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OCTOBER 2012 VOL 23 NO 9

AFRICA www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Cardiotoxicity of plants in South Africa • Right ventricular dysfunction • Doppler indices in aortic coarctation after stenting • Amoxicillin, clindamycin and chlorhexidine in post-extraction bacteraemia • Outcomes in ST-segment depression and ST-segment elevation treated with emergency PCI • Elevated salivary C-reactive protein predicted • Neo-intimal hyperplasia

Cardiovascular Journal of Africa . Vol 23, No 9, October 2012

Printed by Tandem Printers

• Obesity and its health impact in Africa • New ESC guidelines on atrial fibrillation • Renal denervation shows blood pressure reduction


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

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VOL 23, NO 9. OCTOBER 2012

CONTENTS

Cardiovascular Journal of Africa

476

www.cvja.co.za

EditoriaL

Cardiotoxicity of plants in South Africa P van der Bijl (jun) • P van der Bijl (sen)

Cardiovascular Topics

478 Right ventricular dysfunction in a hypertensive population stratified by patterns of left ventricular geometry KM Karaye • H Sai’Du • MN Shehu 483 Doppler echocardiographic indices in aortic coarctation: a comparison of profiles before and after stenting S Hajsadeghi • S-M Fereshtehnejad • M Ojaghi • HA Bassiri • MR Keramati • M Chitsazan • S Gholami 491 A comparative study of amoxicillin, clindamycin and chlorhexidine in the prevention of post-extraction bacteraemia B Maharaj • Y Coovadia • AC Vayej 495

Comparison of outcomes in ST-segment depression and ST-segment elevation myocardial infarction patients treated with emergency PCI: data from a multicentre registry J Knot • P Kala • R Rokyta • J Stasek • B Kuzmanov • O Hlinomaz • J Bělohlavek • F Rohac • R Petr • D Bilkova • S Djambazov • M Grigorov • P Widimsky

501

Elevated salivary C-reactive protein predicted by low cardio-respiratory fitness and being overweight in African children T Naidoo • K Konkol • B Biccard • K Dubose • AJ McKune

490

William Nelson ECG Quiz

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INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors

SUBJECT Editors

Editor-in-Chief (South Africa) PROF AJ BRINK

Nuclear Medicine and Imaging DR MM SATHEKGE

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

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

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

PROF PETER SCHWARTZ Italy (Dysrhythmias)

DR J LAWRENSON Paediatric Heart Disease

Publishing Consultant

PROF H DU T THERON Invasive Cardiology

PROF ERNST VON SCHWARZ USA (Interventional Cardiology) Mike Gibbs


507

Review Articles

Neo-intimal hyperplasia, diabetes and endovascular injury D Kruger

512 Obesity and its health impact in Africa: a systematic review B Adeboye • G Bermano • C Rolland

VOL 23, NO 9. OCTOBER 2012

CONTENTS

522

Drug Trends

European Society of Cardiology congress 2012, Munich, Germany

New ESC guidelines on atrial fibrillation accept reality of next generation of anti-coagulants J Aalbers

524 Renal denervation in Symplicity trials and real-life setting continue to show significant blood pressure reduction in all treatment groups J Aalbers 525 Rivaroxaban in acute coronary syndromes and atrial fibrillation: rivaroxaban shown to reduce cardiovascular deaths in STEMI patients J Aalbers 528 Ivabradine reduces total hospital burden in heart failure J Aalbers 528

GARFIELD: a window on the real-life treatment of atrial fibrillation. South Africa joins the GARFIELD registry J Aalbers

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

e1 Acute anterior myocardial infarction in an 85-year-old male patient, complicated by the deadly duo: ventricular septal rupture and pseudoaneurysm AC Aykan • R Zehir • CY Karabay • S Cakal • N Poci • K Sönmez e4

Giant pseudoaneurysm of the left axillary artery following a stab wound M Fokou • VC Eyenga • A Chichom Mefire • ML Guifo • JJ Pagbe • W Sandmann

e7 Acute ST-elevation inferior myocardial infarction in a patient with a non-obstructive mechanical mitral valve thrombosis AC Aykan • M Özkan • NE Duran • M Yildiz e9 Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning HA Cakmak • S Altay • GC Boz • S Koca • Y Velibey

managing editor

julia aalbers Tel: 021 976 4378 Fax: 086 610 3395 e-mail: julia@clinicscardive.com

Production Editor

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

Editorial Assistant & Circulation ELSABÉ BURMEISTER Tel: 021 976 8129 e-mail: elsabe@clinicscardive.com

development editor

GLENDA HARDY Cell: 071 8196 425 e-mail: glenda@clinicscardive.com

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WENDY WEGENER Tel: 021 976-4378 e-mail: wendy@clinicscardive.com

GAUTENG CONTRIBUTOR

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CONTENT MANAGER

Copyright: Clinics Cardive Publishing (Pty) Ltd. Layout: Martingraphix Printer: Durbanville Commercial Printers ONLINE SERVICES: Design Connection All submissions to CVJA are to be made online via www.cvja.co.za

Michael Meadon (Design Connection) Tel: 021 975 3785 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

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

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.

Tel/Fax: 021 976 8129 Int.: +27 21 976 8129

Postal address: PO Box 1013, Durbanville, 7551

e-mail: info@clinicscardive.com

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


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The Cardiovascular Journal of Africa will be publishing the conference proceedings and abstracts of the 6th World Congress of Paediatric Cardiology and Cardiac Surgery in the February issue of the journal. To register for our e-alert system, visit our website on www.cvja.co.za For further information on our events, including conference promotions, contact wendy@clinicscardive.com

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Professor Andries Jacob Brink, FRCP (London), FACC (USA), Dr Sc Med, Stellenbosch

29 August 1923 – 17 October 2012 It is with great regret that we announce the death of our editorin-chief, Prof Andries Brink, former dean of the Medical Faculty and head of Cardiology at Tygerberg Hospital, University of Stellenbosch, and previously the president of the South African Medical Research Council. Prof Brink was among the modern pioneers who brought South African cardiology to the attention of the medical community worldwide. He achieved this through his original research, and later in his career, by creating opportunities for others to conduct research, which enhanced patient care throughout our continent. In South Africa, he was a founder of the Faculty of Medicine, University of Stellenbosch, first president of the South African Medical Research Council and a driving force in establishing the South African Heart Foundation. He also contributed significantly to the development and subsequent success of more than 25 organisations, including the South African Medical and Dental Council, the South African Council for Scientific Research (CSIR), the Prime Minister’s Scientific Advisory Council and the Council of the University of Stellenbosch. Prof Brink’s many achievements were recognised by academic institutions, professional organisations and societies. These honours included an honorary doctorate from the University of Stellenbosch, the Havenga prize from the Suid

Afrikaanse Akademie vir Wetenskap en Kuns, the Claude Leon Harris merit award, the South African Decoration for Meritorious Service and the Wellcome Trust gold medal. Throughout his career, Prof Brink was a prolific author of many widely cited scientific articles. Additionally, he was a passionate believer in the academic development of Afrikaans as a modern medical language. After more than two decades of intense work, this resulted in the publication with co-workers of the authoritative Woordeboek van Afrikaanse Geneeskundeterme, which at last provided healthcare professionals and patients with the comprehensive medical terminology now used throughout South Africa. More recently Prof Brink dedicated himself to bringing cardiology in Africa to a global audience. As always he led from the front. In 1990, he founded the Cardiovascular Journal of South Africa, which he was determined from the outset should be ‘world class’. As a result of the standards he set, the Journal achieved full Medline recognition within 10 years. Then, as South Africa became a member of the African cardiology community, Prof Brink, with the support of the Pan-African Society for Cardiology, opened this Journal to the African continent, providing another unique contribution to the development of medical education in Africa. For nearly seven decades, Prof Brink’s tireless energy, dedication to scientific excellence and innovative spirit inspired generations of cardiologists. We will always be immensely proud of this Journal as one of the unique achievements of a remarkable man. The editors and editorial team

Editorial Cardiotoxicity of plants in South Africa PIETER VAN DER BIJL (jun), PIETER VAN DER BIJL (sen) The floral kingdom of southern Africa comprises well over 30 000 species of higher plants, many of which have the potential to be toxic to animals and humans.1,2 Livestock losses due to poisoning by plants have been significant over the years and have prompted extensive research efforts. Although there is a considerable body of information in the veterinary field, there is a paucity of published data on human poisoning in South Africa.3 While poisoning in livestock and humans is mainly accidental (e.g. confusing toxic with edible species, contamination of foodstuffs, for example by mycotoxins and other toxin-elaborating organisms, or perhaps overwhelmingly by medicinal use of plants in traditional medical practice), it may be deliberate. The medicinal benefits of plants were recognised by the Egyptians and Romans who used an extract of Urginea maritima

as diuretic, cardiotonic, expectorant and emetic.4 Furthermore, the medicinal value of Digitalis purpurea (foxglove, which contains cardiac glycosides) was reported by William Withering in 1785 after observing that patients with dropsy (cardiac failure) could be treated by using an extract from this plant.5 The use of plant-derived materials is widespread in the practice of traditional medicine in South Africa. It has been estimated that approximately 80% of the South African population consult traditional healers regularly.6 Traditional medicines (muti) are usually administered orally or as an enema by traditional healers. Laboratory analyses of muti have shown that these medicines often consist of aqueous plant materials, such as roots, bark stem or leaves, sometimes mixed with metallic salts, mushrooms and insects.5 Plant components are sometimes pulverised or sliced


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into small pieces, making botanical identification difficult or impossible. Plants known to be toxic contain chemical constituents that can affect a wide range of organ systems; these have been documented in a number of publications. As far as the cardiovascular system is concerned, cardiac glycoside-containing plants are important in both lethal livestock and human poisonings.3,7 The cardiac glycosides, which are highly toxic and found in a number of plants, are usually phytochemicals consisting of an aglycone (structurally related to steroid hormones) linked to one or more sugar molecules. The aglycones of cardiac glycosides can be divided into two chemical groups, the cardenolides and bufadienolides. The primary pharmacological effect of these cardiac glycosides is to inhibit the Na+/K+ ATPase exchanger, which increases intracellular Na+ concentration, thus reducing the Na+ gradient across the membrane and decreasing the amount of Ca2+ pumped out of the cell by the Na+/Ca2+ exchanger during diastole. Consequently, the intracellular Ca2+ concentration rises, thereby occasioning positive inotropy. Cardiac glycosides have very narrow therapeutic indices and acute toxicity is most commonly associated with ingestion of plant material, although chronic toxicity may also sometimes be seen. In cases of acute intoxication, nausea, emesis and abdominal pain typically occur, as well as central nervous system effects including lethargy and weakness. Cardiac effects may manifest as nearly any type of dysrhythmia, and sudden death with few premonitory signs may occur. Prominent among the garden-variety cardiac glycosidecontaining plants is Nerium oleander (oleander, selonsroos), which contains two cardenolides (oleandroside and neriin) characterised as potent cardiotoxins. Thevetia peruviana and Thevetia thevetioides (yellow oleander) contain thevetin, a potent toxic cardenolide that is widespread throughout the plant, but particularly concentrated in the fruits. Toxicity is retained when oleander is dried, and the plant material is very poisonous for both animals and humans. Ingestion of a single leaf by a child can be lethal. It is significant that the high toxicity of the plant is reflected in one of its colloquial names, the ‘Be-still tree’, and its fruit is referred to as the ‘Be-still nut’. Other well-known cardiac glycoside-containing plants, such as Digitalis purpurea (foxglove), contain the cardenolide digoxin that is used therapeutically in the treatment of cardiac failure and supraventricular tachycardias. Its use in modern cardiology is currently limited, primarily because of its toxicity, narrow therapeutic index and the availability of superior treatment modalities. Acokanthera oppositifolia (bushman poison bush, boesmansgif) sap contains cardenolides and has been used by the San people for applying to the tips of their hunting arrows. It is also used for treating headaches, snakebite, toothache, colds, anthrax and tapeworm infestation.2 The cardiotoxic bufadienolides present in Drimia sanguinea (sekanama, slangkop) and Bowiea volubilis (climbing potato, knolklimop) species have also been implicated in human poisoning.2 These plants are used by traditional healers as ‘blood purifiers’ and for treating a variety of conditions, such as headaches, oedema, infertility and bladder complaints. It may be challenging to establish the diagnosis of plant poisoning in patients. It primarily relies on a history of ingestion

477

of cardiotoxic plant material and/or suspicion generated by cardiac dysrhythmias. However, obtaining a history may be difficult as the constituents of many traditional medicines are often tightly guarded secrets not shared with patients or third parties. Laboratory analyses for cardiac glycosides are available, and an immunoassay developed for the detection of digoxin also potentially cross-reacts with other cardiac glycosides, such as oleandrin. However, more specific tissue and biological fluid assays for oleandrin have been developed.8 Of further interest has been the roles of other African plant materials which have been claimed to produce antihypertensive as well as negative inotropic and chronotropic effects.9-11 While some of the claims made for these plant materials can be supported by animal studies, more rigorous preclinical, clinical and toxicity (including cardiotoxicity) studies will have to be undertaken. Management of plant-intoxicated patients includes immediate discontinuation of further exposure to the toxic plant materials, administration of activated charcoal and gastric lavage (caveat: within one hour of ingestion) and monitoring for dysrhythmias. Digoxin-specific antibody fragments appear to cross-react with at least some other cardiac glycosides, and therefore have a potential application in the treatment of poisoning in humans with the latter phytochemicals.8 If dysrhythmias are present, appropriate intervention and general supportive measures should be instituted. However, the mainstays of protection against the potentially toxic effects of plant materials remain in the educational realm and the prevention of ingestion. PIETER VAN DER BIJL (jun), pieter.vanderbijl@gmail.com Division of Cardiology, Department of Medicine, Faculty of Health Sciences, Stellenbosch University and Tygerberg Academic Hospital PIETER VAN DER BIJL (sen), pietervanderbijlcpt@gmail.com Emeritas professor, Department of Pharmacology, Faculty of Health Sciences, Stellenbosch University

References 1. Watt JM, Breijer-Brandwijk. Medicinal and Poisonous Plants of Southern and Eastern Africa. 2nd edn. Edinburgh: E&S Livingstone, 1962. 2. Van Wyk B, van Oudtshoorn B, Gericke N. Medicinal Plants of South Africa. Pretoria: Briza Publications, 2000. 3. Botha CJ, Penrith M-L. Poisonous plants of veterinary and human importance in southern Africa. J Ethnopharmacol 2008; 119: 549–558. 4. Naudé TW. The occurrence and significance of South African cardiac glycosides. J S Afr Biol Soc 1977; 18: 7–20. 5. McVann A, Havlik I, Joubert PH, Monteagudo FSE. Cardiac glycoside poisoning involved in deaths from traditional medicines. S Afr Med J 1992; 81: 139–141. 6. Mugabo P, Khan F, Burger A. Effects of Leonotis leonuris aqueous extract on the isolated perfused rat heart. Int J Med Arom Plants 2012; 2: 281–292. 7. Snyman LD, Schulz RA, van den Berg H. Variability of yellow tulp (Moraea pallida Bak.) toxicity. J S Afr Vet Ass 2011; 82: 131–132. 8. Poppenga RH. In: Andreas Luch, ed. Poisonous Plants: Molecular, Clinical and Environmental Toxicology, Vol. 2: Clinical Toxicology. Basel: Birkhäuser Verlag AG, 2010. 9. Ojewole JAO, Musabayane CT. Therapeutic claims of African potato: fact or fiction? Cardiovasc J South Afr 2006; 17: 225–226. 10. Ojewole JAO, Ojewole SO. Hypoglycaemic and hypotensive effects of Globimetula cupilata (DC) Van Tieghem (Loranthaceae) aqueous leaf extract in rats. Cardiovasc J South Afr 2007; 18: 9–15. 11. Ojewole JAO. Hypoglycaemic and hypotensive effects of Harpephyllum caffrum Bernh ex CF Krauss (Anacardiaceae) stem-bark aqueous extract in rats. Cardiovasc J South Afr 2007; 18: 67–72.


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Cardiovascular Topics Right ventricular dysfunction in a hypertensive population stratified by patterns of left ventricular geometry KAMILU M KARAYE, HADIZA SAI’DU, MOHAMMED N SHEHU

Introduction: The aim of this study was to assess the prevalence, determinants and correlates of right ventricular (RV) systolic and diastolic dysfunction (RVSD and RVDD, respectively) in hypertensives, stratified by left ventricular (LV) geometric patterns. Methods: The study was carried out in Aminu Kano Teaching Hospital in Kano, Nigeria, and was cross-sectional in design. Hypertensive subjects referred for echocardiography were consecutively recruited after satisfying the inclusion criteria. RVSD was defined as either tricuspid annular plane systolic excursion (TAPSE) of < 16 mm, or peak velocity of the systolic wave (Sm) in tissue Doppler imaging (TDI) of the RV lateral tricuspid annulus of < 10 cm/s, or both. RVDD was defined as the ratio of < 1.0 of the peak velocities of the early (Em) to late (Am) diastolic waves in the TDI of the RV lateral tricuspid annulus. Subjects with normal LV geometry (NG) served as controls, and were compared with those who had eccentric (EH) or concentric (CH) LV hypertrophy or concentric LV remodelling. Results: A total of 128 subjects were recruited. Overall, the prevalence of RVDD almost doubled that of RVSD in the studied subjects (61.72 vs 32.03%, respectively). Subjects with EH had the highest prevalence of RVSD (52.63%), while those with CH had the lowest prevalence (20.69%) (p < 0.01). By contrast, the prevalence of RVDD was high across the four groups without significant statistical difference; as high as 68.52% in subjects with NG and as low as 42.86% in those with CR. LVEF was the only independent determinant of RVSD after controlling for confounding variables, while age was the only determinant of RVDD. Likewise, age was the only correlate for Em:Am ratio, while the best correlate for both TAPSE and Sm was LVEF. Conclusion: The study has revealed that about two-thirds of the hypertensives had RVDD while about one-third had RVSD. Subjects with EH had the highest prevalence of

Department of Medicine, Bayero University, Kano, Nigeria KAMILU M KARAYE, MBBS, DIC, MSc, FWACP, kkaraye@yahoo.co.uk

Aminu Kano Teaching Hospital, Kano, Nigeria KAMILU M KARAYE, MBBS, DIC, MSc, FWACP HADIZA SAI’DU, MBBS, FWACP MOHAMMED N SHEHU, MBBS, FWACP

RVSD, while RVDD was common across all the groups. LVEF and age were the only independent determinants of RVSD and RVDD, respectively. Keywords: hypertension, RV dysfunction, LV geometry, Nigeria Submitted 16/10/11, accepted 24/2/12 Published online 2/5/12 Cardiovasc J Afr 2012; 23: 478–482

www.cvja.co.za

DOI: 10.5830/CVJA-2012-014

Right ventricular (RV) systolic and diastolic functions have repeatedly been studied in hypertensive subjects.1,2 Abnormal RV function has been found to be an independent, poor prognostic factor in subjects with heart failure (HF) of various aetiologies, including hypertension, and is associated with increased morbidity and mortality.3 Meluzin et al.3 assessed the prognostic power of RV systolic and diastolic functional parameters derived from Doppler tissue imaging (DTI) of tricuspid annular motion, and whether their combination might improve the risk stratification of patients with heart failure. They found that the combination of RV systolic and diastolic functional parameters represents a very powerful tool for risk stratification of patients with symptomatic heart failure.3 Abnormal LV geometry is also common in hypertensive subjects.4 Consideration of the level of LV mass and the LV wall thickness/chamber radius ratio [relative wall thickness

Relative wall thickness ≤ 0.42 > 0.42

Abstract

Concentric remodelling

Concentric hypertrophy

Normal geomety

Eccentric hypertrophy

< 125 g/m2

≥ 125 g/m2

LV mass index

Fig. 1. Determination of LV geometric patterns in subjects with hypertension.


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(RWT)] has identified four different geometric patterns of LV adaptation to hypertension.5 These are concentric LV hypertrophy (CH) (increased mass and relative wall thickness), eccentric hypertrophy (EH) (increased mass, normal relative wall thickness), concentric remodelling (CR) (increased relative wall thickness with normal mass) and normal LV geometry (NR) (see Fig. 1).5 Concentric hypertrophy is associated with especially high arterial pressure while eccentric hypertrophy is associated with obesity and elevated volume load.5 A long-term follow-up study has revealed that those with CH had the highest rates of all-cause mortality and cardiovascular morbid events, while patients with EH or CR had rates of morbidity that fell between those of patients with CH and the low-risk group with normal LV geometry.6 Although studies have shown that assessing the right and left ventricles are important in prognostication, and that hypertensive LV geometric patterns are different from each other in several respects, as mentioned above,1-6 it has not previously been well described whether RV function in subjects with the various LV geometric patterns are also different. The aims of the present study were therefore to assess the prevalence, determinants and correlates of RV systolic and diastolic dysfunction (RVSD and RVDD, respectively) in a hypertensive population, grouped according to the various LV geometric patterns. It is hoped that this information would further characterise the structure and function of both the right and left ventricles in hypertensive subjects.

Methods The study was carried out in the echocardiography laboratory of Aminu Kano Teaching Hospital in Kano, north-western Nigeria. The Research Ethics Committee of the Hospital reviewed and approved the study protocol, which conformed to the ethical guidelines of the Declaration of Helsinki, on the principles for medical research involving human subjects.7 The study was cross-sectional in design. Hypertensive subjects referred for echocardiography to Aminu Kano Teaching Hospital, Kano, Nigeria, were recruited consecutively from October 2009 to April 2010, after obtaining informed consent. Minimum sample size was estimated at 94 subjects using a validated formula,8 applying a prevalence of hypertensive heart disease (HHD) in Kano of 56.7% (among patients referred for echocardiography),9 and a sample error of 10%. Transthoracic echocardiography was performed by the authors using the Aloka Cardiac Ultrasound System (model SSD 4000 PHD), and the procedures were carried out according to the recommendations of the American Society of Echocardiography.10 Left ventricular ejection fraction (LVEF) was calculated using Teicholz’s M-mode formula while LV mass index (LVMI) was calculated using Devereux’s formula.11,12 Patients were examined in the left lateral decubitus position. Tricuspid annular plane systolic excursion (TAPSE) was recorded from the apical four-chamber view with the M-mode cursor positioned at the free-wall angle of the tricuspid valve annulus.13 Right ventricular long-axis excursion amplitude (i.e. TAPSE) was taken from end-systole to end-diastole.13 Tracings for TAPSE and TDI of the RV lateral tricuspid annulus were obtained from the apical approach during held end-expiration. Care was taken to align M-mode or TDI beam along the direction of tricuspid annulus motion. TDI sample volume was positioned 10 mm from the insertion site of the tricuspid leaflets or 10

479

mm away within the right ventricle lateral wall and adjusted to cover the longitudinal excursion of the tricuspid annulus in both systole and diastole.14 All the recruited subjects were hypertensive on treatment and in sinus rhythm. Subjects with other conditions that could cause LV hypertrophy (LVH) or myocardial disease, such as ischemic heart disease (IHD), valvular heart disease and cor pulmonale were all excluded. IHD was defined by the presence of any of the following: history of angina or IHD, electrocardiographic changes suggestive of myocardial infarction, and regional wall motion abnormalities on echocardiography. None of the subjects had a history of any form of cardiac surgery. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg, according to standard recommendations by the World Health Organisation.15 Hypertensive LV geometric patterns were defined as above and illustrated in Fig. 1.5 RWT was calculated using the following formula: RWT =

2 (LV posterior wall thickness at end-diastole) (in mm) 2 . LV end-diastolic dimension (in mm)

Normal RWT was defined as values ≤ 0.42, and was increased if RWT was > 0.42. Increased LV mass index (LVMI) was defined as values > 125 g/m2 for all subjects.5 Proximal RV outflow tract dimension at end-diastole (RVOTd) was used as the measure for right ventricle size.13,16 RVSD was defined as either TAPSE of < 16 mm, or peak velocity of < 10cm/s of the systolic wave (Sm) in tissue Doppler imaging (TDI) of the RV lateral tricuspid annulus, or both.17 RVDD was defined as the ratio of < 1.0 of peak velocities of the early (Em) to late (Am) diastolic waves in the TDI of the RV lateral tricuspid annulus, which was reported to represent global RV diastolic function.2 Pulmonary artery systolic pressure (PASP) was estimated using continuous-wave Doppler echocardiography, which was used to measure the maximum velocity of the tricuspid regurgitant jet (v), with which the trans-tricuspid pressure gradient was calculated using the modified Bernoulli equation (4v2).18 RV systolic pressure (RVSP) was then estimated by adding the transtricuspid pressure gradient to the right atrial pressure (RAP).18 RVSP was then equated to the PASP, given that pulmonary valve stenosis was excluded.18 RAP was then estimated using the diameter and collapse of the inferior vena cava (IVC) during spontaneous respiration, as previously described.19 Subjects in the NG group were used as controls to compare with the others who had abnormal LV geometric patterns. Data were analysed with SPSS version 16.0. Means and standard deviations were computed and presented for quantitative variables. Student’s t-test, Fisher’s exact and Chi-square (χ2) tests were used for comparison between groups, as appropriate. Univariate regression and binary logistic regression models, and Pearson’s correlation (r) coefficient were used to analyse the associations between indices for RVSD and RVDD and a number of variables. Results for regression models were expressed in odds ratios (OR) and 95% confidence intervals (95% CI). A p-value < 0.05 was regarded as significant.

Results A total of 128 subjects were serially recruited, and the results for RV function and clinical characteristics are presented in Table 1.


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There were more females (69; 53.9%) than males (59; 46.1%) in the series. The mean age of all subjects was 51.04 ± 14.24 years, while the mean SBP was 154.91 ± 32.39 mmHg and mean DBP was 94.89 ± 18.51 mmHg. Overall, the prevalence of RVDD almost doubled that of RVSD in the studied subjects (61.72 vs 32.03%, respectively). The majority of subjects (54; 42.2%) had NG, while 38 of them (29.7%) had EH, 29 (22.7%) had CH, and seven (5.5%) had CR. Subjects with EH had the highest prevalence of RVSD, the largest cardiac chambers, lowest mean blood pressures, and highest mean LVMI and PASP. The prevalence of RVDD was high across the groups, but the differences between them were not statistically significant (p > 0.05). The pattern of antihypertensive prescriptions is presented in Table 2, and was similar across the groups (p ≥ 0.05). Overall, only 38 subjects (29.7%) had controlled systolic (< 140 mmHg) and diastolic (< 90 mmHg) blood pressures at the time of recruitment into the study, and blood pressure was controlled in the majority of subjects with EH (55.3%). Univariate regression analyses were carried out to test for variables associated with RVSD or RVDD. Age was found to be the only variable that was associated with RVDD, with an OR of 1.032, 95% CI of 1.004–1.060, and p-value of 0.023. Several variables were found to be significantly (p < 0.05) associated with RVSD in univariate analyses. These variables were left atrial dimension, LV end-diastolic dimension (LVEDD) and volume (LVEDV), LV end-systolic dimension (LVESD) and volume (LVESV), LVEF and PASP. However, LVEF was the

only variable that was independently associated with RVSD after controlling for the confounding factors (OR = 0.943; 95% CI = 0.897–0.993; p = 0.025). The correlates for the indices of RVSD and RVDD are presented in Table 3. The only correlate for the Em:Am ratio was age (r = –0.237, p = 0.016), while several variables were found to correlate with both TAPSE and Sm. In univariate analyses, the main determinants of having NG in the present series were higher BMI and LVEF, and reduced RVOTd, left atrial diameter, LVEDD, LVESD and PASP (p < 0.01 for each). However, BMI (OR = 2.011; 95% CI = 1.100–3.679; p = 0.023) and LVEF (OR = 1.273; 95% CI = 1.042–1.555; p = 0.018) were the only determinants of NG that maintained their significance after controlling for other factors.

Discussion This study describes the pattern of RVSD and RVDD in a hypertensive population grouped by LV geometric patterns. The TABLE 2. PATTERN OF ANTIHYPERTENSIVE PRESCRIPTIONS AMONG ALL SUBJECTS Type of antihypertensive

EH 38 (29.7)

CH 29 (22.7)

CR 7 (5.5)

NG 54 (42.2)

CCB

8 (21.1)

5 (17.2)

3 (42.9)

8 (14.8)

Thiazides

7 (18.4)

7 (24.1)

2 (28.6)

12 (22.2)

ACEI/ARB

5 (13.2)

4 (13.8)

0

4 (7.4)

Combinations/others

18 (47.4)

13 (44.8)

2 (28.6)

30 (55.6)

CCB, calcium channel blockers; ACEI, angiotensin converting enzyme inhibitors, ARB, angiotensin II receptor blockers. All values are expressed as numbers with percentages in parentheses.

TABLE 1. PATTERN OF RV DYSFUNCTION AND CHARACTERISTICS OF SUBJECTS GROUPED ACCORDING TO LV GEOMETRIC PATTERNS CH (n = 29)

EH (n = 38)

CR (n = 7)

NG (n = 54)

RVSD

6 (20.69)

20 (52.63)**

3 (42.86)

12 (22.22)

RVDD

16 (55.17)

23 (60.53)

3 (42.86)

37 (68.52)

Characteristics

TAPSE (mm)

19.35 ± 4.33

17.12 ± 4.92**

19.52 ± 4.47

20.48 ± 5.00

Sm (cm/s)

15.21 ± 4.63

12.61 ± 5.31**

15.28 ± 5.95

16.30 ± 5.56

Em:Am

0.92 ± 0.52

0.95 ± 0.59

1.11 ± 0.94

0.99 ± 0.64

RVOTd (mm)

28.62 ± 7.34

29.47 ± 5.83**

28.17 ± 3.60

26.08 ± 4.21

19/10**

21/17*

2/5

17/37

Age (years)

49.97 ± 13.34

52.95 ± 15.20

59.67 ± 22.21

49.35 ± 12.90 30.14 ± 6.88

M/F BMI (kg/m )

25.01 ± 3.88**

25.18 ± 4.15**

22.22 ± 3.77*

SBP (mmHg)

173.57 ± 35.00

136.31 ± 26.48

160.35 ± 21.05 153.56 ± 28.11

DBP (mmHg)

102.14 ± 21.19

83.08 ± 14.37*

100.62 ± 18.23 97.50 ± 16.11

Heart rate/min

2

89.55 ± 35.80

93.50 ± 14.36

82.82 ± 18.69

85.12 ± 16.96

Smoking

2 (6.9)

2 (5.3)

0

4 (7.4)

LA (mm)

39.90 ± 7.64**

42.03 ± 7.24**

40.14 ± 6.87*

34.33 ± 6.07

LVEDD (mm)

50.93 ± 4.78**

64.95 ± 8.87**

46.71 ± 13.46

46.85 ± 5.74

LVEF (%)

53.13 ± 14.55** 32.99 ± 15.76** 54.00 ± 17.61* 65.36 ± 10.10

MV E:A

1.54 ± 1.72

1.85 ± 1.56

PASP (mmHg) 34.59 ± 22.18** 47.47 ± 33.02** LVMI (g/m2)

0.68 ± 0.26

1.17 ± 1.02

22.93 ± 16.23

22.80 ± 14.43

189.03 ± 4015** 192.16 ± 57.47** 114.57 ± 8.40** 83.91 ± 22.52

M/F, male/female; BMI, body mass index; SBP and DBP, systolic and diastolic blood pressures, respectively; LA, left atrium; LVEDD, LV end-diastolic dimension; LVEF, left ventricular ejection fraction; MV, mitral valve; E:A, ratio of early to late peak filling velocities; PASP, pulmonary artery systolic pressure; LVMI, LV mass index; RVOTd, RV outflow tract proximal dimension at end-diastole. *p-value statistically significant at < 0.05 level, for comparisons between subjects with NG and others. **p-value statistically significant at < 0.01 level, for comparisons between subjects with NG and others. All values are expressed as means ± standard deviations, or as numbers with percentages in parentheses.

TABLE 3. CORRELATES OF INDICES OF RVSD AND RVDD IN ALL SUBJECTS Variables

TAPSE (mm)

Sm (cm/s)

Em:Am

–0.089

< 0.081

–0.237

0.351

0.398

< 0.152

< 0.081

+0.000

0.183

0.487

0.999

–0.126

–0.166

< 0.320

0.204

0.103

0.746

–0.230

–0.299

< 0.320

Age (years) r p-value

0.016*

BMI (kg/m2) r p-value RVOTd (mm) r p-value LVEDD (mm) r p-value

0.014*

0.001*

0.746

LVEF (%) r

< 0.410

< 0.360

–0.064

p-value

< 0.001*

< 0.001*

0.519

–0.189

–0.146

–0.070

0.122

0.478

< 0.005

–0.173

< 0.064

0.957

0.073

0.521

r

–0.353

–0.190

< 0.147

p-value

< 0.001*

0.059

0.152

LVMI(g/m2) r p-value

0.045*

MV E:A ratio r p-value PASP (mmHg)

All values are expressed as means ± standard deviations or as numbers with percentages in parentheses; *p-value is statistically significant.


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overall prevalence of RVDD was higher than that of RVSD, and the highest prevalence of the latter was recorded in subjects with EH, while prevalence of RVDD was high across the groups. The study has also described the determinants and correlates of RVSD and RVDD. Several studies have previously reported that RV disease develops in parallel with a similar process on the left side among hypertensive patients,1,2 likely as a result of ventricular interdependence. Ventricular interdependence is defined as the forces that are transmitted directly from one ventricle to the other through the myocardium and pericardium, independent of neural, humoral or circulatory effects. It is a consequence of the close anatomical association between the ventricles: the ventricles are encircled by common muscle fibres, share a septal wall, and are enclosed within the pericardium.20 In agreement with this hypothesis, LVEF, the index for LV systolic function, was the only independent determinant of RVSD. In addition, the present study also recorded the highest prevalence of RVSD among subjects with EH who had the lowest mean LVEF and the worst LV systolic function, while the lowest prevalence of RVSD was recorded among those with NG, who correspondingly had the highest mean LVEF. The prevalence of RVSD in the present study (32.03%), determined using both TAPSE and Sm, was only slightly higher than what we reported previously (29.06%) using TAPSE alone.1 This suggests that the inclusion of Sm in the determination of RVSD contributes very little over that of using TAPSE alone. This finding therefore supports the use of TAPSE alone to determine RVSD in hypertensive subjects. The prevalence of RVSD in the present study was lower than what was reported by Puwanant et al. (58%) among hypertensive subjects using reduced TAPSE (< 15 mm) alone, perhaps because 51% of the patients in their series had coronary artery disease, 37% had diabetes mellitus and 32.5% had cardiomyopathies.21 In addition, the patients in the latter study were older than ours (mean age 72 ± 14 vs 51 ± 14 years), and we have previously shown that older age is significantly associated with reduced TAPSE.1 Furthermore, differences in the aetiology of heart disease in the two studies could have amplified the disparities in RVSD.21 The prevalence of RVDD was high across the LV geometric groups, without significant statistical differences. Therefore, the pattern of RVDD in the studied population was not similar to that of RVSD. In the present study, subjects with NG, who had a mean mitral filling E:A ratio of 1.17 and the lowest mean age and RVOTd, turned out to have (albeit non-significantly) the highest prevalence of RVDD. We found that age was the only determinant of RVDD (p = 0.023), and correlated significantly and negatively with the lateral tricuspid annular Em:Am ratio; the index of RVDD (r = –0.237; p = 0.016). The relatively lower mean age of patients with NG could therefore have influenced the observed high prevalence of RVDD in them, in view of the negative correlation between age and the Em:Am ratio. Innelli et al. recently reported that the Em:Am ratio consistently and progressively decreased with age in an apparently healthy population, from 1.9 ± 0.8 in the 10–19-year-olds to 0.95 ± 0.3 in 50–59-year-old age group.22 It then appears that an Em:Am ratio of < 1.0 may not be reliable for the assessment of RVDD in a young population, such as those in the NG group. The dependence of RVDD on age could be attributed to the increase in arterial

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stiffness of the pulmonary vessels with ageing.23 Another possible explanation for the high prevalence of RVDD across the groups in our study could be the fact that RVDD in hypertensives has been shown to develop early, before apparent systolic dysfunction, and before RV dilatation or RV hypertrophy.17 This implies that RVDD could be the earliest index of RV affectation in hypertension, and perhaps occurs before LV geometry becomes abnormal. Therefore, the Em:Am ratio could potentially be used as a high-sensitivity screening tool for RV disease, but taking the age of the individual into consideration. In contrast to our finding, Cicala et al. previously reported that mitral annular Em:Am ratio and body mass index were the only predictors of RVDD, while age, DBP, heart rate, septal and RV wall thickness were not associated with the RVDD.2 We found no relationship between RVDD and LVMI, but did not assess the relationship between RVDD and mitral annular or mitral valve filling variables in the present study. Several conditions have been associated with RVDD, including both RV pressure and volume overload pathologies, primary lung disease, IHD, congenital heart disease, cardiomyopathies, LV dysfunction (via ventricular interdependence), systemic diseases and the physiological aging process.17 IHD is still uncommon in sub-Saharan Africa, previously found among 8.7% of subjects referred for echocardiography in Kano, Nigeria, and among 10.4% of the Soweto community in South Africa.9,24 We excluded subjects with IHD, however, from the present study. The limitations of the present study include the use of Em:Am ratio alone to assess RVDD. However, this index is one of the recommended indices approved by the American Society of Echocardiography for assessing RVDD, and has been shown to represent global RV diastolic function.2,17 Secondly, magnetic resonance imaging appears to be superior to echocardiography and other techniques in studying the right ventricle.25 However, echocardiography has acceptable sensitivity, and is widely available and affordable, and therefore has an important role in studying the right ventricle, despite its limitations. Another limitation was the use of Teicholz’s formula to estimate LVEF, which has the inherent tendency to over-estimate it in the presence of abnormal LV geometry.14 To minimise the inaccuracy of the Teichholz’s formula, subjects with regional wall motion abnormality were excluded from the study. The formulae that estimate LV mass using measurements obtained from two-dimensional guided M-mode echocardiography have several limitations, including sub-optimal accuracy in the presence of abnormal LV geometry, large inter-observer variability and poor inter-study reproducibility.14,16 To minimise this, about 50% of the echocardiograms were carried out by the principal author (KMK), while the remaining 50% were carried out by the co-authors (HS and MNS). We are presently in the process of estimating the inter-observer variability for our echocardiography laboratory.

Conclusion This study has described, perhaps for the first time, the pattern of RVSD and RVDD in hypertensive subjects grouped according to pattern of LV geometry. The majority of subjects (42.2%) had NG, while 29.7% had EH, 22.7% had CH, and 5.5% had CR. The highest prevalence of RVSD was recorded in subjects with EH who had the lowest mean LVEF and the worst LV systolic function,


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while the prevalence of RVDD was high across the groups. LVEF was the only independent determinant of RVSD after controlling for confounding variables, while age was the only determinant of RVDD. Likewise, age was the only correlate for Em:Am ratio, while the best correlate for both TAPSE and Sm was LVEF. These results have further characterised both LV and RV geometry and function in subjects with hypertension. We thank Prof Karen Sliwa-Hahnle of the Hatter Cardiovascular Research Institute, Cape Heart Centre and Groote Schuur Hospital, Cape Town, South Africa, for her useful criticism and comments on the manuscript.

References 1.

Karaye KM, Habib AG, Mohammed S, Rabiu M, Shehu MN. Assessment of right ventricular systolic function using tricuspid annular plane systolic excursion, among Nigerians with systemic hypertension. Cardiovasc J Afr 2010; 21(4): 186–190. 2. Cicala S, Galderisi M, Caso P, Petrocelli A, D’Errico A, de Divitiis O, et al. Right ventricular diastolic dysfunction in arterial systemic hypertension: analysis by pulsed tissue Doppler. Eur J Echocardiogr 2002; 3: 135–142. 3. Meluzin J, Spinarova L, Hude P, Krejci J, Kincl V, Panovsky R, et al. Prognostic importance of various echocardiographic right ventricular functional parameters in patients with symptomatic heart failure. J Am Soc Echocardiogr 2005; 18: 435–444. 4. Karaye KM, Habib AG, Mohammed S, Rabiu M, Shehu MN. Assessment of right ventricular systolic function using tricuspid annular plane systolic excursion, among Nigerians with systemic hypertension. Cardiovasc J Afr 2010; 21(4): 186–190. 5. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, et al. Patterns of left ventricular hypertrophy and geometric remodelling in essential hypertension. J Am Coll Cardiol 1992; 19: 1550–1558. 6. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in men and women with essential hypertension. Ann Intern Med 1991; 114: 345–352. 7. World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. J Postgrad Med 2002; 48: 206–208. 8. Lwanga SK, Lemeshow S. Sample size determination in health studies: a practical manual. Geneva: WHO 1991: 15. 9. Karaye KM, Sani MU. The impact of income on the echocardiographic pattern of heart diseases in Kano, Nigeria. Niger J Med 2008; 17(3): 350–355. 10. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for Quantification of Doppler Echocardiography. A Report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. 11. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37(1): 7–11.

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12. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458. 13. Lindqvist P, Henein M, Kazzam E. Right ventricular outflow tract fractional shortening: an applicable measure of right ventricular systolic function. Eur J Echocardiogr 2003; 4: 29–35. 14. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7: 79–108. 15. World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO) – International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11): 1983–1992. 16. Galderisi M, Henein MY, D’hooge J, Sicari R, Badano LP, Zamorano JL, et al., on behalf of the European Association of Echocardiography. Recommendations of the European Association of Echocardiography how to use echo-Doppler in clinical trials: different modalities for different purposes. Eur J Echocardiogr 2011; 12: 339–353. 17. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasckaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of echocardiography. Endorsed by the European Society of Cardiology, and the Canadian Society of echocardiography. J Am Soc Echocardiogr 2010; 23: 685–713. 18. Sciomer S, Magri D, Badagliacca R. Non-invasive assessment of pulmonary hypertension: Doppler echocardiography. Pulm Pharmacol Ther 2007; 20: 135–140. 19. Posteraro A, Salustri A, Trambaiolo P, Amici E, Gambelli G. Echocardiographic estimation of pulmonary pressures. J Cardiovasc Med 2006; 7: 545–554. 20. Santamore WP, Gray L. Significant left ventricular contributions to right ventricular systolic function: mechanisms and clinical implications. Chest 1995; 107: 1134–1145. 21. Puwanant S, Priester TC, Mookadam F, Bruce CJ, Redfield MM, Chandrasekaran K. Right ventricular function in patients with preserved and reduced ejection fraction heart failure. Eur J Echocadiogr 2009; 10: 733–737. 22. Innelli P, Esposito R, Olibet M, Nistri S, Galderisi M. The impact of ageing on right ventricular longitudinal function in healthy subjects: a pulsed tissue Doppler study. Eur J Echocardiogr 2009; 10: 491–498. 23. Sandstede J, Lipke C, Beer M, Hofmann S, Pabst T, Kenn W, et al. Ageand gender-specific differences in left and right ventricular cardiac function and mass determined by cine magnetic resonance imaging. Eur Radiol 2000; 10: 438–442. 24. Sliwa K, Wilkinson D, Hansen C, Ntyintyane L, Tibazarwa K, Becker A, et al. Spectrum of heart disease and risk factors in black urban population in South Africa (The Heart of Soweto Study): a cohort study. Lancet 2008; 371: 915–922. 25. Blecker GB, Steendijk P, Holman ER, Yu C-M, Breithardt OA, Kaandorp TA, et al. Assessing right ventricular function: the role of echocardiography and complementary technologies. Heart 2006; 92(Suppl I): i19–i26.


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Doppler echocardiographic indices in aortic coarctation: a comparison of profiles before and after stenting SHOKOUFEH HAJSADEGHI, SEYED-MOHAMMAD FERESHTEHNEJAD, MAHSHID OJAGHI, HOSSEIN ALI BASSIRI, MOHAMMAD REZA KERAMATI, MITRA CHITSAZAN, SAEID GHOLAMI

Abstract Background: Diagnosis of aortic coarctation is important as it is a difficult condition to evaluate, especially in adults. A Doppler echocardiographic index could provide a simple tool to evaluate coarctation. This study was performed to compare Doppler echocardiographic profiles before and after stenting and to assess the diagnostic value of a complete list of echocardiographic indices for detecting aortic coarctation. Methods: This prospective study was conducted on 23 patients with a diagnosis of aortic coarctation based on angiography. Echocardiographic assessment was done twice for all patients before and after stenting. Each time, two-dimensional and Doppler echocardiographic imaging modalities were performed and complete lists of indices were recorded for each case. After comparing the values of indices before and after stenting, diagnostic values of each index were calculated in order to diagnose significant coarctation. Results: Twenty-three patients, including 16 males and seven females with a mean age of 26.14 ± 10.17 years, were enrolled in this study. Except for the mean velocity and mean pressure gradient of the abdominal aorta, the values of the other indices of the abdominal/descending aorta showed enough change after stenting to indicate significant diagnostic accuracy for detecting aortic coarctation. The velocity–time integral and the pressure half-time were among the indices with Department of Cardiology, Rasoul-e-Akram Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran SHOKOUFEH HAJSADEGHI, MD

Firoozgar Clinical Research Development Center (FCRDC), Firoozgar Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran SEYED-MOHAMMAD FERESHTEHNEJAD, MD, MPH, sm_fereshtehnejad@yahoo.com

Department of Echocardiography and Cardiology, Shaheed Rajaie Cardiovascular Medical and Research Centre, Tehran University of Medical Sciences (TUMS), Tehran, Iran MAHSHID OJAGHI, MD HOSSEIN ALI BASSIRI, MD

Department of Surgery, Firoozgar Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran MOHAMMAD REZA KERAMATI, MD

Medical Students’ Cardiology Research Centre, Shaheed Rajaie Cardiovascular Medical and Research Centre, Tehran University of Medical Sciences (TUMS), Tehran, Iran MITRA CHITSAZAN, MD

Medical Students’ Research Committee (MSRC), Tehran University of Medical Sciences (TUMS), and Rasoul-eAkram Hospital, Tehran, Iran SAEID GHOLAMI, MD

the highest accuracy rates for this purpose (all p < 0.001). Conclusion: Post-stenting echocardiographic profiles could provide a reliable reference value of the normal aortic haemodynamics as a unique identification of each patient and it is presumed that these indices could be used as reliable indicators of response to treatment. Keywords: aortic coarctation, Doppler echocardiography, index, diagnostic values Submitted 2/10/11, accepted 11/5/12 Cardiovasc J Afr 2012; 23: 483–490

www.cvja.co.za

DOI: 10.5830/CVJA-2012-044

As one of the most common congenital heart defects,1 aortic coarctation has a wide morphological spectrum that varies from transverse arch and isthmal hypoplasia, which are seen most commonly in new-born babies, to discrete stenosis or membranelike obstructions, which are typically observed in older patients.2 Aortic coarctation presenting during adult life most frequently represents cases either of re-coarctation following previous transcatheter or surgical therapy, or missed cases of native coarctation.3 Nowadays, percutaneous stenting is an accepted form of treatment for isolated coarctation of the aorta.4 Balloonexpandable endovascular stents have been used in various locations since the 1980s.5-15 Stents support the integrity of the vessel wall after balloon dilation by opposing the recoil of the elastic vascular stenosis and re-adhering the torn intima to the media. This minimises the extension of wall tears and subsequent dissection or aneurysm formation.7,11,13,15,16 Moreover, stents provide a homogenous framework for smooth endothelial growth along the aortic wall that reduces the risk of thrombosis, neo-intimal hyperplasia and subsequent restenosis.5 Diagnosis and evaluation of coarctation is of great importance, not only before stenting but also after implantation, in order to assess the occurrence of restenosis. With regard to evaluation of aortic coarctation, cardiovascular magnetic resonance (CMR) imaging is the procedure of choice.17 However, its use may be limited because of lack of availability or clinical contraindications. On one hand, due to the wide availability, in the presence of clinical suspicion of aortic coarctation, echocardiography is the only available bedside diagnostic tool. It is also used in the initial assessment and follow up after the intervention of patients with coarctation. On the other hand, two-dimensional and colour Doppler echocardiographic techniques including analysis of pulse-wave and continuous-wave Doppler across the coarctation site and at the abdominal aorta are also used for the indirect evaluation of coarctation.4 Therefore a Doppler echocardiographic index, independent of cardiac function or other lesions and based on two-dimensional measurements of the


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transverse aortic arch would provide a simple tool to improve the accuracy of diagnosing coarctation. Previous investigations have produced a few echocardiographic indices, which were validated in a limited group of patients, to evaluate the condition of patients with aortic coarctation.4,18-20 However, the age groups of the patients differed and the various echocardiographic indices assessed were incomplete. Therefore we aimed to evaluate the changes in a complete list of echocardiographic profiles in patients with aortic coarctation before and after stenting, and to determine the diagnostic value of these indices as an indicator of aortic coarctation.

Methods This prospective study was conducted on 23 consecutive patients with the diagnosis of aortic coarctation who were referred to Rajaei Heart Centre (affiliated to Tehran University of Medical Sciences), Tehran, Iran, from April 2008 to August 2009. For this purpose, 40 patients with a definite diagnosis of aortic coarctation, based on an angiographic study, were referred to the ECHO Research Centre of the hospital for further assessment. All cases had primary unoperated coarctation. Patients with other concomitant lesions, including aortic stenosis or regurgitation, patent ductus arteriosus, anomalies of the head and neck vessels, and long-segment aortic coarctation or hypoplastic arch were excluded. According to their lesions, these 40 patients were candidates for balloon angioplasty, and stenting of the aortic coarctation was performed on all of them. Among these patients, 23 who had been proven to have no gradient and residual stenosis at the time of stenting were enrolled into the study. In addition to baseline and demographic variables (e.g. age, gender, blood pressure and length of stenosis), the characteristics

Fig. 1. Continuous-wave Doppler echocardiography of the abdominal aorta. AT: systolic acceleration time is measured from the onset of the systolic upstroke to the systolic peak. DT: deceleration time is measured from Peak E velocity to the point where the slope of the slowing flow would intercept the baseline. EDV: early diastolic velocity: maximum diastolic velocity on early diastole. LDV: late diastolic velocity: maximum diastolic velocity on late diastole. PHT: pressure half-time (of diastole) is the time interval for the peak diastolic pressure gradient to be reduced by one half. PSV: peak systolic velocity: maximum systolic velocity. TSV: time to peak systolic velocity: time beginning from onset of QRS complex to peak systolic velocity. VTI: velocity time integral: the area under the curve, shown in both systole and diastole.

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of stenting, including length and width of stent, length and width of balloon, and before- and after-stent peak gradient of the catheter were recorded for all patients. All gradients were directly measured during catheterisation. Informed written consent was obtained from all patients. The research project was approved by the ethics committee of Tehran University of Medical Sciences.

Echocardiographic evaluation Echocardiographic assessment was done twice on all patients, 24 hours before and 24 hours after stenting. Two-dimensional and Doppler echocardiographic imaging studies were performed using a Vivid 3 Imaging System (GE, USA) in accordance with institutional guidelines. All echocardiographic studies were done by one echocardiologist before and after stenting. Both the abdominal and descending aorta were evaluated during Doppler echocardiography. The standard suprasternal position was used to measure the maximum velocity across the coarctation site and then continuous-wave Doppler recordings were obtained. Pulsed-wave Doppler from the standard subcostal view was also performed to document the flow pattern of the abdominal aorta. The measurements obtained in the abdominal and/or descending aorta were peak systolic velocity (PSV) (m/s), early diastolic velocity (EDV) (m/s), late diastolic velocity (LDV) (m/s), systolic acceleration time (AT) (m/s), pressure half-time (PHT) (m/s), mean velocity (m/s), mean of peak gradient (mean PG), diastolic velocity/systolic velocity (D/S ratio velocity), velocityâ&#x20AC;&#x201C;time integral (VTI), time to peak systolic velocity (m/s), pulse delay, and pulsatility index (PI). Samples of pulse-wave Doppler echocardiography of the abdominal and descending aorta are shown in Figs 1 and 2, respectively. All studies, including pre- and post-stenting profiles, were performed with simultaneous electrocardiographic monitoring (ECG based), and the onset of diastole was assumed at the end of the electrocardiographic T wave. Moreover, three measurements

Fig. 2. Continous-wave Doppler echocardiography of descending aorta. AT: systolic acceleration time, DT: deceleration time, EDV: early diastolic velocity, LDV: late diastolic velocity, PHT: pressure half-time (of diastole), PSV: peak systolic velocity, TSV: time to peak systolic velocity.


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were taken from three consecutive cycles and the averaged values were calculated and reported as the main records. Intra- and inter-observer variability of the measurements were checked and calculated on a sample of patients by means of re-measurement of systolic and diastolic velocities by the same observer (intra-observer variability) and a second blinded observer (inter-observer variability). The calculated mean percentage error or disagreement was so low as to be considered negligible. Pre-stenting values of the Doppler echocardiographic profile were assumed to represent so-called ‘significant coarctation’, while post-stenting data corresponded with ‘no coarctation’.

Definitions Echocardiographic indices performed were defined as follows: • Deceleration time (DT) was measured from peak E velocity to the point where the slope of the slowing flow would intercept the baseline.21 • Systolic acceleration time was measured from the onset of the systolic upstroke to the systolic peak.21 • Pressure half-time (PHT) was the time interval for the peak pressure gradient to be reduced by one half (PHT = 0.29 × DT).21 • Abdominal aortic pulse delay was quantified by measuring the time to peak velocity in the abdominal aorta and comparing it with the same value measured from flow at the aortic annulus. This value should be indexed to the heart rate by dividing the absolute value by the square root of the PR interval.21 • Pulsatility index was the systolic velocity minus diastolic velocity divided by the mean velocity systolic velocity – diastolic velocity

_____________________      ​].22 [​     mean velocity

• Early diastolic velocity (EDV) was maximum diastolic velocity in early diastole. • Late diastolic velocity (LDV) was maximum diastolic velocity in late diastole (atrial contraction).23 • Peak systolic velocity was maximum systolic velocity.24 • Velocity time integral was the area under the velocity curve. • Time to peak systolic velocity was the time from onset of the QRS complex to peak systolic velocity measured by pulsewave Doppler echocardiography. • Pulse delay index was calculated by means of the following equation: Time to peak systolic velocity of LVOT – Time to peak systolic velocity of abdominal aorta ____________________________________________________ _________      ​ ​        ​√RRinterval   ​

Statistical analysis Data were analysed using SPSS v 17 software (Chicago, IL, USA). For each of the measured variables or indices, descriptive values were expressed as the mean ± SD for normally distributed variables, and median and interquartile range (IQR) in the case of non-normal distributions. All data were initially analysed using the Kolmogorov–Smirnov test to assess for normality. The within-group changes of each Doppler echocardiographic index were evaluated using the paired t-test. Pearson’s correlation analysis was also used to assess the relationship between baseline aortic gradient measured by catheter and Doppler echocardiographic indices.

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Receiver operating characteristic curve (ROC) analysis was performed to assess the predictability of significant coarctation (pre-stenting condition) with the quantitative indices of the study, and then to compare area under the curve (AUC) of these variables. For this purpose, the first measured profiles before stenting were considered to be the values of patients with significant aortic coarctation, while the next measured indices after stenting were taken as the profiles of the individuals without coarctation. The cut-off points were then determined in each ROC analysis. The best predictive cut-off value was the one that gave the highest sensitivity and specificity simultaneously. The diagnostic values of each cut-off point, including sensitivity and specificity, were calculated and reported. All p-values were two-tailed and p < 0.05 was considered statistically significant.

Results Twenty-three patients, including 16 (69.6%) males and seven (30.4%) females with a mean age of 26.14 ± 10.17 years (range 14–56) were enrolled in this study. The median time since diagnosis of disease was 12.00 (IQR = 31) months and the mean length of the stenosis was 20.44 ± 10.47 mm. In addition, the mean baseline ejection fraction was 54.55 ± 5.10% (range 35–60%) and 16 ± 69.6% of patients were hypertensive. All baseline and stenting characteristics of the patients are listed in Table 1. The patients underwent Doppler echocardiography at the time of enrolment and after stenting. All Doppler echocardiographic profiles of the abdominal and descending aorta (before and after stenting) are given in Table 2. The differences between the two measurements were calculated and mean percentages are listed in Table 2. TABLE 1. BASELINE AND STENTING CHARACTERISTICS OF THE PATIENTS Patients’ age (years) 26.14 ± 10.17 Patients’ gender (%) Male 16 (69.6) Female 7 (30.4) Blood pressure Systolic blood pressure (mmHg) 158.18 ± 24.18 Diastolic blood pressure (mmHg) 85.23 ± 10.96 Time since diagnosis (months) 12.00 (IQR = 31) Aortic valve (%) BAV 13 (56.5) TAV 10 (43.5) Ejection fraction (%) 54.55 ± 5.10 Length of the balloon (mm) 18.55 ± 4.44 Width of the balloon (mm) 5.350 ± 3.95 Length of the stent (mm) 37.16 ± 3.67 Width of the stent (mm) 8.47 ± 1.94 Peak before-stenting gradient of the catheter (mmHg) 57.05 ± 12.69 Peak after-stenting gradient of the catheter (mm Hg) 2.38 ± 5.39 Before-stenting gradient of the catheter (%) 85.00 ± 7.69 After-stenting gradient of the catheter (%) 14.17 ± 9.96 Length of the stenosis (mm) 20.44 ± 10.47 All values for continuous variables are mean ± SD except for time since diagnosis, which is median (IQR).


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TABLE 2. DOPPLER ECHOCARDIOGRAPHIC PROFILE OF ABDOMINAL AND DESCENDING AORTA BEFORE AND AFTER STENTING (IN PERCENTAGE CHANGE COLUMN, POSITIVE VALUES SHOW REDUCTION WHEREAS NEGATIVES SHOW INCREASE IN VALUES AFTER STENTING) Mean values before stenting Mean values after stenting Mean percentage change after stenting (%) Abdominal Descending Abdominal Descending Abdominal Descending Doppler echocardiographic profile aorta aorta aorta aorta aorta p-value aorta p-value PSV (m/s) 0.58 ± 0.13 3.84 ± 0.77 0.77 ± 0.20 2.41 ± 0.51 –37.60 ± 35.37 < 0.001 34.88 ± 18.83 < 0.001 EDV (m/s) 0.42 ± 0.15 1.93 ± 0.67 0.21 ± 0.10 0.56 ± 0.33 44.76 ± 32.92 < 0.001 65.04 ± 29.45 < 0.001 LDV (m/s) 0.27 ± 0.09 0.87 ± 0.51 0.19 ± 0.07 0.29 ± 0.14 22.83 ± 32.91 0.002 61.45 ± 27.27 < 0.001 AT (m/s) 229.07 ± 75.48 101.30 ± 56.11 102.14 ± 34.47 68.99 ± 26.32 50.35 ± 23.33 < 0.001 12.45 ± 64.18 0.020 PHT (m/s) 196.39 ± 91.86 163.68 ± 82.72 61.00 ± 19.54 57.26 ± 27.24 59.51 ± 29.14 < 0.001 48.50 ± 62.49 < 0.001 Mean velocity (m/s) 0.38 ± 0.10 1.86 ± 0.45 0.35 ± 0.10 0.96 ± 0.24 1.00 ± 35.74 < 0.001 45.15 ± 21.28 < 0.001 Mean PG 0.69 ± 0.33 19.81 ± 7.96 0.70 ± 0.44 6.58 ± 3.08 –26.95 ± 86.39 0.932 57.81 ± 36.62 < 0.001 D/S ratio velocity 0.72 ± 0.24 0.50 ± 0.15 0.27 ± 0.13 0.22 ± 0.10 59.68 ± 19.65 < 0.001 48.54 ± 37.37 < 0.001 VTI 31.96 ± 9.41 152.85 ± 56.39 24.02 ± 6.90 58.65 ± 17.59 18.34 ± 33.39 0.005 57.37 ± 19.97 < 0.001 Time to peak systolic velocity (m/s) 370.61 ± 76.40 239.59 ± 43.47 243.35 ± 36.05 203.30 ± 41.56 31.48 ± 17.40 < 0.001 11.00 ± 27.40 0.026 Pulse delay – 8.11 ± 3.36 – 3.19 ± 1.78 – – 54.62 ± 26.91 < 0.001 Pulsatility index – 0.89 ± 0.30 – 1.75 ± 0.51 – – –119.57 ± 110.16 < 0.001 PSV: peak systolic velocity, EDV: early diastolic velocity, LDV: late diastolic velocity, AT: systolic acceleration time, PHT: pressure half-time, PG: peak gradient, D/S: diastolic velocity/systolic velocity, VTI: velocity time integral. All p-values are from paired t-test and p < 0.05 is considered significant.

Stenting decreased the pulse-delay index from 8.11 ± 3.36 to 3.19 ± 1.78 (p < 0.001). Additionally, significant reductions were

noted in the EDV (pAb < 0.001, pDs < 0.001), LDV (pAb = 0.002, pDs < 0.001), AT (pAb < 0.001, pDs = 0.020), PHT (pAb < 0.001,

TABLE 3. DIAGNOSTIC VALUES OF DIFFERENT CUT-OFF POINTS OF ECHOCARDIOGRAPHIC PROFILES OF ABDOMINAL AND DESCENDING AORTA TO DIFFERENTIATE SIGNIFICANT COARCTATION (PRE-STENTING CONDITION) FROM POSTSTENTING CONDITION OR WITHOUT COARCTATION (ALL DATA DERIVED FROM ROC CURVE ANALYSIS) Echocardiographic index Abdominal aorta PSV (m/s) EDV (m/s) LDV (m/s) AT (m/s) PHT (m/s) Mean velocity (m/s) Mean PG D/S ratio velocity VTI Time to peak systolic velocity (m/s) Descending aorta PSV (m/s)

AUC

p-value

Cut-off point

Sensitivity (%)

Specificity (%)

0.816 0.902 0.747 0.940

< 0.001 < 0.001 0.004 < 0.001

0.960

< 0.001

0.616 0.560 0.968 0.757 0.953

0.177 0.489 < 0.001 0.003 < 0.001

0.655 0.325 0.205 131.00 146.50 83.5 106.00 0.43 27.5 308.5

73.9 82.6 69.6 91.3 82.6 91.3 87 95.7 73.9 82.6

73.9 87 65.2 87 91.3 82.6 100 87 69.6 100

0.938

< 0.001

3.09 90.9 87 3.37 81.8 100 EDV (m/s) 0.965 < 0.001 0.96 90.9 87 LDV (m/s) 0.922 < 0.001 0.385 90.9 82.6 AT (m/s) 0.696 0.025 77.43 68.2 69.6 PHT (m/s) 0.900 < 0.001 85.5 81.8 87 Mean velocity (m/s) 0.969 < 0.001 1.18 95.5 87 1.33 90.9 91.3 Mean PG 0.949 < 0.001 10.50 90.9 91.3 D/S ratio velocity 0.931 < 0.001 0.365 81.8 91.3 VTI 0.980 < 0.001 87.50 90.9 91.3 94.5 86.4 100 Time to peak systolic velocity (m/s) 0.698 0.023 242.50 50 91.3 Pulse delay 0.957 < 0.001 5.98 87 95.7 Pulsatility index 0.945 < 0.001 1.21 87 91.3 PSV: peak systolic velocity, EDV: early diastolic velocity, LDV: late diastolic velocity, AT: systolic acceleration time, PHT: pressure half-time, PG: peak gradient, D/S: diastolic velocity/systolic velocity, VTI: velocity time integral, AUC: area under curve.


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TABLE 4. EVALUATION OF THE CORRELATION BETWEEN SEVERITY OF COARCTATION (BASELINE PEAK GRADIENT OF THE CATHETER) AND PRE-STENTING ECHOCARDIOGRAPHIC PROFILES OF ABDOMINAL AND DESCENDING AORTA Correlation Echocardiographic index coefficient (r) p-value Abdominal aorta PSV (m/s) –0.093 0.681 EDV (m/s) 0.087 0.701 LDV (m/s) –0.026 0.909 AT (m/s) 0.014 0.952 P.H.T (m/s) 0.637 0.001 Mean velocity (m/s) 0.066 0.769 Mean PG 0.115 0.610 D/S ratio velocity 0.054 0.811 VTI 0.446 0.038 Time to peak systolic velocity (m/s) –0.004 0.987 Descending aorta PSV (m/s) 0.265 0.245 EDV (m/s) 0.474 0.030 LDV (m/s) 0.592 0.005 AT (m/s) 0.093 0.688 PHT (m/s) 0.613 0.003 Mean velocity (m/s) 0.473 0.030 Mean PG 0.436 0.048 D/S ratio velocity 0.374 0.095 VTI 0.548 0.010 Time to peak systolic velocity (m/s) –0.020 0.931 Pulse delay –0.075 0.739 Pulsatility index 0.084 0.710 PSV: peak systolic velocity, EDV: early diastolic velocity, LDV: late diastolic velocity, AT: systolic acceleration time, PHT: pressure half-time, PG: peak gradient, D/S: diastolic velocity/systolic velocity, VTI: velocity time integral, AUC: area under curve. All data derived from two-sided Pearson correlation analysis.

pDs < 0.001), mean velocity (pAb < 0.001, pDs < 0.001), mean PG (pDs < 0.001), D/S ratio velocity (pAb < 0.001, pDs < 0.001), VTI (pAb = 0.005, pDs < 0.001) and time to peak systolic velocity (pAb < 0.001, pDs = 0.026). While the PSV of the abdominal aorta was significantly increased after stenting (pAb < 0.001), the corresponding value of the descending aorta had decreased (pDs < 0.001). The largest percentage increase (119.57%) was achieved in the pulsatility index, which increased from 0.89 ± 0.30 to 1.75 ± 0.51 (pDs < 0.001). The ROC curve analysis was performed to evaluate the

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diagnostic values of different Doppler echocardiographic indices in order to differentiate significant coarctation (pre-stenting condition) from post-stenting conditions or without coarctation. Diagnostic values of all 12 Doppler echocardiographic indices in both the abdominal and descending aorta are given in Table 3. As shown in Table 3, except for the mean velocity (pAb = 0.177) and mean PG (pAb = 0.489) of the abdominal aorta, other indices of the abdominal or descending aorta had a statistically significant area under the curve (AUC) to distinguish patients with significant aortic coarctation or a pre-stenting condition. The VTI of the descending aorta had the greatest AUC of 0.980 (pDs < 0.001) such that the velocity–time integral of > 87.50 had 90.9% sensitivity and 91.3% specificity, and the values of > 94.50 had 86.4% sensitivity and 100% specificity for detection of significant aortic coarctation. A pulse delay of > 5.98 had a sensitivity of 87% and specificity of 95.7% to diagnose significant aortic coarctation (Fig. 3). Moreover, as illustrated in Fig. 4, a pulsatility index of > 1.21 had 87% sensitivity and 91.3% specificity to differentiate significant coarctation (pre-stenting condition) from the poststenting condition or without coarctation. As shown in Table 4, the baseline peak aortic gradient measured by catheter was significantly correlated with some of the pre-stenting echocardiographic profiles of the abdominal and descending aorta. In both the abdominal and descending aorta, the strongest correlation of the peak gradient was observed with pressure half-time as a direct relationship (rAb = 0.637, pAb = 0.001; rDs = 0.613, pDs = 0.003). The velocity–time integral of the descending aorta was also directly correlated with before-stenting peak gradients (rDs = 0.548, pDs = 0.010). Other correlations are shown in Table 4. The possible correlation of the baseline peak aortic gradient with the mean percentage change in echocardiographic profiles after stenting was also evaluated. Our findings showed a reverse correlation between severity of coarctation and changes in LDV after stenting. The higher the gradient, the lower the change in the LDV of the abdominal aorta (rAb = –0.455, pAb = 0.033). By contrast, changes in the PHT of the abdominal aorta were directly correlated with the baseline catheter gradient (rAb = 0.436, pAb = 0.043). Changes in the other echocardiographic indices were not significantly correlated with the baseline aortic gradient.

Discussion Coarctation of the aorta is characterised by anatomical obstruction in the descending aorta. It is difficult to evaluate this obstruction because of the variability in cardiac output, number and size of collaterals, and peripheral resistance.25 Primary clinical diagnosis and subsequent assessment of the severity of coarctation and Pulsatility index

Pulse delay

20

10 5 0

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Severe coarctation (pre-stenting condition)

Post-stenting

Fig. 3. Cut-off points of 5.98 for pulse delay of descending aorta to differentiate significant coarctation (prestenting condition) from post-stenting condition or without coarctation.

3 2 1 0

Severe coarctation (pre-stenting condition)

Post-stenting

Fig. 4. Cut-off points of 1.21 for pulsatility index of descending aorta to differentiate significant coarctation (pre-stenting condition) from post-stenting condition or without coarctation.


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re-coarctation of the aorta have traditionally been made based on the judgment of the character of the femoral pulse. Also known as a secondary event, absent, weakened or delayed femoral pulses occur as a result of obstruction in aortic coarctation. The pressure drop across the obstruction (the gradient), pressure half-time, and diastolic flow are widely used but inaccurate indices to diagnose aortic coarctation. They can be affected by many other factors such as cardiac output,26 lesion length,27 the presence of collateral networks,26 and aortic compliance.28 Stent implantation has been used as a reliable treatment for coarctation of the aorta. It has several advantages, rendering it superior to angioplasty alone.29 The effect of stents on blood flow dynamics are not well known. Moreover, despite the importance of close follow up to evaluate complications and the long-term effect on the blood pressure of these patients, there are no adequate long-term follow-up indices for these patients. Therefore the present study was carried out to find reliable, quantitative Doppler echocardiographic indices for assessment of the severity of coarctation of the aorta before stenting and comparing these indices with the post-stenting condition. This would provide a valuable profile to indicate successful stent implantation. All previous methods, including monitoring the blood pressure, two-dimensional echocardiography, cardiac magnetic resonance (CMR) and angiography have failed to give favourable results. Persistent hypertension, even in the absence of a recurrent or residual stenosis,25,30 insufficient anatomical evaluation of two-dimensional echocardiography,31 and disrupted MRI by metallic artifacts (or noise) have limited the value of these indices to assess the patient at post-intervention follow up.32 Furthermore, angiography as an invasive procedure has known complications. Doppler echocardiography overcomes these problems in the follow up of such patients. However, echocardiography may be less sensitive than angiography, spiral computed tomography and MRI in detecting aneurysms after stent placement.32 Based on our results, the Doppler echocardiographic profile was found to be valid for differentiating significant coarctation from the normal condition (after stenting), with high diagnostic values. As demonstrated in the results, continuous flow was significantly decreased from before to after stenting in both the descending and abdominal aorta. Moreover, monophasic systolic flow was shown to increase significantly after stenting. In comparison with a few similar studies,4,20 we assessed more indices, which we will discuss below. According to our results, aortic pulse delay decreased after stenting. The results also showed that a pulsatility index of < 1.21 was suggestive of significant coarctation of the aorta. This cut-off point was calculated as < 2 in a study by Silvilairat et al.33 Currently, it is known that obstructed blood flow due to aortic coarctation leads to pressure drop and loss of the pulse wave distal to the stenosis. This can be observed by echocardiography typically as decreased pulsatility of the abdominal aorta after cardiac systole.34 Early and late diastolic velocities were found to be significant markers in the assessment of the severity of coarctation. In addition, mean peak gradient of the descending aorta was significantly reduced by as much as 58% following stenting. This could be the result of changed flow dynamics along the stent.4

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However, in some patients, there was an under- or overestimation of the pressure gradient across the coarctation site on Doppler echocardiography. As mentioned, these are affected by other factors, such as cardiac output,26 lesion length,27 the presence of collateral networks,26 and aortic compliance.28 Therefore pressure gradient alone as an index of aortic narrowing is often inadequate. Although the mean velocity in both the descending and abdominal aorta significantly decreased after stenting, the difference was more significant in the descending aorta, with an approximately 45% reduction. Similarly, the acceleration time in the descending aorta was different from the corresponding measurement in the ascending aorta in coarctation.31 This is manifested clinically by radial femoral delay and diminished pulses distal to the coarctation. After stent implantation, the acceleration time showed statistically significant decreases in both the descending and abdominal aorta. Based on our findings, the velocityâ&#x20AC;&#x201C;time integral and time to peak systolic velocity can be also used as new markers of significant coarctation. Both indices significantly decreased after stenting. We also found pressure half-time indices (systolic and diastolic velocity half-times, systolic and diastolic pressure half-times) can be used to assess the severity of coarctation, with sensitivities of 87 and 81.8% and specificities of 100 and 87% for the abdominal aorta and descending aorta, respectively. These findings were in keeping with the results of previous investigations by Carvalho et al.35 and Tan et al.,4 which reported a significant effect of coarctation of the aorta on these indices. A study by Lim and Ralston however was in disagreement with regard to systolic indices.36 Diastolic velocities (DVs) and diastolic pressure decays have been shown to provide invaluable information for assessing the severity of coarctation.35-37 The index of D/S ratio velocity was first used by Tan et al.4 as a marker of significant coarctation. They demonstrated that a D/S ratio velocity of > 0.53 had a sensitivity of 100% and specificity of 96% for detecting significant aortic coarctation. They believed that by correlating diastolic with systolic velocity, this ratio would be less affected by variations in heart rate, stroke volume, systemic blood pressure and aortic compliance.4 However, we found a lower cut-off point for D/S ratio velocity. The D/S ratio of > 0.365 in the descending aorta had a sensitivity of 95.7% and specificity of 87%, whereas the ratio of > 0.43 in the abdominal aorta had a sensitivity of 81.8% and specificity of 91.3% in defining significant coarctation of the aorta. D/S ratio velocity appears to be a good marker of this condition. Recently, the D/S ratio as a non-invasive measurement of coronary flow velocity has been used to evaluate left anterior descending artery (LAD) stenosis. By contrast with the aorta, the D/S ratio was found to be significantly lower in patients with more critical stenosis of the LAD.38 Besides evaluation of the diagnostic value of the echocardiographic indices, a correlation analysis was also performed in our study to assess the relationship between the severity of coarctation before stenting and the echocardiographic indices. As shown, PHT and VTI of the abdominal aorta and EDV, EDV, PHT, mean velocity and mean peak gradient of the descending aorta correlated significantly with the peak gradient in the coarctation site, measured by catheterisation prior to stent implantation.


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In addition, the higher pre-stenting gradients were associated with lower changes in LDV of the abdominal aorta, while changes in PHT of the abdominal aorta were directly correlated with the baseline gradient. The observed correlation between the baseline severity of coarctation and the changes in PHT after stenting leads us to conclude that this index (PHT) is probably the best to determine stenting outcome and the probable occurrence of restenosis. Nevertheless, it should be evaluated in further studies. Although our study had some limitations, including small sample size, no long-term follow up and no CMR imaging for evaluation of the aortic coarctation index, it had some findings which have not been reported before. One must also consider the problem of using a functional technique to predict anatomical obstruction, especially in adults where the haemodynamics are directly and significantly affected by the presence and extent of collateral blood flow. Doppler techniques are more valuable in neonates with coarctation, where collateral flow has not had time to develop, and the haemodynamic consequences are more clearly related to the anatomical obstruction. The results of the present study showed that a complete set of Doppler echocardiographic profiles could potentially provide a valid method to diagnose significant aortic coarctation. Velocity–time integral, time to peak systolic velocity, systolic acceleration time and mean velocity were sensitive and specific enough to detect significant aortic coarctation, as were peak systolic, early diastolic and late diastolic velocities, pressure half-time, peak gradient and D/S ratio velocity, which were validated in previous studies. To the best of our knowledge this is the first evaluation of such a complete list of Doppler echocardiographic indices to detect significant coarctation of the aorta. Our findings emphasise the advantages of Doppler echocardiography for close monitoring of patients with aortic coarctation. Although these echocardiographic indices do improve dramatically in patients who undergo stenting, they never return to normal values even if no residual stenosis exists.

Conclusion We found a significant difference between pre- and post-stenting echocardiographic values, which could provide valuable insight for evaluation of follow up and response to treatment in patients with aortic coarctation. Post-stenting echocardiographic profiles of each patient could therefore provide an individualised and reliable reference value of his/her normal aortic haemodynamics, and early detection of restenosis could be achieved by comparison of post-stenting values with follow-up values. A similar clinical approach is used in echocardiographic follow up of patients with prosthetic heart valves.39 We suggest that these echocardiographic indices could be used as reliable detectors of the patient’s response to treatment, and their predictive role in the follow up of these patients is obvious. However, in order to evaluate recurrent stenosis, it would be important to re-evaluate patients during longer-term follow up, which could be undertaken in further studies.

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cal obstruction by Doppler echocardiography and magnetic resonance imaging in patients with coarctation of the aorta. Br Heart J 1993; 69: 352–355. Houston AB, Simpson IA, Pollock JC, Jamieson MP, Doig WB, Coleman EN. Doppler ultrasound in the assessment of severity of coarctation of the aorta and interruption of the aortic arch. Br Heart J 1987; 57: 38–43. Teirstein PS, Yock PG, Popp RL. The accuracy of Doppler ultrasound measurement of pressure gradients across irregular, dual, and tunnel like obstructions to blood flow. Circulation 1985; 72: 577–584. Tacy TA, Baba K, Cape EG. Effect of aortic compliance on Doppler diastolic flow pattern in coarctation of the aorta. J Am Soc Echocardiogr 1999; 12: 636–642. Chessa M, Carrozza M, Butera G, Piazza L, Gabriela Negura D, Bussadori C, et al. Results and mid–long-term follow-up of stent implantation for native and recurrent coarctation of the aorta. Eur Heart J 2005; 26: 2728–2732. Eicken A, Pensl U, Sebening W, Hager A, Genz T, Schreiber C, et al. The fate of systemic blood pressure in patients after effectively stented coarctation. Eur Heart J 2006; 27; 1100–1105. Shaddy RE, Snider AR, Silverman NH, Lutin W. Pulsed Doppler findings in patients with coarctation of the aorta. Circulation 1986; 73: 82–88. Hamdan MA, Maheshwari S, Fahey JT, William E. Endovascular stents for coarctation of the aorta: initial results and intermediate-term follow-

William Nelson ECG Quiz Question These are the ECGs of a 73- and 71-year-old man. Lead V1 is normally very good. For rhythm analysis, what is the rhythm in these two patients?

The answer will be provided on page 494.

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up. J Am Coll Cardiol 2001; 38: 1518–1523. 33. Silvilairat S, Cetta F, Biliciler-Denktas G, Ammash NM, Cabalka AK, Hagler DJ, et al. Abdominal aortic pulsed wave Doppler patterns reliably reflect clinical severity in patients with coarctation of the aorta. Congenit Heart Dis 2008; 3(6): 422–430. 34. Pfammatter JP, Stocker FP. Quantitative echocardiographic characterization of abdominal aortic pulsatility in children with coarctation. Pediatr Res 1999; 46(1): 126–130. 35. Carvalho JS, Redington AN, Shinebourne EA, Rigby ML, Gibson D. Continuous wave Doppler echocardiography and coarctation of the aorta: gradients and flow patterns in the assessment of severity. Br Heart J 1990; 64: 133–137. 36. Lim DS, Ralston MA. Echocardiographic indices of Doppler flow patterns compared with MRI or angiographic measurements to detect significant coarctation of the aorta. Echocardiography 2002; 19: 55–60. 37. Hoadley SD, Duster MC, Miller JF, Murgo JP. Pulsed Doppler study of a case of coarctation of the aorta: demonstration of a continuous Doppler frequency shift. Pediatr Cardiol 1986; 6: 275–277. 38. Tani T, Tanabe K, Kitai T, Yamane T, Kureha F, Katayama M, et al. Detection of severe stenosis and total occlusion in the left anterior descending coronary artery with transthoracic Doppler echocardiography in the emergency room. Echocardiography 2009; 26(1): 15–20. 39. Hage FG, Nanda NC. Guidelines for the evaluation of prosthetic valves with echocardiography and Doppler ultrasound: value and limitations. Echocardiography 2010; 27(1): 91–93.


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A comparative study of amoxicillin, clindamycin and chlorhexidine in the prevention of post-extraction bacteraemia BREMINAND MAHARAJ, YACOOB COOVADIA, AHMED C VAYEJ

Abstract We evaluated some of the regimens recommended for the antimicrobial prophylaxis of infective endocarditis prior to dental extraction in 160 patients. Group A patients served as the control group, group B subjects rinsed their mouths with chlorhexidene, group C subjects took 3 g amoxicillin orally and group D patients took 600 mg clindamycin orally. The proportion of patients who had post-extraction bacteraemia in groups A, B, C and D was 35, 40, 7.5 and 20%, respectively. The differences between the control and amoxicillin groups (p = 0.003) and between the chlorhexidine and amoxicillin groups (p = 0.0006) were statistically significant. Streptococci were not isolated in any patients in the amoxicillin and clindamycin groups. In our study, none of the regimens were effective in preventing post-extraction bacteraemia. Keywords: antibiotics, prophylaxis, infective endocarditis, dental extraction, bacteraemia Submitted 30/11/11, accepted 5/6/12 Cardiovasc J Afr 2012; 23: 491–494

www.cvja.co.za

DOI: 10.5830/CVJA-2012-049

The rationale for antibiotic prophylaxis against infective endocarditis has been as follows: following a bacteraemia, bacteria may lodge on damaged or abnormal heart valves or near anatomical defects, resulting in infective endocarditis. Certain healthcare procedures induce bacteraemia with organisms that can cause endocarditis; these bacteria are usually sensitive to antibiotics. Therefore antibiotics should be given to patients with pre-disposing heart disease before procedures that may cause bacteraemia.1 On this basis, prophylaxis against infective endocarditis has become routine in most countries,2-4 even though no prospective study has proved that it is effective.1,4-7 The use of topical antiseptics has been another approach to reduce the entry of bacteria into the blood stream.8 Since studies on the efficacy of antibiotic prophylaxis for

Department of Therapeutics and Medicines Management, University of KwaZulu-Natal, Durban, South Africa BREMINAND MAHARAJ, MB ChB, FCP (SA), MD, PhD, FRCP (London), maharajb4@ukzn.ac.za

Department of Medical Microbiology, University of KwaZuluNatal, Durban, South Africa YACOOB COOVADIA, MB ChB, FCPath (Micro)

Programme: Oral Health, Department of Health, KwaZuluNatal, Durban, South Africa AHMED C VAYEJ, BDS

infective endocarditis in humans cannot be done for ethical and practical reasons, clinical studies have focused on the prevention of bacteraemia by administration of antimicrobial agents before dental treatment. There is a paucity of data on the effectiveness of amoxicillin, clindamycin and the oral antiseptic, chlorhexidine in eliminating post-extraction bacteraemia in black patients. We therefore carried out a study to assess and compare the effectiveness of these drugs.

Methods Adult black patients attending the dental clinic in Prince Mshiyeni Memorial Hospital, Umlazi, near Durban were included in the study after informed consent had been obtained. They were healthy, had no history of cardiovascular disease, had not received antibiotics in the previous two weeks and were not allergic to penicillin. Any patient found to have a dental abscess or who required the extraction of more than one tooth was excluded. Using a computer-generated randomisation table, patients were randomised into four groups of 40 each. Group A served as a control group and was given no therapy prior to dental extraction. Group B rinsed their mouths vigorously with 10 ml of 0.2% chlorhexidine for one minute and expectorated. This procedure was repeated one minute later. Groups C and D took 3 g amoxicillin or 600 mg clindamycin orally, respectively. All treatments were given one hour prior to the dental extraction. Only one tooth was extracted per patient. The same dental surgeon performed the procedure using dental forceps. No surgical procedures were used in any patient. The skin at the site of the venepuncture was prepared using 0.5% chlorhexidine in 70% alcohol. Using standard aseptic techniques, 8–10 ml of blood was drawn three minutes after the extraction in each patient. Three to 5 ml of blood were injected directly into BACTEC (Becton Dickinson, Maryland, USA) blood culture vials type 6b (aerobic) and 7d (anaerobic), after the used needle was replaced with a new sterile needle, and the rubber septum on the BACTEC vials was disinfected with alcohol. The blood culture bottles were transported to the Microbiology Department, King Edward VIII Hospital, Durban within two hours of collection and were immediately incubated at 37°C. In the case of the aerobic bottles, this also included agitation on BACTEC shakers for the first 24 hours. The blood culture vials were tested on days one, three, five and seven, and positive vials were sub-cultured and Gram-stained smears were prepared. The aerobic vials were sub-cultured onto chocolate, blood and MacConkey agar plates, which were incubated for 48 hours in air plus 10% CO2. The anaerobic vials were sub-cultured onto 10% blood agar plates with and without amikacin, which were incubated for 48


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to 72 hours in anaerobic gas pak (Becton Dickinson, USA) jars with appropriate controls. The organisms isolated were further identified using conventional laboratory methods and the identity of streptococcal isolates was confirmed using the API Strep 20 (API, France) system.9 The study was approved by the ethics committee of the Nelson R Mandela School of Medicine, University of Natal, Durban.

Statistical analysis Results in each group were arranged in a contingency table and were analysed using Fisher’s exact test (one-tailed probability). Since there were six comparisons, the Bonferroni correction was applied (p < 0.05/6) and a p-value < 0.0083 was taken as the level of significance. To analyse the difference in the occurrence of bacteraemia between the control and antibiotic groups as well as between the antiseptic and the antibiotic groups, the Chi-square test was used, employing Yates’ correction for continuity. The level of significance was taken at p < 0.05.

Results One hundred and sixty black patients, 50 males and 110 females, entered the study. The four groups were comparable with regard to age and gender (Table 1). In the control group, 14 (35%) patients had positive blood cultures after dental extraction. Post-extraction bacteraemia was detected in 16 (40%), three (7.5%) and eight (20%) patients in the chlorhexidine, amoxicillin and clindamycin groups, respectively. Only the differences between the amoxicillin and control groups (p = 0.003), and between the amoxicillin and chlorhexidine groups (p = 0.0006) were statistically significant When the antibiotic groups were combined, the number of patients with post-extraction bacteraemia differed significantly from those in the control group (p = 0.014) and in the antiseptic group (p = 0.003). The bacteria that were cultured after dental extraction in the four groups of patients are shown in Table 2.

Discussion In this study, we compared the efficacy of two antibiotics, amoxicillin and clindamycin, given orally, and an oral antiseptic, chlorhexidine, in the prevention of post-extraction bacteraemia in adult black patients. None of these treatments was effective in preventing bacteraemia after dental extraction. Oral amoxicillin given prior to dental extraction produced a significant reduction in post-extraction bacteraemia in our patients (7.5 vs 35% in the control group). Streptococci were not isolated in any patient in the amoxicillin group. Shanson et al. compared amoxicillin with penicillin V in the TABLE 1. PATIENT DEMOGRAPHICS

Males Females Age (years) Range Mean

Control group (n = 40) 12 28

Chlorhexidine group (n = 40) 8 32

Amoxicillin group (n = 40) 14 26

Clindamycin group (n = 40) 16 24

18–60 32.1

18–55 28.0

18–56 29.9

18–66 28.1

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prophylaxis of post-extraction bacteraemia in two groups of 40 patients each.10 Both drugs were given as a 2-g oral dose one hour prior to extraction. A control group of 40 patients received no treatment. Bacteraemia was reduced from 70% in control patients to 25 and 20% in those who had received amoxicillin and penicillin V, respectively. Streptococci were isolated from the blood cultures of 40% of the control patients, 5% of the amoxicillin patients and 12% of the penicillin V patients. The difference between the number of patients with bacteraemia in the control and amoxicillin groups was statistically significant; the differences between the two antibiotic groups and between the penicillin V and control groups were not significant. The viridans streptococci isolated from the blood of patients in this study were sensitive to both penicillin V and amoxicillin and the sensitivity was similar. Serum antibiotic levels exceeded the minimum inhibitory concentrations and minimum bactericidal concentrations for both drugs. We did not measure serum antibiotic levels in our study. The use of 3 g amoxicillin given orally as prophylaxis against bacteraemia associated with dental surgery was investigated by Oakley et al.11 They cultured bacteria in 7.1% of their 42 patients. In a study to determine the efficacy of oral amoxicillin (50 mg/ kg body weight) given prior to dental extraction in children, 47 children were allocated to the amoxicillin group and 47 to the control group.12 Bacteraemia following extraction was detected in 38% of control patients and 2% of amoxicillin patients; this difference was statistically significant. All streptococci were sensitive to amoxicillin and serum amoxicillin levels exceeded the minimum inhibitory concentrations for viridans streptococci. In another study, post-extraction bacteraemia was present in 10% of patients treated with 3 g amoxicillin compared to 89% of control patients; this difference was statistically significant.13 Lockhart et al. administered an amoxicillin elixir 50 mg/kg to children prior to dental extraction.14 At 1.5 min after the initiation of dental extraction, bacteraemia occurred in 15% of patients who were given amoxicillin compared to 76% of patients in the control group (p < 0.001). The use of 2 g amoxicillin given orally as prophylaxis against TABLE 2. NUMBER OF PATIENTS WITH POSITIVE CULTURES AFTER DENTAL EXTRACTION Groups ChlorAmoxiClindaOrganisms Control hexidine cillin mycin Streptococcus mitis 1 Streptococcus sanguis 1 2 Streptococcus anginosus group 4 2 Viridans streptococci 5 5 Streptococcus pneumonia 1 Staphylococcus epidermidis 1 Enterococcus faecalis 1 Neisseria species 1 5 Corynebacterium species 3 Gram-negative bacilli 1 1 Moraxella species 1 Peptostreptococcus species 1 Prevotella melaninogenica 1 Eikenella corrodens 1 Gemella haemolysans 1 Mixed growth 2* Total 14 16 3 8 *Streptococcus sanguis + Streptococcus anginosus group; Viridans streptococci + Neisseria species


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bacteraemia associated with dental extraction was investigated by Lockhart et al.15 There was a statistically significant decrease in the cumulative incidence of endocarditis-related bacteraemia in the amoxicillin group (33 vs 60%). In contrast to these studies, Hall et al. allocated 60 patients to receive placebo, penicillin V (2 g) or amoxicillin (3 g) one hour before dental extraction and used a lysis-filtration technique to process the blood samples.16 The overall incidence of bacteraemia after the extraction was 90, 90 and 85% in the three groups, respectively. The differences in the incidence of bacteraemia among the three groups were not statistically significant. The lack of reduction in both incidence and magnitude of bacteraemia in the two penicillin groups was not due to high minimum inhibitory concentrations or minimum bactericidal concentrations. For all strains except two, the minimum inhibitory concentrations and the minimum bactericidal concentrations were below the antimicrobial serum concentrations that were measured during the dental procedure. The incidence of post-extraction bacteraemia after clindamycin prophylaxis in our study was 20%. Compared to the control group (35%), this difference was not statistically significant. No streptococci were cultured in the clindamycin group. Aitken et al. compared the efficacy of oral doses of 600 mg of clindamycin and 1.5 g of erythromycin in the prevention of post-extraction streptococcal bacteraemia in 40 patients.17 Forty five per cent of patients who had taken clindamycin and 60% of those who had taken erythromycin developed streptococcal bacteraemia; statistical tests were not done. Clindamycin caused fewer adverse gastrointestinal effects than erythromycin. Mean levels of both drugs were not significantly different in those with and without streptococcal bacteraemia. Serum antibiotic levels exceeded the minimum inhibitory concentrations for oral streptococci. Using a lysis-filtration technique to process blood samples, Hall et al. compared the efficacy of clindamycin 600 mg orally and erythromycin 1 g orally given 1.5 hours before dental extraction in 38 patients.18 The overall incidence of bacteraemia with viridans streptococci was 74% in the clindamycin group and 79% in the erythromycin group; the difference between the groups was not statistically significant. All viridans streptococci (except for one strain) were susceptible to both drugs. In the study by Göker and Güvener, the prevalence of bacteraemia immediately following surgical removal of impacted third molars was similar in the group given clindamycin and the control group (40 and 44%, respectively).19 The efficacy of amoxicillin, clindamycin and moxifloxacin was compared by Diz Dios et al.20 The prevalence of postextraction bacteraemia in the control, amoxicillin, clindamycin and moxifloxacin groups at 30 s was 96, 46, 85 and 57%, respectively and at 15 min, it was 64, 11, 70 and 24%, respectively. When compared to the control group, the reductions in the amoxicillin and moxifloxacin groups were statistically significant. Our results also showed a significant reduction for amoxicillin but not for clindamycin. Chlorhexidine did not reduce the incidence of post-extraction bacteraemia in our study. Bacteria were cultured in 40% of patients in the chlorhexidine group compared to 35% in the control group. Lockhart carried out a randomised, doubleblind, placebo-controlled study in 70 patients to evaluate the antibacterial effect of mouth rinses with chlorhexidine in patients

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having a single extraction.8 Blood cultures after dental extraction were positive for organisms in 94% of 33 patients in the control group and in 84% of 37 patients in the chlorhexidine group; differences were not statistically significant. Lockhart8 and Lockhart and Schmidtke21 have drawn attention to the fact that antimicrobial rinses and irrigations do not permeate more than 3 mm into the gingival sulcus and therefore do not reach the area where bacteria gain entrance into the systemic circulation. However, chlorhexidine produced a statistically significant reduction in post-extraction bacteraemia in another study (96 vs 79% at 30 s and 64 vs 30% at 15 min.)22

Conclusion Since studies on the efficacy of antibiotic prophylaxis of infective endocarditis in humans cannot be done for ethical and practical reasons, clinical studies have focused on the prevention of bacteraemia by administration of antimicrobial agents before dental treatment. Our study showed that none of the treatments prevented post-extraction bacteraemia and confirmed earlier reports that bacteraemia is not completely eliminated by antibiotics.1,23-25 It is noteworthy that after reviewing the data on antibiotic prophylaxis, the British Society for Antimicrobial Chemotherapy26 and the American Heart Association27 recommended prophylaxis for high-risk patients undergoing dental procedures. However, the National Institute for Health and Clinical Excellence (NICE) did not recommend antibiotic prophylaxis against infective endocarditis for patients undergoing dental procedures.7

References 1. 2.

3. 4.

5. 6.

7. 8.

9. 10.

11.

12. 13.

Durack DT. Prevention of infective endocarditis. N Engl J Med 1995; 332: 38–44. Endocarditis working party of the British Society for Antimicrobial Chemotherapy. The antibiotic prophylaxis of infective endocarditis. Lancet 1982; ii: 1323–1326. Simmons NA. Recommendations for endocarditis prophylaxis. J Antimicrob Chemother 1993; 31: 437–438. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. J Am Med Assoc 1997; 227: 1794–1801. Simmons NA, Ball AP, Cawson RA, et al. Antibiotic prophylaxis and infective endocarditis. Lancet 1992; 339: 1292–1293. Oliver R, Roberts GJ, Hooper L, Worthington HV. Antibiotics for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Database of Syst Rev 2008 (4): CD003813 National Institute for Health and Clinical Excellence. Prophylaxis against infective endocarditis. 2008. www.nice.org.uk/CG064. Lockhart PB. An analysis of bacteremias during dental extractions. A double-blind, placebo-controlled study of chlorhexidine. Arch Intern Med 1996; 156: 513–520. Cowan ST. Cowan and Steele’s Manual for the Identification of Medical Bacteria. 2nd edn. Cambridge: Cambridge University Press, 1974: 238. Shanson DC, Cannon P, Wilks M. Amoxycillin compared with penicillin V for the prophylaxis of dental bacteraemia. J Antimicrob Chemother 1978; 4:431-436. Oakley CM, Perez G, Darrell JA. Single dose oral amoxycillin for prophylaxis of bacteraemia associated with dental surgery. Br Heart J 1981; 45: 343. Roberts GJ, Radford P, Holt R. Prophylaxis of dental bacteraemia with oral amoxycillin in children. Br Dent J 1987; 162:179–182. Vergis EN, Demas PN, Vaccarello SJ, Yu VL. Topical antibiotic prophylaxis for bacteraemia after dental extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91:162–165.


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14. Lockhart PB, Brennan MT, Kent ML, et al. Impact of amoxicillin prophylaxis on incidence, nature, and duration of bacteremia in children after intubation and dental procedures. Circulation 2004; 109: 2878–2884. 15. Lockhart PB, Brennan MT, Sasser HC, et al. Bacteremia associated with toothbrushing and dental extraction. Circulation 2008; 117: 3118–3125. 16. Hall G, Hedström SA, Heimdahl A, Nord CE. Prophylactic administration of penicillins for endocarditis does not reduce the incidence of postextraction bacteremia. Clin Infect Dis 1993; 17: 188–194. 17. Aitken C, Cannell H, Sefton AM, et al. Comparative efficacy of oral doses of clindamycin and erythromycin in the prevention of bacteraemia. Br Dent J 1995; 178: 418–422. 18. Hall G, Nord CE, Heimdahl A. Elimination of bacteraemia after dental extraction: comparison of erythromycin and clindamycin for prophylaxis of infective endocarditis. J Antimicrob Chemother 1996; 37: 783–795. 19. Göker K, Güvener O. Antibacterial effects of ofloxacin, clindamycin and sultamicillin on surgical removal of impacted third molars. J Marmara Univ Dent Fac 1992; 1: 237–249. 20. Diz Dios P, Carmona IT, Posse JL, et al. Comparative efficacies of amoxicillin, clindamycin, and moxifloxacin in prevention of bacteremia following dental extractions. Antimicrob Agents Chemother 2006; 50: 2996–3002. 21. Lockhart PB, Schmidtke MA. Antibiotic considerations in medically

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compromised patients. Dent Clin North Am 1994; 38: 381–403. 22. Tomás I, Alvarez M, Limeres J et al. Effect of a chlorhexidine mouthwash on the risk of postextraction bacteremia. Infect Control Hosp Epidemiol 2007; 28: 577–582. 23. Hall G, Heimdahl A, Nord CE. Bacteremia after oral surgery and antibiotic prophylaxis for endocarditis. Clin Infect Dis 1999; 29: 1–10. 24. Hupp JR (1993). Changing methods of preventing infective endocarditis following dental procedures: 1943 to 1993. J Oral Maxillofac Surg 1993; 51: 616–623. 25. Hess J, Holloway Y, Dankert J. Incidence of postextraction bacteremia under penicillin cover in children with cardiac disease. Pediatrics 1983; 71: 554–558. 26. Gould FK, Elliott TSJ, Foweraker J, et al. Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2006; 57: 1035–1042. 27. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–1754.

William Nelson ECG Quiz Answer

The old-timers in the club will remember the days when only single-channel recording was available, and the reviewer was forced to make judgments regarding rhythm based on the single lead. How often were we fooled into an incorrect DX, as is evident in this DTT (dirty trick tracing). Sorry about that!


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Comparison of outcomes in ST-segment depression and ST-segment elevation myocardial infarction patients treated with emergency PCI: data from a multicentre registry JIRI KNOT, PETR KALA, RICHARD ROKYTA, JOSEF STASEK, BOYKO KUZMANOV, OTA HLINOMAZ, JAN BĚLOHLAVEK, FILIP ROHAC, ROBERT PETR, DANA BILKOVA, SLAVEJKO DJAMBAZOV, MLADEN GRIGOROV, PETR WIDIMSKY

Abstract Background: Traditionally, acute myocardial infarction (AMI) has been described as either STEMI (ST-elevation myocardial infarction) or non-STEMI myocardial infarction. This classification is historically related to the use of thrombolytic therapy, which is effective in STEMI. The current era of widespread use of coronary angiography (CAG), usually followed by primary percutaneous coronary intervention (PCI) puts this classification system into question. Objectives: To compare the outcomes of patients with STEMI and ST-depression myocardial infarction (STDMI) who were treated with emergency PCI. Methods: This multicentre registry enrolled a total of 6 602 consecutive patients with AMI. Patients were divided into the following subgroups: STEMI (n = 3446), STDMI (n = 907), left bundle branch block (LBBB) AMI (n = 241), right bundle branch block (RBBB) AMI (n = 338) and other electrocardiographic (ECG) AMI (n = 1670). Baseline and angiographic characteristics were studied, and revascularisation therapies and in-hospital mortality were analysed.

Results: Acute heart failure was present in 29.5% of the STDMI vs 27.4% of the STEMI patients (p < 0.001). STDMI patients had more extensive coronary atherosclerosis than patients with STEMI (three-vessel disease: 53.1 vs 30%, p < 0.001). The left main coronary artery was an infract-related artery (IRA) in 6.0% of STDMI vs 1.1% of STEMI patients (p < 0.001). TIMI flow 0–1 was found in 35.0% of STDMI vs 66.0% of STEMI patients (p < 0.001). Primary PCI was performed in 88.1% of STEMI (with a success rate of 90.8%) vs 61.8% of STDMI patients (with a success rate of 94.5%) (p = 0.012 for PCI success rates). In-hospital mortality was not significantly different (STDMI 6.3 vs STEMI 5.4%, p = 0.330). Conclusion: These data suggest that similar strategies (emergency CAG with PCI whenever feasible) should be applied to both these types of AMI. Keywords: coronary artery disease, acute myocardial infarction, primary PCI Submitted 3/10/11, accepted 8/6/12 Cardiovasc J Afr 2012; 23: 495–500

www.cvja.co.za

DOI: 10.5830/CVJA-2012-053

Third Faculty of Medicine, Charles University, Prague, Czech Republic JIRI KNOT, MD, knot@fnkv.cz FILIP ROHAC, MD, ROBERT PETR, MD DANA BILKOVA, MD PETR WIDIMSKY, MD, DSc JAN BĚLOHLAVEK, MD, PhD

Faculty Hospital, Brno, Masaryk University, Czech Republic PETR KALA, MD, PhD

Faculty of Medicine, Pilsen, Charles University Prague, Czech Republic RICHARD ROKYTA, MD, PhD

Faculty of Medicine, Hradec Kralove, Charles University Prague, Czech Republic JOSEF STASEK, MD, PhD

UniCardio Clinic Pleven, Bulgaria BOYKO KUZMANOV, MD SLAVEJKO DJAMBAZOV, MD MLADEN GRIGOROV, MD PhD

Faculty Hospital St Anne, Masaryk University, Brno, Czech Republic OTA HLINOMAZ, MD, PhD

ST-segment elevation (STEMI) and ST-segment depression (STDMI) myocardial infarctions have a common pathogenesis – a vulnerable plaque ruptures, followed by luminal thrombus formation.1-4 Thrombosis may lead to rapid changes in the severity of coronary artery stenosis, which may cause subtotal or total vessel occlusion. The thrombus may completely occlude the major epicardial coronary artery in cases of STEMI,5 or cause partial or intermittent vessel occlusion in cases of non-STelevation myocardial infarction (NSTEMI).6 This traditional classification of patients with acute myocardial infarction (AMI), based on baseline electrocardiographic (ECG) recordings, has practical implications for guidelines and in clinical practice especially, as it refers to the use of reperfusion therapy. The separation of STEMI from other types of acute myocardial infarction has its historical roots in the thrombolytic era. The current widespread use of primary percutaneous coronary intervention (pPCI) makes use of modified reperfusion treatment for myocardial infarction patients. Recently published randomised trials and meta-analyses,7-12 as well as the guidelines of the European Society of Cardiology (ESC) for myocardial infarction in patients presenting with persistent ST-segment


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elevation,13 indicate that pPCI is the preferred reperfusion strategy in AMI patients when performed by an experienced team as soon as possible after first medical contact. The pPCI reperfusion modality remains superior to immediate thrombolysis, even if transfer to an angioplasty centre is necessary. Similarly, an early invasive strategy with early coronary angiography and revascularisation has become the preferred approach for patients with NSTEMI.14-17 Additionally, the ESC guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes (ACI) appropriately recognises AMI with ongoing or recurrent chest pain and ST-segment depression as the highest risk subgroup and is an indication for emergency coronary angiography, followed by revascularisation, when appropriate.18 From the sub-analysis of two previously published trials19,20 and a meta-analysis,21 it has been shown that the greatest benefit of early invasive treatment was found in patients with elevated cardiac enzymes and ST-segment changes, i.e. in patients with STDMI. The aim of this study was to analyse a large group of AMI patients presenting with different ECG records and to assess the similarities and differences between baseline and angiographic characteristics, to assess in-hospital management and mortality, and to test the hypothesis that an emergency PCI strategy should be used in both ST-segment elevation MI as well as in ST-segment depression MI.

Methods This retrospective, multicentre, observational registry included a total of 6 602 consecutive patients admitted to five participating centres (four in the Czech Republic and one in Bulgaria; all university-type hospitals with catheterisation facilities) for an acute myocardial infarction during a three-year recruitment period (except for the centre in Bulgaria, where the recruitment period was only one year). All participating hospitals followed the guidelines of the Czech Society of Cardiology. All patients underwent emergency coronary angiography (CAG). Patients with STEMI, new left bundle branch block (LBBB) or right bundle branch block (RBBB) and STDMI with ongoing chest pain underwent CAG immediately after hospital arrival. In all remaining cases, the procedure was performed within 24 hours of onset of AMI symptoms. Subjects had to be 18 years or older. Based on admission ECG records, patients were divided into one of five subgroups: ST-elevation AMI (n = 3446; 52.2%), ST-depression AMI (n = 907; 13.7%), LBBB AMI (n = 241; 3.7%), RBBB AMI (n = 338; 5.1%), other baseline ECG AMI (n = 1670; 25.3%). STEMI was defined as new ST-elevation at the J-point in two contiguous leads with cut-off points of ≥ 0.2 mV in men or ≥ 0.15 mV in women in leads V2–3 and/or ≥ 0.1 mV in other leads. STDMI was defined as a new horizontal or down-sloping ST depression ≥ 0.05 mV in two contiguous leads or transient ST-segment elevations. The other ECG group represented all remaining ECG patterns excluding STEMI, STDMI, LBBB and RBBB. Patients entered into the registry were admitted for an acute myocardial infarction using only the ESC/ACC myocardial infarction redefinition.22 Symptoms consistent with ischaemia, new ECG changes and a typical rise and fall of cardiac enzymes levels (troponin I and/or T and/or creatine phosphokinase-MB)

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were mandatory for inclusion. Moreover, the diagnosis of MI had to be confirmed at the time of discharge from hospital. Baseline characteristics, such as age, gender, diabetes mellitus, history of previous myocardial infarction, Killip class on admission and ECG pattern (including information regarding any bundle branch blocks – old, new or of unknown origin) were analysed. Coronary angiographic (or autopsy) data were analysed to estimate the number of diseased major coronary arteries, to identify the infarct-related artery (IRA), and assess thrombolysis in myocardial infarction (TIMI) flow in the infarct-related artery before and after PCI (whenever PCI was performed). To identify the ejection fraction, pre-discharge echocardiographic examinations were performed. Revascularisation strategies used during the index hospital stay were studied. Patients were followed until transfer to a referral hospital or hospital discharge/death. Death was defined as all-cause mortality during hospitalisation. The in-hospital mortality was also analysed.

Statistical analysis Patients with STEMI and STDMI were compared based on demographics, medical history and risk factors, infarctrelated artery and segment, initial and post-procedural TIMI flow, reperfusion success and in-hospital mortality. Statistical comparisons between subgroups were performed using Chi-square and Fisher’s exact tests for categorical variables; data are expressed in percentages. Continuous variables are presented as means ± standard deviations and were compared using the two-sample Student’s t-test. For ordinary variables, the Mann–Whitney test was applied. All tests were two-tailed, and a p-value < 0.05 was considered statistically significant. A logistic regression model was used to adjust the differences in mortality for covariate effects. The following factors and covariates were used in the model: age, gender, previous diabetes and myocardial infarction, Killip class > I on admission, and pre-discharge ejection fraction.

Results During the study period, a total of 6 602 patients were enrolled in the registry from five participating centres. There were 3 446 patients with STEMI and 907 with STDMI. Patients presenting with STEMI were younger than those with STDMI. The mean age in the STEMI group was 64.5 years and in the STDMI group 69.5 years (p < 0.001). There were more patients under 75 years in the group with STEMI than in the STDMI group (74.5 vs 63.6%, p < 0.001). Compared to STEMI patients, STDMI patients were more likely to have a history of a previous MI (STDMI 29.3% vs STEMI 13.8%, p < 0.001) and diabetes mellitus (36.8 vs 24.1%, p < 0.001). The gender distribution was equal between the STEMI and STDMI groups (females 31.3 vs males 34.6%, p = 0.055). Patients in the STEMI group were more likely to be in cardiogenic shock on admission. Killip class IV on admission was present in 6.7% of STEMI patients compared to 4.4% in STDMI patients (p < 0.001). Acute heart failure defined as Killip class > 1 on admission (pulmonary rales or third heart sound and pulmonary oedema) was present in 29.5% of STDMI vs 27.4% of STEMI patients (p < 0.001) (Table 1).


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TABLE 1. BASELINE CHARACTERISTICS IN STEMI AND STDMI PATIENTS

TABLE 2. ANGIOGRAPHIC CHARACTERISTICS AND PROCEDURAL OUTCOMES IN STEMI AND STDMI PATIENTS

STEMI STDMI p-value Age in years ± SD 64.5 ± 12.4 69.5 ± 10.7 < 0.001 Age < 75 years (%) 74.5 63.6 < 0.001 Females (%) 31.3 34.6 0.055 Previous myocardial infarction (%) 13.8 29.3 < 0.001 Diabetes mellitus (%) 24.1 36.8 < 0.001 Killip class > I (%) 27.4 29.5 < 0.001 Killip class IV (%) 6.7 4.4 < 0.001 STEMI: ST-elevation myocardial infarction; STDMI: ST-depression myocardial infarction.

STEMI STDMI p-value Number of involved vessels (%) One-vessel disease 37.3 17.2 < 0.001 Two-vessel disease 28.2 19.9 Three-vessel disease 30.0 53.1 Infarct-related artery (%) Left main 1.1 6.0 < 0.001 Left anterior descending 45.0 31.5 Left circumflex 14.0 37.5 Right coronary 39.1 21.2 CABG 0.8 3.8 Pre-PCI TIMI flow (%) TIMI flow 0 57.2 27.3 < 0.001 TIMI flow 1 8.8 7.7 TIMI flow 2 18.5 24.5 TIMI flow 3 15.5 40.6 Post-PCI TIMI flow (%) TIMI flow 3 90.8 94.5 < 0.012 LVEF (%), mean ± SD 46.3 ± 12.0 50.1 ± 13.5 < 0.001 STEMI: ST-elevation myocardial infarction; STDMI: ST-depression myocardial infarction; TIMI: thrombolysis in myocardial infarction flow; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; LVEF: left ventricular ejection fraction.

STEMI patients had less-extensive coronary atherosclerosis than STDMI patients. There were more patients with three- or two-vessel disease in the STDMI group than in the STEMI group (73.0 vs 58.2%, p < 0.001). Severe left main stenosis was also more often present in STDMI patients compared to STEMI patients (6.0 vs 1.1%, p < 0.001). The left circumflex artery was more likely to be the infarct-related artery in STDMI compared to STEMI patients (37.5 vs 14%, p < 0.001). Moreover, nearly one-third of all STDMI patients had a TIMI 0 flow before PCI. The infarct-related artery was more often totally occluded in STEMI patients compared to STDMI patients (57.2 vs 27.3%, p < 0.001). Emergency PCI was performed in 88.1% of STEMI patients versus 61.8% of STDMI patients. The success rates were higher in STDMI patients (94.5 vs 90.8%, p < 0.012) (Table 2). Rates of acute coronary bypass grafts were significantly higher in patients with STDMI (Fig. 1). Despite the higher mean ejection fraction, in-hospital mortality was slightly but insignificantly higher in STDMI patients compared to STEMI patients (6.3 vs 5.4%, p = 0.330). There was no significant difference regarding in-hospital mortality between STEMI and STDMI patients who were treated 100 90 80 70

89.1

88.1

69.8

16

61.8

60

using emergency PCI (5.3 vs 6.78%, p = 0.274). However, there was a large difference regarding in-hospital mortality between STDMI patients treated using PCI (6.78%) and STDMI patients without revascularisation (13.19%) (p = 0.032). Using logistic regression analysis, the independent risk factor for mortality was patient age (OR 1.03, 95% CI: 1.015–1.049, p < 0.001); there was a 1.03-fold increased risk for every additional year of age. Killip class > I on admission was also a strong predictor of mortality (OR 2.54, 95% CI: 1.754–3.685, p < 0.001). A lower risk of death was associated with higher ejection fractions (OR 0.982, 95% CI: 0.967–0.997, p < 0.024). Patients presenting with MI and any bundle branch block (left or right bundle branch block ± left anterior/posterior hemiblock) represented the highest risk group, with in-hospital

14

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8

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6 8.0

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Any revascularisation

Acute PCI

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Fig. 1. Bar graphs show the type of revascularisation therapy used in ST-segment elevation (STEMI) and ST-segment depression (STDMI) myocardial infarctions. All values are percentages (p < 0.001). CABG: coronary artery bypass graft.

13.1

5.4

14.3

6.3

4

2.9

2 0

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LBBB

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Fig. 2. Bar graph demonstrates the in-hospital mortality rates in different ECG groups of acute myocardial infarction patients. All values are percentages (p < 0.001). STEMI/STDMI: ST-segment elevation/depression myocardial infarction. LBBB/RBBB: left/right bundle branch block.


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mortality more than double compared to patients who presented with STDMI (risk ratios 2.03, 95% CI: 1.46–2.83, p < 0.001) or STEMI (risk ratios 2.36, 95% CI: 1.83–3.04, p < 0.001). On the other hand, patients presenting with minor or no ECG abnormalities (without ST-segment shifts and without bundle branch block/s) had a significantly lower risk (acute heart failure was rare and in-hospital mortality was very low). The in-hospital mortality in this group of patients was 2.9% (p < 0.001). Fig. 2 presents a comparison between patients with minor or no ECG changes and each of the other groups (STEMI, STDMI, LBBB, RBBB).

Discussion STEMI and STDMI have a common pathogenesis: vulnerable plaque erosion or rupture followed by thrombus formation, resulting in impaired vessel patency. Impaired or no flow in a coronary artery causes ischaemic symptoms and ECG changes. The release of myocardial necrosis markers defines the diagnosis of myocardial infarction. The current guidelines recommend different reperfusion approaches based on the admission ECG in patients with acute MI. On the other hand, ECG changes can be altered by a bundle branch block, previous MI and other conditions. Also, the infarctrelated artery and infarct-related segment can influence the final ECG pattern. For example, acute occlusion of the circumflex artery may have no ST-segment elevation on a 12-lead ECG. Instead, ST-segment depressions are frequently present – this is sometimes called a hidden STEMI. In our registry the most common IRA in STDMI patients was the circumflex branch. Moreover, nearly one-third of all STDMI patients had a TIMI grade 0 flow before PCI. Infarction in the circumflex artery bed is very often under-diagnosed and these patients undergo coronary angiography very late or not at all. Based on these facts, there is an increasing effort to find real differences or similarities between STEMI and STDMI regarding their risk factors, prognosis, mortality and appropriate revascularisation strategy. In previously published studies, baseline characteristics of patients with STEMI compared to those without ST-segment elevation were significantly different, and the same was true in this study. Patients with STEMI were younger and had less often had a previous MI and/or diabetes mellitus. Cardiogenic shock was also found to be more common in STEMI patients. Rosenberger et al.23 investigated whether risk factors were related differently to ST-elevation and non-ST-elevation ACS. The main finding from this large survey of more than 10 000 patients was that different risk factors were related to different types of ACS. Smoking was related to STEMI patients, whereas obesity and high blood pressure were more common among MI patients without ST-elevation. Our findings confirm the results of the Opera registry.24 The primary objective of the nationwide Opera study was to describe the in-hospital management and cardiovascular outcomes (at one year) of MI patients. The results show that patients suffering from MI with and without ST-elevation had comparable in-hospital (4.6 vs 4.3%) and long-term prognoses (9% in STEMI vs 11.6% in NSTEMI, log-range p = 0.09). Cox et al.25 showed (in the Comparative early and late outcomes after primary percutaneous coronary intervention

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in ST-segment elevation and non-ST-segment elevation acute myocardial infarction from the CADILLAC trial) that patients with myocardial infarction without ST-elevation tended to have lower mortality rates than those with STEMI (0.4 vs 2.2%, p = 0.06). Similarly, the mortality rates at one year were comparable in STEMI and NSTEMI patients (3.4 vs 4.4%, respectively, p = 0.43). In a study by Savonitto et al.,26 the 30-day mortality rate between STEMI and STDMI was not statistically different (5.1 vs 5.1%, respectively). Granger et al.27 attempted to develop a single model to assess the risk for in-hospital mortality of ACS patients. Killip class was the most powerful predictor with a two-fold increased risk of death with each worsening class. Age was associated with nearly the same prognostic significance, with a 1.7-fold increased risk for every 10 years’ increase in age. The next most important variables were systolic blood pressure, resuscitated cardiac arrest and initial serum creatinine levels. The strongest predictors of one-year mortality in the Opera study were heart failure and age. Moreover, similar predictors were found in STEMI and NSTEMI patients.24 The same was true in our registry, with age and heart failure being strong independent in-hospital mortality risk factors. There is no doubt that timely reperfusion of STEMI patients is critical. The current guidelines of the European Society of Cardiology appropriately recognise acute myocardial infarction with ongoing or recurrent chest pain and ST-segment depressions as the highest-risk subgroup and an indication for emergency coronary angiography, followed by revascularisation when appropriate. Chan et al.28 investigated mortality differences and timing of revascularisation of patients undergoing cardiac catheterisation for STEMI and NSTEMI. During the six-year accrual period, a total of 1 974 patients were classified as having STEMI, and 2 413 patients as having NSTEMI. NSTEMI was associated with a higher risk of long-term mortality (unadjusted mortality at one year for STEMI was 9.5 vs 14.3% for NSTEMI). Compared with no or late revascularisation, early revascularisation was associated with a similar reduction in long-term outcomes for both STEMI and NSTEMI (lower adjusted risk of mortality for STEMI and NSTEMI, p = 0.22). The Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC-2) invasive trial showed for the first time a significant event rate (MI, death or both) reduction, favouring the invasive over the non-invasive strategy at six months in the NSTE-ACS population. The greatest benefit of invasive treatment, when evaluated using electrocardiography, was seen in the subset of patients with ST-segment depression MI.19 The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI) trial revealed that the greatest benefits of invasive treatment were achieved in patients presenting with cardiac enzyme elevation and ST-segment changes,20 i.e. in STDMI patients. Also, a metaanalysis of seven randomised trials that included a total of 9 212 patients showed that invasive management should be considered for all patients with NSTEMI, and in particular those with ST-segment depression.21 In our study, there was no difference related to in-hospital mortality between STEMI and STDMI patients treated by emergency PCI (5.3 vs 6.78%, respectively, p = 0.274). There was a significant in-hospital mortality reduction in STDMI patients


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who were treated using emergency PCI compared to STDMI patients who went without revascularisation. Moreover, the PCI success rate was significantly higher in STDMI compared to STEMI patients (p = 0.012). All these factors indicate that emergency CAG and PCI, when appropriate, should be used in all STDMI patients. Early versus delayed invasive intervention in patients with ACS without ST-segment elevation was studied in the TIMACS trial.29 Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, MI or refractory ischaemia, and was superior to delayed intervention in high-risk patients. Our study demonstrates the apparent positive development in invasive reperfusion treatment for acute myocardial infarction. Some form of reperfusion therapy was used in 89.1% of STEMI and 69.8% of NSTEMI patients. Of those, emergency PCI was used in 88.1% of STEMI and in 61.8% of NSTEMI patients. By comparison, in the GRACE study (1999–2000),30 the use of pPCI was a relatively rare reperfusion modality in STEMI. Lytic therapy was used in more than 75% of patients who received reperfusion therapy; only 62% of STEMI patients received any form of reperfusion. The in-hospital fatality rates were 7% in STEMI and 6% in NSTEMI patients (p = 0.0459). This positive and increasing trend of invasive treatment in AMI patients should be minimally maintained in STEMI cases, and there should be an effort made to increase the number in STDMI patients. The presence of bundle brunch block(s) (BBBs) is associated with poor outcomes in patients suffering from an AMI. In our MI population, these patients represented the highest risk group, with in-hospital mortality more than double that of STDMI or STEMI patients. Patients with BBBs were older and more frequently had a history of diabetes mellitus. The mean left ventricular ejection fraction was lower compared with AMI patients without BBBs (p < 0.001). These findings support the results of Guerrero et al.31 who sought to evaluate the outcome of patients with AMI and BBBs, who were treated using emergency PCI. The in-hospital mortality was significantly different (LBBB 14.6% vs RBBB 7.4% vs no BBB 2.8%). Patients presenting with minor or no ECG abnormalities (without ST-segment shifts and without a bundle branch block) had the lowest mortality compared with all other groups (2.9%, p < 0.001). Additionally, heart failure was rare (Killip class I on admission was seen in 84.5% of all patients in this group).

Limitations This study was based on the data from a registry that was retrospectively analysed. The very short follow-up period was a limitation. Our results did not evaluate long-term outcomes. No data were collected regarding previous or in-hospital drug treatment. Post-discharge treatment (secondary prevention) was also not studied.

Conclusions The results of our study demonstrate that ST-depression AMI may represent an emergency similar to ST-elevation AMI. Therefore it would be accompanied by the same need for emergency coronary angiography and PCI when appropriate. STDMI

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patients in our study had comparable in-hospital mortality and were much closer, relative to treatment strategies and outcomes, to STEMI patients than to AMI patients without ST-segment shifts. Therefore, in the ‘post-thrombolytic’ era, emergency CAG and PCI, when appropriate, should be considered for high-risk patients with STDMI. This work was supported by the research project of the Charles University Prague no. MSM0021620817. We thank all those who contributed to the creation of the registry.

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Davies MJ, Thomas AC. Plaque fissuring – the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985; 53: 363–373. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-671. Falk E: Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006; 47: C7–12. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: A comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262–1275. Rittersma SZ, van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: A pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005; 111: 1160–1165. Brilakis ES, Reeder GS, Gersh BJ. Modern management of acute myocardial infarction. Curr Probl Cardiol 2003; 28: 7–127. Keeley EC, Grines CL. Primary coronary intervention for acute myocardial infarction. J Am Med Assoc 2004; 291: 736–739. Dalby M, Bouzamondo A, Lechat P, Montalescot G. Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: A meta-analysis. Circulation 2003; 108: 1809–1814. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. Shock investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999; 341: 625–634. Kastrati A, Mehilli J, Nekolla S, et al. A randomized trial comparing myocardial salvage achieved by coronary stenting versus balloon angioplasty in patients with acute myocardial infarction considered ineligible for reperfusion therapy. J Am Coll Cardiol 2004; 43: 734–741. Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar F, Suryapranata H. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 2000; 21: 823–831. Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial – PRAGUE-2. Eur Heart J 2003; 24: 94–104. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008; 29: 2909–2945. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein iib/iiIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–1887. Invasive compared with non-invasive treatment in unstable coronaryartery disease: Frisc ii prospective randomised multicentre study. Fragmin and fast revascularisation during instability in coronary artery disease investigators. Lancet 1999; 354: 708–715. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive


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strategy in unstable coronary-artery disease: The frisc ii invasive randomised trial. frisc ii investigators. Fast revascularisation during instability in coronary artery disease. Lancet 2000; 356: 9–16. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-stelevation myocardial infarction: The British Heart Foundation rita 3 randomised trial. Randomized intervention trial of unstable angina. Lancet 2002; 360: 743–751. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-st-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598–1660. Boden WE. ‘Routine invasive’ versus ‘selective invasive’ approaches to non-st-segment elevation acute coronary syndromes management in the post-stent/platelet inhibition era. J Am Coll Cardiol 2003; 41: 113S–122S. Popma JJ, Suk J. Use of coronary revascularization in patients with unstable and non-st-segment elevation acute myocardial infarction. Am J Cardiol 2001; 88: 25K–29K. Choudhry NK, Singh JM, Barolet A, Tomlinson GA, Detsky AS. How should patients with unstable angina and non-ST-segment elevation myocardial infarction be managed? A meta-analysis of randomized trials. Am J Med 2005; 118: 465–474. Myocardial infarction redefined – a consensus document of the joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction. Eur Heart J 2000; 21: 1502–1513. Rosengren A, Wallentin L, Simoons M, et al. Cardiovascular risk factors and clinical presentation in acute coronary syndromes. Heart 2005; 91: 1141–1147. Montalescot G, Dallongeville J, van Belle E, et al. STEMI and

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NSTEMI: Are they so different? 1 year outcomes in acute myocardial infarction as defined by the esc/acc definition (the opera registry). Eur Heart J 2007; 28: 1409–1417. Cox DA, Stone GW, Grines CL, et al. Comparative early and late outcomes after primary percutaneous coronary intervention in ST-segment elevation and non-ST-segment elevation acute myocardial infarction (from the cadillac trial). Am J Cardiol 2006; 98: 331–337. Savonitto S, Ardissino D, Granger CB, et al. Prognostic value of the admission electrocardiogram in acute coronary syndromes. J Am Med Assoc 1999; 281: 707–713. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003; 163: 2345–2353. Chan MY, Sun JL, Newby LK, et al. Long-term mortality of patients undergoing cardiac catheterization for st-elevation and non-st-elevation myocardial infarction. Circulation 2009; 119: 3110–3117. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med 2009; 360: 2165–2175. Steg PG, Goldberg RJ, Gore JM, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the global registry of acute coronary events (GRACE). Am J Cardiol 2002; 90: 358–363. Guerrero M, Harjai K, Stone GW, Brodie B, Cox D, Boura J, et al. Comparison of the prognostic effect of left versus right versus no bundle branch block on presenting electrocardiogram in acute myocardial infarction patients treated with primary angioplasty in the primary angioplasty in myocardial infarction trials. Am J Cardiol 2005; 96: 482–488.

Think before you say ‘pass the salt please’ South Africans are eating twice as much salt as they should. Even more alarming, a fifth of South Africans are so entrenched in the salt habit, they add salt to their food without tasting it first. Men are the worst offenders. As a result the country’s already heavy health burden is getting worse, with lifestyle diseases such as diabetes, high blood pressure and coronary heart disease reportedly on a sharp increase. So worrying are the statistics that national health minister Dr Aaron Motsoaledi is planning to introduce legislation that will control the amount of salt that is allowed to be introduced into food products manufactured and sold in South Africa. During a briefing to Parliament recently, Motsoaledi said that an acceptable daily average per adult was between 4 and 6 g. ‘But from our investigation, the average South African consumes an average of 9.8 g a day, which is far too much for a healthy lifestyle’, he said. Processed foods, said Motsoaledi, were the main source of salt intake, rather than what consumers added at the table. Durban-based Unilever conducted a national survey earlier this year to ascertain the level of understanding about the dangers of a diet containing too much salt. Unilever’s focus on salt reduction is in line with Unilever’s Sustainable Living Plan launched in 2010, where the FMCG has committed globally to help more than one billion people take action to improve their health and well-being. In South Africa Unilever is making good progress reducing salt levels in its products and the goal is to reduce the level further to help consumers meet the recommended level of 6 g of salt per day. Nazeeia Sayed, Unilever’s national nutrition and health manager and convener of a salt-reduction workshop at the North

Coast estate of Zimbali last week, said that the findings were ‘extremely illuminating’. She said it was clear from the nearly 1 000 interviews that the majority of people had no idea how much salt was in their food, or how much they should be consuming on a daily basis. It was clear, she said, that the salt issue was ‘not top of mind’ for the majority of consumers who took part in the survey. ‘However, some people, for instance those with high blood pressure, were particularly interested in learning more about salt reduction and how a lower intake of salt could potentially help them maintain a healthy blood pressure.’ The survey found that most sodium comes from purchased foods, accounting for 77% of intake. This included seasonings, bread, processed meat and breakfast cereals. The people who consumed the most salt were between the ages of 18 and 34 years, mostly single and studying. People suffering from high blood pressure were also among the high salt users. Consumers surveyed said that they would be willing to reduce their salt intake, and that there should be greater awareness made of the alternatives, such as herbs and spices, and how to cook low-salt meals and use low-salt substitutes. ‘Consumers also wanted better salt signage on food labels’, said Sayed. ‘A fun masterchef programme on tasty low-salt meals was also suggested as a way to get South Africans to reduce their salt intake.’ Among those who participated in the survey and those who will be targeted for support of the national salt-reduction programme … continued on page 521


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Elevated salivary C-reactive protein predicted by low cardio-respiratory fitness and being overweight in African children T NAIDOO, K KONKOL, B BICCARD, K DUBOSE, AJ MCKUNE

Abstract Introduction: C-reactive protein (CRP) is a sensitive marker of systemic inflammation and is an independent risk factor for cardiovascular disease. The aim of the study was to examine the relationship between salivary CRP, cardio-respiratory fitness and body composition in a paediatric population. Methods: This was a cross-sectional study of 170 black South African children (age 9.41 ± 1.55 years, 100 females, 70 males) in grades 3 to 7. Unstimulated whole saliva samples were obtained for the analysis of CRP. Height, mass, skin-fold thickness, resting blood pressure, and waist and hip circumference measurements were obtained. Cardio-respiratory fitness was assessed using a 20-m multi-stage shuttle run. Children were classified as overweight/obese according to the Center for Disease Control and Prevention (CDC) body mass index (BMI) percentile ranking, and meeting percentage body fat recommendations, if percentage body fat was ≤ 25% in boys and ≤ 32% in girls. The cut-off point for low cardio-respiratory fitness was a predicted aerobic capacity value ≤ the 50th percentile for the group. Contributions of low cardio-respiratory fitness, overweight/obesity, and not meeting percentage body fat recommendations, to elevated salivary CRP (≥ 75th percentile) concentration and secretion rate were examined using binary logistic regression analysis with a backward stepwise selection technique based on likelihood ratios. Results: Poor cardio-respiratory fitness was independently associated with elevated salivary CRP concentration (OR 3.9, 95% CI: 1.7–8.9, p = 0.001). Poor cardio-respiratory fitness (OR 2.7, 95% CI: 1.2–6.1, p = 0.02) and overweight/obesity (BMI ≥ 85th percentile) (OR 2.5, 95% CI: 1.1–5.9, p = 0.03) were independent predictors of elevated salivary CRP secretion rate. Conclusion: The results suggest a strong association between poor cardio-respiratory fitness and/or overweight/obesity and inflammatory status in children, based on elevated salivary CRP levels. Department of Biokinetics, Exercise and Leisure Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa T NAIDOO, BSpSc K KONKOL, MA AJ MCKUNE, DTech, mckunea@ukzn.ac.za

Perioperative Research Group, Department of Anaesthetics, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa B BICCARD, MB ChB, FCA (SA), FFARCSI, MMed Sci, PhD

Physical Activity Promotion Laboratory, Department of Kinesiology, East Carolina University, USA K DUBOSE, PhD

Keywords: inflammation, C-reactive protein, body composition, children, cardio-respiratory fitness Submitted 20/2/12, accepted 6/8/12 Cardiovasc J Afr 2012; 23: 501–506

www.cvja.co.za

DOI: 10.5830/CVJA-2012-058

Inflammation has been hypothesised as a potential mediator of the association between obesity, physical inactivity and the development of chronic diseases, such as cardiovascular disease (CVD), type 2 diabetes, depression and cancer.1 Low-grade systemic inflammation, a condition marked by a chronic twoto three-fold increase in circulating inflammatory markers,2 is considered important in the chronic disease process through promoting the development of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth.3 Systemic C-reactive protein (CRP) is a sensitive marker of low-grade systemic inflammation and is an independent risk factor for CVD.4-6 It is therefore important to characterise the determinants of individual differences in inflammatory markers such as CRP.7 The current worldwide pandemic of childhood obesity and low levels of cardio-respiratory fitness (CRF) makes the understanding of inflammation and interventions to reduce inflammation, important areas of research.8,9 Obese children have higher levels of systemic CRP compared to children of normal weight, suggesting that chronic low-grade systemic inflammation is an early complication of childhood obesity.8 In addition, elevated systemic CRP in young children is a risk factor for the development of the metabolic syndrome.9 Research has revealed an association between elevated systemic CRP and low CRF.10 By contrast, several studies show that systemic CRP is lowered by a reduction in visceral fat mass and/or increased physical activity or exercise.11,12 In healthy, pre-pubertal children, elevated CRF was shown to protect against low-grade inflammation.10 There is limited research in this area in Africa, although a recent study of black South African adolescents reported a trend for increased levels of serum CRP in individuals with a higher percentage body fat.13 The study also found a negative correlation between fitness levels and serum CRP.13 However, the investigation of inflammatory levels is delayed by the lack of non-invasive methods to assess inflammation that would enable research in large representative populations and in children.7 The investigation of inflammatory biomarker levels are commonly measured in blood collected through venipuncture. However, venipuncture is an invasive procedure and requires skilled professionals, laboratory equipment and considerable financial resources.7 By contrast, saliva collection is non-invasive, stress- and pain-free and constitutes an alternative strategy to prospectively assess immune activity in large samples.7 The measurement of biomarkers in saliva to examine


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numerous clinical conditions has increased over the last decade.14,15 Recently, a high-sensitivity commercially available enzyme-linked immunoassay (ELISA) adapted to measure CRP in human saliva was validated against serum CRP.7 The findings provided initial support for the use of salivary CRP as an alternative marker of inflammation, with a moderateto-strong association (r = 0.72, p < 0.001) between CRP measured in saliva and serum.7 In addition, salivary and plasma CRP were shown to be moderately correlated (r = 0.61) in females, and salivary CRP was able to discriminate between high and low levels of plasma CRP, using a clinically relevant cut-off point of 3 mg/l.16 These results were consistent with strong correlations between saliva and serum CRP levels in earlier animal studies, specifically in pigs (r = 0.73),17 and in healthy and diseased dogs (r = 0.87 and r = 0.84, respectively).18 In addition to being non-invasive, the assessment of CRP in the saliva allows data collection to take place in the participant’s natural environments (home and school). Furthermore, CRP in saliva is stable at room temperature for up to eight hours after collection, making the sampling of saliva outside of research facilities a viable option.7 Previous studies have also shown that serum CRP does not have a circadian rhythm19,20 and therefore saliva sampling aimed to measure salivary CRP does not require one to follow a standardised time-collection schedule to avoid diurnal variations.7 Recently, salivary CRP was shown to be a good measure of discrimination for the clinically relevant serum CRP cut-off point in adults.7 Participants with high salivary CRP levels were more likely to have higher IL-6 levels and body mass index (BMI) and to smoke, compared to participants with low salivary CRP levels.7 The results suggested that salivary CRP may represent an alternative marker of cardiovascular risk in adults,7 however the association with a major risk factor for the development of chronic diseases, low CRF,21 was not included in the analysis. There is limited research on the relationship between body composition, CRF and salivary CRP in adults and specifically in paediatric populations. The aim of this study was to examine the relationship between salivary CRP, body composition and cardio-respiratory variables in grade 3 to 7 children.

Methods One hundred and seventy black South African children (100 females, 70 males) in grades 3 to 7 (age 9.41 ± 1.55 years) participated in the study. Participants were recruited from an urban, combined junior and senior primary school in Pietermaritzburg, KwaZulu-Natal. Gate-keeper permission to perform the study was obtained from the KwaZulu-Natal Department of Education, the school’s headmaster and governing body. The study was approved by the institution’s Biomedical Ethics Research Committee. Once permission to continue was obtained, a meeting was held with parents/guardians and children to discuss the research details and expectations of the participants. Written informed consent was obtained at the meeting. The guardians/parents completed a medical history form that included sections on infectious, immune and salivary gland disorders. The parents/guardians were trained in the salivary collection procedure and were provided with instructions regarding brushing teeth and the intake of food and drink on the morning of the saliva collection. These standardised instructions are outlined below.

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Saliva collection and C-reactive protein analysis Each grade was tested on a separate morning over a week, starting with grade 3 on Monday and ending with grade 7 on Friday. Saliva samples were collected between 07:30 and 08:30, approximately 90 minutes after waking. The parents/guardians and children were requested to adhere as closely as possible to the following standardised saliva collection instructions (Salimetrics 2010): The children should (1) not eat a major meal (breakfast) within 60 minutes of sample collection, (2) not brush their teeth prior to sample collection (this may cause the gums to bleed causing blood contamination of the saliva), (3) avoid dairy products for 20 minutes before sample collection, (4) avoid foods with high sugar, acidity, or high caffeine content immediately before sample collection (these have all been shown to impact on the saliva pH, altering assay results), (5) rinse their mouths with water to remove food residue before sample collection, and swallow to increase hydration, and (6) wait at least 10 minutes after rinsing before collecting saliva to avoid sample dilution. Upon arriving in the school hall at 07:00 the children sat for 20 minutes. Based on completion of a short health questionnaire and interview with the researchers upon arrival, no participant reported symptoms suggesting that he/she was sick (e.g. fever, flu, diarrhoea) and there were no reports of ‘bleeding gums’ or ‘tooth ache’ on the day of data collection. Saliva samples were collected via unstimulated passive drool over a time period of five minutes. While seated, the children were asked to lean slightly forward, tilt their heads down and accumulate saliva in the floor of the mouth for a minute, which was subsequently swallowed. Following this, there was a fourminute collection where the children dribbled saliva through a 5-cm plastic straw into a pre-weighed polypropylene cryovial (5 ml capacity). Care was taken to allow saliva to dribble into the collecting tubes with minimal orofacial movement. After collection, the cryovial was weighed in order to determine the saliva flow rate. The concentration of salivary CRP was expressed as the secretion rate of salivary CRP (pg/min) or the total amount of salivary CRP appearing on the mucosal surface per unit time. Salivary CRP secretion rate was calculated by multiplying absolute salivary CRP concentration (pg/ml) by saliva flow rate (ml/min). This latter value was calculated by dividing the total volume of saliva obtained in each sample (ml) by the time taken to produce each sample (4 min). Samples were placed on dry ice immediately and kept frozen until reaching the laboratory, upon which they were stored at –70oC until analysis. Salivary CRP concentration (pg/ml) was determined in duplicate by the salivary C-reactive protein ELISA kit (Salimetrics, State College, PA, USA). The coefficients of variation (CV) of all duplicate samples were less than 20%.

Body composition, cardiovascular and cardiorespiratory fitness These measures were determined after saliva collection. Body composition was assessed by measuring height and weight to calculate BMI, skinfold thickness to predict body fat percentage, and waist and hip circumferences to calculate waist-to-hip ratios. Height was measured to the nearest millimetre using a portable stadiometer (Nagata bw-1122h) and body mass was measured to the nearest 0.1 kg using a calibrated electronic


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scale (Nagata bw-1122h). Participants were asked to remove footwear and only wore their school physical education outfit that included shorts and a short-sleeve T-shirt. Seated resting heart rate, measured to the nearest beat per minute (bpm). Resting blood pressure, measured to the nearest millimetre of mercury (mmHg) were recorded after a resting period of ten minutes. Body fat percentage was determined using the four-site skinfold method.22 Triceps, biceps, supra-iliac and sub-scapular skinfolds were measured on the right side of the body using Harpenden© (West Sussex, UK: Quality Measurement, Ltd) skinfold calipers. Each site was measured twice to the nearest millimetre and the mean value was recorded. Circumferences at the waist (narrowest part of the torso) and hip (level of maximum extension of the buttocks) were measured to the nearest millimetre with a tape measure and the waist-to-hip ratio was calculated.23 CRF was assessed using the 20-m multi-stage shuttle run test that predicts an individual’s maximal aerobic capacity (VO2max).24 This test has been shown to be an appropriate predictor of CRF for the age groups participating in the study.25

Statistical analysis The Shapiro-Wilk algorithm was used to assess whether the body composition, cardiovascular and CRF variables, and salivary CRP concentration and secretion rates demonstrated a normal distribution. Both salivary CRP concentration and secretion rate were found to have skewness and kurtosis and so the values were log transformed before analysis. Mean and standard deviations were calculated for the log-transformed CRP values as well as the demographic, body composition, cardiovascular and CRF variables. One-way ANOVA examined the differences in body composition, cardiovascular and CRF variables, and salivary CRP concentration and secretion rates by BMI categories. Tukey’s post hoc analysis was completed when appropriate. Binary logistic regression was performed to determine the unadjusted and adjusted odds ratios for the prediction of elevated salivary CRP concentration and secretion rate by specific risk factors. The unadjusted odds ratio indicates the combined contribution of the three risk factors to elevated salivary CRP, while calculation of the adjusted odds ratio adjusts for the interrelationships between them. The choice of these risk factors was based on an a priori decision. The non-log transformed salivary CRP concentration and secretion rate data as well as the risk factors were divided into quartiles. The data for each child was then coded depending on whether they were positive or negative for the presence of each of the risk factors (defined below) and either positive or negative for the presence of a salivary CRP concentration or secretion rate ≥ 75th percentile. Elevated salivary CRP was entered as the dependant variable with the risk factors entered into the model as covariates, using the enter method (unadjusted odd ratios) backward stepwise selection technique (adjusted odds ratios), based on likelihood ratios with entry and exit probabilities set to 0.05 and 0.1, respectively. The risk factors selected included the following: • Not meeting percentage body fat recommendations of ≤ 25% for boys and ≤ 32% for girls. The body fat recommendations

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are based on the Fitnessgram Health Fitness Zone standards for body composition.25 • Being overweight/obese: ≥ 85th percentile for BMI, which was calculated as mass (kg) divided by height (m) squared. Growth charts have been published by the Center for Disease Control and Prevention (CDC) for BMI in boys and girls, two to 20 years old. These charts are percentiles showing the distribution of BMI at a given age and can be used to identify children who are at risk of being overweight (BMI > 85th percentile) or obese (BMI > 95th percentile).25 According to these CDC BMI-for-age standards, the participants were grouped into the following CDC BMI-for-age categories: normal weight (< 85th percentile), overweight (≥ 85th percentile to < 95th percentile), and obese (≥ 95th percentile).26 These cut-off points are unchanged from the 1998 expert committee recommendations and CDC and Institute of Medicine recommendations.24 • Demonstrating poor CRF (≤ 50th percentile) for predicted VO2max: ≤ 24.66 ml/kg/min. There are currently no standardised VO2max data that can be used to categorise the CRF of children.27 However, for the present study, the authors divided the VO2max data into quartiles and used VO2max values ≤ 50th percentile to represent poor CRF in the children. Statistical analysis was performed using SAS (version 9.2, Research Triangle, NC, USA) and SPSS 19.0 (SPSS) software. Significance level was set at p < 0.05.

Results Demographic, body composition, cardiovascular and CRF data and logged salivary CRP concentration and secretion rates for the children were divided according to three BMI categories (normal weight, overweight and obese). They are presented as means ± standard deviations. The outcomes of the one-way ANOVAs examining the differences by BMI categories are indicated in Table 1. There were significant differences in age (F = 3.37, df = 2, 167, p = 0.037), height (F = 9.19, df = 2, 167, p < 0.001), mass (F = 127.52, df = 2, 167, p < 0.001), BMI (F = 248.89, df = 2, 167, p < 0.001), body fat percentage (F = 185.14, df = 2, 167, p = 0.001), systolic blood pressure (SBP) (F = 19.94, df = 2, 167, p < 0.001), diastolic blood pressure (DBP) (F = 23.95, df = 2, 167, p < 0.001), VO2max (F = 17.76, df = 2, 167, p < 0.001), salivary CRP concentration (F = 5.89, df = 2, 167, p = 0.0034) and salivary CRP secretion rate (F = 5.90, df = 2, 167, p = 0.0033) between children of different BMI categories. Tukey’s post hoc analyses revealed that obese children had significantly (p < 0.05) higher body fat percentages, SBP and DBP, as well as a significantly (p < 0.05) lower aerobic capacity (VO2max) than both normal weight and overweight children. In addition, there was a significant difference in salivary CRP concentration and salivary CRP flow rate between normal weight and obese children (p < 0.05). There were no significant differences between the normal versus overweight and overweight versus obese categories for salivary CRP concentration or secretion rate. The non-log transformed salivary CRP concentrations ranged from 217.99 to 24562.94 pg/ml (median = 700.10 pg/min and interquartile range = 546.45–1372.14 pg/ml) and salivary CRP secretion rate ranged from 113.90 to 20694.28 pg/min (median


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TABLE 1. DEMOGRAPHIC, BODY COMPOSITION, CRF DATA FOR NORMAL WEIGHT, OVERWEIGHT AND OBESE CHILDREN. VALUES ARE MEAN ± STANDARD DEVIATION Normal Overweight Obese (n = 93) (n = 24) (n =53) (males 38; (males 8; (males 24; females 55) females 16) females 29) Age (years) 9.71 (1.84) 9.25 (1.67)* 9.55 (1.63) Height (cm) 137.12 (12.10) 137.75 (11.59) 140.75 (9.73)# Mass (kg) 32.24 (7.68)** 37.90 (9.09)** 52.49 (13.68)** 16.88 (1.50)** 19.64 (1.49)** 26.17 (5.03)** BMI (kg/m2) Waist–hip ratio 0.77 (0.04) 0.79 (0.05) 0.83 (0.06) Body fat (%) 19.39 (5.03)** 27.81 (5.02)** 36.42 (7.10)** Resting HR (bpm) 85.96 (13.64) 84.54 (10.80) 85.57(13.53) SBP (mmHg) 94.62 (11.99) 94.08 (7.63) 105.65 (12.06)# DBP (mmHg) 62.25 (12.18) 62.67 (5.77) 72.55 (10.40)# VO2max (ml/kg/min) 28.61 (5.45) 25.02 (3.89) 22.72 (3.28)# Salivary CRP (pg/ml) 6.77 (0.92) 6.85 (0.85) 7.31 (0.93)& Salivary CRP (pg/min) 6.68 (0.98) 6.79 (0.75) 7.25 (0.99)& *p < 0.05 for overweight vs normal weight; **p < 0.001 for all weight categories different from each other; # p < 0.05 for obese vs normal weight and overweight; & p < 0.05 for obese vs normal weight.

= 683.41 pg/min and interquartile range = 500.26–1276.29 pg/ min). These data were used in the binary logistic regression analysis (Table 2). Table 2 describes the magnitude of the relationship (unadjusted and adjusted odds ratios) between the selected risk factors (BMI ≥ 85th percentile; body fat % ≥ 25% for boys and ≥ 32% for girls; VO2max ≤ 50th percentile) and elevated (defined as ≥ 75th percentile) salivary CRP concentration and secretion rate, calculated as ≥ 1372.14 pg/ml and ≥ 1276.39 pg/min, respectively. Only a poor CRF (≤ 50th percentile) was independently associated with elevated salivary CRP concentrations (≥ 75th percentile, ≥ 1372.14 pg/ml) (OR 3.9, 95% CI: 1.7–8.9, p = 0.001). However, both poor CRF (OR 2.7, 95% CI: 1.2–6.1, p = 0.02) and overweight/obesity (BMI ≥ 85th percentile) (OR 2.5, 95% CI: 1.1–5.9, p = 0.03) were independent predictors of elevated salivary CRP secretion rates (≥ 75th percentile, ≥ 1276.39 pg/ml).

Discussion The present study aimed to determine the relationship between salivary CRP, a non-invasive alternative marker of systemic inflammation, and body composition and/or CRF in black South African children. The main findings of this study were that poor

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CRF was an independent predictor of elevated salivary CRP concentration, while poor CRF and being overweight/obese were independent predictors of elevated salivary CRP secretion rate. The study suggests that both CRF and body composition are associated with elevated inflammatory status in black South African children and provides initial evidence that the measurement of salivary CRP may be a useful tool for examining the health status of children. The study found that a normal BMI does not induce a state of inflammation as reflected by significantly lower salivary CRP concentration and secretion rates in normal weight compared to obese children. In addition, a normal weight was associated with a higher aerobic capacity (VO2max) and lower SBP and DBP compared to obesity. The binary logistic regression analysis indicated the magnitude of the relationship between the risk factors and inflammatory status of the children. The results demonstrated that the odds ratio for the association between poor CRF and elevated salivary CRP concentration in children was 3.9. However, the odds ratio for elevated salivary CRP secretion rate if the children had both poor CRF and were overweight/obese was 6.8 (2.7 × 2.5). These results are similar to previous research examining the relationship between serum CRP, CRF and body composition in Canadian children and young adults (6–24 years),23 and black South African children (13–18 years).13 The results for salivary CRP concentration is supported by a recent study demonstrating an inverse relationship between serum CRP levels and CRF that was independent of body composition and fat distribution.7 In addition, serum CRP concentrations in the overweight and obese categories were significantly higher in the low CRF category.7 The results from the present study therefore seem to support the hypothesis that regular exercise or physical activity and/or decreased visceral fat mass decreases low-grade inflammation.1,6,11 The present results, together with the recent finding that salivary CRP is a good measure of discrimination for the clinically relevant serum CRP cut-off point in adults,7,16 suggest that salivary CRP could be used as an alternative marker of cardiovascular or chronic disease risk in children. However, research is required to establish the relevance and cost effectiveness of this inflammatory marker in clinical practice. In future, the determination of a clinically relevant index of salivary CRP may facilitate the prospective measurements of CRP levels in large epidemiological samples and contribute to understanding the mechanisms by which inflammation may be associated with the development of chronic disease in children. In addition, a clinically relevant index of salivary CRP may also be integrated into a broader multi-systemic

TABLE 2. UNADJUSTED AND ADJUSTED RISK FACTORS FOR ELEVATED SALIVARY CRP IN CHILDREN

Risk factor Salivary CRP concentration VO2max ≤ 50th percentile BMI ≥ 85th percentile B  ody fat (%) ≥ 25% for boys and ≥ 32% for girls Salivary CRP secretion rate VO2max ≤ 50th percentile BMI ≥ 85th percentile B  ody fat (%) ≥ 25% for boys and ≥ 32% for girls

% of children with elevated % of children with elevated salivary CRP and risk salivary CRP and risk Unadjusted odds factor present (%) factor absent (%) ratio (95% CI)

Adjusted odds ratio (95% CI)

p-value

35.3 30.6 34.3

12.3 17.8 17.0

3.9 (1.7–8.9) 2.0 (1.0–4.3) 2.5 (1.2–5.3)

3.9 (1.7–8.9) 1.0 (0.3–3.2) 1.7 (0.7–3.7)

0.001 0.944 0.221

34.5 34.1 37.1

13.5 13.7 14.8

3.4 (1.2–7.5) 3.3 (1.5–7.3) 3.4 (1.6–7.3)

2.7 (1.2–6.1) 2.5 (1.1–5.9) 1.8 (0.6–5.5)

0.02 0.03 0.40


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non-invasive characterisation of chronic disease risk in children, together with other salivary biomarkers (e.g. cortisol, α-amylase, dehydroepiandrosterone) and BMI, CRF and percentage body fat. There are a number of limitations that may have influenced the salivary CRP measurements in our study. Although salivary flow rate was controlled for, blood contamination, saliva pH, and health condition of the children’s gums were not determined using standardised methods. Specifically, a competitive immunoassay to quantify the presence of transferrin should be used to determine blood contamination of saliva,7 while saliva pH should be determined using calibrators with a known pH.7 It is possible that the determination of salivary CRP could be contaminated by small blood leakages or crevicular fluid overflow due to microinjuries or in participants with poor oral health, as well as local inflammatory processes, which may elevate salivary CRP levels.7 However, in an attempt to reduce the impact of these confounding variables, clear instructions were provided to the parents as well as the participants regarding brushing teeth as well as dietary and hydration practices prior to saliva collection. It is recommended that future studies should include a complete oral health examination as part of the participant’s health assessment to eliminate the possibility that bucco-dental features trigger high CRP levels in saliva in the absence of elevations in the serum.7 Related to the issue of oral health in the children and the possible existence of periodontitis, a link was recently found between periodontitis, systemic inflammation and CVD.28 Specifically, it was found that intensive periodontal therapy reduced local as well as systemic reductions in inflammation, which correlated with an improvement in endothelial functioning.28 This finding suggests that children with a high CRF and normal weight may still have elevated serum/salivary CRP levels (systemic/local inflammation) and be at risk for developing chronic disease, if they have poor oral health.

Conclusion The study provides initial support for a possible association between poor CRF and/or overweight/obesity and inflammatory status in children, based on elevated salivary CRP levels. Saliva sampling is non-invasive, stress-free, can easily be performed in a participant’s natural setting and can be repeated over time. Furthermore, saliva collection has considerable economic and logistic advantages over venipuncture because it does not require immediate manipulations, access to specialised laboratory equipment and qualified personnel. Replication of the study with larger samples is required together with longitudinal follow up of clinical outcomes. This may contribute to a better understanding of the pathways mediating the development and treatment of inflammation and chronic disease in children and subsequently adults. The authors thank Miss Melissa Naidoo for her technical assistance.

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Walsh NP, Gleeson M, Shephard RJ, et al. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev 2011; 17: 6–63. Arikawa AY, Thomas W, Schmitz KH, Kurzer MS. Sixteen weeks of exercise reduces C-reactive protein levels in young women. Med Sci Sports Exerc 2011; 43(6): 1002–1009. Handschin C, Spiegelman B. The role of exercise and PGC1alpha in

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inflammation and chronic disease. Nature 2008; 454: 463–469. Fortmann SP, Ford E, Criqui MH, et al. CDC/AHA Workshop on markers of inflammation and cardiovascular disease: Application to clinical and public health practice: Report from the population science discussion group. Circulation 2004; 110(25): e554–559. Hubacek J, Peasey A, Pikhart H, Bobak M. APOE polymorphism and its effect on plasma C-reactive protein levels in a large general population sample. Hum Immunol 2010; 71(3): 304–308. Mathur N, Pedersen B. Exercise as a means to control low-grade systemic inflammation. Mediators Inflamm 2008: ID 109502. doi: 10.1155/2008/10950. Ouellet-Morin I, Danese A, Williams B, Arseneault L. Validation of a high-sensitivity assay for C-reactive protein in human saliva. Brain Behav Immun 2011; 25: 640–646. Parrett AL, Valentine RJ, Arngri’msson SA, Castelli DM, Evans EM. Adiposity, activity, fitness, and C-reactive protein in children. Med Sci Sports Exerc 2010; 42(11): 1981–1986. Siegrist M, Hanssen H, Lammel C, Haller B, Halle M. A cluster randomised school-based lifestyle intervention programme for the prevention of childhood obesity and related early cardiovascular disease (JuvenTUM 3). BMC Public Health 2011; 11(258): 1–10. doi: 10.1186/1471-2458-11-258. Christodoulos AD, Douda HT, Tokmakidis SP. Cardiorespiratory fitness, metabolic risk and inflammation in children. Int J Pediatr 2012; 2012; ID 270515. doi: 10-1155/2012/270515. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005; 98: 1154–1162. Brandt C, Pedersen BK. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. J Biomed Biotechnol 2010; ID 520258. doi: 10.1155/2010/520258. Harmse B, Kruger HS. Significant differences between serum CRP levels in children in different categories of physical activity: the PLAY study. Cardiovasc J Afr 2010; 21(6): 316–322. Christodoulides N, Mohanty S, Miller CS, Langub MC, Floriano PN, Dharshan P. Application of microchip assay system for the measurement of C-reactive protein in human saliva. Lab Chip 2005; 5: 261–269. Lee Y, Wong D. Saliva: An emerging biofluid for early detection of diseases. Am J Dent 2009; 22(4): 241–248. Out D, Hall RJ, Granger DA, Page GG, Woods SJ. Assessing salivary C-reactive protein: Longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain Behav Immun 2012; 26: 543–551. Gutierrez AM, Martı´nez-Subiela S, Eckersall PD, Cero´n JJ. C-reactive protein quantification in porcine saliva: A minimally invasive test for pig health monitoring. Vet J 2009; 181: 261–265. Parra MD, Tecles F, Martinez-Subiela S, Ceron JJ. C-reactive protein measurements in canine saliva. J Vet Diagn Invest 2005; 17: 139–144. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107(3): 499–511. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Inv 2003; 111: 1805–1812. Blair SN. Physical inactivity: the biggest public health problem of the 21st Century. Br J Sports Med 2009; 43: 1–2. Deurenberg P, Pieters J, Hautvast J. The assessment of the body fat percentage by skinfold thickness measurements in childhood and young adolescence. Br J Nutr 1990; 63: 293–303. Isasi CR, Deckelbaum RJ, Tracy RP, Starc TJ, Berglund L, Shea S. Physical fitness and C-reactive protein level in children and young adults: The Columbia University BioMarkers Study. Pediatrics 2003: 111; 332. Ledger LA, Lambert J. A maximal multistage 20-m shuttle run test to predict VO2max. Eur J Appl Physiol 1982; 49: 1–12. Tomkinson GR, Léger LA, Olds TS, Cazorla G. Secular trends in the performance of children and adolescents (1980–2000): An analysis of 55 studies of the 20-m shuttle run test in 11 countries. Sports Med 2003; 33(4): 285–300.


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26. Ogden VL, Flegal KM. Changes in terminology for childhood overweight and obesity. National health statistics reports, 2010. National Center for Health Statistics. 27. Meredith M, Welk G. FITNESSGRAM/ACTIVITYGRAM: Test

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Administration Manual. Illinois, USA: Human Kinetics, 2005. 28. Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar Mea. Treatment of periodontitis and endothelial function. N Engl J Med 2007; 9(356): 911–920.

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The Cardiovascular Journal of Africa will be publishing the conference proceedings and abstracts of the 11th PASCAR congress and 4th All-Africa conference of the Pan-African Society of Cardiology as a supplement to the May issue of the journal. To register for our e-alert system, visit our website on www.cvja.co.za For further information on our events, including conference promotions, contact wendy@clinicscardive.com

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Review Articles Neo-intimal hyperplasia, diabetes and endovascular injury DEIRDRÉ KRUGER

Abstract Diabetes is a significant major risk factor for peripheral arterial disease (PAD) and critical limb ischaemia (CLI), the latter which is also the most common cause of amputation in these patients. Revascularisation of the lower extremities of such patients is imperative for limb salvage and has become first-line therapy. However, the incidence of restenosis following endovascular stenting is very high and is largely due to neo-intimal hyperplasia (NIH), the regulation of which is for the greater part not understood. This article therefore reviews our understanding on the regulation of NIH following stent-induced vascular injury, and highlights the importance of future studies to investigate whether the profile of vascular progenitor cell differentiation, neo-intimal growth factors and lumen diameters predict the severity of post-stent NIH in the peripheral arteries. Results from future studies will (1) better our understanding of the regulation of NIH in general, (2) determine whether combinations of any of the vascular factors discussed are predictive of the extent of NIH postoperatively, and (3) potentially facilitate future therapeutic targets and/ or change preventive strategies. Keywords: neo-intimal hyperplasia, diabetes, critical limb ischaemia, endovascular stenting, vascular progenitor cells Submitted 1/6/11, accepted 5/3/12 Published online 22/5/12 Cardiovasc J Afr 2012; 23: 507–511

www.cvja.co.za

DOI: 10.5830/CVJA-2012-019

The World Health Organisation projects that diabetes-related mortality will double between 2005 and 2030.1 On the other hand, the incidence of peripheral artery disease (PAD), which is usually secondary to atherosclerosis, is expected to rise by 14 to 45% by 2030.2 Half of the people with diabetes die of cardiovascular disease, and half of those with diabetes are affected by diabetic nephropathy. This combination of reduced blood flow and neuropathy in the feet of diabetics increases the risk of foot ulcers and eventual limb amputation. Revascularisation in the lower extremities of these patients is imperative for limb salvage, Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa DEIRDRÉ KRUGER, PhD, deirdre.kruger@wits.ac.za

which not only improves the quality of life of these patients but also reduces overall healthcare costs and mortality.

Diabetes and PAD From the African Program on Genes in Hypertension (APOGH), the prevalence of diabetes in our local South African setting is reaching 11% (unpublished data; correspondence with APOGH principle investigator, Prof Gavin Norton, 3 May 2011). Diabetes is a significant major risk factor of PAD and critical limb ischemia (CLI), and its incidence and prevalence is on the increase due to the aging of the population. CLI is defined as the presence of gangrene or non-healing ulceration, rest pain and objective evidence of diffuse pedal ischaemia. The prevalence of diabetes is particularly high in patients with CLI, which is also the most common cause of amputation. Early arterial revascularisation undoubtedly improves the prognosis in these patients.3-7 CLI progresses to gangrene in 40% of diabetic patients compared with 9% of non-diabetic patients.8 A large national vascular registry-based survey from Finland found that diabetes was not an independent risk factor for early postoperative mortality in CLI, as increased morbidity in diabetic patients was associated with old age, male gender, known coronary artery disease, renal insufficiency and, interestingly, urgent surgery.6 Be that as it may, limb salvage rates following superficial femoral artery (SFA) endoluminal interventions are lower for diabetic patients compared to non-diabetics presenting with CLI, despite similar patency and restenosis rates.9

Endovascular interventions of the tibial artery and CLI Limb salvage not only improves the CLI patient’s quality of life, but also reduces his/her mortality rate and lowers overall healthcare costs.10,11 As a result, many studies in the last few years have contributed to the change in paradigm of surgical revascularisation for CLI and these endovascular interventions have become first-line therapy for many surgeons at the femoral and popliteal levels.12-14 Recently, several studies have reported on the efficacy of infra-popliteal interventions for the treatment of CLI.15-17 However, limited data on the efficacy of tibial artery endovascular intervention (TAEI) in the treatment of CLI, specifically with regard to limb salvage and wound healing, have resulted in recommendations for infra-popliteal disease being rather ambiguous.18,19 Last year Fernandez et al. reported acceptable rates of limb salvage and wound healing following TAEI,18


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albeit with high rates of re-intervention. Even so, limited data exist and further investigations are required before definitive recommendations for the endovascular treatment of tibial vessel disease can be formulated.

Neo-intimal hyperplasia and the incidence of restenosis Within six months of a successful angioplasty, restenosis occurs in up to 55% of patients. Restenosis following angioplasty and stenting is largely due to neo-intimal hyperplasia (NIH) â&#x20AC;&#x201C; the thickening of the tunica intima of a blood vessel as a physiological healing response to a reconstructive procedure or endarterectomy. It is currently understood that NIH involves the proliferation and migration of medial smooth muscle cells (SMCs) into a region as it becomes stenotic.20 Although therapeutic interventions and continued stent design and coating have been applied, restenosis, even after drug-eluting stent implantation, remains a significant clinical problem.21,22 Also, therapeutic interventions seem to have preceded the understanding of the biology of the process of restenosis. Moreover, the regulation of NIH is largely not understood and, as a result, advancements in therapeutic interventions are restricted. The incidence of restenosis a year after coronary angioplasty and bare-metal stenting is approximately 30%,23 whereas restenosis a year after carotid artery stenting has been reported as approximately 18%.24 A meta-analysis of the incidence of restenosis three years after bare-metal stenting for peripheral artery disease, specifically femoro-popliteal disease, was 61%.25 In another study that investigated the efficacy of sub-intimal stent implantation for long, multi-segmental lower limb occlusive lesions, 37% restenosis after approximately one year was reported,26 whereas a 17% incidence at two years of re-occlusions and restenosis was reported by a prospective study for sub-intimal angioplasty of the femoro-popliteal or tibial arteries.27 While limb salvage, ulcer healing and re-intervention rates are relatively low after below-the-knee endovascular intervention, restenosis rates remain extremely high.7 This highlights the importance of understanding the regulation of NIH.

Therapeutic management of CLI In CLI patients who are not amenable to surgical intervention for revascularisation, treatment options are very limited. Even though the optimal treatment has yet to be identified, therapeutic angiogenesis is increasingly being used in the non-operative management of CLI. This new strategy includes the administration of growth factors, transcription factors and progenitor cells to induce angiogenesis. Surprisingly, the cytokines used in therapeutic angiogenesis, such as VEGF and FGF, are the also the factors thought to influence NIH following revascularisation. Similarly, and discussed below, the profile of progenitor cell differentiation in the acute phase post stenting has been suggested as a predictor of restenosis following endovascular intervention. Having said that, clinical trials of cytokine-based therapy in patients not amenable to surgery have produced mixed results, while those using autologous cell transplantation have been much more promising.28 Specifically, the safety and efficacy of autologous endothelial progenitor cell therapy has been established from small cohort studies and results from

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larger trials currently underway will further consolidate this evidence.29,30 The following sections describe the necessity of investigating the role of cytological and biochemical factors in vessel wall injury and other cardiovascular co-morbidities in an attempt at attenuating NIH following future revascularisation procedures. From this published evidence, it is clear that new strategies in preventing NIH are imperative. Furthermore, a better understanding of the regulation of NIH could facilitate future therapeutic targets.

Cytological factors and neo-intimal hyperplasia At the site of stent-induced vascular cell injury, an abundance of cytokines and growth factors are released, and circulating mononuclear cells are mobilised to the site of injury. The local abundance of cytokines and growth factors provides an appropriate environment for cell growth, cell differentiation and cell proliferation.

Vascular progenitor cells (VPCs) Circulating mononuclear cells have been implicated in the process of in-stent NIH and VPCs form part of this population of cells.31 VPCs differentiate into either endothelial or smooth muscle lineage, depending on the local environment they find themselves in. Only in the last decade have studies suggested the involvement of VPCs in the development of NIH,32-34 and in 2007, Inoue et al. showed a relationship between NIH and the mobilisation of VPCs into the circulation at the acute phase after vascular stent-induced injury.35 Moreover, inhibition of NIH by the drug sirolimus is mediated through its potent inhibitory effect on circulating VPCs.36 Very recently, Wang et al. (2011) showed a strong correlation between the VPC differentiation profile and the severity of post-stent NIH following coronary stenting.20 This suggests that VPC differentiation may potentially be a future tool in identifying patients at risk of restenosis after coronary stenting. However, this relationship has not been investigated in any other areas of stent-induced vascular injury. Future studies should investigate the relationship, if any, between the acute-phase VPC differentiation profile and extent of NIH following either femoro-popliteal or tibial artery stenting.

Biochemical factors and neo-intimal hyperplasia As mentioned above, an abundance of biochemical factors such as cytokines and growth factors are released at the site of stentinduced vascular cell injury. These factors are important in the regulation of angiogenesis. However, data on their involvement in regulating NIH following lower limb revascularisation are either limited or non-existent.

Cellular adhesion molecules (CAMs) CAMs, glycoproteins present on cell surfaces, bind with other cells or the extracellular matrix. The firm adhesion of leukocytes and lymphocytes to endothelial cells are, however, mainly mediated by immunoglobulin CAMs, such as intercellular


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CAM (ICAM) and vascular CAM (VCAM). Where ICAM binds to integrins present on all leukocytes, VCAM binds to the VLA-4 ligand which is present on lymphocytes, monocytes and eosinophils. Both have been implicated in atherosclerotic lesions.37 Activated vascular endothelial cells express elevated levels of CAMs at their surface in the initial phases of atherosclerostic plaque formation. Even though the role of arterial pressure on atherosclerotic plaque development is not fully known, reports have shown high concentrations of circulating ICAM, VCAM, E-selectin and MCP-1 in hypertensive patients.38,39 Where E- and P-selectin are thought to play a role in atherogenesis, E-selectin participates in the binding of neutrophils and monocytes to endothelial surfaces. Following vascular injury, CAMs such as ICAM, and E-, L- and P-selectin are responsible for the leukocyte and specifically neurophil accumulation on the injured vessel wall, and various experimental studies have shown their potential role in the initiation and/or development of NIH in both animals and humans.40-42 Also, Shimazawa et al. (2005) showed that the interaction between neutrophil L- and P-selectin with sulfatides, which are ligands for L- and P-selectin, potentially contribute to the development of NIH following vascular injury.42

Nuclear factor kappa B (NF-κB) NF-κB is a nuclear transcription factor which regulates at least 200 genes involved in cellular proliferation and immune and inflammatory responses. As atherosclerosis is a chronic inflammatory disease, it is not surprising that NF-κB plays an essential role in the development of atherosclerosis. Riou et al. (2007) showed a direct link between hypertension and the development of atherosclerosis through the induction of NF-κB.43 Rather than affecting SMC proliferation, it has been suggested that NF-κB is involved in apoptotic and inflammatory signalling of vascular SMCs.44 Furthermore, NF-κB plays a crucial role in controlling vascular inflammation and NIH.45 A recent study by Bu et al. (2010) suggested that activation of NF-κB in neo-intimal SMCs following vascular injury induces the expression of a catalytic telomerase reverse transcriptase (TERT). This is one of two core components of the enzyme telomerase, which is responsible for adding DNA sequence repeats to the 3′ ends of DNA strands and is essential to the replicative longevity of vascular cells.45 In addition, studies have shown that neutrophil accumulation after vascular endothelial injury contributes not only to the development but also to the initiation of NIH.46 Moreover, the pre-operative neutrophil NF-κB status has been suggested as a marker of post-operative organ dysfunction and future studies are warranted to assess the role of NF-κB in neutrophil activation and organ dysfunction following surgery.47 The activated neutrophil plays a central role in sepsis (secondary or severe systemic inflammation), which is often present in a patient post vascular intervention. The importance of NF-κB activation in clinical sepsis has not been investigated in patients at risk of lower limb amputations.

Growth factors Studies have stressed the role of growth factors on the development of NIH.48 Several growth factors stimulate migration

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and proliferation of medial SMCs into the neo-intima and are released from activated platelets, leukocytes, local endothelial cells and medial SMCs during the cellular proliferation phase of NIH. Furthermore, the release of growth factors by inflammatory cells in the vasculature specifically is of great importance, as atherosclerosis is a chronic inflammatory disease. These growth factors include vascular endothelial growth factor (VEGF), platelet-derived growth factor A and B (PDGF A and B), fibroblast growth factor (FGF) and insulin-like growth factor (IGF). The relationship of the latter factors to NIH is discussed below. VEGF: VEGF is a glycoprotein that stimulates angiogenic and vascular permeability-enhancing activities specific for endothelial cells. The role of the members of the VEGF family in NIH is unknown. Where a number of studies suggest that VEGFs reduce NIH, others propose that they promote restenosis and atherosclerosis. A study in rabbits demonstrated that the strongly angiogenic VEGF-A, VEGF-D and VEGF-D∆N∆C increased NIH in the carotid artery, which correlated strongly with adventitial angiogenesis.49 In fact, several studies have linked adventitial angiogenesis with restenosis.50-52 VEGF-C-positive macrophages, which were present in the early neo-intima in rats, were later found in the adventitia after its removal, suggesting their involvement in adventitial lymphangiogenesis.53 This is of importance as it delivers and activates inflammatory cells that release growth factors which, in turn, promote neo-intimal infiltration and hyperplasia. Apart from the ischaemic myocardium, the angiogenic effects of VEGF-B are minimal in most organs and many recent studies have described it as a potent neuroprotective factor.54,55 Surprisingly, it has also been shown to play a role in modulating endothelial fatty acid transportation.56 Stefanadis et al. (2007) showed a significant reduction in neovessel growth and neo-intimal thickness in New Zealand rats after four weeks of being treated with antibodies specific for VEGF while on a atherogenic diet.57 Whether the inhibition of VEGF correlates with a reduced smooth muscle content or has a direct anti-proliferative effect, has yet to be determined. Nevertheless VEGF inhibition showed a possible favourable effect on NIH. An editorial by Simons (2009) summarised recent evidence suggesting that the role of VEGF in neo-intimal formation occurs in the adventitia.52 Specifically, stent-induced damage to the adventitia initiates the local inflammatory response, the production of VEGF, which subsequently induces monocyte chemo-attractant protein-1 (MCP-1) expression in medial SMCs. This results in monocyte accumulation in the adventitia, which also secretes VEGF, to further amplify the cascade that ultimately leads to SMC phenotypic modulation, allowing migration of SMC to the intima. This altered state of SMCs has been established as a critical role in the pathogenesis of NIH.58 PDGF-A, PDGF–B, IGF and FGF: PDGF, IGF and FGF are important regulators of angiogenesis, and vascular injury increases the availability of many such growth factors. PDGF is a crucial regulator of SMC proliferation and migration. Based on the two polypeptide chains, A and B, different isoforms of PDGF exist. It has been shown that SMCs from injured arteries only secrete PDGF-A. However, such injury exposes these SMCs to


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platelets within the circulation which not only are a source of PDGF-B, but also, in turn, adhere to the injured artery. Rat studies have been shown to halt the formation of NIH by specific inhibition of the PDGF receptor, tyrosine kinase.37 Similarly, FGF is an important growth factor for SMC, as well as endothelial cell proliferation. Vascular injury releases FGF from the extracellular matrix, after which it is free to bind to its receptors on both SMCs and endothelial cells, promoting cellular proliferation and, as a result, NIH. IGF may play an important role in remodelling the extracellular matrix and, to a lesser extent, increase the ability of PDGF to induce SMC proliferation. The role of VEGF along with other growth factors (FGF, PDGFs and IGF) involved in stimulating the change required by SMCs to proliferate and migrate to form the neo-intima, as well as its influence on the degree of NIH in the tibial or femoropopliteal artery has not been investigated.

Conclusion This research review highlights the need for future studies to investigate whether the profile of VPC differentiation also predicts the severity of post-stent NIH in the femoro-popliteal or tibial artery, as well as the association of neo-intimal growth factors, NF-κB and CAMs with VPC differentiation and formation of the neo-intima. Results from future studies will (1) better our understanding of the regulation on NIH in general, (2) determine whether combinations of any of the vascular factors discussed are predictive of the extent of NIH post operatively, and (3) potentially facilitate future therapeutic targets and/or change preventive strategies. Specifically, studies from Africa are needed to not only establish and record the incidence of NIH from our local population, as currently, no published data exist, but also to determine which of these factors could predict neo-intimal formation in our population. We also need to determine whether this profiling differs from that of others internationally.

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Obesity and its health impact in Africa: a systematic review BRIDGET ADEBOYE, GIOVANNA BERMANO, CATHERINE ROLLAND

Abstract Obesity and its association with co-morbidities in Africa are on the rise. This systematic review examines evidence of obesity and its association with co-morbidities within the African continent. Comparative studies conducted in Africa on adults 17 years and older with mean body mass index (BMI) ≥ 28 kg/m2 were included. Five electronic databases were searched. Surveys, case–control and cohort studies from January 2000 to July 2010 were evaluated. Of 720 potentially relevant articles, 10 met the inclusion criteria. Prevalence of obesity was higher in urban than rural subjects with significant increases in obesity rates among women. Inflammatory marker levels were significantly elevated among Africans compared with Caucasians. The co-relationship between obesity and chronic diseases was also highlighted. This systematic review demonstrates that while obesity remains an area of significant public health importance to Africans, particularly in urban areas, there is little evidence of proper diagnosis, treatment and/or prevention. Keywords: obesity, Africa, prevalence, cardiovascular risk Submitted 11/11/11, accepted 3/5/12 Cardiovasc J Afr 2012; 23: 512–521

www.cvja.co.za

DOI: 10.5830/CVJA-2012-040

Obesity has long been acknowledged as a significant contributing factor in the development of various chronic diseases such as cardiovascular disease, hypertension, type 2 diabetes mellitus, stroke, osteoarthritis and certain cancers.1-3 As a risk factor for non-communicable diseases, obesity has become a global public health concern with more than one billion adults estimated to be overweight and over 400 million of them obese.4,5 Recent global figures from the World Health Organisation (WHO) indicate that the prevalence of obesity is not just a problem of the developed countries but is also on the increase in the developing world, with over 115 million people suffering from obesity-related problems.5 This significant acceleration in the incidence of obesity also indicates that low-income countries are now confronted with a double burden where both communicable and chronic non-communicable diseases co-exist.6-8 While the threat of communicable and poverty-related diseases (such as malaria, malnutrition, cholera and infant mortality) exists in several African countries, the prevalence Centre for Obesity Research and Epidemiology (CORE), Faculty of Health and Social Care, Robert Gordon University, Aberdeen, Scotland BRIDGET ADEBOYE, MSc GIOVANNA BERMANO, PhD CATHERINE ROLLAND, PhD, c.rolland@rgu.ac.uk

of chronic diseases continues unabated.2,9-12 In fact, several researchers predict that in many developing countries, the burden of chronic diseases will equal the burden of acute infectious diseases in the near future.7,13,14 For instance, the WHO projects by 2030 a doubling in mortality rates resulting from ischaemic heart disease in the African region,15 as well as a prediction by 2025 of the largest increase in prevalence of diabetes mellitus in developing countries.16 Despite this increasing need to tackle chronic diseases with additional resources and effort,17 under-nutrition and communicable infectious diseases remain a core focus of researchers and policy makers within the African continent,11,18 with insignificant attention assigned to obesity and chronic, non-communicable diseases.2,6 The lack of attention given to the obesity epidemic may have been spurred on by the earlier misrepresentation of health information, which led to the misperception of ‘healthy’ or ‘benign’ obesity.19,20 This concept, widely propagated in places such as South Africa from the 1960s until the late 1980s,20,21 led to gross neglect of the problem of obesity and treatment of the attendant co-morbidities.19,20 Although the misperception of ‘benign obesity’ is being rectified by the increasing number of recent studies that spell out the reality of obesity,22,23 the threat of diseases such as HIV/AIDS and the high economic toll it takes on the continent make it increasingly difficult to divert resources to tackling the obesity epidemic.24-26 This systematic review focuses on epidemiological studies (surveys, case–control and cohort) with comparative subgroups. It aimed to unearth the current evidence on obesity and its association with increased co-morbidities among obese individuals on the African continent. The pattern of obesity in Africa was explored, comparing the differences in prevalence between urban and rural subjects. General outcome, such as prevalence of obesity among urban residents, was highlighted to show the impact of urbanisation and Westernisation. The review also highlights the impact of obesity on cardiovascular and inflammatory bio-markers, comparing Africans and Caucasians. Co-morbidities of obesity and their prevalence among the obese in comparison with the non-obese population were also evaluated.

Methods A comprehensive electronic literature search of five databases (Cochrane library, Medline, EMBASE, CINAHL and Amed) was conducted using both medical subject headings (MeSH) and key text such as ‘obesity’, ‘overweight’, and ‘BMI’. Using the appropriate Boolean operators, key search words were combined with Africa, exploding searches to include West Africa, East Africa, Africa sub-Sahara, South Africa, Central Africa and North Africa. The search was restricted to studies on human subjects published between January 2000 and July 2010. Language restrictions were applied, limiting searches to


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publications in only the English language. The eligibility criteria for inclusion were: randomised control, epidemiological, case-controlled, cohort studies, and surveys with a mean body mass index (BMI) of ≥ 28 kg/m2 involving participants aged 17 years and older. The rationale for a lower BMI cut-off point was to allow the consideration of co-morbidities. Moreover, at that level of body fat and age, individuals of African descent have been shown to have a lower BMI compared to that of Caucasians.27 Studies also had to be conducted in an African country to be included, and had to have a comparative aspect (urban vs rural, African-based population vs Westernised counterpart, gender, etc). Titles and abstracts were screened and potentially relevant articles were retrieved. Reference lists of review articles were searched manually and a few eligible articles were retrieved. Full texts of potential articles were retrieved and examined for inclusion by two reviewers. Data from each eligible study were extracted based on a standard protocol format recommended by the Cochrane collaboration.28,29 The data-extraction form was adapted for this review after piloting a few studies and making alterations where necessary, to ensure standardisation prior to final data extraction. Data were extracted by one reviewer and independently reviewed by a second reviewer. Uncertainties and discrepancies were rectified and resolved by discussion with the two reviewers.

Results The initial search generated 720 titles of potentially relevant articles. Further scanning of titles and abstracts yielded 58 potentially relevant articles for which full texts were obtained. A total of 10 articles met the inclusion criteria and were included in the review. Fig. 1 outlines a summary of the selection process with reasons for the exclusions. All the included studies had comparative subgroups. Of the 10 studies included (Table 1), two were observational,30,31 three cross-sectional;32-34 three case–case controlled studies,35-37 and two were surveys.2,38 The age of the participants ranged from 17 to 74 years. Six of the included studies were conducted on both males and females,2,10,30,33,34,36 while four were exclusively on female populations.31,32,35,37 Sample sizes varied widely, ranging from 98 to 4 731 participants.33,37 Two studies reported results from rural and urban populations, while two others reported findings from rural and urban populations and compared them with their Western counterparts.30,34 The study by Rush et al.31 was the only one conducted within an urban population, comparing BMI and percentage body fat differences between women from five ethnic groups. Schutte was the first author of three of the studies included.32,35,37 Participants from Schutte’s studies, known as POWIRS (Profiles of Obese Women with Insulin Resistance Syndrome), were all recruited from affluent parts of South Africa. Two of Schutte and co-workers’ studies compared inflammatory and cardiovascular risk markers between two ethnic groups (African women vs Caucasians).32,35 The third by Schutte et al. considered only African women, exploring the association of leptin and BMI between overweight/obese hypertensive (HT) and normotensive (NT) participants.37

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Ibhazehiebo’s was the only study conducted within an institution of higher learning (medical students in a private university in Nigeria).36 Ibhazehiebo compared blood pressure changes between obese and non-obese (control group) participants following graded exercise.36 Asfaw’s on the other hand was the only study that compared the effects of obesity on four doctor-diagnosed chronic diseases, reporting results from both Senegal and South Africa.2

Comparison of demographic variables and BMI across groups/gender (crude prevalence of obesity by gender and locality) Table 2 shows the four studies that reported on demographic variables. The prevalence of obesity varied extensively between and within studies. In all the regions studied, the difference in the prevalence of obesity between males and females was significant, with women as much as three times more likely to Total number of references retrieved from database and manual search (n = 720) Duplicates excluded (n = 23) Titles/abstract screening (n = 697)

Reasons for exclusion: •• Not pertaining to Africa or obesity (n = 562) •• Not a comparative study (n = 38) •• Age not appropriate (n = 27) •• Reviews (n = 7) •• BMI not appropriate (n = 5)

Full text retrieved for evaluation (n = 58)

Reason for exclusion: •• Not a comparative study (n = 14) •• BMI not reported (n = 5) •• No obese subgroup (n = 4) •• Age not appropriate (n = 4) •• Weight not reported (n = 3) •• Review (n = 4) •• Study not in Africa (n = 1)

Potential articles eligible for inclusion (n = 23)

Reasons for exclusion: •• Age not appropriate (n = 5) •• No obese subgroup or no weight reported (n = 7) •• Study not in Africa (n = 1)

Total studies included for review (n = 10)

Fig. 1. Summary of literature search.


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TABLE 1. CHARACTERISTICS AND CONTEXTUAL DETAILS OF ALL THE INCLUDED STUDIES

Study Agyemang et al.34

Sample size total (women) 1 471 (ND)

Study design Cross sectional

Country of origin Ghana and Netherlands

4 731 (2 874)

Cross sectional

Ghana

Inclusion criteria Urban and rural adults and their Netherlands counterparts ≥ 17 years

Urban and rural adults ≥ 25 years

Aim of study To assess the differences in overweight and obesity between Dutch– Ghanaian migrants in Netherlands and their rural/urban counterparts in Ghana. To determine the association between obesity and socio-demographic factors in Ghana The effects of obesity on doctordiagnosed chronic diseases in Africa

Outcome measured (comparison evaluated) BMI, obesity (urban vs rural population with their European counterparts (males vs females)

BMI, %obesity prevalence (urban vs rural population, males vs females) 3 190 Health South Africa Adults in South Africa and BMI, age, doctor-diagAsfaw2 (ND) survey and Senegal Senegal ≥ 18 years nosed comorbidities (obese vs non-obese population) 3 160 Cross Cameroon Urban and rural adults ≥ To compare the 10-year changes in BMI, WC (urban vs rural Fezeu et al.10 (ND) sectional 24 years the distribution of adiposity in rural population, males vs vs urban Cameroonian population females) 120 Case– Nigeria 18–22 years To determine the association of BMI, weight, SBP, DBP Ibhazehiebo et al.36 (60) control obesity with premature increase (obese vs non-obese, in BP males vs females) 2 855 Cross Cameroon, Age 25–74 years; not preg- To determine the relationship BMI, socio-demographic Jackson et al.30 (ND) sectional Jamaica and nant and of African descent between diet and obesity factors (rural vs urban and UK by ancestry, observed race Africans in diaspora) with and self-assignment age taken into account 721 ObservaSouth Africa 18–60 years To investigate the relationship BMI, %BF , WC (South Rush et al.31 (721) tional and New between BMI and %BF among 5 African black vs South Zealand ethnic groups African European) 98 Case– South Africa Urban adults ≥ 18 years Determine the relationship between BMI, weight, leptin level Schutte et al.37 (98) control HBP and leptin levels in African (normotensive vs hypertenwomen sive African women) 217 Case–case South Africa Urban adults 20–50 years Relationship between inflammaCardiovascular and inflamSchutte et al.35 (217) control tion, obesity and cardiovascular matory bio-markers (SBP, disease. DBP, CO, TRP, leptin, HsCRP and fibrinogen (Africans vs Caucasians) 217 Cross South Africa Urban adults 20–55 years To determine the relationship BMI, DBP, SBP, leptin, Schutte et al.32 (217) sectional between BMI, HBP and cardiovas- CRP and hypertension % cular and inflammatory biomarkers (Africans vs Caucasians) ND, not defined; hsCRP, high-sensitivity C-reactive protein; %BF, percentage body fat; WC, waist circumference; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HBP, high blood pressure; CO, cardiac output; TPR, total peripheral resistance. Amoah33

be obese than their male counterparts in some regions (22.5 and 5.9%, respectively).33 When studies on urban and rural populations were analysed, the prevalence of obesity was found to be higher in the urban than the rural population (Table 2).33,34 One study from Ghana investigated the differences in overweight and obesity between rural and urban Ghanaians and compared them with

first-generation Dutch–Ghanaian migrants in the Netherlands.34 Findings showed the prevalence to be lowest for both males and females in the rural regions and highest among their Western counterparts. A similar trend was observed in a study by Jackson et al.,30 which examined overweight and obesity among populations of African origin in Cameroon, Jamaica and the UK. They reported

TABLE 2. PREVALENCE OF OBESITY ACROSS LOCATION/GENDER Urban subjects Rural subjects Western counterparts Author Country Men Women Men Women Men Women Agyemang et al.34 (Ghana/ 11 (3.0)a 71 (17.0)a 1 (0.5) 20 (6.3)b 13 (19.1)b 23 (25.9)b Netherlands) Dutch Ghanaians Dutch Ghanaians 5.9% 22.5% 2.0% 15.8% – – Amoah33 (Ghana) 28.2% 11.9 % 1.5% 2.1% Fezeu et al.10 (Cameroon) (95% CI) (24.6–32.1) (9.1–15.2) (0.4–3.4) (1.0–4.0) – – 1994 data 27.4% 13.8% 1.8% 7.8% 2003 data (23.6–31.5) (10.6–17.7) (0.4–5.0) (4.2–12.4) – – 27.0 (5.0) 25.0 (3.6) 22.3 (3.3) 21.7 (2.6) 28.6 (5.7) 27.3 (3.5)a Jackson et al.30 (Cameroon and UK) (25.2%) (10.0%) (3.3%) (0.7 %) (37.1 %) (21.6%) Data are presented as means and standard deviations in brackets unless stated otherwise. a p < 0.001 significant difference between groups and between genders (the degree of difference is the same across a and b) b p < 0.001 statistically significant comparing urban to rural counterpart. 95% CI: 95% confidence interval.


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TABLE 3. COMPARISON OF CARDIOVASCULAR PARAMETERS AND INFLAMMATORY BIO-MARKERS ACROSS ETHNIC GROUPS Outcome measured (cardiovascular parameters and inflammatory bio-markers) Control vs experimental groups SBP (mmHg) DBP (mmHg) Leptin (ng/ml) hsCRP (mg/l) Fibrinogen (g/l) OW/OB NT (n = 46) 124 ± 1.9 77 ± 1.2 73.6 ± 3.4 – – OW/OB HT (n = 17) 156 ± 1.9a 91 ± 2.1a 69.8 ± 5.7 – – 125 (123; 128) 72.5 (70.8; 74.1) 51.4 (45.3; 57.5) 3.27 (2.56; 3.98) 3.05 (2.95; 3.15) Schutte et al.26 Caucasians (n = 115) Africans (n = 102) 130 (126; 134)a 77.7 (75.6; 79.8)b 57.6 (51.6; 63.6)a 4.59 (3.17; 6.01) 3.89 (3.67; 4.10)b 23 Schutte et al. Caucasians (n = 115) 119 ± 12.1 74.3±8.78 51.4 ± 32.9 3.27 ± 3.84 3.05 ± 0.56 Africans (n = 102) 128 ± 20.3a 78.5±12.0 57.6 ± 30. 2a 4.59 ± 7.20 3.89 ± 1.08a All three studies took place in South Africa. OW/OB NT, overweight/obese normotensive; HT, hypertensive; SBP, systolic blood pressure; DBP, diastolic blood pressure; hsCRP, high-sensitivity C-reactive protein. Schutte et al. 2005 results report mean ± (standard deviation); Schutte et al. 2006 values are mean ± (95% confidence intervals); Schutte et al. 2008 values are mean ± (standard deviation). a p < 0.05 when comparing the control versus the experimental group b p < 0.001 when comparing the control versus the experimental group Author Schutte et al.28

that levels of overweight and obesity were higher in those who had migrated to the UK than those who lived in Cameroon or Jamaica. Compared to other sites, obesity was found to be at its lowest level in rural males and females in Cameroon. In fact, due to the rarity of obesity in rural Cameroon, the site was omitted from the analyses of obesity. Rural Cameroon was used however as the reference category for analyses of overweight, and urban Cameroon for analyses of obesity.30 Two other studies reported on the age- and gender-specific prevalence of obesity.33,34 In all localities, the prevalence of overweight/obesity among men was higher in the older age group than the younger age group. In addition, a significant prevalence was observed in younger and older Dutch–Ghanaian men (50.0 and 84.2%) compared with their urban (14.1 and 39.2%) and rural Ghanaian counterparts (5.6 and 16.7%). A higher prevalence of overweight and obesity was also evident among younger and older Dutch–Ghanaian women (65.0 and 94.7%) compared with their urban (44.5 and 61.0%) and rural Ghanaian counterparts (17.8 and 28.4%).34 In one study,33 the most significant prevalence of obesity in both genders occurred between the ages of 55 and 65 years, at 7.8 and 32.9% in men and women, respectively.33 In another study,30 middle-aged urban men were found to be more prone to becoming obese than younger men. However, only risk of obesity and not overweight was evident among older men (60–74 years) compared with younger men. Similarly, women within the same age group (41 years and older) in urban Cameroon were also found to be at increased risk of developing obesity. When compared with younger men, the risk of overweight and obesity increased among men aged 41 to 59 years. When age was adjusted for, the rural population in Cameroon were excluded from the analysis because of non-significant results. However, at age 41 to 59 years, there was a significant increase in obesity across the two geographic areas (urban Cameroon and the UK), which began to decline from age 60 to 70 years. Data from Jamaican subjects were excluded in this review as they were not considered to be European counterparts.30

Comparison of cardiovascular parameters and inflammatory markers Three studies by Schutte et al. investigated the association between cardiovascular and inflammatory bio-markers with obesity (Table 3).32,35,37 They were part of the POWIRS study and

were carried out in South Africa by the same group. With the exception of the study by Schutte et al.,37 which compared normotensive and hypertensive African women, the remaining two studies investigated the differences in response between African and Caucasian women.32,35 Schutte and co-workers’ findings showed a significant elevation of leptin levels (p < 0.05) in the overweight and obese normotensive (OW/ OB NT) and hypertensive (HT) groups in comparison with the lean NT group, but it was similar in the OW/OB NT and HT groups.37 Matching healthy African (n = 102) and Caucasian (n = 115) women for age and BMI, Schutte et al.35 sought to determine the role of ethnicity. In their investigation of the relationship between inflammation, obesity and cardiovascular disease in a South African population, they found significantly increased levels of leptin, high-sensitivity C-reactive protein (hsCRP) and fibrinogen (p < 0.05) in the African women compared with their Caucasian counterparts (Table 3). Similarly, Schutte et al.32 investigated the differences in blood pressure (BP) for age- and BMI-matched African women and their Caucasian counterparts. Their study sought to determine whether obesity was strongly connected to reported cardiovascular risk markers in black African women. The results revealed that although the mean BMI and age were matched between the two groups, the Caucasians were significantly taller (1.68 ± 0.07 vs 1.59 ± 0.06 m; p < 0.01) and heavier (80.7 ± 21.0 vs 70.6 ± 15.8 kg; p < 0.01). Moreover, the African women had higher systolic blood pressure than the Caucasians (128 ± 20.3 and 119 ± 12.1 mmHg, respectively) (p < 0.01) with higher peripheral vascular resistance.

Comparison of the effects of obesity on blood pressure and doctor-diagnosed chronic diseases Ibhazehiebo and colleagues’ case–control study reported hypertension and blood pressure responses to graded exercise in young obese and non-athletic Nigerian university students (Table 4).36 By contrast, Asfaw’s study considered the impact of obesity on the prevalence of chronic diseases (four doctordiagnosed chronic diseases) in South Africa and Senegal (Table 5).2 Although these two studies were not comparable, both their findings demonstrated a greater incidence of disease in the obese than in their non-obese counterparts. Results from Ibhazehiebo et al.36 revealed a significant (p < 0.001) increase in the incidence of hypertension among the


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TABLE 4. EFFECTS OF OBESITY ON BLOOD PRESSURE FOLLOWING GRADED EXERCISE IN OBESE AND NON-OBESE SUBJECTS27 Exercise Blood pressure changes following graded exercise Sample size Males Females 60 60

SBP (mmHg) SBP (mmHg) DBP(mmHg) Author, country Degree of exercise obese non-obese obese Mild (M) 156.3 ± 14.0 135.0 ± 7.4 87.9 ± 10.0 Ibhazehiebo et al.36 Nigeria Mild (F) 141.0 ± 9.0a 134.5 ± 10.5 86.4 ± 10.1 Mild overall 150.4 ± 10.3b 94.3 ± 8.6 84.5 ± 8.6 148.2 ± 14.8 93.6 ± 7.0 Moderate (M) 163.4 ± 10 140.3 ± 11.6 92.0 ± 6.0 Moderate (F) 152.3 ± 11.0a 161.7 ± 9.6 b 113.8 ± 10.1 91.7 ± 6.0 Moderate overall 153.0 ± 13.1 98.5 ± 10.0 Severe (M) 173.1 ± 14.0 148.8 ± 11.8 95.4 ± 10.0 Severe (F) 163.1 ± 9.0a 169.4 ± 11.2b 126.0 ± 10.8 97.4 ± 8.9 Severe overall SBP, systolic blood pressure; DBP, diastolic blood pressure (mmHg); M, males; F, females; mean ± (standard deviation) a p < 0.05 between genders. b p < 0.001 between obese and non-obese groups.

obese participants, with no incidence of hypertension recorded in the non-obese group (Table 4). Ibhazehiebo also found a considerable increase (p-value not reported) in the systolic (SBP) and diastolic blood pressure (DBP) of the obese subjects following graded exercise. The increase heightened as the intensity of the exercise progressed from mild to severe (Table 4). By contrast, only modest increases were observed in the SBP and DBP values of the non-obese subjects. When increases in BP were compared in both groups following graded exercise, highly significant increases in SBP were observed in the obese groups (p < 0.01) (Table 4). Asfaw’s study displayed similar trends, suggesting a clear relationship between obesity and four diagnosed chronic diseases (arthritis, asthma, diabetes and heart diseases).2 When compared with non-obese subjects, each chronic disease was more prevalent in the obese respondents (Table 5).

Discussion We systematically reviewed the available literature in this article to assess current evidence on obesity and its association with increased co-morbidities among obese individuals on the African continent. The results of this review demonstrate a higher prevalence of obesity in urban populations compared with their rural counterparts. Studies from both Amoah33 and Agyemang et al.34 reported similar findings in their urban and rural populations, however, it was intriguing to see Agyemang et al.34 compare rural and urban Ghanaians with their Dutch counterparts. The large disparity found between Ghanaian residents in the Netherlands and their urban/rural counterparts suggests that

DBP (mmHg) non-obese 70.1 ± 7.4 74.6 ± 4.2 78.3 ± 9.4 84.6 ± 12.4 78.3 ± 9.2 83.9 ± I7.5 89.2 ± 11.5 85.8 ± 10.9 89.3 ± 9.2

environmental factors are implicated in the aetiology of obesity.34 This provides new insights into the possible role of migrationrelated factors on overweight and obesity in Western countries. This further signals a great need to address overweight and obesity among migrant populations living in Western countries. It also provides an essential bedrock for further studies to ascertain migration-related lifestyle changes and factors that lead to overweight and obesity among these populations in Western countries. Studies reporting a higher prevalence of overweight and obesity among urban residents are consistent with recent studies in African countries;6,38,39-41 however, the results from the studies presented in this review seem to be at variance with most urban– rural analyses of obesity in some developed countries.42 For instance, in the UK and USA, some studies reported a higher proportion of obesity and overweight in the rural than the urban population.30,43 Higher prevalence of obesity was also found in those with a lower income and least education in developed countries,44,45 contradicting the findings in this review that associated obesity with affluence and literacy among African populations. Most observational studies conducted in industrialised countries also suggested a positive association of obesity with low-income and deprived neighbourhoods.46-50 This obvious contradiction has been suggested to be due to heightened deprivation42 and exposure to poor-quality foods, which are the default choice due to low income42 among the poor in Western countries. On the contrary, a possible explanation for the higher prevalence of obesity in affluent and urban populations in Africa may be explained by the increasing evolvement of urbanisation

TABLE 5. PREVALENCE OF CHRONIC DISEASE AMONG OBESE AND NON-OBESE INDIVIDUALS FROM TWO DIFFERENT COUNTRIES2 Author, country Asfaw 2 South Africa/Senegal

Sample size total 3 190

Doctor-diagnosed chronic diseases Arthritis

Obesity status Non-obese Obese Asthma Non-obese Obese Diabetes Non-obese Obese Heart disease Non-obese Obese Values are mean (95% confidence interval); significant differences were not clearly reported

Senegal 17.3 (15.4–19.2) 24.1 (15.8–32.3) 4.2 (3.2–5.2) 10.0 (4.1–15.9) 1.6 (1.0–2.2) 2.9 (0.4–6.2) 7.8 (6.7–9.1) 13.7 (7.0–20.4)

South Africa 17.1 (14.1–20.0) 22.4 (16.9–27.1) 5.4 (4.1–6.9) 7.6 (5.3–10.5) 5.4 (4.1–6.8) 7.6 (5.1–10.2) 13.3 (11.3–15.3) 19.4 (15.7–23.3)


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within the African continent. The majority of African countries are undergoing swift changes in their social and economic environments, concommitant with changes in food-consumption patterns.51 The increasing availability of food and its diversity in urban areas has been shown to particularly influence the quality of diets and nutritional well-being.52 These changes in diet and lifestyle, especially in urban settings, often involve a shift from the consumption of traditional staple foods low in fat and rich in fibre, to processed and refined foods, meat and dairy products, high in saturated fats and sugar.52-54 The consequence of urbanisation, which is often connected with the adoption of a lifestyle commonly referred to as ‘westernisation’, is the increased intake of energy-dense foods and high-calorie sugary meals and drinks.55-57 Urbanisation is also associated with less energy-demanding jobs, complemented by increased sedentary lifestyles and the adoption of detrimental eating habits, which include the regular consumption of fast food and so called ‘eat out’.55-57 With increasing economic development and urbanisation comes the proliferation of fast-food chains, and easy and cheaper means of transport, which are mostly patronised by the affluent. All of these factors above may have contributed to the higher prevalence of obesity noticed in the urban and affluent populations of African countries. Changes in lifestyle are therefore convincingly implicated as causative factors in the observed higher prevalence of obesity in urban than in rural populations. Existing studies have also implicated urbanisation in the increasing burden of co-morbidities of obesity such as cardiovascular disease (CVD), type 2 diabetes and hypertension. For instance, the study by Niakara and co-workers in a West African urban environment revealed a high incidence of hypertension (40.2% in a sample of 2 087 participants).58 A similar study by Sobngwi et al.59 also associated urbanisation and socio-economic factors as driving forces in the increasing prevalence of hypertension in West Africa.59 Similarly, Amoah33 and Jackson et al.30 reported a positive association of age with overweight and obesity. They identified middle-aged respondents as having the highest prevalence of obesity, which began to decline from the age of 65 years. This links increasing age with the development of obesity, a factor that should be considered by policy makers when addressing obesity in the African continent. The decline in prevalence of obesity in older age has also been noticed in other parts of the world.60,61 The results of this review also suggest a higher prevalence of obesity in the female population compared to their male counterparts. This higher prevalence in women depicts the global situation in most populations of African origin, including those in the diaspora.34,62,63 Although there is no direct comparison, about 77% of African women in the diaspora are reportedly overweight or obese, typifying the female gender as the most obese population compared with their male counterparts as well as with males of all other ethnic groups.43,61 Preferred body image may be a key factor in obesity among African women.64 Numerous studies suggest a preference for overweight over normal BMI among African women.65,66 Moreover, cultural perceptions concerning obesity and overweight may also have played a role in the high prevalence of overweight and obesity among women, and central obesity among affluent men in this review.

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Culture is known to shape health behaviour and serves as a mirror for perceiving and interpreting experiences.67,68 In several parts of Africa, obesity is currently held with little opprobrium,69,70 people generally associating fatness with beauty, fame and evidence of good living and health,33,65,71 particularly in women.72 In some cases, women are fattened up for suitors prior to marriage,73,74 as a sign of beauty and fertility. Furthermore, African men are purported to have a preference for overweight over thin women.33 Although affluence, effects of urbanisation and excess consumption of food are mainly implicated in the increased prevalence of obesity on the African continent (as suggested by this review), food insecurity may also be a factor to consider at the other end of socio-economic spectrum.64 Townsend and colleagues75 suggested a positive association of food insecurity with overweight in women, while Chaput et al.76 linked food insecurity to overweight status in women but not in men in Uganda. Conclusively, women of all socio-economic strata in the African continent can be said to be at risk of developing overweight and obesity, albeit through diverse mechanisms, which may necessitate further research. From all three studies comparing cardiovascular and inflammatory bio-markers, results showed that the levels of leptin, hsCRP and fibrinogen were significantly higher in African women. African women also had higher blood pressures and vascular resistance than their Caucasian counterparts. However this condition may have been induced by different factors, such as sodium sensitivity, which is an important condition in the African population.77 It is also notable that, although black South Africans had higher blood pressures, vascular resistance, and fibrinogen and leptin levels than their Caucasian counterparts, the relationships of these markers with obesity were markedly weaker than those of Caucasians, suggesting that the mechanisms to elucidate the weaker correlations of cardiovascular indices and obesity in the African population remain unresolved.32 The above results also imply that the level of clinical markers should not necessarily be compared between ethnic groups, as the effectiveness and sensitivity of a specific biochemical marker might be completely different in an ethnically distinct group. Findings further raise the question whether obesity should be regarded as a cardiovascular threat to these women. By contrast, given that the obesity measures of African women were strongly linked with markers that are more associated with type 2 diabetes, such as triacylglycerols, inflammation and insulin resistance, this suggests that obesity in African women may have a primary effect on the development of diabetes, and secondarily on cardiovascular disease. Earlier studies in South Africa have shown ischaemic heart disease (IHD) to be more prevalent among Europeans,21,78-80 while type 2 diabetes81-83 and hypertension84 were more common among Africans. Although the metabolic reasons behind these differences remain complex, more recent studies suggest that black South Africans have a less atherogenic fasting lipid profile than their white counterparts.85-87 Crowther et al. 87 also observed greater amounts of visceral fat and waist-to-hip ratios in obese whites than in obese black individuals.87 Given that the study by Schutte et al.32 did not include environmental influences in its investigation of these relationships, caution should be applied in the interpretation of these results. The seasonal variation in the collection of data and assay dates


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between the two ethnic groups could have induced bias and may have influenced the resulting differences found in the levels of inflammatory markers. Another consideration in the interpretation of the results is the age of the women in this study, as they were relatively young (mean age 31.3 years). Although their inflammatory markers were elevated due to obesity, it is likely that established atherosclerosis and vascular dysfunction (and related inflammatory conditions) were non-existent in this group.32 Other results from this review also suggest an association of obesity with a premature increase in blood pressure. A considerable number of obese young adults in the study by Ibhazehiebo et al.36 were hypertensive compared with the non-obese control group. Marked increases in SBP were also observed in the obese individuals compared to the controls at all levels of graded exercise, with the highest values seen during extreme exercise. These findings suggest that obese young individuals were prone to early onset of hypertension, a situation that makes them susceptible to cardiovascular complications and other health problems in the future. The findings of Ibhazehiebo et al.36 were also consistent with several other studies that associated increased BMI with increased risk of hypertension. The study by Wolf et al.88 found that the risk of hypertension was up to five times higher among obese people than in their normal-weight counterparts.88 Obesity was also positively associated with type 2 diabetes,6,89,90 and it was noted that nearly 90% of individuals who progressed to type 2 diabetes had BMIs above 23.0 kg/m². The compelling association between obesity, hypertension and diabetes among populations of African descent has also been documented.91-93 Asfaw’s comparison of the prevalence of diagnosed chronic diseases between obese and non-obese subjects also provides an indication of the effect of obesity on the prevalence of chronic diseases.2 Each chronic disease included in the study was more prevalent in obese respondents than in their non-obese counterparts. In both countries (South Africa and Senegal), the results indicated that obese subjects were more likely to be diagnosed with two or more chronic diseases than their lean counterparts.2 Asfaw’s findings are congruent with numerous studies conducted in both developed and low-income countries.14,94-97

Limitations As with many other reviews, this study has a number of limitations, hence the need to apply caution in the interpretation of its findings. Despite the fact that this review sought to incorporate studies from all African countries, all the studies retrieved were articles published in English and from Englishspeaking countries, reflecting a language bias. It is noteworthy that most studies from African countries are likely to be published in non-indexed and non-English journals.98 Moreover, the multilingual, multicultural, multi-ethnic and racial divides that characterise the African continent make it difficult to generalise the findings of this study. A further limitation was the limited number of studies that fitted the inclusion criteria. Initially, the protocol for this systematic review was designed to evaluate the impact of obesity on the health of participants on the African continent, focusing mainly on ramdomised, controlled trials (RCTs). However, due to the paucity of RCTs, the reviewers settled for comparative

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studies. This resulted in the omission of some key articles reporting on the extent of the obesity epidemic in Africa.99,100 Although the comparative aspect of this review is unusual and it resulted in variable data, it did allow us to touch on a broader spectrum of the effects of obesity (from epidemiological to clinical) in Africa. This would not have been feasible if purely epidemiological studies had been included. Also, the inclusion of three non-population based studies from the same author32,35,37 posed a limitation on the interpretation of the findings in this review. Although the articles met the inclusion criteria of comparative studies, conducting such studies with a larger sample size would have provided more insight into the differences observed in these groups. This highlights the need for larger and more numerous studies of this kind. Finally, due to the limited number of articles that met the inclusion criteria, as well as the considerable heterogeneity, it is difficult to justify these data as being an accurate representation for the whole of Africa. Hence the need for more specific and structured research on obesity on the African continent.

Conclusion The key findings of this review are: (1) obesity was more prevalent in urban than rural areas, particularly in women; (2) obesity was more prevalent in Africans who migrated to Western countries than in their counterparts on the African continent; (3) there was a co-relationship between obesity and chronic disease. However, inflammatory marker levels differed between black and Caucasian individuals and therefore should not necessarily be compared between ethnic groups. These findings have important public health implications and call for immediate action to combat the increasing prevalence of obesity. This may require a policy shift towards organised and co-ordinated strategies geared at both prevention and treatment of existing obesity. Provision of facilities that promote physical activities within communities, residential areas and workplaces is essential. Moreover, negative social pressures, cultural perceptions associated with obesity such as ‘fat is beautiful or prosperous’ should be dispelled through educational programmes.33 Creation of awareness on individual and community levels of the associated health risks of obesity, augmented by population-based health-promotion programmes are needed. These will highlight the importance of physical activity and healthy eating habits, which will constitute an integral part of forestalling the obesity epidemic and managing its sequelae where it already exists. Uncurbed, the direct and indirect burden of obesity will be a severe challenge to the future development of Africa as a continent, as well as other developing countries. Neglecting to immediately deal with the problem of obesity and leaving it unchecked will impose additional burdens on the economy and health sector of the African continent, as well as threaten its future development.

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66. Duda RB, Kim MP, Darko R, Adanu RMK, Seffah J, Anarfi JK, Hill AG. Results of the Women’s Health Study of Accra: Assessment of blood pressure in urban women. Int J Cardiol 2007; 117: 115–122. PMID: 16887210. 67. Niang CI. The Dimba of Senegal: A support group for women. Reprod Health Matters 1994; 2: 39–45. 68. Dutta–Bergman MJ. The unheard voices of Santalis: Communicating about health from the margins of India. Comm Theory 2004; 14: 237–263. DOI: 10.1111/j.1468-2885.2004.tb00313.x. 69. Walker ARP. Epidemiology and health implications of obesity, with special reference to African populations. Ecol Food Nutr 1998; 37: 21–55. 70. Walker A, Adam F, Walker B. World pandemic of obesity: the situation in Southern African populations. Public Health 2001; 115: 368–372. PMID: 11781845. 71. Siervo M, Grey P, Nyan O, Prentice A. Urbanization and obesity in The Gambia: a country in the early stages of the demographic transition. Eur J Clin Nutr 2005; 60: 455–463. PMID: 16306924. 72. Mvo Z, Dick J, Steyn K. Perceptions of overweight African women about acceptable body size of women and children. Curationis 1999; 22: 27–31. PMID: 11040616. 73. Rguibi M, Belahsen R. Fattening practices among Moroccan Saharawi women. East Med Health J 2006; 12: 619. PMID: 17333802. 74. Smith AD. Girls being force-fed for marriage as fattening farms revived. URL http://www.guardian.co.uk/world/2009/mar/01/mauritania-force-feeding-marriage (accessed September 2010). 75. Townsend MS, Peerson J, Love B, Achterberg C, Murphy SP. Food Insecurity is positively related to overweight in women. J Nutr 2001; 131: 1738-1745. PMID: 11385061. 76. Chaput JP, Gilbert JA, Tremblay A. Relationship between food insecurity and body composition in Ugandans living in urban Kampala. J Am Diet Assoc 2007; 107: 1978–1982. PMID: 17964319. 77. Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005; 112: 3562. PMID: 16330697. 78. Isles CG, Milne FJ. Low mortality from ischaemic heart disease among urban Blacks in South Africa. J Clin Hypertens 1987; 3: 749–775. PMID: 3502585. 79. Seftel HC, Asvat MS, Joffe BI, et al. Selected risk factors for coronary heart disease in male scholars from the major South African population groups. S Afr Med J 1993; 84: 891–897. PMID: 8115914. 80. Wyndham CH. Mortality from cardiovascular disease in the various population groups in the Republic of South Africa. S Afr Med J 1979; 56: 1023–1030. PMID: 550436. 81. Van der Merwe MT, Crowther NJ, Schlaphoff G, Gray IP, Joffe BI, Lönnroth PN. Evidence for insulin resistance in Black women from South Africa. Int J Obes Relat Metab Disord 2000; 24: 1340–1346. PMID: 11093297. 82. Joffe BI, Seftel HC. Diabetes mellitus in black communities of southern Africa. J Int Med 1994; 235: 137–142. PMID: 8308476. 83. Omar MAK, Seedat MA, Motlala AA, Dyer RB, Becker P. The prevalence of diabetes mellitus and impaired glucose tolerance in a group of urban South African blacks. S Afr Med J 1993; 83: 641–643. PMID:8310354. 84. Seedat YK. Prevalence of hypertension in South Africa. J Hum Hypertens 1999; 7: 2–4. 85. Van der Merwe M-T, Wing JR, Celgow LH, Gray IP, Lönn L, Joffe BI, Lönnroth PN. Metabolic indices in relation to body composition changes during weight loss on dexfenfluramine in obese women from two South African ethnic groups. Int J Obes 1996; 20: 768–776. PMID: 8856402. 86. Punyadeera C, Van der Merwe MT, Crowther NJ, Toman M, Schlaphoff GB, Gray IP. Ethnic differences in lipid metabolism in two groups of obese South African women. J Lipid Res 2001; 43: 760–767. PMID: 11352983. 87. Crowther NJ, Ferris WF, Ojwang PJ, Rheeder P. 2006. The effect of abdominal obesity on insulin sensitivity and serum lipid and cytokine concentrations in African women. Clin Endocrinol 64: 535–541. PMID: 16649973. 88. Wolf HK, Tuomilehto J, Kuulasmaa K, Domarkiene S, Cepaitis Z, Molarius A, et al. Blood pressure levels in the 41 population of the


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… continued from page 500 are the food industry, local food producers, nutrition and health scientists, consumer groups, healthcare professionals and local authorities. According to the UK Food Standards Agency, high-visibility campaigns on salt have increased consumer awareness. However, in the USA only 42% of Americans are concerned with their sodium intake, while four in 10 Americans continue to believe that low-sodium products do not taste as good. Sayed said that the aim of the workshop was to gain insights into consumer perspectives on salt, salt usage and barriers to reducing salt intake. ‘We also wanted to brainstorm and create ideas for new approaches to promote salt-intake reduction based on consumer insights, and establish collaborations to help consumers. The work has just begun. The collaborative group now has to work together to introduce a salt-awareness campaign for all South African consumers.’

Salt facts • Right up to the 20th century, pound bars of salt (called amoleh) were the basic currency in Abyssinia (now Ethiopia). • The amazing Salar de Uyuni (the world’s largest salt flat at 4 000 square miles) in Bolivia becomes mirror like when a thin layer of water lies on top. This reflectivity makes it a very useful tool in calibration of scientific equipment from outer space. This amazing salt flat also contains half of the world’s supply of lithium. • Salt is so essential to the body that if you drink too much water it can flush it out of your system and cause fatal hyponatraemia. • Consumption of too much salt can also be deadly – you need to take about 1 g of salt per kg of weight to die and this was used as a method of ritual suicide in China – especially among the nobility, as salt was so expensive. • Good-quality sea salt contains many essential minerals for the body. The best type of sea salt should be slightly wet from the sea it was taken from.

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waiting to happen. Nether J Med 2003; 61: 32–36. PMID: 12735418. 95. Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases. J Am Med Assoc 2004; 291: 2616. PMID: 15173153. 96. Kengne AP, Amoah AGB, Mbanya JC. Cardiovascular complications of diabetes mellitus in sub-Saharan Africa. Circulation 2005; 112: 3592. PMID: 16330701. 97. Fezeu L, Balkau B, Kengne AP, Sobngwi E, Mbanya JC. Metabolic syndrome in a sub-Saharan African setting: central obesity may be the key determinant. Atherosclerosis 2007; 193: 70–76. PMID: 17011567. 98. Gulmezoglu AM, Say L, Betran AP, Villar J, Piaggio G. WHO systematic review of maternal mortality and morbidity: methodological issues and challenges. BMC Med Res Methodol 2004; 4: 16. PMID: 15236664. 99. Ritchter L, Norris S, Pettifor J, Yach D, Cameron N. Cohort profile: Mandela’s children: The 1990 birth to twenty study in South Africa. Int J Epidemiol 2007; 36: 504–511. PMID: 17355979. 100. Monyeki KD, Kemper HCG, Makgae PJ. The association of fat patterning with blood pressure in rural South African children: the Ellisras longitudinal growth and health study. Int J Epidemiol 2006; 35:114– 120. PMID: 16260449.

• In the Middle Ages, salt was so expensive it was sometimes referred to as ‘white gold’. The medieval pavement of one of the transportation routes for salt still exists in Germany where it links the inland city of Lüneburg to the German Baltic coast. • Black salt is made in India by mixing salt water with harad seeds. The mixture is left to evaporate leaving behind black lumps of salt. When the salt is ground, the resulting powder is pink • In Guerande, France, salt is still gathered in the same way as it was by the ancient Celts, using baskets through which the sea water is strained. This salt is sprinkled on food prior to serving – it is never used in cooking. • There is a very common misconception that Roman soldiers were paid in salt (hence the word salary), but in fact they were paid in normal money. The connection with salt is possibly through the fact that the soldiers protected the salt roads leading to Rome (Via Salarium). • Before biblical Judaism ceased to exist, salt was mixed with animal sacrifices. This originated from Moses in Leviticus 2:13 which states: ‘Whatsoever sacrifice thou offerest, thou shalt season it with salt, neither shalt thou take away the salt of the covenant of thy God from thy sacrifice. In all thy oblations thou shalt offer salt.’ The salt was a symbol of wisdom and discretion. • After aviation fuel is purified, salt is mixed with it to remove all traces of water before it can be used. • Sodium chloride (salt) is formed when the unstable metal sodium reacts with chlorine gas. It is the only family of rocks regularly eaten by humans. • In the early 1800s salt was four times as expensive as beef on the frontier – it was essential in keeping people and livestock alive. • Only 6% of the salt used in the United States is used in food; another 17% is used for de-icing streets and highways in the winter months. • In the late 17th century, salt was the leading cargo carried from the Caribbean to North America. It was used to feed slaves on sugar plantations.


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Drug Trends in Cardiology New ESC guidelines on atrial fibrillation accept reality of next generation of anti-coagulants ‘The development of dabigatran and the first results from the use of the novel anticoagulant in the RE-LY trial mark an extremely important time in medical history; the first time in 75 years that physicians have agents that are better than the extremely effective warfarin in secondary stroke prevention.’ Speaking at the 2012 European Society of Cardiology (ESC) congress in Munich, Germany, Prof Hans-Christoph Diener, Department of Neurology, University of Duisburg-Essen, Germany, also referred to the daily reality of poor warfarin control with low INR values resulting in intracranial bleeds. ‘In fact warfarin, despite its efficacy when INR levels are well controlled (INR 2–3), due to its very unpredictable pharmacokinetic and pharmacodynamic profile, might not have been approved if the novel anticoagulants were first on the scene and warfarin second.’ The conclusion that the new anticoagulants are superior to warfarin in stroke prevention, with a reduced risk of intracranial bleeds, is now part of the reality of the new ESC guidelines in stroke prevention. Prof Gregory Lip, Centre for Cardiovascular Sciences, University of Birmingham, UK, strongly endorsed the ESC approach and pointed out that the winds of change are altering stroke prevention globally. ‘The latest American College of Chest, Physicians Guidelines, the Canadian Stroke Guidelines, the American Heart Association and American Stroke Association are in agreement that most atrial fibrillation (AF) (non-valvular) patients at intermediate to high risk of stroke should receive one of these novel agents in preference to warfarin’, Prof Lip said. ‘We are also recommending a practice shift to no antithrombotic therapy if the CHA2DS2-VASC score is zero, and

a “must-use” strategy in patients with a CHA2DS2-VASc score. This is a practicechanging guideline’, Prof Lip concluded.

Experience with dabigatran in one million patient-years of treatment At the ESC congress, Boehringer Ingelheim announced that the combined treatment experience with Pradaxa® has crossed one million patient-years1 in the prevention of thromboembolic events in patients after surgery, and patients with non-valvular AF represented the majority of patient years. This provides the greatest body of clinical experience among all novel oral anticoagulants. The announcement reaffirms the confidence physicians have in Pradaxa® to effectively prevent stroke and systemic embolism in patients with non-valvular AF and venous thromboembolic events following hip- or knee-replacement surgery. One million patient-years of treatment experience is unprecedented for a novel oral anticoagulant and highlights the broad adoption of dabigatran in more than 70 countries worldwide following regulatory approvals in stroke prevention in AF. This level of clinical use shows strong endorsement for the substantial benefits Pradaxa® demonstrated in the RE-LY trial, and for its positive benefit– risk profile, as recently reconfirmed by the European Medicines Agency. Commenting on the news, Prof Hans-Christoph Diener said ‘Preventing ischaemic stroke is of utmost clinical importance for healthcare professionals treating patients with AF. With dabigatran 150 mg bid, clinicians have a treatment available that prevents more ischaemic strokes than well-controlled warfarin, and it reduces intracranial haemorrhage at

the same time. The estimated number of strokes prevented shows the relevance of dabigatran as a safe and efficacious preventive treatment for patients with AF at risk of stroke.’ In addition, the RE-LY-ABLE trial, which is a long-term multicentre extension of dabigatran treatment in patients with AF who completed the RE-LY trial, is close to its target of a further 28 months of active therapy with the two dabigatran doses of 110 and 150 mg bid. These results will reflect the outcomes in patients continuously on dabigatran for five years, and will be presented at the 2013 American Heart Association congress.

Reversing the effects of dabigatran For patients treated with dabigatran, a range of options are available to reverse the anticoagulant effect of treatment and manage bleeding in an emergency situation. Dabigatran is the only novel oral anticoagulant that has the additional option of removal from the blood system via dialysis. Emergency dialysis can remove about 60% of the dabigatran concentration in four hours. Further to the existing reversal strategies already established in clinical practice, a specific antidote may provide another option for patient management during rare critical-care situations where rapid reversal may be helpful. Consequently and as part of Boehringer Inghelheim’s commitment to scientific innovation, the Company is currently developing a specific antidote to dabigatran etexilate to broaden the reversal options available to physicians. J Aalbers


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AFRICA

Renal denervation in Symplicity trials and real-life setting continue to show significant blood pressure reduction in all treatment groups Medtronic announced at the 2012 European Society of Cardiology (ESC) congress in Munich, Germany, new results from the Symplicity HTN-2 trial, the only randomised clinical trial investigating safety and efficacy of renal denervation. The 18-month follow-up data presented at the ESC congress showed the Symplicity system continues to provide superior and sustained blood pressure reduction in patients with treatmentresistant hypertension. The safety of renal denervation with the Symplicity system was also maintained at 18 months, with no device-related serious adverse events and no newly reported vascular complications from 12 to 18 months.1 ‘We continue to see significant and sustained improvement in blood pressure levels for patients who receive renal denervation with the Symplicity system, as these 18-month average blood pressure reductions are consistent with the 12-month follow-up data for both groups’, said Murray Esler, principal investigator of the Symplicity HTN-2 trial and associate director of the Baker IDI Heart and Diabetes Institute of Melbourne, Australia. ‘This is encouraging since patients with treatment-resistant hypertension are often taking more than three antihypertensive medications and are still unable to control their blood pressure, which can put them at risk for various cardiovascular events such as heart attack, stroke or heart failure.’ In this trial, 43 patients initially randomised to renal denervation with the Symplicity system had an average blood pressure reduction of –32/–12 mmHg from baseline (p < 0.01) at 18 months. Thirty-one control patients who received renal denervation following the six-month primary endpoint (crossover group) had an average blood pressure reduction of –28/–11 mmHg (p < 0.01) at 18 months. These 18-month average blood pressure reductions were maintained for both groups from the 12-month follow up [–28/–10 mmHg (p < 0.01) for the initial treatment group; –24/–10 mmHg (p < 0.01) for the crossover group]. The average number of medications for patients in this trial did not change from baseline to 18 months. At 18 months,

pulse pressure improved significantly for patients in this analysis following treatment with the Symplicity system [–20 mmHg from baseline for the initial treatment group (p < 0.01); –18 mmHg from baseline for the crossover group (p < 0.01]. Pulse pressure is the numeric difference between systolic and diastolic blood pressure and may have predictive value in terms of cardiovascular complications, especially in older patients. It may be important to evaluate changes in pulse pressure as well as systolic and diastolic blood pressure when assessing the efficacy of antihypertensive therapy. This analysis showed three new hospitalisations in the initial renal denervation group due to hypertensive events. The Symplicity system’s catheter and proprietary generator and algorithms were carefully and specifically developed through years of clinical experience to enhance the safety and effectiveness of the renal denervation procedure. The Symplicity renal denervation system has been successfully used for five years to treat nearly 5 000 patients with treatmentresistant hypertension worldwide. It is not approved by the US Food and Drug Administration for commercial distribution in the United States. Transcatheter renal denervation represents a novel therapy for treating patients with treatment-resistant hypertension, a condition which greatly increases the risk of myocardial infarction and stroke.

Further evidence of the value of renal denervation in clinical practice ‘The Symplicity Hypertension I and II studies have suggested that this procedure significantly lowers blood pressure in those patients with few remaining options in terms of treatment’, said Dr Mylotte, Paris. ‘However, patients included in clinical trials are often highly selected, and therefore may not reflect the typical patient encountered by physicians on a day-to-day basis. Therefore the results of these trials may not be applicable to lessselected patient populations.’ In light of this potential problem,

the investigators sought to evaluate the effect of transcatheter renal denervation in a group of patients with resistant hypertension in their own clinical practice at the Institut Cardiovasculaire de Paris Sud, Paris, France. The study intended to perform transcatheter renal denervation on 35 consecutive patients referred to the service with resistant hypertension. The study used the same definition as the Symplicity trials to define resistant hypertension.2 Among these patients, 36.5% were female, 36.4% were diabetic, and 15.2% had kidney dysfunction. Baseline office blood pressure (BP) was 181.1 ± 21.9/100.8 ± 16.8 mmHg, despite an average of 4.6 ± 1.0 medications per patient. Successful bilateral sympathetic denervation was performed in 33 out of 35 patients (one patient was not treated due to a stenosis of the renal artery; one patient had treatment on one side only, as multiple small renal arteries were found on the other side). No procedural complications occurred. At six months’ follow up, the average office BP reduction from baseline was 30.3 ± 21.1/14.6 ± 15.3 mmHg (p < 0.0001). Similarly, ambulatory BP was reduced 23.3 ± 12.1/10.2 ± 9.9 mmHg from baseline (p < 0.001). There were no adverse events during follow up (death, myocardial infarction or stroke) and no deterioration in renal function was observed. ‘Transcatheter renal denervation is a safe and efficacious treatment, which results in significant reductions in blood pressure in real-world patients with treatment-resistant hypertension’, said Dr Mylotte. ‘Although longer-term results are required, renal denervation should be considered for all patients with treatmentresistant hypertension, as it is likely to lower their blood pressure and reduce their chances of myocardial infarction and stroke.’3 J Aalbers 1. 2.

3.

Abstract 116, 2012 ESC Congress. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M, Symplicity HTN-2 investigators. Lancet 2010; 376: 1903–1909. ESC press release, 27 Aug 2012.


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Rivaroxaban in acute coronary syndromes and atrial fibrillation: rivaroxaban shown to reduce cardiovascular deaths in STEMI patients The addition of rivaroxiban to dual therapy for ST-elevation myocardial infarction (STEMI) patients has been shown to reduce recurrent cardiovascular events and cardiovascular death without increasing fatal bleeding, although TIMI non-coronary artery bypass graft (CABG) major bleeding was increased. Presenting the results of this pre-specified sub-group of the ATLAS ACS 2-TIMI 51 trial,1 at the 2012 ESC congress, Dr Jessica Mega, Brigham and Women’s Hospital, Boston, USA, noted that the primary-efficacy benefit, a significant 19% reduction in cardiovascular (CV) death, myocardial infarction (MI) or stroke emerged early in the first two to three weeks of rivaroxaban therapy. These results are consistent with the results from the overall ATLAS ACS 2-TIMI 51 phase III study. ‘The value of rivaroxaban relates to the blocking of excess thrombin generation, not only at the time of the index event but also over time’, Dr Mega said. In the overall ATLAS ACS 2-TIMI trial, more than 15 000 patients with the whole spectrum of acute coronary syndrome (ACS) were recruited; 50.3% of patients presented with STEMI, 25.6% with non-STEMI (NSTEMI) and 24% with unstable angina. The 7 817 STEMI patients were stabilised according to the study design after a median of 4.7 days and stratified by thienopyridine use according to the attending physician’s discretion, given aspirin 75–100 mg/day and randomised to placebo, or rivaroxaban 2.5 or 5 mg bid; 97% of patients were on either clopidogrel or ticlopidine, although some stopped taking this medication over the course of the study. The primary efficacy endpoint was cardiovascular death, myocardial infarction (MI) or stroke. Safety was according to TIMI major bleeding not associated with CABG. There was no reduction in cardiovascular death in patients receiving the 5-mg dose but there was a 40% reduction in CV deaths and a significant reduction in all-cause mortality in patients receiving the 2.5-mg dose of rivaroxaban. There was an increase in TIMI major

and minor bleeding, with fewer bleeds on the lower dose. There was no increase in fatal bleeding on either dose. Dr Mega concluded that very low doses of rivaroxaban (2.5 mg twice daily) offer an effective treatment strategy to reduce thrombotic events in patients following STEMI (Table 1). The use of the 2.5-mg bid rivaroxaban dose has been taken up in the new ESC guidelines on STEMI with a class IIa, level 1B recommendation as follows: ‘In selected patients who do receive aspirin and clopidogral, lower-dose 2.5-mg rivaroxaban may be considered if the patient is at low bleeding risk.’

Taking clinical studies in stroke prevention in atrial fibrillation into practice There is a high level of evidence to support the use of the new anticoagulants in stroke prevention in atrial fibrillation (AF). This has been taken up by the ESC in their newly released guidelines, which recommend the use of these novel agents as being broadly preferable to vitamin K antagonists for the majority of AF patients (level 1B recommendation). This view was substantiated by Prof Robert M Califf, primary co-investigator of the ROCKET studies of rivaroxaban at a special symposium at the ESC, which evaluated the three series of studies in RE-LY, ROCKET and ARISTOTLE, involving dabigatran, rivaroxaban and apixaban, respectively. ‘Fundamentally, in my view, the data for these agents look more similar than different and without head-to-head comparisons in large populations, we will have to make appropriate decisions for individual patients based on our interpretation of the available data.’ The RE-LY study had the advantage

of examining two doses of dabigatran compared to warfarin and was able to show equivalence at the lower dose (110 mg twice daily), with less bleeding than with warfarin. The higher dose (150 mg twice daily) was shown to be superior to warfarin in stroke prevention with the same level of bleeding complications but with fewer life-threatening major bleeds and somewhat higher gastrointestinal bleeding rates. The ROCKET-AF trial was based on a single, once-daily dose of rivaroxaban (20 mg daily), which showed non-inferiority to warfarin with regard to the reduction of stroke and non-central nervous system embolism, with a decrease in serious bleeds such as intracranial and fatal bleeding, although overall bleeding rates were the same. It is important to note that the ROCKET trial intentionally included patients at considerable risk of stroke, and the overall risk score in ROCKET was much higher than in the other two trials. Prof Werner Hacke, neurologist from Heidelberg University, Germany pointed out that the CHADS2 score for ROCKET was 3.5, while average risk scores for RE-LY and ARISTOTLE were much lower at 2.1. Focusing on the neurologist’s experience of encountering AF patients only after they have experienced their first stroke, Prof Hacke presented important insights from the published data of the three trials in the pre-specified patient sub-group with prior stroke or transient ischaemic attack (TIA). This evaluation of secondary prevention shows that in prior stroke patients in RE-LY and ARISTOTLE, some 20% of patients had higher CHADS scores and were more comparable to the overall ROCKET experience with its inclusion of patients at higher stroke risk. ‘In this group of patients who are more vulnerable to a further stroke and

TABLE 1. ATLAS ACS 2-TIMI 51 RESULTS IN STEMI PATIENTS AT TWO YEARS CV death/MI/stroke CV death All-cause death TIMI non-CABG major bleeding

Rivaroxaban 2.5 mg 8.7 2.5 3.0 1.7

Placebo 10.6 4.2 4.7 0.6


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experience almost twice as many strokes as the stroke-naïve patients, the higher dose of dabigatran loses its superiority in stroke prevention to warfarin but is still better than warfarin with regard to reducing intracranial bleeds. This is in concordance with the overall results of the RE-LY trial.’ ‘Similarly, if the data from the ARISTOTLE trial with apixaban is analysed with regard to these patients, the stroke rate was three times higher than in those without a prior stroke. Apixaban for these patients was shown to be non-inferior to warfarin with fewer haemorrhagic strokes and intracranial bleeding events. Again concordance is seen with regard to the overall results of ARISTOTLE.’ ‘ROCKET-AF included 55% of patients with prior stroke or TIA and most patients were at risks above 2; only 13% had a CHADS score of 2 and few had a score of 1. Prof Hacke noted that the patients with a prior stroke in ROCKET were at even higher risk of stroke (CHADS score > 4) than the already high risk levels within the ROCKET patient cohort who had to have had a stroke, TIA or systemic embolism or at least two risk factors for inclusion in the trial.’ In these very vulnerable patients, there were once again twice as many strokes as in stroke-naïve patients, and rivaroxaban treatment reduced the number of strokes, with a clear trend towards lower rates of intracranial and fatal bleeding’, he noted.

Practical advice on use of these novel agents The importance of counselling patients when prescribing these new agents was stressed by Prof Jafna Cox, Canada, who

noted that patients should be instructed to not stop the drug without prior consultation with their physician. Also they need to be told how to manage a missed dose of dabigatran using the six-hour rule, and with rivaroxaban to just take the drug even if later on the same day. Not doubling the dose is an essential warning for all of these agents. ‘Inevitably, as we treat these patients, we encounter patients with recent ACS and they require on-going surveillance. I avoid dabigatran in this situation, rather choosing rivaroxaban but nonetheless keeping a watchful, concerned eye over developments.’ Withdrawal of these agents may not always be necessary, particularly when patients are undergoing low-risk procedures. If there is bleeding on an anticoagulant, tests such as the aPTT for dabigatran and PT for rivaroxaban are useful, as higher values indicate the patient is still taking the drug. Action can be initiated as for any bleeding event.

Expert comments Dr Mike Bennett, Wilgers Hospital, comments on the developments related to novel anticoagulant use in AF Atrial fibrillation patients are poorly treated. Physicians are afraid of warfarin side effects and patients on warfarin are often poorly controlled. They face limitations with regard to diet and lifestyle, with the required regular monitoring intruding on their peace of mind. The new oral agents are simple to use and as safe as warfarin. It comes as no surprise to me that the new ESC guidelines recommend their use above warfarin for most patients.

AFRICA

It is absolutely clear that aspirin has no place in stroke prevention in AF, yet it is still commonly prescribed in South Africa. Other absolutes for me in stroke prevention in AF are that patients older than 75 years and those of any age who have had a stroke require oral anticoagulation. With regard to stroke patients, the absence of any remaining symptoms of the incident does not mean that the patient does not require anticoagulation; the risk of a second stroke remains. The elderly are at particularly high risk for a stroke and warfarin presents particular challenges, so it is often not prescribed. The older patient is usually on multiple other medications, may have cognitive problems and if living in a retirement or old-age home is dependent on others to give the medication. They are dependent on their carers to get them to clinics or doctors’ rooms where the INR checks are done and their time in therapeutic range (TTR) is frequently less than ideal. With regard to rivaroxaban, it is attractive as a once-daily, fixed dose, it requires no monitoring, is as safe and as effective as warfarin, while also reducing the risk of intracranial bleeds. It has no food or drug interactions and allows the patient to live without continually being concerned about its use. Affordability is an issue but this needs to be evaluated against the significant healthcare costs of warfarin. J Aalbers 1.

Mega JL, Braunwald E Wiviott SD, et al. Rivaroxiban in pateints with a recent acute coronary syndrome. N Engl J Med 2012; 366(1): 9–19.


Mor 1 millio e than worldw n patients with X ide treated are ® THR an lto 10 in d TKR .*

Leading the way in new ORAL anticoagulation More than 75 000 patients enrolled

Clinical Trial Programme Study Programme

Venous thromboembolism (VTE) prevention in total hip replacements.

Dosage

n

Rivaroxaban 10 mg OD

4,541

Main Outcome Measures Efficacy:

Composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality Safety:

Venous thromboembolism prevention in total hip replacements - extended prophylaxis.

Venous thromboembolism prevention in total knee replacements.

Venous thromoboembolism prevention in total knee replacements - compared to enoxaparin 30mg BD.

Outcome Superior efficacy vs enoxaparin, comparable safety. Superior efficacy of long term (5 week) prophylaxis with rivaroxaban vs short term (2 week) prophylaxis with enoxaparin, comparable safety.

NEJM 2008

ANCET THE L008 2

Rivaroxaban 10 mg OD

2,509

Rivaroxaban 10 mg OD

2,531

Superior efficacy vs enoxaparin, comparable safety.

NEJM

Rivaroxaban 10 mg OD

3,148

Superior efficacy vs enoxaparin, comparable safety.

ANCET THE L009 2

Major bleeding

2008

Xarelto® 10 OD is approved for clinical use for VTE prevention in adult patients undergoing major orthopaedic surgery of the lower limbs. OD = once daily.

Study Programme

Prevention of venous thromboembolism in hospitalised medically ill patients.

Treatment of acute symptomatic deep vein thrombosis.

Treatment of acute pulmonary embolism with or without symptomatic DVT.

Continued treatment of deep vein thrombosis or pulmonary embolism.

Prevention of stroke and embolism in atrial fibrillation.

Anti-Xa therapy to lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in subjects with acute coronary syndrome.

Dosage

n

Rivaroxaban 10 mg OD

~8,000

Rivaroxaban 15 mg BID, first 3 weeks Continue with Rivaroxaban 20 mg OD

3,464

4,300

Rivaroxaban 20 mg OD

1,197

Rivaroxaban 20 mg OD or Rivaroxaban 15 mg OD 30-49 ml/min CrCl

14,269

Rivaroxaban 15 mg OD

1,280

Rivaroxaban 2.5 mg BID Rivaroxaban 5 mg BID

Main Outcome Measures Efficacy: Composite of VTE (DVT and/or PE) and VTE related death Safety: Major and clinically relevant non-major bleeding Efficacy: Symptomatic recurrent VTE Safety: Major and clinically relevant non-major bleeding

Efficacy: Symptomatic recurrent VTE Safety: Major bleeding Efficacy: Composite of stroke and non-CNS systemic embolism Safety: Composite of major and clinically relevant non-major bleeding Efficacy: Composite of CV death, MI and stroke

~16,000

Safety: Major bleeding events not associated with CABG surgery

Outcome

Study completed

Study completed

Study completed

TED PRESEN

ACC

2011

NEJM 2010

NEJM 2012

NEJM Study completed

2010

NEJM Study completed

2011

D

TE PRESEN

Study completed

ISTH

Study completed

NE JM

2011

2011

OD = once daily BID = twice daily CrCl = creatinine clearance. Rivaroxaban 2.5 mg, Rivaroxaban 5 mg, Rivaroxaban 15 mg and Rivaroxaban 20 mg are in Clinical Development; and thus not recommended for clinical use in all Indications under investigation.

The most extensive Phase III Clinical Trial Programme of any new oral anticoagulant ** www.thrombosisadviser.com *THR - total hip replacement. TKR - total knee replacement. **http://clinicaltrial.gov RECORD1: Eriksson BI, et al. N Engl J Med. 2008; 358(26):2765-2775. RECORD2: Kakkar AK, et al. Lancet. 2008; 372(9632):29-37. RECORD3: Lassen MR, et al. N Engl J Med. 2008; 358(26):2776-2786. RECORD4: Turpie AGG, et al. Lancet. 2009; 373(9676):1673-1680. MAGELLAN: http://clinicaltrials.gov/ct2/show/NCT00571649. EINSTEIN DVT and EXT: Einstein Investigators. N Engl J Med. 2010. EINSTEIN PE: http://clinicaltrials.gov/ct2/show/NCT00439777. ROCKET AF: Patel, et al. N Engl J Med. 2011. J-ROCKET AF: http://clinicaltrials.gov/ct2/show/NCT00973323. ATLAS ACS TIMI 51: http://clinicaltrials.gov/ct2/show/NCT00809965. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC) S4 XARELTO® 10 (Film-coated tablets). Reg.No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041 DATE: February 2012 L.ZA.GM.02.2012.0377


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Ivabradine reduces total hospital burden in heart failure Heart rate reduction using ivabradine in patients with chronic heart failure who were in sinus rhythm and with heart rates of at least 70 beats/min resulted in substantially reduced clinical deterioration in total hospitalisations for worsening heart failure and in an increase in time to first and subsequent hospitalisations.1 This was despite patients being treated with guideline-based background therapy, including maximally treated betablockade. Presenting the results of the posthoc analysis of the SHIfT study, which focused on recurrent hospitalisation, Prof Jeffrey Borer, New York, stressed that ivabradine therapy did not unmask any other problems that would lead to hospitalisation. ‘In the Total Time Analysis,

the time to occurrence of hospitalisation for heart failure was reduced for first events by 25%, for second events by 34%, and for a third event by 29%. All of these reductions were highly statistically significant’, Prof Borer pointed out. Another way of evaluating the hospitalisation data focused on the causes of hospitalisation. In this review, hospitalisation for worsening heart failure was reduced by 25%, hospitalisation for any cause by 15%, and hospitalisation for cardiovascular-related events by 16%. Overall hospitalisations other than for worsening heart failure were reduced by 8%, which did not, however, reach statistical significance. Acknowledging some of the normal limits of a post-hoc study and the fact

that the treatment effect is dependent on previous hospitalisations (the cumulative effect of the first, second and third event) and differences in hospitalisation burden in different countries, Prof Borer nonetheless concluded that ivabradine reduces the total burden on the patient and the healthcare system. ‘The financial burden can be expected to be substantially reduced when ivabradine is added to guideline-based heart-failure therapies’, he concluded. J Aalbers 1.

Borer JS, Böhm M, Ford I, Komajda M, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT study. Eur Heart J. 12 Sept 2012 [Epub ahead of print]. doi:10.1093/ eurheartj/ehs259.

GARFIELD: a window on the real-life treatment of atrial fibrillation South Africa joins the GARFIELD registry The results of the evaluation of the first cohort of 10 000 newly diagnosed atrial fibrillation (AF) patients in the GARFIELD registry, which reflects contemporary global real-life treatment of AF, has shown that fewer than half of the eligible patients received anticoagulant therapy with vitamin K antagonists. In addition, those patients at significantly increased risk of experiencing stroke or systemic emboli with a CHADS2 risk score greater than 2 were poorly treated. Patients who were not really at risk (those with a CHADS2 score of zero) and who did not generally require anticoagulation treatment were frequently given anticoagulant therapy in some 80% of cases. The GARFIELD (Global Anticoagulant Registry in the FIELD) seeks better understanding of these contradictions in an academically driven project, led by the UK-based Thrombosis Research Institute and funded with an unrestricted grant from Bayer Healthcare. Prof Barry Jacobson, haematologist, Witwatersrand University, will lead the South African arm of the registry which

has now begun to document and track non-valvular AF patients with at least one additional cardiovascular risk factor. Patients will be recruited at both primary and specialist-care levels in the country. Speaking at a special symposium at the 2012 ESC congress, Prof Lord Ajay Kakkar, University College Hospital, London, noted that the registry aims to describe treatment patterns that reflect the real world beyond so-called centres of excellence. ‘It includes the many diverse places where doctors are working, including those placed in less well-resourced settings. We need to be sensitive to the extent of the strokeprevention challenges the world will face over the next 30 years, as the number of stroke cases are set to double in both middle- and low-income countries. This registry will help us to develop valuebased healthcare approaches which can be applied in a wide variety of clinical settings’, he concluded. Patients in the registry will be followed for at least two years. Importantly, the registry includes a patient-satisfaction questionnaire and seeks to explore the

in-practice bridging of anticoagulation when vitamin K antagonist therapy is interrupted. Prof Alex Turpie, McMaster University, Canada pointed out that experience within GARFIELD will also allow evaluation of combination therapies in patients with AF and other cardiovascular co-morbidities. ‘All of the new anticoagulant agents have been Q-tested in phase II trials in ACS and appear to have potential. However, rivaroxiban is the only drug to date that has been shown in phase III trials to be beneficial in this setting’, he pointed out.

Expert comment Prof Barry Jacobson’s views on the new SA-based initiative ‘I feel that this study will help us understand not only how patients who have access to First-world medicine are treated but also how indigent patients are managed in a Third-world setting’, says Prof Jacobson. J Aalbers


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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012

e1

Case Report Acute anterior myocardial infarction in an 85-year-old male patient, complicated by the deadly duo: ventricular septal rupture and pseudoaneurysm AHMET C AYKAN, REGAYIP ZEHIR, CAN Y KARABAY, SINEM CAKAL, NERTILA POCI, KENAN SÖNMEZ

Abstract Ventricular septal rupture and ventricular pseudoaneurysm formation are rare complications of acute myocardial infarction. Immediate intervention is mandatory in these circumstances. Our case is a unique presentation of an anterior myocardial infarction in an 85-year-old male, complicated by ventricular septal rupture and ventricular pseudoaneurysm formation. Keywords: ventricular septal rupture, pseudoaneurysm, acute anterior myocardial infarction Submitted 23/3/11, accepted 3/5/12 Cardiovasc J Afr 2012; 23: e1–e3

www.cvja.co.za

DOI: 10.5830/CVJA-2012-039

Case report An 85-year-old man complaining of mild dyspnoea was admitted Department of Cardiology, Kartal Kosuyolu Heart Research and Educational Hospital, Istanbul, Turkey AHMET C AYKAN MD, ahmetaykan@yahoo.com REGAYIP ZEHIR, MD CAN Y KARABAY, MD SINEM CAKAL, MD NERTILA POCI MD, KENAN SÖNMEZ, MD

to the emergency department. He had had an anterior myocardial infarction eight days earlier and was hospitalised for four days in the intensive care unit of a local hospital. He was discharged with standard anti-ischaemic medication. He had presented at the 18th hour of myocardial infarction, therefore thrombolytic therapy was not administered. At admission the patient was tachycardic (110 beats/min) and mildly dyspnoeic. His blood pressure was 130/85 mmHg. On physical examination, a 4/6 systolic murmur was apparent on the apex, radiating to the axilla. He had crepitant pulmonary rales at the bases. There were no neurological signs. The 12-lead electrocardiogram showed sinus rhythm of 110 beats/min, with a right bundle branch block, low QRS voltage in the limb leads, Q waves and a 4-mm ST-segment elevation in the precordial leads (Fig. 1A). The serum troponin T level was 5 ng/ ml and the BNP level was 3 000 pg/ml. Transthoracic echocardiography showed a ventricular septal rupture (VSR) (Fig. 2C, D) causing a left-to-right shunt (Fig. 2A, B), a small ventricular pseudoaneurysm (Fig. 2C, D) and moderate mitral regurgitation. The left ventricular systolic ejection fraction was 35%. Moderate pericardial effusion was evident. Transoesophageal echocardiography was not performed because of the urgency of the situation. Coronary angiography showed 95% stenosis of the middle and distal segments of the left anterior descending artery (Fig. 1B) and non-critical stenosis in the circumflex and right coronary arteries (Fig. 1C). The patient was immediately sent to

A

Fig. 1A. A 12-lead electrocardiogram showing sinus tachycardia with right bundle branch block, low QRS voltage in the limb leads, Q waves, and 4-mm ST-segment elevation in the precordial leads.


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B

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C

Fig. 1B. Coronary angiography showing 95% stenosis in the middle and distal part of the left anterior descending artery, thrombus in the proximal segment of the left anterior descending artery and non-critical stenosis in the circumflex artery. C. Non-critical stenosis in the right coronary artery.

the cardiovascular surgery department. An operation was decided on, with the consent of the patient and family. He underwent successful coronary artery bypass graft surgery and primary suturing of the VSR. He was asymptomatic at follow-up visits.

Discussion VSR is a life-threatening complication of acute myocardial infarction (MI) requiring early intervention. It was common (1â&#x20AC;&#x201C;3%) in the era before reperfusion therapy but has decreased with the introduction of thrombolytic therapy and primary

A

B

C

D

Fig. 2A. A regurgitant jet is evident through the interventricular septum in the parasternal short-axis echocardiographic view. B. A regurgitant jet is evident through the apical interventricular septum in the apical four-chamber axis echocardiographic view. C. Ruptured apical interventricular septum and thinning apical wall is evident in a focused apical four-chamber view. D. Ruptured apical interventricular septum, pseudoaneurysm and pericardial effusion is seen in the apical four-chamber view.


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percutaneous interventions.1-3 VSR is more rare than a rupture of the ventricular free wall. Women are affected more often than men. Age, smoking and hypertension are other risk factors.4 A VSR usually occurs two to eight days after the infarction and often precipitates cardiogenic shock. The magnitude of the left-to-right shunt is determined by the size of the defect and hence causes haemodynamic deterioration, which affects survival. Spontaneous closure of this defect is extremely rare.5 There are three types of VSR: in type I there is an abrupt tear in the wall without thinning; in type II, the infarcted myocardium erodes before rupture and is covered by a thrombus; and type III represents the perforation of a previously formed aneurysm.6 The blood supply to the septum originates from branches of the left anterior descending coronary artery, the posterior descending branch of the right coronary artery or the circumflex artery. A VSR has equal frequency in anterior and non-anterior infarctions.7 An anterior MI is associated with rupture of the apical septum. In an inferior MI, the base of the heart is often affected. An MI associated with a VSR is usually extensive. Early treatment of the MI with thrombolytic therapy or primary percutaneous intervention may reduce the incidence of the VSR by reducing the infarct area. Restoring the blood flow therefore improves the outcome. Ventricular free-wall rupture is a catastrophic complication of MI. Its prevalence is 4% in patients with MI and 23% in those who die of MI.8 Rarely the rupture is contained by an adherent pericardium, creating a pseudoaneurysm that needs emergency surgery. Our case is unique, illustrating an acute anterior MI, complicated by a VSR and ventricular pseudoaneurysm formation, which are both lethal. The patient survived with moderate symptoms until successful intervention.

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Conclusion Early coronary angiography and primary percutaneous intervention in acute coronary syndromes is life-saving and may prevent lethal complications, including VSR and free-wall rupture.

References 1.

2.

3. 4.

5.

6. 7.

8.

Birnbaum Y, Fishbein MC, Blanche C, Siegel RJ. Ventricular septal rupture after acute myocardial infarction. N Engl J Med 2002; 347: 1426–1432. Gueret P, Khalife K, Jobic Y, et al. Echocardiographic assessment of the incidence of mechanical complications during the early phase of myocardial infarction in the reperfusion era: a French multicentre prospective registry. Arch Cardiovasc Dis 2008; 101: 41–47. Murday A. Optimal management of acute ventricular septal rupture. Heart 2003; 89(12): 1462–1466. Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) trial investigators. Circulation 2000; 101: 27–32. Ilia R, Goldfarb B, Wanderman KL, Gueron M. Spontaneous closure of a traumatic ventricular septal defect after blunt trauma documented by serial echocardiography. J Am Soc Echocardiogr 1992; 5: 203–205. Becker AE, van Mantgem JP. Cardiac tamponade: a study of 50 hearts. Eur J Cardiol 1975; 3: 349–358. Batts KP, Ackerman DM, Edwards WD. Postinfarction rupture of the left ventricular free wall: clinicopathologic correlates in 100 consecutive autopsy cases. Hum Pathol 1990; 21: 530–535. Pollak H, Nobis H, Miczoc J. Frequency of left ventricular free wall ruptures complicating acute myocardial infarction since the advent of thrombolysis. Am J Cardiol 1994; 74: 184–186.


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Case Report Giant pseudoaneurysm of the left axillary artery following a stab wound M FOKOU, VC EYENGA, A CHICHOM MEFIRE, ML GUIFO, JJ PAGBE, W SANDMANN

Abstract Axillary artery pseudoaneurysms are rare. We report on a 30-year-old patient with a 6.5-cm post-traumatic pseudoaneurysm of the left axillary artery two months after a knife stab wound of the shoulder. The patient showed axillary fullness and signs of severe brachial plexus compression. A surgical repair was undertaken. The aneurysm was excluded and a saphenous vein interposition was performed. The early and late postoperative periods were uneventful. This is probably not only the largest axillary artery pseudoaneurysm ever reported, but also the first secondary to a stab wound. Keywords: axillary artery, pseudoaneurysm, stab wound Submitted 12/2/10, accepted 5/6/12 Cardiovasc J Afr 2012; 23: e4–e6 DOI: 10.5830/CVJA-2012-045

Aneurysms and pseudoaneurysms of the axillary arteries (AA) are extremely rare but well-documented phenomena.1-5 Only five cases have been reported in the surgical literature up to 1990. Most AA pseudoaneurysms are late consequences of blunt arterial injuries around the shoulder, and particularly anterior shoulder dislocation2-6 or humeral head fractures.7,8 Although not reported, penetrating wounds such as gunshot and stabbing may also result in such conditions. The major complications are from the initial brachial plexus injury or its secondary compression. Rupture with haemorrhage can be life threatening, and distal embolisation may result in ischaemia of the arm.

We present a rare case of a patient with a 6.5-cm pseudoaneurysm of the left AA. The patient was treated surgically. To the best of our knowledge, this is the first pseudoaneurysm of an AA secondary to a stab wound.

Case report The patient, a 30-year-old labourer, was seen at the surgery department of the Yaoundé General Hospital in Cameroon. He presented with a history of gradually increasing swelling of his left axilla over the previous two months. There had been a penetrating shoulder injury caused by a long knife during a fight three weeks before the start of the axillary swelling. Profuse haemorrhage was managed by a blood transfusion and wound closure in a peripheral centre. No other past medical illness was reported by the patient. Due to an increase in the axillary mass, associated with neurological dysfunction of the upper extremity, he was advised to come to our vascular department. On examination, the axillary mass measured 8 cm, was firm, slightly painful and pulsatile. No bruit was audible on auscultation (Fig. 1). The distal pulses were difficult to detect but the arm was warm with normal colouration. Hypo-aesthesia, paralysis and amyotrophy of the upper extremity were present. Ultrasonography followed by computed tomography angiography (CTA) showed a left AA pseudoaneurysm, 6.5 mm

Department of Surgery, Yaoundé General Hospital, Cameroon M FOKOU, MD, mfokou@yahoo.com VC EYENGA, MD JJ PAGBE, MD

Department of Surgery, Limbé General Hospital, Cameroon A CHICHOM MEFIRE, MD

Departments of Surgery and Radiology, Yaoundé General Hospital, and Department of Surgery, Yaoundé University Teaching Hospital, Cameroon ML GUIFO, MD

Department of Vascular Surgery and Kidney Transplantation, University of Düsseldorf, and Vascular Centre, Kampt-Lintford, Germany W SANDMANN, MD

Fig. 1. External view of the axillary artery pseudoaneurysm.


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Fig. 2. CTA demonstrating the axillary artery pseudoaneurysm.

in diameter, involving the second and third segments of the AA. The humeral artery was patent (Figs 2, 3). Electromyography revealed diffuse brachial plexus lesions corresponding to the C5, C6 and C8 roots. The pre-operative work-up showed no other abnormality. Conventional surgical treatment was decided on, with exeresis of the aneurysm, brachial plexus liberation and axillo-humeral bypass with a vein. Under general anaesthesia, the patient was placed in a supine position, with the shoulder slightly elevated and the arm in a horizontal position, forming a 90Âş angle with the body. Exposure of the left AA was achieved proximally using an infraclavicular approach and distally using the classic humeral

Fig. 3. Axillary artery pseudoaneurysm demonstrating the patency of the humeral artery.

approach. A prolongation in the delto-pectoral groove was performed to divide the pectoralis major and transect the pectoralis minor. The large pseudoaneurysm was identified. Before the 45-min clamping, 5 000 IU heparin sulfate was administered intravenously. A total exeresis of the aneurysm was performed and a mild brachial plexus laceration was found. A 12-cm saphenous vein interposition was done using a 5-0 polypropylene (Fig. 4). The postoperative period was uneventful. The intervention site and the patency of the AA were evaluated clinically and with ultrasound daily until discharge (eight days), then weekly for one month, monthly for one trimester, and subsequently every six months. Physiotherapy and six-month oral anticoagulation were recommended after discharge. To date, two and half years after the surgery, on ultrasound the AA is patent without stenosis or enlargement. The neurological deficit has improved and the patient has resumed duty with the affected limb.

Discussion Epidemiology

Fig. 4. Surgical view of the saphenous vein graft (arrow).

Axillary artery peudoaneurysms are rare and the published experience is limited to around five cases reported in the last 20 years, as determined from a Medline search of the literature. The aetiologies are post-traumatic, severe or recurrent anterior shoulder dislocation,2-6 and humeral head fractures.7,8 Blunt arterial injuries of the shoulder account for only 5% of all arterial injuries in this area, whereas penetrating wounds, as was the case here, are more frequent, representing 95%.8 Fortunately, false aneurysms secondary to penetrating wounds have not been reported. This is probably due to the fact that vascular wounds are easy to discover and manage immediately,


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compared to blunt vascular trauma where the clinical presentation can be misleading.

Manifestations The natural history of AA pseudoaneurysms is poorly understood. Most aneurysms are likely to be asymptomatic despite there being no reports supporting such an assessment. Among the patients described in the surgical literature, a pulsatile mass of the arm axilla with a bruit is a common presentation.1-6 As is the case for any aneurysm, rupture may occur. Spontaneous rupture of an AA pseudoaneurysm has not been described, probably due to the surrounding muscular protection. Neurological symptoms may be the presenting symptoms in some patients with large pseudoaneurysms due to primary lesions or secondary compression of the brachial plexus. Mild primary lesion and severe compression of the brachial plexus was found in our patient. The question of initial brachial plexus injury, which is described in up to 44% of these patients,7-9 can be answered by the delay in onset of the neurological symptoms. Some patients, unlike this case, may suffer upper extremity oedema resulting from venous and/or lymphatic compression. A lymph node, pulsatile haematoma or axillary tumour may be the differential diagnosis. Ultrasonography, arteriography, CTA or MRI angiography are particularly useful to establish the diagnosis and proceed to operative therapy.1-6,9

Treatment Operative intervention is recommended for all symptomatic axillary artery aneurysms or pseudoaneurysms with manifestations related to arm ischaemia, local discomfort or brachial plexus compression. A diameter greater than 2 cm may be considered the threshold in asymptomatic cases. Because of its rarity, the natural history of asymptomatic pseudoaneurysms is not known, therefore a threshold is difficult to define.1-6 Due to the high risk of embolisation, surgical management at a smaller diameter is perhaps the best choice. Several types of AA reconstructions have been proposed according to the size, location and aetiology of the pseudoaneurysm. The most common is resection or exclusion of the aneurysm, with reconstruction using interposition with a saphenous vein graft. Other options include a resection and primary anastomosis, aneurysmorrhaphy and reconstruction using a venous or prosthetic patch.4-6,10 Surgery is the traditional definitive treatment even though endovascular therapy is also now well established. Endovascular therapy using stent grafts can be considered for patients with

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extensive medical co-morbidities, making open operative repair too risky. Patients with small non-compressive aneurysms and no concomitant lesions may also be good candidates for the endovascular approach.1-3 In our patient, although endovascular treatment of this lesion could seem attractive, we preferred to use an open surgical technique. This allowed us to perform decompression of the axillary fossa since the pseudoaneurysm was large, and to explore the brachial plexus.

Conclusion Despite its clinical magnitude, axillary artery pseudoaneurysms are uncommon and the published experience of this condition is limited. Surgical repair may control the aneurysm but morbidity from brachial plexus injuries could leave the patient with poor recovery of the upper extremity function.

References 1.

Kumar RM, Reddy SS, Sharma R, Mahajan R, Talwar KK. Endovascular repair of a traumatic axillary artery pseudoaneurysm. Cardiovasc Intervent Radiol 2009; 32: 598–600. 2. Stahnke M, Duddy MJ. Endovascular repair of a traumatic axillary pseudoaneurysm following anterior shoulder dislocation. Cardiovasc Intervent Radiol 2006; 29: 298–301. 3. Bennett JD. Evidence-based radiology problems. Covered stent treatment of an axillary artery pseudoaneurysm: June 2003-June 2004. Can Assoc Radiol J 2003; 54: 140–143. 4. Julià J, Lozano P, Gomez F, Corominas C. Traumatic pseudoaneurysm of the axillary artery following anterior dislocation of the shoulder. Case report. J Cardiovasc Surg (Torino) 1998; 39: 167–169. 5. Gaspar M, Petrescu LP, Fluture V, Drăgulescu I, Cosma O, Martin P, et al. Posttraumatic pseudoaneurysm of the axillary artery after anterior dislocation of the shoulder: a case report. Chirurgia (Bucur) 1996; 45: 317–320. 6. Zieren J, Kasper A, Landwehr P, Erasmi H. Traumatic pseudoaneurysm of the axillary artery after shoulder dislocation. Chirurg 1994; 65: 1058–1060. 7. Matheï J, Depuydt P, Parmentier L, Olivie F, Harake R, Janssen A. Injury of the axillary artery after a proximal humeral fracture: a case report and overview of the literature. Acta Chir Belg 2008; 108: 625–627. 8. Mouzopoulos G, Lassanianos N, Mouzopoulos D, Tzurbakis M, Georgilas I. Axillary artery injury associated with proximal humerus fractures. Vasa 2008; 37: 274–277. 9. Gonzalez RP, Falimirski ME. The role of angiography in periclavicular penetrating trauma. Am Surg 1999; 65(8): 711–713. 10. Hyre CE, Cikrit DF, Lalka SG, Sawchuk AP, Dalsing MC. Aggressive management of vascular injuries of the thoracic outlet. J Vasc Surg 1998; 27(5): 880–884.


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Case Report Acute ST-elevation inferior myocardial infarction in a patient with a non-obstructive mechanical mitral valve thrombosis AHMET CAGRİ AYKAN, MEHMET ÖZKAN,NİLUFER EKSİ DURAN, MUSTAFA YİLDİZ

Abstract The risk of systemic embolisation in patients with prosthetic heart valves who are receiving anticoagulation therapy is 0.5 to 1.7% per patient year and most cases present with cerebrovascular events. Here we report the case of a 42-year-old woman who was uneventfully treated with a low dose, prolonged infusion of tissue plasminogen activator because of non-obstructive prosthetic mitral valve thrombosis. It presented as coronary embolism and resulted in acute ST-elevation inferior myocardial infarction. Keywords: coronary embolism, prosthetic valve thrombosis, thrombolytic theraphy, prosthetic heart valve, acute coronary syndrome Submitted 26/12/10, accepted 5/6/12 Cardiovasc J Afr 2012; 23: e7–e8

www.cvja.co.za

DOI: 10.5830/CVJA-2012-047

On warfarin therapy, the incidence of major thromboembolism (resulting in death or persistent neurological deficit) in patients with prosthetic valve thrombosis (PVT) is 0.5 to 1.7%.1-3 Multiple prosthetic valves, cage ball valves and aortic valve prostheses increase the risk of embolisation.1,2 Age over 70 years, atrial fibrillation and depressed left ventricular functions also increase the risk of embolisation with prosthetic valves.4 Acute pulmonary oedema, circulatory collapse or progressive dyspnoeas (NYHA class III and IV) may be the presentation of PVT.5 Up to 25% of patients suffer from systemic embolism before a diagnosis is made.6 The typical findings are diminished mechanical valve sounds, decreased valve area on Doppler and increased transvalvular gradients. Both obstructive and non-obstructive PVTs are best diagnosed by transoesophageal echocardiography (TEE).7,8 Generally, patients with non-obstructive PVT are in NYHA class I and II.5 An autopsy series of coronary embolism cases reported 14% incidence of mitral valve disease with atrial fibrillation and 8%

with prosthetic heart valves.9 Because of haemodynamic factors favouring diastolic blood flow into the left coronary artery, the embolic myocardial infarctions mostly affected the anterior wall. Seventy-five per cent of cases were typical transmural infarcts while 25% were atypical.

Case report A 42-year-old woman was admitted to the emergency department with a history of sudden-onset retrosternal chest pain radiating to the left arm. Her physical examination was normal with audible mechanical heart valve sounds. She had a history of rheumatic mitral stenosis and had received a mechanical mitral valve (27 St Jude, bileaflet) three years earlier. She was on 5 mg warfarin therapy and her international normalised ratio (INR) was 1.9 two months prior to admission and 1.5 at presentation. Her electrocardiogram revealed normal sinus rhythm and 2-mm ST-segment elevation in leads DII, DIII and AVF. She was started on unfractioned heparin, and immediate coronary angiography demonstrated an occlusive thrombus in the distal

Department of Cardiology, Kosuyolu Kartal Heart Training and Educational Hospital, Istanbul, Turkey AHMET CAGRİ AYKAN, MD, ahmetaykan@yahoo.com MEHMET ÖZKAN, MD NİLUFER EKSİ DURAN, MD MUSTAFA YİLDİZ, MD, PhD

Fig. 1. The arrow shows cessation of the blood flow in the distal segment of the left anterior descending artery, which is a sign of thrombotic occlusion of the coronary artery.


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coronary atherosclerotic disease rather than PVT-derived emboli,10 our case suggests the possibility of a small thrombus burden, which embolised to the distal part of the LAD, with no prosthetic valve dysfunction or secondary emboli to other organs. While present data suggest the administration of 100 mg t-PA with the usual protocol for myocardial infarction, due to its risk of complications, the decision was made to administer low-dose (25 mg), prolonged infusion (6 hours) of t-PA to achieve gradual lysis at the lowest effective dose to minimise thromboembolic and haemorrhagic complications. We recently presented the efficacy and safety of this treatment modality in patients with PVT.12 Inadequate anticoagulation is the most likely complicating factor.

Fig. 2. Transoesophageal echocardiographic imaging showing a mobile, non-obstructive thrombus on the mechanical prosthetic mitral valve (arrows).

segment of the left anterior descending artery (LAD) (Fig. 1). Transthoracic echocardiography (TTE), performed in the coronary intensive care unit, revealed inferior wall hypokinesia with an ejection fraction of 55%, mechanical mitral valve area of 2 cm2 and 8 mmHg mean gradient. No obvious thrombus was seen. For futher evaluation, TEE was performed and a non-obstructive prosthetic mitral valve thrombosis was seen (Fig. 2). Low dose (25 mg) and slow infusion (6 hours) of tissue plasminogen activator (t-PA) was administered. Control coronary angiography was normal without any residual thrombus in the LAD. A day after thrombolysis, TEE revealed complete lysis of the prosthetic valve thrombus.

Discussion Patients with a prosthetic heart valve and acute coronary syndrome who present with non-ST elevation myocardial infarction are a rare subgroup, more likely to be elderly, with risk factors for atherosclerosis. It is reported that the pathogenesis of acute coronary syndrome is commonly coronary atherosclerotic disease rather than prosthetic heart valve-derived emboli.10 Coronary embolism is a rare entity with prosthetic heart valves, and even rarer with mitral prostheses. In the literature, most cases were caused by aortic valve prostheses with obvious thrombus burden. Optimal management of these situations remains controversial, although surgery is usually favoured.7,11 The use of thrombolysis may be limited by the increased risk of dislodgement of the embolus, distal embolisation and haemorrhagic complications. Additionally, rapid infusion of thrombolytic agents has also been associated with higher complication rates.8 By determining the lowest effective infusion dosage and duration, the risk of thromboembolism and haemorrahage can be minimised. Our patient presented with acute inferior transmural myocardial infarction in Killip class I. She had been asymptomatic for three years following mitral valve replacement and was in normal sinus rhythm throughout. At presentation, there was no clinical evidence of PVT on TTE but TEE revealed a non-obstructive trombus on the prosthetic mitral valve. Although it is reported that the pathogenesis of acute coronary syndromes is usually

Conclusion We report the occurence of a coronary embolism, presenting as an acute ST-elevation myocardial infarction, in a young patient with a mitral valve replacement. It was found to be a non-obstructive prosthetic valve thrombosis. She was successfully treated with low-dose, prolonged infusion of tPA.

References 1.

Cannegieter SC, Rosendaal FR, Brier E. Thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis. Circulation 1994; 89: 635–641. 2. Sun JCJ, Davidson MJ, Lamy A, Eikelboom JW. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 2009; 374: 565–576. 3. Salem DN, Stein PD, Ahmad AA, Bussey HI, Horstkotte D, Miller N, et al. The Antithrombotic therapy in valvular heart disease – native and prosthetic: Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 457–482. 4. Burchfiel CM, Hammermeister KE, Krause-Steinrauf H, Sethi GK, Henderson WG, Crawford MH, et al. Left atrial dimension and risk of systemic embolism in patients with prosthetic heart valve. J Am Coll Cardiol 1990; 45: 32–41. 5. Cáceres-Lóriga FM, Pérez-López H, Santos-Gracia J, MorlansHernandez K. Prosthetic heart valve thrombosis: pathogenesis, diagnosis and management. Int J Cardiol 2006; 110: 1–6. 6. Horstkotte D, Burkhardt D. Prosthetic valve thrombosis. J Heart Valve Dis 1995; 4: 141–153. 7. Lengyel M, Horstkotte D, Völler H, Mistiaen WP; Working Group Infection, Thrombosis, Embolism and Bleeding of the Society for Heart Valve Disease. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005; 14(5): 567–575. 8. Özkan M, Kaymaz C, Kirma C, Sönmez K, Özdemir N, Balkanay M, et al. Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: a study using serial transesophageal echocardiography. J Am Coll Cardiol 2000; 35(7): 1881–1889. 9. Charles RG, Epstein EJ, Holt S, Coulshed N. Coronary embolism in valvular heart disease. Q J Med 1982; 51: 147–161. 10. Iakobishvili Z, Eisen A, Porter A, Cohen N, Abramson E, Mager A, et al. Acute coronary syndromes in patients with prosthetic heart valves – A case-series. Acute Cardiac Care 2008; 10(3): 148–151. 11. Tong AT, Roudaut R, Ozkan M, Sagie A, Shahid MS, Pontes Júnior SC, et al. prosthetic valve thrombolysis-role of transesophageal echocardiography (PRO-TEE) registry investigators. J Am Coll Cardiol 2004; 43(1): 77–84. 12. Biteker M, Duran NE, Gündüz S, Kaya H, Kaynak E, Çevik C, et al. Comparing different intravenous thrombolytic treatment regimens in patients with prosthetic heart valve thrombosis under the guidance of serial transesophageal echocardiography: A 15-year study in a single center (TROIA Trial). Circulation 2008; 118: 932.


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Case Report Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning SERVET ALTAY, HUSEYIN ALTUG CAKMAK, GULSAH CEMILOGLU BOZ, SINAN KOCA, YALCIN VELIBEY

Abstract Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 109 /l, haematocrit of 28% and platelet count of 280 × 109 /l. The prothrombin time (PT) was > 200 s (normal range 10.5–15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20–45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8–1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversedphase liquid chromatography. Keywords: superwarfarin,brodifacoum,vitamin K, rodenticides, coagulopathy Submitted 9/5/11, accepted 8/6/12 Cardiovasc J Afr 2012; 23: e9–e11

www.cvja.co.za

DOI: 10.5830/CVJA-2012-051

Department of Cardiology, Siyami Ersek Thoracic and Cardiovascular Surgery Center Training and Research Hospital, Istanbul, Turkey SERVET ALTAY, MD YALCIN VELIBEY, MD

Department of Cardiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey HUSEYIN ALTUG CAKMAK, MD, altugcakmak@hotmail.com

Department of Internal Medicine, Goztepe Training and Research Hospital, Istanbul, Turkey GULSAH CEMILOGLU BOZ, MD SINAN KOCA, MD

Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats.1 They are long-acting, fat-soluble anticoagulants with half-lives between 16 and 220 days. They are 100 times more potent than warfarin due to phenyl groups replacing the terminal methyl group in the molecular structure.1,2-4 Superwarfarins and warfarins are metabolised in the liver after ingestion. Warfarin and superwarfarin interfere with vitamin K metabolism by inhibiting both vitamin K epoxide reductase and vitamin K reductase enzymes, causing accumulation of vitamin K epoxide (the inactive form of vitamin K), thus preventing γ-carboxylation of the vitamin K-dependent clotting factors II, VII, IX and X.3,5 The most commonly used superwarfarin is brodifacoum (4-hydroxy coumarin with a 4-bromo side chain, sold as D-Con: Reckitt & Colman, Montvale, NJ).6 Since superwarfarins are widely used in stores and homes in both rural and urban areas, there can easily be overexposure and intoxication, leading to abnormal coagulopathy or bleeding and resulting in severe clinical outcomes. Over 16 000 cases of superwarfarin intoxication have been reported annually by the Poison Control Centre’s toxic exposure surveillance system in the United States.7 Epidemiological data show an increasing incidence of human exposure to superwarfarins worldwide. The majority of cases are related to accidental ingestion, mostly by children under six years old. However, attempted suicide, psychiatric diseases, deliberate self poisoning with denial (Munchausen syndrome) and homicide are among other reported causes.8,9 Here we report on a young man with severe upper and lower gastrointestinal haemorrhage caused by superwarfarin poisoning after ingestion for attempted suicide.

Case report A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. He also denied any renal, hepatic or gastrointestinal diseases. There was no history of excessive alcohol ingestion or smoking habit and his dietary recall showed an adequate intake of vitamin K. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide, including brodifacoum orally for five days prior to admission to hospital. The physical examination revealed a blood pressure of


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105/75 mmHg and a pulse rate of 92 beats/min. Heart and respiratory auscultation findings were normal. The patient was in a depressive mood over his family problems and had never received treatment for depression. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Electrocardiography (ECG), abdominal ultrasonography (USG) and abdominal X-ray showed no pathological findings. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 109/l, haematocrit of 28% and platelet count of 280 × 109/l. The prothrombin time (PT) was > 200 s (normal range 10.5–15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20–45 s). The INR (international normalised ratio) was > 17 (normal range 0.8–1.2). The thrombin time and plasma fibrinogen levels were in the normal range. All coagulation deficits were corrected by mixing with normal pooled plasma in a 1:1 ratio. The liver, renal and thyroid function tests, and serum protein electrophoresis were normal, but urinalysis revealed microscopic haematuria. The results of factor assays were consistent with vitamin K deficiency: factor II: 68% (79–150), factor VII: 28% (67–175), factor IX: 40% (82–162), factor X: 46% (68–153), factor V: 98% (73–150), and factor VIII: 82% (59–150). Because no other cause of vitamin K deficiency could be determined, warfarin abuse was suspected. However, analysis of two blood samples for warfarin gave negative results with reversed-phase liquid chromatography. The endoscopic examination performed for his melena revealed mucosal erosion in the antrum, and pantoprazole infusion was started along with 30 mg/day intravenous vitamin K1 and two units of fresh frozen plasma. Over the next five days, the melena resolved and his INR and aPTT levels decreased to 1.62 and 41 s, respectively. The patient was psychiatrically evaluated and he was put on alprazolam 0.5 mg three times a day. He started psychotherapy sessions for his depressive mood. Two days after the second measurement of coagulation parameters, the patient had epistaxis and his INR level was found to be elevated again (> 17). Two units of fresh frozen plasma along with 10 mg intravenous vitamin K1 were given twice a day in order to control the acute bleeding, and phenobarbital 200 mg/day was given for microsomal enzyme induction. The patient’s failure to respond to vitamin K treatment and the negative blood test result for warfarin led to a suspicion of superwarfarin poisoning. A serum sample was sent to a reference laboratory for investigation by reversed-phase liquid chromatography.7 The results showed the presence of brodifacoum at a concentration of 61 ng/ml. The patient’s INR level showed fluctuations and it remained high for his entire hospital stay of 72 days (Fig. 1). When his INR levels increased concomitant with active bleeding, fresh frozen plasma and intravenous vitamin K1 treatments were increased up to three units/day and/or 40 mg/day, respectively. The patient was discharged from hospital on 30 mg/day oral vitamin K1, with an INR level of 2.6. During follow-up visits over a period of 92 days, the INR level regressed to the normal range. A repeat brodifacoum level of 15 ng/ml was found 92 days after hospital discharge. The vitamin K1 treatment was stopped and the patient was referred to a psychiatric clinic for medical and psychotherapeutic treatment of major depression.

AFRICA

Discussion Warfarin was first identified by Karl Link in 1933 as the active component of mouldy sweet clover and has since been used as a rodenticide. Increasing resistance to warfarin in rats has led to the development and use of the superwarfarins (derivatives of 4-hydroxycoumarin, such as difenacoum, bromadiolone and brodifacoum, and indanedione derivatives such as chlorophacinone, pindone and diphacinone).1 Superwarfarins are long-acting, colourless, odourless and fat-soluble anticoagulants with a terminal half-life varying between 16 and 220 days and are 100 times more potent than warfarin.3,10 They show their anticoagulant effect by inhibiting the conversion of vitamin K 2,3-epoxide to vitamin K hydroquinone, the co-factor required by r-glutamyl carboxylase for the posttranslational modification of coagulation factors II, VII, IX and X, and protein C and protein S, thereby leading to decreased functional activities and antigenic levels of vitamin K-dependent coagulation factors and proteins. Brodifacoum, which is a derivative of 4-hydroxy coumarin, is the most commonly used rodenticide worldwide, especially in homes and businesses. It is more potent than warfarin as a vitamin K antagonist and the elimination half-life in rats is 156 hours compared to the 17-hour half-life of warfarin.11 In humans, the half-life varies between 243 and 1 656 hours for brodifacoum,12,13 compared to 17 and 37 hours for warfarin. The main side effect of brodifacoum is toxicity leading to coagulopathy, which can be encountered with relatively small doses.14 The most common clinical feature of superwarfarin intoxication is bleeding from any mucosal site or organ. Epitaxis, haematuria, gingival bleeding, ecchymosis, gastrointestinal bleeding, haemoptysis, and intracranial haemorrhage have been reported in studies by Chua et al.4 and Spahr et al.8 In our case, gastrointestinal haemorrhage and gingival bleeding were present. We also found reduced levels of vitamin K-dependent factors II, VII, IX and X. The incidence of superwarfarin poisoning has increased over the past 10 years.7,8 While the most common cause of this poisoning is accidental ingestion, especially in children, other causes include suicide, homicide, surreptitious administration, and usage as a drug of abuse. Since most adult cases are related to suicide,5,8,12,15 obtaining a psychiatric consultation is needed 18 16 14 12 10 8 6 4 2 0

0

50

100

150

200

Fig. 1. INR level showing elevation and fluctuations during the hospital stay of 72 days.


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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012

to reveal the cause of superwarfarin ingestion. In our case, the patient’s history was remarkable, implying suicidal intentions as the motive behind ingestion of this drug. The diagnosis of superwarfarin toxicity should be suspected in any patient who has a history of drug abuse or depression, has a depressive mood and/or presents with a markedly prolonged PT, PTT and INR levels and severe deficiency of vitamin K-dependent clotting factors, with a transient or no response to standard doses of vitamin K therapy. Since superwarfarins may lead to relative vitamin K deficiency, biochemical assays including plasma vitamin K, PIVKA-II (protein-induced in vitamin K absence, a measurement of the non-carboxylated proteins) levels, decreased urinary Gla (g-carboxyglutamic acid) levels should be carried out. Increased vitamin K 2,3-epoxide levels, increased plasma vitamin K epoxide-to-vitamin K ratio (used to detect vitamin K deficiency) may also support this diagnosis. In our case, we detected markedly prolonged PT, PTT and INR levels, together with a deficiency of vitamin K and related factors (factors II, VII, IX, and X). The treatment modalities of superwarfarin poisoning are administration of vitamin K1, fresh frozen plasma, prothrombin complex concentrate and recombinant factor VIIa.8 For cases in which recent ingestion of superwarfarin is certain, syrup of ipecac and charcoal may be given to decrease subsequent absorption of the drug into the circulation. The standard treatment of superwarfarin toxicity is administration of large doses of vitamin K. There are multiple forms of vitamin K: vitamin K1 (phylloquinone) is an active vitamin K that is typically produced by green plants. Vitamin K2 (menaquinone) is a group of compounds made by intestinal bacteria. Vitamin K3 (menadione) is the parent compound lacking the necessary side chain and is inactive in vitro. Vitamin K1 is recommended for the treatment of superwarfarin toxicity. Management of patients with superwarfarin poisoning involves prolonged administration of high doses of vitamin K1. The oral route is preferred to intramuscular or intravenous injection to avoid haematoma formation. Intravenous administration is preferred only if severe bleeding is present, due to the risk of an anaphylactic reaction with this route of administration.8 If the patient is actively bleeding or at high risk of bleeding, fresh frozen plasma infusions are given to replace deficient vitamin K-dependent coagulation factors. In our case, since the patient had a history of ingesting superwarfarin for five days and was admitted to the emergency department with epigastric pain, gingival bleeding and melena concomitant with extended coagulation parameters (PT, aPTT, INR), vitamin K1 and fresh frozen plasma infusions were administered intravenously for prolonged periods of time. Despite this intensive therapy, his INR level regressed to the normal range only after three months.

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Conclusion Superwarfarin ingestion can be a serious problem, resulting in life-threatening bleeding. Although awareness of the condition has increased, its incidence is not decreasing. The prevalence of superwarfarin poisoning should be determined in every country, considering these recently published cases. Supervision of rodenticide usage and education of people who deal with rodenticides in their homes or workplaces are also necessary. Further studies are needed in order to achieve faster and more accurate diagnosis of this condition.

References 1. 2.

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Hadler MR, Shadbolt RS., Novel 4-hydroxycoumarin anticoagulants active against resistant rats. Nature 1975; 253: 275–277. Park BK, Leck JB. A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit. Biochem Pharmacol 1982; 31(22): 3635–3639. Veenstra GE, Owen DE, Huckle KR. Metabolic and toxicological studies on the anticoagulant rodenticide, flocoumafen. Arch Toxicol (Suppl) 1991; 14: 160–165. Chua DJ, Friedenberg WR. Superwarfarin poisoning. Arch Intern Med 1998; 158(17): 1929–1932. Wu YF, Chang CS, Chung CY, Lin HY, Wang CC, Shen MC. Superwarfarin intoxication: hematuria is a major clinical manifestation. Int J Hematol 2009; 90(2): 170–173. Epub 2009 July 9. Rumack BH, Hess AJ, Gelman CR (eds). POISINDEX System. Englewood, Colo: Micromedex Inc; 1996: 89. Bronstein AC, Spyker DA, Cantilena LR jun, et al. Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th annual report 2008. Clin Toxicol (Phila) 2009; 47: 911–1084. Spahr JE, Maul S, Rodgers GM. Superwarfarin poisoning: a report of two cases and review of the literature. Am J Hematol 2007; 82(7): 656–660. Babcock J, Hartman K, Pedersen A, Murphy M, Alving B. Rodenticideinduced coagulopathy in a young child. A case of Munchausen syndrome by proxy. Am J Pediatr Hematol Oncol 1993; 15(1): 126–130. Watt, BE, Proudfoot AT, Bradberry SM, et al. Anticoagulant rodenticides. Toxicol Rev 2005; 24(4): 259–269. Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology 1983; 27: 281–288. Weitzel JN, Sadowski JA, Furie BC, et al. Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: Clinical and metabolic studies of three cases. Blood 1990; 76: 2555–2559. Stanton T, Sowray P, Mcwaters D, et al. Prolonged anticoagulation with long-acting coumadin derivatives: case report of a brodifacoum poisoning with pharmacokinetic data. Blood 1988; 72: 310A. Swigar ME, Clemow LP, Saidi P, et al. Superwarfarin ingestion. A new problem in covert anticoagulant overdose. Gen Hosp Psychiatry 1990; 12(5): 309–312. Kim HY, Jeon HJ, Ko BS, et al. Two cases of brodifacoum poisoning from inhalation route. Korean J Hematol 1996; 31: 473–479. Lee JH, Kim H, Han HS, et al. A case of superwarfarin intoxication without a definitive history of brodifacoum exposure. Korean J Hematol 2009; 44: 53–57.


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