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APRIL 2012 VOL 23 NO 3

AFRICA www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Surgical treatment of renovascular hypertension • Stented tissue mitral and aortic heart valve replacement • Helicobacter pylori infection in acute coronary syndrome • Tachycardia-induced cardiomyopathy • Serum tumour markers in pericardial effusion • Left ventricular structural changes after antihypertensive treatment • Factors in pre-eclamptic African women • Cardiac surgery risk-stratification models

Cardiovascular Journal of Africa . Vol 23, No 3, April 2012

Printed by Durbanville Commercial Printers Tel: 021 946 4074

• Cardiac surgery for African children • New anticoagulants in atrial fibrillation


EVERY DAY IN SOUTH AFRICA

44** PATIENTS WILL HAVE AN AF* RELATED STROKE1, 2, 3

22** OF THEM WILL DIE

WITHIN A YEAR (50 %)4

90 % OF STROKE PATIENTS WITH KNOWN AF WERE NOT THERAPEUTICALLY ANTICOAGULATED4

THINGS ARE ABOUT TO CHANGE IN ANTICOAGULATION THERAPY

*AF – Atrial Fibrillation ** Best Estimate

HEALTHCARE

REFERENCES: 1. Stats South-Africa. Stats-Online. P0302 - Mid-year population estimates. Updated 20 July 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03022010.pdf 2. Connor M. Stroke Management in South Africa – Who is responsible? S Afr Psychiatry Rev 2005; 8: 125-126. 3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a populationbased study. Stroke 2005; 36:1115-9. 4. Gladstone DJ, Bui E,Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40;235-240.

Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348 2400 • Fax: +27 (011) 787 3766 • Company Reg. No. 1966/008618/07. BI Ref No. 254/2010 (Nov 10)


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

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VOL 23, NO 3. APRIL 2012

CONTENTS

Cardiovascular Journal of Africa

125

www.cvja.co.za

From the Editor’s Desk

Electronic innovation and readership AJ Brink

Cardiovascular Topics

126 The design and development of a stented tissue mitral and aortic heart valve replacement for human implantation M Legg • E Mathews • R Pelzer 131 Prognostic role of Helicobacter pylori infection in acute coronary syndrome: a prospective cohort study R Eeskandarian • R Ghorbani • M Shiyasi • B Momeni • K Hajifathalian • M Madani 136 The clinical, electrocardiographic and echocardiographic characteristics and long-term outcome of patients with tachycardia-induced cardiomyopathy A Chin • A Okreglicki • M Badri 143 The value of serum tumour markers in the prediction of aetiology and follow up of patients with pericardial effusion U Bildirici • U Celikyurt • E Acar • O Bulut • T Sahin • G Kozdag • D Ural 147 Prevalence of residual left ventricular structural changes after one year of antihypertensive treatment in patients of African descent: role of 24-hour pulse pressure E Libhaber • G Norton • C Libhaber • A Woodiwiss • G Candy • M Essop • P Sareli 153 The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia L Govender • I Mackraj • P Gathiram • J Moodley

INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors

Topic 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 Electrophysiology and Pacing dr a okreglicki 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


Review Articles

160 Cardiac surgery risk-stratification models C Prins • I de V Jonker • L Botes • FE Smit 165 The challenges of cardiac surgery for African children AOH Mocumbi

VOL 23, NO 3. APRIL 2012

CONTENTS

Your life and your heart

170 Coenzyme Q10, an anti-oxidant of value to reduce oxidative stress; also useful to reduce statin-induced myalgia J Aalbers

drug Trends

168

New anticoagulants offer consistent stroke-reduction benefit in atrial fibrillation J Aalbers

171

From the ACC congress, 24–27 March 2012 J Aalbers

172 South African Hypertension Society 2012 congress report J Aalbers • G Hardy

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

e1 Iatrogenic hydropneumopericardium F Peters • A Patel • R Essop e3 Spontaneous coronary artery dissection associated with Leriche syndrome CY Karabay • MM Can • IH Tanbonga • SM Aung • A Kalayci • C Gecmen • C Kirma e6

Multiple gene polymorphisms predisposing to the prothrombotic state in an adolescent with acute myocardial infarction A Doğan • A Icli • E Varol • D Erdogan

e9 Very late thrombosis of a paclitaxel-eluting stent after 72 months in a patient on dual anti-platelet therapy V Subban • L Kalidoss • MA Sankardas e12 Post-infarction myocardial rupture: a case of pericardial tamponade salvaged by auto-blood transfusion AK Khaledi • F Larti • S Safari e14

Heart failure and cardiogenic shock associated with the TB-immune reconstitution inflammatory syndrome C Kenyon • N Schrueder • M Ntsekhe • G Meintjes

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

Production Co-ordinator

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

GAUTENG CONTRIBUTOR

PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za

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

HEALTHCARE

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 For subscription enquiries contact Wendy Wegener on wendy@clinicscardive.com 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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NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. TEL: +27(0) 861 70 0 90 0. FA X: +27(0)11 525 3401. R e f e r e n c e s: 1. Vi l a i n e J P e t a l. J C a rd i ova s c P h a rm a c o l 2 0 0 3;42:68 8 - 696 . 2 . C a m m A e t a l. D ru g s R &D 20 03;4:83 - 89. 3. Borer J et al. Circulation 20 03;107:817- 823. 4. Swedberg K et al. Lancet 2010;376: 875 - 885.

Coralan ® improves outcomes in heart failure patients with a heart rate above 70bpm - SHIFT 4


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Cardiovascular From the Editor’s Topics Desk Electronic innovation and readership The Cardiovascular Journal of Africa (CVJAfrica) has updated its electronic presence with a modern website to provide for quick and easy access to the Journal’s contents and services. Importantly, for narrow-band users in developing regions, the Journal has ensured that access to its articles is direct to text in compact PDFs. For our advertisers, within both the pharmaceutical and academic environments, the Journal site has links via advertisements to further product details. For authors, their articles are indexed in PubMed, Medline, Embase and Scopus and are tracked by Thompson Reuters (Web of Knowledge – ISI) which provides the Journal’s impact factor. Reassuringly, in the current debate on ‘open access’, all articles published in the CVJAfrica are provided as full text, free of charge on the Pubmed and CVJAfrica site. The copyright of published articles is held by the CVJAfrica and if these articles are reproduced internationally, payment is made via the US-based Copyright Clearance System. Again, the charge for academic use is extremely low (0.1 American cents per page) while commercial use reflects the actual costs more closely.

Printed versions of the Journal are provided to South African reference libraries and to relevant specialists in South Africa. Increasingly, the Journal is accessed electronically, with 1 800 visitors to the site monthly, who view on average four pages of Journal content. In addition, 2 500 articles are downloaded per month globally by readers using the Pubmed full-text facility. The challenge for all e-based, independent journals is how to ensure sufficient financial support. We have reluctantly introduced a modest ($50) submission fee to help us cover the significant costs of Editorial Manager; the well-known and highly regarded Aries manuscript submission system. Many open-access journals such as those in BioMedCentral charge a $1 000 author submission fee. The CVJAfrica focus is to publish quality research articles in the field of vascular disease. We thank our authors, reviewers and editors across the country for their support of the Journal’s activities.

AJ Brink Editor-in-Chief


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Cardiovascular Topics The design and development of a stented tissue mitral and aortic heart valve replacement for human implantation MURRAY LEGG, EDWARD MATHEWS, RUAAN PELZER

Abstract A study was conducted into the development of a mitral and aortic heart valve replacement that caters for patients having suffered valve damage due to stenosis or rheumatic fever. The appeal of the valve is that it is constituted from a solid frame housing pericardial tissue leaflets, and allows the patient freedom from post-operative blood-thinning medication. The valve is designed to appeal to patients in developing areas of the world, as it features a clip-in mechanism to secure the valve assembly into the sewing ring, which is stitched in independently of the frame and leaflets. Re-operative valve replacement would then be made possible when the pericardial leaflets began to calcify. Novel aspects of the design added value to the science of heart valve replacements, through the use of sintered chrome cobalt in the valve components, the insights gained into mechanical testing of pericardium, and the patient benefits offered by the complete design. Further work is planned to fatigue test the assembly, undergo animal trials and make the valve available for commercial use. Keywords: aortic valve replacement, mitral valve replacement, tissue valve Submitted 13/5/10, accepted 16/8/10 Cardiovasc J Afr 2012; 23: 126–130

www.cvja.co.za

Tissue valves do not present the risk of stroke to the patient, but are constructed from porcine or bovine pericardial tissue. The body’s immune response to this generally causes calcification and tissue hardening, ultimately detracting from the ideal functioning of the heart valve replacement and it requires re-operative surgery within a 10- to 15-year period. It has been estimated that worldwide, around 380 000 valve replacements take place annually.5 The majority of these patients are elderly and from first-world countries. Developing countries, however, actually face a greater need for valve replacements due to high instances of rheumatic fever. It is purely a socioeconomic limitation that prevents valve surgery being more commonplace in these developing countries. Long-term follow-up studies focusing largely on elderly recipients may skew the opinions on favourable valvereplacement methodologies because minimal emphasis is given to patients’ long-term follow up in developing countries. Unger and Ghosh5 discuss this, noting that 85% of all openheart procedures are performed in countries representing 11% of the current world population. Lack of education and the distances from healthcare facilities may still impede evasion of post-operative complications associated with anti-coagulation. Therefore, there is a need for a valve replacement that requires little or no ongoing supportive treatment.

DOI: 10.5830/CVJA-2010-065

Heart valve replacements

Two main but divergent solutions address heart valve replacements, namely bioprosthetic types and mechanical valve replacements. Rapid advances in the chemical treatment of tissue valves by glutaraldehyde fixation1 and the progression from balland-cage valves2 to tilting disc3 and bi-leaflet4 designs were all limited to a few exciting, pioneering years. Current valve designs, particularly those of the mechanical form, create turbulent blood flow. This turbulence leads to the formation of blood thromboses and haemolysis and ultimately a thrombo-embolic event. Blood-thinning medication must be prescribed on an ongoing basis. This is a major logistical and financial limitation to patients in outlying and impoverished areas.

Two main failure modes are experienced in natural mitral and aortic valves, namely stenosis and regurgitation. These can occur in isolation or together at both valve positions. Mitral stenosis occurs where the mitral valve obstructs flow from the left atrium into the left ventricle. Mitral regurgitation occurs when the mitral valve allows reverse flow of blood to the left atrium, rather than it all being pumped during systole through the aortic valve into the aorta. Developing countries, because of infrastructural limitations in the use of antibiotics, generally have high instances of aortic regurgitation induced by rheumatic fever. Such occurrences in the developed world are typically limited to the elderly who contracted rheumatic fever in their youth but were not administered antibiotics.

Centre for Research and Continued Engineering Development, North West University, Pretoria, South Africa and consultant to TEMM International (Pty) Ltd MURRAY LEGG, PhD EDWARD MATHEWS, PhD RUAAN PELZER, PhD, rpelzer@researchtoolbox.com

Mechanical valves The largest load placed on mechanical valves is that of transvalvular pressure, which occurs just after valve closure. This causes two types of wear stress, namely impact- and


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friction-wear stress. Impact-wear stress occurs between the valve occluder and ring, while friction-wear stress occurs between the occluder and strut pivots. The catastrophic failure of the BjorkShiley valve6 was due to a transient occlusion impact of the disc onto the outlet strut, causing bending stresses in excess of its elastic material limit. Material fatigue is another area of concern in mechanical heart valve replacements. To this end, the majority of valve manufacturers make use of either a silicon carbon blend, or pure pyrolytic carbon for the formation of their leaflets. The housing and struts are required to be manufactured from particularly strong metals such as titanium. Cavitation is another significant mode of failure in mechanical heart valves. It is caused by a localised and significant drop in pressure, equal to or below that of the blood vapour pressure, causing the blood to vaporise and form bubbles in the bloodstream. In mechanical heart valves, the sudden closing of the tilting leaflet causes localised high-pressure jets of blood to squeeze past the closing boundary and form vortices and cavitation. Pitting and surface erosion from this cavitation were found on failed Duromedics valves.

Tissue valves Development in pursuit of a solution not incurring the limitations that are placed on mechanical valves followed in the form of tissue valve replacements. Bioprosthetic valves have the major advantage of not being susceptible to the thrombo-embolic effects created by the functioning of mechanical valves. Animal tissues, most commonly bovine pericardium or porcine valves are used for these valves. To allow for the facilitation of these tissues to be integrated into a human heart, antigen masking through treatment of glutaraldehyde fixation has been the status quo since the mid 1960s.7 Acknowledging at the outset that tissue valves require masking of antigenicity and that the absence of living tissue prevents any possible form of self-repair, the major research on tissue valves has focused on the implications of this parameter. The treatment of leaflet tissue with glutaraldehyde reduces immunogenicity but does not totally eliminate it. This causes the tissue to respond with cellular immune responses as the body acts to reject the tissue. Studies indicate that the level of cross-linking of the collagen fibres has the effect of reducing the antigenicity.8 However, the major challenge facing tissue valve use is still the link between immune response and calcific degeneration, and hence to be able to trace poorly masked immunogenicity.9 Inflammatory degradation causes explanted valves to typically be covered in inflammatory cells, or be penetrated by giant cells and macrophages.10 Bovine pericardium heart valve prostheses often have macrophages invade the prosthetic collagen, and in porcine valves, as many as 82% of failed valves showed signs of collagen phagocytosis.11 Mechanical leaflet damage is a concern in tissue valves, as the use of glutaraldehyde mitigates any option of self-repair mechanisms. Valves in the mitral position are more stressed than those in the aortic position. Studies by Maxwell et al.12 indicated that up to 75% of failed porcine valves showed a rupture of a free cusp edge. In a study by Guangqiang et al.,13 a comparison is drawn between the aortic valve repair (AVR) of 518 patients using Carpentier Edwards (CE) porcine valves between 1974 and 1996

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and the AVR with CE pericardial valves from 1991 to 2002. Ten-year survival rates for the porcine and pericardial valves were 34 ± 2 and 38 ± 6%, respectively. Adverse cardiac events of thrombo-embolism (20 ± 2 and 13 ± 2%, respectively) and endocarditis (2 ± 1 and 1 ± 1%, respectively) over a 10-year span were limited and similar for both. Interestingly, the 10-year follow up requiring no re-operation was lower for porcine (90 ± 2%) than for pericardial (97 ± 1%) valves. Major reasons for explant included structural valve degeneration (SVD), endocarditis and periprosthetic leak. The durability of the pericardial valve offered is superior to the traditional CE porcine valve. The pericardial valve’s freedom from SVD and re-operation makes it a favourable bioprosthetic choice for AVRs.

Bovine pericardium Fixation with glutaraldehyde was initially considered to greatly reduce the immune response to tissue xenografts. It is now evident, though, that immune responses to glutaraldehydefixed pericardium do still occur,14,15 Antibody generation and immune rejection in bioprosthetic heart valve degeneration is now accepted, but the actual proteins responsible for triggering the immune response are largely unknown. Antigen masking or antigen removal is considered and implemented to improve the durability and lower the body’s rejection response to implanted bioprostheses. A study was conducted into the material properties of the two types of unfixed bovine pericardium supplied at Glycar Pty (Ltd). These comprised a thin and thick version of unfixed pericardium, forming 16 randomised batches, each batch containing 10 thin and 10 thick sheets. The pericardial sacs used were sourced in Namibia from animals, by circumferential dissection around the top of the heart adjacent to the major vessels. The tissue was in the form of a cone with a spherical tip, obtained from cattle aged between 12 and 36 months. The mean thicknesses of the thin and thick pericardium were 0.25 ± 0.03 mm and 0.34 ± 0.04 mm, respectively. The tensile strength of the samples was calculated to be 20.75 ± 2.38 and 24.09 ± 3.85 MPa for the thin and thick samples, respectively. The experimental results indicate that there is an associated increase in tensile strength with an increase in thickness. The increase in strength that the glutaraldehyde provides is a further benefit in support of the use of the thicker version of pericardium, and would ultimately prolong the fatigue life of the leaflets. The major drawback of using glutaraldehyde-fixed porcine or bovine tissue in prosthetic implantation is calcification.16 Although the exact details of the methods with which such calcification occur are not known, it is felt that the aldehyde elements do have an impact on the rate at which the degradation occurs.17 In lieu of this drawback, certain pre- and postprocessing techniques are implemented to reduce the risk of calcification. These treatments result in the modification of the amino acids, forming a protein mass that is insoluble in the harshest of denaturing environments.18 Hardening of the pericardium is prevented by immersing it in distilled water after glutaraldehyde treatment. Any swelling that may then occur is thus catered for once integrated into the frame geometry. Grabenwöger et al.19 conducted a study into the denaturing of glutaraldehyde-preserved and dye-medicated photo-oxidised


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pericardium of rats, by measurement of the growth properties of seeded umbilical vein endothelial cells on biological tissues. Post-processed pericardium treated with L-glutamic acid, which acts to reduce free, unbound aldehyde groups, was then also tested. It was found that severe calcification occurred on the glutaraldehyde-treated pericardium (165 ± 20 mg) but no cell proliferation occurred. Post-fixation-treated pericardium had a greatly reduced development of calcification (89 ± 14 mg) and also suffered no damage. The photo-oxidised tissue had no calcification but extreme cell proliferation did occur.

Heart valve design The valve design ultimately converged on a solution by the balancing and contrasting of design considerations and constraints. The physical geometry, the aspects of the valve assembly and the techniques of surgical implantation all share significant importance in the actual functioning of the valve. A significant aspect of the valve design was the decision taken on the method of surgical implantation, and the technique within which the valve should be inserted into the heart. The principles behind this allowed the valve assembly to be clipped into the sewing ring, once the ring had been stitched into place in the heart. Design considerations would stem primarily from these criteria. The materials used in the valve assembly needed to be biocompatible and reasonably accessible. The design of the valve must take into consideration the potential of mass production and assembly to cater for significant demand. The choice of production method should consider the complexity of the design, and the accuracy and reproducibility within given tolerances within practical time limits and at an acceptable cost. The surgical team’s interaction with the device, including its placement, ease of sizing and means of attachment into the tissue should all be as infallible as possible. These should all ensure that no aspect of the placement or valve functioning could create an opportunity for significant error. The selection of pericardial tissue and its treatment and fixing is a further design consideration. Also of vital importance is the method of forming the valve leaflets on the frame to the desired shapes and forms, as well as the creation of continuous free leaflet edges. A number of design iterations were carried out, each version realising shortcomings in the previous design and limitations of the manufacturing process. The first conceptual designs consisted of machined stainless steel bars. The restrictions

of having a uniform frame width led to the investigation of manufacturing by means of a wire cutter, and ultimately a chrome cobalt powder sintering machine. This machine is typically used for the accurate manufacture of dental bridges. The final design provided the best possible solution to the design criteria mentioned. Fig. 1 shows the assembled valve components without the leaflets, comprising the upper and lower components of the leaflet-bearing frame, together with the receptacle, but without the sewing ring in place. Fig. 1 also shows the continuous gap between the upper and lower frame components, and the area where the pericardium meets at the base of the posts in the upper frame. From this base region to the apex of the post, the pericardium leaflets come into surface contact with each other and are held in position by a clip that is located outside the post. The radial width of the support frame and its receptacle was kept to a minimum of 2.5 mm along the scallops, and 3.0 mm at the posts. The valve frame receptacle is intended for supraannular insertion. A running 2.0-mm circumferential footprint of the receptacle will lie outside the confines of the native aortic valve annulus. The effective orifice of the valve will therefore be within a 10 to 15% tolerance of the natural orifice of the native valve. A potential disadvantage is that in some patients, the openings to the coronary arteries lie just above the frame annulus, so that the placement of the posts would have to be rotated and positioned accordingly. The cross section of the lower frame is hydrodynamically shaped and flared. The surface that opposes a similar-shaped surface on the upper frame to form the gap in which the pericardium is gripped has a width of 1.0 mm and the edges are rounded to avoid the risk of damaging the pericardium as it flexes. The complete bottom frame is shown in Fig. 2. The shape of the lower edge of this component conforms accurately to the shape of the corresponding surface of the upper edge of the lower component, allowing a gap between the components that is inclined at 10 degrees to the horizontal, sloping up toward the centre of the valve. The gap between the frames, within which the pericardium is held, is designed to be on average 300 µm wide (assuming a pericardium approximately 250 µm thick, with polymer coating of 25-µm thickness on each side of the gap). The pericardial thickness may vary between 200 and 300 µm, and the thickness of the polymer coatings will vary depending on the exact nature of the polymer, its viscosity and drying conditions. Therefore, a locking mechanism has been designed to allow the upper and lower components of the frame to be locked with a gap. This

Post Scallop Upper Frame Lower Frame Receptacle Grooved outer surfaced to receive sewing ring

Fig. 1. Image of assembled upper and lower frame and receptacle.

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Fig. 2. Image of lower frame.


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Leaflet material protruding through the post gap. To be secured with a hemaclip.

Fig. 3. A fully assembled valve constituted from upper and lower frame supporting pericardial leaflets.

gap takes into account variable pericardial thicknesses, and moreover, can be locked once a predetermined compressive force has been applied to close the gap in which the pericardium is located. The grooved outer surface of the receptacle has a series of rings that restrain the suture that binds the sewing ring material to the receptacle (see Fig. 1). This material is rolled into a standardshaped sewing ring for passage of the surgical sutures used to anchor the valve. The flared areas of the receptacle receive the locking mechanism of the upper and lower frames, which engage in a double-clip system at each of the three post regions. The assembly of the valve components, as well as the integration of the pericardial tissue into the frame was undertaken to prove the viability of the concept. The frame components used in this experiment were manufactured from a polymer certified for surgical assistance and suitable for human tissue contact. The assembled pericardial and frame components are shown in Fig. 3. Chrome cobalt sintering was used for the first time in recorded heart valve literature to manufacture valve stents. Used currently for dental applications, the sintering approach provided an intricately manufactured product, with accurate reproducibility from biostable material at an attractive cost and production time. The leaflet material protruding through the posts combined to form a tissue thickness of between 0.55 and 0.70 mm. The post, containing a gap of 0.90 mm, allowed for ease of protrusion of this fold of tissue. In order to secure the pericardium in place, a surgical hemaclip, made from approved stainless steel grade 5, is accurately applied after the pericardium has been pulled through the gap. The hemaclip, together with the tissue, form a composite section wider than the post-gap opening, preventing it from pulling though the gap in the posts. The integrity of the hemaclip also supports the vertical aspect of the pericardium, ensuring that it does not fold and collapse under gravity.

Conclusion As the world population fast approaches seven billion and the growth rate of developing nations leads the way, the instances of heart valve disease become more prevalent. Currently, the market supplies heart valve replacements largely to those older than 65 years of age and who reside in developed parts of the world. A

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vast portion of the market is limited by low income and poor access to medical facilities. Lack of financial support prevents any hope of a prolonged life after heart valve replacement. From criteria pertaining to developing world infrastructure, surgical expertise and patient lifestyle, a valve was designed for use in these countries. In order to ensure a successful final product, the components, materials, assembly and manufacturing techniques were all chosen to be cost effective and accessible. The related surgical procedures are simplified so that the risk of complications is reduced after implantation by surgeons. Mechanical pericardium tests were performed to understand whether there was an association between thickness and tensile strength. It was found that for unfixed pericardium, tensile strength increased with an increase in tissue thickness. This motivated an appropriate choice of pericardium in the valve assembly, offering sufficient residual tensile strength to successfully undergo the millions of cycles of testing. Novel heart valve design features, which had not been implemented in valve designs before or patented in any country prior to this study, were integrated into this valve design. These included the use of a mechanical clipping device between the valve assembly and receptacle, which allowed the surgeon to first stitch in the sewing ring and then secure the valve and leaflet assembly in place. This would further permit less-experienced surgeons to perform valve replacements, with a reduction in risk of complications. Attractive benefits offered in this valve design addressed the issue of re-operation in patients having received a valve implant in their youth. The valve could easily be swapped for new leaflets, clipping back into the receptacle without removing it from the natural valve annulus. This is complemented by the fact that glutaraldehyde-treated pericardium tissue valves give these patients freedom from ongoing anticoagulation medication. Although the design of the valve addressed the technical aspects of constraint in a theoretical approach, further work would be required to understand the valve functioning in a simulated and fatigue-testing environment. As a result of findings in these areas, a final product could be made available for commercial use.

References 1.

2. 3. 4.

5. 6. 7.

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Carpentier A, Lemaigre G, Robert L, Carpentier S, Dubost C. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Surg 1969; 58(4): 467–483. Starr A, Edwards ML. Mitral replacement: clinical experience with a ball-valve prosthesis. Ann Surg 1961; 154: 726–740. Bjork VO. Aortic valve replacement with the Bjork-Shiley tilting disc valve prosthesis. Br Heart J 1971; 33(Suppl): 42–46. Emery RW, Mettler E, Nicoloff DM. A new cardiac prosthesis: the St. Jude Medical cardiac valve: in vivo results. Circulation 1979; 60(2, Part 2): 48–54. Unger F, Ghosh P. International cardiac surgery. Semin Thorac Cardiovasc Surg 2002; 14(4): 321–323. Blackstone EH. Could it happen again? The Bjork-Shiley convexoconcave heart valve story. Circulation 2005; 111(21): 2717–2719. Klepetko W, Moritz A, Mlczoch J, Schurawitzki H, Domanig E, Wolner E. Leaflet fracture in Edwards-Duromedics bileaflet valves. J Thorac Cardiovasc Surg 1989; 97(1): 90–94. Human P, Zilla P. Characertisation of the immune response to valve bioprostheses and its role in primary failure. Ann Thorac Surg 2001; 71(5, Supple); S385–388. Vincentelli A, Latremouille C, Zegdi R, Shen M, Lajos P, Chachques J,


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et al. Does glutaraldehyde induce calcification of bioprosthetic tissues? Ann Thorac Surg 1998; 66(6, Suppl): S255–258. Schoen J, Shemin R, Cohn L. Pathologic evaluation of a unileaflet pericardial bioprosthesis after implantation as tricuspid and mitral valve replacements in sheep. Trans Soc Biomater 1986; 9: 76. Trantina-Yates A, Weissenstein C, Human P, Zilla P. Stentless bioprosthetic heart valve research: sheep versus primate model. Ann Thorac Surg 2001; 71(5, Suppl): S422–427. Maxwell L, Gavin J, Barratt-Boyes B. Uneven host tissue ongrowth and tissue detachment in stent mounted heart valve allografts and xenografts. Cardiovasc Res 1989; 23(8): 709–714. Guangqiang G, YingXing W, Grunkemeier GL, Furnary AP, Starr A. Durability of pericardial versus porcine aortic valves. J Am Coll Cardiol 2004; 44(2): 384–388. Isishara T, Ferrans VJ, Jones M, Boyce SW, Kawanami O, Roberts WC. Histological and ultrastructural features of normal human parietal peri-

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cardium. Am J Cardiol 1980; 46: 744–753. 15. Isishara T, Ferrans VJ, Jones M, Boyce SW, Roberts WC. Structure of bovine parietal pericardium and of unimplanted Ionescu-Shiley paericardial valvular bioprostheses. J Thorac Cardiovasc Surg 1981; 81: 747–757. 16. Schoen FJ, Levy RJ. Bioprosthetic heart valve failure: pathology and pathogenesis. Cardiol Clin 1984; 2: 717–739. 17. Grimm M, Eybl E, Grabenwöger M, Böck P, Müller MM, Wolner E. Glutaraldehyde affects biocompatibility of bioprosthetic heart valves. Surgery 1992; 111: 74–78. 18. Golomb G, Ezra V. Prevention of bioprosthetic heart valve tissue calcification by charge modification: effects of protamine binding by formaldehyde. J Biomed Mater Res 1991; 25: 85–98. 19. Grabenwöger M, Sider J, Fitzal F, Zelenka C, Windberger U, Grimm M, et al. Impact of glutaraldehyde on calcification of pericardial bioprosthetic heart valve material. Ann Thorac Surg 1996; 62: 772–777.

Diabetes congress diary Date APRIL 2012 19–22 April 20–22 April 21 April MAY 2012 5–9 May 9–12 May 24–27 May JUNE 2012 8–12 June JULY 2012 9–12 July 24–26 July 25–28 July

Conference

Venue

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SEMDSA/NOFSA 2012 Congress Paediatric and Adolescent Diabetes Pain Symposium 2012

Bantry Bay, South Africa Birmingham, UK Houghton, Johannesburg, South Africa

www.semdsa.org.za

European Congress of Endocrinology 19th European Congress on Obesity 27th Annual Clinical Conference on Diabetes

Florence, Italy Lyon, France Florida, USA

www.easo.org/eco2012/ plowe@diabetes.org

72nd American Diabetes Association Scientific Sessions

Pennsylvania, USA

http://professional.diabetes.org

The 3rd International Congress on Abnormal Obesity (ICAO) CDE Centres for Diabetes and Endocrinology 1st African Diabetes Congress

Quebec City, Canada Johannesburg, South Africa Arusha, Tanzania

Icao2012.myhealthwaist.org

Berlin, Germany Istanbul, Turkey

www.easd.org

Phuket, Thailand

www.apsavd2012.com

OCTOBER 2012 1–5 October 48th EASD Annual Meeting 10–13 October ISPAD 2012 – 38th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes 20–22 October 8th Asian Pacific Society of Atherosclerosis and Vascular Disease DECEMBER 2012 4–6 December 1st American Diabetes Association Middle East Congress: Diabetes Prevention and Treatment

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Dubai, UAE

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Prognostic role of Helicobacter pylori infection in acute coronary syndrome: a prospective cohort study R ESKANDARIAN, R GHORBANI, M SHIYASI, B MOMENI, K HAJIFATHALIAN, M MADANI

Abstract In a prospective cohort study, we evaluated the effect of Helicobacter pylori seropositivity on the risk of future adverse cardiovascular outcomes among patients with acute coronary syndrome (ACS). In 433 patients, IgA and IgG antibodies to H pylori, along with classic risk factors, including hypertension, diabetes, hyperlipidaemia, smoking and family history of coronary artery disease (CAD) were determined. Shortand long-term follow-up information on adverse outcomes, defined as recurrence of unstable angina, myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, and sudden cardiac death was obtained. None of the classic CAD risk factors correlated with incidence of either short- or long-term outcomes. Seropositivity for H pylori was significantly associated with risk of short-term adverse outcomes, and independently predicted their incidence in multivariate regression (R = 3.05, p < 0.001). Results failed to show such an association between H pylori seropositivity and long-term adverse outcomes. H pylori infection may affect short-term prognosis in patients with ACS. Randomised trials are needed to evaluate the role of H pylori eradication in these patients. Keywords: H pylori, acute coronary syndrome, prognosis Submitted 8/11/10, accepted 15/4/11 Cardiovasc J Afr 2012; 23: 131–135

www.cvja.co.za

DOI: 10.5830/CVJA-2011-016

Coronary artery disease (CAD) is the leading cause of death in developed and transitioning countries.1 Classic CAD risk factors, such as dyslipidaemia, hypertension, smoking, family history of CAD, and diabetes mellitus have not been able to fully explain the variations in CAD incidence, morbidity and mortality,2,3 and there is a need to search for possible new causal mechanisms affecting pathogenesis and prognosis of CAD.4 Certain bacterial and viral pathogens have been suggested to play a role in development and/or prognosis of CAD, including Chlamydia pneumonia, Helicobacter pylori, cytomegalovirus, Coxsackie virus, Hepatitis A virus and Herpes simplex virus.5-7 Numerous studies, mostly cross-sectional or case-control studies, have assessed the association between H pylori infection and Department of Cardiology, Faculty of Medicine, Seman University of Medical Sciences, Semnan, Iran R ESKANDARIAN, MD M MADANI, MD, swt_f@yahoo.com

Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran R GHORBANI, PhD M SHIYASI, MD B MOMENI, MD K HAJIFATHALIAN, MD

CAD.8-11 Various mechanisms have been proposed to explain the role of H pylori infection in the pathogenesis of CAD, namely causing persistent local or systemic inflammation, and initiating autoimmune responses.12,13 However, studies provide discordant data on the association between H pylori infection and CAD. While some studies report a significant relationship between the two,14-18 others suggest no, or at best a weak association between H pylori infection and CAD.19-23 As a result of this discrepancy, the actual role of H pylori in the pathogenesis and prognosis of CAD has remained largely controversial,24-26 and many authors suggest well-designed prospective studies to further investigate the association between H pylori and CAD.27,28 Moreover, H pylori diagnosis is fairly simple and its treatment much easier and less costly, compared to that of classic CAD risk factors.4 Therefore finding a causal relationship between H pylori infection and prognosis in patients with CAD, especially patients presenting with acute coronary syndrome (ACS), may enable clinicians to decrease morbidity and mortality simply by treating H pylori infection in these patients.18 In the light of this, the present study was designed as a prospective cohort to investigate the effect of current H pylori infection on short- and long-term prognosis in patients presenting with ACS. The results of this study will help to clarify the relationship between H pylori infection and CAD. In addition, it will provide information regarding the possible role of H pylori eradication in patients presenting with ACS.

Methods This was a prospective cohort study carried out at the Fatemieh Hospital, Semnan, Iran. Between January 2004 and November 2006, a total of 450 patients admitted for ACS to the emergency ward or critical care unit agreed to participate in the study and were enrolled. Patient selection was done by the census sampling method. The objective and necessary procedures were clearly explained to these patients and all participants provided informed written consent before enrollment. The study was approved by the medical ethics committee of the hospital. ACS (inclusion criteria) was defined as presenting with either unstable angina (clinical diagnosis) or myocardial infarction (MI), defined as significant ST elevation or new left bundle branch block in electrocardiography or increased levels of cardiac enzymes. During the one-year follow-up period, 17 participants were excluded from the study due to either receiving treatment for H pylori infection or becoming unavailable for follow up. Risk factors evaluated in this study were: hypertension, diabetes mellitus (DM), hyperlipidaemia, cigarette smoking, and family history of CAD. Hypertension was defined as arterial blood pressure ≥ 140/90 mmHg or being treated with antihypertensive drugs. DM was defined as fasting blood sugar levels ≥ 126 mg/dl or being treated for this diagnosis with either diet or medication. Hyperlipidaemia was defined as low-density lipoprotein (LDL) cholesterol levels ≥ 130 mg/dl or being treated


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with lipid-lowering medication. Patients were considered to be smokers if they were current smokers or had stopped smoking less than three years before enrollment. Positive family history of CAD was considered in patients with a history of at least one first-degree relative affected by CAD before the age of 55 and 65 years for male and female relatives, respectively. The main outcome evaluated in this study was recurrence of a cardiovascular event, defined as recurrence of unstable angina (UA), MI, performing coronary angioplasty during the study period, coronary artery bypass graft (CABG) surgery, or sudden cardiac death (SCD). Data regarding these outcomes were collected when patients were visited at pre-scheduled one-month and one-year intervals from their enrollment, to be evaluated for short- and long-term prognosis, respectively. When patients did not attend their appointments, they or their families were contacted by telephone. If the participant had died, the cause of death was determined by taking a history from family members and reviewing medical documents. Otherwise participants were asked to attend an appointment for follow up. The main independent variable evaluated in the study was H pylori infection, defined as seropositivity for anti-H pylori antibodies. Both IgG and IgA antibodies against H pylori were tested for each participant at enrollment, and a patient was considered seropositive if positive for either IgA or IgG antibodies. All participants were enrolled on their first day of admission for ACS, and all blood samples were collected the next morning and tested the same day. H pylori IgG and IgA antibodies were determined using commercially available ELISA assays (RADIM kit, Milan, Italy). According to the kit’s reference values, levels of more than 30 and less than 15 units? were considered positive and negative, respectively. Levels between these values were considered borderline. A total of 10 participants had borderline levels for H pylori IgA, and were designated as having a negative result. At enrollment and during each follow-up visit, patients underwent a complete evaluation, including a physical examination, electrocardiography, and review of all paraclinical data and medical history pertaining to study outcomes and/or H pylori eradication.

Statistical analysis Data are presented as number (percent) or mean (± SD).

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Possible association between categorical variables was assessed using the χ2 test. Relative risk was calculated to estimate the increase in risk of incidence of outcomes among H pylori seropositive patients, compared to seronegative participants. Logistic regression models were used to identify significant determinants of incidence of outcomes. All statistical tests used are reported with two-tailed estimates of type I error (p-value); p < 0.05 was considered significant. All statistical analysis was done using SPSS, version 13.0 (SPSS Inc, Chicago, USA).

Results A total of 450 subjects were enrolled in the study, of whom 433 completed the study and were followed up for one year. Seventeen patients were excluded either because of H pylori eradication during the study period or becoming unavailable for follow up. Patients’ ages ranged between 29 and 85 years, with a mean of 60.9 (± 12.3) years. Of 433 patients, 245 (56.6%) were male. Of all the participants, 204 patients (47.1%) were seropositive for H pylori. Of the whole study population, 69 (15.9%) patients developed short-term outcomes, defined as being diagnosed with UA or MI, or undergoing angioplasty, CABG or SCD during the first month after enrollment; 194 (44.8%) participants developed long-term outcomes, defined as occurrence of the same conditions mentioned above during the one-year follow-up period. Table 1 summarises the prevalence of the five evaluated classic risk factors among the participants at the time of enrollment. Hypertension had the highest prevalence, as 221 (51.0%) patients were hypertensive, and DM showed the lowest prevalence, as only 109 (25.1%) subjects were diabetic. Table 1 presents the number and percentage of patients with each risk factor who ultimately developed short- and long-term outcomes. When evaluated by χ2 test, the rate of short- and longterm outcomes among patients with and without each risk factor did not differ significantly (p > 0.05). In other words, none of the classic risk factors including hypertension, DM, smoking, hyperlipidaemia and family history of CAD were associated with occurrence of cardiovascular events during the study period. In addition, the classic risk factors did not show any association with H pylori seropositivity, as similar numbers of patients with or without each risk factor were positive for H pylori antibodies (p > 0.05).

TABLE 1. PREVALENCE OF CLASSIC CAD RISK FACTORS AMONG PARTICIPANTS, INCIDENCE OF ADVERSE OUTCOMES IN PATIENTS WITH AND WITHOUT EACH RISK FACTOR, AND DISTRIBUTION OF H PYLORI SEROPOSITIVITY ACROSS RISK FACTORS

Hypertension Diabetes Smoking Hyperlipidaemia Family history of CAD

+ + + + + -

Total study population (n = 433) n (%) 221 (51.0) 212 (49.0) 109 (25.2) 324 (74.8) 137 (31.6) 296 (68.4) 126 (29.1) 307 (70.9) 111 (25.6) 322 (74.4)

Patients with short-term outcomes n (%) 33 (14.9) 36 (16.9) 19 (17.4) 50 (15.4) 20 (14.6) 49 (16.5) 22 (17.4) 47 (15.3) 15 (13.5) 54 (16.7)

Patients with long- term outcomes n (%) 100 (45.2) 94 (44.3) 55 (50.5) 139 (42.9) 55 (40.1) 139 (46.9) 53 (42.1) 141 (45.9) 53 (47.7) 141 (43.8)

Patients with positive antibody to H pylori n (%) 106 (47.9) 98 (46.2) 51 (46.7) 153 (47.2) 63 (45.9) 141 (47.6) 57 (45.2) 147 (47.9) 49 (44.1) 155 (48.1)


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To evaluate H pylori infection as a possible risk factor, the rate of developing outcomes was compared between seropositive and seronegative patients. As shown in Table 2, of 204 seropositive patients, in 48 (23.5%) subjects a cardiovascular event (as defined earlier) occurred during the first month after enrollment, compared to only 21 (9.1%) patients who developed short-term outcomes among 229 seronegative participants (p < 0.000). H pylori-infected patients were more than 2.5 times more likely to develop short-term adverse outcomes, as defined in this study (risk ratio: 2.58). H pylori seropositivity did not show any significant association with long-term adverse outcomes during the one-year follow up of patients; 97 (47.5%) patients among the 204 H pylori-positive participants developed long-term adverse outcomes, compared to 97 (42.5%) of 229 subjects who were negative for H pylori antibodies (p > 0.05). Seropositive patients were only marginally more likely to develop long-term adverse outcomes compared to their seronegative counterparts (risk ratio: 1.12). When short-term adverse outcomes were compared individually between seropositive and seronegative participants, the results showed a significantly higher incidence of UA, MI, coronary angioplasty and SCD during the first month of follow up among H pylori-infected patients (p < 0.01). However, eight (3.4%) patients among the seronegative participants underwent CABG surgery during the first month, compared to four (1.9%) in the seropositive group (p < 0.01). Regarding longterm adverse cardiovascular outcomes, none of the individual events, including UA, MI, angioplasty, CABG and SCD differed between seronegative and seropositive participants (p > 0.05). To evaluate the effect of risk factors on incidence of adverse cardiovascular events, a multivariate logistic regression model was built using age, gender and classic risk factors, including hypertension, DM, hyperlipidaemia, smoking and positive family history for CAD, in addition to seropositivity for H pylori. From all these risk factors, only H pylori infection proved to be a significant and independent predictor of short-term adverse cardiovascular outcomes (R = 3.05, p < 0.001). When this model was used for long-term outcomes, only age was a significant determinant of incidence of cardiovascular events (R = 1.04, p < 0.001).

Discussion In this study, we prospectively evaluated the effects of H pylori seropositivity and classic cardiovascular risk factors on incidence of future cardiovascular events among a cohort of 433 patients presenting with ACS. The main new finding of this study was to show a positive association between H pylori seropositivity TABLE 2. INCIDENCE OF SHORT- AND LONGTERM ADVERSE OUTCOMES BASED ON PATIENTS’ SEROPOSITIVITY FOR H PYLORI IGA AND/OR IGG. DATA PRESENTED AS NUMBER (PERCENT) Total study population (n = 433) n (%) 204 (47.1) 229 (52.9)

H pylori + IgA and/or – IgG *For χ2 test, p < 0.000.

Patients with short-term outcomes* n (%) 48 (23.5) 21 (9.1)

Patients with long-term outcomes n (%) 97 (47.5) 97 (42.4)

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and incidence of short-term adverse cardiovascular events in participants during the first month after presenting with ACS. However, we failed to provide evidence for such an association with long-term adverse outcomes during one year of follow up. Furthermore, in this study we did not find any significant relationship between H pylori seropositivity and any of the studied risk factors. Some viral and bacterial infections, such as Chlamydia pneumonia, Hepatitis A virus, cytomegalovirus and Herpes simplex virus have been implicated in affecting development and course of coronary atherosclerotic diseases.29 H pylori is similar to these pathogens as it is also an obligatory intracellular pathogen and causes life-long persistent infection.30 H pylori also establishes persistent antibodies targeted to it. Several pathological mechanisms have been postulated to explain the effect of H pylori infection on atherosclerosis. It has been suggested to initiate an acute-phase response and to activate TNF-α, IL-6 and fibrinogen, which are inflammatory cytokines that can directly or indirectly propagate an inflammatory process in arterial walls.8,31 H pylori has been also shown to cause platelet aggregation, an important aspect of acute destabilisation of atherosclerotic disease.32 Another possible mechanism by which H pylori may cause endothelial damage is by causing aggravated autoimmune hormonal responses because of antigenic mimicry,13 such as immunological cross reactivity between bacterial and human heat-shock proteins,33 which can lead to coronary calcification and early atherosclerosis.34 In addition, direct colonisation of the arterial wall by H pylori has been suggested,21 and H pylori has been found in atheromas using the polymerase chain reaction (PCR) technique.35 We measured both H pylori IgG and IgA antibodies in the participants. IgA and IgG seropositivity were measured in this study, as it has been suggested that IgA seropositivity may reflect more recent and active infection,36 and its use may be appropriate to evaluate the association between H pylori infection and ischaemic heart disease.37 In our study, we failed to show any significant association between presence of the classic cardiac risk factors, including hypertension, DM, hyperlipidaemia, smoking and positive family history of CAD, and incidence of future adverse cardiovascular outcomes. This was consistent with the results reported by Zhu et al., who also did not demonstrate a prognostic role for these classic risk factors on future adverse cardiovascular events in their study on 890 patients with CAD.38 This may have been partly due to extensive treatment of these risk factors among patients diagnosed with CAD, which could have lessened their observed prognostic effects in the study population. Therefore, longer follow-up duration on larger sample populations may be needed to document the prognostic effects of these factors. It has previously been suggested that there may be a relationship between the classic CAD risk factors and H pylori infection, which could explain the association between H pylori infection and CAD.39,40 However, this study did not demonstrate any significant association between H pylori seropositivity and the presence of classic risk factors. Our results are in agreement with those of Danesh et al., who did not find such an association to be present in their meta-analysis of 18 different studies.41 Interestingly, results from the present study exhibited a positive association between H pylori infection and short-term adverse cardiovascular outcomes. Patients who were seropositive


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for H pylori at enrollment showed a higher risk for incidence of adverse cardiovascular events during the first month of follow up. They were 2.58 times more likely to be diagnosed with recurrence of UA, MI or SCD, or to undergo coronary angioplasty or CABG one month after presenting with ACS, compared to their seronegative counterparts. Additionally, in the logistic regression model used to predict incidence of shortterm outcomes, which also included age, gender and classic risk factors, only H pylori infection proved to be a significant determinant of these events. Previous studies report conflicting data regarding the relationship between H pylori infection and incidence of future cardiovascular events. Some studies did not find any association,42,43 whereas, others revealed a significant association.44,45 This discrepancy may be due to differences in the study populations. For example, some studies enrolled healthy adult subjects, while others assessed cohorts of patients with CAD. Furthermore, most of the previous studies measured only H pylori IgG antibodies,43,46 while in our study, we used both IgG and IgA antibodies to detect H pylori infection. In a previous study by Rupprecht et al.,44 while there was no relationship between H pylori IgG seropositivity and risk of fatal cardiovascular events, IgA seropositivity was significantly associated with fatal cardiovascular events, with a hazard ratio of 2.5, which is similar to our results. Most importantly, in this study H pylori infection was only linked to short-term adverse outcomes, such as UA, MI and SCD, and did not show a significant long-term association with the same outcomes during the one year of follow up. This is in line with previous suggestions that H pylori infection would probably play a role in the early events of ACS.32 As mentioned, H pylori has been shown to cause platelet aggregation.32,47 During the acute phase of ACS and plaque disruption, this could lead to local inflammation, aggravating platelet aggregation, a crucial event leading to acute myocardial ischaemia. However, these effects would diminish as the plaque becomes stable in the weeks after the ACS. This process may explain why H pylori seropositivity was only associated with risk of shortterm outcomes, in spite of varying length of infection among participants. If a causal relationship between H pylori infection and early ACS morbidity and mortality could be established with further prospective studies, this valuable information could be used to improve ACS patients’ survival, hypothetically by treatment of H pylori infection in patients presenting with ACS. A previous randomised clinical trial on 325 patients with ACS has shown a significant reduction in incidence of cardiac death or readmission due to ACS as a result of antibiotic treatment for H pylori and Chlamydia pneuminiae.18 However, further prospective studies and randomised trials are needed in order to confirm the role of antibiotic therapy in CAD patients. As a prospective cohort, this study may suffer from limitations such as unsuspected selection bias or unidentified confounding factors. It has been suggested that H pylori seropositivity may reflect the socio-economic status of patients or their early childhood environment,48 which may be the actual causes of the observed relationships. However, the present study was carried out on a fairly socially homogenous population, as typical for a relatively small town, and the participants were only recruited from a single hospital, which further identifies

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them as having a similar socio-economic status. Therefore we suggest it is unlikely that the observed differences were due to socio-economic disparities reflected by H pylori seropositivity. Moreover, H pylori seropositivity did not show any relationship with other cardiac risk factors among our participants.

Conclusion The results of this prospective study provide further evidence that H pylori infection could affect the early prognosis in CAD patients. Randomised clinical trials are needed to establish this causal relationship and evaluate the role of antibiotic treatment in these patients. We thank the Farzan Institute for Research and Technology for technical assistance.

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The clinical, electrocardiographic and echocardiographic characteristics and long-term outcome of patients with tachycardia-induced cardiomyopathy ASHLEY CHIN, MOTASIM BADRI, NB NTUSI, ANDRZEJ OKREGLICKI Introduction: The clinical, electrocardiographic and echocardiographic features and long-term outcome of patients with tachycardia-induced cardiomyopathy (TIC) have not been well described in the past. Methods: A retrospective study was performed at our institution of patients with a diagnosis of TIC. Results: Thirty-three patients with pure TIC and 12 patients with impure TIC were identified. Compared to patients with dilated cardiomyopathy (DCMO), pure TIC patients were less symptomatic, as judged by NYHA class (p = 0.02), they had fewer clinical signs of heart failure (p = 0.007) and were more likely to report palpitations (p = 0.007) at presentation. Electrocardiographically, pure TIC patients had fewer Q waves (p = 0.002), less left ventricular hypertrophy (LVH) (p = 0.004) and repolarisation abnormalities (p = 0.048), and shorter QRS durations (p = 0.024). Echocardiographically, pure TIC patients had significantly smaller left ventricular internal diameter in diastole (LVIDd) (p < 0.001), ventricular internal diameter in systole (LVIDs) (p = 0.001) and left atrial dimensions (p = 0.048) at presentation compared to DCMO patients. Patients with pure TIC had a trend towards increased residual LVIDd dimensions compared to a control group with normal echocardiograms, indicating a persistence of adverse LV remodelling late after control of the causative tachycardia (p = 0.06). Recurrent tachycardia occurred in three patients, which resulted in a precipitous decline in left ventricular ejection fraction (LVEF). Conclusions: This study is the first to compare features of pure and impure TIC. Patients with pure TIC had shorter QRS durations, fewer Q waves, and less LVH and repolarisation abnormalities at presentation compared to DCMO patients. TIC patients tended to have smaller LVIDd dimensions at presentation and have persistence of adverse LV remodelling, as characterised by persistent enlargement of LVIDd dimensions, at late follow up. Keywords: tachycardia-induced cardiomyopathy, cardiomyopathy, tachycardia, tachycardiomyopathy, tachycardia-mediated cardiomyopathy Submitted 2/1/11, accepted 9/5/11 Cardiovasc J Afr 2012; 23: 136–142

www.cvja.co.za

DOI: 10.5830/CVJA-2011-019

Cardiac Clinic, Groote Schuur Hospital, and Department of Medicine, University of Cape Town, Cape Town, South Africa ASHLEY CHIN, MB ChB, MPhil, ashley.chin1@gmail.com MOTASIM BADRI, PhD NB NTUSI, MB ChB ANDRZEJ OKREGLICKI, MB ChB, MMed

Tachycardia-induced cardiomyopathy (TIC) is an important reversible cause of cardiomyopathy (CMO) and heart failure. Until recently, TIC was considered to be a rare cause of reversible left ventricular (LV) dysfunction.1 Over the past few years, several publications have established that this disease is much more prevalent than once thought,2,3 but most reports of TIC have been isolated case reports or small retrospective cohorts comprising less than 20 to 30 patients. LV dysfunction may either develop in the setting of no underlying structural heart disease, so-called ‘pure’ TIC, or in the setting of pre-existing structural heart disease, ‘impure’ TIC.4 TIC studies have mostly enrolled patients with pure TIC and have excluded those with impure TIC. However, impure TIC is probably more common than pure TIC,4 but less well investigated and reported in the literature. The presenting clinical, electrocardiographic and echocardiographic features of TIC have not been well described. At presentation, TIC may be indistinguishable from dilated cardiomyopathy (DCMO) with secondary tachycardia – the so-called ‘chicken–egg dilemma’.5 Factors influencing the rate and extent of recovery of LV function are poorly understood. Lastly, the long-term outcome and prognosis of patients with TIC have not been well defined. In order to examine some of these questions, we conducted a retrospective study of TIC at our institution. In this study, we report the clinical, electrocardiographic and echocardiographic features of a relatively large cohort of 45 patients with pure and impure TIC. One of the aims of this study was to identify clinical, electrocardiographic and echocardiographic features that could help the clinician recognise this condition, by comparing 25 patients with pure TIC with 25 patients with DCMO. We report on the response to treatment and compare 17 patients who had normalised LV function after control of the tachycardia with 17 control patients with normal echocardiograms, to assess for persistence of adverse LV remodelling. Finally, we report on the long-term outcome and prognosis of these patients.

Methods We conducted a retrospective study of patients with a diagnosis of TIC who presented to the cardiac clinic at Groote Schuur Hospital, Cape Town between 1994 and 2009. The study protocol was approved by the University of Cape Town’s ethics committee. We included patients with a diagnosis of TIC made by the attending cardiologist if the presenting left ventricular ejection fraction (LVEF) was < 50% and there was an LVEF improvement of ≥ 5% after rate or rhythm control of the tachycardia with medical or ablative therapy. Patients were included in the pure TIC group if no underlying structural heart disease could be identified. Patients with a prior history of


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underlying structural heart disease were included in the impure TIC group and analysed separately. Patients with a diagnosis of hypertension were included in the impure TIC group. The cohort of 33 patients with pure TIC was compared to 12 patients with impure TIC. We were able to compare 25 patients with pure TIC with 25 control patients with DCMO (matched for age, gender and presenting LVEF) with regard to clinical, electrocardiographic and echocardiographic parameters. The DCMO patients were obtained from the CMO registry at Groote Schuur Hospital (unpublished data). To assess for persistence of adverse LV remodelling after recovery of LV function, the last available echocardiograms of 17 patients with pure TIC who had recovered LV function (post-treatment LVEF ≥ 50%) were compared to normal echocardiograms of 17 patients matched for age and LVEF. For the purposes of this article, TIC includes pure and impure TIC unless otherwise specified. Retrospective data collection included clinical, electrocardiographic and echocardiographic characteristics and long-term follow up of patients diagnosed with pure or impure TIC and matched DCMO controls. Patients’ clinical records were extensively reviewed. All previous electrocardiograms (ECGs) of patients with TIC were retrieved from an ECG archival system (MUSE CV system) and reviewed to calculate mean heart rate prior to the diagnosis of TIC. All 24-hour Holter monitors performed prior to and at the time of the diagnosis of TIC were analysed to determine mean and maximum heart rates during a 24-hour period. Transthoracic echocardiography was performed to measure LVEF, left ventricular internal diameter in diastole (LVIDd), left ventricular internal diameter in systole (LVIDs), left atrial (LA) size, and to quantitate the severity of mitral regurgitation (MR) using standard M-mode or modified Simpson’s method according to the recommendations of the American Society of Echocardiography. Radionucleotide imaging that calculated LVEF was used when available. Serial echocardiograms, if available, were reviewed in patients with TIC to assess the rate and magnitude of LV functional improvement. All subsequent visits were reviewed and recurrences of any tachycardias were documented. Patients who had been discharged to follow up or who were no longer attending the cardiac clinic were telephonically contacted. The choice of treatment of the causative tachycardia was at the discretion of the attending cardiologist. Generally, in patients with atrial fibrillation (AF), rate control using atrio-ventricular (AV) nodal blockers (beta-blockers, calcium channel blockers), anti-arrhythmic drugs or Digoxin was initially preferred. Patients with drug-resistant AF who continued to have poor rate control despite the above treatment, were referred for AV node ablation (AVNA) and permanent pacemaker (PPM) implantation. Catheter ablation was considered first-line therapy for certain arrhythmias [atrial flutter (AFL), atrial tachycardia (AT), atrio-ventricular nodal re-entry tachycardia (AVNRT), atrio-ventricular re-entry tachycardia (AVRT) and fascicular ventricular tachycardia (VT)].

Statistical analysis Results are expressed as mean (standard deviation) or median (interquartile range). Clinical and socio-demographic characteristics of the groups studied were compared using the

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Student’s t-test, Chi-square test, Mann-Whitney test or Wilcoxon signed rank test, whichever was appropriate. A p-value of < 0.05 was considered significant. Non-parametric tests were used due to the non-normality of some of the variables studied. Receiver operating characteristic (ROC) curves were plotted to examine the diagnostic utility of some variables, which was expressed as an area under the curve and measured using the C-statistic. Data were analysed using SPSS version 17 (Chicago, Illinois; 2009).

Results Patient demographics, clinical features, investigations, treatment and long-term outcomes of the pure and impure TIC cohort are displayed in Table 1. The pure TIC cohort consisted of 33 patients (25 males, eight females). The median age was 44 (30–62) years with a marked male predominance (76%). Twenty-one (64%) patients presented with severe effort intolerance [New York Heart Association (NYHA) class III, IV]. The median duration of dyspnoea and palpitations prior to presentation was two (0.6–7.5) months and seven (1.3–51.0) months, respectively. The arrhythmic causes were AF (n = 20), AFL (n = 7), AT (n = 4), AVNRT (n = 1) and fascicular VT (n = 1). The most common ECG abnormalities were repolarisation abnormalities (55%), followed by LV hypertrophy (12%) and LA hypertrophy (9%). Q waves, left bundle branch block (LBBB) and right bundle branch block (RBBB) were seen in less than 7% of presenting ECGs. The mean LVEF at presentation was 32.4 ± 9.5%. The mean LVIDd and LVIDs dimensions were 5.7 ± 0.7 and 4.8 ± 0.8 cm, respectively. The mean LA size was 4.2 ± 1.0 cm. The impure TIC cohort consisted of 12 patients (nine males, three females). Patients had a history of hypertension (n = 3), viral myocarditis (n = 2), valvular heart disease (n = 3), ischaemic heart disease (n = 2), patent ductus arteriosus (n = 1) and peripartum cardiomyopathy (n = 1). The median age was 39 (23–59) years with a marked male predominance (75%). Eleven (92%) patients presented with severe effort intolerance (NYHA III, IV). The median duration of dyspnoea and palpitations prior to presentation was 0.5 (0.2–2.0) months and 3 (0.6–4.5) months, respectively. The arrhythmic causes were AF (n = 5), AFL (n = 4), AVNRT (n = 2) and AVRT (n = 1). The most common ECG abnormalities were repolarisation abnormalities (70%) and LV hypertrophy (70%). The mean LVEF at presentation was 29.2 ± 1.0%. The mean LVIDd and LVIDs dimensions were 5.7 ± 1.0 cm and 4.8 ± 0.8 cm, respectively. The mean LA size was 4.8 ± 1.5 cm. Compared to patients with pure TIC, patients with impure TIC had shorter durations of dyspnoea (p = 0.04) and more clinical signs of heart failure at presentation (p = 0.003). Patients with impure TIC displayed more ECG features of underlying structural heart disease [LA hypertrophy (p = 0.05), LV hypertrophy (p < 0.001) and larger RV6 voltages (p = 0.04)]. There were no significant differences in presenting echocardiographic features between the two groups. In order to identify characteristics that may be useful to differentiate between pure TIC and DCMO at presentation, we compared 25 patients with pure TIC with 25 patients with DCMO, matched for age, gender and LVEF. The clinical, electrocardiographic and echocardiographic features of the two groups are displayed in Table 2. Clinically, pure TIC patients were less symptomatic according


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TABLE 1. COHORT OF PURE AND IMPURE TIC PATIENTS Dyspnoea duration (months

Paipitations (yes/no)

1 2 1 2

Palpitations duration (months)

Age (years)

Gender (M/F)

NYHA (Class)

Rhythm

Heart rate (bpm)

Initial LVEF

Last LVEF

30 20 62 30 68 42 52 46 45 40

F M M F M M F M M M

3 2 3 3 3 3 2 3 1 2

2 3 96 0 3

Yes Yes Yes Yes Yes Yes Yes No Yes Yes

AT AT AF AT AFL AFL AF AF AFL/AF AFL

197 136 89 128 148 102 156 100 102 165

14% 42% 30% 16% 35% 38% 45% 21% 49% 13%

53% 47% 50% 53% 85% 60% 54% 36% 67% 63%

Patient 11

54

M

3

12

Yes

AF, previous AFL

84

22%

*

Patient 12 Patient 13 Patient 14

28 38 68

M M F

2 4 3

1

1

1

Yes Yes Yes

AF AF AVNRT

123 132

27% 30% 30%

35% 63% 40%

Patient 15 Patient 16 Patient 17 Patient 18 Patient 19 Patient 20 Patient 21 Patient 22

17 47 56 33 41 65 46 79

F F M F M M M F

3 3 2 1 3 4 3 3

2 12 9 0 1 8 1 1

Yes Yes Yes No No No Yes No

2 24 3

0 11 0

AT AF AFL AF/WPW AF AF AFL AF

131 126 123 240 133 136 144 167

23% 48% 33% 33% 22% 23% 31% 30%

40% 59% 64% 41% 49% 60% 51% 50%

Patient 23

38

M

1

0

Yes

6

AF/AFL

82

40%

53%

Patient 24

16

M

4

0

Yes

0

178

29%

56%

3

12

Yes

108

Fascicular VT AFL

Patient 25

47

M

95

37%

58%

Patient 26

64

M

3

6

Yes

72

AFL/AF

105

37%

50%

Patient 27 Patient 28 Patient 29 Patient 30 Patient 31 Patient 32 Patient 33 Impure TIC Patient 34 Patient 35 Patient 36 Patient 37

50 71 62 57 48 55 66

M M M M M M M

2 3 4 3 1 2 3

Yes No Yes Yes Yes Yes Yes

60 0 120 144

AF AF/AFL AF AF/AFL AFL AF AF

100 130 133 102 150 86 93

41% 35% 39% 40% 42% 35% 38%

50% 41% 45% 50% 65% 49% 64%

37 53 62 40

F M M F

2 3 3 4

Yes

0

No No

6

66 96 102 72

38% 35% 31% 27%

43% 48% 47% 64%

Patient 38 Patient 39 Patient 40 Patient 41 Patient 42

52 63 35 56 20

M M M M M

4 3 3 3 3

0 1

Yes Yes Yes Yes

144 12 3 1

114 126 94 72

48% 42% 30% 21% 20%

67% 54% 47% 48% 51%

Patient 43 Patient 44 Patient 45

39 25 28

M F M

4 4 4

3 0 1

Yes Yes Yes

3 0 1

AFL AFL AF/AFL Atypical AVNRT AF AF AF AVRT Atypical AFL AF/AFL AFL AVNRT

136 78 84

19% 17% 22%

64% 72% *

Patient Pure TIC Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10

24 3 36 0 12

1 0

1 2 1 8 6 60 3 240 3

1

6 12

0

Recurrent TIC

Alive

Medical Rx AT ablation AVNA/PPM Medical Rx AFL ablation AFL ablation Medical Rx AVNA/PPM AVNA/PPM AVNA/PPM/ AFL ablation Medical Rx,AFL ablation AVNA/PPM Medical Rx AVNRT ablation Medical Rx AVNA/PPM AFL ablation WPW ablation AVNA/PPM AVNA/PPM AFL ablation Medical Rx/ AVNA/PPM Medical Rx/ AFL ablation VT ablation

No No No Yes No No No No No No

No Yes Yes Yes Yes Yes Yes Yes

No

Yes

No No No

Yes

No

Yes

AFL ablation/ medical Rx AFL ablation/ medical Rx AVNA/PPM AFL ablation AVNA/PPM AVNA/PPM AFL ablation Medical Rx AVNA/PPM

No

Yes

No

Yes

Treatment

AVNA/PPM Medical Rx Medical Rx AVNRT ablation AVNA/PPM AVNA/PPM AVNA/PPM AVRT ablation Medical Rx

No No No No No No No No

Yes Yes Yes Yes No Yes

Yes

No No No No No No No

Yes Yes Yes No

No No No No

Yes

Yes

No No No Yes No

Yes Yes Yes Yes Yes

AFL ablation No AVNA/PPM No Yes AVNRT ablaNo tion AF: atrial fibrillation, AFL: atrial flutter, AT: atrial tachycardia, AVNRT: atrio-ventricular nodal re-entrant tachycardia, AVRT: atrio-ventricular re-entrant tachycardia, AVNA: atrio-ventricular node ablation, LVEF: left ventricular ejection fraction, NYHA: New York Heart Association, PPM: permanent pacemaker, Rx: treatment, VT: ventricular tachycardia, WPW: Wolff-Parkinson-White syndrome; * LVEF not documented, but improvement noted; blank space = unknown.

to NYHA class (p = 0.02), had fewer clinical signs of heart failure (p = 0.007) and were more likely to report palpitations (p = 0.007) at presentation. Electrocardiographically, TIC patients had fewer Q waves (p = 0.002), less LV hypertrophy (p = 0.004) and repolarisation abnormalities (p = 0.048), and shorter QRS durations (p = 0.024). Six DCMO patients

had underlying paroxysmal or permanent AF. There were no significant differences in the prevalence of LA enlargement, LBBB, RBBB, RV6 voltage or RV6/RVmax ratio between the two groups. Echocardiographically, pure TIC patients had significantly smaller LVIDd (p < 0.001), LVIDs (p = 0.001) and LA dimensions (p = 0.048) compared to DCMO patients at


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TABLE 2. COMPARISON OF CLINICAL, ELECTROCARDIOGRAPHIC AND ECHOCARDIOGRAPHIC FEATURES OF PURE TIC AND DCMO MATCHED FOR AGE, GENDER AND LVEF Patient demoPure TIC group DCMO group graphics and clinical features (n = 25) n (%) (n = 25) n (%) Age 46 (16–67) 46 (21–65) Gender Male 19 (76) 19 (76) Female 6 (24) 6 (24) NYHA NYHA I, II 9 (36) 4 (16) NYHA III, IV 16 (64) 21 (84) Palpitations Yes 21 (84) 12 (48) No 4 (16) 13 (52) ¶ Mann-Whitney test, *Chi-square test, #Student’s t-test. Signs of heart failure Yes 12 (48) 21 (84) No 13 (52) 4 (16) ECG features Sinus rhythm Yes 5 (20) 19 (76) No 20 (80) 6 (24) LA enlargement Yes 3 (12) 8 (32) No 5 (20) 11 (44) Unable to assess 17 (68) 6 (24) Q waves Yes 1 (4) 10 (40) No 24 (96) 15 (60) LBBB Yes 2 (8) 6 (24) No 23 (92) 19 (76) RBBB Yes 1 (4) 0 (0) No 24 (96) 25 (100) LVH Yes 4 (16) 14 (56) No 21 (84) 11 (44) Repolarisation abnormalities Yes 16 (64) 22 (88) No 9 (36) 3 (12) QRS width (ms) 88 (82-102) 100 (92-110) RV6 (mm) 15.8 ± 7.5 15.0 ± 11.2 RV6/Rmax 1.84 ± 0.8 1.69 ± 1.2 Echocardiographic features LVEF (%) 30.8 ± 9.5 27.8 ± 10.2 LVIDd (cm) 5.7 ± 0.7 6.6 ± 0.6 LVIDs (cm) 4.9 ± 0.8 5.7 ± 0.6 LA size (cm) 4.1 ± 1.0 4.6 ± 0.5

p-value* 0.846¶

1.00

0.02

0.007

0.007

< 0.001

0.546

0.002

0.123

0.5

0.004

0.048 0.024¶ 0.79# 0.63# 0.29# < 0.001# 0.001# 0.048#

presentation. Despite significant differences in LVIDd dimensions and QRS duration between the two groups, we could not identify any LVIDd dimension [area under the receiver operating curve

139

(ROC) = 0.1989] or QRS duration (ROC = 0.2558) that could predict a diagnosis of pure TIC with a high sensitivity and specificity. The pre- and post-treatment echocardiographic parameters of pure and impure TIC are displayed in Table 3. In the pure TIC group, the mean LVEF improved significantly from 32.4 ± 9.5 to 53.2 ± 10.5% (p < 0.001). Both the LVIDd (p = 0.004) and LVIDs (p = 0.001) dimensions improved significantly post treatment. There was no significant decrease in LA size preand post treatment. In the impure TIC group, the mean LVEF improved significantly from 29.2 ± 10.0 to 55.0 ± 9.9% (p < 0.001). The LVIDs dimension (p = 0.04), but not the LVIDd dimension, improved significantly post treatment. There was no change in LA size pre- and post treatment in the impure TIC group. TIC patients with dilated ventricles at presentation were more likely to have residual LV dilatation at follow up (r = 0.68, p = 0.002). We identified variable rates of LV improvement after control of the tachycardia. Thirteen pure TIC patients had at least three echocardiograms performed: at initial diagnosis, when improvement of LV function was documented, and at last available follow up. In seven (54%) patients, maximal recovery was noted early, within the first three to six months after control of the tachycardia (Fig. 1: group A). All seven patients had prompt, effective rate or rhythm control of the causative tachycardia. However, in six (46%) patients, maximal LV improvement occurred late, after six months, with improvement seen even after a year (Fig. 2: group B). Of these six patients, two had LVEF < 20%. Two AF patients had initial suboptimal heart rate control as defined by the AFFIRM trial targets6 before AVNA and PPM implantation, and two patients had ATs that were initially difficult to control with medical therapy (Table 4). Seventeen patients with pure TIC who had an improvement in LVEF > 50% after control of the tachycardia were compared to 17 control patients with normal echocardiograms, matched for age and LVEF (Table 5). Patients with pure TIC had a trend of increased residual LVIDd dimensions compared to the control group, indicating a persistence of adverse LV remodelling late after control of the causative tachycardia (p = 0.06). There were no significant differences between the LVIDs and LA dimensions between the two groups.

Discussion Our relatively large study of TIC has several important findings. This is the first study to compare patients with pure and impure TIC. Patients with impure TIC had shorter durations of dyspnoea and more clinical signs of heart failure at presentation. Our study supports the observation that patients with underlying structural heart disease may develop LV dysfunction more quickly and present earlier with symptoms and signs of heart failure.4 At initial presentation, TIC may be indistinguishable from DCMO with secondary tachycardia – the chicken–egg dilemma.5 Pure TIC patients had a better effort tolerance (NYHA class), complained of more palpitations and had fewer clinical signs of heart failure at initial presentation compared to patients with DCMO. Pure TIC patients also had fewer ECG conduction system abnormalities (with shorter QRS durations, and were less likely to have Q waves, LVH and repolarisation abnormalities) compared to patients with DCMO. A previous study showed that certain electrocardiographic


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70

70

60

60

50

Patient 24 Patient 12

40

Patient 16

30

Patient 30 Patient 21 Patient 11

20

Presentation

3–6 months

Time

50

Patient 33 Patient 22

40

Patient 1

30

Patient 4

Patient 15 Patient 17

10 0

Last available

Fig. 1. Group A (early recovery)

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20

Patient 19

10 0

LVEF (%)

LVEF (%)

140

Presentation

6–12 months

Time

Last available

Fig. 2. Group B (late recovery)

TABLE 3. PRE- AND POST-TREATMENT ECHOCARDIOGRAPHIC PARAMETERS OF PURE AND IMPURE TIC Pure TIC at presentation (n = 33) LVEF (%) 32.4 ± 9.5 LVIDd (cm) 5.7 ± 0.7 LVIDs (cm) 4.8 ± 0.8 LA size (cm) 4.2 ± 1.0 # Student’s t-test, ¶Mann-Whitney test.

Pure TIC post-treatment (n = 33) 53.2 ± 10.5 5.3 ± 0.8 3.6 (2.2-4.6) 4.1 ± 0.8

p-value# < 0.001 0.004 0.001¶ 0.19

features may be useful for differentiating between DCMO and ischaemic CMO.7 DCMO was characterised by higher RV6 voltages and higher RV6/Rmax (leads I, II or III) ratios. The authors stated that RV6 voltage is determined by the distance from the LV to the RV6 chest lead and is a marker of LV dilatation. Limb voltages in leads I, II, III are not affected by the distance of the LV to the chest wall and are markers of voltage-producing cardiac mass. In patients with DCMO, replacement fibrosis or infiltrates reduce R-wave voltages in these limb leads. When we compared TIC patients with DCMO patients, there were no significant differences in RV6 voltages and RV6/Rmax ratios between the two groups. By inference, RV6 voltages and RV6/Rmax ratios may be useful parameters to distinguish DCMO or TIC from ischaemic CMO but not useful to distinguish between DCMO and TIC. A previous echocardiographic study by Jeong et al. showed that TIC patients tended to have smaller LV mass indices, volume dimensions and LV dimensions compared to patients with DCMO.8 They suggested that a LVIDd ≤ 6.1 cm at presentation predicted TIC with a sensitivity of 100% and a specificity of 71%. Our study confirmed that pure TIC patients had significantly smaller LVIDd, LVIDs and LA dimensions when compared to DCMO patients at presentation. However, in contrast to their study, we could not confirm a LVIDd dimension that predicted TABLE 4. PURE TIC PATIENTS WITH LENIENT HEART RATE CONTROL AND LATE IMPROVEMENT OF LEFT VENTRICULAR FUNCTION Patient nunber Patient 33 Patient 1 Patient 15 Patient 4

Average resting heart rate on treatment (beats/min) 111 92 100 96

Impure TIC at presentation (n = 12) 29.2 ± 10.0 5.7 ± 1.0 4.8 ± 0.8 4.81 ± 1.5

Impure TIC post-treatment (n = 12) 55.0 ± 9.9 5.5 ± 0.8 3.8 (2.7-4.4) 4.7 ± 1.3

p-value# < 0.001 0.86 0.04¶ 0.92

TIC with a high degree of sensitivity and specificity. In our study, we noted in four patients with AF (n = 2) and AT (n = 2) that although pharmacological rate control was suboptimal (according to the AFFIRM trial targets), LV function improved in all patients at a slower rate over a year. In contrast, we noticed that in patients who had AVNA and PPM implanted for failed pharmacological rate control, the LV function generally had maximal improvement by three to six months. These findings suggest that although strict rate control is required for optimal LV recovery, lenient rate control may still result in improvement. In the RACE II trial,9 a randomised trial of optimal heart rate control versus lenient heart rate control in patients with permanent AF, researchers found no difference between the two strategies. However, TIC patients were under-represented in this trial. Currently, it seems that TIC patients may benefit from stricter heart rate control. A previous study showed that although the LVEF improved significantly with control of the tachycardia, LV dimensions and volumes remained significantly elevated when compared to control patients late after control of the tachycardia.10 When

TABLE 5. POST-TREATMENT ECHOCARDIOGRAPHIC PARAMETERS OF PATIENTS WITH PURE TIC WITH COMPLETE LV IMPROVEMENT, AND NORMAL CONTROLS MATCHED FOR AGE AND LVEF

LVEF (%) LVIDd (cm) LVIDs (cm) LA size (cm) # Student’s t-test.

Pure TIC group (n = 17) 58.9 ± 8.9 5.2 ± 0.6 3.5 ± 0.5 4.2 ± 0.7

Normal controls (n = 17) 60.4 ± 9.2 4.8 ± 0.5 3.2 ± 0.6 3.9 ± 0.5

p-value# 0.5 0.06 0.18 0.19


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we compared TIC patients who had complete improvement, with age and LVEF-matched control subjects with normal echocardiograms, TIC patients showed a trend of greater LVIDd dimensions, indicating persistence of adverse LV remodelling at follow up. LA dimensions also remained significantly elevated at follow up. TIC patients with dilated ventricles at presentation were more likely to have residual LV dilatation at follow up. This observation stresses the importance of serial echocardiographic measurements at follow up. The clinical importance is that beta-blockers and renin–angiotensin system inhibitors should probably be prescribed to all TIC patients with residual LV dysfunction or dilated left ventricles at follow up, although data to support this recommendation are limited. Nerheim et al. reported five patients with recurrent tachycardia, which caused a rapid decline in LV function and development of heart failure in all patients.11 These patients had an abrupt fall in LVEF within six months and reversed again within a similar period. Since that initial observation, another study reported two patients with recurrence of the tachycardia and TIC.12 Notably, these two patients had a very short period of symptoms from the tachyarrhythmia (12 days, one day) to presentation. Our study is the third report with recurrent tachycardias occurring in three patients. Patient 41 developed an impure TIC secondary to an orthodromic AVRT with a previous inferior myocardial infarction. The presenting LVEF was 21%. He was started on metoprolol, enalapril and diuretics. At a three-week followup visit, his symptoms had markedly improved, with a repeat echocardiogram showing a LVEF of 51%, confirming a diagnosis of TIC. Unfortunately, he defaulted on medical therapy and re-presented with recurrence of the AVRT four months later. An echocardiogram confirmed that his LV function had deteriorated to a LVEF of 35%. His accessory pathway was successfully ablated. At two years’ follow up, he reported no recurrences of palpitations or AVRT. His last follow-up echocardiogram showed a LVEF of 48%. This case highlights the observation that recurrence of tachycardia may lead to a rapid decline in LV function. Patient 4 developed a pure TIC secondary to two different ATs, with a presenting LVEF of 16%. Only one of the ATs could be ablated. Nevertheless, the LVEF improved to 61% one year after ablation. The patient was continued on anti-arrhythmia therapy. Eighteen months later, the first AT recurred, with deterioration in LVEF to 50% and mean heart rates on Holter of 119 beats/min. Pharmacological rhythm control was preferred. At the last follow up, the LVEF had improved to 53%. Patient 23 developed a pure TIC secondary to rapid AFL with a presenting LVEF of 40%. While awaiting ablation of the AFL, the LVEF improved to 50% with pharmacological rate control. AFL ablation was unsuccessful. His AFL persisted and pharmacological AFL rate control (mean heart rates 97 beats/ min) was noted to be suboptimal. This led to a slow progressive decline in LV function over three years (LVEF 32%). Successful AFL ablation led to improvement in LV function to a LVEF of 53% five months after ablation. The long-term prognosis of TIC has not been established. Nerheim et al. documented three TIC patients who had recovered LV function and had sudden cardiac death.11 A study by Fujino et al.13 showed that cardiac death and recurrent hospitalisations

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were significantly less in the TIC group than the DCMO group. In our study, 33 pure TIC patients were followed up for a mean period of 6.8 (range 1–19) years. Twenty patients were confirmed alive at the time of writing this article. There were three confirmed deaths. The nature of one death was due to a cholangiocarcinoma. The causes of death in the other two patients could not be determined from clinical records. Ten out of 33 patients could not be contacted. Of the 10 patients, four were discharged in a stable condition from the cardiac clinic. Three patients were discharged in a stable condition to other hospitals around South Africa. Three patients did not return for routine follow-up visits. We cannot exclude sudden cardiac deaths in patients who were not confirmed to be alive. In contrast, 14 out of 25 patients were alive in the DCMO control group. As a large number of TIC patients were lost to follow up, we could not make a meaningful comparison with DCMO patients regarding long-term prognosis and outcome.

Limitations This was a retrospective study with a small number of TIC patients. The patients represent a select group of non-consecutive patients referred to a regional referral hospital. It is likely that a sizeable number of patients with TIC were not included in this study. The true prevalence of TIC in patients with tachycardia can only be answered by a prospective study or CMO registry. Although care was taken to examine all ECGs prior to presentation to calculate average heart rate, this may not be a true reflection of average heart rate during a 24-hour period. An accurate duration of the tachycardia before presentation was difficult to determine. Patients cannot always recall the exact duration of palpitations and patients could have a tachycardia for a variable length of time before an ECG is performed. Not all patients with pure TIC had coronary angiography to exclude coronary artery disease, although no coronary intervention was performed between presentation and when LV function had recovered to account for improvement in LV function. Not all patients at presentation had echocardiography performed in sinus rhythm. The calculation of LV systolic function in the presence of a shortened diastolic filling time may result in an underestimate of LVEF. In this study we were unable to control for the effects of differences in heart rate or rhythm in the assessment of LV function at initial presentation and after control of the tachycardia. Unfortunately, heart rate and rhythm at the time of the initial LV assessment at echocardiography were not routinely recorded on the echocardiography or radionucleotide imaging reports at our institution. However, echocardiographic reports at slower heart rates were preferentially recorded for LV functional assessment for better accuracy of LV function. When more than one echocardiogram was performed in short succession, an average of the LVEF and LV dimensions were calculated from serial echocardiograms to improve accuracy. In some cases, echocardiography was not performed at our institution. Echocardiography and interpretation of ECGs were often the interpretation of one cardiologist. The small control group of 25 DCMO patients was limited by the number of DCMO patients available in the CMO registry. Treatment of tachycardia varied between cardiologists and was not administered uniformly. The long-term prognosis of TIC


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could not be accurately determined because a large number of patients were lost to follow up as they were not contactable. There was no standard follow-up time. Not all patients had repeat echocardiograms and echocardiograms were performed at variable time periods by different echocardiographers.

2.

Conclusions

4.

This is one of the largest retrospective studies of TIC and the first large series from Africa. This study is the first to compare features of pure and impure TIC. Impure TIC patients have shorter duration and more severe symptoms at presentation. This study reports the first description of ECG findings of TIC. Patients with pure TIC have shorter QRS durations, fewer Q waves, and less LVH and repolarisation abnormalities at presentation compared to DCMO patients. This is the second study to report that TIC patients have smaller LVIDd dimensions at presentation and have persistence of adverse LV remodelling as characterised by persistent enlargement of LVIDd dimensions at late follow up. Patients who have larger LVIDd dimensions at presentation tended to have larger LVIDd dimensions at late follow up, identifying a subgroup of patients where careful follow up is required. This study confirms that maximal improvement of LV function generally occurs by three to six months. However, we noted slower improvement in LV function over 12 months in patients who had severe LV dysfunction and in patients with lenient heart rate control. We managed to identify 45 patients with this condition at a large regional referral centre in Cape Town over a 15-year period, suggesting that this condition is frequently under-diagnosed and missed.

3.

5. 6.

7.

8.

9.

10.

11.

12.

References 1.

Kasper EK, Agema WR, Hutchins GM, Deckers JW, Hare JM, Baughman KL. The causes of dilated cardiomyopathy: a clinicopathologic review of 673 consecutive patients. J Am Coll Cardiol 1994; 23(3): 586–590.

13.

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Pizzale S, Lemery R, Green MS, Gollob MH, Tang AS, Birnie DH. Frequency and predictors of tachycardia-induced cardiomyopathy in patients with persistent atrial flutter. Can J Cardiol 2009; 25(8): 469–472. Gentlesk PJ, Sauer WH, Gerstenfeld EP, Lin D, Dixit S, Zado E, et al. Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007; 18(1): 9–14. Fenelon G, Wijns W, Andries E, Brugada P. Tachycardiomyopathy: mechanisms and clinical implications. Pacing Clin Electrophysiol 1996; 19(1): 95–106. Gallagher JJ. Tachycardia and cardiomyopathy: the chicken-egg dilemma revisited. J Am Coll Cardiol 1985; 6(5): 1172–1173. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al.; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347(23): 1825–1833. Momiyama Y, Mitamura H, Kimura N. ECG differentiation of idiopathic dilated cardiomyopathy from coronary artery disease with left ventricular dysfunction. J Electrocardiol 1995; 28(3): 231–236. J Jeong YH, Choi KJ, Song JM, Hwang ES, Park KM, Nam GB, et al. Diagnostic approach and treatment strategy in tachycardia-induced cardiomyopathy. Clin Cardiol 2008; 31(4): 172–178. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, et al.; RACE II investigators. Lenient versus strict rate control in patients with atrial fibrillation. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362(15): 1363–1373. Dandamudi G, Rampurwala AY, Mahenthiran J, Miller JM, Das MK. Persistent left ventricular dilatation in tachycardia-induced cardiomyopathy patients after appropriate treatment and normalization of ejection fraction. Heart Rhythm 2008; 5(8): 1111–1114. Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation 2004 110(3): 247–252. Watanabe H, Okamura K, Chinushi M, Furushima H, Tanabe Y, Kodama M, et al. Clinical characteristics, treatment, and outcome of tachycardia induced cardiomyopathy. Int Heart J 2008; 49(1): 39–47. Fujino T, Yamashita T, Suzuki S, Sugiyma H, Sagara K, Sawada H, et al. Characteristics of congestive heart failure accompanied by atrial fibrillation with special reference to tachycardia-induced cardiomyopathy. Circ J 2007 71(6): 936–40.


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The value of serum tumour markers in the prediction of aetiology and follow up of patients with pericardial effusion U BILDIRICI, U CELIKYURT, E ACAR, O BULUT, T SAHIN, G KOZDAG, D URAL

Abstract Background: The aim of this study was to evaluate the value of tumour markers in the differential diagnosis of pericardial effusions and to assess their changing levels during follow up. Methods: Sixty-nine patients who were admitted to hospital with a diagnosis of pericardial effusion were included in the study. Serum tumour markers were measured on admission and after a mean of 18 ± 7 months’ follow up. An aetiological diagnosis was made on clinical evaluation, imaging techniques and biochemical, microbiological and pathological analysis. The patients were divided into five groups according to the aetiology of their pericardial effusions. Results: Carbohydrate antigen (CA) 12-5 and CA 15-3, and carcinoembryonic antigen (CEA) levels were significantly higher in patients with malignancies than in those with viral/ idiopathic pericarditis. With multivariate analysis, CA 15-3 levels were found to be the most significant determinant (p = 0.027). In the ROC curve analysis, CA 15-3 values above 25 U/ml predicted a malignancy with 71% sensitivity and 78% specificity. Conclusion: Tumour markers, particularly CA 15-3, may be useful in the differential diagnosis and prediction of malignancies in patients with pericardial effusion. In patients with viral/idiopathic aetiology, these serum tumour markers were slightly elevated in the acute phase, but after a mean of one year of follow up, their levels returned to normal, contrary to those with malignancies. Keywords: pericardial effusion, CA 125, CA 15-3, CEA Submitted 1/4/10, accepted 3/6/11 Cardiovasc J Afr 2012; 23: 143–146

www.cvja.co.za

DOI: 10.5830/CVJA-2011-029

Pericardial effusions (PE) are common and produced by a wide variety of diseases,1,2 including viral and bacterial infections, tuberculosis, malignancy, heart failure, chronic renal failure and rheumatic diseases.1,2 However, despite all the diagnostic tests available, the most common cause is idiopathic.1-3 Malignancy

Department of Cardiology, Kocaeli University Medical Faculty, Kocaeli, Turkey U BILDIRICI, MD, ihubildir@gmail.com U CELIKYURT, MD E ACAR, MD T SAHIN, MD G KOZDAG, MD D URAL, MD

Seka State Hospital, Kocaeli, Turkey O BULUT, MD

is not the main cause of PE, but PE may be the first indication of cancer, and therefore early detection would enable rapid diagnosis, which is important in improving the survival rate of cancer patients.4 Sampling of pericardial fluid (pericardiocentesis) and pericardial biopsy play an important role in identifying the underlying aetiology of PE.5 It is not always possible to perform pericardial biopsy, however, due to its potential complications. Although pericardiocentesis is easier to perform than pericardial biopsy, it has a low probability of detection of malignant cells (30–50%).6 High complication rates in mild and moderate effusions also limit its diagnostic application. There are a limited number of markers available for the evaluation and differential diagnosis of PE,6,7 including carbohydrate antigen (CA) 125, CA 15.3 and carcinoembryonic antigen (CEA).6,8 CEA has been identified as a useful marker for differentiating PE related to malignant pathology of the gastrointestinal system.5,9,10 Increased levels of CA 15-3 in the blood are primarily observed in breast cancer.11,12 CA 15-3 has also be used to evaluate both pleural and pericardial effusions.13-16 CA 125 levels may be detected in pericardial fluid secretions related to both malignant and benign aetiologies.16,17 Therefore, the prognostic value of CA 125 for the detection of malignancies is limited.18 The aim of this study was to evaluate the relationship between tumour markers and the underlying aetiology in patients with PE. We also examined the diagnostic value of these tumour markers in detecting malignancies in patients with PE, and determined their changing levels during follow up.

Methods A total of 76 patients with PE who were admitted or referred to our hospital between January 2004 and March 2007 were included in the study. The mean follow-up period was 18 ± 7 months (range 8–27 months). The aetiological evaluation included complete blood count, measurement of troponin I, erythrocyte sedimentation rate, viral disease determination (Epstein Barr, cytomegalo virus, coxsackie A virus, parva virus, hepatitis A, B, C), thyroid-stimulating hormone, and rheumatological markers [rheumatoid factor (RF), anti-nuclear antibody, anti-smooth muscle antibody, anti-double-stranded DNA]. All patients underwent computerised tomography of the thorax. Patients with heart failure (ejection fraction < 45%) and severe pericardial effusion were excluded (as it could have affected the marker levels). Patients who refused follow-up visits were also excluded. In total, seven patients were excluded from the study. Echocardiography was performed on all patients and CA markers were checked at the time of hospitalisation and at the end of the follow-up period. Pericardiocentesis was not


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performed because the patients had only mild or moderate pericardial effusions and there was no sign of compression of the heart. CEA, CA 15-3 and CA 19-9 levels were measured in blood samples using an electrochemiluminescence immunoassay on a Roche Modular E170. CA 125 levels were measured with a quantitative immunoassay technique. All results were evaluated by a biochemist who did not know the patients. Echocardiographic examinations were performed by an experienced cardiologist who was blinded to the tests. They were performed using standard protocol and a standard device (Vivid 7, GE Medical Systems, Horten, Norway). Measurement of the cardiac walls was done according to the American Society of Echocardiography guidelines. Since the number of patients with PE was not large enough to establish quantitative amounts of fluid, these were arbitrarily established by echocardiography using the sum of the epicardial and pericardial separations in the anterior and posterior spaces.19 The effusions were graded as mild (less than 10 mm), moderate (10–20 mm) and severe (more than 20 mm).19

Statistical analysis SPSS Inc for Windows, standard version 11.0 was used for statistical analysis. All data are given as mean and standard deviation. Comparison between patients with malignant and other aetiologies was done using the Student’s t-test, and for unequally distributed variables, the Mann-Whitney U-test. Logistic regression analysis adjusting for CA 125, CA 15-3, CA 19-9, alpha-fetoprotein (AFP), prostate membrane antigen (PSA) and CEA was done to evaluate the relationship between malignancies and tumour markers. Threshold values of tumour markers were established by ROC analysis.

Results A total of 69 patients (32 women and 37 men with an average age of 58 ± 17 years) were included in the study. Aetiological diagnosis was done on clinical evaluation, imaging techniques and biochemical markers. The patients were grouped into categories depending on the aetiology of the PE (group 1: viral/ TABLE 1. CHARACTERISTICS OF PATIENTS WITH PE OF MALIGNANT AND BENIGN AETIOLOGIES Patient (M/F) Age (years) Glucose (mg/dl) Urea (mg/dl) Creatinine (mg/dl) Sedimentation (mm/h) WBC × 1 000 CRP (mg/dl) Duration of hospitalisation (days) Treatment type NSAID Corticosteroid NSAI + colchicine

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Malignant PE 27 (14/13) 57.7 ± 17.8 123 ± 50.2 48 ± 22.9 1.1 ± 0.4 83.2 ± 40.4 18.4 ± 19.3 14.5 ± 11.2 28.3 ± 11.4

Benign PE 42 (23/19) 52.1 ± 13.9 121.7 ± 46.3 39.2 ± 22.9 1.3 ± 0.7 67.6 ± 37.9 20.6 ± 21.9 10.5 ± 9.1 17.3 ± 9.7

p NS NS NS NS NS NS NS NS NS

14 20 3 3 10 19 NSAID; non-steroid anti-inflammatory drug, WBC; white blood cell, M; male, F; female, NS; not significant.

Malignancy

27

Viral/idiopathic

27

Tuberculosis

4

Bacterial

2

Others

9 0

5

10

15

20

25

30

patients

Fig. 1. Diagnostic groups of the patients.

idiopathic; group 2: bacterial; group 3: tuberculosis; group 4: malignancy; group 5: other). Twenty-one patients were found to have malignancies and 48 had benign aetiologies after the first examination. During the follow-up period, cancer (three lymphoma, one thymoma, one lung cancer, one gastrointestinal malignancy) developed in six patients who had been considered idiopathic at the first examination. Finally, we had 42 patients with benign and 27 with malignant aetiologies (11 lymphoma, six breast cancer, five lung cancer, three thymoma, one ovarian cancer, one gastrointestinal malignancy). The aetiology in 27 patients could not be identified and they were considered as the viral/idiopathic PE group. Aortic dissection (one patient), tuberculosis (four patients), bacterial microorganism (two patients), autoimmune or rheumatic disease (three patients), chronic renal disease (four patients) and coronary bypass graft operation (one patient) were benign underlying causes of PE in 15 patients (Fig. 1). The characteristics of the patients with malignancies and those with other aetiologies of PE are shown in Table 1. The clinical and echocardiographic characteristics of the patients are shown in Table 2. Fibrin bands were detected most commonly in patients with tuberculosis (2: 50%), however, this was statistically insignificant. Levels of CA 125, CA 15-3 and CEA in the group with malignancies were significantly higher than in the group with no malignancies (Table 3). No significant differences were detected between the levels of CA 19.9, PSA and AFP. The relationship between malignant aetiology and tumour markers was evaluated with multivariate analysis, adjusting for CA 125, CA 15-3 and TABLE 2. ECHOCARDIOGRAPHIC PARAMETERS OF PATIENTS WITH PE OF MALIGNANT AND BENIGN AETIOLOGIES Malignant PE Non-malignant PE (n = 27) (n = 42) p LVEDD 48.1 ± 6.1 47.4 ± 5.3 NS LVESD 12.1 ± 1.7 11.6 ± 2.1 NS 11.1 ± 1.5 NS PWD 11.3 ± 2.3 63.1 ± 17.2 NS EF 64.5 ± 15.6 36.2 ± 7.3 NS LAD 39.6 ± 5.9 1.2 ± 0.7 NS E 1.2 ± 0.9 1.1 ± 0.6 NS RA 1 ± 0.8 24.1 ± 4.1 NS RV 24.7 ± 2.9 LVEDD; left ventricular end-diastolic dimension, LVESD; left ventricular end-systolic dimension, PWD; posterior wall dimension, EF; ejection fraction, LAD; left atrial diameter, E; mitral early flow, RA; right atrium, RV; right ventricle; NS; not significant.


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CEA. The only significant relationship was observed with CA 15-3 (0.027). ROC analyses were applied to detect the threshold levels of tumour markers for detecting effusions of malignant origin. In the ROC curve analyses, a CA 15-3 level above 25 U/ml had a sensitivity of 71% and specificity of 78% for predicting pericardial effusions caused by malignancies (AUC = 0.83, SE = 0.05, p = 0.002). Elevated levels of the three markers (cut-off for CA 125 = 66 U/ml; CA 15-3 = 25 U/ml; CEA = 4.2 U/ml) had a sensitivity of 69% and specificity of 88% for the prediction of pericardial effusions caused by malignancies. In the follow-up period, levels of CA 125 and CA 15-3 decreased significantly in the patients in the idiopathic/viral group. Levels of CA 125 also decreased significantly in the patients in the malignancy and tuberculosis groups. However CA 15-3 levels remained constant in the group of patients with malignancies. Levels of CEA did not change significantly in any group. Levels of CA 125 were significantly higher at the beginning, but this significance decreased in the follow-up period. During the follow-up period, malignancy was detected in six patients in the idiopathic group (three lymphoma, one thymoma, one lung cancer, one gastrointestinal malignancy). CA 125 and CA 15-3 levels were high in five and three patients, respectively.

Discussion In this study, we examined the diagnostic value of the CA 19-9, CA 125, CEA, CA 15-3, AFP and PSA for the diagnosis of tumour aetiology in patients with PE. The levels of CA 15-3, CEA and CA 125 were significantly higher in PE patients with malignancies. In the follow-up period, the levels of CA 15-3 and CA 125 decreased in patients in the idiopathic/viral group and remained constant in those with malignancies. The levels of CA 15-3 were more significant in detecting malignancies than those of CA 125. CEA levels are known to increase in heart failure and this marker has also been used to diagnose pleural effusions with malignant aetiologies.10 In many studies, a relationship has been found between high levels of CEA and pericardial effusions with malignant aetiologies.5,20,21 Szturmowicz et al. found CEA levels above 5 U/ml had a 90% specificity for the detection of malignancy.5 Similarly, in our study, the levels of CEA were significantly higher in patients with cancer. In the follow-up period, this significance did not change. Lindgren et al. showed a relationship between CA 125 levels and ovarian cancer.22 More recently it was realised that CA 125 levels can also increase in benign serous effusions.8,16,17 Unlike TABLE 3. TUMOUR MARKER LEVELS OF THE PATIENTS WITH AND WITHOUT CANCER

CA 125 (U/ml) CA 15-3 (U/ml) CA 19-9 (U/ml) CEA (ng/ml) AFP (U/ml) PSA (mg/ml) NS; not significant.

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CEA and CA 15-3, CA 125 is secreted from mesothelial cells in patients with PE of benign aetiology.7 For this reason, it can be used to determine the existence of fluid but it does not inform on the aetiology.10,16,17 Two other studies revealed that CA 12523 and CEA24 levels increased in heart failure, and that these levels could be related to the amount of pericardial fluid present.25 In our study, the levels of these markers were significantly higher in the PE patients with malignancies and remained high during the follow-up period. High levels of CA 15-3 were first detected in breast cancer patients and this was used to evaluate recurrence in the followup period.11,12 In later studies, high levels of CA 15-3 were also found in effusion patients with malignancies.13 Romero et al. reported that CA 15-3 markers could be used to detect the underlying aetiology of the effusion.14 In our study, in patients with no malignancies, CA 15-3 and CA 125 levels decreased significantly in the follow-up period. The levels of CA 15-3 were significantly higher in patients with malignancies and this increase remained significant in the follow-up period. CA 15-3 was found to be a valuable marker in the multi-analysis. In ROC curve analysis, CA 15-3 levels above 25 U/ml had a 71% sensitivity and 55% specificity for the prediction of malignancies underlying the pericardial effusions. Malignancy was developed during the follow-up period in six of our patients whose initial diagnosis was idiopathic. At least one marker was high in five of these patients and CA 15-3 levels were high in three patients. These results indicate that if the underlying aetiology of the PE is unknown but there are high levels of CEA, CA 125 and CA 15-3, one should investigate for malignancy. Use of all three markers had a low sensitivity (29%) but a high specificity (97%) for detecting malignancy. Therefore determination of levels of these markers is very useful in the early diagnosis of malignancies. Pericardiocentesis and pericardial biopsy are the best diagnostic tests for detecting malignant aetiologies of PE. However, where pericardiocentesis is not indicated, there are a limited number of other tests available. This study indicates that CA 125, CA 15-3, CEA are useful markers for detecting malignant aetiologies of PE. High levels of all three markers or increased levels of only CA 15-3 appeared to be predictive of effusions caused by malignancy. High levels of CA 15-3 in the follow-up period supported our hypothesis. Effusions categorised as idiopathic with high levels of these markers must be followed up closely or re-examined for possible malignancies. There were some limitations to our study. The patient numbers in the groups according to the aetiology of PE were not equal. The number of patients was limited and they were heterogenous in aetiology.

Conclusion

Malignant PE (n = 27)

Non-malignant PE (n = 42)

p

90.3 ± 88.6 32.3 ± 14.6 18.9 ± 20.2 4.5 ± 5.2 1.9 ± 1.7 2.1 ± 2.5

55.2 ± 67.8 17.0 ± 8.9 18.7 ± 19.4 2.0 ± 1.2 1.7 ± 0.8 3.1 ± 4.1

0.03 0.002 NS 0.04 NS NS

CA 125, CA 15-3 and CEA markers can be used in the differential diagnosis of benign and malignant aetiologies in patients with chronic pericardial effusions. Combined use of these three markers improves their prognostic value. Importantly, we must suspect malignancy in patients with PE whose aetiology cannot be determined.

References 1.

Goland S, Caspi A, Malnick SD. Idiopathic chronic pericardial effusion. N Engl J Med 2000; 342(19): 1449–1450.


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3. 4. 5.

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7.

8.

9.

10.

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Sagristà-Sauleda J, Angel J, Permanyer-Miralda G, Soler-Soler J. Longterm follow-up of idiopathic chronic pericardial effusion. N Engl J Med 1999; 341(27): 2054–2059. Sochocky S. Chronic pericardial effusion. S D J Med 1970; 23(3): 9–14. García-Riego A, Cuiñas C, Vilanova JJ. Malignant pericardial effusion. Acta Cytol 2001; 45(4): 561–566. Szturmowicz M, Tomkowski W, Fijalkowska A, Burakowski J, Sakowicz A, Filipecki S. The role of carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) evaluation in pericardial fluid for the recognition of malignant pericarditis. Int J Biol Markers 1997; 12(3): 96–101. Szturmowicz M, Tomkowski W, Fijalkowska A, Kupis W, Cieślik A, et al. Diagnostic utility of CYFRA 21-1 and CEA assays in pericardial fluid for the recognition of neoplastic pericarditis. Int J Biol Markers 2005; 20(1): 43–49. Pawlak-Cieślik A, Szturmowicz M, Fijałkowska A, Tomkowski W, Kupis W, et al. Neoplastic pericarditis--the role of different diagnostic procedures. Pol Arch Med Wewn 2006; 115(1): 37–44. Terracciano D, Di Carlo A, Papa P, Cicalese M, Maietta P, et al. New approaches in the diagnostic procedure of malignant pleural effusions. Oncol Rep 2004; 12(1): 79–83. Svenberg T. Carcinoembryonic antigen-like substances of human bile. Isolation and partial characterization. Int J Cancer 1976; 17(5): 588–596. Shitrit D, Zingerman B, Shitrit AB, Shlomi D, Kramer MR. Diagnostic value of CYFRA 21-1, CEA, CA 19-9, CA 15-3, and CA 125 assays in pleural effusions: analysis of 116 cases and review of the literature. Oncologist 2005; 10(7): 501–507. Ohuchi N, Sato S, Akimoto M, Taira Y, Matoba N, et al. The correlation between the immunohistochemical expression of DF3 antigen and serum CA15-3 in breast cancer patients. Jpn J Surg 1991; 21(2): 129–137. Nicolini A, Anselmi L, Michelassi C, Carpi A. Prolonged survival by ‘early’ salvage treatment of breast cancer patients: a retrospective 6-year study. Br J Cancer 1997; 76(8): 1106–1111. Porcel JM, Vives M, Esquerda A, Salud A, Pérez B, RodríguezPanadero F. Use of a panel of tumor markers (carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 15-3, and cytokeratin 19 fragments) in pleural fluid for the differential diagnosis of benign and malignant effusions. Chest 2004; 126(6): 1757–1763.

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14. Romero S, Fernández C, Arriero JM, Espasa A, Candela A, et al. CEA, CA 15-3 and CYFRA 21-1 in serum and pleural fluid of patients with pleural effusions. Eur Respir J 1996; 9(1): 17–23. 15. Shimokata K, Totani Y, Nakanishi K, Yamamoto M, Hasegawa Y, et al. Diagnostic value of cancer antigen 15-3 (CA15-3) detected by monoclonal antibodies (115D8 and DF3) in exudative pleural effusions. Eur Respir J 1988; 1(4): 341–344. 16. Mezger J, Permanetter W, Gerbes AL, Wilmanns W, Lamerz R. Tumor associated antigens in diagnosis of serous effusions. J Clin Pathol 1988; 41(6): 633–643. 17. Kandylis K, Vassilomanolakis M, Baziotis N, Papadimitriou A, et al. Diagnostic significance of the tumor markers CEA, CA 15-3 and CA 125 in malignant effusions in breast cancer. Ann Oncol 1990; 1(6): 435–438. 18. Ammon A, Eiffert H, Reil S, Beyer JH, Droese M, Hiddemann W. Tumor-associated antigens in effusions of malignant and benign origin. Clin Investig 1993; 71(6): 437–444. 19. Galve E, Garcia-Del-Castillo H, Evangelista A, Batlle J, PermanyerMiralda G, Soler-Soler J. Pericardial effusion in the course of myocardial infarction: incidence, natural history, and clinical relevance. Circulation 1986; 73(2): 294–299. 20. Tatsuta M, Yamamura H, Yamamoto R, Ichii M, Iishi H, Noguchi S. Carcinoembryonic antigens in the pericardial fluid of patients with malignant pericarditis. Oncology 1984; 41(5): 328–330. 21. Koh KK, In HH, Lee KH, Kim EJ, Cho CH, et al. New scoring system using tumor markers in diagnosing patients with moderate pericardial effusions. Int J Cardiol 1997; 61(1): 5–13. 22. Lindgren J, Kuusela P, Hellström PE, Pettersson T, Klockars M. The ovarian cancer associated antigen CA 125 in patients with pleural effusions. Eur J Cancer Clin Oncol 1988; 24(4): 737–739. 23. Faggiano P, D’Aloia A, Brentana L, Bignotti T, Fiorina C, et al. Serum levels of different tumor markers in patients with chronic heart failure. Eur J Heart Fail 2005; 7(1): 57–61. 24. Whiteside TL, Dekker A. Diagnostic significance of carcinoembryonic antigen levels in serous effusions. Correlation with cytology. Acta Cytol 1979; 23(6): 443–448. 25. Seo T, Ikeda Y, Onaka H, Hayashi T, Kawaguchi K, Kotake C, Toda T, Kobayashi K. Usefulness of serum CA125 measurement for monitoring pericardial effusion. Jpn Circ J 1993; 57(6): 489–494.


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Prevalence of residual left ventricular structural changes after one year of antihypertensive treatment in patients of African descent: role of 24-hour pulse pressure ELENA N LIBHABER, GAVIN R NORTON, CARLOS D LIBHABER, ANGELA J WOODIWISS, GEOFFREY P CANDY, MOHAMMED R ESSOP, PINHAS SARELI

Abstract Objectives: One year of antihypertensive therapy may normalise left ventricular (LV) structure in 51% of hypertensive patients of European descent. Whether similar effects can be achieved in patients of African descent, who have a high prevalence of concentric LV hypertrophy (LVH) and remodelling, is unknown. Methods: In 103 hypertensive patients in the Baragwanath Hypertension study we evaluated the prevalence of residual LV structural changes (echocardiography) after four and 13 months of stepwise antihypertensive therapy. Results: After 13 months of therapy, 24-hour blood pressure control was achieved in 47% of patients. At baseline, 51.5% of patients had concentric LVH, 19% eccentric LVH and 12% concentric LV remodelling. Despite changes in LV mass index (p < 0.01) and relative wall thickness (p < 0.05) with treatment, the proportion of patients with a normal LV mass or geometry increased only from 17.5 to 25% (p > 0.05), while 26% remained with concentric LVH (p < 0.001 compared to baseline), 25% with eccentric LVH and 23% with concentric LV remodelling (p < 0.05 compared to baseline). Residual structural changes were associated with 24-hour pulse pressure (p = 0.02), but not with 24-hour systolic or diastolic blood pressure or clinic blood pressure. Conclusions: Even after a year of antihypertensive therapy, a high proportion (74%) of hypertensives of African ancestry retained residual LV structural changes, an effect that was associated with 24-hour pulse pressure but not systolic or diastolic blood pressures or clinic blood pressure in this ethnic group. Department of Cardiology, University of the Witwatersrand, and Chris Hani Baragwanath Hospital, Johannesburg, South Africa ELENA N LIBHABER, PhD, Elena.libhaber@wits.ac.za MOHAMMED R ESSOP, MD

Department of Nuclear Medicine, University of the Witwatersrand, Johannesburg, South Africa CARLOS D LIBHABER, MD

Department of Surgery, University of the Witwatersrand, Johannesburg, South Africa GEOFFREY P CANDY, PhD

Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ELENA N LIBHABER, PhD GAVIN R NORTON, PhD ANGELA J WOODIWISS, PhD PINHAS SARELI, MD

Keywords: left ventricular geometry, antihypertensive therapy, ambulatory blood pressure, pulse pressure Submitted 6/9/11, accepted 11/1/12 Cardiovasc J Afr 2012; 23: 147–152

www.cvja.co.za

DOI: 10.5830/CVJA-2012-001

Left ventricular hypertrophy (LVH) is an established independent predictor of morbidity and mortality.1-3 However, the geometry of the heart in hypertensive LVH is a heterogeneous change. Some patients develop a concentric pattern where wall thickness increases out of proportion to chamber diameter, while others develop eccentric LVH where wall thickness increases in parallel with chamber diameters.4 The possibility that LV geometric patterns may refine the ability to predict cardiovascular events beyond LVH was suggested two decades ago,5 and more recent evidence provides substantial support for this notion in hypertensives6,7 in the general population8 following myocardial infarction,9 in diabetes mellitus,10 and in those with a normal LV ejection fraction.11,12 Therefore an important goal of therapy in hypertensives and other patient groups should be to reduce the prevalence of concentric LVH, eccentric LVH and LV remodelling. Although some13-18 but not all19,20 studies have demonstrated that antihypertensive therapy decreases both LVH and relative wall thickness, these studies were largely conducted in ethnic groups with a low prevalence of concentric LVH at baseline (6–30%).11,13-15 Those studies reporting on the prevalence of concentric LVH and remodelling before and after drug therapy suggest that after therapy, six to 16% of patients may have concentric LVH and only a small proportion, concentric LV remodelling.13-15 Whether the same low residual prevalence rates of concentric LVH or remodelling remain after drug therapy in patient populations with a high prevalence of concentric LVH or remodelling at baseline is unknown. In this regard it is well recognised that LV relative wall thickness is higher in patients of African ancestry than in other patient populations.21 Therefore, in the present study, we aimed to identify the ability of 13 months of antihypertensive therapy to normalise LV structure in hypertensives of African ancestry and the blood pressure parameter most closely associated with residual LV structural abnormalities.

Methods The protocol was approved by the University of the Witwatersrand Committee for Research in Human Subjects (approval number: M940106). The Baragwanath Hypertension Study was a singlecentre, randomised, open-label trial conducted at the Chris Hani-Baragwanath Hospital from 1994 to 1997. The enrolment


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criteria have previously been described.22,23 Briefly, men and women of African descent were enrolled if they were 18 to 70 years of age and free of clinically significant cardiovascular or non-cardiovascular disorders. All patients gave informed, written consent. Patients diagnosed as being hypertensive after a two-week placebo run-in period were randomised if in addition, their daytime diastolic blood pressure was 90 to 114 mmHg on ambulatory monitoring. Eligible patients were randomised to receive therapy as previously described.23 Patients were followed up at monthly intervals and if at the first monthly follow-up visit the target blood pressure was not reached, the daily dose of the first-line drug was increased. At two months, patients who had still not achieved target blood pressure values received additional antihypertensive agents and at a further follow-up visit, daily doses were either increased or additional therapy added.23 All patients randomised in the Baragwanath trial underwent echocardiography at baseline. Patients were followed up for 13 months. However, only patients in whom high-quality echocardiograms could be obtained were eligible for inclusion in the follow-up echocardiographic sub-study. Of the 233 patients included in the sub-study, data on 103 were available at 13 months. No significant differences were found in the baseline characteristics between the 103 patients included in the sub-study and the non-participants, except for body mass index (BMI), which was higher in the participants (31.1 ± 6.0 kg/m2) than in the non-participants (29.5 ± 5.9 kg/m2, p = 0.04). At baseline and at follow-up visits, nurse-derived clinic blood pressure was assessed after the patient had rested in the sitting position for 10 minutes. Measurements were obtained three times, consecutively, according to guidelines. The same nurse performed the clinic blood pressure readings in all patients. Pulse pressure was calculated as differences between systolic and diastolic blood pressure. Furthermore, oscillometric SpaceLabs (model 90207) devices were programmed to obtain blood pressure readings every 15 minutes from 06:00 to 22:00 and every 30 minutes from 22:00 to 06:00. The intra-individual blood pressure means were weighted by the time interval between successive blood pressure readings.23 Twenty-four-hour blood pressure control was defined as mean values of < 130/80 mmHg, and clinic blood pressure control as values of < 140/90 mmHg. At randomisation, four months and 13 months, two-dimensional targeted M-mode (short-axis view) echocardiograms were obtained with a Hewlett-Packard Sonos 2500 system using a 2.5-MHz transducer and analysed according to the American Society of Echocardiography Convention.24 All measurements were recorded on videotape and analysed by the same experienced echocardiographer who was unaware of the clinical data of the patients. Replicate measurements of LVM index showed that in the present study population, the interobserver and intra-observer coefficients of variation were 12.4 and 11.4%, respectively. Left ventricular mass (LVM) was determined as previously described and indexed (LVMI) to height2.7. Left ventricular end-diastolic mean wall thickness (MWT) was calculated from (LV end-diastolic septal wall thickness + LV end-diastolic posterior wall thickness)/2. Left ventricular end-diastolic relative wall thickness (RWT) was calculated from (LV end-diastolic septal wall thickness + LV end-diastolic posterior wall thickness)/ LV end-diastolic diameter. Left ventricular hypertrophy (LVH)

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was defined as an LVMI > 51 g/m2.7 in both women and men.25 Concentric LVH was defined as the presence of LVH and a RWT > 0.45. Eccentric LVH was defined as the presence of LVH and a RWT ≤ 0.45. Concentric remodelling was defined as the presence of a RWT > 0.45, but without LVH. Normal LV geometry was considered as the absence of LVH and a RWT ≤ 0.45. An abnormal LV geometry was considered as the presence of concentric LVH, eccentric LVH and or concentric LV remodelling.

Statistical analysis Database management and statistical analyses were performed with SAS software, version 9.13 (SAS Institute Inc, Cary, NC, USA). Data are expressed as mean ± SD. Differences in continuous variables between the patients assigned to each of the four LV geometric patterns were identified on an ANOVA, followed by the test of Scheffe, or the Kruskal-Wallis test when the distribution was abnormal. To assess changes in continuous variables from zero to four and 13 months of treatment, a repeated-measurements ANOVA was performed. To compare the prevalence rates of the four patterns of LV geometry at zero and 13 months of therapy, a Chi-square test followed by Bonferroni correction was performed. To evaluate longitudinal changes in the prevalence rates of the four LV geometric patterns, a Mantel-Haenszel strategy for repeated measurements (according to the SAS program) or a McNemar test was performed. To identify predictors of abnormal geometry, a stepwise multiple logistic regression model was used, where age, gender, BMI and blood pressure were included in the model. A p < 0.05 was considered to be statistically significant.

Results Table 1 shows the characteristics at baseline of patients grouped according to the mass and geometry of the left ventricle. At baseline, 51.5% of patients had concentric LVH, while 19% had eccentric LVH and 12% concentric LV remodelling. Therefore, only 17.5% of the patients at baseline had a normal left ventricle. The age and gender distribution across the four groups was similar. However, patients with concentric LVH had a higher BMI and off-treatment 24-hour clinic systolic blood pressure (BP) and pulse pressure (PP). Patients with eccentric LVH had a higher BMI. Table 2 shows mean BP values and the percentage BP control at baseline and after four and 13 months of antihypertensive treatment. Over the four-month treatment period, 46% of patients achieved clinic BP values of < 140/90 mmHg, and by 13 months of therapy, 64% had clinic BP values that were < 140/90 mmHg. Over the four-month treatment period, 46% of patients achieved 24-hour BP values of < 130/80 mmHg and by 13 months of therapy 47% had 24-hour BP values that were < 130/80 mmHg. At four and 13 months of follow up, one (1%) and 12 (11%) patients, respectively were receiving three or more antihypertensive drug classes. Forty-one per cent (42/103) of the patients after 13 months of treatment were receiving two or more antihypertensive drug classes. Table 2 also shows LVM, LV wall thickness, LV internal diameters, the prevalence of LVH and the prevalence of an increased LV relative wall thickness at baseline and after four


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TABLE 1. BASELINE CHARACTERISTICS OF PATIENTS GROUPED ACCORDING TO LEFT VENTRICULAR STRUCTURE Geometry Geometry Normal Concentric LVH Concentric remodelling Eccentric LVH Number (%) 18 (17.5) 53 (51.5)** 12 (12) 20 (19) 28.6 ± 7.8 32.4 ± 5.1** 28.0 ± 3.1 31.7 ± 6.7** BMI (kg/m2) Age (years) 51.9 ± 9.7 52.4 ± 9.2 48.3 ± 10.2 50.1 ± 10.3 Female gender [n (%)] 14 (78) 44 (83) 10 (83) 17 (85) 24-hour SBP (mmHg) 146 ± 11 158 ± 16** 148 ± 20 147 ± 11 24-hour DBP (mmHg) 96 ± 7 98 ± 6 94 ± 8 96 ± 7 Clinic SBP (mmHg) 164 ± 19 178 ± 20* 161 ± 25 168 ± 17 Clinic DBP (mmHg) 99 ± 2 104 ± 9 100 ± 9 101 ± 9 Clinic PP (mmHg) 65.7 ± 16.1 73.5 ± 16.7** 60.2 ± 20.0 67.6 ± 15.1 24-hour PP (mmHg) 50.5 ± 8.9 59.4 ± 11.8* 53.1 ± 15.3 52.1 ± 9.5 LVM (g) 151 ± 29 248 ± 62** 159 ± 32 222 ± 36** 42.8 ± 8.8 74.3 ± 16.5** 44.0 ± 3.4 66.0 ± 11.7** LVMI (g/m2.7) LV mean wall thickness (mm) 9.4 ± 1.2 11.4 ± 1.6** 11.5 ± 1.4** 11.0 ± 1.1** LV relative wall thickness (ratio) 0.38 ± 0.06 0.56 ± 0.10 0.56 ± 0.10 0.39 ± 0.04** BMI, body mass index; LV, left ventricular; LVH, left ventricular hypertrophy; SBP, systolic blood pressure; DBP, diastolic BP; PP, pulse pressure; LVM, left ventricular mass; LVMI, left ventricular mass index. *p < 0.05, **p < 0.01 for comparisons between the four left ventricular geometric patterns.

and 13 months of antihypertensive treatment. Treatment resulted in a decreased LVM and LVMI, largely through reductions in wall thickness and only minor decreases in internal diameters. Treatment produced maximal decreases in LVM, LVMI and LV wall thickness, and a maximal decrease in the proportion of patients with LVH or an increased relative wall thickness by four months of therapy, with no further changes occurring over the following nine months of therapy. Fig. 1 shows the changes in prevalence of a normal left ventricle, concentric LVH, concentric LV remodelling and eccentric LVH after four and 13 months of antihypertensive

therapy. The proportion of patients with concentric LVH decreased from 51.5 to 25% (p < 0.01), while the proportion with concentric LV remodelling increased from 12 to 23% (p < 0.05). The proportion of patients with eccentric LVH increased from 19 to 25% but this did not achieve significance. The proportion of patients with a normal left ventricle increased from 17.5 to 26% but this also failed to achieve significance. From the 53 (51.5%) patients with concentric LVH at baseline, only seven (13%) normalised the LV structure, but 15 (28%) changed to eccentric LVH, 13 (24.5%) to concentric LV remodelling and 18 (34%) remained in the concentric LVH

TABLE 2. BLOOD PRESSURE AND ECHOCARDIOGRAPHIC VALUES AT BASELINE AND AFTER FOUR AND 13 MONTHS OF TREATMENT (n = 103) Baseline 4 months 13 months Clinic SBP/DBP (mmHg) 171 ± 21/102 ± 10 148 ± 21/91 ± 11** 135 ± 19/85 ± 10** Clinic heart rate (beats/min) 71 ± 10 72 ± 10 72 ± 11 24-hour SBP/DBP (mmHg) 152 ± 16/97 ± 7 129 ± 15/87 ± 9** 127 ± 12/80 ± 8** 24-hour heart rate (beats/min) 77 ± 9 76 ± 10 75 ± 10 0 47 (46) 66 (64) Clinic BP control† [n (%)] 0 47 (46) 48 (47) 24-hour BP control† [n (%)] Clinic PP (mmHg) 69.5 ± 17.1 56.7 ± 15.3** 49.8 ± 14.6** 24-hour PP (mmHg) 55.7 ± 11.9 46.0 ± 9.8** 46.3 ± 8.7** LV end-diastolic diameter (mm) 46.6 ± 5.8 45.3 ± 5.3* 45.2 ± 5.1* LV end-systolic diameter (mm) 30.1 ± 5.6 29.0 ± 5.0** 28.6 ± 5.4** LV septal wall thickness (mm) 12.5 ± 2.1 11.4 ± 1.9** 11.4 ± 1.9** LV posterior wall thickness (mm) 11.3 ± 2.2 10.5 ± 1.7** 10.4 ± 1.8** LV mean wall thickness (mm) 11.9 ± 2.0 11.0 ± 1.5** 10.9 ± 1.5** LV relative wall thickness (ratio) 0.50 ± 0.11 0.47 ± 0.10* 0.47 ± 0.11* LVM (g) 215 ± 64 182 ± 48** 179 ± 43** 63.7 ± 19.0 53.7 ± 13.9** 52.8 ± 12.3** LVMI (g/m2.7) LVH [n (%)] 73 (71) 48 (47)** 52 (50)** LV relative wall thickness [n (%)] 65 (63) 55 (53)* 50 (49)** LV, left ventricular; LVH, left ventricular hypertrophy; SBP, systolic blood pressure; DBP, diastolic BP; PP, pulse pressure; LVM, left ventricular mass; LVMI, left ventricular mass index. † Percentage of clinic BP (< 140/90 mmHg) and 24-hour BP control (< 130/80 mmHg), *p < 0.05, **p < 0.01 versus baseline values.


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51.5

17.5

TABLE 4. PREDICTORS OF ABNORMAL GEOMETRY AFTER 13 MONTHS OF THERAPY ** ** 26 25

27 26

* * 26 23 12

Normal

Concentric LVH Baseline

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Concentric remodelling

4 months

19 20

25

Eccentric LVH

13 months

Fig. 1. Changes in the prevalence of a normal left ventricular (LV) structure, concentric LV hypertrophy (LVH), concentric LV remodelling and eccentric LVH after four and 13 months of antihypertensive therapy. *p < 0.05 ,**p < 0.01 compared to 0 months (baseline).

category after 13 months of treatment. Moreover, from 20 (19%) patients initially with eccentric LVH, only six (30%) normalised the LV structure, while four (20%) converted to concentric remodelling, and nine (45%) remained with eccentric LVH. From the 12 patients with concentric remodelling, six (50%) normalised their LV structure and five changed to eccentric LVH. Table 3 shows the characteristics after four and 13 months of therapy of hypertensive patients, grouped according to the mass and geometry of the left ventricle. At four months of antihypertensive therapy, no significant differences were observed in age, gender, BMI, any BP measurements, BP control rates, or type of antihypertensive medication between patients grouped according to LV geometric patterns (data not shown). After 13 months of antihypertensive therapy no significant differences were noted in age, gender, ambulatory or clinic systolic or diastolic BP, clinic PP, BP control rates, or type of antihypertensive medication between patients grouped according to LV geometric patterns. However ambulatory and clinic PP were higher in patients with concentric and eccentric LVH. In multiple regression analysis with age, gender, 24-hour PP and BMI included in the models, at 13 months, 24-hour (p = 0.02)

Odds ratio

95% CI odds ratio

p-value Logistic regression model with 24-hour PP 1.087 0.985–1.198 0.096 BMI (kg/m2) Age (years) 1.032 0.979–1.088 0.245 Gender (female) 1.550 0.369–6.503 0.549 Baseline RWT (ratio) 0.874 0.528–1.448 0.601 24-hour PP (mmHg) 1.087 1.012–1.168 0.023 Logistic regression model with day PP 1.094 0.993–1.205 0.071 BMI (kg/m2) Age (years) 1.030 0.977–1.086 0.269 Gender (female) 1.543 0.372–6.328 0.554 Baseline RWT (ratio) 0.875 0.527–1.453 0.606 Day PP (mmHg) 1.087 1.012– 1.168 0.023 BMI, body mass index; PP, pulse pressure; RWT, relative wall thickness.

and day PP (p = 0.02) were independently related to an abnormal residual LV structure after treatment (Table 4). Moreover, when baseline LVM was added to the model, 24-h PP (p = 0.004) still showed an independent association with residual LV structural abnormalities. Clinic PP was not a significant predictor of abnormal residual LV structural abnormalities after 13 months of therapy (p = 0.09). Neither 24-hour systolic/diastolic nor clinic systolic/diastolic BP control was independently associated with residual LV structural abnormalities (data not shown).

Discussion The main findings of this study are that in hypertensives of African ancestry, after more than a year of stepwise antihypertensive therapy, which achieved clinic BP control in 64% of patients and 24-hour BP control in 47% of patients by 13 months of therapy,

TABLE 3. CHARACTERISTICS OF PATIENTS AFTER 13 MONTHS OF ANTIHYPERTENSIVE THERAPY GROUPED ACCORDING TO LEFT VENTRICULAR STRUCTURE Geometry Normal Concentric LVH Concentric remodelling Eccentric LVH Number (%) 27 (26) 26 (25) 24 (23) 26 (25) 28.9 ± 8.6 32.3 ± 5.3** 31.8 ± 5.0** 31.7 ± 5.0** BMI (kg/m2) Age (years) 48.9 ± 10.1 52.3 ± 10.0 52.8 ± 8.0 51.8 ± 10.0 Female gender [n (%)] 22 (81) 22 (85) 20 (83) 21 (81) 24-hour SBP/DBP (mmHg) 122 ± 12/80 ± 7 128 ± 13/79 ± 7 128 ± 11/83 ± 8 128 ± 12/79 ± 9 Clinic SBP/DBP (mmHg) 129 ± 14/84 ± 8 139 ± 20/84 ± 10 135 ± 17/89 ± 9 137 ± 22/84 ± 11 24-hour BP control [n (%)] 10 (37) 14 (54) 15 (58) 9 (38) Clinic BP control [n (%)] 19 (70) 17 (64) 19 (73) 11 (46) 24-hour PP (mmHg) 42.1 ± 8.3 49.1 ± 9.9** 45.5 ± 6.0 48.8 ± 8.5** Clinic PP (mmHg) 44.4 ± 10.9 55.4 ± 17.3** 45.8 ± 12.2 53.3 ± 14.8** LVM (g) 146 ± 21 208 ± 33** 148 ± 26 211 ± 36** 41.2 ± 5.8 62.1 ± 8.5** 43.7 ± 5.5 63.7 ± 6.9** LVMI (g/m2.7) LV mean wall thickness (mm) 9.3 ± 0.8 12.3 ± 1.1* 11.1 ± 1.0* 10.9 ± 1.1* LV relative wall thickness (ratio) 0.38 ± 0.04 0.55 ± 0.08** 0.57 ± 0.07** 0.39 ± 0.05 Concentric LVH at baseline [n (%)] 7 (26) 18 (69)** 13 (54) 15 (58) LV, left ventricular; LVH, left ventricular hypertrophy. SBP, systolic blood pressure; DBP, diastolic BP; PP, pulse pressure; LVM, left ventricular mass; LVMI, left ventricular mass index. *p < 0.05, **p < 0.01 compared to the normal group.


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the proportion of patients with a normal LV mass or geometry did not significantly increase (17.5 to 26%), while 25% remained with concentric LVH and 25% with eccentric LVH. Moreover, the proportion of patients with concentric LV remodelling increased from 12 to 23% (p < 0.05). These residual abnormalities in LV structure were noted even though therapy resulted in a decrease in LVM and relative wall thickness. Although a number of studies have demonstrated that antihypertensive therapy can regress LVH as well as reduce LV relative wall thickness, few studies have reported on the ability of therapy to normalise LV structure. In this regard, in contrast to the outcome of the present study where 25% of patients remained with concentric LVH and only 26% had a normal LV structure after one year of therapy, in the LIFE study after one year of therapy in 853 patients with electrocardiographic LVH at baseline, the prevalence of residual concentric LVH was 6% and the proportion of patients with a normal LV structure was 51%.13 In another study conducted in 182 patients, 30% of whom had concentric LVH at baseline, only 14% of 182 patients had concentric LVH after one year of therapy.14 An explanation for the markedly higher prevalence of residual concentric LVH and lower prevalence of a normal LV structure after one year of antihypertensive therapy in our study compared to previous studies13,14 is most likely the higher proportion of patients with an increased baseline concentric LVH. Indeed, in previous studies,13,14 the prevalence of concentric LVH at baseline was approximately 10 to 30%, compared to the approximately 51% of patients with concentric LVH in our study. Moreover, in previous studies13,14 mean baseline LV relative wall thickness ranged from 0.41 to 0.45, while in the present study, mean baseline LV relative wall thickness was 0.50. The markedly higher prevalence of concentric LVH (> 50%) and mean relative wall thickness values noted in our study, which was conducted in a group of patients of African descent, compared to previous studies conducted in patients of European descent,13,14 is consistent with ethnic disparities in the extent of concentric LV remodelling previously reported to exist between groups of African and European descent.21 Furthermore, the markedly higher prevalence of concentric LVH and mean relative wall thickness values noted in the present compared to previous studies13,14 is consistent with the high prevalence of obesity in our sample. In this regard, we have recently demonstrated a strong relationship between central obesity and concentric LVH and remodelling in patients of African descent.26 The high prevalence of a residual abnormality in LV structure even after a year of antihypertensive therapy in the present study is not explained by poor systolic and diastolic BP control. Neither clinic nor 24 hour systolic/diastolic BP and clinic BP control was independently associated with residual LV structural abnormalities. Indeed, in the present study the clinic BP control rates were 64% compared to 60% in previous studies reporting on a low prevalence of residual LV structural abnormalities after one year of therapy.14 Moreover, unlike in other studies,13,14 we used ambulatory BP monitoring to further evaluate the effect of therapy on 24-hour BP profiles. In this regard, 47% of patients achieved 24-hour BP values below 130/80 mmHg. Importantly however, in a separate model, 24-hour PP was independently related to an abnormal LV structure. In contrast, office PP could not account for the variability in left ventricular mass or relative wall thickness in

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the LIFE study after one year of antihypertensive treatment.13 Similarly, we were unable to show a relationship between clinic PP and residual LV structural changes. The high prevalence of a residual abnormality in LV structure even after a year of antihypertensive therapy in the present study is not explained by a poor response of the left ventricle to therapy. Indeed, in the present study, the mean decrease in LV relative wall thickness produced by antihypertensive therapy was similar to that noted in other studies reporting on a low prevalence of residual LV structural abnormalities after a year of therapy.13,14 Although the present study was not designed to assess the effects of specific drug classes, we were also unable to identify a relationship between drug class and the LV response to therapy. Importantly, of the 51.5% of patients with concentric LVH at baseline, 28% changed their LV geometric pattern to eccentric LVH, and 24.5% normalised their LVMI but maintained a concentric LV geometry, while 34% remained in the concentric LVH category after 13 months of treatment. Therefore, although approximately half of these patients no longer remained in the concentric LVH category, only 13% normalised their geometry after a year of therapy. These data suggest that, at least in our population sample, concentric LVH is difficult to normalise. In this regard, one previous study conducted in patients of European descent has demonstrated similar outcomes where only 27% of those with concentric LVH at baseline normalised LV structure.14 In contrast however, in the LIFE study, 75% of patients with concentric LVH at baseline normalised LV structure after one year of therapy.13 A reason for these discrepancies is not apparent and further studies are required to address this issue. The limitations of the present study include the following. A large proportion of the study group consisted of females and hence the outcomes may be specific to females. Second, the patients participating in the trial were recruited from an urban African community with a high unemployment rate, and a number of participants relocated to alternate areas where employment was available. Therefore retention rates at 13 months were low.23 Third, antihypertensive treatment was based on drug combinations from a variety of classes to achieve BP control and therefore we cannot draw conclusions as to whether the effect noted in our study applies to all antihypertensive agents. However, the present approach is in line with what is likely to occur in clinical practice where combination therapy with different classes of agents is the most likely method of achieving BP control. Lastly, we did not assess the effect of treatment beyond 13 months and hence we do not know what antihypertensive therapy for two to three years may have achieved. However, we do not believe that further significant changes in LV structure would have occurred, as maximal changes were already present at four months of therapy and no further changes were noted from four to 13 months of therapy.

Conclusion In this study we show that after more than a year of antihypertensive therapy in hypertensives of African ancestry, including combination therapy where required, no significant change in the proportion of patients with a normal left ventricle occurred. Twenty-five per cent still had residual concentric LVH, and a further 25% eccentric LVH, while the proportion with


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concentric LV remodelling increased. Neither clinic systolic/ diastolic nor 24-hour systolic/diastolic BP control accounted for these residual changes. Twenty-four-hour and day PP were associated with residual LV structural changes. These findings suggest that optimal therapeutic strategies for reducing cardiovascular risk in hypertensives of African ancestry have yet to be achieved. Further studies are required to evaluate whether reducing PP to acceptable target levels would improve the capacity to reverse LV structural abnormalities. This work was supported by an open educational grant from Bayer. GRN and AJW are supported by the Medical Research Council of South Africa, the Circulatory Disorders Research Trust, the University Research Council of the University of the Witwatersrand, and the South African National Foundation for Research.

References 1.

Levy D, Salomon M, D’Agostino RB, Belanger AJ, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994; 90: 1786–1793. 2. Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, Snapinn S, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. J Am Med Assoc 2004; 292: 2343–2349. 3. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Prognostic significance of left ventricular mass change during treatment of hypertension. J Am Med Assoc 2004; 292: 2350–2356. 4. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992; 19: 1550–1558. 5. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114: 345–352. 6. Gerdts E, Cramariuc D, de Simone G, Wachtell K, Dahlöf B, Devereux RB. Impact of left ventricular geometry on prognosis in hypertensive patients with left ventricular hypertrophy (the LIFE study). Eur J Echocardiogr 2008; 9: 809–815. 7. Muiesan ML, Salvetti M, Monteduro C, Bonzi B, Paini A, Viola S, et al. Left ventricular concentric geometry during treatment adversely affects cardiovascular prognosis in hypertensive patients. Hypertension 2004; 43: 731–738. 8. Bluemke DA, Kronmal RA, Lima JAC, Olson J, Liu K, Burke GL, et al. The relationship of left ventricular mass and geometry to incident cardiovascular events. The MESA (Multi-Ethnic Study of Atherosclerosis) Study. J Am Coll Cardiol 2008; 52: 2148–2155. 9. Verma A, Meris A, Skali H, Ghali JK, Arnold JM, Bourgoun M, et al. Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan in Acute myocardial iNfarcTion) Echocardiographic Study. J Am Coll Cardiol (Cardiovasc Imaging) 2008; 1: 582–591. 10. Eguchi K, Ishikawa J, Hoshide S, Ishikawa S, Pickering TG, Schwartz JE, et al. Differential impact of left ventricular mass and relative wall thickness on cardiovascular prognosis in diabetic and nondiabetic hypertensive subjects. Am Heart J 2007; 154: 79.e9–15. 11. Milani RV, Lavie CJ, Mandeep R, Mehra MR, Ventura HO, Kurtz JD, et al. Left ventricular geometry and survival in patients with normal left

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ventricular ejection fraction. Am J Cardiol 2006; 97: 959–963. 12. Lavie CJ, Milani RV, Ventura HO, Messerli FH. Left ventricular geometry and mortality in patients > 70 years of age with normal ejection fraction. Am J Cardiol 2006; 98: 1396–1399. 13. Wachtell K, Dahlöf B, Rokkedal J, Papademetriou V, Nieminen MS, Smith G, et al. Change of left ventricular geometry pattern after 1 year of antihypertensive treatment: The Losartan Intervention for Endpoint reduction in hypertension (LIFE) Study. Am Heart J 2002; 144: 1057–1064. 14. Cuspidi C, Muiesan ML, Valagussa L, Salvetti M, Di Biagio C, AgabitiRosei E, et al. On behalf of the CATCH investigators. Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the candesartan assessment in the treatment of cardiac hypertrophy (CATCH) study. J Hypertens 2002; 20: 2293–2300. 15. Heesen WF, Beltman FW, Smit AJ, May JF, de Graeff PA, Muntinga JHJ, Havinga TK, Schuurman FH, van der Veur E, Meyboom-de Jong B, Lie KI. Reversal of pathophysiologic changes with long-term lisinopril treatment in isolated systolic hypertension. J Cardiovasc Pharmacol 2001; 37: 512–521. 16. Taniguchi I, Kawai M, Date T, Yoshida S, Seki S, Taniguchi M, et al. Effects of spironolactone during angiotensin II receptor blocker treatment on the left ventricular mass reduction in hypertensive patients with concentric left ventricular hypertrophy. Circ J 2006; 70: 995–1000. 17. Grandi AM, Solbiati F, Laurita E, Maresca AM, Nicolini E, Marchesi C, et al. Effects of dual blockade of Renin-Angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a Randomized, Controlled Pilot study. Am J Hypertens 2008; 21: 231–237. 18. Cuspidi C, Meani S, Valerio C, Fusi V, Sala C, Maisaidi M, Zanchetti A. Effects of Angiotensin II receptor blockade-based therapy with losartan on left ventricular hypertrophy and geometry in previously treated hypertensive patients. Blood Press 2006; 15: 107–115. 19. Bleumink GS, Deinum J, Mosterd A, Witteman JC, Hofman A, Stricker BH. Antihypertensive treatment is associated with improved left ventricular geometry: the Rotterdam Study. Pharmacoepidemiol Drug Saf 2004; 13: 703–709. 20. Agabiti-Rosei E, Ambrosioni E, Dal Palu C, Muiesan ML, Zanchetti A on behalf of the RACE Study Group. ACE inhibitor ramipril is more effective than the β-blocker atenolol in reducing left ventricular mass in hypertension. Results of the RACE (ramipril cadioprotective evaluation) study. J Hypertens 1995; 13: 1325–1334. 21. Kizer JR, Arnett DK, Bella JN, Paranicas M, Rao DC, Province MA, et al. Differences in left ventricular structure between black and white hypertensive adults. The Hypertension Genetic Epidemiolgy Network Study. Hypertension 2004; 43: 1182–1188. 22. Skudicky D, Sareli P, Libhaber E, Candy G, Radevski I, Valtchanova Z, et al. Relationship between treatment-induced changes in left ventricular mass and blood pressure in black African hypertensive patients. Results of the Baragwanath Trial. Circulation 2002; 105: 830–836. 23. Sareli P, Radevski IV, Valtchanova ZP, Libhaber E, Candy GP, Den Hond E, et al. Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg. Arch Intern Med 2001; 161: 965–971. 24. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurement. Circulation 1978; 58: 1072–1083. 25. Nunez E, Arnett DK, Benjamin EJ, Liebson PR, Skelton TN, Taylor H, et al. Optimal threshold value for left ventricular hypertrophy in blacks: the Atherosclerosis Risk in Communities Study. Hypertension 2005; 45: 58–63. 26. Woodiwiss AJ, Libhaber CD, Majane OHI, Libhaber E, Maseko M, Norton GR. Obesity promotes left ventricular concentric rather than eccentric geometric remodeling and hypertrophy independent of blood pressure. Am J Hypertens 2008; 21: 1144–1151.


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The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia LUCINDA GOVENDER, IRENE MACKRAJ, PREM GATHIRAM, JACK MOODLEY

Abstract The pathogenesis and aetiology of pre-eclampsia (PE) is still unclear. We investigated the role of angiogenic, antiangiogenic and vasoactive factors in black South African women with early- and late-onset PE. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were determined using the ELISA technique, and placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 receptors were determined using real-time PCR. Serum sFlt-1 levels were significantly elevated and PlGF significantly reduced in early-onset PE compared to the normotensive group. Placental VEGF mRNA expression levels were significantly reduced in the late-onset preeclamptic group compared with the normotensives. The placental mRNA expression of AT1 receptor in the late-onset pre-eclamptic group was relatively raised compared to the normotensives, suggesting hypersensitivity to pressor agents. We believe that the excess of serum sFlt-1 and reduced VEGF and PlGF levels favour an anti-angiogenic state and endothelial dysfunction leading to PE, and that the aetiology and pathogenesis of early- and late-onset PE differ. Keywords: pre-eclampsia, angiogenic factors, anti-angiogenic factors, sFlt-1, VEGF, PlGF, placental AT1, VEGF, PlGF and sFlt-1 mRNAs Submitted 30/5/11, accepted 16/1/12 Cardiovasc J Afr 2012; 23: 153–159

www.cvja.co.za

DOI: 10.5830/CVJA-2012-003

Pre-eclampsia (PE) is a pregnancy-specific syndrome that causes substantial maternal, foetal and neonatal morbidity and mortality worldwide.1,2 It is characterised by new-onset hypertension and significant proteinuria after 20 weeks of gestation, and the remission of these signs following delivery. Department of Physiology and Physiological Chemistry, University of KwaZulu-Natal, Durban, South Africa LUCINDA GOVENDER, MMedSci IRENE MACKRAJ, PhD, mackraji@ukzn.ac.za

Department of Family Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa PREM GATHIRAM, PhD

Department of Obstetrics and Gynaecology and Women’s Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa JACK MOODLEY, MD, jmog@ukzn.ac.za

Despite years of research, the exact aetiology of PE remains unknown.3 Much is, however, known about its underlying pathophysiology.4 It is recognised that PE is a multi-systemic syndrome, affecting several organ systems and is posited to occur in two stages. Stage 1 comprises reduced placental perfusion, which is postulated as the root cause that leads to stage 2; the maternal syndrome.5 The cause of the reduced perfusion and the mechanism by which this is translated into the maternal syndrome are still being investigated. The link between stages 1 and 2 may be the key to understanding and eventually treating PE. It is believed that placental ischaemia during stage 1 may lead to placental production of a soluble factor or factors that cause maternal endothelial dysfunction.1,6 One such anti-angiogenic factor is soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble vascular endothelial growth factor (VEGF) receptor 1, which has binding sites for soluble VEGF and placental growth factor (PlGF). Therefore, excessive production of sFlt-1 in PE results in a concomitant reduction of free, circulating angiogenic factors, VEGF and PlGF.7-9 When the maternal endothelium is deprived of these angiogenic factors (VEGF and PlGF) and in the presence of excess antiangiogenic factors such as sFlt-1, it becomes dysfunctional and leads to the clinical syndrome of hypertension and proteinuria.1,10 In addition to an imbalance between angiogenic and antiangiogenic factors, the renin–angiotensin system (RAS) has also been implicated in the pathogenesis of PE.11-13 Most studies on angiogenic/anti-angiogenic factors, however, have been done in high-income countries. Furthermore, there may be racial variations in both the incidence of PE and the clinical features at presentation. For example, the incidence of PE is much higher in South Africa and it has a much more aggressive and rapid clinical course of presentation, leading to significant mortality.14 We therefore investigated the role of serum and the placental mRNA expressions of angiogenic and anti-angiogenic factors in African women with early- and lateonset PE in a low- to middle-income setting.

Methods Following institutional ethical permission, pregnant women who gave written, informed consent were recruited from the labour ward of a regional hospital in the KwaZulu-Natal province, South Africa. Following enrolment, the participants were grouped as follows: clinically healthy normotensive controls (n = 30); chronic hypertensives (n = 9) (experimental control); early-onset pre-eclamptics (≤ 27 weeks gestation) (n = 10) and late-onset pre-eclamptics (≥ 28 weeks gestation) (n = 9). Definitions: pre-eclampsia was defined as new-onset hypertension (blood pressure 140/90 mmHg) and proteinuria (≥ 2+ on testape) after the 20th week of pregnancy. Chronic hypertension was defined as women with a history of hypertension


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in the non-pregnant state and who had hypertension at the first antenatal visit prior to 20 weeks’ gestation. All clinical data were recorded on a structured form and included the highest blood pressure measurement, level of proteinuria, maternal age, parity, gestational age, mode of delivery and neonatal outcomes. Pre-partum blood samples were obtained from participants who were in early labour. Postpartum central placental samples were obtained soon after delivery of the babies. The blood samples were centrifuged at 4°C at 3 000 rpm for 30 minutes and aliquots of serum samples and placental tissue samples were stored at –70°C until used. All participants with hypertension (chronic hypertensives and pre-eclamptics) were on antihypertensive medication, namely methyldopa. The quantitative sandwich enzyme immunoassay technique was performed on serum samples to analyse for the levels of sFlt-1, VEGF and PlGF using Quantikine ELISA kits (R & D Systems, Minneapolis, USA). All assays were performed in duplicate according to the manufacturer’s instructions. RNA was extracted from placental samples using a protocol previously described,15,16 and synthesis of cDNA was performed using the Bio-Rad iScript cDNA synthesis kit according to the manufacturer’s protocol (Bio-Rad Laboratories (Pty) Ltd). Thereafter, real-time PCR was performed to determine the levels of mRNA expressions of sFlt-1, VEGF, PlGF and AT1 using standard methods.16-18

Statistical analysis All values are expressed as means ± SEM (standard error of mean). Statistical tests were performed using SPSS version 15.0 (SPSS Inc, Chicago, Illinois, USA). A p-value of < 0.05 was considered statistically significant. The Kruskal-Wallis test was done to assess for any overall significant differences across the four groups within each variable in clinical data, as well as between the groups for each mRNA gene expression. This was followed by the Mann-Whitney test to determine which groups displayed these differences. One-way ANOVA was performed to determine if there were

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significant differences in the serum concentrations of sFlt-1, PlGF and VEGF, and the mRNA expression levels of sFlt-1, VEGF, PlGF and the AT1 receptor among the groups. The TukeyKramer multiple comparison test and the Mann-Whitney test compared each group against the other and determined which two groups displayed a significant difference (p < 0.05).

Results Table 1 shows the demographic and clinical data including neonatal outcomes of all patients. Except for changes in blood pressure and proteinuria, there were no significant differences in any of the parameters among the four groups. The body mass of the neonates in the early-onset (2.83 ± 0.38 kg) and late-onset (3.03 ± 0.16 kg) pre-eclamptic groups were lower than those of the normotensive (3.24 ± 0.08 kg) and chronic hypertensive (3.34 ± 0.17 kg) groups. However, these differences were not statistically significant (p > 0.05). The serum sFlt-1 concentrations in the normotensive controls (9 603 ± 1 797 pg/ml) were significantly less than those in the early-onset pre-eclamptic group (26 682 ± 5 482 pg/ ml) (p < 0.05) (Fig. 1). The levels in the early- and late-onset pre-eclamptic (16 069 ± 4 305 pg/ml) groups were higher than those in the chronic hypertensive group (8 811 ± 2 008 pg/ml) but these changes were not significantly different. The serum concentrations of VEGF in all four groups were below the detectable limit of the assay. Fig. 2 shows that the normotensive group (0.83 ± 0.11 pg/ml) had significantly raised serum PlGF levels compared to the early-onset pre-eclamptic group (0.23 ± 0.031 pg/ml) (p = 0.001). Furthermore, there was a significant difference in the levels of PlGF between the normotensive (0.83 ± 0.11 pg/ml) and chronic hypertensive (0.42 ± 0.063 pg/ml) groups (p < 0.05) (Fig. 2). In addition, the early-onset pre-eclamptic group had relatively lower serum PlGF levels compared with the late-onset group (0.45 ± 0.103 pg/ml). The relative placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 were compared across the four groups and were normalised to the housekeeping gene, GAPDH. Data are expressed as fold changes.

TABLE 1. DEMOGRAPHIC DATA AND CLINICAL CHARACTERISTICS OF ALL PATIENTS

Group Variable Maternal age (years) Parity Gestational age (weeks) Blood pressure (mmHg) Systolic Diastolic HIV status (%) Positive Negative Unknown Mass of neonate (kg)

Normotensive controls (n = 29) 28.48 ± 1.19 2 ± 0.23 38.46 ± 0.26 (n = 28)

Chronic hypertension (n = 9) 28.78 ± 1.86 2 ± 0.40 38.44 ± 0.47

Early-onset pre-eclampsia (n =10) 29.88 ± 3.40 2 ± 0.53 36.38 ± 1.72

Late-onset pre-eclampsia (n = 9) 28.33 ± 2.05 1 ± 0.33 37.67 ± 0.73

118.59 ± 1.79

139.67 ± 3.16

152.75 ± 6.39*

161.78 ± 3.68*#

72.24 ± 1.57

91.33 ± 2.74

94.63 ± 5.79*

102.22 ± 3.08* #

44.83 51.72 3.45 3.24 ± 0.08

44.44 55.55 0 3.34 ± 0.17

25 62.5 12.5 2.83 ± 0.38 (n = 9)

66.66 33.33 0 3.03 ± 0.16

*Significant difference in comparison with normotensive control group (p < 0.05). Significant difference in comparison with chronic hypertensive group (p < 0.05).

#


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2.5

⁕ p < 0.05

30000 20000 10000

N

CH

EO

LO

Fig. 1. Serum concentrations (conc) of sFlt-1 in normotensive (N) (n = 27), chronic hypertensive (CH) (n = 9), early-onset pre-eclamptic (EO) (n = 8) and lateonset pre-eclamptic (LO) (n = 8) groups. *Significant difference (p < 0.05) between the early-onset pre-eclamptic and normotensive groups.

The highest mRNA expression level of sFlt-1 was found in the late-onset pre-eclamptic group (1.789 ± 0.513 fold) and the lowest level was found in the chronic hypertensive group (1.009 ± 0.162 fold) (Fig. 3). The level of sFlt-1 mRNA expression in the normotensive group (1.62 ± 0.24 fold) was slightly higher than that of the the early-onset pre-eclamptic group (1.401 ± 0.237 fold). There were no significant differences in the sFlt-1 concentrations among the four groups. The highest level of VEGF mRNA expression was found in the normotensive group (2.261 ± 0.42 fold) (Fig. 4). The VEGF mRNA expression level in the normotensive group was significantly higher than in the late-onset pre-eclamptic (1.059 ± 0.4338 fold) and chronic hypertensive (0.682 ± 0.113 fold) groups (2.14 and 3.24 fold, respectively) (p < 0.05). The VEGF mRNA expression level in the normotensive group compared with the early-onset pre-eclamptic group (0.943 ± 0.28) had a p-value very close to being significant (p = 0.051). As shown in Fig. 5, the ratio of sFlt-1 to VEGF was 2.6-fold higher in the early-onset pre-eclamptic group than in the normotensive group (p = 0.055). The ratio in the late-onset pre-eclamptic group and chronic hypertensive group were 2.17and 2.34-fold greater, respectively than the normotensive group. Although the differences in mRNA expression levels of PlGF among the four groups were not statistically significant, the late-onset pre-eclamptic group had the lowest level (0.81

sFIt-1/GAPDH

sFIt-1 conc (pg/ml)

40000

0

1.5 1.0 0.5 N

CH

EO

LO

Fig. 3. Placental mRNA expression levels of sFlt-1 in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 8) and late-onset (LO) (n = 9) pre-eclamptic groups.

± 0.34) while the chronic hypertensive group had the highest level (2.17 ± 0.94) and the latter was 1.80-fold higher than in the normotensive group (1.205 ± 0.4818) (Fig. 6). The early-onset pre-eclamptic group (1.704 ± 0.5854) had a relatively higher level of PlGF expression level than the late-onset pre-eclamptic group but the level was lower than in the chronic hypertensive group. Among all four groups, the late-onset pre-eclamptic group (23.20 ± 13.36 fold) had the highest level of AT1 mRNA expression (Fig. 7). Furthermore, the normotensive group (7.86 ± 3.34 fold) showed higher AT1 receptor mRNA expression levels than in the early-onset pre-eclamptic (2.13 ± 0.73 fold) and chronic hypertensive (2.63 ± 0.73 fold) groups. Notably, the difference in AT1 receptor mRNA expression level between the early-onset and late-onset pre-eclamptic groups showed a p-value very close to significance (p = 0.0592 fold). In addition, a positive correlation was found between the AT1 receptor concentration and diastolic blood pressure in the late-onset pre-eclamptic group (p < 0.05).

Discussion In this study healthy, normotensive, pregnant women served as an appropriate control by representing the physiological changes that occur during uncomplicated pregnancy, which was a point of reference for the pathological conditions of chronic hypertensive pregnancy and PE. Chronic hypertensive pregnancy was a 3

0.8

VEGF/GAPDH

PIGF conc (pg/ml)

2.0

0.0

1.0

0.6 0.4 0.2 0.0

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N

CH

EO

LO

Fig. 2. Serum placental growth factor (PlGF) concentrations in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 10), and late-onset pre-eclamptic (LO) (n = 9) groups. *Significant difference between normotensive and chronic hypertensive groups. **Highly significant difference between normotensive and early-onset pre-eclamptic groups (p = 0.001).

2

⁕ p < 0.05 ⁕ p < 0.05

1

0

N

CH

EO

LO

Fig. 4. Placental mRNA expression levels of VEGF in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 8) and late-onset (LO) (n = 9) pre-eclamptic groups. *Significant difference (p < 0.05) between the chronic hypertensive and normotensive group, and between the late-onset pre-eclamptic and normotensive group.


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4

40

3

30

AT1/GAPDH

sFIt-1/VEGF

156

2 1 0

N

CH

EO

LO

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20 10 0

N

CH

EO

LO

Fig. 5. Placental mRNA expression levels of sFlt-1/VEGF in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 8) and late-onset (LO) (n = 9) pre-eclamptic groups.

Fig. 7. Mean placental mRNA expression levels of AT1 in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 8) and late-onset (LO) (n = 9) pre-eclamptic groups.

significant reference for the pre-eclamptic groups, indicating that any observations that were common to these groups may be attributed to the high blood pressure that was a common characteristic. Therefore if an observation was made in the pre-eclamptic groups but not the chronic hypertensive group, it could possibly be attributed to the disease pre-eclampsia. The lower gestational ages in the early- and late-onset pre-eclamptic groups in comparison with the normotensive group may have been as a result of early delivery preventing further complications, as the only known cure for the syndrome is delivery of the baby and placenta. As expected, the systolic and diastolic blood pressure measurements in the chronic hypertensive and pre-eclamptic groups were significantly higher than in the normotensive controls. Interestingly, the systolic and diastolic blood pressures in the late-onset pre-eclamptic group were significantly higher than in the chronic hypertensive group, indicating that the hypertension in late-onset PE may be more severe than that of chronic hypertension. This may be attributed to the hypertensioninducing effects of sFlt-1, as previously shown in the murine model.19 Recent reports suggest that hypertension in response to sFlt-1 may be associated with increased circulating vascular superoxide concentrations and that reactive oxygen species could be involved in mediating the blood pressure response to excessive sFlt-1 during pregnancy. It has been suggested that higher serum sFlt1 concentrations could play a role in endothelial dysfunction.10 The serum VEGF levels in all our groups were below the

detectable limit of the assay, which is to be expected in the antenatal period20 and has been shown in previous studies.21 This could have been due to the mopping-up effect of the excessive levels of sFlt-1 that were observed in this study. Interestingly, the highest level of VEGF mRNA expression was found in the normotensive group. The level of VEGF mRNA expression was significantly lower in the late-onset pre-eclamptic group, and very close to being significantly lower in the early-onset pre-eclamptic group (p = 0.051), compared with the normotensive group. These findings could also have been contributing to the VEGF deficiency in the serum of the pre-eclamptic women. Our study therefore concurs with previous reports showing evidence of reduced VEGF expression in the placentae from pregnancies complicated by PE.22-25 Such placentae have previously been shown to exhibit morphometric changes such as altered spiral artery remodelling, deficient growth and differentiation of terminal villi, and reduced foetal capillary branching, which could be attributed to reduced VEGF levels.26 These studies suggest that VEGF may be implicated in the molecular mechanisms in abnormal placental development and is, therefore an important factor involved in the pathogenesis of PE and its complications. We believe that the relatively high VEGF mRNA expression in the normotensive group compared to the pre-eclamptic groups may indicate that VEGF plays a role in ensuring normal placentation in this group. On the other hand, an immunohistochemical study showed that VEGF levels were significantly higher in placental biopsies of patients with PE than normotensive controls,27 while other studies reported no difference in the VEGF mRNA expression levels at term in placentae from pre-eclamptic and normotensive women.28,29 We postulate that the variations could be due to different techniques used for assessments or to different ethnic populations. We also observed the circulating level of PlGF to be significantly higher in the normotensive group compared with the pre-eclamptic groups. This finding has also been shown by other workers.1,30-32 It is well documented that during normal pregnancy, the levels of PlGF increase but are dramatically reduced postpartum, since PlGF is produced by syncytiotrophoblast and extravillous cytotrophoblast cells.33 However, we did not observe any significant differences in placental tissue mRNA expression levels among the four groups. Further studies may help to shed more light on the control of PIGF levels. In the present study, the low serum sFlt-1 levels in chronic hypertensive patients corresponded with the low placental sFlt-

3.5

PIGF/GAPDH

3.0 2.5 2.0 1.5 1.0 0.5 0.0

N

CH

EO

LO

Fig. 6. Placental mRNA expression levels of PlGF in normotensive (N) (n = 30), chronic hypertensive (CH) (n = 9), early-onset (EO) (n = 8) and late-onset (LO) (n = 9) pre-eclamptic groups.


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1 mRNA levels, similar to the normotensive group, whereas in the late-onset pre-eclamptic group, both values were raised. This may indicate that the causes of hypertension in the chronic and late-onset pre-eclamptic groups were not the same and that in the latter group the raised serum sFlt-1 levels could be from other sources. Furthermore, in the early-onset pre-eclamptic group, the serum sFlt-1 level was significantly greater than the normotensive control group yet no significant differences in the placental mRNA expression levels existed between these groups. This may indicate either that there are other sources of sFlt-1 production in early-onset PE other than the placenta, or that the placental tissue sample may not have been a representative sample of placental villi. The serum sFlt-1 concentration in the late-onset pre-eclamptic group was relatively less than in the early-onset pre-eclamptic group. Our results support previous studies showing that alterations in the serum sFlt-1 levels are more pronounced in the early-onset pre-eclamptic group than in the late-onset pre-eclamptic group.34,35 A number of other studies have shown that serum sFlt-1 levels in pre-eclamptic women are increased,7,8,36-38 or unchanged,39 when compared with normotensive patients. These studies, along with ours, suggest that the placenta is possibly a source of circulating sFlt-1.38 In the normotensive group, although the sFlt-1 mRNA expression levels appeared high, the VEGF mRNA expression levels were equally high. Therefore, placental sFlt-1/VEGF mRNA expression ratios were assessed to determine if there was an imbalance between the levels of the angiogenic and antiangiogenic factors. In the normotensive group this ratio was nearer to 1, indicating that the mRNA expression levels of sFlt-1 and VEGF were similar and therefore balanced. On the other hand, the sFlt-1/VEGF mRNA expression ratios in early-onset PE were very close to being significantly higher than the normotensive group. The high serum sFlt-1 levels found in the early- and late-onset pre-eclamptic groups corresponded with the high placental sFlt-1/VEGF mRNA expression ratio, suggesting that the imbalance in angiogenic and anti-angiogenic factors begins at the placental level in early- and late-onset PE, promoting an anti-angiogenic state. Serum sFlt-1 concentrations have been extensively investigated as a key protein that may be involved in the aetiology or as a secondary phenomenon of PE.40,41 Hypoxia is considered to be the cause of the pathological excessive sFlt-1 production in pre-eclamptic placentae.1,42 It is believed that this soluble VEGF receptor 1 or sFlt-1 exerts its anti-angiogenic functions by binding to and inactivating VEGF and PlGF. This is the basis of the antagonistic relationship between sFlt-1 and VEGF. The authority of sFlt-1 lies in the fact that it is capable of upsetting the delicate equilibrium, and tipping the balance towards the anti-angiogenic state in PE. This would, in turn, have a negative effect on the vasculature since VEGF plays crucial roles in important processes such as the control of angiogenesis. Notably, autocrine VEGF has a trophic effect on the endothelium, distinct from its control of angiogenesis. By inhibiting this effect, elevated sFlt-1 levels may lead to systemic endothelial cell dysfunction, which is the hallmark of the maternal stage of PE.43,44 Another meaningful relationship has been demonstrated between sFlt-1 and the RAS.45 In addition to hypoxia causing

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increased sFlt-1 production, recent studies have revealed that AT1 autoantibody induces excess sFlt-1 production, secretion and impaired angiogenesis in PE through undefined mechanisms.11,46 The AT1 autoantibody and hypoxia-induced overproduction of sFlt-1 could activate a dangerous positive feed-forward cycle wherein high sFlt-1 levels severely inhibit angiogenesis and exacerbate the placental hypoxia observed in PE, which subsequently causes an increase in placental sFlt-1 production.40,47 Furthermore, recent studies have shown that AT1 receptor signalling regulates the genes encoding for proteins associated with angiogenesis, such as sFlt-1.47 In this study the AT1 receptor expression levels were relatively lower in the normotensive, chronic hypertensive and early-onset pre-eclamptic groups than in the late-onset pre-eclamptic group. This can be expected in the normotensive group since in normal pregnancies there is a reduced response to vasopressors.48 However, AT1 receptor mRNA expression level in the lateonset pre-eclamptic group was very close to being significantly higher than in the early-onset pre-eclamptic group (p = 0.059), suggesting that the RAS may be implicated in the pathogenesis of PE in this group. This may also indicate that late-onset PE is a different disease from early-onset PE and, therefore may actually be a disease that has a closer association with the RAS than the angiogenic/anti-angiogenic theory, as is the case in early-onset PE. The raised AT1 receptor mRNA expression level in late-onset PE may be due to raised AT1 autoantibodies in this group.40,49 Furthermore, we also found a significant correlation between AT1 receptor mRNA levels and diastolic blood pressure in the late-onset pre-eclampsia group (p < 0.05). Unfortunately, the factors that activate the AT1 receptors, including angiotensin II and the AT1 auto-antibodies were not quantified in this study. Further studies using a larger sample size and measuring AT1 receptor mRNA expressions, AT1 autoantibodies and blood pressure in these two groups are necessary to prove this hypothesis. Interestingly, a recent study showed that the increase in AT1 autoantibodies might represent a better marker for lateonset PE, whereas sFlt-1 is a better marker for early-onset PE.50 To the best of our knowledge, this is the first time it has been shown in black South African women that placental AT1 gene expression levels were relatively elevated in late-onset PE compared with the early-onset pre-eclamptic, normotensive and chronic hypertensive groups. In another study conducted on black South African women, it was shown that the common RAS polymorphisms could not be used to predict PE.51 It has previously been shown that the blunted response to angiotensin II during normal pregnancy is lost in pre-eclamptic patients, who show a hypersensitivity to vasopressors.48 This may imply that there is no quantitative increase in vasopressors, but rather an increase in sensitivity to the existing quantity of vasoactive factors present in pre-eclamptic women. Our study provides proof of this by showing elevated expression of the AT1 receptors in late-onset pre-eclamptic patients compared to the normotensive controls, chronic hypertensive and early-onset pre-eclamptic groups, thereby accounting for the heightened sensitivity to the powerful vasoconstrictor angiotensin II, which is in accordance with previous studies.52,53 Most studies on PE have been conducted on Caucasian participants, and there is a paucity of information on other ethnic groups. It is well documented that socio-demographic


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factors such as race have an influence on the incidence of PE in a population.54 The high incidence of PE in South Africa as well as the increased risk of mortality associated with PE in black women stress the need for research on homogenous population groups. We recommend that future research should also incorporate the investigation of the heterodimerisation of the AT1 and bradykinin B2 receptors in black South African women. Furthermore, the interplay between the angiogenic/anti-angiogenic pathway, RAS and other theories, such as that of oxidative stress and the role of the inflammatory system in PE, should be explored. Two of the limitations of this study were the small sample size that affected the statistical analysis, and the fact we did not measure serum levels of angiotensin II and AT1 autoantibodies.

Conclusion The findings of this study lead us to conclude that the aetiology and pathogenesis of early- and late-onset PE are, to some extent different, especially in our population sample. Our data demonstrate that while a predominance of an anti-angiogenic state may be an important role player in both early- and lateonset PE, in the latter, AT1 receptor up-regulation and the RAS could also play a role. We are grateful to the South African Medical Research Council for financial assistance and the Africa Centre, University of KwaZulu-Natal, for allowing us the use of their laboratories for ELISA studies.

References 1.

Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649–658. 2. Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res 2008; 75: 1–8. 3. Founds SA, Dorman JS, Conley YP. Microarray technology applied to the complex disorder of preeclampsia. J Obstet Gynecol Neonatal Nurs 2008; 37: 146–157. 4. Hawfield A, Freedman BI. Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection. Therapeut Adv Cardiovasc Dis 2009; 3: 65–73. 5. Roberts JM, Gammill H. Pre-eclampsia and cardiovascular disease in later life. Lancet 2005; 366: 961–962. 6. Pottecher J, Huet O, Degos V, Bonnet MP, Gaussem P, Duranteau J, et al. In vitro-induced endothelial oxidative stress and circulating markers of endothelial dysfunction in preeclampsia: an observational study. Hypertens Preg 2009; 28: 212–223. 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. New Engl J Med 2004; 350: 672–683. 8. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004; 191: 1240–1246. 9. Foidart JM, Schaaps JP, Chantraine F, Munaut C, Lorquet S. Dysregulation of anti-angiogenic agents (sFlt-1, PIGF, and sEndoglin) in preeclampsia – a step forward but not the definitive answer. J Reproduc Immunol 2009; 82: 106–111. 10. Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta 2009; 30(Suppl A): S38–42. 11. Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, et al. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res 2007; 100: 88–95. 12. Shah DM. Role of the renin-angiotensin system in the pathogenesis of

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preeclampsia. Am J Physiol Renal Physiol 2005; 288: F614–625. 13. Dechend R, Gratze P, Wallukat G, Shagdarsuren E, Plehm R, Brasen JH, et al. Agonistic autoantibodies to the AT1 receptor in a transgenic rat model of preeclampsia. Hypertension 2005; 45: 742–746. 14. Moodley J. Maternal deaths associated with hypertension in South Africa: lessons to learn from the Saving Mothers report, 2005–2007. Cardiovasc J Afr 2011; 22: 31–35. 15. Perou CM, Jeffrey SS, van de Rijn M, Rees CA, Eisen MB, Ross DT, et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci USA 1999; 96: 9212–9217. 16. Singh R, Mackraj I, Naidoo R, Gathiram P. Sanguinarine downregulates AT1a gene expression in a hypertensive rat model. J Cardiovasc Pharmacol 2006; 48: 14–21. 17. Eisenberg E, Levanon EY. Human housekeeping genes are compact. Trends Genet 2003; 19: 362–365. 18. Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res 1996; 6: 986–994. 19. Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD, et al. The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol 2007; 196: 396 e1–7; discussion e7. 20. Malamitsi-Puchner A, Tziotis J, Protonotariou E, Sarandakou A, Creatsas G. Angiogenic factors in the perinatal period: diversity in biological functions reflected in their serum concentrations soon after birth. Ann NY Acad Sci 2000; 900: 169–173. 21. Semczuk-Sikora A, Krzyzanowski A, Kwiatek M, Semczuk M. [Maternal serum concentration of placental growth factor (PIGF) and endothelial growth factor (VEGF) in pregnancies complicated by preeclampsia]. Ginekologia Polska 2007; 78: 873–876. 22. Sun SG, Shen N, Zheng YH, Shang T. [Expression of hypoxia-inducible factor-1alpha, vascular endothelial growth factor and sFlt-1 in preeclampsia placenta]. Zhonghua fu Chan Ke Za Zhi 2006; 41: 440–444. 23. Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T, Osuga Y, et al. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology 2004; 145: 4838–4845. 24. Cirpan T, Akercan F, Terek MC, Kazandi M, Ozcakir HT, Giray G, et al. Evaluation of VEGF in placental bed biopsies from preeclamptic women by immunohistochemistry. Clin Exp Obstet Gynecol 2007; 34: 228–231. 25. Milovanov AP, Sidorova IS, Solonitsyn AN, Borovkova EI. [Immunohistochemical evaluation of the distribution of vascular endothelial growth factor in the placenta, placental bed in normal pregnancy and in women with preeclampsia]. Arkhiv Patologii 2008; 70: 12–15. 26. Cooper JC, Sharkey AM, Charnock-Jones DS, Palmer CR, Smith SK. VEGF mRNA levels in placentae from pregnancies complicated by preeclampsia. Br J Obstet Gynaecol 1996; 103: 1191–1196. 27. Akercan F, Cirpan T, Terek MC, Ozcakir HT, Giray G, Sagol S, et al. The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia. Arch Gynecol Obstet 2008; 277: 109–114. 28. Ranheim T, Staff AC, Henriksen T. VEGF mRNA is unaltered in decidual and placental tissues in preeclampsia at delivery. Acta Obstet Gynecol Scand 2001; 80: 93–98. 29. Sgambati E, Marini M, Zappoli Thyrion GD, Parretti E, Mello G, Orlando C, et al. VEGF expression in the placenta from pregnancies complicated by hypertensive disorders. Br J Obstet Gynaecol 2004; 111: 564–570. 30. Kulkarni AV, Mehendale SS, Yadav HR, Kilari AS, Taralekar VS, Joshi SR. Circulating angiogenic factors and their association with birth outcomes in preeclampsia. Hypertens Res 2010; 33: 561–567. 31. Dwyer BK, Krieg S, Balise R, Carroll IR, Chueh J, Nayak N, et al. Variable expression of soluble fms-like tyrosine kinase 1 in patients at high risk for preeclampsia. J Matern Fetal Neonatal Med 2010; 23: 705–711. 32. Tjoa ML, Levine RJ, Karumanchi SA. Angiogenic factors and preeclampsia. Front Biosci 2007; 12: 2395–2402.


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33. Mittal P, Espinoza J, Hassan S, Kusanovic JP, Edwin SS, Nien JK, et al. Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia. J Matern Fetal Neonatal Med 2007; 20: 651–659. 34. Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W. Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol 2006; 195: 255–259. 35. Wikstrom AK, Larsson A, Eriksson UJ, Nash P, Norden-Lindeberg S, Olovsson M. Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol 2007; 109: 1368–1374. 36. Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol 2006; 194: 1034–1041. 37. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, et al. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab 2005; 90: 4895–4903. 38. Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. A Rev Med 2008; 59: 61–78. 39. Savvidou MD, Yu CK, Harland LC, Hingorani AD, Nicolaides KH. Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction. Am J Obstet Gynecol 2006; 195: 1668–1673. 40. Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the ‘chicken-and-egg’ question. Endocrinology 2004; 145: 4835–4837. 41. Karumanchi SA, Epstein FH. Placental ischemia and soluble fms-like tyrosine kinase 1: cause or consequence of preeclampsia? Kidney Int 2007; 71: 959–961. 42. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160: 1405–1423. 43. Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD,

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et al. Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol. 2007; 109: 1316–1324. Smith GC, Wear H. The perinatal implications of angiogenic factors. Curr Opin Obstet Gynecol 2009; 21: 111–116. Hirokoshi K, Maeshima Y, Kobayashi K, Matsuura E, Sugiyama H, Yamasaki Y, et al. Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia. Nephron 2007; 106: c43–50. Zhou CC, Ahmad S, Mi T, Abbasi S, Xia L, Day MC, et al. Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 2008; 51: 1010–1019. Irani RA, Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29: 763–771. Anguiano-Robledo L, Reyes-Melchor PA, Bobadilla-Lugo RA, PerezAlvarez VM, Lopez-Sanchez P. Renal angiotensin-II receptors expression changes in a model of preeclampsia. Hypertens Preg 2007; 26: 151–161. Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM, et al. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 2007; 49: 612–617. Herse F, Verlohren S, Wenzel K, Pape J, Muller DN, Modrow S, et al. Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational agematched case study. Hypertension 2009; 53: 393–398. Roberts CB, Rom L, Moodley J, Pegoraro RJ. Hypertension-related gene polymorphisms in pre-eclampsia, eclampsia and gestational hypertension in black South African women. J Hypertens 2004; 22: 945–948. Wang Y, Gu Y, Lewis DF. Endothelial angiotensin II generation induced by placenta-derived factors from preeclampsia. Reproduct Sci 2008; 15: 932–938. Doering TP, Haller NA, Montgomery MA, Freeman EJ, Hopkins MP. The role of AT1 angiotensin receptor activation in the pathogenesis of preeclampsia. Am J Obstet Gynecol 1998; 178: 1307–1312. Smith RA, Baker PN. Risk factors, prevention and treatment of hypertension in pregnancy. Minerva Ginecolog 2005; 57: 379–388.


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Review Articles Cardiac surgery risk-stratification models CARLA PRINS, I DE VILLIERS JONKER, LEZELLE BOTES, FRANCIS E SMIT

Abstract Risk models are widely used to predict outcomes after cardiac surgery. Not only is risk modelling applied in the assessment of the relative impact of specific risk factors on surgical outcomes, but also in patient counselling, the selection of treatment options, comparison of postoperative results, and quality-improvement programmes. At least 19 risk-stratification models exist for open-heart surgery. The focus of risk models was originally on pre-operative prediction of mortality. However, major morbidity is in general more common than mortality and the ability to predict only operative mortality is not an adequate method of determining surgical outcome. Multiple intra- and postoperative variables have been excluded in the majority of models and the possible effect of their future inclusion remains to be seen. The unique patient population of sub-Saharan Africa requires a unique risk model that reflects the patient population and levels of care. Keywords: risk-stratification models, open-heart surgery, intraand postoperative variables, surgical outcomes Submitted 15/9/10, accepted 6/9/11 Cardiovasc J Afr 2012; 23: 160–164

www.cvja.co.za

DOI: 10.5830/CVJA-2011-047

Risk models are widely applied in the assessment of the relative impact of specific risk factors on surgical outcomes. These models enable surgeons to select the ideal treatment option for a specific patient and to counsel patients accordingly. They allow for comparison of postoperative results and assist in assessment of quality-improvement programmes.1,2 One of the original aims for the development of cardiac risk models was risk adjustment, allowing fair comparison of treatment outcomes among different institutions or surgeons.2 Risk models were then also applied in clinical decision making, advising individual patients of their peri-operative risk, qualityimprovement programmes comparing year-to-year outcomes, as well as allocation of healthcare resources through the prediction of length of stay and postoperative complication rates.1,3 Department of Cardiothoracic Surgery, University of the Free State, Bloemfontein, South Africa

CARLA PRINS, BMed Sc (Hons), carla.prins@integriumsa.co.za I DE VILLIERS JONKER, MD, devilliers.jonker@ualberta.ca FRANCIS E SMIT, MB ChB, MMed

School of Health Technology, Central University of Technology, Bloemfontein, South Africa LIZELLE BOTES, DTech

The first widely used risk model, the Parsonnet score, was based on a retrospective analysis of data collected during the 1980s.1,4 Risk modelling since then has been significantly influenced by advances made in diagnostic and interventional technology. The advances in interventional cardiology are believed to have adversely changed the risk profile of patients presenting for cardiac surgery. A greater number of elderly patients, those with associated illnesses, and patients presenting for re-operation are now seen.3,5 At least 19 risk-stratification models exist for open-heart surgery.4 These models are summarised in Table 1. The focus of risk models was originally on pre-operative prediction of mortality. However, major morbidity is in general more common than mortality, and the ability to predict only operative mortality is not an adequate method of determining surgical outcome.6 Risk modelling has therefore now in some instances, for example the STS score, been expanded to also allow for the calculation of postoperative morbidity.1 The assessment of variables that may affect patient outcome, which are not necessarily related to pre-operative patient characteristics, are also often not taken into account. These variables include factors related to the skill and experience of the surgical and postoperative care teams, which in turn influence various aspects of the intra-operative and immediate postoperative period.1 Knowledge of adverse intra-operative events has been shown to enhance pre-operative risk prediction, and it is reasonable and necessary to include these variables in risk models.7 Cardiac risk models are generally comparable with regard to the pre-operative risk factors included. The most widely used models (e.g. EuroSCORE) were usually designed for various cardiac surgical procedures and cannot necessarily account for co-morbid diseases and aspects of the underlying pathophysiology/disease progression not included in the calculation of risk.1 However, over-complication of models has also received a lot of criticism from strong supporters of the concept that ‘simple models will sometimes outperform more complex models...’.8 Nevertheless, when the problem is complex, deliberate limitation of the complexity of a model may be unproductive.8 The objective of this article is to provide a review of the most common currently used risk-stratification models in cardiac surgery, with critique in general that relates to practice in sub-Saharan Africa.

Currently used models There are a number of risk-stratification models in cardiac surgery. Three of the most widely used models, applicable to


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multiple cardiac procedures, include the European System for Cardiac Operative Risk Evaluation (EuroSCORE), the Society of Thoracic Surgeons (STS) algorithms, and the Parsonnet score.1 These will be briefly discussed.

The European System for Cardiac Operative Risk Evaluation Combining the most important pre-operative risk factors, the EuroSCORE method has been shown to be a valuable measure for prediction of immediate death after adult cardiac surgery.9 It has been studied widely and is believed by many to be the gold standard.1 The clinical aim of the logistic EuroSCORE was to construct a scoring system predicting early mortality in cardiac surgical patients in Europe on the basis of objective risk factors.3 It was developed from a large European database and eventually included 13 302 patients.3 Prospective data collection took place in eight European countries between September and December of 1995.10 The EuroSCORE provides two methods for calculating predicted outcome: the additive model and the logistic model.3 Validation of the EuroSCORE took place all over the world in a variety of population settings.1,11,12 The logistic EuroSCORE uses logistic regression and the risk has to be calculated in a very complex way. The simpler additive model was derived from the full logistic model by approximating the odds ratios (OR) or

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modified coefficients from the logistic equation with integers, which can then be added together at the bedside to provide a useful estimate of risk in an individual patient.13,14 Although well established and validated in patient populations, the additive EuroSCORE sometimes underestimates the risk when certain combinations of risk factors co-exist.14 The logistic EuroSCORE on the other hand, has been reported by various centres to over-predict risk despite gradual worsening of the risk profiles of patients and the improvement in cardiac surgical outcomes observed.15 Although the additive model is easier to use, the logistic EuroSCORE has been reported to have a better risk-predictor ability, especially in high-risk patient groups.16,17 The logistic EuroSCORE lacks the prediction of possible morbidity and does not include any intra-operative variables. Evidence that the EuroSCORE might be out of date led to the collection of new data to enable re-evaluation. Data collection started early in 2010. It was estimated that if enough centres participated, data collection would only take three weeks, but the longest period asked for would be three months.18

The Society of Thoracic Surgeons Algorithms The Society of Thoracic Surgeons National Cardiac Database (STS NCD) was created in 1989 and it has become the largest clinical database of its kind. The primary aim for the development of the STS model was the support of national quality-improvement programmes. Now it is also used for

TABLE 1. A SUMMARY OF CARDIAC SURGERY RISK-STRATIFICATION MODELS4,31 (WITH PERMISSION) Year of data Number of patients Model Region collection Year of publication (centres) Risk variables Amphiascore Netherlands 1997-2001 2003 7 282 (1) 8 Cabdeal Finland 1990-1991 1996 386 (1) 7 Cleveland Clinic USA 1986-1988 1992 5 051 (1) 13 EuroSCORE (additive) Europe 1995 1999 13 302 (128) 17 EuroSCORE (logistic) Europe 1995 1999 13 302 (128) 17 French score France 1993 1995 7 181 (42) 13 Magovern USA 1991-1992 1996 1 567 (1) 18 NYS USA 1998 2001 18 814 (33) 14 NNE USA 1996-1998 1999 7 290 (N/A) 8 Ontario Canada 1991-1993 1995 6 213 (9) 6 Parsonnet USA 1982-1987 1989 3 500 (1) 16 Parsonnet (modified) France 1992-1993 1997 6 649 (42) 41 Pons Spain 1994 1997 1 309 (7) 11 STS risk calculator* USA 2002–2006 2007 isolated CABG 774 881 (819) 49 valve procedures 109 759 50 CABG and valve 101 661 50 Toronto Canada 1993-1996 1999 7 491 (2) 9 Toronto (modified) Canada 1996-1997 2000 1 904 (1) 9 Tremblay Canada 1989-1990 1993 2 029 (1) 8 Tuman USA N/A 1992 3 156 (1) 10 UK national score UK 1995-1996 1998 1 774 (2) 19 Veterans Affairs USA 1987-1990 1993 12 712 (43) 10 USA = United States of America, EuroSCORE = European System for Cardiac Operative Risk Evaluation, NYS = New York State, NNE = Northern New England, STS = Society of Thoracic Surgeons, CABG = coronary artery bypass graft surgery, UK = United Kingdom. *The STS risk calculator consists of seven risk-prediction models in three main categories, namely isolated CABG, valve procedures, and combined CABG and valve procedures. Data represented for the STS risk calculator reflect the number of patients and risk variables captured in the database used for the latest models developed (version 2.61).


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research focusing on improvement of patient care and outcome.19 The STS NCD is unparalleled in terms of its size and comprehensiveness: data were collected prospectively from more than 950 participating centres in the United States.3,20 The STS NCD now also includes more than 3.6 million surgical procedures.20 STS risk models for various cardiac procedures have been developed since 1999 and have undergone periodic revisions.1,20 A wide variety of endpoints are included in some of the models calculating risk for isolated coronary artery bypass grafting, valve surgery or combined surgeries.1 Twenty-seven new STS adult cardiac surgery models for 2008 have been developed and validated.21 The predictive performance of the STS algorithms is in general comparable with other systems and remains the most widely used model in the United States.1,3 The STS NCD also does not predict possible morbidity and does not include relation to any intra-operative variables.

Parsonnet score The Parsonnet score was first described in 1989 by Victor Parsonnet. The aim was to construct a straightforward uniform reporting system for levels of operative mortality risk in all cardiac surgical procedures, which included data that are readily available. It includes objective risk factors in order to leave little room for bias.3 Development took place in the United States and included data from 3 500 patients collected between 1982 and 1987. Retrospectively, analyses included uni- and multivariate logistic regression models. The model was prospectively tested in an additional 1 332 procedures at a single site. A second, additive model was also developed. This method was tested at two other centres and the outcomes were comparable to those of the hospitals.3 The Parsonnet score received widespread acceptance, but the predictive accuracy has been diminished as a result of advances in treatment.1 The original score was later modified in 1994 to include 30 new risk factors, according to the SUMMIT system, and is known as the ‘modified Parsonnet score’.22 Again, no morbidity or relation to intra-operative events are being predicted.

Major critique of current models In recent years, several models have predicted a rising probability of operative mortality while the observed mortality has decreased.23 This is due to an increasing prevalence of highrisk patients, believed to be attributed to significant advances made in diagnostic and interventional cardiology.3,5 Risk models from earlier periods (or retrospectively collected data) can as a result not be used when the goal of the outcome analysis includes determination of the trend of mortality over time. Retrospective data do not only fail to take into calculation the advances in treatment, but also the evolution of the case mix. Therefore, the gold standard for data collection should be speciality-specific, prospectively maintained clinical databases that ought to contain a core set of variables that have been demonstrated to be associated with outcome.24 It is furthermore believed that risk models usually predict outcome more accurately in the setting where it was originally

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developed.5 Socio-economic conditions, living standards, healthcare funding, and geographic and ethnic origins affect the applicability of risk models in different regions.3 To date no sub-Saharan African country has developed a risk-stratification model applicable to the unique pathology of their native population. Risk models have diverse clinical aims. The choice of inclusion/exclusion of risk factors as well as the number of risk factors included in the model is influenced by the clinical aim.25 Variables that may affect patient outcome but which are not necessarily related to pre-operative patient characteristics are often not taken into account. These include variables related to adverse intra-operative events as well as co-morbid diseases and aspects of the disease progression not included in the calculation of risk.1 There is no general agreement about the inclusion and exclusion of these factors.8 Risk factors associated with outcomes generally are likely to reflect concurrent, disease-specific variables whereas factors associated with increased resource utilisation reflect serious co-morbid disease.26 It has been suggested that the strength of scores should be that some kind of grouping is provided for patient cohorts.27 Models are sometimes criticised for multicollinearity. Intercorrelations between independent variables included in risk models are known as multicollinearity (e.g. obesity and diabetes mellitus). Including large numbers of independent variables increases the risk of multicollinearity and the consequent inclusion of redundant information in the model.8 Excessively complex models with too many variables will appear to have an extremely good fit in the training set, but generalise poorly to test samples and have limited predictive abilities. This is known as overfitting.18 It is recommended that instead of including all statistically significant variables, one should confine the model to the most powerful predictors or combinations of variables that are the most powerful predictors.8 Different operators will provide different interpretations to categorical risk factors, such as chronic obstructive pulmonary disease and unstable angina. Even with clearly stated definitions, a degree of personal interpretation takes place, resulting in different final risk scores.8 Wherever practical, continuous data should be used and there should be strict standardisation of definitions for the risk factors and the outcomes measured.18 Some models have been criticised for not being able to predict individual risk. Currently utilised models are derived from the studies of very large populations and although very effective at predicting population outcomes, are not necessarily suited for the prediction of risk of an individual patient.1,26 As previously stated, it is generally accepted that the number of independent variables that can be included in a multivariate logistic regression depends on the number of events: there should be a variable-to-event ratio of 1:10 .8,25 For that reason, to contemplate a 15 risk-factor model with a mortality rate of 3%, at least 5 000 cases are required to achieve adequate sample size.25 This also means that even in a unit performing 500 surgeries per annum, it would take at least 10 years to meet the required sample size. Most of the scores are unsuitable for individual risk prediction despite the sample size. This is due to a simple methodological reason: the application of logistic regression models mathematically describes a multiphasic, more complex behaviour of a survival curve that cannot achieve enough


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statistical power to achieve enough statistical accuracy for individual predictions.27 Lastly, the focus of cardiac risk models was originally on pre-operative prediction of mortality, but complications and potentially preventable morbidity are also important outcomes.1,3 Ideally, a range of outcomes should be reported: mortality, morbidity, changes in functional status and quality of life, cost of care as well as patient-reported perceptions of the non-technical aspects of care.3

Discussion Open-heart surgery is one of the most expensive surgical procedures in a hospital. The cost of surgery can vary enormously between patients with an uncomplicated recovery and those who suffer from postoperative complications.28 Risk stratification is not only essential for improvement of surgical outcomes, but also allows quality analysis and meaningful comparison of outcomes. Kolh (2006) stated that it should be an integral part of cardiac surgical practice, and quoted ‘... being as essential to the surgeon as the knowledge of anatomy and techniques’. Clinical research and treatment strategies of cardiovascular disease as well as risk-prediction models have largely been developed in North America and Europe. However, the applicability of results derived from these investigations is unknown.29 Popular risk models have been studied extensively around the world. Of these models, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) has been validated in different population settings and remains for many, the gold standard.1,12 Even though the mortality outcome predicted with the EuroSCORE seems applicable in South African practice, different stages of epidemiological transition are often at work in South Africa and changing patterns in the development of cardiovascular disease are observed in the various ethnic populations.11,30 Predictions of postoperative recovery in the South African setting are therefore less well established. Given the economic impact of interventional therapy and complications related to intervention, it is incumbent on clinicians in South Africa to ensure the optimal application of interventional therapy and resource allocation. As a result, cardiac surgeons in South Africa face three options with regard to risk stratification: to simply use external risk scores, knowing that the identified risks and attributed weights might not correctly reflect their patient population; to adjust the weight of the risk factors on the basis of their own data; or to derive a new internal model from their own data and recalibrate it periodically.8 Despite continuous research, no perfect risk-prediction model exists and the shortcomings of the different models and criticism of the modelling processes have been comprehensively discussed.1,3,25 Variables that may affect patient outcome but which are not necessarily related to pre-operative patient characteristics, are often not taken into account. These include the skill and experience of the surgical and postoperative care team, which influences various aspects of the intra-operative and immediate postoperative period.1 For that reason, current risk-stratification models can only score the risk of care and not the quality of suitable care.

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Conclusion It is our hypothesis that the development of an integrated model that includes hitherto unutilised intra-operative risk factors as well as other known peri-operative risk factors predictive of outcome should enable more accurate risk stratification and consequently improved quality management of surgical treatment of patients with cardiovascular disease in the South African setting. Such a model would allow for improved clinical decision making, assessment of surgical performance and quality of care. Increasing efficiency through prediction of postoperative complications would ultimately facilitate decisions to operate, allocate resources and estimate costs.28

References 1. 2.

3. 4.

5. 6.

7.

8.

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Granton J, Cheng D. Risk stratification models for cardiac surgery. Semin Cardiothorac Vasc Anesth 2008; 12(3): 167–174. Shahian DM, Blackstone EH, Edwards FH, Grover FL, Grunkemeier GL, Naftel DC, et al. Cardiac Surgery Risk Models: A Positon Article. Ann Thorac Surg 2004; 78: 1868–1877. Heijmans JH, Maessen JG, Roekaerts HJ. Risk stratification for adverse outcome in cardiac surgery. Eur J Anaesth 2003; 20: 515–527. Nilsson J, Algotsson L, Hoglund P, Luhrs C, Brandt J. Comparison of 19 preoperative risk stratification models on open-heart surgery. Eur Heart J 2006; 27: 867–874. Kolh P. Importance of risk stratification models in cardiac surgery. Eur Heart J 2006; 27: 768–769 Chong C-F, Li Y-C, Wang T-L, Chang H. Stratification of adverse outcomes by preoperative risk factors in coronary artery bypass graft patients: An artificial neural network prediction model [online]. AMIA Ann Symp Proc 2003; 160–164. Available from: http://pubmedcentral. nih.gov/articlerender.fcg?artid=1480326. [Accessed 13.03.2008]. Stoica SC, Sharples LD, Ahmed I, Roques F, Large SR, Nashef SAM. Preoperative Risk Prediction And Intraoperative Events In Cardiac Surgery. Eur J Cardiothorac Surg 2002; 21: 41–46. Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Risk of asessessing mortality risk in elective cardiac operations – age, creatinine, ejection fraction, and the law of parsimoy. Circulation 2009; 119: 3053–3061. Biancari F, Kangasniemi O-P, Luukkonen J, Vuorisalo S, Satta J, Pokela R, Juvonen T. Euroscore predicts immediate and late outcome after coronary artery bypass surgery. Ann Thorac Surg 2006; 82: 57–61. Roques F, Nashef SAM, Michel P, Gauducheau E, Vincentiis C, Baudet E, et al. Risk factors and outcome in European cardiac surgery: Analysis of the Euroscore multinational database of 19030 patients. Eur J Cardiothorac Surg 1999; 15: 816–823. Swart MJ, Joubert G. The Euroscore does well for the surgeon outside Europe (Letter to the Editor). Eur J Cardiothorac Surg 2004; 25: 145. Cortina Romero JM. Criteria for using risk models in cardiac surgery. Rev Esp Cardiol 2008; 61(6): 567–571. Jin R, Grunkemeier GL. Additive vs. logistic risk models for cardiac surgery mortality. Eur J Cardiothorac Surg 2005; 28: 240–243. European System For Cardiac Operative Risk Evaluation (EuroSCORE). What is EuroSCORE [online]. Available from: http://www.euroscore. org/what_is_euroscore.htm. [Accessed: 09.12.2010]. Nashef SAM. The new EuroSCORE project. Kardiol Pol 2010; 68: 128–129. Michel P, Roques F, Nashef SAM, The EuroSCORE Project group. Logistic or additive EuroSCORE for high risk patients? Eur J Cardiothorac Surg 2003; 23: 684–687. Zingone B, Pappalardo A, Dreas L. Logistic versus additive EuroSCORE. A comparative assessment of the two models in an independent population sample. Eur J Cardiothorac Surg 2004; 26: 1134–1140. European System for Cardiac Operative Risk Evaluation (EuroSCORE). New EuroSCORE 2010 [online]. Available from: http://www.euroscore. org/EuroSCORE2010.htm. [Accessed: 09.03.2010].


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19. Welke KF, Ferguson TB (jnr), Coombs LP, Dokholyan RS, Murray CJ, Schrader MA, Peterson ED. Validity of the Society of Thoracic Surgeons national adult cardiac surgery database. Ann Thorac Surg 2004; 77(4): 1137–1139. 20. Shahian DM, O’Brien SM, Filardo G, Ferraris VA, Haan CK, Rich JB, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: Part 1 – coronary artery bypass grafting surgery. Ann Thorac Surg 2009; 89(1) Suppl 1: S2–S22. 21. Shahian DM, Edwards FH. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: Introduction. Ann of Thorac Surg 2009; 88(1) Suppl 1: S1. 22. Hattler BG, Madia C, Johnson C, Armitage JM, Hardesty RL, Kormos RL, et al. Risk stratification using the Society of Thoracic Surgeons programme. Ann Thorac Surg 1994; 52: 1348–1352. 23. Ivanov J, Tu JV, Naylor CD. Ready-made, recalibrated, or remodelled? Circulation 1999; 99: 2098–2104. 24. Shahian DM, Blackstone EH, Edwards FH, Grover FL, Grunkemeier GL, Naftel DC, et al. Cardiac surgery risk models: A positon article. Ann Thorac Surg 2004 78: 1868–1877. 25. Omar RZ, Ambler G, Royston P, Eliahoo J, Taylor KM. Cardiac surgery risk modelling for mortality: A review of current practice and suggestion for improvement. Ann Thorac Surg 2004; 77: 2232–2237.

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26. Ferraris VA, Ferraris SP. Risk stratification and comorbidity. In Cohn LH, Edmunds LH (jun) (eds). Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003; 187–224. 27. Gummert JF, Funkat A, Osswald B, Beckmann A, Schiller W, Krian A, et al. EuroSCORE overstimates the risk of cardiac surgery: Results from the national registry of the German Society of Thoracic and Cardiovascular Surgery. Clin Res Cardiol 2009; 98: 363–369. 28. Kurki TS, Hakkinen U, Lauharanta J, Ramo J, Leijala M. Evaluation of the relationship between preoperative risk scores, postoperative and total length of stays and hospital costs in coronary bypass surgery. Eur J Cardiothorac Surg 2001; 20: 1183–1187. 29. Steyn K, Sliwa K, Hawken S, Commerford P, Onen C, Damasceno A, et al. for the INTERHEART investigators in Africa. Risk factors associated with myocardial infarction in Africa. Circulation 2005; 112: 3554–3561. 30. Opie LH, Mayosi BM. Cardiovascular disease in sub-Saharan Africa. Circulation 2005; 112: 3536–3540. 31. The Society of Thoracic Surgeons (STS). STS Web Risk Calculator Descriptor v2.61 [online]. Available from: http://209.220.160.181/ STSWebRiskCalc261/de.aspx. [Accessed 09.12.2010].

Cardiovascular congress diary Date

Conference

Venue

Contact details to register

30 March – 2 April

Cardiology and Diabetes at the Limits

University of Cape Town

www.atthelimits.org

10–13 April

Echocardiography course

Protea Hotel, Stellenbosch

www.sunecho.co.za

18-21 April

World Congress of Cardiology

Dubai, United Arab Emirates

www.world-heart-federation.org

21 April

Pain Symposium 2012

Johannesburg, South Africa

www.painsa.co.za

3–5 May

EuroPRevent

Dublin, Ireland

www.escardio.org/congresses/europrevent-2012

5 May

LAA 2012 Asia–Pacific

Singapore

www.csi-laa.org

17–20 May

Congress on Cardiac Problems in Pregnancy (CPP 2012)

Berlin, Germany

www.cppcongress.com

18/20 May

1st Annual Congress of the Faculty of Consulting Physicians of South Africa Internal Medicine SA

CTICC, Cape Town, South Africa

www.physician.co.za

8–9 June

CCC 2012 – Cardiovascular Complications Conference

Frankfurt, Germany

www.complications2012.org

27 June

ICI 2012 – Imaging in Cardiovascular Interventions

Frankfurt, Germany

www.ici-congress.org

28–30 June

CSI 2012 – Catheter Interventions in Congenital & Structural Heart Disease

Frankfurt, Germany

www.csi-congress.org

9–12 July

18th World Congress of the International Society for the Study of Hypertension in Pregnancy

Geneva, Switzerland

www.isshp2012.com

13–15 July

ASEAN Federation of Cardiology Congress (AFCC)

Singapore

www.afcc2012.com

19–22 Jul y

13th Annual SA Heart Congress

Sun City, South Africa

www.saheart.org

2012 ESC, European Society of Cardiology Congress

Munich, Germany

www.escardio.org

Trend 2012 Asia–Pacific

Hong Kong

www.csi-trend.org

5 October

New Horizons in Echocardiography

Sandton, South Africa

baraecho@gmail.com

10–13 October

8th World Stroke Congress

Brasilia, Brazil

www.2.kenes.com/stroke/pages/home.aspx

20 October

The Many Faces of AF symposium

Cape Town, South Africa

franciska@cassa.co.za

20–22 October

Acute Cardiac Care

Istanbul, Turkey

www.escardio.org

24 October

The Many Faces of AF symposium

Durban, South Africa

franciska@cassa.co.za

27 October

The Many Faces of AF symposium

Johannesburg, South Africa

franciska@cassa.co.za

3–7 November

American Heart Association Scientific Sessions

Los Angeles, US

www.americanheart.org

16–17 November

LAA 2012

Frankfurt, Germany

www.csi-laa.org

The 16th Annual EUROECHO and other imaging modalities

Athens, Greece

www.euroecho.org

APRIL 2012

MAY 2012

JUNE 2012

JULY 2012

AUGUST 2012 25–29 August SEPTEMBER 2012 29 September OCTOBER 2012

NOVEMBER 2012

DECEMBER 2012 5–8 December

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


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The challenges of cardiac surgery for African children ANA OH MOCUMBI

Abstract

Rheumatic heart valve disease

In Africa the specific pattern of cardiovascular diseases and lack of adequate measures for disease prevention and control result in the frequent need for open-heart surgery for the management of complications of cardiomyopathies in children. Several strategies and innovative ways of providing cardiovascular surgical care in African countries have been used, from agreements to send patients overseas, to programmes for the creation of local services to provide comprehensive care locally. This article attempts to outline the challenges faced by underdeveloped countries in Africa wanting to embark on programmes of cardiac surgery and the need for several sectors of society to play a role in the process. It discusses issues related to the establishment of centres performing cardiac surgery in Africa, describes the treatment of congenital heart disease, and reviews the aspects of management of conditions highly prevalent in or mostly confined to this continent, such as rheumatic heart valve disease and endomyocardial fibrosis.

Although preventable, RHVD is still a very common condition in Africa, affecting young people and progressing quickly to severe forms that need heart valve surgery.1 Patients usually present in a poor general and nutritional condition, increasing the operative risk, and multiple lesions are frequent, requiring sub-optimal solutions on many occasions.2 Valve replacement presents a dilemma due to the generalised lack of adequate facilities for anticoagulation. Of major importance also are the issues related to the logistics of rheumatic fever prophylaxis, prevention of infective endocarditis and contraception in poor and remote areas. These factors lead to results that suggest that surgery for rheumatic heart valve disease in children is essentially a palliative procedure.2 In African studies researching the epidemiology of RHVD, the most frequent lesion is pure mitral valve regurgitation.3 This is in contrast with data from the developed world, where haemodynamically severe rheumatic mitral valve disease generally presents in the fourth decade or later, with thickened valve leaflets usually manifesting as mitral stenosis with or without concurrent regurgitation.4 The aortic valve is the second most frequently affected, but tricuspid regurgitation is also very common due to late diagnosis, when severe mitral and/or aortic disease cause pulmonary hypertension and dilatation of the right ventricle. The choice of surgical technique is challenging and the results of valve repair performed during the active phase of rheumatic heart disease preclude a durable long-term result,4 highlighting the importance of correct pre-operative evaluation and preparation. Mitral valve repair is advised whenever technically feasible to maximise survival and reduce morbidity, even considering that good surgical results are inversely related to age,5 and that there is a risk of early re-operation due to inadequate secondary prophylaxis. On the other hand, while it has been recognised that good results can be achieved in children without the use of annuloplasty rings,6 the advantages of this strategy need to be confirmed in the long term. Regarding treatment of the aortic valve, the Ross procedure has advantages in young and deprived populations since use is made of autologous and living tissue, there is excellent haemodynamics, allowance is made for growth and there is no need for anticoagulation. However, it also has some drawbacks, namely the need for homography in the pulmonary position and the fact that it is a technically demanding procedure. Some authors feel that the Ross operation it is not suitable for young patients with RHVD. Although there is no sudden dilatation in children, some degree of aortic regurgitation appears in up to 18.3% after 2.4 years of follow up, and it is known that young age and associated mitral valve disease are significant risk factors for autograft failure.7 Finally, rheumatic involvement of the autograft has been reported, leading some to contraindicate the Ross operation in young patients with rheumatic heart valve disease.8,9 However, we feel that in Africa, it still the most valuable option for management of aortic disease

Keywords: paediatric cardiology, cardiac surgery, Africa Submitted 12/8/09, accepted 24/2/12 Cardiovasc J Afr 2012; 23: 165–167

www.cvja.co.za

DOI: 10.5830/CVJA-2012-013

Adequate measures for disease prevention and control are difficult to implement in Africa due to low levels of literacy, and poor sanitation and governance. On the other hand, timely diagnosis and management of cardiovascular diseases is hampered by shortage of qualified human resources and financial constraints. For these reasons, surgery is frequently needed for the management of cardiac conditions in African children. Cardiac surgery imposes a huge burden on limited healthcare resources and is therefore not available in most sub-Saharan countries. Where it is available, surgery is performed in small numbers due to financial constraints and shortage of human resources. Therefore, several countries are running collaborative programmes between local institutions and teams from Europe and America, mostly sponsored by local or international non-governmental organisations. We review here the challenges of surgical management of conditions that affect predominantly children, which are either highly prevalent in or confined to the African continent, namely rheumatic heart valve disease (RHVD), congenital heart disease (CHD) and endomyocardial fibrosis (EMF).

Instituto do Coração, Maputo, Mozambique

ANA OH MOCUMBI, MD, amocumbi@gmail.com


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in females. The double autograft, also considered in poor settings due to shortage of homographs, needs high levels of surgical skill and increases the operative risk.

Congenital heart disease There is a large underserved population of children with congenital heart disease in Africa, since most paediatric services are oriented to the diagnosis and management of endemic infectious diseases, and there is a shortage of trained personnel capable of diagnosing congenital heart defects, resulting in late diagnosis, usually in the presence of heart failure, pulmonary hypertension and severe polycythaemia. The number of facilities for cardiac surgery is also small and, as a result, there is a wide range of native abnormalities.10 Malformations ranked as the second most common form of heart disease, with a frequency of 26% among black patients of all ages in hospital-based studies, which also revealed that congenital cardiac defects were the dominant conditions rather than rheumatic or other acquired heart diseases.10 In this study, the mean age at referral to a paediatric cardiologist was high and a pattern of late presentation was found with under-representation of lesions that have a high mortality in infancy, suggesting that a significant number of patients miss the opportunity to have optimal surgical intervention. Several paediatric hospital series show the importance of CHD in Africa. These conditions ranked first, with a frequency of 53% in a series from South Africa that considered only children aged 15 years or under,11 and are responsible for one-quarter of the cases of heart failure in Ibadan.12 The predominant lesions are ventricular septal defect, tetralogy of Fallot and patent ductus arteriosus.10,11 In Africa, surgery for CHD is frequently performed in adults or adolescents, in whom the operative risks are increased and related to myocardial fibrosis and irreversible pulmonary changes. The main reasons for late surgery are late diagnosis, time delay between the diagnosis and actual surgery, loss to follow up, and refusal of surgery earlier in life. The choice between complete repair and two-stage ‘palliative + corrective’ procedures in underdeveloped countries may be influenced by socio-economic factors affecting the physical condition of the patient. Palliation by pulmonary artery banding, atrial septectomy or a systemic–pulmonary shunt is still preferable in those conditions in which total correction in infancy carries a high risk or is not feasible. On the other hand, palliative procedures may constitute a way of selecting those patients in whom eventual complete correction would be justified.13 However, if inadequately performed, pulmonary artery band and systemic–pulmonary shunt may adversely affect outcome and demand further aggressive management prior to definitive repair.14

Endomyocardial fibrosis EMF is a disease of unknown aetiology, characterised by fibrosis and thickening of the mural endocardium and valvular apparatus, causing restriction to ventricular filling and severe atrioventricular valve dysfunction. The disease has several forms and can be classified haemodynamically as predominantly restrictive when it affects mainly the mural endocardium, predominantly valvular when the subvalvular apparatus is severely affected,

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or mixed when both restrictive and valvular lesions are present. There is no effective treatment for EMF. Surgery is indicated for patients in NYHA class III/IV but is technically very demanding and has been associated with high morbidity and mortality, especially when predominantly murally affected. The initially described Dubost technique15 has been evolving to reduce the complications associated with valve replacement and radical endocardectomy, mostly low-cardiac output syndrome and complete atrio-ventricular block. An atrial approach is the most frequently used but offers poor visualisation of the apex and lateral wall of the left ventricle. Therefore apical ventriculotomy or a transaortic–transatrial approach may be needed when complete endocardial resection is required in those regions.16 The post-operative period demands intensive-care management in patients with poor nutritional status and longstanding heart failure. The early mortality was initially around 20% but has now been reduced to 10%.17-19 This is mainly caused by incapacity to wean from cardiopulmonary bypass, low-cardiac output syndrome, cerebral embolism, arrhythmias, renal failure and pulmonary embolism.17,20,21 In the immediate post-operative period, re-interventions may be needed as a rescue procedure in patients with right heart failure and low-cardiac output syndrome, to relieve persistent pericardial effusion with repetitive tamponade and to implant partial cavo–pulmonary shunts.22,23 Most patients have dramatic clinical improvement with regression of ascitis and congestive failure, as well as improvement in quality of life, although the ultimate prognosis is probably not altered.24 However, mortality remains high during the first two post-operative years, reaching 13%.20 Good long-term results may be obtained with early diagnosis and timely intervention before shrinkage of the ventricle occurs. Promising results have been obtained in terms of restoration of both structural and functional changes, with better understanding of the pathophysiology and the use of a new tailored approach for relief of right ventricular cavity obliteration.25 Although there was no evidence of recurrence over a short follow-up period, further research and longer follow up is needed, since recurrence of endocardial fibrosis has been reported in a Brazilian series.26

The challenges for sub-Saharan Africa The African paediatric population is extremely underserved by paediatricians in general and by paediatric cardiologists in particular, most working in the major referral units in urban areas. Families have therefore to travel long distances in search of medical care for their children with heart disease. The state-run health infrastructures are mostly directed at prevention and treatment of the major endemic diseases, such as malaria, tuberculosis, leprosy, HIV/AIDS, parasitic infections and diarrhoeal diseases. Due to lack of financial and human resources, both interventional cardiology and open-heart surgery have been introduced in Mozambique, Kenya, Sudan, Ethiopia, Senegal and Nigeria through collaboration programmes between local institutions and non-governmental organisations from Europe and North America. Comprehensive paediatric cardiovascular services are needed in Africa. These should include research aimed at understanding the mechanisms underlying conditions geographically restricted


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to this continent, targeting country-specific conditions, and investigating the role of toxins and traditional practices in the pathogenesis of cardiovascular conditions. Apart from providing the means to enable the clinical services to achieve excellence, research provides important tools to define the size of local problems, and helps the evolution of appropriate solutions by local researchers.27 However, creation and sustainability of such comprehensive services is hampered by several problems, the most important being the lack of human resources for healthcare and research. The major challenges for surgery for cardiovascular diseases in African children include (1) building local capacity and expertise in the diagnosis and management of congenital heart diseases; (2) training local surgeons in the management of conditions that are geographically restricted to Africa, using indigenous techniques that can be applied locally at lower costs; (3) improving the efficiency of equipment and systems for adequate maintenance of equipment; (4) creating infrastructure for the management of and research into cardiovascular diseases in children; (5) creating systems for financial support of the communities served by these infrastructures; (6) addressing the issue of poor local governance and low commitment from policy makers. The success of the institutional collaborations currently in place, and their acceptance and recognition by the community will hopefully encourage local governments to increase their support, making an effort to become partners with these initiatives while giving enough independence to the projects. Indeed, we think that although individuals or private institutions can start these networks, political support and willingness are crucial to ensure their sustainability in the medium and long term. Finally, the institutions that are running successful programmes must be reinforced as regional referral centres.

5. 6.

7. 8.

9.

10.

11. 12. 13. 14.

15. 16.

17.

18.

19.

Conclusion The surgical treatment of cardiovascular diseases in children remains a major challenge in most African countries. Although requiring major investments, surgical programmes must be stimulated, allowing comprehensive management of patients and offering a unique opportunity for research into the particular aspects of geographically restricted diseases, namely the development and testing of approaches to management tailored to the specific conditions of the continent.

References 1.

2. 3.

4.

McLaren MJ, Markowitz M, Gerber MA. Rheumatic heart disease in developing countries: the consequence of inadequate prevention. Ann Int Med 1994; 120(3): 243–245. Moraes CR. Some aspects of cardiac surgery in the tropics. Eur J Cardiothorac Surg 1990; 4: 235–237. Marcus RH, et al. The spectrum of severe rheumatic mitral valve disease in a developing country: correlations among clinical presentation, surgical pathologic findings and hemodynamic sequelae. Ann Int Med 1994; 120(3): 177–183. Essop MR, Nkomo VT. Rheumatic and non-rheumatic valvular

20.

21.

22.

23.

24.

25.

26.

27.

167

heart disease: Epidemiology, management and prevention in Africa. Circulation 2005; 112: 3584–3591. Duran CM, Gometza B, Saad E. Valve repair in rheumatic heart disease: an unsolved problem. J Card Surg 1994; 9(2 suppl): 282–285. Reddy PK, Dharmapuram AK, Swain SK, Ramdoss N, Raghavan S, Murthy KS. Valve repair in rheumatic heart disease in pediatric age. Asian Cardiovasc Thorac Ann 2008; 16: 129–133 Kumar AS, Talwar S, Saxena A, Singh R. Ross procedure in rheumatic aortic valve disease. Eur J Cardiothorac Surg 2006; 29(2): 156–161 Choudary SK, Mathur A, Sharma R, et al. Pulmonary autograft: should it be used in young patients with rheumatic disease? J Thorac Cardiovasc Surg 1999; 118: 483–491. Al-Halees Z, Kumar N, Gallo R, Gometza B, Duran CM. Pulmonary autograft for aortic valve replacement in rheumatic disease: a caveat. Ann Thorac Surg 1995; 60(suppl): S172–176. Okoromah CA, Ekure EN, Ojo OO, Animasahun BA, Bastos MI. Structural heart disease in children in Lagos: profile, problems and prospects. Niger Postgrad Med J 2008; 15(2): 82–88. Van der Horst RL. The pattern and frequency of congenital heart disease among blacks. S Afr Med J 1985; 68(6): 375–378. Omokhodoin SI, Lagunju IA. Prognostic indices in children heart failure. West Afr J Med 2005; 24(4): 325–328. Antunes MJ. Current status of surgery for congenital heart disease in infancy. S Afr Med J 1985; 67(10): 359–362. Pinho P, von Oppell UO, Brink J, Hewitson J. Pulmonary artery banding: adequacy and long-term outcome. Eur J Cardiothorac Surg 1997; 11(1): 105–111. Dubost C, Maurice P, Carbaux A, et al. L’endocardite fibreuse constrictive. Traitment chirurgical. Arch Mal Coeur 1977; 70: 155–162. Joshi R, Abraham S, Kumar AS. New approach for complete endocardectomy in left ventricular endomyocardial fibrosis. J Thorac Cardiovasc Surg 2003; 125: 40–42. Dubost C, Chapelon C, Deloche A, Piette JC, Chavaud S, Fabianni JN, Carpentier A. Chirurgie des fibroses endomyocardiques. Arch Mal Coeur 1990; 83: 481–486. Da Costa FDA, Moraes CR, Rodrigues JV, et al. Early surgical results in the treatment of endomyocardial fibrosis: a Brazilian cooperative study. Eur J Cardiothorac Surg 1989; 3: 408–413. Chavaud S. Fibrose endomyocardique: traitment chirurgical. Encycl Méd Chir, Techniques chirurgicales – Thorax 42–730. Valiathan MS, Balakhrishnan KG, Sankarkumar R, Kartha CC. Surgical treatment of endomyocardial fibrosis. Ann Thorac Surg 1987; 43: 68–73. Moraes F, Lapa C, Hazin S, Tenorio E, Gomes C, Moraes C. Surgery for endomyocardial fibrosis revisited. Eur J Cardiothorac Surg 1999; 15: 309–313. Mishra A, Krishna Manohar SR, Sankar Kumar R, Valiathan MS. Bidirectional Glenn shunt for right ventricular endomyocardial fibrosis. Asian Cardiovasc Thorac Ann 2002; 10(4): 351–353. Anbarasu M, Krishna Manohar SR, Titus T, Neelakandhan KS. One-and-half ventricular endomyocardial fibrosis. Asian Cardiovasc Thorac Ann 2004; 12(4): 363–365. Cherian KM, John TA, Abraham KA. Endomyocardial fibrosis: clinical profile and role of surgery in management. Am Heart J 1983; 108(4): 706–709. Mocumbi AO, Sidi D, Vouhe P, Yacoub M. An innovative technique for the relief of right ventricular trabecular cavity obliteration in endomyocardial fibrosis. J Thorac Cardiovasc Surg 2007; 134(4): 1070–1072. Moraes C R, Buffolo E, Moraes Neto F, et al. Recidiva de Fibrose apos correccao cirurgica da endomiocardiofibrose. Arq Bras Cardiol 1996; 67(4): 297–299. Yacoub MH. Establishing pediatric cardiovascular services in the developing world: a wake-up call. Circulation 2007; 116: 1876–1878.


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Drug Trends in Cardiology New anticoagulants offer consistent stroke-reduction benefit in atrial fibrillation Poor warfarin therapy set to benefit from renewed interest in effective anticoagulation in atrial fibrillation ‘All the new anticoagulants, dabigatran, rivaroxaban and apixaban are non-inferior to warfarin in the prevention of stroke and embolic events in atrial fibrillation (AF), offering an approximate relative reduction in risk (RRR) of 10% per year when compared to current warfarin therapy’, Dr Louis van Zijl, physician and clinical trial investigator, based in Worcester, Western Cape noted in his presentation at the SA Hypertension congress. ‘While we envisage that warfarin therapy will still be the control arm for randomised clinical trials for years to come, we need to face up to our failure to use this agent properly during the past 50 years’, he noted. Warfarin’s development originated in the early 1900s in the veterinary arena where ‘spoilt clover delivering a sweet smell’ led to anticoagulation and death in cattle. Coumarin was identified as the active agent in 1939 and named warfarin in recognition of the Wisconsin Alumini Research Foundation’s (plus -arin from Coumarin) role in funding the research. In 1948, an attempted suicide due to ingestion of warfarin (as used in rat poison) was reversed by giving vitamin K, leading to warfarin’s celebrated use in 1954 when Dwight Eisenhouer suffered a myocardial infarction (MI). Its widespread application in AF had, however, to wait many years before numerous trials1 showed that warfarin versus placebo resulted in a 64% RRR for stroke, leading to its ‘gold-standard usage’ in this condition. The need for a more accurate risk calculator is evident on reviewing this early article,1 which noted that ‘the numbers of AF patients that would need to be treated for one year to prevent one ischaemic stroke are about 200, 70 and 20 for those at low, moderate and high risk, respectively’. The most recent ESC guidelines for the management of atrial fibrillation2 advise the initial use of the older risk calculator, the CHADS2 score, in AF patients. ‘If patients are then adjudged to

be at intermediate risk, the newer scoring system, the CHA2DS2VASC score, which involves more risk factors, should be used. ‘A further innovation in the new guidelines is the assessment of bleeding risk using the HASBLED score. ‘However, clinical dilemmas remain as the factors of ageing, high blood pressure and previous cerebrovascular disease occupy both sides of the benefit and risk scale’, Dr van Zijl noted. ‘This means that we must use extreme caution in these patients not to cause them any harm.’ In the real world, clinical registries have added to our insights on treating these patients. In a large Danish registry of more than 130 000 patients with non-valvular AF,3 there was a neutral or positive clinical benefit using vitamin K antagonists alone in patients with a CHADS2 score greater than 0 and in those with a CHA2DS2VASC score greater than 1. ‘There was no sufficient beneficial effect of giving aspirin alone, or vitamin K antagonists together with aspirin, so aspirin does not have a role to play in preventing strokes in AF’, Dr van Zijl pointed out. ‘It is clear from the guidelines and the real-world clinical data that medium- and high-risk patients should be treated aggressively with anticoagulants. I believe we all have to become assertive anticoagulators’, Dr van Zijl stressed. The vitamin K antagonists have a narrow therapeutic window and this complicates the clinician’s ability to reach an optimal INR of 2.5 and also to avoid the increased risk of intracranial haemorrhage when an INR higher than 3 is prevalent. ‘The time in therapeutic range (TTR) is the measure of our clinical success, as a failure to stay within the TTR does not come without risk’, he said. ‘The promise of the new anticoagulants, rivaroxiban and apixaban as factor Xa inhibitors, and dabigatran, a direct factor IIa inhibitor, are their simple dosing regimen, fewer food and drug interactions, less labour- and cost intensive with regard to on-going INR

monitoring, and an increased quality of life for patients due to their increased efficacy’, Dr van Zijl said. For the clinician, challenges remain in the selection of which agent to use, as the clinical trials differ with regard to many aspects such as study design, with blinding being double or single blinded, type of patients at risk included in the study, demographics, and definition of major bleeding. Also interpretation is complicated by data presented in a variety of ways, from intention to treat, to modification of treatment analyses. ‘I was privileged to be involved in most of the studies, in ROCKET, ARISTOTLE and ENGAGE, which is still underway, but unfortunately not in the RE-LY studies’, Dr van Zijl noted. Dr van Zijl discussed these various aspects, which constitute the current clinical challenges, also using data provided by Dr Michael Gibson, one of the senior investigators of anticoagulant trials. ‘It is becoming clearer that we will use the differing pharmacokinetics of the three agents, rivaroxaban, apixaban and dabigatran to make our choice of oral anticoagulant agent in AF. For example, dabigatran is 80% eliminated via the kidneys and in patients with renal insufficiency, we would consider this fact’, he said With regard to usage of these agents in resource-constrained settings, Dr van Zijl noted that there are some predictors that can identify patients who will be poor warfarin responders (such as those whose warfarin control is not in place by 30 days), which can be used as predictors of an at-risk situation under warfarin. ‘In these patents, we will certainly have to strongly consider these new anticoagulants’, he concluded. J Aalbers 1. Hart RG, et al. Neurology 1998; 51(3): 674–681. 2. Camm AJ, et al. Eur Heart J 2010; 31(19): 2369–2429. 3. Olesen JB, et al. Thrombosis Haemost 2011; 106(4) 739–749.


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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.

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Treatment of acute symptomatic deep vein thrombosis.

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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.

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~8,000

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

3,464

4,300

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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

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Outcome

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Study completed

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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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Your life and your heart Coenzyme Q10, an anti-oxidant of value to reduce oxidative stress; also useful to reduce statin-induced myalgia Complementary medicine is frequently used by patients, particularly those with chronic diseases such as at-risk cardiovascular and diabetes patients. A recent survey in Australia1 showed that almost 50% of diabetic patients are accessing products such as cinnamon and coenzyme Q10 to complete their oral antidiabetic therapy. Recently, the role of coenzyme Q10 as a useful adjuvant to reducing statininduced myalgia has been under the spotlight. Dr Dirk Blom, University of Cape Town Lipid Research Unit recently noted that there was physiological support for the role of coenzyme Q10 in reducing statin-induced myalgia and evidence that some patients benefit from the therapy. A decrease in coenzyme Q10, a product of the mevalonate pathway, could contribute to statin-induced myopathy. Other mechanisms include mitochondrial

dysfunction and genetic predisposition. A recent double-blind, placebocontrolled trial of coenzyme Q10 supplementation2 has shown that in patients with left ventricular systolic dysfunction (LVSD) (ejection fraction < 45%), eight weeks of supplementation with coenzyme Q10 improved mitochondrial function and brachial flow-mediated dilatation (FMD). The improvement in FMD correlated with the change in mitochondrial function, suggesting that coenzyme Q10 improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD. The anti-oxidant value of coenzyme Q10 has also been assessed in patients with multiple cardiovascular risk factors. While outcome studies with anti-oxidants such as vitamins C and E have been disappointing, there is accumulating evidence of vascular benefit, namely

improvements in glucose and blood pressure levels and lipid metabolism.3 J Aalbers 1.

2.

3.

Manya K, Champion B, Dunning T. The use of complementary and alternative medicine among people living with diabetes in Sydney. BMC Complement Altern Med 2012; 12: 2. Dai YL, Luk TH, Yiu KH, Wang M, Yip PM, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis 2011; 216(2): 395â&#x20AC;&#x201C;401. Epub 2011 Feb 17. Shargorodsky M, Debby O, Matas Z, Zimlichman R. Effect of long-term treatment with antioxidants (vitamin C, Vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. Nutr Metab (Lond) 2010; 7: 55.

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From the ACC congress, 24–27 March 2012 Ivabradine shows benefit in diastolic heart failure patients with normal ejection fraction The addition of ivabradine to optimal medical care for those patients with heart failure and a normal ejection fraction (HFNEF) resulted in an improvement in both diastolic function and exercise capacity.1 This study was presented at the recent American College of Cardiology meeting in Chicago and is important to clinical practice because 50% of all congestive heart failure (CHF) patients have a normal ejection fraction, and to date there is no evidence of an effective treatment for improving outcome in these patients. In this study of more than 100 patients in New York Heart Association (NYHA) class II–IV and with an ejection fraction of 50% or higher, patients were randomised to ivabradine 5 mg bid or placebo on top of standard medical care. Ivabradine therapy was subsequently uptitrated to 7.5 mg bid. Clinical assessment of NYHA class, exercise duration and echocardiographic evaluation of diastolic function was performed at baseline and after two months of ivabradine therapy. After two months of therapy, the resting heart rate was decreased significantly in the ivabradine-treated group, from 82 beats/min to an average of 67.5 beats/min. Exercise and diastolic capacity improved significantly in the ivabradine-treated group.

REALITY registry confirms value of ivabradine usage in achieving targeted heart rate in stable angina REALITY, a German registry, was examined by the Heart Infarction Research Institute, Ludwigshaven and the University of Heidelberg, to assess the real-world capability of reaching the recommended resting heart rate of 55 to 60 beats/min in stable angina patients.2 Between November 2007 and July 2008,

TABLE 1. PATIENT CHARACTERISTICS IN FOUR HEART RATE QUARTILES HR < 60 bpm (n = 869) (25.3%)

HR 60–64 bpm HR 65–>72 bpm (n = 882) (n = 907) (25.6%) (26.4%)

HR > 72 bpm (n = 7 811) (22.7%)

Age

69

68

69

69

Female (%)

28

28

31.4

31.0

Prior MI (%)

55.5

51.2

52.1

53.5

Prior PCI (%)

54

55

54

47

Prior bypass (%)

38

33

30

29

Diabetes mellitus (%)

30

31

34

38

Multi-vessel disease (%)

62

63

62

64

LVEF 40%

10

10.2

13.9

Beta-blocker

78

81

74

Ivabradine

10

9.7 83 5.3

6

7.8

HR = heart rate; bpm = beats per min; MI = myocardial infarction; PCI = percutaneous coronary intervention; LVEF = left ventricular ejection fraction.

a total of 4 047 consecutive outpatients with stable angina and known coronary artery disease (CAD) were enrolled in the registry (Table 1). Patients with stable angina were most often male and were treated with aspirin (83%), beta-blockers (80%), statins (83%) and ACE inhibitors (63%). Heart rate was a mean 66 beats/min; still above the recommended targets of 55–60 beats/min (measured after 5-min resting period). Only 25% of patients achieved the recommended target. The strongest predictor against achieving heart rate < 60 beats/min was atrial fibrillation recorded at enrolment, while patients receiving ivabradine were significantly more likely to achieve a resting heart rate < 60 beats/ min.

Ivabradine-treated patients with mild-to-moderate mitral stenosis show similar improvement to beta-blocker therapy In a small study of patients (33 patients) in normal sinus rhythm with mild-to-

moderate mitral stenosis, ivabradine was compared to metoprolol.3 Patients were allocated to maximal tolerated doses for six weeks (metoprolol 100 mg bid, ivabradine 10 mg bid) and then subjected to crossover to the alternative therapy. Ivabradine decreased the resting heart rate and was as effective as metoprolol in increasing exercise duration, reducing transmitral gradient and pulmonary artery systolic pressure in these patients. J Aalbers 1.

2.

3.

De Masi De Luca G. Ivabradine and diastolic heart failure. Abstract 222.424. ACC 2012. Anselm KG, et al. Determinants of achieving recommended resting heart rate in stable coronary artery disease in Germany. Results of the REALITY registry. Abstract 1206.404. ACC 2012. Aran RK, et al. Ivabradine produces similar improvement in exercise tolerance and haemodynamics in patients with mild to moderate mitral stenosis as compared to metoprolol. Abstract 1150-252. ACC 2012.


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South African Hypertension Society 2012 congress report Optimal combination therapy for hypertension Prof Neil Poulter Hypertension is currently the single biggest cause of death globally. In 2000, there were a staggering 1 billion hypertensive individuals worldwide and this is predicted to increase to 1.56 billion by 2025. An increasing prevalence of hypertension is being witnessed in all nations, with numerous risk factors contributing to this upward trend. These sobering statistics formed the introduction to this presentation, which examined optimal combination therapy for hypertension by investigating a variety of guidelines and recent trial data. Prof Neil Poulter, Imperial College, London, listed among the risk factors for hypertension an increasing life expectancy in many nations (hence a larger number of elderly) and a trend towards a sedentary lifestyle. Other factors include decreased fresh fruit and vegetable consumption, an increase in obesity and smoking, and an increased intake of saturated fats, salt and alcohol.

Hypertension guidelines for first-line therapy Prof Poulter emphasised, ‘It is important to get treatment of hypertension right, in order to prevent cardiovascular disease down the line.’ He then compared the Prof Neil Poulter Preventive Cardiovascular Medicine, Imperial College London, currently co-director of the International Centre for Circulatory Health and the Imperial Clinical Trials Unit Prof Poulter has played a senior management role in several international trials, including the AngloScandinavian Cardiac Outcomes Trial (ASCOT) and the ADVANCE study. Other research activities include the optimal investigation and management of essential hypertension and dyslipidaemia, the association between birth weight and various cardiovascular risk factors, the cardiovascular effects of exogenous oestrogen and progesterone, the aetiology and prevention of type 2 diabetes, and ethnic differences in cardiovascular disease.

different guidelines: JNC7, ESH-ESC, WHO-ISH and BHS/NICE2006. They were found to have differing opinions on optimal first-line therapy. BHS states that monotherapy is usually inadequate therapy. Both JNC7 and ESH-ESC recommend two drug combinations (dual therapy), and the 2009 ESH-ESC guidelines selected five preferred combinations: • angiotensin converting enzyme inhibitor (ACE) + diuretic • angiotensin receptor blocker (ARB) + diuretic • calcium channel blocker (CCB) + diuretic • ACE + CCB • ARB + CCB (no trial evidence). ‘The advantages of dual therapy in reduction of stroke and coronary risk is evident in more than one trial’, Prof Poulter noted and he also drew attention to an all-cause mortality benefit of combination therapy. He questioned which agents to use in combination therapy.

Trial evidence on therapeutic agents ‘Although beta-blockers have been recommended as therapy, they have a weak effect on decreasing stroke and there is an absence of effect on coronary heart disease.’ Prof Poulter supported this statement with results of the LIFE comparison between losartan (ARB) and atenolol (beta-blocker), where losartan was found to be superior, with a 25% reduction in stroke. The PROGRESS trial (post-stroke therapy in elderly patients) had significant results for the combination of perindopril (ACE inhibitor) with indapamide (diuretic), showing a 28% decrease in next stroke. Adding perindopril in the HYVET trial of the very elderly showed a 21% decrease in all-cause mortality, with active treatment greatly improving quality of life. Prof Poulter turned his attention to the ASCOT-BPLA trial in which amlodipine (CCB) was found to have stroke protection beyond the benefits of blood pressure management. Beta-blockers (atenolol) only had a benefit on heart rate. Of

particular interest in this trial, Prof Poulter noted, was the relationship between blood pressure variability, stroke and coronary heart disease. It was found that risk of stroke and chronic heart disease increased with increasing blood pressure variability, which was the measure most strongly associated with risk. From this, Prof Poulter concluded that intermittent hypertension is more dangerous than constant hypertension and that the combination of amlodipine and perindopril was found to be better at controlling long-term variability of blood pressure. Mean blood pressure in-trial has minimal association with stroke outcome and no association with coronary heart disease, he pointed out.

Single-pill combinations The advantages of single-combination pills were highlighted by Prof Poulter, referring to the ADVANCE trial where the single-pill combination (ACE inhibitor + diuretic) had good results in type 2 diabetes patients. In the ACCOMPLISH trial, a single-pill combination (ACE inhibitor + CCB) was found to have an advantage in reducing cardiovascular events compared with an ACE inhibitor + thiazide. These benefits were most evident in high-risk subjects, of whom two-thirds were diabetic.

BHS/NICE guidelines for anti-hypertensive therapy Choice of first-line therapy is affected by age. For patients younger than 55 years and of European descent, an ACE inhibitor or ARB is recommended. For patients older than 55 years and all black Africans or people of Caribbean descent, a CCB is recommended. Second-line recommendations are dual therapy of an ACE inhibitor or ARB + CCB, irrespective of age or ancestry. Third-line therapy recommends a tripletherapy combination of ACE inhibitor or ARB + CCB + diuretic. Prof Poulter’s final advice, ‘most patients need two antihypertensive agents with a statin added to the regimen’. J Aalbers, G Hardy


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S3 PREXUM® PLUS Tablets. Perindopril 4 mg and Indapamide 1,25 mg. Reg. No. 38/7.1.3/0028. S3 COVERSYL® PLUS Tablets. Perindopril 4 mg and Indapamide 1.25 mg. Reg. No.: 33/7.1.3/0363. S3 PREXUM® 4 mg Tablets. Perindopril 4 mg. Reg. No. 36/7.1.3/0020. S3 PREXUM® 10 mg Tablets. Perindopril 10 mg. Reg. No. A39/7.1.3/0233. S3 COVERSYL® 4 mg Tablets. Perindopril 4 mg. Reg. No.: X/7.1.3/314. S3 COVERSYL® 10 mg Tablets. Perindopril 10 mg. Reg. No. A39/7.1.3/0236. S3 CORALAN® 7,5 mg Tablets. Ivabradine 7,5 mg. Reg. No. A39/7.1.4/4011. For full prescribing information, refer to package insert approved by medicines regulatory authority. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27 (0) 861 700 900. Fax: +27(0)11 525 3401. 144592


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Victoza® is the first and only human GLP-1 analogue with 97 % homology to natural GLP-1 Reductions in HbA1C1-3 Reductions in weight1-3 Reductions in systolic blood pressure1-3 Improvements in beta-cell function4

References: 1. Nauck M, et al; for the LEAD-2 Study Group. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination with Metformin, in Type 2 Diabetes. The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32(1):84-90. 2. Gallwitz B, et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64(2):267-276. 3. Garber A, et al; on behalf of the LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes, Obes Metab. 2011; 13: 348-356. 4. Chang AM, et al. The GLP-1 Derivative NN2211 Restores ß-cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose. Diabetes. 2003;52:1786-1791. Proprietary Name: Victoza®. Scheduling Status: S4 Composition: Liraglutide 6 mg/ml. Indications: As an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus. Registration Number: 43/21.13/0781. For full prescribing information refer to package insert approved by the medicines regulatory authority. Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 2nd Floor, Building A, 345 Rivonia Boulevard, Edenburg, Rivonia, Sandton 2128, South Africa. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/5281/January/2012/ver1


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Getting to the root of diabetes and the effect of GLP-1 on the cardiovascular system Prof Wolfgang Schmidt

The need to initiate tight glycaemic control immediately after a diagnosis of diabetes is essential for cardiovascular benefits in the years to come, achieving significant reductions in myocardial infarctions and all-cause mortality. Prof Schmidt stressed that even patients with no cardiovascular history and those with HbA1c levels ≤ 8.0% will benefit from tight glycaemic control.

Limitations of diabetes treatment The traditional classes of oral anti-diabetic agents and human insulin formulations are limited in their ability to help patients achieve their targets of glycaemic control. These agents are associated with adverse events that relate to their mode of action, and pharmacokinetic and pharmacodynamic properties. Prof Schmidt examined a variety of problems and limitations of diabetes treatment, referring to outcomes of the ACCORD, VADT and ADVANCE trials. His first concern was therapy-induced hypoglycaemia, found to increase in the intensive-treatment arms, with severe hypoglycaemia being directly related to cardiovascular events and possibly associated with dementia. A second concern was treatmentrelated weight gain, of which insulin was found to be the most potent inducer. Apoptosis and loss of beta-cell function was a third concern that arose from these trials. It emerged that progressive beta-cell loss is already occurring in the Prof Wolfgang Schmidt Chair and professor of Internal Medicine, Ruhr University, Bochum School of Medicine, Germany Major research areas include the entero-insular axis, incretins, regulatory gut–brain peptides, type 2 diabetes (pathophysiology and novel therapeutic strategies), pancreatitis and gastrointestinal malignancies.

pre-diabetic stage of insulin resistance, with as much as 50% of beta-cell function lost by the time of diagnosis. Beta-cell apoptosis increases with the use of sulfonyl urea in the treatment of diabetes. Prof Schmidt’s final concern was that reduction of HbA1c level is efficient for the first year or two, regardless of therapeutic agent utilised, but then begins to slip and diabetes disease progresses. Considering the above limitations, there is a need for new, effective agents that can attain targets of glycaemic control and weight reduction without inducing hypoglycaemia, while addressing other comorbidities commonly associated with type 2 diabetes.

Incretin therapy Prof Schmidt elaborated on the need for long, outcome-directed studies to finally determine the place for incretin mimetic therapy in diabetes management. The basis of incretin mimetic therapy is two-fold. Incretin mimetics inhibit gastric emptying through direct action on the ileum and stomach, and indirect effects on the endocrine pancreas; as well as decreasing appetite and increasing satiety through brain action. Early use of incretin therapy in the diabetic patient has the benefits of glycaemic control without induced hypoglycaemia (it only occurs in combination with other agents), weight loss (average loss of 7.7 kg within 26 weeks), a decrease in systolic blood pressure, and improved beta-cell function.

Liraglutide Liraglutide, the first human GLP-1 analogue, acts on multiple physiological systems and demonstrates beneficial effects on several aspects of glycaemic control. The protracted half-life of liraglutide allows for once-daily, mealindependent dosing. Prof Schmidt stated that liraglutide also has anti-hypertensive effects,

evidenced in all instances and in all trials. The beneficial weight loss seen with liraglutide is accompanied by improvements in other cardiovascular risk factors, including blood pressure, triglyceride levels and cardiovascular risk biomarkers. In a 14-week trial of liraglutide monotherapy, systolic blood pressure decreased by 7.9 mmHg vs placebo (p = 0.002) and triglyceride levels demonstrated a 22% reduction vs placebo (p = 0.01). There are currently liraglutide trials at every stage of the type 2 diabetes continuum. Liraglutide has been shown to improve biomarkers for cardiovascular risk. Relief from the side effect of nausea is faster with liraglutide than with any other incretin mimetics and liraglutide has been shown to be superior to sitagliptin in improving HbA1c levels and weight reduction. When compared to onceweekly exenatide, once-daily liraglutide had benefit for HbA1c levels, weight loss and hypoglycaemic events. Liraglutide has a good safety and tolerability profile. Nausea is found in up to 15% of patients but it appears to be transient and the rate of reporting decreases over the first few weeks. The risk of pancreatitis is similar to that of other agents. In general, there is no strong evidence for increased risk of pancreatitis when considering the incidence of pancreatitis in this population, and the combination of multiple risk factors for pancreatitis (including obesity) in the diabetic patient. In summary, Professor Schmidt recommended individualising treatment according to patient need to attain targets of glycaemic control as soon after diagnosis as possible, in order to avoid hypoglycaemic episodes and weight gain. Attention should also be directed towards the lowering of other cardiac risks such as blood pressure. G Hardy Source: Schmidt WE. Early clinical studies with liraglutide. Int J Clin Pract 2010; 64(suppl 167): 12–20.


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Difficult-to-control blood pressure Prof Henry Krum

Prof Krum used data from the National Health and Nutrition Examination Surveys (NHANES) 2003–2008 to highlight the prevalence of childhood hypertension. Uncontrolled and untreated hypertension was evident in 30% of the study population, 9% of the study subjects displayed resistant hypertension; whereas 40% were controlled on less than two drugs and 21% on less than three drugs.

Resistant hypertension ‘A significant proportion of the hypertensive population has resistant hypertension’, Prof Krum said. He defined resistant hypertension as not being able to reach a blood pressure target of 140/90 mmHg (130/80 mmHg for diabetic patients), despite full adherence to triple hypertensive therapy, including a diuretic. Examination of causes of resistant hypertension revealed non-adherence (16%) and drug-related causes (58%) as the predominant factors; with office resistance or white-coat effect (6%), psychological reasons (9%), secondary hypertension (5%), interfering substances (1%), and other factors of unknown origin (5%) also resulting in resistant hypertension. Prof Henry Krum Head of the Clinical Pharmacology Unit, chair of Medical Therapeutics and director of the Monash University Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine and Department of Medicine, Melbourne, Australia

Assessment and treatment of resistant hypertension Initial clinical assessment of the resistant hypertensive patient should include a history and physical examination, urinalysis and blood chemistry. Prof Krum advised to carefully consider adherence issues, particularly the medication schedule (dosing), and to look for interacting drugs (taken regularly, often or occasionally) that may raise blood pressure. In the case of sub-optimal therapy, investigate medication intolerance and drug–drug interactions. Spironolactone, as an addition to triple-therapy hypertensive agents, has been found to be useful in refractory and resistant hypertension. Prof Krum drew attention to the ASPIRANT study, which compared the effect of spironolactone vs placebo on ambulatory and office blood pressure. Spironolactone was shown to be of therapeutic benefit. Prof Krum also noted that there is a well-established relationship between both obesity and sleep apnoea (through activation of the sympathetic nervous system), and hypertension. Treatment of both conditions will decrease the hypertensive burden, with nonpharmacological interventions including weight loss and a reduction of sodium intake.

Baroreflex activation therapy Prof Krum then went on to discuss baroreflex activation therapy, an invasive procedure that requires the implantation of leads and a pulse generator. This sensitisation device exploits the relationship between stimulation and

response to retrain the baroreflex and improve sensitivity. Increasing voltage results in a progressive reduction in blood pressure and heart rate.

Renal denervation Another invasive procedure entails denervation of the renal sympathetic nerves, which contribute considerably to progressive hypertension. This procedure targets the renal efferent nerves (disrupting renin release and sodium retention, and decreasing renal blood flow and proteinuria) and the renal afferent nerves (affecting the heart and smooth muscle). These nerves follow the renal artery to the kidney within the adventitia. Denervation by radio frequency catheter, via the endovascular femoral approach, results in a progressive blood pressure reduction. Typically, patients with a systolic blood pressure higher than 160 mmHg despite three or more medications are suitable candidates to benefit from this procedure. This technique is currently being used successfully in South Africa.

Conclusion In light of the hypertension epidemic currently being faced, Prof Krum concluded with three considerations: a reminder that target blood pressure levels are being continually revised downwards, that evidence suggests existing therapeutic agents are being sub-optimally utilised, and that the need to explore novel agents, novel procedures and devices is imperative in these difficult-to-treat patients. G Hardy

News from 2012 ACC congress Prof Krum also reported on long-term follow up in the Symplicity HTN-1 trial using the Medtronic renal denervation (RDN) catheter over a two-year period.1 HTN-1 was an open-label cohort study which enrolled 153 patients with resistant hypertension at sites in Australia, Europe and the United States. The patients all had systolic blood pressure ≥ 160 mmHg despite being on at

least three antihypertensive medications including a diuretic, at target/maximum tolerated doses. Patients with an eGFR < 45 ml/min or those with type 1 diabetes were excluded.) Importantly, blood pressure progressively declined over the two years in this cohort, suggesting that functional re-innervation was unlikely to be occurring, at least up to two years

post-RDN procedure. Only one case of renal artery stenosis was reported in the 12 months. In the same session, Dr Murray Esler reported on a randomised, controlled trial of RDN versus medical treatment only (Symplicity HTN-2) at one year.2 The primary endpoint was change in continued on page 179


Introducing the Symplicity Renal Denervation System: TM

Significant and sustained blood pressure reductions

Safe, straightforward procedure with proven clinical results in treatment-resistant hypertension patients:1,2 • Over 2000 clinical and commercial patients treated to date • No evidence of vascular injury/stenosis at treatment site by imaging at 6 months • Sustained renal function (eGFR and creatinine) with no orthostatic or electrolyte disturbances • SYMPLICITY HTN-2: 106-patient randomised study proving treatment effect vs. medical management • SYMPLICITY HTN-1: 153 patients enrolled in a series of nonrandomised studies show durable results to 2 years1 1

SYMPLICITY HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:911–917.

2

SYMPLICITY HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. The Lancet. 2010;376:1903–1909. Symplicity is a tradmark of Medtronic, Inc. and is registered in one of more contries of the world. Not for distribution in the USA or Japan. © 2012 Medtronic, Inc. All rights reserved. UC201205084EE 2/12

Six-Month Change in Blood Pressure2 0 -10 -20

1 0 Control (n = 51)

Systolic Diastolic

-30 Renal denervation (n = 49) -40

Innovating for life.


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continued from page 176 systolic blood pressure at six months. Medically controlled patients were eligible to crossover to RDN at six months. All patients were followed for one year to assess long-term effectiveness and safety of RDN. At least 12 months’ data for 47 RDN patients and 35

crossover patients were available with regard to efficacy. Both groups showed a similar significant drop of 25–30 mmHg systolic blood pressure and 10 mmHg diastolic blood pressure, whether they underwent the procedure at zero or six months. The procedure was safe with no adverse events, except for one patient who had a right renal artery dissection.

1.

2.

Krum R, et al. Long-term follow-up of catheter-based renal sympathetic denervation for resistant hypertension confirms durable blood pressure reduction. ACC congress 2012, Abstract 926-3. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of resistant hypertension: one year results from the simplicity HTN-2 randomised controlled trial. ACC congress 2012, Abstract 926-4.

The young hypertensive Prof Brian Rayner Hypertension is increasingly becoming a health concern in the younger population. Prof Rayner illustrated this point by comparing current statistics with data from the 1970s, when hypertension in children was extremely rare and almost always prompted investigation to search for an underlying secondary cause. Recent American studies have shown that the prevalence of childhood hypertension has risen as high as 4.5%. The Harvard Alumni study assessing coronary heart disease mortality in normal subjects and those with pre-, primary and secondary hypertension found that 5–15% of adolescents displayed secondary hypertension.

Factors contributing to childhood hypertension ‘The current epidemic of obesity is the key issue in childhood hypertension’, said Prof Rayner. Obesity is defined as a body mass index above the 85th percentile, leading to a rise in leptin levels and heart rate, and also linked to insulin resistance. He noted that a definite relationship between blood pressure and fasting insulin has been observed. A number of other factors are also strongly linked to the rise in childhood Prof Brian Rayner Head of Division of Nephrology, Groote Schuur Hospital and University of Cape Town Active research interests are therapy of hypertension, mutations in the ENaC, genetic determinants of salt sensitivity, HIVAN, vascular calcification and chronic kidney disease, primary aldosteronism and the genetics of severe hypertension in blacks.

hypertension, including low birth weight and predisposing genetic factors (family history of risk factors or hypertensive disease). Also contributing are reduced nephron number (Barker-Brenner hypothesis) and elevated uric acid. There are multiple health concerns around elevated blood pressure in childhood. Childhood blood pressure (especially systolic) tracks blood pressure into adulthood. Elevated blood pressure is associated with subclinical cardiovascular disease and is a significant driver of overall mortality, cardiovascular mortality and coronary heart disease.

Assessing hypertension in the child Key pointers to primary hypertension in the child include adolescence, obesity, and a family history of hypertension, cardiovascular disease and type 2 diabetes. Pre-hypertension and hypertension were defined as a blood pressure persistently above the 90th and 95th percentiles, respectively. Adult norms of blood pressure should be used from 18 years of age. Prof Rayner advised that assessment of blood pressure should be based on frequent measures; full 24-hour ambulatory monitoring is ideal to avoid misdiagnosis. Clinical examination should evaluate for potential secondary causes of hypertension, particularly use of illicit drugs (cocaine, tik) and oral contraceptives, and chronic kidney disease. Other investigations advised included a dipstick for urine, and creatinine assessment, as well as kidney ultrasound. Blood tests (electrolyte, uric acid and fasting glucose levels, lipogram), an

electrocardiogram and an echocardiogram were also considered important.

Treatment of childhood hypertension Lifestyle modification, Prof Rayner emphasised, forms the basis of treatment of the pre-hypertensive or hypertensive child. Weight loss and increased exercise are of particular importance. The use of therapeutic agents should be considered in those children with symptomatic hypertension, secondary hypertension, organ damage and type 1 and 2 diabetes. Also consider those with persistent hypertension despite lifestyle modification. There are some concerns over the use of diuretics in the young, but the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), calcium channel blockers and beta-blockers has been safely established. Prof Rayner did comment that weight gain and poor exercise tolerance arising from beta-blocker use predisposes the patient to type 2 diabetes. G Hardy

HEALTHCARE


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With Prof Brian Rayner (current president of the Southern African Hypertension Society) are three stalwarts of the hypertension community in South Africa, who received a special award for their dedication to improving hypertension research and practice in South Africa. From left to right: Prof Krisela Steyn, Prof Yosuf Variava and Prof F John Milne.

Colleagues of many years’ standing met at the recent South African Hypertension Congress. Left: Prof Andries Brink, editor of CVJAfrica and founding president of the South African Medical Research Council; middle: Dr Derek Yach, senior vice president of Global Health and Agriculture Policy, PepsiCo, based in New York; right: Prof Krisela Steyn, director of the MRC’s Chronic Diseases of Lifestyle Unit and now a consultant to the Department of Health, University of Cape Town and other organisations.

Erratum We regret the drug name Riociguat was wrongly spelt in the article on page 120 of volume 23 number 2. Below is the correct title.

Recruitment of pulmonary hypertension patients for PATENT trial with Riociguat completed Sub-Saharan pulmonary hypertension study launched

SUBSCRIBE to CVJAfrica & SAJDVD Fully searchable data set of CVJAfrica (2001-2012) & SAJDVD (2004-2012). You can subscribe to both these journals online.

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Case Report Iatrogenic hydropneumopericardium F PETERS, A PATEL, R ESSOP

Abstract We report a case of iatrogenic hydropneumopericardium in a patient with diffuse scleroderma. The transthoracic echocardiogram revealed classical features of this condition. This case resolved spontaneously after five days using only 60% oxygen, which may have augmented resolution in this instance. Keywords: iatrogenic, hydropneumopericardium, scleroderma Submitted 7/7/10, accepted 15/4/11 Cardiovasc J Afr 2012; 23: e1–e2

The patient remained stable in the intensive care unit and was put on a 60% oxygen face mask. The tract where the pericardiocentesis was performed appeared to have closed spontaneously. An echocardiogram four days later showed almost complete resolution of the air bubbles, with a large residual pericardial effusion (Fig. 4). The patient was subsequently started on steroids and remained stable. She was followed up as an outpatient, with partial resolution of her pericardial effusion on discharge. After investigation we concluded that this patient’s pericardial

www.cvja.co.za

DOI: 10.5830/CVJA-2011-014

Case report A 47-year-old woman with diffuse scleroderma was found on chest X-ray to have cardiomegaly and was referred for an echocardiogram. The examination of the cardiovascular system was normal except for the presence of severe uncontrolled hypertension. Her blood results were normal, including her renal function. The transthoracic echocardiogram revealed normal left ventricular systolic function, concentric left ventricular hypertrophy with a large pericardial effusion, accompanied by diastolic collapse of the right ventricular free wall and systolic collapse of the right atrium. The rest of the heart and aorta were normal. Echo-guided pericardiocentesis using the subxiphoid approach was done to drain 800 ml of serous fluid. This exudate had normal adenosine deaminase levels, as well as cytology and microbiological analysis. A transthoracic echocardiogram performed the next day revealed a large pericardial effusion with multiple swirling ‘hyperdensities’ within the fluid with no echo signs of tamponade (Figs 1, 2). A chest X-ray confirmed a large pneumopericardium (Fig. 3). A CT scan of the thorax and upper abdomen with hexabrix follow-through confirmed the hydropneumopericardium and revealed no communication with the oesophagus, lungs and stomach. The mediastinum was normal and there was no air in the subcutaneous tissue of the chest.

Fig. 1. Apical four-chamber view demonstrating the swirling echogenic bubbles within the large pericardial effusion.

Division of Cardiology, Chris Hani Baragwanath Hospital, Johannesburg, South Africa F PETERS, MB BCh, FCP (SA), Cert Cardiology (SA), ferande. peters@gmail.com A PATEL, MB BCh, FCP (SA) R ESSOP, MB BCh, FCP (SA), FACC, FRCP (London)

Fig. 2. Parasternal short-axis view demonstrating the large pericardial effusion within which the swirling echogenic bubbles can be seen.


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Fig. 3. Chest X-ray demonstrating the air–fluid level, confirming the hydropneumopericardium on both the anteroposterior and lateral projections.

following surgery. Spontaneous hydropneumopericardium following unsuccessful percutaneous pericardiocentesis for a postcardiac surgical pericardial effusion has been noted, as well as following serofibrinous pericarditis, and also in a patient with endomyocardial fibrosis.3,4 Due to the underlying cause being a fistula, most patients require surgical drainage to prevent tamponade and to address the underlying cause.5 Surgery is usually performed as an emergency procedure and the mortality rate of this condition has been reported to be as high as 58%.

Conclusion

Fig. 4. Parasternal short-axis view demonstrating the large pericardial effusion with only a few air bubbles left four days later.

effusion was most likely due to the scleroderma. We postulated that after pericardiocentesis, the tract created by the needle remained open for a period of time due to the nature of the skin and subcutaneous tissue as a result of her scleroderma. Also a flap valve was created transiently by her being in the antiTrendelenburg position.

Discussion Hydropneumopericardium is a rare condition which usually arises from a fistula created between the pericardium and the oesophagus, or a diaphragmatic hernia, and in one instance a pancreatic pseudocyst.1,2 This can also arise after trauma or

This case illustrates the classic echo features of hydropneumopericardium in the context of an unusual clinical scenario and is to our knowledge the first documented case of spontaneous resolution. It also highlights documented serious complications of percutaneous pericardiocentesis, a procedure that is not without problems.

References 1.

2.

3.

4. 5.

Vidi V, Singh PP, Alhumaid AC, Lee RS, Kinnunen PM. Hydropneumopericardium. Presenting as an acute coronary syndrome: a rare complication of paraesophageal hernia. Tex Heart Inst J 2009; 36(3): 255–258. Hardikar JV, Mistry RC, Patel CV. Hydropneumopericardium due to ruptured traumatic pseudocyst of pancreas (a case report). J Postgrad Med 1986; 32(4): 241–242. Wu M, He X, Yang G. Spontaneous tension hydropneumopericardium complicating serofibrinous pericrditis. Eur J Cardiothorac Surg 2006; 29(3): 422–424. Aidal E, Valori A, Abbruzzenese PA. Postoperative hydropneumopericardium. Heart 2004; 90(9): 1058. Cummings RG, Wesly RL, Adams DH, Lowe JE. Pneumopericardium resulting in cardiac tamponade. Ann Thorac Surg 1984; 37(6): 511–518.


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Case Report Spontaneous coronary artery dissection associated with Leriche syndrome CY KARABAY, MM CAN, IH TANBOGA, SM AUNG, A KALAYCI, C GECMEN, C KIRMA

Abstract Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. SCAD has been observed in three groups of patients; those with coronary atherosclerosis, women in the peripartum period, and those with an idiopathic cause. SCAD may also be associated with other conditions. Herein, we present a 44-year-old man who developed SCAD concomitant with Leriche syndrome. Keywords: spontaneous coronary artery dissection, Leriche syndrome Submitted 13/4/10, accepted 15/5/11 Cardiovasc J Afr 2012; 23: e3–e5

www.cvja.co.za

DOI: 10.5830/CVJA-2011-012

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome and sudden cardiac death.1 SCAD has been described in young women during the peripartum period and in women using oral contraceptive pills.1 The majority of cases of SCAD appear to be idiopathic, although dissections have been linked to Marfan’s syndrome, atherosclerotic cardiovascular disease, blunt chest trauma, intense physical exercise, use of contraceptives, Kawasaki disease, systemic lupus erythematosus and other conditions. The management of these patients has been controversial. Here, we present a 44-year-old man who developed SCAD concomitant with Leriche syndrome.

the precordial leads. Transthoracic echocardiography revealed hypokinesia of the anterior, anteroseptal and apical walls of the left ventricle with an ejection fraction of 40% (by Simpson’s method). Concurrent biochemical markers were consistent with myocardial necrosis (TnI: 17.1 ng/dl, reference: 0–0.1 ng/ml). On physical examination, the bilateral femoral arteries could not be palpated. Coronary angiography was performed via the brachial artery due to the absence of pulsations of the femoral arteries. Coronary angiography showed a flap-like filling defect in the middle third of the left anterior descending artery (LAD) (Fig. 1) but no plaque was detected in the LAD. We did not perform IVUS to exclude plaques with positive remodelling. An atherosclerotic plaque was noted in the distal segment of the right coronary artery (RCA). Aortography showed the occlusion of the abdominal aorta at the infra-renal level (Fig. 2). The levels of AT III, proteins C and S, plasminogen, fibrinogen, and factor V Leiden were evaluated for thrombophilia and found to be normal. Markers of autoimmune disorders such as complement, cryoglobulins, antinuclear, antineutrophil, cytoplasmic, anti-DNA and antiphospholipid antibodies were also found to be negative. Therefore atherosclerosis was assumed to be the underlying pathology of the distal aortic occlusion. Cardiac positron emission tomography, performed after the patient had stabilised, revealed no viable myocardium. We planned medical treatment for the coronary artery disease and aorto-bifemoral bypass for the peripheral disease.

Case report A 44-year-old man presented to our emergency department with pain in the chest and left arm of two days’ duration. He had hypertension, hyperlipidaemia and a 20-pack-year history of smoking but no history of coronary artery disease. He had intermittant claudication of approximately three months’ duration. His ECG showed pathological Q waves and deep T waves on

Cardiology Clinic, Kartal Kosuyolu Heart and Research Hospital, Istanbul, Turkey

CY KARABAY, MD, karabaymd@yahoo.com MM CAN, MD IH TANBOGA, MD SM AUNG, MD A KALAYCI, MD C GECMEN, MD C KIRMA, MD

Fig. 1. Coronary angiography showing flap-like filling defect in the middle third of the left anterior descending artery (arrow).


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Fig. 2. Occlusion at the infra-renal level of the abdominal aorta.

Discussion SCAD is a rare cause of myocardial infarction. The incidence of SCAD has been estimated to vary from 0.1 to 1.1%.1 SCAD usually occurs as a consequence of haemorrhage within the outer third of the media or between the media and the external elastic lamina of a coronary artery. Expansion of the false lumen by further bleeding and separation of the dissected layers leads to compression of the true lumen, with subsequent myocardial ischaemia or infarction.2 Disruption and bleeding from the vasa vasorum has been suggested as a possible mechanism. An underlying inflammatory process has been discussed by several authors.3 In patients with atherosclerosis, plaque rupture that disrupts the intima–media junction, with the formation of an intramural haematoma is believed to be the underlying cause. In women who develop dissection during pregnancy or puerperium, hormonal changes are thought to impair collagen synthesis, loosen the ground substance, and cause changes in the media of the coronary walls.1-3 Clinically, SCAD may present with the entire spectrum of coronary syndromes, varying from unstable angina to myocardial infarction. The pattern and severity of presentation are primarily related to the vessel involved, the extent of dissection, its rate of development and the presence of coronary artery disease.1 SCAD has been described in healthy young women,4 among whom 25–30% were pregnant or in the peripartum period.4 SCAD probably accounts for up to 30% of the myocardial infarctions during pregnancy or during the early postpartum period.4 SCAD has been described in the setting of atherosclerotic coronary artery disease,5 isolated fibromuscular dysplasia of the coronary arteries,6 hypertrophic cardiomyopathy,7 oral contraceptive use,8 cocaine abuse,9 cyclosporine use,10 Marfan or Ehlers–Danlos syndrome,11 and sarcoidosis.12 In rare cases, the occurrence of SCAD is a cause of acute myocardial infarction after heavy lifting in male patients who have coronary risk factors. However, SCAD associated with Leriche syndrome has not been reported before.

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Leriche’s syndrome13 is an aorto-iliac occlusive disease in men, with associated signs and symptoms of intermittent claudication, atrophy of the leg muscles, impotence and reduced femoral pulses. The main cause of this syndrome is an atherosclerotic obstruction of the aorto-iliac arteries. It typically begins at the origin of the distal aorta or common iliac artery. The progression is quite variable, but it may ultimately extend to the level of the renal arteries or result in total aortic occlusion. Surgical treatment is important for these patients.14 SCAD predominantly occurs as single-vessel disease, and the LAD is most often involved (in 75% of cases), followed by the RCA, and the left main and circumflex arteries.1-12 Only a few cases of multi-vessel dissection have been reported.15 The majority of patients with left coronary artery dissection sustain myocardial infarction (vs only 50% of patients with RCA dissection).15 Several treatment modalities (coronary artery bypass grafting, PTCA and/or stenting) have been reported with variable success.15 Medical therapy alone in patients who completed their infarctions after dissections and without residual ischaemic symptoms produced good long-term outcomes.15 To the best of our knowledge, this is the first reported case with the concomitant presence of SCAD and Leriche syndrome. Although our patient presented with a recent myocardial infarction, he was discharged with anti-anginal and anti-ischaemic medication without percutaneous or surgical interventions because no viable myocardium was detected. Aorto-bifemoral bypass was planned for the Leriche syndrome.

Conclusion SCAD is a rare cause of acute coronary artery syndrome but should be considered in the differential diagnosis of patients at risk, especially pregnant women who present with chest pain in the peripartum period.

References 1. 2.

3.

4. 5.

6.

7.

8.

9.

Almeda FQ, Barkatullah S, Kavinsky CJ. Spontaneous coronary artery dissection. Clin Cardiol 2004; 27: 377–380. Mulvany NJ, Ranson DL, Pilbeam MC. Isolated dissection of the coronary artery: a postmortem study of seven cases. Pathology 2001; 33: 307–311. Robinowitz M, Virmani R, McAllister HA. Spontaneous coronary artery dissection and eosiniphilic inflammation: a cause and effect relationship? Am J Med 1982; 72: 923–928. Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. Ann Intern Med 1996; 125: 751–762. Celik SK, Sagcan A, Altintig A, et al. Primary spontaneous coronary artery dissections in atherosclerotic patients Report of nine cases with review of the pertinent literature. Eur J Cardiothorac Surg 2001; 20: 573–576. Lie JT, Berg KK. Isolated fibromuscular dysplasia of the coronary arteries with spontaneous dissection and myocardial infarction. Hum Pathol 1987; 18: 654–656. Lette J, Gagnon A, Cerino M. Apical hypertrophic cardiomyopathy with spontaneous post partum coronary artery dissection. Can J Cardiol 1989; 5: 311–314. Azam MN, Roberts DH, Logan WF. Spontaneous coronary artery dissection associated with oral contraceptive use. Int J Cardiol 1995; 48: 195–198. Jaffe BD, Broderick TM, Leier CV. Cocaine-induced coronary-artery dissection. N Engl J Med 1994; 330: 510–511.


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10. Tsimikas S, Giordano FJ, Tarazi RY, et al. Spontaneous coronary artery dissection in patients with renal transplantation. J Invasive Cardiol 1999; 11: 316–321. 11. Bateman AC, Gallagher PJ, Vincenti AC. Sudden death from coronary artery dissection. J Clin Pathol 1995; 48: 781–784. 12. Ehya H, Weitzner S. Postpartum dissecting aneurysm of coronary arteries in a patient with sarcoidosis. South Med J 1980; 73: 87–88.

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13. Leriche R, Morel A. The syndrome of thrombotic obliteration of the aortic bifurcation. Ann Surg 1948; 127: 193–206. 14. Takigawa M, Akutsu K, Kasai S, Tamori Y, Yoshimuta T, Higashi M, Takeshit S. Angiographic documentation of aortoiliac occlusion in Leriche’s syndrome. Can J Cardiol 2008; 24(7): 568. 15. Mohamed HA, Eshawesh A, Habib N. Spontaneous coronary dissection. A case and review of the literature. Angiology 2002; 53: 205–211.


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Case Report Multiple gene polymorphisms predisposing to the prothrombotic state in an adolescent with acute myocardial infarction A DOĞAN, A ICLI, E VAROL, D ERDOGAN

Abstract

Case report

Acute myocardial infarction with ST-segment elevation (STEMI) is rare in adolescents and its pathogenesis is unclear. Growing evidence shows an association between the prothrombotic state and acute STEMI. Prothrombotic genetic factors may be involved in the pathogenesis of STEMI. We present a case of an adolescent with acute STEMI who had multiple prothrombotic gene polymorphisms: in the beta fibrinogen, methylenetetrahydrofolate reductase and cholesteryl ester transfer protein genes, as well as genotypes in plasminogen activator inhibitor-1 and human platelet antigen type-1. He had normal coronary arteries with catheterinduced spasm and was treated with a calcium antagonist and aspirin.

A 15-year-old boy presented with about 16 hours of oppressive chest pain in association with sweating and nausea. He had no known disease, and did not use any therapeutic or recreational drugs. However, he smoked cigarettes intermittently. There was no history of vascular thromboembolic events in his first-degree relatives. His blood pressure was 120/80 mmHg and heart rate 84 beats/minute. The examination of cardiac and other systems was normal. An electrocardiogram (ECG) showed a 2-mm ST-segment elevation in leads II, III-aVF and V5-6, and ST-segment depression in leads aVL and V1-3 (Fig. 1A). Cardiac bio-markers were elevated; troponin T was 1.3 ng/ml (normal value < 0.01 ng/ml) and mass creatine phosphokinase MB (CK-MB) was 57 ng/ml (normal limits: 0.0–4.9 ng/ml). Other routine haematological and biochemical tests were normal. Echocardiograhy revealed an ejection fraction of 60% and mild hypokinesia in the mid- and apical segments of the inferior walls of the left ventricle. He was thought to have acute infero-posterolateral STEMI and given clopidogrel (300 mg), aspirin (300 mg), unfractioned heparin (60 U/kg intravenous bolus, followed by 12 U/h) and oral nitrate. When he was admitted to the coronary care unit, his chest pain was markedly reduced and the ST-segment elevation was resolved. Spontaneous recanalisation was assumed. At the follow-up, his ECG had returned to normal (Fig. 1B) and chest pains did not recur. After 24 hours of hospitalisation, coronary angiography showed a normal right coronary artery with slow blood flow in association with catheter-induced spasm. The spasm was resolved after 200 µg intracoronary nitroglycerin (Fig. 2A). The left anterior descending artery was normal in appearance with stasis and a slow-flow phenomenon in its proximal segment (Fig. 2B). The left circumflex artery was also normal. Thrombotic and genetic tests were performed to identify the aetiology of the STEMI. The activities of protein C, protein S, antithrombin and activated protein C were within normal limits. Serum homocysteine and compliment C3 were also normal. Rheumatological tests, antiphospholipid and anticardiolipin antibodies were negative as well factor V Leiden mutation. Genetic analyses showed heterozygous polymorphisms of beta fibrinogen (455G>A), MTHFR (C677T and A1298C) and CETP (TaqIβ). In addition, PAI-1 4G/4G and HPA1 a/a genotypes were recognised. It was recommended he receive a calcium antagonist

Keywords: myocardial infarction, adolescent, gene polymorphisms, prothrombotic state Submitted 6/5/11, accepted 31/5/11 Cardiovasc J Afr 2012; 23: e6–e8

www.cvja.co.za

DOI: 10.5830/CVJA-2011-025

Acute ST-segment elevation myocardial infarction (STEMI) rarely occurs in adolescents. Its pathogenesis remains largely unknown.1 Growing evidence shows that there is considerable relationship between the prothrombotic state and/or thrombophilia and acute STEMI.2,3 There was also a synergistic effect reported between prothrombotic polymorphisms and traditional risk factors for atherosclerosis.4 There is evidence that beta fibrinogen,5,6 methylenetetrahydrofolate reductase (MTHFR),4,7-9 cholesteryl ester transfer protein (CETP),10 plasminogen activator inhibitor-1 (PAI-1),3,9,11 and human platelet antigen type-1 (HPA1)12 gene mutations may be associated with early-onset STEMI and other cardiovascular events. In this case report, we presented an adolescent with acute STEMI who had multiple gene polymorphisms, most likely predisposing to the prothrombotic state.

Department of Cardiology, Medical School, Suleyman Demirel University, Isparta, Turkey A DOĞAN, MD, adogan35@hotmail.com A ICLI, MD E VAROL, MD D ERDOGAN, MD


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A

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B

Fig. 1. A: Electrocardiogram shows ST-segment elevation in leads II, III-aVF and V5-6, and ST-segment depression in leads aVL and V1-3 . B: At follow up, these changes had disappeared.

(Diltiazem) and aspirin. He has remained well and asymptomatic for 22 months.

In adolescents, the pathogenesis of STEMI is unclear and often different from that of adult STEMI.1 The coronary arteries are usually normal in young patients. The pathogenetic mechanisms may be coronary vasospasm, hypercoagulable state secondary to hereditary thrombophilia, collagen vascular disease and embolisation. However, in most reported cases there is no obvious cause.1-3 Prothrombotic factors may also contribute to the development of STEMI at a young age.1-3 In our case, we observed multiple gene polymorphisms, such as heterozygote beta fibrinogen (455G>A), MTHFR (C677T and A1298C) and CETP (TaqIβ), which most likely predisposed to the prothrombotic state. In addition, PAI-1 4G/4G and HPA1 a/a genotypes were also present.

It has been reported that heterozygous mutation in the beta fibrinogen gene can be associated with STEMI and coronary artery disease.5,6 Similarly, the reduced activity of MTHFR may predispose to coronary events.4,7-9 However, it is unclear if there is a significant association between two common MTHFR mutations (C677T and A1298C) and hyperhomocysteinaemia.7 The homocysteine level was normal in our case. On the other hand, C677T and A1298C MTHFR mutations have been reported to be associated with acute STEMI in adolescents and young adults.4,7-9 CETP mediates the transfer of cholesteryl esters and triglycerides among lipoprotein particles and plays a crucial role in reverse cholesterol transport. The Taq1β polymorphism of CETP may be associated with the early onset of STEMI and coronary atherosclerosis, independent of high-density lipoprotein cholesterol levels.10 The PAI-1 4G/4G genotype may increase PAI-1 levels and/or activity, especially in young males.3,9,11 Over-expression of PAI-1 may induce thrombosis and vulnerability to atherosclerotic

A

B

Discussion

Fig. 2. A: Coronary angiogram demonstrates the right coronary artery with no stenosis after intracoronary nitroglycerin injection. B: The left coronary system appears to be normal. However, there was stasis and slow-flow phenomenon in the proximal segment of the left anterior descending artery.


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plaque, thereby leading to acute STEMI.3,9,11 Despite divergent results on STEMI risk in small studies on carriers of the 4G allele of PAI-1, a large-sized meta-analysis has showed a relationship between PAI-1 4G/4G and the development of STEMI.3 Several platelet allo-antigen systems reside on glycoproteins IIb and IIIa, of which the HPA-1 system is important. However, there are conflicting data about the relationship between HPA-1 polymorphisms and STEMI.12,13 HPA1a or HPA-1b phenotypes may induce platelet aggregation and binding to fibrinogen, thereby increasing the risk of STEMI.12 Coronary spasm can lead to acute STEMI with normal coronary arteries, in association with thrombotic complications, especially in patients with variant angina. Its ergonovineinduced prevalence may increase by 20 to 55% in acute coronary syndromes.14 We did not provoke coronary spasm with ergonovine because of its potential risks; however, there was a catheter-induced spasm in the right coronary artery. Accordingly, we concluded that coronary spasm was most likely to have induced the occurrence of acute STEMI in the presence of a prothrombotic state in our case. However, it is unclear whether multiple gene polymorphisms without simultaneous evaluation of their phenotypes may be associated with arterial thrombotic events.

Conclusion Multiple gene polymorphisms associated with the prothrombotic state may contribute to the development of acute STEMI in adolescents who have a tendency to coronary spasm. Dual antiplatelet or anticoagulant therapy in addition to a calcium antagonist may be considered in such patients with recurrent cardiac events.

References 1.

Kardasz I, de Caterina R. Myocardial infarction with normal coronary arteries: a conundrum with multiple etiologies and variable prognosis:

2. 3.

4.

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14.

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an update. J Int Med 2007; 261: 330–348. Yamada Y, Matsuo H, Segawa T, et al. Assessment of genetic risk for myocardial infarction. Thromb Hemost 2006; 96: 220–227. Ye Z, Liu EH, Higgins JP, et al. Seven hemostatic gene polymorphisms in coronary disease: meta-analysis of 66155 cases and 91307 controls. Lancet 2006; 367: 651–658. Inbal A, Freimark D, Modan B, et al. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood 1999; 93: 2186–2190. Linenberger ML, Kindelan J, Bennett RL, Reiner AP, Cote HCF. Fibrinogen Bellingham: A g-chain R275C substitution and a b-promoter polymorphism in a thrombotic member of an asymptomatic family. Am J Hematol 2000; 64: 242–250. French JK, Van de Water NS, Sutton TM, et al. Potential thrombophilic mutations/polymorphism in patients with no flow-limiting stenosis after myocardium infarction. Am Heart J 2003; 145: 118–124. Rallidis LS, Gialeraki A, Komporozos C, et al. Role of methylenetetrahydrofolate reductase 677C->T polymorphism in the development of premature myocardial infarction. Atherosclerosis 2008; 200: 115–120. Koestenberger M, Nagel B, Gamillscheg A, et al. Myocardial infarction in an adolescent: anomalous origin of the left main coronary artery fro the right coronary sinus in association with combined prothrombotic defects. Pediatrics 2007; 120: e424–427. Picchi A, Pasqualini P, D’Aiello I, et al. Acute ST-elevation myocardial infarction in a 15-year-old boy with celiac disease and multifactorial thrombotic risk. Thromb Hemost 2008; 99: 1116–1118. Meiner V, Friedlander Y, Milo H, et al. Cholesteryl ester transfer protein (CETP) genetic variation and early onset of non-fatal myocardial infarction. Ann Human Genetics 2008; 72: 732–741. Van der Bom JG, Bots ML, Haverkate F, Kluft C, Grobbee DE. The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1. Blood 2003; 101: 1841–1844. Pontiggia L, Lassila R, Pederiva S, et al. Increased platelet-collagen interaction associated with double homozygosity for receptor polymorphisms of platelet GpIa and GpIIIa. Arterioscler Thromb Vasc Biol 2002; 22: 2093–2098. Benze G, Heinrich J, Schulte H, et al. Association of the GPIa C807T and GPIIIa PlA1/A2 polymorphisms with premature myocardial infarction in men. Eur Heart J 2002; 23: 325–330. Romagnoli E, Lanza GA. Acute myocardial infarction with normal coronary arteries: role of coronary artery spasm and arrhythmic complications. Int J Cardiol 2007; 117: 3–5.


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Case Report Very late thrombosis of a paclitaxel-eluting stent after 72 months in a patient on dual anti-platelet therapy V SUBBAN, L KALIDOSS, MA SANKARDAS

Abstract Very late thrombosis continues to be a major cause of concern in the era of drug-eluting stents. The duration of vulnerability to this complication remains undefined. A 62-year-old diabetic male underwent primary percutaneous coronary intervention with a Taxus Express stent (Boston Scientific, Natick, Mass) implantation in 2003 for anterior wall myocardial infarction (AWMI). The patient was on dual anti-platelet treatment. He was asymptomatic and his stress test was negative in 2008. After 72 months, the patient was admitted with acute AWMI resulting from stent thrombosis, which was treated successfully. This case underscores the importance of realising that very late stent thrombosis may occur when patients present with angina symptoms. Keywords: very late stent thrombosis, drug-eluting stent, Taxus Express stent Submitted 29/12/10, accepted 31/5/11 Cardiovasc J Afr 2012; 23: e9–e11

www.cvja.co.za

DOI: 10.5830/CVJA-2011-022

Drug-eluting stents (DES) are widely used in contemporary practice and this has made percutaneous coronary intervention (PCI) an accepted treatment for diabetic patients and those Institute of Cardio-Vascular Diseases, Madras Medical Mission, Chennai, India V SUBBAN, MD, DM, drvijay1977@yahoo.com L KALIDOSS, MD, DM MA SANKARDAS, MD, DM

A

B

with complex coronary artery disease.1 Drug-eluting stents effectively suppress neo-intimal hyperplasia and resulting restenosis, but inadequate stent endothelial coverage results in late stent thrombosis (LST). The exact period of time required for complete neo-intimal healing and susceptibility to stent thrombosis is largely unknown.2 Here we report a case of very late stent thrombosis 72 months after primary percutaneous intervention (primary PCI) to the left anterior descending coronary artery (LAD).

Case report A 62-year-old diabetic male suffered an anterior wall ST-elevation myocardial infarction in 2003. The patient was taken up for primary PCI. The angiogram showed the right coronary artery with no significant stenosis and a totally occluded LAD after the first septal branch. The LAD lesion was pre-dilated with a 2 × 10-mm Maverick balloon (Boston Scientific Corporation, Natick, Massachusetts) and then a 2.75 × 32-mm Taxus Express stent (Boston Scientific Corporation, Natick, Massachusetts) was implanted, with good angiographic results. The peri-procedural period was uneventful. The patient was continued on aspirin, clopidogrel and statin. The ejection fraction with echocardiography was 48% on discharge. The patient was on regular follow up with an indefinite dual anti-platelet regimen. His stress test was negative for inducible ischaemia in 2008. The patient presented to the emergency department in October 2009 with a history of chest discomfort of two hours’ duration. The electrocardiogram showed ST-segment elevation from V1-V6. The echocardiogram revealed regional wall motion C

Fig. 1. Left coronary artery angiogram in the antero-posterior cranial (A), right anterior oblique caudal (B), and left anterior oblique caudal (C) views, showing the totally occluded left anterior descending coronary artery at the proximal end of the stent.


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Discussion

Fig. 2. Two pieces of aspirated thrombus using the Export catheter.

abnormality in the LAD territory and the ejection fraction was 34%. The patient was loaded with 600 mg of clopidogrel and 325 mg of aspirin and was taken up for primary PCI. The left coronary angiogram with a 6 Fr JL 3.5 guiding catheter (Medtronic, Inc. Minneapolis, MN) showed a totally occluded LAD at the proximal end of the stent (Fig. 1). The lesion was easily crossed with a 0.14˝ Balance Middle Wight universal guide-wire (Abbott Vascular, Santa Clara, CA). Intravenous eptifibatide was started. Thrombosuction was done with a 6 Fr Export XT catheter (Medtronic, Inc, Minneapolis, Minnesota), which recovered a substantial amount of thrombus (Fig. 2) and established thrombolysis in myocardial infarction TIMI-3 distal flow with minimal haziness at the proximal end of the stent. The stent segment was dilated serially with a 3 × 10-mm Sprinter balloon catheter (Medtronic, Inc, Minneapolis, Minnesota) at 9–10 atmospheric pressure. The final angiogram showed TIMI-3 distal flow (Fig. 3). The patient had good ST-segment resolution. The peri-procedural period was uneventful. The patient was discharged with dual anti-platelet treatment. He was asymptomatic at one-year follow up. A

B

Late stent thrombosis occurs in 0.6% of patients following DES implantation and is associated with increased mortality, non-fatal myocardial infarction and the need for target-vessel revascularisation.2 DES thrombosis is a multi-factorial process with impaired neo-intimal healing as the common denominator. Other proposed mechanisms of stent thrombosis, from various autopsy and imaging studies, are stenting across major arterial side branches, incomplete stent expansion, stent mal-apposition, stent fracture, long stent length, stent strut penetration of the necrotic core, disruption of vulnerable plaque near the stent, discontinuation of dual anti-platelet therapy, anti-platelet resistance, radiation therapy and hypersensitivity vasculitis.3 The process of neo-intimal healing, characterised by development of an endothelialised layer of smooth muscle cells and extracellular matrix completely covering the stent struts, is delayed and incomplete after the implantation of drug-eluting stents due to the inhibitory properties of the drugs. This has been demonstrated repeatedly in autopsy and angioscopic studies.3 In the angioscopic follow-up study by Awata et al., incomplete neo-intimal covering with uncovered stent struts was seen after two years, following sirolimus-eluting stent implantation, whereas neo-intimal covering was complete with bare-metal stents after six months. They also demonstrated yellow plaques beneath the stent struts. However, none of their patients had stent thrombosis as all were on dual anti-platelet therapy throughout the period of follow up.4 Chen et al., in their study on sirolimus-eluting stents with optical coherence tomography (OCT), have shown similar findings.5 Velero et al. reported a case of stent thrombosis 53 months after sirolimus stent implantation. With OCT, they reported uncovered stent struts with overlying thrombi after a long period of time. They also showed lipid-rich plaque distal to the stent border.6 In our case, even though DES was implanted in the setting of acute ST-elevation myocardial infarction, the procedure was uneventful and the patient was asymptomatic for six years. The patient continued to be on dual anti-platelet therapy until the day of the event. The mechanism of stent thrombosis was not clear in our patient. Intravascular ultrasound and OCT were not performed due to unavailability. Focal thrombotic obstruction in the vicinity of the proximal end of the stent may have been due to unstable plaque rupture in this area. Plaques covered with dysfunctional endothelium forming, despite administration of an anti-mitotic drug and persistent C

Fig. 3. Final angiogram in the antero-posterior cranial (A), right anterior oblique caudal (B), and left anterior oblique caudal (C) views, showing TIMI-3 distal flow.


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polymer, are more common in the peri-stent area. These plaques are prone to rupture even long after the implantation of drugeluting stents.4,6 To the best of our knowledge, this case is the longest reported event of thrombosis following implantation of a paclitaxeleluting stent on dual anti-platelet therapy.

Conclusion Stent thrombosis is an infrequent but serious event with devastating consequences. It may occur years after implantation of first-generation DES, even on dual anti-platelet therapy, as in our case. In future, new-generation DES and biodegradable stents with enhanced vessel-healing properties may prevent late stent thrombosis. Currently, appropriate patient selection, optimal stent deployment, long-term dual anti-platelet therapy, assessment of anti-platelet responsiveness, and aggressive treatment of risk factors may reduce the incidence of this complication.

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References 1. 2. 3.

4.

5.

6.

Garg S, Serruys PW. Coronary stents current status. J Am Coll Cardiol 2010; 56: S1–42. Windecker S, Meier B. Late coronary stent thrombosis. Circulation 2007; 116: 1952–1965. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 2003; 108; 1701–1706. Awata M, Kotani J, Uematsu M, Morozumi T, Watanabe T, Onishi T, Iida O, Sera F, Nanto S, Hori M, Nagata S. Serial angioscopic evidence of incomplete neointimal coverage after sirolimus-eluting stent implantation: Comparison with bare-metal stents. Circulation 2007; 116: 910–916. Chen BX, Ma FY, Luo W, Ruan JH, Xie WL, Zhao XZ, et al. Neointimal coverage of bare-metal and sirolimus eluting stents evaluated with optical coherence tomography. Heart 2008; 94: 566–570. Valero SJ, Moreno R, Recalde AS. Very late drug-eluting stent thrombosis related to incomplete stent endothelialization. J Invasive Cardiol 2009; 21: 488–490.


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Case Report Post-infarction myocardial rupture: a case of pericardial tamponade salvaged by auto-blood transfusion AK KHALEDI, F LARTI, S SAFARI Left ventricular free-wall rupture (LVFWR) is a serious and lethal complication of acute myocardial infarction. Although this complication is not common, the fatality rate is high due to haemodynamic collapse in the setting of cardiac tamponade. We report a case of LVFWR in a patient with a rare blood group, who survived because of an innovative technique for pericardiocentesis and simultaneous transfusion of the aspirated blood into the femoral sheath. A video of the patient’s ventriculography is provided. Keywords: myocardial rupture, auto-transfusion, cardiac tamponade, myocardial infarction Submitted 3/5/10, accepted 1/6/11

Cardiovasc J Afr 2012; 23: e12–e13

www.cvja.co.za

DOI: 10.5830/CVJA-2011-026

Case report A 65-year-old man presented to the emergency department (ED) with a history of retrosternal chest pain of some hours before admission. His condition was stable. The ECG showed non-significant ST-T changes. With a working diagnosis of acute coronary syndrome, the patient was transferred to the critical care unit. His cardiac enzymes were normal. The standard medical therapy for unstable angina was started. The patient’s ECG on the second day of admission showed evidence of evolving inferior myocardial infarction (MI). An echocardiography showed an ejection fraction of 50% and mild infrobasal hypokinesia. On the third day, an exercise tolerance test (ETT) was negative until the end of stage III of the Bruce protocol. The patient was discharged one day after the normal ETT with a recommendation of undergoing elective angiography if he desired. He came back to the ED one day after discharge, with typical chest pain. His condition was stable. This time the ECG showed reappearance of ST elevation in the inferior leads. The patient received streptokinase (SK) and his chest pain resolved. Nine hours later, the patient became agitated and hypotensive

(BP = 70/50 mmHg). Immediately bedside echocardiography was performed and massive pericardial effusion with cardiac tamponade was detected. Cardiac surgeons were consulted and the patient was transferred to the catheterisation laboratory for pericardiocentesis. Because of the patient’s rare blood group, the blood bank could not afford even one unit of packed cells and required at least one hour for blood preparation. An arterial femoral sheath was inserted, both for performing coronary angiography and auto-transfusion of the blood aspirated from the pericardial sac. The patient’s ventriculography is shown in Fig. 1 and a supplementary video is provided at www.cvja.co.za/online journal/vol23/vol23_issue3/videos/DOI-10-5830-CVJA -2011-026.php. Coronary angiography showed triple-vessel disease: the left anterior descending artery (LAD) had 50% stenosis after the first diagonal branch, the left circumflex artery (LCX) had 80% stenosis after the second obtuse marginal branch, and the right coronary artery (RCA) was totally cut off after the acute marginal branch. The patient underwent emergency coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass, and the ventricular free-wall rupture was repaired with a synthetic patch. After three days in the intensive care unit and a total hospital stay of two weeks, the patient was discharged home in a good condition. At the 18-month follow-up visit, he was still doing well.

Department of Cardiology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran AK KHALEDI, MD F LARTI, MD, larti78@yahoo.com

Department of General Surgery, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran S SAFARI

Fig 1. Left ventriculogram showing entrance of contrast media into the pericardial sac. This indicates a free-wall rupture (arrowhead).


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Discussion Among the mechanical complications of acute MI, acute or sub-acute LVFWR is serious and often lethal. The prevalence of LVFWR among patients who die of STEMI is relatively high (14–26%); however, the prevalence is much lower when all STEMI patients are included. The risk factors for LVFWR are identified in several studies and include: absence of previous history of angina or MI, absence of collateral blood flow, infarct size, persistent ST-segment elevation, recurrent or persistent chest pain, age over 70 years, female gender, and anterior location of MI.1,2 The most common site of rupture is the anterior or lateral aspect of the ventricular free wall. Isolated posterior infarction is uncommon and inferior wall infarction is unusual unless associated with infarction of the lateral or posterior wall.3 The type of reperfusion therapy will also affect the risk of cardiac rupture. Early thrombolytic therapy (within six hours of onset of symptoms) has been shown to reduce the risk of cardiac rupture. Late thrombolytic therapy seems to accelerate the occurrence of cardiac rupture, but not its prevalence.4 Although clinical guidelines allow the performance of ETT in stable post-MI patients to assess the extent of residual ischaemia, using a submaximal stress test three to five days after MI, there are some reports of LVFWR during ETT or a few days thereafter.3,5 In our case, one possibility was that performing an early and ‘over-submaximal’ ETT in the setting of SK infusion after re-infarction may have promoted myocardial rupture. The clinical picture of LVFWR is diverse. Acute rupture of the left ventricle usually results in haemopericardium and cardiac tamponade, leading to death. Emergency pericardiocentesis confirms the diagnosis and temporarily relieves the haemodynamic instability. In sub-acute rupture, the defect is occluded by an organised thrombus and the pericardium. It presents with recurrent or persistent chest pain, nausea, agitation, sudden hypotension and ECG manifestations of localised pericarditis.

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Suspicious myocardial rupture necessitates emergency bedside echocardiography; the presence of pericardial effusion must persuade the physician to do pericardiocentesis. A bloody aspirate must be followed by emergency cardiac surgery. Meanwhile, stabilising the patient’s haemodynamic status with any, or a combination of the following measures is the rule: intravenous fluid administration, blood transfusion, inotropic and vasopressor support, continued pericardiocentesis or intra-aortic balloon pump insertion. Timely management is associated with improved survival, especially in sub-acute ruptures.

Conclusion In recent years, there have been increasing reports of patients surviving after LVFWR. To our knowledge, there is no report of auto-transfusion as a life-saving measure. This innovative measure saved time for our moribund patient and allowed him to recover. Another interesting aspect of this case report is the patient’s unusual ventriculography, which shows a rupture in the inferior wall of the left ventricle with contrast media entering into the pericardial sac.

References 1. 2.

3. 4.

5.

Figueras J, Cortadellas J, Soler-Soler J. Left ventricular free wall rupture: clinical presentation and management. Heart 2000; 83: 499. Moreno R, Lopez-Sendon J, Garcia E, et al. Primary angioplasty reduces the risk of left ventricular free wall rupture compared with thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2002; 39: 598. Weinberg L, Kandasamy K, Evans SJ, et al. Fatal cardiac rupture during stress exercise testing: Case series and review of the literature. Sthn Med J 2003; 96: 11. Becker RC, Charlesworth A, Wilocox RG, et al. Cardiac rupture associated with thrombolytic therapy: Impact of time to treatment in the late assessment of thrombolytic efficacy (LATE) study. J Am Coll Cariol 1995; 25: 1063–1068. Pedersen P, Nielsen IB. Myocardial rupture during exercise ECG. Ugeskr Laeger 1998; 160: 1331–1334.


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Case Report Heart failure and cardiogenic shock associated with the TB-immune reconstitution inflammatory syndrome CHRIS KENYON, NESHAAD SCHRUEDER, MPIKO NTSEKHE, GRAEME MEINTJES

Abstract Heart failure has not been described in the setting of TB-immune reconstitution inflammatory syndrome (IRIS). We describe a case of cardiogenic shock in the setting of TB-IRIS four weeks after commencement of antiretroviral therapy. Possible aetiologies and pathophysiology as well as suggested diagnostic and therapeutic approaches to this problem are discussed. Keywords: TB-IRIS, heart failure, HIV, antiretroviral Submitted 4/6/11, accepted 11/9/11 Cardiovasc J Afr 2012; 23: e14–e17

www.cvja.co.za

DOI: 10.5830/CVJA-2011-062

Case report A 34-year-old man was diagnosed with pulmonary tuberculosis (TB). Mycobacterium tuberculosis (susceptible to rifampicin and isoniazid) was cultured from his sputum. After commencing the intensive phase of TB treatment (rifampicin, isoniazid, pyrazinamide and ethambutol) his TB symptoms improved. He tested HIV seropositive and his CD4 count was 34 cells/ml. He commenced antiretroviral therapy (ART) with stavudine, Department of Medicine, GF Jooste Hospital, Cape Town, South Africa CHRIS KENYON, MB ChB, PhD, chriskenyon0@gmail.com NESHAAD SCHRUEDER, MB ChB GRAEME MEINTJES, MB ChB

Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, South Africa CHRIS KENYON, MB ChB, PhD GRAEME MEINTJES, MB ChB

Department of Medicine, University of Cape Town, South Africa NESHAAD SCHRUEDER, MB ChB

Division of Cardiology, Department of Medicine, University of Cape Town, South Africa MPIKO NTSEKHE, MB ChB

Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa GRAEME MEINTJES, MB ChB

Imperial College London, UK GRAEME MEINTJES, MB ChB

lamivudine and efavirenz two weeks after starting TB treatment. Four days after ART initiation he developed a dry cough, worsening shortness of breath, central cramping abdominal pains, and recurrence of drenching night sweats. He was admitted to another hospital and was treated with high-dose cotrimoxazole and prednisone 80 mg daily for a presumptive diagnosis of Pneumocystis jiroveci pneumonia (which in our opinion was an incorrect diagnosis). ART was temporarily interrupted then restarted. He initially responded to this therapy, but symptoms worsened five days after he had completed a 14-day course of prednisone. Over the next few days, he developed progressively worsening shortness of breath as well as orthopnoea, paroxysmal nocturnal dyspnoea and pedal oedema. He was then referred to our facility, four weeks after the initiation of ART. On admission, he was in severe cardiogenic shock. His peripheries were cold and radial pulses were not palpable. His systolic blood pressure, detectable only on palpation, was 60 mmHg. He had a regular heart rate of 130 beats/min. His apex beat was laterally displaced, diffuse and hypokinetic, his jugular venous pressure was elevated 10 cm and there was a third heart sound. On chest auscultation there were extensive bilateral coarse crepitations. He had tender hepatomegaly. A chest radiograph showed worsening of the right mid-zone infiltrate that had been present prior to ART and was related to his pulmonary TB, as well as a marked increase in the cardiothoracic ratio (Fig. 1). Echocardiography confirmed a globally dilated heart with a fractional shortening of 13%. The ECG on presentation showed sinus tachycardia with a heart rate of 122 beats/min (Fig. 2). The QRS axis was –30 degrees, there was evidence of both left atrial and left ventricular hypertrophy by Cornell criteria,1 the QTc interval was prolonged at 453 ms, and there were widespread non-specific T-wave abnormalities. No other QRS or ST-segment abnormalities were noted. A cardiac magnetic resonance image (MRI), performed after the patient was stabilised, showed no evidence of focal inflammation in the myocardium. The left ventricular ejection fraction was 15% on the MRI. Renal function was normal, haemoglobin was 10.6 g/dl, white cell count was 2.3 × 109/l, platelet count was 163 × 109/l and thyroid stimulating hormone level was 3.16 mU/l (normal range = 0.49–5.66). There was no history of significant ethanol abuse to suggest alcoholic cardiomyopathy. Two diagnoses were made. Firstly, we made a diagnosis of paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). This was supported by his initial diagnosis of drug-susceptible pulmonary TB, his response to TB treatment


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A

B

C

D

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Fig. 1. Chest radiographs of the case: (A) at the time of initiation of ART he had a right middle lobe infiltrate ascribed to pulmonary TB. (B) Four weeks later at the time of presentation with TB-IRIS and cardiogenic shock the infiltrate had extended and there was a marked increase in cardiothoracic ratio (CTR). (C) Seven weeks on ART, when he was clinically much improved, the infiltrate had decreased in size and the CTR had decreased. (D) Ten weeks on ART, when TB-IRIS recurred after weaning prednisone, there was again an increase in the pulmonary infiltrate.

Fig. 2. ECG on admission.

prior to ART and then recurrence of TB symptoms associated with worsening of the pre-existing infiltrate of TB on the chest radiograph soon after ART commencement. Secondly, the patient had presented with severe acute heart failure four weeks after starting ART, coincident with the development of TB-IRIS.

The cause of his heart failure was unclear and our considerations regarding the aetiology are discussed below. He was transferred to the high-care unit and commenced on a dobutamine infusion, and once his blood pressure had improved over the next few days, furosemide, enalapril and


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spironolactone were introduced and the dobutamine weaned. His ART was stopped and he was recommenced on prednisone 100 mg daily initially. TB treatment was continued. Broad-spectrum antibiotics (ampicillin plus amikacin) were prescribed to cover the possibility of a bacterial pneumonia, but a blood culture was negative. He was also prescribed intravenous thiamine. Carvedilol was added later. ART was re-introduced after two weeks. During the next two months, two attempts at weaning prednisone resulted in a return of his night sweats, dyspnoea, dry cough and worsening of his pre-existing infiltrates (Fig. 1) but not worsening of heart failure. On both occasions, he had rapid symptomatic improvement after reintroduction of high-dose prednisone. At evaluation three months after initial presentation, he was able to walk two kilometres on the flat, had no signs of heart failure and a repeat echocardiogram measured his fractional shortening as 22%. Prednisone was gradually weaned and he received six months in total. After six months on ART his CD4 count was 359 cells/ml, his HIV viral load was undetectable and his sputum TB culture was negative.

myocarditis is present in nine to 52% of HIV-infected patients. In only 10 to 15% of these cases of myocarditis can evidence of a bacterial, fungal or protozoal infection be found.10-12 The majority of other cases of DCMO are thought to be a result of the direct or immune-mediated effects of HIV itself. A direct role for HIV infection in the development of DCMO was suggested by a study of 952 asymptomatic HIV-infected patients who were followed for 60 months.13 DCMO was diagnosed by echocardiogram in 8%, most of whom had evidence of a myocarditis on endomyocardial biopsy. Among these patients, 76% had HIV nucleic acid sequences present in the myocytes, while 26% had evidence of Coxsackie virus, cytomegalovirus, or Epstein-Barr virus infection. HIV may induce myocardial injury through three putative mechanisms.14 Firstly, HIV may have a direct cytotoxic effect on the myocytes.15 Secondly, HIV-related immune activation may result in high levels of pro-inflammatory cytokines, which result in dysfunction and apoptosis of cardiac myocytes. Thirdly, this immune activation may drive an auto-immune reaction targeting host myocardial cells.

Discussion Paradoxical TB-IRIS

IRIS myocarditis

TB-IRIS affects approximately eight to 43% of patients who commence ART while on treatment for active TB, and it manifests with recurrence or new symptoms, clinical signs and/ or radiographic features of TB despite effective TB treatment.2 A recent meta-analysis reported the pooled cumulative incidence across studies as 15.7%.3 Onset is typically within the first four weeks of ART. IRIS is thought to result from rapid but dysregulated restoration of antigen-specific immunity during early ART.4 In paradoxical TB-IRIS this results in inflammation at the sites of TB disease directed at the residual MTB antigen.5 In addition, TB-IRIS has been shown to be accompanied by marked cytokine elevation in peripheral blood, in particular the pro-inflammatory cytokines IL-6, TNF-α and IFN-γ.6 Since high levels of these pro-inflammatory cytokines have been implicated in the pathogenesis of HIV-associated dilated cardiomyopathy (DCMO),6 it would be plausible to expect that patients who experience severe TB-IRIS accompanied by high pro-inflammatory cytokine concentrations and have pre-existing subclinical DCMO could develop overt heart failure as a consequence. Both TNF-α and inducible nitric oxide synthetase (the production of which is increased in the presence of TNF-α and IL-6) have been implicated in the pathogenesis of DCMO in patients with and without HIV infection.6 It is thought that by a similar cytokine-mediated mechanism, bacterial sepsis may precipitate myocardial depression, particularly in patients with underlying cardiac disease.7 The cytokine-mediated upregulation of inducible nitric oxide synthetase in sepsis results in increased production of reactive oxygen species and interference with calcium homeostasis, thereby impairing myocyte contractility.8

HIV cardiomyopathy DCMO is common in late-stage HIV infection. A Rwandan study found the prevalence of echocardiogram-diagnosed DCMO to be 17.7% among 416 consecutively screened HIV-infected patients without a previous history of heart disease.9 In autopsy studies,

IRIS may affect any organ system and has been described in association with a wide variety of pathogens as well as autoimmune conditions and with HIV itself.3 To our knowledge, there has been one published case of IRIS-associated myocarditis. The patient was a 29-year-old HIV-infected man with a CD4 count of 56 cells/ml who presented five weeks after commencing ART, with acute myocarditis complicated by fatal polymorphic ventricular tachycardia.16 At post mortem, he was found to have evidence of a cytomegalovirus (CMV) pneumonia and a predominantly CD8 lymphocytic infiltrate of his myocardium and conduction system. Immunohistochemical staining for CMV in his myocardium was negative. The myocarditis was attributed to IRIS, given the timing of the presentation, the marked reduction in HIV viral load on ART and the prominent inflammatory infiltrate of the myocardium. The antigenic target of the IRIS was likely HIV itself or an undiagnosed pathogen. In the case we present here, it was not possible to exclude a cellular infiltrate of the myocardium due to IRIS myocarditis because we did not perform an endomyocardial biopsy, but the MRI findings did not suggest myocardial inflammation, making this unlikely.17 We also considered the possibility that our patient’s heart failure resulted from inflammation in the myocardium due to TB-IRIS myocarditis. However, because of the MRI showing no evidence of inflammation in the myocardium, we think this unlikely. We would expect TB myocarditis to be characterised by areas of focal gadolinium enhancement on cardiac MRI.18

Conclusion This patient had no symptoms of heart failure prior to ART. After starting ART he developed paradoxical TB-IRIS, a diagnosis that we made on the basis of the characteristic clinical features described above and which was supported by his having exacerbations of TB-IRIS symptoms on weaning prednisone but improvement when recommenced on higher doses. Prednisone has been shown to result in symptomatic improvement in TB-IRIS.19


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On admission to our hospital, the patient had features of acute, severe heart failure; the heart shadow had increased markedly in size on chest radiograph and he was in cardiogenic shock. He had a good response to inotropes, anti-failure treatment, high-dose prednisone and temporary interruption of ART. There was no cause other than HIV found for his DCMO. We hypothesise that he had an underlying subclinical HIV-associated DCMO, and the development of TB-IRIS with the associated hypercytokinaemia resulted in rapid and severe deterioration in cardiac function. The precipitation of heart failure during IRIS seems to be a rare event. One explanation for this is that the diagnosis may be missed. We would therefore encourage clinicians to at least entertain the diagnosis in patients who present with features of heart failure soon after starting ART, and especially if they present with other features of IRIS. The optimal management of such patients is not determined and will depend on the severity and co-morbidities. In severe cases, consideration should be given to ART interruption and corticosteroid therapy in addition to anti-failure therapy. Given the rarity of this event, however, there is no prospective evidence on which to base management decisions. Prospective studies of changes in cardiac function using echocardiography in patients starting on ART are warranted. So too are autopsy studies that include examination of the myocardium of patients who die during periods of IRIS.

5.

6.

7. 8. 9.

10. 11. 12.

13.

Graeme Meintjes is supported by the Wellcome Trust and received SATBAT research training that was Fogarty International Center and NIH-funded (NIH/FIC 1U2RTW007373 and 5U2RTW007370).

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Casale PN, Devereux RB, Alonso DR, Campo E, Kligfield P. Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings. Circulation 1987; 3: 565–572. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al. for the International Network for the Study of HIV-associated IRIS 2008. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8(8): 516–523. Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M, for IeDEA Southern and Central Africa. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10(4): 251–261. Dhasmana DJ, Dheda K, Ravn P, Wilkinson RJ, Meintjes G. Immune

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reconstitution inflammatory syndrome in patients receiving antiretroviral therapy. Pathogenesis, clinical manifestations and management. Drugs 2008; 68(2): 191–208. Meintjes G, Rabie H, Wilkinson RJ, Cotton MF. Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. Clin Chest Med 2009; 30(4): 797–810. Tadokera R, Meintjes G, Skolimowska KH, Wilkinson KA, Matthews K, Seldon R, et al. Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur Respir J 2011; 37(5): 1248–1259. Merx MV, Weber C. Sepsis and the heart. Circulation 2007; 116: 793–802. Ntsekhe M, Mayosi BM. Cardiac manifestations of HIV infection: an African perspective. Nat Clin Pract Cardiovasc Med 2009; 2: 120–127. Twagirumukiza M, Nkeramihigo E, Seminega B, Gasakure E, Boccara F, Barbaro G. Prevalence of dilated cardiomyopathy in HIV-infected African patients not receiving HAART: a multicenter, observational, prospective, cohort study in Rwanda. Curr HIV Res 2007; 5: 129–137. Lewis W. AIDS: cardiac findings from 115 autopsies. Prog Cardiovasc Dis 1989; 32(3): 207–215. Anderson DW, Virmani R, Reilly JM, O’Leary T, Cunnion RE, Robinowitz M, et al. Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome. J Am Coll Cardiol 1988; 11(4): 792–799. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. AIDS Res Hum Retroviruses 1998; 14(12): 1071–1077. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med 1998; 339(16): 1093–1099. Currie PF, Boon N. Immunopathogenesis of HIV-related heart muscle disease: current perspectives. AIDS 2003; 17(suppl 1): s21–s28. Fiala M, Popik W, Qiao JH, Lossinsky AS, Alce T, Tran K, et al. HIV-1 induces cardiomyopathy by cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. Cardiovasc Toxicol 2004; 4(2): 97–107. Rogers JS, Zakaria S, Thom KA, Flammer KM, Mehra R. Immune reconstitution inflammatory syndrome and human immunodeficiency virus-associated myocarditis. Mayo Clin Proc 2008; 83(1): 1275–1279. De Cobelli F, Pieroni M, Esposito A, Chimenti C, Belloni E, Mellone R, et al. Delayed gadolinium-enhanced cardiac magnetic resonance in patients with chronic myocarditis presenting with heart failure or recurrent arrhythmias. J Am Coll Cardiol 2006; 47(8): 1649–1654. Jagia P, Gulati GS, Sharma S, Goyal NK, Gaikwad S, Saxena A. MRI features of tuberculoma of the right atrial myocardium. Pediatr Radiol 2004; 34: 904–907. Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010; 24(15): 2381–2390.


EVERY DAY IN SOUTH AFRICA

44** PATIENTS WILL HAVE AN AF* RELATED STROKE1, 2, 3

22** OF THEM WILL DIE

WITHIN A YEAR (50 %)4

90 % OF STROKE PATIENTS WITH KNOWN AF WERE NOT THERAPEUTICALLY ANTICOAGULATED4

THINGS ARE ABOUT TO CHANGE IN ANTICOAGULATION THERAPY

*AF – Atrial Fibrillation ** Best Estimate

HEALTHCARE

REFERENCES: 1. Stats South-Africa. Stats-Online. P0302 - Mid-year population estimates. Updated 20 July 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03022010.pdf 2. Connor M. Stroke Management in South Africa – Who is responsible? S Afr Psychiatry Rev 2005; 8: 125-126. 3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a populationbased study. Stroke 2005; 36:1115-9. 4. Gladstone DJ, Bui E,Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40;235-240.

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• Surgical treatment of renovascular hypertension • Stented tissue mitral and aortic heart valve replacement • Helicobacter pylori infection in acute coronary syndrome • Tachycardia-induced cardiomyopathy • Serum tumour markers in pericardial effusion • Left ventricular structural changes after antihypertensive treatment • Factors in pre-eclamptic African women • Cardiac surgery risk-stratification models

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• Cardiac surgery for African children • New anticoagulants in atrial fibrillation


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