CVJA Volume 23, Issue 4

MAY 2012 VOL 23 NO 4

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CardioVascular Journal of Africa (official journal for PASCAR)

• Endothelial dysfunction • Cardiac surgery and haematological malignancies • Cardiovascular risk factors in coronary artery disease • Changes in NT-proBNP • Effusive–constrictive pericarditis in Ibadan • Pneumonia in post cardiac surgery • Cardiovascular disease in the Seychelles, Tanzania and Mauritius

PUBLISHED ONLINE:

Cardiovascular Journal of Africa . Vol 23, No 4, May 2012

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• Mobile atheromatous plaque of the aortic arch • Images in carcinoid heart disease

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VOL 23, NO 4. MAY 2012

CONTENTS

Cardiovascular Journal of Africa 184

www.cvja.co.za

Editorial

Endothelial dysfunction: are we ready to heed the vasculature’s early-warning signal?

H Strijdom

Cardiovascular Topics

186 Association between troponin T and ICU mortality, a changing trend S Hajsadeghi • S Gholami • G Gohardehi • NS Moghadam • AS Sabet • SRJ Kerman • M Moradi • R Mollahoseini 191

Nebivolol therapy improves QTc and QTcd parameters in heart failure patients SM Aksoy • S Cay • G Cagirci • N Sen

194 Can cardiac surgery be performed safely on patients with haematological malignancies A Guler • MA Sahin • F Cingoz • E Ozal • U Demirkilic • M Arslan 197 The impact of cardiovascular risk factors on the site and extent of coronary artery disease AF Zand Parsa • H Ziai • L Haghighi 200 The time-course changes of NT-proBNP and tissue Doppler indices in patients undergoing mitral valve replacement DR Prakaschandra • T Esterhuizen • DP Naidoo 206 Presentation pattern and management of effusive–constrictive pericarditis in Ibadan MA Salami • PO Adeoye • VO Adegboye • OA Adebo 212 Risk factors for the development of pneumonia post cardiac surgery AE Topal • MN Eren 216 An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: a five-year experience B Mazibuko • H Ramnarain • 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

Letter to the Editor

VOL 23, NO 4. MAY 2012

CONTENTS

205 Cohort studies of cardiovascular disease in the Seychelles, Tanzania and Mauritius P Bovet • C Shamlaye

Review Article

222

Endothelial dysfunction: the early predictor of atherosclerosis M Mudau • A Genis • A Lochner • H Strijdom

232

Expert report on the 22nd European meeting on hypertension and cardiovascular protection, London, 26–29 April 2012 N Rapeport • S Middlemost

Conference Report

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

e1

Non-obstructive membranes of the left atrial appendage T Bordonali • A Saporetti • E Vizzardi • A D’Aloia • E Chiari • L dei Cas

e3

Mobile atheromatous plaque of the aortic arch diagnosed by transthoracic echocardiography prior to coronary artery bypass surgery Which one would you choose: scepticism or wishful thinking?

AC Hatemi • O Omay • M Başkurt • S Kücükoğlu • B Öz • K Süzer

e6 Successful stenting of catheter-induced unprotected left main coronary artery dissection G Ertaş • E Ural • WJ van der Giessen e8

New images in carcinoid heart disease M Klobučić • MH Paar • RŠ Padovan • J Vincelj • B Fila

e11 Aortic dissection, a complication during successful angioplasty of chronic total occlusion of the right coronary artery, was treated conservatively S Chunlai • PR Stella • A Belkacemi • P Agostoni

managing editor

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

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

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

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CONTENT MANAGER

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

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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.

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Electronic abstracts available on Pubmed Audited circulation Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact julia@clinicscardive.com 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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CRESTOR® 5 mg is suitable for select patients who need less aggressive lipid lowering1 CRESTOR® is the more effective statin at lowering LDL-C and raising HDL-C2 CRESTOR® 10 mg will get most patients to LDL-C goal1,3 CRESTOR® is well-tolerated and has a favourable benefit-risk profile4,5 S4 CRESTOR® 5 (Tablet) Each CRESTOR® 5 tablet contains 5 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 10 (Tablet) Each CRESTOR® 10 tablet contains 10 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 20 (Tablet) Each CRESTOR® 20 tablet contains 20 mg of rosuvastatin as rosuvastatin calcium. S4 CRESTOR® 40 (Tablet) Each CRESTOR® 40 tablet contains 40 mg of rosuvastatin as rosuvastatin calcium. PHARMACOLOGICAL CLASSIFICATION: A. 7.5 Serum-cholesterol reducers INDICATIONS: Primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate. Indicated in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments. CRESTOR® 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of CRESTOR® or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated. REGISTRATION NUMBERS: CRESTOR® 5: 41/7.5/0298, CRESTOR® 10: 36/7.5/0349, CRESTOR® 20: 36/7.5/0350, CRESTOR® 40: 36/7.5/0351. DETAILS OF THE REGISTERED LICENCE HOLDER: AstraZeneca Pharmaceuticals (Pty) Ltd Reg No. 1992/005854/07. No. 5 Leeuwkop Road, Sunninghill, 2157, South Africa. Tel: 011 797 6000. Fax: 011 797 6001. www.astrazeneca.co.za. For full details relating to any information mentioned above please refer to the package insert of CRESTOR® 5 mg, 10 mg, 20 mg and 40 mg. CRESTOR® is a registered trademark of AstraZeneca group.

Licensed from Shionogi & Co Ltd, Osaka, Japan. EPI Date: 13/05/2008. Date compiled: March 2011.

References: 1. CRESTOR® package insert 2. Jones P, Davidson MH, Stein EA, et al. Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR* Trial). Am J Cardiol 2003;92:152-160. 3. Schuster H, Barter PJ, Stender S, et al. Effects of switching statins on achievement of lipid goals. Measuring Effective Reduction in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J 2004;147:705-712. 4. Rosenson RS. Statins: can the new generation make an impresssion? Expert Opin Emerg Drugs 2004;9(2):269-279. 5. Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosuvaststin. Am J Cardiol 2004;94:882-888.

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Editorial Endothelial dysfunction: are we ready to heed the vasculature’s early-warning signal?

HANS STRIJDOM Endothelial dysfunction (ED) refers to a spectrum of pathophysiological changes in the vascular endothelium that ultimately results in a loss of vascular homeostasis. Traditional cardiovascular risk factors (e.g. diabetes mellitus, smoking, dyslipidaemia and hypertension) are all associated with the development of ED via sustained and harmful effects, mediated by circulating stimuli such as pro-inflammatory tumour necrosis factor-alpha (TNF-alpha), oxidised low-density lipoprotein (ox-LDL), asymmetrical dimethyl-arginine (ADMA), angiotensin II and hyperglycaemia.1 The underlying cellular mechanisms of ED are directly or indirectly related to the development of oxidative stress (particularly increased superoxide anion production via NADPHoxidase and xanthine oxidase), which reduces the bioavailability of the main endothelial-derived vasodilator, nitric oxide (NO) via the reaction of superoxide with NO (thereby scavenging NO) to form peroxynitrite (ONOO-), a highly reactive molecule. The latter has the ability to uncouple endothelial NO synthase (eNOS), which further reduces NO production and simultaneously increases superoxide anion generation.2 As a result, vascular endothelial function becomes compromised, manifesting as a loss of endothelium-dependent vasorelaxation, increased thrombosis, the development of a generalised pro-inflammatory state (increased expression of vascular adhesion molecules) and increased vascular permeability.3 Ultimately, ED can develop into atherosclerosis.2 The importance of ED as a potential predictor of long-term development of atherosclerosis and cardiovascular event rate2 is evident by the high number of research articles on this topic (PubMed search with keywords: endothelial + dysfunction revealed 51 600 hits and approximately 3 000–4000 articles per year on this topic since 2005). Herein, however, lies both the greatest potential and challenge of current research into ED, namely translating the wealth of data obtained with laboratorybased research into scientifically validated predictive, diagnostic and even therapeutic tools in the clinical setting.

As Mudau et al. explain in their comprehensive review article on the cellular mechanisms and clinical applications of ED in the current issue of this journal, there is no doubt that ED serves as a crucial pathophysiological link between traditional cardiovascular risk factors and the eventual development of atherosclerosis and ischaemic heart disease (IHD).4 Particularly helpful in this regard is the fact that ED is an early, reversible event.5 This presents researchers and clinicians with a golden opportunity to not only predict the development of atherosclerosis, IHD and possibly other cardiovascular events, but also prevent the development of these conditions by therapeutically reversing early vascular dysfunction.

As Mudau and co-workers report, there are several biomarkers that could be used to assess endothelial function.

However, currently elevated ADMA levels appear to be the most promising biomarker of ED in terms of prognostic value and positive correlation with cardiovascular risk. Promising data have also been obtained from studies investigating ex-vivo functional endothelial assessment techniques (current gold standard: flow-mediated dilatation) with regard to their ability to predict cardiovascular risk.

Despite many promising studies showing that biomarkers of ED and ex-vivo endothelial function assessment are strongly correlated with cardiovascular risk, a consensus for their universal clinical usefulness remains elusive.6 Reaching consensus is hampered by factors such as the availability of special equipment in everyday practice, the lack of data on the predictive value of more recent endothelial function assessment techniques, and the lack of studies investigating which patient groups will benefit most from ex-vivo endothelial function measurement.6 Finally, more studies demonstrating that putative anti-ED therapies actually achieve their clinical benefit by the improvement of endothelial function are required.

In the South African/African context, research into ED, its underlying mechanisms and potential clinical application is equally relevant. Indications are pointing to significant increases in the incidence of cardiovascular disease among people of African heritage in South Africa as a result of epidemiological transition and chronic diseases of lifestyle.7 Data from the Heart of Soweto (HOS) study in 2006 indicated a high prevalence of traditional cardiovascular risk factors such as hypertension and obesity, with almost two-thirds of the patients in the study cohort presenting with multiple risk factors.7 Approximately 10% of the patients in the HOS study were diagnosed with coronary artery disease. In addition, recent research has drawn attention to the interaction between HIV infection, anti-retroviral treatment and the increased rate of coronary artery disease in HIV-infected patients.8 Due to the fact that HIV-infected patients on treatment live longer, they are subjected to traditional cardiovascular risk factors similar to the non-infected population. However, of concern is the additional burden of non-traditional risk factors, namely the direct vascular effects of the HI virus and the anti-retroviral drugs.7,8 Consequently, HIV-infected patients on treatment now face the risk of developing premature ED and accelerated atherosclerosis.

In a recent study in South Africa, significantly higher levels of inflammatory biomarkers associated with ED were detected in newly diagnosed, untreated HIV-infected participants of African descent compared to non-infected participants, which was accompanied by age-related increases in arterial stiffness.9 In view

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012

of potentially unprecedented increases in ED and atherosclerosis in particularly the sub-Saharan African region, and the subsequent burden of health this could introduce, it is imperative that researchers and research funding institutions prioritise ED, with respect to both basic scientific and clinical research.

In conclusion, ED is an early and potentially reversible event in the development of atherosclerosis and can therefore be regarded as a vascular early-warning signal. As cardiovascular researchers and clinicians, we should not ignore the importance of this window of opportunity offered to us by ED, since proper detection followed by therapeutic or lifestyle interventions could prevent potentially catastrophic cardiovascular events later in the lives of affected patients.

As explained above, this has become particularly relevant in the sub-Saharan African region, as we are entering unchartered waters with regard to a predicted surge in the incidence of cardiovascular diseases previously unheard of in patients of African descent. This is due to a double burden of both traditional risk factors introduced by epidemiological transition and chronic diseases of lifestyle, but recently also due to non-traditional risk factors introduced by the HI virus and anti-retroviral drugs, particularly with regard to their targeted pro-ED effects. As basic research findings in the context of ED are moving ever closer to effective and potentially standardised clinical applications (i.e. early detection of ED followed by effective and targeted reversal of ED), it is crucial that researchers and clinicians in South Africa and Africa remain abreast of the latest developments. Are we up to the challenge?

MARK YOUR CALENDAR

HANS STRIJDOM, jgstr@sun.ac.za Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, South Africa

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal.

Cardiovasc Diabetol 2006; 5: 4. DOI: 10.1186/1475-2840-5-4.

Münzel T, Sinning C, Post F, Warnholtz A, Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med 2008; 40: 180–196.

Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med 2004; 117: 109–117.

Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction – the early predictor of atherosclerosis. Cardiovasc J Afr 2012; 23(4): 222–231.

Chhabra N. Endothelial dysfunction – A predictor of atherosclerosis.

Internet J Med Update 2009; 4(1): 33–41.

Lekakis J, Abraham P, Balbarini A, et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 2011; 18(6): 775–789.

Pretorius S, Stewart S, Sliwa K. Lessons from the Heart of Soweto Study and future directions. SA Heart 2011; 8: 104–113.

Fedele F, Bruno N, Mancone M. Cardiovascular risk factors and HIV disease. AIDS Rev 2011; 13(2): 119–129.

Fourie C, Van Rooyen J, Pieters M, Conradie K, Hoekstra T, Schutte A. Is HIV-1 infection associated with endothelial dysfunction in a population of African ancestry in South Africa? Cardiovasc J Afr 2011; 22(3): 134–140.

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Cardiovascular Topics Association between troponin T and ICU mortality, a changing trend S HAJSADEGHI, S GHOLAMI, G GOHARDEHI, NS MOGHADAM, AS SABET, SRJ KERMAN, M MORADI, R MOLLAHOSEINI

Abstract Background: Initially elevated levels of troponin predict adverse outcomes in patients admitted to the intensive care unit (ICU). No research team has investigated the changes in concentration of cardiac troponin T (cTnT) during ICU stay and their association with patient outcome.

Objective: We investigated whether the change in cTnT levels during ICU stay could predict outcomes (death or survival).

Methods: In this cohort study, all patients admitted to the medical ICU (10 beds) from January to July 2008 were enrolled. Troponin levels were evaluated within the first 24 hours of ICU admission and on the fourth, seventh and 10th days after admission.

Results: The study population (135 patients) had a mean age of 60.9 ± 21.5 years. The outcome was significantly different with regard to normal or elevated cTnT concentrations on the first and seventh days of follow up (p = 0.03 and 0.023, respectively). This difference was non-significant for cTnT levels on the fourth and 10th days after admission (p = 0.69 and 0.78, respectively). The change in cTnT levels was not significantly different between the deceased and discharged patients (p = 0.4).

Conclusion: Changes in cTnT levels during ICU stay did not show a significant trend (power: 0.26). Patients whose cTnT levels were increased on the first and seventh days of ICU stay had a worse survival, which could be associated with cardiac events on admission or at specific times during the stay in ICU. Department of Cardiology, Rasoul-e-Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran S HAJSADEGHI, MD

Firoozgar Clinical Research Development Centre, Firoozgar Hospital, Tehran University of Medical Sciences, Tehran, Iran S GHOLAMI, sgholami_iums@yahoo.com

Medical Student Research Committee, Tehran University of Medical Sciences, Tehran, Iran G GOHARDEHI NS MOGHADAM AS SABET SRJ KERMAN M MORADI

Department of Neurosurgery, Firoozgar Hospital, Tehran University of Medical Sciences, Tehran, Iran R MOLLAHOSEINI, MD

Keywords: troponin T, ICU, mortality, serial measurement, changing trend Submitted 23/8/10, accepted 7/6/11 Cardiovasc J Afr 2012; 23: 186–190

www.cvja.co.za

DOI: 10.5830/CVJA-2011-034

Dysfunction of, or injury to the myocardium was recently found to be an important complication in non-cardiac critically ill patients, including those with sepsis, pulmonary embolism, renal insufficiency and acute stroke, resulting in increased concentrations of cardiac troponinT (cTnT).1-5The pathophysiology of myocardial injury in critically ill patients is believed to be multifactorial, including the underlying disease process, hypoxaemia and acidosis, as well as therapeutic activities.6,7 Over the past decade, several studies have indicated that cardiac dysfunction is a frequent and important factor in determining the outcome of critically ill patients.8,9 Damage to the myocardial cells results in the release of contractile regulating proteins such as cTnT, which is a highly sensitive and specific marker of myocardial injury.10,11 More importantly, elevated levels of troponin predict a poor prognosis in patients with acute coronary syndromes12-16 and may also predict adverse outcomes in other patients admitted to the intensive care unit (ICU).

In a medical ICU, patients with elevated levels of troponin T or troponin I admitted without a diagnosis of acute coronary syndrome exhibited a fourfold higher mortality rate.17 In patients in a surgical ICU, moderate elevations in troponin I were associated with higher mortality rates, and a longer stay in hospital and in the ICU.16-18 Some studies19,20 have shown that increased cTnT levels are associated with increased mortality, but others did not confirm this association.21,22 The association between elevated troponin level and adverse outcome was uncertain, so the interpretation of elevated troponin levels during critical illness remains unclear.

Cardiac events resulting in elevated biomarkers may occur during ICU stay and have an important effect on patient outcome.

There is no research evaluating the relationship between changing levels of any cardiac biomarkers during ICU stay and patients’ outcome. We therefore hypothesised that patients admitted to the ICU with increased cTnT levels were at increased risk of death, and determined whether elevated troponin levels were related to outcome and length of stay and mortality in the ICU. We also investigated whether the change in cTnT levels during ICU stay could predict outcomes (death or survival).

Correlation of troponin levels with the most popular disease

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severity classification system, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, was also evaluated.

Methods In this cohort study, all 135 patients admitted to the medical ICU (10 beds) from January to July 2008 were enrolled consecutively. The patients mostly suffered from sepsis (n = 21, 15.5%), stroke (n = 11, 8.1%) and pulmonary disease, including chronic obstructive pulmonary disease (COPD) and pneumonia (n = 11, 8.1%). This investigation was approved by the ethics committee of the Iran University of Medical Sciences. Verbal consent was obtained from all patients (or from their next of kin) after detailed explanations and a letter of explanation was given.

On admission to the medical ICU, demographic and baseline clinical characteristics, including age, gender and APACHE II score and the diagnoses of all patients were recorded. The APACHE II system incorporates acute physiological variables and chronic health evaluation into a measurement of the risk of in-hospital mortality.23 Levels of cardiac biomarkers such as creatine kinase (CK) and creatine kinase isoenzyme (CK-MB), and history of cardiovascular disease were included. All patients in the ICU had electrocardiography (ECG) within 24 hours of admission. The length of stay in the ICU was also recorded. The clinical endpoint was death or discharge from the ICU at any time during hospitalisation.

Troponin measurements were collected within the first 24 hours of ICU admission and on the fourth, seventh and 10th day after admission. This was suggested by the ICU team and was based on their clinical judgment. Troponin T was measured using a radio-immunoassay. The analytical sensitivity (lower detection limit) of this assay is 0.01 µg/l. Troponin concentration of 0.1 µg/l was considered normal. Because of a laboratory mistake, 16 patients did not have troponin T levels measured on admission, but troponins were measured on days four, seven and 10; these data were included in the analysis. Of all patients, 74 patients had the first two, 47 had the first three, and 25 had four serial measurements for cTnT concentrations. Patients did not have cTnT levels measured on discharge or on death.

Statistical analysis Baseline characteristics of the negative (normal levels) and positive (elevated levels) cTnT groups were compared using the Pearson’s chi-square test. Continuous variables were compared using the Student’s t-test for normally distributed variables, and the Mann–Whitney U test if either of these conditions were not met. Linear regression analysis was done to evaluate the independent association between APACHE score and cTnT levels.

For evaluation of the changes in cTnT levels during ICU stay, repeat-measurement ANOVA analysis was carried out.

The Breslow method was used to compare patient survival in the Kaplan–Meier analysis. Data are presented as mean ± SD. A p-value less than 0.05 was considered significant. Receiver operating characteristics (ROC) were used for the detection of cut-off points for APACHE to predict elevated cTnT levels.

Results The study population consisted of 135 patients admitted to the ICU over a period of seven months. There were 73 (54%) men

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and 62 (46%) women, with a mean age of 60.9 ± 21.5 years, ranging from 15 to 100 years old.

The most common diagnosis was infectious disease, including sepsis (n = 21, 15.5%), stroke (n = 11, 8.1%), and pulmonary disease, including chronic obstructive pulmonary disease and pneumonia (n = 11, 8.1%). There was no significant difference in measured cTnT levels on the first, fourth, seventh and 10th days of ICU stay between patients with different diseases (p > 0.05).

History of cardiovascular disease, including MI, hypertension and heart failure was positive in 51 (37%) patients. The frequency of patients with elevated cTnT levels was not significantly different in patients with and without a history of cardiac disease.

On admission, 83 patients (70.3%) had normal cTnT levels, whereas 35 (29.7%) had elevated levels > 0.01 ng/ml, mean = 0.28 ± 0.5 ng/ml (range 0.03–2.00 ng/ml). The clinical and laboratory characteristics of the two groups are shown in Table 1. There was no significant difference between the two groups with normal and elevated cTnT levels in some baseline characteristics, including Glasgow coma score (GCS) (p = 0.223) and partial arterial oxygen tension (PaO2; p = 0.607) on admission. A significant difference was found in the APACHE II score (p = 0.003) and serum creatinine levels (p = 0.003) between the two groups with different troponin results.

Patients with negative baseline troponin T levels had a significantly lower APACHE II score (17.75 ± 7.76 vs 24.3 ± 8.8, p = 0.003). The APACHE II score on the fourth day after ICU admission was significantly higher in patients with positive TABLE 1. BASELINE LABORATORY PARAMETERS OF 118 CRITICALLY ILL PATIENTS ON ADMISSION TO ICU Negative Positive cTnT level cTnT level Baseline parameters (n = 83) (n = 35) p-value Age (years) 59.8 ± 21.63 61.3 ± 20 0.732 APACHE II score 17.75 ± 7.76 24.3 ± 8.8 0.003 Mean arterial pressure (mmHg) 93.47 ± 13.43 95.17 ± 16.24 0.569 Heart rate (beats/min) 91.56 ± 19 94.74 ± 22.69 0.446 Respiratory rate (per min) 21.41 ± 4.52 20.48 ± 5.7 0.363 97.5 ± 56.6 91.2 ± 46.7 0.607 PaO2 (mmHg) 61.9 ± 27.5 61 ± 26.4 0.887 FiO2 (%) 25.1 ± 8.34 25.11 ± 12.67 0.995 HCO3 (mmol/l) Sodium (mmol/l) 141 ± 7.05 140.5 ± 6.69 0.713 Potassium (mmol/l) 4.11 ± 0.6 4.11 ± 0.7 0.998 Creatinine (mg/dl) 1.19 ± 0.96 2.58 ± 2.53 0.003 Haematocrit (%) 35.55 ± 9.33 32.5 ± 8.33 0.114 White blood cell count (per ml) 12.22 ± 6.49 12.22 ± 4.97 0.999 pH 7.36 ± 0.09 7.34 ± 0.1 0.422 Systolic blood pressure (mmHg) 127.4 ± 18.6 129.7 ± 18.7 0.545 Diastolic blood pressure (mmHg) 76.49 ± 12.58 77 ± 17.8 0.854 GCS (median) 9 10 0.223 CK (U/l) 236.12 ± 255 420 ± 735 0.262 CK-MB (ng/ml) 28.63 ± 21 128.3 ± 190 0.72 Male/female (ratio) 45/38 17/18 0.531 History of cardiac disease 29/54 12/23 0.959 (yes/no) ST change on ECG (yes/no) 36/47 18/15 0.29 PaO2: arterial O2 tension, FiO2: fraction of inspired oxygen, HCO3-: bicarbonate, GCS: Glasgow coma scale, CK: creatine kinase, CK-MB: creatine kinase-MB.

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TABLE 2. THE RESULTS OF ROC ANALYSIS APACHE score Sensitivity Specificity 18.5 0.684 0.552 19.5 0.684 0.603 20.5 0.684 0.621 21.5 0.632 0.655 22.5 0.526 0.69 23.5 0.526 0.741 24.5 0.526 0.793 25.5 0.526 0.828 27 0.474 0.879 28.5 0.368 0.897 The italicised rows are suggested as the best points to predict cTnT.

cTnT levels (25.07 ± 8.01 vs 19.06 ± 8.57, p = 0.026). According to ROC analysis, an APACHE score of more than 20.5 indicated a positive cTnT with 66.7% sensitivity and 62.1% specificity.

An APACHE II score higher than 25.5 indicated a positive cTnT with 50% sensitivity and 83% specificity (p = 0.006, area under the curve = 0.712 and standard error = 0.072) (Table 2, Fig. 1).

Serial blood sampling for cTnT levels was done in the first 24 hours, and on the fourth, seventh and 10th day after ICU admission (Fig. 2). No significant difference was seen in the changes in troponin levels between deceased and discharged patients (p = 0.4). This difference was also non-significant when different diseases were evaluated separately. The difference between troponin levels was not significant between deceased and discharged patients (p > 0.05).

The outcome was significantly different with regard to normal or elevated cTnT concentrations on the first and seventh days after admission (Table 3) but there was a non-significant difference between patients with different levels of cTnT on the fourth and 10th days of admission (Table 3). The cTnT concentration was not significantly different between deceased and discharged patients (Table 4).

There was a significant association between patients’ outcome and change in cTnT levels in the first and fourth days after admission using chi-square analysis (p = 0.029). All patients with a reduced cTnT level died, whereas all patients with an increased cTnT level survived. Also a significant relationship was found between the outcome of patients and the level of cTnT on the fourth and the seventh days of ICU stay (p = 0.02).

All patients with an elevated cTnT level from the fourth to the seventh day survived, whereas all patients with a decreased cTnT

cTnT-3 on the 7th day cTnT-4 on the 10th day

0.4

Deceased n (%) 33 (40) 19 (63) 29 (53) 11 (58) 18 (44) 13 (65) 16 (57) 5 (62)

p-value 0.03 0.69 0.024 0.78

TABLE 4. cTnT CONCENTRATION IN DECEASED OR DISCHARGED PATIENTS Deceased (µg/l, mean ± SD) 0.042 ± 0.061 0.103 ± 0.277 0.094 ± 0.25 0.121 ± 0.365

1st day 4th day 7th day 10th day

Discharged (µg/l , mean ± SD) 0.03 ± 0.084 0.028 ± 0.066 0.852 ± 0.175 0.053 ± 0.119

p-value 0.4 0.12 0.86 0.42

level from the fourth to the seventh day died.

The survival rate of patients on the fourth, seventh and 10th days after admission was 87, 74 and 72% in normal patients, and 83, 61 and 56% in patients with elevated cTnT levels, respectively. The estimated mean survival time of patients with elevated cTnT levels on admission was 16.77 (SE = 3.38) days, and it was significantly lower than the group with normal levels on admission, with a mean survival time of 26.08 (SE = 3.15) days (p = 0.027). This difference was also significant for cTnT concentration on the seventh day after admission [mean survival 31.6 (SE = 3.6) days in patients with normal cTnT levels vs 19.7 (SE = 2.5) days in patients with elevated cTnT levels, p = 0.012] (Fig. 3A, B).

Discussion The present study shows that in critically ill patients, elevated cTnT levels were significantly associated with increased mortality, and the survival time was significantly shorter in patients with elevated cTnT than in those with normal cTnT levels.

Means of cTnt

Sensitivity

cTnT-2 on the 4th day

0.10

0.6

cTnT concentration (µg/l) < 0.1 > 0.1 < 0.1 > 0.1 < 0.1 > 0.1 < 0.1 > 0.1

cTnT-1 on the 1st day

0.12

0.8

0.8

Outcome died discharged

0.6 0.4 0.2

0.2 0.0

TABLE 3. MORTALITY RATE BASED ON NORMAL OR ELEVATED cTnT CONCENTRATION IN DIFFERENT MEASUREMENTS

ROC curve

1.0

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0.0

0.2

0.4

0.6 Specificity

0.8

1.0

Fig. 1. The results of ROC analysis (area under the curve = 0.712 and standard error = 0.072).

0.0

1st

4th 7th Day of measurment

10th

Fig. 2. Trend in cTnT levels over four time periods for 25 patients (± SD).

Cum survival

A

< > < >

1.0 0.8 0.6

0.1 0.1 0.1-censored 0.1-censored

0.4 0.2 0.0

0

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30 40 Length of hospital stay (days)

B Cum survival

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1.0 0.8 0.6 0.4 0.2 0.0

60

cTnT < 0.1 cTnT > 0.1 censored

0

20 40 Length of hospital stay (days)

60

Fig. 3. Patient survival and comparison between patients with high and low cTnT levels on (A) first day of admission (p = 0.027), (B) seventh day of ICU stay (p = 0.012).

Cardiac troponin I and troponin T are the most specific and sensitive laboratory markers of myocardial cell injury. However, they may be elevated in patients presenting with many conditions other than acute coronary syndrome.24 Elevated levels of cTnT were previously considered a specific marker for the diagnosis of MI. Several recent studies have reported unexpectedly high cTnT levels in the serum of ICU patients who did not have underlying coronary syndrome,9,10,25–28 indicating unrecognised myocardial injury during their disease process.

It is reasonable to suggest that critically ill patients are at increased risk of myocardial cell injury. This is due to exposure to many stresses that increase myocardial oxygen demand, whereas the myocardial oxygen supply can be limited by shock, anaemia, tachycardia, hypoxaemia and impaired tissue perfusion.9 These events can result in the release of troponin from cardiomyocytes into the serum. In addition, tumour necrosis factor (TNF), produced by inflammatory cells, can depress myocardial function and induce cardiomyocyte apoptosis, which results in low coronary artery flow and decreased ejection fraction, which may lead to necrosis and cTnT release from cardiomyocytes.29,30 It was found that patients with higher cTnT levels had a shorter survival rate.

The APACHE II scoring system predominately evaluates haemodynamic changes rather than heart function, but cTnT levels could provide a direct marker for cardiac injury, even if clinically unrecognised. In the present study, the APACHE II score on ICU admission was significantly different between patients with elevated and normal cTnT levels. This could have been due to a more serious baseline condition.

Levels of cTnT on admission and on the seventh day could predict an adverse prognosis in critically ill patients, whereas troponin levels on the fourth and 10th days could not. The peak concentration of cTnT was different in these two groups (fourth day in surviving patients and seventh day in patients who died), which in addition to the other findings, represents some undefined importance in the time of assessment of cTnT levels.

Although serial measurements did not provide additional statistical value for risk stratification, the different peaks of troponin levels in deceased and discharged patients are shown in Fig. 2. Different outcomes during ICU stay related to decreasing or increasing cTnT levels have not been reported before. We found that whenever cTnT levels begin to decrease, an adverse outcome could be expected, and increasing cTnT level was a predictor of a favourable outcome. This indicates the significant role that daily changes in cTnT levels play, independent of baseline cTnT levels.

Ammann et al.17 showed that troponin positivity on admission was associated with a fourfold increased risk of mortality in 58 critically ill patients without acute coronary syndrome. In their study, a significant difference in survival between troponinpositive and troponin-negative patients was found mainly in a subgroup of patients without volume-refractory shock. This implied that the analysis of troponin level could predict mortality in the early but not the late stage of the disease. In another study by Vlad et al., high levels of cTnT on admission had an independent association with in-hospital, short- and long-term mortality in 2 078 patients with acute respiratory distress.31 A limitation of the study was that we did not measure renal function in any patient. Renal function is an important factor in cTnT concentrations because the kidney filters cTnT from the blood. An investigation with a larger sample size is also necessary. An inevitable limitation of the sample size was the decreasing number of patients over time because of the death of some between admission and the 10th day. Another limitation was the assay method, which could not detect a cTnT concentration less than 0.01 µg/l, so we did not have exact concentrations for many patients, who were reported to have zero cTnT concentrations.

Conclusion We found that levels of cTnT could predict outcome in critically ill patients at specific times. There was a significant association between outcome and cTnT level on the first and seventh days of ICU stay, and a non-significant association with cTnT level on the fourth and 10th days. The level of cTnT had an association with outcome and survival, and was shown to be a predictor of outcome. Cardiac TnT levels during ICU stay did not show a significant trend overall, which may have been due to the small sample size (power: 0.26) but changes in cTnT levels at specific times could be a useful predictor. A study focusing on defining the best time for measurement of cTnT levels would also provide crucial data.

References 1.

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Wu AH. Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med 2001; 27: 959–961.

Parker MM. Myocardial dysfunction in sepsis: injury or depression?

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Guest TM, Ramanathan AV, Tuteur PG, et al. Myocardial injury in critically ill patients. A frequently unrecognized complication. J Am Med Assoc 1995; 273: 1945–1949.

Kollef MH, Ladenson JH, Eisenberg PR. Clinically recognized cardiac dysfunction: an independent determinant of mortality among critically ill patients. Is there a role for serial measurement of cardiac troponin I? Chest 1997; 111: 1340–1347.

Hamm CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum troponin in unstable angina. N Engl J Med 1992; 327: 146–150.

Ohmann EM, Armstrong PW, Christenson RH, et al. Risk stratification with admission cardiac troponin T levels in acute myocardial ischemia.

N Engl J Med 1996; 335: 1333–1334.

Christensen RH, Duh SH, Newby LK, et al. Cardiac troponin T and cardiac troponin I: relative values in short-term risk stratification of patients with acute coronary syndromes. Clin Chem 1998; 44: 494–501.

Jaffe AS, Ravkilde J, Roberts R, et al. It’s time for a change to a troponin standard. Circulation 2000; 102: 1216–1220.

Turner A, Tsamitros M, Bellomo R. Myocardial cell injury in septic shock. Crit Care Med 1999; 27: 1775–1780.

Cunnion RE, Schaer GL, Parker MM, et al. The coronary circulation in human septic shock. Circulation 1986; 73: 637–644.

Stubbs P, Collinson P, Moseley D, et al. Prospective study of the role of cardiac troponin T in patients admitted with unstable angina. Br Med J 1996; 313: 262–264.

Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease.

The FRISC study group. Circulation 1996; 93: 1651–1657.

Galvani M, Ottani F, Ferrini D, et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina.

Circulation 1997; 95: 2053–2059.

Newby LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. The GUSTO-IIa Investigators. Circulation 1998; 98: 1853–1859.

Ammann P, Maggiorini M, Bertel O, et al. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003; 41: 2004–2009.

Relos RP, Hasinoff IK, Beilman GJ. Moderately elevated serum

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troponin concentrations are associated with increased morbidity and mortality rates in surgical intensive care unit patients. Crit Care Med 2003; 31: 2598–2603.

Jensen JK. Kristensen SR, Bak S, et al. Frequency and significance of troponin T elevation in acute ischemic stroke. Am J Cardiol 2007; 99: 108–112.

Di AE, Fiorelli M, Toni D, et al. Prognostic significance of admission levels of troponin I in patients with acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2005; 76: 76–81.

Etgen T, Baum H, Sander K, et al. Cardiac troponins an N-terminal pro-brain natriuretic peptide in acute ischemic stroke do not relate to clinical prognosis. Stroke 2005; 36: 270–275.

Barber M, Morton JJ, Macfarlane PW, et al. Elevated troponin levels are associated with sympathoadrenal activation in acute ischaemic stroke. Cerebrovasc Dis 2007; 23: 260–266.

Ammann P, Pfisterer M, Fehr T, et al. Raised cardiac troponins. Br Med J 2004; 328: 1028–1029.

Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13(10): 818–829.

Hamm CW. Risk stratifying acute coronary syndromes: gradient of risk and benefit. Am Heart J 1999; 138: 6–11.

Willging S, Keller F, Steinbach G. Specificity of cardiac troponin I and T in renal disease. Clin Chem Lab Med 1998; 36: 87–92.

Spies C, Haude V, Fitzner R, et al. Serum cardiac troponin-T as a prognostic marker in early sepsis. Chest 1998; 113: 1055–1063.

Arlati S, Brenna S, Prencipe L, et al. Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study. Intensive Care Med 2000; 36: 31–37.

Paterson D, Beyne P, Laperche T, et al. Elevated circulating troponin I in patients with cirrhosis. Hepatology 1999; 29: 640–643.

Meldrum DR: Tumor necrosis factor in the heart. Am J Physiol 1998; 274: 577–595.

Shames BD, Barton HH, Reznikov LL, et al. Ischemic alone is sufficient to induce TNF-mRNA and peptide in the myocardium. Shock 2002; 17: 114–119.

Vasile VC, Chai HS, Khambatta S, et al. Significance of elevated cardiac troponin T levels in critically ill patients with acute respiratory disease. Am J Med 2010; 123: 1049–1058.

Diabetes congress diary Date MAY 2012 24–27 May JUNE 2012 8–12 June JULY 2012 9–12 July 24–26 July 25–28 July

Conference

Venue

Contact details to register

27th Annual Clinical Conference on Diabetes

Florida, USA

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

www.africadiabetescongress.org

Dubai, UAE

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

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Nebivolol therapy improves QTc and QTcd parameters in heart failure patients SM AKSOY, S CAY, G CAGIRCI, N SEN

Abstract Aim: It has previously been shown that β-blocker therapy reduces QT dynamics in heart failure patients. The aim of this study was to demonstrate this improvement with the third-generation β-blocker, nebivolol.

Methods: A total of 72 heart failure patients with systolic dysfunction were included in the study. Corrected QT (QTc) and QT dispersion (QTcd) were measured manually by two independent observers at baseline and after nebivolol use (5 mg/day) in the first and third months of follow up.

Results: Both QTc and QTcd were found to be significantly reduced in the first (455.3 ± 26.7 vs 441.2 ± 25.7 ms, p < 0.001 for QTc, and 65.6 ± 5.3 vs 58.2 ± 5.6 ms, p = 0.001 for QTcd) and third months (455.3 ± 26.7 vs 436.0 ± 28.7 ms, p < 0.001 for QTc, and 65.6 ± 5.3 vs 56.0 ± 6.2 ms, p < 0.001 for QTcd) compared with baseline values.

Conclusion: Nebivolol was associated with improved QT dynamics in heart failure patients with systolic dysfunction.

Keywords: improvement, nebivolol, QT dynamics Submitted 18/2/10, accepted 30/8/11 Cardiovasc J Afr 2012; 23: 191–193

www.cvja.co.za

DOI: 10.5830/CVJA-2011-046

Heart failure, both systolic and diastolic, is a clinical syndrome with different treatment modalities and a poor prognosis, especially in the advanced stages. β-blocker therapy, including nebivolol, improves survival in these patients by modulating several neurohormonal mechanisms.1-4 Nebivolol is a selective β1-blocker with vasodilatory properties due to modulation of nitric oxide release, which decreases peripheral vascular resistance.5,6 In addition, it has been demonstrated that in patients with hypertension, nebivolol reduces QT dispersion and corrected QT interval (QTc) and corrected QT dispersion (QTcd), which are indicators of the heterogeneity of myocardial repolarisation and electrical instability.7 Abnormality of these parameters has been also found to be associated with adverse cardiac events and mortality.8 In the current study, we aimed to demonstrate the beneficial

Department of Anesthesiology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey

effect of nebivolol on QTc and QTcd in patients with heart failure with systolic dysfunction.

Methods Consecutive β-blocker-naïve (no use during the four weeks before study entry) systolic heart failure patients were selected for the study. A total of 75 patients were possible candidates and were included in the study. However, three were subsequently excluded because of side effects of the drug. At the end of the follow-up period, 72 patients taking the drug remained.

All the participants had depressed left ventricular ejection fraction (< 40%) as per the study protocol. Patients were interviewed about any cardiovascular drug use, and NYHA functional class was determined. Systolic and diastolic blood pressure and heart rates were measured at the beginning of the study and in the third month. Laboratory parameters including serum electrolytes were assayed. Nebivolol 5 mg/day was started in all patients and the same dose was continued throughout the study period.

Patients with β-blocker use in the previous four weeks, electrolyte abnormalities, any drug use prolonging QT interval, coronary artery disease or acute coronary syndromes, pacemakers, atrial fibrillation, and significant hepatic and renal dysfunction were excluded from the study.

The electrocardiograms (ECG) were recorded after 10 minutes of rest in the supine position, using 12 simultaneously recording leads: three standard (DI, DII, DIII), three unipolar (aVR, aVL, aVF) and six precordial (V1–V6), at a paper speed of 25 mm/s.

Readings were done manually by the same two cardiologists blinded to the study. There is evidence that manual measurement is superior to automatic measurement of QTd.9,10 The QT interval was measured in each lead from the onset of the QRS complex: the beginning of the Q wave to the terminal inscription of the T wave in the lead with clearly identified T-wave termination, or from the beginning of the R wave if the Q wave was absent. The terminal inscription of the T wave was determined as the return to the TP baseline. When a U wave was present, the QT interval was measured to the nadir of the curve between the T and U waves. The QTcd was defined as the difference between the maximum and minimum of the QTc intervals, measured in milliseconds in any of the measured ECG leads.

SM AKSOY, MD

Statistical analysis

Department of Cardiology, Yuksek Ihtisas Heart Education and Research Hospital, Ankara, Turkey

Data were analysed with SPSS software version 15.0 for Windows (SPSS Inc, Chicago, Illinois, USA). Continuous variables are presented as mean ± SD and categorical variables as frequency and percentage. The Kolmogorov–Smirnov test was applied to assess the distribution of continuous variables.

The Student’s t-test was used to compare normally distributed continuous variables and the Mann–Whitney U-test for variables

S CAY, MD, cayserkan@yahoo.com N SEN, MD

Department of Cardiology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey G CAGIRCI, MD

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without normal distribution. Pearson correlation was used for the correlation analysis. The mean inter-observer difference and inter-class coefficients were used to evaluate inter-observer variability. A two-tailed p-value < 0.05 was considered statistically significant.

Results Baseline characteristics of patients including demographic, clinical and laboratory parameters are outlined in Table 1. The study population was mostly elderly patients and 69.4% were over 65 years. Approximately two-thirds of the patients were white males. All patients were on a drug affecting the renin– angiotensin–aldosteron system. NYHA functional class II was the most common category in the population. No discontinuation of the study drug was observed during the study period.

At the end of the study, vital parameters of patients including systolic (110 ± 15 vs 100 ± 15 mmHg, p < 0.001) and diastolic (72 ± 10 vs 68 ± 10 mmHg, p < 0.001) blood pressure and heart rates (84 ± 11 vs 74 ± 11 bpm, p < 0.001) were significantly decreased, as expected. However, there were no significant changes in the left ventricular ejection fraction and NYHA functional class of the patients between the baseline and followup values at one and three months (32.3 ± 5.0 vs 32.4 ± 4.9%, p = 0.327 and 2.3 ± 0.6 vs 2.2 ± 0.5%, p = 0.103), respectively.

QTc and QTcd were measured at baseline and in the first and third month of the study. The measurements and calculations were performed by two independent observers blinded to the study protocol. The mean values of the QT dynamics from two independent observers are given in Table 2. In the whole TABLE 1. BASELINE DEMOGRAPHIC, CLINICAL AND LABORATORY CHARACTERISTICS OF THE STUDY POPULATION Characteristic Value (n = 72) Age (years) 71.0 ± 10.4 Male (%) 45 (62.5) Diabetes mellitus (%) 6 (8.3) Smoking (%) 13 (18.1) Hypertension (%) 23 (31.9) CCB use (%) 5 (6.9) ACE inhibitor use (%) 62 (86.1) ARB use (%) 10 (13.9) Statin use (%) 10 (13.9) Aldosterone antagonist use (%) 21 (29.2) Diuretic use (%) 68 (94.4) Digoxin use (%) 16 (22.2) NYHA class I (%) 4 (5.6) II (%) 47 (65.3) III (%) 19 (26.4) IV (%) 2 (2.8) LVEF (%) 32.3 ± 5.0 Creatinine (mg/dl) 0.96 ± 0.27 Na (mmol/l) 136.3 ± 4.2 K (mmol/l) 4.2 ± 0.6 Ca (mmol/l) 2.37 ± 0.12 ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.

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population, both QTc and QTcd were significantly decreased in the first and third months compared to baseline values (Table 2). QTc and QTcd values correlated significantly between the two observers. Inter-class coefficients and mean inter-observer differences at baseline and in the first and third months are presented in Table 3.

In male subjects, both QTc and QTcd were significantly decreased in the first and third months compared to baseline values. In female subjects, both QTc and QTcd were significantly decreased in the third month compared to baseline values.

However, in the first month of follow up, no significant decrease was detected in QTc or QTcd compared to baseline values. In addition, both QTc and QTcd were significantly decreased in the third month compared to the first month (data not presented).

There was a significant positive correlation between age and baseline QTcd in the whole study population (β = 0.567, p < 0.001). There was no significant difference between patients in NHYA class I–II and III–IV, according to QTc and QTcd at baseline and in the first and third months (p > 0.05 for all).

Discussion We found that nebivolol therapy significantly improved both QTc and QTcd parameters in patients with systolic heart failure, which has not been reported in the literature before. Sympathetic tone, excitation–contraction coupling and myocardial fibrosis may be the reasons for impaired QT dynamics in heart failure.

Both QTc and QTcd are the indicators of the heterogeneity of myocardial repolarisation and electrical instability.8,11 The action potential is prolonged and repolarisation is delayed in heart failure patients.

The QT interval on the surface ECG is a readily measurable reflection of cardiac repolarisation. The QT interval is an index of ventricular repolarisation that is directly influenced by myocardial health and autonomic nervous system activity.

Patients with heart failure and prolonged action potential durations have abnormalities of the QT interval. In a small group TABLE 2. QT DYNAMICS IN THE WHOLE POPULATION Characteristic Baseline First month Third month QTc (ms) 455.3 ± 26.7 441.2 ± 25.7* 436.0 ± 28.7* QTcd (ms) 65.6 ± 5.3 58.2 ± 5.6** 56.0 ± 6.2* The mean values of two independent observers are presented. *p < 0.001 for baseline to first month and baseline to third month. **p = 0.001 for baseline to first month.

TABLE 3. INTER-OBSERVER DIFFERENCES AND INTER-CLASS COEFFICIENTS BETWEEN TWO OBSERVERS FOR QT DYNAMICS Mean interobserver difference Characteristics (ms) QTc baseline –2.8 QTcd baseline –0.5 QTc month 1 –3.0 QTcd month 1 –0.5 QTc month 3 –2.6 QTcd month 3 –0.5

Range (ms) –15 to +20 –2.5 to +3.5 –20 to +20 –2.5 to +3.5 –15 to +20 –3.0 to +3.5

Interclass coefficient 0.986 0.999 0.995 0.999 0.993 0.999

95% CI 0.978–0.991 0.999–1.000 0.993–0.997 0.999–1.000 0.988–0.995 0.999–1.000

p-value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

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of heart failure patients, QT dispersion has been shown to be a marker of electrical instability and increased risk of sudden death.12 In patients with known repolarisation abnormalities, the QTcd has been demonstrated to be a better prognostic indicator of arrhythmic risk than the QT itself.13 Unstable ventricular repolarisation may contribute to the development of ventricular tachycardia and fibrillation.

It is well known that β-blockers are the only anti-arrhythmic drug class effectively reducing mortality and arrhythmic sudden death in patients with heart failure.14 These drugs have been also shown to improve QT dynamics.15-17 It has been demonstrated that nebivolol therapy reduced the composite risk of all-cause mortality or cardiovascular hospital admission compared with placebo in patients with heart failure.4 Nebivolol therapy as an antihypertensive drug has been extensively studied and approved. Its effect on QT dynamics in hypertensive patients has shown that nebivolol significantly reduced QTcd in hypertensive subjects without affecting left ventricular mass.7 In our study, no statistically significant difference was found between hypertensive and non-hypertensive patients according to QTc and QTcd at baseline and in the first and third months of follow up (p > 0.05 for all).

Statin therapy has also been found to be associated with improved QT dynamics in heart failure patients.18 In our study there was no significant difference between patients on statin therapy and those without statins, according to QTc and QTcd parameters at baseline (p > 0.05 for all). We found that in female subjects, neither QT dynamic significantly decreased in the first month compared to baseline. The reason for this could be the small number of females, which did not reach statistical significance.

Although ACE inhibitor therapy has been shown to decrease QTd,19 in our study no significant difference was found between patients on ACE inhibitors and those not on them at baseline (p > 0.05). Also, no significant difference was found between those on digoxin and those not on digoxin at baseline (p > 0.05).

Neither QTc nor QTcd were different among NHYA functional classes at baseline and in the first and third months of follow up.

This demonstrates that QT dynamics were impaired regardless of NYHA functional class. Since there were no significant changes in the left ventricular ejection fraction and NYHA functional class, this indicates that the QT changes were the result of the drug’s effect on the heart rate and blood pressure and not due to improvement in the heart failure.

A limitation of this study was that this was a case–control observational study without primary end-points such as hospitalisation for heart failure, cardiac and total mortality.

Therefore, randomised blinded studies with longer follow-up periods are needed. In addition, we only studied heart failure patients with systolic dysfunction and normal coronary arteries.

Similar studies should be performed in heart failure patients with preserved systolic function and coronary heart disease.

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patients in our study can partly be attributed to improvement in their QT dynamics.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Conclusion

18.

Similar to other older-generation β-blockers, nebivolol is a selective β1-blocker with vasodilator properties that have the potential to improve QT dynamics in patients with heart failure.

Therefore the good clinical results obtained in the heart failure

19.

The MERIT-HF study group. Effects of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353: 2001–2007.

The CIBIS-II investigators and committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomised trial. Lancet 1999; 353: 9–13.

Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. for the Carvedilol Prospective Randomized Cumulative Survival study group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658.

Flather MD, Shibata MC, Coats AJ, van Veldhuisen DJ, Parkhomenko A, Borbola J, et al.; SENIORS investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005; 26: 215–225.

Zanchetti A. Clinical pharmacodynamics of nebivolol: new evidence of nitric-oxide mediated vasodilating activity and peculiar haemodynamic properties in hypertensive patients. Blood Pressure 2004; 13: 18–33.

Kuroedov A, Cosentino F, Luscher TF. Pharmacological mechanisms of clinically favorable properties of a selective beta1-adrenoceptor antagonist, nebivolol. Cardiovasc Drug Rev 2004; 22: 155–168.

Galetta F, Franzoni F, Magagna A, Femia FR, Pentimone F, Santoro G, Carpi A. Effect of nebivolol on QT dispersion in hypertensive patients with left ventricular hypertrophy. Biomed Pharmacother 2005; 59: 15–19.

Vrtovec B, Delgado R, Zewail A, Thomas CD, Richartz BM, Radovancevic B. Prolonged QTc interval and high B-type natriuretic peptide levels together predict mortality in patients with advanced heart failure. Circulation 2003; 107: 1764–1769.

Glancy JM, Weston PJ, Bhullar HK, et al. Reproducibility and automatic measurement of QT dispersion. Eur Heart J 1996; 17: 1035–1039.

Murray A, McLaughlin NB, Campbell RWF. Measuring QT dispersion: man versus machine. Heart 1997; 77: 539–542.

Haigney MC, Zareba W, Gentlesk PJ, Gentlesk PJ, Goldstein RE, Illovsky M, et al., Multicenter Automatic Defibrillator Implantation Trial II investigators. QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Implantation Trial (MADIT) II patients. J Am Coll Cardiol 2004; 44: 1481–1487.

Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden unexpected death in chronic heart failure. Lancet 1994; 343: 327–329.

Day CP, McComb JM, Matthews J, Campbell RWF. Reduction in QT dispersion by sotalol following myocardial infarction. Eur Heart J 1991; 12: 423–427.

Singh BN. CIBIS, MERIT-HF and COPERNICUS trial outcomes: do they complete the chapter on beta-adrenergic blockers as antiarrhythmic and antifibrillatory drugs? J Cardiovasc Pharmacol Ther 2001; 6: 107–110.

Singh JP, Musialek P, Sleight P, Davey P, Marinho M, Hart G. Effect of atenolol or metoprolol on waking hour dynamics of the QT interval in myocardial infarction. Am J Cardiol 1998; 81: 924–926.

Hintze U, Mickley H, Moller M. Effects of beta-blockers on the relation between QT interval and heart rate in survivors of acute myocardial infarction. Ann Noninvas Electrocardiol 1998; 3: 319–326.

Bonnar CE, Davie AP, Caruana L, Fenn L, Ogston SA, McMurray JJ, Struthers AD. QT dispersion in patients with chronic heart failure: beta blockers are associated with a reduction in QT dispersion. Heart 1999; 81: 297–302.

Xie RQ, Cui W, Liu F, Yang C, Pei WN, Lu JC. Statin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failure. Int J Cardiol 2008 Nov 28. [Epub ahead of print].

Barr CS, Naas AA, Fenwick M, et al. Enalapril reduces QT dispersion in patients with mild congestive heart failure secondary to coronary artery disease. Am J Cardiol 1997; 79: 328–333.

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Can cardiac surgery be performed safely on patients with haematological malignancies A GULER, MA SAHIN, F CINGOZ, E OZAL, U DEMIRKILIC, M ARSLAN

Abstract Introduction: Surgical strategy in patients with haematological malignancies must be planned and carried out with the specific aim of decreasing postoperative complications. The aim of this study was to present our experience on patients previously diagnosed with haematological malignancies who subsequently underwent cardiac surgery. We include data to assist other surgeons predict factors affecting postoperative morbidity and mortality in this group of patients.

Methods: Fifteen patients diagnosed with haematological malignancies who had cardiac surgery were retrospectively analysed. Eight patients had chronic lymphocytic leukaemia, six had non-Hodgkin’s lymphoma and the rest had chronic myelocytic leukaemia. Coronary artery bypass graft surgery was performed on all of them.

Results: There were no hospital mortalities. The average follow-up period was 35 ± 11 (23–56) months. Three patients required early postoperative re-operation because of excessive bleeding. No mortalities were seen in the early postoperative period. There were five (33%) deaths during the late follow-up period. Three patients were lost due to intracranial bleeding (confirmed by autopsy) in the 16th, 23rd and 38th months after surgery. The remaining two patients had sudden death in the eighth and 55th months from nondetectable causes.

Conclusion: Cardiac surgery can be performed with acceptable early postoperative outcomes in patients with haematological malignancies. Intracranial bleeding is an important factor contributing to late mortality and patient selection and risk stratification are crucial to improving surgical benefits.

Keywords: haematological malignancy, cardiac surgery, intracranial bleeding Submitted 4/9/10, accepted 6/9/11 Cardiovasc J Afr 2012; 23: 194–196

www.cvja.co.za

DOI: 10.5830/CVJA-2011-053

Increased surgical experience and technological advances in cardiac surgery have encouraged surgeons to perform complex cardiac operations in patients with unrelated complications.

Department of Cardiovascular Surgery, Gulhane Military Medical Academy, Etlik, Ankara, Turkey A GULER, MD MA SAHIN, MD, mali_irem@yahoo.com F CINGOZ, MD E OZAL, MD U DEMIRKILIC, MD M ARSLAN, MD

Several procedures are performed nowadays on patients with co-morbidity factors, with acceptable morbidity and mortality rates.1 Haematological malignancies are diagnosed in all age groups but the chronic forms are predominantly seen in elderly populations.2 Great strides have been made to improve the quality of life of these patients and many clinicians are now focusing on finding solutions to other symptoms these patients may have. In an era when atherosclerotic heart disease shows an increasing prevalence, cardiac surgeons are encountering this population more frequently.

The operative risk of patients with malignant haematological disorders is increased, as this may include coagulation defects, changes in blood viscosity, immune suppression and bone marrow insufficiency.3 When surgically treating these patients, one must be concerned about postoperative infection, haemorrhage and leukaemic transformation. Surgical trauma and cardiopulmonary bypass (CPB), because of their immune-depressing effects, have the potential risk of increasing the haematological problems, leading to fatal or morbid complications.4 There are few reports on how to deal with these patients, and also little knowledge on their progress after cardiac surgery. Due to these concerns, the aim of our study was to detail our clinical experience and data on the postoperative period.

Methods We retrospectively reviewed hospital records of 15 patients with haematological malignancies who underwent cardiac surgery at the Cardiovascular Surgery Department of our institution between 2003 and 2009. Eight patients suffered from chronic lymphocytic leukemia (CLL), six had non-Hodgkin’s lymphoma (NHL), and the rest had chronic myelocytic leukaemia. Coronary artery bypass graft (CABG) surgery was performed on all patients.

The diagnosis of haematological malignancy was assigned based on the international ICD-10 code. Patients received routine intravenous antibiotic prophylaxis (cephazolin Na 1 g) for three days, beginning the night before surgery. CPB was performed after the standard heparinisation (ACT > 400 s). All the patients were given antegrade cold crystalloid cardioplegia with moderate hypothermia, and topical cold slush solution was used.

The left internal mammary artery (LIMA) and saphenous vein grafts were prepared for CABG surgery. Distal anastomoses were performed with 7/0 polypropylene sutures and a continuous suture technique. Proximal anastomoses were performed with 6/0 polypropylene sutures and a continuous suture technique with a side clamp. Salicylic acid 100 mg was started on the first postoperative day in all patients.

Patients’ hospital charts, demographics, peri-operative data and complications were reviewed. Follow-up data were obtained by review of subsequent hospital admissions and telephone

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interviews. The average follow-up period was 35 ± 11 (23–56) months.

In statistical analysis, values were expressed as mean ± standard deviation for continuous variables, and number and percentage for dichotomous variables. In comparisons, the Student’s t-test was used for continuous variables and the MannWhitney U-test for dichotomous variables. Comparison of gender was done using the Chi-square test. A p-value below 0.05 was set as significant.

Results There were a total of 15 patients, 11 were male and four female.

Their pre-operative data are summarised in Table 1. Mean age was 65 ± 14 (range 27–76) years. The mean time interval from the diagnosis of the haematological malignancy to the CABG surgery was 4.6 years (7 months to 9 years). All were in remission and under supervision of the Haematology Department.

An average of 2.75 ± 1.2 grafts was placed in the 15 patients undergoing isolated CABG. LIMA grafts were used in 14 patients. All were operated on with an arrested heart under CPB. Two patients required intra-aortic balloon pump during the perioperative period. Haematology reports reflected the expected ranges in all patients during the postoperative period.

In patients with CLL and NHL, the average length of stay in ICU was 1.2 ± 0.3 and 1.5 ± 0.5 days, respectively. The average of packed red blood cells required was 2.1 ± 0.6 and 1.5 ± 0.6 units, respectively, and the average of fresh frozen plasma required was 1.3 ± 0.5 and 1.5 ± 0.6 units, respectively. There was no apparent difference in the postoperative course and mean postoperative stay between the two groups (Table 2).

Four postoperative complications occurred in four patients (26%). Three of them required early re-operation because of bleeding. They were respectively, 55-, 63- and 69-year-old male patients, diagnosed with NHL. More bleeding was seen in the patients with NHL than in those with CLL, and the difference was statistically significant (p < 0.05). The hospital stay was uneventful after the second operation.

TABLE 1. CLINICAL DATA NonHodkgin’s Diagnosis CLL lymphoma p-value CML Number 8 6 1 Gender (male/female) 6/2 4/2 0.733 0.733** M Age (years) 66 ± 16 60 ± 12 0.128* 78 Body mass index 24 ± 4.2 26.5 ± 4.9 0.096* 22 Pre-operative EF (%) 49 ± 13 52 ± 18 0.226* 44 Pre-operative haemoglobin (g/dl) 13.3 ± 3.6 12.8 ± 2.9 0.258* 15.4 Post-operative haemoglobin (g/dl) 11.9 ± 7.2 10.8 ± 8.6 0.086* 12.3 Pre-operative platelets (× 109 /dl) 206 ± 74 254 ± 89 0.068* 139 Post-operative platelets (× 109 /dl) 174 ± 51 152 ± 73 0.070* 128 Pre-operative prothrombin time (s) 12.8 ± 4.1 12.5 ± 2.8 0.825* 13.3 Post-operative prothrombin time (s) 13.2 ± 7.2 12.9 ± 9.4 0.652* 13.1 Pre-operative WBC (× 109 /dl) 33.2 ± 9.1 38.5 ± 10.8 0.075* 20.0 Post-operative WBC (× 109 /dl) 36.1 ± 1.4 34.8 ± 5.3 0.348* 17 CLL: chronic lymphocytic leukemia, CML: chronic myelocytic leukemia, EF: ejection fraction, WBC: white blood cells, Postoperative: 14th day. *Student’s t-test, **Chi-square test; p-value represents the comparison between CLL and non-Hodkgin’s lymphoma patients.

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A 27-year-old male patient diagnosed with CLL was hospitalised one month after the first operation due to mediastinitis. This patient was treated with antibiotics according to bacterial culture and he then underwent sternal dehiscence revision surgery. The hospital course was uneventful after the second operation and he soon returned to work. Clinical and peri-operative variables of patients with CLL and NHL were similar (Tables 1, 2). No mortality was seen in the early postoperative period.

The three-year survival rate was 80%. There were five (33%) late deaths during the follow-up period. All deaths were of a non-cardiac nature. Three patients were lost due to intracranial bleeding in the 16th, 23rd and 38th months after surgery. The other two patients had sudden death in the eighth and 55th months and the reason for death could not be determined. One of these patients was brought to the emergency department with cardiopulmonary arrest. Resuscitation was performed but the patient died and the family refused an autopsy.

Discussion Haematological malignancies, particularly the lymphocytic types, affect mainly elderly patients. Survival of these patients can range from one year to several decades.2,5 Over the past few years, treatment options have continued to improve survival rates.

Cardiac surgical experience in patients with haematological malignancies is limited and detailed investigation is mandatory in decision making.2 It is obvious that CPB affects all systems, including the haematopoietic system. CPB, which aggravates cell damage, also has immune-depressant properties, resulting in an increased incidence of infection.6,7 Furthermore, haematological malignancies may lead to antibody deficiency, leucopenia or impaired T-cell function. Previous reports demonstrate infection as the primary cause of morbidity.2,3,8 Some studies show morbidity rates of between 23 and 57%. Samuels et al. reported the incidence of infectious complications as 42%, underlining the major role they play in the hospital stay.2,5 Some investigations emphasise the use of additional intravenous immunoglobulin, as broad-spectrum antibiotic prophylaxis was found to be insufficient to prevent or control infection in these patients.2

TABLE 2. PERI-OPERATIVE DATA NonHodkgin’s Diagnosis CLL lymphoma p-value CML CPB time (min) 83 ± 21 88 ± 16 0.215* 95 Cross-clamp time (min) 64 ± 19 69 ± 24 0.083* 72 Packed red blood cells (units) 2.1 ± 0.6 2.3 ± 0.8 0.573** 3 Fresh frozen plasma (units) 1.3 ± 0.5 1.5 ± 0.6 0.755** 1 Post-operative IABP 1 1 0.950** – ICU stay (days) 1.2 ± 0.3 1.5 ± 0.5 0.491* 1 Mortality early/late –/3 –/2 0.950** – Bleeding complications – 3 0.030** Infection 1 – 0.755** CLL: chronic lymphocytic leukaemia, CML: chronic myelocytic leukaemia, CPB: cardiopulmonary bypass, IABP: intra-aortic balloon pump, ICU: intensive care unit, *Student’s t-test, **Mann-Whitney U-test, p-value represents the comparison between CLL and non-Hodkgin’s lymphoma patients.

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According to the advice of our infections committee, we used only cephazolin Na for prophylactic antibiotic therapy.

Mediastinitis was observed in one patient and it was the only infection-related complication encountered in our cases. This was an acceptable infection rate and comparable with that of open-heart surgery in the general population.

White blood cell count generally increases after open-heart surgery, and CPB may stimulate a leucomoid reaction, which can lead to a relapse in an otherwise quiescent illness.6,7 In our study, white blood cell count increased between acceptable ranges, as seen in Table 1. The general opinion on cardiac surgery is that it does not exacerbate haematological malignancies in low-risk patients or those with low-grade disease (in the remission period). However patients with an intermediate to high risk or grade of disease may show progression and this may be the cause of late death.5 Our patients were all in complete remission and there was no leucomoid reaction or relapse of the disease in the follow-up period, as confirmed by the Haematology Department.

Bleeding is another potential complication in this group of patients. Fecher et al.5 reported a 16.6% rate of bleeding and it was the main postoperative complication they observed. They had only one mediastinal bleeding that led to re-operation, and two cases of gastrointestinal and one of femoral artery haemorrhage. They were not group related.

In our series, three patients (20%) had excessive bleeding in the early postoperative period, showing a similar rate to that of Fecher et al.5 However, all were of mediastinal origin and led to re-operation and all were patients with NHL. One of the cases of haemorrhage was surgery related while a general leakage was observed in the other two cases. We did not detect any significantly low platelet count or elevated INR peri-operatively.

Bleeding was the only statistically significant difference observed between the patients with CLL and NHL. We did not find any reports in the literature regarding NHL and tendency to haemorrhage and we felt that statistical analysis was not feasible for some factors because of the small size of our study group.

However, it may be valuable in future clinical decisions.

This article has some limitations. It was retrospective and lacked a control group of standard patients with CABG. The number of patients and types of malignancies were different among different institutions, therefore it was difficult to find a large series of patients to determine the morbidity and mortality rates in a homogeneous group.

Incomplete follow-up data was another shortcoming. In previous reports, 30-day mortality rates ranged from zero to 17%.2,5,9 In our series, there was no early mortality, but late mortality was somewhat higher (33%). Three patients died because of intracranial bleeding and two others due to unknown reasons.

Samuels et al. pointed out that these patients’ long-term outcomes are variable and non-cardiac related.2 The high latemortality rate of our patients may be partially related to our limited experience in this specific group of patients. Appropriate long-term anti-aggregant therapy should be designed in collaboration with haematology departments.

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We surmise that the small number of patients seriously affected the late-period outcomes and no predictive factors for identifying such high-risk patients were found. Although intracranial bleeding was a significant mortality factor, prothrombin time, bleeding time and thrombocyte level were in the normal range in all patients. Aspirin 100 mg was the anti-aggregant therapy and it may have been responsible for intracranial bleeding. However, there is no evidence and future guidelines should describe a detailed approach and treatment.

It is reasonable to use less-invasive techniques (percutaneous coronary interventions) in high-risk patients when they meet the operative indications. However, these procedures require heavy post-intervention anti-agregant therapy, and the risk for intracranial bleeding would therefore remain high.

Predictive scores such as the Euroscore or the Society of Thoracic Surgeons’ score have no predictive values for mortality and morbidity in patients with haematological malignancies undergoing cardiac surgery. Therefore, future studies giving accurate rates of post-operative morbidity or mortality would be of great use to provide a general approach for these patients.

Conclusion Cardiac surgery can be undergone with acceptable early postoperative outcomes in patients with haematological malignancies. The expectations of the patient and surgeon should be appropriately discussed and the medical team should be focused on potential complications such as bleeding, infection and prolonged hospital stay. Long-term multidisciplinary follow up and adequate medical treatment are essential in prolonging survival.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

Avery GJ, Ley SJ, Hill JD, et al. Cardiac surgery in the octogenarian: evaluation of risk, cost, and outcome. Ann Thorac Surg 2001; 71: 591–596.

Samuels LE, Kaufman MS, Morris RJ, et al. Open heart surgery in patients with chronic lymphocytic leukemia. Leukemia Res 1999; 23: 71–75.

Christiansen S, Schmid C, Löher A, et al. Impact of malignant hematological disorders on cardiac surgery. Cardiovasc Surg 2000; 8: 149–152.

Haiston P, Manos JP, Graber CD, et al. Depression of immunologic surveillance by pump oxygenator perfusion. J Surg Res 1969; 9: 587–593.

Fecher AM, Birdas TJ, Haybron D, et al. Cardiac operations in patients with hematologic malignancies. Eur J Cardiothorac Surg 2004; 25: 537–540.

Drury N, Ali A, Mussa S, et al. Acute leukaemoid reaction following cardiac surgery. J Cardiothorac Surg 2007; 9: 2–3.

Ghosh P, Carroll I, Kanhere A, et al. Cardiac operations in patients with low-grade small lymphocytic malignancies. J Thorac Cardiovasc Surg 1999; 118: 1033–1037.

Finck SJ, Cockerill KJ, Jeter JE, et al. Coronary artery bypass grafting in patients with chronic lymphocytic leukemia. Ann Thorac Surg 1993; 55: 1192–1196.

Sommer SP, Lange V, Yildirim C, Schimmer C, Aleksic I, Wagner C, et al. Cardiac surgery and hematologic malignancies: a retrospective single-centeranalysis of 56 consecutive patients. Eur J Cardiothorac Surg 2010; Dec 9 (Epub ahead of print).

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The impact of cardiovascular risk factors on the site and extent of coronary artery disease AF ZAND PARSA, H ZIAI, L HAGHIGHI

Abstract Background: In patients with coronary artery disease (CAD), the site and extent of coronary artery involvement in terms of proximal versus distal stenosis and multi- versus single-vessel disease have a crucial effect on patients’ outcome. This study was designed to evaluate the relationship between cardiovascular risk factors and the site and extent of coronary artery involvement.

Methods: In this study of patients who had undergone coronary angiography in our hospital, 125 with proximal lesions were enrolled as the case group (group 1) and an equal ageand gender-matched number of patients with non-proximal lesions were selected as the control group (group 2). The two groups were compared based on the presence or absence of diabetes mellitus (DM), hypercholesterolaemia, hypertriglyceridaemia, hypertension (HTN) and cigarette smoking.

Results: The frequency of DM was 33.6 and 10.4% in the case and control groups, respectively, which was statistically significant (p < 0.0001). However, the frequency of hypercholesterolaemia in the case and control groups was 30.4 and 29.6% (p = 0.89), respectively; for hypertriglyceridaemia it was 19.2 and 16.8% (p = 0.062), respectively; for HTN it was 33.6 and 28.8% (p = 0.4), respectively; and for cigarette smoking it was 28.8 and 39.2% (p = 0.08), respectively, which were not statistically significant. Diabetic patients compared to non-diabetics had more multi-vessel disease (89.1 vs 61%, p < 0.0001, respectively), which was statistically significant.

There was no relationship between hypercholesterolaemia, hypertriglyceridaemia, HTN and cigarette smoking and extent (multi-vessel involvement) of CAD (p = NS).

Conclusion: Proximal and multi-vessel involvement of the coronary arteries in patients with CAD was related to a history of DM but not of hypercholesterolaemia, HTN, cigarette smoking and hypertiglyceridaemia.

Keywords: coronary artery disease, coronary angiography, proximal versus distal stenosis, cardiovascular risk factors Submitted 15/10/10, accepted 6/9/11 Cardiovasc J Afr 2012; 23: 197–199

www.cvja.co.za

a heterogeneous disease in terms of severity, extent and site of involvement, these are the most important predictors of outcome of patients with coronary artery disease. The main question is whether or not these heterogeneities have any relationship with cardiovascular risk factors, and if so, which is responsible for which kind of lesion.

Although in some studies a relationship between diabetes mellitus (DM)1-5 and hyperlipidaemia,4-6 and severity of CAD has been reported, these studies were focused on the severity of lesions according to the scoring system used and not to the site of lesion in terms of proximal versus distal stenosis. In our study we tried to evaluate the impact of major cardiovascular risk factors such as DM, hypercholesterolaemia, hypertriglyceridaemia, hypertension (HTN) and cigarette smoking on the site and extent of coronary artery involvement in terms of proximal versus distal and multi- versus single-vessel disease.

Methods This study was a prospective case–control study that included patients who had undergone coronary angiography in our hospital. Patients with normal coronary arteries were excluded from the study. The case group included 125 patients with significant proximal coronary artery stenosis (≥ 50% luminal narrowing) and the control group included 125 patients with significant non-proximal stenosis, and matched with case group regarding gender and age.

Coronary angiography of all patients was re-evaluated by an expert cardiologist and in the case of controversy, by two experts who were not aware of the patients’ risk factors or other clinical conditions. The two groups were compared for major cardiovascular risk factors such as hyperlipidaemia, HTN, DM and cigarette smoking.

Statistical analysis SPSS version 11.5 was used for analysing the data. The Student’s t-student test and Chi-square test were used for numerical and continuous variables, respectively. For evaluating data, odds ratio (OR) with 95% confidence interval (CI) were used and p > 0.05 was considered significant.

DOI: 10.5830/CVJA-2011-052

Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality worldwide. As atherosclerotic CAD is Division of Cardiology, Imam Khomeini Medical Center, Tehran University of Medical Sciences, Tehran, Iran AF ZAND PARSA, MD, zandparsa@tums.ac.ir H ZIAI, MD

Shahid Akbari Hospital, Iran University of Medical Sciences, Tehran, Iran L HAGHIGHI, MD

Results In the case group 87 patients (69.6%) and in the control group 95 patients (76%) were male. The mean age in the case and control groups was 59.6 ± 10.8 and 58.8 ± 10.9 years, respectively.

Regarding gender and age, there was no significant difference between the two groups (p = 0.556 and p = 0.256, respectively).

Clinical and demographic characteristics of patients are presented in Table 1.

Diabetes mellitus was more prevalent in the case group than the control (33.6 vs 10.4%, p < 0.0001, OR = 4.36; 95% CI: 2.2–8.6, respectively) and it was statistically significant. There

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was no difference between the two groups regarding HTN (OR = 1.25; 95% CI: 0.732–2.14, p = 0.41), hypercholesterolaemia (OR = 1.04; 95% CI: 0.60–1.78, p = 0.86), hypertriglyceridaemia (OR = 1.18; 95% CI: 0.62–2.25, p = 0.62) and cigarette smoking (OR = 0.63; 95% CI: 0.37–1.06, p = 0.08). The frequency of cardiovascular risk factors in both groups is presented in Fig. 1.

Regarding the extent of CAD, multi-vessel disease was more frequent than single-vessel disease in the diabetics than the non-diabetics (89.1 and 10.9% vs 61 and 39%, respectively, p < 0.0001). In hypercholestrolaemic compared to non-hypercholestrolaemic patients, the trend was in favour of more multi-vessel disease but the difference was not statistically significant (76 and 24% vs 63.4 and 36.6%, respectively, p = 0.052). Hypertriglyceridaemia, HTN and cigarette smoking had no impact on the extent of coronary artery involvement in terms of multi-vessel versus single-vessel disease. The relationship of these cardiovascular risk factors to the extent of coronary artery involvement is presented in Table 2.

Discussion Although the relationship between cardiovascular risk factors and CAD has held investigators’ attention for a long time, there are no clear data regarding the impact of risk factors on the site, extent and complexity of coronary artery involvement in terms of proximal or distal and diffuse or segmental involvement.

Most studies that have been conducted in this regard were based on index of atheroma burden and extension score of CAD in patients with DM. In the majority of these studies, a strong relationship between DM and increased index of atheroma 60 50 40

42 33.6%

42 33.6%

36 28.8%

49 39.2% 38 37 30.4% 29.6%

30 20 10 0

24 19.2% 21 16.8%

13 10.4%

DM

36 28.8%

HTN

DM = diabetes mellitus HTN = hypertension HCL = hypercholesterolaemia case group

HCL

HTG

burden and extension score have been reported.1,2,4,5,7 However Pajumen et al. in their study did not find any relationship between diabetes and extent of CAD compared to non-diabetics.8 Uddin et al.1 and Synkija et al.2 studied site of coronary artery involvement (proximal versus distal involvement) in diabetic patients versus non-diabetics. Although the trend was towards proximal involvement in diabetic patients, it was not statistically significant (p > 0.05).

Synkija reported more multi-vessel disease in hypertensive patients than in non-hypertensives (p < 0.0003).2 Hong et al.9 also reported more multi-vessel than single-vessel disease in hypertensive patients (p < 0.01). However, Sposito et al.10 did not find any relationship between hypertension and extent of coronary artery involvement (multi-vessel disease), which was similar to what we found in our study.

Synkija et al.2 and Sposito et al.10 found no relationship between hypercholesterolaemia and extent of CAD. Syvanne et al.,5 Kosuge et al.6 and Hong et al.9 reported a relationship between low-density lipoprotein cholesterol and total cholesterol:highdensity lipoprotein cholesterol ratio and extent of coronary artery involvement, based on ABI or index of extent of artery involvement (p = 0.027, p = 0.01 and p < 0.01, respectively), but not to the site of coronary artery involvement (proximal versus distal).

In the study of Sposito et al.,10 post-menopausal women with hypertrygliceridaemia had more extensive CAD compared to those without hypertrygliceridaemia (p = 0.0013). Wilson et al.11 reported more extensive coronary artery involvement in smokers compared to non-smokers based on score of extent of artery involvement (p < 0.005), which was opposite to what we found in our study.

None of these studies assessed relationship between hypertriglyceridaemia or cigarette smoking and site of coronary artery stenosis (proximal versus distal stenosis). In our study the trend was towards distal stenosis in smokers compared to non-smokers but it was not statistically significant (p = 0.08).

Also we did not find a relationship between hypertriglyceridaemia and hypertension and the site of coronary involvement (p = NS).

Uddin et al.1 and Synkija et al.2 were the only investigators who considered relative frequency of proximal versus distal involvement in their patients. According to their findings,

C/S

HTG = hypertriglyceridaemia C/S = cigarette smoking control group

TABLE 2. RELATIONSHIP BETWEEN CARDIOVASCULAR RISK FACTORS AND EXTENT OF CORONARY ARTERY DISEASE

Fig. 1. Frequency of cardiac risk factors in the two groups.

TABLE 1. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF PATIENTS

Demographic characteristics Males, n (%) Age mean ± SD (years) Diabetes mellitus, n (%) Hypertension, n (%) Hypercholesterolaemia, n (%) Hypertriglyceridaemia, n (%) Cigarette smoking, n (%)

Case group n = 125 (100%) 87 (69.6) 59.6 ± 10.8 42 (33.6) 42 (33.6) 38 (30.4) 24 (19.2) 36 (28.8)

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Control group n = 125 (100%) p-value 95 (76) NS 58.8 ± 10.9 NS 13 (10.4) < 0.0001 36 (28.8) NS 37 (29.6) NS 21 (16.8) NS 49 (39.2) 0.08

Subgroups Diabetic Non-diabetic Hypertensive Non-hypertensive Hypercholesteraemic Non-hypercholestraemic Hypertriglyceridaemic Non-hypertriglyceridaemic Cigarette smoker Non-cigarette smoker

Extent of CAD Single-vessel Multi-vessel disease disease n (%) n (%) 6 (10.9) 49 (89.1) 76 (39) 119 (61) 20 (25.6) 58 (74.4) 62 (36) 110 (64) 18 (24) 57 (76) 64 (36.6) 111 (63.4) 12 (26.7) 33 (73.3) 70 (34.1) 135 (65.9) 31 (36.5) 54 (63.5) 51 (30.9) 114 (69.1)

p-value < 0.0001 NS 0.052 NS NS

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proximal involvement was more frequent in diabetic patients, but it was not statistically significant (p > 0.05). In our study, not only frequency of proximal stenosis but also frequency of multivessel involvement was significantly higher in diabetics than in non-diabetics (p < 0.0001).

Conclusion From our findings, proximal involvement of the coronary arteries and more extensive coronary artery disease (multi-vessel disease) were strongly related to a history of DM, but less so to a history of hypercholesterolaemia, and not to a history of hypertriglyceridaemia, hypertension and cigarette smoking.

References 1.

2.

3.

Uddin SN, Malik F, Bari MA, et al. Angiographic severity and extent of coronary artery diseases in patients with type 2 diabetes mellitus.

Mymentsingh Med J 2005; 14(1): 32–37.

Synkija R, Aronow WS, Najak D, et al. Increased fasting plasma insulin consentration are associated with the severity of angiographic CAD. Angiology 2005; 56(3): 249–251.

Ammann P, Brunner- La, Rocca H, Fehr T, et al. Coronary anatomy and LVEF in patients with type 2 diabetes admitted for elective coronary angiography. Catheter Cardiovasc Inter V 2004; 62(4): 432–438.

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4.

Fallow GD, Singhj. The prevalence, type and severity of cardiovascular disease in diabetics and non diabetic patients: amathced – paired retrospective analysis using CAG as the diagnosis tools. Mol cell Biochem 2004; 261(1–2): 263–269.

5. Syvanne M, Pajunen P, Kahri J. Determination of the severity and extent of CAD in patients with type 2 diabetes and non-diabetes subjects.

Coron Arter Dis 2001; 12(2): 99–106.

6. Kosuge M, Kimmurak, Ishikawa T, et al. Different clinical and coronary angiographic findings according to ratios of total cholesterol to HDL during the acute phase of MI. J Cardiol 2004; 43(6): 251–258.

7. Pajunen P, Tashinen MR, Nieminen MS, Syvanne M. Angiographic severity and extent of coronary artery disease in patients with type I diabetes mellitus. Am J Cardiol 2000; 86(10): 1080–1085.

8. Pajunen P, Nieminen MS, Taskinen MR. Quantitative comparison of angiographic characteristics of coronary artery disease in patients with NIDDM compared with matched non-diabetic control subjects. Am J Cardiol 1997; 80: 550–556.

9. Hong MK, Romm PA, Peagan K, Green CE Rackleyce. Usefulness of the total cholesterol to HDL ratio in predicting angiographic coronary artery disease in woman. Am J Cardiol 1991; 68(17): 1646–1650.

10. Sposito AC, Mansur AP, Maranhao RC, et al. Triglyceride and LPL (a) are markers of coronary artery disease severity among post-menopausal women. Maturitas 2001; 39(3): 203–208.

11. Wilson SH, Celermajer DS, Nakagomi A, Wydhom RN, Janu MR. Benfreedoms. Vascular risk factors correlate to the extent as well as severity of coronary atherosclerosis. Coron Artery Dis 1999; 10(7): 449–453.

Cardiovascular congress diary Date

Conference

Venue

Contact details to register

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

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 time-course changes of NT-proBNP and tissue Doppler indices in patients undergoing mitral valve replacement DR PRAKASCHANDRA, T ESTERHUIZEN, DP NAIDOO

Abstract

Submitted 20/9/10, accepted 15/9/11

Background: In severe mitral regurgitation, a subset of patients who are asymptomatic may develop left ventricular decompensation before changes in echocardiographic parameters become evident. Since N-terminal brain natriuretic peptide (NT-proBNP) is used to detect early heart failure, we hypothesised that NT-proBNP would be activated in patients with mitral regurgitation.

Methods: Patients submitted to surgery were prospectively evaluated over eight months in the Department of Cardiology at Inkosi Albert Luthuli Central Hospital. Control patients with severe mitral regurgitation were obtained from the outpatient clinic. In order to define their value in identifying left ventricular decompensation, NT-proBNP levels and tissue Doppler imaging (TDI) indices were simultaneously measured and compared with conventional echocardiographic indices at baseline and this was repeated at one week and at six weeks after valve replacement.

Results: Mean NT-proBNP levels were markedly elevated pre-operatively in all surgical cases compared to controls (p = 0.0001). The diastolic E-mitral/E-annulus ratio, measured using TDI, was higher in the study group, indicating higher left ventricular filling pressure present in the study group. NT-proBNP levels increased further at one week after surgery and subsided at the six-week follow-up visit to levels similar to the control group. The TDI diastolic ratio also decreased at one week, and increased slightly again at the six-week follow up. These changes were accompanied by significant reduction in left atrium and left ventricular chamber dimensions with an increase in the ejection fraction from one to six weeks.

Conclusion: Marked differences in mean NT-proBNP levels and TDI ratios between the study and control groups suggest that using TDI and NT-proBNP assays may detect covert left ventricular decompensation.

Cardiovasc J Afr 2012; 23: 200–205

Keywords: mitral regurgitation, tissue Doppler imaging, NT-proBNP, mitral valve replacement Department of Biomedical and Clinical Technology, Durban University of Technology; and Department of Cardiology, University of KwaZulu-Natal, Durban, South Africa DR PRAKASCHANDRA, MMed Sci (Cardiology), RosaleyPRA@dut.ac.za

Department of Cardiology, University of KwaZulu-Natal, Durban, South Africa DP NAIDOO, MD, FRCP, FESC, naidood@ukzn.ac.za

Department of Biostatistics, University of KwaZulu-Natal, Durban, South Africa T ESTERHUIZEN, MSc (Biostatistics)

www.cvja.co.za

DOI: 10.5830/CVJA-2011-057

Chronic organic mitral regurgitation (MR) has a variable course and requires careful monitoring by the clinician. Symptoms often occur late due to the compliance properties of the left atrium that allow it to accommodate large volumes of blood without a significant rise in pressure. As the regurgitation becomes more severe, contractile dysfunction may precede the onset of symptoms associated with disease progression as the ejection fraction (EF) declines but it may still remain in the normal range. An EF less than 60% has been shown to be associated with poorer survival rates after corrective surgery and is likely to indicate covert contractile dysfunction in MR patients.1 Although numerous qualitative and quantitative echocardiographic modes have been developed, previous studies have demonstrated that existing measures of severity of MR correlate poorly with clinical signs and symptoms.2 There are few data on the newer echocardiographic modalities, notably tissue Doppler imaging (TDI), the predictive values of which have not been determined. While the mitral inflow measurements are preloaddependent, diastolic tissue velocities measured using TDI are far less influenced by these parameters and may be more reliable in assessing contractile changes.

The development of contractile dysfunction and its relation to the severity of volume overload in MR is not clearly understood.

Prolonged contractile dysfunction eventually becomes irreversible even after the MR is corrected and is predictive of both congestive heart failure and death.1 In chronic organic MR, there are as yet no clear definitions of BNP physiological determinants and outcome implications. We hypothesised that N-terminal brain natriuretic peptide (NT-proBNP) would be activated in MR and, because this is a validated diagnostic test in heart failure, it could prove to be an early marker for the development of left ventricular (LV) dysfunction.

In this study we evaluated tissue Doppler imaging and NT-proBNP levels in patients with severe chronic MR and determined their time-course patterns following mitral valve replacement.

Methods The study population was selected from Inkosi Albert Luthuli Central Hospital, Durban. Informed consent was obtained from each patient, and in the case of minors, from the parent or legal guardian. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Ethics approval was given by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, Nelson R Mandela School of Medicine (Ref No. H112/06).

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The study enrolled patients prospectively from February to September 2007. Patients with severe, chronic isolated MR underwent comprehensive quantitative Doppler echocardiography performed by one trained echocardiographer (RP). Patients were excluded if they had acute MR, MR due to ischaemic heart disease or cardiomyopathy, previous valve surgery and associated aortic or congenital valve disease. Patients with associated mitral stenosis were excluded if the valve area was less than 2.0 cm2.

Clinical evaluation and management of the patients were conducted by their independent clinicians. Assessment of symptoms was determined clinically by the New York Heart Association (NYHA) classification, and atrial fibrillation was evaluated by electrocardiography. Doppler echocardiographic recordings and blood samples were collected simultaneously and estimation of the NT-proBNP levels were processed independently.

Control subjects with severe MR were selected from the cardiology outpatient follow-up clinic where they were assessed as not requiring surgery in the short term and were receiving medical therapy. Controls were selected as severe MR, but without evidence of ischaemic heart disease, as it is known that NT-proBNP is activated in the presence of ischaemia.3 Colour Doppler echocardiography was performed on all patients using a Siemens Sequoia machine (Acuson, Germany).

Dimensions and wall thickness were measured according to the American Society of Echocardiography guidelines using the leading-edge method,4 and EF was measured from the apical four-chamber view using the modified Simpson’s method. The rate of rise of pressure (dP/dT) was also calculated as a measure of ventricular systolic function. The six frequently applied echocardiographic variables described by Thomas et al.5 were used to evaluate MR. Mitral regurgitation was quantified by measurement of the regurgitant volume and fraction.

TDI was performed in the apical four-chamber view. The myocardial systolic wave (Sm) velocity, the diastolic indices, namely early myocardial (Em) and atrial contraction (Am) peak velocities, Em/Am ratio, and early diastolic filling ratios (transmitral/annular) (Em/Ea ratio) were measured. The ratio of the E wave across the mitral valve to the annulus E wave on tissue Doppler (E/Ea) was used as an estimate of the LV filling pressure. All echocardiographic measurements were performed by a single echocardiographer (RP) blinded to all other measurements. The images and measurements were reviewed off-line by a trained cardiologist (DPN). The intra-observer variability for the measurements of proximal isovelocity surface area (PISA) and TDI was < 5%.

For measurement of NT-proBNP, venous blood samples were taken in gel-filled tubes with the patient resting quietly at the time of echocardiography. Additional samples were taken from subjects undergoing mitral valve replacement at one and six weeks post surgery.

Statistical analysis SPSS for Windows version 15.0 was used for the statistical analysis. Clinical variables were normally distributed and expressed as mean ± SD. NT-proBNP levels were log-transformed for statistical analysis. Group comparisons were performed with ANOVA, t-test or chi-square tests. Associations of baseline NT-proBNP were tested with linear and non-parametric regression (categorical variables). The time course of NT-proBNP within

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the cases was evaluated using paired t-tests. The discriminating capacity of the NT-proBNP for separating surgical cases from controls was assessed by the construction of ROC curves.

Bivariate analysis was performed to assess the ability of the different parameters in predicting a favourable outcome using an NT-proBNP level of 50 pmol/l.

Results A total of 54 patients with severe rheumatic mitral regurgitation were enrolled in the study and surgical cases were followed up for six weeks. Their baseline characteristics are shown in Table 1. All but one of the patients in our sample population were of African descent (98%). There were 27 control patients with severe chronic rheumatic mitral regurgitation who were recruited from the cardiology follow-up clinic.

Only one patient in the control group had markedly elevated systolic pressure (63 mmHg) together with NYHA class III symptoms. This patient subsequently had a valve replacement seven months after the echocardiographic and NT-proBNP assessment.

The orifice area was markedly increased in 12 patients in the study group (Table 2). Group comparisons revealed that early diastolic filling ratios (E-mitral/E-annulus) was higher in the study group (p = 0.04). A similar pattern was observed with NT-proBNP level, which was elevated in both groups, but was markedly higher (p < 0.001) in the study group (Table 3).

The immediate post-operative period showed a rise in NT-proBNP levels from pre-operative levels (262 ± 224 pmol/l) to a mean of 395 pmol/l at one week, and subsiding thereafter to 94 pmol/l at six weeks (see Fig. 1). These changes were mirrored by a significant reduction in the left atrium (LA) size and volume, as well as in the LV chamber dimension to levels similar to the control population group (Table 4). It is noteworthy that inasmuch as there was a slight reduction in the end-diastolic volume (EDV) and end-systolic volume (ESV), these changes were not statistically significant. Although the TDI systolic wave indices were unchanged between the two time points, there was a significant increase noted in the early diastolic filling ratios, suggesting a further rise in the left ventricular filling pressures at six weeks.

Four patients exhibited persistently elevated NT-proBNP levels at six weeks compared to the other study cases. The ejection fraction fell in three of these patients post-operatively, and was accompanied by little change in the end-systolic dimension (ESD) and NT-proBNP values compared to pre-operative levels.

TABLE 1. BASELINE (PRE-OPERATIVE) CHARACTERISTICS IN SEVERE MR Variables Controls (n = 27) Study (n = 27) p-value Age 23 ± 13 20 ± 11 0.08 Males/females 7/20 7/20 1.000 NYHA I–II 24 10 0.001 NYHA III–IV 3 17 Heart failure 1 5 EF (mean ± SD) 67 ± 6 67 ± 9 1.000 Diuretics 24 20 0.307 ACE inhibitors 25 25 1.000 Atrial fibrillation 6 10 0.372 NYHA = New York Heart Association class; EF = ejection fraction.

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TABLE 2. BASELINE QUANTIFICATION OF THE SEVERITY OF MR

TABLE 4. POST-OPERATIVE EVALUATION AT ONE AND SIX WEEKS’ FOLLOW UP

Variables Controls (n = 27) Study (n = 27) p-value RF < 70% 6 2 70–80% 6 3 0.192 > 80% 15 19 RV > 60 ml 27 27 1.000 EOA < 0.35 3 1 0.36–0.40 2 4 0.058 0.41–0.90 17 10 > 0.90 5 12 PAS < 30 mmHg 0 0 30–39 10 6 0.192 40–59 16 18 > 60 mmHg 1 4 LA size < 40 mm 4 0 40–49 mm 5 2 0.074 > 49 mm 20 25 EF < 50% 0 1 51–60% 1 5 0.123 > 60% 26 21 RF = regurgitant fraction; RV = regurgitant volume; LA = left atrium; RV = right ventricle; PAS = pulmonary artery systolic pressure; EOA = effective orifice area; EF = ejection fraction.

1 week 6 weeks CI p-value LA size (mm) 64 ± 16 58 ± 16 2.0; 11.2 0.009 LA volume (ml) 234 ± 152 182 ± 140 21.2; 82.9 0.003 EDV (ml) 139 ± 52 125 ± 55 –15.7; 43.8 0.326 ESV (ml) 86 ± 47 73 ± 47 –10.7; 37.5 0.250 EDD (mm) 59 ± 9 54 ± 8 2.5; 10.2 0.004 ESD (mm) 45.5 ± 13 38.7 ± 9 12.7; 1.0 0.03 EF 42 ± 13 51 ± 13 –17.9; –1.0 0.0032 TDI syst (m/s) 0.07 ± 0.016 0.07 ± 0.015 –0.01; -0.2 0.821 TDI Em/Ea 12 ± 4 15 ± 3 –6.7; –0.2 0.418 NT-proBNP (pmol/l) 395 ± 460 94 ± 161 87.5; 514.1 0.009 LA = left atrium; EDV = end-diastolic volume; ESV = end-systolic volume; EDD = end-diastolic dimension; ESD = end-systolic dimension; EF = ejection fraction, TDI = tissue Doppler imaging; TDI Em/Ea = diastolic filling ratio.

TABLE 3. PRE-OPERATIVE QUANTIFICATION OF LV FUNCTION Controls Study p-value LA size (mm) 59.6 ± 13 76 ± 16 < 0.001 LA volume (ml) 177 ± 119 309 ± 183 0.003 EDV (ml) 177 ± 69 165 ± 48 0.472 ESV (ml) 58 ± 25 57 ± 25 0.898 EDD (mm) 67 ± 6 67 ± 9 0.06 ESD (mm) 38 ± 9 43 ± 8 0.043 EF 65 ± 10 67 ± 7 1.000 TDI (m/s) 0.09 ± 0.02 0.1 ± 0.07 0.377 TDI Em/Ea 14 ± 8 20 ± 8 0.004 NT-proBNP (pmol/l) 57 ± 88 262 ± 224 < 0.001 LA = left atrium; EDV = end-diastolic volume; ESV = end-systolic volume; EDD = end-diastolic dimension; ESD = end-systolic dimension; EF = ejection fraction, TDI = tissue Doppler imaging; TDI Em/Ea = diastolic filling ratio.

Discussion This is one of the first studies to use new modalities of measuring left ventricular function with TDI and NT-proBNP assays. NT-proBNP level has been shown to be a marker of left ventricular dysfunction and has been used to predict diastolic abnormalities in patients with normal systolic function,7 limiting the need for expensive cardiac imaging modalities.8,9 In this study, NT-proBNP level yielded the highest predictive value for discriminating between cases selected for surgery and controls followed up at the cardiology outpatients’ clinic (sensitivity of 96%). The ESD at the established cut-off point of 45 mm that defines the need for surgery had a higher specificity of 81%.

95% CI log BNP (pmol/l)

There was an increase in the diastolic filling ratios (Em/Ea) and a decrease in the TDI systolic wave. The fourth patient had a large drop in the NT-proBNP level, as well as an increase in the TDI systolic wave, in keeping with the preserved LV contractility.

There was a small decrease in the ESD post-operatively (Fig. 1). These four were identified by NT-proBNP cut-off levels set by Januzzi’s rule-in criteria (450 pg/ml, ~53 pmol/l) for the diagnosis of heart failure in the PRIDE study6 at six weeks.

A ROC curve was constructed for each variable to assess its discriminating capacity to distinguish between surgical cases and controls. The area under the curve was highest for NT-proBNP; this was the only parameter that approached 90% (Fig. 2). However, at established cut-off levels for normality, NT-proBNP (12 pmol/l = 125 pg/ml) yielded the highest sensitivity of 96% but had a low specificity of 45%. Using cut-off criteria established by Januzzi6 for the detection of

heart failure (NT-proBNP > 53 pmol/l), the specificity for NT-proBNP improved to 74%, and the positive predictive value to 84%. Of interest, eight patients in the control group had BNP levels > 53 pmol/l, and of these, six underwent surgery within the ensuing six months.

A second ROC curve (Fig. 3) was constructed using all the variables to separate NYHA classes I–II from III–IV. Once again, NT-proBNP emerged with the highest area under the curve, followed closely by the ESD. Bivariate analysis was performed to assess the ability of the different parameters to predict a favourable outcome, defined arbitrarily as NT-pro BNP level < 50 pmol/l. These were an effective orifice area (EOA) (p = 0.014), tissue Doppler S wave (p = 0.049) and left atrium (LA) size (p = 0.027), all pointing to the interrelationship between severe regurgitation, systolic function and NT-proBNP levels.

3.00

case control

2.50 2.00 1.50 1.00 0.50

Baseline

1st week post op Time points

Fig. 1. NT-pro BNP time-course changes.

6 weeks post op

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Source of the Curve LV Esd EF (%) BNP pmol/l s (l) E/Ea (l) EOA dP/dT Regurg. Fraction Reference Line

ROC curve

1.0

Sensitivity

0.8

0.6

0.4

0.2 dP/dT 0.0

0.0

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0.2

0.4 0.6 1 – Specificity Digital segments are produced by tiers.

0.8

1.0

LV Esd EF (%) BNP pmol/l s(l) E/Ea(l) EOA dP/dT Regurg. fraction

0.704 0.529 0.882 0.545 0.614 0.673 0.364 0.711

Area under the curve

Fig. 2. Receiver operating characteristics curve: surgical cases and controls.

In a study similar to ours, Pillai et al.10 assessed pre-operative NT-proBNP levels in a group of 20 patients with rheumatic heart disease. They showed that elevated pre-operative NT-proBNP levels were an indicator of underlying myocardial dysfunction, which was not evident by routine two-dimensional echocardiography, and advocated pre-operative assessment of NT-proBNP levels to detect underlying myocardial dysfunction.

Two other studies have examined patients with varying degrees of MR, and showed that changes in ventricular function occur early in the disease process, even before they could be detected echocardiographically.11,12 The diastolic filling ratios were higher in the study group, indicating LV decompensation and a rise in the filling pressures. However, the diastolic ratios were also elevated in the control group, suggesting that LV decompensation with elevated LV filling pressure was already present in patients deemed by the clinician to be stable enough to be followed up at the clinic.

The six-week correlation between NT-proBNP levels and chamber dimensions suggests that in MR, changes in volume load may be paralleled by changes in the NT-proBNP level and that the fall in NT-proBNP was related to corrections in volume and removal of the diastolic run-off into the left atrium. These results are also in keeping with those found by the Mayo Clinic,13 which showed that the severity of mitral regurgitation, although univariately associated with NT-proBNP concentrations, was not an independent predictor of high NT-proBNP levels. They examined a group of 124 patients with varying degrees of organic mitral regurgitation and showed that NT-proBNP level was independently predictive of mortality/heart failure over a 4.4-year follow-up period.

Increased Em/Ea (> 12) ratios and elevated NT-proBNP (> 170 pg/ml) have been shown to be useful parameters to identify patients at increased risk of developing paroxysmal atrial fibrillation (AF) as well as to reflect early left ventricular Source of the Curve LV Esd EF (%) BNP pmol/l s (l) E/Ea (l) EOA dP/dT Regurg. Fraction Reference Line

ROC curve

1.0

Sensitivity

0.8

0.6

0.4

0.2

0.0

0.0

0.2

0.4 0.6 1 – Specificity Digital segments are produced by tiers.

Fig. 3. Receiver operating characteristics curve: NYHA all classes.

0.8

1.0

LV Esd EF (%) BNP pmol/l s(l) E/Ea(l) EOA dP/dT Regurg. fraction

0.769 0.556 0.797 0.373 0.623 0.602 0.326 0.577

Area under the curve

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dysfunction.14 We found that NT-proBNP and tissue Doppler levels in patients with AF were elevated, both in the study and in the control groups, indicating that symptomatology was not an early marker of ventricular decompensation and that our patients needed to be evaluated and referred for surgical intervention at an earlier stage in the course of their illness.

The challenge in evaluating mitral regurgitation is a determination of what really constitutes normal ventricular function in these patients. The limitations of using the ejection fraction in the timing of surgery become clear in subjects with apparently normal ejection fraction and minimal symptoms.

In a study of 84 asymptomatic patients who underwent surgical correction for MR, Agricola et al.15 demonstrated that TDI systolic indices could predict postoperative left ventricular function. In contrast, our study has shown that the TDI systolic wave cut-off point of 0.06 m/s, which has been previously used to rule out systolic dysfunction,16 had very low sensitivities in separating surgical cases from controls (see Fig. 2). Using a higher cut-off point of 0.085 m/s only marginally improved the specificity. It is possible that different cut-off points in conjunction with strain measurements17 may be more sensitive in determining impaired LV contractile function in MR, which can only be established in future studies with serial evaluations at different time intervals.

Left ventricular contractile dysfunction is present in many patients with severe MR despite a normal ejection fraction and returns to normal after corrective mitral valve surgery in most but not all patients.18 This was very apparent in our patients. In fact, all our patients experienced more than 10% decline in the EF immediately post surgery. This was improved at the six-week follow-up visit in all but three of our patients. Despite symptomatic improvement, postoperative left ventricular dysfunction (EF < 50%) has been shown to occur frequently, occurring in close to a third of the patients successfully operated on.19 In our study, 15 (15/27) of the patients referred for surgery had ejection fractions above 60% and ESD values below 45 mm, indicating that the reason for surgery in these patients was the presence of significant symptoms while on medical treatment.

There is an inherent subjectivity in defining significant valverelated symptoms. Indeed, when the second ROC curve was constructed using NYHA class as the determinant, NT-proBNP again emerged as the strongest discriminator of advanced NYHA class.

The low specificity of 45% for NT-proBNP indicates a high number of false positive cases, i.e. patients selected

by NT-proBNP level as requiring surgery when in fact they were still being followed up in the clinic on medical therapy.

We believe that what is considered the high false-positive rate with NT-proBNP actually indicates that many of these control subjects with or without minimal symptoms actually required surgery, rendering them true positives. Waiting for more advanced symptoms or change in dimensions increases the risk of left ventricular dysfunction postoperatively. Two studies, both from the Mayo Clinic, have highlighted the poor outcomes in patients with severe MR who were managed conservatively rather than surgically.20,21 In another study, Pizzaro et al.22 reported that NT-proBNP level was a stronger prognostic marker than ESD or EOA and contributed independent prognostic information additional to other echo parameters. They showed that the BNP cut-off of 105

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pg/ml (12.4 pmol/l for NT-proBNP) identified asymptomatic patients with severe MR who were at higher risk.

Most of the subjects in our control group had values above this level, indicating that all our patients were at risk while being followed up at the clinic. We attributed this to the subtle nature of symptoms, or particularly in our study, lack of awareness (on the part of patients or patients’ caregivers) of worsening symptoms and poor referral guidelines from peripheral healthcare centres.

This low rate of intervention has also been reported in other centres as well.23 The Euro Heart Survey suggests that 31% of patients with severe valve disease and symptoms were not operated on.24 In our study, no parameter could discriminate pre-operatively between the four patients who exhibited persistently elevated NT-proBNP levels at six weeks and the rest of the sample.

All four of these patients had atrial fibrillation pre-operatively, which persisted at six weeks and at six months. There was no indication of difficulties with myocardial preservation to suggest this as the cause for the decline in postoperative EF by almost 30% from normal pre-operative levels.

One of the limitations of this study was that it was performed only in patients with severe MR. The study needs to be repeated in different subgroups with varying degrees of MR in order to determine the time course of NT-proBNP levels in the different stages of MR as well as in patients with ischaemic MR. Finally, we need to determine the association of NT-pro BNP levels in a longer follow-up study with hard end-points such as heart failure and death.

Conclusion We have shown that decision making regarding the timing of surgery in this cohort of rheumatic heart disease patients was determined largely by advanced symptomatology, so that patients are referred to surgery late in the course of severe MR, with a risk of permanent LV decompensation. We propose that NT-proBNP level be an additional marker, particularly in less symptomatic patients, even if the EF is normal. In time, it may prove to be the composite marker for the assessment of LV decompensation. These findings support those of Detaint et al.25 in that the BNP level reflects the severe haemodymamic, ventricular and atrial consequences of MR.

References 1.

2.

3.

4.

5.

6.

7.

Griffin BP. Timing of surgical intervention in chronic mitral regurgitation: is vigilance enough? Circulation 2006; 113(18): 2169–2172.

Rosenhek R, Rader F, Klaar U, Gabriel H, Krejc M, Kalbeck D, et al.

Outcome of watchful waiting in asymptomatic severe mitral regurgitation. Circulation 2006; 113: 2238–2244.

Weber M, Dill T, Arnold R, et al. N-terminal B-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris. Am Heart J 2004; 148: 612–620.

Zoghbi WA, Enriquez-Sarano M, Fosrer E, et al. American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003; 16: 777–802.

Thomas L, Foster E, Hoffman JIE, Schiller NB. The mitral regurgitation index: an echocardiographic guide to severity. J Am Coll Cardiol 1999; 3320: 16–2022.

Januzzi JL, Carlos AC, Saif A, et al. The N-terminal pro-BNP Investigation of Dyspnoea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–954.

Cowie MR, Jourdain P, Maisel J, Dahlstrom U. Clinical applications of B-type natriuretic peptide testing. Eur Heart J 2003; 24(19):

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1710–1718.

Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002; 105: 595–601.

Mair J, Hammerer-Lercher A, Puschendorf B. The impact of cardiac natriuretic peptide determination on the diagnosis and management of heart failure. Clin Chem Lab Med 2001; 39: 571–588.

Pillai S, Hemalatha R, Saibabu Meena Rani, Mullasari Ajit S. Assessment of preoperative pro-BNP levels in patients with rheumatic heart disease with normal left ventricular function; Institute of Cardiovascular Diseases. Indian Heart J 2003; 55(5): 450.

Shimamoto K, Kusumoto M, Sakai R, Watanabe H, Ihara S, Koike N, et al. Usefulness of the brain natriuretic peptide to atrial natriuretic peptide ratio in determining the severity of mitral regurgitation. Can J Cardiol 2007; 24(4): 295–300.

Brookes CI, Kemp MW, Hooper J, Oldershaw PJ, Moat NE. Plasma brain natriuretic peptide concentrations in patients with chronic mitral regurgitation. J Heart Valve Dis 1997; 6: 608–612.

Enriquez-Sarano M, Schaff H, Orszulak T, et al. Congestive heart failure after surgical correction of mitral regurgitation. A long-term study.

Circulation 1995; 92: 2496–2450.

Nakamura S, Naruse M, Naruse K, et al. Atrial natriuretic peptide and brain natriuretic peptide coexist in the secretory granules of human cardiac myocytes. Am J Hypertens 1991; 4: 909–912.

Agricola E, Galderisi M, Oppizzi M, et al. Pulsed tissue Doppler imaging detects early myocardial dysfunction in asymptomatic patients with severe mitral regurgitation. Heart 2004; 90: 406–410.

Pai RG, Bodenheimer MM, Pai SM, et al. Usefulness of systolic excursion of the mitral anulus as an index of left ventricular systolic function.

Am J Cardiol 1991; 67: 222.

17. Carlhall CJ, Nguyen TC, Itoh A, et al. alterations in transmural myocardial strain. Circulation 2008; 118: S256–S262.

18. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005; 352: 875–883.

19. Kouris N, Ikonomidis I B, Kontogianni D. Mitral valve repair versus replacement for isolated non-ischemic mitral regurgitation in patients with preoperative left ventricular dysfunction. A long-term follow-up echocardiography study. Eur J Echocardiogr 2005; 6(6): 435–442.

20. Kernis SJ, Nkomo VT, Messika-Zeitoun D, Gersh BJ, Sundt TM III, Ballman KV, et al. Atrial fibrillation after surgical correction of mitral regurgitation in sinus rhythm: incidence, outcome, and determinants.

Circulation 2004; 110: 2320–2325.

21. Enriquez-Sarano M. Timing of mitral valve surgery. Heart 2002; 87: 79–85.

22. Pizaro R, Bazzino O, Oberti P, et al. Prospective validation of the prognostic usefulness of brain natriuretic peptide in asymptomatic patients with chronic severe mitral regurgitation. J Am Coll Cardiol 2009; 54(12): 1099–1106.

23. Bach DS, Awais M, Gurm HS, Kohnstamm S. Failure of guideline adherence for intervention in patients with severe MR. Am Coll Cardiol 2009; 54(9): 860–865.

24. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003; 24: 1231–1243.

25. Detaint D, Suitton M, Avierinos JF, et al. B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome.

Circulation 2005; 111: 2391–2397.

Letter to the Editor Cohort studies of cardiovascular disease in the Seychelles, Tanzania and Mauritius We read with interest the review by Kengne et al. on cohort studies of cardiovascular disease in sub-Sahara Africa.1 We agree with the authors that cohort studies are important tools to advance our knowledge of cardiovascular disease in the region and inform appropriate clinical and public health responses.

We recognise the difficult challenge of identifying all cohort studies in the region. We wish however to mention several cohort studies in the Seychelles, Tanzania and Mauritius, which were published in leading medical journals but were not included in the review, although they met inclusion criteria set by the authors of the review.

The Republic of Seychelles, which lies in the Indian Ocean around 1 000 km east of Kenya, belongs to south Saharan Africa.

Seychelles is part of WHO AFRO, is a member of the South African Development Community (SADEC) and contributes epidemiological data to the Global Burden of Disease project for estimates of the east Africa region. The majority of the population of Seychelles is of African descent.

In a cohort study of 5 514 Seychelles children, there was a strong association between weight gain during the first year of life and overweight/obesity at age five to 17 years.2 Adherence to

antihypertensive treatment was low in 50 hypertensive patients followed for 12 months, despite free healthcare.3 In this study adherence was measured with electronic pill containers, the gold standard for assessment of therapeutic adherence. In a cohort study of 153 smokers followed for six months, smokers who were shown pictures of their own atherosclerotic plaques in their carotid arteries (B-mode ultrasonography) had improved rates of smoking cessation.4 A cohort study among 644 Seychelles children enrolled at birth showed no overall effect of pre-natal exposure to organic mercury on blood pressure (BP) levels at age 12 and 15 years.5 In Tanzania, 653 participants with BP ≥ 160/95 mmHg and 653 with BP < 160/95 mmHg from a population survey of 9 254 subjects in Dar es Salaam had BP readings on three additional visits over an eight-week follow-up period. Their BP decreased markedly over subsequent visits, irrespective of baseline BP levels, and the prevalence of hypertension dropped by approximately 50% based on BP values on the second, third or fourth visits, compared to BP values on the first visit.6 continued on page 215 …

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Presentation pattern and management of effusive– constrictive pericarditis in Ibadan MA SALAMI, PO ADEOYE, VO ADEGBOYE, OA ADEBO

Abstract

Keywords: pericarditis, effusive, constrictive, Ibadan, African

Background: Effusive–constrictive pericarditis is a syndrome in which constriction by the visceral pericardium occurs in the presence of a dense effusion in a free pericardial space.

Treatment of this disease is problematic because pericardiocentesis does not relieve the impaired filling of the heart and surgical removal of the visceral pericardium is challenging.

We sought to provide further information by addressing the evolution and clinico-pathological pattern, and optimal surgical management of this disease.

Methods: We conducted a prospective review of a consecutive series of five patients managed in the cardiothoracic surgery unit of University College Hospital, Ibadan, in the previous year, along with a general overview of other cases managed over a seven-year period. This was followed by an extensive literature review with a special focus on Africa.

Results: The diagnosis of effusive–constrictive pericarditis was established on the basis of clinical findings of features of pericardial disease with evidence of pericardial effusion, and echocardiographic finding of constrictive physiology with or without radiological evidence of pericardial calcification. A review of our surgical records over the previous seven years revealed a prevalence of 13% among patients with pericardial disease of any type (11/86), 22% of patients presenting with effusive pericardial disease (11/50) and 35% who had had pericardiectomy for constrictive pericarditis (11/31). All five cases in this series were confirmed by a clinical scenario of non-resolving cardiac impairment despite adequate open pericardial drainage. They all improved following pericardiectomy.

Conclusion: Effusive–constrictive pericarditis as a subset of pericardial disease deserves closer study and individualisation of treatment. Evaluating patients suspected of having the disease affords clinicians the opportunity to integrate clinical features and non-invasive investigations with or without findings at pericardiostomy, to derive a management plan tailored to each patient. The limited number of patients in this series called for caution in generalisation. Hence our aim was to increase the sensitivity of others to issues raised and help spur on further collaborative studies to lay down guidelines with an African perspective.

Submitted 24/5/10, accepted 5/10/11

Department of Surgery, Cardiovascular and Thoracic Surgery Division, University College Hospital and College of Medicine, University of Ibadan, Ibadan, Nigeria MA SALAMI, MBBS, MRCS (Glasgow), FWACS, drmudathirsalami @yahoo.com PO ADEOYE, MBBS, FWACS VO ADEGBOYE, MBBS, FMCS

College of Health Sciences, Bowen University, Iwo, Nigeria OA ADEBO, FRCSC

Cardiovasc J Afr 2012; 23: 206–211

www.cvja.co.za

DOI: 10.5830/CVJA-2011-066

Effusive–constrictive pericarditis is a clinical syndrome characterised by concurrent pericardial effusion and pericardial constriction where constrictive haemodynamics are persistent after the pericardial effusion is removed. The treatment of effusive–constrictive pericarditis is problematic because pericardiocentesis does not relieve the impaired filling of the heart, and surgical removal of the fibrinous exudate coating the visceral pericardium may not be possible.1 Pericardiectomy following development of a pericardial skin that is amenable to surgical stripping is usually the most successful treatment option.

The objectives of this case series were to document the evolution and clinico-pathological pattern of this disease in Nigerians.

Methods We conducted a prospective review of a consecutive series of five patients managed in the cardiothoracic surgery unit of University College Hospital, Ibadan in the previous year, along with a general overview of other cases managed over a seven-year period. This was followed by an extensive literature review with a special focus on Africa. The diagnosis of effusive–constrictive pericarditis was established on the basis of clinical findings of features of pericardial disease with evidence of pericardial effusion, and echocardiographic finding of constrictive physiology with or without radiological evidence of pericardial calcification.

Results A review of our surgical records over the previous seven years revealed a prevalence of 13% among patients with pericardial disease of any type (11/86), 22% of patients presenting with effusive pericardial disease (11/50) and 35% who had pericardiectomy for constrictive pericarditis (11/31).

The present subset was chosen for the prospective follow up due to the unusual consecutive presentation and a dearth of studies specifically on this subset of patients from Africa.

All five cases in this series were confirmed by a clinical scenario of non-resolving cardiac impairment despite adequate open pericardial drainage. All five patients were prospectively followed up. One patient, who we treated for effusive–contrictive pericarditis, is described in detail and four other cases are summarised in tabular form (Table 1).

Case studies A 20-year-old, HIV sero-negative lady presented to the

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TABLE 1. SUMMARY OF CASES OF EFFUSIVE–CONSTRICTIVE PERICARDITIS Patient 1. SB Pre-op NYHA III 2. DS Pre-op NYHA III 3. AO Pre-op NYHA IV 4. MN Pre-op NYHA IV 5. OS Pre-op NYHA IV

Age (years) Gender 46 M 19

M

20

F

19

F

20

M

HIV Post-op status Initial procedure Pericardial histology NYHA Negative Pericardial window and Tuberculous pericarditis II biopsy – Pericardial window and Non-specific calcific I biopsy pericarditis – Negative Pericardial window and Non-specific chronic I biopsy pericarditis Endomyocardial fibrosis Negative Pericardial window and Pericardial fibrosis I Tricuspid regurgitation biopsy Fournier’s gangrene Negative Pericardial window Non-specific chronic I Upper gastrointestinal bleeding pericarditis Comorbid conditions Superficial thigh wound from gunshot Haemoglobin AS

cardiothoracic unit of the University College Hospital, Ibadan with a three-year history of easy fatigability, exertional dyspnoea and weight loss. There was a history of cough productive of whitish sputum. There was an associated history of orthopnoea, chest discomfort and bulging chest, but no history of leg swelling.

The patient was wasted and afebrile with a respiratory rate of 32 breaths/min. Her blood pressure and pulse were, respectively, 105/80 mmHg and 102 per min. Her neck veins were distended and she had a bulging anterior chest and hepatomegaly.

The patient’s packed cell volume was 40%. Her blood chemistry findings were normal. The chest radiograph showed a globular heart shadow (Fig. 1). The ECG revealed low-voltage waves. An echocardiogram revealed a large pericardial effusion with echo speckles within it and a thickened pericardium.

There was septal bounce and a dilated inferior vena cava with blunted respiratory fluctuations in diameter. A diagnostic pericardiocentesis yielded serosanguinous fluid.

The patient underwent a subxiphoid tube pericardiostomy with pericardial biopsy. A postoperative chest radiograph showed evidence of pericardial calcification (Fig. 2). She was scheduled for an elective pericardiectomy, which was declined.

The pericardiostomy tube was removed one week post operation.

A subsequent radiograph revealed evidence of re-accumulation of pericardial fluid. The patient and her relatives still declined surgery and asked for a discharge.

She represented about 48 hours later with evidence of massive pericardial effusion and cardiac tamponade. She then had an emergency pericardiocentesis under echocardiographic guidance, during which 1 940 ml of haemorrhagic effusion was aspirated and another 2 250 ml four days later. She improved following this and then had a pericardiectomy.

Findings at surgery included a thickened parietal and visceral pericardium, about 1.5 l of serosanguinous fluid in the pericardial space, and an area of calcification particularly over the right atrium (Fig. 3A, B). Both the parietal and visceral pericardium were stripped. The patient had an uneventful postoperative recovery period and was discharged home 10 days after surgery.

She has been seen twice since discharge, the last visit eight months post operation, with remarkable recovery, and NYHA class I status.

SM had a pre-operative (pericardial window) echo, which showed effusion with constrictive physiology. He had modest

Fig. 1. Radiograph showing massive globular heart shadow.

Fig. 2. Radiograph showing evidence of pericardial calcification.

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A

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B

Fig. 3. (A) Thickened pericardium and a large pericardial space. (B) Final phase of visceral pericardial stripping.

postoperative improvement and was discharged but he represented three months later with worsening of pre-operative symptoms. He then had a pericardiectomy, following which he improved progressively.

Following tube pericardiostomy, DS had very transient improvement in his symptoms. Repeat lateral chest X-ray showed evidence of pericardial calcification while echocardiography showed moderate pericardial effusion and diastolic dysfunction (Fig. 4). He made a rapid recovery following pericardiectomy.

MN had minimal improvement following tube pericardiostomy, remaining dyspnoeic at rest. Postoperative chest radiography and echocardiography showed pericardial calcification. In addition, there was a markedly enlarged right atrium, grade III–IV tricuspid regurgitation and a small right ventricle with endocardial thickening, suggestive of endomyocardial fibrosis.

We elected to go ahead with a pericardiectomy on account of the pericardial thickening with calcification. She improved following pericardiectomy, with NYHA class I status.

OS had pericardiostomy with slight improvement and was discharged home on anti-tuberculous therapy. He had a pericardiectomy three months later, during which he had an intraoperative complication of right ventricular wall injury, which was promptly repaired. He had an uneventful postoperative recovery until the 12th and 19th days postoperatively, when he developed Fournier’s gangrene and upper gastrointestinal bleeding, respectively. These were successfully managed and he was discharged home on the 36th day postoperatively.

Discussion Effusive–constrictive pericarditis is said to be an uncommon pericardial syndrome.2 In a prospective study of 1 184 patients with pericarditis, Sagrista-Sauleda et al. reported a prevalence of only 1.3% among patients with pericardial disease of any type (15/1 184) and 6.9% among patients with clinical tamponade (15/218).3 However, a recent observational study by Mayosi et al. reported 28 (15.1%) of 185 patients with tuberculous pericarditis as belonging to that subset.4 This is quite similar to

the prevalence of 13% among patients with pericardial disease of any type in our seven-year review (11/86). We are not aware of any specific series from Africa.

Patients with effusive–constrictive pericarditis present with symptoms due to limitation of diastolic filling. These findings are secondary not only to the pericardial effusion but also the pericardial constriction. Symptoms and physical findings vary, while a moderate-to-large pericardial effusion may occur.

Management of effusive–constrictive pericarditis is therefore fraught with challenges.

The diagnosis is usually made by echocardiography, which should demonstrate diastolic dysfunction. The diagnosis can easily be missed by an unwary clinician because of the usual superimposed features of accompanying pericardial effusion or tamponade. This may have accounted for the premature discharge and re-admission of one of our patients (SB).

Pericardial effusion is seen as an echo-free space around the heart on echocardiography (Fig. 4). The presence of a large pericardial effusion with frond-like projections and a thick ‘porridge-like’ exudate is suggestive of an exudate but not specific for a tuberculous aetiology.1 Patients with acute haemorrhagic effusions may have pericardial thrombus appearing as an echo-dense mass.5 Small pericardial effusions are only seen posteriorly, while those large enough to produce cardiac tamponade are usually circumferential. In large pericardial effusions, the heart may move freely within the pericardial cavity (‘swinging heart’). In the parasternal long-axis view, pericardial fluid reflects at the posterior atrio-ventricular groove, while pleural fluid continues under the left atrium, posterior to the descending aorta. Rarely, tumour masses are found within or adjacent to the pericardium and may masquerade as tamponade.6 Diagnostic criteria for cardiac tamponade include diastolic collapse of the right atrial and ventricular anterior free wall, and left atrial and very rarely left ventricular collapse. Right atrial collapse is more sensitive for tamponade, but right ventricular collapse lasting more than one-third of diastole is a more specific finding for cardiac tamponade. Doppler findings include

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A

B

C

Fig. 4. Echocardiography showing moderate pericardial effusion (PE). RV = right ventricle; LV = left ventricle; RA = right atrium; LA = left atrium.

distension of the inferior vena cava that does not diminish with inspiration, which is a manifestation of the elevated venous pressure in tamponade.6 In addition, there can be marked reciprocal respiratory variation in mitral and tricuspid flow velocities. Tricuspid flow increases and mitral flow decreases during inspiration (the reverse in expiration).

A challenging differential diagnosis is endomyocardial fibrosis, a common form of restrictive cardiomyopathy (RCM) in Africa.7

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Because constrictive pericarditis can be corrected surgically, it is important to distinguish chronic constrictive pericarditis from restrictive cardiomyopathy, which has a similar physiological abnormality, i.e. restriction of ventricular filling. Helpful in the differentiation of these two conditions are right ventricular trans-venous endomyocardial biopsy (by revealing myocardial infiltration or fibrosis in RCM) and echocardiography, CT scan or cardiac magnetic resonance imaging (by demonstrating a thickened pericardium in constrictive pericarditis but not in RCM).8 Our fourth patient (MN) actually presented this challenge but a convincing thickening of the pericardium at echocardiography was enough to help us clarify the diagnosis.

Another important problem is the lack of placebo-controlled trials from which appropriate therapy may be selected, and of guidelines that assist in important clinical decisions. As a result, the practitioner must rely heavily on clinical judgment.9 The absence of guidelines specific to this subset of pericardial disease may be due to its relative rarity in the Western world.

The recent European Society of Cardiology guidelines on management of pericardial diseases was also silent on the subset of patients with effusive constrictive pericarditis, presumably due to a paucity of data on the subject.6 Other reasons could be difficulty in reaching a diagnosis and varied aetiopathogenesis, necessitating different evolution patterns.

While there is an abundance of diagnostic armamentarium in the West, practitioners in sub-Saharan Africa largely have to cope with severe limitations in diagnostic facilities. An exception to this may be South Africa, where a recent report highlighted the value of contrast-enhanced magnetic resonance imaging (MRI) in delineating epicardial and pericardial inflammation in effusive窶田onstrictive pericarditis.10 Cost is still an issue even if MRI becomes widely available. Clinical acumen and reasoning therefore still form the bedrock of clinical practice in most centres.

The cases managed in this series illustrate this point. In only two of the five cases was there a hint of constrictive physiology at the initial echocardiography, even though it is known there is a phase of transient sub-acute constriction, which may improve after pericardial drainage and medical treatment, especially with anti-tuberculous therapy in those arising secondary to tuberculosis. The only strong evidence of a high likelihood of need for pericardiectomy was the duration of the history in the first three patients. They all had a history longer than two years, suggestive of a chronic process.

Reaching an aetiological diagnosis is a real challenge globally but more problematic in our local practices. The results of pericardial fluid culture are frequently falsely negative and pericardial biopsy has a higher yield of diagnostic specimens.11-13 One therefore has to rely on pericardial tissue biopsy microbiology and histology. None of our patients had positive evidence from pericardial fluid microbiology or cytology. The histology of their pericardia is shown in Table 1. Three of the patients were therefore treated empirically with anti-tuberculous therapy.

The difficulty in establishing a bacteriological or histological diagnosis is foremost among unresolved issues in patients with pericarditis.14 A definite or proven diagnosis is based on demonstration of tubercle bacilli in the pericardial fluid or on histological section of the pericardium. A probable or presumed diagnosis is based on proof of tuberculosis elsewhere in a patient with otherwise unexplained pericarditis, a lymphocytic

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pericardial exudate with elevated biomarkers of tuberculous infection, and/or appropriate response to a trial of antituberculosis chemotherapy.

The diagnostic difficulty is best demonstrated by a recent series of patients with tuberculous pericarditis where most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients.4 Hence, the focus currently is on indirect tests for tuberculous infection, including ADA levels and more importantly, lysozyme or IFN-γ assay, which appears to hold promise for reaching diagnosis of cases arising secondary to tuberculosis.14-18 Technical and financial constraints may, however, limit the diagnostic utility of IFN-γ in many developing countries.1 These tests are currently not available in our centre.

The importance of recognising the haemodynamic syndrome of tamponade and constriction characteristic of effusive– constrictive pericarditis lies in an acknowledgment of the contribution of the visceral layer of the pericardium to the pathogenesis of constriction and of the need to remove it surgically.

However, not only is it sometimes surgically challenging to do an epicardectomy in some patients due to a flimsy, fibrinous visceral pericardium with attendant risk of haemorrhage; some patients may recover with medical treatment alone – so-called transient effusive–constrictive pericarditis.3,19 Three of the patients in this series actually had intra-operative haemorrhage from atrial or ventricular injury during the epicardectomy part of the procedure.

Visceral pericardiectomy is therefore a much more difficult and hazardous procedure than parietal pericardiectomy, but it is necessary for a good clinical result in cases of effusive– constrictive pericarditis. The clinical decision as to which patients need to be observed on medical treatment depends on presumed or confirmed aetiology, timing of presentation, and response to medical therapy.

Decision based on aetiology Causes of effusive–constrictive pericarditis are varied and usually practice-dependent. Tuberculosis is said to be responsible for approximately 70% of cases of large pericardial effusion and most cases of constrictive pericarditis in developing countries.

However, in industrialised countries, tuberculosis accounts for only 4% of cases of pericardial effusion and an even smaller proportion of instances of constrictive pericarditis.14 Series from Europe and North America report a predominance of idiopathic cases, followed by cases that occur after radiotherapy or cardiac surgery, or as a result of neoplasia or tuberculosis.3,11,20 The aetiological spectrum indeed reflects the general aetiological spectrum of pericardial diseases in each area and can be influenced by the changing aetiological spectrum of pericarditis in general and constrictive pericarditis in particular.3,21,22 The varying aetiological spectrum impacts on the need for and timing of pericardiectomy.17 In the Sagrista-Sauleda series, pericardiectomy was not performed in eight of 15 patients; in five of them owing to a poor general prognosis (four patients with neoplastic pericarditis) or a high surgical risk (one patient with radiation pericarditis), and in three patients (all with idiopathic pericarditis) because of progressive improvement and eventually resolution of the illness after pericardiocentesis. Wide anterior pericardiectomy

was performed in seven patients between 13 days and four months after pericardiocentesis owing to the persistence of severe right heart failure. The diagnoses in these seven patients were idiopathic pericarditis in four, radiation pericarditis in one, tuberculous pericarditis in one, and postsurgical pericarditis in one.

The patients in our limited series, as in others cases due to tuberculosis, usually had attendant pericardial calcification with no room for improvement without pericardectomy. This partly explains the need for pericardectomy in these patients.

Decision based on timing of presentation and response to medication Related to aetiology is the timing of presentation. Transient sub-acute effusive–constrictive pericarditis is known to resolve after pericardiocentesis without the need for pericardiectomy.3,23,24 In fact in two of three patients with idiopathic pericarditis who had resolution of their symptoms following pericardiocentesis in the Sagrista-Sauleda series, the onset of their illness was stated to be very recent. The monitoring of intra-cardiac and intrapericardial pressures as part of a pericardiocentesis procedure has been suggested in patients who present with a sub-acute course of pericardial tamponade, particularly those in whom the condition is idiopathic or is related to infection, neoplasm or rheumatological disease.2 The duration of pericardial disease in three of our patients was more than two years, suggesting chronicity and need for pericardectomy. Although the duration in the fourth and fifth patients was relatively short, non-resolution of their symptoms and presence of pericardial calcification in the fourth patient appeared to be a predictor of need for pericardial stripping.

Effusive–constrictive pericarditis diagnosed?

• Based on radiological finding of cardiomegaly • Evidence of constrictive physiology on echocardiography Clinical or echo findings of tamponade?

Yes

No

Pericardiostomy + pericardial biopsy

Duration less than 1 year Yes

No

Medical treatment +/– pericardiocentesis Tuberculous/calcification/ persistent symptoms/ elevated venous pressures Pericardiectomy including visceral pericardium

Fig. 5. Potential algorithm for the management of effusive–constrictive pericarditis.

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Management One can propose a management algorithm from the above discussion (Fig. 5). We would suggest pericardiocentesis followed by pericardiostomy and pericardial biopsy for bacteriology and histology as a first step in patients with tamponade or imminent tamponade. Duration of illness should be the next guide in those without tamponade, with those patients with duration more than one year offered pericardiostomy and biopsy. Other patients could be tried on medical treatment for six to eight weeks and operated on when there is persistent evidence of constriction. Presence of pericardial thickening with calcification following pericardiocentesis is an absolute indicator of need for a pericardiectomy. This can be further confirmed on a cardiac CT scan.

We believe this management algorithm is preliminary at best and is subject to improvement with more collaborative research.

The current on-going multicentre study on the role of steroids in the prevention of constrictive pericarditis, involving centres in South Africa, Nigeria and other African countries, is one such study.4 Other studies could focus on influence of aetiology and duration of pericardial disease on the need for pericardiectomy in other areas.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Conclusion

14.

Effusive–constrictive pericarditis as a subset of pericardial disease deserves closer study and individualisation of treatment.

Evaluating patients suspected of having the disease affords clinicians the opportunity to integrate clinical features and non-invasive investigations with or without findings at pericardiostomy to expeditiously arrive at a patient-specific management plan. The limited number of patients in this series is a limitation, which calls for caution in generalisation. Hence our aim was to increase the sensitivity of others to issues raised and help spur on further collaborative studies to lay down guidelines with an African perspective.

15.

References 1.

2.

3.

4.

Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis.

Circulation 2005; 112: 3608–3616.

Hancock EW. A clearer view of effusive-constrictive pericarditis.

Circulation 2004; 350: 435–437.

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Mayosi BM, Wiysonge CS, Ntsekhe M, Volmink JA, Gumedze F, Maartens G, et al. Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry.

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Risk factors for the development of pneumonia post cardiac surgery AE TOPAL, MN EREN

Abstract Objectives: Postoperative pneumonia is a devastating complication after cardiac surgery that increases morbidity and mortality. The objective of this study was to identify potential risk factors for the development of nosocomial pneumonia post cardiac surgery by the way of logistic regression analysis.

Design: Data of the last 162 patients undergoing cardiac surgery before November 2009 were retrospectively collected and analysed.

Results: The mean age of the patients was 65.57 ± 10.48 years and 83 (51%) were male. Postoperative pneumonia was diagnosed in 21 (13%) patients. The mean remaining time in the intensive care unit and mean length of hospitalisation were longer for patients with postoperative pneumonia.

Pre-operative heart rate, previous diabetes mellitus, previous chronic obstructive pulmonary disease, postoperative urea, creatinine and potassium levels, extubation time, postoperative atrial fibrillation, and number of units of transfused packed red blood cells (pRBC) and fresh frozen plasma were associated with higher occurrence of postoperative pneumonia on univariate analysis.

Conclusions: On logistic regression analysis, pRBC transfusion, previous chronic obstructive pulmonary disease and postoperative atrial fibrillation remained as independent predictors for the development of postoperative pneumonia.

Keywords: cardiac surgery, pneumonia, atrial fibrillation, transfusion, chronic obstructive pulmonary disease Submitted 29/7/10, accepted 17/1/12 Cardiovasc J Afr 2012; 23: 212–215

www.cvja.co.za

DOI: 10.5830/CVJA-2012-005

Despite the progress made in surgery and anaesthesia, the risk of developing nosocomial infections remains a real threat as more patients of greater age and with more co-morbidities are operated on.1 Particularly cardiac surgery creates a high risk for the development of hospital infections and among these, pneumonia plays an important role as it increases morbidity and mortality by causing pulmonary dysfunction or multi-organ failure.

Patients undergoing cardiovascular operations are currently older and with serious co-morbid disease. Compared to their younger counterparts, heart surgery in elderly patients has been implicated in the higher risk of mortality and recurrent pulmonary complications.2 Moreover, emergence of antibiotic-resistant pathogens increases the incidence of refractory pneumonia.

The aim of our study was to identify potential risk factors for Cardiovascular Surgery Department, Dicle University Medical Faculty, Diyarbakır,Turkey

AE TOPAL, MD, aendertopal61@hotmail.com, aetopal@dicle.edu.tr MN EREN, MD

the development of nosocomial pneumonia post cardiac surgery and thus contribute to decreasing the incidence of pneumonia by identifying preventable risk factors.

Methods This retrospective study was performed on the last 162 patients who underwent cardiac surgery (coronary artery bypass graft surgery, valve-replacement surgery) at our reference centre up to November 2009. The exclusion criteria were usage of immunosuppressive agents and an identifiable infection prior to surgery.

All patients received standardised anaesthetic management.

In the operating room, leads II and V5 on the electrocardiogram (ECG) and arterial blood pressure were continuously monitored.

Anaesthesia was induced with intravenous midazolam (0.03–0.07 mg/kg), sufentanil (1.5–3.0 mg/kg) and rocuronium bromide (0.9 mg/kg), and maintained with sevoflurane (0.8–1.5%) and continuous infusion of sufentanil (0.5–1.5 mg/kg/h).

All surgical procedures were performed through a median sternotomy. All patients included in the study received prophylactic administration of intravenous cefazolin perioperatively (1 g intravenously 30 minutes prior to the first incision, every eight hours during surgery and postoperatively for three days).

Pneumonia was considered clinically present as a new radiographic pulmonary infiltrate, consolidate, cavitation or pneumatocele in the presence of the following conditions: fever (> 38°C) without other recognised causes, leucocytosis (> 12 000/μl) or leucopenia (< 4 000/μl) and new-onset purulent sputum with a Gram-positive stain finding.

Possible risk factors and outcomes associated with pneumonia post cardiac surgery were analysed, including pre-operative variables [age, gender, heart rate, mean blood pressure, body surface area, urea, creatinine and potassium levels, co-morbidities, NYHA class, and left ventricular ejection fraction (LVEF)], operative variables [on/off pump surgery, cross-clamp time, cardiopulmonary bypass (CPB) time, total operation time, and need for intra-operative inotropic support], and postoperative variables [extubation time, chest tube drainage, number of units of transfused packed red blood cells (pRBC) and fresh frozen plasma (FFP), urea, creatinine and potassium levels, and postoperative atrial fibrillation (AF)].

Statistical analysis The normality of the variables was analysed by Kolmogorov– Smirnov test. Continuous variables are presented as means with standard deviations and were compared among groups using the Student’s t-test or Mann-Whitney U-test when appropriate (non-parametric data). Dichotomous variables are presented as percentages and were compared among groups using a Chi-square or Fisher exact test when appropriate.

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All variables showing an association (p ≤ 0.05) with pneumonia post cardiac surgery were then entered into a forward stepwise multivariate logistic regression model. A two-sided p-value < 0.05 was considered significant in the multivariate logistic regression model. Adjusted odds ratios (AORs), 95% confidence intervals (CIs), and two-tailed p-values were calculated for all variables retained in the multivariate logistic regression model. Statistical analyses were carried out using the statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA).

TABLE 1. EFFECT OF PATIENTS’ CHARACTERISTICS AND PERI-OPERATIVE VARIABLES ON DEVELOPMENT OF PNEUMONIA POST CARDIAC SURGERY Patients without pneumonia (n = 141) 72 (51.1) 65.3 ± 10.4

Patients with pneumonia (n = 21) 11 (52.4) 67.5 ± 11.0

p-value Male, n (%) 0.911** Age (years) 0.362* Pre-operative variables NYHA class, n (%) 0.889** I 17 (12.1) 3 (14.3) II 89 (63.1) 12 (57.1) III 35 (24.8) 6 (28.6) Ejection fraction (%) 50.5 ± 8.7 47.6 ± 9.4 0.170* Heart rate (/min) 92.2 ± 6.3 89.2 ± 7.4 0.047* Mean blood pressure (mmHg) 91.7 ± 9.7 88.3 ± 6.9 0.130* 1.7 ± 0.1 1.7 ± 0.2 0.242* Body surface area (m2) Urea (mg/dl) 40.2 ± 14.3 44.7 ± 13.1 0.174* Creatinin (mg/dl) 1.0 ± 0.2 1.0 ± 0.2 0.403* Potassium (mmol/l) 4.3 ± 0.4 4.2 ± 0.5 0.855* Hypertension, n (%) 97 (68.8) 14 (66.7) 0.845** Hyperlipidaemia, n (%) 89 (63.1) 14 (66.7) 0.753** Tobacco usage, n (%) 79 (56) 12 (57.1) 0.924** Peripheral arterial disease, n (%) 9 (6.4) 1 (4.8) 0.774** Atrial fibrillation, n (%) 25 (17.7) 4 (19) 0.884** COPD, n (%) 27 (19.1) 16 (76.2) < 0.001** Diabetes mellitus, n (%) 88 (62.4) 18 (85.7) 0.037** Intra-operative variables Off pumpn, n (%) 13 (9.2) 3 (14.3) 0.469** Cross-clamp time (min) 36.2 ± 10.8 37.8 ± 9.8 0.552* CPB time (min) 60.4 ± 16.9 61.2 ± 15.0 0.859* Total operation time (min) 114.9 ± 20.3 114.8 ± 15.0 0.971* Need for inotropic support, n (%) 30 (21.3) 8 (38.1) 0.091** Postoperative variables Extubation time (hour) 7.5 ± 2.8 25.0 ± 21.3 < 0.001* Chest tube drainage (ml) 610.6 ± 733.3 ± 0.069* 286.0 287.4 Units of transfused FFP 2.9 ± 1.5 4.8 ± 3.3 < 0.001* Units of transfused pRBC 5.8 ± 1.6 10.8 ± 3.3 < 0.001* Urea (mg/dl) 45.2 ± 15.7 57.8 ± 21.6 0.001* Creatinine (mg/dl) 1.1 ± 0.4 1.3 ±.5 0.009* Potassium (mmol/l) 3.7 ± 0.7 4.1 ± 1.0 0.008* Atrial fibrillation, n (%) 25 (17.7) 13 (61.9) < 0.001** *Student’s t-test, **Fisher’s exact test.

COPD: chronic pulmonary obstructive disease, CPB: cardiopulmonary bypass, FFP: fresh frozen plasma, pRBC: packed red blood cells.

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Results The study group comprised 162 patients who underwent cardiac surgery. The mean age of the patients was 65.57 ± 10.48 years (range 43–84 years), and 83 (51%) were male. Of 162 operations, 140 were coronary artery bypass graft (CABG) surgery, and 22 patients underwent valve replacement surgery. Sixteen CABG operations were performed without cardiopulmonary bypass (CPB).

Before surgery, 20 patients were in New York Heart Association (NYHA) functional class I, 101 patients were in class II, and 41 were in class III. Pre-operative co-morbid diseases were diabetes in 106 patients, hypertension in 111 patients, chronic obstructive pulmonary disease (COPD) in 43 patients, peripheral artery disease in 10 patients and AF in 29 patients. Ninety-one (56.2%) patients were tobacco users. The patients’ characteristics and peri-operative variables are shown in Table 1.

Postoperative pneumonia was detected in 21 (13%) patients.

Mean remaining time in the intensive care unit and mean length of hospitalisation were longer for patients with postoperative pneumonia compared to the patients without postoperative pneumonia (4.5 ± 2.7 vs 3.1 ± 1.1 days, p < 0.001; 13.1 ± 9.4 vs 8.8 ± 4.3 days, p = 0.001). There was no difference between CABG and valve-replacement surgery regarding postoperative development of pneumonia (p = 0.435).

Pre-operative heart rate was related to postoperative incidence of pneumonia (p = 0.047). The percentage of patients with previous COPD and diabetes was greater in the group with postoperative pneumonia. The remaining patients’ characteristics regarding pre-operative variables were similar between the groups.

Whereas none of the intra-operative variables had any effect on development of pneumonia, many postoperative variables were significant risk factors. In patients with postoperative pneumonia, intubation time was longer, postoperative urea, creatinine and potassium levels were higher, more chest tube drainage was encountered, and the need for transfusion of pRBC and FFP was increased.

All variables showing an association (p ≤ 0.05) with occurrence of postoperative pneumonia were then entered into a forward stepwise multivariate logistic regression model. The following variables were included in the multivariate model: pre-operative heart rate, previous diabetes, previous COPD, postoperative urea, creatinine and potassium levels, extubation time, number of transfused FFP units, number of transfused pRBC units and postoperative AF. Upon logistic regression analysis of these risk factors, pRBC transfusion, previous COPD and postoperative AF remained as independent predictors for the development of pneumonia post cardiac surgery (Table 2).

TABLE 2. THE OUTCOMES OF FORWARD STEPWISE BINARY LOGISTIC REGRESSION AND ODDS RATIO β Variables SE Wald OR (95% CI) p-value pRBC transfusion 0.910 0.220 17.131 2.484 (1.614–3.821) < 0.001 Previous COPD 3.026 0.932 10.530 20.613 (3.315–128.191) 0.001 Postoperative AF 1.732 0.855 4.100 5.653 (1.057–30.228) 0.043 pRBC: packed red blood cells, COPD: chronic obstructive pulmonary disease, AF: atrial fibrillation.

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Discussion Although cardiac surgery-related mortality has substantially reduced due to advances in surgical techniques and perioperative care, the incidence of pneumonia post cardiac surgery is still high, varying between 1.5 and 21% in most series.3-8 Hortal et al.9 reported a 45.9% incidence of pneumonia in the sub-group of patients needing mechanical ventilation for longer than 48 hours. This wide range in the incidence rates was attributed to the difference in the characteristics of the study population and the diagnostic criteria used to define nosocomial pneumonia.3 Surgical technique plays an important role in the occurrence of nosocomial infections. For instance, inadequate haemostasis can lead to hypovolaemia, resulting in an increased need for blood transfusion, inotropic support, duration of surgery, or even possible re-operation. However, besides the surgical technique, several risk factors for pneumonia post cardiac surgery have been identified: age,4,9 unnecessary use of broad-spectrum antibiotics,5,10,11 duration of mechanical ventilation,4-6,9,12,13 CPB time,3,9 re-intubation,3,4,9 emergency surgery,4,5,9 intra-operative inotropic support,9 and pre-operative renal dysfunction.14 In univariate analysis of our study, duration of mechanical ventilation had a significant effect on postoperative pneumonia, whereas age, gender, CPB time and need for inotropic support had no association with pneumonia. Postoperative but not pre-operative high creatinine and urea levels, indicating renal dysfunction, were more common among patients with pneumonia compared to those without pneumonia. However, multivariate analysis depicted only prior COPD, transfusion of pRBC and postoperative atrial fibrillation as independent risk factors for pneumonia.

COPD was reported to cause postoperative pneumonia in another series.5 Nosocomial pneumonia is a frequent event in the course of acute exacerbation of COPD. There is clear evidence that in up to 50% of stable COPD patients, the lower airways are colonised by potential pulmonary pathogens. Advanced age and severity of lung disease are strongly associated with increased risk for pneumonia.

Cardiac surgery, especially CPB, aggravates COPD. Moreover the use of inhaled corticosteroids among patients with COPD significantly increases the risk of developing pneumonia.15,16 According to Lomas,17 inhaled corticosteroid use for at least 24 weeks is associated with a 60 to 70% higher relative risk of pneumonia. Corticosteroid use before elective cardiac surgery may be limited or at least the dose may be decreased in order to decrease the incidence of pneumonia. In addition, immunisation against influenza in older patients with COPD is associated with a 52% reduction in hospitalisations for pneumonia.18 The second independent risk factor for the occurrence of pneumonia following cardiac surgery was the need for blood transfusion, consistent with previous reports.3-5,8,9 Blood transfusions may cause transient immune suppression, thus increasing the susceptibility to infection. It was found to be an independent risk factor of deep sternal wound infections.19 The mechanism of the immunomodulatory effect of allogenic blood transfusion remains elusive. The infusion of foreign antigens in either soluble or cell-associated form has been shown to induce immune suppression, anergy and clonal deletion, most likely mediated by allogenic white blood cells.8 Another concern is the altered function of macrophages.

After transfusion macrophages lose migratory ability in response

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to chemotactic stimuli and produce more prostaglandin E2, resulting in decreased activity of antigen-presenting cells and the production of interleukin 2.3 There is an association between the length of storage of transfused red blood cells and the development of postoperative pneumonia,3,8 which is seen more rarely among patients with fresh red blood cell transfusions. Various immunosuppressive substances are released from white blood cell granules into red blood cell components during blood storage, contributing to transfusion-induced immunomodulation.8 Furthermore, the deleterious effect of stored blood may be due to depleted levels of 2,3-diphosphoglycerate and decreased deformability of stored red blood cells, both impairing oxygen delivery to the tissues.3 Recently, the involvement of inflammation in atrial fibrillation has been documented, and high levels of pro-inflammatory proteins, such as C-reactive protein, have been suggested to promote the persistence of atrial fibrillation by inducing structural and/or electrical remodelling of the atria. Atrial biopsies taken from patients in AF have also demonstrated evidence of inflammatory infiltrates within the atrial tissue, with evidence of oxidative damage or occult myocarditis, even among persons who were thought to have had lone AF.20 The fact that inflammation plays an important role in the development of both AF and pneumonia may explain the concomitance of these complications after cardiac surgery. It is classic knowledge that pneumonia is one of the non-cardiac causes of AF, predominantly in elderly patients. However, in our study, AF was an independent risk factor for pneumonia post cardiac surgery.

In patients with AF, contraction of the ventricles averages 150/minute. At that rate, the ventricles may not have enough time to fill maximally with blood before the next contraction, particularly without the normal contraction of the atria.21 Moreover, the contractility of the ventricle decreases after CPB. Therefore AF decreases the amount of blood pumped by the ventricles and the body begins to compensate by retaining fluid, resulting in the accumulation of fluid in the lungs. Alveolar oedematous fluid is a good culture medium for the development of secondary pneumonia. CPB contributes to this process by aggravating the pulmonary oedema and inflammation.22 Also, AF may play an active role in the development of postoperative pneumonia by prolonging the postoperative intubation time. However, postoperative AF has not been suggested as a cause of pneumonia post cardiac surgery in any previous reports. Our findings must be confirmed in larger series and it must be clarified whether pneumonia is only a cause or also a consequence of AF. The main limitations in our study were the retrospective nature of the analysis and the small sample size, affecting particularly the subgroup with postoperative pneumonia. Therefore any claim about an associative relationship between pre- or peri-operative variables and outcomes should be viewed with caution. The study group was also not treated entirely uniformly, as off-pump CABG patients were included. However, peri-operative care was standardised, which serves to strengthen conclusions on the results.

Conclusion On logistic regression analysis, pRBC transfusion, previous

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chronic obstructive pulmonary disease and postoperative atrial fibrillation remained as independent predictors for the development of postoperative pneumonia. AF particularly should be investigated in future series as a cause of pneumonia.

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… continued from page 205 In a subsequent 12-month cohort study, 161 untreated Tanzanian participants who had BP ≥ 160/95 mmHg on four separate visits were advised to seek healthcare. Twelve months later, only 34% reported to have attended a healthcare provider and antihypertensive treatment was taken by only 34% at some point during and 3% at the end of the 12-month follow up.7 Mauritius is also part of sub-Saharan Africa although a substantial proportion of the population is of Indian descent.

Many large cohort studies have been performed there. We mention just two,8,9 as it is not possible to include all of them in the context of this letter.

Pascal Bovet, MD, MPH, pascal.bovet@chuv.ch, bovet.pascal@gmail.com University Institute of Social and Preventive Medicine, Lausanne, Switzerland Conrad Shamlaye, MD, MSc, shamlaye@gmail.com Ministry of Health, Republic of Seychelles

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14. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP. Renal dysfunction and serious infections after open-heart surgery. Kidney Int 2003; 64: 239–246.

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A population-based study. Scand Cardiovasc J 2008; 42: 208–213.

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21. Shehab A. Heart rate variability as an indicator of left ventricular systolic dysfunction. Cardiovasc J Afr 2009; 20: 278–283.

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Bovet P, Burnier M, Madeleine G, Waeber B, Paccaud P. Monitoring one-year compliance to antihypertension medication in the Seychelles.

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An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: a five-year experience B MAZIBUKO, H RAMNARAIN, J MOODLEY

Abstract

Submitted 3/11/10, accepted 6/3/12

Background: Cardiac disease in pregnancy is a common problem in under-resourced countries and a significant cause of maternal morbidity and mortality. A large proportion of patients with cardiac disease have prosthetic mechanical heart valve replacements, warranting prophylactic anticoagulation.

Aim: To evaluate obstetric outcomes in women with prosthetic heart valves in an under-resourced country.

Methods: A retrospective chart review was performed of 61 pregnant patients with prosthetic valve prostheses referred to our tertiary hospital over a five-year period.

Results: Sixty-one (6%) of 1 021 pregnant women with a diagnosis of cardiac disease had prosthetic heart valves.

Fifty-nine had mechanical valves and were on prophylactic anticoagulation therapy, three had stopped their medication prior to pregnancy and two had bioprosthetic valves. There were forty-one (67%) live births, two (3%) early neonatal deaths, 12 (20%) miscarriages and six (10%) stillbirths.

Maternal complications included mitral valve thrombosis (n = 4), atrial fibrillation (n = 8), infective endocarditis (n = 6), caesarean section wound haematomas (n = 7), broad ligament haematoma (n = 1) and warfarin embryopathy (n = 4).

Haemorrhagic complications occurred in five patients and all five required blood transfusions.

Conclusion: Prophylactic anticoagulation with warfarin in patients with mechanical heart valve prostheses was associated with high rates of maternal and neonatal complications, including significant foetal wastage in the first and early second trimesters of pregnancy. Health professionals providing care for pregnant women with prosthetic heart valves must consistently advise on family planning matters, adherence to anticoagulation regimes and consider the use of prophylactic anticoagulant regimens other than warfarin, particularly during the first trimester of pregnancy.

Cardiovasc J Afr 2012; 23: 216–221

Keywords: prosthetic heart valves, anticoagulation, maternal and foetal outcomes

Department of Obstetrics and Gynaecology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa B MAZIBUKO, MD H RAMNARAIN, MD

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

www.cvja.co.za

DOI: 10.5830/CVJA-2012-022

Women with mechanical prosthetic heart valves (MPHV) are at greater risk of developing complications than those with cardiac disease without MPHV.1 The main reason is that MPHV require lifelong anticoagulation to reduce the high risk of associated thrombo-embolic complications.1,2 In addition pregnancy, being a hypercoaguable state, further increases the risk of thrombo-embolic complications and results in a 35% functional deterioration of MPHV.2 It is therefore not surprising that complications associated with cardiac valvular disease in pregnancy carry with them significant mortality and morbidity, particularly in under-resourced countries.3-6 Prophylactic anticoagulation treatment options for patients with MPHV in pregnancy include warfarin, unfractionated heparin (UH) and low-molecular weight heparin (LMWH).1,7 These agents are associated with increased maternal and foetal complications, treatment failures, high financial costs and potential teratogenic effects.1-4,8 Warfarin usage in the first trimester of pregnancy, for example is associated with high rates of congenital malformations and foetal losses.1-4 Therefore many authors suggest that warfarin be replaced by heparin, at least in the first trimester.1,4-6 High rates of treatment failure and mortality with the use of UH have also been reported.6 Low-molecular weight or fractionated heparin does not cross the placental barrier and is not reported to have teratogenic potential. Its use for prophylactic anticoagulation therapy may be preferred in pregnancy.2,7 In addition, LMWH has a longer half-life than UH. However, its use in pregnancy is still controversial due to the lack of adequate clinical trials.1,8 The majority of pregnant patients with MPHV have been managed at a single tertiary/quaternary facility in Durban by a multidisciplinary team since 2003. It is therefore likely that a single approach to prophylactic anticoagulation was used at this facility. The opportunity was therefore taken to conduct a retrospective chart review of management of patients with MPHV in pregnancy.

Methods This was a retrospective study of pregnant patients with MPHV, referred to a tertiary facility for management over a five-year period (January 2005 to December 2009). Ethical and hospital permission were obtained from the appropriate authorities.

At every patient visit, relevant data were captured on a software package (Medicom, Medicom Solutions, India). Baseline data recorded included demographic obstetric information,

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investigations done and all maternal and foetal complications.

All data were captured onto a structured data form.

The policy states that pregnant women with MPHV receive heparin in the first trimester, which is switched to warfarin in the second trimester and then replaced by intravenous heparin at 37 weeks prior to delivery. Heparin is stopped six hours before elective caesarean section (C/S) or induction of labour and re-started 12 hours post C/S or six hours post vaginal delivery if no bleeding complication has occurred. Warfarin, usually 10 mg, is given on the first day, simultaneously with intravenous heparin and the doses adjusted until the INR is 2.5–3 on two consecutive occasions; heparin is then stopped. All patients were treated according to this policy.

Descriptive statistics were used and all results are presented as frequencies, means and percentages.

Results Over the five-year study period, 1 021 hospital records of patients with cardiac disease were identified. Sixty-one (6%) had TABLE 1. BASELINE CHARACTERISTICS OF ALL PREGNANT WOMEN WITH PROSTHETIC HEART VALVES Characteristics Number (n = 61) Maternal age (years) Mean (range) 24 (16–45 ) Age groups (years) 15–20 17 21–25 23 26–30 13 > 30 8 Parity P0 34 P1 17 P2–3 4 P0+1 3 P0+4 1 P1+1 2 Gestational age (weeks) on admission < 14 18 14–28 32 28–38 11 History of previous pregnancies Miscarriage 6 Intrauterine death 3 Stillbirth (MSB) 2 Neonatal death 2 HIV status Negative 43 Positive 16 14 CD4 > 200 cells/ml 2 CD4 < 200 cells/ml Declined 2 NYHA functional class 1 49 11 6 111 4 1V 2 NYHA – New York Heart Association classification.9

prosthethic valves, mean age 24 (15–45) years. Thirteen (21%) presented in the first trimester; 37 (61%) in the second and 11 (18%) in the third trimester. Fifty-three (85%) were aged ≤ 30 years and 34 (56%) were primigravidae. The demographic and relevant clinical details are shown in Table 1.9 In addition to prosthetic heart valve replacements, five patients had associated medical conditions, namely systemic lupus erythematous (n = 1), tuberculosis (n = 1), insulin-dependent diabetes mellitus (n = 1), parathryoidism (n = 1) and epilepsy (n = 1).

The dosage details of prophylactic anticoagulation therapy are shown in Table 2 (n = 56). Two patients had bioprosthetic valves and were not on any anticoagulation therapy, while three with MPHV had stopped anticoagulation of their own accord prior to pregnancy. Forty-seven patients had isolated mitral valve replacements, 11 had mitral and aortic valve replacements and one an aortic valve replacement for a mean duration of 10 (7–21) years.

Five patients had thrombotic events. Four with isolated mitral valve prostheses were found on admission to hospital to have thrombosis on echocardiography. The characteristics of four patients with mechanical heart valve thrombosis are shown in Table 3. Three of these patients had repeat MPHV surgery prior to delivery and one at the time of elective C/S. The details of all valve replacement data are shown in Fig. 1.

The fifth patient with a thrombotic event resulted in a maternal death. The brief details are as follows: a 24-year-old P1G2 presented at 34 weeks gestational age, had a mitral valve replacement and was on warfarin 5 mg daily. Following the stabilisation of her INR at a warfarin dose of 2.5 mg for five to seven days, she complained of severe headache and her INR was 6. The patient was given frozen plasma to stabilise her INR. Shortly thereafter she complained of severe headache and had a low Glasgow coma scale (GCS). CT scan revealed a large left intracerebral bleed. A post mortem C/S was performed and a 2.6-kg live baby with good Apgar scores was delivered.

Echocardiography was performed in all patients. The mean ejection fraction in 57 patients was 55% (range: 34–70) and in four patients < 45%. Five patients showed dilated right ventricle and right atrium. Another patient showed dilated right atrium; one had an ascending aortic aneurysm and another patient had an aneurysm of the aortic root. Two patients had secondary pulmonary hypertension; three had vegetations and were treated for infective endocarditis.

There were 41 live births, two of which ended in early neonatal deaths. There were six stillbirths and 12 miscarriages.

The mode of delivery and foetal outcomes are shown in Table 4.

TABLE 2. DOSAGE DETAILS OF ANTICOAGULATION USED BY PATIENTS ON PRESENTATION AT THE FIRST ANTENATAL VISIT (n = 56) Dose of anticoagulation drug Warfarin 2.5 mg 5 mg 7.5 mg 10 mg 40 mg 7.5 mg alt 5 mg 10 mg alt 7.5 mg

Trimester 1 (n = 12) n (%)

Trimester 2 (n = 35) n (%)

Trimester 3 (n = 9) n (%)

1 (8) 6 (50) 3 (25) 0 (0) 1 (8) 1 (8) 0 (0)

0 (0) 23 (66) 7 (20) 1 (3) 0 (0) 2 (6) 2 (6)

0 (0) 5 (56) 3 (33) 1 (11) 0 (0) 0 (0) 0 (0)

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TABLE 3. CHARACTERISTICS OF FOUR PATIENTS WITH MECHANICAL HEART VALVE THROMBOSIS Patient Age GA at 1st Age at valve no (years) antenatal visit Parity surgery Anticoagulant at 1st antenatal visit 1 22 21 1 12 Defaulted on therapy prior to pregnancy 2 25 36 1 15 Warfarin 5 mg 3 21 12 0 11 Warfarin 5 mg 4 18 19 0 9 Defaulted on therapy prior to pregnancy IUD = intrauterine death; NVD = normal vaginal delivery; C/S – caesarean section.

Neonatal outcome IUD Alive Alive IUD

Prosthetic heart valves (n = 61)

TABLE 4. DELIVERY DETAILS Characteristics Number Anaesthetic Spinal 9 Epidural 28 General anaesthetic 4 Live babies (n = 41) Spontaneous labour Delivered vaginally 2 (epidural) Emergency caesarean 3 (1 epidural + 2 GA) Induced labour Delivered vaginally 3 (epidural) Emergency caesarean 2 (2 epidural + GA) Elective caesarean (n = 31) Epidural 21 Spinal 9 Emergency (GA) 1 (failed spinal) Stillbirths (n = 6) NVD (spontaneous) 2 Induced 4 Miscarriages (n = 12) Warfarin exposure in 1st trimester (NVD) 12 GA = general anaesthetic; NVD = normal vaginal delivery.

Mode of delivery NVD C/S NVD NVD

Percentage 22 68 10

40 60 50 50 67 30 03 33 67 100

There were four cases of warfarin embryopathy (three presented for antenatal care in the second trimester and the other in the third trimester). The maternal and foetal characteristics together with the dose of warfarin at admission and sonographic findings are outlined in Table 5. The most common maternal complications during the antenatal period and immediately post delivery are listed in Table 6.

Discussion In this retrospective audit on prosthetic heart valves in pregnancy, the mean age was 24 years and 56% were primigravidae. The low mean age and high number of primigravidae are in keeping with studies originating from other under-resourced countries,4,10

Mechanical heart valves (n = 59) Position of valve replacement Prophylactic anticoagulation

mitral (n = 44)* yes

Valve thrombosis yes (n = 4)

Maternal death

yes (n = 1)

Tissue heart valves (n = 2)

aortic (n = 1)

mitral and aortic (n = 11)

mitral (n = 2)

no

no

no

yes

no

yes

no

no

no

*Three patients with MPHV stopped medication of their own accord prior to pregnancy.

Fig. 1. Flow diagram showing position of prosthetic heart valve replacement.

but not from those of affluent societies.11,12 A Canadian study reported that the mean age at first antenatal booking was 32 years.13 This implies that the severity of rheumatic heart disease may be greater in under-resourced countries, warranting valve replacement at an early age. Furthermore, rheumatic heart disease is uncommon in affluent countries and congenital abnormalities form the majority of cardiac conditions seen in pregnancy.13 The high number of pregnancies at an early age in our study may also be due to cultural and socio-economic factors. Such factors may have influenced late booking for maternity care, as 37 (61%) patients attended antenatal care in the second trimester of pregnancy. Late booking for antenatal care and large patient numbers on warfarin throughout the first and second trimesters of pregnancy may indicate that women with cardiac disease do not receive adequate and/or consistent information on family planning, contraceptive services, sexually transmitted infections and the hazards of warfarin therapy in the first trimester.

The challenge for health professionals in under-resourced countries, irrespective of their medical discipline, is to ensure that such information is provided, not only to the individual woman, but also to partners, families and the community at large. Further, it begs the question whether a family planning

TABLE 5. CONGENITAL ABNORMALITIES DUE TO WARFARIN EMBRYOPATHY Patient Maternal GA (weeks) at 1st Foetal outcomes no age (years) antenatal visit Parity Anticoagulant and dose Sonography – congenital abnormalities of pregnancy 1 20 32 1 Warfarin 7.5 mg Choanal atresia/ microcephaly nasal hypoplasia ENND 2 22 26 1 Warfarin 5 mg/2. 5 mg Hydrocephalus, flattening of nasal bone polyhydraminos SB 3 36 10 2 Warfarin 7.5 mg Skeletal deformity of spine, nasal hypoplasia, hydrocephalus SB 4 30 29 0 Warfarin 5 mg Nasal hypoplasia, mid-facial hypoplasia diaphragmatic hernia ENND ENND = early neonatal death; SB = stillbirth; GA = gestational age.

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TABLE 6. MATERNAL COMPLICATIONS DURING THE ANTEPARTUM AND POSTPARTUM PERIOD Complications Number Antepartum 3 Epistaxis 2° anticoagulation* Atrial fibrillation 8 Infective endocarditis 6 Valve thrombosis 4 Warfarin embryopathy 4 Postpartum C/S wound haemotomas 7 1 Primary postpartum haemorrhage* 3 Postpartum haemorrhage 2° anticoagulation* Data expressed as mean (range) or as number (percentage) *Patients requiring blood transfusion.

Percentage 5 14 10 7 7 12 2 1

professional should be attached to cardiac clinics to provide and reinforce appropriate information and prescribe a wide range of contraceptives where necessary. Similar recommendations have been made in the Saving Mothers Reports over the last decade in South Africa.5 It is difficult to relate the number of pregnancies to the time from valve replacement. The average age of patients was 24 years, most were primigravidae and the average age of valve replacement was 12 years.

In our audit, the majority of patients were fitted with MPHV. The probable reason for this was that MPHV are cheaper and have greater longevity than bioprosthetic heart valves. However, because of the propensity of MPHV to undergo thrombosis, prophylactic anticoagulation is strongly recommended, if not mandatory.14-16 Most of our patients with MPHV had either St Jude or Orynx valves. These new-generation MPHV were designed to improve blood flow dynamics, prolong longevity and decrease thrombogenicity. However, our findings and those of others show that these new-generation MPHV are still associated with thrombo-embolism.17-19 There is therefore no doubt that prophylactic anticoagulant therapy is necessary, but which prophylactic anticoagulation regimen should be used in young women with MPHV, or should women requiring heart valve replacement have bioprosthetic valves inserted prior to pregnancy? Two patients in our study had bioprosthetic valves. Although patients fitted with these valves do not require prophylactic anticoagulation, as they are less thrombogenic than MPHV, the main issues with bioprosthetic valves are their cost, limited lifespan and the possibility of an increased risk of structural valve deterioration (SVD) during pregnancy.20 In addition, serious SVD can require re-surgery during pregnancy to replace failing bioprosthetic valves, and all such operations are associated with mortality and morbidity.

Elkayam and Bitar stated that about 50% of women of childbearing age will require valve replacement owing to SVD seven to 10 years after the original operation.20 They also reported SVD in 47% of patients with a history of pregnancy compared with only 14% in non-pregnant patients.20 In our study four patients required replacements; three prior to delivery. All three were symptomatic, did not have antenatal care and did not respond to medical treatment. In two of the three cases, the pregnancies ended in intrauterine deaths, while the baby in the third case was born alive. In the fourth patient who had a repeat valve

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replacement, an elective C/S was planned because she had severe cephalo-pelvic disproportion and a tight mitral stenosis, requiring valve replacement. Both mother and baby did well.

These cases illustrate the high perinatal mortality associated with valve replacements during pregnancy.

The morbidity and mortality associated with anticoagulation with warfarin is also high and is probably due to high doses of warfarin in the last two trimesters of pregnancy and the immediate postpartum period. This is illustrated in our study by five cases of thrombosis and the maternal death associated with high doses of warfarin.

There is no current consensus as to the best approach to anticoagulation in pregnant women with MPHV,19 as there are no large randomised studies to guide decision making.18 In women with MPHVs, the types of anticoagulation that can be used during pregnancy include warfarin, UH and LMWH. Warfarin, a vitamin K antagonist, crosses the placental barrier, is teratogenic and has been associated with an increased incidence of spontaneous abortion, prematurity, stillbirths and central nervous system developmental disorders.7 Furthermore, it would appear that the pivotal period for the risk of foetal congenital abnormalities is between six and 12 weeks of gestation, resulting in a 6–10% risk of embryopathy.21,22 There are also reports suggesting that warfarin is associated with intracranial foetal bleeding and an increased incidence of stillbirths.21,23,24 Nevertheless because of its ease of use and monitoring, it is commonly prescribed in most under-resourced countries.

Warfarin is also still used in affluent countries. North et al. reported high foetal waste rates but low valve thrombotic rates in their series of patients with MPHV using prophylactic warfarin therapy.25 If warfarin dosage does not exceed 5 mg daily, the risk of foetal warfarin embryopathy is extremely small.7 Vitale et al. studied 58 pregnancies in 43 women with MPHV who took warfarin ≤ 5 mg or > 5 mg (target INR 2.5–3.5) until delivery.

There were significantly fewer foetal complications in women taking ≤ 5 mg warfarin. It was suggested that warfarin at doses ≤ 5 mg to achieve a therapeutic INR may be safe during the first trimester.7 In our study, 29 (50%) patients were on warfarin ≤ 5 mg in the first trimester and did not have congenital foetal anomalies, which was similar to reports from India, Oman and Lebanon.26,27 However, the four (7%) patients who had embryopathies had warfarin doses of > 5 mg daily.

The risk of miscarriages and stillbirths are also reported to be high in women taking warfarin in the first trimester of pregnancy.8 In our study, we had 41 live births, with two resulting in neonatal deaths, 12 miscarriages and six stillbirths. The miscarriages and stillbirths were probably related to high dosages of warfarin and lack of close monitoring of anticoagulant therapy.21,24 This highlights the need for close and intensive monitoring of warfarin during pregnancy, particularly at the time of switching from one type of anticoagulant to another in the first trimester of pregnancy.

Lack of intensive monitoring at the time of switching from one form of anticoagulant to another is also demonstrated by the high wound haematoma rate in our study, namely seven cases of wound haematomas, three of which required surgical intervention, and one case of broad ligament haematoma, which settled on conservative treatment. There were also four cases

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TABLE 7. ANTICOAGULATION REGIMEN IN PREGNANT WOMEN WITH MECHANICAL PROSTHETIC VALVES Pre-pregnancy • Discuss anticoagulation regimen with patient • Continue warfarin until pregnancy is achieved • When menstruation is delayed, perform pregnancy test every few days until positive or until menstruation (in order to detect pregnancy at an early stage) • Give patient and health professional responsible for anticoagulation written instructions about anticoagulation regimen during pregnancy Sixth to 12th week of pregnancy • If warfarin daily dose is < 5 mg, consider continuation of warfarin throughout pregnancy • Alternatively, substitute warfarin with subcutaneous LMWH twice daily • Adjust LMWH dose to achieve peak anti-Xa levels of 0.7–1.2 U/ml four hours post dose • If trough levels are sub-therapeutic with therapeutic peak levels, dose three times daily • Check anti-Xa levels twice a month 13th to 35th week of pregnancy • Resume warfarin • Or use LMWH adjusted dose 36th week of pregnancy • Substitute warfarin with subcutaneous LMWH twice daily • Adjust LMWH dose to achieve peak anti-Xa levels of 0.7–1.2 U/ml four hours post dose • If trough levels are sub-therapeutic with therapeutic peak levels, dose three times daily • Check anti-Xa levels weekly

of postpartum haemorrhage (Table 6) following the switching of anticoagulants. These cases occurred at C/S, highlighting the need for intense monitoring of coagulation indices at this time. McLintock et al. also reported high rates of anteand postpartum haemorrhagic complications using LMWH throughout pregnancy.11 A number of studies report that UH and LMWH therapy is safe for the foetus.21,23 Unfractionated heparin does not cross the placenta and does not have the potential to cause foetal bleeding or teratogenecity. Heparin is generally considered safer than warfarin during pregnancy in terms of embryopathy, however the efficacy of heparin in the prevention of thrombo-embolic complications during pregnancy is contentious. Several reports indicate that its use is associated with high incidence of thromboembolic complications, including fatal valve thrombosis in high-risk pregnant women managed with subcutaneous UH and LMWH therapy.18,19,22,23 Chan et al. reviewed pregnancy outcomes in women with MPHV and reported thrombo-embolic complications in 3.9% of pregnancies using warfarin only; 9.2% in women who received UH in the first trimester followed by warfarin, and 33% in pregnancies treated with UH heparin throughout pregnancy.14 Oran et al. reviewed pregnant women with MPHV managed with LMWH and reported complications related to valve thrombosis in 10/81 pregnancies.28 Similarly, another review reported thrombotic events in 22% of pregnant women (n = 76) managed with LMWH.29 More recently, data are emerging that dose-adjusted LMWH (enoxaparin) may be administered safely in pregnancy when there is a dosage adjustment throughout pregnancy to maintain

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an anti-Xa of 1.0–1.2 U/ml.30 There were no thrombo-embolic events in this study of 15 women with MHVP. These reports follow a randomised study in South Africa, comparing UH with enoxaparin, which was stopped prematurely because of two deaths from thrombo-embolism in the enoxaparin group. AntiXa levels were measured but no dose adjustment was done.31 There is evidence that increasing doses of heparin are required with increasing gestational age because of the increased blood volume and greater renal clearance as pregnancy progresses.30 There was one maternal death in our study. Earlier studies originating from under-resourced countries have reported two maternal deaths in 312 patients studied,4 one in 229 patients,32 and 10 in 480 patients studied.33 There was a high rate of maternal complications in our study.

Four (7%) patients on warfarin ≥ 5 mg daily developed valve thrombosis in the mitral position. The mitral position is prone to thrombosis and our audit confirms similar findings from other studies.31,34 Throbo-embolic events and embryopathy are not the only risks that are associated with pregnancies in women with MHVP. Atrial fibrillation, infective endocarditis and C/S wound haematomas were relatively common complications observed in our study.

Conclusions This study confirms that the use of warfarin throughout pregnancy carries a significant risk of embryopathy. This risk may be greater with doses of > 5 mg but no definite conclusions can be drawn. In addition, the use of warfarin in the second trimester of pregnancy is associated with significant foetal losses, probably due to poor monitoring and control of warfarin dosages. The switching of warfarin to heparin at the time of delivery may be associated with maternal complications.

Recommendations for management of anticoagulation in pregnant women with MHVP are found in guidelines produced by the American College of Cardiology/American Heart Association.35 These guidelines are based on the opinions of experts. An anticoagulation regimen reported by Pieper et al. has been modified and shown in Table 7;8 and takes into account, the key points of the American guidelines. Large randomised trials of dose-adjusted LMWH are necessary before firm recommendations on an acceptable prophylaxis anticoagulation regimen for prevention of thrombosis of MHVP can be made.

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Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999; 33: 1637–1641.

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Hameed A, Karaalp IS Tummala PP, et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol 2001; 37: 893–899.

McLintock C, McCowan LME, North RA. Maternal complications and pregnancy outcomes in women with mechanical prosthetic valves treated with enoxaprin. Br J Obstet Gynecol 2009; 16: 1585–1592.

Quinn J, Von Kiemperer K, Brooks R, Peebles D, Walker F, Cohen H. Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single centre experience. Haematologica 2009; 94(11): 1608–1612.

Silversides CK, Colman JM, Sermer M, Siu SC. Cardiac risk in pregnant women with rheumatic mitral stenosis. Am J Cardiol 2003; 91: 1382–1385.

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Caceres-Loriga FM. Prosthetic valve thrombosis: is it time for a new consensus conference? Euro J Echocardiogr 2008; 9: 413–414.

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Warnes CA. Prosthetic heart valves. In: Steer PJ, Gatzoulis MA, Baker P, eds. Heart Disease in Pregnancy. London: RCOG, 2006: 157–168.

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Khamooshi AJ, Kashfi F, Hoseini S, Tababaei MB, Javadpour H, Noohi F. Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer? Asian Cardiovasc Thorac Ann 2007; 15(6): 493–496.

Maxwell C, Poppas A, Dunn E, Sermer M. Pregnancy, mechanical heart valves and anticoagulation navigating the complexities of management during gestation. In: Rosene-Montella K, Keeley EJ, Barbour LA, Lee RV, eds. Medical Care of Pregnant Patient. 2nd edn. Philadelphia: American College of Physicians, 2007: 344–355.

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25. North RA, Sadler I, Stewart AW, McCowan LM, Kerr AR. White HD. Long term survival and valve-related complications in young women with cardiac valve replacement. Circulation 1999; 99: 2669–2676.

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28. Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004; 92: 747–751.

29. James AH, Brancazio LR, Gehring TR, Wang A, Ortel TL. Low molecular weight heparin for thrombo-prophylaxis in pregnant women with mechanical heart valves. J Matern Fetal Neonatal Med 2006; 19: 543–549.

30. Chitsike RS, Jacobsen BF, Manga P, Rhemtula HA, Moodley S, Toweel GD. A prospective trial showing the safety of adjusted dose enoxaparin for thromboprophylaxsis of pregnant women with mechanical prosthetic heart valved. Clin Appl Thromb Hemost 2010, June13. (Epub ahead of print).

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Review Article Endothelial dysfunction: the early predictor of atherosclerosis MASHUDU MUDAU, AMANDA GENIS, AMANDA LOCHNER, HANS STRIJDOM

Abstract Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED).

ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body’s vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.

Keywords: endothelium, endothelial dysfunction, nitric oxide bioavailability, eNOS uncoupling, oxidative stress, atherosclerosis Submitted 7/6/11, accepted 11/11/11 Cardiovasc J Afr 2012; 23: 222–231

Atherosclerosis is a chronic progressive vascular disease, characterised by plaque formation and subsequent fissure, erosion or rupture of the plaque with thrombosis of the plaque surface.3 A complication of coronary atherosclerosis can be the development of myocardial ischaemia and ultimately myocardial infarction.4 Hypertension, tobacco use, dyslipidaemia, diabetes mellitus, physical inactivity and obesity, all of which are associated with the development of atherosclerosis and IHD, are considered to be the top risk factors for cardiovascular mortality worldwide.2 Chronic exposure to cardiovascular risk factors and the harmful circulating stimuli associated with these conditions overwhelms the defense mechanisms of the vascular endothelium, hence compromising its integrity and ultimately initiating endothelial dysfunction (ED).5 Mounting evidence is pointing to ED as one of the major pathophysiological links between exposure to cardiovascular risk factors and the development of atherosclerotic disease (Fig. 1).6 ED is commonly associated with reduced nitric oxide (NO) bioavailability, and hence an inability of the endothelium to

EXPOSURE TO CARDIOVASCULAR RISK FACTORS: • Hyperglycaemia/insulin resistance (diabetes mellitus) • Smoking • Hypertension • Obesity • Hyperlipidaemia

www.cvja.co.za

DOI: 10.5830/CVJA-2011-068

Between 1995 and 2004, cardiovascular diseases accounted for about 195 deaths per day in South Africa. Particularly disturbing is that cardiovascular mortality is expected to escalate by a staggering 41% in the working age group (35–64 years) in the South African population by the year 2030.1 In 2004, the World Health Organisation (WHO) reported cardiovascular diseases/ ischaemic heart disease (IHD) to be the leading cause of death worldwide and that cardiovascular deaths are envisaged to escalate to 23.4 million by the year 2030.2 Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Stellenbosch, South Africa MASHUDU MUDAU, MSc AMANDA GENIS, MSc AMANDA LOCHNER, PhD HANS STRIJDOM, BMedSc, MB ChB, PhD, jgstr@sun.ac.za

If sustained and not reversed DEVELOPMENT OF ENDOTHELIAL CELL CHANGES: • Endothelial activation • Endothelial dysfunction Associated with reduced NO bioavailability; pro-vasoconstriction; pro-oxidative stress; pro-coagulation; pro-inflammation If sustained and not reversed PROGRESSION TO ATHEROSCLEROSIS: • Plaque formation and sequelae • Myocardial ischaemia • Myocarial infarction Fig. 1. Exposure of endothelial cells to cardiovascular risk factors and the resultant pathophysiological changes, i.e. endothelial activation and dysfunction, with progression to atherosclerosis if risk-factor exposure is sustained.

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initiate vasodilation in response to vasodilatory stimuli such as acetylcholine or shear stress. It represents an initial reversible step in the development of atherogenesis, and for this reason, early clinical identification of ED may become an important tool in the prevention or reversal of progression to atherosclerosis and IHD.7 ED comprises a loss of balance between endothelialderived vasodilatory and vasoconstrictory factors, where the pro-vasoconstrictory state becomes dominant, leading to progressive pathophysiological changes. These changes appear as sequentially occurring responses in endothelial cells, also referred to by some as the endothelial activation–dysfunction– injury triad.8,9 Collectively, these endothelial changes exhibit pro-inflammatory, pro-oxidant, proliferative, pro-coagulation and pro-vascular adhesion features.7,10

effects.12 The vasodilatory state is mediated by factors such as nitric oxide (NO), endothelium-derived hyperpolarising factor (EDHF) and prostacyclins, while a vasoconstrictory state is mediated by factors such as endothelin-1 (ET-1), angiotensin II and thromboxane A2.7,12 Of these endothelial-derived factors, NO, which was originally identified as the endothelial-derived relaxing factor (EDRF), has since evoked much interest as it is considered to be the most potent endogenously synthesised vasodilator in the body, and a key marker of endothelial function and dysfunction.

The vasoactive factors released by endothelial cells and their effects are summarised in Table 1. In view of the physiological, pathophysiological and clinical importance of NO in vascular physiology, we have included a brief discussion on the physiology of NO below.

The endothelium: a functional organ

Nitric oxide

The vascular endothelium consists of approximately 1–6 × 10 endothelial cells and accounts for about 1 kg of total body weight.

For many years after its discovery, the endothelium was believed to be an inert, semi-permeable barrier between circulating blood and the underlying sub-endothelial tissues.11 However, extensive research has since revealed a far more complex role for the endothelium. We now know that the endothelium is in fact a metabolically active organ, playing a crucial role in the maintenance of vascular homeostasis by releasing a variety of vasoactive factors that can either dilate or constrict the blood vessels, depending on the type of the stimulus.7 Vascular homeostasis entails keeping a tightly controlled balance between a vasodilatory state, which is often associated with anti-oxidant, anti-inflammatory and anti-thrombotic effects on one hand, and a vasoconstrictory state on the other, which is associated with pro-oxidant, pro-inflammatory and pro-thrombotic 13

The realisation in the 1980s that the identity of EDRF was in fact NO was rather astonishing, as NO had until then been perceived as nothing more than a toxic environmental pollutant found in cigarette smoke, exhaust fumes of motor cars and harmful gases generated by industrial processes.13,14 The ground-breaking discovery that NO is also synthesised in the body and functions as a chemical messenger with important physiological effects introduced a novel paradigm in cardiovascular physiology and pathophysiology. In addition to its vasodilatory properties, NO was also found to exert anti-inflammatory and cardioprotective effects.15 Owing to its gaseous and free-radical nature, NO is able to diffuse easily between cells and tissues and react with a variety of molecules in the body.13 NO is synthesised from the amino acid L-arginine by a family of enzymes known as nitric oxide synthase (NOS).14 The NOS enzyme occurs as

TABLE 1. OVERVIEW OF ENDOTHELIUM-DERIVED VASO-ACTIVE FACTORS Endothelium-derived factors Physiological effects Nitric oxide (NO) • Potent vasodilator • Inhibits inflammation, VSMC proliferation and migration, platelet aggregation and adhesion, and leukocyte adhesion • Regulates myocardial contractility • Regulates cardiac metabolism • Cardioprotective during ischaemia–reperfusion injury • Vasodilatory agent Prostacyclin (PGI2) • Inhibits platelet aggregation Endothelium-derived • Exerts vasodilatory effects, particularly in small arterhyperpolarising factor ies of diameter ≤ 300 μm (EDHF)

Endothelin-1 (ET-1)

• A potent vasoconstrictor

Thromboxane A (TXA2) Angiotensin ll

• A potent vasoconstrictor • A potent vasoconstrictor

Enzymatic source and mechanism of action • Synthesised by the enzymes: eNOS, nNOS and iNOS, with eNOS the major endothelial source of NO during physiological conditions • Diffuses from endothelial cells to underlying VSMCs where it binds to soluble guanylyl cyclase, leading to a cascade of events that ultimately result in vascular relaxation • Derived from arachidonic acid by cyclooxygenase-2 (COX-2) • Its identity is still under suspicion with proposed candidates such as potassium ions and hydrogen peroxide • Causes relation of VSMCs by means of membrane hyperpolarisation • Synthesised by endothelin-converting enzyme • Exerts its effects via two receptors: ETA expressed on endothelial cells and ETB on VSMCs. ETA receptors promote vasoconstriction, whereas ETB receptors promote NO production and ultimately reduction in ET-1 production • Derived from arachidonic acid by COX-1 • Synthesised by angiotensin converting enzyme • Elicits its effects via two receptors: AT1 which promotes vasoconstriction and cell proliferation, and AT2 which antagonises the effects of AT1

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Anti-inflammation: leukocyte adhesion and migration Vascular lumen Anti-oxidation Anti-platelet aggregation NO Endothelial cells eNOS NO

Vasodilation

VSMCs

cGMP

Fig. 2. Synthesis of NO, downstream mechanisms and physiological effects. NO is synthesised by eNOS in the endothelial cells and diffuses into the underlying vascular smooth muscle cells (VSMCs), where it activates the second messenger, cyclic guanosine monophosphate (cGMP). Further downstream, signalling eventually leads to VSMC relaxation and vasodilation. In addition, NO regulates vascular homeostasis by anti-oxidation, antiinflammatory and anti-platelet aggregation effects.

mechanism in the underlying vascular smooth muscle cells (VSMCs) and ultimately, relaxation19 (Fig. 2).

Failure of the eNOS protein to dimerise, or the absence of some of the cofactors mentioned above will lead to the enzyme catalysing the formation of O2– instead of NO, a mechanism referred to as eNOS uncoupling20 (Fig. 3). As will be discussed later, eNOS uncoupling is an important mediator of ED during a pathophysiological state.

Cardiovascular risk factors associated with the development of ED Type 1 diabetes mellitus and insulin resistance/type 2 diabetes mellitus

three isoforms, namely neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS).14,16,17 Physiologically, eNOS and nNOS are constitutive, calcium-dependent enzymes and continuously produce low levels of NO. On the other hand, iNOS is calcium independent, its expression is provoked by inflammatory cytokines, and it produces large amounts of NO, about 1 000-fold more than eNOS or nNOS.13 This can have potentially harmful consequences as excess NO can react with the free radical superoxide anion (O2–), yielding a harmful and highly reactive species, peroxynitrite.13 All NOS isoforms require cofactors such as (6R)-5,6,7,8tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and iron protoporphyrin IX (haem).18 Of the three isoforms, it has been proposed that eNOS is the major isoform responsible for NO production under physiological conditions in the cardiovascular system and endothelial cells in particular, leading to the classical signalling

Both type 1 and type 2 diabetes are independent risk factors for the development of accelerated atherosclerosis, IHD and cardiovascular disease in general.11 Similarly, type 1 diabetes mellitus, insulin resistance and type 2 diabetes mellitus have been shown to be strongly associated with the development of ED.21 In fact, the temporal progression from insulin resistance to type 2 diabetes mellitus has been postulated to be mirrored by the progression of ED to atherosclerosis.22 ED observed in diabetes mellitus is primarily attributable to (1) oxidative stress (increased O2– generation due to upregulated expression of NADPH oxidase), and (2) increased formation of advanced glycation end-products (AGEs).23,24 Aside from scavenging NO, causing decreased NO bioavailability and producing peroxynitrite, O2– also modifies the activity and regulation of eNOS, and promotes vascular smooth muscle cell (VSMC) proliferation and inflammation.24 Hyperglycaemia, as occurs in diabetes mellitus, results in non-enzymatic glycation of intracellular and extracellular proteins and lipids, which leads to the generation of AGEs. The latter subsequently accumulate in the vascular wall and reduce NO activity by quenching NO.24,25 AGEs also bind to specific surface receptors, called receptors for AGEs (RAGE), which are expressed on cells such as monocytes, macrophages and VSMCs, resulting in the amplification of an inflammatory response,24,25 increased vascular permeability and oxidative stress.25

A

B

HOOC–

NADP+

e–

FAD

e–

FMN

e–

HOOC–

Monomer

NADP+

N2H– NO + citrulline

e–

FAD

e–

FMN

e–

Monomer

H2N– BH4

O2 + l-arginine

Haem/Fe2+

Hommodimer: eNOS = Coupled

Zn O2 + l-arginine

Haem/Fe2+

Monomer

e–

O2–

NO + citrulline

BH4

e–

FAD

e–

NADP+

Zn

BH3

ONOO– O2 + ↓ l-arginine

Haem/Fe2+

Monomer

e–

eNOS = Uncoupled

O2– –NH2

–NH2 FMN

O2 + ↓ l-arginine

Haem/Fe2+

-COOH

FMN

e–

FAD

e–

NADP+

-COOH

Fig. 3. Coupled and uncoupled eNOS. (A) In the presence of sufficient levels of substrates and co-factors, and the absence of harmful reactive species, eNOS monomers will form a dimerised, coupled enzyme and produce physiological amounts of NO. (B) Decreased levels of the substrate, L-arginine and/or harmful effects exerted by increased levels of ONOO–, cause failure of the enzyme to dimerise, leading to the uncoupling of eNOS and the production of O2– instead of NO.

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Furthermore, hyperglycaemia is also known to activate protein kinase C (PKC), which decreases eNOS activity, leading to reduced NO and increased ET-1 production.24 In the setting of ED, ETB receptor-mediated vasodilatory effects of ET-1 are blunted (refer to Table 1) and therefore the vasoconstrictory state predominates.26 PKC also enhances the expression of adhesion molecules such as ICAM, VCAM and E-selectin,24 which is associated with endothelial cell activation.

ED has been reported to occur early in insulin resistance.22 Often insulin resistance is associated with central adiposity and hence the metabolic syndrome, i.e. hypertriglyceridaemia, low high-density lipoprotein (HDL) levels, high low-density lipoprotein (LDL) levels and hypertension, all of which could potentially favour the development of ED and eventually atherogenesis.22

Hyperlipidaemia Hyperlipidaemia constitutes increased circulating lipids including cholesterol and triglycerides, a state which can predispose to ED. Possible mechanisms underlying hyperlipidaemia-induced ED include: (1) upregulation of NADPH oxidase, increased O2– production and oxidative stress, (2) increased plasma levels of asymmetric dimethylarginine (ADMA),25 and (3) oxidation of LDL.27 ADMA is an endogenous inhibitor of eNOS and competes with L-arginine for the same binding site on eNOS, thus resulting in eNOS uncoupling, increased O2– production and hence decreased NO production. Plasma concentrations of ADMA have been reported to be increased in hypercholesterolaemia,28,29 and this compound is considered to be both a marker and risk factor of ED.28 In addition to scavenging NO, excess O2– modifies LDL cholesterol to form oxidised LDL (ox-LDL), which plays a major role in the development of endothelial activation and atherogenesis.30 Ox-LDL has been reported to promote ET-1 production,31 expression of adhesion molecules and chemoattractants, as well as VSMC migration and proliferation.27 Furthermore, ox-LDL can be engulfed by macrophages forming foam cells which adhere to the vessel wall and contribute to the initiation of an atherosclerotic plaque.27 Both LDL and ox-LDL have been shown to increase the activity of S-adenosylmethionine-dependent methyltransferases, which lead to increased ADMA synthesis. Therefore, LDL and ox-LDL may be accountable for the increased plasma levels of ADMA in hypercholesterolaemia.32 LDL or ox-LDL can also upregulate caveolin-1 synthesis and thus inhibit eNOS activity33,34 (Fig. 4).

reduced or absent in hypertensive patients.37 In addition to this, Iaccarino et al.38 observed decreased protein kinase B (PKB)/ Akt-dependent activation of eNOS in a model of spontaneously hypertensive rats (SHR).

In a recent study, the role of oxidative stress and ED in the development of hypertension in spontaneously hypertensive rates was investigated.35 The results showed that early treatment with the antioxidant reservatrol was associated with reduced oxidative stress markers, improved endothelium-dependent vasodilatation and an attenuation in the development of hypertension in these animals.

Smoking Tobacco smokers exhibit decreased NO bioavailability, increased levels of ox-LDL, and impaired flow-mediated vasodilation, phenomena which are all highly suggestive of ED.39 Passive smoking has recently also been implicated in impairment of endothelial function.39,40 It appears that the harmful effects of smoking on endothelial cells are dose dependent and reversible upon smoking cessation.39 As with other cardiovascular disease risk factors, oxidative stress appears to be the major mechanistic link between smoking and ED.39,41 Cigarette smoke is rich in free radicals and directly delivers free radicals to the body. Besides being the supplier of free radicals, cigarette smoke facilitates endogenous release of ROS via activation of inflammatory cells.41,42 Furthermore, smoking has been reported to decrease the levels of HDL cholesterol, which is known to have anti-endothelial dysfunction and antiatherosclerotic properties.43

Aging Increasing age has been recognised as one of the factors that predisposes to ED.43,44 With aging, the ability of the endothelium to produce NO is reduced.45 Furthermore, some studies have reported reduced expression and activity of eNOS as well as decreased expression of a major downstream target molecule of NO, soluble guanylyl cyclase (sGC) in VSMCs, and its activity in older animals.45 In addition to the decreased NO production, other endothelial-derived relaxing factors (EDRFs) (prostacyclin and EDHF) are also reduced, while endothelial-derived contracting factors (EDCFs) such as ET-1 and COX-derived prostanoids, and ROS production are increased.44,45 Plasma levels of ADMA ↑ cholesterol + O2– ox-LDL

Hypertension ED is a prominent underlying feature of hypertension,35 and patients with hypertension have been shown to demonstrate blunted forearm blood flow in response to vasodilatory stimuli such as acetylcholine and bradykinin,36 which is indicative of ED. Increased production of ROS and endothelial-derived contracting factors (EDCFs) such as ET-1, angiotensin II, PGH2 and TXA2, and decreased NO bioavailability are all observed in patients with hypertension.26,36 Shear stress is known to be one of the most important mechanisms of inducing NO-mediated vasodilation in both the micro- and macrovasculature. However, this response is

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Endothelial cells: ↑ ADMA, ↑ caveolin–1: + Macrophages ↑ endothelin–1 eNOS coupling Foam cells ↑ adhesion molecules ↓ eNOS activation ↓ NO bioavailability Endothelial activation

Endothelial dysfunction

Atherosderotic plaque

Fig. 4. Pathophysiological effects and the interplay between increased plasma cholesterol and O2– levels, and endothelial cell responses.

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are also known to rise with increased age.45 One of the mechanisms contributing to reduced NO levels in aging may be the increased activity of arginase I.43,44 Arginase I is an enzyme that catalyses conversion of L-arginine to L-ornithine and urea, and it thus competes with eNOS for L-arginine.43 Hence, the increased activity of this enzyme as observed with advancing age may result in uncoupling of eNOS, reduced NO production and hence ED.43,44 Clearly the balance between EDRFs and EDCFs is lost with advancing age, establishing aging as a risk factor for the development of ED. Moreover, aging is often associated with co-morbid conditions such as diabetes, hypertension and hypercholesterolaemia, further exacerbating the risk of developing ED, atherosclerosis and ultimately cardiovascular diseases.44

Proposed mechanisms of ED

essential hypertension, as well as in chronic smokers.20 In addition to peroxynitrite-induced eNOS uncoupling, other oxidants such as hydrogen peroxide have also been shown to uncouple the enzyme. Therefore, during conditions of oxidative stress, eNOS deviates from its role of being an essential regulator of the functioning of the cardiovascular system to being an O2– releasing enzyme. A vicious circle therefore develops, whereby uncoupled eNOS synthesises O2– at the expense of NO, further aggravating oxidative stress.

Inflammation is another common underlying mechanism of ED.53 Under physiological conditions, the endothelium regulates vascular inflammation (including expression of adhesion molecules and leukocyte adhesion) via the release of NO.54 It is therefore more likely that ED will promote sustained vascular inflammation, which is detrimental to the vascular system.

However, several studies have reported that inflammation also promotes ED and it is therefore recognised as a novel risk factor for cardiovascular diseases.53,55 There seems to be a causal relationship between oxidative stress and inflammation. Oxidative stress may amplify vascular inflammation signalling pathways,56 and conversely inflammatory cells increasingly release O2–. Inflammation is often associated with the overexpression of inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1).

These inflammatory cytokines in turn prompt endothelial cells or macrophages to express adhesion molecules such as VCAM1 and ICAM-1, MCP-1, interleukin-6 (IL-6) resulting in a state of endothelial activation, which is a precursor of ED57 (Fig. 1).

The role of TNF-α in ED has received considerable attention in recent years, and is now well appreciated. High levels of TNF-α have been associated with cardiovascular diseases such as acute myocardial infarction, chronic heart failure, atherosclerosis and myocarditis.58 Increased TNF-α levels are also significantly correlated with obesity, which is an independent risk factor for ED.59 This inflammatory cytokine has been reported to promote NADPH oxidase Mitochondria Xanthine oxidase

O

– 2

SOD K = 2.0 × 109

Catalase = H2O2

H2O + O2

K = 7 6. × 9

10

Oxidative stress appears to be the common underlying cellular mechanism for the development of ED in all the risk factors discussed above. According to the literature, cardiovascular risk factors are associated with upregulation of ROS sources, especially NADPH oxidase.7,20 However, other sources of ROS such as xanthine oxidase, cyclooxygenase (COX) and mitochondria also play a role.23 In fact, eNOS per se becomes a potential ROS generator when in the uncoupled state.20 Harmful effects of oxidative stress include increasing VSMC proliferation (resulting in thickening of the vascular wall), endothelial cell apoptosis, and increased expression and activity of matrix metalloproteinases, which are involved in the establishment of an atherosclerotic plaque.39 Oxidative stress comprises increased rates of oxidant production and decreased levels of antioxidant activity [e.g. superoxide dismutase (SOD), vitamin C and E, etc.].46 Under physiological conditions, the enzyme SOD regulates the levels of O2–.47 However, increased generation of O2– overwhelms the defensive mechanisms of SOD, leaving O2– free to react with other molecules, particularly NO, for which it has a greater affinity.47 O2– is implicated in the direct induction of ED by the scavenging of NO, leading to the production of the highly reactive and harmful reactive nitrogen species (RNS), peroxynitrite.48 In fact, the reaction between O2– and NO has been reported to occur much faster (rate constant = 6.7 × 109 m/s) than that of dismutation of O2– by SOD (rate constant = 2.0 × 109 m/s).49 High levels of peroxynitrite are injurious to the cells, oxidatively damaging DNA, lipids and proteins. In addition to being cytotoxic, peroxynitrite damages the intricate eNOS structure, leading to eNOS uncoupling, which further perpetuates the ED vicious circle50 (Fig. 5).

Peroxynitrite has been reported to oxidise the essential cofactor of eNOS, BH4 to its inactive form, trihydrobiopterin radical (BH3–), which in turn leads to uncoupling of eNOS.20,50,51 Furthermore, peroxynitrite may oxidise the zinc thiolate cluster in the centre of the eNOS enzyme, resulting in the loss of the zinc ion and the formation of disulfide bonds between the enzyme monomers, and thus disruption of the binding site for BH4 and L-arginine20,52 (Fig. 3). Vitamin C is able to recycle BH3– to BH4,50,51 and supplementation with BH4 has been reported to restore endothelial function in conditions such as insulin resistance, hypercholesterolaemia,51 diabetes mellitus and

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NO = ONOO– eNOS uncoupling

NO2– + OH– Protein nitration Apoptosis Necrosis

Fig. 5. Oxidative and nitro-oxidative stress. Superoxide anion (O2–) released from sources such as NADPH oxidase, mitochondria and xanthine oxidase is dismutated to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), which is then converted to water and oxygen by catalase. However, O2– has a higher affinity for NO than SOD, and when in excess, it preferentially combines with NO to produce peroxynitrite with various pathophysiological consequences.

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ROS formation via NADPH oxidase and xanthine oxidase.60 For example, Gao et al. reported that TNF-α induces ED via increased NADPH oxidase activity in coronary arterioles of mice with type 2 diabetes.61 In addition, TNF-α has been implicated in the downregulation of eNOS expression (and therefore decreased NO production) by accelerating eNOS mRNA degradation.34,60,62 According to Zhang et al., ED observed in myocardial ischaemia–reperfusion injury may be attributable to increased TNF-α expression via the enhancement of xanthine oxidase activity.63 Other harmful stimuli-induced mechanisms associated with the development of increased oxidative stress and decreased eNOS activation/eNOS uncoupling include activation of cholesterylester transport protein (CETP), downregulation of lipoprotein lipase, downregulation of peroxisome-proliferator activated receptor (PPAR), downregulation of protein kinase A (PKA), activation of caveolin, activation of rho-kinase and downregulation of sphingosine-1-phosphate.64

Assessment of endothelial function Direct mechanical endothelial function measurements Direct endothelial function measurement in humans has the potential to become an important clinical tool in diagnosing or predicting the development of cardiovascular disease in the presence or absence of cardiovascular risk factors. Furthermore, in recognition of evidence pointing towards a pathophysiological link between ED and IHD, a number of human experiments have been conducted in which clinical assessment of ED is explored as a possible predictor or prognostic marker of cardiovascular events.65 An ideal method for the direct measurement of endothelial function should be safe, cost-effective, non-invasive, repeatable, reproducible and standardised between laboratories.5,65 Current methods of assessing endothelial function include flow-mediated dilation (FMD), forearm plethysmography, finger-pulse plethysmography, pulse curve analysis and quantitative coronary angiography65 (Table 2).

In a recent review article, FMD was recognised as a commonly undertaken, non-invasive technique to assess endothelial function.66 In this article, a meta-analysis of 14 studies (more than 8 300 subjects) showed that FMD was strongly predictive of future cardiovascular events. Despite the evidence in favour of

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the independent prognostic value of vascular/endothelial function measurements, the authors conceded that more and larger human studies should be undertaken to confirm this finding.

Biomarkers Although many biomarkers of endothelial function have been identified, only some may have potential clinical use. Therefore, the measurement of endothelial biomarkers remains a tool mainly utilised in the experimental animal and in vitro laboratory setting.

Reduction of NO bioavailability Reduction in endothelial-derived NO production or bioavailability represents a measurable parameter that is suggestive of the development of ED. Laboratory-based studies most often make use of indirect NO measurements (measurements of metabolic products of NO) to confirm ED, such as nitrogen oxide levels67 or levels of stable degradation products, nitrite and nitrate.68 Many researchers also measure expression and/or activation of eNOS, the main enzymatic source of NO in endothelial cells, to further validate their findings.69,70 In humans, changes in NO production can also be detected in plasma by measurement of NO metabolites. Kiettisanpipop et al. reported a decrease in plasma NO metabolite levels in patients with severe pulmonary hypertension compared to those with moderate hypertension.71 Oestrogen replacement therapy has been shown to increase plasma NO levels while decreasing ET-1 levels and thus improving endothelial function in postmenopausal women.72 Heiss et al. demonstrated that plasma levels of NO derivatives (nitrosyl/nitroso species) were decreased in patients with endothelial dysfunction.73 It remains to be seen, however, whether the measurement of plasma NO or NO-derived metabolites will become a widely used clinical tool with predictive properties.

ADMA ADMA has emerged as a mediator, independent risk factor and, from a clinical perspective, potentially promising marker of ED.29 As explained earlier, ADMA is endogenously synthesised via methylation of arginine residues in the nuclear proteins74 and competitively inhibits eNOS, resulting in decreased NO production, which may induce eNOS uncoupling. Synthesis

TABLE 2. CLINICAL DETECTION TECHNIQUES OF ENDOTHELIAL FUNCTION Method Forearm plethysmography

Brief description Involves intrabrachial infusion of endothelial-dependent vasodilators such as acetylcholine, metacholine, substance P and bradykinin, with subsequent measurement of changes in endothelial function of forearm arterioles Flow-dependent dilation of the brachial artery This method employs a high-resolution ultrasound to quantify flow-mediated dilation of the brachial artery Finger-pulse plethysmography (ENDO-PAT) A novel non-invasive technique that measures changes of the pulse-wave amplitude during reactive hyperaemia. Low pulse-wave amplitudes are associated with compromised endothelial function and are therefore good predictors of cardiovascular disease Pulse curve analysis A non-invasive technique that relies on the measure of arterial stiffness to quantify endothelial function Quantitative coronary angiography following An invasive approach of quantifying endothelial function, which involves intracoronary infusion intracoronary infusion of acetylcholine of the endothelium-dependent vasodilator, acetylcholine, and subsequent measurment of the vasomotor response

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of ADMA is catalysed by protein arginine methyltransferases (PRMTs) and its degradation is catalysed by dimethylarginine dimethylaminohydrolases (DDAH).75 DDAH levels are often decreased in a variety of cardiovascular diseases, which leads to the upregulation of ADMA. For example, treatment of endothelial cells with TNF-α, ox-LDL and glucose has been reported to diminish the activity of DDAH.74,75 Furthermore, PRMTs and DDAH are ROS-sensitive; the activity of the DDAH is impaired, whereas the activity of the PRMTs is increased in conditions of oxidative stress.75 Indeed, increased plasma levels of ADMA have been documented in patients with conditions such as hyperlipidaemia, hypertension, coronary artery disease, stroke and end-stage renal disease.75 Furthermore, ADMA was found to be significantly elevated in patients with unstable angina, and reduced plasma levels of ADMA at six weeks post-percutaneous coronary intervention was found to be possibly indicative of a reduced risk of recurrent cardiovascular events.76 A recent study investigated the prognostic value of ADMA with regard to cardiovascular disease and death (fatal or non-fatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or TIA, intermittent claudication or heart failure) in Framingham Offspring study participants.77 Although ADMA was significantly associated with all-cause mortality in this population, the study could not find an association between ADMA and cardiovascular disease incidence.

Circulating endothelial cells and endothelial microparticles Circulating endothelial cells (CECs), which are mature cells that have detached from the endothelium, represent a novel biomarker of endothelial injury.78,79 In a healthy person, the endothelium is constantly refurbished at a replication rate of < 1% and levels of CECs are very low. Studies using a flowactivated cell sorter (FACS) isolation technique reported CECs ranging from 50–7 900 cells/ml in healthy individuals and up to 39 100 cells/ml in individuals with vascular diseases.79 Potential mechanisms underlying endothelial cell detachment may be mechanical injury, action of proteases and/or cytokines, defective endothelial cell adhesion to the extracellular matrix, cellular apoptosis, and injurious actions of cardiovascular risk factors, such as occur during the induction of ED. Increased levels of CECs are associated with ED, cardiovascular diseases and a variety of other diseases.78,79 Apoptotic CECs expressing surface marker (CD146) have been reported to be increased in patients with cardiovascular disease.65 Other circulating cellular markers of endothelial injury include endothelial microparticles (EMPs), which are small cell membrane vesicles released into the circulation by activated or apoptotic cells.5,65 Patients with hypertension and coronary artery disease have been reported to demonstrate high levels of EMPs,65 and according to Tramontano et al., statins can diminish the release of EMPs in cultured coronary endothelial cells.

Nitrotyrosine upregulation In addition to its ability to directly uncouple the eNOS enzyme, which can lead to ED, peroxynitrite undergoes protonation to form peroxynitrous acid (ONOOH), or it can combine with carbon dioxide (CO2) to form nitroso-peroxocarboxylate (ONOOCO2–),

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both of which yield tyrosine-nitrating compounds.80,81 Via formation of these compounds, peroxynitrite leads to nitration (addition of a NO2 group) of tyrosine residues of proteins, leading to formation of nitrotyrosine.82 Under normal conditions, low levels of free or protein-bound nitrotyrosine are detectable, which may indicate low levels of oxidants and nitrating species produced during physiological processes. However, significant nitrotyrosine upregulation is observed in conditions that are associated with nitroxidative stress such as inflammation, cardiovascular disease (including ED and atherosclerosis) and neurodegenerative disorders.80 Tyrosine nitration may modify the structure and function of proteins, leading to alterations in catalytic activity of enzymes, production of antigenic epitopes, and impaired cell signal transduction.82 It has recently been proposed that nitrotyrosine levels can be clinically detected in urine samples using a surface plasmon resonance (SPR) sensor83 or high-performance liquid chromatography.84 However, nitrotyrosine measurements in the context of ED research remain confined to the experimental laboratory setting.

Other biomarkers of ED/vascular injury Recently, the European Society of Cardiology Working Group on Peripheral Circulation published a position statement on methods for evaluating endothelial function.85 In this comprehensive review, several biochemical markers and assays that are used to examine different aspects of endothelial function were discussed.

The working group mooted plasma ADMA levels as a potential biomarker of endothelial function; however the authors cautioned that currently, direct endothelial function measurements remain a superior indicator and should not be replaced by plasma ADMA level measurements due to inconsistent prognostic data obtained with the latter.

Another biomarker with potential clinical application is oxidised LDL levels; however this biomarker also presents with some limitations. It is difficult to determine ox-LDL levels in vivo and the ability of elevated plasma ox-LDL to independently predict the development of coronary heart disease is still equivocal.

In a recent study on a model of rat carotid injury, proteomic analysis of blood proteins showed significantly differential expression of vitamin D binding protein (VDBP), aldolase A (aldo A) and apolipoprotein E (ApoE) two weeks after injury.86 Reduced circulating levels of all three of these plasma markers were associated with the presence of vascular injury and may represent novel markers of ED; however, further research is necessary.

Summary of assessment of endothelial function With the development of an ever-increasing number of measurement techniques of endothelial function (both direct mechanical endothelial function assessment and measurement of biomarkers of endothelial function), most authors agree that more and larger human-based studies are necessary to validate their clinical usefulness. The overall objective of such studies should ultimately be to establish standardised protocols allowing for the clinical diagnosis of ED, and quantification of cardiovascular risk, followed by the reversal of ED by means of

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anti-ED therapies. We are not there yet. The various endothelial function assessment tools at our disposal should be compared in studies that account for, among others, pathophysiological relevance and reproducibility, predictability in diverse patient populations, ease of use, cost-effectiveness, and risk assessment abilities that are superior to the tools currently in use.85 Another shortcoming in our understanding of the clinical significance of ED is the lack of studies where the effects of therapies that specifically target endothelial biology are investigated. In this regard, promising observations were made in a study which showed that dietary supplementation with the NO-donor, L-arginine significantly improved endotheliumdependent dilatation in young adults with hypercholesterolaemia.87 Similarly, in another study on rabbits, dietary supplementation with L-arginine prevented hypercholesterolaemia-induced ED by augmentation of NO-production.88

Progression of ED to atherosclerosis ED has emerged as a potentially valuable prognostic tool in predicting the development of atherosclerosis and ultimately IHD.89 The progression from the early changes observed in compromised vascular endothelium (endothelial activation and dysfunction) to atherosclerosis is complex and multifactorial.89 The healthy, intact endothelium is a highly selectively permeable barrier and does not promote leukocyte adhesion and invasion, or platelet aggregation and adhesion.53 However, as the endothelium progresses to a dysfunctional state, vascular homeostasis becomes impaired, leading to reduced anti-oxidant, anti-inflammatory and anti-thrombotic properties (due to reduced NO bioavailability), enhanced endothelial permeability (barrier dysfunction), upregulated pro-inflammatory cytokine levels, and expression of adhesion molecules such as VCAM-1 and ICAM1, which facilitate leukocyte adhesion to the endothelium.53 Leukocyte adhesion represents one of the first steps in the initiation of atherosclerosis. After adhering to the endothelium, leukocytes (monocytes and lymphocytes) cross the endothelium and migrate into the intima.54,90 Migration to the intima is mediated by chemo-attractants such as monocyte chemotactic protein-1 (MCP-1).91 Upon reaching the intima, monocytes transform into macrophages and express receptors that facilitate uptake of lipids. Uptake and accumulation of lipids lead to the transformation of macrophages into foam cells, which initiate an atherosclerotic lesion and further enhance release of inflammatory cytokines.54,90 Through these complex mechanisms, a cascade of events, which begins with the formation of an early atherosclerotic lesion, leading to an advanced lesion characterised by a plaque formation ensues.90

Anti-endothelial dysfunction therapies It has been shown that interventions such as lifestyle modification (exercise and diet) and various classes of pharmacological drugs can improve endothelial function, and in some instances reduce the risk of cardiovascular diseases.22,92 The anti-ED properties of statins have been extensively studied. Statins such as pravastatin, atorvastatin, simvastatin and fluvastin have all been shown to play an important role in correction of ED by improving endothelium-dependent vasodilation, in addition to their plasma cholesterol-lowering effects.33 Indeed, statin-induced eNOS activating effects have been

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demonstrated in investigations where addition of an eNOS inhibitor (L-NMMA) to pravastatin-treated hypercholesterolaemic patients hampered the endothelium-dependent vasodilation.93 Moreover, statins have been reported to stimulate activity of PKB/Akt, a major upstream activating signalling molecule of eNOS, and increase stability of eNOS mRNA, thus enhancing eNOS expression.33 In addition to statins and NO donors (discussed above), other drugs that have been shown to improve endothelial function include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor (AT1 receptor) blockers, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, antioxidants and oestrogen replacement.22,92 In a recent review article, Balakumar et al. identified potentially novel target sites for the pharmacological improvement of vascular function.64 These target sites include rho-kinase, poly (ADP ribose) polymerase, protein tyrosine phosphatase (PTPase), Akt, protein kinase A (PKA), caveolin, cholesterylester transfer protein (CETP), lipoprotein lipase, sphingosine-1-phosphate (S1P), advanced glycation end-product (AGE) and transketolase, geranylgeranyltransferase (GGT), epoxide hydrolase and Janus kinase (JAK).

Conclusion In view of the ever-increasing prevalence of ischaemic heart disease in the developed and developing world, it has become imperative to identify and investigate mechanisms of early, potentially reversible pre-atherosclerotic changes in the endothelium. To date, the most clearly defined and wellunderstood early precursor of atherosclerosis is ED. In fact ED can be regarded as the primum movens of atherosclerotic disease. Several cellular mechanisms and markers of ED that could potentially lead to the development of early detection and therapeutic interventions have been determined. However, more research aiming at improving our understanding of ED is necessary in order to establish its detection and reversal as essential and routinely utilised future tools in the prevention of IHD. This study was sponsored in part by the Medical Research Council (MRC) of South Africa, National Research Fund (NRF) of South Africa and the Harry Crossley Foundation, University of Stellenbosch.

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Conference Report Expert report on the 22nd European meeting on hypertension and cardiovascular protection, London, 26–29 April 2012 Following the release of the updated NICE (British Hypertension Society) guidelines last year and the South African guidelines recently, this meeting presented an opportunity to hear opinion leaders analyse, debate and discuss the best way to detect and manage hypertension in the 21st century.

Regarding treatment, the issue of diuretics was highlighted. The NICE guidelines advocate the use of thiazide-like diuretics (indapamide) and chlorthalidone. The South African guidelines also advocate these agents; however the choice of diuretic still includes low-dose hydrochlorothiazide.

Prof Franz Messerli, an eminent American opinion leader, was asked what is used in his country and the answer was thiazides, often in fixed combination.

The lesson is to use the thiazides with caution, be aware of the metabolic side effects and understand that the agents now advocated have been shown to have better outcomes data. Prof G Bakris stressed the need to ensure that patients are not hypokalaemic, as this contributes to vasoconstriction of vessels and resistant hypertension. It is important to correct potassium levels before adding in more therapy.

A focus of the meeting was renal nerve denervation (RDN) in resistant hypertension. Prof M Esler gave the Bjorn Folkow award lecture titled ‘The clinical physiology of the sympathetic nervous system: no longer a promissory note in hypertension’. He highlighted the pathophysiology of the sympathetic nervous system and why surgical splanchnicectomy, done from 1934 to 1960, did not work.

Renal denervation using radiofrequency laser is a minimally invasive percutaneous procedure characterised by short recovery times and the absence of systemic side effects. It appears that this technique will be considered an adjunctive therapy in the future. The European Society of Hypertension position paper, ‘Renal denervation – an interventional therapy

of resistant hypertension’, intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN. The meeting covered issues of cardiovascular protection. The cardio– ankle vascular stiffness index (CAVI) is a non-invasive technique used in Japan to assess arterial stiffness. It is expressed as a ratio between the internal pressure in blood vessels (blood pressure) and changes in vascular diameter, and measures pulse-wave velocity between the heart and femoral artery. The clinical implications are whether it will be a useful tool to assess arterial disease independent of blood pressure levels.

There is also an association between CAVI and atherosclerosis. All the work has previously been done in Asians and Japanese, and data were presented on the reliability of this index in a cohort of 4 000 Swiss subjects. Of note is that the index increases with age and women have a lower score than men.

A workshop dedicated to Bill Kannel, father of the Framingham study, was delivered by co-workers. Prof S Franklin, nephrologist, discussed the five seminal articles published regarding blood pressure, ageing and cardiovascular disease, and highlighted findings that changed our understanding of the disease.

Prof D Levy, involved with cardiovascular gene therapy, highlighted the genotype and phenotype genome-wide association data from this study.

Although it was predicted in June 2000 that within 10 years one would be able to find out what particular genetic conditions patients have, the individual singlenucleotide polymorphisms identified do not really contribute to the magnitude of hypertension. Those identified for systolic hypertension only contribute to a 1-mmHg increase, and diastolic to 0.5 mmHg. There are associations with stroke risk and left ventricular mass but no association with renal markers of hypertension.

Regarding the Framingham

scoring system for cardiovascular risk assessment, it was fascinating to hear how the scoring system was developed.

Prof RB D’Agostino, mathematician and statistician, discussed the validation of this score in the non-Framingham population; the transportability and external validation, which allows one to use it for other populations such as non-Caucasians. It has also been validated for non-US populations such as the Chinese.

Acute and chronic cardiovascular responses to endurance and ultra-endurance exercise During this session the Morganroth hypothesis was revisited. The question was asked whether the heart adapts differently to endurance and resistance exercise.

In the 1970s, using only non-twodimensional guided echocardiography, it was concluded that left ventricular mass index is increased in athletes who undertake either isotonic or isometric exercise. The mechanism underlying the increased left ventricular mass related to chamber dilatation in the endurance athlete versus an increase in left ventricular wall thickness in the athlete undertaking isometric exercise.

Use of more modern technology such as cardiac magnetic resonance imaging (MRI) confirmed that cyclists, swimmers and runners, at peak training, did demonstrate left ventricular chamber dilatation (42–62 mm) and that the septal wall thickness ranged from 6–14 mm. In addition, right ventricular mass was increased, mainly as a result of an increase in end-diastolic volume. There was balanced eccentric hypertrophy of both the right and left ventricle. However, in athletes undertaking strength training, there was no evidence of concentric left ventricular hypertrophy. In fact less than 2% had a left ventricular wall thickness in excess of 13 mm.

In another session, Rob Shave from

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Cardiff in the United Kingdom asked the question whether there is potential for harm from too much exercise. Troponin is released after prolonged exercise. After the London Marathon, 56% of athletes have troponin levels above the cut-off for myocardial infarction. He concluded that troponin release was ‘physiological and not related to any functional abnormality of the heart’.

After endurance exercise, such as a marathon or a 100-miler, the pressure in the right ventricle was increased, while there was a reduction in strain, strain rate and diastolic function in the right ventricle. Speckle tracking confirmed an abnormality of radial strain in the septum with septal flattening. The intense duration caused acute dysfunction of the right ventricle and although the right ventricular function had usually normalised by the end of the first week, chronic structural changes, as demonstrated on MRI, with reduced right ventricular function were found in some of the most practiced athletes.

Beta-adrenergic receptor desensitisation has been found after exercise and this attenuates cardiac function because of reduced chronotropic and inotropic response. Furthermore, changes in loading conditions did not explain the reduced function of the right ventricle.

Highly trained athletes differ from amateur athletes in that cardiac remodelling is more profound and may persist despite detraining. Cardiac MRI has shown myocardial fibrosis in athletes with an extensive history of competition in endurance sport. The long-term clinical significance of the fibrosis is unknown and warrants further study.

Prof Neil Poulter discussed the ASCOT trial, which has influenced the newest set of NICE/BHS guidelines. In these guidelines, patients under the age of 55 years should be given an ACE inhibitor as first-line therapy, whereas older or black patients should start initial therapy with a calcium channel blocker. If the blood pressure remains uncontrolled, the next step would be the combination of an ACE inhibitor and calcium channel blocker. This combination was associated with a more favorable outcome than the beta-blocker and thiazide–diuretic combination. Blood pressure variability was much less using the former combination and was associated with an improved cardiovascular outcome.

The ACE inhibitor–CCB combination was better even in those patients with a relative tachycardia.

Cardiovascular risk in obstructive sleep apnea Obstructive sleep apnea (OSA) is found in 25% of heart failure patients, 60% of patients who have had a stroke, 85% of patients with resistant hypertension, 50% of hypertensives and 30% of patients with acute coronary syndrome. About 30% of obese patients have unrecognised OSA. Patients with hypertension, OSA and obesity are at increased risk of atrial fibrillation, sudden cardiac death, reduced cardiac function, coronary disease and atrio-ventricular block. There is a ninefold increase of developing the metabolic syndrome and more silent cerebrovascular lesions.

There is much more blood pressure and heart rate variability in patients with OSA. Alternating bradycardia and tachycardia at night on 24-hour ECG monitoring is another clue to the presence of OSA. Clues to the diagnosis of OSA include excessive daytime sleepiness, choking at night, night sweats, nocturnal diuresis, motor activity during sleep, headaches, dry mouth, impotence and cognitive impairment. Clinical signs relate to the waist and neck circumference, hypertrophy of the tonsils, adenoids, the soft palate and even the uvula.

Contributing lifestyle parameters include excessive alcohol consumption, smoking, sedatives, as well as sleeping in a supine position.

Avoiding these factors is key to management. Continuous positive airway pressure via a nasal mask should be administered for five to six hours per night to improve outcome.

Prof Somers then discussed sleep, obesity and cardiovascular disease. In 1910, the average sleep duration was nine hours per night and in 2005 it was 6.5 hours per night. A third of people are sleep deprived on a daily or regular basis.

In an elegant experiment conducted at the Mayo Clinic, it was shown that less sleep was associated with higher caloric intake (500 calories a day) and this translated into 3 kg of extra fat accumulation in one month.

Normally, leptin levels increase at night during sleep and this tells the brain to stop

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eating. Patients who have less sleep have lower leptin but higher ghrelin levels. The latter is produced by the stomach and causes the sensation of hunger. Sleepdeprived people had no difference in energy expenditure versus those who were not sleep deprived. Obese patients report less sleep than lean patients and this has been linked to the pathogenesis of obesity. In the Nurses Health study, those who slept less than five versus more than seven hours per night had a 1.5-fold increased risk of developing obesity.

Another study conducted by Somers evaluated subjects sleeping less or more than seven hours per night. In those who were sleep deprived, 50% snored, 45% fell asleep in the day for no reason and 5% fell asleep while driving in the last 30 days of observation.

If subjects sleep less and have a disrupted sleep cycle, less insulin is secreted by the pancreas, even though blood glucose levels are higher after meals than in those who are not sleep deprived. The metabolic rate is reduced and the subjects have higher nighttime and daytime blood pressure. Chronic sleep deprivation (< five hours per night) was associated with a two-fold increase in incidence of acute coronary syndrome in the Nurses Health study.

Hypertension in the elderly The VALISH trial enrolled patients with isolated systolic hypertension (age range 70–84 years). These patients were divided into two groups. In one group, target systolic blood pressure was < 140 mmHg whereas in the second group the target systolic blood pressure was between 140 and 149 mmHg. They found no difference in outcome with strict versus less strict blood pressure control (< 140 vs 140–149 mmHg).

There was some discussion about the J-shaped curve regarding diastolic blood pressure in elderly patients. The data suggest that if diastolic blood pressure is lowered to < 80 mgHg in patients who have coronary heart disease at baseline, there is an increase in cardiovascular mortality.

Prior to blood pressure measurement, patients must have rested for at least five minutes and the readings are repeated. In the elderly, particular emphasis should be placed on standing blood pressure.

The HYVET trial recruited patients

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over the age of 80 years with a systolic blood pressure of > 160 mmHg. Patients were eligible for the trial if the systolic blood pressure was > 160 mmHg but not if the standing systolic blood pressure was < 140 mmHg. In this study, target blood pressure was < 150/80 mmHg. Active treatment with indapamide-based therapy was associated with a significant reduction in total mortality (25%), cardiovascular mortality (35%), stroke mortality (60%) and heart failure (50%).

The JATOS trial, published in Hypertension Research in 2008, confirmed that a systolic blood pressure of < 140 mmHg was associated with more deaths in those over the age of 75 years. It was finally concluded that the target blood pressure in the very elderly is 150/80 mmHg. Currently, there are no data on the optimal blood pressure goal in patients with mild hypertension

in systolic blood pressure is a strong predictor of stroke, independent of mean systolic blood pressure. Increased residual variability in systolic blood pressure in patients with treated hypertension is associated with a high risk of vascular events.

To most effectively prevent stroke, blood pressure-lowering drugs should reduce mean blood pressure without increasing variability. Ideally they should do both.

(140–160/< 90 mmHg) as trials have only recruited patients with a systolic blood pressure > 160 mmHg.

Blood pressure variability This refers to visit–visit variability, withinvisit variability, as well as variability over a longer period of time such as a week or a month. The greater the variability in blood pressure, the higher the risk. No specific number was given for the cut-off measure which predicted higher versus lower variability.

A good technique to assess variability entailed home blood pressure monitoring with three successive measurements a day, over a period of seven days. The greater the variability in readings, the higher the risk.

Recent data published in the Lancet in 2010 confirmed that visit–visit variability

Dr Naomi Rapeport, cscham@global.co.za Specialist physician, Milpark Hospital, Johannesburg Dr Shirley Middlemost, sjm55@telkomsa.net Cardiologist, Hermanus MediClinic, Western Cape

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Case Report Non-obstructive membranes of the left atrial appendage TANIA BORDONALI, ALBERTO SAPORETTI, ENRICO VIZZARDI, ANTONIO D’ALOIA, ERMANNA CHIARI, LIVIO DEI CAS

Abstract The left atrial appendage (LAA) is a blind-ending, complex structure distinct from the body of the left atrium and is sometimes regarded as a minor extension of the atrium.

However, it should routinely be analysed as part of a transoesophageal echocardiographic examination. In this study we describe the presence of a non-obstructive membrane traversing the cavity of the LAA, found incidentally on transoesophageal echocardiography.

Keywords: left atrial appendage, transoesophageal echocardiography, left atrial thrombosis Submitted 6/6/10, accepted 31/5/11 Cardiovasc J Afr 2012; 23: e1–e2

www.cvja.co.za

DOI: 10.5830/CVJA-2011-020

A 70-year-old man without traditional risk factors presented to our emergency room with palpitations and dyspnoea. A 12-lead electrocardiogram showed atrial fibrillation with a high ventricular rate. Two-dimensional echocardiogram revealed a hypertrophic left ventricle with reduced left ventricular function (ejection fraction 45%). Pre-cardioversion transoesophageal echocardiography (TEE) showed an enlarged left atrial appendage (LAA) with moderate spontaneous echo contrast and a long, thin structure traversing the body of the LAA without obstructing it.

This image was first ascribed to a thrombus, so oral anticoagulation was started. After four weeks on good anticoagulation, a second TEE was performed and the same image with the same dimensions was noted. After electrical cardioversion the patient recovered his ventricular function and was discharged on standard therapy.

Measurement of the two-dimensional (2D) LAA area is not reproducible or helpful, in view of this complex structure.

Improved imaging techniques and the use of biplane and multi-plane TEE have allowed visualisation of the LAA, which previously was difficult to do using other imaging methods.

The presence of membranes on the left LAA cavity is rare, and their origin is not clear.9 Embryologically, the trabecular LAA is a remnant derived from the left wall of the primary atrium, which forms during the third and fourth weeks of embryonic development.10 The main smooth-walled left atrial cavity develops later and is formed from an outgrowth of the pulmonary veins.10 Reviewing variations in size and morphological characteristics of the LAA,1,3,7,8 no mention was made of these membranes.

When performing a TEE in patients with atrial fibrillation, the pectinate muscles should not be confused with a thrombus.

Because the accuracy of LAA thrombus detection with TEE is important in the pre-cardioversion evaluation of these patients, it is vital to know what variations, especially in location and size of the pectinate muscle, exist in the normal anatomy of the LAA. Larger pectinate muscles (≥ 1 mm) occur in 97% of LAAs and constitute another potential pitfall in TEE imaging of the LAA. Small (< 1 mm) pectinate muscles are seen only in the first and last decades of life.11 The differential diagnosis of long, thin structures in the LAA may therefore include prominent pectinate muscles, side lobe artefacts and partial resolution of thrombi. The images in our case, however, seemed different.

The clinical origin and implications of these membranes are not certain, however, they may represent an anatomical variant that the echocardiographer should be aware of.

Discussion When investigating the LAA by TEE, it is important to keep in mind that the LAA is a three-dimensional (3D), multi-lobed structure.1-8 Therefore, evaluation should include imaging in multiple planes, including orthogonal views, in order to image the entire complex 3D structure.

Istitute of Cardiology, University of Brescia, Spedali Civili Brescia, Italy TANIA BORDONALI, MD, tbordonali@libero.it ALBERTO SAPORETTI, MD ENRICO VIZZARDI, MD ANTONIO D’ALOIA, MD ERMANNA CHIARI, MD LIVIO DEI CAS, MD

Fig. 1. Left atrial appendage in transoesophageal echocardiography.

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References 1.

2.

3.

4.

5.

Agmon Y, Khandheria BK, Gentile F, et al. Echocardiographic assessment of the left atrial appendage. J Am Coll Cardiol 1999; 34: 1867–1877.

Pollick C, Taylor D. Assessment of left atrial appendage function by transesophageal echocardiography: Implications for the development of thrombus. Circulation 1991; 84: 223–231.

Yao SS, Meisner JS, Factor SM, et al. Assessment of left atrial appendage structure and function by transesophageal echocardiography: A review. Echocardiography 1998; 15: 243–256.

Mugge A, Kuhn H, Nikutta P, et al. Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: Identification of a subgroup of patients at increased embolic risk. J Am Coll Cardiol 1994; 23: 599–607.

Rubin DN, Katz SE, Riley MF, et al. Evaluation of left atrial appendage anatomy and function in recentonset atrial fibrillation by transesopha-

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geal echocardiography. Am J Cardiol 1996; 78: 774–778.

Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999; 82: 547–555.

7. Veinot JP, Harrity PJ, Gentile F, et al. Anatomy of the normal left atrial appendage: A quantitative study of age-related changes in 500 autopsy hearts: Implications for echocardiographic examination. Circulation 1997; 96: 3112–3115.

8. Ernst G, Stollberger C, Abzieher F, et al. Morphology of the left atrial appendage. Anat Rec 1995; 242: 553–561.

9. Coughlan B, Lang RM, Spencer KT. Left atrial appendage stenosis. J Am Soc Echocardiogr 1999; 12: 882–883.

10. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999; 82: 547–555.

11. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: The SPARC study. Mayo Clin Proc 1999; 74: 862–869.

6.

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Case Report Mobile atheromatous plaque of the aortic arch diagnosed by transthoracic echocardiography prior to coronary artery bypass surgery Which one would you choose: scepticism or wishful thinking?

AC HATEMI, O OMAY, M BASKURT, S KÜCÜKOGLU, B ÖZ, K SÜZER

Abstract A routine pre-operative chest X-ray of a patient admitted to our institution for an elective coronary artery bypass operation revealed a mildly dilated mediastinal silhouette, which led the cardiovascular surgery resident to schedule emergency transthoracic echocardiography (TTE), with a special note asking for detailed evaluation of the ascending aorta and aortic arch. TTE revealed a mobile atheroma at the aortic arch, which obliged the cardiac surgery team to modify their strategy to combined hemi-arcus aortae replacement and coronary artery bypass grafting (CABG). Although with transoesophageal echocardiography (TEE) a small portion of the ascending aorta may be obscured by the trachea, TEE provides higher resolution images than TTE. Therefore one can conclude that TEE is the imaging modality of choice for detecting aortic atheromatous plaques but in patients with low risk for stroke and aortic atheromas, a detailed TTE may be sufficient for the pre-operative assessment.

Keywords: aortic arch, atherosclerosis, aorta, echocardiography, circulatory arrest, coronary artery bypass grafts, CABG Submitted 26/1/10, accepted 3/6/11 Cardiovasc J Afr 2012; 23: e3–e5

www.cvja.co.za

DOI: 10.5830/CVJA-2011-027

The aorta is an important source of athero-emboli, as recent studies have confirmed the strong correlation between severe aortic atheromatous plaques and stroke/death in the elderly.1 The dimensions of the aortic arch atheroma (larger and thicker Department of Cardiovascular Surgery, Institute of Cardiology, Istanbul University, Istanbul, Turkey AC HATEMI, MD, PhD, hatemi@superonline.com O OMAY, MD K SÜZER, MD

Department of Cardiology, Institute of Cardiology, Istanbul University, Istanbul, Turkey M BASKURT, MD S KÜCÜKOGLU, MD

Department of Pathology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey B ÖZ, MD

than 4 mm) and the complexity of the plaque (ulcerative and/ or mobile) are important risk factors for unexplained arterial embolic events such as stroke, transient ischaemic attack and peripheral emboli, together with multi-organ failure and death.

Furthermore, mobile atheromas of the aortic arch are associated with increased peri-operative strokes in patients undergoing cardiac surgery.2 Stroke incidence was found to be around 25% in patients with mobile plaques of the aortic arch, while it was only 2% in patients with quiescent non-mobile plaques.3 Potential aetiological risks independently associated with complex plaque formation are advanced age, history of hypertension, hypercholesterolaemia, increased body mass index, diabetes, and past or present tobacco use. Similarly, established risk for stroke occurrence are advanced age, male gender, previous stroke history, heredity, hypertension, smoking, diabetes mellitus, carotid artery disease, coronary artery disease and polycythaemia.4,5 We can clearly conclude that risk factors for atherosclerosis and stroke overlap. In fact, in cardiac patients without clinical evidence of severe atherosclerotic disease, a high prevalence of combined aortic and carotid plaques was reported.4 Surgeons should consider these patients as strong candidates for pre-operative and postoperative athero-embolic complications.

Transoesophageal echocardiography (TEE), which is a safe and relatively less invasive procedure with a very low risk of complication is the modality of choice for the diagnosis of aortic atheromas, although CT, MRI and intra-operative epi-aortic ultrasonography are known to be complementary examination techniques.6 The progress in TEE technology has enabled surgeons to obtain a detailed view of the aorta pre- and peri-operatively, to quantify atheromatous plaques according to their thickness and the presence of mobile components, therefore classifying them as simple or complex. In one study, TEE was able to find aortic arch atheromatous disease in 55% of patients with a normal chest X-ray, and 91% of those had heavily calcified aortic knobs.7 We assumed that TEE evaluation of the aorta is useful in older patients with risk factors for stroke and those with radiographic evidence of aortic calcification, to determine the presence of severe atheromatous disease of the aortic arch pre-operatively.

However, TEE is a semi-invasive procedure, which mostly requires sedation, is not always readily available, and may not be suitable for haemodynamically unstable patients. In this report, we highlight that in some patients such as ours but not in all, TTE may be used instead of TEE in this manner.

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Fig. 1. Pre-operative chest X-ray showing a dilated and mildly calcified aortic arch (arrows).

Case report A 65-year-old man with a history of stable angina was admitted to our institution for an elective CABG operation.

He had hypertension, hypercholesterolaemia, diabetes mellitus controlled with oral medication and a smoking history of 50 years. The patient had no neurological complaints. The central nervous system and cardiovascular system were normal.

On his chest X-ray, the aortic arch seemed dilated and mildly calcified (Fig. 1). Coronary angiography revealed triple-vessel disease with a left main coronary artery lesion of 60%. In our protocol, all patients scheduled for CABG operations are simultaneously scheduled for a pre-operative TTE examination for evaluation of their valvular and ventricular functions. In this patient with a mildly enlarged mediastinal silhouette on chest X-ray, the referring cardiovascular surgeon involved the echocardiograhy laboratory for a detailed evaluation of the ascending aorta and aortic arch. TTE performed at our institution showed minimal aortic regurgitation with an ejection fraction of 60% and a mobile atheroma at the aortic arch with minimal aortic dilatation (Fig. 2).

Fig. 2. Transthoracic echocardiographic examination revealing a mobile atheroma at the aortic arch with minimal aortic dilatation. Asc Ao: ascending aorta, LCCA: left common carotid artery, LSCA: left subclavian artery, Desc Ao: descending aorta, M: mobile atheroma.

Fig. 3. Photograph taken at the end of the operation. Hemi-arcus replacement (no: 28 gel-coated dacron vascular graft) with proximal coronary anastomoses of the saphenous grafts constructed directly to the aortic graft. SVG: saphenous vein graft, Ao: dacron vascular graft.

The surgical strategy was modified due to these findings and the arterial cannulation site was moved to the innominate artery with a regular two-staged venous cannulation, followed by a hemi-arcus aorta replacement with a quadruple CABG (left internal thoracic artery–left anterior descending artery bypass graft, aorta–diagonal artery–obtuse marginal branch

A B C D Fig. 4. Macroscopic and histopathological view of the aortic arch specimen. A. Excisional aortic specimen with the mobile atheroma in the aortic arch (arrow) showing rupture of the tunica intima, atheromas with ulceration, and a pedunculated thrombus formation attached to the arterial wall. B, C and D. Histopathological examination of the specimen showing atherosclerotic intimal changes, chronic fibrosis and full-thickness degeneration of the artery.

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012

of the circumflex artery bypass with saphenous vein graft, aorta–right coronary artery bypass with sapheneous vein graft) (cardiopulmonary bypass time: 123 min, total circulatory arrest time at 18°C: 25 min, cross-clamp time: 81 min).

After distal coronary anastomoses, a segment from the supracoronary aorta to the left subclavian artery ostium was excised and the hemi-arcus was replaced with a number 28 gel-coated dacron vascular graft. Lastly, proximal coronary anastomoses of the saphenous grafts were performed directly to the aortic graft (Fig. 3). No operative/postoperative embolic or other complications were experienced following the successful operation.

Pathological examination of the specimen revealed macroscopically: rupture of the tunica intima, an atheromatous plaque with ulceration, and a pedunculated thrombus formation attached to the arterial wall, and microscopically: atherosclerotic intimal changes, chronic fibrosis, and full-thickness degeneration of the artery (Fig. 4). The patient was discharged from the ICU on the third postoperative day and from hospital on the 15th postoperative day. The patient presented for routine cardiology and cardiovascular surgery follow up without any complaints.

Discussion Although several variables were identified as risk factors for peri-operative stroke, the majority of strokes occur in patients where no definitive aetiological factors can be identified. All patients undergoing cardiac surgery may have atherosclerotic aortic plaques with no clinical evidence, and these are a potential source of serious peri-operative or postoperative athero-embolic complications. Thorough pre-operative echocardiographic evaluation of the patient, and particularly of the elderly, is crucial for an uneventful surgical outcome.

TTE compares favourably with TEE in the identification of atheromatous plaques of the aortic arch and distal ascending aorta, although it is less effective in identifying simple plaques of the proximal ascending aorta. The demonstration of aortic plaque with TEE has a sensitivity of 91%, specificity of 82%, and positive and negative predictive values of 72 and 95%, respectively.8 However, TEE, which is a sensitive technique to determine protruding aortic atheromas with or without a mobile component, cannot always visualise plaques located in the distal ascending aorta and proximal aortic arch.9 Weinberger et al. reported that TTE could be used to visualise plaques in the distal ascending aorta and aortic arch, and particularly plaques at the junction of the ascending aorta and aortic arch that could be obscured by the bronchi and may be missed by TEE.9 TTE was able to detect simple plaques undetected with TEE, particularly in the proximal ascending aorta. Konstadt et al. reported that up to 42% of the ascending aorta cannot be visualised by TEE, so potential embolic plaques can be missed by that modality.10 All complex plaques, morphologically similar and visualised with TEE were also demonstrated with TTE. Both techniques are able to identify the plaques as pedunculated or proliferative and to picture their mobility.

To our knowledge, there is no study comparing TTE with TEE in detecting mobile atheromatous plaques. Most echocardiographers feel that TEE is more accurate than TTE for the critical measurement of plaque thickness and for the diagnosis of mobile thrombi (high resolution and proximity

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to the aorta). The small portion of the ascending aorta that is masked by the trachea near the origin of the innominate artery may not be seen on TEE and only 2% of the plaques may be missed with this modality.11 As a significant proportion of aortic plaques of stroke patients can be demonstrated with TTE, the necessity for a TEE evaluation, which is a relatively invasive procedure, will automatically diminish. Unfortunately, combined TEE and TTE examinations of the aortic arch may still be mandatory in a subgroup of patients, to rule out the presence of atherosclerotic plaque. TTE imaging of the aortic arch is also useful for sequential evaluation of the plaques already identified with TEE, and therefore helps physicians to omit repetitive TEE examinations.

Conclusion Routine TTE evaluation is a valuable modality, particularly for elderly candidates, for aortic cannulation in open-heart surgery.

In our case, the pre-operative TTE examination of the patient enabled the surgeon to make the correct and custom-designed operative decision, which assured a safe procedure and better surgical outcome.

References 1.

Sharifkazemi MB, Aslani A, Zamirian M, Moaref AR. Significance of aortic atheroma in elderly patients with ischemic stroke. A hospitalbased study and literature review. Clin Neurol Neurosurg 2007; 109(4): 311–316.

2. Tunick PA, Kronzon I. Atheromas of the thoracic aorta: clinical and therapeutic update. J Am Coll Cardiol 2000; 35(3): 545–554.

3. Barbut D, Lo YW, Hartman GS, Yao FS, Trifiletti RR, Hager DN, et al.

Aortic atheroma is related to outcome but not numbers of emboli during coronary bypass. Ann Thorac Surg 1997; 64(2): 454–459.

4. Tribouilloy C, Peltier M, Colas L, Senni M, Ganry O, Rey JL, Lesbre JP. Fibrinogen is an independent marker for thoracic aortic atherosclerosis. Am J Cardiol 1998; 81(3): 321–326.

5. Katz ES, Tunick PA, Rusinek H, Ribakove G, Spencer FC, Kronzon I. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20(1): 70–77.

6. Daniel WG, Erbel R, Kasper W, Visser CA, Engberding R, Sutherland GR, et al. Safety of transesophageal echocardiography. A multicenter survey of 10,419 examinations. Circulation 1991; 83(3): 817–821.

7. Marschall K, Kanchuger M, Kessler K, Grossi E, Yarmush L, Roggen S, et al. Superiority of transesophageal echocardiography in detecting aortic arch atheromatous disease: identification of patients at increased risk of stroke during cardiac surgery. J Cardiothorac Vasc Anesth 1994; 8: 5–13.

8. Tribouilloy C, Peltier M, Colas L, Rida Z, Rey JL, Lesbre JP. Multiplane transoesophageal echocardiographic absence of thoracic aortic plaque is a powerful predictor for absence of significant coronary artery disease in valvular patients, even in the elderly. A large prospective study. Eur Heart J 1997; 18(9): 1478–1483.

9. Weinberger J, Azhar S, Danisi F, Hayes R, Goldman M. A new noninvasive technique for imaging atherosclerotic plaque in the aortic arch: an initial report of stroke patients by transcutaneous real-time B-mode ultrasonography. Stroke 1998; 29; 673–676.

10. Konstadt SN, Reich DL, Quintana C, Levy M. The ascending aorta: how much does transesophageal echocardiography see? Anesth Analg 1994; 78: 240–244.

11. Krinsky GA, Freedberg R, Lee VS, Rockman C, Tunick PA. Innominate artery atheroma: a lesion seen with gadolinium-enhanced MR angiography and often missed by transesophageal echocardiography. Clin Imaging 2001; 25: 251–257.

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Case Report Successful stenting of catheter-induced unprotected left main coronary artery dissection G ERTAŞ, E URAL, WJ VAN DER GİESSEN

Abstract Catheter-induced left main coronary artery (LMCA) dissection is a dramatic, although uncommon complication of diagnostic coronary angiography and requires prompt treatment.

We describe a case of iatrogenic occlusive dissection of the LMCA during coronary angiography, treated by subsequent percutaneous recanalisation.

Keywords: LMCA, coronary artery dissection, stent Submitted 30/12/09, accepted 26/6/11 Cardiovasc J Afr 2012; 23: e6–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2011-033

Case report A 58-year-old female with a 10-year history of hypertension was admitted with stable angina pectoris (Canadian Cardiovascular Society class II). On admission, the patient’s arterial pressure was 130/70 mmHg and her heart rate was 84 beats/min. The ECG showed negative T waves in leads V4–6. An exercise treadmill test was inconclusive. Transthoracic echocardiography revealed global left ventricular hypokinesia with a left ventricular ejection fraction of 40%.

She underwent diagnostic coronary angiography. Left coronary angiography revealed a normal arterial tree (Fig. 1A). After the first two contrast injections, the patient experienced severe chest pain and became hypotensive. The electrocardiogram showed ST-segment elevation. Coronary injection revealed there was no contrast medium passing beyond the distal left main coronary artery (LMCA) (Fig. 1B). Catheter-induced LMCA dissection was concluded and because of the haemodynamic deterioration, urgent percutaneous coronary intervention was performed.

After a loading dose of 600 mg clopidogrel and 300 mg of aspirin, an intra-aortic balloon pump was inserted from the left

common femoral artery for haemodynamic support during the procedure. A floppy coronary guide wire could not be advanced to the distal left anterior descending (LAD) artery, so with the wire in the first septal branch, a bare-metal stent (4 × 24-mm Liberté) was implanted in the LMCA towards the LAD (Fig. 2A). Circumflex coronary arterial flow was restored but because of a spiral dissection, there was no flow in the distal LAD (Fig. 2B).

Subsequent attempts to advance the wire were unsuccessful.

Leaving the first wire in the mid-LAD, a second floppy wire could easily be advanced to the distal vessel. A second baremetal stent (3 × 32-mm Liberté) was implanted, overlapping with the first stent. TIMI 3 flow was obtained (Fig. 2C).

Post-procedure troponin levels remained negative and the echocardiogram revealed no change in wall-motion abnormality compared to baseline. After an uneventful period, the patient was discharged on post-procedural day nine. She remained asymptomatic during one year of follow up.

A

B

Fig. 1. (A) Left coronary angiography revealed a normal arterial tree. (B) Coronary injection revealed there was no contrast medium passing beyond the distal LMCA. A

B

C

Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey G ERTAŞ, MD, drgokhanertas@yahoo.com.tr

Department of Cardiology, Medical Faculty, and Interventional Cardiology Research and Application Unit, Kocaeli University, Kocaeli, Turkey E URAL, MD

Department of Cardiology, Thoraxcentre, Erasmus MC, Rotterdam, and Interuniversity Cardiology Institute of the Netherlands, ICIN-KNAW, Utrecht, the Netherlands WJ VAN DER GİESSEN, MD, PhD

Fig. 2. (A) A bare-metal stent from the LMCA to the LAD was implanted. (B) After stent placement, flow to the circumflex artery was restored, but there was no flow in the distal LAD because of the dissection. (C) A second bare-metal stent was implanted slightly overlapping with the first stent. TIMI 3 flow was obtained.

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Discussion Catheter-induced LMCA dissection is a rare complication of diagnostic coronary angiography, but has a very high mortality rate if not treated. In previous reports, authors have defined this situation as the ‘nemesis of interventional cardiologists’.1 The incidence of catheter-induced LMCA dissection has been reported as less than 0.1% in several articles,2,3 but more than 10 times higher in patients with left main coronary artery stenosis (1.05%).4 Vigorous contrast injections while the catheter is not co-axial, not using a soft-tipped catheter, deep intubation, and careless catheter manipulation can all cause LMCA dissection. After LMCA stenosis, patients with hypertension, Marfan syndrome, congenitally unicuspid and bicuspid aortic valves, and cystic medial necrosis have been reported to have a higher risk factor for dissection.5

Conclusion Traditionally, CABG has been the treatment of choice, but it delays the time until normal flow is restored. Good long-

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term survival has been reported for percutaneous coronary intervention in patients with LMCA dissection. No cardiac deaths have occurred during a mean follow up of 30 months, with 84.6% angiographic success. Therefore, particularly in PCI centres, it should be considered as the first treatment option.2

References 1.

2.

3.

4.

5.

Jain D, Kurowski V, Katus HA, Richardt G. Catheter-induced dissection of the left main coronary artery, the nemesis of an invasive cardiologist a case report and review of the literature. Z Kardiol 2002; 91: 840–845.

Cheng CI, Wu CJ, Hsieh YK, Chen YH, Chen CJ, Chen SM, et al.

Percutaneous coronary intervention for iatrogenic left main coronary artery dissection. Int J Cardiol 2008; 126: 177–182.

Dunning DW, Kahn JK, Hawkins ET, O’ Neill WW. Iatrogenic coronary artery dissections extending into and involving the aortic root. Cathet Cardiovasc Intervent 2000; 51: 387–393.

Kovac JD, de Bono DP. Cardiac catheter complications related to left main stem disease. Heart 1996; 76: 76–78.

Awadalla H, Sabet S, El SA, Rosales O, Smalling R. Catheter-induced left main dissection incidence, predisposition and therapeutic strategies experience from two sides of the hemisphere. J Invasive Cardiol 2005; 17: 233–236.

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Case Report New images in carcinoid heart disease M KLOBUČIĆ, MH PAAR, RŠ PADOVAN, J VINCELJ, B FILA

Abstract Echocardiography was the main imaging technique in the diagnosis and follow up of carcinoid heart disease but in the last decade magnetic resonance imaging (MRI) has evolved into a new diagnostic modality. Most of the reported MRI features were similar to those observed by echocardiography – tricuspid and/or pulmonary valve thickening and immobility with consequent valvular dysfunction and right heart enlargement. To our knowledge, this is the first report describing endocardial enhancement of the right cardiac chambers, tricuspid valve and subvalvular apparatus, which corresponds with histologically seen fibrous carcinoid plaques.

deposition of fibrous tissue on the endocardial surfaces of the heart. They are mainly found on the right side of the heart and are truly pathognomonic. Echocardiography was the main imaging technique in the diagnosis and follow up of CHD, but in the last decade, magnetic resonance imaging (MRI) has evolved into a new diagnostic modality.

Case report A 62-year-old woman was admitted to surgery in 1996 with symptoms of small-bowel obstruction. Exploration of the

Keywords: carcinoid heart disease, magnetic resonance imaging, echocardiography Submitted 30/1/11, accepted 18/7/11 Cardiovasc J Afr 2012; 23: e8–e10

www.cvja.co.za

DOI: 10.5830/CVJA-2011-038

Carcinoid tumours are rare (1.2 to 2.1 per 100 000 general population per year), slow-growing, malignant tumours arising from the neural crest amine precursor uptake and decarboxylation cells (APUD cells), in particular from those situated in the gastrointestinal tract. When these tumours metastasise to the liver, their vasoactive products (5-hydroxytryptamine or serotonin, histamine, tachykinins, prostaglandins etc.), which are regularly metabolised in the endothelium of the liver and lung vasculature, can reach the circulation and thereafter produce symptoms of carcinoid syndrome (CS), characterised by dermal flushing, diarrhoea, bronchospasm and valvular carcinoid heart disease (CHD). The latter is the most serious manifestation of CS, leading to heart failure and death in 40% of all affected.

Cardiac lesions are a consequence of serotonin-induced Department of Internal Medicine, Bjelovar General Hospital, Croatia M KLOBUČIĆ, MD, mislav.klobucic@bj.t-com.hr

Department of Diagnostic and Interventional Radiology, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia MH PAAR, MD RŠ PADOVAN, MD

Institute of Cardiovascular Diseases, Dubrava University Hospital, Zagreb, Croatia J VINCELJ, MD

Department of Surgery, Bjelovar General Hospital, Croatia B FILA, MD

Fig.1. Echocardiography demonstrating severe thickening, retraction, shortening and almost complete immobilisation of the tricuspid valve (TV) leaflets (a), leading to severe tricuspid regurgitation (b). Severe dilatation and trabeculation of the right ventricle (RV) with flattening of the interventricular septum (c). Characteristic daggershaped signal of tricuspid regurgitation; mild tricuspid stenosis (d). RA – right atrium, LV – left ventricle.

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Fig. 2. Magnetic resonance imaging. FSE T1-weighted black-blood four-chamber-view image presenting thickened and retracted tricuspid valve leaflets (white arrows, a). Systolic (b), and diastolic (c) phase of ciné SSFP four-chamberview images demonstrating the signal void of tricuspid regurgitation (black arrowhead) and tricuspid stenosis (white arrowhead). A small pericardial effusion (asterisk) and enlargement of the right atrium (RA) and right ventricle (RV) were also observed. Endocardial delayed enhancement of the right atrium, tricuspid valve leaflets and right ventricle (black arrows, d).

abdominal cavity revealed a large, inoperable tumour of the terminal ileum. A carcinoid tumour was diagnosed from the histological specimens. The first liver metastases were detected in 1997.

After the first symptoms of CS (flushing, diarrhoea, oedema of the ankles) emerged in 2002, somatostatine analogue therapy was introduced. This led to good control of the CS symptoms, and the urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), a byproduct of serotonin degradation used for the detection and follow up of patients with carcinoid tumours, significantly decreased.

In 2007 the patient started to complain of fatigue and dyspnoea on exertion. An echocardiographic examination (Aloka SD 4000 and Philips i22) revealed pathognomonic signs of CHD – severe thickening, retraction, shortening and almost complete immobilisation of the tricuspid valve leaflets (Fig. 1a) with severe tricuspid regurgitation (Fig. 1b), mild tricuspid stenosis, pulmonary valve stenosis and severe dilatation and trabeculation of the right ventricle (Fig. 1c).

The continuous-wave Doppler signal analysis showed a characteristic dagger-shaped signal of tricuspid regurgitation with a maximal velocity of 240 cm/s, demonstrating rapid decline in pressure difference between the right ventricle and right atrium (Fig. 1d). As a result of volume overload of the right ventricle, diastolic flattening of the interventricular septum was noticed.

No pericardial effusions were detected but hyperechogenicity

of the pericardium was noted and MR imaging of the heart was performed to exclude pericardial involvement. Cardiac MRI was performed using the 3.0-Tesla MRI system (Magnetom Trio, Siemens Medical Solutions, Erlangen, Germany) with a 12-element cardiac array coil, breath-hold technique and electrocardiographic gating. After obtaining axial half-Fourier acquisition single-shot turbo spin-echo (HASTE) images and localiser images in three planes, ciné loops of long- and shortaxis views were acquired using the steady-state free precession technique (SSFP). In addition, anatomical ‘black-blood’ fastspin-echo (FSE) T1-weighted and short-tau inversion recovery (STIR) T2-weigted four-chamber view images were obtained.

Delayed enhancement was evaluated 10 to 15 minutes after intravenous injection of a ‘double dose’ (0.2 mmol/kg) of gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma AG, Berlin, Germany) using the inversion prepared gradientecho technique with inversion time set to nullify the myocardial signal. Systolic function of both ventricles was measured using semi-automatic contour-detection software (ARGUS, Siemens Medical Solutions, Forchheim, Germany).

The right atrium was severely enlarged, while the leaflets of the tricuspid valve were thickened and barely mobile (Fig. 2a).

The right ventricle was enlarged with diastolic flattening of the interventricular septum due to right ventricle volume overload.

Signal voids caused by the turbulent flow through the tricuspid valve during systole and diastole were observed, pointing to

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significant tricuspid regurgitation and stenosis, respectively (Fig. 2b, c).

After intravenous administration of gadolinium-based contrast agent, delayed enhancement of the tricuspid valve and endocardial layer of the right cardiac chambers was evidenced, indicating a fibrous carcinoid plaque deposited on the endocardium (Fig. 2d).

The global systolic function of both ventricles was maintained.

A small circular pericardial effusion was present, without pericardial thickening or pathological enhancement. No signs of left-sided carcinoid heart disease were found.

Discussion Carcinoid tumours are slow growing and indolent, but development of CHD symptoms dramatically reduces life expectancy. Standard palliative therapy in CS, therapy with somatostatine analogues, although reducing levels of serotonin and achieving good control of other CS symptoms in almost 80% of patients, does not induce regression of the cardiac manifestations and most of the patients with carcinoid tumours die from progressive right heart failure as a consequence of regurgitation and stenosis of the tricuspid and pulmonary valves.

As surgical intervention with annuloplasty or valve replacement is often the only therapeutic option, it is important to follow up the patients regularly to detect the proper timing for surgery. In recent reports, operative risk has declined to below 10% when surgical intervention was performed before the development of severe right heart failure, in even mildly symptomatic patients where the referral to surgery was based on severe valvular dysfunction and signs of right ventricular volume overload.

Therefore, the most precise imaging technique should be used for evaluation of right ventricular volumes and function.

While interobserver variability of quantitative assessment of the right ventricular ejection fraction by two-dimensional echocardiography is up to 15 ± 13%,1 MRI shows much lower values, around 4%,2 and should be in our opinion, the reference standard for follow up of patients with CHD. Since the first description of the MRI findings of CHD,3 only

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a few reports of the MRI features of this condition have been published.4-7 Most of these features are similar to those observed echocardiographically, as shown in our patient – tricuspid and/ or pulmonary valve thickening and immobility with consequent valvular dysfunction and right heart enlargement.

A single article reporting contrast-enhancement characteristics of CHD was found where delayed enhancement of the tricuspid septal leaflet, mostly marked at the annulus, was demonstrated.4 In our patient, endocardial enhancement of the right atrium, right ventricle including the endocardial surface of the subvalvular apparatus, and both sides of the tricuspid valve was observed.

Conclusion We believe that this type of late enhancement, not previously described in the literature, perfectly corresponds with the wellknown histological features of CHD.

References 1.

2.

3.

4.

5.

6.

7.

Miller D, Farah MG, Liner A, Fox K, Schluchter M, Hoit BD. The relation between quantitative right ventricular ejection fraction and indices of tricuspid annular motion and myocardial performance. J Am Soc Echocardiogr 2004; 17: 443–447.

Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady state free precession cardiovascular magnetic resonance. Eur Heart J 2006; 27: 2879–2888.

Mirowitz SA, Gutierrez FR. MR and CT diagnosis of carcinoid heart disease. Chest 1993; 103: 630–631.

Martos R, Ridge C, Quinn M, Dodd J. Cardiac carcinoid: tricuspid delayed hyperenhancement on cardiac 64-slice multidetector CT and magnetic resonance imaging. Ir J Med Sci, published online: 22 January 2009. doi: 10.1007/s11845-008-0273-5.

Franzen D, Boldt A, Raute-Kreinsen U, Koerfer R, Erdmann E. Magnetic resonance imaging of carcinoid heart disease. Clin Cardiol 2009; 32: E92–E93.

Mollet NR, Dymarkowski S, Bogaert J. MRI and CT revealing carcinoid heart disease. Eur Radiol 2003; 13(Suppl 6): L14–L18.

Bastarrika G, Cao MG, Cano D, Barba J, de Buruaga JDS. Magnetic resonance imaging diagnosis of carcinoid heart disease. J Comput Assist Tomogr 2005; 29: 756–759.

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Case Report Aortic dissection, a complication during successful angioplasty of chronic total occlusion of the right coronary artery, was treated conservatively S CHUNLAI, PR STELLA, A BELKACEMI, P AGOSTONI

Abstract Aortic dissection is an uncommon but potentially lethal complication that can occur during the engagement of a guiding catheter. We report a case of a 59-year-old woman with acute aortic dissection due to percutaneous coronary intervention. This resulted in a retrograde extension of the dissection into the proximal part of the ascending aorta. With haemodynamic stability, we decided to treat the aortic dissection medically. As a result, a complete resolution of the aortic dissection was documented by coronary angiography and the follow-up computed tomography scan.

Keywords: aortic dissection, percutaneous coronary intervention Submitted 15/6/11, accepted 6/9/11 Cardiovasc J Afr 2012; 23: e11–e13

www.cvja.co.za

DOI: 10.5830/CVJA-2011-050

Dissection of the ascending aorta is a very rare iatrogenic complication of percutaneous coronary intervention (PCI).1 We report here on a case of accidental aortic dissection that occurred during PCI of a chronic total occlusion (CTO) lesion.

Case report

was 80% stenosis in the first obtuse marginal branch and 30% stenosis in the distal left circumflex coronary artery. The mid-portion of the RCA was occluded, with poor collateral flow to the distal RCA (Fig. 1).

After discussion with the cardiac surgeons, we decided on a staged PCI; first a PCI of the RCA and then a PCI of the obtuse marginal branch was planned. A 7 french Judkins JR4 guiding catheter (Bosotn Scientific) was used in combination with a 0.014-inch Pilot 50 and Persuader 3 guide wire to cross the occlusion of the RCA. After successful recanalisation with the CTO wire, we changed to a normal floppy guide wire (Cougar, Medtronic) and performed gradual pre-dilations with a 2.0 × 10-mm Sapphire, 3.0 × 15-mm Sapphire, 3.0 × 30-mm Pantera and 3.50 × 15-mm XTRM Force balloon. Then we deployed three Endeavor REsolute stents (2.5 × 24 mm/2.75 × 24 mm/3.0 × 30 mm) from the distal to mid-RCA. During placement of the second stent, the guiding position was lost and re-inserted.

At the end of the procedure, we noticed an aortic dissection in the proximal part of the ascending aorta (DeBakey type II, Stanford type A) with good antegrade flow and no residual stenosis in the RCA (Fig. 2). The patient reported slight transient chest pain not associated with nausea, vomiting, shortness of breath or palpitations. Her blood pressure was 120/75 mmHg (equal on both arms) and the pulse 78 beats per minute.

A 59-year-old woman with stable angina on limited effort was admitted to our hospital for PCI of a CTO lesion, which was located at the level of the mid-right coronary artery (RCA) after a previous non-Q-wave acute myocardial infarction. Echocardiography showed normal left ventricular systolic function without regional wall-motion abnormalities. Her coronary risk factors were hypertension, diabetes, hypercholesterolaemia, family history of coronary artery disease and smoking.

On coronary angiography, the left main coronary artery and left anterior descending coronary artery were normal. There Department of Cardiology, Second Affiliated Hospital of Soochow University, SuZhou, China S CHUNLAI, MD

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands S CHUNLAI, MD, C.shao@umcutrecht.nl PR STELLA, MD, PhD A BELKACEMI, MD P AGOSTONI, MD, PhD

Fig. 1. Coronary angiography showed the mid-portion of the RCA occluded, with poor collateral flow to the distal RCA.

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A

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B

Fig. 2. During injection of the right coronary artery, angiography showed Stanford type A (DeBakey type II) dissection in the proximal part of the aorta (A), and good anterograde flow in the RCA (B).

Since both haemodynamically and angiographically there were no changes, even after 25 minutes, we decided to stop the procedure and not bring the patient in for surgery. Cardiac computed tomography (CT) revealed a type A dissection with a predominantly intramural haematoma. The dissection did not extend into the coronary arteries and cerebral vessels, but stopped at the origin of the arteria brachiocefalica (Fig. 3).

Because of her haemodynamic stability, we decided to treat the aortic dissection medically, so the patient was transferred to the coronary care unit. Metoprolol tartrate 300 mg/day, telmisartan 80 mg/day, amlodipine 5 mg/day, enteric-coated aspirin 100 mg/day and clopidogrel 75 mg/day were given to the patient. After five days, a follow-up CT showed a stable situation with a considerable amount of sub-intimal haemorrhage at the proximal part of aorta, with unchanged dimensions. A small

Fig. 3. Computed tomographic scan revealed a type A dissection with a predominantly intramural haematoma.

pericardial effusion was present with no evidence of tamponade (Fig. 4).

The patient was discharged uneventfully and seen in the cardiology outpatient clinic after 10 days. She had no complaints, with stable systolic blood pressure between 100 and 110 mmHg. Four weeks later, during the scheduled second procedure for PCI of the right circumflex coronary artery, aortography showed no sign of the dissection in the proximal part of the aorta, and a well-maintained result of the RCA-CTO (Fig. 5).

Discussion Aortic dissection is a rare complication after percutaneous coronary intervention,1 with a reported incidence of 0.03 to

Fig. 4. Five days after the event, a computed tomographic scan showed decreased echogenity with a considerable amount of sub-intimal haemorrhage at the proximal part of the aorta. The thrombosed false lumen was not expanding to arch.

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A

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B

Fig. 5. After four weeks, aortic angiography showed that the dissection was absent in the proximal part of the aorta (A), and the RCA was patent (B).

0.1%.2,3 The exact mechanism of aortic dissection caused by PCI is unclear. Aortic dissections generally relate to retrograde extension of a proximal dissection of a coronary artery.

Forceful manipulation of guide wires, vigorous injection of the contrast medium, and accidental manipulation of the guiding catheter have also been suggested to trigger coronary and aortic dissections during PCI.1 In this case, the aortic dissection may have been caused by mechanical trauma caused by the tip of the guiding catheter while re-inserting into the ostium of the RCA. Acute dissections involving the ascending aorta (DeBakey type I and II, Stanford type A) are considered surgical emergencies requiring swift repair of the aortic root or reconstruction of the ascending aorta and the arch to improve prognosis. By contrast, dissections confined to the descending aorta (DeBakey type II, Stanford type B) are treated medically unless progression of the dissection, intractable pain, organ hypo-perfusion or extra-aortic blood are demonstrated.4 If a surgical strategy is selected, there is a high risk of potentially life-threatening bleeding complications due to aggressive anti-platelet treatment for these stent-treated patients. With β-blockers, in combination with other antihypertensives, blood pressure levels between 100 and 120 mmHg are achievable.4 As this dissection remained localised to the anterolateral portion of the ascending aorta, combined with

a stable haemodynamic status, a conservative, medical treatment was chosen with strict blood pressure control in order to prevent further extension.

Conclusion Aortic dissection is an uncommon but potentially lethal complication that can occur during PCI. Provided there is good haemodynamic stability and no interference with other vessels coming out of the ascending aorta, vigilant medical therapy, as described in our case report, may be preferable to surgery.

References 1.

2.

3.

4.

Ruda-Vega M. Aortic dissection – exceedingly rare complication of coronary angioplasty. Catheter Cardiovasc Diagn 1997; 42(4): 416.

Yip HK, Wu CJ, Yeh KH, et al. Unusual complication of retrograde dissection to the coronary sinus of Valsalva during percutaneous revascularization: a single center experience and literature review. Chest 2001; 119: 493–501.

Alfonso F, Almeria C, Fernandez-Ortiz A, et al. Aortic dissection occurring during coronary angioplasty: angiographic and transesophageal echocardiographic findings. Cathet Cardiovasc Diagn 1997; 42: 412–415.

Ince H, Nienaber CA. Diagnosis and management of patients with aortic dissection. Heart 2007; 93(2): 266–270.

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CardioVascular Journal of Africa (official journal for PASCAR)

• Endothelial dysfunction • Cardiac surgery and haematological malignancies • Cardiovascular risk factors in coronary artery disease • Changes in NT-proBNP • Effusive–constrictive pericarditis in Ibadan • Pneumonia in post cardiac surgery • Cardiovascular disease in the Seychelles, Tanzania and Mauritius

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Cardiovascular Journal of Africa . Vol 23, No 4, May 2012

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• Mobile atheromatous plaque of the aortic arch • Images in carcinoid heart disease