Youn Moon, MD Woo-In Yang, MD In Jai Kim, MD Sang-Wook Lim, MD, swlim@cha.ac.kr

The reported rate of device embolisation is about 0.55 to 1.7%.2 Generally, most cases of device embolisation are apparent during the procedure, but delayed embolisation may also occur.1 We report on this rare complication of an ASD closure device, which occurred about a month after successful implantation. It caused partial obstruction of the left ventricular outflow tract (LVOT).

Case report A 54-year-old male visited the out-patient clinic due to symptoms of dyspnoea, and oedema of the lower extremities. He showed atrial fibrillation on electrocardiography, and cardiomegaly on chest X-ray. Transthoracic echocardiography (TTE) was performed, which revealed a secondum-type atrial septal defect (ASD). The estimated size of the ASD on TTE was 23 mm, and a markedly enlarged right atrium and right ventricle, moderate pulmonary hypertension (right ventricular systolic pressure: 53.3 mmHg) and severe tricuspid regurgitation were observed. He was admitted for percutaneous ASD closure. Transoesophageal echocardiography (TEE) confirmed the presence of a moderately large secundum ASD that measured 25 mm, and all the rims of the ASD were adequate for device closure. The procedure was performed under general anaesthesia with TEE guidance. Right-side catheterisation revealed Qp/Qs of 2.22. A 34-mm balloon was positioned across the defect and measured with both quantitative angiography and TEE at 25 mm. A 30-mm Amplatzer ASD closure device was implanted successfully. Echocardiography immediately after the procedure (Fig. 1a) and the next day (Fig. 1b) showed a well-positioned device. The patient was discharged the following day on 100 mg aspirin daily and warfarinisation due to atrial fibrillation. A month later, he revisited the hospital due to recurrence of dyspnoea, and a grade 2 systolic murmur was heard on the left parasternal border. Chest X-ray showed abnormal location of the closure device (Fig. 2). TTE revealed reappearance of the ASD and an embolised Amplatzer device in the LVOT with partial obstruction (Fig. 3). As the Amplatzer device was trapped in the LVOT, it would be dangerous to retrieve it percutaneously, so we requested surgery to remove the device. The patient received an ASD patch repair, tricuspid valve repair and modified Maze operation concurrently. He is now in routine follow up without any other complications.

Discussion King and Mills reported on the first patient to receive percutaneous ASD closure in 1974.3 Since then the technology

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Fig. 1. T he well-positioned ASD closure device (arrow). Transoesophageal echocardiography immediately after the procedure (A), and transthoracic echocardiography the following day (B).

has evolved and percutaneous closure of ASDs has been proven to be safe and effective. It has become the standard treatment for secondum-type ASD. Nowadays, percutaneous ASD closure has largely replaced surgical treatment of secundum ASD, except in the case of large defects (â&#x2030;¤ 38-mm diameter), insufficient septal rims, or insufficient left atrial size to accommodate a device. An adequate septal rim requires 5 mm of septal tissue from the ASD to the superior and inferior vena cava, right upper and lower pulmonary veins, coronary sinus and mitral/tricuspid valves.1

Fig. 2. C hest radiograph of the displaced Amplatzer closure device (arrow), compared with the usual position of the closure device (circle).

The reported complication rate of percutaneous ASD closure is relatively low; several reports reveal a 1.2 to 2.5% major complication rate and a 3.4 to 6.1% minor complication rate.4-6 Major complications include device embolisation, erosion, pericardial effusion with tamponade, device thrombus, stroke and endocarditis. Minor complications include excessive inflammatory reactions, cardiac arrhythmias and complications of the femoral access site. The reason for device embolisation has not been clarified, however, suggestions are the type of device used, larger size of defect, thin rim of atrial tissue, mobility of the implanted device, use of an undersized device, and deficiency or absence of the aortic rim.7-9 The aortic rim is important and a margin less than 5 mm may predispose to both early and late device embolisation. Another potential cause of late device embolism is acute change in intracardiac pressure due to physical activity. A sudden increase in afterload to the left heart in conjunction with diminished right heart filling (Valsalva) may cause the migration of the device to the right, and subsequently to the pulmonary artery. Devices usually embolise in the main pulmonary artery.9 Some physicians recommend six months of abstinence from strenuous exercise to avoid device embolisation.10 However in our case, the device embolised to the left side and the patient had not done strenuous exercise during the follow-up period. We could not determine the exact reason for delayed embolisation of our patient, however, since our patient had received his ASD at a relatively advanced age, he had already developed complications such as atrial fibrillation with an enlarged right atrium, increased right ventricular systolic pressure and severe tricuspid regurgitation. In our opinion, the severe tricuspid regurgitation led to an increase in right atrial pressure and this increase may have been one of the mechanisms for device displacement to the left side.

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Fig. 3. T ransthoracic echocardiography of the displaced Amplatzer closure device (arrow), which was trapped in the LVOT, with partial obstruction.

Most cases of displacement of the closure device after successful implantation occur relatively early.11,12 However, delayed embolisation may happen and it can be dangerous. Most embolised devices can be retrieved by percutaneous techniques,13,14 however, some patients require surgical removal and subsequent surgical closure of the ASD. We report on the delayed and silent embolisation of an Amplatzer device, which caused partial obstruction of the LVOT one month after successful percutaneous ASD closure. There is a possibility that the embolisation had occurred earlier and symptoms had only developed later. However, in the out-patient department on follow up 14 days after his discharge, the patient had not complained of any symptoms and there was no systolic murmur. This was only heard at the second visit due to symptom recurrence at one month. Some reports recommend routine TTE during the follow-up period,10 however, careful physical examination or a simple chest X-ray could replace routine echocardiography, with a lower cost expenditure, as seen in our case.

Conclusion Percutaneous ASD closure is a relatively safe procedure with a low complication rate. However, even after successful implantation, as in our case, complications such as device embolisation may occur at a later stage. Therefore close monitoring, with a physical examination, chest X-ray and/or TTE, should be continued for a longer period of time after successful implantation of an ASD closure device. This study was supported by a grant from the Korea Healthcare Technology R+D project, Ministry of Health, Welfare and Family Affairs, Republic of Korea (HI13C1398).

3. 4.

10.

11.

12. 13.

References 1. 2.

Tobis J, Shenoda M. Percutaneous treatment of patent foramen ovale and atrial septal defects. J Am Coll Cardiol 2012; 60: 1722–1732. Levi DS, Moore JW. Embolization and retrieval of the Amplatzer septal occluder. Catheter Cardiovasc Intervent 2004; 61: 543–547.

14.

King TD, Mills NL. Nonoperative closure of atrial septal defects. Surgery 1974; 75: 383–388. Du ZD, Hijazi ZM, Kleinman CS, Silverman NH, Larntz K. Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol 2002; 39: 1836–1844. Jones TK, Latson LA, Zahn E, et al. Results of the U.S. multicenter pivotal study of the HELEX septal occluder for percutaneous closure of secundum atrial septal defects. J Am Coll Cardiol 2007; 49: 2215–2221. Fiarresga A, De Sousa L, Martins JD, et al. Percutaneous closure of atrial septal defects: a decade of experience at a reference center. Portuguese J Cardiol 2010; 29: 767–780. Misra M, Sadiq A, Namboodiri N, Karunakaran J. The ‘aortic rim’ recount: embolization of interatrial septal occluder into the main pulmonary artery bifurcation after atrial septal defect closure. Interact Cardiovasc Thorac Surg 2007; 6: 384–386. Berdat PA, Chatterjee T, Pfammatter JP, Windecker S, Meier B, Carrel T. Surgical management of complications after transcatheter closure of an atrial septal defect or patent foramen ovale. J Thorac Cardiovasc Surg 2000; 120: 1034–1039. Chessa M, Carminati M, Butera G, et al. Early and late complications associated with transcatheter occlusion of secundum atrial septal defect. J Am Coll Cardiol 2002; 39: 1061–1065. Mashman WE, King SB, Jacobs WC, Ballard WL. Two cases of late embolization of Amplatzer septal occluder devices to the pulmonary artery following closure of secundum atrial septal defects. Catheter Cardiovasc Intervent 2005; 65: 588–592. Balbi M, Pongiglione G, Bezante GP. Percutaneous rescue of left ventricular embolized amplatzer septal occluder device. Catheter Cardiovasc Intervent 2008; 72: 559–562. Chan KT, Cheng BC. Retrieval of an embolized amplatzer septal occluder. Catheter Cardiovasc Intervent 2010; 75: 465–468. Poommipanit P, Levi D, Shenoda M, Tobis J. Percutaneous retrieval of the locked helex septal occluder. Catheter Cardiovasc Intervent 2011; 77: 892–900. Errahmouni A, Hattaoui ME, Drighil A, Boumzebra D. Silent embolization of an Amplatzer septal occluder into the left ventricular outflow tract requiring emergent surgical retrieval. Ann Ped Cardiol 2012; 5: 89–91.

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Case Report Emergency endovascular aortic repair of a ruptured mycotic aorto-iliac aneurysm presenting with lumbar radiculopathy Ting-Ying Lee, Chien-Sung Tsai, Yi-Ting Tsai, Chih-Yuan Lin, Yi-Chang Lin, Po-Shun Hsu Abstract Ruptured abdominal aortic aneurysm is life-threatening without immediate management. The initial clinical presentation is non-specific and impending rupture is easily missed, especially without a CT scan. We present a case of a 56-year-old man with low-back pain and left lower-extremity numbness, which was diagnosed as a herniated intervertebral disc (HIVD) with left acute sciatica syndrome. He also complained of persistent fever and abdominal discomfort. Routine blood work-up revealed leukocytosis and decreasing haemoglobin levels. CT angiography (CTA) showed impending rupture of the left aorto-iliac aneurysm. We therefore performed endovascular aneurysm repair (EVAR). Blood culture revealed Salmonella enterica, for which he received antibiotics. No acute sciatica syndrome was present immediately after the EVAR. No EVAR-related complications were noted in the one-year CTA follow up. Keywords: endovascular aortic repair, mycotic aortic aneurysm, lumbar radiculopathy Submitted 9/3/14, accepted 25/4/14 Cardiovasc J Afr 2014; 25: e4–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2014-022

Mycotic aortic aneurysms (MAAs) are rare (1–1.8%) in aortic abdominal aneurysms.1 This is a secondary infection with an abnormal aortic dilation and a pre-existing aneurysm, and may result in an intractable infection or fatal complication. It may be caused by direct bacterial inoculation, bacteraemic seeding, contiguous infection, or septic emboli.2

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan Ting-Ying Lee, MD Chien-Sung Tsai, MD Yi-Ting Tsai, MD Chih-Yuan Lin, MD Yi-Chang Lin, MD Po-Shun Hsu, MD, hsuposhun@yahoo.com.tw

The clinical presentation of MAA is non-specific and includes fever, chills and abdominal or back pain, and may therefore lead to delayed diagnosis, resulting in aneurysm rupture and associated fatal complications or mortality. Ruptured MAAs that involve paravertebral soft tissue or the psoas muscle may cause symptoms of lumbosacral radiculopathy, including neurological deficits such as low-back pain, unilateral sciatica, limping, flank pain or paraplegia.3 Here, we present a rare case of a 56-year-old man with a mycotic aortic aneurysm that presented as lumbosacral radiculopathy with acute left sciatica syndrome, which was treated with endovascular aneurysm repair (EVAR) and antibiotics.

Case report The patient was a 56-year-old Taiwanese man who presented to the emergency department with low-back pain radiating to the posterior and lateral aspects of the left lower extremity, which he had experienced over the last week. His vital signs were stable and he had a mild fever (38.5°C). He complained of abdominal fullness but had no obvious tenderness. The straight leg-raising test was positive at 30°C for the left lower extremity. Laboratory tests revealed leukocytosis (white cell count: 15 560 cells/µl) and elevated C-reactive protein (CRP: 17.27 mg/dl). The initial impression was infectious spondylitis, and spinal magnetic resonance imaging (MRI) was performed to confirm the diagnosis. However, abdominal fullness persisted, and decreased haemoglobin levels were noted (Hgb: from 12.6 to 9.7 g/dl) within 12 hours of admission. CT angiography (CTA) revealed a saccular-type aneurysm with an intramural thrombus measuring about 5.5 × 4.3 × 5.7 cm (width, anterior–posterior depth and length) located at the distal abdominal aorta, which resulted in acute haematoma formation in the left lateral aspect of the aneurysm with the left psoas and left iliac muscle extension. The size measured about 7.8 × 4.4 × 8 cm (width, depth and length). The proximal end of the aneurysm was located 6.5 cm inferior to the left renal artery. In addition, total occlusion of the left common iliac artery as well as the proximal portion of the left external iliac artery was noted. The contrast resulted in the development of an image over the distal external iliac and left superficial femoral artery (Fig. 1). We performed acute resuscitation and emergency EVAR. Due to total occlusion of the left common iliac artery, the guide-wire would not pass through the vessel. We implanted an aortic–uni-iliac stent, 24 to 12 mm in diameter and an iliac stent

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Fig. 1. P seudolumen located over the distal aorta to the left of the common iliac artery (white arrow). The left common iliac artery caused total compression and haematoma formation over the left psoas muscle with fat stranding (black arrows).

graft, 14 mm in diameter. We also performed femoral-to-femoral artery artificial graft bypass (8 mm in diameter) due to the total occlusion of the left common iliac artery (Fig. 2). Blood culture revealed Salmonella enterica, which was treated with the antibiotic, Ertapenem at a dose of 1 g/day. His symptoms of radiculopathy were relieved but fever persisted despite surgical intervention and antibiotic treatment for a week. A subsequent abdominal CT revealed a fluid-filled lesion with rim enhancement expanding the left iliac and left psoas muscles. We suspected abscess formation and therefore performed CT-guided percutaneous catheter drainage, following which the fever subsided within three days. After sustained treatment with an intravenous antibiotic (Ertapenem: 1 g/day) for six weeks, and

an oral antibiotic (ciprofloxacin: 500 mg twice per day) for two weeks, he was discharged in a stable condition. There were no EVAR-related complications or recurrent infections noted at the one-year out-patient follow up.

Discussion The clinical non-specific symptoms of mycotic aortic aneurysm present as lumbosacral radiculitis with sciatica and make diagnosis challenging for clinicians.3 When the infection process begins in the aorta, the ulcerated artherosclerotic plaques become infected, followed by thrombi deposits. The vasa vasorum of the arterial wall becomes destroyed, resulting in repeated

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Fig. 2. A n aortic-to-right iliac stent graft was placed (black arrows), and a femoral-to-femoral bypass with a prosthetic graft was performed (white arrow).

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haemorrhage and contiguous spread of the infection to the neighbouring spine or paravertebral soft tissue. This leads to soft tissue swelling and compression of the vertebral neural root, resulting in neurological deficits.3 The clinical approach for diagnosing MAA includes laboratory tests and radiological imaging. On laboratory examination, leukocytosis is found in 64 to 71% of patients,4 and inflammatory markers, including CRP, as well as the erythrocyte sedimentation rate (ESR) are usually elevated. Blood cultures may be negative in 25 to 50% of patients,5 and are therefore not sufficient to exclude an infected aneurysm. An MRI scan may be the most sensitive and specific imaging technique for detecting infected soft tissue, bone destruction and abscess formation in the early stage of infection. However, a disadvantage is its longer duration and inability to easily distinguish rupture of the pseudolumen. Enhanced CT is also useful for diagnosing MAA, and for revealing the pseudolumen, soft tissue swelling, as well as abscess formation, and is of shorter duration. It is optimal for studying infected aneurysms, particularly if the patient’s haemodynamic status is unstable.3 Management of MAA using traditional open aortic repair is a major surgical challenge in diseased patients because of the high associated rates of mortality and morbidity (13–40%).1,6,7 Traditional open aortic repair has a complicated management strategy, including surgical resection and debridement of the infected aorta and surrounding tissues, the use of muscle ﬂaps or omentum to cover the infected ﬁeld, and either an in situ interposition graft or an extra-anatomical bypass. In the report by Chen et al.,3 there were six patients with MAA who presented with radiculopathy (Table 1). Most of the pathogens were Salmonella. The patients were treated with aggressive surgical debridement and aneurysm resection. Four patients survived a two-year follow up; two were walking with walking aids.3 EVAR provides a less invasive approach, lower surgical risk compared to conventional open repair, and more favourable result. It also has the advantage of avoiding a large incision, full heparinisation and extracorporeal circulation, and minimises the need for blood transfusion. However, complex anatomy, an unresected infective aneurysm, and remnant paravertebral soft tissue are the major problems of EVAR. Recurrent infection may result in disastrous consequences, so further antibiotic therapy and adjunct procedures, such as surgical debridement or

Table 1. Summary of clinical details, surgical methods and outcome of six patients with MAA presenting with radiculopathy (from Chen et al.3) Case Age/ No gender Clinical symptoms 1 60/M Back pain with fever

Lesion site Symptom of radicuduration lopathy Pathogen 8 weeks T12–L1 Salmonella

Outcome Survived

50/M

Back pain with fever

2 weeks

L3–L4

Survived

79/M

1 week

L3–L4

72/M

3 weeks

L3–L4

81/M

Back pain with fever, abdominal pulsating mass, lower limb weakness Back pain with fever, abdominal pulsating mass Back pain with fever, abdominal pain

4 weeks

Surgical methods Open surgical aneurysm resection + debridement + vertebral reconstruction Salmonella Open surgical aneurysm resection + debridement Salmonella Open surgical aneurysm resection + Mycobacterium debridement + vertebral reconstruction Salmonella Open surgical aneurysm resection + debridement Streptococcus None

59/F

Back pain with fever, papaplegia

1 week

Staphylococcus None

Survived Survived Died (aneurysm rupture) Died (septic shock)

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percutaneous drainage to eliminate the source of infection are strongly advised.7 The optimal duration of postoperative antibiotic therapy is controversial. It depends on the immune competency of the patients, the specific bacteria involved, the location of the infection, autogenous versus prosthetic graft, and the patient’s response to treatment (white cell count, fever, haemodynamic stability). Most commonly, parenteral antibiotics are administered for two to eight weeks.6 Although postoperative antibiotics cannot ensure that the foci of infection are eradicated, these patients have an improved outcome. Adjunct procedures are also necessary to decrease the rate of persistent infection and achieve therapeutic goals.7

Conclusion EVAR combined with long-term antibiotic therapy and adjunct procedures was the ideal treatment strategy in this case. However, the optimum duration of oral antibiotics treatment is debatable and close follow up is necessary.

References 1.

2. 3.

4. 5.

Corso JE, Kasirajan K, Milner R. Endovascular management of ruptured, mycotic abdominal aortic aneurysm. Am Surgeon 2005; 71: 515–517. Bisdas T, Teebken OE. Mycotic or infected aneurysm? Time to change the term. Eur J Vasc Endovasc Surg 2011; 41: 570; author reply: 1. Chen SH, Lin WC, Lee CH, Chou WY. Spontaneous infective spondylitis and mycotic aneurysm: incidence, risk factors, outcome and management experience. Euro Spine J 2008; 17: 439–444. Moneta GL, Taylor LM, Jr., Yeager RA, et al. Surgical treatment of infected aortic aneurysm. Am J Surg 1998; 175: 396–399. Maeda H, Umezawa H, Goshima M, et al. Primary infected abdominal aortic aneurysm: surgical procedures, early mortality rates, and a survey of the prevalence of infectious organisms over a 30-year period. Surg Today 2011; 41: 346–351. Kan CD, Lee HL, Yang YJ. Outcome after endovascular stent graft treatment for mycotic aortic aneurysm: a systematic review. J Vasc Surg 2007; 46: 906–912. Sorelius K, Mani K, Bjorck M, Nyman R, Wanhainen A. Endovascular repair of mycotic aortic aneurysms. J Vasc Surg 2009; 50: 269–274.

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