cvja volume 22, issue 6

AFRICA

NOVEMBER/DECEMBER 2011VOL 22 NO 6

CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

Cardiovascular Journal of A

frica . Vol 22, No 6, N

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ecember 2011

Bilocor contains the highly cardio-

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At a significant cost saving to your

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Bilocor 5. Each tablet contains 5 mg bisoprolol fumarate. Reg. No. S3 38/5.2/0053. NAM NS2 06/5.2/0061. Bilocor 10. Each tablet contains 10 mg bisoprolol fumarate. Reg. No. S3 38/5.2/0051. NAM NS2 06/5.2/0062.

• Asymptomatic left ventricular systolic dysfunction in hypertensive Nigerians

• Metabolic syndrome in Asian Indians

• Down syndrome and congenital heart disease

• Diagnosis and follow up of primary cardiac tumours

• Stromal-derived factor-1<alpha>/CXCR4 in neo-intimal repair

• Omega-3 fatty acid content of fish oil supplements

• Increasing rates of hypertension in women

• Anaesthesia for emergency Caesarean section in peripartum cardiomypathy

• 3D transoesophageal echocardiography in prosthetic mitral valve thrombosis

References: 1. CRESTOR® package insert 2. Jones P, Davidson MH, Stein EA, et al. Comparison of the Effi cacy 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.

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.

16162

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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 benefi t-risk profi le4,5

The only ICD with SmartShockTM technology that dramatically reduces the incidence of inappropriate shocks while maintaining senstivity.

Protecting patients physically and emotionally, now and in the future.

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

Assistant EditorPROF JAMES KER (JUN)

Regional EditorDR A DzUDIE

Regional Editor (Kenya)DR F BUKAChI

Regional Editor (South Africa)PROF R DELPORT

topic EditorsNuclear Medicine and ImagingDR MM SAThEKGE

heart FailureDR G vISAGIE

PaediatricDR S BROwN

Renal hypertensionDR BRIAN RAyNER

SurgicalDR F AzIz

Adult SurgeryDR J ROSSOUw

Electrophysiology and PacingDR A OKREGLICKI

Epidemiology and PreventionistDR AP KENGNE

Editorial BoardPROF PA BRINKExperimental & Laboratory Cardiology

PROF R DELPORTChemical Pathology

PROF MR ESSOPhaemodynamics, heart Failure & valvular heart Disease

DR OB FAMILONIClinical Cardiology

DR v GRIGOROvInvasive Cardiology & heart Failure

PROF J KER (SEN)hypertension, Cardiomyopathy, Cardiovascular Physiology

DR J LAwRENSONPaediatric heart Disease

PROF A LOChNERBiochemistry/Laboratory Science

PROF BM MAyOSIChronic Rheumatic heart Disease

DR MT MPECardiomyopathy

PROF DP NAIDOOEchocardiography

PROF B RAyNERhypertension/Society

PROF MM SAThEKGENuclear Medicine/Society

PROF yK SEEDATDiabetes & hypertension

PROF h DU T ThERONInvasive Cardiology

AFRICA

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

Cardiovascular Journal of Africa www.cvja.co.za

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iNtErNatioNal advisory BoardPROF DAvID CELEMAJERAustralia (Clinical Cardiology)PROF KEITh COPELIN FERDINANDUSA (General Cardiology)DR SAMUEL KINGUECameroon (General Cardiology)DR GEORGE A MENSAhUSA (General Cardiology)PROF wILLIAM NELSONUSA (Electrocardiology)DR ULRICh vON OPPELwales (Cardiovascular Surgery)PROF PETER SChwARTzItaly (Dysrhythmias)PROF ERNST vON SChwARzUSA (Interventional Cardiology)

pUBlisHiNg coNsUltaNtMike Gibbs

Editorial295 Metabolic syndrome: a definition dilemma

A Ghosh

cardiovascUlar topics297 prevalence of asymptomatic left ventricular systolic dysfunction in hypertensive

Nigerians: echocardiographic study of 832 subjectsOS Ogah • RO Akinyemi • GD Adegbite • OI Udofia • SB Udoh • JO Adesina • OS Ojo • AA Alabi • T Majekodunmi • JKL Osinfade • RF Ogundipe • AO Falase

303 prevalence of the metabolic syndrome in people of asian indian origin: outcomes by definitionsM Das • S Pal • A Ghosh

306 down syndrome and congenital heart disease: why the regional difference as observed in the libyan experience?z Elmagrpy • A Rayani • A Shah • E habas • Eh Aburawi

310 diagnosis and follow up of patients with primary cardiac tumours: a single-centre experience of myxomasS Manduz • N Katrancioğlu • O Karahan • O yucel • MB yilmaz

313 role of stromal-derived factor-1<alpha>/cXcr4 in neo-intimal repairJ Sheng • w-w Cai • N-y Fang • S-Q wang • J-J wu

319 the effect of mebudipine on cardiac function and activity of the myocardial nitric oxide system in ischaemia–reperfusion injury in ratsR Ghyasi • M Mohammadi • R Badalzadeh • B Rashidi • G Sepehri

324 analysis of omega-3 fatty acid content of south african fish oil supplementsMaretha Opperman • De wet Marais • AJ Spinnler Benade

MaNagiNg EditorJULIA AALBERSTel: 021 976 4378Fax: 086 610 3395e-mail: [email protected]

prodUctioN EditorShAUNA GERMIShUIzENTel: 021 785 7178Fax: 086 628 1197e-mail: [email protected]

Editorial assistaNt & circUlatioNELSABÉ BURMEISTERTel: 021 976 8129e-mail: [email protected]

dEvElopMENt EditorGLENDA hARDyCell: 071 8196 425e-mail: [email protected]

prodUctioN co-ordiNatorwENDy wEGENERTel: (021) 976-4378e-mail: [email protected]

gaUtENg coNtriBUtorPETER wAGENAARCell 082 413 9954e-mail : [email protected]

Editorial BoardThe Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published six times a year, the deemed publication date being the seventh day of the second designated month, i.e. 7 February, 7 April, 7 June, 7 August and 7 October.

COPyRIGhT: Clinics Cardive Publishing, Pty, Ltd.

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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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330 potential increasing rates of hypertension in women of childbearing age and during pregnancy – be prepared!J Moodley

casE rEports335 a rare complication after coronary artery bypass graft surgery: ogilvie’s syndrome

A Guler • MA Sahin • K Atilgan • M Kurkluoglu • U Demirkilic

337 anaesthesia for emergency caesarean section in a patient with peripartum cardiomypathyB Osinaike • J Ogah

340 diagnostic assessment of prosthetic mitral valve thrombosis by real-time three-dimensional transoesophageal echocardiography and successful thrombolytic treatment h Morais • T Martins • J Roberto • F Cáceres-Lóriga

drUg trENds344 dramatic reductions in plaque volumes on maximum statin therapy

345 raft of rivaroxaban good news from the Usa, implications for south african clinical practice

348 Medical devices in cardiovascular medicine

pUBlisHEd oNliNE (Available on www.cvja.co.za and in Pubmed) a giant pericardial cyst

İ KaklikkayaDOI: 10:5830/CvJA-2010-076

right common iliac artery stenosis and stent insertion in Behçet’s diseasez Ulusan • AS Karadag • A harman • F Boyvat • S BilgicDOI: 10:5830/CvJA-2010-077

percutaneous closure of a tricuspid paravalvular leak with an aamplatzer duct occluder ii via antegrade approachA Iyisoy • h Kursaklioglu • T Celik • O Baysan • M CelikDOI: 10:5830/CvJA-2010-079

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011AFRICA 295

Editorial

the metabolic syndrome: a definition dilemma ARNAB GhOSh

The metabolic syndrome (MS) is a common phenotype asso-ciated with an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Although there is no universally accepted definition for the MS, affected individu-als commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidaemia and dysglycaemia.1-4

The first formal definition of the MS was proposed by the World Health Organisation (WHO) in 1999. In the same year, the European Group for the Study of Insulin Resistance (EGIR) suggested a similar definition to that of the WHO, but excluded the microalbuminuria and diabetes components. In 2001, the United States National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) published a more practical definition for the MS, which eliminated insulin resistance as a criterion.1

A few years later, in 2005, the cut-off point for fasting plasma glucose was lowered, resulting in the modified NCEP ATP III (modified ATP III) definition.2 In 2005, the International Diabetes Federation (IDF) proposed a new definition for the MS, which made abdominal obesity, classified by ethnic-specific cut-off points, a necessary condition for the MS. In 2007, the IDF presented a definition of the MS for use in children and adolescents, thus becoming the first major organisation to do so.

Throughout the Asia-Pacific region, there are differences in the prevalence of obesity and metabolic disturbances. People of Indian origin (PIO) are ethnically a particularly vulnerable group from the standpoint of metabolic abnormalities.3 Keeping this in mind, researchers in the Indian diaspora are now using South Asian Specific (SAS) cut offs to define the MS in people of Indian origin.

The SAS definition of the MS is otherwise similar to the modi-fied ATP III with the exception of cut offs for waist circumfer-ence (WC) (lower vs modified ATP III) and triglycerides (higher vs modified ATP III). However, it is noteworthy to mention that whether using the modified ATP III or SAS definition of the MS, a large number of individuals may be misclassified due to lack of a common minimum platform required to better comprehend the problem in people of Indian origin.3-5

Although widely used in epidemiological research, there has been ongoing concern that the WC cut-off points in the modi-fied ATP III definition, which were predominantly intended for Americans, might not be appropriate for other ethnic groups, such as Asian Indians. South Asians (e.g. Asian Indians) have a more centralised distribution of body fat and a markedly higher mean waist–hip ratio (WHR) for a given level of body mass index (BMI) compared to Europeans.5 In Asian popula-tions, morbidity and mortality is occurring in people with lower BMI and smaller WC. Therefore they tend to accumulate intra-abdominal fat without developing generalised obesity.4,5

Although the IDF definition of the MS in most instances failed to identify a subgroup of subjects who had the highest risk for CVD, before the IDF’s definition of the MS, the effect of ethnicity on the individual criteria for diagnosing the MS was not considered. Recently, comparisons of the prevalence of the MS between different ethnic groups have raised concerns about the validity of the WHO, NCEP ATP III, modified ATP III and IDF definitions when applied across different ethnic groups. The originally accepted criteria for the MS were based on risk prediction in non-Asian populations.6 However, recent data from the Asian population, including Asian Indians, indicate that these definitions may not be satisfactory for risk prediction.3

Although genetics most likely plays a crucial role in develop-ment of the MS, elucidating the exact genes involved has been hindered by the lack of a consistent definition of the MS,7 the varying combination of phenotypes even within a single defini-tion, ethnic disparities, and gender influences. Recently, a large body of literature has emerged on early-life origins of the risk for the MS and associated diseases, such as coronary heart disease (CHD). Findings that experiences during the individual’s whole lifetime affect risk for disease highlight the need for an approach to understanding ethnic differences considering these early childhood conditions.

Moreover, research on the MS among children and adoles-cents and the implications of having the MS is limited. Because the roots of many adult chronic diseases originate in childhood, establishing a universally agreed definition of the MS in children and adolescents may help to identify children and adolescents who are at high risk for developing the MS, and allow for early prevention of possible adverse health events in early adulthood.

Differences in the prevalence of the MS and its components using the various definitions, both within and between popula-tions, indicate that caution is required when comparing studies from different countries.7 Determining the clinical significance of these differences will require prospective outcome studies. Furthermore, to make the definition of the MS more sensitive, factors such as family history, habitual physical activity and smoking, along with region-specific cut offs for individual MS components are required to better comprehend the MS.4-7

ARNAB GhOSh, PhD, [email protected] of Anthropology, Biomedical Research Laboratory, Visva Bharati University, Sriniketan, West Bengal, India

References1. NCEP. Executive summary of the third report of the National

Cholesterol Education Program (NCEP): expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011296 AFRICA

Treatment Panel III). J Am Med Assoc 2001; 285: 2479–2486.2. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin

BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (executive summary). Circulation 2005; 112: e285–e290.

3. Misra A, Chowbey P, Makkar BM, Vikram NK, Wasir JS, Chadha D, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommenda-tions for physical activity, medical and surgical management. J Assoc Physicians India 2009; 57: 163–170.

4. Ghosh A. Comparison of risk variables associated with metabolic

syndrome in pre- and postmenopausal Bengalee women. Cardiovasc J Afr 2008; 19: 183–187.

5. Ghosh A. Interrelationship of waist circumference and subcutaneous fat with metabolic and blood pressure measures among Asian Indian men. Anthropol Anz 2007; 65: 75–85.

6. Ghosh A, Liu T, Khoury MJ, Valdez R. Family history of diabetes and prevalence of the metabolic syndrome in U.S. adults without diabetes: 6-year results from the national health and nutrition examination survey (1999–2004). Publ Hlth Genomics 2010; 13: 353–359.

7. Das M, Pal S, Ghosh A. Prevalence of metabolic syndrome in people of Asian Indian origin: outcomes by definitions. Cardiovasc J Afr 2011; 22(6): 303–305.

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cardiovascular topics

prevalence of asymptomatic left ventricular systolic dysfunction in hypertensive Nigerians: echocardiographic study of 832 subjectsOS OGAh, RO AKINyEMI, GD ADEGBITE, OI UDOFIA, SB UDOh, JO ADESINA, OS OJO, AA ALABI, T MAJEKODUNMI, JKL OSINFADE, RF OGUNDIPE, AO FALASE

abstractBackground: We sought to determine the prevalence of echocardiographically determined left ventricular systolic dysfunction in asymptomatic hypertensive subjects seen in Abeokuta, Nigeria.Methods: Echocardiography was performed in 832 consecu-tive hypertensive subjects referred for cardiac evaluation over a three-year period. Results: Data were obtained in 832 subjects (50.1% women) aged 56.0 ± 12.7 years (men 56.9 ± 13.3 years, women 55.0 ± 12.0 years, range 15–88). The prevalence of left ventricular systolic dysfunction (LVSD) was 18.1% in the study popula-tion (mild LVSD = 9.6%, moderate LVSD = 3.7% and severe LVSD = 4.8%). In a multivariate analysis, male gender, body mass index and LV mass were the predictors of LVSD.Conclusion: Significant numbers of hypertensive subjects in this study had varying degrees of left ventricular systolic dysfunction. Early introduction of disease-modifying drugs in these patients, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers may retard or prevent the progression to overt heart failure.

Keywords: hypertension, echocardiography, systolic dysfunc-tion, Nigeria

Submitted 19/9/09, accepted 16/8/10

Cardiovasc J Afr 2011; 22: 297–302 www.cvja.co.za

DOI: 10.5830/CVJA-2010-063

High blood pressure affects about a billion people worldwide.1-3 It has been predicted that by 2025, more than 1.5 billion adults will have hypertension.1-3 In the year 2001, hypertension was esti-mated to be responsible for 7.6 million premature deaths world-wide (13.5% of total global mortality) and it was also responsible for 92 million disability-adjusted life years (DALYs).1-3 The condition has been rightly described as the foundation of cardio-vascular disease in sub-Saharan Africa.4 The overall prevalence has been put at 10 to 15% but rates as high as 30 to 32% have been reported.5

Hypertension and its complications are responsible for about 25% of urban hospital medical admissions in Nigeria,6 as well as for over 80% of cardiac clinic consultations in the country. It is the most frequently diagnosed medical illness in elderly popula-tions7 and senior executives.8

High blood pressure is also by far the commonest cause of chronic renal failure, stroke, heart failure and sudden unexpected death in Nigeria.9

In Nigeria, the prevalence of asymptomatic left ventricular systolic dysfunction (LVSD) among people with hypertension is unknown. The aim of the study was therefore to determine the prevalence of asymptomatic LVSD in hypertensive subjects in Abeokuta, Nigeria.

MethodsThe study was conducted at the Federal Medical Centre (FMC), Idi-Aba and the Sacred Heart Hospital (SHH), Lantoro, both in Abeokuta, the capital city of Ogun State in south-western Nigeria. FMC was established in 1993 by the federal government of Nigeria to cater for the health needs of the people of Ogun State and its environs in south-western Nigeria. The state has a population of about 3.2 million and a surface area of about 16 409.26 km2. SHH is one of the oldest hospitals in Nigeria, estab-lished in 1897 by the German Catholic Mission.

Cardiological services commenced in the city in September 2005 and since then a registry of patients and services rendered has been kept. A cardiologist (OSO) covers the two cardiac units,

department of Medicine, Federal Medical centre, idi-aba, abeokuta, ogun state, NigeriaOS OGAh, AIMLS, FMLS, MSc, [email protected] AKINyEMI, MBBSJO ADESINA, MBBSJKL OSINFADE, MBBS, FwACPRF OGUNDIPE, MBBS, FMCP

department of Medicine, sacred Heart Hospital lantoro, abeokuta, ogun state, NigeriaGD ADEGBITE, MDOI UDOFIASB UDOhOS OJO, MBBSAA ALABI, MBBS

division of adult congenital Heart disease, department of cardiology, royal Brompton Hospital, london, United KingdomT MAJEKODUNMI, MBBS, PhD, MRCP

department of Medicine, University of ibadan, oyo state, NigeriaAO FALASE, MBBS, MD, FMCP, FwACP, FRCP


which are about 5 km apart, assisted by senior medical officers and postgraduate resident doctors and well as nurses. Facilities available for cardiac evaluation include chest radiography, 12-lead electrocardiography (ECG), exercise ECG, Holter ECG, ambulatory blood pressure-monitoring devices, spirometry and echocardiography (ECHO).

This was a cross-sectional study, conducted within a three-year period. Hypertensive patients were eligible for the study if they fulfilled the following criteria: (1) no evidence of valvular abnormality. This was based on clinical examination and absence of features of valvular heart disease at echocardiography; (2) absence of congestive heart failure based on previous history of admission for heart failure or symptoms and signs of heart fail-ure in the past or at the time of evaluation, using the Framingham criteria; (3) absence of sickle cell disease based on self-report-ed haemoglobin electrophoretic pattern of the subject and/or absence of stigmata of the disease; (4) absence of self-reported history of renal failure or serum creatinine ≥ 2 mg/dl; (5) absence of ischaemic heart disease based on history, as well as absence of ischaemic ECG changes at the time of the study (other than left ventricular hypertrophy with strain pattern); (6) other exclusion criteria included morbid obesity, pulmonary heart disease (cor pulmonale), chest abnormality that obscured echo-window and left bundle branch block pattern on the 12-lead ECG.

Using a simple questionnaire, a nurse screened the patients for history or symptoms of these and history of previous hospital admissions relating to the exclusion criteria. All the echocardiog-raphy request forms were also assessed for evidence of exclusion criteria. Fig. 1 shows how the patients were selected for final analysis. Both treated and untreated hypertensive subjects were recruited. Hypertension was defined according to international criteria.10

Baseline clinical and demographic characteristics were obtained from the subjects. These included date of birth, age, gender and history of diabetes. Blood pressure measurements were obtained according to standard guidelines,11 with a mercury sphygmomanometer (Accosson London). Systolic and diastolic blood pressures were measured at Korotkoff sounds phases I and V, respectively. Blood pressure was measured three times on the right arm, after a five-minute rest, and averaged. Subjects were weighed without shoes and in light clothing on a standard beam balance. Height was measured to the nearest centimetre using an anthropometrical plane with the subjects without shoes or head-gear. Body mass index (BMI) was calculated using the formula: BMI = weight (kg)/height (m)2. Body surface area (BSA) was calculated using the formula of Dubois.12

M-mode, two-dimensional (2-D) and Doppler echocardiogra-phy were performed using a standard protocol and an ALOKA SSD 4000 echocardiography machine (Aloka Co, Ltd, Tokyo, Japan). Two-dimensional guided M-mode measurements were made according to the recommendations of the American Society of Echocardiography (ASE).13 Left ventricular internal dimension, posterior wall thickness and interventricular septal thickness were measured at end-diastole and end-systole. Where optimal M-mode imaging could not be obtained, 2-D linear measurements were obtained according to the ASE criteria.13 Left atrial end-systolic diameter was obtained from the trail-ing edge of the posterior aortic–anterior left atrial complex. Measurements were obtained in up to three cardiac cycles, according to the ASE convention.13

One experienced cardiologist performed all the echocardiog-raphy. In our laboratory, the intra-observer concordance correla-tion coefficient and measurement error have been reported.14

Left ventricular systolic performance (LVSP) was assessed using the fractional shortening of the left ventricle and the ejection fraction. Left ventricular ejection fraction (LVEF) was calculated using the Teichholz formula.15 Fractional shortening was calculated from LV internal dimensions in diastole and systole:

Fractional shortening = LVIDd – LVIDsLVID

× 100

Left ventricular mass (LVM) was calculated using the formula of Devereux and Reichek.16 This has been shown to yield LVM closely related to autopsy measurements (r = 0.90)17 and it had good inter-observer reproducibility (p = 0.93) in one study.18 Relative wall thickness (RWT) was derived from 2 × posterior wall thickness/LV internal diameter.

Left ventricular hypertrophy (LVH) was defined by LV mass indexed by allometric signal (height2.7) > 51 g/m2.7.19 This partition value of 51 g/m2.7 was used since this was the only criterion that demonstrated as the optimal threshold value for left ventricular hypertrophy in blacks, irrespective of gender, in two previous studies. Left ventricular systolic function was categorised as follows:20 normal LV function, EF ≥ 50%; mild LVSD, EF 40–49%; moderate LVSD, EF 30–39%; and severe LVSD, EF < 30%.

Statistical analysisSPSS version 11.0 software (SPSS, Chicago, IL, USA) was used in the analysis of the data. Continuous variables were expressed as mean ± SD, while categorical variables were expressed as counts (percentages). Comparison between the two groups was assessed with the Student’s t-test for independent variables, while the χ2 analysis was used to compare proportions. Analysis of variance (ANOVA) with Scheffe’s post hoc test was used for the comparison of multiple groups. A two-tailed p-value of 0.05 was assumed statistically significant.

resultsA total of 832 subjects, 415 men (49.9%) and 417 women (50.1%) were eligible for analysis. Fig. 1 shows the criteria for selection of subjects for analysis.

The overall mean age of the population was 56.0 ± 12.7 years (range 15–88). Fig. 2 is a histogram showing the age distribu-Fig. 1. criteria for selection of the subjects for analysis.

1406 individuals were referred for evaluation of their Lv function or assessment for presence of Lvh

832 subjects (417 women and 415 men eligible for final analysis

546 subjects with hypertensive heart failure or symptoms of heart failure and 28 individuals with imcomplete data were excluded


tion of the subjects. The majority of the subjects fell within the middle-aged group, with a peak age of 50 years. Forty-six subjects (5.5%) had a self-reported history of diabetes (25 men, 6.0% and 21 women, 5.0%).

Tables 1 and 2 show the clinical and demographic charac-teristics of the subjects in the men and women, respectively. Patients with LVSD were older. Those with normal left ventricu-lar systolic function (LVSF) were heavier and had a larger body surface area. Diastolic blood pressure as well as mean arterial blood pressure were higher in individuals with severe LVSD.

Normal LVSF, defined as ejection fraction (EF) ≥ 50% was present in 89.9% of the subjects. The remaining 18.1% had LVSD (mild 9.6%, moderate 3.7% and severe 4.8%). Figs 3 and 4 depict the distribution of the subjects according to LVSF and gender.

Men had a higher prevalence of LVSD than women (24.4 and 12.3%, respectively) and this was statistically significant (p < 0.0001). Compared with individuals with normal LVSF

TABLE 1. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF THE MALE SUBJECTS

Parameter Normal LVSF Mild LVSD Moderate LVSD Severe LVSDANOVAp-value

Age (years) 56.4 (13.8) 62.7 (9.0) 58.9 (12.5) 61.5 (16.8) 0.039

Weight (kg) 77.9 (15.5) 72.3 (14.8)* 63.0 (14.8)* 68.2 (20.0)* 0.0001

Height (cm) 169.0 (7.4) 169.8 (5.3) 166.4 (9.1) 167.5 (8.2) NS

BMI (kg/m2) 27.3 (5.0) 25.0 (4.7)* 22.6 (5.9)* 24.3 (7.0)*∞ 0.0002

BSA (m2) 1.88 (0.19) 1.83 (0.18)* 1.69 (0.24)*∞ 1.76 (0.23)* 0.0001

Systolic BP (mmHg) 84.5 (14.9) 81.2 (11.1) 83.4 (12.4) 88.9 (13.8) NS

Diastolic BP (mmHg) 91.0 (14.9) 84.2 (12.7)* 85.6 (11.5) 99.0 (15.9)*∞ 0.018

Pulse pressure (mmHg) 57.0 (17.3) 57.8 (17.3) 59.4 (19.5) 53.9 (16.1) NS

MAP (mmHg) 110.0 (15.9) 103.4 (14.7)* 105.4 (11.9) 116.9 (29.0)∞ 0.024

BMI = body mass index, BSA = body surface area, BP = blood pressure, MAP = mean arterial pressure. NS = not significant, *p < 0.05 versus normal LVSF, ∞p < 0.05 versus mild LVSD.

TABLE 2. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF THE FEMALE SUBJECTS


Age (years) 56.4 (13.3) 60.1 (10.1) 60.1 (13.5) 55.4 (17.0) NS

Weight (kg) 76.2 (14.9) 74.5 (154.6) 64.2 (16.4) 71.0 (19.9) NS

Height (cm) 168.4 (7.5) 169.2 (9.4) 166.3 (9.1) 167.6 (7.7) NS

BMI (kg/m2) 26.9 (4.9) 26.4 (7.8)* 23.1 (5.4)∞ 25.2 (6.3)∞ 0.007

BSA (m2) 1.86 (0.19) 1.84 (0.17) 1.71 (0.22) 1.79 (0.24)*∞ 0.001

Systolic BP (mmHg) 147.2 (22.3) 142.0 (21.7) 143.2 (19.1) 148.5 (33.5) NS

Diastolic BP (mmHg) 90.4 (14.7) 85.1 (12.5)* 85.5 (11.0) 98.5 (24.9) 0.002

Pulse pressure (mmHg) 57.4 (16.5) 57.6 (17.1) 58.5 (18.7) 52.1 (17.5) NS

MAP (mmHg) 110.2 (16.0) 103.5 (14.5) 105.5 (11.3) 116.3 (28.2) 0.023

BMI = body mass index, BSA = body surface area, BP = blood pressure, MAP = mean arterial pressure. NS = not significant, *p < 0.05 versus normal LVSF, ∞p < 0.05 versus mild LVSD.

Fig. 3. distribution of lvsF.

Normal lvF 81.9%

Mild lvsd 9.6%

Moderate lvsd 3.7%

severe lvsd 4.8%

Fig. 4. distribution of lvsF according to gender.

100

80

60

40

20

0pe

rcen

tsevere lvsd

Moderate lvsd

Mild lvsd

Normal lvsF

Female Malelv function

Fig. 2. Histogram of the age distribution of the subjects.

200

100

0

Freq

uenc

y

age in years15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

std dev = 12.71

Mean = 56.0

n = 832.00


or mild LVSD, those with severe LVSD were older, more likely to be men, had larger left atrial diameter, larger LV dimensions and LV mass, and as expected, lower fractional shortening and ejection fraction. This finding was consistent in both genders and progressed from normal LVSF to severe LVSD (Tables 3, 4).

We developed a linear regression model for the whole popula-tion (as the pattern was similar in both genders). LVEF was used as the dependent variable, while independent variables were taken from clinical variables (age, gender, body mass index, body surface area) and echocardiographic variables [left atrial diameter, LV internal dimensions, LV mass, relative wall thick-ness (RWT)] that were significant in the univariate analysis.

Although LV dimensions were significantly related to LVEF in the univariate analysis, they were not added in the final model since these parameters were used in the determination of LVM.

Categorical variables such as gender and presence or absence of diabetes mellitus were entered as indicator variables. None of the blood pressure variables were significant in the univariate analysis.

In the univariate analysis, EF was related to age [B (unstand-ardised regression coefficients) = –0.84, b (standardised regres-sion coefficient) = –0.72, p = 0.036]; gender (B = –5.42, b = –1.84, p < 0.0001); BMI (B = 0.31, b = 0.13, p = 0.0002); left atrial diameter (B = –5.72, b = –0.25, p < 0.0001); end-diastolic diameter (B = –7.70, b = –0.45, p < 0.0001), end-systolic diam-eter (B = –11.97, b = –0.76, p ≤ 0.0001); LVM (B = –0.48, b = –0.32, p < 0.0001); and RWT (B = 14.38, b = 0.19, p < 0.0001).

In a multivariate analysis, lower LVEF was independently related to BMI, gender, LV mass, left atrial diameter and relative wall thickness.

TABLE 3. LV FINDINGS IN MALE SUBJECTS ACCORDING TO FUNCTIONAL STATUS


AO diameter (cm) 3.10 (0.44) 3.25 (0.41)* 3.07 (0.39) 3.15 (0.45) NS

LA diameter (cm) 3.78 (0.58) 4.03 (0.58)* 4.34 (0.79)* 4.45 (0.67)* < 0.0001

IVSd (cm) 1.20 (0.31)∞ 1.32 (0.25) 1.13 (0.23)∞ 1.20 (0.34) NS

IVSs (cm) 1.59 (0.39) 1.47 (0.33) 1.30 (0.16)* 1.41 (0.48)* 0.0003

LVIDd (cm) 4.67 (0.69) 5.24 (0.86)* 6.11 (0.98)*∞ 6.06 (1.11)*∞ < 0.0001

LVIDs (cm) 3.01 (0.61) 4.15 (0.88)* 5.07 (0.87)*∞ 5.20 (1.13)*∞ < 0.0001

PWTd (cm) 1.28 (0.36) 1.27 (0.41) 1.29 (0.31) 1.32 (0.41) NS

PWTs (cm) 1.85 (0.38) 1.66 (0.37)* 1.61 (0.39)*∞ 1.66 (0.43)∞ 0.0003

FS (%) 35.7 (8.0) 21.1 (7.1)* 17.0 (4.5)*∞ 14.4 (8.3)*∞ < 0.0001

EF (%) 65.9 (9.3) 45.0 (2.8)* 33.6 (2.5)*∞ 23.5 (7.0)*∞ < 0.0001

LVM (g) 221.0 (91.2) 286 (121.6)* 337.1 (122.1)*∞ 356.4 (169.6)*∞ < 0.0001

LVM/BSA (g/m2) 119.6 (48.6) 155.3 (62.9)* 201.8 (78.3)*∞ 203.0 (99.9)*∞ < 0.0001

LVM/HT2.7 (g/m2.7) 54.3 (22.1) 68.9 (27.0)* 85.6 (29.8)*∞ 89.7 (45.1)*∞ < 0.0001

AO = aortic root, LA = left atrium, IVSd = interventricular septum in diastole, IVSs = interventricular septum in systole, LVIDd = left ventricular internal diameter in diastole, LVIDs = left ventricular internal diameter in systole, PWTd = posterior wall thickness in diastole, PWTs = posterior wall thickness in systole, FS = fractional shortening, EF = ejection fraction, LVM = left ventricular mass, BSA = body surface area, HT = height.NS = not significant, *p < 0.05 vs normal LVSF, ∞p < 0.05 vs mild LVSD.

TABLE 4. LV FINDINGS IN FEMALE SUBJECTS ACCORDING TO FUNCTIONAL STATUS


AO diameter (cm) 3.08 (0.44) 3.22 (0.42) 3.07 (0.39) 3.15 (0.45) NS

LA diameter (cm) 3.75 (0.58) 4.01 (0.56)* 4.34 (0.79)* 4.45 (0.67)* < 0.0001

IVSd (cm) 1.20 (0.31)∞ 1.33 (0.25) 1.13 (0.23)∞ 1.20 (0.34) 0.027

IVSs (cm) 1.57 (0.38) 1.47 (0.32) 1.30 (0.16)* 1.20 (0.34)* 0.0006

LVIDd (cm) 4.63 (0.71) 5.25 (0.87)* 6.11 (1.00)* 6.06 (1.11)* < 0.0001

LVIDs (cm) 2.99 (0.62) 4.17 (0.85)* 5.07 (0.87)* 5.20 (1.13)* < 0.0001

PWTd (cm) 1.27 (0.52) 1.24 (0.40) 1.29 (0.31) 1.66 (0.43) NS

PWTs (cm) 1.84 (0.38) 1.67 (0.36)* 1.61 (0.39)* 1.66 (0.43) 0.0003

FS (%) 35.6 (7.9) 21.0 (6.6)* 17.0 (4.5)* 14.4 (8.3)* < 0.0001

EF (%) 65.9 (9.3) 44.7 (2.7)* 33.5 (2.5)* 23.5 (2.5)*∞ < 0.0001

LVM (g) 145.7 (38.3)* 174.3 (73.0)* 198.1 (77.5) 218.3 (48.8)* < 0.0001

LVM/BSA (g/m2) 113.5 (45.9) 128.3 (48.8) 145.7 (38.3)* 174.3 (73.0)*∞ 0.0001

LVM/HT2.7 (g/m2.7) 56.5 (22.5) 64.023.6)* 73.4 (18.2)* 81.8 (30.5)*∞ < 0.0001

AO = aortic root, LA = left atrium, IVSd = interventricular septum in diastole, IVSs = interventricular septum in systole, LVIDd = left ventricular internal diameter in diastole, LVIDs = left ventricular internal diameter in systole, PWTd = posterior wall thickness in diastole, PWTs = posterior wall thickness in systole, FS = fractional shortening, EF = ejection fraction, LVM = left ventricular mass, BSA = body surface area, HT = height. NS = not significant, *p < 0.05 vs normal LVSF, ∞p < 0.05 vs mild LVSD.


discussionHypertension is the commonest cardiovascular disease in Nigeria and sub-Saharan Africa. It is the commonest risk factor for heart failure, stroke and chronic renal impairment. In Nigeria and most African countries, the majority of patients first present with evidence of target-organ damage such as overt heart failure. Most often, overt heart failure is preceded by asymptomatic left ventricular systolic dysfunction. Information on the prevalence and burden of both symptomatic and asymptomatic LVSD is based on population studies as well as studies done in hyperten-sive subjects in Europe and America.21-23

The burden of LVSD (symptomatic or asymptomatic) in hypertensive subjects is largely unknown in Nigeria and in most African countries, hence the reason for the present study. Echocardiographic methods have been shown to provide a high yield of quantitative measurement of LV function and can be used to assess the determinants of LV function, both in hyperten-sive and general populations.

The main findings of the study are: the majority of our hyper-tensive patients fell within the middle-aged group with a peak age of 50 years, about 18% of our hypertensive subjects had asymptomatic LVSD, the prevalence of LVSD was higher in men than in women, LVSD increased with age, although LVSD was independent of age, and the main predictors of LVSD were male gender, body mass index, left ventricular mass and LV relative wall thickness.

All over sub-Saharan Africa, the peak age of presentation of cardiovascular diseases such as hypertension has been well defined.24-26 As in the present study, most patients are within the age group of 40 to 60 years, often with a peak age of 45 to 50 years, as observed in this study. The implication is that where complications arise, it is usually associated with high DALYs, with a huge impact on the socio-economic growth of the family and nation, as the population affected is in the prime of life. This is contrary to the situation in developed countries where most cardiovascular diseases manifest after the age of 65 years.

In a univariate analysis, age was related to LVEF. However, when other factors such as gender, LV mass, relative wall thick-ness and BMI were factored in, the association with age became insignificant. The plausible reason for this is that the impact of age on LVSF is probably mediated through other factors. Our finding is similar to the report of other workers.22,23,27,28

The study shows that the prevalence of impaired LVSF is about twice as common in men as in women. In a multivariate analysis, male gender was found to be an independent predictor of impaired LVSF. This is similar to the findings of authors in studies done in hypertensive subjects or in the general popula-tion.21-23,28 The reasons for this are not clear but it is well known that cardiovascular diseases generally occur earlier in men than in women. In our setting, women are also more likely to attend follow-up clinics as well as take their medication as prescribed.

Tables 1 and 2 show that diastolic blood pressure and mean arterial blood pressure were higher in the group with severe LVSD compared to other groups. No significant difference was found in the systolic blood pressure and pulse pressure among the groups.

In univariate and multivariate analyses, blood pressure was not found to be related to LVSF. This finding is similar to that of Devereux et al.,22 but at variance with studies done in the general population, where the relationship of blood pressure with LVSF

persisted in the multivariate analysis.21,29,30 This may be may be due to the fact that most of our patients were on antihypertensive medications.

In this study, BMI was found to decrease from subjects with normal LVSF to those with severe LVSD (although the lowest BMI was in those with moderate LVSD in both men and women). The impact of BMI persisted in the multivariate analy-sis. This relationship between LVSF and BMI was also reported by Devereux et al.22 Because our population was relatively lean, one plausible reason for the finding may be the known relation-ship between chronic LVSD and weight loss (cardiac cachexia).

In a univariate analysis, we did not find any relationship between LVSD and the presence of diabetes in this study. This is at variance with the report by some workers.21,22 The reason for the negative finding in our study may be that we relied on self-reported history of diabetes. Many more subjects with diabetes could have been detected if metabolic profiles were run in our study subjects.

The left atrial size was found to be independently related to LVSF. The larger the left atrium, the poorer the LVSF. Similar findings have been reported by other investigators.31,32 Left atrial size is a known strong marker or surrogate of left diastolic func-tion. The latter is known to have a positive relationship with LVSF.33,34

Limitations of the studyWe noted the following limitations with this study. It was a hospital-based study and may not reflect the situation in the general population. We did not run metabolic profile functions (blood glucose, lipid, uric acid, insulin levels, etc) in the present study, as was done in studies in industrialised nations, due to lack of funds

Newer measures of assessment of LVSF such as LV mid-wall shortening, circumferential end-systolic measurements as well as measures of arterial wall stiffening (pulse pressure/stroke index) were not assessed in our study. Absence of ischaemic heart disease was only assessed based on clinical history and 12-lead ECG. This may not exclude sub-clinical ischaemic heart disease.

conclusionsLVSD, assessed as ejection fraction < 50%, was detected in 18.1% of our hypertensive population, who did not have symp-toms of overt heart failure. Male gender, body mass index, LVM and relative wall thickness were found as independent predictors of LVSF in our study.

Significant numbers of hypertensive subjects in this study had varying degrees of left ventricular systolic dysfunction. Early introduction of disease-modifying drugs in these patients, such as angiotensin converting enzyme inhibitors/angiotensin receptor blockers may retard or prevent the progression to overt heart failure.

It must be stated that since echocardiography is expensive, it cannot be placed as the first line of systematic screening of hypertensive patients, however, the predictive factors of LVSD are accessible to primary-care physicians. For instance, the combination of male gender and obesity should draw the atten-tion of clinicians to the possible presence of LVSD, a pathogenic precursor of heart failure.


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5. Addo J, Smeeth L, Leon DA. Hypertension in sub-Saharan Africa: a systematic review. Hypertension 2007; 50(6): 1012–1018.

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7. Ogunniyi A, Baiyewu O, Gureje O, et al. Morbidity pattern in a sample of elderly Nigerians resident in Idikan community, Ibadan. West Afr J Med 2001; 20(4): 227–231.

8. Okojie OH, Isah EC, Okoro E. Assessment of health of senior execu-tives in a developing country. Publ Hlth 2000; 114(4): 273–275.

9. Ogah OS. Hypertension in sub-Saharan African populations: the burden of hypertension in Nigeria. Ethn Dis 2006; 16(4): 765.

10. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc 2003; 289(19): 2560–2572.

11. American Society of Hypertension. Recommendations for routine blood pressure measurement by indirect cuff sphygmomanometer. Am J Hypertens Suppl 1992: 207–209.

12. Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916; 17: 863–871.

13. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regard-ing quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978; 56: 1072–1083.

14. Ogah OS, Adebanjo AT, Otukoya AS, Jagusa TJ. Echocardiography in Nigeria: use, problems, reproducibility and potentials. Cardiovasc Ultrasound 2006; 4: 13.

15. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocar-diographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37(1): 7–11.

16. Devereux RB, Reichek N. Echocardiographic determination of LVM in man: anatomic validation of the method. Circulation 1977; 5: 613–618.

17. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assess-ment of left ventricular hypertrophy:comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458.

18. Palmieri V, Dahlof B, De Quattro V, et al. Reliability of echocar-diographic assessment of left ventricular structure and function. The PRESERVE study. J Am Coll Cardiol 1999; 34: 1625–1632.

19. Roman MJ. How best to identify prognostically important left ventricu-lar hypertrophy. J Am Coll Cardiol 1997; 29: 648–650.

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21. Devereux RB, Roman MJ, Paranicas M, et al. A population-based assessment of left ventricular systolic dysfunction in middle-aged and older adults: the Strong Heart study. Am Heart J 2001; 141(3): 439–446.

22. Devereux RB, Bella JN, Palmieri V, et al. Left ventricular systolic dysfunction in a biracial sample of hypertensive adults: the Hypertension Genetic Epidemiology Network (HyperGEN) study. Hypertension 2001; 38(3): 417–423.

23. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban popula-tion. Lancet 1997; 350(9081): 829–833.

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25. Mayosi BM. Contemporary trends in the epidemiology and manage-ment of cardiomyopathy and pericarditis in sub-Saharan Africa. Heart 2007; 93(10): 1176–1183.

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27. Rodeheffer RJ, Jacobsen SJ, Gersh BJ, et al. The incidence and preva-lence of congestive heart failure in Rochester, Minnesota. Mayo Clin Proc 1993; 68(12): 1143–1150.

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29. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. J A Med Assoc 1996; 275(20): 1557–1562.

30. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prog-nosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 1995; 26(7): 1565–1574.

31. Adebiyi AA, Aje A, Ogah OS, Ojji DB, Oladapo OO, Falase AO. Left ventricular diastolic function parameters in hypertensives. J Natl Med Assoc 2005; 97(1): 41–45.

32. Zamora E, Lupon J, Lopez-Ayerbe J, et al. [Left atrium diameter: a simple echocardiographic parameter with high prognostic value in heart failure]. Med Clin (Barc) 2007; 129(12): 441–445.

33. Spevack DM, Blum L, Malhotra D, et al. Ratio of left atrial to left ventricular size: an anatomical marker of the diastolic left ventricular pressure-volume relationship. Echocardiography 2008; 25(4): 366–373.

34. Chinali M, de Simone G, Liu JE, et al. Left atrial systolic force and cardiac markers of preclinical disease in hypertensive patients: the Hypertension Genetic Epidemiology Network (HyperGEN) Study. Am J Hypertens 2005; 18(7): 899–905.

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prevalence of the metabolic syndrome in people of asian indian origin: outcomes by definitionsM DAS, S PAL, A GhOSh

abstractBackground: The prevalence of the metabolic syndrome (MS) is high among south Asian Indians. In order to better comprehend the MS, its definition and modifications require region-specific cut-off values and common minimum criteria for people of Indian origin.Methods: To define the MS, the criteria as defined in the National Cholesterol Education Program (NCEP): expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) (ATP III 2001), followed by the modified ATP III of 2005 were used, along with a modified version specific to the people of south Asian origin (ATP III SAS, 2009).Results: The three definitions showed differences in preva-lence of the MS among the adult Asian Indians. According to the criteria of NCEP ATP III 2001, the prevalence was found to be 32.3%. Using the modified ATP III 2005, the prevalence was 48.3%, and for south Asian-specific (SAS) ATP III, it was 31.4%. For all three definitions, females had a considerably higher prevalence of the MS than males. It was also observed that that a large number of individuals were misclassified due to lack of common minimum criteria.Conclusion: In order to curb the growing threat of the MS, and to aid clinical management among people of Indian origin, a more comprehensive definition of the MS is urgently required.

Keywords: obesity, metabolic syndrome, CVD, diabetes, Asian Indians



DOI: 10.5830/CVJA-2010-070

People of Indian origin are ethnically a particularly vulner-able group from the standpoint of metabolic abnormalities. Throughout the Asia–Pacific region, there are differences in the prevalence of obesity and metabolic disturbances. South Asians (e.g. Indians) have a more centralised distribution of body fat and

a markedly higher mean waist–hip ratio (WHR) for a given level of body mass index (BMI) compared to Europeans. In Asian populations, morbidity and mortality is occurring in people with lower BMI and smaller waist circumference (WC). Therefore they tend to accumulate intra-abdominal fat without developing generalised obesity.1,2

The metabolic syndrome (MS), which can be defined as the constellation of cardiovascular disease (CVD) risk factors, is one of the growing public health burdens in the Asia–Pacific region, although the populations are no more overweight than Europeans and Americans.1 The MS is a phenotype and there-fore is used to identify subjects with a high risk, based on easily measurable biological variables. However, it lacks some critical variables, which are population specific, in order to better predict the population’s risk. It therefore needs further validation among Asian Indians.3,4

The present work was an attempt to study the prevalence of the MS using different definitions of the MS in people of Indian origin.

MethodsThe cross-sectional study comprised 350 adult Asian Indians (≥ 30 years) (184 males and 166 females) living in and around Calcutta, India. Written consent was obtained from all participants. The institutional ethics committee of the Human Genetic Engineering Research Center (HGERC), Calcutta, India approved the study. Written consent from participants was also obtained prior to actual commencement of the study.

Anthropometric measures, namely height, weight and waist circumference were obtained using standard techniques.5 BMI (kg/m2) was computed accordingly.

Left arm systolic (SBP) and diastolic (DBP) blood pressure measurements were taken twice using a sphygmomanometer and stethoscope and were averaged for the analyses. A third meas-urement was taken only when the difference between the two measurements was ≥ 5 mmHg. Prior medical records for blood pressure were also taken into consideration.

A fasting blood sample (~7 ml) was collected from each subject for the determination of metabolic profiles. All subjects maintained an overnight fast of approximately 12 hours prior to blood collection. The serum was separated by centrifugation within two hours of collection. Determination of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) choles-terol and fasting blood glucose (FBG) levels was carried out on the separated serum using a semi-autoanalyser. Low-density lipoprotein (LDL) cholesterol was then calculated using the standard formula:

LDL = TC – (HDL + TG/5).

All biochemical parameters were analysed at the HGERC and were measured in mmol/l.


Definition of the metabolic syndromeTo define the metabolic syndrome, the criteria as set out in the National Cholesterol Education Program (NCEP): expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) (ATP III, 2001),6 followed by the ATP III as modified in 2005,7 were used, plus the modified version specific to the people of south Asian origin (ATP III SAS 2009).8-10 These criteria were as follows: • waist circumference: male > 90 cm; female > 80 cm• triglycerides: ≥ 2.25 mmol/l• HDL: male < 1.03 mmol/l; female < 1.29 mmol/l• blood pressure: SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg• fasting blood glucose: ≥ 5.56 mmol/l.

Statistical analysesParameters were expressed as mean and standard deviation (SD), separately for males and females in the study population. The prevalence (%) of the MS and its confounding factors were calculated using standard cut-off values. All statistical analyses were performed using SPSS (PC + version 10.0).

resultsThe mean and standard deviation by gender of obesity values, lipid profiles and blood pressure is presented in Table 1. It was observed that males had significantly (p < 0.05) higher mean total cholesterol and fasting blood glucose values (p < 0.01) than females.

The difference in prevalence of the MS according to the three definitions is presented in Table 2. Using the original ATP III (2001) definition, the overall prevalence of the MS in the study was found to be 32.3%. However, according to the ATP III modified criteria (2005), the prevalence was found to be 48.3% among the participants. When the south Asian-specific cut-off values were taken into consideration, the prevalence was found to be 31.4%.

Out of five confounding factors, the three factors playing a crucial role were high abdominal obesity (61.1%), low HDL

cholesterol (50.9%) and high blood pressure (63.7%). It was also observed that for all three definitions (NCEP ATP III 2001, ATP III modified 2005, and ATP III SAS 2009), female participants had a considerably higher prevalence of the MS compared to male subjects (Fig. 1).

discussionIt was observed that the prevalence of the MS was different, depending on the three definitions used. Moreover, the preva-lence of elevated triglyceride levels (hypertriglyceridaemia), which is a distinctive feature of people of Indian origin, varied considerably in the study population owing to the use of the south Asian-specific cut-off value for elevated triglycerides. The marked difference in the overall prevalence of the MS from the ATP III (2005) definition to the SAS (2009) definition (48.3 vs 31.4%) was due to the use of the south Asian-specific cut-off values for WC and triglyceride levels. Importantly, whether the modified ATP III (2005) or the revised SAS (2009) definition is used, a large number of individuals are likely to be misclassified due to lack of a common minimum criterion required to better comprehend the problem of the MS among Asian Indians.

Several other studies have shown such discrepancies, not only in the Indian population but also in other Asian countries, such as China and Iran. In a study from India,10 the World Health Organisation (WHO), ATP III and IDF criteria of the MS identi-fied a differential prevalence of the MS in the study population. The WHO criteria identified a greater number of coronary artery disease (CAD) subjects in males, but not in females.10

Studies pertaining to Asian Indians revealed that the ATP III criteria identified a significantly higher proportion of people with the MS compared with the WHO criteria.11,12 It was mentioned that lower cut-off values of WC and BMI to define the MS might be critical for the accurate assessment of the MS among Asian Indians. Moreover, inclusion of BMI and making WC a non-obligatory criterion, more cases of the MS were detected. However, for Asian Indians, making WC a mandatory

TABLE 2. PREVALENCE (%) OF METABOLIC SYNDROME PHENOTYPES BY DEFINITIONS

Factors ATP III 2001 ATP III 2005 SAS 2009

Waist circumference (cm) 30.9 61.1 61.1

Triglycerides (mmol/l) 39.7 39.7 2.3

High-density lipoprotein (mmol/l) 50.9 50.9 50.9

Blood pressure (mmHg) 63.7 63.7 63.7

Fasting blood glucose (mmol/l) 10.0 21.7 21.7

Metabolic syndrome (%) 32.3 48.3 31.4

SAS = South Asian specific.

TABLE 1. DESCRIPTIVE STATISTICS OF THE STUDY POPULATION (n = 350)

Variables

Male (n = 184) Female (n = 166) Total (n = 350)

Mean SD Mean SD Mean SD

Age (years)** 54.04 12.40 48.48 11.57 51.40 12.31

BMI (kg/m2) 22.37 4.09 23.20 4.37 22.76 4.24

WC (cm) 89.81 10.04 88.90 9.69 89.38 9.87

SBP (mmHg) 132.97 24.02 137.21 24.52 134.98 24.31

DBP (mmHg) 82.22 11.41 83.48 10.55 82.82 11.01

TC (mmol/l)* 2.23 0.31 2.24 0.26 2.27 0.29

TG (mmol/l) 1.61 0.30 1.57 0.25 1.59 0.28

HDL (mmol/l) 1.13 0.12 1.13 0.11 1.13 0.12

LDL (mmol/l) 3.39 0.70 3.25 0.59 3.32 0.65

VLDL (mmol/l) 0.32 0.006 0.31 0.005 0.31 0.005

FBG (mmol/l)** 5.17 1.30 4.92 0.93 5.05 1.15

BMI = body mass index; WC = waist circumference; WHR = waist–hip ratio; SBP = systolic blood pressure; DBP = diastolic blood pressure; TC = total cholesterol; TG = triglyceride; HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein; FBG = fasting blood glucose. Significant gender difference at *p < 0.05; **p < 0.01.

Fig. 1. prevalence of the metabolic syndrome by defini-tions and gender.

706050403020100

%

atp iii 2001

atp iii modified 2005

atp iii sas 2009

FemaleMale


5. Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics, 1988.

6. NCEP. Executive summary of the third report of the National Cholesterol Education Program (NCEP): expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2479–2486.

7. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (executive summary). Circulation 2005; 112: e285–e290.

8. Das M, Pal S, Ghosh A. Synergistic effects of ACE (I/D) and ApoE (HhaI) gene polymorphisms among the adult Asian Indians with and without metabolic syndrome. Diab Res Clin Prac 2009; 86: e58–61.

9. Ho SC, Chen YM, Woo JL, Leung SS, Lam TH, Janus ED. Association between simple anthropometric indices and cardiovascular risk factors. Int J Obes Relat Metab Disord 2001; 25: 1689–1697.

10. Deepa M, Farroq S, Datta M, Deepa R, Mohan V. Prevalence of metabolic syndrome using WHO, ATPIII and IDF definitions in Asian Indians: the Chennai Urban Rural Epidemiology Study (CURES-34). Diab Metab Res Rev 2007; 23:127–134.

11. Kanjilal S, Shanker J, Rao VS, Khadrinarasimhaih NB, Mukherjee M, Iyengar SS, Kakkar VV. Prevalence and component analysis of meta-bolic syndrome: an Indian atherosclerosis research study perspective. Vasc Hlth Risk Manag 2008; 4:189–197.

12. Wasir JS, Misra A, Vikram NK, Pandey RM, Gupta R. Comparison of definitions of the metabolic syndrome in adult Asian Indians. J Assoc Physicians India 2008; 56: 158–164.

13. Tong PC, Kong AP, So WY, Yang X, Ho CS, Ma RC, et al. The usefulness of the International Diabetes Federation and the National Cholesterol Education Program’s Adult Treatment Panel III defini-tions of the metabolic syndrome in predicting coronary heart disease in subjects with type 2 diabetes. Diabetes Care 2007; 30:1206–1211.

14. Zabetian A, Hadaegh F, Azizi F. Prevalence of metabolic syndrome in Iranian adult population, concordance between the IDF with the ATP-III and the WHO definitions. Diab Res Clin Prac 2007; 77: 251–257.

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down syndrome and congenital heart disease: why the regional difference as observed in the libyan experience?z ELMAGRPy, A RAyANI, A ShAh, E hABAS, Eh ABURAwI

abstract Background: Children with Down syndrome (DS) have about a 40 to 50% incidence of congenital heart disease (CHD). The objectives of this study were to evaluate the distribution and frequency of CHD patterns in Libyan children with DS.Methods: All patients with DS who were referred to the cardiology clinic between January 1995 and December 2008 were reviewed. Results: Of the 1 193 patients reviewed, 537 (45%) had an associated CHD. Overall there were 349 (65%) patients who had a single cardiac lesion, and 188 (35%) had multiple cardiac lesions. The most common isolated cardiac lesion was atrial septal defect (ASD), found in 125 (23%) patients, followed by atrioventricular septal defect (AVSD) in 103 (19%), and ventricular septal defect (VSD) in 76 (14%). Conclusion: Atrial septal defect was the most common cardi-ac lesion. The distribution of CHDs in Libyan children with DS was similar to what has been reported internationally, but the frequency was not compared with international rates.

Keywords: congenital heart disease, Down syndrome, geograph-ical difference, Libya



DOI: 10.5830/CVJA-2010-072

Down syndrome (DS) or trisomy 21 is a chromosomal disorder frequently associated with a varied combination of morphologi-cal and structural birth defects. These defects are in the form of congenital mental disability, hypotonia, characteristic body features, heart defects, and other systemic congenital malforma-tions. The frequency and severity of these morphological and functional defects vary significantly among affected individuals. The incidence of moderate to severe forms of congenital heart disease (CHD) in Libya is about 5/1 000 live births.1

In 1866, John Langdon Haydon Down first characterised DS as a distinct disease with intellectual impairment.2 In the late fifties, Lejeune and Jacobs independently reported that DS resulted from an extra chromosome 21. Since then the condi-tion has been known as trisomy 21.3,4 This particular trisomy is the most common form of chromosomal abnormality, affecting about one in 700 live births.5,6 It is characterised by the whole chromosomal aneuploidy in about 95% of cases. The remaining 5% is in the form of translocations and mosaics.7 The risk of pregnancy with DS increases with the mother’s age, and it can occur with a frequency as high as one in 30 in those older than 45 years.8

Approximately 40 to 60% of children with DS have heart defects and among those with CHD, four to 10% are associated with DS.9 The cardiac defects are commonly single, but they can be multiple as well. It is highly recommended that DS patients be referred early for cardiac screening. Chest infection, CHD, blood disorders, leukaemia and lymphoma are not uncommon causes of death.10,11 Nowadays, almost all CHD in DS patients are surgi-cally manageable, with good results. Moreover, the postoperative morbidity and mortality associated with cardiac surgery has fallen dramatically in recent years due to advances in intensive care units, peri-operative care and improved treatment related to respiratory illnesses.12,13

The aim of this study was to determine the mode of presenta-tion, and type and distribution of CHD affecting DS patients in Libya, and to compare this with previously reported studies.

MethodsIn a retrospective descriptive study, medical records of clinically diagnosed DS patients were reviewed. There were 1 193 children with DS who had presented to Alfateh University Children’s Hospital, Tripoli, between January 1995 and December 2008. After detailed histories and thorough physical examinations were recorded, two-dimensional echocardiography and Doppler stud-ies were performed using the ALOKA SSD-800 before 2005, and the Philips EnVisor C HD, Philips Medical Systems after 2005.

The data were analysed by descriptive statistics, using Microsoft Excel and Minitab version 16 statistical software pack-ages. Previously reported literature was reviewed to compare our results with the international geographical distribution of cardiac defects in patients with DS.

resultsThere were 1 193 patients with DS who attended the cardiac clinic and of these, 537 (45%) had CHD. The male-to-female ratio was 1:1.4. The reasons for presentation are given in Table 1, with the commonest being routine screening (44%). Cardiac

the children’s Hospital, Faculty of Medicine, alfateh Medical University, tripoli, libyaz ELMAGRPy, MDA RAyANI, MDA ShAh, MD

Medical department, Faculty of Medicine, alfateh Medical University, tripoli, libya E hABAS, MD

department of paediatrics, Faculty of Medicine and Health science, United arab Emirates University, al-ain, United arab EmiratesEh ABURAwI, MD, MSc, FRCPCh, FACC, PhD, [email protected]


murmur was the reason for referral in 177 (33%) patients, heart failure in 62 (12%), chest infection in 36 (7%), and cyanosis in 19 patients (4%).

Of the overall number of patients with CHD, 349 (65%) had a single cardiac lesion, whereas the remaining 188 (35%) had multiple defects. The most common single defect was atrial septal defect (ASD), which was found in 125 (24%) patients, followed by atrioventricular septal defect (AVSD) in 103 (19%), and ventricular septal defect (VSD) in 76 (14%) cases. Patent ductus arteriosus (PDA) occurred in 28 (5%) cases.

Other common defects such as combined ASD plus VSD with other complex lesions was found in 77 (14%) patients, VSD plus PDA was found in 42 (8%), and 40 (7%) had ASD plus PDA. PDA was the most common cardiac defect associated with other cardiac lesions. It was found in association with VSD and ASD in 82 patients (15%) (Table 2).

The median age (range) at diagnosis with ASD was three months (three days – 15 years) and for those with complex and mixed cardiac lesions it was four months (two days – 18 years) (Table 2). The rare associations of complex CHD were those of double-outlet right ventricle and transposition of the great arter-ies in two patients, pulmonary atresia with VSD in one patient and a combination of complete atrioventricular septal defect with tetrology of Fallot in three patients.

discussionApproximately 50% of the patients evaluated for DS had an asso-ciated CHD. This finding is similar to internationally reported figures.9 ASD of secondum type was the most common single congenital cardiac defect and was found in 125 of the 537 DS patients (24%). This finding was not consistent with what has previously been reported in Europe, Sudan and the USA, where ASD was reported to occur in only 5% of the DS patients in Europe and Sudan and 8% in the USA patients.14-16 ASD of secondum type has been reported in Mexico in 38% and Saudi Arabia in 21% of patients with DS.17,18 These high distributions are similar to that in our report.

In most of the European countries, Sudan, Turkey and the USA, AVSD was the most common cardiac defect.14-16,19 In Asia on the other hand, VSD was the most common single cardiac defect, followed by ASD or AVSD.18,20,21 In our series, AVSD with a common atrioventricular valve was the second most common CHD, found in 103 (19%) patients. In Guatemala, PDA (29%) followed by VSD (28%) were the most common cardiac defects22

The isolated cardiac lesions represented about 65% of all CHD in our study, compared with 80% in Guatemala,22 74% in Mexico,17 and 78% in Turkey19 (Table 3). Furthermore, patients’ age at diagnosis with ASD was younger than those with complex and other associated cardiac lesions. This minimised the possible bias that patients with more complex lesions died earlier before diagnosis, compared with those with ASD.

On reviewing the literature (Table 3), it appears that the frequency and distribution of CHD in DS varies in different geographical regions. The reason for this difference in the

TABLE 1. CARDIAC EVALUATIONS OF THE PATIENTS STUDIED

Number 537

M:F ratio 1:1.4

Reason for cardiac evaluation

Screening 237 (44%)

Murmur 177 (33%)

Heart failure 62 (12%)

Cyanosis 19 (4%)

Chest infection 36 (7%)

Others 6 (1%)

Age at diagnosing CHD

0–1 months 149 (28%)

> 1–6 months 230 (43%)

> 6 months – 1 year 66 (12%)

> 1–3 years 44 (8%)

> 3–5 years 18 (3%)

> 5–10 years 19 (4%)

> 10–18 years 11 (2%)

CHD, congenital heart disease.

TABLE 2. THE FREQUENCY AND TYPES OF CONGENITAL HEART DISEASE

Cardiac lesions Patients, n = 537 (%) Age* M:F ratio

Single lesion 349 (65%) 4 months (3 days –18 years) 1:1.4

ASD 125 (23%) 3 months (3 days –15 years) 1.1:1

AVSD 103 (19%) 3 months (3 days – 12 years) 1:1.6

VSD 76 (14%) 4 months (4 days – 14 years) 1:1

PDA 28 (5%) 5 months (1 moth – 18 years) 1:2

TOF 13 (2%) 3 months (3 weeks – 9 months) 1:1

COA 4 (1%) 5 months (1 week – 6 months) 1:0.3

Multiple lesions 188 (35%) 4 months (2 days – 18 years) 1:1.4

ASD with VSD plus others 77 (14%) 1 year (2 days – 18 years) 1:1.5

VSD with PDA plus others 42 (8%) 1.5 months (1–3 months) 1:0.8

ASD plus PDA with others 40 (7%) 4 months (1.5 months – 1.5 years) 1:0.8

ASD with pulmonary stenosis 11 (2%) 30 days (4 days – 3 years) 1:3

Other rare associations 19 (4%) 2 months (2 days – 2 years) 1:1

ASD, atrial septal defect; AVSD, atrioventricular septal defect; VSD, ventricular septal defect; PDA, patent ductus arteriosus; TOF, tetralogy of Fallot; CoA, coarctation of aorta.*Median (range) age at diagnosing congenital heart disease.


distribution of CHD among DS patients is not clear, although some consistency is observed between certain global areas. This variation in geographical distribution may be caused by numer-ous factors, one of which could be the genetic make up of each nation or global region; or it could be due to specific embryo-logical mechanisms.

Types of CHD can also be determined by cell characteristics in each nation or population.23 The embryology and anatomy of VSD, ASD and PDA are quite different from that of AVSD.24-26 Some publications have suggested that ethnicity and different geographic factors, such as high altitude with lower partial pressures of oxygen may contribute to a higher frequency of PDA.17,27,28 However, these hypotheses need to be tested by further large-scale multinational collaborative studies.

The most common mode of presentation of CHD in DS was the routine referral to cardiology clinics, but only 44% of the cases were presented in this manner. There were 62 patients (12%) who presented with heart failure; this was probably due to the fact that these patients were missed or not referred at an earlier age for cardiac screening. This stresses the importance of early referral to cardiac clinics.1,29

The mother’s age is an important risk factor for DS, with the risk of giving birth to a child with DS increasing from 1 in 1 250 at age 25, to 1 in 1 000 at age 30, to 1 in 400 at age 35, to 1 in 100 at age 40, to 1 in 30 at age over 45 years.30 Nevertheless, about 80% of infants with DS are born to mothers who are under 35 years of age.28 In our series, CHD was more common in children whose mothers were in the age range of 31 to 45 years (71%), which is comparable with international figures. In addition, the single and multiple cardiac lesions were nearly doubled in those of older mothers.

On the other hand, there was no specific association between ASD and mothers’ ages. Interestingly, we found tetrology of Fallot in 13 children of mothers who were over 30 years of age, and not in younger mothers. Coarctation of the aorta is unusual in patients with DS; however, we found this to occur in 1% of the cases, which is similar to a previous report from the USA.15

There are a number of limitations in our study, such as the fact that the figures reported herein are not population based, and any patients with DS who died at home or at other hospitals and had never been diagnosed with CHD were not included. Moreover,

cytogenetic studies were not routinely performed on all patients because diagnosis was mainly based on clinical grounds. Due to poor organisation and infrastructure at our cardiac centre in previous years, we were unable to accompany the presented figures with any surgical results. Irrespective of these limita-tions, we believe that we have made some progress in document-ing the distribution of CHD in Libyan children with DS.

conclusionThis is the first study to document the types, distribution and frequency of CHDs in Libyan children with DS. ASD was the most common single cardiac lesion in DS. The distribution of CHDs in Libyan children with DS was similar to what has been reported internationally but the frequency was not compared with international rates. We stress the importance of early refer-ral and screening for CHDs in this group of patients.

References1. Aburawi EH. The burden of congenital heart disease in Libya. Libyan

J Med 2006; 1: 120–122.2. Down JLH. Observations on an ethnic classification of idiots. Clinical

Lecture Reports. London Hospital 1866; 3: 259–262.3. Lejeune J. Le mongolisme. Premier example d’aberration autosomique

humaine. Ann Genet 1959; 1: 41–49.4. Jacobs PA, Baikie AG, Court Brown WM, Strong JA. The somatic

chromosomes in mongolism. Lancet 1959; 1: 710.5. Hoffman JI. Incidence of congenital heart disease. J Am Coll Cardiol

2002; 39: 1890–1900. 6. Hoffman JI. Incidence, mortality and natural history. Paediatric

Cardiology, 2nd edn. Philadelphia: Churchill Livingstone, 2002; 1: 111–131.

7. Hamertone JL, Briggs SM, Giannelli F, Carter CO. Chromosome stud-ies in detection of parents with high risk of second child with Down syndrome. Lancet 1961; 2: 788–791.

8. Hoe TS, Chan KC, Boy NY. Cardiovascular malformations in Malasian neonates with Down syndrome. Singapore Med J 1990; 31: 474–476.

9. Stoll C, Alembik Y, Dott B, Roth MP. Study of Down syndrome in 238,942 consecutive births. Ann Genet 1998; 41: 44–51.

10. Laursen HB. Congenital heart disease in Down syndrome. Br Heart J 1976: 38: 32–38.

11. Tubman TR, Shields MD, Craig BG, Mulholland HC, Nevin NC. Congenital heart disease in Down syndrome: two years prospective early screening study. Br Med J 1991; 302: 1425–1427.

12. Roussot MA, Lawrenson JB, Hewitson J, Smart R, de Decker H P. Is cardiac surgery warranted in children with Down syndrome? A case-controlled review. S Afr Med J 2006; 96: 926–930.

13. Kabbani MS, Giridhar S, Elbarbary M, Elgamal MA, Najm H, Godman M. Postoperative cardiac intensive care outcome for Down syndrome children. Saudi Med J 2005; 26: 943–946.

14. Placidi S, Digilio MC, Marino B. Types of cardiac defects in children with Down’s syndrome. Cardiol Young 2006; 16: 198–199.

15. Ali SK. Cardiac abnormalities of Sudanes patients with Down syndrome and their short-term outcome. Cardiovasc J Afr 2009; 20: 112–115.

16. Freeman SB, Taft LF, Dooley KJ, Allran K, Sherman SL, Hassold TJ, et al. Population based study of congenital heart defects in Down syndrome. Am J Med Genet 1998; 80: 213–217.

17. De Rubens Figueroa J, del Pozzo Magaña B, Pablos Hach JL, Calderón Jiménez C, Castrejón Urbina R. Heart malformations in children with Down syndrome. Rev Esp Cardiol 2003; 56: 894–899.

18. Abbag FI. Congenital heart diseases and other major anomalies in patients with Down syndrome. Saudi Med J 2006; 27: 219–222.

19. Nisli K, Oner N, Candan S, Kayserili H, Tansel T, Tireli E, et al. Congenital heart disease in children with Down’s syndrome: Turkish experience of 13 years. Acta Cardiol 2008; 63: 585–589.

20. Lo NS, Leung PM, Lau KC, Yeung CY. Congenital cardiovascular

TABLE 3. COMPARISON OF CONGENITAL HEART DISEASES IN LIBYAN TRISOMY 21 PATIENTS

(n = 537) WITH OTHER NATIONS

CardiopathyASD %

AVSD %

VSD %

PDA %

TOF %

CoA %

Others %

Libya 24 19 12 4 2 1 39

Mexico17 38 9 30 21 1 0 1

Guatemala22 13 10 28 29 0 0 22

Saudi Arabia18 21 23 33 14 5 0 4

India21 12 3 26 5 16 0 39

China20 13 15 44 12 13 0 2

Italy14 5 55 25 5 6 0 4

USA16 8 45 35 7 4 1 1

Sudan15 5 48 23 7 6 0 11

ASD, atrial septal defect; AVSD, atrioventricular septal defect; VSD, ventricular septal defect; PDA, patent ductus arteriosus; TOF, tetral-ogy of Fallot; CoA, coarctation of aorta.


malformations in Chinese children with Down’s syndrome. Chin Med J (Engl) 1989; 102: 382–386.

21. Kava MP, Tullu MS, Muranjan MN, Girisha KM. Down syndrome: clinical profile from India. Arch Med Res 2004; 35: 31–35.

22. Vida VL, Barnoya J, Larrazabal LA, Gaitan G, Garcia FM, Castaneda AR. Congenital cardiac disease in children with Down’s syndrome in Guatemala. Cardiol Young 2005; 15: 286–290.

23. Ferencz CH, Neill C, Boughman J, Rubin J, Brenner J, Perry L. Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr 1989; 114: 79–86.

24. Park SC, Mathews AR, Zuberbuhler RJ, Rowe RD, Neches WH, Cora CL. Down syndrome with congenital heart malformation. Am J Dis Child 1977; 131: 29–33.

25. Marino B, Vairo U, Corno A, Nava S, Guccione P, Calabro R, et al.

Atrioventricular canal in Down syndrome. Am J Dis Child 1990; 144: 1120–1122.

26. Evans PR. Cardiac anomalies in mongolism. Br Heart J 1950; 12: 258–262.

27. Velásquez T, Martínez C, Pezzia W, Gallardo N. Ventilatory effects of oxygen in high altitude natives. Respir Physiol 1968; 5(1): 211–220.

28. Diaz GF, Velez J. Ductus arteriosus. In: Diaz GF, Sandoval N, Velez JF, Carrillo G (eds). Cardiologia Pediatrica. Bogota: McGraw-Hill 2003: 296–313.

29. American Academy of Pediatrics Committee on Genetics. Health Supervision for Children with Down syndrome. Pediatrics 2001; 107: 442–449.

30. American College of Obstetricians and Gynecologists (ACOG). Your Pregnancy and Birth, 4th edn. Washington, DC: ACOG, 2005.

international society of cardiovascular disease Epidemiology and prevention

44th 10-day international teaching seminar on cardiovascular disease

Epidemiology and prevention

15–27 January 2012

cape town, south africa

The International Society of Cardiovascular Disease Epidemiology and Prevention announces the 44th 10-day international teaching seminar on cardiovascular disease epidemiology and prevention to be held 15–27 January 2012 in Cape Town, South Africa in conjunction with the South African Medical Research Council and the University of Cape Town.

Approximately 36 fellows can be accepted. The Society’s seminar committee will make the final selection. Nominees should ideally be at the postgraduate level with residency training or its equivalent, and be interested in cardiovascular disease epidemiology.

Normally, preference is given to younger candidates, with little or no formal training in epidemiology. Tuition, board and accommodation are provided without cost to fellows. Fellows and their sponsors are responsible for their own travel costs to the seminar. Should any accepted fellow be unable to attend, no substitute not reviewed by the seminar committee may be sent as an alternate by the institution.

FlUENcy iN ENglisH is aN aBsolUtE EssENtial

Applications, including (1) a letter of nomination by the chief of department or institution, or other relevant sponsor, (2) a personal letter of application from the nominee, and (3) the applicant’s curriculum vitae, should be received before 15 September 2011 by the seminar coordinator, address below. Applications can be sent by e-mail but a signed hard copy should follow in the post.

Professor Kay-Tee Khaw,Clinical Gerontology Unit, PO Box 251University of Cambridge School of Clinical Medicine,Addenbrooke’s Hospital,Cambridge CB2 2QQ,England

Fax: +44-1223-336928Tel: +44-1223-217292

e-mail: [email protected]


diagnosis and follow up of patients with primary cardiac tumours: a single-centre experience of myxomasS MANDUz, N KATRANCIOGLU, O KARAhAN, O yUCEL, MB yILMAz

abstractObjective: In this study, 12 patients who were diagnosed as having cardiac tumours and were operated on in the Department of Cardiovascular Surgery following referral from the Department of Cardiology were enrolled between January 1995 and October 2007. Methods: The symptoms, clinical findings, diagnostic meth-ods, localisation of masses and surgical applications were recorded retrospectively. Results: There were 10 female (83%) and two (17%) male patients; their ages ranged from 35 to 70 years (mean 68.7 years). Twelve patients were diagnosed with myxomas, nine of which were located within the left atrium and three in the right atrium. The most common symptoms at clinical presentation were those associated with heart failure or embolisation. Diagnosis of the tumours was made by echo-cardiography in all patients. The masses were completely resected in eight patients and the interatrial septae were partially excised with mass resection in two patients. The defect was reconstructed with a pericardial patch in one of the patients, and primarily reconstructed in the other. We carried out debridement with mass resection in another case. Femoro–popliteal aorto–iliac thrombo-endarterectomy was performed with mass resection in a further case. Conclusion: Atrial myxomas are the most common primary cardiac tumours. They can cause valvular or inflow–outflow tract obstruction, thrombo-embolism, arrhythmias, or peri-cardial disorders. Most atrial myxomas are benign but due to non-specific symptoms, early diagnosis may be a challenge and they must be removed by surgical resection. Diagnosis and follow up with the collaboration of cardiology and cardiovascular surgery departments is important for meticu-lous care of these patients.

Keywords: myxoma, diagnosis, surgery



DOI: 10.5830/CVJA-2010-073

Primary cardiac tumours are rare. Their prevalence ranges from 0.0017 to 0.28% in various autopsy series, and they are up to 20

times less frequent than are secondary tumours of the heart.1,2 The prevalence of primary cardiac tumours other than benign myxomas is even lower.1-3 In 1954, Clarence Crafoord removed an intra-atrial myxoma for the first time. Echocardiography has enabled better visualisation of the cardiac structures and accurate diagnosis.4

Approximately 75% of sporadic myxomas occur in females. Myxomas have been reported in patients aged three to 83 years.3-5 They are rarely seen in children, accounting for only nine to 15% of all cardiac tumours from birth to adolescence.5

Early diagnosis and surgical removal of the tumour with decreased mortality and morbidity is related to the symptoms produced, such as tumour embolism, heart failure, mechanical valvular obstruction, and various constitutional symptoms.6 We retrospectively reviewed our case series with particular attention to myxomas.

MethodsIn this study, 12 patients who suffered from myxomas were diagnosed and operated on in the Departments of Cardiology and Cardiovascular Surgery, respectively, between January 1995 and October 2007. Symptoms, clinical findings, diagnostic methods, localisation of the mass and surgical application were evaluated retrospectively.

Echocardiographic examinations were performed by an expe-rienced echocardiographer using available ultrasound equipment (GE-Vivid 4 with a 3.5 MHz transducer, Wisconsin, USA) at baseline, and as required during follow up. Pre-operative coro-nary angiography was performed in patients with known or suspected coronary artery disease.

resultsThere were 10 female (83%) and two (17%) male patients; their ages ranged from 35 to 70 years (mean 68.7 years). All patients were diagnosed as having myxomas on pathological verification. Nine of these myxomas were in the left atrium and three were in the right atrium. All myxomas were sporadic. The most common symptoms at clinical presentation were those associated with cardiac insufficiency or embolisation. There was haemoptysis in one patient with bronchiectasis.

Diagnosis of the tumours was made by echocardiography before surgery in all patients (Fig. 1). Computed tomography and angiocardiography were also used in some of the patients as required. The masses were completely resected in eight patients and the interatrial septae were partially excised with mass resec-tion in two patients (Fig. 2). The defect was reconstructed with a pericardial patch in one patient and primarily reconstructed in the other. We carried out debridement with mass resection in another case. Femoro–popliteal aorto–iliac thrombo-endarterec-tomy was performed with mass resection in a further case and the embolectomy material was confirmed as a myxoma. Coronary

department of cardiovascular surgery, Faculty of Medicine, cumhuriyet University, sivas, turkeyS MANDUz, MD N KATRANCIOGLU, MDO KARAhAN, MD, [email protected]

department of cardiology, Faculty of Medicine, cumhuriyet University, sivas, turkeyO yUCEL, MD MB yILMAz, MD


artery bypass surgery was performed in a patient with coronary artery disease (Table 1).

The minimum follow-up period was 12 months and the maximum was 132 months (median, 60 months). One of the patients with myxoma died in the early postoperative period due to cerebrovascular accident.

In some of the cases, pleural effusion was detected with computed tomography and chest X-ray (Fig. 3). We used abdom-inal and peripheral Doppler ultrasound in case 12, and found a subacute thrombus which totally obstructed the abdominal aorta, extending 3 cm in the proximal part down to the bifurcation and including 4 cm proximally in the common femoral artery. The details of the cases are presented in Table 1.

discussionCardiac myxomas most commonly occur in the third to fourth decade of life, and approximately 75% of sporadic myxomas occur in females.2 They frequently occur in the left atrium in 75% of cases. The right atrium is involved in 15 to 20% of cases. There is no difference in terms of frequency of involvement of the ventricles (6–8%).2 There were 10 female (83%) and two (17%) male patients. In addition, left atrial involvement was observed in 67% of the cases in our study, in accordance with the current literature.

Cardiac myxomas originate from primitive, multipotential mesenchymal cells present in the heart wall as embryonic remnants. Histopathologically, a myxoma is composed of an abundant acid mucopolysaccharide matrix in which polygonal cells and immature endothelial cells forming blood vessels are embedded in chronic inflammation.5,7,8 Masses from the 12 cases in our study were histopathologically typical of myxomas.

Myxomas cause peripheral embolisms, in which fragments of the tumour break away into the blood stream and cause clots or blockages. Systemic embolism is encountered in 30 to 45% of myxoma cases.9-11 A massive embolism can cause death. There were two cases with femoral artery embolism in our series, which were confirmed on pathological evaluation. Fortunately, in our series, no patient had a cerebral embolism, which may have been fatal.

On the other hand, aneurysms may also occur in these patients, causing symptoms associated with central nervous system involvement.12 Therefore a careful examination for any symptom that could possibly be associated with nervous system involvement should be an essential part of the therapeutic approach.

An important aspect of our study was that the tumour was detected in all patients by echocardiography, which was performed due to the non-specific symptoms of the patients. Coronary angiography, however, was performed in older patients who were thought to have coronary artery disease. Echocardiographic follow up was done on a routine basis in the third, sixth and twelfth months and thereafter annually in all patients. We feel that routine echocardiographic follow up may help in earlier diagnosis and timely intervention to avoid neuro-logical sequelae.

Operative resection of the myxomas is the treatment of choice. Some authors believe that resection should be performed immediately after the diagnosis is made.2-4 We performed our operations immediately after the diagnosis.

conclusionThe development of diagnostic techniques and the routine practice of echocardiography have enabled us to define cardiac tumours earlier, important for both the initial diagnosis and for detecting a recurrence. Hence, mortality and morbidity were

Fig. 1. left atrial mass (4.8 × 7.5 cm) near the interatrial septum (case 2).

Fig. 2. Excised mass (case 2).

Fig. 3. ct report: 4 × 5-cm hypo-dense lesion (myxoma) that caused a filling defect in the right atrium.


quite low in our series. Untreated benign cardiac tumours can be distressing to both patient and physician.

Treatment of myxomas is usually done by surgical removal of the tumour. Complete resection, given the low operative mortal-ity rate that can be accomplished in experienced hands, and then follow up by serial echocardiography over five or six years to monitor for recurrences are crucial for an appropriate therapeutic approach, although late recurrences with neurological symptoms have been noted in the literature.12,13

References1. Parry AJ, Pillai R. Miscellaneous cardiac disease. In: Morris PJ, Malt

RA, eds. Oxford Textbook of Surgery. Oxford University Press, 1994: 1848–1854.

2. Reardon MJ, Smythe WR. Cardiac neoplasms In: Cohn LH, Edmunds LH (jun), eds. Cardiac Surgery in the Adult. 2nd edn. New York: McGraw-Hill, 2003: 1373–1400.

3. Giuliani ER, Piehler JM. Cardiac neoplasms. In: Catterjee K, Karliner J, Rapaport E, Cheitlin MD, Parmley WW, Scheinman M, eds. Cardiology. Philadelphia: JB Lippincott, 1991: 12.45–12.54.

4. Safaei N, Maghamipour N, Karimian E. Surgical experience with intra-cardiac myxomas. Acta Medica Iranica 2007; 45: 369–372.

5. Becker AE, Losekoot TG. Cardiac tumours. In: Andrson RH, Macartney

FJ, Shinebourne EA, Tynan M, eds. Paediatric Cardiology. Edinburgh: Churchill Livingstone, 1987: 1153–1161.

6. Lukács L, Lengyel M, Szedö F, Haán A, Nagy L, Thomka I. Surgical treatment of cardiac myxomas: A 20-year follow-up. Cardiovasc Surg 1997; 5: 225–228.

7. Kairemo KJA, Blomqvist CP, Miettinen M, Stern R, Reynen K, Daniel WG. Cardiac myxomas. N Engl J Med 1996; 334: 1407–1409.

8. Yin Z, Jones GN, Towns WH, Zhang X, Abel ED, Binkley PF. Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 2008; 117: 1414–1422.

9. Ha JW, Kang WC, Chung N, Chang BC, Rim SJ, Kwon JW. Echocardiographic and morphologic characteristics of left atrial myxo-ma and their relation to systemic embolism. Am J Cardiol 1999; 83: 1579–1582.

10. Larrieu AJ, Jamieson WR, Tyers GF, Burr LH, Munro AI, Miyagishima RT. Primary cardiac tumors: experience with 25 cases. J Thorac Cardiovasc Surg 1982; 83: 339–348.

11. Silverman J, Olwin JS, Graettinger JS. Cardiac myxomas with systemic embolization: review of the literature and report of a case. Circulation 1962; 26: 99–103.

12. Yilmaz MB, Akin Y, Guray U, Kisacik HL, Korkmaz S. Late recur-rence of left atrial myxoma with multiple intracranial aneurysms. Int J Cardiol 2003; 87: 303–305.

13. Grande AM, Ragni T, Viganò M. Primary cardiac tumors. A clinical experience of 12 years. Tex Heart Inst J 1993; 20: 223–230.

TABLE I. PRIMARY CARDIAC TUMOURS

Case Age GenderFinal

diagnosisPresenting symptom

BP (mmHg)

Pulse (beats/min) Rhythm NYHA

Diagnostic methods

Valve disease

Pericardial effusion Surgical procedure Outcome

1 35 F LA myxoma Dyspnoea 120/60 82 AF 2 Echo 2º MR2º TR

– Tumour resection Healing

2 70 M LA myxoma Dyspnoea + palpitations

110/60 88 Sinus rhythm

4 Echo + CAG

3º TR – Tumour resection Healing

3 65 F LA myxoma Dyspnoea + haemoptysis

130/70 116 AF 2 Echo + CAG

2–3º TR – Tumour resection Healing

4 58 F LA myxoma Pain and pares-tesia in right leg

130/70 90 AF 2 Echo 1º MR – Tumour resection + pericardial patch

Healing

5 35 F RA myxoma Eleve fever + palpitations


3 Echo 2º TR – Tumour resection + debridement

Healing

6 60 F RA myxoma + CAD

Fatigue + emesis


2 Echo + CAG

1º MR1º TR

– Off-pump LIMA–LAD bypass + tumour

resection

Healing

7 66 F LA myxoma Dyspnoea + palpitations

110/70 68 AF 3 Echo + CAG

2–3º TR + Tumour resection + tricuspid De Vega plasty

Healing

8 62 F RA myxoma Dyspnoea + ankle oedema


4 Echo + CAG

– – Tumour resection Died

9 61 M LA myxoma Dyspnoea + palpitations


2 Echo + CT – – Tumour resection Healing

10 57 F LA myxoma Pallor + pain bilaterally down extremities and

enuresis

120/70 115 AF 2 Echo + abdominal

CDUS

1º MR2º TR

Min AR

+ Tumor resection + femoro-popliteal

aorto-iliac thrombo-endarterctomy

Healing

11 60 F LA myxoma Dyspnoea + palpitations


3 Echo 2–3º MRMS

– Tumour resection + MVR

Healing

12 58 F LA myxoma Dyspnoea + fatigue


3 Echo 2º TR – Tumour resection + tricuspid De Vega plasty

Healing

RA = right atrial, LA = left atrial, AF = atrial fibrillation, Echo = echocardiography, CAG = coronary angiography, CT =computed tomography, CDUS = colour Doppler ultrasonography, MR = mitral regurgitation , TR = tricuspid regurgitation, AR = aortic regurgitation, MS = mitral stenosis, LIMA–LAD = left internal mammary artery–left anterior descending artery, De Vega plasty = De Vega’s tricuspid annuloplasty, MVR = mitral valve repair.


role of stromal-derived factor-1<alpha>/cXcr4 in neo-intimal repairJ ShENG, w-w CAI, N-y FANG, S-Q wANG, J-J wU

abstract Neo-intimal hyperplasia is one of the major causes of reste-nosis in which stromal cell-derived factor-1<alpha> (SDF-1a) and its receptor CXCR4 play an important role. In a rat common carotid artery balloon injury model, the number of CD34+CXCR4+ cells was significantly increased immediately after injury (p < 0.01), followed by a gradual decrease to baseline seven days after the injury. Furthermore, the plasma (SDF-1a) level was markedly elevated, and peaked 24 hours after injury (p < 0.01), followed by a rapid decrease to base-line level seven days after the injury. In the injured common carotid artery, the mRNA expression of (SDF-1a) was elevat-ed immediately after injury, followed by a gradual decline, but that of CXCR4 was increased four days after injury.

Immuno-histochemistry displayed CXCR4-positive stain-ing one day after injury, which then gradually increased and continued for at least one month. In addition, administration of AMD3100 (200 ng/kg, i.p.), a CXCR4 antagonist, did not affect the number of CD34+CXCR4+ cells, the elevated level of plasma (SDF-1a) and expression of (SDF-1a) mRNA. The expression of CXCR4 mRNA and protein however was markedly decreased, and detectable CXCR4-positive cells occurred four days after injury, followed by a decreased intensity of staining. We also found that, three months after balloon injury, stenosis of the carotid artery intima in the group that received AMD3100 was significantly less than in the untreated group (p < 0.05). Therefore, (SDF-1a)/CXCR4 played a crucial role in the intimal hyperplasia, and resteno-sis may have be attenuated after inhibition of CD34+CXCR4+ cells in the intima.

Keywords: percutaneous transluminal coronary angioplasty, percutaneous coronary intervention, restenosis, chemokine, stromal cell-derived factor-1<alpha>, CXCR4



DOI: 10.5830/CVJA-2010-075

Percutaneous transluminal coronary angioplasty (PTCA) and percutaneous coronary intervention (PCI) are effective tech-niques in the treatment of cardiovascular diseases, including acute myocardial infarction (AMI). But a relatively high inci-dence of restenosis after PTCA or PCI is a major problem, caus-ing failure of treatment. Neo-intimal hyperplasia after vascular injury plays an important role in post-treatment restenosis, which is mainly caused by excessive cell deposition in the neo-intima. Therefore, blocking cell deposition may be a promising strategy in the prevention of post-injury restenosis.

Stromal cell-derived factor-1 (SDF-1) is one of the chemokines that belong to the intercrine family and is officially designated as chemokine (C-X-C motif) ligand 12 (CXCL12).1 The recep-tor for this chemokine is CXCR4, which was previously called fusin. SDF-1 is a strong chemo-attractant in directing progenitor cell trafficking, cell migration and angiogenesis.2,3 It has been confirmed that the expression of SDF-1 was elevated in the peri-infarct area after AMI,4 which recruited CXCR4+ cells to participate in myocardial repair and angiogenesis.

In humans and rats, both SDF-1 and CXCR4 show a high degree of sequence homology. In rats, the SDF-1 gene encodes three splice variants: a, b and γ. In the present study, a rat carotid artery balloon injury model was used to mimic human coronary neo-intimal repair after PTCA or PCI. By investigating the expression of SDF-1a and CXCR4 after injury and using a CXCR4 antagonist (AMD3100) to block the interaction between SDF-1 and CXCR4, we found that SDF-1a/CXCR4 played a critical role in neo-intimal hyperplasia.

MethodsA total of 156 male Sprague Dawley rats weighing 286 ± 14.3 g were purchased from the SLAC Laboratory Animal Co, Ltd, Shanghai, China, and housed in a temperature-controlled envi-ronment (22–24°C) with a 12-h light–dark cycle. The local ethics committee of the School of Medicine, Shanghai Jiao-Tong University (No. 0708253) approved all procedures.

The rats were randomly divided into three groups: a control group (group C; n = 12), a surgical group (group S; n = 72), and the AMD3100 treatment group (group A, n = 72). The rats in groups S and A were further divided into six sub-groups (n = 12 per group).

The rats were sacrificed as follows. Groups S0 and A0 were sacrificed 30 min after surgery, groups S1d and A1d one day after surgery, groups S4d and A4d four days post surgery, groups S7d and A7d seven days after surgery, groups S1m and A1m one month after surgery, and groups S3m and A3m three months post surgery.

The rat common carotid artery balloon injury model was carried out in groups S and A as previously described,5 and rats in the control group underwent a sham operation. Briefly, the rats were intraperitoneally anaesthetised with 2.5% pentobarbital sodium (40 mg/kg) and fixed in the supine position. A midline incision was made in the neck, and then the left common carotid

department of geriatrics, 9th Hospital, shanghai Jiao-tong University school of Medicine, shanghai, chinaJ ShENG, MDw-w CAI, csj [email protected] S-Q wANG,

department of geriatrics, ren-Ji Hospital, shanghai Jiao-tong University school of Medicine, shanghai, chinaN-y FANG, MD

shanghai tissue Engineering laboratory, shanghai Jiao-tong University school of Medicine, shanghai, chinaJ-J wU


artery and the bifurcation of the internal and external carotid arteries were exposed. A V-shaped incision was made on the external carotid artery followed by insertion of a 2F thrombotic balloon catheter (Edward Life Sciences, USA) deeply into the common carotid artery. The balloon was dilated by infusing ~ 0.10–0.15 ml of normal saline. The catheter was subsequently drawn back to cause damage to the intima. Then normal saline was withdrawn and the catheter was again pushed into the common carotid artery. The procedure was performed twice in order to completely remove the intima. Finally, the incision was sutured and the rats were given free access to food and water.

The rats in group A were intraperitoneally injected with 200 ng/kg/d AMD3100 (octahydrochloride, Sigma, USA) immedi-ately before surgery for five consecutive days. The rats in group C were sacrificed two weeks later and those in the other groups were killed at the designated time. The left common carotid arteries were removed and rinsed with normal saline. Part of the artery was stored at –80°C for detection of mRNA or protein expression (n = 6), and the remainder was fixed for immuno-histochemistry (n = 6).

Flow cytometric analysisThe peripheral blood (300 μl) was incubated with FITC-conjugated anti-mouse CD34 (eBioscience, USA) and phyco-erythrin-conjugated anti-human CXCR4 (eBioscience, USA) monoclonal antibodies for 30 min at 4°C (n = 12 per group). The cells were double-labelled with CD34 and CXCR4. The red blood cells and platelets were subsequently lysed in erythrocyte lysis buffer for 15 min, followed by centrifugation and washing.

The cells were then re-suspended in phosphate-buffered saline (PBS) and analysed on an FACS Caliber flow cytometer (BD FACSCalibur, America).6 Isotype-matched FITC-conjugated and phycoerythrin-conjugated antibodies (eBioscience, USA) were used as controls. The number of CD34+CXCR4+ cells was presented as the absolute number in a total of 50 000 leukocytes.

Enzyme-linked immunosorbent assay of plasma SDF-1a The plasma level of SDF-1a was determined by the enzyme-linked immunosorbent assay (ELISA) using an ELISA kit (R&D system, USA) according to manufacturer’s instructions.

Real-time polymerase chain reaction analysis of SDF-1a and CXCR4Total RNA was extracted from the injured arteries. For synthe-sis of cDNA, 1 μg of total RNA was reverse-transcribed with Promega RT system. Then the transcribed cDNA was amplified by polymerase chain reaction (PCR) (T3000 PCR instrument, Biometra, Germany) with specific primers as follows:

SDF-1a forward: 5′- CCAATCAGAAATGGGAACAAGA-3′,reverse: 5′- GTAGGAGGCTTACAGCACGAA-3′ (381 bp); CXCR4 forward: 5′- GTGGGCAATGGGTTGGTAAT-3′, reverse: 5′- GGTGGCGTGGACAATGGCAAGGTAG-3′ (267 bp).

The primers were synthesised by Shanghai Sangon Biological Engineering Technology & Services Co, Ltd (Shanghai, China). Reactions involved 10 min at 95°C, 40 cycles at 95°C for 15 sec, and then 60°C for one min. The products of PCR were detected

with 1.8% agarose electrophoresis and visualised under a gel imaging and analysis system (Alpha FluorchemTM8900, USA).

Western blot analysis The artery tissues were lysed in radio-immunoprecipitation assay (RIPA) buffer (n = 6 per group). The protein concentration in the supernatant was measured spectrophotometrically at 595 nm. Forty μg of protein was loaded onto SDS polyacrylamide gel for electrophoresis (Invitrogen, China) and transferred to PVDF membranes (Millipore, USA).

The membrane was incubated with anti-CXCR4 antibody (1:500; rabbit anti-mouse; eBioscience, USA) and anti-<beta> actin antibody (1:1000; goat anti-mouse, Santa Cruz, USA) over-night at 4°C. The membrane was then incubated with secondary antibodies (donkey anti-rabbit antibody, 800DX 1:5000, eBiosci-ence, USA; donkey anti-goat antibody, 700DX 1:2000 Sigma, USA) for one hour, followed by detection with an infrared fluor-escence imaging and analysing system (Odyssey v1.2) (FIAS, Odyssay LI-COR USA).

Immuno-histochemistrySections were then treated with 1.5% peroxide to inactivate peroxidase activity, followed by blocking with 3% bovine serum albumin. These sections were subsequently incubated with anti-CXCR4 antibody (1:250, eBioscience, USA) overnight at 4°C. The sections were then incubated with biotin-conjugated second-ary antibody (1:500; Sigma, USA) or immunoglobulin G (1:500; Santa Cruz, USA).

The sections were stained with haematoxylin/eosin (H&E), dehydrated and mounted. H&E staining was performed on other sections from each group (n = 6) to observe the intimal change after balloon injury. The thickness of the intima was determined using the Image 45 pro analysis program.

Statistical analysis Experiments were performed at least three times and data were presented as the mean ± standard deviation (SD). Statistical anal-ysis was performed with SPSS version 11.0 (SPSS Inc, Chicago, IL, USA). The unpaired t-test was used for comparisons between two groups and one-way ANOVA between multiple groups. A value of p < 0.05 was considered statistically significant.

resultsAs shown in Table 1, compared with group C, the number of peripheral CD34+CXCR4+ cells in groups S and A was signifi-cantly increased immediately after intimal injury (S0/A0) (p < 0.01), followed by a gradual decline to baseline seven days after injury. In group A, the number of CD34+CXCR4+ cells was increased within 24 hours after intraperitoneal administration of AMD3100, followed by a rapid decline (p < 0.05), which may have been related to stimulation of the bone marrow by AMD3100.

As shown in Table 2, the plasma level of SDF-1a after intimal injury was markedly increased and reached a maximum one day after injury (p < 0.01), followed by a rapid decrease to baseline on day seven. The administration of AMD3100 did not affect the plasma level of SDF-1a.

Total RNA was extracted from the injured common carotid


arteries for detection of SDF-1a and CXCR4 mRNA with RT-PCR. Results showed the expression of SDF-1a mRNA in groups S and A was detectable immediately after injury, followed by a gradual decrease, but it was undetectable one month later. Administration of a CXCR4 antagonist seemed to have no effect on expression of SDF-1a mRNA (Fig. 1).

However, the expression of CXCR4 mRNA was detected four days after injury and continued for one month (Fig.1). AMD3100 is an antagonist of CXCR4, which inhibits the interaction between SDF-1a and CXCR4, so the expression of CXCR4 mRNA was decreased in group A compared with that in group S (Fig. 2).

Western blot assay was performed to evaluate the expression of CXCR4 protein in the arteries. As shown in Fig. 3, the expres-sion of CXCR4 protein was reduced immediately after injury, followed by a gradual increase and it lasted for three months. Results also indicated the expression of CXCR4 protein in group S was markedly higher than in group A.

Spatial localisation of CXCR4 in the injured common carotid artery was determined by immuno-histochemical assay (Fig. 4). CXCR4-positive staining was observed in the neo-intima of the common carotid artery (Fig. 4A, B). The positive staining in group S was noted as early as one day after injury, followed by a gradual increase. However, in group A, it was delayed to four days after injury, with low intensity of staining, when compared with that in group S. CXCR4 expression no longer appeared

after three months in either group S or A. The rat carotid artery sections one day, one month and three

months after balloon injury from groups S and A were evaluated for carotid artery stenosis. After H&E staining, the sections were detected with the Image 45 pro analysis program to measure the extent of arterial intimal hyperplasia. It was found that, after one and three months, vascular intimal hyperplasia in groups S and A was significantly higher than in the control group (p < 0.05 and 0.01). The degree of intimal hyperplasia in group A was lower than in group S after one month (p < 0.05), and the difference between the two groups remained after three months (p < 0.05) (Table 3, Fig. 5).

discussionCoronary heart disease is one of the commonest causes of death. Since the use of PTCA in the treatment of coronary athero-sclerosis, numerous patients with coronary heart disease have benefited from PCI, but the relatively high incidence of resteno-sis after PCI has been a major problem, despite the short-term success of this technique. So far, no effective treatment strategies have been successful in preventing restenosis after PCI. Studies have demonstrated that excessive proliferation of the neo-intima plays a critical role in restenosis. Therefore, appropriate inhibi-tion of neo-intimal proliferation may be a promising strategy in the prevention of restenosis.

Proliferation of stem/progenitor cells occurs following tissue ischaemia or damage such as acute myocardial infarction.4 Many cells may migrate into the ischaemic region to participate in tissue repair and angiogenesis.7,8 So far, the mechanisms under-lying the progenitor cell migration to the injured site are poorly understood. Recently, stem or progenitor cell therapy has been a treatment choice for the improvement of neovascularisation and left ventricular function following acute myocardial infarc-tion. Various types of stem cells and progenitor cells have been successfully used in the experimental acute myocardial infarc-

TABLE 1. PERIPHERAL CXCR4+CD34+ CELLS AFTER INTIMAL INJURY (x ± SD, n = 12 PER GROUP)

Group C

Group S Group A

S0 S1d S4d S7d S1m S3m A0 A1d A4d A7d A1m A3m

CXCR4+CD34+ cells 0.021 ± 0.002

1.260 ±0.003**

0.729 ±0.019**

0.187 ±0.004**

0.019 ± 0.004

0.022 ± 0.001

0.020 ±0.038

1.411 ±0.021**#

0.889 ±0.012**#

0.185 ±0.005**

0.023 ±0.004

0.022 ±0.011

0.019 ±0.055

**p < 0.01 vs group C; #p < 0.05 vs group S; d = day; m = month.

TABLE 2. PLASMA LEVEL OF SDF-1a AFTER INTIMAL INJURY (x ± SD, ng/ml, n = 12 PER GROUP)

Group C

Group S Group A

S0 S1d S4d S7d S1m S3m A0 A1d A4d A7d A1m A3m

SDF-1<alpha> (ng/ml) 0.312 ±0.006

0.885 ±0.022*

1.328 ±0.009*

1.119 ±0.013*

0.323 ±0.005

0.320 ±0.006

0.309 ±0.056

0.855 ±0.024*

1.191 ±0.039*

1.083 ±0.004*

0.324 ±0.056

0.319 ±0.012

0.303 ±0.027

*p < 0.01 vs group C.

Fig. 1. Expression of sdF-1a mrNa (381 bp) in an injured common carotid artery.

s4d a4d s1d a1d marker s1m a1m s3m a3m s7d a7d

s0 a0 marker c

Fig. 2. Expression of cXcr4 mrNa (267 bp) in an injured common carotid artery.

marker s0 a0 s1d s4d a4d a1d

c a7d s7d a1m s1m marker a3m s3m

Fig. 3. Expression of cXcr4 protein (67 kd) in an injured common carotid artery.

a4d s4d a7d s7d marker c s1m a1m s3m a3m

Marker a1d s1d a0 s0


tion models.9 We speculated that, besides stem/progenitor cells being involved in intimal repair, their abnormal implantation in the neo-intima may be the main cause of vascular restenosis, in which SDF-1, an important chemokine, plays a crucial role.

SDF-1, a small (~ 8–14 kDa) pro-inflammatory chemokine,10 is the main regulator of cell trafficking and adhesion.11 It binds and activates a subset of G protein-coupled receptors with seven transmembrane domains called CXCR4, which are expressed on the surface of target cells.12 Although CXCR7 is also the receptor

of SDF-1, CXCR4 is the only receptor known to have a definite physical role in cell trafficking, and SDF-1 is the only physical ligand for CXCR4.

The rat SDF-1 gene encodes three splice variants: a, b and γ. SDF-1a is mainly observed in the liver, spleen, kidney, heart, brain and lung and SDF-1b in the liver, kidney, spleen and thymus. SDF-1γ is predominately noted in the heart, lung, brain and peripheral nerve system.13 Although the levels of SDF-1γ in the heart are high, significant changes in the expression of

Fig. 4. a: in group s, the positive staining for cXcr4 was detectable one day after injury and lasted for at least one month. discontinuous brown spots were shown at the injured area. with time, the spots gradually fused to form a brown line with a slowly enhancing intensity. B: in group a, the positive staining was observed four days after injury and was sustained for one month, with a weak intensity when compared with that in group s.

a

s0 (40 ×) s1d (40 ×) s4d (40 ×)

s7d (40 ×) s1m (40 ×) s3m (40 ×)

B

a0 (40 ×) a1d (40 ×) a4d (40 ×)

a7d (40 ×) a1m (40 ×) a3m (40 ×)


SDF-1a were found after cardiac injury. The interaction between SDF-1a and CXCR4 plays a crucial

role in immune defense and SDF-1a is up-regulated by numer-ous stimuli including antigens, polyclonal stimulants, cell irri-tants and cytokines.14,15 In the present study, results show plasma levels of SDF-1a were significantly increased after injury, followed by a decrease to baseline four days after injury.

The number of CD34+CXCR4+ cells was markedly increased immediately after injury, followed by a gradual decline. The administration with AMD3100 increased the number of CD34+CXCR4+ cells, but no statistical significance was observed in the number of CD34+CXCR4+ cells and plasma levels of SDF-1a. Therefore, the increased plasma levels of SDF-1a and the elevated numbers of CD34+CXCR4+ cells after arterial injury may have been related to neo-intimal repair.

Numerous studies have found that SDF-1a not only stimu-lated haematopoietic stem cell engraftment but also recruited progenitor cells to the ischaemic region by interacting with CXCR4.16 After heart surgery or acute myocardial infarction, the expression of SDF-1a in the peri-injury zone was up-regulated, with profoundly increased numbers of stem/progenitor cells in

the injured region.17,18 Inhibition of the SDF-1a/CXCR4 axis could partially block

the recruiting of progenitor/stem cells to the injured tissues or peri-infarct myocardium.19 Likewise, inhibition of CXCR4 with the anti-CXCR4-antibody could also significantly reduce SDF-1a-induced adhesion of EPC to mature endothelial cells, the in vitro migration of EPC,17 and the in vivo recruitment of myeloid EPC to the ischaemic limb in a hind limb ischaemia model.20 Moreover, over-expression of SDF-1a enhanced the homing and incorporation of stem cells into ischaemic tissues.21,22 These findings support the notion that SDF-1a played a crucial role in the recruitment of circulating or intravenously infused cells.

In this study, our results showed the expression of SDF-1a mRNA was elevated immediately after injury and reached a maximum four days later, followed by a decline to baseline seven days after injury. However, the expression of CXCR4 mRNA was increased four days after injury and reached a maximum seven days after injury, followed by a gradual decrease to baseline.

Immuno-histochemistry indicated CXCR4-positive staining was found in the neo-intima (Fig. 4A, B) of the common carotid

Fig. 5. a: Normal rat carotid artery. B: the carotid artery intima of injured rats gradually underwent hyperplasia with time in group s. c: the carotid artery intima of injured rats also gradually underwent hyperplasia with time in group a, but the degree of proliferation was less than in group s.

c (100 ×)

s1d (100 ×) s1m (100 ×) s3m (100 ×)

a1d (100 ×) a1m (100 ×) a3m (100 ×)

a

B

c

TABLE 3. MEASUREMENT OF RAT CAROTID ARTERY STENOSIS (x ± SD, mM, n = 12 PER GROUP)

Group CGroup S Group A

S1d S1m S3m A1d A1m A3m

Intima thick-ness (μm)

45.367 ± 17.486

47.018 ± 5.967

106.195 ± 15.342*

129.816 ± 17.114**

45.918 ± 12.584

78.368 ± 16.511*#

88.734 ± 15.326*#

*p < 0.05, **p < 0.01 vs group C; #p < 0.05 vs group S.


artery after injury, followed by a gradual increase in staining intensity. After the administration of AMD3100, an antagonist against the interaction between CXCR4 and SDF-1a, the expres-sion of CXCR4 mRNA and protein was significantly decreased. The intensity of CXCR4-positive staining was also less and the time to when CXCR4-positive staining occurred was delayed. After three months, the two groups were no longer showing CXCR4-positive staining, which may have been because the interaction between SDF-1a and CXCR4 occurred only in the early injury period.

Carotid artery hyperplasia was observed with H&E staining after balloon injury. We found that compared with the control group after one and three months, hyperplasia of the neo-intima had occurred in groups S and A (p < 0.05 and 0.01). The degree of intimal hyperplasia in group A was lower than in group S after one month (p < 0.05), and the difference between the two groups remained after three months (p < 0.05).

We therefore postulated that the expression of SDF-1a mRNA in the left common carotid artery was increased after injury, leading to an elevated plasma level of SDF-1a, which exerted chemotactic effects on the migration of CD34+CXCR4+ cells into the injured tissues as a result of the concentration gradient of SDF-1a. The deposited cells then took part in the neo-intimal repair or even caused restenosis.

The results demonstrated that intimal repair was closely associated with the interaction between SDF-1a and its recep-tor CXCR4. The elevated plasma levels of SDF-1a after injury recruited peripheral CD34+CXCR4+ cells into the damaged endothelium, thus leading to formation of the neo-intima. In the injured artery, the expression of CXCR4 mRNA and protein, as well as the CXCR4-positive staining in the neo-intima was observed to be increased.

With an antagonist (AMD3100) against the interaction between SDF-1a and CXCR4, the expression of CXCR4 mRNA and protein, as well as the CXCR4-positive staining was decreased. H&E staining also showed that after the intervention of AMD3100, the rat carotid artery neo-intimal thickness was still more than the normal control group, but thinner than in the non-intervention group. Therefore, we speculated that the SDF-1a/CXCR4 axis played an important role in neo-intimal proliferation.

conclusionIn this study, we investigated short- and long-term changes in the SDF-1a/CXCR4 axis in the rat common carotid artery neo-intima after injury. More studies are required to explore the long-term changes in neo-intimal proliferation after administration of AMD3100, and the specific signalling pathway involved in the SDF-1a/CXCR4 axis. This may provide useful information for prevention of restenosis after PTCA or PCI.

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7. Hou D, Youssef EA, Brinton TJ, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 2005; 112: I150–156.

8. Brenner W, Aicher A, Eckey T, et al. 111In-labeled CD34+ hematopoi-etic progenitor cells in a rat myocardial infarction model. J Nucl Med 2004; 45: 512–518.

9. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scien-tific foundations of cardiac repair. J Clin Invest 2005; 115: 572–583.

10. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121–127.

11. Schier AF. Chemokine signaling: rules of attraction. Curr Biol 2003; 13: R192–R194.

12. Murphy PM, Baggiolini M, Charo IF, et al. International union of phar-macology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000; 52: 145–176.

13. Pillarisetti K, Gupta SK. Cloning and relative expression analysis of rat stromal cell derived factor-1 (SDF-1)1: SDF-1 alpha mRNA is selectively induced in rat model of myocardial infarction. Inflammation 2001; 25: 293–300.

14. Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemo-tactic cytokines–CXC and CC chemokines. Adv Immunol 1994; 55: 97–179.

15. Taub DD, Oppenheim JJ. Chemokines, inflammation and the immune system. Ther Immunol 1994; 1: 229–246.

16. Lapidot T. Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions. Ann N Y Acad Sci 2001; 938: 83–95.

17. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell traf-ficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

18. De Falco E, Porcelli D, Torella AR, et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 2004; 104: 3472–3482.

19. Abbott JD, Huang Y, Liu D, et al. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocar-dial infarction but is not sufficient to induce homing in the absence of injury. Circulation 2004; 110: 3300–3305.

20. Walter DH, Haendeler J, Reinhold J, et al. Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res 2005; 97: 1142–1151.

21. Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362: 697–703.

22. Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003; 107: 1322–1328.


the effect of mebudipine on cardiac function and activity of the myocardial nitric oxide system in ischaemia–reperfusion injury in ratsR GhyASI, M MOhAMMADI, R BADALzADEh, B RAShIDI, G SEPEhRI

abstractObjectives: Previous studies have suggested that failure of the synthesis of nitric oxide is involved in the pathophysiology of myocardial ischaemia–reperfusion injury. In this study, we investigated the effect of mebudipine, a new dihydropyridine calcium channel blocker, on cardiac function and activity of the myocardial nitric oxide system in ischaemia–reperfusion injury in isolated rat hearts.Methods: Forty male Wistar rats (250–300 g) were divided into four groups (n = 10): sham, control, vehicle and drug groups. The animals were anesthetised with sodium pento-barbital (6 mg/kg intraperitoneal). The hearts were quickly removed, mounted on a Longendorff apparatus and perfused with Krebs-Henseleit solution under constant pressure at 37°C. After 20 min stabilisation period, the ischaemic groups received 30 min global ischaemia and 120 min reperfu-sion. For the drug and vehicle groups, before ischaemia the hearts were perfused with mebudipine (10-3 μM) or ethanol-enriched solution (0.01%) for 25 min, respectively. Myocardial function, and creatine kinase, lactate dehydog-enase and total nitric oxide metabolite (nitrite and nitrate) levels were analysed.Results: Cardiac functions had recovered significantly in the mebudipine group (p < 0.01). Furthermore, mebudi-pine remarkably reduced the levels of lactate dehydogenase and creatine kinase in the coronary effluent and increased myocardial nitric oxide metabolite levels compared with the control group. Conclusion: Our results indicate that mebudipine reduced the intensity of myocardial ischaemia–reperfusion injury, and that activation of the myocardial nitric oxide system played an important role in this regard.

Keywords: ischaemia, nitric oxide, reperfusion, mebudipine, isolated heart



DOI: 10.5830/CVJA-2010-078

Early reperfusion is an absolute prerequisite for the survival of ischaemic myocardium. However, reperfusion has been consid-ered a double-edged sword because reperfusion itself may lead to additional accelerated myocardial injury beyond that generated by ischaemia alone. This results in a spectrum of reperfusion-associated pathologies, collectively called reperfusion injury.1 The underlying pathophysiological mechanisms of ischaemia–reperfusion have not been fully elucidated. It has been suggested that an overproduction of oxygen-derived free radicals2 and intracellular calcium overload during the first minutes of reflow might be involved.3 However, oxygen-derived free radicals and hypercontracture due to calcium overload are not the only candidates responsible for reperfusion injury. Other factors of importance in the pathogenesis of reperfusion injury include platelet- and neutrophil-mediated injury, the renin–angiotensin system and the complement activation.2

It is known that nitric oxide (NO) is involved in the regulation of myocardial contractility and contributes to myocardial protec-tion in ischaemic pre- and postconditioning.4 NO plays multiple roles in the cardiovascular system, mediating a number of physiological and pathophysiological processes. In smooth muscle cells, NO activates guanylate cyclase by a hem-dependent mechanism, resulting in an increased concentration of guanosine 3′,5′-cyclic monophosphate (cGMP), which leads to a decreased intracellular concentration of Ca2+ and subsequent relaxation of the vessels.5

Reduced basal availability of NO and impairment of endothe-lial NO-dependent mechanisms due to dysfunction of the normally protective endothelium may be involved in the patho-genesis of several cardiovascular diseases, including atheroscle-rosis, hypertension, heart failure, coronary heart disease, arterial thrombotic disorders and stroke.6 In cardiomyocytes, the NO/cGMP pathway is involved in the inhibition of Ca2+ influx by cGMP-dependent phosphorylation of L-type Ca2+ channels,7 antagonism of the effects of b-adrenergic stimulation, and decrease in myocardial contractility and heart rate, as well as in reduction in myocardial oxygen consumption and opening of the sarcolemmal KATP channels. Reduced Ca2+ current may alleviate Ca2+ overload associated with acute myocardial ischaemia as one of the major mechanisms of ischaemic injury.5

Ca2+ channel antagonists are used for a variety of diseases, including heart and coronary disease and have become one of the standard first choices of drugs for essential hypertension. They

physiology and Neuroscience research centre, Faculty of Medicine, Kerman University of Medical sciences, Kerman, iranR GhyASI, MScG SEPEhRI, PhD

department of physiology, drug applied research centre, Faculty of Medicine, tabriz University of Medical sciences, iranM MOhAMMADI, PhD, [email protected] BADALzADEh, PhD, [email protected]

the young researchers club of tabriz, islamic azad University, tabriz, iranR BADALzADEh, PhD

department of anatomy, Faculty of Medicine, isfahan University of Medical sciences, isfahan, iranB RAShIDI, PhD


have also become established as therapeutic drugs for angina pectoris, together with b-adrenoceptor antagonists and nitrates.8 Ca2+ channel antagonists have several features that may relate to myocardial protection during ischaemia and reperfusion. The main effect is reduction in oxygen demand due to a decrease in heart rate and myocardial contractility.8 Interference with neutro-phil mobilisation and activation may protect against the produc-tion of free radicals and the release of proteolytic enzymes.9 A direct protective effect may also be produced by interference with ischaemia-induced intracellular Ca2+ overload.10,11

Dihydropyridine Ca2+ channel blockers were reported to protect the endothelial function of renal resistance arteries in hypertensive rats12 and the mesenteric arteries of rats in circula-tory shock.13 Endothelial function is important for the preserva-tion of the organ function against ischaemic or hypertensive stress.14,15 Many studies have reported that Ca2+ channel blockers such as amlodipine, nifedipine and benidipine increase NO production.16,17

Mebudipine is a new calcium channel blocker with a dihy-dropyridine structure that has a comparable pharmalogical effect while offering some advantages, such as a longer biological half-life to reach peak effect and vasoselectivity.18,19 There are no reports on the cardioprotective activity of mebudipine and it seems that it may attenuate endothelial dysfunction and increase the production of NO in ischaemic hearts. Therefore, this study was designed to examine the effect of mebudipine on cardiac function and the activity of the myocardial nitric oxide system following ischaemia–repefusion injury in isolated rat hearts.

MethodsForty male Wistar rats (250–300 g) were obtained from the labo-ratory animal house at Tabriz University of Medical Sciences. They were housed in an animal room at 22–24ºC and given free access to commercial rat chow and tap water. All the experi-mental procedures used, as well as rat care and handling were in accordance with guidelines provided by the Experimental Animal Laboratory and approved by the Animal Care and Ethics Committee of the Tabriz University of Medical Sciences. The animals were randomly divided into four groups (n = 10): a sham group (without ischaemia), control group (ischaemia with-out drug), drug group (ischaemia with drug) and vehicle group (ischaemia with ethanol: 0.01%).

Longendorff protocolAll animals were anaesthetised intraperitoneally with sodium pentobarbital (60 mg/kg) and heparinised with sodium heparin (300 IU intraperitoneally). After opening the chest cavity, the hearts were quickly excised and immersed in ice-cold Krebs-Henseliet (K-H) solution. Then the aortae were cannulated and the hearts were retrogradely perfused via the aorta in a Longendorff apparatus with K-H solution containing (in mM): 118 NaCl, 4.8 KCl, 1.2 MgSO4, 1.0 KH2PO4, 27.2 NaHCO3, 10 glucose and 1.25 CaCl2. A mixture of 95% O2 and 5% CO2 was bubbled through the perfusate. A thermostatically controlled water circulator (Satchwell Sunvic, UK) maintained the perfu-sate and bath temperatures at 37°C.

The hearts were perfused at a constant mean pressure of 75–80 mmHg. During the stabilisation period, a latex balloon (Harvard) attached to the end of a piece of stiff polyethylene tubing was

inserted into the left ventricle through the mitral valve. The balloon and tubing were connected to a pressure transducer and filled with normal saline to produce a left ventricular end-diastolic pressure (LVEDP) of 5–10 mmHg at baseline, and the balloon volume was maintained constant throughout the experi-ment. The LVEDP, LV peak systolic pressure (LVSP) and the peak rates of positive and negative changes in LV pressure (± dp/dt) were measured with a Power Lab System (ADInstruments, Australia). The LV developed pressure (LVDP) was calculated as follows:

LVDP = LVSP – LVEDP (mmHg). The haemodynamic data were recorded continuously on a computer using a Powerlab system. The heart rate (HR) was calculated using a bioelectric amplifier (ADInstruments, Australia) from the electrocardiogram that recorded via two electrodes attached to the apex and the right ventricle of the heart and one reference electrode.

Ischaemia–reperfusion protocolsThe hearts were allowed to equilibrate for 20 min prior to each study. For the ischaemic control group, the hearts were perfused with the K-H solution for 20 min, and then global ischaemia was conducted by interrupting the aortic flow for 30 min, followed by reperfusion with K-H solution for up to 120 min. In the drug and vehicle groups, before ischaemia, the hearts were perfused with mebudipine (0.1 nm) or an ethanol-enriched solution (0.01%) for 25 min, respectively.

Several experimental studies have proven Ca antagonists to be cardioprotective when applied in a concentration that does not produce a negative inotropic or chronotropic effect.20-22 Mebudipine was therefore applied throughout the study at a concentration of 0.1 nm, which did not cause a negative inotropic or chronotropical effect.

Biochemical measurementsDuring the first 10 min of the reperfusion period, the coronary effluent was sampled for lactate dehyrogenase (LDH) and myocardial creatin kinase (CK-MB) measurement. The concen-tration of LDH and CK in the coronary effluent was measured using related kits (Parsazmoon, Iran) and expressed as units per litre. NO production (nmol/g protein) in the heart homogenates was determined by measuring the total nitrite and nitrate concen-tration (NO metabolites), using the Griess method.23

Deproteinised heart homogenates were used for determina-tion of NO metabolite concentrations (NOx). Briefly, 100 μl of supernatant was applied to a microtitre plate well; 100 μl vana-dium (III) chloride (8 mg/ml) was added to each well (for reduc-tion of nitrate to nitrite) and this was followed by the addition of the Griess reagents, 50 μl sulfanilamide (2%) and 50 μl N-(1-naphthyl) ethylendiamine dihydrochloride (0.1%). After 30 min incubation at 37ºC, the absorbance was read at 540 nm using an ELISA reader (Lab System, Fanland). The concentration of NOx in the heart homogenates was determined from standard linear curves established from 0–150 μmol/l sodium nitrite.

Statistical analysesAll numerical data are expressed as mean ± SEM. Data on cardiac function were subjected to a two-way analysis of vari-


ance (ANOVA), and if statistical significance was established, values were compared using Turkey’s post hoc test. The NOx concentrations, and LDH and CK levels were analysed using one-way ANOVA followed by Turkey’s test.

resultsThere were no significant differences in baseline values between all groups (Table 1). In the isolated hearts, when experimental ischaemia was produced by the cessation of coronary perfusion, LVDP and HR rapidly decreased and stopped. A progressive increase in LVEDP was noted in all groups. During the reperfu-sion periods (10, 30 and 60 min), mebudipine attenuated the increase in LVEDP in the drug-treated group compared with the control group (p < 0.01). The administration of mebudipine before ischaemia caused cardiac function to return during the reperfusion period. Mebudipine significantly increased the LVDP and + dp/dt (time = 10, 30 min) (p < 0.05), and increased the coronary flow and – dp/dt notably (Table 1).

LDH and CK release in the coronary effluent, as an indicator of cell damage and tissue injury, decreased in the drug-treated group compared with the control group (p < 0.01) (Fig. 1). Pretreatment with mebudipine (0.1 nm) increased the concentra-tion of NO metabolites (nitrite and nitrate) in the hearts of the drug-treated group compared with the control group (p < 0.01) (Fig. 2).

discussionWe examined the influence of mebudipine on myocardial injury resulting from global ischaemia and reperfusion in isolated rat hearts, determined mechanically and biochemically. The find-ings of this study were that exposure to mebudipine 25 minutes before global ischaemia facilitated the recovery of contractility, decreased LDH and CK levels (indicators of cardiac cellular injury during reperfusion), and attenuated the increase in LVEDP

during reperfusion.Previous studies indicated that mebudipine improved char-

acteristics such as tissue selectivity and significant negative chronotropic effects, and had no noticeable negative effect on the contractility of the heart,23 but there have been no studies on the cardioprotective effects of mebudipine against ischaemia–reperfusion injury. This is the first report that a dihydropyridine calcium channel blocker, mebudipine, has the capability of increasing cardiac NO levels in ischaemic hearts, which attenu-ates the severity of the myocardial ischaemia–reperfusion injury.

It was reported that the other members of this group of drugs, amlodipine, nifedipine and benidipine have cardioprotective effects against myocardial ischaemia–reperfusion injury via

TABLE 1. LEVELS OF HR, LVEDP, LVDP, ± DP/DT AND CF IN THREE GROUPS OF RATS

Parameter/groupStabilisa-

tion

Reperfusion

10 min 30 min 60 min 120 min

HR (pulse/min)

Control 284 ±6.7 20.4 ± 220 243 ±11.8 233 ± 11.1 212 ± 14.2

Vehicle 275 ± 8.2 19.1 ± 216 256 ±13.2 247 ±13.1 227 ± 15.2

Drug 261 ±13.4 17.3 ± 205 213 ±19.4 210 ± 19.5 195 ±18.1

LVEDP (mmHg)

Control 7.4 ±0.3 2.5 ±29.3 27 ±1.5 23.8 ±1.2 19.6 ± 1.1

Vehicle 7 ± 0.3 3.1 ±33.3 31.1 ±1.1 26.3 ± 0.9 22.5 ±1.4

Drug 6.7* ± 0.4 1.2** ± 15.5 15.3 ± 1.3** 14.5 ± 1.1* 13.8 ± 1.3

LVDP (mmHg)

Control 89.8 ±5.6 42 ± 3.8 45 ±3.9 45.8 ±6.7 47.3 ±4.4

Vehicle 93 ±7.1 46 ±5.1 49 ±4.2 47 ±7.1 50.4 ±3.6

Drug 81.6 ± 5.6 69 ± 8** 67 ±7** 58 ±5.6 51.8 ± 2.9

+dp/dt (mmHg/s)

Control 3388 ±310 1494 ±468 1575 ±217.5 1532 ±189 1445 ± 227

Vehicle 3229 ±270 1522 ±259 1590 ±110 1585 ±233 1566 ±210

Drug 3066 ±336 439* ± 2755 2460 ±381* 2010 ±211 1920 ±200

–dp/dt (mmHg/s)

Control 1999 ±217 127 ± 974 1138 ± 149 1054 ±170 1014 ± 150

Vehicle 1909 ± 264 248 ± 1050 1199 ±198 1151 ±109 1106 ± 93

Drug 1863 ± 259 1563 ± 196 1563 ± 196 1343 ± 110 1301 ± 89

CF (ml/min)

Control 9.8 ± 0.54 7.5 ±0.18 5.3 ±0.24 4.5 ±0.18 3.9 ±0.27

Vehicle 9.5 ± 0.27 6 ±0.44 4.9 ±0.27 4.3 ±0.16 3.9 ± 0.24

Drug 10.1 ±0.35 8.2 ±0.88 6.1 ±0.37 5.3 ± 0.38 4.6 ±0.4

Results are expressed as mean ± SEM. for each group (n = 10). *p < 0.05 compared with control group and **p < 0.01 compared with control group.

Fig. 2. Effect of ischaemia–reperfusion on No levels in three groups of rats. **p < 0.01 compared with control group.

180160140120100806040200

No1 (

limiti

ng p

rote

in)

control vehicle druggroups

**

900800700600500400300200100

0

ldH

(U/l)


*

Fig. 1. Effect of ischaemia–reperfusion on ldH and cK-MB levels in three groups of rats. **p < 0.01 compared with control group.

600500400300200100

0

cK-M

B (U

/l)


**


NO-dependent mechanisms.16,17,24 Therefore the enhancing effects of NO may not be attributable to the mebudipine, although its capability to increase NO levels due to calcium channel antago-nists may be different.

NO is not only produced by endothelial cells,25 but also by cardiomyocytes,26 erythrocytes,27 platelets,28 leukocytes and fibroblasts17,29 in the heart. Several stimuli facilitate NO produc-tion. Acetylcholine, bradykinin, purine and norepinephrine stimulate NO synthase.17 NO is believed to attenuate the severity of myocardial ischaemia via several mechanisms. NO increases coronary flow, and reduces leukocyte and platelet aggregation.17 In our study, the enhancement of coronary flow was notable but not significant, possibly due the concentration of mebudipine that we used. Furthermore, other known physiological effects of NO, such as reduction of ventricular pressure and augmentation of collateral coronary flow30 may have contributed to the protec-tive effect of mebudipine against ischemia–reperfusin injury.

In addition, NO may have regulated oxidant-induced altera-tions in the intracellular Ca2+ concentration that caused cytoskel-eton derangement, changes in cell shape and ultimately cell necrosis.31 In the first minutes of reperfusion, the myocardium may be damaged by the development of contracture (a sustained shortening and stiffening of the myocardium), causing mechani-cal stiffness, tissue necrosis and the stone-heart phenomenon. Reperfusion-induced contracture can have two different causes, Ca2+ overload and depletion of ATP.1 Because the volume of the balloon was kept constant during ischaemia and reperfusion in this preparation, an increase in LVEDP reflected an increase in left ventricular wall stiffness or contracture.

Mebudipine significantly attenuated the increase in LVEDP during reperfusion, therefore this drug could decrease cell damage and tissue necrosis. Since this study revealed that mebudipine increased NO levels and reduced LDH and CK release, mebudipine may be effective as a calcium channel antagonist in ischaemic hearts.

conclusionThe results of this study confirmed the protective effect of mebudipine against ischaemia–reperfusion injury due to preven-tion of increased LVEDP, enhanced LVDP and the metabolites of NO, and decreased levels of LDH and CK. Therefore, it may be beneficial for reducing ischemia–reperfusion injuries.

This work was supported by the Physiology and Neuroscience Research Centre of the Kerman University of Medical Sciences and the Drug Applied Research Centre of the Tabriz University of Medical Sciences, Iran.

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ischemia/reperfusion-injury, a clinical view on a complex pathophysi-ological process. Int J Cardiol 2005; 100: 179–190.

2. Gross GJ, Auchampach JA. Reperfusion injury: Does it exist? J Mol Cell Cardiol 2007; 42: 12–18.

3. De Groot H, Rauen U. Ischemia-reperfusion injury: Processes in patho-genetic networks. Transplant Proc 2007; 39: 481–484.

4. Rastaldo R, Pagliaro P, Capello S, Losano G. Nitric oxide and cardiac function. Life Sci 2007; 81: 779–793.

5. Andelova E, Bartekova M, Pancza D, Styk J, Ravingerova T. The role of NO in ischemia/reperfusion injury in isolated rat heart. J Gen Physiol 2005; 24: 411–426.

6. Ignarro L. J, Napoli C, Loscalzo J. Nitric oxide donors and cardiovas-cular agents modulating the bioactivity of nitric oxide: an overview. Circulation 2002; 90: 21–28.

7. Mery P. F, Lohmann S. M, Walter U, Fischmeister R. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci 1991; 88: 1197–1201.

8. Katsumata Naoki, Ma Xin, Higuchi Hiroshi. Protective effect of diltiazem against ischemia-induced decreases in regional myocardial flow in rat heart. Eur J Pharmacol 2000; 398: 83–91.

9. Rousseau G, Provost P, Tran D, Caille G, Latour JG. Clentiazem given at reperfusion improves subendocardial reflow and reduces myocardial infarct size in the dog. J Pharmacol Exp Ther 1994; 268: 1252–1260.

10. Ver Donck, L, Van Reempts J, Vandeplassche G, Borgers M. A new method to study activated oxygen species induced damage in cardio-myocytes and protection by Ca2q-antagonists. J Mol Cell Cardiol 1988; 20: 811–823.

11. Tamura K, Suzuki Y, Koga T, Akima M, Kato T, Nabata H. Actions of CP-060S on veratridine-induced Ca2+ overload in cardiomyocytes and mechanical activities in vascular strips. Eur J Pharmacol 1996; 312: 195–202.

12. Dohi Y, Kojima M, Sato K. Benidipine improves endothelial function in renal resistance arteries of hypertensive rats. Hypertension 1996; 28: 58–63.

13. Karasawa A, Rochester A, Lefer A. Protection of endothelial damage and systemic shock by benidipine, a calcium antagonist, in rat subjected to splanchnic ischemia and reperfusion. Circ Shock 1991; 116: 77–165.

14. Node K, Kitakaze M, Yoshikawa H, Kosaka H, Hori M. Decreased plasma levels of nitric oxide in patients with essential hypertension. Hypertension 1997; 30: 405–408.

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16. Sakaguchi M, Shibata T, Ahattori K, Hirai H, Hosono M, Aoyama T, et al. Orally administered benidipine and manidipine prevent ischemia-reperfusion injury in the rat heart. Circ J 2004; 68: 241–246.

17. Asanuma H, Kitakaze M, Funaya H, Takashima S, Minamino T, Node K, et al. Nifedipine limits infarct size via NO-dependent mechanisms in dogs. Basic Res Cardiol 2001; 96(5): 497–505.

18. Rouzrokh A, Ebrahimi SA, Rahbr-Roshandel N, Mahmoudian M. Effect of mebudipine and dipodipine, two new channel blockers on voltage-activated calcium current in pc12 cells. Acta Physiol Hung 2007; 94(3): 199–207.

19. Mirkhani H, Dirin M, Yossef-Zadeh I. Mechanism of vasoselective action of mebodipin, a new calcium channel blocker. Vasc Pharmacol 2004; 42; 23–29.

20. Becker BF, Mobert J. Low-dose calcium anagonists reduce energy demand and cellular damage of isolated hearts during both ischemic and reperfusion. Naunyn-schmiedebergs Arch Pharmacol 1999; 360: 287–294.

21. Massoudy P, Bexker BF, Gerlach E. Preischemic as well as post-ischemic application of a calcium antagonist afford cardioprotection in the iscolated guinea pig heart. Cardiovas Res 1995; 29: 577–582.

22. Van der Heide R, Schwartz LM, Reimer KA. The novel calcium antag-onist Ro 40-5967 limits myocardial infract size in the dog. Cardiovas Res 1994; 28: 1526–1532.

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25. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci 1987; 84: 9265–9269.

26. Nakano A, Liu GS, Heusch G, Downey JM, Cohen MV. Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning. J Mol Cell Cardiol 2000; 32: 1159–1167.


27. Chen LY, Mehta JL. Evidence for the presence of L-arginine-nitric oxide pathway in human red blood cells: relevance in the effects of red blood cells on platelet function. J Cardiovasc Pharmacol 1998; 32: 57–61.

28. Berkels R, Stockklauser K, Rosen P, Rosen R. Current status of platelet NO synthases. Thromb Res 1997; 87: 51–55.

29. Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibro-

blasts. Circ Res 1996; 78: 759–768.30. Rossoni G, Manfredi B, Colonna VD, Brini AT, Polvani G, Clement

MG, Berti F. Nitric oxide and Prostacyclin pathway: an integrated mechanism that limits myocardial infarction progression in anaesthized rats. Pharmacol Res 2006; 53: 359–366.

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analysis of omega-3 fatty acid content of south african fish oil supplementsMAREThA OPPERMAN, DE wET MARAIS, AJ SPINNLER BENADE

abstractIntroduction: Substantial evidence describes the protec-tive effects of marine-derived omega-3 (n-3) polyunsatu-rated fatty acids (PUFA) on cardiovascular diseases as well as many other conditions. Numerous fatty acid preparations are marketed for supplementing the Western diet, which is low in n-3 fats. Since these preparations may vary in their n-3 PUFA content, we tested 45 commercially available products on the South African market for their fatty acid composition. Method: Forty-five commercially available n-3 fatty acid supplements were analysed using gas–liquid chromatogra-phy to determine their fatty acid content.Results: More than half of the n-3 supplements available on the South African market contained ≤ 89% of the claimed content of EPA and/or DHA as stated on the product labels. To meet ISSFAL’s recommendation of 500 mg EPA + DHA/day can cost consumers between R2 and R5 per person per day (R60 to R150 p/p/month). Regarding rancidity, the majority of capsules contained conjugated diene (CD) levels higher than that of vegetable oil obtained from opened containers (three months) used for domestic cooking purpos-es, despite the addition of vitamin E as antioxidant.Conclusion: Since no formal regulatory structure for dietary supplements currently exists in South Africa, consumers depend on self-regulation within the nutraceutical industry for assurance of product quality, consistency, potency and purity. Our results indicate that more than half of the n-3 fatty acid supplements on the South African market do not contain the claimed EPA and/or DHA contents as stated on product labels, and they contained CD levels higher than that in unused vegetable oils obtained from opened containers used for domestic cooking purposes.

Keywords: supplements, eicosapentaenoic acid (EPA), docosa-hexaenoic acid (DHA), conjugated dienes (CD), fish oil



DOI: 10.5830/CVJA-2010-080

During the past few years, evidence-based nutritional research has confirmed the importance of omega-3 (n-3) fatty acids in reducing the risk for cardiovascular disease (CVD). Recently,

there has been increasing understanding of the essentiality of n-3 fatty acids in reducing cardiovascular disease (CVD).1 N-3 fatty acids possess a wide range of biological effects, including reducing inflammatory responses, lowering triglyceride levels, reducing risk of arrhythmias, a small dose-dependent hypoten-sive effect, anti-atherogenic effects and a reduction in platelet aggregation, all of which contribute to protection against CVD.2

The n-3 fatty acids of particular concern for the prevention of CVD are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are very-long-chain n-3 fatty acids. The ability of the body to manufacture them from the precursors is limited and to ensure adequate supply of these fatty acids, their dietary source is of vital importance.3 These fatty acids are predominantly found in fish and fish oils.4 Fatty fish such as herring, mackerel, tuna, salmon and trout are rich dietary sources of EPA and DHA.1

Since solid and voluminous scientific backing for the health benefits of n-3 fatty acids exists, a high level of public awareness and acceptance of n-3 fatty acids is becoming more apparent. Considering the fact that it is not always possible to consume adequate amounts of n-3 fatty acids through the diet, the inter-est in n-3 fatty acid supplements has soared. The position of the American Dietetic Association1 on nutritional supplements is that supplements can help some individuals meet their nutrient needs when their diet is inadequate due to different circumstanc-es, including being in an ‘at-risk’ life-stage group for a nutrient deficiency. Examples of such risk groups include the geriatric population, pregnant women, individuals with compromised nutritional status and those with a limited variety in food selec-tion, which prevents achieving nutrient adequacy.

However, although research has shown beneficial effects with increased intakes in n-3 fatty acids, excess intakes can be just as harmful as a deficiency and therefore n-3 fatty acids should be supplemented with caution. Detrimental effects of excess intake of n-3 fatty acids in healthy populations include depression of the immune function, bleeding and increased risk of haemorrhagic stroke, as well as increased lipid peroxidation resulting in oxida-tive damage to various tissues.5 At this point in time there is not sufficient supporting data to establish an upper limit (UL) or safe intake of n-3 fatty acids, however, the FDA has ruled that intakes of up to 3 g/d of marine n-3 fatty acids are generally recognised as safe (GRAS) for inclusion in the diet.6

Undesirable effects from consuming n-3 fatty acids have also been identified in a few selected populations. It has been suggest-ed that diabetics or individuals with impaired glucose tolerance must use n-3 fatty acid supplements with caution since it might have detrimental effects on glucose homeostasis. Increased incidences of nosebleeds have also been reported in individuals with hypercholesterolaemia with n-3 fatty acid supplementa-tion. Furthermore, simultaneous intake of n-3 fatty acids with medication such as aspirin and warfarin will excessively prolong bleeding times in individuals using anti-coagulants.5

Functional Food research Unit, department of agriculture and Food science, cape peninsula University of technology, cape town, south africaMAREThA OPPERMAN, PhD, [email protected] SPINNLER BENADE, DSc

the Nutritional intervention research Unit, Medical research council of south africa, cape town, south africaDE wET MARAIS, MSc


Recommendations regarding the daily intake of n-3 fatty acids vary between 400 and 1 000 mg EPA + DHA in the form of food or supplements.7-13 Nevertheless, it is still not known what the optimal daily intake of EPA and/or DHA should be and how these fatty acids affect the metabolism of 18-carbon fatty acids and longer n-6 and n-3 fatty acids, and whether this might result in any adverse health outcomes. Based on the available evidence, n-3 fatty acid supplements provided in the appropriate dose would be expected to confer health benefits, especially in individuals who do not eat fish.1

To obtain these suggested daily intakes might be challeng-ing for the consumer if only fatty fish is eaten, since ample amounts of about 220 to 240 g fatty fish (e.g. salmon) must be consumed weekly to reach a daily intake of 500 mg EPA + DHA.14 Therefore, fish oil preparations may be helpful to reach the daily recommended n-3 fatty acid intake. However, the actual long-chain n-3 fatty acid content of fish may fluctuate greatly, even within a single species, and is dependent on geographic origin, season and preparation.15,16

In a recent study17 in Belgium, 15 food supplements formu-lated as soft capsules containing n-3 fatty acids were evaluated by desegregation, determination of peroxide values and assay of the n-3 fatty acid content. All the products contained purified fish oil rich in n-3 fatty acids, mainly EPA and DHA, and were available as triglycerides, ethyl esters or free fatty acids. Seven of the 15 food supplements deviated from one or more of the criteria with regard to the recommended peroxide value and the content of one or more of the fatty acids.

In an analysis of n-3 fatty acids in fish oil supplements conducted in Austria, nine supplements were analysed using capillary gas chromatography to determine the n-3 fatty acid content. In comparison with the manufacturer’s information, four supplements did not differ significantly from the concentrations given, whereas four supplements contained substantially more EPA and DHA than stated on the label. One of the manufactur-ers did not declare the amount of n-3 fatty acids in the product. Regarding manufacturer’s recommendations for daily intake, one of the supplements exceeded the amount recommended by healthcare organisations. Five of the nine supplements lacked more than 30% EPA and DHA to meet the American Heart Association’s recommendations. Additionally, two supplements failed to achieve the range of 0.5 to 1.8 g n-3 fish oil found to be effective in most studies.18

Currently, no similar existing data are available for n-3 fatty acid supplements offered on the South African market. Although n-3 fatty acids in the form of supplements appear to be the safer and more controllable way of consuming n-3 fatty acids, all preparations rely on fish oil as a source of EPA and DHA, which may show the same variability as the natural product these prepa-rations are derived from. Additionally, South African consum-ers have grown accustomed to the high quality inherent in the manufacture of conventional medicinal products and usually accept without question the consistency, purity and potency of prescription and non-prescription medications. Consequently, consumers have little reason to doubt the package label claims on conventional medications.

However, a similar claim cannot be made for dietary supple-ments in South Africa since no regulatory structure for dietary supplements currently exists. As a result, consumers of nutri-tional supplements must depend on self-regulation within the

nutraceutical industry for assurance of product quality, consist-ency, potency and purity. Reliable and trustworthy nutritional information is vitally important for the consumer since mislead-ing nutritional information can lead to errors in daily dosage, with serious dose-related side effects.

The aim of this study was therefore to analyse the fatty acid content, composition and the level of rancidity of commercially available n-3 supplements on the South African market. The objectives of the analyses were to compare analysed EPA and DHA content of capsules to manufacturers’ labelling informa-tion, to compare the number of capsules and price of supple-ments to meet international recommended dietary intakes, to supply an indication of the EPA to DHA ratio of commercially available capsules, and to measure the conjugated diene content (early indication of lipid peroxidation) in n-3 fatty acid supple-ments on the South African market. In addition, the mercury content of all the products was determined.

MethodsThe fatty acid content, composition and conjugated diene content of 45 commercially available n-3 fish oil supple-ments were analysed. Brands analysed, in no particular order, included: Amipro®, Biogen®, Equazen®, Vital®, Clicks®, Clicks Health Basics®, Bettaway®, Thinkwell®, AddVance®, NutriLida®, Dischem®, Golden Products®, Health Balance®, Holstix Fish®, AddAway®, Tslim Plus®, Amway Nutrilite®, Rejuvenesse®, The Real Thing®, Solal®, Durbell®, Natrodale®, Optimega®, Revite®, Vitaforce®, Mum Omega®, Preg Omega®, OmegaCare®, Brain Child®, Bioter Health® and Unique Formulations®.

The conjugated diene (CD) content of oils represents an early stage of oxidation (rancidity). The content of conjugated dienes in the 45 n-3 capsules were determined spectrophotometrically as described by Recknagel and Glende.19 Since no CD reference values were available for oils, the CD content of fresh, unopened sunflower, olive palm and canola oil were used against which to compare the supplements’ CD contents. The CD contents of sunflower, olive and canola oil were 4.28, 6.68 and 8.28 μM, respectively. The CD contents of sunflower, olive and canola oil of which half of the contents had already been used were 16.8, 18.2 and 18.7 μM, respectively.

The content of mercury in the 45 n-3 capsules was determined by atomic absorption spectroscopy according to the method of Aduna de Paz et al.20 Samples were digested with nitric acid (HNO3) and hydrogen peroxide (H2O2) in a microwave oven (Milestone MLS-1200 MEGA, Milestone GmbH) equipped with a high-pressure rotor for six teflon vessels. Total mercury (Hg) was determined by cold vapour generation on a Thermo atomic absorption spectrophotometer (SOLAAR M Series) coupled to a vapour generator (Thermo model VP100, Thermo Scientific), using SnCl2 as the reductant. Standard quality-control procedures were adopted throughout. Spiked samples gave an average recov-ery of 94.1%.

A Varian model 3300 chromatograph was used and fitted with a BPX-70 fused silica capillary column (30 m × 0.32 mm i.d., 0.25-mm film thickness). The injector and flame ionisation detector was at 240 and 280°C, respectively. The column temper-ature was programmed from 160 to 220°C at a rate of 3°C per minute. A hydrogen column flow rate of 30 cm.sec-1 was used.

The method of fatty acid extraction and methylation as


described by Christie21 was slightly modified to suit our analyti-cal requirements: 100 mg of sample was dissolved in 20 ml chloroform/methanol (2:1); 200 μl of this solution was then dried under a stream of nitrogen and 2 ml of a fresh solution of 5% sulphuric acid in methanol was added in glass-stoppered tubes and incubated in a water bath at 70°C for two hours. After cooling, 1 ml of distilled water and 2 ml of hexane were added to the sample and vortexed for one minute. The hexane phase was allowed to separate and was then transferred to a glass tube to be evaporated under a stream of nitrogen at 40°C.

The residue was then re-dissolved in 50 μl carbon disul-phide (CS2) and 1 μl was injected into the gas chromatograph. Heptadecanoic acid was used as an internal standard. Butylated hydroxy toluene was added as an antioxidant to all samples. The EPA and DHA content of the samples were quantified and expressed as a percentage of EPA and DHA of total fatty acid content.

One of the objectives of this research was to compare the EPA and DHA contents, as claimed by manufacturers on the supplement label, with the actual measured contents. An accept-able range between 90 and 110% of the manufacturers’ claimed content for EPA and DHA was proposed. Therefore, supplements containing ≤ 89% of the claimed EPA and/or DHA content were perceived as substandard supplements, while those containing more than 110% were considered to be excessive. The coeffi-cient of variance (CV) for the analysis of EPA and DHA was 2%.

resultsComparison with the manufacturers’ labelling information (Fig 1) showed that 56% (n = 25) and 51% (n = 23) of the supple-ments failed to meet the lowest range of 89% for EPA and DHA concentrations, respectively. Only 31% (n = 14) of the EPA and 36% (n = 16) of the DHA contents of supplements were within the acceptable range of 90 to 110%. Thirteen per cent (n = 6) of the preparations held more EPA than stated, while a similar number (13%; n = 6) of supplements had a higher DHA content than indicated.

Number of capsules and price to reach recommendationsCurrently there are no South African daily dietary intake recom-mendations for n-3 fatty acids. However, manufacturers of n-3 fatty acid supplements suggest a daily dosage of capsules on their labels, with no indication of the basis on which these

recommendations were made. For the purpose of this publica-tion, the International Society for the Study of Fatty Acids and Lipids (ISSFAL)14 recommendation of 500 mg EPA + DHA per day for the prevention of cardiovascular disease was applied as guideline. Fig. 2 provides a summary of the number of capsules needed to reach ISSFAL’s12 recommendations while Fig. 3 high-lights the cost (ZAR) to achieve a daily intake of 500 mg EPA + DHA/day.

Forty-two per cent (n = 19) of supplements were able to supply 500 mg EPA + DHA/day with the administration of two capsules per day, while only 7% (n = 3) of supplements could provide the recommended intake by consumption of one capsule per day. In 20% (n = 9) of the supplements, more than five capsules per day had to be ingested daily to meet the ISSFAL14 recommendation.

The majority (38%; n = 17) of the supplements varied between R2.01 and R5.00 per day to meet the ISSFAL14 recom-mendation of 500 mg EPA + DHA/day. This represents an amount of R60.30 to R150.00 per month. Less than a third (31%; n = 14) of the supplements were priced between R1.01 and R2.00 per day (R30.30 to R60.00 per month). Some supplements (4%; n = 1) even cost up to R30.00 to R40.00 per day to supply a 500-mg EPA + DHA dosage.

Fig. 1. percentage of claimed Epa and/or dHa content. *acceptable range = 90–110%.

454035302520151050

supp

lem

ents

(n =

45)

56% 51%

< 89% 90–99% 100–109% > 110%percentage (%)

24% 20%7%

16% 13% 13%

% claimed Epa % claimed dHa

Fig. 2. summary of the number of capsules needed to meet issFal14 (500 mg Epa + dHa per day) recommenda-tion.

3/day 18%

4/day 13%

1/day 7%

2/day 42%

> 5/day 20%

(n = 45)

Fig. 3. price (r) to achieve daily intake of 500 mg Epa + dHa.

454035302520151050

supp

lem

ents

(n =

45)

< r1.00 r1.01–r2.00

r2.01–r5.00

r5.01–r10.00

r10.01–r15.00

r30.00–r40.00

price (r)

31%38%

4%18%

4%5%


EPA to DHA ratioFish oils from different sources contain variable mixtures of EPA and DHA. Most commercially available fish oils contain a proportion of 2:1 EPA to DHA.22 Regarding the EPA to DHA ratio in South African n-3 fatty acid supplements, most of the studied supplements (40%; n = 18) had an EPA:DHA ratio of 1.51–2.0:1, while 36% (n = 16) of supplements had a 2.1–2.5:1 EPA:DHA ratio. Only a few (13%; n = 6) supplements had a higher DHA:EPA ratio (EPA:DHA ratio < 0.5) (see Table 1).

Conjugated dienesThe majority (73%; n = 33) of commercially available n-3 fatty acid supplements had a CD content higher than 21 μM. Only 27% (n = 12) of the n-3 fatty acid preparations contained a CD content of less than 20 μM, while barely any supplements (n = 4; 9%) contained a CD content comparable to fresh, unopened oils (see Fig. 4). These values were measured notwithstanding the presence of added vitamin E as an antioxidant.

Mercury contamination Mercury was virtually absent from the oils in the supplements and was therefore not of any health concern in these samples.

discussionAn extensive variety of n-3 fatty acid supplements are available to the South African consumer, however, our results have shown that supplements vary to a large extent in terms of claimed and measured EPA and/or DHA content, levels of fatty acid oxida-tion, EPA to DHA ratio, as well as numbers of capsules and price to meet international dietary recommendations. When comparing claimed to measured contents of EPA and DHA in South African n-3 fatty acid supplements, it is of concern that information appearing on almost two-thirds of these supplements’ labels was not a true reflection of the actual contents of the supplements. It was decided to compare supplements against an arbitrary 90 to 110% standard. In other words, supplements’ label information was considered as a truthful reflection of the measured content if the EPA and/or DHA content analyses were between 10% less or 10% more, compared to the claimed content.

More than half of commercially available South African n-3 fatty acid supplements failed to attain 90% of the claimed contents of EPA or DHA or both, while approximately 15% of supplements contained more than 110% of the claimed contents of EPA or DHA or both. Since the typical Western diet is

characterised by a low n-3 and very high n-6 fatty acid intake, many consumers rely on supplements to increase their daily n-3 intakes. Unfortunately, if unreliable information is published on labels, consumers are supplied with misleading information, leading to erroneous dosages, with subsequent consequences.

If a supplement contains less n-3 fatty acids than claimed, consumers waste their money without optimal improvement of their n-3 fatty acid status. In contrast, excess n-3 fatty acid intakes can be just as detrimental as a deficiency. Adverse effects of excess intake of n-3 fatty acids in healthy populations include suppression of the immune function, bleeding and increased risk of haemorrhagic stroke, as well as increased lipid peroxidation, resulting in oxidative damage to various tissues. Furthermore, simultaneous intake of n-3 fatty acids with medication such as aspirin and warfarin will excessively prolong bleeding times in individuals using anti-coagulants.5 The FDA has ruled that intakes of up to 3 g/d of marine n-3 fatty acids are generally recognised as safe (GRAS) for inclusion in the diet.5

Regarding the number of capsules needed to meet optimal n-3 fatty acid intakes, our results indicate that only a few supple-ments were able to provide the daily need in one capsule. Some supplements even required a dosage of more than five capsules to meet international recommendations. In addition to this, our analyses have shown that the majority of n-3 supplements on the South African market were priced between R2.01 and R5.00 per day to meet the ISSFAL recommendation of 500 mg EPA + DHA per day. This represents an amount of R60.30 to R150.00 per individual per month. To provide a family of four with the daily recommended intake of 500 mg EPA + DHA adds up to between R242.40 and R600.00 per family per month.

Since malnutrition, especially in poverty-stricken areas, is a major health problem in South Africa, it can be accepted that many people have either a marginal or deficient n-3 fatty acid status. Considering the current financial situation in South Africa, in combination with a large part of the South African population living in poverty, this amount is substantial in terms of monthly expenses for the average South African family. Hence, it is impossible for the average South African to consume an n-3 fatty acid supplement on a regular basis. Some supple-ments are even more expensive and can cost up to R1 060 per person per month to meet the recommended intake of 500 mg EPA + DHA per day.

The ratio of EPA to DHA in n-3 supplements has become an important point of discussion. Gorjão et al.22 reported that most commercially available fish oils present with a 2:1 ratio of EPA to DHA, while numerous cold-water oily fish sources

TABLE 1. EPA TO DHA RATIO IN SOUTH AFRICAN N-3 FATTY ACID SUPPLEMENTS

Ranges EPA:DHA ratio (n) EPA:DHA ratio (%)

< 0.5:1 6 13

– 1.5:1 2 4

1.51–2.0:1 18 40

2.1–2.5:1 16 36

2.51–3.0:1 0 0

3.0–3.5:1 1 2

> 5:1 2 4

Fig. 4. conjugated diene content of south african n-3 fatty acid supplements.

454035302520151050

supp

lem

ents

(n =

45)

< 10 11–20 21–30 31–40 > 41conjugated dienes (µM)

9%18% 16%

39%

18%


have higher DHA to EPA ratios.23 According to Kris-Etherton et al.,16 the majority of commercially available n-3 fatty acid supplements in the United States provide 180 mg EPA and 120 mg DHA per capsule, representing a ratio of 1.5:1 EPA to DHA. EPA and DHA have different effects on various health aspects and under certain conditions it seems that a higher DHA to EPA ratio is preferable.

In the brain, DHA is the main n-3 polyunsaturated fatty acid,24 and the importance of DHA in neural and visual develop-ment and function, especially during pregnancy, lactation and infancy,25,26 is well documented. Additionally, deficits in DHA appear to contribute to inflammatory signalling, apoptosis and neuronal dysfunction in the progression of Alzheimer’s disease (AD), a common and progressive age-related neurological disor-der unique to structures and processes of the human brain.27

With regard to cell function, Gorjão et al.22 reported that some studies have shown that EPA and DHA have diverse effects on cell functions such as leukocyte functions. EPA and DHA also modulate the expression of genes in lymphocytes differently, and affect the activation of intracellular signalling pathways involved with lymphocyte proliferation in a different way, therefore neces-sitating different EPA to DHA ratios to ensure optimal function.

Mori and Woodman28 compiled a review on the independ-ent effects of EPA and DHA on risk factors for cardiovascular disease in humans. From their report, it seems that EPA and DHA have diverse haemodynamic and anti-atherogenic effects. According to Mori and Woodman,28 both EPA and DHA are effective in reducing serum triglyceride levels but only DHA has the ability to increase high-density lipoprotein cholesterol (HDL-C). DHA also increases low-density lipoprotein (LDL) particle size, a potential anti-atherogenic effect. Neither EPA nor DHA show any effects on total cholesterol, while it appears that DHA is more effective in reducing blood pressure and heart rate when compared to EPA.

However, most clinical data available on the cardiovascular effects of n-3 fatty acids used a combination of EPA + DHA supplementation. Future research studies should therefore assess the individual effects of EPA and DHA in a variety of clinical settings and target populations, before decisions can be made on specific ratios of EPA to DHA in supplements and food fortified with either EPA or DHA.

Conjugated dienes (CDs) contain two or more double bonds and are formed during the oxidation process of unsaturated fatty acids to ensure a more stable radical.30 CDs are used to deter-mine primary oxidation products and therefore provide an early indication of the levels of lipid oxidation.31 Although primary oxidation products such as CDs have no colour or flavour of their own, they can readily be decomposed to secondary products such as aldehydes, ketones and alcohols. These secondary oxidation products have distinctive flavours and contribute to the offensive taste of decomposed seafood and marine oils.31

Considering the CD content of commercially available South African n-3 fatty acid supplements, it seems that the majority contain high amounts of primary oxidation products. No clear relationship could be established between the expiry dates and the CD content of the n-3 supplements. These results therefore suggest that a considerable variation exists in the quality of the fish oil present in n-3 capsules in South Africa. This indicates that the oils present in many of the supplements are in the first stages of rancidity and hence negatively influence the quality of

the product that consumers buy. An additional health concern related to fish and fish oil

supplements is that some species of fish may contain consider-able levels of heavy metals such as methyl mercury.8 Methyl mercury may be present at low levels in fresh waters and oceans but tends to concentrate in the aquatic food chain such that levels are generally highest in older, larger, predatory fish and marine mammals. Fish and seafood are a major source of human expo-sure to methyl mercury.

Methyl mercury has a relatively long half-life in human tissue and can accumulate in individuals who consume contaminated fish and fish oils on a regular basis. Skinning and trimming is usually recommended to reduce exposure to contaminants but because methyl mercury is distributed throughout the muscle, skinning and trimming does not significantly reduce mercury concentrations in fillets. Pregnant and lactating women as well as children are generally advised against the consumption of shark, swordfish, king mackerel and tilefish, since these species may contain higher levels of mercury.32 Our analysis has shown that mercury was virtually absent in the oils present in the South African samples and it is therefore not of any health concern.

It is undoubtedly the responsibility of manufacturers to provide accurate information on supplement labels to protect the consumer against misleading health and nutrient claims, to ensure the safety of the consumer and to guarantee a high-quality, consistent product. However, in South Africa this does not seem to be the case.

Possible reasons for substandard supplements on the South African market may include: poor quality of imported fish oil, seasonal differences in EPA and/or DHA concentrations of imported fish oils, lack of proper labelling legislation of food supplements, inappropriate handling of fish oil when harvested, improper storage conditions of both fish oil and supplements, oxidation of fatty acids, ineffective quality assurance by supple-ment manufacturers, and infrequent or poor batch-control analy-ses. If these issues are not addressed and legislation on food supplements is not enforced, South African consumers will have to deal with substandard dietary supplements.

conclusionMore than half of the n-3 supplements available on the South African market contained less than the amount of EPA and/or DHA content as claimed on the labels of the products, which has considerable cost implications for the consumer. Early indicators of rancidity in the majority of capsules suggest a wide variation in the quality of the marine oils present in the n-3 capsules avail-able on the South African market. This is despite the addition of vitamin E as antioxidant. South African n-3 fatty acid supple-ments appear to be virtually free of methyl mercury.

We thank Mr Francois Wewers from the Department of Chemistry, CPUT for the determination of the mercury content of the fish oil capsules.

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review article

potentially increasing rates of hypertension in women of childbearing age and during pregnancy – be prepared!J MOODLEy

abstract The incidence of hypertension in young women is likely to increase in the near future because of the rising rates of the metabolic syndrome, obesity and dyslipidaemia worldwide. Consequently, more women will be on antihypertensive agents, which have the potential for teratogenecity. It is also likely that the increasing number of young women with essential hypertension who become pregnant will develop pregnancy-specific disorders such as pre-eclampsia. Health professionals should be aware of the effects of hyperten-sion in women during the childbearing years, as well as the impact of pre-eclampsia on cardiovascular disease in later life. Pre-conception counselling skills, and knowledge on the use of antihypertensives and the changes that occur during pregnancy should be added to the clinical armamentarium of all health professionals.

Keywords: pregnancy hypertension, childbearing years, antihy-pertensive medication



DOI: 10.5830/CVJA-2010-074

Hypertensive disorders are the commonest medical complica-tions occurring in pregnancy. They occur in approximately 6–8% of all pregnancies in the USA and cover a spectrum of disorders, such as chronic hypertension, gestational hypertension and pre-eclampsia/eclampsia syndrome.1 In South Africa, rates of hypertensive disorders in pregnancy are higher. A community-based study found a 12% incidence of hypertensive disorders in pregnancy in KwaZulu-Natal,2 while a tertiary facility-based study reported a rate of prevalence of 18%.3

Of recent concern is the increasing prevalence worldwide of obesity and the metabolic syndrome. Pregnant women who develop pre-eclampsia de novo share many of the risk features of the metabolic syndrome, namely, dyslipidaemia, obesity and insulin insensitivity. Therefore, increasing numbers of women could develop hypertension in their childbearing years and during pregnancy.

An increase in the numbers of young women presenting with hypertension would create challenges for general medical

practitioners, obstetricians and specialist physicians. Firstly, significant hypertension requires investigation for an underlying cause. Secondly, the selection of antihypertensive agents for the treatment of essential hypertension in women of childbearing age poses challenges, as most antihypertensive medications are potentially teratogenic. Thirdly, several well-defined clinical hypertensive conditions, such as pre-eclampsia, are associated with high rates of maternal and neonatal morbidity and mortal-ity. Lastly, hypertensive pregnancy disorders were tradition-ally not considered to have any long-term deleterious effects on cardiovascular health. However, recent studies have shown that pregnancy-specific hypertension is a risk factor for cardiovascu-lar health later in life.4,5

Intensive counselling on the long-term impact of hypertensive disorders in pregnancy, the potential teratogenic effects of anti-hypertensive agents, appropriate diagnosis of pregnancy-specif-ic hypertensive conditions and timely interventions therefore require an interdisciplinary approach if complications arising from these conditions are to be minimised.

treatment of essential hypertension in women of childbearing ageAlthough the Joint National Committee (JNC7) definition of hypertension and the treatment goals do not vary according to age and gender, the use of antihypertensive drugs in women of childbearing age and during pregnancy should be carefully considered in respect of their teratogenic potential.6 It is well established that angiotensin converting enzymes and receptor blockers have similar foetal effects in that they are associated with foetal renal agenesis, especially if used in the first trimester. However, several other antihypertensive agents seem to carry minimal teratogenic risks to the foetus (Table 1).

Women of childbearing age with class I hypertension usually do not require antihypertensive mediations.6 Successful lifestyle modifications and exercise in this group have been reported to demonstrate better blood pressure control.7-10 Furthermore, essen-tial hypertension is independently associated with pre-eclampsia, and antihypertensive therapy in this group does not prevent the development of pre-eclampsia/eclampsia.

Normal haemodynamic changes in pregnancy Physiological changes in pregnancy may mimic signs of early congestive cardiac failure, and all health professionals should be aware of this. Briefly, changes in the cardiovascular system begin early in pregnancy, reaching a maximum at 28 weeks’ gestation. Within the first 12 weeks of pregnancy, the total intravascular

women’s Health and Hiv research Unit, department of obstetrics and gynaecology, Nelson r Mandela school of Medicine, University of KwaZulu-Natal, durban, south africaJ MOODLEy, MB ChB [email protected]


plasma volume increases by 30–40%.11 Red blood cell mass increases by approximately 20%, but with the increased volume there is a relative decrease in the haematocrit.

The cardiac output increases on average by approximately 35%, commencing early in the first trimester, reaching a peak at 14 to 16 weeks and remaining at a plateau until labour. In labour, cardiac output increases moderately with each contraction and more appreciably with each expulsive effort in the second stage of labour. Most of the increase in cardiac output falls dramati-cally very soon after delivery (Fig. 1).

The increase in cardiac output in pregnancy is the result of an increase in pulse rate and stroke volume. The heart rate increases on average by 15 to 20 beats per minute and the stroke volume by 5–10 ml.11

Cardiac output is also influenced by maternal position. In the supine position (the patient lying on her back), venous return is reduced owing to pressure exerted by the pregnant uterus on the inferior vena cava. This reduced return leads to reduced output and hypotension (supine hypotension syndrome). This phenom-enon is most often seen in late pregnancy.

Arterial blood pressure (Fig. 2)In the lateral recumbent position, the blood pressure is higher in the upper arm than the lower (10–12 mmHg). While sitting,

the blood pressure is slightly higher than in the supine position. Peripheral vascular resistance decreases during pregnancy due to the relaxing effect of progesterone on the smooth muscles. The subsequent decrease in blood pressure reaches a nadir in the second trimester compared with the early third trimester – the well-known drop in blood pressure.

The average decrease in systolic blood pressure is 5–10 mmHg and the decrease in diastolic is 10–15 mmHg. If this decrease fails to occur, it is reported that such women are more likely to develop hypertension in the third trimester of preg-nancy.12

definition of hypertension in pregnancy Hypertension in pregnancy is defined as systolic blood pres-sure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg (Korotkoff 5). It should be noted that because elevations of both systolic and diastolic blood pressure have been associated with adverse maternal and foetal outcomes, both are important. Also, detecting a rise in blood pressure from ‘booking’ or pre-concep-

TABLE 1. ANTIHYPERTENSIVE DRUGS FOR USE DURING PREGNANCY

Drug Route Dose Time Action Side effects

Methyldopa po 0.25–1.5 g twice/day 3–5 days False neurotransmitter Orthostasis, sleepiness, depression

Labetalol po

iv

200–1200 mg/d two or three times/day in divided doses20–40 mg iv every 30 min as needed

2–4 hacts within 5 min

Non-selective b-blockade Tremulousness, headache

Nifedipine po 30–120 mg/day 30 min Calcium channel blocker Oedema, orthostasis, dizziness

Monohydralazine po 50–300 mg/d two or three times/day 1–2 h/ 20–30 min

Direct vasodilator Lupus-like syndrome with chronic use

Dihydralazine ivpo

10 mg every 2 h as needed12.5–25 mg daily

Hydrochlorothiazide po 12.5–25 mg daily 3–5 d Diuretic

Emergency medicationsLabetalol as notedhydralazine as notedNifedipine as notedDiazoxide

ivivpoiv 30–50 mg every 5–15 min 2–4 min Direct vasodilator Hypotension, hypoglycaemia

Nitroprusside iv 0.25 μg/kg/min 1–2 min Direct vasodilator Hypotension, cyanide toxicity if used > 4 h

po = per os; iv = intravenous

Fig. 1. Maternal cardiac output during pregnancy.

100

75

50

25

0

card

iac

outp

ut in

crea

se (%

)

12 28 40duration of pregnancy (weeks)

Increase during labour and delivery

Increase during pregnancy

Increase in cardiac outputIn some studies a decrease was shown in the late second and early third trimesters

Fig. 2. variation in arterial blood pressure during preg-nancy.

150

125

100

75

50

0

Bloo

d pr

essu

re

First trimester

second trimester

third trimester

labour and delivery

immediate

Blood pressure in mmhg

120110

120130

120

8060

80 80 85

100

90

80

70puls

e ra

te

72

87

65

Pulse rate in beats per minute


tion blood pressure (> 30/15 mmHg) should lead to closer moni-toring, but it is not diagnostic of hypertension in pregnancy.12

chronic hypertension Chronic hypertension presents prior to pregnancy or before the twentieth week of gestation. It is reported to complicate 3% of all pregnancies and is more common in women who are obese or those over the age of 35 years. It is important to note that 20–30% of women with chronic hypertension go on to develop superimposed pre-eclampsia.13

pre-eclampsia/eclampsia syndromePre-eclampsia is a syndrome of new-onset hypertension (> 140/90 mmHg) occurring after the twentieth week of gesta-tion, with proteinuria (2+ on dipstick on two occasions six hours apart or > 3 g/24-hour urine collection).12

The aetiology remains elusive but current views suggest that it is a two-stage disorder.14 Put simply, the first stage is one of placental hypoperfusion, resulting in the release of a variety of substances (apoptotic cells, trophoblastic debris and anti-angiogenic factors) which cause multisystemic endothelial damage. The second stage presents as the clinical syndrome of hypertension, proteinuria, hepatic and central nervous system dysfunction.14 It is difficult to predict which organ system will be predominantly affected, but in general terms, the clinical signs of hypertension and proteinuria are the commonest. Pre-eclampsia therefore represents a spectrum of endothelial damage leading to downstream health effects.

Pre-eclampsia is divided into mild and severe categories. Severe disease is characterised by hypertension, namely, blood pressure values above 160/100 mmHg, proteinuria above 5 g per 24 hours, neurological symptoms (headache, visual distur-bances), renal compromise (elevated serum creatinine and urea), hepatic dysfunction and haemolysis, and intra-uterine growth restriction. The presence of these symptoms and signs constitutes a medical/obstetric emergency, requiring admission to hospital and a multi-disciplinary approach to management.12

Although the exact aetiological mechanism is not known, epidemiological evidence suggests that pre-eclampsia affects the future health of the woman and her baby. Women with a history of pre-eclampsia are twice as likely to develop hypertension and two to five times more likely to have an ischaemic stroke in later life.4,5 It is unlikely that placental dysfunction on its own (stage I) leads to the pre-eclamptic disorder, but interactions with mater-nal constitutional factors (genetic, behavioural or environmental) may also be involved in the second stage of the disease process.

The ultimate therapy for pre-eclampsia is delivery of the baby, because the exact cause of the disease is not known. Clinical management is therefore individualised. In women with early-onset superimposed pre-eclampsia, blood pressure levels may increase quickly, be labile and require therapy as for a hypertensive emergency.15,16 In such circumstances, rapid lowering of high blood pressure and delivery of the baby, even if premature, may be required to prevent maternal complications.17 Treatment of high blood pressure alone will not prevent obstetric complications in such settings, and delivery of the foetus may be necessary to prevent adverse events in pregnancy, labour and the puerperium.

There is no doubt in the literature that women with sustained

blood pressure values above 160 mmHg systolic and/or 110 mmHg diastolic should be treated with antihypertensive agents.16-18 On the other hand, there is little evidence to support antihypertensive therapy in pregnant women with blood pressure values below 160/100 mmHg. Nevertheless, in the clinical situ-ation, there is a tendency to use antihypertensive medications in such circumstances, together with lifestyle modifications (diet and exercise).

Lifestyle modifications should ideally be initiated prior to conception in women with chronic hypertension, and continued in pregnancy. Exercise has been associated with reductions in gestational hypertension and a lower risk of eclampsia/pre-eclampsia. Due consideration however, needs to be given when making recommendations to maintain calorie intake and prevent-ing injury.8-10

antihypertensive drugs in pregnancy Table 1 lists the commonly used antihypertensive drugs. First-line agents include methyldopa, nifedipine and labetalol. Methyldopa is the most commonly used antihypertensive medication and the most studied. It has a long history of safety, is well tolerated and efficacious, and is often the first medication attempted in pregnant women. Methyldopa can be used three times daily, particularly if high doses are required. This dose makes it a cost-effective method of treatment. Labetalol has also been studied extensively and found to be effective, although some studies have associated it with foetal growth restriction.

Angiotensin converting enzymes/angiotensin receptor block-ers should be avoided in pregnancy and in women intending to become pregnant. These agents are associated with renal agen-esis and foetal death.19 If a woman becomes pregnant while on angiotensin converting enzymes/angiotensin receptor blockers, these agents should be stopped immediately and alternate agents that have been found to be safe in pregnancy should be used. It is also important to note that if these agents are to be considered for use in young women of childbearing age, careful counselling and contraceptive advice must be offered.13,20

There are theoretical concerns regarding the use of diuretics during pregnancy. These include decreased placental perfusion and neonatal thrombocytopenia; therefore diuretics are not first-line agents. Calcium channel blockers are used in pregnancy. Most of the literature is on the use of nifedipine and it is regarded as safe for use in pregnancy.18,21 Other calcium channel blockers are probably safe although the manufacturers do not recommend their use. Selective b-blockers are considered safe during preg-nancy but high doses are associated with neonatal hypoglycae-mia and low birth-weight babies.18

Antihypertensive medication needs to be continued after delivery because blood pressure remains elevated for at least three to five days following delivery.18,19 Observational studies suggest that up to 25% of women with severe pre-eclampsia have ongoing postnatal hypertension.22 Consequently, a step-down approach to reducing the use of antihypertensive agents should be taken rather than stopping abruptly. Most antihypertensive agents are expressed in breast milk in minimal quantities.

Hypertension in young women: pregnancy and the general practitionerIn South Africa, the general practitioner is often faced with


women requesting a diagnostic test for pregnancy. It is incum-bent on these professionals to ensure that blood pressure meas-urements are taken, so that careful counselling is given about the options of antihypertensive agents in respect of their safety in pregnancy. General practitioners also need to be aware of the supine hypotensive syndrome associated with pregnancy and the fact that Koratokoff 5 is used for measurement of diastolic blood pressure in pregnancy.23

Furthermore, general practitioners may be faced with a preg-nant women presenting with severe hypertension during preg-nancy, with or without symptoms and signs of a hypertensive emergency. These situations must be recognised and antihyper-tensive therapy initiated prior to referral to an appropriate health facility or specialist.

Figs 3 and 4 summarise clinical management and may be useful for general practitioners, obstetricians and physicians. Ideally, such patients should be managed in referral centres, staffed by experts in hypertensive disorders of pregnancy.

conclusionsHypertension in pregnancy is associated with significant mater-nal and perinatal morbidity and mortality. Regular blood pres-sure monitoring, detection of signs of pregnancy-associated

hypertensive conditions and management by health professionals experienced in this field will minimise sequaelae associated with hypertensive disorders in pregnancy, and may have a positive impact on women’s cardiovascular events and outcomes years after the affected pregnancies.

References1. Report on the National High Blood Pressure Education Program

Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183: S1–S22.

2. Panday M, Mantel GD, Moodley J. Audit of severe acute morbidity in hypertensive pregnancies in a developing country. J Obstet Gynaecol 2004; 24(4): 387–391.

3. Moodley J, Kalane G. A review of the management of eclampsia: prac-tical issues. J Hypertens Pregnancy 2006; 25: 47–62.

4. Harskaqmp RE, Zeeman GG. Pre-eclampsia: at risk for remote cardio-vascular disease. Am J Med Sci 2007; 334: 291–295.

5. Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. Br Med J 2003; 326: 845–851.

6. Chobanian AV, Bakrsi GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. and the National High Blood Pressure Education Program Co-ordinating committee. The 7th Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure : the JNC 7 Report. J Am Med Assoc 2003; 289: 2560–2572.

Fig. 3. Management of mild gestational hypertension or pre-eclampsia.

Mild gestational hypertension or pre-eclampsia (BP 140/90–160/110 mmhg and no symptoms)

Maternal and foetal evaluation

Maternal monitoring:Expectant management:– measure BP ≥ 2/week– lab result weekly (FBC, U & E)– assess for proteinuria: screen

with dipstick or spot protein/creatinine ratio and periodic 24-hr urine collections

≥ 40 weeks of gestation≥ 37 weeks of gestation

Bishop score ≥ 6 Noncompliant patient

≥ 34 weeks of gestation Labour or rupture of membranes Abnormal foetal testing results Intra-uterine growth restriction?

< 37 weeks of gestation

> 37–39 weeks of gestation

Inpatient or outpatient managementMaternal and foetal evaluation

Delivery

Delivery

yes No

worsening maternal or foetal condition40 weeks of gestationRipe cervix (Bishop score ≥ 6) at ≥ 37 weeks of gestationLabour

DeliveryFig. 4. Management of severe pre-eclampsia.

Admit to labour and delivery areaMaternal and foetal evaluation for 24 hours

Magnesium sulphate for 24 hoursAntihypertensives if systolic blood pressure ≥ 160 mmhg

Diastolic blood pressure ≥ 110 mmhg or mean arterial pressure > 125 mmhg

Severe pre-eclampsia

Maternal distress, *non-reassuring foetal status, labour or rupture of membranes, > 34 weeks of gestation?

yes No

Delivery Severe intra-uterine growth restriction?

Delivery

< 23 weeks of gestation

23–32 weeks of gestation

33–34 weeks of gestation

SteroidsTermination of pregnancy

– Steroids 24–32 weeks of gestation

– Antihypertensives– Daily evaluations

of maternal and foetal conditions

– Delivery at 34 weeks of gestation

Magnesium sulphate

Delivery

* Symptoms and signs of impending eclampsia rapid-acting antihypertensive agents

yes

yes No


7. Gavard JA, Artal R. Effect of exercise on pregnancy outcome. Clin Obstet Gynecol 2008; 51: 467–480.

8. Sorensen TK, Williams MA, Lee IM, Dashow EE, Thompson ML, Luthy DA. Recreational physical activity during pregnancy and risk of pre-eclampsia. Hypertension 2003; 41: 1273–1280.

9. Saftlas AF, Logsden-Sackett N, Wang W, Woolson R, Bracken MB. Work, leisure-time physical activity, and risk of pre-eclampsia and gestational hypertension. Am J Epidemiol 2004; 160: 758–765.

10. Rudra CB, Sorensen TK, Luthy DA, Williams MA, Luthy DA. A prospective analysis of recreational physical activity and pre-eclampsia risk. Med Sci Sports Exerc 2008; 40: 1836–1841.

11. Kruger TF, de Bruijn JM. Physiological adaptations in pregnancy. In: Obstetrics in Southern Africa. Cronje HS, Grobler CJF, eds. Pretoria: Van Schaik Publishers, 2008: 15–22.

12. Lowe SA, Brown MA, Dekker GA, et al. Guidelines for the manage-ment of hypertensive disorders of pregnancy 2008. A NZ J Obstet Gynaecol 2009; 42: 242–246.

13. Yoder SR, Thornburg MD, Bisognano JD. Hypertension in pregnancy and women of childbearing age. Am Med J 2009; 122: 890–895.

14. Roberts JM, Rajakumar a. pre-eclampsia and soluble fms-like tyrosine kinasel. J Clin Endocrinol Metab 2009; 94(7): 2252–2254.

15. Moodley J. Hypertensive emergencies in pregnancy in under-resourced countries. Curr Opin Obstet Gynecol 2008; 20(2): 91–95.

16. Panday M, Moodley J. Management of the unconscious pregnant patient. Best Prac Res Clin Obstet Gynaecol 2009; 23: 327–328.

17. Paruk F, Moodley J. Untoward effects of rapid-acting antihypertensive agents. Best Prac Res Clin Obstet Gynaecol 2001; 15(4): 491–506.

18. Magee LA. Antihypertensives. Best Prac Res Clin Obstet Gynaecol 2001; 15(6): 827–845.

19. Martin JN Jr, Thigpen BD, Brad D, et al. Stroke a pre-eclampsia and eclampsia: a paradigm shift focussing on systolic blood pressure. Obstet Gynecol 2005; 105(2): 246–254.

20. Briggs GG, Freeman RF, Yaffe SJ. Drugs in Pregnancy and Lactation: a Reference Guide to Fetal and Neonatal Risk. 8th edn. Baltimore: Lippincourt Williams and Wilkins, 2008.

21. Smith P, Anthony J, Johanson R. Nifedipine in pregnancy. Br J Obstet Gynaecol 2000; 107: 299–307.

22. Broughton-Pipkin F, Roberts JM. Hypertension in pregnancy. J Hum Hypertens 2000; 14(10-11): 705–724.

23. Roberts JM, Hubel CA. The two stage model of pre-eclampsia: vari-ations on the theme. Placenta 30 suppl A. Trophoblast Res 2009; 23: S32–S37.

photograph kindly supplied by SA Cardiology & Stroke Journal

cardiovascular Journal of africa 2010 winner of best scientific articleThe first Andries Brink Kaye award for the most outstanding article published in 2010 in the Cardiovascular Journal of Africa was awarded during the South African Heart Congress in East London.

Prof Andries Brink, left, with award winner Andrea de Kock, for her article titled “Coping and metabolic syndrome indicators in urban black South African men: the SABPA study”.


case reports

a rare complication after coronary artery bypass graft surgery: ogilvie’s syndrome A GULER, MA SAhIN, K ATILGAN, M KURKLUOGLU, U DEMIRKILIC

abstractGastrointestinal (GI) complications occur in less than 2% of patients undergoing open-heart surgery. Acute colonic pseudo-obstruction, known as Ogilvie’s syndrome, is also a rare complication encountered in 0.046% of patients undergoing coronary artery bypass graft surgery. It is char-acterised by massive colonic dilatation without mechanical obstruction in patients with underlying medical or surgical conditions. In this report we describe a patient who suffered from acute renal failure requiring haemodialysis, and subse-quently Ogilvie’s syndrome, which was treated with high-dose neostigmine.

Keywords: Ogilvie’s syndrome, neostigmine, coronary bypass surgery



DOI: 10.5830/CVJA-2010-064

Gastrointestinal (GI) complications occur in less than 2% of patients undergoing open-heart surgery, with a morbidity and mortality rate of almost 30%. They are often difficult to diagnose, resulting in delayed treatment.1-4 GI bleeding, mesen-teric ischaemia, pancreatitis, cholecystitis, perforated ulcers and ileuses are some of the complications.5 Acute colonic pseudo-obstruction (ACPO) is characterised by massive colonic dilata-tion without mechanical obstruction in patients with underlying medical or surgical conditions.4 In this report, we describe a patient who suffered from acute renal failure requiring haemo-dialysis, and subsequent ACPO syndrome after coronary artery bypass graft surgery (CABG).

case reportThe patient was a 55-year-old male with a 15-year history of non-insulin-dependent diabetes mellitus, and hypertension for the past three years. He had been referred the previous year to the cardiol-ogy department for chest pain on exertion. A coronary angiogram showed serious coronary artery disease, which suggested he

needed CABG surgery. His pre-operative medications included oral antidiabetics, beta-blockers and angiotensin receptor block-ers. His pre-operative blood analyses were within normal limits, except that he was anaemic with a haemoglobin/haematocrit of 10.1 g/dl (27.3%) and serum urea/creatinine of 102/2.0 mg/dl.

After undergoing six-vessel CABG surgery, the patient devel-oped oliguria and required continuous venovenous haemofiltra-tion at the bedside in the intensive care unit. He also required two additional re-explorations for bleeding, the first six hours, and the second four days after the initial surgery. During the re-explorative surgery, eight fresh, frozen plasmas and six eryth-rocyte suspensions were transfused to the patient. At the end of the 14th postoperative day, the patient was haemodynamically stable and his general condition had improved, but he began to complain of abdominal distention without stool or flatus passage.

On physical examination, the bowel sounds were diminished and the abdomen was markedly distended and painful, but there was no sign of peritoneal inflammation. Therefore, supportive measures including nil per os with total parenteral nutrition, fluid and potassium supplements, and placement of a rectal tube were undertaken to decompress the dilated colonic segments.

As the patient’s renal failure failed to resolve, he began to receive intermittent dialysis with fluid restriction, which made it harder to regulate is caloric intake and potassium supple-mentation. He had already been weakened by surgery. Bedside abdominal ultrasound showed dilated and unmovable bowel segments, with generalised fluid accumulation between them. An abdominal antero-posterior radiography (Fig. 1) and a computer-ised tomography (CT) scan of the patient (Fig. 2) showed dilated colonic segments full of flatus and faeces, and caecal distension of 11 cm, with normal-appearing small bowel segments.

Despite supportive measures, no passage of flatus or stool was observed and the abdominal distention failed to resolve. One week after the onset of the abdominal symptoms, we decided to administer intravenous neostigmine, since we had not been able to find any evidence supporting obstruction, even on CT or ultra-sonography. Half an hour after intravenous administration of 2 mg neostigmine, ordered for three days, we observed the passage of stool and gradual relief of the abdominal distention. Thereafter, enemas and oral laxatives were ordered to facilitate colonic decompression. After 10 days, the patient reported no abdomi-nal problems, describing regular bowel movements every day.

discussionAcute colonic pseudo-obstruction is a rare complication, encoun-tered in 0.046% of patients undergoing CABG surgery.6 Its first description is attributed to William Heneage Ogilvie, who

department of cardiovascular surgery, gülhane Military Medical academy, Etlik, Ankara,TurkeyA GULER, MDMA SAhIN, MD, [email protected] K ATILGAN, MDM KURKLUOGLU, MDU DEMIRKILIC


described this syndrome in two patients with sudden onset of abdominal pain, constipation and large bowel dilatation without an organic cause of obstruction.7 The syndrome is therefore known as Ogilvie’s syndrome. Even though the pathophysiol-ogy of ACPO is not fully demonstrated, it is deemed to be the result of large bowel parasympathetic dysfunction.6 Agents that increase parasympathetic tone have been shown to be successful in resolving pseudo-obstruction without colonic decompression or surgical manipulation. Various studies have shown initial success rates between 73 and 88% and long-term response rates between 88 and 100% with the use of neostigmine methyl sulfate in patients with this condition.8

Appropriate assessment of the markedly dilated colon involves urgent gastroenterological evaluation to rule out any cause of obstruction because this condition may lead to subsequent ischaemia and perforation of the colon.8 It is encountered after almost all types of surgical procedures, including cardiac surgery.

ACPO is characterised by abdominal distension, nausea and/or vomiting, with failure to pass flatus and stools, and occurs in up to 60% of patients.8 In 3 to 15% of patients, massive colonic dilatation may cause ischaemia and perforation, with subsequent clinical findings of peritonitis.6 There is no common size of caecal distension mandating intervention. According to vari-ous authors, surgical treatment is indicated if the caecal size is greater than 8 to 12 cm. However, the symptoms, the patient’s condition, and progression of the disease are considered when deciding on surgical intervention.9,10

ACPO occurs in about 1% of hospitalised patients and 0.046% of patients undergoing CABG surgery.6 The prevalence is higher in late middle age (around 60 years) and it is slightly more common (60%) in men. Because of delayed diagnosis and inappropriate treatment, ACPO is responsible for considerable morbidity, with an overall mortality rate of 25 to 31%, and 40 to 50% of patients developing ischaemia or perforation.8

Diagnosis relies on accurate clinical observation and simple abdominal radiography, showing variable degrees of colonic dilatation, mainly involving the proximal colon. A water-soluble

contrast enema (a sensitivity of 96% and specificity of 98%) or computed tomography (a sensitivity and specificity of 91%) should be performed to differentiate mechanical obstruction from pseudo-obstruction.8

Based on the concept of parasympathetic dysfunction, intrave-nous neostigmine has been tested in controlled trials and remains the mainstay of treatment. In various studies, the success rate of neostigmine treatment has been shown to be 73 to 94% after the first dose, and up to 100% after the second.8 Conservative treatment consisting of a nasogastric tube, fluid resuscitation and enemas may be helpful in almost half the patients (53%). Colonoscopic decompression is successful in 77% of patients, but there is a high rate of recurrence and complications associ-ated with the procedure.6 Therefore colonoscopic or surgical decompression is reserved for situations when conservative treatment fails, or if the caecum is on the verge of perforation.

In our case, haemodialysis, fluid restriction due to low urine output, lack of early mobilisation because of surgical complica-tions and multiple blood transfusions may have contributed to the occurrence of ACPO. Additionally, calorie, fluid and electrolyte administration was not optimal in our case because of general-ised oedema and the patient’s dependence on dialysis. This is an unfavorable situation in a postoperative patient.

conclusionAlthough ACPO is an unexpected and rare complication after CABG surgery, rapid and effective treatment is generally possible with neostigmine. Therefore, early recognition of this syndrome is important to prevent fatal complications.

References1. Alebouyeh N, Toefigh M, Ghasemzadeh N, Mirheydari S, Azargashb E.

Predictors of gastrointestinal perforation in patients undergoing coro-nary artery bypass graft (CABG) surgery in Tehran, Iran. Ann Thorac Cardiovasc Surg 2007; 13(4): 251–253.

2. Ghosh S, Roberts N, Firmin R, Jameson J, Spyt TJ. Risk factors for intestinal ischemia in cardiac surgical patients. Eur J Cardiothorac Surg 2002; 21: 411–416.

3. Yilmaz AT, Arslan M, Demirkilic U, Ozal E, Kuralay E, Bingol H, et al. Gastrointestinal complications after cardiac surgery. Eur J Cardiothorac Surg 1996; 10: 763–767.

4. Recht MH, Smith JM, Woods SE, Engel AM, Hiratzka LF. Predictors and outcomes of gastrointestinal complications in patients undergoing

Fig. 2. caecal dilatation of around 11 cm is shown in abdominal computerised tomography.

Fig. 1. abdominal antero-posterior radiography in the erect position shows high-grade colonic distension.


coronary artery bypass graft surgery: a prospective, nested case-control study. J Am Coll Surg 2004; 198(5): 742–747.

5. Musleh GS, Patel NC, Grayson AD, Pullan AD, Keenan DJ, Fabri BM, et al. Off-pump coronary artery bypass surgery does not reduce gastro-intestinal complications. Eur J Cardiothorac Surg 2003; 23: 170–174.

6. Tenofsky PL, Beamer L, Smith RS. Ogilvie syndrome as a postopera-tive complication. Arch Surg 2000; 135(6): 682–686.

7. Ogilvie H. Large intestine colic due to sympathetic deprivation: a new

clinical syndrome. Br Med J 1948; 2: 671–367.8. De Giorgio R, Knowles CH. Acute colonic pseudo-obstruction Br J

Surg 2009; 96(3): 229–239.9. Meier C, Di Lazzaro M, Decurtins M. Ogilvie syndrome with cecal

perforation. A rare complication after isolated thoracic trauma. Case report and current literature review. Swiss Surg 2000; 6(4): 184–191.

10. Zerr B, Fogliani J, Bouchet P. Treatment of colectasia occurring in intensive care. Ann Fr Anesth Reanim 1987; 6(3): 159–162.

anaesthesia for emergency caesarean section in a patient with peripartum cardiomypathyBABATUNDE OSINAIKE, JOhNSON OGAh

abstractPeripartum cardiomyopathy (PPCM) is defined as the onset of acute heart failure without demonstrable cause in the last trimester of pregnancy or within the first six months after delivery. We report a case of PPCM (LVEF < 39%) in a 30-year-old housekeeper requiring emergency Caesarean section, who was successfully managed with combined spinal–epidural anesthesia, using low-dose fentanyl for the spinal anesthesia.

Keywords: peripartum cardiomyopathy, combined spinal–epidural anesthesia, Caesarean section



DOI: 10.5830/CVJA-2010-067

Peripartum cardiomyopathy (PPCM) is a relatively rare form of acute heart failure associated with pregnancy,1 and defined as the onset of acute heart failure in the last trimester or early postpartum period, in the absence of infectious, metabolic, toxic, ischaemic and valvular causes of myocardial dysfunction.2 Many terms are used to describe this disorder, including toxic post-partal heart failure, postpartum heart disease, postpartum myocardosis, Meadows’ syndrome, idiopathic myocardial degen-eration associated with pregnancy, Zaria syndrome, and postpar-tum cardiomyopathy.3-4

The diagnosis of this disorder is said to depend on the follow-ing criteria: (1) development of congestive heart failure (CHF) secondary to decreased left ventricular systolic function in the last month of pregnancy or within five months after delivery; (2) absence of pre-existing cardiac dysfunction; (3) absence of determinable cause of cardiomyopathy; and more recently, (4) left ventricular systolic dysfunction demonstrated by classic

echocardiographic criteria: left ventricular ejection fraction less than 45%, or M-mode fractional shortening less than 30%, or both, and end-diastolic dimension more than 2.7 cm/m2.5,6

The Hausa tribe of northern Nigeria has the highest known incidence in the world; about 13% of all female admissions having this condition,7 and the incidence has been reported to be as high as 1:100. This is probably related to a local Hausa custom of ingesting a form of lake salt in the immediate postpartum peri-od, a practice that can produce significant volume overload.8 The disease is less common among other ethnic groups in Nigeria.

The anaesthetic management of labour and delivery in pregnant patients with peripartum cardiomyopathy is not well defined and we are unaware of any case report on the anaesthetic management of this subset of patients presenting for Caesarean section (CS) in West Africa. We therefore present a patient with peripartum cardiomyopathy requiring CS who was managed with combined spinal–epidural (CSE) anaesthesia.

case reportA 30-year-old housekeeper with body mass index of 22.2 kg/m2, G4P0+3, was transferred from a peripheral hospital where she had presented at 34 weeks of gestation with pregnancy-induced hypertension and symptoms of cardiac failure. On admission, she gave a history of a week of breathlessness, with cough productive of scanty, whitish, frothy sputum, and associated orthopnoea. She had a previous history of pedal oedema of one month’s duration before presentation. She was not a known hypertensive, diabetic or asthmatic and had no history of drug allergy. There was no previous hospital admission except for a voluntary termination of pregnancy six years earlier.

At the time of admission, she was dyspnoeic lying down, her heart rate was 120 beats per minute and blood pressure (BP) was 160/120 mmHg. On auscultation of the chest, there were bilateral coarse crackles along with a triple rhythm. The chest radiograph showed cardiomegaly with bilateral pleural effusion. The electrocardiogram (ECG) showed sinus tachycardia with widespread ST–T changes in the anterolateral leads and left atrial enlargement. The echocardiogram showed a dilated left atrium, poor left ventricular systolic function, restrictive diastolic dysfunction and mild pericardial effusion about 1 cm over the left ventricle with left ventricular ejection fraction of 39%. More

department of anesthesia, college of Medicine, University of ibadan, NigeriaBABATUNDE OSINAIKE, MB ChB, DA, FMCA, [email protected]

department of anesthesia, University college Hospital, ibadan, NigeriaJOhNSON OGAh, MBBS, DA


investigations and results are listed in Table 1. Treatment included intravenous (iv) furosemide 20-mg bolus,

then 20 mg 12 hourly, iv magnesium sulphate (MgSO4) 4-g bolus then 5 g in 500 ml 0.9% saline to run over five hours for five doses. Also, iv hydralazine 5-mg bolus over 15 minutes, to repeat if systolic and diastolic blood pressure are ≥ 160 and 110 mmHg, respectively, intra-nasal oxygen at 6 l/min and nursed in the cardiac position.

Some improvements in clinical condition were observed about eight hours after commencement of therapy. The respira-tory rate reduced to 36/min, the diastolic blood pressure reduced to less that 100 mmHg and the chest became clearer, however some episodes of foetal tachycardia were observed. Following the improvement in cardiac symptoms, the decision was taken to urgently deliver the baby by Caesarian section. The anesthetist was informed, and in view of the urgency involved, no invasive monitoring could be provided.

On arrival in the operating room, her blood pressure was 119/86 mmHg, pulse rate was 102 bpm, and oxygen saturation was 98%. On auscultation, she still had a few crepitations in both lung bases bilaterally. Peripheral venous cannulation was done with an 18-guage iv cannula and a 0.9% saline infusion was started. ECG leads, a pulse oximetry probe and non-invasive blood pressure cuff were attached for continuous monitoring.

In view of the cardiac condition and the desire of the obste-trician to urgently deliver the baby, combined spinal–epidural (CSE) was chosen. After preloading with 250 ml of 0.9% saline over 30 minutes, CSE was performed at the L4–L5 interspace in the sitting position; 25 μg of fentanyl was injected through a 27-guage 120-mm Sprotte needle into the cerebrospinal fluid, which was introduced through a 16-guage Tuohy needle.

An epidural catheter was inserted through which two doses of 5 ml of 0.5% plain bupivacaine was administered. The patient was placed in the supine position and a wedge was placed under the right hip to minimise aorto-caval compression. Oxygen was administered with a facemask at a flow rate of 5 l/min. The upper levels of sensory block obtained were T8 at three minutes and T6 at five minutes; 250 ml of 0.9% saline and 500 ml of pentastarch were administered intra-operatively to treat hypotension. A vaso-pressor was not administered.

The operation proceeded uneventfully and a healthy female baby of 1.45 kg was delivered eight minutes later (Apgar score 9/10). Intravenous oxytocin 10 mg was administered slowly at the delivery of the placenta and 30 mg was put into 500 ml of 0.9% saline to run as an infusion for five hours. The patient was

haemodynamically stable throughout the procedure. The surgery lasted 30 minutes and estimated blood loss was 500 ml.

The patient’s husband declined admission to the intensive care unit because of financial constraints; hence the patient remained under high-dependency care in the labour ward. Epidural analge-sia was employed for the first 14 hours post-operatively.

discussionAlthough the aetiology of peripartum cardiomyopathy is uncer-tain, viral, autoimmune and idiopathic causes have been consid-ered.9 Some cases of PPCM are being postulated to be part of the spectrum of familial dilated cardiomyopathy (DCM) presenting in the peripartum period.10 It is usually a diagnosis of exclusion, however there is an increased incidence of PPCM with multi-ple gestation, pre-eclampsia, obesity, advanced maternal age,11 African descent and prolonged tocolysis.12

Worldwide, the frequency of peripartum cardiomyopathy is highest where a large proportion of the women are of African descent, such as Nigerian, Haitian and South African.13,14 The lowest frequency of peripartum cardiomyopathy has been reported in studies where women of African descent were less common.15,16 The highest reported incidence is in Nigeria, at 980 out of 100 000 deliveries.17 This very high incidence may be related to a local custom of ingesting salt in the postpartum period, which increased the detection of peripartumn cardio-myopathy by increasing heart failure symptoms.17 Desai et al.14 found a case incidence of 100 out of 100 000 deliveries in South Africa. Fett et al.13 reported an incidence in a predominately rural population in Haiti of 334 out of 100 000 deliveries. The high incidence of PPCM in our region requires that peri-operative management of this subset of patients be well reported.

The presence of PPCM in a parturient requires expert anaesthetic management for labour or for Caesarean section. Aggressive pain management for labour is indicated to keep the heart rate and systemic vascular resistance under control and to attenuate the volume overloading effect of each uterine contrac-tion.18 The literature regarding the anaesthetic management of peripartum cardiomyopathy is sparse, although several anaes-thetic options for CS have been reported. These include general anaesthesia (GA) with inhalational agents,19 general anaesthesia with remifentanil,20 epidural anaesthesia,21 spinal anaesthesia,22 and combined spinal–epidural anaesthesia (CSE).23

Considerations for regional anaesthesia in patients with PPCM are similar to those with other causes of heart failure. With regard to anaesthesia for Caesarean section, general anaesthetic techniques involve drugs, which cause myocardial depression and reduced systemic vascular resistance (SVR); and positive-pressure ventilation, which decreases the venous return to the heart. Also, the effects of stimulation of the sympathetic nervous system following laryngoscopy and endotracheal intu-bation may be inimical for a failing heart. General anaesthesia may be necessary for urgent CS.24 However, performing a rapid-sequence induction on a patient with compromised cardiac func-tion can be very challenging. When time permits, a carefully administered regional anaesthetic seems to be advantageous.

In addition to avoiding the stress of GA, the vasodilatation produced by regional anaesthesia is beneficial with isolated left ventricular dysfunction.25 The goals during the management of anaesthesia in patients with cardiomyopathy include avoidance of drug-induced myocardial depression, maintenance of normo-

TABLE 1. HAEMATOLOGICAL AND BIOCHEMICAL INVESTIGATIONS

Investigation/test Before surgery After surgery

Packed cell volume (PCV) 47%, 34%

White cell count (WBC) 15 400/cm

Platelet count 136 000/μl

International normalised ratio (INR) 1.1

Serum electrolytes

potassium 5.2 meq/l 3.3 meq/l

sodium 134 meq/l 135 meq/l

bicarbonate 17 meq/l 18 meq/l

urea 31 mg/dl 51 mg/l

creatinine 1.0 mmol/dl 0.9 mmol/l


volaemia and prevention of increased ventricular afterload.26 These were factors that guided our choice of regional anaesthesia in this patient. Epidural anaesthesia produces changes in preload and afterload that mimic pharmacological goals in the treatment of patients with cardiomyopathy.

With this in mind and the need to urgently deliver the baby, we opted for a CSE and, considering the fact that spinal anaesthesia may lead to a sudden and rapid reduction in systemic vascular resistance and thereby preload, which might be disastrous in a low-cardiac output condition, we used a low dose of fentanyl as the spinal anesthetic. With this technique, the patient was ready for surgery in five minutes and we had stable cardiovascular haemodynamics. Usually volume preloading with 500 ml to one litre of crystalloid or colloid is employed to minimise the hypo-tension that follows sympathetic blockade. However, preloading in this patient was restricted to 250 ml of 0.9% saline to prevent worsening of the cardiac symptoms.

Indira et al.,18 in a similar case report, employed CSE in a patient with ejection fraction less than 25%. They injected 5 mg of 0.5% hyperbaric bupivacaine with 20 μg fentanyl intrathecally and fractionated doses of 5 ml of 2% lidocaine into the epidural space. They reported no hypotension intra-operatively. Similarly, Shnaider et al.23 reported a case of peripartum dilated cardio-myopathy presenting for CS who was successfully managed with CSE. They injected 6 mg of hyperbaric bupivacaine (0.8% ml of 0.75%) together with 15 μg of fentanyl in the subarachnoid space. Supplementation of the subarachnoid block was done with epidural bupivaicane 5 ml of 0.5 and 0.25% at 60 and 105 minutes, respectively. Their patient had stable haemodynamics throughout the procedure. Epidural lidocaine, titrated in small aliquots together with fentanyl, has been successfully employed in a patient with pulmonary hypertension and cardiomyopathy.27

Oxytocin has been known to decrease mean arterial pressure by 30% and systemic vascular resistance by 50%, and increase cardiac output by 50% and heart rate and stroke volume by 20 to 30%.28 These effects may worsen the condition of a patient with cardiac failure. However, this creates a dilemma since with-holding oxytocin may lead to haemorrhage, which may also be dangerous in these patients. We slowly administered the oxytocin following the delivery of the placenta to reduce these effects, and subsequently commenced an infusion using a reduced dose. Dob and Yentis29 recommended giving 5 units of oxytocin in 20 ml saline over five to 10 minutes, followed by 40 units in 500 ml saline to run for four to five hours.

Several authors19,25 have used invasive monitoring to manage more symptomatic cases, while others27,30 have used a non-inva-sive monitoring technique for asymptomatic and haemodynami-cally stable patients. Elective use of invasive monitoring (arterial and central venous) is justified in a symptomatic patient with an elevated jugular venous pressure, third and fourth heart sounds, orthopnoea, paroxysmal nocturnal dyspnoea or shortness of breath at rest, with clinical evidence of a low cardiac output or echocardiographic evidence of significant myocardial depression (poor contractility, left ventricular wall motion abnormalities).30

Although our patient had some significant symptoms, she did not have any form of invasive monitoring before presenting for anaesthesia and we were unable to provide one because of the urgency required to deliver the baby. Colloid was employed to restrict intra-operative fluid therapy, and supplemental oxygen was administered to ensure that oxygen saturation remained between

98 and 100%. Non-invasive cardiac monitors such as Doppler ultrasound and impedance cardiography have been used with good results in patients with PPCM, although limitations include cost and technical difficulties, especially in low-resource countries.

conclusionOur opinion is that combined spinal–epidural, employing low-dose fentanyl for the spinal anaesthesia is a suitable option for patients with PPCM scheduled for emergency Caesarean section.

References1. Morrison WL, Petch MC. Peripartum cardiomyopathy. Hosp Update

1991; 17: 693–698.2. Report of the WHO/ISFC task force on the definition and classification

of cardiomyopathies. Br Heart J 1980; 44: 672–673.3. Veille JC. Peripartum cardiomyopathies: a review. Am J Obstet Gynecol

1984; 148: 805–818.4. Danbauchi SS. Echocardiographic features of peripartum cardiac fail-

ure: the Zaria syndrome. Trop Doct 2002; 32: 24–27.5. Hibbard JU, Lindheimer M, Lang RM. A modified definition for

peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 1999; 94: 311–316.

6. Chapa JB, Heiberger HB, Weinert L, Decara J, Lang RM, Hibbard JU. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol 2005; 105: 1303–1308.

7. Sanderson JE, Adesanya CO, Anjorin FI, Parry EH. Postpartum cardiac failure-heart failure due to volume overload? Am Heart J 1979; 97: 613.

8. Fillmore SJ, Parry EH. The evolution of peripartal heart failure in Zaria. Circulation 1977; 56: 1058.

9. Heider AL, Kuller JA, Strauss RA, Wells SR. Peripartum cardiomyopa-thy: a review of the literature. Obstet Gynecol Surv 1999; 54: 526–531.

10. Van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010; 121(20): 2169–2175.

11. Thornhill ML, Camann WR. Cardiovascular disease. In: Chestnut DH (ed.). Obstetric Anesthesia. St. Louis: Mosby, 1994: 765.

12. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart J 1995; 130: 860–870.

13. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc 2005; 80: 1602–1606.

14. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experi-ences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct 1995; 25: 118–123.

15. Brar SS, Khan SS, Sandhu GK, et al. Incidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol 2007; 100: 302–304.

16. Chee KH, Azman W. Prevalence and outcome of peripartum cardio-myopathy in Malaysia. Int J Clin Pract 2009; 63: 722–725.

17. Isezuo SA, Abubakar SA. Epidemiologic profile of peripartum cardio-myopathy in a tertiary care hospital. Ethn Dis 2007; 17: 228–233.

18. Indira K, Sanjeev K, Sunanda G. Sequential combined spinal epidural anesthesia for caeserean section in peripartum cardiomyopathy. India J Anaesth 2007; 51(2): 137–139.

19. Kaufman I, Bondy R, Benjamin A. Peripartum cardiomyopathy and thromboembolism: anesthetic management and clinical course of an obese diabetic patient. Can J Anaesth 2003; 50: 161–165.

20. McCarroll CP, Paxton LD, Elliott P, Wilson DB. Use of remifentanyl in a patient with peri-partum cardiomyopathy requiring caesarean section. Br J Anaesth 2001; 86: 135–138.

21. Peng TC, Chuah EC. Peripartum cardiomyopathy – a case report. Acta Anaesthesiol Sin 2001; 39: 47–51.

22. Domenech Asensi P, Hernundez-Palazon J, Tortosa Serrano JA, Burguillos Loez S, Alonso Miranda B. Peuperal cardiomyopathy and pulmonary edema after caesarean section. Rev Esp Anestesiol Reanim


diagnostic assessment of prosthetic mitral valve thrombosis by real-time three-dimensional transoesophageal echocardiography and successful thrombolytic treatment hUMBERTO MORAIS, TELMO MARTINS, JOSÉ ROBERTO, FIDEL CÁCERES-LÓRIGA

abstractProsthetic valve thrombosis (PVT) is a rare but serious complication of valve replacement, most often encountered with mechanical prostheses. The different therapeutic modal-ities for PVT (fibrinolysis with heparin treatment or surgery) will largely be influenced by the presence of valvular obstruc-tion, the valve location (left or right sided), the patient’s clinical status, the existence of and expertise in therapeutic modalities at the institution, and the patient’s decision. This report describes a patient with thrombosis of a prosthetic mitral valve, which was successfully treated with recombi-nant streptokinase in a hospital without cardiac surgery. In this context, the authors present the real-time transoesopha-geal echocardiographic appearance of this complication, and give a brief review of the literature.

Keywords: prosthetic valve thrombosis, fibrinolysis, real-time three-dimensional transoesophageal echocardiography, transtho-racic echocardiography, Angola



DOI: 10.5830/CVJA-2010-071

Prosthetic valve thrombosis (PVT) is a non-frequent but serious complication of cardiac valve replacement, most often encoun-

tered with mechanical prostheses. The significant morbidity and mortality associated with this condition requires rapid diagnostic evaluation. However, the diagnosis can be challenging, mainly because of variable clinical presentations and the degree of valvular obstruction. Cinefluroscopy (for mechanical valves), transthoracic (TTE) and transoesophageal echocardiography (TEE) represent the main diagnostic tools.1

The different therapeutic modalities for PVT (fibrinolysis with heparin treatment or surgery) will largely be influenced by the presence of valvular obstruction, the valve location (left or right sided), the patient’s clinical status, the existence of and expertise in therapeutic modalities at the institution, and the patient’s decision. This report describes a patient with thrombo-sis of a prosthetic mitral valve, who was treated with recombi-nant streptokinase in a hospital without cardiac surgery. In this context we present a review of the literature.

case report A 25-year-old black man was admitted to the hospital with a history of progressive dyspnoea and fatigue in the previous two weeks. He had a history of heart failure due to severe mitral regurgitation since 2005. A 31-mm Sorin bicarbonic pros-thetic valve had been inserted in the mitral position three years earlier in South Africa. Since then, he had been taking warfarin and bisoprolol, and had been in NYHA class I. The last TTE performed a few months previously had revealed normal func-tion of the prosthetic mitral valve. Two months prior to presenta-tion he stopped taking warfarin.

On admission, the physical examination revealed a patient with a supine blood pressure of 110/80 mmHg, a pulse rate of 100 beats/min, a regular rhythm, and elevated jugular venous pressure. A precordial examination revealed a muffled first heart sound, a normal second heart sound, and a diastolic rumble at the apex. No trill was present. The lungs revealed bibasilar crackles.

departamento de cardiologia do Hospital Militar principal/instituto superior, luanda, angolahUMBERTO MORAIS, MD, [email protected] MARTINS, MDJOSÉ ROBERTO, MD

institute of cardiology and cardiovascular surgery, Havana, cubaFIDEL M CÁCERES-LÓRIGA, PhD

2002; 49: 156–159.23. Shnaider R, Ezri T, Szmuk P, Larson S, Waters RD, Katz J. Combined

spinal-epidural anesthesia for caesarean section in a patient with peri-partum dilated cardiomyopathy. Can J Anaesth 2001; 48: 681–683.

24. Chan F, Kee WDN. Idiopathic dilated cardiomyopathy presenting in pregnancy. Can J Anaesth 1999; 46: 1146–1149.

25. Sharrock NE, Bading B, Mineo R, Blumenfeld JD. Deliberate hypo-tensive epidural anesthesia for patients with normal and low cardiac output. Anesth Analg 1994; 79: 899–904.

26. Shrestha BR, Thapa C. Peripartum cardiomyopathy undergoing caesar-ean section under epidural anaesthesia. Kathmandu Univer Med J 2006:

4(16): 503–505.27. Breen TW, Janzen JA. Pulmonary hypertension and cardiomyopathy:

anesthetic management for caesarean section. Can J Anaesth 1991; 38: 895–899.

28. Weis FR, Markello R, Mo B, Bochiechio P. Cardiovascular effects of oxytocin. Obstet Gynecol 1975 ; 46: 211–214.

29. Dob DP, Yentis SM. Practical management of the parturient with congenital heart disease. Int J Obstet Anesth 2006; 15: 137–144.

30. Gambling DR, Flanagan ML, Huckell VF, Lucas SB, Kim JH. Anesthetic management and non-invasive monitoring for caesarean section in a patient with cardiomyopathy. Can J Anaesth 1987; 34: 505–508.


No hepatomegaly or oedema were found.Haematological parameters and serum biochemistry were

normal. The INR was not available at this time. A 12-lead ECG revealed a sinus rhythm, with a heart rate of 100 beats/min, mean frontal QRS axis of +75 and signs of left atrial enlargement. A chest X-ray showed status pos implantation of a mechanical prosthesis in the mitral position, pulmonary interstitial oedema, and cephalisation of the pulmonary vasculature.

Two-dimensional echocardiography showed an enlarged left atrium and normal left ventricle with paradoxical septal motion. Doppler interrogation of the mitral valve prosthesis showed a maximum gradient of 21 mmHg, a mean gradient of 16 mmHg, and a mitral valve area of 0.71 cm2, consistent with a dysfunc-tional prosthetic valve.

TEE revealed a thrombus in the left atrial appendage (LAA) (Fig. 1A), a thrombus in the atrial side of the prosthesis, with minimal excursion of the disc (Fig 1C). TEE confirmed the gradients and mitral area found on TTE (Fig. 1B). The real-time three-dimensional TEE zoom-mode acquisition, frontal view of the left atrium showed a large thrombus in the valve (Fig. 1D) and in the LAA.

According to protocol, the patient received recombinant streptokinase (rSK) 250 000 IU within 30 minutes (charge dose), followed by 100 000 UI per hour over 72 hours. Unfractionated heparin was introduced immediately after discontinuation of rSK, and warfarin and aspirin were administered 24 hours later.

A dramatic improvement in symptoms was observed. The metallic S1 heart sound became audible and the diastolic rumble disappeared. There was no evidence of embolic complications or bleeding. Seventy-two hours after admission, TTE showed a dramatic improvement in the mitral valve area (1.15 cm2) and the mean gradient fell to 6 mmHg. A chest X-ray five days after admission showed no pulmonary interstitial oedema.

On discharge, the patient was on therapeutic warfarin, aspirin 100 mg, furosemido 20 mg and bisoprolol 2.5 mg per day, and

was in NYHA class I. The mitral valve area and the mean gradi-ent were 1.76 cm2 and 6 mmHg, respectively.

discussionPVT is a serious complication of valve replacement, associated with high mortality rates. The main pathogenic factors of PVT have been identified, including mitral position of the prosthe-sis, type of prosthesis, atrial fibrillation, atrial enlargement, ventricular dysfunction, multivalve replacements, and pregnan-cy. However, the most common cause is a sub-therapeutic level of anticoagulation,1 which had been the case with our patient (the patient had stopped taking warfarin two months earlier). This shows the importance of adherence by these patients to their antithrombotic treatment, and the necessity of INR control.

When PVT is first suspected, a careful physical examination should be performed, with particular attention being paid to muffling or disappearance of prosthetic sounds and the appear-ance of a new regurgitant or obstructive murmur. The initial diagnostic work up includes transthoracic echocardiography and cinefluoroscopy for mechanical valves.2 Transthoracic Doppler echocardiography is the imaging technique more frequently used.

PVT may be suspected with increased transvalvular gradients. However, this measurement is non-specific as the gradient may be increased by other conditions. On the other hand, normal gradients do not rule out obstruction in the presence of left ventricular dysfunction or hypovolaemia.3

Cinefluoroscopy is an important part of the diagnostic evalu-ation of a suspected PVT, however this technique is not helpful in identifying non-obstructive PVT or differentiating pannus from thrombus.2,3 Transoesophageal echocardiography is the diagnostic tool with a higher sensitivity for identifying an abnor-mal cardiac mass. Moreover, TTE provides important additional information to guide therapy and is often performed to complete the investigation.2

Recent reports show that diagnostic use of three-dimensional real-time TEE offered a useful and comprehensive evaluation of prosthetic thromboses (number, size and precise location).4 In spite of its unique features, it is not clear if this new technique is cost effective in the management of PVT. Certainly, more information is needed.

In our case, we used three echocardiographic modalities (TTE Doppler, TEE, real-time 3D TEE) to complement each other in the diagnosis of the PVT and for guidance in the thrombolytic therapy.

Emergency surgical treatment (thrombectomy or valve replacement) has been considered the traditional management for PVT. However, recent surgical series report high mortality, particularly in severe NHYA functional classes. Durrleman et al.5 presented a series of 39 patients with PVT over a 20-year period, who underwent thrombectomy or valve replacement, with an associated mortality of 25 and 41%, respectively. Oskokeli et al.,6 in 30 patients with left-side PVT, reported a post-operative early hospital mortality of 7.1% (NYHA classes II–III) and 31.3% (NYHA class IV), and Toker et al.,7 in 63 cases, a total mortality of 20.6%.

The current guidelines for the management of PVT remain controversial. Recent guidelines still recommend surgery as first-line therapy in critically ill patients (NYHA class III–IV)

Fig. 1. transoesophageal echocardiography. a: show-ing thrombus in the left arterial appendage (arrow). B: confirming the data of ttE (gradients in mitral valve area). c: showing thrombus in atrial face of the mitral valve prosthesis (arrow). d: showing the real-time three-dimensional (frontal view from the atrium) appearance of the thrombus (arrow) in the mitral valve prosthesis, and the limited diastolic excursion of the disc. la: left atrium, laa: left arterial appendage, lv: left ventricle.


and in those with large clots. Thrombolysis remains an alterna-tive therapy for patients with a high surgical risk or contraindica-tion to surgery, or if surgery is not available.8,9

The individual experience of several authors has led to the decision to recommend thrombolysis as first-line therapy in PVT.3,10-17 Accordingly, in the recent PVT guidelines of the Society of Heart Valve Disease, thrombolysis was recommended as first-line therapy in all patients with PVT and a thrombus diameter ≥ 5 mm, regardless of the obstruction and NYHA functional class. Surgery is reserved only for cases with failed thrombolytic therapy or where there was a contraindication to thrombolysis (evidence B).3,18

Nagy et al.,19 in a study with the objective of analysing the predictors of the outcome of thrombolytic therapy in 62 events of prosthetic mitral valve thrombosis, showed that, based on previous data and the present findings, thrombolysis may be considered a first-line treatment in all patients with PVT, since the complication and success rates of thrombolysis are independ-ent of valve type, NYHA functional class, and thrombus size.

In a recent systematic review on the role of thrombolysis in the treatment in left-sided PVT, Reyes et al.20 reported on 904 patients treated between January 1970 and January 2007. Clinical improvement was observed in 86% of the patients and failure in 14%. The peripheral and cerebral embolism rate was 5 and 4%, respectively. Major bleeding was 4% and intracranial haemorrhage was 1%.

Shapira et al.,21 in a current review, affirms that thrombus size is probably the most important determinant of complications. If small, thrombolysis is probably advised across all degrees of functional class, as suggested by the American College of Chest Physicians.

Taljaard and Doubell22 report the results of a case series of a total of 32 patients presented on 34 occasions with prosthetic valve obstruction at Tygerberg Hospital between January 1991 and February 2001. Valve replacement was performed on 20 patients, six received thrombolysis and the remaining eight patients did not receive any treatment. The conclusion of this study was that, given the extremely high mortality rate with current management, the treatment of prosthetic valve obstruc-tion with thrombolysis in selected patients deserves considera-tion in a prospective study.

We chose thrombolysis as first-line therapy in our patient. This is another case where the benefits and safety of thromboly-sis in the treatment of PVT are evident.

conclusionIn the absence of randomised, controlled trial data, thrombolysis appears to be an effective treatment. It should be considered in all patients, even when a surgical strategy is readily available. In the absence of on-site cardiothoracic surgical support, it is reasonable to consider this first-line treatment in appropriate patients.

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Hernandez K. Prosthetic heart valve thrombosis: Pathogenesis, diagno-sis and management. Int J Cardiol 2006; 110: 1–6.

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6. Ozkokeli M, Sensoz Y, Ates M, Ekinci A, Akcar M, Yekeler I. Surgical treatment of left-sided prosthetic valve thrombosis: short and long-term results. Int Heart J 2005; 46: 105–111.

7. Toker ME, Eren E, Balkanay M, Kirali K, Yarartas M, Caliskan A, et al. Multivariate analysis for operative mortality in obstructive prosthetic valve dysfunction due to pannus and thrombus formation. Int Heart J 2006; 47: 237–245.

8. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the manage-ment of valvular heart disease. The Task Force on the management of valvular heart disease of the European Society of Cardiology. Eur Heart J 2007; 28: 230–268.

9. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the manage-ment of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease) endorsed by the Society of Cardiovascular Anaesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008; 52; e1–e142.

10. Alpert J. The thrombosed prosthetic valve. Current recommendations based on evidence from the literature. J Am Coll Cardiol 2003; 41: 659–660.

11. Cáceres-Lóriga FM. Prosthetic valve thrombosis: Is it time for a new consensus conference? Eur J Echocardiogr 2008; 9: 413–414.

12. Lengyel M. Thrombolysis should be regarded as first line therapy for prosthetic valve thrombosis in the absence of contraindications. J Am Coll Cardiol 2005; 45: 325.

13. Ozkan M, Kaymaz C, Kirma C, et al. Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: A study using serial transesophageal echocardiography. J Am Coll Cardiol 2000; 35: 1881–1889.

14. Rinaldi CA, Heppell RM, Chambers JB. Treatment of left-sided pros-thetic valve thrombosis: Thrombolysis or surgery? J Heart Valve Dis 2002; 11: 839–843.

15. Azpitarte J, Sanchez-Ramos J, Urda T, et al. Prosthetic valve throm-bosis: Which is the most appropriate initial therapy? Rev Esp Cardiol 2001; 54: 1367–1376.

16. Renzulli A, Vitale N, Caruso A, et al. Thrombolysis for prosthetic valve thrombosis: Indications and results. J Heart Valve Dis 1997; 6: 212–218.

17. Cáceres-Lóriga FM, Pérez-López H, Morlans-Hernández K, Facundo-Sánchez H, Santos-Gracia J, Valiente-Mustelier J, et al. Thrombolysis as first choice therapy in prosthetic heart valve thrombosis. A study of 68 patients. J Thromb Thrombolysis 2006; 21: 185–190.

18. Lengyel M, Horstkotte D, Völler H, Mistiaen WP. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005; 14: 567–575.

19. Nagy A, Dénes M, Lengyel M. Predictors of the outcome of thrombo-lytic therapy in prosthetic mitral valve thrombosis: a study of 62 events. J Heart Valve Dis 2009; 18: 268–275.

20. Reyes-Cerezo E, Jerjes-Sanchez C, Archondo-Arce T, Garcia-Sosa A, Garza-Ruiz A, Ramirez-Rivera A, et al. Fibrinolytic therapy in left side prosthetic valve acute thrombosis. In depth systematic review. Arch Cardiol Mex 2008; 78: 309–317.

21. Shaspira Y, Vaturi M, Sagie A.Obstructive left-sided prosthetic valve thrombosis. Acute Card Care 2009; Jun 25: 1–9.

22. Taljaard JJ, Doubell AF. Prosthetic valve obstruction at Tygerberg Hospital between January 1991 and February 2001. Cardiovasc J South Afr 2003; 14: 182– 188.

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drug trends in cardiology

dramatic reductions in plaque volumes on maximum statin therapylargest ivUs trial shows equal plaque regression with atorvastatin and rosuvastatin

The SATURN trial, which evaluated the extent of plaque regression in patients with symptomatic coronary artery disease (CAD) over a two-year period using maximum doses of atorvastatin and rosu-vastatin, showed no difference between these two statins with regard to the prima-ry endpoint of percentage reduction of atheroma volume.1

‘The extent of regression with both statins at maximum dose was unprec-edented in our experience and relates well to the very low event rate seen in this clinical trial’, Dr Stephen Nicholls from the Cleveland Clinic, USA and principal investigator of this Astrazeneca-sponsored study noted (Fig. 1).

The SATURN study (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN), a prospective randomised, multicentre, double-blind study, is the largest imaging study in cardiovascular medicine to date and adds to the collec-tive experience of using intravascular ultrasound (IVUS) to detect changes in coronary atheroma volume (Fig. 2).

The primary-efficacy parameter of the SATURN trial was set as the change in percentage atheroma volume in matched coronary artery segments performed at baseline and at the end of the 104-week treatment period.2 The

secondary endpoints included the change in total atheroma volume on therapy, change in lipid and lipoprotein values, and a safety evaluation, including analysis of adverse events and laboratory data. The incidence of major adverse cardiovascular events was explored in the total patient

cohort as a function of changes in IVUS variables, but did not have the power to directly compare the treatment groups with regard to clinical events.

A total of 1 385 subjects aged 18 years and older with at least 20% or more lumen stenosis in a native epicardial

TABLE 1. CLINICAL CHARACTERISTICS OF PATIENTS

Parameter Cohort (n = 1 385) n (%)

Age (years) 57.6 ± 8.6

Males 998 (72)

BMI (kg/m2) 29.3 ± 5.3

Overweight (BMI ≤ 25 to < 30 kg/m2 617 (45)

Obese (BMI ≥ 30 kg/m2 522 (38)

Previous MI 329 (24)

Previous PCI 303 (22)

Previous CVA/TIA 34 (2)

Hypertension 945 (69)

Diabetes 207 (15)

Current smoking 442 (32)

Peripheral artery disease 85 (8)

Baseline aspirin use 1114 (80)

Baseline statin use 823 (59)

Baseline beta-blocker use 923 (67)

Baseline ACE inhibitor use 582 (42)

Baseline ARB use 180 (13)

Continuous data presented as mean (± 80) and categorical data as n (%). Baseline medications included selected medication that was taken within 90 days of consent.ACE, angiotensin converting enzymes; ARB, angiotensin receptor blocker; BMI, body mass index; CVA, cerebrovascular accident; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischaemic attack.

Fig. 1. primary ivUs efficacy parameter.

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coronary artery (on visual estimation of a clinically indicated coronary angiogram) and a target vessel for imaging with less than 50% obstruction were randomised in the trial. The clinical characteristics of patients enrolled in SATURN are summa-rised in Table 1.

Screening processPatients who were not on a statin had to have an LDL cholesterol higher than 2.6 mmol/l, while those on treatment were required to have a level higher than 2.1 mmol/l. Patients with uncontrolled hyper-tension, heart failure, renal dysfunction or liver disease were excluded from the trial.

In the screening period, patients were randomly assigned to either atorvasta-tin 40 mg or rosuvastatin 20 mg daily for two weeks to ascertain side effects and compliance. Patients with an LDL cholesterol less than 3 mmol/l and a triglyceride level of less than 5.6 mmol/l again underwent randomisation, this time to a full dose of atorvastatin (80 mg daily) or rosuvastatin (40 mg daily) for the two-year study period, at the end of which a second IVUS assessment of the originally imaged target vessel was performed.

Clinical events were adjudicated by members unaware of the treatment assignments. Lipids were measured at six, 12, 18 and 24 months, while C-reactive protein was measured annually.

After 104 weeks of treatment, 1 039 patients remained in the study (75%). Of these, 519 were in the atorvastatin and 520 in the rosuvastatin groups, with no significant differences between the two treatment groups. During treatment, levels of LDL cholesterol were lower in the rosuvastatin group (1.6 vs 1.8 mmol/l) and HDL cholesterol levels were different (1.25 mmol/l in the atorvastatin vs 1.3 mmol/l in the rosuvastatin group). There was also a difference in the LDL:HDL cholesterol ratio, with those in the rosu-vastatin group having lower values than those in the atorvastatin group. Median C-reactive protein levels were similar.

ResultsThe results showed that the primary-efficacy endpoint of percentage atheroma volume was not significantly different between the two treatment groups and cardiovascular events were also similar with regard to total atheroma volume.

With regard to the secondary-efficacy evaluation, rosuvastatin treatment led to a greater reduction in total atheroma volume than in the atorvastatin-treated group. The rate of abnormal laboratory levels was low and glycated haemoglobin levels did not change significantly in either group during the two-year period.

‘The SATURN study has provided strong validation for the benefits of high-dose statins and, reassuringly, these doses were well tolerated’, Dr Nicholls pointed out. ‘This underscores the clinical approach of treating patients with higher doses of statins to halt disease progression. In this study, two-thirds of the patients showed regression of atherosclerosis on higher doses of statin therapy’, he concluded.

1. Nicholls SJ, et al. Effect of 2 intensive statin regimens on progression of CAD. Doi 10:1056/NEJMoa1110874

2. Nicholls SJ, Borgman M, Nissen SE, Raichlen JS, et al. Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Conorany Atheroma by InTravascular Ultrasound: effect of Rosuvastatin versus AtorvastatiN). Curr Med Res Opin 2011; 27(6): 1119–1129. Epub 2011 Mar 30.

raft of rivaroxaban good news from the Usa, implications for south african clinical practiceRivaroxaban has been approved by the US Food and Drug Administration (FDA) for the prevention of stroke and systemic embolism in non-valvular atrial fibrilla-tion. From the American Heart Association (AHA) 2011 congress earlier this week, the results of the ATLAS ACS 2-TIMI 51 trial have shown rivaroxaban improves cardiovascular outcomes and reduces cardiovascular and all-cause mortality in acute coronary syndromes (ACS).1,2

With the added recognised use of rivar-oxaban in knee and hip arthroplasty and in the prevention and treatment of venous thromboembolism, deep-vein thrombosis and pulmonary embolism,3 South African medicine regulators will need to widen their assessment of the value of this factor Xa inhibitor locally.

The ATLAS ACS 2-TIMI 51 trial results were widely welcomed at the AHA, with the lead investigator, Dr

Michael Gibson of Harvard Medical School noting that rivaroxaban treatment for about two years in ACS patients resulted in a very robust reduction in the primary endpoint of cardiovascular death, myocardial infarction and stroke (RRR of 16%). The risk of all-cause death was reduced by 30% with the addition of rivar-oxaban to the standard treatment of ACS.

‘Importantly, this benefit in reduced deaths was also seen as a reduction in sudden unwitnessed deaths, which we know from autopsy studies is primarily due to thrombotic events. Also rivaroxa-ban reduced stent thrombosis by 31%. These two aspects together give me confi-dence that the benefits we are seeing are due to the inhibition of thrombin genera-tion. We now know we have a new target of blocking thrombin production as an important way of improving outcomes in ACS’, Dr Gibson noted.

The beneficial results of rivaroxaban treatment are very important to patient care, as there is a large unmet need in ACS management. This is seen in the fact that despite the widespread use of dual antiplatelet therapy, patients who have had a recent ACS event continue to be at increased risk of major cardiovascular events, at an annual rate of 10%.

Dr Paul W Armstrong, Edmonton, Canada was the discussant at the clinical trial session and he noted that this study is a welcome and transforming advance in the management of ACS. In evaluat-ing the ATLAS ACS 2-TIMI 51 trial, it is important to note which patients benefit-ted in this large multi-centre trial conduct-ed in 766 sites in 44 countries. The more than 15 000 adult patients included in the study had symptoms of ACS and were diagnosed with ST-segment eleva-tion myocardial infarction (STEMI), non-

346 AFRICACARDIOVASCULAR JOURNAL OF AFRICA • Advance Online Publication, November 2011

STEMI or unstable angina.Key exclusion criteria were patients

with a history of stroke (ischaemic stroke or transient ischaemic events despite being on aspirin and a thienopyridine), previous gastrointestinal or intracranial bleeding, or evidence of bleeding seque-lae such as a platelet count of less than 90 000 per mm3, a haemoglobin level lower than 10 g/dl and a low creatinine clearance rate of less than 30 ml/min on screening for possible study entry.

‘The reason for excluding patients who had had a stroke derives from our knowl-edge that if you have had a stroke, even dual anti-platelet therapy may not be opti-mal. To support this approach, a few stroke patients did slip into the ATLAS study and their outcome was poor’, Dr Gibson noted during the post-clinical trial interviews.

‘However, in patients who did experi-ence a stroke during this TIMI trial, those on rivaroxaban had a better neurological recovery. This may well be due to the fact

that thrombin is known to increase apop-tosis in the neural system and inhibition of thrombin generation can reduce neural apoptosis, offering a useful hypothesis for some of the benefits on stroke severity seen in this trial’, Dr Gibson explained.

The ATLAS ACS 2-TIMI 51 trial was a phase-three trial initiated with an oral dosage of either 2.5 or 5 mg rivaroxaban twice daily (bid). This dosage was based on a previous phase-two dose-finding trial. Patients received aspirin, a thieno-pyridine and placebo, or one of the two rivaroxaban doses on an average of 4.7 days after revascularisation procedures had been done and the patient was stable.

Importantly patients did as well on the lower dose, with less bleeding than on the higher dose. There was an increase in major bleeding rates not related to coronary bypass grafting and intracranial bleeding without a significant increase in fatal bleeding or adverse events in patients receiving rivaroxaban compared to standard therapy.

Expert opinionProf Sylvia Haas, Technical University, Munich, Germany, a well-known expert from Munich and frequent visitor to South Africa commented on the impor-tance of this study for clinical practice.

The results of ATLAS ACS 2-TIMI 51 have the potential to lead into a new era in secondary prevention of thrombo-embolic complications after ACS. This landmark study aimed to lower cardiovas-cular events in patients with recent ACS compared to standard care and this has

been successfully achieved for both doses of the oral factor Xa inhibitor rivaroxaban tested, and for each dose alone.

A cumulative incidence of 10.7% for the combined endpoint, consist-ing of cardiovascular death, myocardial infarction (MI) and stroke, was seen in patients randomised to placebo and this was reduced to 8.9% for both rivaroxa-ban groups combined. In patients treated with the higher dose of rivaroxaban of 5 mg bid, this endpoint was significantly reduced to 8.8%, and for patients treated with 2.5 mg bid to 9.1%, which was also statistically significant. There were also reductions in rates of death from both cardiovascular causes and any cause for the 2.5-mg dose but not for the 5-mg dose.

As expected, the bleeding rates were higher for the patients receiving the combination of anticoagulation and anti-platelet therapy. This effect was dose related, i.e. bleeding rates were lower in the 2.5- than in the 5.0-mg group. Although the rate of intracranial bleeding was higher than with placebo, there was no increase in fatal bleeding events.

In conclusion, rivaroxaban is the first new oral anticoagulant to demonstrate a clinically relevant benefit in ACS.

1. FDA Announcement,11 November 2011.2. Mega JL, Braunwald E, Wiviott SD, Bassand

JP. Rivaroxaban in patients with recent acute coronary syndrome. DOI:10:1056/NEJMoa1112277.13 November 2011.11.13.

3. Einstein investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499–2510.

Fig. 1. Efficacy and safety endpoints for three treatment arms

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placebo 5.0 mg rivaroxaban

2.5 mg rivaroxaban

Hr 0.85, p = 0.028

Hr 3.46, p = 0.001

Hr 4.47, p < 0.001

cardiovascular diary for 2012 congresses

DATE PLACE CONFERENCE WEBSITE

1–3 February New Orleans, USA Internatioanl Stroke Conference www.heart.org

18 February Frankfurt, Germany TrenD 2012 – Transcatheter renal denervation www.ici-congress.org

3–5 MarchSouthern Sun Cape Sun, Cape Town, South Africa

17th Biennial Congress of the SA Hypertension Society Congress (SAHS) www.hypertension.org.za

18–21 April Dubai, United Arab Emirates World Congress of Cardiology www.world-heart-federation.org

17–20 May Berlin, Germany Congress on cardiac problems in pregnancy (CPP 2012) www.cppcongress.com

27 June Frankfurt, Germany ICI 2012 – Imaging in cardiovascular interventions www.ici-congress.org

28 June Frankfurt, Germany CSI 2012 – Catheter interventions in congenital and structural heart disease

19–22 July Sun City, South Africa 13th Annual SA Heart Congress www.saheart.org

25–29 August Munich, Germany 2012 ESC – European Society of Cardiology Congress www.escardio.org

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Medical devices in cardiovascular medicineglobal paNoraMa study collects largest database on 10 000 patients from the Middle East and africa

Medtronic in the Middle East and Africa area has recently announced that the PANORAMA study has successfully enrolled its ten thousandth patient. This study is the first in the world to include more than 31% of its patient population from the Middle East and African region (MEA), and more specifically from 20 different enrolling centres in South Africa, Saudi Arabia, Kuwait and Turkey.

This is expected to allow healthcare practitioners in the field to better assess and understand patient characteristics specific to our region and help evaluate whether treatment required for patients in the MEA should be different from that in other countries, especially Europe and the USA. To date, there is very little evidence available to shed light on regional differences in practice patterns, but PANORAMA is expected to provide the missing data.

‘The PANORMA study is an important international registry; yet, it will be our local data that will be unique’, comment-ed Prof A Okreglicki, director of the Interventional Cardiac Electrophysiology Laboratory at the Groote Schuur Hospital in Cape Town. Some of the first results from this study were presented at the recent SA Heart meeting held in East London.

Unitas Hospital, Gauteng sheds light on South African responder patterns in patients undergoing cardiac resynchronisation therapyThis study of mainly male patients (22 in total), average age 65 years, has shown an

overall significant improvement in ejec-tion fraction (EF) in patients who received cardiac resynchronisation therapy (CRT).1 The majority were normal responders (improvement in left ventricular EF in the range of 3–5%) but the percentage of hyper-responders (13.6%) and super-responders (18%) was higher than in other previously described studies. The authors noted this might be due to the highly selected population and the initial broad QRS duration, a mean of 141.4 ms, which improved on average by 19 ms.

Pacemaker implantation in South Africa: patient demographics and implant dataIn this first overview of 904 patients from 13 hospitals in South Africa, of which 12 were in the private sector, differences in approach between a well-resourced public hospital (Groote Schuur Hospital) and the private sector were noted.2

In common were baseline character-istics where the patients were mainly Caucasian (85%), 57% male and aged 68 ± 16 years; 20% were in atrial fibrillation and 23% had heart failure.

The primary indication at enrolment varied, with atrio-ventricular block being more common in the public sector (70 vs 19%), and sinus node disease being more common in the private sector (67 vs 20%).

Use of devices also differed, with one-chamber devices being more commonly used in the public sector and two- and three-chamber devices being used in the private sector.

Focus on baseline characteristics and demographic differences in ICD patients in the Gulf region (Saudi Arabia and Kuwait)Between May 2005 and November 2010, 610 patients (age 58.7 ± 14.6 years, 79.7% male) were implanted with an ICD in one centre in Kuwait and six centres in Saudi Arabia. The data were compared with 1 205 patients in the rest of the world (age 59.1 ± 15.0 years, 82.3% male).

PANORAMA shows that the popu-lation from the Gulf region has some specific characteristics and that patient treatment is different from that in the rest of the world.3 More often patients suffer from diabetes mellitus, hypertension and hypercholesterolaemia, less often they have myocardial infaction and atrial fibril-lation, are treated for primary prevention, receive a dual-chamber device and the RV defibrillation lead is more often placed in the septal areas to mimic more physico-logical ventricular activation.

1. Ebrahim IO, Van der Walt A, Meyer R. A prospective study based on a cohort from the PANORAMA study evaluating CRT non-responders, hyper-responders and super-responders. SA Heart 2011; 8(4): 232–233.

2. Okgreglicki A. Pacemaker implantation in South Africa: Implant practices and differ-ences in indications, modes and demograph-ics from the Panorama Registry. SA Heart 2011; 8(4): 253.

3. Al-Kandari F, Sweidan R, Al Fayyadh M. Baseline characteristics and demographic differences of patients implanted with an implantable cardioverter defibrillator and PANORAMA-Gulf observational study. SA Heart 2011; 8(4): 227.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011AFRICA e1

case report

a giant pericardial cyst İSLAM KAKLIKKAYA

abstractPericardial cysts are rare, benign, congenital anomalies. Most are asymptomatic and are found incidentally on chest radio-graphs. Some may cause symptoms and complications. Giant pericardial cysts are even more rare, and few reports on their natural history, presentation and management are available. This report describes a giant pericardial cyst that exerted pressure on the heart and lungs and was excised surgically. Subsequently, the patient has been asymptomatic for nine years and appears to be in complete remission.

Keywords: pericardial cyst, surgical treatment


Cardiovasc J Afr 2011; 22 (6): online publication www.cvja.co.za

DOI: 10.5830/CVJA-2010-076

Pericardial cysts are caused by the incomplete coalescence of foetal lacunae during the development of the pericardium.1 They are usually unilocular, well-marginated, spherical or teardrop-shaped cysts that may be attached to the pericardium directly or by a pedicle.2 Pericardial cysts are lined by endothelium or mesothelium and contain clear serous fluid (‘spring water’). These cysts do not connect with the pericardial space.

They are asymptomatic in more than 50% of cases and are detected incidentally on chest X-ray. They are generally more likely to be found in middle-aged adults, most frequently in the third or fourth decade of life, and equally in men and women.3 Some pericardial cysts may cause symptoms and complications such as right ventricle outflow obstruction, pulmonary stenosis, pericardial tamponade and partial erosion of the superior vena cava.4

case reportThe patient was a 39-year-old man who had reported several episodes of left pleuritic chest pain and who had been diagnosed elsewhere with a Morgagni diaphragmatic hernia. His medical history included severe hypertension (220/120 mmHg). The patient was generally active and was otherwise in good health. He had smoked one packet of cigarettes daily for 25 years, and had a dry cough. He had had palpitations, non-specific gastroin-testinal system complaints, nausea, vomiting and dyspepsia for five years. He had seen many doctors, including psychiatrists,

for these complaints. He was transferred from a state hospital to our clinic with the working diagnosis of diaphragmatic hernia for surgical treatment.

On examination, he was in no distress. His blood pressure was 180/90 mmHg, the heart rate was 90 beats/min, and he had a regular heartbeat with normal heart sounds and no murmurs. An electrocardiogram revealed a sinus tachycardia and non-specific ST-T changes in V5–6.

The breath sounds were absent on auscultation of the lower two-thirds of the left hemithorax. On percussion, there was dull-ness in the fifth left intercostal area, which indicated Traube’s space was obliterated.

He was afebrile, acyanotic, normal coloured and anicteric. No jugular venous distention was seen. The postero-anterior chest X-ray showed atelectasis of the inferior lobe of the left lung, caused by a mass in the left hemithorax, massive pleural effusion in the left lower hemithorax, and mild cardiomegaly (Fig. 1).

Routine laboratory tests were unremarkable. The purified protein derivative of tuberculin test was equivocal.

The transthoracic echocardiogram suggested that the mass was a thin-walled, cyst-like structure adherent to the left ventri-cle. No intracardiac masses or other echocardigraphic abnormal-ities such as a prominent fad pad, solid tumour, aortic aneurysm, left ventricle aneurysm and prominent left atrial appendage were found.

Subsequent contrast-enhanced computed tomography (CT) revealed a cystic mass in the left mediastinum above the diaphragm, surrounding the left cardiac border (Fig. 2). The mass measured 22 × 15 × 17 cm (transverse × anteroposterior

department of cardiovascular surgery, school of Medicine, Karadeniz technical University, trabzon, turkeyİSLAM KAKLIKKAYA, MD, PhD, [email protected]

Fig. 1. the postero-anterior chest radiograph shows a large, homogeneous radiodense mass in the basal left hemithorax.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011e2 AFRICA

× craniocaudal). In addition, a subpleural bulla approximately 2 cm in diameter was observed in the anterior apex of the left upper lobe, and marked compressive atelectasis of the left lower lung was noted. No additional mediastinal, hilar, airway or lung parenchyma abnormalities were identified.

As the mass was symptomatic and the diagnosis remained in question, the patient was scheduled for operative exploration. The mass, thought to be a pericardial cyst, was removed via an open thoracotomy.

After a left-sided thoracotomy, 2 000 ml of serosanguinous fluid were aspirated from the pericardial cyst sac, with complete excision of the mediastinal mass, measuring 22 × 15 × 17 cm (Fig. 3). The cyst was full of golden-yellow liquid and was adher-ent to the lung and phrenic and anterior vagus nerves laterally. The pericardial cyst was connected to the inferior pericardial surface by a thin, mobile, vascular pedicle, which was ligated when the mass was resected.

The mass was bright and soft. It was on the left side of the diaphragm, and exerted pressure on the left side of the heart and pericardium and on the lower lobe of the left lung, causing compressive atelectasis. The atelectic lung was expanded manu-ally. The 2 × 2-cm bulla in the left upper lobe of the lung was sutured. The procedure was finished successfully in the usual manner after closed drainage (water-sealed drainage) of the thoracic cavity.

Histological examination confirmed the diagnosis of a peri-cardial cyst (fibrovascular cyst wall) with no evidence of malig-nancy or tissue other than pericardium. Cultures of both the cystic and pericardial liquids were negative. Notably, no giant cells, granulomata, acid-fast bacilli or fungi were identified.

No postoperative complications were noted. The patient had an unremarkable recovery and was discharged on postoperative day six.

discussionPericardial cysts are benign intrathoracic lesions that occur in one in every 100 000 persons and constitute 7% of all mediastinal tumours.5 Pericardial cysts can be suspected if the patient complains of non-specific chest pain, dyspnoea, cough or epigastric fullness. Although complications are uncommon,

unexpected life-threatening events have been reported, such as acute cardiac tamponade,6 and sudden death.7 No cases of malig-nant degeneration have been reported. Spontaneous resolution of pericardial cysts is unusual, although two cases of presumed spontaneous resolution have been reported.8

The cysts range in size from 2–3 cm, up to a maximum of 28 cm reported by Braude et al.9 In our case, the pericardial cyst measured 22 × 15 × 17 cm. As the patient had seen many differ-ent doctors, including a psychiatrist, with various complaints, the diagnosis was rather belated.

Of all pericardial cysts, 70–75% are located at the right cardiophrenic angle, 22% at the left, and the rest are in the posterior or anterior superior mediastinum.3 In our case, the pericardial cyst occurred in the left cardiophrenic area, to which it was attached by a pedicle over the fat tissue on the left side of the pericardium.

Solid tumours should be considered in the differential diagno-sis, including angiomas, lipomas, neurogenic tumours, sarcomas, lymphomas, bronchogenic carcinomas, metastases, granuloma-tous lesions, and abscesses, along with interstitial bronchogenic cysts, lymphangiomas, diaphragmatic hernias, aneurysms of the heart or great vessels, and other diseases.10

Once a pericardial cyst is suspected on the chest X-ray, thoracic CT with intravenous contrast is commonly used to confirm the diagnosis. However, the diagnosis of a pericardial cyst using CT can be challenging, and the exact location cannot always be ascertained.11 In our case, although CT was conducted in another hospital, a diaphragmatic hernia was diagnosed, and the patient was transferred to our clinic for surgery.

Fig. 2. chest computed tomography shows a unilocular cystic mass at the left cardiophrenic angle.

Fig. 3. intra-operative view of intact pericardial cyst (top) and pericardial cyst wall after fluid drainage (bottom).


Hynes et al. first used two-dimensional echocardiography to diagnose a pericardial cyst.5 Transoesophageal echocardiography can be useful if transthoracic echocardiography is inadequate for making the diagnosis.12 However, no studies have been done to ascertain the superiority of contrast CT over MRI and echocardi-ography for diagnosis or follow up.

The treatment options for pericardial cysts include simple observation, excision by thoracotomy, thoracoscopic surgical removal, and percutaneous aspiration with the injection of a sclerosing agent such as ethanol to decrease the likelihood of cyst recurrence. The indications for resection of pericardial cysts include large size, symptoms, patient concern, uncertain malignant potential, and the prevention of complications.13 Histologically, these cysts contain a single layer of mesothelial cells, with the remainder of the wall composed of connective tissue with collagen and elastic fibres.14

Pericardial cysts can cause complications via the erosion of adjacent structures, such as the right ventricle wall15 or superior vena cava.16 Other complications include cyst rupture,12 cardiac tamponade,17 mitral valve prolapse,8 obstruction of the right main-stem bronchus,18 and even sudden death.5

Treatment is usually required in symptomatic patients or in those with an unclear diagnosis. In other patients, close follow up is sufficient.

conclusionPericardial cysts are rare, benign, mediastinal lesions. They occur most frequently in the third or fourth decade of life and equally among men and women. In order to prevent complica-tions, pericardial cysts can be resected if the cyst is large, symp-tomatic, or of uncertain malignant potential.

References1. Satur CM, Hsin MK, Dussek JE. Giant pericardial cysts. Ann Thorac

Surg 1996; 61(1): 208–210.2. Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary mediastinal

tumors: part II. Tumors of the middle and posterior mediastinum. Chest 1997; 112: 1344–1357.

3. Nina VJ, Manzano NC, Mendes VG, Salgado Filho N. Giant pericardial

cyst: case report. Rev Bras Cir Cardiovasc 2007; 22(3): 349–351.4. Moschos C, Kalomenidis I, Roussos C, Stathopoulos GT. A 35-year-old

male with chronic cough. Eur Respir J 2007; 29(3): 608–611.5. Hynes JK, Tajik AJ, Osborn MJ, Orszulak TA, Seward JB. Two dimen-

sional echocardiographic diagnosis of pericardial cyst. Mayo Clin Proc 1983; 58(1): 60–63.

6. Shiraishi I, Yamagishi M, Kawakita A, Yamamoto Y, Hamaoka K. Acute cardiac tamponade caused by massive hemorrhage from pericardial cyst. Circulation 2000; 101: E196–197.

7. Fredman CS, Parsons SR, Aquino TI, Hamilton WP. Sudden death after a stress test in a patient with a large pericardial cyst. Am Heart J 1994; 127: 946–950.

8. Kruger SR, Michaud J, Cannom DS. Spontaneous resolution of a peri-cardial cyst. Am Heart J 1985; 109(6): 1390–1391

9. Braude PD, Falk G, McCaughan BC, Rutland J. Giant pericardial cyst. Aust NZ J Surg 1990; 60(8): 640–641.

10. Caramori JE, Miozzo L, Formigheri M, Barcellos C, Grando M, Trentin T. Dyspnea through compression of mediastinal structures due to peri-cardial cyst. Arq Bras Cardiol 2005; 84(6): 486–487. Epub 2005 Jun 28.

11. Parienty RA, Fontainey, Dufour G. Transformation of a pericardial cyst observed on long-term follow-up. J Comput Tomogr 1984; 8(2): 125–128.

12. Padder FA, Conrad AR, Manzar KJ, Thayapran N, Jonas EE, Freeman I. Echocardiographic diagnosis of pericardial cyst. Am J Med Sci 1997; 313(3): 191–192.

13. Moratalla MB, Garcia LG, Salvador RL, Bisquert BC. Giant pericar-dial cyst located at the left cardiophrenic angle. Eur J Radiol Extra 68(2008): e111–e112.

14. Abad C, Rey A, Feijoo J, Gonzales G, Martin-Suarez J. Pericardial cyst: surgical resection in two symptomatic cases. J Cardiovasc Surg 1996; 37(2): 199–202.

15. PS Chopra, DJ Duke, JR Pellet, PS Rahko. Pericardial cyst with partial erosion of the right ventricular wall. Ann Thorac Surg 1991; 51: 840–841.

16. Mastroroberto P, Chello M, Bevacqua E, Marchese AR. Pericardial cyst with partial erosion of the superior vena cava. J Cardiovas Surg 1996; 37(3): 323–324.

17. Bandeira FC, de Sá VP, Moriguti JC, Rodrigues AJ, Jurca MC, Almeida-Filho OC, et al. Cardiac tamponade: an unusual complication of pericardial cyst. J Am Soc Echocardiogr 1996; 9(1): 108–112.

18. Davis WC, German J, Johnson NJ. Pericardial diverticulum causing pulmonary obstruction. Arch Surg 1961; 82: 285–289.

19. Ozturk E, Aparci M, Haholu A, Sonmez G, Mutlu H, Basekim CC, et al. Giant dumbbell-shaped pericardial cyst. Tex Heart Inst J 2007; 34(3): 386–387.


case report

right common iliac artery stenosis and stent insertion in Behçet’s diseasez ULUSAN, AS KARADAG, A hARMAN, F BOyvAT, S BILGIC

abstractBehçet’s disease is a multisystem inflammatory disorder that is classified among the vasculitides and can affect all types and sizes of blood vessels. Vascular manifestations of Behçet’s disease are venous and arterial occlusion, and arte-rial aneurysms. As vasculitis of the vasa vasorum is the main pathological hallmark of Behçet’s disease, it is generally seen as superficial thrombo-phlebitis or occlusion of the major veins; however arterial obstruction and aneurysms may also be seen to a lesser extent. Iliac artery stenosis is highly uncommon.

Here, a case of common iliac stenosis in a 48-year-old patient with Behçet’s disease is reported. As the risk of aneurysm during an operation was high in this patient, he was treated with vascular stent implantation. Due to stent occlusion two months after the operation, percutaneous transluminal angioplasty was performed with an 8-mm balloon. During the three-year follow up, no obstruction was observed.

Keywords: artery stenosis, stent, Behçet’s disease



DOI: 10.5830/CVJA-2010-077

Behçet’s disease (BD) is a recurrent, inflammatory disorder involving multisystems of the body. It was originally described as a triad including oral aphthous ulcers, genital ulcers and uveitis.1 After the triad was described, systemic involvement of the central nervous system, pulmonary, gastrointestinal, vascular and musculoskeletal systems were also defined related to BD.2

The disease is called vasculo-BD when the vascular system is

involved. There is a 2–7% arterial involvement in 20- to 40-year-old male BD cases. Arterial involvement is more prevalent in this group of patients when the eyes are also involved. Pseudo-aneurysm is the most frequent form of arterial involvement and occlusion is less common.3 It is almost impossible to estimate the incidence of iliac artery stenosis since it is very uncommon and there were no data for its incidence in the literature.4 Here, a case of common iliac artery stenosis in a 48-year-old patient with Behçet’s disease is reported, together with its management.

case reportA 48-year-old man was admitted to our hospital with an acute, severe, cramp-like pain reflecting on his right thigh and leg. The patient had been suffering from recurrent oral ulcers and attacks of genital ulcers and uveitis since the age of 22 years. He later developed erythema nodosum. A skin pathology test was positive at 48 hours. He had previously been diagnosed with BD 24 years earlier, and he was on colchicine treatment. There were no other features in his history, and he was a non-smoker.

The patient’s pain started during a 1 000-m walk, and it

department of cardiovascular surgery, ankara Kecioren research and training Hospital, ankara, turkeyz ULUSAN, MD, [email protected]

department of dermatology, ankara Kecioren research and training Hospital, ankara, turkeyAySE SERAP KARADAG, MD

department of radiology, Baskent University Hospital, ankara, turkey ALI hARMAN, MDFATIh BOyvAT, MD

department of radiology, ankara University, ankara, turkey SADIK BILGIC, MD Fig. 1. right common iliac artery stenosis.


gradually got worse. Over the next two months he could walk only about 200 m without pain, which was acute, cramp-like and recurrent, and mostly resolved spontaneously. On physical examination, his pulses on the right femoral, popliteal, tibial and dorsalis pedis arteries were palpated weakly. There were aphthous ulcers in the oral cavity. The skin pathology test was positive. Blood pressure measured on the right arm was 110/70 mmHg and his heart rate was 80 beats per minute.

On laboratory examination, his erythrocyte sedimentation rate was 45 mm/h, white blood cell count was 12 000/mm3, haematocrit was 43%, haemoglobin was 14.4 g/dl, triglycerides were 100 mg/dl, total cholesterol was 180 mg/dl, high-density lipoprotein cholesterol was 43 mg/dl, low-density lipoprotein cholesterol was 118 mg/dl, and very low-density lipoprotein cholesterol was 20 mg/dl. Serum complements were normal, there were no anti-nuclear antibodies, and the rheumatoid factor was negative. His body mass index was 24 kg/m2.

Doppler ultrasonography (US) showed 80% stenosis in the right iliac artery. Since the patient was symptomatic, digital subtraction angiography was performed. Ninety per cent steno-sis was detected at the right common iliac artery (Fig. 1), with a pressure gradient of 32 mmHg, and the patient underwent an 8-mm-diameter stent implantation (express, Boston Scientific, Natick, MA, USA) into the iliac artery (Fig. 2).

One month later, the symptoms recurred. On Doppler US, intrastent obstruction was observed. Digital subtraction angio-graphy was performed and 90% stenosis of the right iliac artery stent was confirmed (Fig. 3). The gradient was measured across the stenosis and it was found to be 28 mmHg. Percutaneous transluminal angioplasty (PTA) was then performed with an 8-mm balloon (Fig. 4). After removal of the 6F vascular sheath, the artery was manually compressed to assure haemostasis at the puncture site. The gradient across the stenosis was lowered to 4 mmHg after PTA.

The patient was discharged on day two without any complica-tions. During the three-year follow up, the patient had no pain and he could walk regular distances. He had a normal ultra-sound examination and on intermittent Doppler US controls, no obstruction was observed in the stent. No femoral aneurysm appeared.

discussionBehçet’s disease has largely been recognised as an unclassified vasculitis affecting blood vessels of all types and sizes.5 One kind of vasculitis is large-artery involvement. Large and small vascu-

Fig. 2. application of ipsilateral catheterisation.

Fig. 4. application of balloon dilation to the intrastent stenosis.

Fig. 3. the recurrence of intrastent stenosis after the first operation.


lar involvement can be single or concurrent. Disconnection, disintegration and perivascular inflammatory cell infiltration of the medial elastic fibres and degeneration in the vasa vasorum have been observed on microscopic examination.6 In one study, pseudo-aneurysms were common in large or medium-sized arteries, whereas obstructions and stenoses were common in the distal run-off arteries of the lower extremities. Different luminal diameters of the involved arteries accounted for the frequent involvement of the distal run-off arteries.

The stage of active vasculitis of BD is pathologically char-acterised by massive infiltration of acute inflammatory cells, particularly involving layers of the media and adventitia. At this stage, the intima is swollen and the lumen is commonly thrombosed. Obstructions and stenoses therefore usually occur in the smaller arteries. If there is no thrombosis in the vessel and there is advanced vasculitis, severe inflammation makes the arterial wall weak and sets the stage for the formation of pseudo-aneurysm.7

Vascular involvement can be observed in up to 40% of patients, and venous disease is more frequent than arterial disease.5 Venous occlusions, superficial venous thrombosis, deep-vein thrombosis, vena cava thrombosis, cerebral venous thrombosis, Budd-Chiari syndrome, portal vein thrombosis and varices can be seen related to the venous system.8

Arterial involvement occurs in only one to 7% of patients with Behcet’s syndrome. Aneurysms, stenoses and obstruc-tions comprise the arterial complications. The most frequently affected artery is the aorta, followed by the pulmonary, femoral, subclavian, popliteal, brachial, iliac and common carotid arter-ies, with decreasing frequency.5,9 Iliac artery aneurysm is seen at a rate of only 0.6%.10

It is very important to identify patients with vasculo-Behçet, because they are at risk of developing recurrent vascular lesions after the first episode of vascular injury, and are predisposed to progressive multifocal vessel-related complications.8,9 Therefore, their prognosis is worse2 and they may need more aggressive treatment.8 Men and patients whose disease started at a younger age are at a higher risk for vascular involvement.9 Male patients are much more likely to be affected with arterial disease, compared to females. Smoking may be a risk factor for arterial disease in patients with BD.8 Due to weakness and fragility of the vessel wall and arteritis, open surgical intervention may result in complications, such as the development of pseudo-aneurysms and thrombosis at the sites of anastomosis.11

Surgical intervention frequently results in complications, such as recurrent pseudo-aneurysms, graft occlusions, or the develop-ment of new aneurysms at the anastomotic or other sites, because of further damage to the vulnerable vessel wall.5 Development of aneurysm ranges from one to 12 months postoperatively. Pseudo-aneurysm is the development of a pulsatile haema-toma as a result of rupture of the whole vessel wall. Aneurysms have the risk of rupture and infection. Aneurysm formation is observed in these patients, even at the insertion sites of venous lines placed for imaging methods.12

Surgery is generally indicated for the treatment of systemic arterial aneurysms, as there is a risk of rupture.8 On the other hand, due to the weakness and fragility of the vessel wall and arteritis, open surgery has complications, such as the develop-

ment of pseudo-aneurysms and thrombosis at the anastomotic sites.11 We therefore did not consider a surgical approach for the present patient, and there was a risk of aneurysm during percutaneous implantation of a stent into the iliac artery. During the three-year follow up of the patient, however, no aneurysm or stent occlusion was observed.

When there are no symptoms, non-operative treatment is elected for obstructive or stenotic lesions. However, cortico-steroids, immunosuppressives or surgical intervention may be appropriate.

Initial success rates of selective stent placement for iliac artery stenosis are 97 to 99%, and the three-year patency rates range from 74 to 86%. Stents have improved the initial rate of endovascular treatment of iliac artery occlusions. The rate of early stent occlusion was reported to be 1% in patients who had stents for iliac artery stenosis.13 The patency rates for three and 10 years after balloon dilatation for intrastent stenosis were 64–85% and 46%, respectively.14 Balloon dilatation is also thought to enhance long-term treatment outcomes.

Occlusion of arteries is less common in BD and stent implan-tation is a good choice of treatment in these patients as the risk of aneurysm is high after surgical intervention.

References1. Sagduyu A, Sirin H, Oksel F, et al. An unusual case of Behçet’s disease

presenting with bilateral internal carotid artery occlusion. J Neurol Neurosurg Psychiatry 2002; 73: 343–351.

2. Sarica-Kucukoglu R, Akdag-Kose A, Kayabali M, et al. Vascular involvement in Behçet’s disease: a retrospective analysis of 2319 cases. Int J Dermatol 2006; 45: 919–921.

3. Yildirim A, Isik A, Koca S. Subclavian artery pseudoaneurysm in Behcet’s disease. Clin Rheumatol 2007; 26: 1151–1154.

4. Tola M, Yurdakul M, Özdemir E, et al. Pseudoaneurysm of the internal iliac artery of a patient with Behçet’s disease: treatment with an endo-vascular stent-graft. Cardiovasc Intervent Radiol 2006; 29: 720–722.

5. Yekeler E, Tunaci A, Tunaci M, et al. Successful medical treatment of abdominal aortic aneurysms in a patient with Behçet’s disease: imaging findings. Australas Radiol 2005; 49:182–184.

6. Ozkurt H, Oztora F, Tunc S, Basak M. Pseudoaneurysm of the renal interlobar artery in Behçet’s Disease. Acta Radiologica 2006; 47: 1000–1002.

7. Ko GY, Byun JY, Choi BG, Cho SH. The vascular manifestations of Behçet’s disease: angiographic and CT findings. Br J Radiol 2000; 73: 1270–1274.

8. Calamiaa KT, Schirmerb M, Melikoglu M. Major vessel involvement in Behçet disease. Curr Opin Rheumatol 2004; 17: 1–8.

9. Jayachandran NV, Rajasekhar L, Chandrasekhara PKS, et al. Multiple peripheral arterial and aortic aneurysms in Behcet’s syndrome – a case report. Clin Rheumatol 2008; 27: 265–267.

10. Düzgün N, Ate A, Aydıntuğ OT, et al. Characteristics of vascular involvement in Behçet’s disease. Scand J Rheumatol 2006; 35: 65–68.

11. Tola M, Yurdakul M, Ozdemir E, et al. Pseudoaneurysm of the internal iliac artery of a patient with Behçet’s disease: treatment with an endo-vascular stent-graft. Cardiovasc Intervent Radiol 2006; 29: 720–722.

12. Honjo O, Yunoki K, Shichijo T, Oba O. Peripheral pseudoaneurysm in active Behçet’s disease: surgical and perioperative therapeutic strate-gies. Ann Vasc Surg 2006; 20: 664–668.

13. Uher P, Nyman U, Lindh M, et al. Long-term results of stenting for chronic iliac artery occlusion. J Endovasc Ther 2002; 9: 67–75.

14. Tsetis D, Uberoi R. Quality improvement guidelines for endovascular treatment of iliac artery occlusive disease. Cardiovasc Intervent Radiol 2008; 31: 238–245.


case report

percutaneous closure of a tricuspid paravalvular leak with an amplatzer duct occluder ii via antegrade approachA IyISOy, h KURSAKLIOGLU, T CELIK, O BAySAN, M CELIK

abstractParavalvular leaks are seen after valve-replacement surgery and most patients with these leaks are asymptomatic, prob-ably due to the small size of the leak. Nevertheless, a para-valvular leak after tricuspid valve replacement is a rare complication and may cause severe haemoylsis and hepatic dysfunction. It is usually treated surgically. There are no data on percutaneous transcatheter closure of paravalvular leaks. In this report, we present a successful percutaneous closure of a paravalvular leak using an Amplatzer duct occluder II device after a tricuspid valve replacement in a patient with high operative risk who had also had mitral and aortic valve replacements.

Keywords: tricuspid valve replacement, paravalvular leak, percutaneous transcatheter closure



DOI: 10.5830/CVJA-2010-079

Almost 210 000 valve-replacement surgeries are performed worldwide annually.1 A paravalvular leak (PVL) is a poten-tial complication of cardiac valve-replacement surgery and may cause severe haemoylsis or haemodynamic instability.2 In such cases, haemolysis rarely resolves spontaneously and usually requires a further operation. Re-operation is associated with higher rates of morbidity and mortality. Also, the risk of recurrent paravalvular insufficiency is high after re-operation. Although, there is no specifically designed transcatheter device available for repair of paravalvular leaks, percutaneous transcath-eter closure of a PVL may be a promising alternative to surgery.

In this report, we present a case of successful percutaneous closure of a tricuspid PVL using an Amplatzer duct occluder (ADO) II device under the guidance of three-dimensional (3D) transoesophageal echocardiography (TEE) in a patient in whom severe haemolysis and hepatic dysfunction had developed due to a PVL after tricuspid valve replacement.

case reportA 57-year-old man with aortic and mitral valve replacements five years earlier, and a tricuspid valve replacement with a 31-mm St Jude Medical valve prosthesis three years earlier, was admitted to our hospital for congestive heart failure (NYHA, class III). Laboratory examination revealed severe haemolysis (serum haemoglobin 9.8 g∕dl, reticulocyte count 3.8%, lactic dehydroxygenase (LDH) 1 080 U/l). The left ventricular ejec-tion fraction measured 40% and a localised moderate PVL was shown on transoesophageal echocardiography (TEE) (Fig. 1).

The patient was symptomatic and the operation was very high risk because of the two previous valve operations. The standard Euroscore of the patient was calculated at 6 points (estimated mortality 10.9–11.5%). Percutaneous closure of this PVL was decided on and informed patient consent was obtained.

The procedure was performed under general anaesthesia with the guidance of 3D TEE. After heparinisation, a 6F multi-purpose diagnostic catheter was placed into the right atrium. A 0.035-inch straight-tipped glide wire (Terumo Inc, Japan) was advanced into the right ventricle passing through the PVL site, and confirmed with 2D and 3D TEE. Subsequently, a 6F multi-purpose diagnostic catheter was advanced through the defect. The glide wire was then changed with a 0.035-inch super-stiff Amplatzer guidewire (260 cm).

The delivery system was placed into the right ventricle over this extra-stiff wire. The ADO II device (waist diameter 6 mm, disc diameter 12 mm) was screwed to the delivery cable, loaded

department of cardiology, gulhane Military Medical academy, school of Medicine, ankara, turkeyA IyISOy, MD h KURSAKLIOGLU, MDT CELIK, MDO BAySAN, MDM CELIK, MD, [email protected]

Fig. 1. transoesophageal echocardiography showing moderate to severe tricuspid paravalvular regurgitation. white arrow shows pvl. ra: right atrium, la: left atrium, pvl: paravalvular leak.


into the sheath, and passed across the PVL. The distal disc was opened and then placed into the orifice of the PVL. Subsequently, the proximal disc was opened in the right atrium. The device was released after establishing that the position of the device was correct (Fig. 2). Closure of the defect was demonstrated with 3D TEE and complete disappearance of the leak was confirmed with 2D TEE (Fig. 3). The total procedural time was 32 minutes and fluoroscopy time was 11 minutes. The post-procedure course was uneventful with normal prosthetic valve function.

discussionParavalvular regurgitation is a complication of prosthetic cardiac valve placement. This may occur soon after or many years post surgery. Small PVLs can be detected in up to half of the patients, using echocardiographic imaging. Larger defects are detected in 3 to 7.5% of patients with valve replacements and the detection rate has increased if TEE is used.3

PVLs are most often found in association with mitral valve prostheses, less often with aortic, and only rarely with pulmo-nary or tricuspid valve prostheses.4 PVLs may develop more commonly in patients with heavy annular calcification and localised infection.5 Technical mistakes, including incomplete apposition of the sewing ring to the native tissue or breaks in one of the sutures may lead to dehiscence and PVLs.6

Most cases of PVLs are small. They have little clinical signifi-cance and tend to improve or disappear over time. However, severe perivalvular regurgitation may lead to some symptoms. These leaks can cause haemolytic anaemia as a result of red cell fragmentation in the high shear-stress regurgitant jet, decreased exercise tolerance or dyspnoea as a result of congestive heart failure, pulmonary hypertension and infective endocarditis.1,7

Spontaneous closure has rarely been encountered. Medical therapy is usually palliative and directed at the congestive heart failure or haemolysis. Re-operation is the gold-standard therapy for symptomatic patients with PVLs, but it is associated with a higher mortality and morbidity rate than that of the initial operation.8 Also, re-operations are associated with increased risk of PVLs.9 Percutaneous repair of perivalvular regurgitation has been proposed as an alternative therapy to avoid the risk of surgery.

Hourihan et al.10 in 1992 reported the first successful percu-taneous closure of a PVL, using a Rashkind umbrella device in a patient with an aortic paravalvular leak. Over the years, many devices have been used for percutaneous closure of PVLs, which are often irregular, tortuous and frequently crescent-shaped. The success rate of this procedure depends on the type of PVL and the shape of the closure device. Regurgitation may persist due to incomplete closure of the PVL because of an unsuitable shape of device for the leak.

There is no specifically designed transcatheter device approved for percutaneous closure of PVLs. ADO II, which is designed for closing a patent ductus arteriosus, has a circular shape with two discs and a smaller waist size. Therefore, an ADO II device can provide effective closure for PVLs and improve-ment of symptoms. For these reasons, an ADO II device was used in our case. Using periprocedural transoesophageal echo-cardiography provided important anatomical details and helped in optimal device selection and delivery.

Despite this technically feasible and safe treatment modality, there are few reported cases of percutaneous closure of PVLs. Most have been involved with the mitral valve, and a successful percutaneous closure of an aortic PVL was reported. There is no reported case in the literature of a transcatheter closure of a PVL after tricuspid valve replacement. This is probably a result of the few patients receiving tricuspid valve replacements, not because of technical difficulties. To the best of our knowledge, this is the

Fig. 3. two-dimensional transoesophageal echocardio-graphy after deployment of the closure device shows the paravalvular regurgitation has completely disappeared. ra: right atrium, la: left atrium, pvl: paravalvular leak.

Fig. 2. the cine-angiography shows the glide wire and 6F multipurpose diagnostic catheter advanced into the right ventricle passing through the pvl site (a). the glide wire was changed to a 0.035-inch super-stiff amplatzer guide wire, which was subsequently advanced into the pulmonary artery (B). releasing the ado ii device after viewing with transoesophageal echocardiography (c).

a B c


first case report showing percutaneous transcatheter closure of a tricuspid PVL using an ADO II device.

conclusionHaemodynamically important PVLs after any valve replacement may be closed percutaneously using an ADO II. Percutaneous transcatheter closure of PVLs is technically feasible and a safe treatment modality, which could be regarded as a promising alternative to surgery in patients with high surgical risk.

References1. O’Rourke DJ, Palac RT, Malenka DJ, Marrin CA, Arbuckle BE, Plehn

JF. Outcome of mild periprosthetic regurgitation detected by intraop-erative transesophageal echocardiography. J Am Coll Cardiol 2001; 38: 163–166.

2. Rallidis LS, Moyssakis IE, Ikonomidis I, Nihoyannopoulos P. Natural history of early aortic paraprosthetic regurgitation: a five-year follow-up. Am Heart J 1999; 138: 351–357.

3. Ionescu A, Fraser AG, Butchart EG. Prevalence and clinical signifi-

cance of incidental paraprosthetic valvar regurgitation: a prospective study using transoesophageal echocardiography. Heart 2003; 89: 1316–1321.

4. Safi AM, Kwan T, Afflu E, Al Kamme A, Salciccioli L. Paravalvular regurgitation: a rare complication following valve replacement surgery. Angiology 2000; 51: 479–487.

5. Schoen FJ. The first step to understanding valve failure: an overview of pathology. Eur J Cardiothorac Surg 1992; 6(Suppl 1): S50–53.

6. Alonso-Lej F. Straight suture plane to avoid periprosthetic leak in aortic valve replacement. Ann Thorac Surg 1975; 19: 571–573.

7. Genoni M, Franzen D, Tavakoli R, Seiffert B, Graves K, Jenni R, et al. Does the morphology of mitral paravalvular leaks influence symptoms and hemolysis? J Heart Valve Dis 2001; 10: 426–430.

8. Genoni M, Franzen D, Vogt P, Seifert B, Jenni R, Kunzli A, et al. Paravalvular leakage after mitral valve replacement: improved long-term survival with aggressive surgery? Eur J Cardiothorac Surg 2000; 17: 14–19.

9. Pansini S, Ottino G, Forsennati PG, Serpieri G, Zattera G, Casabona R, et al. Reoperations on heart valve prostheses: an analysis of operative risks and late results. Ann Thorac Surg 1990; 50: 590–596.

10. Hourihan M, Perry SB, Mandell VS, Keane JF, Rome JJ, Bittl JA, et al. Transcatheter umbrella closure of valvular and paravalvular leaks. J Am Coll Cardiol 1992; 20: 1371–1377.

References: 1. CRESTOR® package insert 2. Jones P, Davidson MH, Stein EA, et al. Comparison of the Effi cacy 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.

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.

16162

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AFRICA

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• Asymptomatic left ventricular systolic dysfunction in hypertensive Nigerians

• Metabolic syndrome in Asian Indians

• Down syndrome and congenital heart disease

• Diagnosis and follow up of primary cardiac tumours

• Stromal-derived factor-1<alpha>/CXCR4 in neo-intimal repair

• Omega-3 fatty acid content of fish oil supplements

• Increasing rates of hypertension in women

• Anaesthesia for emergency Caesarean section in peripartum cardiomypathy

• 3D transoesophageal echocardiography in prosthetic mitral valve thrombosis

cvja volume 22, issue 6

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