CVJA Volume 28 Issue 3 by Clinics Cardive Publishing

MAY/JUNE 2017 VOL 28 NO 3

Spartan

Strength at Spartan Price Up to

35%

more affordable than the originator1

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Cardiometabolic risk factors in sub-Saharan Africa • Myocardial repolarisation with Mediterranean fever • Asthma treatment and elastic properties of the aorta • Community health workers screen for CVD risk • Effects of Ramadan fasting on children’s heart rate • Indirect inflammatory markers in myocardial bridging • Telmisartan and microalbuminuria in diabetes after CABG • Perceptions of radiation safety training in South Africa

50 mg 100 mg

LOSARTAN 50 mg HCTZ 12,5 mg

100 mg 25 mg

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za ZARTAN 50 and 100 mg. Each tablet contains 50, 100 mg losartan potassium respectively. S3 A41/7.1.3/0287, 0289. NAM NS2 08/7.1.3/0067, 0086. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 10 August 2007. ZARTAN CO 50/12,5 and 100/25. Each tablet contains 50, 100 mg losartan potassium respectively and 12,5, 25 mg hydrochlorothiazide respectively. S3 A42/7.1.3/1068, 1069. NAM NS2 12/7.1.3/0070, 0071. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 5 August 2011. 1) Database of Medicine Prices (14 March 2017). Department of Health website. http://www.mpr.gov.za - Accessed on 10 April 2017. ZNCF298/04/2017.

Cardiovascular Journal of Africa . Vol 28, No 3, May/June 2017

LOSARTAN

PUBLISHED ONLINE: • Early repolarisation in a boy with chest pain: myocardial bridging

S U STA I N E D R E LE ASE META B OLI C A LLY N E U T RA L 1

ECG rhythms CPD CPD developed by Prof Rob Scott Millar, Cardiac Clinic, UCT/Groote Schuur Hospital CPD overview: Following the introductory “Approach to Rhythms”, this online educational CPD quiz will consist of a series of ECGs with a variety of important cardiac rhythms. Each will be accompanied by a series of questions, followed by a detailed analysis and explanation. Target audience: Cardiologists, physicians, emergency unit doctors and anaesthetists. Including those studying for FCP and certificate in cardiology. Total time commitment: ± 30 to 60 minutes. Assessment information: A pass mark of 70% is required. A candidate has 60 days to complete the CPD after registration. CPD certificate: A PDF certificate of completion will be issued on successful completion the CPD. CPD enrollment fee: Free / no charge. Important notice: The CPD was made possible by an unrestricted educational sponsorship from Bayer Pharmaceuticals South Africa, which had no control over the content.

only generic 1,5 mg sustained release formulation

R36,70

Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.

For more information please visit www.cvja.co.za

Cardiovascular Journal of Africa For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Dyna Indapamide SR. Each tablet contains 1,5 mg indapamide. S3 A42/7.1/0790. NAM NS2 12/7.1/0138. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 25 November 2011. 1) Weidmann P. Metabolic profile of indapamide sustained-release in patients with hypertension. Drug Safety 2001;24(15):1155-1165. 2) Database of Medicine Prices (10 March 2017). Department of Health website. http://www.mpr.gov.za - Accessed on 10 March 2017. DINE279/03/2017.

AFRICA

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

Vol 28, No 3, MAY/JUNE 2017

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial 139 Radiation safety: time to act SC Brown

Cardiovascular Topics 141 Resveratrol did not alter blood pressure in rats with nitric oxide synthase-inhibited hypertension M Aydin • B Gungor • AS Akdur • HE Aksulu • C Sılan • I Susam • AK Cabuk • G Cabuk 147 Prevalence of selected cardiometabolic risk factors among adults in urban and semi-urban hospitals in four sub-Saharan African countries S Kingue • S Rakotoarimanana • N Rabearivony • FL Bompera 154 Assessment of myocardial repolarisation parameters in patients with familial Mediterranean fever K Karaman • M Karayakalı • E Erken • A Demirtaş • M Öztürk • F Altunkaş • A Arısoy • OE Turan • K Ceyhan • A Çelik 159 Saliva/serum ghrelin, obestatin and homocysteine levels in patients with ischaemic heart disease N Kilic • N Dagli • S Aydin • F Erman • Y Bek • O Akin • SS Kilic • HK Erdemli • H Alacam 165 The effects of treatment in patients with childhood asthma on the elastic properties of the aorta O Bektaş • ZY Günaydin • A Karagöz • R Akgedik • A Bayramoğlu • A Kaya 170 Training community health workers to screen for cardiovascular disease risk in the community: experiences from Cape Town, South Africa T Puoane • S Abrahams-Gessel • TA Gaziano • N Levitt 176

Effects of Ramadan intermittent fasting on North African children’s heart rate and oxy-haemoglobin saturation at rest and during sub-maximal exercise MA Fenneni • I Latiri • A Aloui • S Rouatbi • K Chamari • H Ben Saad

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

Editors

SUBJECT Editors

Editorial Board

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

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

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

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

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

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

182 Assessment of indirect inflammatory markers in patients with myocardial bridging L Cerit

Vol 28, No 3, MAY/JUNE 2017

CONTENTS

186 Symptom-to-balloon time and myocardial blush grade are predictors of left ventricular remodelling after successful primary percutaneous coronary intervention E‑SM Farag • MM Al-Daydamony 191 Telmisartan decreases microalbuminuria in patients with type 2 diabetes mellitus following coronary artery bypass grafting C Furat • R Dogan • G Ilhan • E Bayar • B Ozpak • H Kara • Ş Bozok 196 Perceptions of radiation safety training among interventionalists in South Africa A Rose • WID Rae

Review Article 201

Xanthine oxidase inhibitors in ischaemic heart disease D Zdrenghea • A Sitar-Tǎut • G Cismaru • M Zdrenghea • D Pop

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

e1 Persistent left superior vena cava KW Tyrak • J Hołda • MK Hołda • M Koziej • K Piątek • W Klimek-Piotrowska e5 A rare cause of early repolarisation in an adolescent boy with chest pain: myocardial bridging M Deveci • K Babaoğlu • Ö Kayabey

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

Production Editor

SHAUNA GERMISHUIZEN Tel: 021 785 7178 Cell: 083 460 8535 e-mail: shauna@clinicscardive.com

CONTENT MANAGER

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

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

All submissions to CVJA are to be made online via www.cvja.co.za

Subscriptions for 6 issues:

Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances.

your postal address, e-mail

Postal address: PO Box 1013, Durbanville, RSA, 7551 Tel: 021 976 8129 Fax: 0866 644 202 Int.: +27 21 976 8129

To subscribe to the journal or change elsabe@clinicscardive.com South Africa: R490 (incl VAT) Overseas: $135 Online subscription: R300 The views and opinions expressed in the articles and reviews published are those

Layout: Martingraphix

e-mail: info@clinicscardive.com

Printer: Tandym Print/Castle Graphics

Electronic abstracts available on Pubmed

reflect those of the editors of the Journal

Audited circulation

or its sponsors. In all clinical instances,

ONLINE publishing & coding SERVICES: Design Connection & Active-XML.com

Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact elsabe@clinicscardive.com

of the authors and do not necessarily

medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

139

Editorial Radiation safety: time to act SC Brown It is an acknowledged fact that interventional cardiologists have the highest occupational radiation exposure of all medical professionals. As a matter of fact, interventional cardiac procedures represent the largest contribution of ionising radiation source after computerised tomography and nuclear medicine. Modern therapies and the need for quality radiological imaging have dramatically increased the use of ionising radiological imaging in cardiology. Radiation safety is rapidly becoming an important issue. The first major drive towards this goal gave rise to the establishment of the international radiation protection association (IRPA) in late 2002, leading to the publication of guiding principles for establishing a radiation-protection culture.1 The aim of such a culture is to substantially reduce radiation dose to both patients and staff.

Biological effects of radiation It should be taken into account that patients, technicians, nurses and cardiologists are at risk of these effects. There are two categories of unwanted effects when exposed to ionising radiation: • Deterministic effects: here an identifiable threshold level exists and the severity of effect intensifies with increasing dosage of exposure. Biological effects occur as a result of cell damage and death. Symptoms are related to the extent of cell death. Dermatological effects and cataracts are typical examples of deterministic effects. • Stochastic effects: these follow a linear non-threshold theory, which essentially means these effects occur by chance. There is no minimum exposure, and risk increases linearly with radiation dose received. Cancer in an exposed individual occurs due to the mutation of cells as a result of chromosomal translocations.

Health hazards • Cataracts: posterior sub-capsular cataracts have been reported in 50% of cardiologists and 41% of nurses working in interventional catheterisation laboratories.2 The authors observed that lens changes were associated with several years of work without eye protection and cumulative doses were in the range of 0.1 to 18.9 Sv.

Department of Paediatric Cardiology, University of the Free State, Bloemfontein, South Africa SC Brown, MMed, FCPaed, DCH, gnpdscb@ufs.ac.za

• Brain tumours: several case reports of brain tumours have emerged in the literature and have occurred in more than 31 physicians working in catheterisation laboratories, mostly interventional cardiologists.3-5 Of particular interest is the fact that up to 85% of brain tumours were left sided – the area of the head closest to the X-ray tubes. The physicians in this report were exposed to ionising radiation over a period of 12 to 30 years. • Other: thyroid changes and neoplasms, hypertension, hyperlipidaemia, reproductive and even psychological effects have been described.6-8 Hair loss and skin damage may follow prolonged exposure during fluoroscopic procedures. These vary from temporary erythema to necrosis of the skin and subcutaneous tissues. A single dose of 6–8 Gy on a 5-cm2 field may trigger tissue damage.9 It should be noted that the hands of operators receive the highest exposure during cardiac interventions.

Food for thought The article by Rose et al. (page 196) in this edition of the journal gives a sobering perspective on radiation protection in South Africa.10 The study included public- and private-sector radiologists and cardiologists. It is obvious from the results that a complacency and lack of knowledge regarding radiation safety is prevalent among cardiologists. In essence, the results show that little or no formal education for cardiology fellows regarding radiation protection is offered during training. Even more disconcerting is the fact that even though heads of units (both adult and paediatric cardiology) acknowledged the need for radiation safety measures and training, precious little appears to be done to address the issue. This is compounded by the fact that junior fellows expressed concerns regarding the effects of radiation exposure on their long-term health, and that only one question regarding radiation safety appeared in the national exit examinations for cardiologists.

What should be done? It is mandatory to establish a radiation safety culture for cardiologists. Basic training should be available for all healthcare workers in the catheterisation laboratory, and ongoing radiation safety courses should be obligatory. Unless training units actively promote and examine fellows on radiation safety, little will change. Simple precautions to minimise exposure to patients, staff and operators should be instituted as enshrined in the ALARA (as low as reasonably achievable) principles. The American Heart Association statement on enhancing radiation safety in cardiovascular imaging may be followed as a guideline – clear

140

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

strategies and action plans to reduce exposure to patients and staff should be followed.11 Institutional insensitivity should also be addressed and the proper fundamental principles of radiation protection should be rigidly applied. The profession should be concerned about how interventionists and young cardiologists with long careers ahead of them can avoid the ravages of exposure to ionising radiation. Over a lifetime, how much radiation exposure is acceptable and how much are we at risk of the complications of prolonged and recurrent exposure? The time to act is now.

AFRICA

tion: more cases reported. EuroIntervention 2012; 8: 169–170. 5.

Roguin A, Goldstein J, Bar O, Goldstein JA. Brain and neck tumors among physicians performing interventional procedures. Am J Cardiol 2013; 111: 1368–1372.

Picano E, Vano E, Domenici L, et al. Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure. BMC Cancer 2012; 12: 157.

Marazziti D, Baroni S, Catena-Dell’Osso M, et al. Cognitive, psychological and psychiatric effects of ionizing radiation exposure. Curr Med Chem 2012; 19: 1864–1869.

Kumar G, Rab ST. Radiation safety for the interventional cardi-

References

ologist – a practical approach to protecting ourselves from the dangers

cles/2015/12/31/10/12/radiation-safety-for-the-interventional-cardiolo-

of ionizing radiation. http://www.acc.org/latest-in-cardiology/arti-

IRPA guiding principles for establishing a radiation protection

gist.

culture. URL: http:// http://www.irpa.net/members/IRPA-Guiding%20 Principles%20on%20RP%20Culture%20-2014%20.pdf. 2.

Vano E, Kleiman NJ, Duran A, Romano-Miller M, Rehani MM. Radiation-associated lens opacities in catheterization personnel: results of a survey and direct assessments. J Vasc Interv Radiol 2013; 24: 197–204.

Leyton F, Canevero L, Dourado A, et al. Radiation risks and the importance of radiological protection in interventional cardiology: a systematic review. Rev Bras Cardiol Invasiva 2014; 22: 87–98.

10. Rose A, Ray W. Perception of radiation safety training among interventionalists in South Africa. Cardiovasc J Afr 2017; 196–200.

Roguin A, Goldstein J, Bar O. Brain tumours among interventional

11. Fazel R, Gerber TC, Balter S, et al. Approaches to enhancing radia-

cardiologists: a cause for alarm? Report of four new cases from two

tion safety in cardiovascular imaging. A scientific statement from the

cities and a review of the literature. EuroIntervention 2012; 7: 1081–1086.

American Heart Association. Intervention. Circulation 2014; 130:

Roguin A, Goldstein J, Bar O. Brain malignancies and ionising radia-

1730–1734.

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

AFRICA

141

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Cardiovascular Topics Resveratrol did not alter blood pressure in rats with nitric oxide synthase-inhibited hypertension Mehmet Aydin, Buket Gungor, A Secil Akdur, Hakki Engin Aksulu, Coskun Sılan, Ibrahim Susam, Ali Kemal Cabuk, Gizem Cabuk

Abstract Background: Inhibition of nitric oxide synthase (NOS) is a well-known experimental model of hypertension (HT). It was shown that oxidative stress contributes to the pathogenesis of HT. Resveratrol is a potent anti-oxidant that is found in red grapes, peanuts and red wine. It improves the NO response and increases endothelial NOS expression, which causes endothelium-dependent vasorelaxation as well as renal vasodilation. We aimed to explore the effects of resveratrol on blood pressure, the water–salt balance and sodium excretion as a reflection of renal function in NOS-inhibited rat models. Methods: Thirty-five male Sprague-Dawley rats (200–250 g) were used in this study. In order to obtain hypertension models, an NOS inhibitor, N-nitro-L-arginin (L-NNA) was used. The rats were randomly divided into five groups: controls (given water and 0.8% salty diet) and four groups [given L-NNA, resveratrol (RSV) eluent, RSV, and L-NNA + RSV]. Blood pressures were measured indirectly by the tailcuff method on the first, seventh and 10th days. At the end of

the study protocol (10th day), fluid balance, glomerular filtration rate, fractional sodium excretion, and blood and urine sodium and creatinine levels were measured. Results: At the end of the study protocol, blood pressures were higher in only the L-NNA group (117.8 ± 3.5 vs 149.5 ± 2.1 mmHg; p < 0.05), as expected. Additional applications of RSV with L-NNA could not prevent the increase in blood pressure (122.8 ± 7.3 vs 155.4 ± 4.4 mmHg; p < 0.05). There were no remarkable changes in water–salt balance and renal function with the application of resveratrol. Conclusion: Resveratrol was unable to prevent or reverse blood pressure increase in NOS-inhibited rats.

Keywords: hypertension, NOS, resveratrol, anti-oxidant, sodium excretion Submitted 30/12/14, accepted 10/7/16 Cardiovasc J Afr 2017; 28: 141–146

www.cvja.co.za

DOI: 10.5830/CVJA-2016-069

Department of Cardiology, Tepecik Training and Research Hospital, Izmir, Turkey Mehmet Aydin, MD Ibrahim Susam, MD Ali Kemal Cabuk, MD, kardio.80@hotmail.com

Department of Clinical Trials, Turkish Medicines and Medical Devices Agency, Turkish Ministry of Health, Ankara, Turkey Buket Gungor, MD

Department of Clinical Pharmacology, Canakkale State Hospital, Turkish Ministry of Health, Canakkale, Turkey A Secil Akdur, MD

Department of Pharmacology, School of Medicine, Canakkale Onsekiz Mart University, Terzioglu Campus, Canakkale, Turkey Hakki Engin Aksulu, MD Coskun Silan, MD

Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Terzioglu Campus, Canakkale, Turkey Coskun Silan, MD

Department of Cardiology, Buca Seyfi Demirsoy State Hospital, Izmir, Turkey Gizem Cabuk, MD

Essential hypertension (HT) is one of the leading causes of preventable deaths and a major risk factor for serious disorders such as coronary heart disease, heart failure, peripheral vascular disease, renal failure and stroke. Pathogenesis of HT is multifactorial and synthesis and/or release of nitric oxide (NO), which regulates local blood flow and modulates sodium reabsorption, plays a role in this process. In order to shed light on the multifactorial pathophysiological mechanisms of hypertension and to improve preventative and therapeutic strategies, many experimental models have been used. One of these experimental models is impairment of NO production in the blood vessel layer, which is a major pathway for the development of hypertension, by using nitric oxide synthase (NOS) inhibitors.1,2 Acute or chronic inhibition of NO production by NOS inhibitors causes hypertension,3-7 and the degree of elevation of blood pressure is dose and time dependent. With total inhibition of NOS with high doses, increased periferal resistance comes to the fore as the underlying cause; however, water and salt retention, activation of the symphathetic system and oxidative stress are important contributors.8-10 Oxidative stress was shown to be related to inadequate natriuresis and vasodilatation by means of impaired expression

142

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

or function of renal dopaminergic receptors, however the mechanism is not clear.11 The exact role of oxidative stress in the development of HT via NOS inhibition and the regulatory effect of the anti-oxidant system in this process remains unresolved. Resveratrol (3,4′,5-trihydroxy-trans-stilbene) (RSV) is a type of natural phenol found in red grapes, peanuts, red wine and other polyphenol-rich food. Anti-proliferative,3,4 anti-inflammatory,5 anti-oxidant5-7,12-14 and cardioprotective15 effects of resveratrol have been shown in different experimental models so far. Human studies established that acute administration of RSV generated dose-dependent improvement of endotheliumdependent vasodilatation.16 Aminopiridin-sensitive potassium channels play a role in that process and a potassium-independent pathway (propably related to voltage-dependent calcium channels) is also thought to be responsible for the vasodilatory efects of RSV.17,18 Furthermore, it was shown that aortic vasodilation, with a low dose of RSV, was generated via the endothelial NOS effect.19 In our study, we aimed to investigate the effect of resveratrol on blood pressure in rats that become hypertensive via NOS inhibition with the application of L-NNA in doses that cause mild hypertension.20 Changes in parameters related to water–salt balance and renal functions were also analysed.

AFRICA

and obtained pulses. Systolic blood pressure and heart rate were measured with the indirect tail-cuff method on the first, seventh and 10th days of the study by investigators who were blinded to the study protocol. An average of three measurements was recorded on each occasion. All rats were put into metabolic cages at the end of study protocol. The total water intake and urine output were determined for 24 hours. We added 0.1 ml 6N HCl to the urine containers and kept the samples in the dark. Urine samples were put into Eppendorf tubes and stored at –80°C (Sanyo Ultra Low Temperature Freezer MDF-U4086S). At the end of the experiment, the animals were anesthetised with 20% urethane (1 g/kg, i.p.). Blood samples were collected by heart puncture, and serum samples were obtained after centrifugation of the blood at 5 400 rpm for 10 minutes and stored at –80°C. We measured urea, creatinine and sodium levels in the blood and urine samples with a Roche Cobas 6000 autoanalyser (Mannheim, Germany). Fluid balance, sodium clearance rate (CNa), glomerular filtration rate (GFR) and fractional sodium excretion (%FENa) were calculated using the following formulae: Fluid balance = water intake – urine volume 24-hour urine volume

_______________ UFR (urine flow rate in min) =          1 440 urine sodium × UFR

_______________ CNa =           plasma sodium

Methods Male Sprague-Dawley rats (230–260 g) from Harlan were housed under standard conditions with a 12-hour light–dark cycle in standard cages in a room with a controlled humidity of 40% and a temperature of 22°C. They had ad libitum access to food and water for 10 days. Experimental procedures were in agreement with institutional and legislator regulations and approved by the local ethics committee for animal experimentation. The rats (n = 35) were randomly divided into five groups (n = 7 in each group): control [intraperitoneal (i.p.) 1 ml 0.9% serum physiological solution applied for 10 days], L-NNA (15 mg/100 ml L-NNA given with drinking water for 10 days), RSV-E [1 ml resveratrol eluent (20% ethanol) i.p. applied for 10 days], RSV50 (50 mg/kg resveratrol i.p. applied for 10 days) and L-NNA + RSV50 (15 mg/100 ml L-NNA given with drinking water and 50 mg/kg resveratrol i.p. applied for 10 days). The amount of consumed water was quantified every day and all applications were performed at the same time of day. The dose of L-NNA was calculated from the amount of consumed water and the drinking water of all groups was refreshed every day. Each subject was placed in a separate box in a quiet area. A tail-cuff pletysmograph (MAY BPHR 9610-PC TAIL-CUFF Indirect Blood Pressure Recorder, Ankara, Turkey) and its sensor were fixed to their tails, which were warmed up to 37–38°C for 10–20 minutes, until it picked up regular signals Table 1. Weight gain in the study groups Groups (n = 7) Control L-NNA RSV50 RSV-E L-NNA + RSV50

First day (g) 154 ± 5.5 155 ± 3.3 151 ± 2.8 188 ± 5.6 186 ± 6.3

Last day (g) 199.4 ± 7.2 209.0 ± 3.3 188.5 ± 4.2 214.8 ± 16.9 194.3 ± 5.2

(urine creatinine × plasma creatinine)

__________________________ GFR =            UFR (plasma creatinine × urine sodium)

_________________________ %FENa =             (plasma sodium × urine creatinine) × 100

Statistical analysis All statistical analyses were performed with IBM SPSS Statistics 16 software (SPSS Inc, Chicago, IL, USA). Data are expressed as mean ± standard error. Blood pressure values were compared with the Student’s t-test and biochemical values via one-way analysis of varience (ANOVA) with post hoc Bonferroni comparison. All p-values were two-tailed and p < 0.05 was considered to be statistically significant.

Results The body weight gains of all groups were similar and are shown in Table 1. The first measured blood pressure values (before the protocol) were similar between the groups (Table 2, Fig. 1). At the end of the study protocol, blood pressures were higher in the L-NNA (117.8 ± 3.5 vs 149.5 ± 2.1 mmHg; p < 0.05) and L-NNA + RSV50 (122.8 ± 7.3 vs 155.4 ± 4.4 mmHg; p < 0.05) groups (Table 2, Fig. 1). Table 2. Blood pressure measurements of the study groups at the beginning and end of the study First measured (mmHg) Last measured (mmHg) Groups (n = 7) Control 123.1 ± 5.5 121.1 ± 3.5 L-NNA 117.8 ± 3.5 149.5 ± 2.1*βγ RSV50 122.4 ± 3.8 124.2 ± 2.4 RSV-E 126.6 ± 6.4 121.7 ± 7.8 L-NNA + RSV50 122.8 ± 7.3 155.4 ± 4.4*βγ * β Compared to the control group, p < 0.05; compared to the RSV50 group, p < 0.05; γcompared to the RSV-E group, p < 0.05.

AFRICA

180

160

✱βγ

Blood pressure (mmHg)

40 Water intake – urine volume (ml/day)

✱βγ

140 120 100 80 60 40 20 0

143

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

✱

35 30 25 20 αβ

15 10 5

Control

L-NNA

RSV50 First

RSV-E

L-NNA + RSV50

Last

✱ Compared to control group, p < 0.05

β Compared to RSV50 group, p < 0.05 γ Compared to RSV-E group, p < 0.05

Control

L-NNA

RSV50

RSV-E

L-NNA + RSV50

✱ Compared to control group, p < 0.05

α Compared to LNNA group, p < 0.05 β Compared to RSV50 group, p < 0.05

Fig. 2. Fluid balances of the study groups. Fig. 1. T he first and the last measured blood pressures of the study groups.

L-NNA (42.0 ± 1.0) and RSV (44.7 ± 3.6 ml) application did not alter the water intake, whereas it was found to be significantly lower in the L-NNA + RSV50 (25.9 ± 2.9 ml) and RSV-E (26.8 ± 4.3 ml) groups compared to the control group (33.7 ± 4.1 ml) (Table 3). Compared to the control group (11.6 ± 1.2 ml), urine volume did not change in the L-NNA (14.0 ± 0.5 ml), RSV50 (10.1 ± 0.3 ml) and L-NNA + RSV50 (12.9 ± 1.2 ml) groups. However, interestingly, urine volume (3.3 ± 1.1 ml) as well as water intake was significantly lower in the RSV-E group (Table 3). Although the application of RSV with L-NNA decreased the fluid balance (13.0 ± 2.4 ml), RSV application alone increased it (34.6 ± 3.5 ml). L-NNA application alone did not alter (28.0 ± 1.0 ml) the fluid balance compared to the control group (22.0 ± 4.0 ml) (Table 3, Fig. 2). Serum and urine sodium concentrations (Table 4) and urea and creatinine (Table 5) levels were similiar between the groups. Applications did not alter the values measured at the end of the study compared with those measured at the beginning of the protocol (data not shown). Table 3. Water intake, urine volume and water balance in the study groups Water intake Urine volume Water balance Groups (n = 7) (ml) (ml) (ml) Control 33.7 ± 4.1 11.6 ± 1.2 2 2.1 ± 4.1 L-NNA 42 ± 1.0 14 ± 0.5 28.0 ± 1.0 RSV50 34.6 ± 3.5* 44.7 ± 3.6 10.1 ± 0.3αγ RSV-E 3.3 ± 1.1*αβ 23.5 ± 3.7 26.8 ± 4.3αβ αβ 12.9 ± 1.2* 13 ± 2.4αβ L-NNA + RSV50 25.9 ± 2.9 α *Compared to the control group, p < 0.05; compared to the L-NNA group, p < 0.05; βcompared to the RSV50 group, p < 0.05; γcompared to the RSV-E group, p < 0.05.

RSV and L-NNA application alone did not alter CNa, however it was lower in the RSV-E (0.0015 ± 0.0007 ml/min) group compared to both the RSV50 (0.0042 ± 0.0007 ml/min) and L-NNA (0.0055 ± 0.0011 ml/min) groups (Table 6, Fig. 3). GFR was significantly lower in the RSV-E group (0.32 ± 0.09 ml/min) compared to the other groups and it was also lower in the RSV50 group (0.87 ± 0.08 ml/min) compared to the L-NNA (1.30 ± 0.16 ml/min) and the L-NNA + RSV50 (1.33 ± 0.14 ml/ min) groups (Table 6, Fig. 4). Fractional sodium excretion values were similar in all groups (Table 6, Fig. 5).

Table 4. Serum sodium concentrations and 24-hour urine samples Groups (n = 7) Control L-NNA RSV50 RSV-E L-NNA + RSV50

Serum Na (mEq/l) 144.0 ± 0.53 143.4 ± 0.4 143.7 ± 0.5 143.5 ± 0.4 143.2 ± 0.4

24-hour urine Na (mEq/l) 0.84 ± 0.11 0.72 ± 0.07 0.86 ± 0.14 0.84 ± 0.15 0.89 ± 0.16

Table 5. Creatinine and urea levels in serum and 24-hour urine samples Serum creatinine Groups (n = 7) (mg/dl) Control 0.38 ± 0.01 L-NNA 0.36 ± 0.02 RSV50 0.39 ± 0.03 RSV-E 0.37 ± 0.02 L-NNA + RSV50 0.38 ± 0.01

Serum urea (mg/dl) 44.60 ± 2.63 48.67 ± 2.74 40.31 ± 2.96 43.65 ± 3.77 44.09 ± 0.73

24-hour urine urea (mg/dl) 57.03 ± 2.81 52.60 ± 4.15 52.21 ± 2.86 53.58 ± 3.38 58.44 ± 3.60

24-hour urine creatinine (mg/dl) 0.58 ± 0.03 0.47 ± 0.05 0.48 ± 0.04 0.55 ± 0.03 0.56 ± 0.01

144

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 6. Sodium clearance rate (CNa), glomerular filtration rate (GFR) and fractional sodium excretion (%FENa) values

Discussion It has been demonstrated that vascular oxidative stress plays an important role in the pathogenesis of essential hypertension,21 and many experimental studies have been published using anti-oxidants to prevent the development of hypertension or to decrease blood pressure. Hu et al.22 showed that apocynin [a nicotinamide dinucleotide phosphate (NADPH) oxidase inhibitor] application prevented and reversed dexamethasoneinduced (via NADPH oxidase-mediated superoxide production) hypertension in rats. Another study revealed that tempol [a superoxide dismutase (SOD) mimetic] application decreased blood pressure and renal vascular resistance in spontaneously hypertensive rats by eliminating unfavourable peroxynitrite formation from the superoxide by competition with NO.23 We aimed to investigate the effects of RSV in preventing the development of hypertension, which was induced by NOS inhibition. RSV application alone did not alter blood pressure in the normotensive rats. Application of RSV plus L-NNA did not reverse the blood pressure increase induced by L-NNA. This may have been related to the dose of RSV or the length of the application period. Various protocols have been used in other studies. Bhatt et al.24 gave RSV dissolved in drinking water to rats at a concentration of 50 mg/l for 10 weeks and revealed that the development of hypertension was attenuated in the spontaneously hypertensive rats. Gordish et al.25 administered RSV at a dose of 5 mg/kg to rats via the femoral vein and proved that the acute renal vasodilatory effect of RSV was mediated

1.40 Glomerular filtration rate (ml/min)

GFR (ml/min) %FENa CNa (ml/min) Groups (n = 7) Control 1.25 ± 0.19γ 0.38 ± 0.04 0.0047 ± 0.0007γ L-NNA 1.30 ± 0.16γβ 0.42 ± 0.07 0.0049 ± 0.0005γ RSV50 0.87 ± 0.08γ 0.53 ± 0.11 0.0042 ± 0.0007γ RSV-E 0.41 ± 0.09 0.0015 ± 0.0007 0.32 ± 0.09*β 1.33 ± 0.14γβ 0.42 ± 0.08 L-NNA + RSV50 0.0055 ± 0.001γ *Compared to the control group, p < 0.05; αcompared to the L-NNA group, p < 0.05; βcompared to the RSV50 group, p < 0.05; γcompared to the RSV-E group, p < 0.05.

1.60 γ

βγ

1.20 γ

1.00 0.80 0.60

0.40 0.20 0.00

Control

L-NNA

RSV50

RSV-E

L-NNA + RSV50

β Compared to RSV50 group, p < 0.05 γ Compared to RSV-E group, p < 0.05

Fig. 4. Glomerular filtration rates of the study groups.

by increased NO production/bioavailability and its superoxidescavenging effect. We did not measure oxidative stress markers such as malondialdehyde (MDA), however we possibly achieved sufficient antioxidant effect by the RSV aplications. In addition, it was shown that abnormalities in vascular NO production and transport resulted in hypertension due to endothelial dysfunction. RSV increased NO synthesis and functioned as a potent in vivo anti-oxidant.26 Interestingly, in the RSV50 group, the water balance was significantly higher compared to the control group despite no significant changes in water intake and urine output. Application of L-NNA plus RSV decreased the water balance compared to the application of RSV only, however it was not significantly different compared to the control group. Decreased urine volume may have been related to diminished water intake, as found in previous studies.27-29 CNa and GFR values were lower in the RSV-E group and these findings were attributed to the RSV eluent (20% ethanol), which

0.7

0.0060 Fractional sodium excretion (%)

Sodium clearnace rate (ml/min)

0.0070

0.0050 0.0040 0.0030

0.0020 0.0010 0.0000

Control

L-NNA

RSV50

RSV-E

α Compared to other groups, p < 0.05

Fig. 3. S odium clearance values of the study groups.

L-NNA + RSV50

0.6 0.5 0.4 0.3 0.2 0.1 0

Control

L-NNA

RSV50

RSV-E

L-NNA + RSV50

Fig. 5. Fractional sodium excretion values of the study groups.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

is comparable with the study of Barrero and co-workers.30 They showed that creatinine and sodium clearance decreased after ethanol application in rats. The kidneys play a critical role in long-term control of blood pressure. Reduction in renal sodium excretion or a rightward shift in the pressure–natriuresis relationship results in persistent hypertension, and NO plays an important role in this process by regulating the renal response to changes in perfusion pressures. Suprisingly, renal functional parameters were not affected by NOS inhibition in our study. Tolins et al.31 revealed that renal and systemic vascular resistance increased, and renal blood flow and sodium excretion were decreased by NOS inhibition. Griffin et al.32 showed that Sprague-Dawley rats from Harlan, which exhibited the expected hypertension, proteinuria and glomerular damage, and those from Charles River, which showed a blunted increase in blood pressure and a resistance to nephropathy, exhibited large differences in susceptibility to nephropathy by L-NAME-induced NOS inhibition over a period of four weeks. We used L-NNA instead of L-NAME for NOS inhibition in order to obtain earlier blood pressure increase, and we evaluated fluid balance, CNa, GFR and %FENa but not proteinuria and morphological parameters of renal damage over a period of 10 days.

145

P. Potent antioxidative activity of Vineatrol30 grapevine-shoot extract. Biosci Biotechnol Biochem 2009; 73: 1831–1836. 7.

Kao CL, Tai LK, Chiou SH, Chen YJ, Lee KH, Chou SJ, et al. Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev 2010; 19: 247–258.

Oktar S, Ilhan S, Aksulu HE. Clonidine prevents development of hypertension in N (omega)-nitro-L-arginine-treated rats. Anadolu Kardiyol Derg 2008; 8: 104–110.

Vapaatalo H, Mervaala E, Nurminen ML. Role of endothelium and nitric oxide in experimental hypertension. Physiol Res 2000; 49: 1–10.

10. Harrison DG, Gongora MC, Guzik TJ, Widder J. Oxidative stress and hypertension. J Am Soc Hypertens 2007; 1: 30–44. 11. Wilcox CS, Welch WJ. Oxidative stress: cause or consequence of hypertension. Exp Biol Med (Maywood) 2001; 226: 619–220. 12. Silan C, Uzun O, Ustundag Comunoglu N, Gokcen S, Bedirhan S, Cengiz M, Gentamicin induced nephrotoxicity in rats ameroliorated and healing effects of Resveratrol. Biol Pharm Bull 2007; 30: 79–83. 13. Ozkan OV, Yuzbasioglu MF, Ciralik H, Kurutas EB, Yonden Z, Aydin M, et al. Resveratrol, a natural antioxidant, attenuates intestinal ischemia/reperfusion injury in rats. Tohoku J Exp Med 2009; 218: 251–258. 14. Silan C. The effects of chronic resveratrol treatment on vascular responsiveness of streptozotocin-induced diabetic rats. Biol Pharm Bull 2008;

Conclusion Although it is a potent anti-oxidant and inceases NO production/ bioavailibilty, resveratrol was incapable of preventing the development of hypertension or reversing the blood pressure increase in L-NNA-induced hypertension models in our study. We cannot generalise this finding, as resveratrol is not a good candidate for the treatment of hypertension developed via the NOS-inhibition pathway. We suggest that further studies are needed to assess this hypothesis, with higher doses and/or longer periods of time.

31: 897–902. 15. Sadruddin S, Arora R. Resveratrol: biologic and therapeutic implications. J Cardiometab Syndr 2009; 4: 102–106. 16. Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 2011; 21: 851–856. 17. Gojkovic-Bukarica L, Novakovic A, Kanjuh V, Bumbasirevic M, Lesic A, Heinle H. A role of ion channels in the endothelium-independent relaxation of rat mesenteric artery induced by resveratrol. J Pharmacol Sci 2008; 108: 124–130. 18. Zhang HY, Xu CQ, Li HZ, Li BX, Zhang YQ, Zhang YN. Effects of

This work was supported by Research Fund of the Canakkale Onsekiz Mart University; project number: 2010/069

resveratrol on isolated thoracic aorta rings of rats. Zhongguo Zhong Yao Za Zhi 2005; 30: 1283–1286. 19. Leblais V, Krisa S, Valls J, Courtois A, Abdelouhab S, Vila AM, et al.

References 1.

Hill C, Lateef AM, Engels K, Samsell L, Baylis C. Basal and stimulated nitric oxide in control of kidney function in the aging rat. Am J Physiol 1997; 272:1747–1753.

Linder L, Kiowski W, Buhler FR, Luscher TF. Indirect evidence for

infarct size. Scand Cardiovasc J 2006; 40(4): 248–252. precedes high blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens 2005; 27: 71–82.

Savio M, Coppa T, Bianchi L, Vannini V, Maga G, Forti L, et al. The

22. Hu L, Zhang Y, Lim PS, Miao Y, Tan C, McKenzie KU, et al. Apocynin

resveratrol analogue 4,4’-dihydroxy-trans-stilbene inhibits cell prolifera-

but not L-arginine prevents and reverses dexamethasone-induced hypertension in the rat. Am J Hypertens 2006; 19: 413–418. 23. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood

Hsieh TC. Antiproliferative effects of resveratrol and the mediating role

pressure and renal vascular resistance in SHR with a membrane-perme-

of resveratrol targeting protein NQO2 in androgen receptor-positive,

able superoxide dismutase mimetic: role of nitric oxide. Hypertension

hormone-non-responsive CWR22Rv1 cells. Anticancer Res 2009; 29: 3011–3017.

1998; 32: 59–64. 24. Bhatt SR, Lokhandwala MF, Banday AA. Resveratrol prevents endothe-

Csiszar A, Labinskyy N, Olson S, Pinto JT, Gupte S, Wu JM, et al.

lial nitric oxide synthase uncoupling and attenuates development of

Resveratrol prevents monocrotaline-induced pulmonary hypertension

hypertension in spontaneously hypertensive rats. Eur J Pharmacol 2011;

in rats. Hypertension 2009; 54: 668–675. 6.

melatonin reduces blood pressure and ischemia/reperfusion-induced

lation in vivo. Blunted response in essential hypertension. Circulation

J Biochem Cell Biol 2009; 41: 2493–2502.

ClinPharmacol 2008; 22: 25–35. 20. Deniz E, Sahna E, Aksulu HE. Nitric oxide synthase inhibition in rats:

21. Nabha L, Garbern JC, Buller CL, Charpie JR. Vascular oxidative stress

tion with higher efficiency but different mechanism from resveratrol. Int 4.

nary arteries: lack of inhibition by NO-synthase inhibitor. Fundam

release of endothelium-derived relaxing factor in human forearm circu1990; 81: 1762–1767. 3.

Relaxation induced by red wine polyphenolic compounds in rat pulmo-

Müller C, Ullmann K, Wilkens A, Winterhalter P, Toyokuni S, Steinberg

30: 258–264. 25. Gordish KL, Beierwaltes WH. Resveratrol induces acute endothelium-

146

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

dependent renal vasodilation mediated through nitric oxide and reac-

of the L-arginine/nitric oxide pathway. Hypertension 1992; 19: 333–338.

tive oxygen species scavenging. Am J Physiol Renal Physiol 2014; 306:

30. Barrero MJ, Ojeda ML, Díaz Castro J, Nogales F, Murillo ML, Carreras

542–550. 26. Turan B, Tuncay E, Vassort G. Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies. J Bioenerg Biomembr 2012; 44: 281–296. 27. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; 2: 997–1000.

O. The effects of ethanol upon hydric balance and arterial pressure in rats: folic acid as a possible hypotensor. Life Sci 2012; 90: 337–342. 31. Tolins JP, Shultz PJ. Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt. Kidney Int 1994; 46: 230–236. 32. Griffin K, Polichnowski A, Licea-Vargas H, Picken M, Long J, Williamson G, et al. Large BP-dependent and -independent differences

28. Granger JP, Alexander BT. Abnormal pressure-natriuresis in hyperten-

in susceptibility to nephropathy after nitric oxide inhibition in Sprague-

sion: role of nitric oxide. Acta Physiol Scand 2000; 168: 161–168.

Dawley rats from two major suppliers. Am J Physiol Renal Physiol 2012;

29. Johnson RA, Freeman RH. Pressure natriuresis in rats during blockade

302: 173–182.

Dear Partner in RHD in Africa

9 May 2017

PASCAR Grant: Advocacy for RHD Eradication – Promoting the AU Communiqué The Pan-African Society of Cardiology (PASCAR) has partnered with RHD Action and the World Heart Federation (WHF) to fund five projects (in five different countries) to advance the “African Union Communiqué on the Eradication of RHD in Africa”. This is a competition for a policy dialogue on the AU Communiqué on National Programmes for RHD. We encourage proposals on your plans for a policy dialogue with policy makers in the Ministry of Health and related departments that will introduce them to the AU Communiqué and lead to government supported national programmes and initiatives. In other words, advocacy for action. The project, with clearly defined deliverables and outcomes, must be designed to achieve implementation of point 6 of the AU Communiqué namely, an “integrated, multidisciplinary, intersectoral national programme for the prevention and control of RHD”. The goal is increased government commitment to sustainable and comprehensive rheumatic heart disease (RHD) control. The project should: • Involve a wide range of stakeholders such as government (Ministry of Health and other relevant ministries), non-governmental organizations, community based organisations, professional associations, RHD champions, and people living with or affected by RHD. • Be aligned with regional/global initiatives for the prevention of RHD in Africa (e.g., Stop RHD A.S.A.P. Programme, RHD Action, World Heart Day). • Have clear, focused, measurable objectives which can be achieved over a period of 6 to 12 months. Funding of US $2,000 per project is available for up to 5 successful applicants. The funding is payable in two tranches; firstly initiation of the project and secondly on confirmation of deliverables. Deliverables for PASCAR are, 1. A narrative and financial report by latest end January 2018. 2. Meeting agendas, photographs, and press coverage of the activity, with as much human interest as possible as well as official government policy statements in this regard. Please see addendum below stipulating how to respond to this request for applications. We look forward to receiving innovative proposals that will move the agenda of the AU Communiqué Programme forward in Africa. With appreciation,

Professor Bongani M Mayosi President, Pan-African Society of Cardiology

Dr Chris Hugo-Hamman PASCAR RHD Task Force Addendum on page 181

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

147

Prevalence of selected cardiometabolic risk factors among adults in urban and semi-urban hospitals in four sub-Saharan African countries Samuel Kingue, Solofonirina Rakotoarimanana, Nirina Rabearivony, Francois Lepira Bompera

Abstract Aim: Cardiovascular diseases (CVDs) are a global challenge but the burden in sub-Saharan African (SSA) countries is less well documented than elsewhere. We aimed to describe the key cardiometabolic risk factors in four SSA countries. Methods: A cross-sectional, multi-national, hospital-based study was carried out among adults (> 35 years) across four SSA countries from 12 December 2011 to 7 February 2013. Risk factors were defined using the World Health Organisation and International Diabetes Federation guidelines. Results: Of the 844 adults (57.4% female, mean age 52.6 years), 76.6% were urban residents. The predominant CVD risk factors were hypertension (74.1%), obesity (36.2%) and excessive alcohol consumption (25.6%). Diabetes (17.7 vs 10.0%), obesity (42.8 vs 16.8%) and hypercholesterolaemia (25.8 vs 18.0%) were more prevalent among the hypertensive subjects (all p < 0.007) than the normotensives. The metabolic syndrome (39.4%) was more common in women and hypertensive subjects. Conclusions: Hospital patients in SSA countries present with excessive rates of cardiometabolic risk factors. Focus on their prevention and control is warranted. Keywords: cardiovascular risk factors, metabolic syndrome, subSaharan Africa Submitted 19/12/15, accepted 10/7/16 Published online 22/8/16 Cardiovasc J Afr 2017; 28: 147–153

www.cvja.co.za

DOI: 10.5830/CVJA-2016-072

Non-communicable diseases (NCDs) are rapidly increasing in incidence in sub-Saharan Africa (SSA). Cardiovascular disease (CVD) is the leading contributor to the global burden of NCDs.1 Hypertension, which is the main driver of CVD, has

Department of Cardiology, Faculty of Medicine of Yaounde, General Hospital of Yaounde, Yaounde, Cameroon Samuel Kingue, MD, samuel_kingue@yahoo.fr

Department of Cardiology, Joseph Raseta Defelatalala University Hospital, Antananariv, Madagascar Solofonirina Rakotoarimanana, MD, Nirina Rabearivony, MD

Division of Nephrology, Department of Internal Medicine, University Clinic, Democratic Republic of Congo Francois Lepira Bompera, MD

been estimated to affect about 972 million adults worldwide, a figure that is projected to increase by 60% by the year 2025.2,3 This high prevalence of hypertension is coupled with poor detection, treatment and control rates.4 Diabetes mellitus is also a leading cause of morbidity and mortality from NCDs and a major precursor of CVD.5 The population of people with diabetes in SSA is growing more rapidly than anywhere else, and is expected to nearly double within the next two decades.6 The co-occurrence of diabetes and hypertension in the same individual compounds the harmful effects of each condition. A recent cross-sectional study conducted in semi-urban Cameroon has indicated the co-occurrence of diabetes and hypertension, affecting up to 5% of adults.7 Other common drivers of NCDs and the CVD burden include physical inactivity, smoking, unhealthy diet, dyslipidaemia, excess weight and alcohol abuse.8,9 Monitoring the risk profile of the population is an extremely important component of the strategy to prevent and control NCDs in general and CVD in particular. This pivotal role was recently highlighted in the World Health Organisation (WHO) global action plan of 2013–2020 for the prevention of NCDs.10 Given the silent nature of hypertension and other risk factors, and the lack of awareness of them in low- and middle-income countries (LMICs), opportunistic screening and awareness have been highlighted by the World Heart Federation as the key ﬁrst steps to improving management and prevention.11 Studies addressing the risk profile of individuals who have contact with hospitals in Africa are lacking, and most of the existing studies are single-country studies, therefore offering less opportunity to examine between-country variabilities. This report is on a multi-country, multi-centre, health facilities-based study to assess the distribution of major cardiometabolic risk factors in adults in urban settings across different countries in SSA.

Methods This was a multi-national, multi-centre, cross-sectional study conducted from 12 December 2011 to 7 February 2013. The following SSA countries participated in the study: Cameroon (13 centres), Nigeria (five centres), Democratic Republic of Congo (DRC) (11 centres) and Madagascar (24 centres). The study centres were purposefully selected from the health districts of the capital cities (urban and semi-urban) in the participating countries. Participating centres included both public and private healthcare facilities. General practitioners working in the selected centres were trained to consecutively recruit all individuals aged over 35 years to their facilities, regardless of the reason for the visit to hospital, if they were resident in the particular city for at least three months.

148

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Ethical approval was obtained from the ethics committees of the participating countries and the patients gave written consent before enrollment. The study complied with the Declaration of Helsinki. Data were collected simultaneously in all study centres of the participating countries, using a standardised case report form (CRF). The following variables were collected: sociodemographic characteristics (age, gender, educational level, alcohol consumption, tobacco use and employment type), history of hypertension, diabetes status and systolic and diastolic blood pressure (BP, in mmHg). BP was measured using an automated BP machine (Omron 750 IT) in the seated position after the participant had been at rest for five to 10 minutes. Three measurements were taken on the right arm and the average of the last two was retained.12 Weight, height, and waist and hip circumference were measured using standard procedures and equipment following WHO guidelines.13 Weight was measured to the nearest 0.5 kg and height to the nearest 0.5 cm. Body mass index (BMI, kg/m2) was calculated as body weight in kg divided by the square of the height in metres. The waist circumference (WC) was measured with a tape midway between the lower rib margin and iliac crest. Waist-to-hip ratio was calculated as waist circumference (cm) divided by hip circumference (cm). Fasting capillary glucose concentration was obtained using a standardised glucometer (Accu-chek Aviva; HoffmannLA Roche, Ltd, Germany) in all the settings. Fasting total cholesterol, high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglycerides, uric acid and serum creatinine concentrations were acquired using locally available routine standard techniques and procedures. Hypertension was diagnosed in the presence of systolic or diastolic blood pressure ≥ 140 or 90 mmHg or ongoing blood pressure-lowering medications over the past 15 consecutive days. Uncontrolled hypertension was defined as blood pressure ≥ 140/90 mmHg in participants on BP control agents for the last 30 consecutive days. Duration of hypertension was defined as date of survey minus date of diagnosis of hypertension. Hyperglycaemia was defined as fasting capillary glucose level ≥ 6.1 mmol/l (110 mg/l) and diabetes was defined as fasting capillary glucose level ≥ 7.1 mmol/l (126 mg/dl) or physician-documented history of diabetes, or patient on glucosecontrolling agents (oral or insulin) for the last 15 consecutive days. Impaired fasting glycaemia was defined as fasting capillary glucose levels between 6.1 and 7.1 mmol/l (110–126 mg/dl). Overweight and obesity were defined using BMI and WHO criteria,14 i.e. normal: 18.5 kg/m2 ≤ BMI ≤ 24.99 kg/m2; overweight: 25 kg/m2 ≤ BMI ≤ 29.99 kg/m2; obesity: 30 kg/m2 ≤ BMI ≤ 39.99 kg/m2, morbid obesity: BMI ≥ 40 kg/m2. Hypercholesterolaemia was defined as a total cholesterol level > 5.18 mmol/l. The metabolic syndrome (MS) was defined according to the International Diabetes Federation (IDF) consensus criteria:15 central obesity plus any two of the following: raised triglyceride levels ≥ 150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality, reduced HDL-C < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/dl (1.29 mmol/l) in women or specific treatment for this lipid abnormality, raised blood pressure (≥ 130/85 mmHg) or treatment of previously diagnosed hypertension, raised fasting plasma glucose level ≥ 100 mg/dl (5.6 mmol/l) or previously diagnosed type 2 diabetes.15

AFRICA

Increased waist circumference was defined as > 102 cm for men and > 88 cm for women. With a BMI > 30 kg/m2, central obesity was assumed without measurement of waist circumference.15 Alcohol consumption was categorised as low-to-moderate consumption (less than or equal to one local beer daily for women and two local beers for men) and excessive consumption (more than two local beers daily).16 Smoking status was determined as current smokers, former smokers (having smoked in the past but having stopped for two or more weeks prior to the survey, however, those who had stopped within two weeks of the survey were considered current smokers), and never smoked.

Statistical analysis Data analysis was done using the Statistical Package for Social Sciences (SSPS Inc, Chicago, IL) software version 20.0. Categorical variables were summarised as counts and percentages while continuous variables were summarised as means, median, standard deviation (SD) and percentiles where appropriate. Group comparisons used the chi-squared or Fisher’s exact tests for categorical variables, and the Student t-test for continuous variables. A p-value < 0.05 was considered statistically significant.

Results Table 1 shows the general characteristics of the study population. A total of 844 adults (57.4% were women and overall mean age was 52.6 ± 11.6 years) were included in the study, among whom 154 and 216, respectively, were from Cameroon and Nigeria, 240 from the DRC and 240 from Madagascar. The majority (76.6%) of the study participants were urban dwellers. The men were more likely to be employed and to be educated than the women (both p < 0.001). The women were more likely to be overweight, obese or morbidly obese than the men (p < 0.001). The men had a significantly higher mean triglyceride levels than the women (2.9 vs 2.2 mmol/l; p = 0.019) and lower mean HDL-C levels (1.6 vs 1.8 mmol/l; p = 0.004). Men also had higher mean normal values of serum creatinine (90.8 vs 75.7 µmol/l, p < 0.001) and uric acid (295.0 vs 233.2 µmol/l, p < 0.001) than the women. Men and women had similar mean systolic (149.5 vs 149.5 mmHg) and diastolic (91.9 vs 90.6 mmHg) blood pressures, respectively. The overall prevalence of hypertension [previously aware/ diagnosed (48.1%) and newly diagnosed (26%)] was 74.1% [Cameroon (91.5%), Nigeria (66.8%), DRC (99.1%) and Madagascar (45.0%)]. The overall prevalence of diabetes in the study was 15.7% and ranged from 24.8% in Nigeria, 15.6% in Cameroon and 15.0% in DRC, to 8.7% in Madagascar (p = 0.003). Excessive alcohol consumption was reported in 25.6% of study participants, with the highest prevalence in Cameroon (36.6%), and the lowest in Nigeria, where all participants reported low-to-moderate consumption (p = 0.007). Of the study participants, 17.3% were either current or former smokers. A significant difference (p < 0.001) in prevalence of smoking across the countries was noted, with the highest prevalence in Madagascar (32.9%), followed by Cameroon (13%), then DRC (10.9%), and Nigeria (10.0%) being the lowest. Of the study participants, 32.3 and 36.3% were overweight and obese (obesity 31.8%), or morbidly obese (4.5%), respectively. Overweight was highest in Madagascar (39.2%) and lowest in

AFRICA

149

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 1. General characteristics and overall profile of study population Cameroon (n = 154) 17.9%

Nigeria (n = 211) 25.9% Male (n = 87)

DRC (n = 239) 28.1%

Female Male (n = 124) p-value (n = 116)

Madagascar (n = 240) 28.1%

Female (n = 484) (57.4%)

Variables

Male (n = 54)

Female (n = 100) p-value

Age (years)

51.5 ± 9.7

56.4 ± 11.2 0.009 50.3 ± 13.2 48.8 ± 11.3 0.369 56.7 ± 11.2 55.7 ± 12.9 0.532 51.4 ± 10.0

49.5 ± 9.9

0.147 52.8 ± 11.5 52.3 ± 11.8

BMI (kg/m2)

29.7 ± 3.8

31.1 ± 6.7

25.0 ± 3.9

0.930

27.5 ± 5.8 127 (35.3)

137 (28.3)

264 (31.3)

0.983

127 (35.3)

146 (30.2)

273 (32.3) 268 (31.8)

0.184

28.6 ± 6.1

31.2 ± 6.4

29 (33.4)

21 (16.8)

0.005

27 (31.0)

32 (25.8)

Female Male (n = 123) p-value (n = 103)

Total (n = 844)

Male Female (n = 360) (n = 137) p-value (42.6%)

0.003

27.7 ± 6.8

30.4 ± 6.2

39 (33.6)

25 (20.4)

0.007

38 (32.8)

37 (30.1)

0.002

25.1 ± 4.0 53 (51.4)

69 (50.4)

0.005

40 (38.8)

54 (39.4)

29.3 ± 6.4

Total (n = 844) p-value 52.6 ± 11.7

0.512

28.5 ± 6.1

0.000

BMI category, n (%) Normal

06 (11.1)

22 (22.0)

Overweight

22 (40.7)

23 (23.0)

Obese

26 (48.2)

43 (43.0)

28 (32.2)

59 (47.7)

38 (32.8)

50 (40.6)

10 (9.7)

14 (10.2)

102 (28.3)

166 (34.3)

00 (0.0)

12 (12.0)

03 (3.4)

12 (9.7)

01 (0.8)

11 (8.9)

00 (0.0)

04(1.1)

35 (7.2)

Morbidly obese WC (cm)

101.2 ± 12.8 102.7 ± 16.1 0.559 91.2 ± 11.5 97.4 ± 15.4 0.001 97.7 ± 17.9 99.9 ± 14.5 0.279 91.2 ± 11.2 88.4 ± 10.5 0.049 94.8 ± 14.5 96.6 ± 15.1

HC (cm)

104.5 ± 12.3 109.4 ± 19.8 0.101 96.8 ± 12.6 106.2 ± 18.2 0.000 101.1 ± 10.0 110.6 ± 14.6 0.000

97.8 ± 7.5

99.4 ± 9.1

0.000

39 (4.6) 95.8 ± 14.8

0.071

0.155 99.6 ± 10.8 106.1 ± 16.2 103.2 ± 14.5 0.000

SBP (mmHg)

168.5 ± 17.4 167.9 ± 17.8 0.855 138.8 ± 24.8 140.4 ± 25.7 0.656 163.6 ± 15.8 166.4 ± 21.2 0.260 132.3 ± 22.7 128.7 ± 23.1 0.231 149.5 ± 25.5 149.5 ± 27.9 149.3 ± 26.9 0.981

DBP (mmHg)

102.9 ± 11.4 100.4 ± 12.2 0.221 84.8 ± 11.8 86.2 ± 14.4 0.462 98.2 ± 11.5 96.4 ± 11.3 0.248 84.8 ± 13.9 82.2 ± 15.2 0.183 91.9 ± 14.4 90.6 ± 15.3

91.1 ± 14.9

0.239 0.729

History of HTN, n (%) Yes

01 (1.9)

05 (5.1)

53 (98.1)

93 (94.9)

0.423

50 (57.5)

82 (66.1)

37 (42.5)

42 (33.9)

0.248

81 (69.8)

93 (75.6)

35 (30.2)

30 (24.4)

0.383

38 (36.9)

55 (40.1)

65 (63.1)

82 (59.9)

0.688

170 (47.2)

235 (48.8)

405 (48.1)

190 (52.8)

247 (51.2)

437 (51.9)

History of DM, n (%) Yes

06 (11.1)

09 (9.1)

48 (88.9)

90 (90.9)

6.2 ± 2.8

6.6 ±7.6

FBS (mmol/l)

0.778 0.685

10 (11.9)

12 (9.7)

74 (88.1)

104 (90.3)

6.2 ±2.9

5.8 ± 4.1

0.820 0.979

11 (9.6)

14 (11.5)

104 (90.4)

108 (88.5)

5.4 ± 1.8

5.1 ± 1.6

0.677 0.084

06 (5.9)

02 (1.5)

97 (94.1)

135 (98.5)

5.9 ± 2.0

5.5 ± 1.6

0.077 0.122

33(9.3)

37(7.8)

70 (8.4)

323(90.7)

437(92.2)

760 (91.6)

5.8 ± 2.3

5.7 ± 4.2

5.8 ± 3.5

0.452 0.798

Lipid profile TG (mmol/l)

2.4 ± 10.0

0.9 ± 0.5

0.144

6.8 ± 5.8

5.8 ± 4.1

0.173

1.1 ± 0.6

1.0 ± 0.4

0.266

2.1 ± 1.4

1.4 ± 0.8

0.000

2.9 ± 5.3

2.2 ± 2.8

2.5 ± 4.1

0.019

HDL-C (mmol/l)

1.2 ± 0.5

1.3 ± 0.7

0.560

2.6 ± 1.1

2.9 ± 1.2

0.075

1.2 ± 0.3

1.4 ± 0.5

0.000

1.3 ± 0.6

1.5 ± 0.3

0.052

1.6 ± 0.9

1.8 ± 0.9

1.7 ± 0.9

0.004

LDL-C (mmol/l)

2.8 ± 0.8

2.5 ± 0.8

0.027

6.1 ± 3.3

6.5 ± 3.4

0.412

2.8 ± 1.2

2.9 ± 1.2

0.349

2.5 ± 0.8

2.7 ± 0.9

0.085

3.4 ± 2.3

3.6 ± 2.4

3.5 ± 2.4

0.436

4.4 ± 0.9

4.2 ± 0.9

0.317

8.8 ± 4.5

9.2 ± 4.8

0.549

4.5 ± 0.9

4.7 ± 1.1

0.154

4.8 ± 0.9

4.9 ± 1.1

0.360

5.5 ± 2.8

5.7 ± 3.0

TC (mmol/l) Creatinine (µmol/l)

108.6 ± 35.4 99.2 ± 40.4 0.153 56.2 ± 21.2 54.5 ± 28.4 0.658 107.2 ± 43.1 84.9 ± 22.1 0.000 88.8 ± 17.2 66.4 ± 11.4 0.000 90.8 ± 37.3 75.7 ± 31.1

Uric acid (µmol/l) 384.6 ± 84.2

298.6 ± 119.9

0.000

300.7 ± 275.4

264.5 ± 242.1

0.350

0.003

–

405.3 ± 109.5

354.7 ± 100.1

0.000 340.6 ± 90.3 249.9 ± 67.9 0.000

5.6 ± 3.0

0.471

82.1 ± 34.6

0.000

295.0 ± 178.5

233.2 ± 154.1

259.3 ± 168.0

0.000

114 (65.9)

115 (85.1)

229 (74.4)

0.000

59 (34.1)

20 (14.9)

79 (25.6)

Alcohol intake, n (%) Low–moderate

22 (46.8)

49 (75.3)

Excessive

25 (53.2)

16 (24.7)

52 (70.3)

45 (91.8)

22 (29.7)

04 (8.2)

Current

05 (9.3)

05 (5.1)

04 (4.6)

00 (0.0)

Former

08 (14.8)

02 (2.0)

17 (19.7)

00 (0.0)

10 (8.7)

01 (0.8)

14 (12.2)

01 (0.8)

Never

41 (75.9)

92 (92.9)

65 (75.7)

122 (100.0)

91 (79.1)

121 (98.4)

0.006

38 (76.0)

20 (100.0)

12 (34.0)

00 (0.0)

0.014

26 (25.2)

22 (16.1)

45 (12.5)

28 (5.7)

73 (8.7)

19 (18.4)

12 (8.7)

58 (16.1)

15 (3.1)

73 (8.7)

58 (56.3)

103 (75.2)

255 (71.4)

438 (91.2)

693 (82.6)

Tobacco use, n (%) 0.004

0.000

0.007

0.000

Employment, n (%) 0 (0.0)

14 (14.3)

01 (1.1)

06 (4.5)

12 (10.4)

16 (13.0)

02 (1.9)

06 (4.4)

15(4.1)

42(8.6)

57 (6.8)

Full time

Unemployed

24 (44.4)

22 (22.4)

22 (24.4)

44 (35.3)

60 (51.7)

18 (14.6)

52 (50.5)

71 (51.8)

158(43.5)

155(31.8)

313 (37.2)

Part time

05 (9.3)

02 (2.0)

03 (3.3)

01 (0.8)

00 (0.0)

07 (6.8)

06 (4.4)

16(4.4)

09(1.9)

25 (2.9)

0.000

0.010

0.000

0.001

Self-employed

13 (24.1)

09 (9.3)

46 (53.4)

50 (40.1)

24 (20.7)

18 (14.6)

29 (28.2)

24 (17.5)

112 (31.4)

101(21.4)

213 (25.3)

Housewife

00 (0.0)

44 (44.9)

00 (0.0)

09 (7.2)

00 (0.0)

63 (51.2)

00 (0.0)

19 (13.8)

01 (0.3)

135(27.8)

136 (16.2)

Retired

12 (22.2)

07 (7.1)

15 (17.8)

15 (12.1)

19 (16.4)

08 (6.5)

13 (12.6)

11 (8.0)

58 (16.3)

40(8.5)

98 (11.6)

0.000

Education, n (%) None

01 (1.9)

15 (15.3)

Primary school

12 (22.2)

38 (38.7)

High school

18 (33.3)

25 (25.5)

Diploma

08 (14.8)

15 (15.3)

00 (0.0)

26 (22.4)

18 (14.6)

25 (24.3)

27 (19.7)

59 (16.4)

60 (12.5)

119 (14.1)

Degree

15 (27.8)

05 (5.2)

23 (26.7)

28 (22.8)

43 (37.1)

14 (11.4)

48 (46.6)

46 (33.6)

129 (35.8)

93 (19.3)

222 (26.5)

113 (97.4)

120 (97.5)

71 (68.9)

100 (72.9)

03 (2.6)

03 (2.5)

32 (31.1)

37 (27.1)

0.000

01 (2.2)

11 (8.9)

54 (61.1)

70 (56.9)

09 (10.0)

14 (11.4)

0.113

02 (1.7)

18 (14.6)

05 (4.3)

31 (25.2)

40 (34.5)

42 (34.1)

0.000

00 (0.0)

01 (0.7)

11 (10.7)

12 (8.8)

19 (18.4)

51 (37.2)

0.024

04 (1.2)

45 (9.4)

49 (5.8)

82 (22.8)

151 (31.4)

233 (27.7)

86 (23.8)

132 (27.4)

218 (25.9)

0.000

Residence, n (%) Urban

47 (87.0)

81 (82.6)

Semi-urban

07 (13.0)

17 (17.4)

0.643

45 (51.7)

70 (56.9)

42 (48.3)

53 (43.1)

0.484

0.942

0.565

276 (76.6)

371 (77.1)

647 (76.9)

84 (23.4)

110 (22.9)

194 (23.1)

0.988

BMI = body mass index; WC = waist circumference; HC = hip circumference; SBP = systolic blood pressure; DBP = diastolic blood pressure; DM = diabetes mellitus; HTN = hypertension; FBS = fasting blood sugar; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; DRC = Democratic Republic of Congo; p-values are for comparison between gender among participating countries.

Nigeria (28.4%), while overall obesity was highest in Cameroon (53.6%) and lowest in Madagascar (10.0%) (p < 0.001). Details of the cardiometabolic risk factors across the countries are shown in Table 2. When participants were assessed according to their hypertension status (Table 3), diabetes mellitus and hypercholesterolaemia were more common among participants with hypertension (17.7 vs 10.0%; p = 0.010 and 25.8 vs 18.0%; p = 0.008, respectively) than in normotensives. With regard to WC, 73.4% of women

had a WC > 88 cm, most (79.4%) of whom were hypertensive, opposed to 67.7% who were non-hypertensive (p = 0.004). This difference was not statistically significant among the men. Overall, participants with hypertension were more likely to be overweight (33.2 vs 30.5%) and obese (42.5 vs 16.8%) (p < 0.001), but reported lower smoking rates (15.0 vs 24.1%; p = 0.002). Hypertension and smoking were more prevalent in participants with diabetes (83.3 vs 71.9%; p = 0.010 and 19.7 vs 17.9%; p = 0.019, respectively). The distribution of other risk factors,

150

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 3, May/June 2017

Table 4. Risk factors according to diabetes status in the study participants

Table 2. Prevalence of selected risk factors across participating countries Cameroon Nigeria n (%) n (%)

Risk factor

Madagascar n (%)

DRC n (%)

Total n (%)

p-value

Hypertension (n = 844) Yes

141 (91.5) 141 (66.8) 237 (99.1) 108 (45.0) 630 (74.1)

13 (8.5)

70 (33.2)

02 (0.9)

0.000

132 (55.0) 220 (25.9)

Diabetes (n = 839) Yes

24 (15.6)

130 (84.4) 154 (75.2) 204 (85.0) 219 (91.3) 707 (84.3)

51 (24.8)

36 (15.0)

21 (8.7)

132 (15.7)

0.000

Alcohol consumption (n = 309) Lowâ&#x20AC;&#x201C;moderate

71 (63.4) 03 (100.0) 98 (79.0)

58 (82.8) 230 (74.4)

Excessive

41 (36.6)

12 (17.2)

00 (0.0)

26 (21.0)

0.007

79 (25.6)

Smoking (n = 844) Current

10 (6.5)

04 (1.8)

11 (4.6)

48 (20.0)

73 (8.6)

Former

10 (6.5)

18 (8.5)

15 (6.3)

31 (12.9)

74 (8.7)

Never

0.000

133 (87.0) 190 (89.7) 213 (89.1) 161 (67.1) 697 (82.7) 28 (18.2)

53 (25.1)

64 (26.7) 122 (50.8) 267 (31.6)

Overweight

45 (29.2)

60 (28.4)

76 (31.6)

94 (39.2) 275 (32.6)

Obese

69 (44.8)

85 (40.3)

88 (36.7)

24 (10.0) 266 (31.5)

Morbidly obese

12 (8.8)

13 (6.2)

11 (5.0)

00 (0.0)

0.000

36 (4.3)

p-values = comparison of variables across countries.

Table 3. Risk factors according to hypertension status in the study participants

Variable

Nonhypertensives n (%)

Total (n = 844) n (%)

p-value 0.002

Tobacco smoking (n = 844) Current

42 (6.7)

31 (14.1)

73 (8.6)

Former

52 (8.3)

22 (10.0)

74 (8.8)

530 (85.0)

167 (75.9)

697 (82.6)

Never Alcohol consumption (n = 309) Low to moderate

195 (73.6)

35 (79.5)

230 (74.4)

Excessive

70 (26.4)

09 (20.5)

79 (25.6)

152 (24.3)

115 (52.7)

267 (31.5)

0.460

Obesity (n = 844) Normal Overweight

208 (33.2)

67 (30.5)

275 (32.5)

Obese

232 (37.1)

34 (15.9)

266 (31.5)

34 (5.4)

02 (0.9)

36 (4.5)

Morbidly obese

0.000

Waist circumference (n = 486) Men (> 102 cm)

76 (31.9)

86 (34.7)

162 (33.3)

0.564

Women (> 88 cm)

189 (79.4)

168 (67.7)

357 (73.4)

0.004 0.007

Diabetes mellitus (n = 839) Yes

110 (17.7)

22 (10.0)

132 (15.7)

509 (82.3)

198 (90.0)

707 (84.3)

Hypercholesterolaemia (n = 811) Yes

102 (25.8)

75 (18.0)

177 (21.8)

293 (74.2)

341 (82.0)

634 (78.2)

p-value = comparison of variables between the two groups.

Nondiabetics n (%)

Total n (%)

p-value

Tobacco smoking (n = 834) Current

07 (5.3)

66 (9.4)

73 (10.6)

Former

19 (14.4)

54 (7.9)

73 (10.6)

Never

106 (80.3)

582 (82.7)

688 (78.8)

Low to moderate

30 (69.7)

199 (75.0)

229 (75.1)

Excessive

13 (30.2)

66 (25.0)

79 (24.9)

0.019

Alcohol consumption (n = 308) 0.456

Obesity (n = 839) Normal

37 (28.0)

228 (32.2)

265 (31.6)

Overweight

42 (31.8)

228 (32.2)

270 (32.2)

Obese

44 (33.3)

222 (31.6)

266 (31.7)

Morbidly obese

09 (6.9)

29 (4.0)

38 (4.5)

0.462

Men (> 102 cm) (n = 359)

10 (29.4)

85 (26.1)

95 (26.4)

0.685

Women (> 88 cm) (n = 478)

29 (76.3)

319 (72.5)

348 (72.8)

0.706 0.007

Hypertension (n = 839) Yes

110 (83.3)

509 (71.9)

619 (73.7)

22 (16.7)

198 (28.1)

220 (26.3)

Hypercholesterolaemia (n = 809)

including hypercholesterolaemia, increased WC, overweight and obesity, and excessive alcohol consumption, was not significantly different between the participants with and without diabetes. Details of the risk factors according to presence or absence of diabetes are shown in Table 4. The overall prevalence of the MS, impaired fasting glucose levels (IFG) and diabetes mellitus was 39.4, 9.3 and 15.7%, respectively. Detailed prevalences of the MS, IFG and diabetes according to urban or rural and hypertensive status, gender and country are presented in Fig. 1. The highest prevalence of the

Hypertensives n (%)

Variable

Diabetics n (%)

Waist circumference

Obesity (n = 844) Normal

AFRICA

0.008

Yes

15 (22.1)

161 (21.7)

176 (21.8)

53 (77.9)

580 (78.3)

633 (78.2)

0.949

Diabetics = participants with diabetes mellitus; non-diabetics = participants without diabetes mellitus; p-values = comparison of variables between both groups.

MS was reported in Nigeria (62.1%), then Cameroon (45.2%), DRC (31.9%), and the lowest in Madagascar (27.7%). IFG was most prevalent in Cameroon (15.3%), followed by Madagascar (10.4%), DRC (8.3%) and Nigeria (4.0%). Nigeria had the highest prevalence of diabetes (25.0%), then Cameroon (15.6%), DRC (15.0%) and finally Madagascar (8.7%). Both the MS and IFG were more prevalent in hypertensive patients than in non-hypertensive subjects (47.8 vs 8.3% and 10.1 vs 6.2%, respectively). Comparing gender, the MS was more prevalent in females (44.7 vs 32.1%), but incidence of IFG and diabetes was higher in males (13.6 and 17.2%) compared to females (6.2 and 12.7%), respectively. With regard to urban and rural status, the MS and diabetes were more prevalent in semi-urban dwellers (57 and 24.1%), opposed to urban dwellers (34.3 and 12.3%, respectively).

Discussion In this self-selected group of participant in a hospital-based study of cardiometabolic risk factors among adults in four SSA countries, we found a high prevalence of the MS, IFG and diabetes mellitus in all countries. In spite of the differences observed between countries, which may reflect differences in healthcare access and resources, and possibly selection bias, these findings clearly signify the rapid growth of cardiovascular risk factors in a region of the world that has traditionally been known as the hotspot of nutritional and infectious diseases. This study is therefore relevant for understanding the epidemiology of cardiovascular and metabolic risk profiles of adults in the region, a pivotal step in the control of the incidence of CVDs. The overall prevalence of the MS in our study population was 39.4% and ranged from 62.1% in Nigeria to 27.7% in

AFRICA

62.1

Percentage (%)

50 40

45.2 39.4

34.3

32.1

31.9

9.3

12.3

Urban

13.6

17.7

17.2

8.1

Semi-urban

27.7

24.8

24.1

47.8

44.7

151

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 3, May/June 2017

12.7 6.2

Males

Females

Metabolic syndrome

10.1

HTN

15.3 15.6 8.3

6.2

N-HTN

Cameroon

Impaired fasting glucose

15.7

10.4

Nigeria

8.3

DRC

10.4 8.7

Madagascar

9.3

Total

Diabetes mellitus

Fig. 1. P revalence of the metabolic syndrome, impaired fasting glucose levels and diabetes across countries, urbanicity, gender and hypertension status. HTN = hypertensives, N-HTN = non-hypertensives

Madagascar. This was particularly for hypertensive subjects, female participants and semi-urban dwellers. The overall prevalence of the MS was lower than reported in Ghana among hypertensive patients. It was however similarly observed that the MS was more prevalent among women than men (OR: 4.88, p = 0.027) in this study.17 Another study among newly diagnosed type 2 diabetes subjects revealed higher prevalences of the MS of 68 and 81%, using IDF and WHO criteria, respectively. Again, as in our study, the MS was common in women and was driven essentially by female gender, family history of diabetes, overweight and obesity.18 IFG overall prevalence was 9.3% and ranged from 15.3% in Cameroon to 4.0% in Nigeria. Our findings are however higher than reported in a community-based study in South Africa,19 and Nigeria.20 These differences could be accounted for by the differences in study types (hospital based vs community based) and also geographical variations in the populations studied. However, the high prevalence of IFG among the participants is significant, as this represents a group of individuals at increased risk for transition to higher cardiovascular risk and the eventual development of diabetes if not properly controlled with lifestyle and dietary modifications. Recent publications have highlighted the rapidly increasing prevalence of hypertension, coupled with under-diagnosis, undertreatment and low control rates in SSA.4,20,21 The high prevalence of hypertension in our hospital-based study and the fact that 25.8% of these patients were newly diagnosed or undiagnosed cases is therefore not surprising. The situation was similar with diabetes mellitus, with an overall prevalence of 15.7%, with 6.9% being undiagnosed cases, as previously described.22 In a recent meta-analysis that focused on the burden of hypertension in Africa,4 the pooled prevalence was 30%. Our prevalence is equivalent to the highest prevalence of 70% in the pooled studies. Another recent population-based study in Cameroon21 reported a prevalence of 47.5%, which was lower than reported in our cohort. The CLARIFY registry, which explored geographical variations in cardiovascular risk factors among coronary artery disease (CAD) patients, reported a high prevalence of hypertension of 48% in Eastern Europe.23 The differences observed in these studies and others could be due to differences in populations studied and methodologies employed. Previous regional-based studies using

similar methodology to ours are non-existent, therefore limiting the possibility for adequate comparison. The high prevalence of diabetes in our study (15.7%) was slightly below the 17% noted among CAD patients in Eastern Europe but far lower than the 60% in the Middle East.23 While we acknowledge the dearth of African regional data on diabetes, some national studies are worth noting. The highest prevalence of diabetes among participating countries was from Nigeria, with a prevalence rate of 24.8%. This was lower than the 28.2% noted in a community-based study in South Africa,19 but higher than the 10.1% reported in a self-selected population study in Cameroon.22 Variations in degree of urbanisation, and differences in lifestyle, environmental factors and study settings (population vs hospital based) as well as sample sizes most likely account for the differences seen in these studies. Overall mean BMI of our study participants was 28.5 kg/m2, which was higher than reported in Benin,8 although it was lower than reported in Ghana among hypertensive subjects.17 About one in three of the study participants was overweight or obese. This is likely to be explained by the increasing adoption of Western lifestyles, especially in urban areas (which were in the majority in our study), limited physical activity and increased sedentary lifestyles, which are wrongly attributed to good living. Similarly, a high prevalence of obesity has been reported in other parts of Africa,8,17,24 in relation to urbanisation and high socio-economic status.25 A community-based study in Cameroon by Fezeu and colleagues in 2010 demonstrated the influence of ethnicity and urbanisation on abdominal adiposity and obesityrelated abnormalities.26 A quarter of participants reported excessive alcohol consumption, and approximately one in five was either a current or former smoker. This is similar to the 19% smoking prevalence reported in Eastern Europe.23 These are well-established drivers for CVD,27 metabolic and other NCDs and most likely account in part for the high rates of hypertension, diabetes and obesity in our cohort. Our findings are supported by a recent meta-analysis of prospective studies on the association of alcohol consumption and CVD risk and mortality, where it was found that low-to-moderate alcohol consumption was inversely significantly associated with the risk of CVD and all-cause mortality among hypertensive patients.27 Risk profiles of the participants were examined according to hypertension status. A high prevalence of diabetes (17.7%)

152

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

was noted among the hypertensive subjects, compared to 10% in non-hypertensives. This was half that reported in Ghana among hypertensive subjects,17 although higher than the 13.5% reported in Cameroon.28 Hypertensive patients were also more likely to be overweight and obese than non-hypertensive subjects, with prevalence rates of 33.1 and 42.8%, compared to 30.5 and 16.8%, respectively. All other studied risk factors, such as hypercholesterolaemia, abdominal adiposity (WC > 88 cm for women and 102 cm for men), and excessive alcohol consumption were more prevalent among hypertensive subjects, except for smoking. The high prevalence of cardiometabolic risk factors reported in our study is similar to reports by Akintunde et al. among university staff in Nigeria.20 Besides factors such as a high-salt diet, low physical activity and high socio-economic status (not examined in our study), these are established risk factors for hypertension, which in itself is a major risk for CVD. Urbanisation, among other determinants, has largely been queried.8,19,29 Our study showed that all risk factors studied were most prevalent among participants with diabetes. About three out of four diabetic subjects had hypertension. Other studies have reported a high prevalence of high blood pressure among diabetic subjects in Cameroon30 and Tanzani,31 although lower than in ours. The higher prevalence of overweight, obesity (abdominal and general) as reflected in WC and mean BMI, hypercholesterolaemia, alcohol abuse and smoking, being more common in diabetic than non-diabetic subjects, is however an expected finding, as they all have individual and associative effects in predisposition to the development of diabetes.8,30 Therefore, while diabetes in itself has been demonstrated to be an independent cardiovascular risk factor,32 the impact of its association or cumulative effect with other traditional risk factors in the development, progression, morbidity and mortality linked with CVDs cannot be overemphasised.

Limitations and strengths of the study Our study has several limitations that deserve mention. First the hospital base of the recruitments and the selected nature of the participants could have increased the chances that those included were at high risk for metabolic risk factors, which therefore could account for the high prevalence of cardiometabolic risk factors in our study. Secondly, the method of diagnosis of hypertension could be subject to debate, but it has been clearly evidenced by Burgess et al. that failure to carry out multiple measurements to conﬁrm the diagnosis may lead to false positives.33 Thirdly, quantity or concentration of alcohol in the local beer may vary from one country to another, and we could not assess non-industrial alcoholic beverages. Lastly, although the overall sample size was large, the number of patients contributed from each participating centre within the countries tended to be small, therefore precluding meaningful centre-level analysis. In spite of these limitations, the multi-centre, multi-national character of this study increased our chances of adequately exploring the prevalence of cardiometabolic risk factors in the participating countries, and demonstrating evidence of the growing cardiovascular risk factors in this region plagued with communicable diseases. The use of well-trained data collectors (medical practitioners) also gave confidence in the measured parameters.

AFRICA

Conclusions This study reports alarmingly high prevalences of cardiometabolic risk factors among adults presenting at urban and semi-urban hospitals in selected countries in SSA, which is in line with IDF projections of NCDs (hypertension and diabetes mellitus) in the region. It also raises the question of the influence of rapid urbanisation on the development of risk factors for imminent cardiovascular and metabolic diseases. This has considerable public health impact for an already economically disadvantaged setting to design new methods or further strengthen existing measures and interventions for the control of chronic diseases in the region. We thank all the investigators who participated in data acquisition: from Madagascar: Rakotoarisoa Bodosoa, Raharimanana Lanto, Rakotoarimanana Jean Jacques,

Ratavilahy Roland, Andrianandrasana Hery, Rabarijoelina

Claude, Rakotoarisoa Holiarivelo, Johanes Abel, Rakotoniaina Beatrice, Razafindramiandra Jacky, Raheliarisoa Julia, Rabetrano Alice, Rasolonjatovo Methouchael, Miandrisoa Rija Mikhael, Rakotozafy Joseline, Raveloarison Marguerite, Ramiandrisoa Bodovololona, Randriamiarisoa Ny Aina, Raniriharisoa Voahirana, Rasolofomanana Ndrina, Rasamimanana Nivo Nirina and Randriantsoa Eric; from Cameroon: Nzundu Anne, Mfulu Papy, Mumbulu Erick, Christian Nsimba Luzolo, Mr Boderal Fundu, Tswakata Masam, Iwnga Kabenba, Lepica Bonpeka, Murielle Longokolo, Tondo, Bandubola Dedie, Kahamba Jean Louis, Massamba Mp Cla, Loshisha-Armod, Bhuvem, Nzambi Mpvngv Stephane, Jimm Pierre K and Toure Wenana Parfait; from the Democratic Republic of Congo: Toko Olivier, Nzundu Annie, Tswakata Masam, Musibisoli Dieudonne, Longokolo Mireille, Bandubola Dedie, Kahamba Jean-Louis, Massamba Mpela and Loshisha Arnold. We also thank the staff of the Clinical Research Education, Networking and Consultancy (CRENC), Cameroon for their assistance in data analysis and interpretation, and for drafting the manuscript. We acknowledge funding support from Sanofi Aventis pharmaceuticals.

References 1.

Kengne AP, Mayosi BM. Readiness of the primary care system for non-communicable diseases in sub-Saharan Africa. The Lancet Global Health 2014; 2(5): e247–248. PMID: 25103156.

Mensah GA. The global burden of hypertension: good news and bad news. Cardiology Clinics 2002; 20(2): 181–185. PMID: 12119794.

Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365(9455): 217–223. PMID: 15652604.

Ataklte F, Erqou S, Kaptoge S, Taye B, Echouffo-Tcheugui JB, Kengne AP. Burden of undiagnosed hypertension in sub-Saharan Africa: a systematic review and meta-analysis. Hypertension 2015; 65(2): 291–298. PMID: 25385758.

Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16(2): 434–444. PMID: 8432214.

International Diabetes Federation. IDF Diabetes Atlas. 5th edn. Brussels, Belgium: International Diabetes Federation; 2011, cited 2016 2 June. Available from: http://www.idf.org/sites/default/files/5E_ IDFAtlasPoster_2012_EN.pdf.

Katte JC, Dzudie A, Sobngwi E, Mbong EN, Fetse GT, Kouam CK, et al. Coincidence of diabetes mellitus and hypertension in a semi-urban Cameroonian population: a cross-sectional study. BMC Public Health 2014; 14: 696. PMID: 25000848.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Sodjinou R, Agueh V, Fayomi B, Delisle H. Obesity and cardio-

153

study. Br Med J Open 2012; 2(4): e001217. PMID: 22923629.

metabolic risk factors in urban adults of Benin: relationship with

22. Echouffo-Tcheugui JB, Dzudie A, Epacka ME, Choukem SP, Doualla

socio-economic status, urbanisation, and lifestyle patterns. BMC Public

MS, Luma H, et al. Prevalence and determinants of undiagnosed diabe-

Health 2008; 8: 84. PMID: 18318907.

tes in an urban sub-Saharan African population. Primary Care Diabetes

Riha J, Karabarinde A, Ssenyomo G, Allender S, Asiki G, Kamali A, et

2012; 6(3): 229–234. PMID: 22682693.

al. Urbanicity and lifestyle risk factors for cardiometabolic diseases in

23. Ferrari R, Ford I, Greenlaw N, Tardif JC, Tendera M, Abergel H,

rural Uganda: a cross-sectional study. PLoS Med 2014; 11(7): e1001683.

et al. Geographical variations in the prevalence and management of

PMID: 25072243.

cardiovascular risk factors in outpatients with CAD: Data from the

10. World Health Organization. Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013–2020. apps.who.int/iris/ bitstream/10665/94384/1/9789241506236_eng.pdf.

contemporary CLARIFY registry. Eur J Prevent Cardiol 2015; B(8): 1056–1065. PMID: 25147344. 24. Kamadjeu RM, Edwards R, Atanga JS, Kiawi EC, Unwin N, Mbanya

11. Adler AJ, Prabhakaran D, Bovet P, Kazi DS, Mancia G, Mungal-Singh

JC. Anthropometry measures and prevalence of obesity in the urban

V, et al. Reducing cardiovascular mortality through prevention and

adult population of Cameroon: an update from the Cameroon Burden

management of raised blood pressure: a World Heart Federation road-

of Diabetes Baseline Survey. BMC Public Health 2006; 6: 228. PMID:

map. Global Heart 2015; 10(2): 111–122. PMID: 26213298.

16970806.

12. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo

25. Njelekela MA, Liu E, Mpembeni R, Muhihi A, Mligiliche N, Spiegelman

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

D, et al. Socio-economic status, urbanization, and cardiometabolic risk

Prevention, Detection, Evaluation, and Treatment of High Blood

factors among middle-aged adults in Tanzania. East Afri J Public Health

Pressure: the JNC 7 report. J Am Med Assoc 2003; 289(19): 2560–2572. PMID: 12748199.

2011; 8(3): 216–223. PMID: 23120960 26. Fezeu L, Balkau B, Sobngwi E, Kengne AP, Vol S, Ducimetiere P, et al.

13. World Health Organization. Waist circumference and waist-hip ratio:

Waist circumference and obesity-related abnormalities in French and

Report of a WHO Expert Consultation, Geneva, 2008. whqlibdoc.who.

Cameroonian adults: the role of urbanization and ethnicity. Int J Obes

int/publications/2011/9789241501491_eng.pdf. 14. World Health Organization. Global database on body mass index [cited 2016 2 June]. Available from: http://apps.who.int/bmi/index.jsp.

2010; 34(3): 446–453. PMID: 20065972. 27. Huang C, Zhan J, Liu YJ, Li DJ, Wang SQ, He QQ. Association between alcohol consumption and risk of cardiovascular disease and all-cause

15. International Diabetes Federation. The IDF concensus worldwide defi-

mortality in patients with hypertension: a meta-analysis of prospec-

nition of the metabolic syndrome. 2006. https://www.idf.org/webdata/

tive cohort studies. Mayo Clin Proc 2014; 89(9): 1201–1210. PMID:

docs/MetS_def_update2006.pdf.

25091872.

16. Mukamal KJ. The effects of smoking and drinking on cardiovascular

28. Dzudie A, Kengne AP, Mbahe S, Menanga A, Kenfack M, Kingue

disease and risk factors. Alcohol Res Health 2006; 29(3): 199–202.

S. Chronic heart failure, selected risk factors and co-morbidities

PMID: 17373409.

among adults treated for hypertension in a cardiac referral hospital in

17. Bello-Rodriguez BM, Sanchez-Cruz G, Delgado-Bustillo F, Asiama G.

Cameroon. Eur J Heart Fail 2008; 10(4): 367–372. PMID: 18353716.

The relationship between metabolic syndrome and target organ damage

29. Helelo TP, Gelaw YA, Adane AA. Prevalence and associated factors of

in Ghanaians with stage-2 hypertension. Ghana Med J 2013; 47(4):

hypertension among adults in Durame Town, southern Ethiopia. PloS

189–196. PMID: 24669025.

One 2014; 9(11): e112790. PMID: 25415321.

18. Hossain S, Fatema K, Ahmed KR, Akter J, Chowdhury HA, Shahjahan

30. Choukem SP, Kengne AP, Dehayem YM, Simo NL, Mbanya JC.

M, et al. Prevalence and determinants of metabolic syndrome among

Hypertension in people with diabetes in sub-Saharan Africa: reveal-

newly diagnosed type 2 diabetic subjects according to different criteria.

ing the hidden face of the iceberg. Diabetes Res Clin Prac 2007; B(2):

Diabetes Metabolic Syndr 2015; 9(2): 120–123. PMID: 25470642.

293–299. PMID: 17184871.

19. Erasmus RT, Soita DJ, Hassan MS, Blanco-Blanco E, Vergotine Z,

31. Mwita JC, Mugusi F, Lwakatare J, Chiwanga F. Hypertension control

Kegne AP, et al. High prevalence of diabetes mellitus and metabolic

and other cardiovascular risk factors among diabetic patients at

syndrome in a South African coloured population: baseline data of

Muhimbili National Hospital, Tanzania. East Afr J Public Health 2012;

a study in Bellville, Cape Town. South Afr Med J 2012; 102(11 Pt 1): 841–844. PMID: 23116739. 20. Akintunde AA, Salawu AA, Opadijo OG. Prevalence of traditional cardiovascular risk factors among staff of Ladoke Akintola University of Technology, Ogbomoso, Nigeria. Nigerian J Clin Prac 2014; 17(6): 750–755. PMID: 25385914. 21. Dzudie A, Kengne AP, Muna WF, Ba H, Menanga A, Kouam Kouam C, et al. Prevalence, awareness, treatment and control of hypertension in a self-selected sub-Saharan African urban population: a cross-sectional

9(2): 70–73. PMID: 23139960. 32. Stamler J, Stamler R, Brown WV, Gotto AM, Greenland P, Grundy S, et al. Serum cholesterol. Doing the right thing. Circulation 1993; 88(4 Pt 1): 1954–1960. PMID: 8403343. 33. Burgess SE, MacLaughlin EJ, Smith PA, Salcido A, Benton TJ. Blood pressure rising: differences between current clinical and recommended measurement techniques. J Am Soc Hypertens 2011; 5(6): 484–488. PMID: 22015319.

154

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Assessment of myocardial repolarisation parameters in patients with familial Mediterranean fever Kayıhan Karaman, Metin Karayakalı, Ertuğrul Erken, Ahmet Demirtaş, Mustafa Öztürk, Fatih Altunkaş, Arif Arısoy, Oğuzhan Ekrem Turan, Köksal Ceyhan, Ataç Çelik

Abstract Background: Familial Mediterranean fever (FMF) is a chronic, recurrent auto-inflammatory disease characterised by self-terminating attacks of fever and sterile polyserositis. The main cause of death in auto-inflammatory diseases is cardiovascular events. Additionally, auto-inflammatory diseases have potential effects on the myocardial repolarisation parameters, including the T-wave peak-to-end (Tp-Te) interval, cTp-Te interval (corrected Tp-Te) and the cTp-Te/ QT ratio. The aim of this study was to analyse the efficacy of myocardial repolarisation alterations in anticipation of cardiovascular risks in patients with FMF. Methods: This study included 66 patients with FMF and 58 healthy control subjects. Tp-Te and cTp-Te intervals and the cTp-Te/QT ratio were measured from the 12-lead electrocardiogram. Results: In electrocardiographic parameters, analysis of QT, QT dispersion, corrected QT (QTc) and QTc dispersion were similar between the groups. The Tp-Te and cTp-Te intervals and Tp-Te/QT and cTp-Te/QT ratios were significantly prolonged in FMF patients. Multivariate linear regression analyses indicated that erythrocyte sedimentation rate was an independent predictor of a prolonged cTp-Te interval. Conclusions: Our study revealed that when compared with control subjects, Tp-Te and cTp-Te intervals and cTp-Te/QT ratio were increased in FMF patients. Keywords: familial Mediterranean fever, myocardial repolarisation, cTp-Te interval, cTp-Te/QT ratio Submitted 2/5/16, accepted 10/7/16 Cardiovasc J Afr 2017; 28: 154–158

www.cvja.co.za

DOI: 10.5830/CVJA-2016-074

Familial Mediterranean fever (FMF) is a chronic, recurrent autoinflammatory disorder with autosomal recessive inheritance characterised by self-limiting attacks of arthritis, peritonitis or

Department of Cardiology, Gaziosmanpasa University School of Medicine, Tokat, Turkey Kayıhan Karaman, MD, drkkaraman55@gmail.com Metin Karayakalı, MD Ertuğrul Erken, MD Ahmet Demirtaş, MD Mustafa Öztürk, MD Fatih Altunkaş, MD Arif Arısoy, MD Oğuzhan Ekrem Turan, MD Köksal Ceyhan, MD Ataç Çelik, MD

pleuritis and fever.1 Around the Mediterranean it is a common disease and most commonly occurs in Jews, Turks, Armenians and Arabs.2 FMF could become a major public health issue in these regions; therefore, early diagnosis and the necessary treatment are very important to the patient’s prognosis. Mutations in the MEFV (MEditerranean FeVer) gene, which encodes for a protein called pyrin, is necessary for a diagnosis of FMF.3 Mutated pyrin is associated with uncontrolled inflammation and it increases circulatory levels of acute-phase reactants and cytokines secreted by the neutrophils.4 It has been shown that underlying subclinical inflammation is present during attack-free periods in patients with FMF.3 Chronic systemic inflammation accelerates the natural process of atherosclerosis. The main cause of death in auto-inflammatory disorders is related to atherosclerosis and cardiovascular events.5 Several studies have shown that the cardiovascular effects of systemic inflammation may include increased frequency of lifethreatening ventricular arrhythmias,6 conduction disturbances,7 and cardiac autonomic dysfunction8 in auto-inflammatory disorders. The T wave on electrocardiography (ECG) indicates myocardial repolarisation, which can be evaluated with several ECG parameters, such as QT interval (QT), QT dispersion (QTd), corrected QT interval (QTc) and transmural dispersion of repolarisation.9,10 These parameters are usually used to diagnose pathology and detect risk of life-threatening ventricular arrhythmias. The Tpeak–Tend interval (Tp-Te), which is the interval between the peak and the end-point of the T wave on a resting ECG, and Tp-Te/QT ratio are accepted as a novel index of myocardial repolarisation. These are associated with an increased risk of ventricular arrhythmias.11 In this study, we investigated the possible effects on myocardial repolarisation of ongoing subclinical inflammation in FMF patients by analysis of ECGs. We aimed to evaluate the efficacy of the prediction of cardiovascular risks of possible non-specific repolarisation changes in patients with FMF.

Methods This study had a cross-sectional and observational design. Between August 2014 and January 2015, 66 FMF patients without cardiovascular involvement (39 females; mean age 28.6 ± 8.7 years), who were diagnosed with FMF according to the Tell– Hashomer diagnostic criteria,12 and 58 healthy controls matched for gender and age (35 females; mean age 28.7 ± 8.5 years), were included in this study. All the patients with FMF were treated chronically with colchicine. Mean duration of time elapsed from diagnosis of FMF was 7.9 ± 4.9 years. Excluded from the study were patients with diabetes mellitus, hypertension, congestive heart failure, smoking, coronary artery disease, valvular heart disease, previous history of myocardial infarction, hyperthyroidism, hypothyroidism, atrial fibrillation,

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

chronic kidney disease, chronic obstructive pulmonary disease, bundle brunch block, atrioventricular block and malignancy. The patients were evaluated with echocardiography and 12-lead ECG at least 10 days after an attack. Levels of haemoglobin and C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) were obtained from laboratory records. The study protocol was approved by the institutional ethics committee. Informed written consent was obtained from each patient. Twelve-lead ECGs (10 mm/mV, 25 mm/s, Cardiofax V; Nihon Kohden Corp, Tokyo, Japan) were obtained with the subject at rest in the supine position. All ECGs were transferred to a computer via a scanner and then used at 400% magnification via Adobe Photoshop software. Measurements of Tp-Te and QT intervals were performed on the computer by two experienced cardiologists, who were blinded to the clinical data of each patient and control subject. QT and R-R intervals were measured in all derivations. The QT interval was defined as the time from the start of the QRS to the point at which the T wave returns to the isoelectric line. The R-R interval, which was measured as the average of three complexes, was used to calculate heart rate, and the QTc was calculated with Bazett’s formula.13 The QTd was defined as the difference between the maximum and minimum QT interval in different leads. Excluded from the study were subjects with U waves and low-amplitude T waves on their ECGs. Although tail and tangent methods can be used in the measurement of Tp-Te interval, the tail method is a better predictor of mortality than the tangent method,14 and was therefore used in this study. In this method, the Tp-Te interval was defined as the interval from the peak to the end of the T wave to the point where the wave reached the isoelectric line.15 Measurement of the Tp-Te interval was obtained from leads V2 and V5, corrected for heart rate (cTp-Te).11 The Tp-Te/QT and cTp-Te/QT ratios were calculated from these measurements. Measurements were made by two independent cardiologists taking the average of three consecutive beats. Intra-observer variability for Tp-Te interval obtained from leads V2 and V5 were 3.4 and 3.8%, respectively. Furthermore, inter-observer variability for the Tp-Te interval obtained from leads V2 and V5 were 2.5 and 2.9%, respectively. All echocardiographic examinations (General Electric Vivid S5, Milwaukee, WI, USA) were performed in all subjects using a 2.5–3.5-MHz transducer in the left decubitus position. Two-dimensional and pulsed Doppler measurements were obtained using the criteria of the American Society of Echocardiography.16 Left ventricular ejection fraction (LVEF) was assessed using Simpson’s method. Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) were performed using Simpson’s method in the apical four- and two-chamber views at end-diastole and end-systole.

Statistical analysis Statistical analyses were performed using SPSS software (SPSS 18.0 for windows, Inc, Chicago, IL, USA). Categorical variables are expressed as n (%) and continuous variables are expressed as mean ± standard deviation. Mean values of continuous variables were compared between the groups using the Student’s t-test.

155

The chi-squared test was used to assess differences between categorical variables. The relationship between parameters was determined using Pearson’s coefficient of correlation. Multivariate linear regression analysis was used to identify the independent predictors of prolonged cTp-Te interval and independent variables that differed significantly in the bivariate analyses (p < 0.1). A p-value < 0.05 was considered significant.

Results Baseline demographic, clinical and echocardiographic characteristics of all subjects are shown in Table 1. Age, gender, body mass index, and glucose and cholesterol levels were similar in both groups. All subjects had similar heart rates, and no significant differences were observed in blood pressure between the groups. The standard echocardiographic values were within normal limits for both groups. Additionally, erythrocyte sedimentation rate (ESR) and and C-reactive protein (CRP) levels were significantly higher in FMF patients compared with the controls. Table 2 shows ECG measurements of the two groups. Heart rate, QT interval, QTd, QTc interval and QTc dispersion were similar between the groups. The Tp-Te and cTp-Te intervals (Fig.1), and Tp-Te/QT and cTp–Te/QT ratios were significantly prolonged in FMF patients compared to the controls. Correlations and regression analyses between the cTp-Te interval in the V5 lead and the study parameters were performed. There were significant correlations between the cTp-Te interval and ESR (r = 0.418, p < 0.001) and CRP levels (r = 0.382, p < 0.001) and neutrophil–lymphocyte ratio (NLR) (r = 0.192, p = 0.033) and mitral E/A ratio (r = –0.190, p = 0.034) (Fig. 2A, B). Table 1. Demographic, echocardiographic and biochemical characteristics in patients with FMF and controls FMF patients Controls (n = 66) (n = 58) p-value Age (years) 26.0 ± 5.0 26.5 ± 5.5 0.616 Female, n (%) 39 (59.1) 35 (60.3) 0.887 24.1 ± 4.3 22.7 ± 4.3 0.079 BMI (kg/m2) 1.96 ± 0.17 1.63 ± 0.18 0.051 BSA (m2) E/A ratio 1.58 ± 0.5 1.46 ± 0.44 0.182 LVEDV (ml) 92.6 ± 6.5 91.3 ± 6.4 0.253 LVESV (ml) 77.4 ± 12.8 79.6 ± 12.4 0.830 LVEF (%) 55.5 ± 3.7 54.9 ± 3.4 0.352 Glucose (mg/dl) 91.5 ± 9.1 89.6 ± 7.6 0.223 (mmol/l) (5.05 ± 0.51) (4.97 ± 0.42) Total cholesterol (mg/dl) 163.9 ± 28.6 162.1 ± 32.5 0.750 (mmol/l) (4.25 ± 0.74) (4.20 ± 0.84) LDL cholesterol (mg/dl) 103.3 ± 26.3 96.4 ± 29.1 0.164 (mmol/l) (2.68 ± 0.68) (2.5 ± 0.75) Haemoglobin (mg/dl) 14.3 ± 1.5 14.8 ± 1.2 0.099 CRP (mg/l) 6.0 ± 4.8 3.8 ± 0.9 < 0.001 ESR (mm/h) 11.4 ± 12.5 6.4 ± 5.7 0.006 NLR 2.09 ± 1.05 2.0 ± 0.68 0.577 7.37 ± 1.82 7.76 ± 1.93 0.244 WBC count (×109/l) BMI = body mass index; BSA = body surface area; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular endsystolic volume; LVEF = left ventricular ejection fraction; LDL = low-density lipoprotein; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; NLR = neutrophil–lymphocyte ratio; WBC = white blood cell. Data are presented as mean ± SD.

156

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 2. Electrocardiographic findings in patients with FMF and controls

Table 3. Bivariate correlation and multivariate linear regression analyses between prolonged cTp-Te interval (lead V5) and study parameters

FMF patients Controls (n = 66) (n = 58) p-value Heart rate (beat/min) 75.3 ± 10.6 78.4 ± 12.6 0.141 V2 351.7 ± 19.7 QT interval (ms) 347.3 ± 22.8 0.256 V5 352.3 ± 19.9 347.3 ± 22.8 0.291 QT dispersion 21.6 ± 9.4 20.7 ± 8.9 0.572 V2 391.0 ± 22.6 QTc interval (ms) 396.7 ± 31.5 0.247 V5 391.7 ± 23.6 397.5 ± 32.2 0.252 QTc dispersion 24.0 ± 10.2 23.9 ± 10.3 0.931 V2 Tp-Te interval (ms) 97.4 ± 10.0 88.0 ± 5.7 < 0.001 V5 93.3 ± 7.7 86.6 ± 10.2 < 0.001 cTp-Te interval (ms) V2 108.7 ± 12.5 100.2 ± 9.7 < 0.001 V5 104.2 ± 11.1 99.0 ± 13.9 0.023 cTp-Te/QT ratio (ms) V2 0.31 ± 0.04 0.29 ± 0.03 0.004 V5 0.29 ± 0.04 0.27 ± 0.03 0.009 QTc = corrected QT; Tp-Te = T-wave peak-to-end interval; cTp-Te: corrected Tp-Te. Data are presented as mean ± SD.

Multivariate linear Bivariate correlation regression Parameters r p-value p-value β ESR 0.418 < 0.001 0.289 0.004 CRP 0.382 < 0.001 0.179 0.070 NLR 0.192 0.033 0.121 0.176 E/A ratio –0.190 0.034 –0.060 0.486 Body mass index 0.165 0.067 0.074 0.387 WBC count 0.163 0.071 0.062 0.487 Age 0.063 0.484 – – LVEF –0.032 0.721 – – Female –0.140 0.120 – – CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; LVEF = left ventricular ejection fraction; NLR = neutrophil–lymphocyte ratio; WBC = white blood cell.

160

Multivariate linear regression analysis demonstrated that the ESR (β = 0.289, p = 0.004) was an independent predictor of a prolonged cTp-Te interval (Table 3). In addition there were significant correlations between the cTp-Te/QT ratio in lead V5 and ESR (r = 0.422, p < 0.001) and CRP levels (r = 0.407, p < 0.001) and NLR (r = 0.207, p = 0.021) and mitral E/A ratio (r = –0.189, p = 0.035).

cTp-Te V5 (ms)

140

Discussion

120 100 80

In the current study, we found that cTp-Te interval and cTp-Te/ QT ratio were significantly increased in the FMF group compared to the control group. In addition we found that the increased cTp-Te interval and cTp-Te/QT ratio were positively correlated with CRP and ESR levels and NLR and mitral E/A ratios. We also found that ESR was an independent predictor of a prolonged cTp-Te interval in patients with FMF. FMF is a hereditary transmitted auto-inflammatory disease characterised by recurrent and paroxysmal fever, peritonitis, pericarditis, arthritis and skin rashes.1 Some researchers have shown that subclinical inflammation continues not only during A

Control

FMF

Fig. 1. Box plot shows the cTp-Te values of FMF patients and controls.

attacks, but also during the attack-free periods in patients with FMF.17,18 Ongoing, low-grade inflammation in chronic inflammatory diseases leads to deterioration of endothelial function, myocarditis, vasculitis and fibrosis of the heart B

160

Control FMF

140 cTp-Te V5 (ms)

cTp-Te V5 (ms)

140

Control FMF

120 100 80

120 100 80 r = 0.418, p < 0.001

r = 0.382, p < 0.001

0.0

5.0

10.0 15.0 CRP (mg/l)

20.0

25.0

20 40 Erythrocyte sedimentation rate

Fig. 2. C orrelations between cTp-Te interval and C-reactive protein (A), and erythrocyte sedimentation rate (B) levels.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

muscle.19-21 It is well known that impaired endothelial function plays an important role in the pathogenesis of atherosclerosis,22 which has been demonstrated in FMF patients.23 Previous studies investigated vascular and cardiac function in FMF. Calıskan et al.24 analysed coronary flow reserve by transthoracic echocardiography and found that coronary microvascular function and left ventricular diastolic function were impaired in patients with FMF. This suggests that an existing inflammatory process also affects the coronary microvascular tree. In another study, Akdogan et al.23 showed impaired flow-mediated dilatation (FMD) of the brachial artery in patients with FMF, and impaired FMD has been shown to be correlated with coronary endothelial dysfunction.25 Although the exact mechanisms of arrhythmia in FMF are unknown, the authors proposed that conduction disturbances and rhythm disorders could be associated with ongoing inflammation-related ischaemia and/or focal fibrosis. Fibrosis in the heart muscle plays an important role in the pathogenesis of ventricular arrhythmias. Parameters of autonomic cardiac tone, such as heart rate variability (HRV), heart rate turbulance (HRT) and QT dynamics, are useful for risk evaluation for ventricular arrhythmias, and abnormalities in these parameters may precede the development of fibrosis.26 To date, subclinical cardiovascular involvement associated with cardiac autonomic dysfunction in FMF has been reported in many studies. Fidanci et al.27 demonstrated that one of the time-domain parameters of HRV calculated and analysed by 24-hour ambulatory electrocardiographic monitoring software was significantly decreased in patients with FMF compared to controls. Similarly, Canpolat et al.28 showed abnormal HRV and HRT values in FMF patients. In light of these studies, we hypothesised that impaired endothelial function reduced coronary flow reserve and caused microvascular ischaemia and inflammation-related fibrosis, which, by affecting ventricular repolarisation, may lead to arrhythmias in FMF patients. Myocardial repolarisation is mostly evaluated using measurements of QT interval and T wave on ECG and it may be affected by some pathophysiological processes such as genetic diseases, acquired clinical conditions, and/or drugs.29,30 Prolonged QT and QTc intervals may be caused by life-threatening ventricular arrhythmias, such as polymorphic ventricular tachycardia, torsades de pointes, and ventricular fibrillation.31 Several investigators have evaluated QT and QTc intervals in inflammatary diseases. In a study by Acar et al.,32 they reported a similar QT interval but significantly longer maximum QTc interval only in rheumatoid arthritis patients compared to control subjects. In another study, Akcay et al.6 showed statistically significantly longer maximum QT and maximum QTc intervals only in FMF patients. In the same study,33 FMF patients had similar QT and QTc intervals compared with healthy controls. In our study, QT and QTc intervals were similar between the groups. QTd is the most frequently used parameter to detect the dispersion of ventricular repolarisation and is accepted as a marker for arrhythmia and sudden death.34 QTd is superior to QT and QTc intervals in the assessment of ventricular arrhythmias. It has been demonstrated that a prolonged QTd is associated with an increased risk of ventricular arrhythmias in patients with hypertrophic cardiomyopathy and long-QT syndrome.35,36 Previous studies have shown that QTd was significantly higher in some inflammatory diseases.32,37

157

A number of studies have investigated the effect on QTd of systemic inflammation in patients with FMF. Akcay et al.6 showed that QTd was increased in FMF patients. On the other hand, in another study by Giese et al.,35 they evaluated the QTd values in 30 FMF patients and found similar findings between FMF patients and healthy controls. We also found the QTd values were similar between the two groups. Tp-Te interval is a new index of dispersion of myocardial repolarisation, which is related to ventricular arrhythmogenesis and sudden cardiac death.10,38 Several investigators showed that the Tp-Te interval is longer in disorders such as long-QT and Brugada syndromes.11 Yamaguchi et al.39 reported that the Tp-Te interval was more significant than QT dispersion in predicting torsade de pointes in patients with acquired long-QT syndrome. Increased Tp-Te interval may also be a predicting index for elevated risk of cardiovascular mortality in inflammatory diseases. It was reported that the Tp-Te interval was prolonged in patients with rheumatoid arthritis and systemic lupus erythematosus.32,37 In another study, Akcay et al.6 reported that the Tp-Te interval was increased in FMF patients. Similar to that study, we found that the Tp-Te interval was statistically significantly prolonged in FMF patients. Tp-Te interval is affected by variations in heart rate and body weight.15 Recently, the cTp-Te interval and cTp-Te/QT ratio were suggested to be more accurate measurements of the dispersion of myocardial repolarisation, compared to the QT, QTd, and Tp-Te intervals. In our study, we found significant differences in the cTp-Te interval and cTp-Te/QT ratio between FMF patients and control subjects. In the light of these data, we evaluated the effect of inflammatory markers on the cTp-Te interval in FMF patients and found that prolonged Tp-Te was positively correlated with ESR and CRP levels and NLR. In addition, we found that ESR was an independent predictor of a prolonged cTp-Te interval in patients with FMF. Our study has several limitations. The major limitation is the small size of the study population and it may have negatively affected the statistical results. Second, the study had a crosssectional design and there was no follow up of arrhythmic episodes in patients.

Conclusions The findings of this study demonstrate that increased cTp-Te interval and cTp-Te/QT ratio may create a specific risk for ventricular arrhythmias in patients with FMF. However, the underlying mechanism and prognostic effects are as yet unknown. Therefore larger, long-term prospective and multicentre followup studies are needed.

References 1.

Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998; 28: 659–664.

Heller H, Sohar E, Pras M. Ethnic distribution and amyloidosis in familial Mediterranean fever. Pathol Microbiol 1961; 24: 718–723.

Lachmann HJ. Clinical Immunology Review Series: an approach to the patient with a periodic fever syndrome. Clin Exp Immunol 2011; 165: 301–309.

Ben-Zvi I, Livneh A. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 2011; 7: 105–112.

158

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Del Rinco´n ID, Williams K, Stern MP, Freeman GL, Escalante A.

23. Akdoğan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Şahiner

not explained by traditional cardiac risk factors. Arthritis Rheum 2001;

L, et al. Are familial Mediterranean fever (FMF) patients at increased

44: 2737–2745.

risk for atherosclerosis? Impaired endothelial function and increased

Akcay A, Acar G, Sayarlioglu M, Sokmen A, Kaya H, Ispiroglu M, et

intima media thickness are found in FMF. J Am Coll Cardiol 2006; 48:

with familial Mediterranean fever. Mod Rheumatol 2009; 19: 550–555. Kaya EB, Yorgun H, Akdogan A, Ates AH, Canpolat U, Sunman H, et al. Heart-rate recovery index is impaired in Behcet’s disease. Tex Heart Inst J 2009; 36: 282–286. 8.

Rozenbaum M, Naschitz JE, Yudashkin M, Rosner I, Sabo E, Shaviv N, et al. Cardiovascular autonomic dysfunction in familial Mediterranean fever. J Rheumatol 2002; 29: 987–989.

Nature 1993; 362: 801–809.

High incidence of cardiovascular events in a rheumatoid arthritis cohort

al. QT dispersion and transmural dispersion of repolarization in patients 7.

AFRICA

Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol 1998; 30: 168–175.

10. Kors JA, Ritsema van Eck HJ, van Herpen G. The meaning of the Tp-Te

2351–2353. 24. Caliskan M, Gullu H, Yilmaz S, Erdogan D, Unler GK, Ciftci O, et al. Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 2007; 195: 161–167. 25. Neunteufl T, Heher S, Katzenschlager R, Wölfl G, Kostner K, Maurer G, et al. Late prognostic value of flow-mediated dilatation in the brachial artery of patients with chest pain. Am J Cardiol 2000; 86: 207–210. 26. Seferovic PM, Ristic AD, Maksimovic R, et al. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. Rheumatology 2006; 45: 39–42. 27. Fidanci K, Gulgun M, Demirkaya E, Acikel C, Kilic A, Gok F,

interval and its diagnostic value. J Electrocardiol 2008; 41: 575–580.

et al. Assessment of autonomic functions in children with familial

11. Castro Hevia J, Antzelevitch C, Tornes Barzaga F, Dorantes Sánchez

Mediterranean fever by using heart rate variability measurements. Int J

M, Dorticós Balea F, Zayas Molina R, et al. Tpeak-Tend and Tpeak-

Rheum Dis 2014. doi: 10.1111/1756-185X.12401.

Tend dispersion as risk factors for ventricular tachycardia/ventricular

28. Canpolat U, Dural M, Aytemir K, Akdoğan A, Kaya EB, Sahiner L.

fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol

Evaluation of various cardiac autonomic indices in patients with famil-

2006; 47: 1828–1834. 12. Livneh A, Langevitz P, Zemer D, Zaks D, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879–1885. 13. Bazett H. An analysis of the time relations of electrocardiograms. Heart 1920; 7: 353–355.

ial Mediterranean fever on colchicine treatment. Auton Neurosci 2012; 167: 70–74. 29. Smetana P, Schmidt A, Zabel M, Hnatkova K, Franz M, Huber K, et al. Assessment of repolarization heterogeneity for prediction of mortality in cardiovascular disease: peak to the end of the T wave interval and nondipolar repolarization components. J Electrocardiol 2011; 44: 301–308.

14. Tatlisu MA, Özcan KS, Güngör B, Ekmekçi A, Çekirdekçi EI,

30. Trinkley KE, Page RL, Lien H, Yamanouye K, Tisdale JE. QT interval

Aruğarslan E, et al. Can the T-peak to T-end interval be a predictor

prolongation and the risk of torsades de pointes: Essentials for clini-

of mortality inpatients with ST elevation myocardial infarction? Coron Artery Dis 2014; 25: 399–404. 15. Antzelevitch C, Sicouri S, Di Diego JM, Burashnikov A, Viskin S, Shimizu W, et al. Does Tpeak-Tend provide an index of transmural dispersion of repolarization? Heart Rhythm 2007; 4: 1114–1116. 16. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: A report from

cians. Curr Med Res Opin 2013; 29: 1719–1726. 31. Ozturk S, Karaman K, Cetin M, Erdem A. Polymorphic ventricular tachycardia (Torsades de pointes) due to licorice root tea. Arch Turk Soc Cardio 2013; 41: 241–244. 32. Acar GR, Akkoyun M, Nacar AB, et al. Evaluation of Tpe interval and Tp-e/QT ratio in patients with rheumatoid arthritis. Arch Turk Soc Cardio 2014: 42: 29–34.

the American Society of Echocardiography’s Guidelines and Standards

33. Giese A, Ornek A, Kurucay M, Kara K, Wittkowski H, Gohar F, et al.

Committee and the Chamber Quantification Writing Group, developed

P wave dispersion and QT dispersion in adult Turkish migrants with

in conjunction with the European Association of Echocardiography, a

familial mediterranean fever living in Germany. Int J Med Sci 2014; 11:

branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440–1463. 17. Uslu AU, Deveci K, Korkmaz S, Aydin B, Senel S, Sancaktar E, et al.

1140–1146. 34. Guntekin U, Gumrukcuoglu HA, Gunes Y, Gunes A, Simsek H, Sahin M, et al. The effects of perindopril on QT duration and dispersion in

Is neutrophil/lymphocyte ratio associated with subclinical inflammation

patients with coronary slow flow. Heart Vessels 2011; 26: 357–362.

and amyloidosis in patients with familial Mediterranean fever? Biomed

35. Buja G, Miorelli M, Turrini P, Melacini P, Nava A. Comparison of QT

Res Int 2013; 2013: 185317. 18. Lachmann HJ, Şengul B, Yavuzşen TU, Booth SE, Bybee A, Gallimore JR, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology 2006; 45: 746–750. 19. Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M. Cardiac involvement in systemic lupus erythematosus. Lupus 2005; 14: 683–686. 20. Sun JP, Khan MA, Farhat AZ, Bahler RC. Alterations in cardiac diastolic function in patients with ankylosing spondylitis. Int J Cardiol 1992; 37: 65–72. 21. Ikonomidis I, Lekakis J, Stamatelopoulos K, Markomihelakis N, Kaklamanis PG, Mavrikakis M. Aortic elastic properties and left ventricular diastolic function in patients with Adamantiades Behcet’s disease. J Am Coll Cardiol 2004; 43: 1075–1081. 22. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.

dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol 1993; 72: 973–976. 36. Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990; 63: 342–344. 37. Avci A, Demir K, Altunkeser BB, Yilmaz S, Yilmaz A, Ersecgin A, et al. Assessment of Inhomogeneities of repolarization in patients with systemic lupus erythematosus. Ann Noninvasive Electrocardiol 2014; 19: 374–382. 38. Gupta P, Patel C, Patel H, Narayanaswamy S, Malhotra B Green JT, et al. T(p-e]/QT ratio as an index of arrhythmogenesis. J Electrocardiol 2008; 41: 567–574. 39. Yamaguchi M, Shimizu M, Ino H, Terai H, Uchiyama K, Oe K, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci 2003; 105: 671–676.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

159

Saliva/serum ghrelin, obestatin and homocysteine levels in patients with ischaemic heart disease Nermin Kilic, Necati Dagli, Suleyman Aydin, Fazilet Erman, Yuksel Bek, Okhan Akin, SS Kilic, Haci Kemal Erdemli, Hasan Alacam

Abstract Background: We aimed to compare ghrelin, obestatin, homocysteine (Hcy), vitamin B12 and folate levels in the serum and saliva of ischaemic heart disease patients. Methods: Serum and saliva were collected from 33 ischaemic heart disease (IHD) patients and 28 age- and body mass index-matched healthy individuals. Levels of acylated and desacylated ghrelin, obestatin and Hcy were determined using the ELISA method. Results: Acylated ghrelin, desacylated ghrelin and obestatin levels in the saliva were found to be higher than those in the serum of the control group, while acylated and desacylated ghrelin levels in the saliva were significantly lower than those in the serum. Obestatin levels were higher in IHD patients (p = 0.001). Saliva and serum vitamin B12 and folate levels in IHD patients were significantly lower than in the control group (p = 0.001). Conclusions: It was determined that serum ghrelin levels increased in ischaemic heart disease patients, while serum levels of obestatin decreased. Keywords: saliva, homocysteine, ghrelin, obestatin, ischaemia Submitted 10/1/15, accepted 17/7/16 Cardiovasc J Afr 2017; 28: 159–164

www.cvja.co.za

DOI: 10.5830/CVJA-2016-075

Department of Medical Biochemistry, School of Medicine, Ondokuz Mayis University, Samsun, Turkey Nermin Kilic, MD

Department of Cardiology, School of Medicine, Firat University, Elazig, Turkey Necati Dagli, MD

Department of Medical Biochemistry, School of Medicine, Firat University, Elazig, Turkey Suleyman Aydin, MD Fazilet Erman, MD

Department of Biostatistics, School of Medicine, Ondokuz Mayis University, Samsun, Turkey Yuksel Bek, MD

Biochemistry Laboratory, Kecioren Education and Research Hospital, Ankara, Turkey Okhan Akin, MD

Department of Infectious Diseases and Microbiology, Training and Research Hospital, Samsun, Turkey SS Kilic, MD

Department of Medical Biochemistry, Corum Training and Research Hospital, Corum, Turkey Haci Kemal Erdemli, MD

Department of Medical Biochemistry, School of Medicine, Hacettepe University, Ankara, Turkey Hasan Alacam, MD, hasanalacam@hotmail.com

Ischaemic heart disease (IHD) is the leading cause of death in developing countries around the world.1 It is characterised by atherosclerosis, endothelial dysfunction, lipoprotein oxidation, leukocyte infiltration, the release of various chemotactic and growth factors, and accumulation of cholesterol, lipid and calcium. Fatty streaks cause atherosclerotic plaques, lipid accumulation, and acute and chronic luminal obstruction. The resulting constriction of arteries leads to lack of sufficient blood and oxygen supply to the target organs, which results in ischaemia and necrosis in these organs.2,3 Hormonal changes are the main alterations that occur in ischaemic heart disease.4 Recent studies have reported that ghrelin, the peptide hormone, plays a host of physiological roles in the cardiovascular system. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesised as a pre-prohormone and then proteolytically processed to yield a 28-amino acid peptide.5 This peptide was reported to induce growth hormone release; a wealth of evidence, however, has indicated many other physiological activities of ghrelin, including regulation of food intake and energy balance as well as of lipid and glucose metabolism. Ghrelin receptors have been detected in the hypothalamus and the pituitary, but also in the cardiovascular system, where ghrelin exerts beneficial haemodynamic activities.6 Ghrelin has been found to exert protective effects on the cardiovascular system.7 These include inhibition of vascular endothelial cell apoptosis,8 promotion of angiogenesis,9 improvement of endothelial dysfunction, enhancement of endothelial nitric oxide synthase (eNOS) expression,10 reduction of pro-inflammatory reactions in human endothelial cells, and suppression of vascular inflammation.11 The n-octanoylation at serine-3 is critical for ghrelin’s activities. Previous studies have demonstrated that desacylated ghrelin (D-ghrelin), unlike the standard form, does not inhibit tumour necrosis factor-alpha (TNF-α)-induced interleukin-8 (IL-8) release.11,12 It was reported in another study that obestatin, which is encoded by the same gene as ghrelin, has a regulatory function in the cardiovascular system.8 Ghrelin is orexigenic, whereas obestatin is anorexigenic; the former regulates body fluid homeostasis, food intake and energy metabolism, while the latter seems to induce the opposite effects.13 The aetiology of endothelial injury relates to many factors, including hyperlipidaemia, hypertension, diabetes mellitus, cigarette smoking and various infectious agents. Elevated homocysteine (Hcy) levels have also proven to be an underdiagnosed cause of endothelial dysfunction. Hcy is a sulphur-containing amino acid involved in two metabolic pathways, catalysed by cystathionine-βsynthase and methionine synthase, depending on vitamin B6, B12 and folate levels and enzymatic activity of methylenetetrahydrofolate.14 Previous studies demonstrated that Hcy decreased endotheliumdependent vasorelaxation and eNOS reactivity, causing endothelial

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

dysfunction in the porcine carotid and coronary arteries.15,16 Individuals with elevated Hcy levels are therefore at increased risk of atherosclerosis and cardiovascular disease.17-19 It is not clear whether ghrelin protects vascular tissue from injury that is secondary to risk factors such as high levels of Hcy. Levels of vitamin B12 and folic acid, which form part of Hcy metabolism, are in inverse correlation with the total Hcy level. Nutritional deficiency or insufficiency of these vitamins increases the risk of hyperhomocysteinaemia.20,21 Saliva, which is among the biological fluids used in the diagnosis of diseases, is also used to monitor treatment. Companies that manufacture devices for diagnostic purposes allocate a significant share to research and development efforts geared towards the measurement of multiple parameters in the saliva. This is because saliva is the most important biological fluid that could be an alternative to using blood for analysis.22 This study aimed to compare ghrelin, obestatin, Hcy, vitamin B12 and folate levels in the serum and saliva samples of ischaemic heart disease patients and those of healthy individuals.

Methods Patients who had acute coronary syndrome or types 1 and 2 diabetes mellitus, were extremely obese [body mass index (BMI) > 35 kg/m2], or had undergone invasive revascularisation in the previous three months were not included in the study. Additionally, individuals were excluded if they were found to have a normal coronary anatomy on angiography but had signs of heart failure and branch blocks on electrocardiography. The study was carried out on 33 patients (female/male: 48.5/51.5%) with IHD and 28 BMI- and age-matched healthy subjects (female/male: 45.5/54.5%). All subjects, including the controls, underwent coronary angiography. IHD was defined as a ≥ 50% diameter stenosis, as diagnosed by angiography. The control group was defined as those having normal coronary arteries, as diagnosed by angiography. Written consent was obtained before the study, together with the institutional ethics committee’s approval of the study protocol (dated 29 August 2007, issue no. 13). Hypertension, family history of IHD and smoking were present in 48.5, 36.4 and 33.4% of patients, respectively, in the IHD group. In the control group, 25, 21.4 and 21.4% of patients demonstrated these risk factors. None of the healthy controls had a family history of obesity or a history of abdominal surgery or gastrointestinal disease. They had taken no medication for at least seven days before sample collection. All subjects were advised not to eat, smoke or drink (except water) during the night before the saliva and blood sample collection. Approximately 2 ml of saliva and 5 ml of blood were taken from the enrolled subjects by the standard procedure described by Hosoda et al.23 Total and acylated ghrelin levels in the serum and saliva samples were measured using an enzyme linked immunosorbent assay (ELISA) kit (Linco Research). As desacylated ghrelin level was calculated by subtracting the acylated ghrelin value from the total ghrelin value, care was taken to use the same commercial kits throughout the study. Serum and saliva obestatin levels were determined using a human obestatin enzyme immunoassay (EIA) kit made by the Bachem brand (Peninsula Laboratories, LLC: a member of the

Bachem group, California, USA). Serum and saliva Hcy levels were measured using an axis homocysteine EIA kit. Levels of vitamin B12 and folate were determined by a Roche Elecsys 2010 hormone analyser.

Statistical analysis The data were statistically analysed using the SPSS for Windows 15.0 software package. First, continuous variables were checked for normality. Upon finding deviations from a normal distribution, the Mann–Whitney U-test was used to compare the groups. Correlations between blood and saliva values were established by calculating the Spearman correlation coefficient. Mean ± SD and median (min, max) values are presented as descriptive statistics. Frequencies and percentage values are presented for the categorical data. Pearson’s chi-squared continuity correlation analysis was used in the comparison. A p-value < 0.05 was accepted as significant.

Results While the age, BMI, diastolic blood pressure, and triglyceride, total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not significantly different between the control and IHD groups (p > 0.05), systolic blood pressure (p = 0.019) and high-density lipoprotein (HDL) cholesterol (p = 0.042) were significantly lower in the IHD group (Table 1). An intra-group comparison of serum and saliva levels of total acylated and desacylated ghrelin, obestatin, vitamin B12 and folate was conducted. These parameters were also compared between the groups. Some differences were seen between serum and saliva levels of the biochemical parameters when we carried out intra- and inter-group comparisons (Table 1). In the control group, saliva levels of total acylated and desacylated ghrelin were higher than in the serum (p = 0.001). Conversely, in the IHD group, serum levels were found to be higher than in the saliva (p = 0.001) (Table 1, Fig. 1). When serum and saliva levels of these parameters were compared between the two groups, total ghrelin, desacylated ghrelin and serum levels of Hcy and acylated ghrelin were found to be higher in the IHD group (p = 0.001) (Table 1, Figs 1, 2). While 70 60 Acyl ghrelin (pg/ml)

160

50 40 30

58 28

20 10 0

Control AG serum

IHD AG saliva

Fig. 1. Serum and saliva acylated ghrelin levels of controls and patients with ischaemic heart disease.

AFRICA

161

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 1. Demographic characteristics, biochemical data and serum and saliva levels of biochemical parameters of the controls and patients with ischaemic heart disease Control Med (min; max) 48.0 (25; 77) 25.6 (20.3; 32.8) 120 (90; 140) 70 (60; 90) 153 (83; 340) [1.73 (0.94; 3.84)] 172 (140; 210) [4.45 (3.63; 5.44)] 126 (81; 152) [3.26 (2.10; 3.94)] 38.5 (3; 54) [1.00 (0.08; 1.40)]

Age BMI (kg/m2) Systolic blood pressure (mm/Hg) Diastolic blood pressure (mm/Hg) Triglycerides (mg/dl) [mmol/l] Total cholesterol (mg/dl) [mmol/l] LDL cholesterol (mg/dl) [mmol/l] HDL cholesterol (mg/dl) [mmol/l] Total ghrelin (pg/ml) Serum 111.4 ± 34.5 Saliva 205.8 ± 30.8 Acylated ghrelin (pg/ml) Serum 16.9 ± 4.8 Saliva 29.6 ± 5.5 Desacylated ghrelin (pg/ml) Serum 93.8 ± 31.4 Saliva 176.5 ± 30.2 Obestatin (pg/ml) Serum 399.5 ± 83.7 Saliva 541.2 ± 57.3 Homocystein (µmol/l) Serum 9.4 ± 1.4 Saliva 1.2 ± 0.2 Vitamin B12 (pg/ml) Serum 255.1 ± 54.4 Saliva 78.8 ± 10.4 Folate (ng/ml) Serum 7.3 ±1.3 Saliva 4.0 ± 0.5 p-values obtained by comparison of control and IHD groups.

IHD Mean ± SD 50.5 ± 11.0 25.5 ± 3.4 126 ± 14.4 75.8 ± 70.1 169 ± 86.5 [1.91 ± 0.98] 194 ± 57.4 [5.02 ± 1.49] 130 ± 50.0 [3.37 ± 1.30] 35.9 ± 8.7 [0.93 ± 0.23]

Med (min; max) 49.1 (24; 75) 26 (21.4; 33.8) 120 (100; 160) 80 (60; 90) 157 (73; 491) [1.77 (0.82; 5.55)] 191 (120; 369) [4.95 (3.11; 9.56)] 126 (73; 270) [3.26 (1.89; 6.99)] 34 (22; 57) [0.88 (0.57; 1.48)]

p-value 0.126 0.860 0.019 0.488 0.633

105.5 (49; 169) 218 (150; 242)

316 ± 82.4 260 ± 68.1

311 (229; 627) 250 (98; 510)

0.001 0.001

16 (10; 29) 31 (19; 39)

53.8 ± 7.9 32.7 ± 8.0

56 (37; 68) 320 (18; 45)

0.001 0.101

89.5 (38; 145) 189.5 (119; 212)

255 ± 67.5 220.2 ± 43.1

254 (171; 435) 211 (125; 314)

0.001 0.001

406.5 (100; 503) 529 (455; 688)

371 ± 62.1 588 ± 63

347 (303; 499) 597 (482; 692)

0.020 0.005

9.2 (7.2; 12.6) 1.1 (1; 1.5)

14.3 ± 3.7 1.2 ± 0.1

13.6 (8.4; 26) 1.2 (1; 1.5)

0.001 0.900

250.6 (57.3; 330) 78.5 (63; 98.8)

175 ± 34.9 58.6 ± 7.4

162.6 (133; 260) 59 (43.8; 80.2)

0.001 0.001

6.8 (5; 9) 4.2 (3; 4.8)

5.1 ± 0.9 2.9 ± 0.8

4.8 (4.0; 7.1) 2.7 (2.1; 5.1)

0.001 0.001

serum levels of obestatin were lower in the IHD group, saliva levels were higher (p = 0.001) (Table 1, Fig. 3). Saliva and serum levels of vitamin B12 and folate were significantly lower in the IHD patients in comparison with the control group (p = 0.001) (Table 1).

Discussion Ghrelin is a 28-amino acid peptide that was initially identified in rat stomachs.12 In humans, it is mainly secreted from the stomach and acts as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R).24,25 There are two subtypes of GHS-R: GHS-R subtype 1a (GHS-R1a) and subtype 1b (GHS-R1b). GHS-R1a is the functionally active and signal-transducing form.26,27 It is expressed in many tissues, such as pituitary and thyroid glands, pancreas and cardiovascular tissues, including myocardial and endothelial cells.9,10,25 Ghrelin has two major endogenous forms, acylated ghrelin (A-Ghr) and unacylated ghrelin (DA-Ghr). A-Ghr can bind GHS-R1a and exert biological functions, unlike the unacylated form.28 Obestatin is a 23-amino acid peptide that is co-secreted with ghrelin from the stomach.29 Although various groups

0.128 0.761 0.042

have reported that obestatin is able to reduce appetite, gastric emptying and jejunal motility, and exert proliferative, survival and anti-apoptotic effects in B-cells, its biological effects remain highly controversial and need to be thoroughly investigated.30,31 In this study, saliva levels of both acylated ghrelin and obestatin were found to be higher than the serum levels in the control group. In the IHD group, however, serum levels of

Homocysteine serum (μmd/l)

Mean ± SD 49.5 ± 12.2 25.1 ± 3.1 116.8 ±10.1 74.0 ± 7.6 179.3 ± 77.4 [2.03 ± 0.87] 177.1 ± 24.7 [4.59 ± 0.64] 121.2 ± 21.7 [3.14 ± 0.56] 39.1 ± 6.3 [1.01 ± 0.16]

25 20 15 10 5 0

Control

IHD

Fig. 2. Serum Hcy levels of controls and patients with ischaemic heart disease.

162

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

acylated ghrelin and saliva levels of obestatin were higher. In our previous study, we found that saliva levels of both parameters were higher than the serum levels in both groups.22 The high ghrelin and obestatin levels found in saliva are very likely a consequence of the function of the salivary gland, since obestatin is produced by this gland. Both our own research team22 and Gröschl et al.32 have previously independently reported that the salivary gland produces its own ghrelin. In our previous study,4 we attributed the significantly higher saliva levels of ghrelin and obestatin, in comparison to serum levels, to the fact that they had undergone greater degradation in the blood due to pre-analysis errors, such as the temperature of collection and centrifugation. In the present study, when the serum and saliva levels of these peptides were compared between groups, it was found that serum ghrelin levels were elevated while serum obestatin levels were reduced in the patients with IHD, compared to the control group. We believe that these elevated ghrelin levels occur in order to curtail ischaemic heart damage. In a study conducted by Laurila et al.,33 high plasma ghrelin concentration was correlated with protection from coronary heart disease. Sax et al. found that pericardial active ghrelin concentration and the pericardial-to-plasma ghrelin ratio were elevated in IHD patients, compared to non-ischaemic subjects, and suggested an increased ghrelin production by the chronically ischaemic myocardium.34 Gnanapavan et al. demonstrated mRNA expression of ghrelin in the myocardium and veins. They determined that GHS-R1a was expressed in the myocardium and not the veins, while GHS-R1b was expressed in both.25 On the basis of these studies, it can be asserted that ghrelin is a critical peptide for the cardiovascular system. Li et al. examined the role of pro-inflammatory cytokines, reporting that ghrelin may inhibit the TNF-α-induced IL-8 release in a concentration-dependent manner.11 Mononuclear cell adhesion molecules are an integral part of vascular inflammation and atherosclerosis, as induced by chemotactic cytokines. Ghrelin inhibits the activity of nuclear factor kappa B (NF-κB), which is crucial in the production of chemotactic cytokines, and adhesion molecule expression, which adversely affects endothelial cell response.11 Ghrelin has also been shown to improve left ventricular function in heart failure.35,36 In addition, ghrelin’s mechanism of action on endothelial 700

Obestatin (pg/ml)

600 500 400 300 200 100 0

Control Obestatin serum

IHD Obestatin saliva

Fig. 3. S erum and saliva obestatin levels of controls and patients with ischaemic heart disease.

AFRICA

cells may be linked to GHS-R, a seven-transmembrane G protein-coupled ghrelin receptor. Stimulation of GHS-R with ghrelin leads to activation of G protein, calcium mobilisation and multiple downstream signalling.37 Ghrelin receptors have been isolated in various tissues, such as the endocrine glands and cardiovascular tissue. In addition, receptor density changes have been demonstrated to be an important part of the cardiovascular effects of ghrelin.38 Ghrelin has also been reported to prevent apoptosis in cardiac cells.8 An inverse correlation was found between serum total ghrelin levels and systolic blood pressure in our study. Studies reporting that ghrelin significantly reduced mean arterial blood pressure confirm our results.35,39,40 In this study, both patients and controls had a mean BMI higher than that considered normal worldwide, although they are not regarded as obese. The mean BMI for the patients in the study was 25.5 ± 3.4 kg/m2, which is classified as overweight. Therefore, the BMIs of the controls (25.1 ± 3.1 kg/m2) were matched to those of the patients. If the BMIs of the controls and patients had not been matched, it may have influenced obestatin and ghrelin secretion independent of the heart disease, as an increase in ghrelin level has been correlated with a decrease in body weight.41 A weakly negative correlation was also found between the serum acylated ghrelin and BMI in the IHD subjects, but there was no correlation in the controls. Several previous studies support our findings.22,32,41,42 Aydin assumed that low serum levels of obestatin also served to reduce ischaemic damage, as obestatin and ghrelin counteract one another.13 However, given that an elevated saliva obestatin level is only related to the circulation via transport from blood to saliva, and that the salivary gland also secretes obestatin, it is presumed that the elevated saliva level may have resulted from the contribution of this gland.2 In addition, Iglesias and colleagues recently found that obestatin had no effect on cardiomyocyte viability and metabolism.43 The pathophysiological role of obestatin in ischaemic heart disease therefore remains an important research topic. Salivary Hcy levels in both groups were found to be significantly lower than serum levels in our study. A possible explanation for this is that Hcy, which is a very weak lipophilic molecule, is bound to plasma proteins in large amounts, with the result that its diffusion to saliva is reduced. In routine clinical chemistry, the measured salivary components diffuse into the saliva from the blood. It has been reported that several factors play a part in the diffusion of serum components, such as Hcy, into saliva, namely that lipophilic components diffuse more easily than lipophobic components, the rate of ionised components in the saliva to those in the plasma changes with salivary pH, and the binding of components to proteins is a crucial factor in this rate.44 While there was no significant difference between the salivary Hcy levels of the control and IHD groups, serum Hcy levels were found to be significantly higher in IHD patients. One reason why serum Hcy levels increase in IHD is believed to be a deficiency of vitamin B12 and folic acid, which function as co-factors and co-substrates in Hcy metabolism.45,46 Serum levels of B12 and folic acid, which act in the pathway of the Hcy metabolism, were also found to be significantly lower in the patient group in our study. An elevated Hcy level is considered to be a risk factor for the development of atherosclerosis. It has been suggested that

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Hcy influences endothelial function, leading to a prothrombotic environment, platelet activation, and endothelial leukocyte interactions.47 In addition, Hcy enhances inflammatory responses, which are recognised for their role in atherosclerotic disease.48,49 Recent studies50,51 suggest that markers of inflammation may reflect different aspects of the atherothrombotic process and have a potential role in the prediction of risk for developing coronary artery disease. Besides the detrimental effects of Hcy on the cardiovascular system,15,52 elevated Hcy levels are also associated with peripheral arterial disease as well as venous diseases such as deep-vein thrombosis.53 Although there is strong evidence to suggest that increased ghrelin levels lead to increased food intake and lipid deposition, its cardiovascular benefits, such as the inhibition of cytokine production and improved left ventricular function, have also been well documented. Ghrelin receptors have been isolated in various tissues, such as the endocrine glands and cardiovascular tissue. In addition, receptor density changes have been demonstrated to be an important part of the cardiovascular effects of ghrelin.38 Targeting specific tissue receptors by modification of the ghrelin molecule may achieve the desired cardiovascular effects without activating the unwanted effects of ghrelin. The mechanism of improvement in endothelial function relates to improved eNOS expression and a reduction in oxidative stress. Ghrelin also has a potent effect on blocking Hcy-induced reduction in eNOS protein levels.54 Disproportion in the quantity of reactive oxygen species (ROS) generated during aerobic metabolism is known to lead to oxidative stress and contribute to vascular disease. This process is carried out through a variety of mechanisms, including nitric oxide (NO) consumption and depletion,55,56 regulation of gene transcription,56 and intracellular alkalinisation.57 Ghrelin reduced the production of superoxide anion, a major type of ROS, in Hcy-treated porcine coronary artery and human endothelial cell rings.54

163

Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease. BMB Rep 2008; 41: 55–61. PMID: 18304451. 5.

Kojima M, Kangawa K. Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2002; 2: 665–668. PMID: 12482728.

Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C. Metabolic and cardiovascular effects of ghrelin. Int J Pept 2010; 2010. pii: 864342. doi: 10.1155/2010/864342.

Wu R, Dong W, Zhou M, Cui X, Hank Simms H, Wang P. Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1. Cardiovasc Res 2005; 68: 318–326. PMID: 16018991.

Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159: 1029–1037. PMID: 12486113.

Li A, Cheng G, Zhu GH, Tarnawski AS. Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release. Biochem Biophys Res Commun 2007; 353: 238–243. PMID: 17184731.

10. Iantorno M, Chen H, Kim JA, Tesauro M, Lauro D, Cardillo C, et al. Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab 2007; 292: 756–764. PMID: 17106060. 11. Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-κB activation in human endothelial cells. Circulation 2004; 109: 2221–2226. PMID: 15117840. 12. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone releasing acylated peptide from stomach. Nature 1999; 402: 656–660. PMID: 10604470. 13. Aydin, S. Discovery of ghrelin hormone: researches and clinical applications. Turk J Biochem 2007; 32: 76–89. 14. Petramala L, Acca M, Francucci CM, D’Erasmo E. Hyperhomocysteinemia: a biochemical link between bone and cardiovascular system diseases? J Endocrinol Invest 2009; 32: 10–14. PMID: 19724160.

Conclusion Serum Hcy, serum acylated ghrelin and saliva obestatin levels were significantly elevated, while serum obestatin level decreased in the IHD group. We believe that ghrelin is a potent and effective protein that inhibits Hcy production and other potentially damaging mechanisms and may underlie the decrease in obestatin level, which counteracts ghrelin. It can also be concluded from this study that saliva could be an alternative to serum in the diagnosis and follow up of disease, but these results should be confirmed with larger groups of subjects.

15. Chen C, Conklin BS, Ren Z, Zhong D. Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries. J Surg Res 2002; 102: 22–30. PMID:11792147. 16. Zhou W, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Ginsenoside Rb1 blocks homocysteine induced endothelial dysfunction in porcine coronary arteries. J Vasc Surg 2005; 41: 861–868. PMID: 15886672. 17. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110: 3674–3679. PMID: 15569841. 18. Kalra DK. Homocysteine and cardiovascular disease. Curr Atheroscler Rep 2004; 6: 101–106. PMID: 15023293.

References

19. Temple ME, Luzier AB, Kazierad DJ. Homocysteine as a risk factor for

20. Kang SS, Wong PWK, Norusis M. Homocysteinemia due to folate defi-

Gaziano T, Reddy KS, Paccaud F, Horton S, Chaturvedi V. Cardiovascular disease. In: Jamison DT, Breman JG, Measham AR,

21. Krajcovicova-Kudlackova M, Blazicek P, Mislanova C, Valachovicova

in Developing Countries. 2nd edn. Washington (DC): World Bank; 2006,

M, Paukova V, Spustova V. Nutritional determinants of plasma homo-

Farmer JA, Torre-Amione G. Atherosclerosis and inflammation. Curr Atheroscler Rep 2002; 4: 92–98. PMID: 11822971.

Mason RP. Mechanisms of plaque stabilization for a charged calcium channel blocker in coronary artery disease. Pharmacotherapy 2001; 21:

ciency. Metabolism 1987; 36: 458–462. PMID: 3574134.

Alleyne G, Claeson M, Evans DB, et al. (eds). Disease Control Priorities Ch 33: 645–662. 2.

atherosclerosis. Ann Pharmacother 2000; 34: 57–65. PMID: 10669187.

cysteine. Bratisl Lek Listy 2007; 108: 510–515. PMID: 18309641. 22. Aydin S, Halifeoglu I, Ozercan IH, Erman F, Kilic N, Aydin S, et al. A comparison of leptin and ghrelin levels in plasma and saliva of young healthy subjects. Peptides 2005; 26: 647–652. PMID: 15752580. 23. Hosoda H, Doi K, Nagaya N, Okumura H, Nakagawa E, Enomoto M,

209–215. PMID: 11560191.

et al. Optimum collection and storage conditions for ghrelin measure-

Ozbay Y, Aydin S, Dagli AF, Akbulut M, Dagli N, Kilic N, et al.

ments: octanoyl modification of ghrelin is rapidly hydrolyzed to deacyl

164

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

ghrelin in blood samples. Clin Chem 2004; 50: 1077–1080. PMID: 15161728. 24. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 4255–4261. 25. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988. PMID: 12050285. 26. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974–977. PMID: 8688086.

AFRICA

stomach. J Cardiovasc Pharmacol 2002; 39: 779–783. PMID: 12021570. 40. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 2004; 43: 977–982. PMID: 14993197. 41. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001; 145: 669–673. PMID: 11720888. 42. Rigamonti AE, Pincelli AI, Corrà B, Viarengo R, Bonomo SM, Galimberti D, et al. Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol 2002; 175: 1–5. PMID: 12379512. 43. Iglesias MJ, Salgado A, Piñeiro R, Rodiño BK, Otero MF, Grigorian

27. McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips

L, et al. Lack of effect of the ghrelin gene-derived peptide obestatin on

MS, et al. Molecular analysis of rat pituitary and hypothalamic growth

cardiomyocyte viability and metabolism. J Endocrinol Invest 2007; 30:

hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415–423. PMID: 9092793. 28. Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and desacyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000; 279: 909–913. PMID: 11162448.

470–476. PMID: 17646721. 44. Boulot-Tolle M, Chadefaux B, Kamoun P. Salivary homocyst(e)ine concentrations. Clin Chem 1992; 38: 1504–1505. PMID: 1643725. 45. Nygard O, Vollset SE, Refsum H, Ueland PM, Vollset SE. Total plasma homocysteine and cardiovascular risk profile. The Hordaland homo-

29. Zhang W, Zhao L, Lin TR, Chai B, Fan Y, Gantz I, et al. Inhibition

cysteine study. J Am Med Assoc 1998; 274: 1526–1533. PMID: 7474221.

of adipogenesis by ghrelin. Mol Biol Cell 2004; 15: 2484–2491. PMID:

46. Brattström L. Vitamins as homocysteine-lowering agents. J Nutr 1996;

15034137.

126: 1276–1280. PMID: 8642470.

30. Gourcerol G, Coskun T, Craft LS, Mayer JP, Heiman ML, Wang

47. Pasterkamp G, Algra A, Grobbee DE, Banga JD, van der Graaf Y.

L, et al. Preproghrelin-derived peptide, obestatin, fails to influence

Homocysteine and the stage of atherosclerotic disease: A study in

food intake in lean or obese rodents. Obesity (Silver Spring) 2007; 15:

patients suffering from clinically silent and clinically manifest athero-

2643–2652. PMID: 18070755.

sclerotic disease. Eur J Clin Invest 2002; 32: 309–315. PMID: 12027869.

31. Tremblay F, Perreault M, Klaman LD, Tobin JF, Smith E, Gimeno RE.

48. Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen

Normal food intake and body weight in mice lacking the G protein-

DW. Homocysteine induces expression and secretion of monocyte

coupled receptor GPR39. Endocrinology 2007; 148: 501–506. PMID:

chemo attractant protein-1 and interleukin-8 in human aortic endothe-

17095592.

lial cells: Implication for vascular disease. Circulation 2001; 103: 2717–

32. Gröschl M, Topf HG, Bohlender J, Zenk J, Klussmann S, Dötsch J, et

2723. PMID: 11390343.

al. Identification of ghrelin in human saliva: production bythe salivary

49. Wang G, Siow YL. Homocysteine induces monocyte chemoattractant

glands and potential role in proliferation of oral keratinocytes. Clin

protein-1 expression by activating NF-kappa B in THP-1 macrophages.

Chem 2005; 51: 997–1006. PMID: 15790755.

Am J Physiol Heart Circ Physiol 2001; 280: 2840–2847. PMID:

33. Laurila M, Santaniemi M, Kesäniemi YA, Ukkola O. High plasma ghrelin protects from coronary heart disease and Leu72Leu polymorphism of ghrelin gene from cancer in healthy adults during the 19 years followup study. Peptides 2014; 61: 122–129. PMID: 25257375.

11356643. 50. Zhong-qun Y, Goran KH. Innate immunity, macrophage activation and atherosclerosis. Immunol Rev 2007; 219: 187–203. PMID: 17850490. 51. Saadeddin SM, Habbab MA, Ferns GA. Markers of inflammation and

34. Sax B, Merkely B, Túri K, Nagy A, Ahres A, Hartyánszky I, et al.

coronary artery disease. Med Sci Monit 2002; 8: 5–12. PMID: 11782689.

Characterization of pericardial and plasma ghrelin levels in patients

52. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset

with ischemic and non-ischemic heart disease. Regul Pept 2013; 186:

SE. Plasma homocysteine levels and mortality in patients with coronary

131–136.

artery disease. N Eng J Med 1997; 337: 230–236. PMID: 9227928.

35. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W,

53. Bhargava S, Parakh R, Manocha A, Ali A, Srivastava LM. Prevalence

et al. Chronic administration of ghrelin improves left ventricular func-

of hyperhomocysteinemia in vascular disease: comparative study of

tion and attenuates development of cardiac cachexia in rats with heart

thrombotic venous disease vis-à-vis occlusive arterial disease. Vascular

failure. Circulation 2001; 104: 1430–1435. PMID: 11560861.

2007; 15: 149–153. PMID: 17573020.

36. Nagaya N, Kangawa K. Ghrelin, a novel growth hormone-releasing

54. Hedayati N, Annambhotla S, Jiang J, Wang X, Chai H, Lin PH, et

peptide, in the treatment of chronic heart failure. Regul Pept 2003; 114:

al. Growth hormone-releasing peptide ghrelin inhibits homocysteine-

71–77. PMID: 12832093.

induced endothelial dysfunction in porcine coronary arteries and human

37. Xu X, Jhun BS, Ha CH, Jin ZG. Molecular mechanisms of ghrelinmediated endothelial nitric oxide synthase activation. Endocrinology 2008; 149: 4183–4192. PMID: 18450953. 38. Katugampola SD, Maguire JJ, Kuc RE, Wiley KE, Davenport AP.

endothelial cells. J Vasc Surg 2009; 49: 199–207. PMID: 19028051. 55. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite the good, the bad, and ugly. Am J Physiol 1996; 271: 1424–1437. PMID: 8944624.

Discovery of recently adopted orphan receptors for apelin, urotensin

56. Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite

II, and ghrelin identified using novel radioligands and functional role

effects on activation of NFkappa B and AP-1 in intact cells AP-1 as

in the human cardiovascular system. Can J Physiol Pharmacol 2002; 80:

secondary antioxidant-responsive factor. EMBO J 1993; 12: 2005–2015.

369–374. PMID: 12056541.

PMID: 8491191.

39. Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H, Kangawa

57. Shibanuma M, Kuroki T, Nose K. Superoxide as a signal for increase

K. Vasodilatory effect of ghrelin, an endogenous peptide from the

in intracellular pH. J Cell Physiol 1988; 136: 379–383. PMID: 2842350.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

165

The effects of treatment in patients with childhood asthma on the elastic properties of the aorta Osman Bektaş, Zeki Yüksel Günaydin, Ahmet Karagöz, Recep Akgedik, Adil Bayramoğlu, Ahmet Kaya

Abstract Introduction: The study aimed to investigate the effects of treatment in patients with childhood asthma on the elastic properties of the aorta and cardiovascular risk. Methods: The study was performed in 66 paediatric patients diagnosed with bronchial asthma (BA). All patients were administered the β2 agonist, salbutamol, for seven days, followed by one month of montelukast and six months of inhaled steroid treatment. All patients underwent conventional transthoracic echocardiographic imaging before and after treatment. Aortic elasticity parameters were considered to be the markers of aortic function. Results: Aortic elasticity parameters, including aortic strain (15.2 ± 4.8 and 18.8 ± 9.5%, p = 0.043), aortic distensibility (7.26 ± 4.71 and 9.53±3.50 cm2/dyn, p = 0.010) and aortic stiffness index (3.2 ± 0.6 and 2.8 ± 0.5, p = 0.045 showed significant post-treatment improvement when compared to pre-treatment values. Tricuspid annular plane systolic excursion (TAPSE) was also observed to improve after treatment (1.81 ± 0.38 and 1.98 ± 0.43, p = 0.049). Conclusion: The study demonstrated that when provided at appropriate doses, medications used in BA may result in an improvement in aortic stiffness. Keywords: aortic stiffness, corticosteroids, bronchial asthma Submitted 2/6/15, accepted 17/7/16 Cardiovasc J Afr 2017; 28: 165–169

www.cvja.co.za

DOI: 10.5830/CVJA-2016-076

Bronchial asthma (BA) is a chronic inflammatory disease of the airways. Exacerbations that develop as a result of bronchial hypersensitivity associated with chronic airway inflammation are accompanied by varying degrees of airway obstruction. The possible causes of airway obstruction include contraction

Department of Cardiology, Faculty of Medicine, Ordu University, Ordu, Turkey Osman Bektaş, MD Zeki Yüksel Günaydin, MD, doktorzeki28@gmail.com Adil Bayramoğlu, MD Ahmet Kaya, MD

Department of Cardiology, Faculty of Medicine, Giresun University, Giresun, Turkey Ahmet Karagöz, MD

Department of Chest Diseases, Faculty of Medicine, Ordu University, Ordu, Turkey Recep Akgedik, MD

of airway smooth muscles, hypersecretion of mucous, mucosal oedema, cell infiltration and epithelial desquamation.1 Studies have shown an association between systemic inflammation and the progression of asthma.2 It has also been established that pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) increase in patients with asthma.2,3 There is also evidence that supports the role of chronic inflammation in the aetiology of atherosclerosis.4 Chronic inflammation may even impair endothelial function and accelerate the progression of atherosclerosis.5 Endothelial dysfunction and arterial stiffness are two distinct components playing an important role in the pathophysiology of arterial diseases. Nitric oxide (NO) released from the endothelial cells has been shown to contribute to arterial compliance and distensibility.6 Arterial stiffness consists of two components that are interrelated; the structural component is formed by the collagen elastin fibres and their associated molecules in the arterial medium, whereas the dynamic component is represented by the tonus of smooth muscle cells and depends on the vasoactive substances released by endothelial cells.7 In case of endothelial damage due to chronic inflammation or increased haemodynamic load, irrespective of the cause, it might be expected that arterial stiffness will also be affected. Indeed, arterial stiffness was shown to be elevated in a study performed on patients with BA.8 Aortic stiffness is a significant risk factor for cardiovascular mortality and morbidity.9 Due to their anti-inflammatory effects on the airways, β2-agonists, leukotriene receptor antagonists and inhaled corticosteroids (ICS) are used for the treatment of asthma. These medications carry the risk of enhancing the cardiovascular risk factors such as hypertension, hypercholesterolaemia, hypertriglyceridaemia and impaired glucose tolerance.10-12 Based on the fact that bronchial asthma is a chronic inflammatory disease, the present study aimed to demonstrate how aortic stiffness is affected by the treatment in paediatric patients with asthma, and to determine the possible impacts on cardiovascular risk.

Methods The study population consisted of children aged nine to 15, who were admitted to the paediatric ward and the chest diseases out-patient clinics of Ordu University between January and August 2012. A total of 240 patients who had been diagnosed with asthma without any treatment in the past three months or patients with newly diagnosed moderate-to-severe asthma were evaluated in the study. In order to ensure standardisation, a treatment protocol of salbutamol 100 mcg 4 × 1 for 14 days, montelukast 5 mg/day for 30 days and budesonide 200 mcg inh 2 × 1 for six months was given to all patients according to the Global Initiative for Asthma

166

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

(GINA) 2012.13 The study was continued with the patients in whom asthma was controlled with this treatment protocol. One hundred and seventy-four patients were excluded because of uncontrolled BA, incompatibility with this protocol, severe asthma in whom intravenous/oral corticosteroid treatment or hospitalisation was required, need for salbutamol use in the control visit at the end of the second week, recurrence of the asthma attack, requirement for salbutamol treatment within six months, interruption of all triple treatment protocol at the end of fourth month, need for montelukast treatment for more than six months and lack of control echocardiography. Finally, 66 patients who had been given salbutamol 100 mcg inh 4 × 1 for 14 days, montelukast 5 mg tablets 1 × 1 for one month and budesonide 200 mcg inh 2 × 1 for six months were included in this study. The right and left atria and ventricles were assessed using conventional transthoracic echocardiography and two-dimensional (2D) speckle tracking echocardiography. The initial echocardiographic evaluation was performed in the first six hours. The echocardiographic assessments were repeated by the same operators at the post-treatment sixth month. The preand post-treatment parameters were compared with each other. All participants gave an informed consent and the study protocol was approved by the local ethics committee. Chest X-ray, complete blood count, CRP and other biochemical parameters were evaluated in order to exclude conditions such as infection, bronchitis and bronchiectasis which can mimic asthma. In accordance with the GINA 2012 guideline,13 bronchial asthma was diagnosed in the presence of 12% or more reversibility in forced expiratory volume 1 (FEV1) and 15% or more reversibility in peak expiratory flow (PEF) with the use of a salbutemol inhaler in the patients who had episodic breathlessness, coughing, chest congestion, wheezing and forceful expirium in their history. Only the patients with moderate and severe bronchial asthma were included. Mild bronchial asthma patients were excluded from the study. Patients were assessed based on attack frequency over the previous three months for classification into controlled and uncontrolled asthma. Furthermore, their current level of asthma control was based on reduced lung function (PEFR), frequency of using reliever treatment, frequency of daytime symptoms, nocturnal symptoms or awakening because of asthma and any limitation of daily activities, including exercise. Controlled asthma was defined as normal or near normal lung function results, no (≤ two times/week) need for reliever treatment, no (≤ two times/week) daytime symptoms, no nocturnal symptoms or awakening because of asthma, no limitation of daily activities including exercise and no exacerbation. Partially controlled asthma was also regarded as uncontrolled asthma. The patient was diagnosed as partially controlled asthma in the presence of any of the following criteria: reduced lung function < 80% of predicted or personal best, any limitation of activity, night-time cough, daytime symptoms more than twice per week and using rescue treatment more than twice per week. The condition was defined as uncontrolled asthma in the presence of three or more of the above criteria. Information on the patient’s age, gender, duration of bronchial asthma, and current treatment was obtained from each subject and checked against their case notes. Conventional transthoracic echocardiographic imaging was

AFRICA

performed by a double-blinded experienced operator while the patients were in the left lateral position and according to the recommendations of the American Echocardiography Society (AES).14 Left ventricular ejection fraction (LVEF, Simpson’s method), left ventricular systolic end-diameter, left ventricular diastolic end-diameter, left ventricle posterior wall thickness, interventricular septum thickness, left atrium diameters and volumes, and left ventricle volumes were evaluated. In addition to these echocardiographic assessments, M-mode, 2-D images, and colour-flow Doppler recordings of all patients were taken using a 2.5–3.5-MHz transducer of the echocardiography device (Philips IE33, Philips Medical Systems, Andover, MA). After routine echocardiographic investigation, recordings of the ascending aorta were obtained from 3 cm above the aortic valve by the M-mode. Aortic diameters were calculated as the distance between the anterior and posterior wall inner edges of the aorta at systole and diastole. Systolic diameter of the aorta (AS) was recorded when the aortic wall was fully open. Diastolic diameter of the aorta (AD) was recorded simultaneously when the QRS peak was seen on electrocardiographic (ECG) recordings. Measurements were taken during five consecutive pulses and the mean was calculated. Echocardiographic assessments were repeated after three months of therapy and compared with the values recorded before therapy. Aortic elasticity parameters were considered as markers of aortic function. Aortic systolic (AS) and aortic diastolic (AD) indices for each patient were calculated by dividing the systolic and diastolic aortic diameters by body mass index. Using these indices, elastic characteristics of the aorta were calculated as follows: • Pulse pressure (mmHg) = SBP – DBP • Aortic strain (%) = 100 (AS – AD)/AD • Distensibility (cm2/dyn/103) = 2 (AS – AD)/PP • Aortic stifness index (ASI) = ln (SBP/DBP)/(AoS − AoD)/AoD Where SBP = systolic blood pressure, DBP = diastolic blood pressure, PP = pulse pressure, AoS = aortic root end-systolic diameter, AoD = aortic root end-diastolic diameter.

Statistical analysis Continuous variables were expressed as mean ± SD or median (interquartile range). Categorical variables were expressed as percentages. An analysis of normality of the continuous variables was performed with the Kolmogorov–Smirnov test. To compare parametric continuous variables, paired samples t-test was used. To compare non-parametric continuous variables, the Mann–Whitney U-test or the Kruskal–Wallis test was used. Two-tailed p-values < 0.05 were considered as statistically significant. All statistical studies were carried out with the SPSS program version 20.0 for Windows.

Results The mean age of the patients was 11.6 ± 2.0 years (age range: 9–15 years) and 50% were males. Baseline characteristics are shown in Table 1. Echocardiographic and haemodynamic assessments did not show any difference between pre- and post-treatment values of heart rate (90.8 ± 7.7 and 89.5 ± 7.0 bpm, p = 0.320), systolic blood pressure (103.8 ± 10.6 and 102.6 ± 9.0 mmHg, p = 0.280), diastolic blood pressure (65 ± 7.2 and 66 ± 8.1 mmHg, p = 0.765),

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 1. Baseline characteristics of overall patients Baseline characteristics n = 66 Mean age (years) 11.6 ± 2.0 Male gender, n (%) 14 (56) BMI (kg/m2) 17.1 ± 2.5 BSA (m2) 1.2 ± 0.5 BMI: body mass index, BSA: body surface area.

pulse pressure (37.5 ± 6.9 and 38.1 ± 6.3 mmHg, p = 0.442), and LVEF (68.5 ± 3.8 and 69.4 ± 3.4%, p = 0.427) (Table 2). Compared to the pre-treatment values, post-treatment TAPSE improved (1.81 ± 0.38 and 1.98 ± 0.43, p = 0.049) (Table 2). Aortic elasticity parameters including aortic strain (15.2 ± 4.8 and 18.8 ± 9.5%, p = 0.043), aortic distensibility (7.26 ± 4.71 and 9.53 ± 3.50 cm2/dyn, p = 0.010) and aortic stiffness index (3.2 ± 0.6 and 2.8 ± 0.5, p = 0.045) showed significant post-treatment improvement when compared to pre-treatment values (Table 3).

Discussion The findings of this study demonstrate that aortic stiffness improved after appropriate dosage medications in asthma patients. Such improvement may be associated with the antiinflammatory effects of therapy. Additionally, the medication had positive effects on right ventricular systolic functions and cardiac output. We suggest that the decrease in aortic stiffness might have contributed to this improvement, and we might have treated the negative cardiac effects while treating bronchial asthma. BA is the most common reason for paediatric respiratory disorders and it is a significant cause of mortality and morbidity.1,13 Exposure to BA-associated repetitive hypoxia Table 2. Haemodynamic and echocardiographic findings before and after treatment of patients Variables Before treatment After treatment p-value HR (bpm) 0.320 90.8 ± 7.7 89.5 ± 7.0 SBP (mmHg) 0.280 103.8 ± 10.6 102.6 ± 9.0 DBP (mmHg) 0.765 65 ± 7.2 66 ± 8.1 Pulse pressure (mmHg) 0.442 37.5 ± 6.9 38.1 ± 6.3 EF (%) 0.427 68.5 ± 3.8 69.4 ± 3.4 LVEDV (ml) 0.124 66.2 ± 13 67.9 ± 15 LVESV (ml) 0.278 24.3 ± 7.3 22.1 ± 6.7 0.985 LVMI (g/m2) 55.5 ± 19.4 56.2 ± 18.9 IVSD (cm) 0.848 6.9 ± 1.1 6.8 ± 1.8 PWD (cm) 0.789 6.8 ± 0.9 6.9 ± 1.0 Mitral E wave (m/s) 0.657 94.0 ± 14.5 95 ± 15.0 Mitral A wave (m/s) 0.433 64.2 ± 15.5 60.3 ± 19.1 Mitral E/A 0.678 1.56 ± 0.78 1.53 ± 0.95 DT 0.388 134.5 ± 30.7 144.7 ± 41.2 TAPSE 0.049 1.81 ± 0.38 1.98 ± 0.43 ePASP 0.230 19.2 ± 4.2 18.0 ± 5.3 LA diameter (mm) 0.568 2.4 ± 0.5 2.5 ± 0.6 HR: heart rate, bpm: beats per minute, SPB: systolic blood pressure, DBP: diastolic blood pressure, EF: ejection fraction, LVEDV: left ventricular end-diastolic volume, LVESV: left ventricular end-systolic volume, LVMI: left ventricular mass index, IVSD: interventricular septal defect, PWD: posterior wall thickness at end-diastole, DT: decelaration time, TAPSE: tricuspid annular plane systolic excursion, ePASP: estimated pulmonary artery systolic pressure, LA, left atrial.

167

Table 3. Aortic elastic properties (strain, stiffness index, distensibility) of patients before and after treatment Properties Aortic velocity (m/s) Aortic diameter in systole (mm) Aortic diameter in diastole (mm) Aortic strain (%) Aortic distensibility (cm2/dyn) Aortic stiffness index Cardiac output (l/min) Stroke volume (ml)

Before treatment 0.8 ± 0.1 20.9 ± 2.9 18.5 ± 2.2 15.2 ± 4.8 7.26 ± 4.71 3.2 ± 0.6 3.85 ± 1.2 42 ± 5.0

After treatment p-value 0.563 0.9 ± 0.2 0.203 21.2 ± 2.5 0.812 18.6 ± 2.4 0.043 18.8 ± 9.5 9.53 ± 3.50 0.010 0.045 2.8 ± 0.5 0.032 4.08 ± 1.1 0.044 45 ± 4.2

results in sustained pulmonary vasoconstriction and long-term obstruction of the pulmonary veins. In addition, pulmonary hypertension develops, resulting in right ventricular hypertrophy and enlargement, which is also known as cor pulmonale.15 In our study, the significant post-treatment increase in TAPSE can be interpreted as improvement in right ventricular function. The negative effects of BA on right heart functions are well known; however, on the contrary to this well-known pathology, there is relatively limited knowledge about how left heart chambers are affected by this condition or how they change after therapy. In a study assessing left ventricular function during acute asthma exacerbations, it has been demonstrated that transmitral peak A wave increased and E/A ratio decreased during an acute severe asthma exacerbation, which implies the development of left ventricular diastolic dysfunction.16 In summary, it can be said that both the right and the left heart functions are negatively affected during the course of BA. In our study, in addition to TAPSE, cardiac output and stroke volume were significantly increased after treatment but there was no significant difference in E/A ratio. These findings can be interpreted as that treatment improves both right and left heart functions. However similar E/A ratios after BA treatment indicate that the medication had no effect on left ventricle diastolic function. A future study designed using novel diastolic parameters and control group could provide clearer results. Apart from the direct impact of hypoxia on impairment of the cardiac function and aortic stiffness in BA, some other aetiological factors may also contribute to this situation. Indeed, Massoud et al. found evidence showing the effects of chronic and sustained inflammation on myocardial function in patients with severe asthma. Inflammatory mediators also increase with inflammation when the respiratory symptoms appear, and it is known that some of these mediators have the potential to significantly depress cardiac contractility (TNF-alpha, IL-1β, IL-2, IL-6, IL-8, IL-10).17 The patients’ symptoms recover and the frequency of repetitions decrease with medications especially steroids, and this might contribute to the decrease in mediator secretion, which in turn may have resulted in an improvement of cardiac functions and aortic stiffness at the same time. In our study, the primary target was to evaluate the relationship between medication and aortic stiffness and no patient had any other chronic inflammatory disease such as diabetes, hypertension or congestive heart failure that may have affected aortic stiffness. In acute severe asthma, cardiovascular function significantly changes as a result of the direct effects of BA or secondary to the drug therapy (β2-adrenergic receptor agonists and steroids

168

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

in particular).18 Several studies have demonstrated that there is a relationship between increased mortality rates and β2-agonists in patients with BA. Moreover, there have been cases of sudden cardiac death19,20 and congestive heart failure21 related to β2-agonists. However, in the present study, we administered the β2-agonist, salbutamol, for only seven days to ease the symptoms, and thereafter we excluded the patients who required additional β2-agonist therapy. We administered only one month of montelukast. After the first month, patients received only ICS therapy for five months. Therefore our study is also important in terms of assessing the effects of inhaled corticosteroids (ICS) on aortic stiffness. The cardiac risk that develops after corticosteroid administration is related to the dosage. ICSs are commonly used in BA. Although ICSs are considered to have far less systemic absorption and possible systemic side effects, there are still some concerns. Therefore, they are recommended to be used in the lowest possible therapeutic doses.22 Lorenzo et al. noted that the risk of acute myocardial infarction (MI) increases in patients using oral corticosteroids; however, there is no such risk increase in patients using ICS.23 Conversely, acute MI risk in patients with BA decreased with the use of ICS therapy in another study.10 In general, this finding supports the studies demonstrating the role of inflammation in the aetiology of atherosclerosis, as well as the results of our study.7 This might be explained by the fact that the dose that enters into the systemic circulation upon ICS therapy is low enough to be below the level to exacerbate cardiovascular risk, but still at a level to have the potential to repress the inflammation associated with atherosclerosis. In line with these studies, an animal study demonstrated that the circulating levels of cholesterol and triglycerides did not increase upon administration of corticosteroids, whereas plaque formation and progression decreased.24 In another study, a decreased cardiovascular mortality rate was demonstrated upon ICS administration in patients with asthma.25 Corticosteroids show cardiovascular effects through direct inhibition of expression of the vascular adhesion molecules, in addition to non-transcriptional activation of endothelial nitric oxide synthase.26 As is already known, nitric oxide (NO) released from the endothelium contributes to arterial compliance and distensibility.6 Chronic inflammation and oxidative stress are known to co-exist in BA.27 The levels of reactive oxygen species such as hydroxyl radicals, superoxides, and peroxides are elevated in BA patients who have inflammation.28 Chronic inflammation is associated with endothelial dysfunction, atherosclerosis and arterial stiffness, all of which are risk factors for future cardiovascular events.29 In paediatric BA patients who do not use ICS therapy, carotid intima–media thickness (CIMT) was increased compared to the control group and a positive correlation was noted between CIMT and total oxidant status.28 In another study, BA patients treated with ICSs had decreased carotid atherosclerosis compared to the control group.30 The results of the present study are not surprising, considering previous studies and keeping in mind that atherosclerosis starts during childhood. However, considering the age group examined in this study, it does not seem right to attribute the improvement in aortic stiffness after ICS therapy only to the role of inflammation in the aetiopathogenesis of atherosclerosis. The suppression of the negative cardiac effects of inflammatory steroids by ICS therapy

AFRICA

may be the dominant mechanism leading to healing, since studies have demonstrated that steroids improve aortic stiffness through a similar mechanism.31 Some studies have established that assessment of aortic stiffness can be used for early detection of atherosclerosis. Moreover, aortic stiffness has been shown to increase with advanced age, and in the presence of various conditions such as hypertension, atherosclerosis, β-thalassaemia, smoking, obesity, Marfan syndrome and Kawasaki disease.32-34 Finally, in the present study the significant improvement in TAPSE and haemodynamic recovery can be explained by the anti-inflammatory effects of medications especially steroids, in addition to being a direct outcome of the decrease in the frequency of acute BA exacerbations; in other words, a decrease in the duration of exposure to hypoxia. Hence, it can be speculated that in addition to improving aortic stiffness, BA medication may also improve right ventricular systolic function. Previous studies have demonstrated that the presence of BA in paediatric populations can result in subclinical ventricular dysfunction as detected by tissue Doppler imaging.35 The limitations of this study include the small number of patients, the treatment regimen including both β2 mimetics, montelukast and steroids, the short duration of treatment and absence of a control group. The number of patients was 60 at the beginning of study; however, 15 patients who required re-initiation of β2 mimetics apart from the standard therapy were excluded. Patients were administered β2 mimetics and montelukast only at the beginning of therapy, and thereafter they were monitored on steroids alone. Therefore, therapies other than steroids can be considered not to have affected aortic stiffness during this period. A control group was not deemed necessary, since the purpose of the study was to assess the effects of ICS therapy on aortic stiffness in BA patients.

Conclusion Contrary to the usual concerns about cardiac effects, medications to treat asthma can be used safely in childhood BA and may improve aortic stiffness through their anti-inflammatory effects, and additionally by decreasing exposure to hypoxia. Moreover, early diagnosis of BA and the initiation of therapy may contribute to a decrease in cardiac mortality and morbidity rates; however, additional long-term studies are required to develop accurate conclusion on this subject. This study was presented at 64th International Congress of the European Society for Cardiovascular and Endovascular Surgery on 26–29 March 2015.

References 1.

Expert Panel Report 3 (EPR-3). Guidelines for the diagnosis and management of asthma: Summary Report 2007. J Allergy Clin Immunol 2007; 120: 94–138.

Wood LG, Baines KJ, Fu J, Scott HA, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest 2012; 142: 86–93.

Deraz TE, Kamel TB, El-Kerdany TA, El-Ghazoly HM. High-sensitivity C-reactive protein as a biomarker for grading of childhood asthma in relation to clinical classification. induced sputum cellularity. and spirometry. Pediatr Pulmonol 2012; 47: 220–225.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Ross R. Atherosclerosis an inflammatory disease. N Engl J Med 1999; 340: 115–126.

Sattar N. Inflammation and endothelial dysfunction: intimate companions in the pathogenesis of vascular disease? Clin Sci 2004; 106: 443–445.

Thorax 1998; 53: 558–621.

et al. Endothelium-derived nitric oxide regulates arterial elasticity in

Inhaled corticosteroids: past lessons and future issues. J Allergy Clin

Polovina MM, Potpara TS. Endothelial dysfunction in metabolic and Steinmann M, Abbas C, Singer F, Casaulta C, Regamey N, Haffner D, et al. Arterial stiffness is increased in asthmatic children. Eur J Pediatr

cardiac failure and ischaemic heart disease with long acting B2 agonists. 22. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ.

vascular disorders, Postgrad Med 2014; 126: 38–53. 8.

Am J Respir Crit Care Med 2000; 161: 827–830. 21. Martin RM, Dunn NR, Freemantle SN, Mann RD. Risk of nonfatal

Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, human arteries in vivo. Hypertension 2001; 38: 1049–1053.

169

Immunol 2003; 112: 1–40. 23. Varas-Lorenzo C, Rodriguez LA, Maguire A, Castellsague J, PerezGutthann S. Use of oral corticosteroids and the risk of acute myocardial infarction. Atherosclerosis 2007; 192: 376–383. 24. Makheja AN, Bloom S, Muesing R, Simon T, Bailey JM. Anti-

2015; 174: 519–523.

inflammatory drugs in experimental atherosclerosis. 7. Spontaneous

Arnett DK, Evans GW, Riley WA. Arterial stiffness a new cardiovascu-

atherosclerosis in WHHL rabbits and inhibition by cortisone acetate.

lar risk factor. Am J Epidemiol 1994; 140: 669–682.

Atherosclerosis 1989; 76: 155–161.

10. Suissa S, Assimes T, Brassard P, Ernst P Inhaled corticosteroid use in

25. Camargo CA Jr, Barr RG, Chen R, Speizer FE. Prospective study

asthma and the prevention of myocardial infarction. Am J Med 2003;

of inhaled corticosteroid use, cardiovascular mortality, and all-cause

115: 377–381. 11. Hanania NA, Moore RH. Anti-inflammatory activities of beta2-

mortality in asthmatic women. Chest 2008; 134: 546–551. 26. Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC,

agonists. Curr Drug Targets Inflamm Allergy 2004; 3(3): 271–277.

Rebsamen MC. Acute cardiovascular protective effects of corticoster-

12. Montelukast sodium. The American Society of Health-System

oids are mediated by non- transcriptional activation of endothelial nitric

Pharmacists. Retrieved 3 April 2011.

oxide synthase. Nat Med 2002; 8: 473–479.

13. From the Global Strategy for Asthma Management and Prevention,

27. Vignola AM, Chanez P, Campbell AM, Souques F, Lebel B, Enander

Global Initiative for Asthma (GINA) 2012. Available from: http://www.

I, et al. Airway inflammation in mild intermittent and in persistent

ginasthma.org/.

asthma. Am J Respir Crit Care Med 1998; 157: 403–409.

14. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka

28. Grisham MB, Jourd’heuil D, Wink DA. Chronic inflammation and

PA, et al. Recommendations for chamber quantification: a report from

reactive oxygen and nitrogen metabolism implications in DNA damage

the American Society of Echocardiography’s Guidelines and Standards

and mutagenesis. Aliment Pharmacol Ther 2000; 14: 3–9.

Committee and the Chamber Quantification Writing Group, developed

29. Libby P. Inflammation in atherosclerosis. Nature 2002: 868–874.

in conjunction with the European Association of Echocardiography, a

30. Otsuki M, Miyatake A, Fujita K, Hamasaki T, Kasayama S. Reduced

branch of the European Society of Cardiology. J Am Soc Echocardiogr

carotid atherosclerosis in asthmatic patients treated with inhaled corti-

2005; 18: 1440–1463.

costeroids. Eur Respir J 2010; 36: 503–508.

15. Leuchte HH, Baumgartner RA, Nounou ME, Vogeser M, Neurohr C,

31. Schillaci G, Bartoloni E, Pucci G, Pirro M, Settimi L, Alunno A, et al.

Trautnitz M, et al. Brain natriuretic peptide is a prognostic parameter

Aortic stiffness is increased in polymyalgia rheumatica and improves

in chronic lung disease. Am J Respir Crit Care Med 2006; 173: 744–750.

after steroid treatment. Ann Rheum Dis 2012; 71: 1151–1156.

16. Elmasry OA, Attia HM, Abdelfattah NM. Assessment of left ventricu-

32. Lacombe F, Dart A, Dewar E, Jennings G, Cameron J, Laufer E.

lar diastolic function in bronchial asthma: Can we rely on transmitral

Arterial elastic properties in man: A comparison of echo-Doppler indi-

inflow velocity patterns? Eur J Echocardiogr 2008; 7: 178–190. 17. Massoud MN, el Nawawy AA, el Nazar SY, Abdel-Rahman GM. Tumour necrosis factor-alpha concentration in severely asthmatic children. East Mediterr Health J 2000; 6: 432–436. 18. Manthous CA. Management of severe exacerbations of asthma. Am J Med 1995; 99: 298–308. 19. Robin ED, McCauley R. Sudden cardiac death in bronchial asthma and inhaled beta-adrenergic agonists. Chest 1992; 101: 1699–1702 20. Au DH, Lemaitre RN, Curtis JR, Smith NL, Psaty BM. The risk of myocardial infarction associated with inhaled B-adrenoceptor agonists.

ces of aortic stiffness. Eur Heart J 1992; 13: 1040–1045. 33. Levent E, Gökşen D, Ozyürek AR. Stiffness of the abdominal aorta in obese children. J Pediatr Endocrinol Metab 2002; 15: 405–409. 34. Ulger Z, Aydinok Y, Gurses D, Levent E, Ozyurek AR. Stiffness of the abdominal aorta in beta-thalassemia major patients related with body iron load. J Pediatr Hematol Oncol 2006; 28: 647–652. 35. Hirono O, Kubota I, Minamihaba O, Fatema K, Kato S, Nakamura H, et al. Left ventricular diastolic dysfunction in patients with bronchial asthma with long-term oral beta2-adrenoceptor agonists. Am Heart J 2001; 142: 11.

170

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Training community health workers to screen for cardiovascular disease risk in the community: experiences from Cape Town, South Africa Thandi Puoane, Shafika Abrahams-Gessel, Thomas A Gaziano, Naomi Levitt

Abstract This article describes a training process to equip community health workers (CHWs) with knowledge and skills to identify individuals at high risk for cardiovascular disease (CVD) in a township in Cape Town. Methods: CHWs were employed by a non-governmental organisation (NGO) primarily focusing on non-communicable diseases (NCDs). They were trained in the theory of CVD, including physiological changes and related risk factors and in obtaining anthropometric and blood pressure measurements. Pre- and post-training tests assessed learning needs and the effectiveness of imparting knowledge about CVD, respectively. Results: Training increased knowledge about CVD risk factors. CHWs were able to screen and identify those at risk for CVD and refer them to health professionals for validation of scores. The initial one-week training was too short, given the amount of information covered. Some CHWs had difficulty with English as the primary instruction medium and as the only language in which tests were offered. Conclusion: Although CHWs could be trained to screen for CVD risk, increased training time was required to impart the knowledge. The language used during training and testing presented challenges for those trainees whose dominant, spoken language was not English. Keywords: community health workers, non-communicable diseases, training, primary healthcare, cardiovascular diseases, screening

School of Public Health, Faculty of Community and Health Sciences, University of the Western Cape, South Africa Thandi Puoane, DPhil, tpuoane@uwc.ac.za

Center for Health Decision Science, Harvard TH Chan School of Public Health, Boston, MA, USA Shafika Abrahams-Gessel, MSc, DPhil

Center for Health Decision Science, Harvard TH Chan School of Public Health, Boston, MA, USA; Chronic Disease Initiative for Africa, Division of Endocrinology and Diabetes, Department of Medicine, University of Cape Town, South Africa Thomas A Gaziano, MD, MSc

Chronic Disease Initiative for Africa, Division of Endocrinology and Diabetes, Department of Medicine, University of Cape Town, South Africa Naomi Levitt, MD, PhD

Submitted 19/6/15, accepted 17/7/16 Cardiovasc J Afr 2017; 28: 170–175

www.cvja.co.za

DOI: 10.5830/CVJA-2016-077

Community Health Workers (CHWs) are individuals who live within the community they serve, understand the culture and speak the language of the people who live around them. In many low- and middle-income countries (LMIC), CHWs have been used largely to manage infectious diseases. In South Africa, CHWs were initially used to promote better health in the communities during the 1980s. However, when the democratically elected government came to power in 1994, its plans to implement a national strategy for primary healthcare did not include using the services provided by CHWs, because it was claimed by the then minister of health that their services provided ‘second rate’ healthcare.1 As a result, the use of CHWs declined, although this was reversed by the government when the HIV epidemic placed increasing demands on the healthcare system. Now that South Africa is faced with a rising burden of non-communicable diseases (NCDs) in addition to injuries and HIV/AIDs, it is essential that the country expand its focus to include NCDs. Indeed, in order to strengthen the current healthcare system, the South African government committed to re-engineering the primary healthcare system (PHC) as part of its strategic plan for NCDs from 2012 to 2016.2 It has undertaken to increase human resource capacity by using CHWs in the management of chronic conditions, with the goal of improving health outcomes. The public health service provides care to about 80% of the population and focuses primarily on management and control of existing conditions and the prevention of complications among individuals with current diseases. There has been no active programme to provide early detection and management through screening for those at risk for NCDs. A large percentage of the population only visit a government health facility when they feel pain, at which point the disease has typically progressed.3 Based on the new public health approach,4 a more holistic, multidisciplinary and multi-sectorial approach is needed to improve the health of the population by tackling risk factors at the individual, community and societal levels. It is therefore important to build the capacity of services delivered by CHWs to include screening in the community, in order to identify those at risk before progression of the disease, and to provide appropriate referrals to health facilities for further assessment and appropriate treatment. Over the past two decades, CHWs have been successfully used in HIV/AIDS programmes to provide palliative care to infected people. In addition, they have played an active

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

role in the tuberculosis programme in areas such as directly observed treatment (DOT) and short-course medications for TB (tuberculosis-DOTs) to support adherence and retention in care.5 There is evidence that supports the role of CHWs in the control of already identified chronic disease.6 A recent review examined the effectiveness of CHWs in providing care for hypertension and noted improvements in keeping appointments, compliance with prescribed medication regimens, reduction in risk, blood pressure control and reduced related mortality rates.7 Studies also show that CHWs are effective in educating their communities about many health conditions, including CVD, diabetes and asthma.8,9 They can also help decrease healthcare costs, increase access to healthcare and information, and strengthen the family, community and local economy.10 Studies undertaken in China, Brazil, Iran and Bangladesh have shown that using CHWs can help improve health outcomes of the populations they serve.11 A study by the Health System Trust found that in communities with poor health services, the use of CHWs to conduct home visits led to an increase in the community’s access to relevant health information.12 Currently there is no standardised training curriculum for CHWs in South Africa. As a result, training is customised by individual organisations or institutions to equip CHWs to perform specific activities only over the lifetime of individual projects.12,13 This article describes the training process to equip CHWs with knowledge and skills to identify individuals who are at a high risk for CVD in Khayelitsha, a peri-urban township of Cape Town. The lessons learned and the challenges identified will inform the teaching methods/processes for training lay workers with varied educational levels. This will assist in the training of a knowledgeable workforce at the community level, which will play a role in addressing the escalating burden of NCDs. For the purpose of this article, a CHW is defined as a lay person who has received some training to deliver healthcare services but is not a health professional.

Methods The CHWs who participated in the training programme were recruited from an NGO that primarily focuses on delivery of services related to NCDs. It was envisaged that the knowledge acquired during the training would be utilised beyond the

171

research period by CHWs in their daily activities. After the training, CHWs were expected to screen and identify people at risk for CVD in households in the community and refer them to four of the closest government health facilities to ensure that they received appropriate further treatment. The study protocol was approved by the National Heart, Lung and Blood Institute (NHLBI), USA, as well as the respective institutional or ethics review boards in each of the four participating sites in the country. All staff members associated with the study successfully completed the ethics courses through the Collaborative Institutional Training Initiative (CITI). In preparation for training, the trainers and the training coordinator visited the NGO to explain the purpose of the research and to recruit CHWs. The NGO agreed to release 10 to 15 CHWs from their daily activities to enable them to attend the training and participate in the field-work for the research project. The actual selection of CHWs for the training was left to the coordinators at the NGO. They were asked to provide typical CHWs employed by them and not only the best performers. The NGO was financially compensated so that they could employ temporary replacements while the selected CHWs participated in training and field-work. To break the ice and to get to know each other, the facilitators of the training briefly introduced themselves, followed by the trainees. In addition, each trainee presented his/her experiences in working with NCDs and expectations from the training. A summary of trainees’ expectations are listed in Table 1. The training was conducted for seven hours per week day from 1 to 12 June 2012. A total of 15 CHWs attended the training sessions. The training manual developed for the training included the teaching of theory about CVD and its risk factors, as well as the practical skills necessary to obtain blood pressure and other anthropometric measurements (weight, height). The training was held at the School of Public Health at the University of the Western Cape by three trainers who had content knowledge, experience in training and working with CHWs, fluency in the local language, could easily relate to the CHWs’ situation, and who had adapted the manual previously used to train the CHWs in various centres of excellence. Based on the principles of andragogy, which uses life experiences and knowledge that adults bring to their learning experiences, the training was participatory in nature and designed to encourage sharing of experiences in delivering care for NCDs.

Table 1. Summary of community health workers’ expectations of the training Expectation 1. To acquire new skills related to chronic disease management 2. To be provided with proper equipment 3. To gain respect from the training

Rationale for expectation New skills would allow them to better serve their community’s NCD needs Proper equipment would improve their ability to assess the health of clients Completing the training at the university would mean that their community and peers would respect them more and regard them as legitimate health workers 4. To learn to provide assistance to persons recovering from They needed to learn how to provide assistance to people who had suffered from chronic disease-related events stroke or complications from diabetes mellitus 5. To learn how to identify resources They wanted to know how to identify government resources and assistance programmes that would allow them to assist the elderly and the young find food, safety and proper shelter 6. To learn how to function as part of a team They wanted to learn how to work as part of a team that was responsible for providing care to the community, as they currently felt unsupported in this aspect of their work 7. To learn how to help sick clients who do not attend clinics They wanted to find ways to help their sick clients who were not able or willing to despite their illness spend an entire day sitting at a clinic 8. To further their career goals They aspired to becoming nurses, doctors or social workers and saw the completion of training as a stepping stone to these goals

172

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Training materials were produced in English but isi-Xhosa was used extensively to provide culturally appropriate expansion of new, challenging concepts for the trainees. A pre-training written test on the first morning of training was given to determine the current knowledge the trainees had on CVD and its risk factors and to assist in planning the teaching accordingly. During the first week, the morning sessions were spent in imparting knowledge about basic concepts of CVD and related risk factors. These included basic information about the heart and its function, hypertension, diabetes and obesity (definitions, symptoms and risk-factor history assessment) and nutrition using the South African food-based dietary guidelines. The afternoon sessions focused on data-collection skills, anthropometry measurements and training in the use of

the non-invasive risk-screening tool (Fig. 1). Trainees were taught to measure the mid-upper arm circumference (MUAC), used to determine the correct cuff size for measuring blood pressure using an automated Omron blood pressure machine®, as well as height and weight using an adjustable height stick and digital scale, respectively. Trainees were taught how to calibrate their blood pressure cuffs and digital scales. Calculation of body mass index (BMI) using a calculator, completion of risk-factor questionnaires through an in-person interview, maintaining confidentiality throughout the recruitment and screening process, assisting in the explanation and completion of informed consent forms, and completion of study forms for data entry were also included in the practical training.

Men No diabetes Age (years)

Non-smoker

AFRICA

Women No diabetes Smoker

Non-smoker

SBP (mmHg)

Smoker

171–180 161–170 151–160 65–74

141–150 131–140 121–130 111–120 171–180 161–170 151–160

55–64

141–150 131–140 121–130 111–120 171–180 161–170 151–160

45–54

141–150 131–140 121–130 111–120 171–180 161–170 151–160 141–150

35–44

131–140 121–130 111–120 15–19.9 20–24.9 25–29.9

>30

15–19.9 20–24.9 25–29.9

BMI (kg/m2)

>30

BMI (kg/m2)

5-year cardiovascular risk (fatal and non-fatal) Low

Moderate < 10%

High 10–20%

31–40%

21–30%

> 40%

15–19.9 20–24.9 25–29.9 BMI (kg/m2)

>30

15–19.9 20–24.9 25–29.9

>30

BMI (kg/m2)

How to use the chart • Choose the section with the gender, diabetes and smoking status • Find the cell that matches the patients risk-factor profile using the age, BMI and blood pressure • Refer to physician those with excessive blood pressure (≥ 180 mmHg)

Fig. 1. R isk-scoring chart used by community health workers to obtain CVD risk scores. Source: Gaziano TA, Young CR, Fitzmaurice G, Atwood S, Gaziano JM. Laboratory-based versus non-laboratory-based method for assessment of cardiovascular disease risk: the NHANES I follow-up study cohort. Lancet 2008; 371: 923–931.

AFRICA

173

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 3, May/June 2017

At the end of the training, the trainees completed a posttraining written test, which was identical to the pre-training test. In addition they underwent a practical examination to assess their use of the risk tool to calculate CVD risk and to obtain anthropometric measures. For the former, the CHWs were given a scenario with all parameters needed to calculate a risk score (age, gender, smoking status, weight, height and average systolic blood pressure) and they had to calculate the CVD risk scores. The practical evaluations were completed individually by the study coordinator and trainers. Only CHWs who obtained 100% on both the use of the risk tool and obtaining anthropometric measurements and at least 60% on the content knowledge test were permitted to conduct screenings in the community. A run-in period of two weeks prior to the start of the fieldwork allowed the study coordinator to assess the ability of CHWs who had qualified to perform screening. The coordinator randomly observed the CHWs during their screening activities and provided feedback at the end of the observations. During this two-week period, CHWs who were not able to perform adequately were withdrawn from further screening activities. CHWs were given a third, post-field-work test six months after the training to assess longer-term knowledge retention. This test did not include evaluating the CHWsâ&#x20AC;&#x2122; ability to obtain anthropometric measurements as they were required to hand in their equipment at the end of the field-work. All test scripts were graded, percentages of scores were calculated for each individual, and each participant was ranked. To maintain confidentiality, only numbers known to each individual were used for feedback.

Results A total of 15 CHWs (14 females) were recruited for the training, ranging between 23 and 36 years. All 15 trainees reported completing grade 12 but only three had passed the final

examination for grade 12. All were receiving a stipend from the NGO (between R1 330 and R1 710 per month). The only previous training they had received was a two-day workshop related to providing support to clients in the management of their diagnosed chronic diseases but none related to screening for CVD. The results of all written tests administered are shown in Fig. 2. Prior to the commencement of training, none of the 15 CHWs scored at least 60% (the passing grade) on the content knowledge test. Since the training was designed to be delivered over five working days, the first post-test was administered at the completion of the training programme (8 June 2012) in order to assess the effectiveness of the training in imparting knowledge. Only seven of the 15 trainees (47%) reached the passing threshold. Based on these scores, it became clear that a second, additional test would be required in order for at least half of the trainees to be fit to conduct the field-work. A second week of training was added, focusing on areas identified by the training team as being poorly understood, through discussions with the trainees. A second post-training test was administered at the end of the second week (15 June 2012). This was identical to the first posttraining examination. At the completion of the second week of training, 13 of the 15 trainees (87%) reached the passing threshold. During the two-week run-in period, two additional CHWs were removed from screening activities due to a failure to perform adequately in the community. Ten of the eleven CHWs continued fieldwork for the post-field-work testing. Out of these 10, 70% had maintained their knowledge levels above the passing threshold. During field-work activities, the CHWs used a standard protocol14 to screen individuals aged 35 to 74 years for CVD risk and referred them to the health facility for further evaluation and treatment. Individuals with a measured systolic blood pressure

100 90 80

Score (% correct)

70 Passing

Threshold

50 40 30 20 10 0

Pre-training score (%)

6 7 8 9 10 Community health worker number

Post-training score 1 (%)

* Note: CHWs 10, 12, 13, 15 did not participate in field work

Fig. 2. P re- and post-test scores of community health workers.

Post-training score 2 (%)

Post-field-work score 1 (%)

174

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

> 180 mmHg were deemed clinically urgent cases and were given an urgent referral letter for immediate evaluation by a health professional at the closest health facility. They were ineligible for the CVD risk-assessment arm of the trial but were eligible for the referral arm. A CVD risk score was calculated for all remaining participants using the risk-scoring tool (Fig. 1). Those whose risk score was > 20% were provided with non-urgent referral letters to see a health professional within two weeks of screening. To validate the scores, a professional nurse who was a field coordinator calculated a second CVD risk score using de-identified data and was blinded to the CHWs’ risk scores and BMI calculations. Each CHW was expected to screen at least 100 people over a four- to six-week period at community screenings or in members’ homes. Table 2 provides information on the number screened and referred for treatment.

Discussion The process described in this article indicates that CHWs can be effectively trained in screening for CVD risk using a non-invasive screening tool. From the training process of the CHWs, three important points regarding the training were noted: (1) pre-training knowledge on NCDs; (2) language used during the training and in the written tests; and (3) knowledge retention over the longer term. From the pre-training test in which no CHW scored more than 60%, it is clear that although they were working with NCDs, their knowledge of NCDs was limited. This raises concern about the appropriateness of current training received by CHWs in this area, given that the CHWs selected for this study were typical of those employed in the community by the largest NGO, so it is not clear what messages they were imparting to the community members during delivery of health services. It also raises questions as to who should be responsible for training the CHWs and how often they should be trained. This is supported by a 2014 study by Tsolekile et al.,15 which found that in the absence of organised training for CHWs, most newly employed CHWs obtain their knowledge from their peers, who themselves do not always have or share correct information. In order for CHWs not to be viewed as providers of cheap or inferior-quality healthcare, they need to be properly trained. If properly trained they can provide an affordable first-contact level of care within the PHC system. Calculation of BMI was a new concept for the CHWs, even though obesity is a major risk Table 2. Field-work activities of the community health workers CHWs trained CHWs selected for field-work Community members screened Community members with CVD risk > 20% (high risk) Persons provided with urgent referrals1

15 10 1 217 7% of all screened persons 32.5% of all high-risk persons Persons provided with non-urgent referrals2 67.5% of all high-risk persons 1 Urgent referrals: screened persons advised to attend a health clinic on the day of screening. 2 Non-urgent referrals: screened persons advised to attend a health clinic within two weeks of screening.

AFRICA

factor for NCDs and a major public health problem in the South African population, especially among black women.16 Similarly, in 2011, Parker et al.,17 who examined knowledge about practical issues related to the prevention and control of non-communicable diseases, found that less than 10% of health professionals at primary-health facilities in the Western Cape attained a score of 80% and above. There is therefore a need for continuing training of health workers to keep them updated. Although the CHWs were keen to be trained in English, it became clear that it was necessary to explain some of the difficult concepts in the local language commonly used by community members, including CHWs. This implies that training teams for CHWs should include trainers who are fluent in the local language of trainees, to ensure effective training. Furthermore, the burden of the requirement that all training materials must be produced and delivered in English is a potential barrier to effective training. Given that CHWs are trained to enable them to impart knowledge and skills to their communities using a local language, the training should be given in their local language. A study that examined the challenges of facilitation in adult education found that facilitators are often not familiar with the language of the learners, which creates a barrier to proper learning, as some learners cannot check their understanding of the subject by communicating in their local language.18 Consideration should be given with regard to the purpose of using English to train this cadre of health professionals to accommodate trainers or learners. Eighty-seven per cent of CHWs scored better in the second post-training test at the end of the second week of training than in the first post-training test administered at the end of the first week of training. This improvement is an indication that the challenges for CHWs in understanding new concepts were appropriately identified and addressed by the training team following exploration of the CHWs’ understanding of why the first week of training had failed. The finding that 70% of the CHWs passed the post-field-work test demonstrates that effective training can facilitate long-term retention of new knowledge, and may also prove to be instructive when considering the need for retraining and the appropriate retraining intervals in future research. This is also an indication that people will remember activities that they perform on a daily basis. The decline in the percentage of CHWs who had retained the knowledge at the post-field-work test is similar to the findings of several studies that reported declining knowledge.19,20 From the training evaluation, it was clear that the training period was too short to cover all the new information. The CHWs reported that they experienced great difficulty in understanding the written examination tests in English rather than in their native isi-Xhosa, which was the language used to address conceptual challenges during the training itself. A retraining session including an extensive familiarisation of basic terminology in English correlating with the concepts under study was therefore necessary in order to get better scores. Further written tests should be administered in the CHWs’ first language or in English once proficiency has been demonstrated.

Study limitations While the ability to generalise the findings of this research is limited by its selection of CHWs working for a particular NGO

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

located in an urban township in South Africa, these findings may not be different in other settings that employ CHWs and focus on NCDs due to lack of standardised training. Since the purpose of this training was to empower CHWs with skills to screen and identify those at risk for CVD, and refer them to the health facility for treatment, counselling on lifestyle modification was not included in this training.

175

can be trained to measure blood pressure: experience from India. Reg Health Forum 2013; 17(1): 26–31. 8.

Brownstein JN, Chowdhury FM, Norris SL, et al. Effectiveness of community health workers in the care of people with hypertension. Am J Prev Med 2007; 32(5): 435–447.

Brownstein JN, Bone LR, Dennison CR, Hill MN, Kim MT, Levine DM. Community health workers as interventionists in the prevention and control of heart disease and stroke. Am J Prev Med 2005; 29(5 Suppl

Conclusion Although CHWs could be trained in screening for CVD risk using a non-invasive risk-screening tool, adequate training time was needed to enable them to grasp important new concepts. The language used in both teaching and testing this cadre of workers should be taken into consideration when measuring their performance. Inadequate or inappropriate training may result in health workers failing to do their work as expected. Sustaining the newly acquired knowledge requires refresher training.

1): 128–133. DOI: 0749-3797. 10. Lehman U and Sanders D. Community health workers: What do we know about them? The state of the evidence on programmes, activities, costs and impact on health outcomes of using community health workers: Evidence and Information for Policy, Department of Human Resources for Health Geneva, January 2007; 1–34. http://www.who.int/ hrh/documents/community_health_workers.pdf. 11. Siraj S,Shabnam F, Jalal CSB, et al. Shasthya Shebika’s role in improving infant and young child feeding practices in rural Bangladesh: BRAC’s Experience. Geneva Health Forum, 2010. 12. Languza N, Lushaba T, Magingxa T, Masuku M, Ngubo T. Community Health Workers. A brief description of the HST experience 2011; 1–8.

This project was funded in part with federal funds from the United

The Health System Trust, South Africa.

States National Heart, Lung, and Blood Institute, National Institutes of

13. Puoane T, Bradley H, Hughes G. Community intervention for the

Health, Department of Health and Human Services, under contract no.

emerging epidemic of non- communicable diseases. S Afr J Clin Nutr

HHSN268200900030C. The funding sources played no role in the study design, data collection, data analysis and interpretation, or the writing of the report.

2006; 19(2): 56–62. 14. Abrahams-Gessel S, Denman CA, Montano CM, Gaziano TA, Levitt N, Rivera-Andrade A, et al. Training and supervision of community health workers conducting population-based, non-invasive screening for

References 1.

15. Tsolekile LP, Puoane T, Schneider H, Levitt NS, Steyn K. The roles

health worker programmes in the late apartheid era in South Africa: An

of community health workers in management of non-communicable

historical analysis. Soc Sci Med 2010; 71(6): 1110–1118. doi: 10.1016/j.

diseases in an urban township. Afr J Prm Health Care Fam Med 2014; 16. Kruger HS, Puoane T, Senekal M, van der Merwe M-T. Obesity in

health system strengthening: Concept paper for discussion at NCD

South Africa: challenges for Government and health professionals. Pub

summit, 2011. Pretoria: National Department of Health.

Health Nutr 2005; 8(5): 491–500. DOI: 10.1079/PHN2005785/PMID:

Igumbor EU, Puoane T, Gansky S, Plesh O. Epidemiology of chronic

but do they? Misalignment of perceptions of lifestyle modification

Tulchinsky TH, Varavikova EA. What is the ‘New Public Health’? Public

knowledge among health professionals. Public Health Nutr 2011; 14(8): 18. Rivombo AM. A study of the challenges of adult learning facilitation

from community health workers on health care delivery in rural

in a diverse setting with special reference to Soshanguve. Dissertation,

10.1086/521122/PMID:18181702 National Center for Chronic Disease Prevention and Health Promotion Division for Heart Disease and Stroke Prevention. Addressing chronic

1429–1438.

Arjun S, Gan K, Carpenter S. Voices from the field: Perspectives KwaZulu-Natal, South Africa. J Infec Dis 2007; 196: 505–511. DOI:

16153330. 17. Parker WA, Steyn NP, Levitt NS, Lombard CJ. They think they know

SA 2011; 6(1): 48 Health Rev 2010; 32: 25–53. 5.

6(1): 1–8. http://dx.doi.org/10.4102/ phcfm.v6i1.69.

Department of Health. Controlling non-communicable diseases through

pain in a peri-urban community in the Eastern Cape Province. J Pain 4.

39–44.

Van Ginneken N, Lewin S, Berridge V. The emergence of community

socscimed.2010.06.009. 2.

CVD in LMIC: Implications for scaling up. Global Heart 2015; 10(1):

UNISA; 2014. URI: http://hdl.handle.net/10500/14198 . 19. Gass DA, Curry L. Physicians’ and nurses’retention of knowledge and skill after training in cardiopulmonary resuscitation. Can Med Assoc J 1983; 128: 550–551.

disease through community health workers: A policy brief on communi-

20. Crofts JF, Fox R, Draycott TJ, Winter C, Hunt LP, Akande VA.

ty health workers www.cdc.gov/dhdsp/docs/chw_brief.pdf date accessed

Retention of factual knowledge after practical training for intrapartum

2014/12/03.

emergencies. Int J Gynaecol Obstet 2013; 123(1): 81–85. DOI: 10.1016/j.

Amarchandi R, Sharmaii H, Krishnaniii A. Community health workers

ijgo.2013.04.015. Epub 2013 Jul 11.

176

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Effects of Ramadan intermittent fasting on North African children’s heart rate and oxy-haemoglobin saturation at rest and during sub-maximal exercise Mohamed Amine Fenneni, Imed Latiri, Asma Aloui, Sonia Rouatbi, Karim Chamari, Helmi Ben Saad

Abstract Aim: To examine the effects of Ramadan intermittent fasting (RIF) on the heart rate (HR) and oxyhaemoglobin saturation levels (oxy-sat) of boys at rest and during a six-minute walking test (6MWT). Methods: Eighteen boys (age: 11.9 ± 0.8 years, height: 153.00 ± 8.93 cm, body mass: 55.4 ± 18.2 kg), who fasted the entire month of Ramadan in 2012 for the first time in their lives, were included. The experimental protocol comprised four testing phases: two weeks before Ramadan (pre-R), the end of the second week of Ramadan (R-2), the end of the fourth week of Ramadan (R-4), and 10 to 12 days after the end of Ramadan (post-R). During each phase, participants performed the 6MWT at approximately 15:00. HR (expressed as percentage of maximal predicted HR) and oxy-sat (%) were determined at rest and in each minute of the 6MWT. Results: R-4 HR values were lower than those of (1) pre-R (in the second minute), (2) R-2 (in the first and second minutes), and (3) post-R (in the first, second, fourth, fifth and sixth minutes). R-2 oxy-sat values were higher than those of pre-R (in the third minute) and those of post-R (in the fifth minute). Post-R oxy-sat values were lower than those of pre-R and R-4 in the fifth minute. These oxy-sat changes were not clinically significant since the difference was less than five points. Conclusion: In non-athletic children, their first RIF influenced their heart rate data but had a minimal effect on oxy-sat values.

Laboratory of Physiology, Faculty of Medicine, University of Sousse, Tunisia Mohamed Amine Fenneni, MSc Imed Latiri, PhD Sonia Rouatbi, MD, PhD Helmi Ben Saad, MD, PhD, helmi.bensaad@rns.tn

Faculty of Sciences, Bizerte, Carthage University, Tunisia Mohamed Amine Fenneni, MSc

High Institute of Sport and Physical Education, University of Gafsa, Gafsa, Tunisia Asma Aloui, PhD

Department of Physiology and Functional Exploration, Farhat Hached University Hospital of Sousse, Tunisia Sonia Rouatbi, MD, PhD Helmi Ben Saad, MD, PhD

Athlete Health and Performance Research Center, ASPETAR, Qatar Orthopedic and Sports Medicine Hospital, Qatar Karim Chamari, PhD

Research Laboratory LR14ES05, Faculty of Medicine, University of Sousse, Tunisia Helmi Ben Saad, MD, PhD

Keywords: Tunisia, Ramadan fasting, heart rate, oxyhaemoglobin saturation, walking test, child Submitted 28/2/16, accepted 22/7/16 Published online 21/10/16 Cardiovasc J Afr 2017; 28: 176–181

www.cvja.co.za

DOI: 10.5830/CVJA-2016-078

Ramadan intermittent fasting (RIF) is the fourth pillar of Islam and, according to most religious scholars, it concerns every healthy Muslim after puberty.1 It is important to know the effects of RIF on human physiology, not only for Muslim-majority countries but also for many countries where Muslims are in the minority.2 In a globalised society, physicians have to deal with issues such as Muslim patients who desire to fast during Ramadan, regardless of whether they are in good health or not.3 Several studies have assessed the effects of RIF on variables such as body mass, biological data or markers, and sleep patterns in healthy adult subjects.2,4-10 However, only a few studies have been performed on healthy children.11-14 This lack of information on the effects of RIF on the health and physical performance of healthy children could lead to confusion worldwide. For example, on 10 June, one week before the start of Ramadan in 2015, the Barclay Primary School in east London, UK, sent a letter to the parents of its students (http://www.telegraph.co.uk/ news/religion/11669767/Primary-schools-ban-children-fromfasting-during-Ramadan.html; visited 8 May 2016): ‘The policy of both Barclay Primary School and all schools within the Lion Academy Trust does not allow any children (aged 6 to 12 years) attending the schools to fast’, suggesting that fasting would endanger the health and education of students. In children, the evaluation of heart rate (HR) and/or oxyhaemoglobin saturation (oxy-sat) dynamics during exercise provides valuable information for making management decisions, resulting in improved quality of life and functional capacity.15,16 During exercise, HR responses reflect subjects’ physical level and aerobic fitness.17,18 To the best of our knowledge, to date, all studies interested in the effects of RIF on HR changes concern adults19-25 and none has been performed in children.26 In addition, conclusions concerning the effect of fasting on healthy adults’ HR changes during exercise were controversial,19-25 with modified (lower19,24 or higher25) or unchanged values reported.20-23 Oxygen desaturation provides information regarding exerciseinduced desaturation.17 However studies on the RIF effects on oxyhaemoglobin saturation seem non-existent. A Medline search (performed on 28 January 2015) using as keywords ‘fasting’ and ‘oximetry or oxyhemoglobin saturation’ and ‘exercise’ found no articles.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

In the four studies concerning the effects of RIF on the sports performance of healthy children, no information was given on HR and/or oxy-sat.11-14 In that regard, a recent article26 has described and criticised these publications,11-14 and the authors recommend studies focusing on the effects of RIF on HR and oxy-sat.26 Therefore, the aim of our study was to examine the effects of RIF on HR and oxy-sat, determined at rest and during a field exercise test in untrained Tunisian boys.

Methods Part of this study’s methodology was previously described in an article reporting on the effects of RIF on first-time fasting boys’ performance in short-term explosive exercises, as well as in sub-maximal endurance exercise.12 The major details concerning the applied methodology are presented below. Eighteen healthy non-athletic boys who fasted for the first time in their lives during Ramadan 2012 were included. The protocol was approved by the local hospital ethics committee, and written informed consent was obtained from all children and their parents. The boys were asked to avoid strenuous activities 24 hours before each testing phase. Participants were informed that their participation was free of pressure and that they could withdraw from the study at any time (including that they could decide to stop fasting). The experimental design consisted of four testing phases: two weeks before Ramadan (pre-R), the end of the second week of Ramadan (R-2), the end of the fourth week of Ramadan (R-4), and 10 to 12 days after the end of Ramadan (post-R). The decimal age (accuracy of 0.10 years) was calculated from the date of measurement and the date of birth. Body mass (± 1 kg) was measured during each phase and height was measured to the nearest 0.1 cm.12 The boys were familiarised with the six-minute walking test (6MWT) to minimise the learning effect.27 6MWTs were conducted at the same time of day in the interval between 15:00 and 17:00.28 This period corresponded to the last fasting hours of the day, with the fast break time ranging from 19:31 at the beginning to 19:04 at the end of Ramadan 2012 at the location of the study. During each testing phase, each boy performed one 6MWT. The following data were collected/calculated: six-minute walking distance (6MWD, in m, % of predicted value27), oxy-sat (%) and HR [bpm, % of maximal predicted HR (= 208–0.7 × age)29] determined at rest and in each minute of the 6MWT, and the 6MWD × sixth minute oxy-sat index (m).17,18 The 6MWTs were performed according to international guidelines.30 At the end of the 6MWT, the 6MWD (m) was noted. HR (Polar RS 800, Polar Electro Oy, Kempele, Finland) and oxy-sat (Nonin Medical, Inc, Minneapolis, MN) were recorded at rest and in each minute of the 6MWT. Additional 6MWT methodology details have been presented in a separate publication.12

Statistical analysis Data are presented as mean values ± standard deviation (SD) for anthropometric data and mean ± SD (95% confidence interval) for HR, oxy-sat and the 6MWD × sixth minute oxy-sat index. The Kolmogorov–Smirnov test for normality revealed that the data were normally distributed. Analysis of variance

177

(ANOVA) was then conducted to compare the HR and oxy-sat data measured at the seven time points of the 6MWT (rest, first, second, third, fourth, fifth and sixth minutes) during the four testing phases. ANOVA was also conducted to compare the 6MWD × sixth minute oxy-sat index in the four phases. When appropriate, significant differences between means were tested using the Tukey post hoc test. Statistical analyses were performed using Statistica software (Statistica Kernel version 6; StatSoft, Paris, France). Significance was set at p < 0.05.

Results The mean ± SD of the 18 boys’ age, height and body mass were 11.9 ± 0.8 years, 153.00 ± 8.93 cm and 55.4 ± 18.2 kg, respectively. The effect of RIF on HR: Fig. 1 shows the HR data (%) determined during the four testing phases at the seven time points of the 6MWT. There was no significant difference between the four testing phases in resting or third-minute HR values [ANOVA (n =18, df = 3, F = 0.82) and ANOVA (n = 18, df = 3, F = 1.253), respectively]. However, there were significant differences between the four testing phases in the: • first-minute 6MWT HR values [ANOVA (n = 18, df = 3, F = 4.32, p < 0.008)]. HR was lower during R-4 (69 ± 7 bpm) compared to R-2 (76 ± 10 bpm; p = 0.04) and post-R (78 ± 6; p = 0.008). • second-minute 6MWT HR values [ANOVA (n = 18, df = 3, F = 5.447, p < 0.0022)]. HR was lower during R-4 (70 ± 9 bpm) compared to pre-R (78 ± 9 bpm; p = 0.029), R-2 (79 ± 10 bpm; p = 0.027) and post-R (81 ± 7 bpm; p = 0.003). • fourth-minute 6MWT HR values [ANOVA (n = 18, df = 3, F = 4.83, p < 0.0045)]. HR was lower during R-4 (72 ± 9 bpm) compared to post-R (84 ± 6 bpm; p = 0.002). • fifth-minute 6MWT HR values [ANOVA (n = 18, df = 3, F = 4.054, p < 0.01)]. HR was lower during R-4 (75 ± 7 bpm) compared to post-R (85 ± 7 bpm; p = 0.009). • sixth-minute 6MWT HR values [ANOVA (n = 18, df = 3, F = 3.43, p < 0.023)]. HR was higher during post-R (86 ± 9 bpm) compared to R-2 (77 ± 10 bpm; p = 0.04) and R-4 (77 ± 8 bpm; p = 0.04). The effect of RIF on oxy-sat: Fig. 2 shows the oxy-sat data (%) obtained during the four phases at the seven time points of the 6MWT. There was no significant difference between the four testing phases in resting or first, second, fourth and sixth minutes oxy-sat values [ANOVA: (n = 18, df = 3, F = 3.52), (n = 18, df = 3, F = 1.83), (n = 18, df = 3, F = 2.12), (n = 18, df = 3, F = 1.41) and (n = 18, df = 3, F = 2.13), respectively]. However, there were significant differences between the four testing phases in the: • third-minute oxy-sat values [ANOVA (n = 18, df = 3, F = 4.07, p < 0.01)]. The Tukey test showed a significant difference between pre-R and R-2 [89 ± 7 vs 95 ± 2%; p = 0.02]. • fifth-minute oxy-sat values [ANOVA (n = 18, df = 3, F = 4.55, p < 0.006)]. The Tukey test showed a significant difference between pre-R and post-R (94 ± 2 vs 89 ± 7%; p = 0.04), between R-2 and post-R (95 ± 3 vs. 89 ± 7%; p = 0.008), and between R-4 and post-R (94 ± 6 vs 89 ± 7%; p = 0.04). Fig. 3 shows the 6MWD × oxy-sat indices calculated in the sixth minute of each 6MWT. A significant difference between the four testing phases was found [F (3, 53) = 3.4191; p = 0.023]. The Tukey test showed a significant difference (p = 0.019) between pre-R (67 573 ± 7 514 m) and R-4 (56 224 ± 12 274 m) values.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

aeg

aceg

102

afg

Rest

1st

AFRICA

adfg

5th

6th

100 98 Oxy-sat (%)

95 90 85 80 75 70 65 60 55 50 45 40 35

96 94 92 90 88 86 84 82

Rest

1st

2nd 3rd 4th 6MWT timing (min)

Four testing phases: pre-Ramadan (pre-R) end of the second week of Ramadan (R-2)

5th

6th

end of the fourth week of Ramadan (R-4) 10–12 days after the end of Ramadan (post-R)

Fig. 1. E ffect of Ramadan intermittent fasting on heart rate determined at rest and in each minute of the six-minute walking test (6MWT) in 18 non-athletic boys fasting for the first time. Heart rate data is expressed as percentage of maximal predicted heart rate. Mean values are shown. Error bars represent 95% confidence intervals. ns: non-significant. ap < 0.05: ANOVA between the four testing phases for the same timing; bp < 0.05 (Tukey post hoc test): pre-R vs R-2 for the same timing; cp < 0.05 (Tukey post hoc test): pre-R vs R-4 for the same timing; dp < 0.05 (Tukey post hoc test): pre-R vs post-R for the same timing; ep < 0.05 (Tukey post hoc test): R-2 vs R-4 for the same timing; fp < 0.05 (Tukey post hoc test): R-2 vs post-R for the same timing; gp < 0.05 (Tukey post hoc test): R-4 vs post-R for the same timing.

Discussion The objective of this study was to evaluate the effects of RIF on HR and oxy-sat data, determined at rest and during a sub-maximal field test in healthy, untrained boys fasting for the first time in their lives during Ramadan 2012. With regard to HR, R-4 values were lower than those of pre-R (second minute), R-2 (first and second minutes) and post-R (first, second, fourth, fifth and sixth minutes), with no significant difference between the four testing phases in resting and third-minute HR values. Concerning oxy-sat, R-2 values were higher than those of pre-R (third minute) and post-R (fifth minute), and post-R values were lower than those of pre-R and R-4 (fifth minute). To the best of our knowledge, only four studies11-14 have recently described the effects of RIF on the exercise performance of healthy children. Our study included boys who lived in KalaaKebira (Sousse region), a small town on the Tunisian east coast, known to have a low level of pollution. Fenneni et al.26 criticised these four articles and recommended studies focusing on the effect of RIF on physiological parameters such as HR and oxy-sat. They discussed in detail the required sample size, study design, 6MWT choice and procedures.26

2nd 3rd 4th 6MWT timing (min)

Four testing phases: pre-Ramadan (pre-R) end of the second week of Ramadan (R-2)

end of the fourth week of Ramadan (R-4) 10–12 days after the end of Ramadan (post-R)

Fig. 2. Effect of Ramadan intermittent fasting on oxyhaemoglobin saturation (oxy-sat; %) determined during the six-minute walking test (6MWT) in 18 non-athletic boys fasting for the first time. Mean values are shown. Error bars represent 95% confidence intervals. ns: non-significant. ap < 0.05: ANOVA between the four testing phases for the same timing; bp < 0.05 (Tukey post hoc test): pre-R vs R-2 for the same timing; cp < 0.05 (Tukey post hoc test): pre-R vs R-4 for the same timing; dp < 0.05 (Tukey post hoc test): pre-R vs post-R for the same timing; ep < 0.05 (Tukey post hoc test): R-2 vs R-4 for the same timing; fp < 0.05 (Tukey post hoc test): R-2 vs post-R for the same timing; gp < 0.05 (Tukey post hoc test): R-4 vs post-R for the same timing.

6MWD x Oxy-sat (103m)

Heart rate (%)

178

80 75 70 65 60 55 50 45

F (3, 53) = 3.4191; p = 0.02373 ac

Pre-R

R-2

R-4

Post-R

Phases

Fig. 3. Effect of Ramadan intermittent fasting on the product of oxyhaemoglobin saturation (oxy-sat) and the sixminute walking distance (6MWD) determined during the sixth minute of the six-minute walking test (6MWT) in 18 non-athletic boys fasting for the first time. Mean values are shown. Error bars represent 95% confidence-intervals. ap < 0.05: ANOVA between the four testing phases; bp < 0.05 (Tukey post hoc test): pre-R vs R-2; cp < 0.05 (Tukey post hoc test): pre-R vs R-4; dp < 0.05 (Tukey post hoc test): pre-R vs post-R; e p < 0.05 (Tukey post hoc test): R-2 vs R-4; fp < 0.05 (Tukey post hoc test): R-2 vs post-R; gp < 0.05 (Tukey post hoc test): R-4 vs post-R.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

RIF is not obligatory for pre-pubescent children, and many observe it from early adolescence.12,26 However, even though Islam requires such a practice only after puberty, it is a relatively frequent practice that pre-pubescent children attempt to fast the whole of Ramadan.12,26

Effect of RIF on HR RIF seemed to have a significant effect on HR, determined during the 6MWT. Our study showed that R-4 HR values were lower than those of pre-R (second minute), R-2 (first and second minutes), and post-R (first, second, fourth, fifth and sixth minutes), with no significant difference between the four testing phases in resting and third-minute HR values (Fig. 1). To our knowledge, this study is the first to examine the impact of RIF on the HR of healthy children. Our results are in line with those observed in some studies conducted on adults,19,24 but opposite to those of Zerguini et al.25 Husain et al.19 showed that resting HR in adults was markedly lowered in sedentary fasting male subjects (aged 20–45 years) during the month of Ramadan, while responses in females were only slightly decreased. Ramadan and Barac-Nieto24 found a small but significant HR reduction in response to sub-maximal exercise during the month of Ramadan in sedentary males aged 35 ± 2 years. Zerguini et al.25 found that HR measured after a 12-minute run was higher during R-4 than pre-R in professional soccer players aged 17–34 years. Karli et al.22 observed that peak HR values determined after a 30-second Wingate test were not significantly different between Ramadan and pre-R in elite power athletes aged 20–40 years. Brisswalter et al.23 found that maximal HR recorded after an incremental maximal running test was not modified during R-4 (vs pre-R) in well-trained runners aged 24 ± 3 years. Also, Güvenç21 found that HR at eight, 10, 11 and 12 km/h of a modified 20-m shuttle-run test and peak HR after this exercise were unchanged during Ramadan in male soccer players aged 17 ± 1 years. Finally, HR during a 60-minute endurance treadmill running test,31 and a multi-stage fitness test20 remained unaffected during Ramadan in moderately trained active men (mean age: 27 ± 7 years) and in elite judokas (mean age: 18 ± 1 years), respectively. There are three possible explanations as to how the decrease in HR during RIF could be explained: • significant reduction in endurance capacity during Ramadan.12 In a previous study, it was shown that the 6MWD was lower during R-4 compared to pre-R but returned to baseline values post-R. Therefore, the RIF-induced attenuation of HR during walking tests should be taken into consideration when assessing human exercise capacity, applying the HR output relationship. • changes in lifestyle during Ramadan.12 This mainly impacts on the schedule of food intake, which may affect HR.32 Indeed, fasting lowers the metabolic rate due to the absence of digestion, which increases HR for two or three hours during the day.33 The possible role of plasma leptin and ghrelin concentrations (i.e. satiety and hunger hormones, respectively, known to affect cardiovascular activity34,35) as an explanation of HR reduction was rejected by Zoladz et al.,36 who found no effect of the overnight fast on pre- and during-exercise plasma leptin and ghrelin concentrations. However, this may be due to the relatively short duration of fasting in their study compared to RIF.37,38 This

179

possible explanation should be considered in future studies. • reduced sympathetic tone during fasting.19 Zoladz et al.36 demonstrated a significant decrease in HR by about 10 bpm after an overnight fast. Their most likely explanation was the observed significant increase in plasma norepinephrine concentration, leading to an increase in systemic vascular resistance, loading of arterial baroreceptors, and causing vagal stimulation.39,40 The validity of the above explanations, taken from studies done in adults, should be demonstrated in children.

Effect of RIF on oxy-sat RIF seemed to have a statistically significant effect on oxy-sat determined during the third and fifth minutes of the 6MWT. R-2 oxy-sat values were higher than those of pre-R (third minute) and post-R (fifth minute), and post-R values were lower than those of pre-R and R-4 (fifth minute). These significant changes between phases were approximately five points (Fig. 2), and could not be considered clinically significant since that requires a change of more than five points.17,18,27 Therefore RIF slightly improved blood oxygenation and oxygen transport by haemoglobin, suggesting that the haemoglobin affinity with oxygen may have increased.41,42 Recently, a novel desaturation index (6MWD × oxy-sat) has been proposed, with the objective of improving the information obtained from the 6MWT.17,18 In our study, this index was lower during R-4 compared to pre-R (Fig. 3). However, during the four testing phases, the desaturation index was in the normal range (minimum–maximum: 32 305–78 720). In chronic respiratory dysfunction patients, a low 6MWD × oxy-sat product (e.g. 20 000 m) was related to a clearly increased hazard ratio for mortality,43 and it predicted quality of life.44 The rationale for HR and oxy-sat measurements in non-diseased children deals with children’s safety. For instance, during school sports practice late in the afternoon, especially when Ramadan occurs in summer, the length of the fast could potentially be a concern with young fasting children. Moreover, such information could help medical and educational authorities to make rational decisions concerning banning/allowing the practice of RIF on school grounds. It is of paramount importance to note that banning of such a religious practice could trigger sharp reactions from the concerned communities; therefore, any potential banning has to be based on sound and powerful data.

Limitations The main limitation of the present study, as observed in previous ones on RIF effects on the physical capacities of healthy children,11-14,26 was the absence of a non-fasting control group. The inclusion of such a group may decrease the risk of learning effects skewing the findings, and circumvent any hazard to the internal strength of the results.12,26 This crucial point was previously discussed.12,26 The second limitation was not measuring the walked distance in each minute of the 6MWT. Therefore, the correlation between HR and the 6MWD in each minute of the 6MWT was not studied. However, as recommended, the boys were invited to walk as far as possible in six minutes along a flat hallway.30 In addition, none of them needed to rest since they knew how to pace themselves, based on pre-experiment tests.12,30

180

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Conclusion

AFRICA

al. Effects of Ramadan on physical capacities of North African boys

This study shows that summer RIF observed for the first time by non-athletic boys aged 12 years had a minimal effect on oxy-sat but significantly impaired HR during the 6MWT.

13. Girard O, Farooq A. Effects of Ramadan fasting on repeated sprint

The authors express their sincere gratitude to all participants and their

14. Meckel Y, Ismaeel A, Eliakim A. The effect of the Ramadan fast on

parents for their effort and cooperation. The Ministry of Higher Education

physical performance and dietary habits in adolescent soccer players.

fasting for the first time. Libyan J Med 2014; 9: 25391. PMID: 25261691. ability in young children. Sci Sports 2012; 27: 237–240. DOI:10.1016/j. scispo.2011.09.006.

and Scientific Research, Tunisia financially supported the study. MA Fennini and I Latiri contributed equally to this work. K Chamari and H Ben Saad contributed equally in this work.

Eur J Appl Physiol 2008; 102(6): 651–657. PMID: 18071743. 15. Connuck D. The role of exercise stress testing in pediatric patients with heart disease. Prog Pediatr Cardiol 2005; 20(1): 45–52. DOI: http:// dx.doi.org/10.1016/j.ppedcard.2004.12.004.

References 1. 2.

Rashed AH. The fast of Ramadan. Br Med J 1992; 304(6826): 521–522.

al. An official European Respiratory Society/American Thoracic Society

Bragazzi NL. Ramadan fasting and biological biomarkers: the new

technical standard: field walking tests in chronic respiratory disease. Eur 18. Singh SJ, Puhan MA, Andrianopoulos V, Hernandes NA, Mitchell KE,

OMICS Group eBooks, 2015. [Downloaded 2016 May 8]. Available

Hill CJ, et al. An official systematic review of the European Respiratory

from: http://www.esciencecentral.org/ebooks/effects-of-ramadan-fast-

Society/American Thoracic Society: measurement properties of field

ing/pdf/biological-biomarkers.pdf.

walking tests in chronic respiratory disease. Eur Respir J 2014; 44(6):

Al Wakeel J, Mitwalli AH, Alsuwaida A, Al Ghonaim M, Usama S, peritoneal dialysis. Perit Dial Int 2013; 33(1): 86–91. PMID: 23349195. Shephard R. Maintaining fluid balance during day fasting in the month

Chtara M, et al. Effect of Ramadan intermittent fasting on aerobic

[Downloaded 2016 May 8]. Available from: http://www.esciencecentral.

and anaerobic performance and perception of fatigue in male elite judo

HadiKhafaji HAR, Al Suwaidi JM. Ramadan fasting and lipid profile.

performance and lactate, heart rate and perceptual responses in young soccer players. J Hum Kinet 2011; 29: 79–91. PMID: 23486092. 22. Karli U, Guvenc A, Aslan A, Hazir T, Acikada C. Influence of

May 8]. Available from: http://www.esciencecentral.org/ebooks/effects-

Ramadan fasting on anaerobic performance and recovery following

of-ramadan-fasting/pdf/Ramadan-fasting-and-lipid-profile.pdf.

short time high intensity exercise. J Sports Sci Med 2007; 6(4): 490–497.

Gumaa KA, Mustafa KY, Mahmoud NA, Gader AM. The effects of

PMID: 24149483. 23. Brisswalter J, Bouhlel E, Falola JM, Abbiss CR, Vallier JM, Hausswirth

Nutr 1978; 40(3): 573–581. PMID: 718840.

C. Effects of Ramadan intermittent fasting on middle-distance running

Iraki L, Bogdan A, Hakkou F, Amrani N, Abkari A, Touitou Y.

performance in well-trained runners. Clin J Sport Med 2011; 21(5):

Ramadan diet restrictions modify the circadian time structure in

422–427. PMID: 21857506.

humans. A study on plasma gastrin, insulin, glucose, and calcium and

24. Ramadan JM, Barac-Nieto M. Cardio-respiratory responses to moder-

on gastric pH. J Clin Endocrinol Metab 1997; 82(4): 1261–1273. PMID:

ately heavy aerobic exercise during the Ramadan fasts. Saudi Med J

9100605.

2000; 21(3): 238–244. PMID: 11533791.

BaHammam A. Assessment of sleep patterns, daytime sleepiness, and

25. Zerguini Y, Kirkendall D, Junge A, Dvorak J. Impact of Ramadan on

chronotype during Ramadan in fasting and nonfasting individuals.

physical performance in professional soccer players. Br J Sports Med

Saudi Med J 2005; 26(4): 616–622. PMID: 15900372. 9.

athletes. J Strength Cond Res 2009; 23(9): 2702–2709. PMID: 19910805. 21. Guvenc A. Effects of ramadan fasting on body composition, aerobic

Performance. OMICS Group eBooks, 2015: 91-107. [Downloaded 2016

fasting in Ramadan. 1. Serum uric acid and lipid concentrations. Br J

PMID: 3620437.

and Athletic Performance. OMICS Group eBooks, 2015: 117–126.

In: Chtourou H, ed. Effects of Ramadan Fasting on Health and Athletic

Ramadan on tropical Asiatic Moslems. Br J Nutr 1987; 58(1): 41–48. 20. Chaouachi A, Coutts AJ, Chamari K, Wong del P, Chaouachi M,

pdf.

1447–1478. PMID: 25359356. 19. Husain R, Duncan MT, Cheah SH, Ch’ng SL. Effects of fasting in

of Ramadan. In: Chtourou H, ed. Effects of Ramadan Fasting on Health

org/ebooks/effects-of-ramadan-fasting/pdf/maintaining-fluid-balance. 5.

Respir J 2014; 44(6): 1428–1446. PMID: 25359355.

ed. Effects of Ramadan Fasting on Health and Athletic Performance.

Hayat A, et al. Recommendations for fasting in Ramadan for patients on 4.

Cardiovasc Dis 2014; 107(5): 319–327. PMID: 24841496. 17. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, et

PMID: 1559053. opportunities of systems biology and omics sciences. In: Chtourou H,

16. Massin MM. The role of exercise testing in pediatric cardiology. Arch

2007; 41(6): 398–400. PMID: 17224435.

Mustafa KY, Mahmoud NA, Gumaa KA, Gader AM. The effects of

26. Fenneni MA, Latiri I, Aloui A, Rouatbi S, Chamari K, Ben Saad

fasting in Ramadan. 2. Fluid and electrolyte balance. Br J Nutr 1978;

H. Critical analysis of the published literature about the effects of

40(3): 583–589. PMID: 718841.

Ramadan intermittent fasting on healthy children’s physical capacities.

10. Trabelsi K, Stannard S, Shephard R, Jamoussi K, Hakim A. Body

Libyan J Med 2015; 10: 28351. PMID: 26059080.

composition, hematological and biochemical modifications during

27. Ben Saad H, Prefaut C, Missaoui R, Mohamed IH, Tabka Z, Hayot M.

Ramadan fasting. In: Chtourou H, ed. Effects of Ramadan Fasting on

Reference equation for 6-min walk distance in healthy North African

Health and Athletic Performance. OMICS Group eBooks, 2015: 108-116.

children 6-16 years old. Pediatr Pulmonol 2009; 44(4): 316–324. PMID:

[Downloaded 2016 May 8]. Available from: http://www.esciencecentral. org/ebooks/effects-of-ramadan-fasting/body-composition.php.

19330774. 28. Chtourou H, Souissi N. The effect of training at a specific time of day:

11. Aloui A, Chtourou H, Hammouda O, Souissi H, Chaouachi A, Chamari

a review. J Strength Cond Res 2012; 26(7): 1984–2005. PMID: 22531613.

K, et al. Effects of Ramadan on the diurnal variations of physical

29. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate

performance and perceived exertion in adolescent soccer players. Biol Rhythm Res 2013; 44(6): 869–875. DOI: 10.1080/09291016.2013.780697. 12. Fenneni MA, Latiri I, Aloui A, Rouatbi S, Saafi MA, Bougmiza I, et

revisited. J Am Coll Cardiol 2001; 37(1): 153–156. PMID: 11153730. 30. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1): 111–117. PMID: 12091180.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

181

31. Aziz AR, Wahid MF, Png W, Jesuvadian CV. Effects of Ramadan fast-

38. Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima

ing on 60 min of endurance running performance in moderately trained

M, et al. Upregulation of ghrelin expression in the stomach upon fast-

men. Br J Sports Med 2010; 44(7): 516–521. PMID: 20519256.

ing, insulin-induced hypoglycemia, and leptin administration. Biochem

32. Maughan RJ, Fallah J, Coyle EF. The effects of fasting on metabolism and performance. Br J Sports Med 2010; 44(7): 490–494. PMID: 20484315. 33. Rivera-Brown AM, Frontera WR. Principles of exercise physiology: responses to acute exercise and long-term adaptations to training. Phys Med Rehab 2012; 4(11): 797–804. PMID: 23174541 34. Winnicki M, Phillips BG, Accurso V, van De Borne P, Shamsuzzaman

Biophys Res Commun 2001; 281(5): 1220–1225. PMID: 11243865. 39. Schachinger H, Weinbacher M, Kiss A, Ritz R, Langewitz W. Cardiovascular indices of peripheral and central sympathetic activation. Psychosom Med 2001; 63(5): 788–796. PMID: 11573027. 40. Malpas SC. What sets the long-term level of sympathetic nerve activity: is there a role for arterial baroreceptors? Am J Physiol Regul Integr Comp Physiol 2004; 286(1): R1–R12. PMID: 14660468.

A, Patil K, et al. Independent association between plasma leptin levels

41. Riggs TE, Shafer AW, Guenter CA. Acute changes in oxyhemoglobin

and heart rate in heart transplant recipients. Circulation 2001; 104(4):

affinity. Effects on oxygen transport and utilization. J Clin Invest 1973;

384–386. PMID: 11468197.

52(10): 2660–2663. PMID: 4199605.

35. Tritos NA, Kissinger KV, Manning WJ, Danias PG. Association

42. Dempsey JA, Rodriquez J, Shahidi NT, Reddan WG, MacDougall JD.

between ghrelin and cardiovascular indexes in healthy obese and lean

Muscular exercise, 2,3-DPG and oxy-hemoglobin affinity. Int Z Angew

men. Clin Endocrinol (Oxf) 2004; 60(1): 60–66. PMID: 14678289.

Physiol 1971; 30(1): 34–39. PMID: 5136941.

36. Zoladz JA, Konturek SJ, Duda K, Majerczak J, Sliwowski Z, Grandys

43. Lettieri CJ, Nathan SD, Browning RF, Barnett SD, Ahmad S, Shorr AF.

M, et al. Effect of moderate incremental exercise, performed in fed

The distance-saturation product predicts mortality in idiopathic pulmo-

and fasted state on cardio-respiratory variables and leptin and ghrelin concentrations in young healthy men. J Physiol Pharmacol 2005; 56(1): 63–85. PMID: 15795476. 37. Jenkins AB, Markovic TP, Fleury A, Campbell LV. Carbohydrate intake and short-term regulation of leptin in humans. Diabetologia 1997; 40(3):

nary fibrosis. Respir Med 2006; 100(10): 1734–1741. PMID: 16545950. 44. Bourbonnais JM, Malaisamy S, Dalal BD, Samarakoon PC, Parikh SR, Samavati L. Distance saturation product predicts health-related quality of life among sarcoidosis patients. Health Qual Life Outcomes 2012; 10: 67. PMID: 22694853.

348–351. PMID: 9084976.

Addendum Time-Line and Next Steps Proposal Submission by 1 June 2017 Decision notification by 15 June 2017 Implementation within 6 months (before end 2017) Eligible recipients: individuals or organisations in members states in Africa Selection Panel: PASCAR, WHF, and RHD Action What is needed? The rheumatic heart disease community in Africa is invited to propose an activity that will achieve at least one (and preferably more) of the following objectives in their countries: 1. Promote policy on the AU Communiqué on National Programmes for the prevention and control of RHD with activities over 12 months (avoiding once off activities) consistent with the objectives of the AU Communiqué http://www.pascar.org/uploads/files/CVJA_Addis-Ababa- Communique-2016.pdf) 2. Achieve implementation of a National Programme for prevention and control of RHD. US $2,000 is available to fund the project or activity designed to achieve these objectives. Applications are invited from rheumatic heart disease champions (organisations) based in Africa spelling out how this may be achieved in their country. PASCAR affiliated national societies will be at an advantage. The proposal should address the following questions: 1. 2. 3. 4. 5. 6.

What is the track record of the applicant in rheumatic heart disease work? What is the status of RHD prevention and control in your country? What is the activity or event or strategy that will be used to achieve the stated objectives? How will the funding be used to achieve the objectives (budget is required). Who are the stakeholders that will be involved in the activity or events? How will you involve the press in the activity or events?

The awards will be made to the five most deserving applicants based on the quality and credibility of the proposal with respect to answering the six questions and likelihood of meeting the objectives outlined above within a period of 6 to 12 month from the award of the grant. Recipients of the grant will be expected to provide a full report at the end of the project per template provided. Applications should be submitted to Mr George Nel, PASCAR Executive Officer, info@pascar.org before 1 June 2017.

182

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Assessment of indirect inflammatory markers in patients with myocardial bridging Levent Cerit

Abstract Introduction: Myocardial bridging (MB) is a congenital variant of the coronary artery in which a portion of the epicardial coronary artery takes an intramuscular course. Although it is considered a benign anomaly, it may lead to such complications as myocardial ischaemia, acute coronary syndrome, coronary spasm, exercise-induced dysrhythmias or even sudden death. MB may be related to increased inflammatory and atherosclerotic processes. This study was conducted with the aim of evaluating the relationship between neutrophil/ lymphocyte ratio (NLR) and MB. Methods: Taking into consideration the inclusion criteria, 86 patients with MB and 88 with normal coronary angiographies (control group) were included in the study. The association between MB and laboratory and other clinical parameters was evaluated. Results: The platelet distribution width (PDW) (17.3 ± 0.40 vs 16.1 ± 0 .5; p < 0.05), NLR (3.2 ± 1.3 vs 2.2 ± 0.9; p < 0.05) and red cell distribution width (RDW) (14.3 ± 1.3 vs 13.1 ± 1.1; p < 0.05) were significantly higher in the MB group than in the control group. Conclusions: This study demonstrated that compared to normal coronary arteries, PDW, NLR and RDW were significantly higher in MB patients. Further studies are needed to clarify the increased inflammatory parameters in patients with MB. Keywords: myocardial bridging, platelet distribution width, neutrophil-to-lymphocyte ratio Submitted 13/6/16, accepted 10/8/16 Published online 19/9/16 Cardiovasc J Afr 2017; 28: 182–185

www.cvja.co.za

DOI: 10.5830/CVJA-2016-080

Myocardial bridging (MB) is an anatomical variation characterised by narrowing during systole of some of the epicardial coronary arterial segments running in the myocardium. It may be encountered in 0.5 to 16% of routine coronary angiographies.1-3 Although it is considered a benign anomaly, it may lead to such complications as myocardial ischaemia, acute coronary syndromes, coronary spasm and exercise-induced dysrhythmias, such as supraventricular tachycardia, ventricular tachycardia, syncope or even sudden death.4,5

Department of Cardiology, Near East University, Nicosia, Cyprus Levent Cerit, MD, drcerit@hotmail.com

Platelet distribution width (PDW) is a direct measure of the variation in platelet size and a marker of platelet activation.6 Red cell distribution width (RDW) is a direct measure of the variation in erythrocyte size, which is measured as a component of routine blood counts.7 The RDW is a well-recognised indicator of chronic inflammation and oxidative stress, and elevated RDW is strongly associated with poor clinical outcomes among patients with coronary artery disease (CAD).8 The neutrophil/lymphocyte ratio (NLR), derived from the white blood cell (WBC) count, is a common prognostic indicator in cardiovascular disease.9 The aim of this study was to evaluate the relationships between MB and PDW and other haematological parameters in an effort to identify useful clinical indicators in patients undergoing coronary angiography.

Methods A retrospective evaluation was conducted of consecutive patients undergoing coronary angiography. Stable angina was defined as discomfort in the chest, back, shoulder, jaw or arms, typically elicited by exertion or emotional stress, and relieved by rest or nitroglycerin. All patients enrolled in the study underwent coronary angiography as a result of chest pain and objective signs of ischaemia during treadmill exercises. Routine laboratory and clinical parameters (e.g. hypertension, hypercholesterolaemia, diabetes mellitus, tobacco use, family history of cardiovascular disease) were obtained from the patients’ medical records. Study exclusion criteria included CAD, mild-to-severe valve disease, heart failure, anaemia, renal failure, inflammatory diseases, coronary ectasia, malignancy, peripheral and cerebral arterial disease and thyroid gland dysfunction (hypohyperthyroidism). All patients underwent transthoracic echocardiography using the Vivid S5 (GE Healthcare) echocardiography device and Mass S5 probe (2–4 MHz). Standard two-dimensional and colour-flow Doppler views were acquired according to the guidelines of the American Society of Echocardiography and European Society of Echocardiography.10 The ejection fraction was measured according to the Simpson’s method.10 Coronary angiography was performed with the Judkins technique11 and Innova 3100-IQ angiographic system (General Electric, Buc Cedex, France). A typical description of bridging on angiographyic view involves systolic narrowing, or ‘milking’ of an epicardial artery, with a ‘step-down’ and ‘step-up’ demarcating the impacted area. Angiographic views were evaluated based on these MB criteria, and ≥ 50% systolic narrowing of an epicardial artery was considered MB. Coronary angiograms were assessed independently for objective evaluation of MB by two invasive cardiologists blinded to the clinical findings. Prior to coronary angiography, eight-hour postprandial venous blood was collected from all patients for routine laboratory

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

testing. Complete blood counts (CBC), including haemoglobin, haematocrit and WBC count were analysed using an automated CBC device (Abbott Cell Dyn; Abbott Laboratories, Effingham, Illinois, USA). Biochemical parameters were measured using an Olympus AU 600 auto-analyzer (Olympus Optical Co. Ltd, Schimatsu-Mishima, Japan). All study parameters were reviewed and approved by the local ethics committee.

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

Results The study population consisted of 1 368 consecutive patients undergoing coronary angiography. Out of the total population, 86 patients with MB were included in the study group. The control group consisted of 88 age-matched subjects with normal coronary angiograms, selected consecutively during the same study period as the study group. The same exclusion criteria were applied to the study and control groups. The distribution of cardiovascular risk factors, demographic characteristics, and laboratory parameters in the two groups are shown in Table 1. The mean age of the MB group was 56 ± 9 years and control group was 54 ± 7 years (p = 0.468). There was no statistically significant difference between the two groups with regard to known CAD risk factors, such as diabetes mellitus and smoking history, except hypertension was more prevalent in the MB group than in the control group (25 vs 36%, p = 0.034; Table 1). The ejection fraction was similar between the two groups (62.4 ± 3.1 vs 60.2 ± 4.2%, p = 0.471; Table 1). The PDW (17.3 ± 0.4 vs 16.1 ± 0.5%, p = 0.003), NLR (3.2 ± 1.3 vs 2.2 ± 0.9%, p = 0.034), and RDW (14.3 ± 1.3 vs 13.1

Table 1. Distribution of baseline characteristic of all patients Normal coronary Myocardial artery bridging Variables (n = 88) (n = 86) p-value Age (years) 0.468 54 ± 7 56 ± 9 Male gender, n (%) 58 (66) 62 (72) 0.342 Family history, n (%) 28 (32) 24 (28) 0.580 Hyperlipidaemia, n (%) 19 (22) 22 (25) 0.385 Smoking, n (%) 23 (26) 21 (24) 0.486 Diabetes mellitus, n (%) 16 (18) 19 (22) 0.385 Hypertension, n (%) 22 (25) 31 (36) 0.034 SBP (mmHg) 0,548 121 ± 11 125 ± 8 DBP (mmHg) 0.783 78 ± 9 81 ±6 Heart rate (bpm) 0.673 74 ± 15 78 ±9 Ejection fraction (%) 0.471 62.4 ± 3.1 60.2 ± 4.2 Values are mean (± SD), SBP: systolic blood pressure, DBP: diastolic blood pressure.

183

± 1.1%, p = 0.032) were significantly increased in the MB group relative to the control group (Table 2).

Discussion In this study we examined the relationship between MB and PDW and other haematological parameters. MB was independently associated with increased values of PDW, NLR and RDW. MB is a congenital variant of the coronary artery in which a portion of the epicardial coronary artery takes an intramuscular course.12 This arrangement of a ‘tunnelled’ segment of the artery under the ‘bridge’ of overlying myocardium frequently results in vessel compression during systole. While this condition is frequently asymptomatic, in many cases it may be responsible for adverse complications, including coronary atherosclerosis, angina, myocardial ischaemia,13 acute coronary syndromes,14-16 left ventricular dysfunction and stunning,17 arrhythmias,18 and even sudden cardiac death.19 Early pathological analysis of myocardial bridging recognised ‘sparing’ of the bridged segments from atherosclerotic lesions.20 The intima of the tunnelled segment is significantly thinner than the proximal segment, and includes a predominance of the ‘contractile’ subtype of smooth muscle cells, thought to be negatively associated with progression of atherosclerotic lesions.21 In addition, known as vasoactive agents, endothelial nitric oxide synthase, endothelin-1 and angiotensin-converting enzyme levels are decreased in the bridged coronary wall.22 These agents have been implicated in the proliferation of smooth muscle cells, resulting in increased size of atherosclerotic lesions. Systolic kinking of the bridged segments and endothelial dysfunction may also predispose to coronary vasospasm and thrombus formation.23 Conversely, the proximal segment of the bridge appears to develop atherosclerosis at an increased rate, approximately 90%.24 Endothelial cell morphology at the entrance to the tunnelled segment reveals a ‘flat, polygonal and polymorphic’ structure, indicative of a low-shear stress state, while the endothelial cells within the tunnel maintain a helical orientation, a sign of laminar flow and high shear.24 This suggests a haemodynamic basis for the increased plaque formation proximal to the tunnel, through impairment of endothelial cell function and morphology. Also, expression of the vasoactive agents, endothelial nitric oxide synthase, endothelin-1 and angiotensin-converting enzyme are all increased in the proximal segment.22 Table 2. Distribution of the haematological parameters of all cases Normal coro- Myocardial nary artery bridging Variables (n = 88) (n = 86) p-value 0.278 White blood cells (103/ µl) 7.9 ± 2.1 8.1 ± 2.3 Mean corpuscular volume (fl) 0.878 88.9 ± 8.3 86.9 ±7.8 0.647 266 ± 38 272 ± 41 Platelets (× 1 000/mm3) Haemoglobin (g/dl) 0.387 13.8 ± 1.9 14.1 ± 1.3 RDW (%) 0.032 13.1 ± 1.1 14.3 ± 1.3 Mean platelet volume (fl) 0.093 8.8 ± 0.9 8.9 ± 1.1 Platelet distribution width (%) 0.003 16.1 ± 0.9 17.3 ± 1.1 NLR 0.034 2.2 ± 0.9 3.2 ± 1.1 RDW: red blood cell distribution width, NLR: neutrophil-to-lymphocyte ratio.

184

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

PDW is a more specific indicator of platelet activation than mean platelet volume in the absence of platelet swelling.25 Elevated PDW directly measures the variability in platelet size during platelet distension and serves as a marker of platelet activation.26 Increased platelet number and size, and the presence of pseudopodia may influence PDW. Significant elevation of PDW has been observed among patients with acute myocardial infarction and unstable angina pectoris.27 Jindal et al.28 reported a significant association between PDW and microvascular dysfunction among diabetic patients. Numerous factors contribute to microvascular and circulatory dysfunction, including coronary microvascular imbalance and increased tonus, endothelial thickening of small vessels and endothelial nitric oxide imbalance, and blood viscosity. In our study, we detected higher PDW levels in patients with MB. We assumed that a higher PDW level was related to increased vasoactive agents, including endothelial nitric oxide synthase, endothelin-1 and angiotensin-converting enzyme in the proximal segment of the MB. The NLR is related to the development of atherosclerosis in the coronary arteries,29 and NLR is an excellent indicator of cardiovascular disease.9 Among patients with acute coronary syndrome, neutrophils are functionally activated, and the presence of localised neutrophil infiltration in atherosclerotic lesions has been demonstrated, assuming that neutrophils play a key role in the mediation and destabilisation of atherosclerotic plaques.30 Our study demonstrated a significant correlation between the presence of MB and NLR, an inflammatory marker linked to early atherosclerosis. Chronic inflammation may act synergistically to raise RDW and augment the atherosclerotic process.31 The RDW is an independent predictor of mortality and coronary morbidity among patients with myocardial infarction.8 In our study, higher RDW was found in patients with MB than in the control group. The relationship between cardiovascular disease and increased platelet activity is well known. In this study, we found a significant relationship between MB and PDW, an established indicator of platelet activity. Additionally, we found a significant relationship between MB and NLR, an indicator of systemic inflammation. These predictive parameters are easily measured and are inexpensive in routine clinical practice. There were some limitations to this study. We evaluated the coronary arteries using coronary angiography. Although it is well known that intravascular ultrasound (IVUS) provides a more accurate evaluation of coronary atherosclerosis, we were unable to perform IVUS assessments. Coronary atherosclerosis is present anatomically in approximately 25% of patients, based on autopsy and computed tomography (CT), but results in angiographically detectable systolic compression in less than 10% of patients. Cardiac CT angiography may be a useful tool to more precisely detect MB, however, we were unable to perform cardiac CT angiography in this study. In addition, the study data are reflective of the crosssectional design and may not reflect the long-term clinical status of the patients.

AFRICA

Our study reveals a significant association between indirect inflammatory markers and MB. Further studies are needed to clarify the relationship between MB and indirect inflamatory markers.

References 1.

Mohlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridging. Circulation 2002; 106: 2616–2622.

Bourassa MG, Butnaru A, Lesperance J, Tardif JC. Symptomatic myocardial bridges: overview of ischemic mechanisms and current diagnostic and treatment strategies. J Am Coll Cardiol 2003; 41: 351–359.

Alegria JR, Herrmann J, Holmes DR Jr, Lerman A, Rihal CS. Myocardial bridging. Eur Heart J 2005; 26: 1159–1168.

Gowda RM, Khan IA, Ansari AW, Cohen RA. Acute ST segment elevation myocardial infarction from myocardial bridging of left anterior descending coronary artery. Int J Cardiol 2003; 90: 117–118.

Ural E, Bildirici U, Çelikyurt U, Kilic T, Sahin T, Acar E, et al. Longterm prognosis of non-interventionally followed patients with isolated myocardial bridge and severe systolic compression of the left anterior descending coronary artery. Clin Cardiol 2009; 32: 454–457.

Herve P, Humbert M, Sitbon O, Parent F, Nunes H, Legal C, et al. Pathobiology of pulmonary hypertension: the role of platelets and thrombosis. Clin Chest Med 2001; 22: 451–458.

Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease. Circulation 2008; 117: 163–168.

Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol 2010; 105: 312–317.

Kaya H, Ertas F, Islamoglu Y, Kaya Z, Atılgan ZA, Çil H, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. Clin Appl Thromb Hemost 2014; 20: 50–54.

10. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7: 79–108. 11. Judkins MP. Selective coronary arteriography. I. A percutaneous transfemoral technic. Radiology 1967; 89: 815–824. 12. Erbel R, Ge J, Mohlenkamp S. Myocardial bridging: a congenital variant as an anatomic risk factor for myocardial infarction? Circulation 2009; 120: 357–359. 13. Yano K, Yoshino H, Taniuchi M, Kachi E, Shimizu H, Watanuki A, et al. Myocardial bridging of the LAD in acute inferior wall myocardial infarction. Clin Cardiol 2001; 24: 202–208. 14. Tauth J, Sullebarger JT. Myocardial infarction associated with myocardial bridging: case history and review of the literature. Cath Cardiovasc Diagn 1997; 40: 364–367. 15. Marchionni N, Chechi T, Falai M, Margheri M, Fumagalli S. Myocardial stunning associated with a myocardial bridge. Int J Cardiol 2002; 82: 65–67. 16. Feld H, Guadanino V, Hollander G, Greengart A, Lichstein E, Shani J. Exercise-induced ventricular tachycardia in association with a myocardial bridge. Chest 1991; 99: 1295–1296. 17. Den Dulk K, Brugada P, Braat S, Heddle B, Wellens HJ. Myocardial bridging as a cause of paroxysmal atrioventricular block. J Am Coll Cardiol 1983; 1: 976–969.

Conclusion To the best of our knowledge, this study is the first to evaluate the relationship between MB and indirect inflammatory markers.

18. Tio RA, van Gelder IC, Boonstra PW, Crijns HJ. Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary Doppler flow measurements and angiography during dobutamine stress in the clinical evaluation. Heart 1997; 77: 280–282.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

19. Cutler D, Wallace JM. Myocardial bridging in a young patient with

26. Herve P, Humbert M, Sitbon O, Parent F, Nunes H, Legal C, et al.

sudden death. Clin Cardiol 1997; 20: 581–583.

Pathobiology of pulmonary hypertension: the role of platelets and thrombosis. Clin Chest Med 2001; 22: 451–458.

20. Ge J, Jeremias A, Rupp A, Abels M, Baumgart D, Liu F, et al. New signs characteristic of myocardial bridging demonstrated by intracoronary

27. Khandekar MM, Khurana AS, Deshmukh SD, Kakrani AL, Katdare

ultrasound and Doppler. Eur Heart J 1999; 20: 1707–1716.

AD, Inamdar AK. Platelet volume indices in patients with coronary artery disease and acute myocardial infarction: an Indian scenario. J

21. Risse M, Weiler G. Die koronare Muskelbrücke und ihre Beziehung

Clin Pathol 2006; 59: 146–149.

zu lokaler Koronarsklerose, regionaler Myokardischämie und Koronarspasmus. Eine morphometrische Studie. Z Kardiol 1985; 74:

28. Jindal S, Gupta S, Gupta R, Kakkar A, Singh HV, Gupta K, et al. Platelet indices in diabetes mellitus: indicators of diabetic microvascular

700–705.

complications. Hematology 2011; 16: 86–89.

22. Masuda T, Ishikawa Y, Akasaka Y, Itoh K, Kiguchi H, Ishii T. The effect of myocardial bridging of the coronary artery on vasoactive

29. Kalay N, Dogdu O, Koc F, Yarlioglues M, Ardic I, Akpek M, et al.

agents and atherosclerosis localization. J Pathol 2001; 193: 408–414.

Hematologic parameters and angiographic progression of coronary atherosclerosis. Angiology 2012; 63: 213–217.

23. Ciampricotti R, el Gamal M. Vasospastic coronary occlusion associated with a myocardial bridge. Cathet Cardiovasc Diagn 1988; 14: 118–120.

30. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, et al. Neutrophil infiltration of culprit lesions in acute coronary

24. Ishikawa Y, Ishii T, Asuwa N, Masuda S. Absence of atherosclerosis

syndromes. Circulation 2002; 106: 2894–2900.

evolution in the coronary arterial segment covered by myocardial tissue in cholesterol-fed rabbits. Virchows Arch 1997; 430: 163–171.

185

31. Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 2008;

25. Vagdatli E, Gounari E, Lazaridou E, Katsibourlia E, Tsikopoulou F,

54: 24–38.

Labrianou I. Platelet distribution width: a simple, practical and specific marker of activation of coagulation. Hippokratia 2010; 14: 28–32.

Accuracy of heart rate apps varies Consumers are being warned about the accuracy of heart rate apps after a study found huge variability between commercially available apps, even those using the same technology. The research is published in the European Journal of Preventive Cardiology.1 ‘Heart rate apps come installed on many smartphones and once people see them it is human nature to use them and compare their results with others’, said last author Dr Christophe Wyss, a cardiologist at Heart Clinic Zurich, Switzerland. ‘The problem is that there is no law requiring validation of these apps and therefore no way for consumers to know if the results are accurate.’ This study tested the accuracy of four commercially available heart rate apps (randomly selected) using two phones, the iPhone 4 and iPhone 5. Some apps use contact photoplethysmography (touching fingertip to the phone’s built-in camera) while other apps use non-contact photoplethysmography (camera is held in front of the face). Accuracy was assessed by comparing the results with the clinical gold-standard measurements. These are the electrocardiogram (ECG), which measures the electrical activity of the heart using leads on the chest, and fingertip pulse oximetry, which uses photoplethysmography. The study included 108 patients who had their heart rate measured by ECG, pulse oximetry, and each app using each phone. The researchers found substantial differences in accuracy between the four apps. In some apps there were differences of more than 20 beats per minute compared to ECG in over 20% of the measurements. The non-contact apps performed less well than the contact apps, particularly at higher heart rates and lower body temperatures. The non-contact apps had a tendency to overestimate higher heart rates. Dr Wyss said: ‘While it’s easy to use the non-contact apps – you just look at your smartphone camera and it gives your heart

rate – the number it gives is not as accurate as when you have contact with your smartphone by putting your fingertip on the camera.’ But the performance of the two contact apps was also different. One app measured heart rate with comparable accuracy to pulse oximetry but the other app did not give the correct measurement. ‘The one contact app was excellent, performing almost like a medically approved pulse oximeter device, but the other app was not accurate even though they use the same technology’, said Dr Wyss. The researchers tried to find the reason for the difference in performance between the two contact apps, but they found that the variation could not be explained by camera technology (iPhone 4 versus iPhone 5), age, body temperature, or heart rate itself. ‘The difference in performance between the contact apps is probably down to the algorithm the app uses to calculate heart rate, which is commercially confidential’, said Dr Wyss. ‘It means that just because the underlying technology works in one app doesn’t mean it works in another one and we can’t assume that all contact heart rate apps are accurate.’ Dr Wyss said: ‘Before you measure your heart rate, have a specific question in mind, don’t just measure it for fun. For example, “is my heart rate too high when I feel something strange in my heart?” or “is it too low when I feel dizzy?”.’ He concluded: ‘Consumers and interpreting physicians need to be aware that the differences between apps are huge and there are no criteria to assess them. We also don’t know what happens to the heart rate data and whether it is stored somewhere, which could be an issue for data protection.’ 1.

Coppetti T, et al. Accuracy of smartphone apps for heart rate measurement. Eur J Prevent Cardiol 2017. DOI: 10.1177/2047487317702044.

Source: European Society of Cardiology Press Office

186

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Symptom-to-balloon time and myocardial blush grade are predictors of left ventricular remodelling after successful primary percutaneous coronary intervention El‑Sayed M Farag, Mohammad M Al-Daydamony

Abstract Introduction: In patients with ST-segment elevation myocardial infarction (STEMI), successful primary percutaneous coronary intervention (PCI) was found to be useful in earlier restoration of TIMI flow 3. However, the incidence of left ventricular (LV) dilatation and remodelling after successful primary PCI is still high. We aimed to determine the independent predictors of LV remodelling after successful primary PCI for patients with first STEMI. Methods: We included 232 STEMI patients treated with primary PCI. Echocardiography was done on the day of PCI and after six months. LV remodelling was defined as ≥ 20% increase in the six-month left ventricular end-diastolic volume (LVEDV). Results: In patients with remodelling, symptom-to-door and symptom-to-balloon times were significantly longer (p < 0.00001 for each), initial ejection fraction (EF) was significantly lower (p = 0.044), six-month LVEDV, left ventricular end-systolic volume (LVESV) and LVEDV increase were significantly higher, and EF was significantly lower (p < 0.00001 for each). Mean myocardial blush grade (MBG) was significantly lower in patients with remodelling (p < 0.00001). There was a significant positive correlation between LVEDV increase and both symptom-to-balloon time (r = 0.603, p < 0.00001) and symptom-to-door time (r = 0.564, p < 0.00001), and a significant negative correlation between LVEDV increase and MBG (r = –0.447, p < 0.00001). Logistic regression showed that the independent predictors of LV remodelling were symptom-to-balloon time (p = 0.00068), symptom to door time (p = 0.0013) and MBG (p = 0.0057). Conclusion: Symptom-to-door time, symptom-to-balloon time and MBG were the only significant predictors of LV remodelling. Keywords: primary PCI, left ventricular remodelling, myocardial blush, symptom-to-balloon time Submitted 6/5/16, accepted 15/9/16 Published online 27/10/16 Cardiovasc J Afr 2017; 28: 186–190

www.cvja.co.za

DOI: 10.5830/CVJA-2016-085

ST-segment elevation myocardial infarction (STEMI) is one of the most important causes of death and disability around the

Cardiology Department, Faculty of Medicine, Zagazig University, Zagazig, Al-Sharkia, Egypt El‑Sayed M Farag, MD Mohammad M Al-Daydamony, MD, m_daydamony@hotmail.com

world.1 Heart failure (HF) is a serious sequel of STEMI. Left ventricular (LV) remodelling was found to be the precursor to developing HF and also an important predictor of prognosis after STEMI.2 When compared with fibrinolytic therapy for STEMI patients, successful primary percutaneous coronary intervention (PCI) was found to be useful in earlier restoration of thrombolysis in myocardial infarction (TIMI) flow grade 3 flow in the infarctrelated artery, it limited the infarction size, and decreased heart failure and mortality rates.3 However, the incidence of LV dilatation after successful primary PCI is still high.4 Previous studies have searched for predictors of LV remodelling after primary PCI. Regional and global LV systolic dysfunction, severe LV diastolic abnormalities,5 lower LV ejection fraction at discharge,6 and poorer myocardial perfusion as assessed by myocardial blush grade (MBG)6,7 were found to be significant predictors of LV remodelling. However, these studies were performed on relatively small numbers of patients. The aim of our study was to determine the independent predictors of LV remodelling after successful primary PCI for patients with first STEMI.

Methods This prospective study was done in the coronary care and cardiac catheterisation units of the Cardiology Department, Zagazig University. The study population consisted of 260 patients who were admitted with acute STEMI during the period between January 2012 and January 2015. The inclusion criteria were: confirmed acute STEMI, defined as the presence of typical chest pain that lasts for at least 20 minutes, and ST-segment elevation ≥ 0.1 mV in at least two contiguous leads;8 primary PCI done within 12 hours of the onset of symptoms; successfully performed PCI with < 20% residual stenosis and TIMI flow 3 of the infarct-related artery defined as normal flow, which fills the distal coronary bed completely.9 Patients were excluded from our study in the presence of one or more of the following: previous history of coronary artery disease (CAD), myocardial infarction, or revascularisation; more than mild valvular stenosis or regurgitation; patients with left bundle branch block; and unsatisfactory echocardiographic images. We had a written informed consent from every patient. The study protocol was approved by the institutional review board of the Faculty of Medicine, Zagazig University. A full history was taken and a complete clinical examination was done on every patient. The time of onset of chest pain (symptom time), the time of the patient’s arrival at the hospital (door time), and the time of first balloon inflation or stent deployment (balloon time) were carefully recorded.

AFRICA

187

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Symptom-to-door time was defined as the interval between the appearance of symptoms and arrival at the hospital. Doorto-balloon time was defined as the interval between the arrival at hospital and the time of balloon inflation. Symptom-to-balloon time was defined as the interval between the onset of symptoms and the time of balloon inflation.10 Complete standard 12-lead electrocardiography was carried out on each patient. Echocardiographic studies were performed on all patients using the GE VIVID E9 machine with 2.5-MHz transducers. The studies were performed by two operators unaware of each other’s measures and of the patients’ clinical and angiographic data. Views were taken while the patients were in the left lateral position. Left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were measured from the apical two-chamber and apical four-chamber views. Ejection fraction (EF) was calculated using the Simpson’s method.11 Echocardiography was done within 24 hours of admission, and was repeated after six months. LV remodelling was defined as ≥ 20% increase in the six-month LVEDV.5 Primary PCI was performed on all patients within 12 hours of onset of symptoms by two expert interventionists; at least one met the criteria of individual operator level volume of the 2007 Clinical Competence Statement on Cardiac Interventional Procedures and its 2013 revision.12 Stenting, balloon dilatation and/or thrombus aspiration were done, and glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide) was given as appropriate, according to operator opinion. TIMI flow and myocardial blush grade (MBG) were assessed by two expert angiographers unaware of each other’s results and of the patients’ other data. MBG was assessed according to the dye density score as follows: MBG 0 = no myocardial blush or contrast density, MBG 1 = minimal myocardial blush or contrast density, MBG 2 = moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non-infarctrelated coronary artery, MBG 3 = normal myocardial blush or contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non-infarctrelated coronary artery.13 After discharge, all patients continued to receive medical treatment, including aspirin, clopidogrel, beta-blockers, statins, aldosterone antagonists and angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptors blockers (ARBs).8

Statistical analysis All data were analysed using the SPSS for windows package (Version 20.0; Armonk, NY, USA: IBM Corp). Differences between the study groups were analysed using the χ2 and student’s t-tests. Correlations between different variables were investigated by Pearson correlation analysis. The logistic regression analysis was evaluated by the Hosmer–Lemes goodness-of-fit test. A p-value < 0.05 was regarded as being statistically significant. In order to assess the intra-observer variability, we repeated the measures offline for echocardiography and angiography in 30 patients within seven days of the first measure. The interand intra-observer variability were calculated by dividing the difference between the two sets of measurements by the mean of the two observations.

Results Twenty-eight more patients were excluded from the initial study group (three patients died, five had a non-fatal MI and were excluded to avoid the effect of a second infarction on LV remodelling, five patients underwent revascularisation before the second echocardiogram, and 15 patients were not adherent with follow up). The remaining 232 patients (121 males and 111 females) constituted the study group. LV remodelling was detected in 68 patients (29.3%). Patients were divided into two groups according to the presence or absence of LV remodelling. Regarding clinical and echocardiographic data, and as shown in Table 1, there was no significant difference between the two groups regarding age, gender, diabetes, hypertension, smoking, dyslipidaemia, door-to-balloon time, incidence of anterior infarction, peak CK-MB level, troponin T level, basal LVEDV or basal LVESV. Mean EF was significantly lower in patents with remodelling (p = 0.044). After six months, mean LVEDV, LVESV and percentage of LVEDV increase were significantly higher, and mean EF was significantly lower in patients with remodelling (p < 0.00001 for each). Mean symptom-to-door and symptomto-balloon times were significantly higher in patients with remodelling (p < 0.00001 for each). Regarding primary PCI data, and as shown in Table 2, there was no significant difference between the two groups regarding stenting, thrombus aspiration, use of GP IIb/IIIa inhibitors, infarct-related artery, incidence of patients with multi-vessel disease, mean baseline stenosis, stent diameter, stent length, or final residual stenosis. There was a significant difference between the two groups regarding MBG, with more patients with MBG 0 and 1, and fewer patients with MBG 2 and 3 among patients with remodelling (p < 0.00001). Mean MBG was significantly lower in patients with remodelling (p < 0.00001). Table 1. Clinical and echocardiographic data Parameters

Remodelling (n = 68)

No remodelling (n = 164)

p-value

Age (years)

58.4 ± 9.73

56.5 ± 10.85

0.193 0.659

Gender, n (%) Male

37 (54.4)

84 (51.2)

Female

31 (45.6)

80 (48.8)

Diabetes, n (%)

22 (32.3)

49 (29.9)

0.71

Hypertension, n (%)

28 (41.2)

60 (36.6)

0.512

Smoking, n (%)

20 (29.4)

53 (31.5)

0.664

Dyslipidaemia, n (%)

23 (33.8)

55 (33.5)

Symptom-to-door time (min) Door-to-balloon time (min) Symptom-to-balloon time (min) Anterior infarction, n (%)

380.2 ± 105.1

289.5 ± 85.6

0.966 < 0.00001

44.5 ± 10.6

46.8 ± 11.2

424.1 ± 107.3

335.8 ± 93.1

< 0.00001

0.14

45 (66.2)

100 (61)

0.267

Peak CK-MB (IU/l)

289.5 ± 102.3

271.3 ± 98.4

0.214

Troponin T (ng/ml)

10.78 ± 3.95

9.85 ± 4.22

0.111

Day 1 LVEDV (ml)

101.3 ± 22.5

95.6 ± 18.8

0.067

Day 1 LVESV (ml)

42 ± 13.6

38.2 ± 14.5

0.059

58.4 ± 5.63

60.1 ± 6.22

0.044

6-month LVEDV (ml)

135.6 ± 26.4

103.5 ± 20.1

< 0.00001

6-month LVESV (ml)

65.6 ± 18.5

40.1 ± 16.3

< 0.00001

6-month EF (%)

51.6 ± 9.63

61.2 ± 7.14

< 0.00001

LVEDV increase (%)

33.9 ± 7.53

8.26 ± 6.53

< 0.00001

Day 1 EF (%)

Data are expressed as mean ± SD or number (%). LVEDV = left ventricular end-diastolic volume, LVESV = left ventricular end-systolic volume, EF = ejection fraction.

188

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Table 2. PCI data

AFRICA

Table 3. Logistic regression analysis for independent predictors of LV remodelling

Remodelling (n = 68)

No remodelling (n = 164)

p-value

Variables

65 (95.6)

161 (98.2)

0.259

Symptom-to-balloon time

Thrombus aspiration, n (%)

23 (33.8)

58 (34.5)

0.823

Symptom-to-door time

GPIIb/IIIa inhibitors, n (%)

31 (45.6)

77 (46.9)

0.849

Myocardial blush grade Baseline EF

2.99

1.12–4.86

0.0744

Peak CK-MB

2.71

1.14–4.28

0.1564

Parameters Stenting, n (%)

Infarct-related artery, n (%) 0.877

95% CI

p-value

3.78

2.41–5.15

0.00068

4.61

3.01–6.21

0.0013

3.44

1.65–5.22

0.0057

LAD

41 (60.3)

LCX

13 (19.1)

35 (21.3)

Baseline LVEDV

1.3

0.63–1.97

0.253

RCA

14 (20.6)

36 (22)

Age

1.06

0.47–1.65

0.365

22 (32.3)

50 (29.8)

0.799

Multi-vessel disease, n (%)

93 (56.7)

Odds ratio

Baseline stenosis (%)

95.3 ± 4.61

94.7 ± 5.34

0.391

Stent diameter (mm)

3.12 ± 0.561

3.24 ± 0.644

0.157

Stent length (mm)

15.8 ± 5.74

16.3 ± 6.33

0.559

Final stenosis (%)

5.76 ± 4.22

6.33 ± 5.11

0.381

MBG: 0

MBG: 1

MBG: 2

MBG: 3

1.102 ± 0.913

Mean MBG

< 0.00001

2.001 ± 1.036

< 0.00001

Data are expressed as mean ± SD or number (%). LAD = left anterior descending artery, LCX = left circumflex artery, RCA = right coronary artery, MBG = myocardial blush grade.

Symptom-to-balloon time (min)

A 700 600 500 400 300 200 r = 0.603 p < 0.00001

100 0 0

Increase in LVEDV (%)

Symptom-to-door time (min)

B 600 500 400 300 200 r = 0.564 p < 0.00001

100 0 0

Increase in LVEDV (%)

Myocardial blush grade

C 3 2

r = 0.447 p < 0.00001

1 0 0

Increase in LVEDV (%)

Fig. 1. C orrelations between increase in LVEDV and symptom-to-balloon time (A), symptom-to-door time (B), and MBG (C).

CI = confidence interval, LVEDV = left ventricular end-diastolic volume, EF = ejection fraction.

Fig. 1 shows the correlations between increase in LVEDV and different PCI parameters. There was a significant positive correlation between LVEDV increase and both symptom-toballoon time (r = 0.603, p < 0.00001, Fig. 1A) and symptomto-door time (r = 0.564, p < 0.00001, Fig. 1B). There was a significant negative correlation between LVEDV increase and MGB score (r = –0.447, p < 0.00001, Fig. 1C). Logistic regression for the independent predictors of LV remodelling is shown in Table 3. The independent predictors of LV remodelling, in order of significance, were symptom-toballoon time (p = 0.00068), symptom-to-door time (p = 0.0013) and MBG (p = 0.0057). Inter- and intra-observer variability for different echocardiographic parameters ranged from 1.5 to 7.1%. For LVEDV, inter- and intra-observer variability were 5.2 ± 2.7 and 6.2 ± 3.4%, respectively. For MBG score, inter- and intraobserver variability were 2.3 ± 1.1 and 4.5 ± 2.4%, respectively.

Discussion In our study, logistic regression analysis showed that the only significant independent predictors for the occurrence of LV remodelling were symptom-to-balloon time, symptom-to-door time and MBG. The great advantage of primary PCI over thrombolysis is the earlier and the more effective restoration of coronary flow. This in turn leads to fewer incidences of recurrent ischaemia, better LV function, and of course better clinical outcome of STEMI patients treated with primary PCI, compared to those treated with thrombolysis.3 However, even after successful restoration of blood flow in the infarct-related artery after STEMI, a considerable number of patients still suffer from LV dilatation and impairment in systolic function. Among 284 STEMI patients treated with primary PCI, Bolognese and colleagues recorded a 30% incidence of LV remodelling, defined as > 20% LVEDV increase.4 This incidence was similar to the 29.3% incidence of LV remodelling in our study group. Primary PCI significantly improves blood flow in epicardial coronary arteries in STEMI patients. However, this improvement does not always include microvascular flow and myocardial perfusion. After restoration of blood flow in the occluded epicardial artery, some pathophysiological changes tend to occur and may contribute to the impairment in microcirculatory flow. These changes include infiltration of neutrophils, endothelial dysfunction, tissue oedema and microembolisation.14 The relationship between microvascular dysfunction and LV function and outcome after primary PCI has been studied by

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

many investigators. Poli and colleagues found that MBG score and ST-segment elevation recovery after successful primary PCI were associated with the degree of early and late recovery of LV function.15 The ability of MBG score to predict survival rate was studied by Stone et al.16 They found a strong relationship between survival rate and MBG score after primary or rescue PCI. Among their study group, one-year survival rate was 6.8% in patients with normal MBG scores, 13.2% in patients with reduced MBG, and 18.3% in patients with absent blush. Bolognese et al. found that microvascular dysfunction, as assessed by intracoronary myocardial contrast echo score index, was able to predict the occurrence of LV remodelling as well as unfavourable long-term outcome.17 De Luca and colleagues found that MBG score was an independent predictor for one-year mortality after primary PCI for STEMI patients presenting with signs of heart failure.18 The value of time to primary PCI was studied by Soon and colleagues. They found that symptom-to-balloon not door-toballoon time was a significant independent predictor of shortand medium-term mortality rates and major adverse cardiac events.10 Symptom-to-balloon time was found by Hahn et al. to be associated with infarct transmurality.19 Why do some STEMI patients, even after successfully performed primary PCI, have poor myocardial perfusion with MBG 0 or 1? In an attempt to answer this question, Prasad et al. studied the effect of prolonged ischaemia on MBG score after primary PCI. Their main finding was that delayed primary PCI was associated with greater injury to the microcirculation and impaired myocardial perfusion. They also found that patients presenting four hours after symptom onset had a higher incidence of MBG 0 and 1, compared to those presenting within two hours.20 Several mechanisms may lead to impaired myocardial perfusion in patients with prolonged ischaemic time. These include endothelial dysfunction and damage, interstitial and cellular haemorrhage/oedema, formation of micro-thrombi within the micro-vessels, and an increase in thrombus organisation with time, which lessens its responsiveness to antiplatelet and anticoagulant therapies and increases the probability for distal macro- or micro-embolisation.21,22 Earlier researchers found that many factors may influence the process of LV remodelling, such as patency of the infarctrelated artery,23 treatment with angiotensin converting enzyme (ACE) inhibitors and/or beta-blockers,24 and baseline BNP concentrations.25 Treatment with renin–angiotensin–aldosterone blockers after MI was found to ameliorate the process of LV remodelling in experimental models26 as well as in humans.3,27 In our study, which was a single-centre study, all our patients were treated in a similar way. This may explain why symptom-toballoon time, symptom-to-door time and MBG score were the only significant predictors for LV remodelling. Mean door-toballoon time was 46.1 ± 11.8 minutes in the whole study group and it did not differ significantly between the two groups. It also did not correlate with increase in LVEDV. The door-to-needle time was also fairly similar in the whole study group, probably since the study was conducted in a single centre with the same treatment strategy applied to all patients. The longer symptom-to-door time in the remodelling group made the symptom-to-balloon time significantly longer as

189

well. This may have been caused by many factors, including lack of public awareness of the symptoms of STEMI and the importance of seeking medical help timeously, the small number of centres capable of performing primary PCI, the large distance between these centres and primary health centres, and the huge traffic problem in a developing country such as Egypt. Limitations of this study are that it was carried out in a single centre, and recording the time of onset of symptoms is totally subjective, which may make measuring of symptom-to-door time inaccurate.

Conclusion Our study showed that after successfully performed primary PCI for STEMI patients, symptom-to-door time, symptom-toballoon time and MBG were the only significant predictors of LV remodelling. Efforts must be made to reduce symptom-todoor time, including promoting health awareness of cardiac symptoms, educating primary healthcare providers, and improving the ambulance system.

References 1.

Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al.; American Heart Association statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation 2012; 125(22): e1002.

St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moyé LA, Dagenais GR, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994; 89(1): 68–75.

Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 2003; 361(9351): 13–20.

Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 2002; 106(18): 2351–2357.

Loboz-Grudzień K, Kowalska A, Brzezińska B, Sokalski L, Jaroch J. Early predictors of adverse left ventricular remodeling after myocardial infarction treated by primary angioplasty. Cardiol J 2007; 14(3): 238–245.

Wita K, Filipecki A, Lelek M, Bochenek T, Elżbieciak M, Wróbel W, et al. Prediction of left ventricular remodeling in patients with STEMI treated with primary PCI: use of quantitative myocardial contrast echocardiography. Coron Artery Dis 2011; 22(3): 171–178.

Hamdan A, Kornowski R, Lev EI, Sagie A, Fuchs S, Brosh D, et al. Impact of myocardial blush on left ventricular remodeling after first anterior myocardial infarction treated successfully with primary coronary intervention. Isr Med Assoc J 2010; 12(4): 211–215.

Krumholz HM, Anderson JL, Bachelder BL, Fesmire FM, Fihn SD, Foody JM, et al.; American College of Cardiology/American Heart Association task force on performance measures; American Academy of Family Physicians; American College of Emergency Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Cardiovascular Angiography and Interventions; Society of Hospital Medicine. ACC/AHA 2008 performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report

190

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

of the American College of Cardiology/American Heart Association

17. Bolognese L, Carrabba N, Parodi G, Santoro GM, Buonamici P,

task force on performance measures (writing committee to develop

Cerisano G, Antoniucci D. Impact of microvascular dysfunction on left

performance measures for ST-elevation and non-ST-elevation myocar-

ventricular remodeling and long-term clinical outcome after primary

dial infarction). J Am Coll Cardiol 2008; 52(24): 2046–2099.

coronary angioplasty for acute myocardial infarction. Circulation 2004;

The TIMI study group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985; 312(14): 932–936.

109(9): 1121–1126. 18. De Luca G, van’t Hof AW, de Boer MJ, Hoorntje JC, Gosselink AT,

10. Soon CY, Chan WX, Tan HC. The impact of time-to-balloon on

Dambrink JH, et al. Impaired myocardial perfusion is a major expla-

outcomes in patients undergoing modern primary angioplasty for acute

nation of the poor outcome observed in patients undergoing primary

myocardial infarction. Singapore Med J 2007; 48(2): 131–136.

angioplasty for ST-segment-elevation myocardial infarction and signs

11. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka

of heart failure. Circulation 2004; 109(8): 958–961.

PA, et al.; Chamber Quantification writing group; American Society of

19. Hahn JY, Song YB, Gwon HC, Choe YH, Kim JH, Sung J, et al.

Echocardiography’s Guidelines and Standards Committee; European

Relation of left ventricular infarct transmurality and infarct size after

Association of Echocardiography. Recommendations for chamber quan-

primary percutaneous coronary angioplasty to time from symptom

tification: a report from the American Society of Echocardiography’s

onset to balloon inflation. Am J Cardiol 2008; 102(9): 1163–1169.

Guidelines and Standards Committee and the Chamber Quantification

20. Prasad A, Gersh BJ, Mehran R, Brodie BR, Brener SJ, Dizon JM, et

writing group, developed in conjunction with the European Association

al. Effect of ischemia duration and door-to-balloon time on myocar-

of Echocardiography, a branch of the European Society of Cardiology.

dial perfusion in ST-segment elevation myocardial infarction: an

J Am Soc Echocardiogr 2005; 18(12): 1440–1463.

analysis from HORIZONS-AMI trial (Harmonizing Outcomes with

12. Harold JG, Bass TA, Bashore TM, Brindis RG, Brush JE Jr, Burke JA, et al. ACCF/AHA/SCAI 2013 update of the clinical competence

Revascularization and Stents in Acute Myocardial Infarction). J Am Coll Cardiol Cardiovasc Interv 2015; 8(15): 1966–1974.

statement on coronary artery interventional procedures: a report of

21. Prasad A, Stone GW, Holmes DR, Gersh B. Reperfusion injury, micro-

the American College of Cardiology Foundation/American Heart

vascular dysfunction, and cardioprotection: the “dark side” of reperfu-

Association/American College of Physicians Task Force on Clinical

sion. Circulation 2009; 120(21): 2105–2112.

Competence and Training (writing committee to revise the 2007 Clinical

22. Basso C, Corbetti F, Silva C, Abudureheman A, Lacognata C,

Competence Statement on Cardiac Interventional Procedures). J Am

Cacciavillani L, et al. Morphologic validation of reperfused hemor-

Coll Cardiol 2013; 62(4): 357–396.

rhagic myocardial infarction by cardiovascular magnetic resonance. Am

13. Van’t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle myocardial infarction study group. Circulation 1998; 97(23): 2302–2306. 14. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, et al. Lack

J Cardiol 2007; 100(8): 1322–1327. 23. Sharpe N. Ventricular remodeling following myocardial infarction. Am J Cardiol 1992; 70(10): 20C–26C. 24. Anthonio RL, van Veldhuisen DJ, van Gilst WH. Left ventricular dilatation after myocardial infarction: ACE inhibitors, beta-blockers, or both? J Cardiovasc Pharmacol 1998; 32(Suppl 1): S1–8.

of myocardial perfusion immediately after successful thrombolysis.

25. Shuichi T, Satoru S, Takeshi B, Hiroshi T, Naohiko A, Yoshio Y, et al.

A predictor of poor recovery of left ventricular function in anterior

Predictors of left ventricular remodeling in patients with acute myocar-

myocardial infarction. Circulation 1992; 85(5): 1699–1705.

dial infarction participating in cardiac rehabilitation. Circ J 2004; 68(3):

15. Poli A, Fetiveau R, Vandoni P, del Rosso G, D’Urbano M, Seveso G,

214–219.

et al. Integrated analysis of myocardial blush and ST-segment elevation

26. Epifanio HB, Zornoff LA, Matsubara BB, de Paiva SA, Inoue

recovery after successful primary angioplasty: Real-time grading of

RM, Matsubara LS. Myocardial remodeling after experimental acute

microvascular reperfusion and prediction of early and late recovery of

myocardial infarction in rats. Effect of renin-angiotensin-aldosterone

left ventricular function. Circulation 2002; 106(3): 313–318.

blockade. Arq Bras Cardiol 2005; 84(1): 10–14.

16. Stone GW, Peterson MA, Lansky AJ, Dangas G, Mehran R, Leon MB.

27. Patten RD, Soman P. Prevention and reversal of LV remodeling with

Impact of normalized myocardial perfusion after successful angioplasty

neurohormonal inhibitors. Curr Treat Options Cardiovasc Med 2004;

in acute myocardial infarction. J Am Coll Cardiol 2002; 39(4): 591–597.

6(4): 313–325.

AFRICA

191

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Telmisartan decreases microalbuminuria in patients with type 2 diabetes mellitus following coronary artery bypass grafting Cevdet Furat, Riza Dogan, Gokhan Ilhan, Ekrem Bayar, Berkan Ozpak, Hakan Kara, Şahin Bozok

Abstract Objective: This prospective study aimed to investigate the effects of the selective angiotensin receptor antagonist, telmisartan, on microalbuminuria after coronary artery bypass surgery in patients with diabetes mellitus. Methods: Patients were divided into two groups with block randomisation, using the sealed envelope technique: group T (telmisartan group) consisted of patients who received the angiotensin receptor blocking agent telmisartan 80 mg daily for at least six months in the pre-operative period; group N-T (non-telmisartan group) consisted of patients who received no telmisartan treatment. Clinical and demographic characteristics, operative and postoperative features, microalbuminuria and high-sensitivity C-reactive protein levels were compared. Results: Forty patients met the eligibility criteria for the study. The groups did not differ with regard to clinical and demographic characteristics, and operative and postoperative features. Microalbuminuria levels between the groups differed significantly in the pre-operative period, first hour postoperatively and fifth day postoperatively. C-reactive protein levels between the groups differed significantly on the fifth day postoperatively. Conclusion: Telmisartan was useful for decreasing systemic inflammation and levels of urinary albumin excretion in patients who had type 2 diabetes mellitus and had undergone coronary artery bypass surgery.

Department of Cardiovascular Surgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey Cevdet Furat, MD Riza Dogan, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey Gokhan Ilhan, MD

Department of Cardiovascular Surgery, Zonguldak Atatürk State Hospital, Zonguldak, Turkey Ekrem Bayar, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Katip Çelebi University, İzmir Atatürk Training and Research Hospital, İzmir, Turkey Berkan Ozpak, MD

Department of Cardiovascular Surgery, Ada Hospital, Giresun, Turkey

Keywords: telmisartan, coronary artery bypass grafting, diabetes mellitus, microalbuminuria Submitted 12/10/15, accepted 16/10/16 Published online 10/11/16 Cardiovasc J Afr 2017; 28: 191–195

www.cvja.co.za

DOI: 10.5830/CVJA-2016-089

Microalbuminuria is considered to be a marker of endothelial dysfunction and is a predictor of cardiovascular disease and mortality.1,2 Studies have implicated systemic vascular damage, extensive endothelial dysfunction, a glomerular haemodynamic state of hyperperfusion and hyperfiltration, a prothrombotic state, and a low-grade chronic inflammatory state.3 Microalbuminuria is also associated with several cardiovascular disease risk factors, such as hyperglycaemia, hypertension, dyslipidaemia, renal dysfunction, obesity and smoking.4 All of these factors contribute to the genesis of atherosclerosis. Proteinuria is also an early marker for potentially serious renal disease in diabetics. It refers to an abnormally increased excretion rate of albumin in the urine, and is a sensitive indicator of generalised microvascular disease and a marker for vascular endothelial injury and multi-organ damage.5 Reduction of microalbuminuria in diabetics may retard its progression to overt diabetic nephropathy.5 Once microalbuminuria is present, the rate of progression to end-stage renal disease can be delayed by inhibition of the renin– angiotensin system.6 There is evidence that the use of agents that block the renin–angiotensin–aldosterone system, notably angiotensin receptor antagonists, may provide cardiovascular protection to diabetic patients with microalbuminuria. Microalbuminuria increases following open-heart surgery where coronary artery bypass grafting (CABG) is utilised.7 CABG activates an inflammatory cascade, which may increase capillary permeability and cause microalbuminuria. The increase in capillary permeability may induce exudation of proteins from the lung capillaries into the capillary–alveolar interspace and alveoli, causing the so-called postperfusion lung, which resembles pulmonary oedema. In a recent study, Loef et al. demonstrated that CABG potentiates transient renal failure and microalbuminuria.8 In this study, we aimed to investigate the effects of the selective angiotensin II receptor antagonist, telmisartan, on microalbuminuria after CABG surgery in patients with diabetes mellitus.

Hakan Kara, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey Şahin Bozok, MD, sahinboz@yahoo.com

Methods This observational study was approved by the local institutional review board (LUT/05/38/2006) and conducted in accordance

192

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

with the amended Declaration of Helsinki and Good Clinical Practice regulations. Written informed consent was obtained from all subjects. Patients admitted to the Department of Cardiovascular Surgery of our tertiary centre between June 2006 and February 2007 who had type 2 diabetes mellitus and had undergone CABG surgery constituted the study group. Patients were divided into two groups with block randomisation, using the sealed envelope technique: group T (telmisartan group) consisted of patients who received the angiotensin receptor blocking agent, telmisartan (Micardis®, Boehringer Ingelheim, Istanbul, Turkey) 80 mg daily for at least six months in the pre-operative period; group N-T (non-telmisartan group) consisted of patients who received neither telmisartan nor any other angiotensin receptor blockers. In both groups, no patients were using angiotensin converting enzyme inhibitors for at least six months prior to the study. Cases with severely impaired left ventricular function, chronic pulmonary obstructive disease, severe systemic non-cardiac disease, severe renal or liver impairment, infectious diseases before surgery, malignancy, those receiving corticosteroids or other immunosuppressive treatment, and patients with stroke, inflammatory disease, and/or previous cardiac surgery, and valvular heart disease were excluded from the study.

Surgical technique and postoperative care Cardiac medication, including beta-adrenergic blocking agents, calcium channel blocking agents and nitrates, was continued until the morning of surgery. The same general anaesthetic drugs were used in all patients. A standard median sternotomy incision was used to expose the heart and place the internal mammary artery and saphenous vein grafts used for coronary anastomosis. In each group, routine surgery was performed using a membrane oxygenator (Edwards Vital, Edwards Lifesciences LLC, Irvine, CA, USA), a 3-mg/kg dose of sodium heparin, 2 000 ml of Ringer’s lactate primer and a roller pump at a body temperature of 28°C. Cardiopulmonary bypass was instituted via the ascending aorta and single two-stage venous cannulation (maintained at 2.2–2.4 l/min/m2). Following cross-clamping of the aorta, the heart was arrested using 10–15 cm3/kg cold blood cardioplegia through the aortic root and topical ice slush was continued every 20 minutes for myocardial protection. Heparin was neutralised with protamine hydrochloride (Protamin 1000; Roche, Istanbul, Turkey). The circuit was primed with 2 000 ml Ringer’s lactate. After completion of the surgery, patients were transferred to the intensive care unit (ICU), where standard care and processes were followed until discharge. Patients were weaned from mechanical ventilation when they were haemodynamically stable, responding to verbal stimulation, and had been fully rewarmed. Patients were discharged from the ICU if they were haemodynamically stable, had normal blood gasses during spontaneous breathing, and had a satisfactory renal function.

Outcome parameters and other variables Smoking, obesity, hypertension, duration of diabetes, family history of coronary artery disease, pre-operative myocardial infarction, and pre-operative haemodynamic data were recorded. During the surgical procedure, haemodynamic parameters,

AFRICA

including heart rate, mean arterial pressure, central venous pressure, arterial blood gasses and urine output were monitored. In the postoperative period in the ICU, cardiovascular and respiratory values and temperature were recorded every 15 minutes before extubation and then hourly until discharge from the ICU. The length of stay in the ICU was also recorded. Microalbuminuria levels were studied pre-operatively, on the first hour postoperatively, and on postoperative days (POD) one and five. High-sensitivity C-reactive protein (hsCRP) levels were studied pre-operatively, and on POD 1 and 5. Patients who were considered to be in a low-cardiac output state received positive inotropic agents (dopamine or adrenaline or both). They were assessed for persistent systemic blood pressure below 90 mmHg, urinary output lower than 20 cm3/h, and the state of peripheral circulation was evaluated for adequate preload and optimal afterload. Urine samples were measured for microalbuminuria using Micral test sticks (Roche).

Statistical analysis Categorical variables were analysed with chi-squared and Fisher’s exact tests, as appropriate, in contingency tables, whereas the unpaired t-test and Mann–Whitney U-test were performed, as appropriate, for comparison of continuous variables. Comparisons for microalbuminuria and hsCRP levels in the groups were done with repeated measures of ANOVA and the Bonferroni test. Data are expressed as means ± standard deviation. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed with the Statistical Package for Social Sciences (SPSS 10.0 for Windows, SPSS, Inc., Chicago, IL). The calculation of sample size was based on a power analysis. At a power of 80% using a significance level of p < 0.05, the sample size required was 20 subjects per study group.

Results Forty patients met the eligibility criteria for the study. Of the 40 patients (29 males, 11 females) whose charts were reviewed, the average age was 65.0 ± 8.6 (range 40–79) years. Group T included 20 patients (15 males, 5 females) with a mean age of 65.6 ± 7.8 years, who had been using telmisartan 80 mg daily for at least six months. Group N-T included 20 patients (14 males, 6 females) with a mean age of 64.4 ± 9.5 years, who used no angiotensin receptor blocking agent prior to the operation. The groups were similar with regard to age and gender (p = 0.680 and p = 0.723, respectively). With regard to clinical characteristics such as body mass index, smoking habit, hypertension, hyperlipidaemia, and history of myocardial infarct, the two groups did not show significant differences and were comparable (Table 1). The groups were also similar with regard to number of bypass grafts, cardiopulmonary bypass time, cross-clamp time, flow, atrial fibrillation, inotrope usage, time of endotracheal intubation and mortality rate (Table 2). Pre-operative, first hour postoperative, POD 1 and POD 5 microalbuminuria levels were 16.5 ± 17.2, 28.5 ± 17.2, 59.0 ± 29.8 and 23.0 ± 20.0 mg/l in group T, and 30.0 ± 17.7, 51.0 ± 28.4, 75.0 ± 25.6 and 52.5 ± 27.5 mg/l in Group N-T, respectively, and there were statistically significant differences between four

AFRICA

Table 1. Clinical and demographic characteristics of the study group Characteristics

Group T

Group N-T

p-value

Age (years)

65.6 ± 7.8

64.4 ± 9.5

0.680

15/5

14/6

0.723

28.0 ± 4.7

26.5 ± 2.8

11 (55)

10 (50)

Gender (M/F) Body mass index Smoking, n (%)

Group N-T Mean ± SD

p-value

Pre-operative

16.5 ± 17.2

30.0 ± 17.7

0.018

0.234

Postoperative 1st hour

28.5 ± 17.2

51.0 ± 28.4

0.008

0.752

Postoperative 1st day

59.0 ± 29.8

75.0 ± 25.6

0.071

Postoperative 5th day

23.0 ± 20.0

52.5 ± 27.5

0.001

Hypertension, n (%)

18 (90)

16 (80)

0.661

19 (95)

18 (90)

1.000

History of myocardial infract, n (%)

12 (60)

13 (65)

0.744

Group T = telmisartan group; group N-T = non-telmisartan group.

microalbuminiria levels in each group (p < 0.001) (Table 3). Pre-operative, first hour postoperative and POD 5 values were statistically significantly different between the groups (p = 0.018, p = 0.008 and p = 0.001, respectively) (Table 3). However, the difference in POD 1 values between the groups was at the threshold of significance (p = 0.071). Pre-operative plasma levels of hsCRP (0.35 ± 0.17 vs 0.50 ± 0.32 mg/l) showed a trend towards significance (p = 0.069). Although POD 1 hsCRP levels (10.0 ± 2.0 vs 17.8 ± 3.9 mg/l) did not differ (p = 0.405) between the groups, a decrease in POD 5 hsCRP levels in group T (8.6 ± 2.9 vs 10.9 ± 3.2 mg/l) was statistically significant between the groups (p = 0.024) (Table 4). All CABG surgeries were performed successfully. There was no repeat surgery for bleeding or peri-operative myocardial infarction in either group. The only complication was one cerebrovascular accident in the N-T group. There was no clinical or laboratory evidence of postoperative renal dysfunction in either group. Urine output during surgery and in the postoperative period did not differ between the groups. No wound infection was observed for any patient.

Discussion Coronary artery bypass grafting is often followed by a systemic inflammatory response. The clinical relevance of CABGrelated systemic inflammation varies with patients and such inflammation may be accompanied by intermittent organ dysfunction and finally, multi-organ failure, including renal and pulmonary dysfunction.9,10 In some patient groups, the effect of extracorporeal circulation is serious after open-heart surgery and it is well known that diabetic patients are frequently associated with renal and cardiovascular disease, requiring surgical and medical intensive care. Some pathophysiological mechanisms such as microalbumiuria and urinary protein over-excretion are responsible for these damaging effects in this particular group of patients. Table 2. Operative and postoperative features of the patients Surgical parameters

Group T

Group N-T

p-value

Number of bypasses

2.9 ± 1.0

2.9 ± 0.9

0.876

Cardiopulmonary bypass time (min)

87.4 ± 31.3

86.6 ± 20.4

0.920

Cross-clamp time (min)

52.6 ± 21.6

53.2 ± 18.5

0.925

Flow (cm )

4469.0 ± 362.4 4491.0 ± 295.0

Table 3. Pre- and postoperative microalbuminuria levels Group T Mean ± SD

Hyperlipidaemia, n (%)

193

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Group T = telmisartan group; group N-T = non-telmisartan group; SD = standard deviation. Group T: Pre-op vs 1st day: p < 0.001; pre-op vs 5th day: p = 0.036; 1st hour vs 5th day: p = 0.021; 1st day vs 5th day: p = 0.036. Group N-T: Pre-op vs 1st day: p < 0.001; 1st hour vs 1st day: p < 0.001; 1st hour vs 5th day: p < 0.001; 1st day vs 5th day: p < 0.001.

In patients with diabetes, angiotensin II is believed to play a main role in the progression of renal damage, not only through haemodynamic effects but also non-haemodynamic effects, including stimulation of growth factors and cytokines and changes in extracellular matrix metabolism.11 Angiotensin II gives rise to glomerular hypertension and can alter the filtration properties of the glomerular basement membrane, leading to proteinuria.12-13 Angiotensin receptor antagonists have been shown to consistently produce favourable mortality and morbidity outcomes in endpoint trials in patients with type 2 diabetes and diabetic nephropathy.14-16 Microalbuminuria refers to the increased excretion of albumin into the urine, which is so slight that it can be detected only by sensitive immunological analysis. Microalbuminuria is measured in diabetic patients to predict incipient nephropathy. The predictive value of microalbuminuria for the expression of cardiovascular diseases has also been investigated and, in fact, is as powerful for predicting hyperlipidaemia or hypertension.17 Microalbuminuria also occurs in acute conditions where capillary permeability increases. Microalbuminuria increases during major surgery such as CABG, and extracorporeal circulation activates an inflammatory cascade, which may increase capillary permeability and cause microalbuminuria. The increase in capillary permeability may induce exudation of proteins from the lung capillaries into the capillary–alveolar interspace and alveoli, causing the so-called post-perfusion lung, which resembles pulmonary oedema. We found that telmisartan, as an angiotensin II receptor antagonist, had a significant lessening effect on microalbuminuria in type 2 diabetes patients undergoing coronary bypass surgery in our study. A significant decrease in hsCRP levels on day 5 was also noticed between the groups. Several previous studies have shown that angiotensin receptor antagonists are effective anti-inflammatory agents, and our patients receiving telmisartan revealed decreased levels of systemic inflammation after CABG. This anti-inflammatory effect of telmisartan may help preserve postoperative renal function and also vascular endothelial function, which may also be seen after bypass surgery. Table 4. High-sensitivity C-reactive protein levels (mg/l). Group T Mean ± SD

Group N-T Mean ± SD

p-value

0.834

Pre-operative

0.35 ± 0.17

0.50 ± 0.32

0.069

Atrial fibrillation, n (%)

4 (20)

6 (30)

0.716

Postoperative 1st day

10.0 ± 2.0

17.8 ± 3.9

0.405

Inotrope usage, n (%)

3 (15)

6 (30)

0.451

Postoperative 5th day

8.6 ± 2.9

10.9 ± 3.2

0.024

2 (10)

0.487

Group T = telmisartan group; group N-T = non-telmisartan group; SD = standard deviation.

Mortality, n (%)

Group T = telmisartan group; group N-T = non-telmisartan group.

194

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

We know that renal dysfunction is a serious complication of coronary revascularisation with CABG and results in increased morbidity and mortality rates and prolonged hospital stay.18 The injurious action of CABG on renal function is caused by several mechanisms, including non-pulsatile perfusion and increased levels of circulating catecholamines, cytokines and free haemoglobin.19 These effects result in damage to the glomerular as well as tubular structures, which, in turn, may cause renal dysfunction, especially in the presence of additional risk factors.20-21 Microalbuminuria is one of the sensitive markers of increased capillary permeability and may be useful to study the systemic inflammatory response after CABG.6,22,23 According to previous investigations, urinary microalbuminuria increased significantly in the early postoperative period and one day after CABG. In our study, peak increase in microalbuminuria was observed in both groups but there was no statistically significant difference (p = 0.071). These levels decreased, particularly on the fifth day in our cases, and the decrease was statistically significantly different in group T. In both groups, hsCRP increased and peaked on the first postoperative day in both groups. However, in group T, hsCRP, as one of the pro-inflammatory agents, decreased significantly on the fifth day. Therefore, the increase in acute inflammatory response was similar in both groups on the first postoperative day, and in group T, both markers had decreased by the fifth day. Borch-Johnsen et al. showed the direct relationship between proteinuria and cardiovascular mortality rate in insulindependent diabetic patients after open-heart surgery in patients undergoing CABG.24 Telmisartan was also shown to reduce or normalise microalbuminuria in 34% of patients with diabetes, and in a second, smaller study including 64 hypertensive and 60 normotensive patients, to reduce the incidence of renal dysfunction. This confirmed that telmisartan reduced microalbuminuria independently of its blood pressure-lowering effects. Restoration of normal urine albumin levels has also been demonstrated by telmisartan.25 Our study showed that telmisartan reduced microalbuminuria, not only pre-operatively, but also after open-heart surgery. The return to baseline levels was also faster than in group N-T. Angiotensin receptor blocking agents decrease some of the postoperative acute inflammatory agents in on-pump CABG patients with diabetes mellitus by lessening the systemic consequences of renal dysfunction, and may have additional cardiovascular effects by exerting beneficial effects on endothelial tissue elsewhere in the body and within the heart in this patients group. The cardiovascular benefits of angiotensin receptor antagonists have been evaluated, not only in terms of their ability to lower blood pressure, but also on their ability to prevent strokes, cardiac events and target-organ damage.14,16 Limitations of our study are the relatively small size of our series and the lack of definite criteria for selection of patients for this study. As most coronary patients are already being treated with angiotensin receptor blocking agents, the results of our study will not have a major impact on clinical practice. Furthermore, it would have been better to test the predictive value of microalbuminuria on prognosis in this category of patients. However, we hope that this study will pioneer further studies on this method.

AFRICA

Conclusion Our results showed that telmisartan decreased systemic inflammation and urinary albumin excretion in diabetic patients after CABG surgery, compared to those not taking angiotensin receptor antagonists. These beneficial effects of telmisartan treatment on diabetic patients after CABG should be investigated further in prospective, randomised studies.

References 1.

Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol 2006; 17: 2106–2111.

Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106: 1777–1782.

Mojiminiyi OA, Abdella N, Moussa MA, Akanji AO, Al Mohammedi H, Zaki M. Association of C-reactive protein with coronary heart disease risk factors in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2002; 58: 37–44.

Jie W, Zhiqiang L. An epidemiological cross-sectional survey of microalbuminuria and risk factors in type 2 diabetic patients. Clin Med J Chin 2005; 12: 859–861.

Venkat KK. Proteinuria and microalbuminuria in adults: significance, evaluation, and treatment. South Med J 2004; 97: 969–979.

Marshall SM. Recent advances in diabetic nephropathy. Postgrad Med J 2004; 80: 624–633.

Gosling P. Microalbuminuria: a marker of systemic disease. Br J Hosp Med 1995; 54: 285–290.

Loef BG, Epema AH, Navis G, Ebels T, van Oeveren W, Henning RH. Off-pump coronary revascularization attenuates transient renal damage compared with on-pump coronary revascularization. Chest 2002; 121: 1190–1194.

Abacilar F, Dogan OF, Duman U, Ucar I, Demircin M, Ersoy U, et al. Changes and the effects of the plasma levels of tumor necrosis factor after coronary artery bypass surgery with cardiopulmonary bypass. Heart Surgery Forum 2006; 9: 703–709.

10. Leehey DJ, Singh AK, Alavi N, Singh R. Role of angiotensin II in diabetic nephropathy. Kidney Int 2000; 77: 93–98. 11. Manley HJ. Role of angiotensin-converting-enzyme inhibition in patients with renal disease. Am J Health Syst Pharm 2000; 57: 12–18. 12. Remuzzi A, Perico N, Amuchastegui CS, Malanchini B, Mazerska M, Battaglia C, et al. Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993; 4: 40–49. 13. Esmatjes E, Flores L, Inigo P, Lario S, Ruilope LM, Campistol JM. Effect of losartan on TGF-beta1 and urinary albumin excretion in patients with type 2 diabetes mellitus and microalbumin-uria. Nephrol Dial Transplant 2001; 16: 90–93. 14. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869. 15. Vogt L, Navis G, Koster J, Manolis AJ, Reid JL, de Zeeuw D, on behalf of the Angiotensin II Receptor Antagonist Telmisartan Micardis in Isolated Systolic Hypertension (ARAMIS) Study Group. The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized,

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

195

double-blind, placebo-controlled trial. J Hypertens 2005; 23: 2055–2061.

21. Loef BG, Epema AH, Navis G, Ebels T, van Oeveren W, Henning RH.

16. Ribeiro AB, Gavras H. Angiotensin II antagonists: clinical experience in

Off-pump coronary revascularization attenuates transient renal damage

the treatment of hypertension, prevention of cardiovascular outcomes

compared with on-pump coronary revascularization. Chest 2002; 121:

and renal protection in diabetic nephropa-thy and proteinuria. Arq Bras Endocrinol Metabol 2006; 50: 327–333.

1190–1194. 22. Morariu AM, Loef BG, Aarts LP, Rietman GW, Rakhorst G, van

17. Seçici S, Battaloğlu B, Uyar İS, et al. Rosuvastatin pretreatment does

Oeveren W, et al. Dexamethasone: benefit and prejudice for patients

not attenuate microalbuminuria after coronary artery bypass grafting.

undergoing on-pump coronary artery bypass grafting: a study on

Turk Gogus Kalp Dama 2014; 22(3): 496–501. Doi: 10.5606/tgkdc.

myocardial, pulmonary, renal, intestinal, and hepatic injury. Chest 2005;

dergisi.2014.8991.

128: 2677–2687.

18. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz

23. Bugra O, Baysal A, Fedakar A, Erdem K, Sunar H, Daglar B. Does

A, Mangano DT. Renal dysfunction after myocardial revascularization:

serum neutrophil gelatinase-associated lipocalin biomarker detect the

risk factors, adverse outcomes, and hospital resource utilization. The

early deterioration in renal functions in patients with insulin-dependent

Multicenter Study of Perioperative Ischemia Research Group. Ann

diabetes mellitus undergoing coronary artery bypass graft surgery?

Intern Med 1998; 128: 194–203.

Turk Gogus Kalp Dama 2014; 22(1): 63–70. Doi: 10.5606/tgkdc.dergi-

19. Ramsay JG. The respiratory, renal, and hepatic systems: effect of cardiac surgery and cardiopulmonary bypass. In: Mora CT, ed. Cardiopulmonary Bypass. New York: Springer-Verlag, 1995: 147–168. 20. Şener T, Köprülü AŞ, Karpuzoğlu OE, et al. The clinical results of

si.2014.7780. 24. Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J 1987; 294: 1651–1654.

off-pump coronary artery bypass surgery in renal dysfunction patients.

25. Montalescot G, Collt JP. Preserving cardiac function in the hyperten-

Turk Gogus Kalp Dama 2013; 21(4): 918–923. Doi: 10.5606/tgkdc.

sive patient: why renal parameters hold the key. Eur Heart J 2005; 26:

dergisi.2013.8168.

2616–2622.

Non-O blood groups associated with higher risk of heart attack Having a non-O blood group is associated with a higher risk of heart attack, according to research presented recently at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure. Lead author Tessa Kole, a Master’s degree student at the University Medical Centre Groningen, the Netherlands, said: ‘It has been suggested that people with non-O blood groups (A, B, AB) are at higher risk for heart attacks and overall cardiovascular mortality, but this suggestion comes from case–control studies, which have a low level of evidence. If this was confirmed, it could have important implications for personalised medicine.’ The current study was a meta-analysis of prospective studies reporting on O and non-O blood groups, and incident cardiovascular events, including myocardial infarction (heart attack), coronary artery disease, ischaemic heart disease, heart failure, cardiovascular events and cardiovascular mortality. The study included 1 362 569 subjects from 11 prospective cohorts, described in nine articles. There were a total of 23 154 cardiovascular events. The researchers analysed the association between blood group and all coronary events, combined cardiovascular events and fatal coronary events. The analysis of all coronary events included 771 113 people with a non-O blood group and 519 743 people with an O blood group, of whom 11 437(1.5%) and 7 220 (1.4%) suffered a coronary event, respectively. The odds ratio (OR) for all coronary events was significantly higher in carriers of a non-O blood group, at 1.09 [95% confidence interval (CI) of 1.06–1.13]. The analysis of combined cardiovascular events included 708 276 people with a non-O blood group and 476 868 people with an O blood group, of whom 17 449 (2.5%) and 10 916 (2.3%) had an event, respectively. The OR for combined cardiovascular events was significantly higher in non-O blood group carriers, at

1.09 (95% CI 1.06–1.11). The analysis of fatal coronary events did not show a significant difference between people with O and non-O blood groups. ‘We demonstrate that having a non-O blood group is associated with a 9% increased risk of coronary events and a 9% increased risk of cardiovascular events, especially myocardial infarction’, said Ms Kole. The mechanisms that might explain this risk are under study. The higher risk for cardiovascular events in non-O blood group carriers may be due to having greater concentrations of von Willebrand factor, a blood clotting protein which has been associated with thrombotic events. Further, non-O blood group carriers, specifically those with an A blood group, are known to have higher cholesterol. And galectin-3, which is linked to inflammation and worse outcomes in heart failure patients, is also higher in those with a non-O blood group. Ms Kole said: ‘More research is needed to identify the cause of the apparent increased cardiovascular risk in people with a non-O blood group. Obtaining more information about risk in each non-O blood group (A, B and AB) might provide further explanations of the causes.’ She concluded: ‘In future, blood group should be considered in risk assessment for cardiovascular prevention, together with cholesterol, age, sex and systolic blood pressure. It could be that people with an A blood group should have a lower treatment threshold for dyslipidaemia or hypertension, for example. We need further studies to validate if the excess cardiovascular risk in non-O blood group carriers may be amenable to treatment.’ Source: European Society of Cardiology Press Office

196

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Perceptions of radiation safety training among interventionalists in South Africa André Rose, William Ian Duncombe Rae

Abstract Exposure to ionising radiation may have deterministic and stochastic health effects, which include skin changes, chromosomal aberrations, cataracts and carcinomas. Formalised training in radiation safety and protection improves knowledge on the subject and facilitates greater compliance in safety practices. This qualitative study included 54 interventionalists (adult and paediatric cardiologists, and interventional radiologists). The participants were purposively selected and interviewed to explore their perceptions about radiation safety. A thematic analysis of the transcripts was done using a deductive and inductive approach. Findings showed participating cardiologists had less knowledge about radiation safety than participating radiologists. Cardiologists reported little or no formal training on radiation safety and did not display a culture of radiation safety. There was no consensus on how the training gap should be addressed. There is a perceived need to change and enhance the radiation safety culture among interventionists, and the participants proffered some ideas. These included the need for re-curricularisation of cardiologists’ training to create awareness of radiation safety practices. Keywords: radiation safety training, interventionalists’ training, radiation awareness, occupational radiation safety, cardiology training Submitted 2/11/16, accepted 13/5/17 Published online 23/5/17 Cardiovasc J Afr 2017; 28: 196–200

www.cvja.co.za

DOI: 10.5830/CVJA-2017-028

Continuous improvements are taking place in radiological imaging technology, with an accompaning reduction in radiation exposures required for imaging.1 There has however also been an increase in patient load, and fluoroscopic procedures are becoming more complex and taking longer to perform.2,3 This consequently increases radiation exposure to operators. Evidence is mounting that even at low-dose exposure, there are important biological consequences.4 Ionising radiation can produce detrimental biological effects, which include acute and chronic skin effects, chromosomal abnormalities, various

carcinomas and cataracts.5-7 The effects of radiation exposure may be deterministic or stochastic.8 It is therefore imperative that health professionals working with ionising radiation are adequately informed and trained on the dangers associated with using this modality, so they can protect themselves better.9 Adequate understanding of the effects of occupational radiation exposure and vigilant radiation safety practices among interventionists are essential to protect the health of this group of healthcare professionals. It is concerning that interventional cardiologists need to make decisions about radiation use for their patients and protection for themselves with the level of training they receive in radiobiology and radiation physics.9 The required knowledge level may be effectively achieved by incorporating changes in their training curriculum and in on-going continued medical education (CME) programmes, as is evidenced by radiology training programmes.1 Training and formal lectures targeted at developing a culture of radiation safety are crucial to developing a culture of radiation safety.10 Radiation physics and radiobiology is part of the curriculum for radiology registrars in South Africa. They are examined on these topics in their Part I examination, but have no subsequent examination on these topics.11 Rehani argues that the intensity of radiation used by interventional cardiologists is no less than that used by interventional radiologists and for this reason, the two disciplines should have similar training in radiobiology and radiation physics.12 This is however not practical at present in South Africa and requires an alternative approach to improving radiation safety knowledge, awareness and practice in non-radiologist clinicians.12 Interventionalists are highly skilled doctors. In South Africa, there is a dearth of skilled medical personnel and an even greater shortage of highly skilled interventionalists. The demand for this skill is not being met by the output of subspecialists qualifying.13 It is therefore crucial to protect the health of those already in service and those who will enter the field. Adequate training is not just about developing skills acumen, but also instilling vigilant radiation safety practices, and this can be entrenched through the formal training curriculum. Influencing changes in a curriculum is challenged by various factors, such as prevailing perceptions from the fraternity. The aim of this article was to report on the perception of South African interventionalists on radiation education and safety training.

Department of Community Health, University of the Free State, Bloemfontein, South Africa

Methods

André Rose, MB BCh, MMed, andrerose2000@yahoo.com

This was a qualitative study in which we conducted group and in-depth interviews. Qualitative research aims to capture the specific voice of the participants on this topic by producing rich insights into the experiences, values and understanding of participants on the matter.14

Department of Medical Physics, University of the Free State, Bloemfontein, South Africa William Ian Duncombe Rae, MB BCh, PhD

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Thirty individual interviews were conducted and six group interviews with between two and six participants were facilitated. Table 1 provides a detailed description of the participants, who were predominantly male (61%). The study population consisted of adult interventional cardiologists, paediatric interventional cardiologists and interventional radiologists, and are referred to collectively as interventionalists. Adult and paediatric cardiologists are collectively referred to as cardiologists, unless otherwise specified. The participants were purposively selected because they could contribute to an understanding of the perception of South African interventionalists on radiation education and safety training.15,16 We used targeted sampling in this study,17,18 and approached specific informants, such as the heads of departments, to participate in the study. The purposive selection also ensured that participants represented the opinions of people with a wide range of demographic characteristics, including those from different regions, levels of training, professions, and sectors where they worked, as shown in Table 1. We therefore attempted to include the full range of people involved, to get a clear impression of the overall feeling within South Africa. We commenced the qualitative data collection in May 2015 and ended in July 2016 when we determined that data saturation had been reached and there was a representative Table 1. Demographic characteristics of the participants (n = 54) Parameters

Number (%)

Gender Male

33 (61.1)

Female

21 (38.9)

Median age (years)

41 (IQR 35–55)

Median years worked

6.5 (IQR 2–20)

Categories of professionals All interventionalists

Radiologists

16 (29.6)

Radiology registrars

13 (24.1)

Adult cardiologists

10 (18.5)

Adult cardiology fellows

6 (11.1)

Paediatric cardiologists

7 (13.0)

Paediatric cardiology fellows

2 (3.7)

Sector worked Public only Private only Public and private

29 (53.7) 9 (13.0) 18 (33.3)

Levels of training In training1 Junior professionals2

21 (38.9) 4 (7.4)

Mid-level professionals3

12 (22.2)

Senior professionals4

11 (20.4)

Heads of departments

6 (11.1)

City worked in Johannesburg

17 (31.5)

Bloemfontein

13 (24.1)

Cape Town

9 (16.7)

Pretoria

5 (9.3)

Other5

7 (12.9)

Outside of South Africa6

3 (5.5)

IQR, interquartile range; 1cardiology fellows and radiology registrars; 2less than five years post qualifying; 3five to 15 years post qualifying; 4more than 15 years post qualifying; 5Durban, Kimberley, Mthatha, Pietermaritzburg; 6Australia, New Zealand, United Kingdom.

197

spread of all categories of professionals. Data were collected at several conferences and workshops using an interview schedule. Participants were asked what they thought the radiation safety training requirements for their respective disciplines were, whether the requirements matched their expectations, and if there was room for improvement, how a change could be executed. The study was approved by the Human Research Ethics Committee of the Faculty of Health Sciences of the University of the Free State (ECUFS 44/2015). Written informed consent was obtained from all participants. In the discussion groups, the participants were asked not to divulge their responses outside the group.

Statistical analysis Thematic analysis using a deductive and inductive approach was used.19,20 The interviews were audio-recorded and transcribed verbatim. We then checked the transcripts against the audio recordings for accuracy. Data included the researcher’s field notes. Data were analysed as we received it. We used Braun and Clarke’s steps in the analysis process.21 The researchers independently read the transcripts and coded the data. The codes were organised into categories and the categories were grouped into themes. We discussed the interpretations that emerged. We debated the themes and then reached consensus on the findings. This article explores only the theme of radiation safety, training and education.

Results The main themes that were formed included: ‘knowledge and awareness of radiation effects’, ‘education and training in radiation safety’, and ‘the role of senior professionals in fostering a culture of education and training’. In the quotes below (AC) refers to adult cardiologists, (PC) to paediatric cardiologists and (R) to radiologists. There was no difference between men and women in how they responded to the training they received.

Knowledge and awareness of radiation effects Radiologists generally had a well-informed opinion about how ionising radiation worked and the effects it could have on their health and the health of their patients. As one radiologist reported: ‘I don’t think there is any theory that we’re missing out on [in training] if you do the proper course work for your primary exams. I think that covers everything that’s necessary’ (R). Radiologists often spoke confidently about how radiation affected health and consistently described the consequences as ‘stochastic and deterministic effects’ (R). They displayed a familiarity with the literature on the topic. This contrasted with the cardiologists whose understanding resonated with what you would expect from a non-radiologist doctor. A paediatric cardiology fellow reflected on the effects of ionising radiation on her health as follows: ‘I haven’t thought about it [laughs] to be completely honest. We go there [the cath lab] each week and we have our little [dosimeter] badges. We don’t really think about what’s happening’ (PC).

198

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

A radiologist from New Zealand corroborated this view stating: ‘It is assumed that the doctors understand about radiation, but this isn’t the case’ (R).

Education and training in radiation safety There was a distinct difference between cardiologists and radiologists in their training in radiobiology and radiation physics. The cardiologists receive very little or no formal training in these subjects while radiologists have it as part of their coretraining curriculum. ‘I think as postgraduates they [radiology registrars] get enough training on radiation safety. I would like to see it [radiation safety] as part of every imaging congress for the staff because it is often neglected. But if you have an imaging congress, that must be part of it; to remind all the people at the congress about radiation protection. I think that will go a far way already in reminding them about safety measures and radiation protection. And then in our normal academic programme to just make sure that it receives enough attention’ (R). ‘Perhaps [there should be] a short course on the amount of exposure that there is you get in relation to how much work you do. You know, a couple of lectures or a lecture on that. Uhmm and to ... implement that into the [cath] lab. But that’s what I think should be done; I had no training about radiation whatsoever, not … in any way’ (AC). ‘Cause they [cardiologists] didn’t do physics, they haven’t done like physics, like part of our training is physics and [it is in] the exam, it is not part of their training. I don’t know if they actually are aware of it [the effects of radiation]’ (R) reflecting on cardiology training in radiation safety. ‘I think it [radiation physics] should be highlighted as something [that should] at least be done at the first year’ (R), in response to training in radiation safety for doctors using ionising radiation as a modality. Junior and recently qualified cardiologists expressed concern that they were using a modality that could have dire consequences to their long-term health, but were not being trained in how to safely use radiation. ‘We don’t really have training, it is just like we do selfstudy for physics’ (AC) fellow. The paediatric cardiology heads of departments that participated in the study unanimously expressed the opinion that it was an important but neglected aspect of the content of their training programmes. They generally held the view that more could and should be done to improve the training and awareness on the topic. They however expressed the concern that their departments were not necessarily equipped to do such training and that other departments such as medical physics should assist with this training. (After the interview with the PC quoted below, a question on radiation safety was asked in the CMSA examinations for paediatric cardiology in April 2016.) ‘I’ve been an examiner in paediatric cardiology for a while. For over 10 years I haven’t seen a question about it [radiation safety]. So, it’s not of importance and nobody discusses it. So, there should be training and it should be in the curriculum…’ (PC). ‘It [radiation safety] is something that we’ve never discussed or ever brought up in a meeting until you came

AFRICA

along actually. How do we incorporate that when we train our fellows? I don’t remember ever been told anything by my consultants with regards to radiation safety for myself when I was being trained. Maybe we can add some training because at the moment there isn’t any. There’s no training!’ (PC). Adult cardiology heads of department (HOD) were divergent on their views. They recognised that radiation safety was important and lacking in their programmes, but did not think that the current training programme needed re-evaluation. They were concerned that the volume of work was already too much for the cardiology fellows. ‘Ja, it’s hard to uhhh, cardiology is vast on its own. Adding a section on radiation is asking a bit much. But I think uhhmm, in the syllabus, that we give, you know there is a syllabus, a cardiologist syllabus for the trainees. Somewhere in that syllabus it should emphasise the fact or some knowledge should be given around radiation and the issues about radiation’ (C) HOD. Participants reflected that education and training was however not a once-off exercise and that frequent and constant reinforcing was needed. ‘I do think education does have a very important role if one is making people aware. I would hope that you would then gradually improve their performance in the lab but it is something I think needs reinforcing regularly because I’ve seen very experienced operators still behaving badly in the cath lab. I’ve seen it a huge amount. And so, I think we just have to keep reinforcing good practice and keep educating them’ (R) UK.

The role of senior professionals in fostering a culture of education and training At one training institution, the head of adult cardiology was very dismissive of the topic. This HOD was reluctant to participate in the study, stating that a more junior cardiologist should be interviewed. Despite explaining the nature of the study and stating that we were interested in hearing his/her voice as HOD on training in radiation safety, the HOD was still not interested in participating in the study. This created the impression that the HODs of some training units were not interested in the topic. This dismissive attitude towards radiation safety was also recognised by other participants in the study: ‘Yes, yes they [heads of departments] are shocking yes. No, no, no that’s exactly true and that’s certainly true and I can promise you that is not just in South Africa. That will be all over ja’ (R) UK.

Discussion The increasing utilisation of ionising radiation for diagnostic, therapeutic and interventional procedures necessitates great vigilance in using the modality. This strengthens the case for interventionalists to be adequately trained in the use of radiation. Improving knowledge on the effects of ionising radiation on the health of patients and operators requires improved access to training and education on the topic. The literature consistently cites that formalising radiation safety and training in the curriculum is essential for improving and maintaining radiation safety practices for interventionalists.1,22

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

In a study by Sadighm et al., they found an increased awareness about radiation among radiology residents compared to non-radiology residents.9 Even though we had not quantified our findings, we interpreted that radiologists were generally more knowledgeable on the effects of radiation and safety precautions compared to cardiologists. We postulate that this is because of the formalisation of radiobiology and radiation physics in their training curriculum. It is concerning that this discrepancy exists, as cardiologists are exposed to similar radiation workloads to radiologists and the dose exposure is likely to increase as the complexity of cardiology procedures increases.12 An effective way to improve the knowledge of radiation safety is to provide opportunities for education and training in the subject during specialisation. Limacher et al. argues that the best way to ensure adequate training in radiation safety is to formalise it in the curriculum.5 Radiobiology and radiation physics is mandatory for radiologists in South Africa and is a formal part of their training programme.11 This is not the case for cardiologists in South Africa (personal communication). Szarmach et al. state that radiation safety can only be addressed by educating all healthcare professionals, irrespective of their position, and that they need to be trained ‘thoroughly and systematically’.23 Reinforcing radiation safety messages and training optimises radiation safety.24 The Colleges of Medicine curriculum prescribes radiation physics and radiobiology as learning outcomes for both radiologists and cardiologists.11 From the interviews and from personal discussions with interventionalists involved with training specialists, it emerged that there was no standardised teaching of radiation safety at the various training institutions. Instruction in the topic ranged from in-house teaching, registrars or clinical fellows attending short courses, or self-learning on the topic. Uniformity in content and instruction will facilitate that interventionalists are adequately trained in this area and that radiation safety is reinforced across South Africa.1,23,24 It is inconsistent, and hence ineffective, if the leadership of a clinical unit does not actively promote radiation safety and training but expects junior staff to adhere to these principles.25 The attitude of the HOD of a unit is key to developing a culture of radiation education and training. Radiation safety as a priority will not permeate the department if those at the helm are not recognising it as a priority and championing the cause. The views expressed by South African interventionalists were corroborated by at least three international interventionalists. The views of these international doctors are included to illustrate that the experience and challenges of training cardiologists and radiologists in radiation safety are not unique to South Africa. Developing, strengthening and sustaining a radiation education and training culture in South Africa among interventionalists will require changes in their formal training and deliberate inclusion in their CME programmes. Education is crucial to establishing a radiation safety culture and will require buy-in at all levels.

The findings highlight that radiation safety is an important aspect of training and that it is imperative to adequately train interventionalists in this field. Further research is needed to better understand this issue and how to incorporate it into interventionalists’ training programmes.

Conclusion Radiobiology and radiation physics is formalised in the training curriculum for radiologists, resulting in greater awareness about radiation dangers and greater vigilance in radiation safety practice. There is a paucity of knowledge about radiation safety practices among cardiologists in South Africa, and cardiologists need to be empowered to make more informed decisions about using ionising radiation, in order to protect themselves and their patients. This can be achieved by including it in their formal training curriculum and raising the expected outcomes to that of radiologists. We thank Dr Asta Rau and André Janse van Rensberg from the Centre for Health Systems Research and Development (UFS), who read the manuscript and offered technical insights into the qualitative methodology. The PhD from which this study emanated was funded by the Medical Research Council of South Africa under SAMRC Clinician Researcher Programme. AR received the Discovery Foundation Scholarship, which funded the data collection of this project. SA Heart (Free State branch) partially funded data collection for this project. WIDR receives NRF Rated Researcher Incentive Funding.

References 1.

The participants were purposively sampled and the findings are not generalisable to the whole population of South African interventionists. The participants however reflect the population of interest and the findings may be transferable in similar settings.

Le Heron J, Padovani R, Smith I, Czarwinski R. Radiation protection of medical staff. Eur J Radiol 2010; 76(1): 20–23.

Bhargavan M. Trends in the utilization of medical procedures that use ionizing radiation. Heal Phys 2008; 95(5): 612–627.

Smilowitz NR, Balter S, Weisz G. Occupational hazards of interventional cardiology. Cardiovasc Revasc Med 2013; 14(4): 223–228.

Shore RE, Neriishi K, Nakashima E. Epidemiological studies of cataract risk at low to moderate radiation doses: (not) seeing is believing. Radiat Res 2010; 174: 889–894.

Limacher MC, Douglas PS, Germano G, Laskey WK, Lindsay BD, Mcketty MH, et al. Radiation Safety in the practice of cardiology. J Am Coll Cardiol 1998; 31(4): 892–913.

Venneri L, Rossi F, Botto N, Andreassi MG, Salcone N, Emad A, et al. Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council’s Biological Effects of Ionizing Radiation VII Report. Am Hear J 2009 Jan; 157(1): 118–124.

Klein LW, Miller DL, Balter S, Laskey W, Haines D, Norbash A, et al. Occupational health hazards in the interventional laboratory : time for a safer environment. Int J Vasc Interv Radiol 2009; 20(2): 147–153.

Navarro VCC, Navarro MVT, Maia AF. Assessments of medical exposures during interventional radiology procedures. Radiat Prot Dosim 2013; 154(2): 229–236.

Limitations of the study

199

Sadigh G, Khan R, Kassin MT, Applegate KE. Radiation safety knowledge and perceptions among residents: A potential improvement opportunity for graduate medical education in the United States. Acad Radiol 2014; 21(7): 869–878.

10. Cole P, Hallard R, Broughton J, Coates R, Croft J, Davies K, et al. Developing the radiation protection safety culture in the UK. J Radiol Prot 2014; 34: 469–484.

200

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

11. Colleges of Medicine of South Africa [Internet]. Available from: www. cmsa.org.za 12. Rehani MM. Training of interventional cardiologists in radiation protection – the IAEA ’s initiatives. Int J Card 2007; 114: 256–260. 13. Sliwa K, Zühlke L, Kleinloog R, Doubell A, Ebrahim I, Essop M, et al. Cardiology–cardiothoracic subspeciality training in South Africa: a position paper of the South Africa Heart Association. Cardiovasc J Afr 2016; 27(3): 188–193. 14. Sofaer S. Qualitative research methods. Int J Qual Heal Care 2002; 14(4): 329–336. 15. Morgan DL. Focus group interviewing. Handb Interview Res Context Method 2002;141–159. DOI: 10.2307/1317652 16. Wilkinson S. Focus group methodology: a review. Int J Soc Res Methodol 1998; 1(3): 181–203. 17. Marshall MN. Sampling for qualitative research Sample size. Fam Pract 1996; 13(6): 522–525. 18. Noy C. Sampling knowledge: the hermeneutics of snowball sampling in qualitative research. Int J Soc Res Methodol 2008; 11(4): 327–344. 19. Vaismoradi M, Turunen H, Bondas T. Content analysis and thematic

AFRICA

analysis: Implications for conducting a qualitative descriptive study. Nurs Heal Sci 2013; 15(3): 398–405. 20. Braun V, Clarke V. What can ‘thematic analysis’ offer health and wellbeing researchers? Int J Qual Stud Health Well-being 2014 Oct 16; 9. 10.3402/qhw.v9.26152. 21. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol 2006; 3(2): 77–101. 22. Lynskey GE, Powell DK, Dixon RG, Silberzweig JE. Radiation protection in interventional radiology: survey results of attitudes and use. J Vasc Interv Radiol 2013; 24(10): 1547–1551.e3. 23. Szarmch A, Piskunowicz M, Świętoń D, Muc A, Mockałło G, Dzierżanowski J, et al. Radiation safety awareness among medical staff. Pol J Radiol 2015; 80: 57–61. 24. Sheyn DD, Racadio JM, Ying J, Patel MN, Racadio JM, Johnson ND. Efficacy of a radiation safety education initiative in reducing radiation exposure in the pediatric IR suite. Pediatr Radiol 2008; 38(6): 669–674. 25. Zisook S, Mcquaid JR, Sciolla A, Lanouette N, Calabrese C, Dunn LB. Psychiatric residents’ interest in psychotherapy and training stage: A multi-site survey. Am J Psychother 2011; 65(1): 47–59.

Unemployment associated with 50% higher risk of death in heart-failure patients Unemployment is associated with a 50% higher risk of death in patients with heart failure, according to research presented recently at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure. The observational study in more than 20 000 heart-failure patients found that not being employed was linked with a greater likelihood of death than a history of diabetes or stroke. ‘The ability to hold a job brings valuable information on wellbeing and performance status’, said lead author Dr Rasmus Roerth, a physician at Copenhagen University Hospital, Denmark. ‘And workforce exclusion has been associated with increased risk of depression, mental health problems and even suicide.’ ‘In younger patients with heart failure, employment status could be a potential predictor of morbidity and mortality’, he continued. ‘If that was the case, employment status could help to risk stratify young heart-failure patients and identify those needing more intensive rehabilitation.’ This study compared the risks of all-cause death and recurrent heart-failure hospitalisation in patients with heart failure, according to whether they were employed at baseline or not. Using the unique personal identification number assigned to all residents in Denmark, individual data were linked from nationwide registries on hospitalisation, prescribed medication, education level, public welfare payments and death. The study included all patients of working age (18 to 60 years) with a first hospitalisation for heart failure in Denmark between 1997 and 2012. Of the 21 455 patients with a first hospitalisation for heart failure, 11 880 (55%) were part of the workforce at baseline. During an average follow up of 1 005 days, 16% of employed and 31% of unemployed patients died, while 40% of employed and 42% of unemployed patients were rehospitalised for heart failure. After adjusting for age, gender, education level and co-morbidities, heart-failure patients unemployed at baseline had a 50% increased risk of death and 12% increased risk of rehospitalisation for heart failure compared to those who were employed. Not being part of the workforce was associated with

a higher likelihood of death than a history of diabetes or stroke. Dr Roerth said: ‘We found that heart-failure patients out of the workforce at baseline had a higher risk of death. Not being part of the workforce was associated with a risk of death comparable to that of having diabetes or stroke. Those without a job also had an increased risk of recurrent heart-failure hospitalisation.’ Dr Roerth said the exact mechanism on how employment status may affect mortality is complex and most likely multifactorial. ‘The ability to work can be seen as a measure of performance status and be interpreted as whether patients meet the physical requirements of a full time job or not’, he said. But he added: ‘Employment status is more than just a physical measurement as it also has an influence on quality of life, and has been shown to be important for mental health and wellbeing. Thus, both from a physical and psychological point of view it makes sense to include employment status in the evaluation of young heart-failure patients’ prognosis.’ Dr Roerth said it was perhaps not surprising that employment status has importance for prognosis. ‘But the observation that employment status is associated with an increased risk of death comparable to that of many other co-morbidities such as diabetes and stroke is notable’, he said. In terms of implications of the findings, Dr Roerth said workforce exclusion could be used to identify heart failure patients at risk of poor outcomes and that efforts to get patients back into work might be beneficial. He said: ‘It could be highly valuable to assess employment status and actually think of workforce exclusion as a prognostic marker in line with suffering from serious chronic diseases. Knowledge on why workforce exclusion has happened for the individual patient might lead to ideas on how it can be prevented – for example with more intensive rehabilitation, physical activity, psychological treatment, or a different job.’ Source: European Society of Cardiology Press Office

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

201

Review Article Xanthine oxidase inhibitors in ischaemic heart disease Mihnea Zdrenghea, Adela Sitar-Tǎut, Gabriel Cismaru, Dumitru Zdrenghea, Dana Pop

Abstract Increased uric acid levels are correlated with cardiovascular disease, particularly with ischaemic heart disease. Xanthine oxidase inhibitors, especially allopurinol, lower the risk of ischaemic heart disease due to their effects on reactive oxygen species and endothelial function. In chronic stable angina pectoris, allopurinol increases the median time to ST depression, time to chest pain, and total exercise time. On the other hand, it has been reported that allopurinol has a beneficial effect on ischaemic patients referred for angioplasty, but there are insufficient data regarding its effect on acute myocardial infarction patients. Moreover, other important actions of allopurinol are regression of left ventricular hypertrophy and improvement in the results of cardiac rehabilitation. The efficacy of allopurinol has recently been acknowledged by the European Society of Cardiology guidelines for stable angina pectoris, but the particular role of allopurinol in ischaemic heart disease patients is not fully established.

Keywords: xanthine oxydase inhibitors, ischaemic heart disease, uric acid Submitted 30/7/14, accepted 10/7/16 Published online 9/9/16 Cardiovasc J Afr 2017; 28: 201–204

www.cvja.co.za

DOI: 10.5830/CVJA-2016-068

There are many cardiovascular conditions and risk factors associated with elevated uric acid levels.1 Uric acid favours hypertriglyceridaemia, being involved in the increase of liver protein synthesis and turnover.2 Hyperuricaemia has been associated with an increased incidence and prevalence of hypertension, stroke and carotid, peripheral and coronary atherosclerotic vascular disease.1

Department of Haematology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Mihnea Zdrenghea, MD, PhD, mzdrenghea@umfcluj.ro

Department of Cardiology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Adela Sitar-Tǎut, MD, PhD Gabriel Cismaru, MD, Dumitru Zdrenghea, MD, PhD Dana Pop, MD, PhD

There is also a correlation between elevated levels of uric acid and inflammatory markers, including C-reactive protein (CRP), plasminogen activator inhibitor type I, and soluble intercellular adhesion molecule (ICAM).3 All these factors represent another possible link between uric acid and atherosclerosis, especially ischaemic heart disease.1 In a review on uric acid levels in cadiovascular disease, Kanbay et al. cite eight prospective studies based on medical and post mortem records, and coronary events registries, which demonstrate an increased risk of coronary heart disease in subjects with hyperuricaemia, with odd ratios (OR) between 1.12 and 2.30.4 These data suggest that a decrease in serum uric acid level could be beneficial in patients either at risk for or with established ischaemic heart disease. The most commonly used drugs to decrease uric acid levels are inhibitors of xanthine oxidase (XO). This enzyme is involved in uric acid synthesis, in the production of superoxide radicals and, consequently, in atherosclerosis.5 Therefore, a decrease in its activity may have anti-atherogenic and anti-ischaemic effects.6 There are three clinically available XO inhibitors: allopurinol, oxypurinol and febuxostat, the first being most widely used in clinical practice.7 The many potential pharmacological cardiovascular benefits of XO inhibitors include improvement in endothelial function, decrease in tissue oxidative stress, increase in ATP synthesis in ischaemic tissue, and improvement in exercise-induced ischaemia. XO inhibitors may also be beneficial in prevention of primary cardiovascular disease, left ventricular hypertrophy, acute coronary syndrome, stroke and heart failure.6 We will briefly discuss the main areas in which XO inhibitors could be or have already proven useful.

Anti-atherogenic effects The anti-atherogenic effects of XO inhibitors have mainly been studied in relation to endothelial function and oxidative stress parameters.8 Inflammatory markers and lipid profile have also been considered.9 XO represents a source of reactive oxygen species that results in both endothelial dysfunction and vascular inflammation. Consequently, lowering serum uric acid levels through XO inhibitors has anti-atherogenic effects. A review and meta-analysis of 40 studies reports that circulating markers of oxidative stress, such as malonaldehyde, were significantly decreased by XO inhibitors in six of the studies.9 Other studies found that brachial artery flow-mediated dilatation was increased, with an OR of 2.50. The forearm blood flow response to acetylcholine infusion was increased by 60.68%.9 In their 2013 review, Kanbay et al. analysed the relationship between reduction in uric acid level and improvement of

202

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

endothelial dysfunction in patients with diseases including congestive heart failure, the metabolic syndrome, diabetes and chronic kidney disease. In all cases, the improvement was significant, between 25 and 100%.4 On the other hand, studies on inflammation and lipid profile yielded controversial data. XO inhibitors did not influence CRP levels in several studies, CRP being decreased in only one.10 ICAM was also reduced in only one of the studies.9 Fibrinogen, interleukin 6 (IL-6), vascular endothelial growth factors (VEGF) and E-selectin levels were not affected. 9 One study found an improved lipid profile, but two further studies did not.8 Ziga et al. reported that in 40 hyperuricaemic patients, levels of triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were slightly increased after three months of allopurinol treatment.11 The authors suggested that in patients with the metabolic syndrome, lipid profile should be monitored after the initiation of allopurinol treatment, as the atherogenic index is increased in these patients. Renin and B-type natriuretic peptide (BNP) levels were decreased by XO inhibitors, this finding being of special relevance to ischaemic and heart failure patients.9,12

Angina pectoris The use of allopurinol improves chronic stable angina. Angina pectoris has a high prevalence of 5.7% in men and 6.7% in women, not all of them being referred for interventional cardiology. In these patients, allopurinol could be useful to increase exercise time, time to 1-mm ST depression, and time to angina.13 This is the main reason why allopurinol is recommended when classical anti-anginal drugs are contra-indicated or not efficient in controlling angina. The previous assertion is in agreement with the 2013 European Society of Cardiology guidelines on the management of stable coronary heart disease, which recommend 600 mg/day allopurinol under the ‘other drugs’ heading.14 Allopurinol has been found to improve exercise capacity by increasing ATP production for the same myocardial oxygen supply. Therefore allopurinol increases not only exercise capacity, but also the double product and peak effort.15 On the other hand, classical anti-anginal drugs increase exercise capacity, but not the double product or myocardial energy production.15 Other beneficial effects of allopurinol are related to endothelial function and coronary vasoconstriction. Rajendra et al. studied endothelial function assessed by forearm venous occlusion plethysmography, flow-mediated dilation and pulsewave plethysmography in 80 patients with coronary heart disease. Compared to the placebo group, allopurinol improved endothelium-dependent vasodilation and completely eliminated oxidative stress.16 In another study, Noman et al. investigated the effects of high-dose allopurinol on exercise in patients with stable angina pectoris.17 The study included 65 patients with positive stress testing, in whom 600 mg/day allopurinol increased time to ST depression from 232 to 298 seconds. The duration of exercise was consequently increased from 301 to 393 seconds. The time to chest pain was increased too, from 234 to 304 seconds, the difference being highly significant. On the contrary, the effect on the number of angina episodes/week or number of tablets of glyceryl trinitrate/week was not significant in comparison with placebo.

AFRICA

Unfortunately, there are further studies which do not confirm the aforementioned results. They describe no significant improvement of exercise capacity in patients with stable angina treated with allopurinol.9,15 Rekraj et al. studied the effect of high-dose allopurinol on left ventricular hypertrophy and endothelial function in patients with chronic stable angina. Using 600 mg allopurinol daily, flowmediated vasodilation increased by 0.82 ± 1.8% at nine months, from 4.1 ± 2.1% at baseline. On the other hand, in the placebo group, the initial flow-mediated vasodilation of 5.68% decreased by 0.69 ± 2.8% at nine months (p = 0.017).18 The data suggested the need for long-term treatment with allopurinol in order to obtain anti-atherosclerotic effects. The same article showed a nine-month left ventricular mass (LVM) and left ventricular mass index (LVMI) decrease of 5.2 g and 2.2 g/m2, respectively, in the allopurinol group, versus 1.3 g and 0.53 g/m2 in the placebo group, the difference being highly significant. They also determined the augmentation index (AIx), which was lower in the allopurinol group, suggesting not only improvement in endothelial function, but also less vascular remodelling. The results suggest that allopurinol is useful in hypertensive patients with ischaemic heart disease. Agarwal et al. recently presented a meta-analysis of 10 studies on the effects of allopurinol in 738 hypertensive patients.19 Compared to the control group, allopurinol-treated patients displayed a 3.3-mmHg systolic and a 1.3-mmHg diastolic blood pressure decrease.

Other manifestations of ischaemic heart disease There are many further studies on the effects of allopurinol in ischaemic heart disease but data are insufficient to allow the formulation of strong evidence-based guidelines.20 Beneficial effects were reported mainly in patients with myocardial revascularisation with coronary artery bypass surgery or angioplasty post myocardial infarction. Available data allow advocating a role for allopurinol in decreasing the number of complications, including arrhythmias, and improving myocardial function in revascularised patients, sustained by experimental data on the effect of allopurinol on cardiomyocyte apoptosis in rats after myocardial infarction.20 Xiao et al. reported a decrease in apoptosis measured through caspase activity in non-infarcted myocardial areas in rats with infarction.21 The study suggests myocardial protection through allopurinol, not only in chronic forms of ischaemic heart disease, but also in acute coronary syndromes. In 2010, Rentoukas et al. reported that acute myocardial infarction patients submitted to primary percutaneous angioplasty and treated with a loading dose of 400 mg allopurinol followed by 100 mg daily for one month displayed a more effective ST-elevation recovery and lower peak values of troponin, CK-MB and creatine phosphokinase (CPK), along with a 13% decrease in major adverse cardiac effects at one-month follow up.22 In a recent review, Grimaldi-Bensouda et al. discussed the impact of allopurinol on the risk of myocardial infarction and compared the drug to colchicine. The myocardial infarction OR in the allopurinol group was 0.80, compared to 1.17 in the colchicine group.23 In a critical review, Robert et al. emphasised that the effects

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

of allopurinol on cardiovascular disease are mediated by XO inhibitors via free radicals and inhibition of oxidative stress.24 Gladden et al. studied the effect of allopurinol on systolic and diastolic left ventricular function in rats with volume overload from aorto-caval fistula.25 Allopurinol increased left ventricular (LV) contractility and ejection fraction, but did not alter LV dilation and diastolic pressure/wall stress rate as a measure of diastolic function, despite XO activity being increased in human myocytes with volume overload.25 The aforementioned data may explain why, in the EXACT-HF study in hyperurcaemic heart failure patients, allopurinol failed to improve LV ejection fraction, symptoms, exercise capacity and time to hospitalisation.26 Recently, Valbusa et al. reported an increase in incidence of atrial fibrillation in type 2 diabetes patients with hyperuricaemia (10.5% in 10 years) with an OR of 2.43, but there are insufficient data to confirm that this increase could be prevented by using XO inhibitors. To date, no trial has been conducted to examine the effect of allopurinol on atrial fibrillation.27 Beveridge et al. reported that allopurinol was associated with significant functional improvement in older rehabilitation patients, including those with cardiovascular disease.28 The improvement in functional status was demonstrated using the Barthel score, which was higher in the allopurinol group (4.7 vs 3.6; p = 0.002). These findings could be attributed to the increase in ATP production by allopurinol.29 Sanchis-Gomar analysed post-exercise cardiovascular markers of injury in 12 football players. They found that 300 mg allopurinol before a football game had no significant effect on these markers, except for promedulin levels, which were higher in the placebo than in the allopurinol group. 29 Many controversial issues will be answered through the CARES trial, which aims at studying the effects of allopurinol and febuxostat in patients with gout and cardiovascular co-morbidities.30 This study includes 7 500 patients with gout and cardiovascular disease, followed up for five years. Cardiovascular end-points, composite cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina requiring urgent coronary revascularisation will be taken into consideration.

203

Wu SH, Shu XO, Milne G, et al. Uric acid correlates to oxidation and inflammation in opposite directions in women. Biomarkers 2015; 20(4): 225–231.

Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013; 99(11): 759–766.

Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58(3): 389–462.

Struthers A, Shearer F. Allopurinol: novel indications in cardiovascular disease. Heart 2012; 98(21): 1543–1556.

Sabán-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta González-Quevedo C. Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem 2013; 12(1): 94–99.

Agabiti-Rosei E, Grassi G. Beyond gout: uric acid and cardiovascular diseases. Curr Med Res Opin 2013; 29(Suppl 3): 33–39.

Higgins P, Dawson J, Lees KR, McArthur K, Quinn TJ, Walters MR. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther 2012; 30(4): 217–226.

10. Muir SW, Harrow C, Dawson J, et al. Allopurinol use yields potentially beneficial effects on inflammatory indices in those with recent ischemic stroke: a randomized, double-blind, placebo-controlled trial. Stroke 2008; 39(12): 3303–3307. 11. Ziga N, Becic F. Allopurinol effect on values of lipid profile fractions in hyperuricemic patients diagnosed with metabolic syndrome. Mater Sociomed 2013; 25(3): 167–169. 12. Gavin AD, Struthers AD. Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure. Heart 2005; 91(6): 749–753. 13. Antony R, Dargie HJ. Allopurinol for chronic stable angina: old drug, new tricks? Lancet 2010; 375(9732): 2126–2127. 14. Montalescot G, Sechtem U, Achenbach S, et al., task force members. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34(38): 2949–3003. 15. Stone MH. Allopurinol: A new anti-ischemic role for an old drug. J Am Coll Cardiol 2011; 58(8): 829–830. 16. Rajendra NS, Ireland S, George J, et al. Mechanistic insights into the

Conclusion XO inhibitors have proven efficacy as second-line drugs in patients with chronic stable ischaemic heart disease, and are recommended in this setting by current evidence-based guidelines. In other manifestations of ischaemic heart disease, data are controversial and further investigation is warranted.

therapeutic use of high-dose allopurinol in angina pectoris. J Am Coll Cardiol 2011; 58(8): 820–828. 17. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of highdose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010; 375(9732): 2161–2167. 18. Rekhraj S, Gandy SJ, Szwejkowski BR, et al. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J

Dr M Zdrenghea was supported by a research grant from the Romanian

Am Coll Cardiol 2013; 61(9): 926–932.

National Authority for Scientific Research CNCS – UEFISCDI, project

19. Agarwal V, Hans N, Messerli FH. Effect of allopurinol on blood

number PN-II-ID-PCE 2012-4-0417. Drs D Zdrenghea and D Pop contrib-

pressure: a systematic review and meta-analysis. J Clin Hypertens

uted equally to this work.

(Greenwich) 2013; 15(6): 435–442. 20. George J, Struthers AD. The role of urate and xanthinee oxidase inhibi-

References 1.

Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359(17): 1811–1821.

tors in cardiovascular disease. Cardiovasc Ther 2008; 26(1): 59–64. 21. Xiao J, She Q, Wang Y, Luo K, Yin Y, Hu R, Huang K. Effect of allopurinol on cardiomyocyte apoptosis in rats after myocardial infarction. Eur J Heart Fail 2009; 11(1): 20–27.

Zdrenghea D, Marta D, Constantinescu M, Cucuianu M. Behaviour

22. Rentoukas E, Tsarouhas K, Tsitsimpikou C, et al. The prognostic

of uricemia in hyperlipoproteinemic subjects. Med Interne 1980; 18(4):

impact of allopurinol in patients with acute myocardial infarction

385–390.

undergoing primary percutaneous coronary intervention. Int J Cardiol

204

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

2010; 145(2): 257–258. 23. Grimaldi-Bensouda L, Alpérovitch A, Aubrun E, et al.; the PGRx MI Group. Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis 2015; 74(5): 836–842. 24. Robert AM, Robert L. Xanthine oxido-reductase, free radicals and cardiovascular disease. A critical review. Pathol Oncol Res 2014; 20(1): 1–10. 25. Gladden JD, Zelickson BR, Guichard JL, et al. Xanthine oxidase

AFRICA

Hyperuricemic Heart Failure Patients (EXACT-HF) study. Circulation 2015; 131(20): 1763–1771. 27. Valbusa F, Bertolini L, Bonapace S, et al. Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. Am J Cardiol 2013; 112(4): 499–504. 28. Beveridge LA, Ramage L, McMurdo ME, George J, Witham MD. Allopurinol use is associated with greater functional gains in older rehabilitation patients. Age Ageing 2013; 42(3): 400–404.

inhibition preserves left ventricular systolic but not diastolic function in

29. Sanchis-Gomar F, Bonaguri C, Aloe R, et al. Effects of acute exercise

cardiac volume overload. Am J Physiol Heart Circ Physiol 2013; 305(10):

and xanthinee oxidase inhibition on novel cardiovascular biomarkers.

H1440–1450.

Transl Res 2013; 162(2): 102–109.

26. Givertz MM, Anstrom KJ, Redfield MM, et al.; NHLBI heart failure

30. White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular

clinical research network. Effects of xanthine oxidase inhibition in

safety of febuxostat and allopurinol in patients with gout and cardiovas-

hyperuricemic heart failure patients: the Xanthine Oxidase Inhibition for

cular comorbidities. Am Heart J 2012; 164(1): 14–20.

Heart failure mortality is inversely related to wealth of country Death rates in patients with heart failure is inversely related to the wealth of the country they live in, according to late breaking results from the INTERCHF study, presented recently at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure. Death rates in India and Africa were three to four times higher than those documented in Western countries. ‘Heart failure is a common condition that causes morbidity and mortality worldwide’, said lead author Dr Hisham Dokainish, a principal investigator at the Population Health Research Institute (PHRI), McMaster University, Hamilton, Canada. ‘Most data on heart failure have come from Western countries but the majority of the world’s population lives elsewhere’, he continued. ‘This study was conducted to fill large gaps in knowledge about congestive heart failure in non-Western countries.’ The International Congestive Heart Failure (INTERCHF) study was an observational cohort study that enrolled 5 823 patients with heart failure in 16 countries grouped into six regions: Africa (Mozambique, Nigeria, South Africa, Sudan, Uganda), China, India, the Middle East (Egypt, Qatar, Saudi Arabia), south-east Asia (Malaysia, the Philippines), and South America (Argentina, Chile, Colombia and Ecuador). Data on each patient was collected at baseline, six months and one year, and entered into the electronic data-management system at PHRI. Baseline data included demographics (age, gender), cardiac and non-cardiac factors (previous heart attack or stroke, duration of congestive heart failure, diabetes mellitus, renal failure, chronic obstructive pulmonary disease), medications, socio-economic factors (education level, literacy, employment, urban/rural setting) and heart failure aetiology. At six months and one year, data were collected on the frequency and cause of any hospitalisations in the previous six months. Information was also recorded on death and cause of death. The investigators calculated death rates in each region and adjusted for 20 variables, which included demographic,

clinical, and socio-economic factors, medications and cause of heart failure. The overall all-cause mortality rate for the entire study population was 17%. It was highest in Africa (34%) and India (23%), intermediate in south-east Asia (15%), and lowest in the Middle East (9%), South America (9%) and China (7%). Dr Dokainish said: ‘Mortality in patients with heart failure was inversely related to the wealth of the country. The poorer the country, the higher the mortality rate, and the richer the country, the lower the mortality rate.’ ‘In Western countries the one-year mortality rate for patients with heart failure is 5–10%’, added Dr Dokainish. ‘We’re finding two to three times that death rate in African and Indian patients.’ ‘We were very surprised by the much higher mortality rates’, he continued. ‘You could say maybe the patients in Africa or India were sicker, or didn’t take their medicines, or had poorer heart function, but we adjusted for all of those things and don’t really understand why their death rates were so much higher.’ The researchers hypothesised that variables not measured in the study contributed to the high death rates, such as access to and quality of healthcare, and cardiac biomarkers. These variables will be measured in the next phase of the research programme, the Global Congestive Heart Failure (G-CHF) study, which aims to recruit 25 000 heart failure patients from all inhabited continents and income levels. Genetic analyses will also be conducted in a G-CHF sub-study. Dr Dokainish said: ‘INTERCHF has shown that there are large differences in the risk of heart failure patients dying at one year depending on where they live. We hope to discover why these differences exist through the G-CHF study. If that identifies barriers to receiving care that are due to the way a healthcare system is structured, access to healthcare, or quality of healthcare, then that would need to be addressed.’ Source: European Society of Cardiology Press Office

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Case Report Persistent left superior vena cava Kamil W Tyrak, Jakub Hołda, Mateusz K Hołda, Mateusz Koziej, Katarzyna Piątek, Wiesława KlimekPiotrowska

Abstract Persistent left superior vena cava (PLSVC) is the most common congenital malformation of thoracic venous return and is present in 0.3 to 0.5% of individuals in the general population. This heart specimen was dissected from a 35-yearold male cadaver whose cause of death was determined as non-cardiac. The heart was examined and we found a PLSVC draining into the coronary sinus. The right superior vena cava was present with a small-diameter ostium. An anomalous pulmonary vein pattern was observed; there was a common trunk to the left superior and left inferior pulmonary veins (diameter 17.8 mm) and an additional middle right pulmonary vein (diameter 2.7 mm) with two classic right pulmonary veins. The PLSVC draining into the coronary sinus had led to its enlargement, which could have altered the cardiac haemodynamics by significantly reducing the size of the left atrium and impeding its outflow via the mitral valve. Keywords: coronary sinus, persistent left superior vena cava, right atrium, left atrium Submitted 17/4/16, accepted 15/9/16 Cardiovasc J Afr 2017; 28: e1–e4

The PLSVC usually drains into the right atrium (in 80–92%) through a dilated coronary sinus (CS),5,6 but in approximately 10 to 20% of cases, it is associated with left atrial (LA) drainage.7,8 The PLSVC may drain directly through the left atrium or via the unroofed CS, which is a cause of right-to-left cardiac shunt. The majority of patients with PLSVC are asymptomatic. In general, only patients with unusual drainage and right-to-left shunting are of clinical significance. Anomalous venous return via the PLSVC may be the cause of cardiac arrhythmias, decreased exercise tolerance, progressive fatigue, chest discomfort, palpitations, syncope or cyanosis.6 The implications of existing PLSVC could be important for clinicians who are involved in placement of central venous-access devices.9 Access to the right side of the heart or pulmonary vasculature through the left subclavian vein is much more difficult in patients with PLSVC. Placement of a central line or cardiac resynchronisation therapy leads and pacemaker implantation in undiagnosed cases with PLSVC can result in incorrect positioning.10 In those cases, access to the right heart and coronary sinus should be performed via the right subclavian vein, allowing for an easier route. Also the presence of PLSVC is a relative contraindication to the administration of retrograde cardioplegia during cardiac surgery.6

www.cvja.co.za

DOI: 10.5830/CVJA-2016-084

Persistent left superior vena cava (PLSVC) is the most common congenital malformation of the thoracic venous return and is present in 0.3 to 0.5% of individuals in the general population with a normal heart, and 4.5% in individuals with congenital heart diseases.1 A PLSVC co-occurs with the right superior vena cava in 80 to 90% of cases,2 and may also be accompanied by other heart abnormalities, such as anomalous connections of the pulmonary veins, aortic coarctation, tetralogy of Fallot, transposition of the great vessels as well as dextroversion.1,3,4 Moreover, cardiac rhythm disturbances concerning impulse formation and conduction have been observed.

Case report This heart specimen was dissected from a 35-year-old male cadaver (BMI 29.9 kg/m2) whose cause of death was determined

PLSVC Department of Anatomy, Jagiellonian University Medical College, Cracow, Poland Kamil W Tyrak, kamiltyrak@gmail.com Jakub Hołda Mateusz K Hołda, PhD Mateusz Koziej, MD Katarzyna Piątek Wiesława Klimek-Piotrowska, MD, PhD

GCV

Fig. 1. The persistent left superior vena cava drains into the coronary sinus in this heart specimen. CS, coronary sinus; GCV, great cardiac vein; PLSVC, persistent left superior vena cava.

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 28, No 3, May/June 2017

EuchV

SVC

IVC

AFRICA

PLSVC CSO

LC Fig. 2. V iew of the internal surface of the right atrium. CSO, coronary sinus ostium; EuchV, Eustachian valve; IVC, inferior vena cava.

as non-cardiac during a routine forensic autopsy. The heart weight was 613 g. After a month of fixation in 10% buffered formaldehyde, the heart was examined and it revealed PLSVC drains into the CS (Fig. 1). The mediolateral (ML) and anteroposterior (AP) diameters of the PLSVC, measured 1 cm above its connection with the CS, were 12.2 and 11.5 mm, respectively. The mean thickness of the LSVC was 0.6 mm. Further examination revealed an enormous coronary sinus with a funnel-shaped expansion at the PLSVC orifice. The CS diameter, measured in the middle of the structure, was greatly enlarged (15.85 mm). The CS ostium was also enlarged, measuring 17.2 mm in diameter. The CS ostium valve (Thebesian valve) was absent (Fig. 2). The great cardiac vein had a relatively small ostium (diameter 2.3 mm) and lacked a Vieussens valve (Fig. 3). Other venous valves were also absent within the ostia of the middle cardiac vein and posterior vein of the left ventricle (diameter of veins < 1 mm).

CSO

Fig. 4. View of the posterior and superior wall of the left atrium. CS, coronary sinus; LC, common trunk of the left superior and left inferior pulmonary veins; PLSVC, persistent left superior vena cava; RI, right inferior pulmonary vein; RM, right middle pulmonary vein; RS, right superior pulmonary vein; SVC, superior vena cava.

The small cardiac vein was absent. The length of the CS, as measured from the ostium of the great cardiac vein to the CS orifice, was 43.7 mm. The right superior vena cava was present with a small ostium diameter (ML = 14.3 mm; AP = 14.9 mm). Distortions of the atrial dimensions were noted; reduction in the AP length of the left atrium and enlargement of the right atrium. The dimensions of the atrioventricular rings were also measured; mitral ring (AP = 26.5 mm; ML = 12.4 mm; area = 2.6 cm2) and tricuspid ring (AP = 31.4 mm; ML = 21.6 mm; area = 5.3 cm2). The inferior vena cava ostium diameters were AP = 28.6 mm and ML = 33.8 mm. The Eustachian valve was present (Fig. 2). An anomaly of the pulmonary vein pattern was observed; there was a common trunk of the left superior and left inferior pulmonary veins (diameter 17.8 mm) and an additional middle right pulmonary vein (diameter 2.7 mm) with two classic right pulmonary veins (Fig. 4). The patent foramen ovale was absent and a left-sided septal pouch was observed.11 Fig. 5 shows how measurements were performed.

MCV

PVLV LC

GCV PLSVC

Fig. 3. V iew of the internal surface of the ostia of the coronary sinus and its main tributaries. CSO, coronary sinus ostium; GCV, great cardiac vein; MCV, middle cardiac vein; PLSVC, persistent left superior vena cava; PVLV, posterior vein of the left ventricle.

Fig. 5. Measurements were performed with electronic calipers with 0.01-mm precision.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Discussion During embryogenesis, the sinus venosus consists of the right and left horns. Each receives blood from the common cardinal, vitelline and umbilical veins. During gestation, the left horn, after obliteration of the above veins, evolves into the coronary sinus and oblique vein of the left atrium, while the right becomes incorporated into the right atrium. The right common cardinal vein and the proximal part of the right anterior cardinal vein build the right superior vena cava. The left anterior cardinal vein changes into the internal jugular vein. The presence of the left anterior cardinal vein and obliteration of the left common cardinal vein leads to the formation of the left superior vena cava, which drains into the right atrium through the coronary sinus.12,13 The presence of a PLSVC has a significant influence on the anatomy of the heart and venous system. Although our autopsy study revealed enlargement of the heart chambers, the largest change concerned the CS. We compared the dimensions of the CS and selected heart structures from this case with mean dimensions obtained by measuring nearly 200 structurally normal hearts (23% female; mean age 46.7 ± 19.1 years) without PLSVC in our previous studies.14,15 The diameter of the CS described in this case report (17.17 mm) was the largest of all observed autopsy specimens, almost twice the average of all previous measurements (mean 9.2 ± 2.7 mm). The existence of a common left pulmonary vein trunk may also have been the result of the PLSVC, which limited the free space in the area where the left inferior pulmonary vein should be.16 The PLSVC drains about 20% of the whole venous return,17 and therefore significantly enhanced venous return via the CS forces an increase in its dimensions. Moreover, an increased blood volume flowing into the CS leads to the atrophy of the Vieussens, Thebesian and other heart vein valves. The enlargement of the CS is also often mentioned by other authors as the most characteristic change in the anatomy of the heart. Furthermore, our observed changes were related to the size of the valves; the mitral valve area was substantially reduced (2.6 cm2; mean value 4.2 ± 1.8 cm2), which may have been an outcome of the pressure exerted by an enlarged CS on the left atrium and mitral ring. The tricuspid valve area (5.3 cm2) did not differ significantly compared to the average value of 4.8 ± 1.6 cm2. Venous return via the right superior vena cava was reduced, due to blood draining from the left arm, neck and head via the PLSVC. These haemodynamic effects explain the reduced dimensions of the right superior vena cava; AP = 17.3 mm and ML = 16.5 mm (mean 20.1 ± 3.6 mm and 18.3 ± 3.4 mm, respectively). Also the weight of the heart (613 g) showed an increase in comparison with the average value of 432.7 ± 112.8 g, with no cause of heart enlargement other than the PLSVC. General and specific haemodynamic effects from the presence of the PLSVC vary between cases and depend largely on the coexistence of other heart abnormalities. The presence of a PLSVC influences mainly the blood flow in the atria and cardiac venous system. Patients with PLSVC are mainly asymptomatic or minimally symptomatic. The most common variant of this anomaly is as follows; the PLSVC drains into the right atrium with a right superior vena cava present, which usually does not cause significant haemodynamic changes and clinical consequences. However, if the PLSVC drains into the left atrium, right-to-left cardiac shunt

with desaturation and cyanosis as a consequence, is observed. The latter case often needs surgical intervention.1,18 Other complications resulting from the existence of PLSVC include difficulty in pulmonary artery catheterisation,10 cerebral abscess,19 arrhythmia and thromboembolic events20 or difficulties in left-sided right heart and cardiac venous system catheterisation.21 Enlarged CS (exerting pressure on the atrioventricular node) or absence of the right superior vena cava are common causes of cardiac rhythm disorders. The presence of a huge CS due to a persistent PLSVC can alter cardiac haemodynamics by significant reduction of the left atrium size and impediment of its outflow via the mitral valve, as presented in this case. A PLSVC often coexists with other congenital heart defects, therefore early detection of this anomaly may be very important for the future outcome of the patient.17 Isolated PLSVC without a superior vena cava is very rare (0.1% of the population).22,23 In the majority of known cases, the CS is unroofed, which causes a right-to-left shunt of blood.17 In 10 to 20% of patients, the PLSVC drains into the left atrium, which may be associated with more dangerous haemodynamic complications. It is also worth mentioning that the incidence of defects in foetuses is higher than in the general population. This is due to the double mechanism: anatomical anomalies may cause spontaneous miscarriage, as well as the existence of PLSVC along with other heart defects may lead to premature death.12 Although diagnosis is not very complicated, the anomaly often remains unnoticed, especially when it is clinically inaudible. PLSVC is very often discovered accidentally during invasive cardiac procedures, mostly during routine left-sided right-heart catheterisation, surgical procedures or insertion of a venous central line.21,24 The presence of PLSVC can result in leftsided heart obstruction, which can cause a decrease in heart compliance and as a result, lower stroke volume.25 On chest X-ray, PLSVC can be seen as a widened shadow of the aorta with a visible venous half-moon shadow from the left side of the aortic arch to the middle of the left clavicle. Basic diagnostic methods include transoesophageal and transthoracic echocardiography. Other commonly used methods comprise conventional contrast venography, computed tomography and magnetic resonance venography.17 Prenatal diagnosis is based on echocardiography and mostly reveals an enlargement of the CS.12

Conclusions We present a case in which the PLSVC significantly affected anatomical relationships and dimensions of the heart. The PLSVC draining into the CS led to its enlargement and to atrophy of the Vieussens and Thebesian valves. The huge CS could have altered cardiac haemodynamics with a significant reduction in the size of the left atrium and impediment of its outflow via the mitral valve. Also the drainage of the pulmonary vein into the left atrium may have been affected due to the presence of the PLSVC.

References 1.

Zhong YL, Long X-M, Jiang L-Y, He B-F, Lin H, Luo P, et al. Surgical treatment of dextroversion, isolated persistent left superior vena cava draining into the left atrium. J Card Surg 2015; 30(10): 767–770.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Ruano, CA, Marinho-da-Silva A, Donato P. Congenital thoracic venous anomalies in adults: morphologic MR imaging. Curr Probl Diagn Radiol 2015; 44(4): 337–345.

Kula S, Cevik A, Sanli C, Pektas A, Tunaoglu FS, Oguz AD, et al. Persistent left superior vena cava: experience of a tertiary health-care center. Pediatr Int 2011; 53(6): 1066–1069.

Buirski G, Jordan SC, Joffe HS, Wilde P. Superior vena caval abnormalities: their occurrence rate, associated cardiac abnormalities and angiographic classification in a paediatric population with congenital heart disease. Clin Radiol 1986; 37(2): 131–138.

electrocardiological procedures. Europace 2015; 17(6): 921–927. 15. Klimek-Piotrowska W, Hołda, MK, Koziej M, Piątek K, Hołda, J. Anatomy of the true interatrial septum for transseptal access to the left atrium. Ann Anat, Anatomischer Anzeiger 2016; 205: 60–64. 16. Klimek-Piotrowska W, Hołda, MK, Piątek K, Koziej M, Hołda J. Normal distal pulmonary vein anatomy. Peer J 2016; 4: e1579. 17. Povoski SP, Khabiri H. Persistent left superior vena cava: review of the literature, clinical implications, and relevance of alterations in thoracic central venous anatomy as pertaining to the general principles of central

needs to know. J Vasc Access 2009; 10(3): 207–211.

venous access device placement and venography in cancer patients.

Goyal SK, Punnam SR, Verma G, Ruberg FL. Persistent left superior

World J Surg Oncol 2011; 9: 173. 18. Lenox CC, Zuberbuhler JR, Park SC, Neches WH, Mathews RA,

2008; 6: 50.

Fricker FJ, et al. Absent right superior vena cava with persistent left

Dinasarapu CR, Adiga GU, Malik S. Recurrent cerebral embolism

superior vena cava: implications and management. Am J Cardiol 1980;

venous structures. Am J Med Sci 2010; 340(5): 421–423. Uçar O, Paşaoğlu L, Ciçekçioğlu H, Vural M, Kocaoğlu I, Aydoğdu S. Persistent left superior vena cava with absent right superior vena cava: a case report and review of the literature. Cardiovasc J Afr 2010; 21(3): 164–166. 9.

variations of the coronary sinus valve (Thebesian valve): implications for

Persistent left superior vena cava: what the interventional nephrologist

associated with indwelling catheter in the presence of anomalous neck 8.

Pathol 2002; 11(3): 149–152. 14. Hołda MK, Klimek-Piotrowska W, Koziej M, Mazur M. Anatomical

Granata A, Andrulli S, Fiorini F, Logias F, Figuera M, Mignani R, et al.

vena cava: a case report and review of literature. Cardiovasc Ultrasound 7.

AFRICA

45(1): 117–122. 19. Lee MS, Pande RL, Rao B, Landzberg MJ, Kwong RY. Cerebral abscess due to persistent left superior vena cava draining into the left atrium. Circulation 2011; 124(21): 2362–2364. 20. Sarodia BD, Stoller JK. Persistent left superior vena cava: case report and literature review. Respir Care 2000; 45(4): 411–416.

Povoski SP. A prospective analysis of the cephalic vein cutdown

21. Elison B, Evans D, Zanders T, Jeanmonod R. Persistent left superior

approach for chronic indwelling central venous access in 100 consecutive

vena cava draining into the pulmonary venous system discovered after

cancer patients. Ann Surg Oncol 2000; 7(7): 496–502.

central venous catheter placement. Am J Emerg Med 2014; 32(8): 943.

10. Lai YC, Goh JC, Lim SH, Seah TG. Difficult pulmonary artery catheterization in a patient with persistent left superior vena cava. Anaesth Intensive Care 1998; 26(6): 671–673. 11. Hołda M, Koziej M, Hołda J, Piątek K, Tyrak K, Chołopiak W, et al. Atrial septal pouch – morphological features and clinical considerations. Int J Cardiol 2016; 220: 337–342. 12. Pasquini L, Belmar C, Seale A, Gardiner HM. Prenatal diagnosis of absent right and persistent left superior vena cava. Prenat Diagn 2006; 26(8): 700–702. 13. Miraldi F, di Gioiga CR, Proietti P, De Santis M, d’Amati G, Gallo

e1–3. 22. Erdoğan M, Karakaş P, Uygur F, Meşe B, Yamak B, Bozkir MG. Persistent left superior vena cava: the anatomical and surgical importance. West Indian Med J 2007; 56(1): 72–76. 23. Heye T, Wengenroth M, Schipp A, Dengler JT, Grenacher L, Kauffmann WG. Persistent left superior vena cava with absent right superior vena cava: morphological CT features and clinical implications. Int J Cardiol 2007; 116(3): e103–105. 24. Luckianow G, Cole D, Kaplan L. Anatomical variant found during catheter insertion. J Am Acad Phys Assist 2009; 22(9): 60, 63.

P. Cardinal vein isomerism: an embryological hypothesis to explain a

25. Liu X, He Y, Tian Z, Rychik J. Persistent left superior vena cava

persistent left superior vena cava draining into the roof of the left atrium

connected to the coronary sinus in the fetus: effects on cardiac structure

in the absence of coronary sinus and atrial septal defect. Cardiovasc

and flow dynamics. Pediatr Cardiol 2016; 37(6): 1085–1090.

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

Case Report A rare cause of early repolarisation in an adolescent boy with chest pain: myocardial bridging Murat Deveci, Kadir Babaoğlu, Özlem Kayabey

Abstract Early repolarisation is a common electrocardiographic (ECG) finding characterised by J-point and ST segment elevation ≥ 0.1 mV in two or more adjacent leads. The ECG pattern of early repolarisation is relatively common in asymptomatic subjects. Early repolarisation pattern may be seen in secondary conditions such as hypothermia, autonomic nervous system disturbances, cocaine abuse, hypercalcaemia and myocardial ischaemia. We present a case of an adolescent boy with chest pain and concurrent ST-segment elevation. Early repolarisation pattern was observed in the inferior leads of the ECG with increased troponin levels. He was shown to have myocardial bridging of the left anterior descending artery. The coronary anomaly was not associated with left ventricular hypertrophy. He was asymptomatic and the ECG changes normalised on the third day after admission. The patient was restricted from strenuous exertion and metoprolol was prescribed for prophylaxis. Keywords: myocardial bridging, early repolarisation, chest pain, adolescent Submitted 10/1/16, accepted 16/10/17 Cardiovasc J Afr 2017; 28: e5–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2016-088

Myocardial bridging is characterised by the systolic compression of a major coronary artery segment by the overlying myocardium. Although early reports considered it as a benign condition, it is currently known to be associated with myocardial ischaemia and infarction.1 Early repolarisation is defined as J-point and ST-segment elevation ≥ 0.1 mV in two or more contiguous leads. The ECG pattern of early repolarisation was initially described as a normal variant because of its occurrence in one to 13% of the general population. Athletes, particularly those

participating in competitive sport, have a higher prevalence of early repolarisation. The judgment that early repolarisation was a benign finding devoid of clinical significance changed as studies determined an association between the presence of early repolarisation and an increased risk for arrhythmic death.2-4 We present a patient with chest pain who had ST-segment elevation (STE) and increased troponin levels and was found to have myocardial bridging. Early repolarisation pattern in the inferior leads was thought to result from ischaemia caused by the myocardial bridging, which adds uniqueness to the presentation.

Case report A 17-year-old boy was admitted to the emergency department with burning, exertional chest pain that persisted for two hours. His past medical history was unremarkable. He was a football player in the school team and trained regularly. The patient was not taking any medication and denied the use of illicit substances. No previous chest pain with or without exercise was described. His family history was unremarkable for hyperhomocysteinaemia, familial hyperlipidaemia and sudden death. Haemodynamic parameters and systemic examination on admission were negligible. The initial ECG showed normal sinus rhythm with early repolarisation pattern in the inferior leads (Fig. 1). Blood test values were all within the normal range, except troponin. On hospital admission, his troponin level was increased to 0.42 mg/ml and over two days at eight-hour intervals, his troponin level was undulant (0.42, < 0.01, 0.34,

Division of Paediatric Cardiology, Department of Paediatrics, Kocaeli University School of Medicine, Umuttepe-Kocaeli, Turkey Murat Deveci, MD, devemurat@gmail.com Kadir Babaoğlu, MD Özlem Kayabey, MD

Fig. 1. ECG on admission shows early repolarisation pattern in leads II, aVF.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

AFRICA

Fig. 4. ECG at a baseline exercise-stress test on the seventh day of admission shows no abnormality. Fig. 2. E CG-gated coronary CT angiography of the patient performed with 64-MDCT. A curved multi-planar reformat image shows a 12-mm bridging of the midsegment of the LAD. The arrow indicates the location of myocardial bridging. MDCT, multi-detector computed tomography; LAD, left anterior descending artery.

< 0.01, 0.13, < 0.01 ng/ml, respectively). Echocardiographic examination revealed no obvious heart disease, wall motion abnormalities or pericardial effusion. As the patient’s chest pain was exertional, persistent and angina-like, in conjunction with the ECG findings and troponin levels, coronary artery imaging with multi-detector computed tomography (MDCT) was performed. Coronary myocardial bridging with a length of 12 mm was found in the middle tract of the left anterior descending artery (LAD) (Figs 2, 3). For the assessment of myocardial perfusion, magnetic resonance imaging (MRI) was performed. Reduced perfusion of segments seven and 12, consonant with ischaemia, and weak contrast uptake, consonant with sub-endocardial infarct, were detected. These lesions matched the areas supplied by the bridged segment of the LAD that was defined by MDCT. The chest pain was relieved with aspirin and beta-blocker (metoprolol) therapy after the second day of admission. In the following days, the patient was asymptomatic, the cardiac

Fig. 3. T hree-dimensional volume-rendered image in which the myocardial bridging covers the upper middle segment of the LAD coronary artery. The arrow indicates the location of myocardial bridging.

enzymes were all within the normal range, and the initial ECG changes were attenuated (Fig. 4). A 24-hour Holter monitor demonstrated neither ectopic beats nor tachyarrhythmias. An exercise stress test, based on the Bruce protocol, revealed no ischaemic changes or arrhythmias. The patient was restricted from strenuous exertion. Metoprolol was prescribed and the patient was discharged without any problems. We decided to remove the bridge surgically if he becomes symptomatic despite physical restriction and drug therapy. After the six-month follow up, the patient had no cardiac symptoms and his ECG remained normal.

Discussion Early repolarisation is defined as either a sharp, well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment, or the presence of slurring at the terminal part of the QRS complex. Several population studies have estimated that the prevalence of early repolarisation ranges from five to 13% of persons.5,6 ‘Early repolarisation pattern’ describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias. On the other hand, ‘early repolarisation syndrome’ applies to the patient with both appropriate ECG findings and symptomatic arrhythmias. Large population studies have shown that the presence of early repolarisation in the inferior leads on surface ECG is associated with an increased risk of death from cardiac causes as well as all-cause mortality.2,3 Our patient had early repolarisation pattern in the inferior leads with no documented arrhythmia. Early repolarisation pattern may be seen in secondary conditions such as hypothermia, autonomic nervous system disturbances, cocaine abuse, antidepressant use, hypercalcaemia, neuropsychiatric disturbances, subarachnoid haemorrhage, metabolic diseases and cardiac diseases (acute coronary syndrome, myocardial ischaemia, hyper-vagotony, hypertrophic cardiomyopathy and pericarditis–myocarditis). Numerous benign and less life-threatening diseases such as early repolarisation, acute pericarditis and vasospastic angina can present with chest pain. ST-segment elevation on an electrocardiogram may occur in all these situations and many others, creating a diagnostic dilemma. Originally considered to be a benign entity, recent reports

AFRICA

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 3, May/June 2017

suggest that bridging of the major coronary arteries may produce myocardial ischaemia, coronary thrombosis and myocardial infarction, as well as predispose the patient to atherosclerosis or sudden death.7,8 When symptoms occur in the presence of myocardial bridges, they are ischaemic in nature. The diagnosis of myocardial bridging of the LAD should be realised in patients who have exertional angina and myocardial perfusion defect but no coronary risk factors, especially those who are young, as in the presentation of our patient. The prevalence of bridging has been reported to be around 25% in necropsy studies and around 2% in angiographic studies. Variation at autopsy may in part be attributable to the care taken in preparation and the selection of hearts. A higher prevalence has been observed in patients with hypertrophic cardiomyopathy and recipients of cardiac transplants.1,9,10 Our patient’s echocardiographic examination revealed no hypertrophy. The site, length and severity of bridging and resultant coronary stenosis vary from patient to patient. Myocardial bridges are located at a depth of 1–10 mm with a typical length of 10–30 mm. Our patient had a 12-mm bridging segment of the LAD. For the treatment of angina caused by myocardial bridging, beta-blockers and calcium channel blockers are preferred for negative chronotropic and inotropic effects. We administered metoprolol as a beta-blocker to our patient and he is presently asymptomatic. Surgical therapy is advised for patients with persistent symptoms and proven ischaemic changes, and for those with high risk, such as ventricular arrhythmias, aborted sudden death, or non-fatal myocardial infarction. There are few reports of survival rates but, when studied, five-year survival ranges between 85 and 98%. Our patient was followed up with medical therapy. The early repolarisation pattern is not always identified on routine ECG due to the intermittent nature of early repolarisation. For example, among 542 persons with baseline early repolarisation who underwent repeat ECG examination five years later, early repolarisation (≥ 0.1 mV) was not observed in approximately 20%.2,5 No systematic evaluation has been undertaken reporting the prevalence of concealed early repolarisation in the general population, and the clinical importance, if any, of concealed early repolarisation remains unclear. We believe that early repolarisation pattern in our patient was due to ischaemia caused by myocardial bridging and was not concealed.

Conclusion Differentiating ST-segment elevation caused by acute myocardial infarction from all other aetiologies, especially acute pericarditis– myocarditis, and early repolarisation, can be challenging. In our patient, anginal chest pain was thought to be due to myocardial bridging of the LAD artery, considering the possibility of a systolic narrowing of the coronary artery with subsequent ischaemia. Early repolarisation pattern in the inferior leads was deemed to result from ischaemia caused by myocardial bridging, which is the main point of this case. Ischaemia caused by myocardial bridging should also be considered in the differential diagnosis of early repolarisation in young patients.

References 1.

Angelini P, Velasco JA, Flamm S. Coronary anomalies: incidence, pathophysiology, and clinical relevance. Circulation 2002; 105: 2449–2445.

Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009; 361: 2529–2537.

Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011; 123: 2931–2937.

Rollin A, Maury P, Bongard V, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012; 110: 1302–1308.

Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011; 58: 722–728.

Wu SH, Lin XX, Cheng YJ, Qiang CC, Zhang J. Early repolarization pattern and risk for arrhythmia death: a meta-analysis. J Am Coll Cardiol 2013; 61: 645–650.

Ishikawa Y, Akasaka Y, Suzuki K, et al. Anatomic properties of myocardial bridge predisposing to myocardial infarction. Circulation 2009; 120: 376–383.

Hostiuc S, Curca GC, Dermengiu D, Dermengiu S, Hostiuc M, Rusu MC. Morphological changes associated with hemodynamically significant myocardial bridges in sudden cardiac death. Thorac Cardiovasc Surg 2011; 59: 393–398.

Möhlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridging. Circulation 2002; 106: 2616–2622.

10. Alegria JR, Herrmann J, Holmes DR Jr, Lerman A, Rihal CS. Myocardial bridging. Eur Heart J 2005; 26: 1159–1168.

Be part of the first-ever Global Evidence Summit 13–16 September 2017 Cape Town, South Africa Abstract submission closes on 1 March 2017 The Global Evidence Summit (GES) will be a unique gathering of five international organisations (Cochrane, Guidelines International Network, Campbell Collaboration, International Society for Evidence-based Healthcare and Joanna Briggs Institute) involved in evidence based practice, policy, methodology and advocacy. The theme of the conference is ‘Using evidence. Improving lives’. The GES aims to advance the use of reliable research evidence in addressing some of the world’s most serious health and social challenges. We expect up to 1500 participants to attend this conference. Bursaries and stipends will be available to help people based in developing countries, consumers and students attend the GES. Don’t miss out on this opportunity to exchange ideas with leaders in the field and discuss fresh thinking about how to generate and package evidence for health and society. Find out more at: www.globalevidencesummit.org Email: contact@globalevidencesummit.org Twitter: @GESummit, #GESummit17 Facebook: facebook.com/globalevidencesummit/

S U STA I N E D R E LE ASE META B OLI C A LLY N E U T RA L 1

only generic 1,5 mg sustained release formulation

R36,70

Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.

For more information please visit www.cvja.co.za

AFRICA

S U STA I N E D R E LE ASE META B OLI C A LLY N E U T RA L 1

only generic 1,5 mg sustained release formulation

R36,70

Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.

For more information please visit www.cvja.co.za

AFRICA