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Cardiovascular Journal of Africa . Vol 23, No 7, August 2012
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VOL 23, NO 7. AUGUST 2012
CONTENTS
Cardiovascular Journal of Africa
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www.cvja.co.za
From the Editor’s DesK
New impact factor and PubMed Central service from the Cardiovascular Journal of Africa AJ Brink
Cardiovascular Topics
365 Management of acute coronary syndrome in South Africa: insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry C Schamroth • ACCESS South Africa investigators 371 Social drift of cardiovascular disease risk factors in Africans from the North West Province of South Africa: the PURE study PT Pisa • R Behanan • HH Vorster • A Kruger 379 Target-organ damage and cardiovascular complications in hypertensive Nigerian Yoruba adults: a cross-sectional study OO Oladapo • L Salako • L Sadiq • K Shoyinka • K Adedapo • AO Falase 384
William Nelson ECG Quiz
385
Prevalence of cardiac dyssynchrony and correlation with atrio-ventricular block and QRS width in dilated cardiomyopathy: an echocardiographic study JB Anzouan-Kacou • MP Ncho-Mottoh • C Konin • AR N’Guetta • KA Ekou • BJ Koffi • KE Soya • ME Tano • R Abouo-N’Dori
389 Different lipid profiles according to ethnicity in the Heart of Soweto study cohort of de novo presentations of heart disease K Sliwa • JG Lyons • MJ Carrington • S Lecour • AD Marais • FJ Raal • S Stewart 396 Effect of perindopril on pulse-wave velocity and endothelin-1 in black hypertensive patients E Osuch • WJ du Plooy • SH du Plooy • LH Böhmer 400 The effect of the metabolic syndrome on the risk and outcome of coronary artery bypass graft surgery MJ Swart • WH de Jager • JT Kemp • PJ Nel • SL van Staden • G Joubert INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors
SUBJECT Editors
Editor-in-Chief (South Africa) PROF AJ BRINK
Nuclear Medicine and Imaging DR MM SATHEKGE
Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT
Heart Failure Dr g visagie Paediatric dr s brown Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Electrophysiology and Pacing dr a okreglicki Epidemiology and Preventionist dr ap kengne
Editorial Board prof PA Brink Experimental & Laboratory Cardiology
PROF A LOCHNER Biochemistry/Laboratory Science
PROF R DELPORT Chemical Pathology
PROF BM MAYOSI Chronic Rheumatic Heart Disease
PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure
PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society
International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)
PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)
PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension
PROF PETER SCHWARTZ Italy (Dysrhythmias)
DR J LAWRENSON Paediatric Heart Disease
Publishing Consultant
PROF H DU T THERON Invasive Cardiology
PROF ERNST VON SCHWARZ USA (Interventional Cardiology) Mike Gibbs
Review Article
405 The promise of computer-assisted auscultation in screening for structural heart disease and clinical teaching L Zühlke • L Myer • BM Mayosi
SA HEART CONFERENCE REPORTS
VOL 23, NO 7. AUGUST 2012
CONTENTS
412 Treating angina pectoris with I f channel blockade: evaluating treatment with a newer agent J Aalbers 415
Catheter ablation of atrial fibrillation: evidence shows significant benefit and reduced progression of disease J Aalbers
PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) S1 SA
CONGRESS OF NEPHROLOGY ABSTRACTS, 2012
Case Reports
e1 Severe cardiac failure due to rapidly progressive rheumatoid arthritis-associated valvulopathy JM Tarkin • N Hadjiloizou • HO Savage • SK Prasad • MN Sheppard • NE Moat • S Kaddoura e4 HIV infection, pulmonary arterial hypertension and pregnancy: a fatal triad MT Lin Nyo • L Schoeman • R Sookhayi • BM Mayosi e7 Triple papillary fibroelastomas in an asymptomatic patient D Kireyev • MH Ashraf • MF Wilson e10
Cardiac mass in a patient with sigmoid adenocarcinoma: a metastasis? HA Ngow • WMN Wan Khairina
e13 Isolated lower limb ischaemia as an unusual presenting symptom of aortic dissection C-H Lee • C-H Chang • Y-T Tsai • C-W Wu
managing editor
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Copyright: Clinics Cardive Publishing (Pty) Ltd. Layout: Martingraphix Printer: Durbanville Commercial Printers ONLINE SERVICES: Design Connection All submissions to CVJA are to be made online via www.cvja.co.za
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The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month.
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Electronic abstracts available on Pubmed Audited circulation Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact julia@clinicscardive.com Subscriptions for 10 issues: South Africa: R650 (excl VAT) Overseas: R1306 Online subscription: R200 The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.
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From the Editor’s Desk New impact factor and PubMed Central Service from the Cardiovascular Journal of Africa The Cardiovascular Journal of Africa is pleased to announce an increase in its 2011 impact factor to 0.767, as provided by Thompson Reuters (ISI). Currently, we rank 161 out of 273 indexed journals in the field of cardiology and cardiovascular medicine throughout the world, according to the Scopus journalrating system. The Cardiovascular Journal of Africa is truly entrenched in Africa and worldwide In order to improve visibility for our authors, the Cardiovascular Journal of Africa has developed the capability of publishing your article to PubMed Central (PMC), which is the free electronic archive of the Biomedical and Life Sciences Journal literature at the US National Institutes of Health National Library of Medicine (NIH/NLM). Currently your article is available on PubMed as a PDF from Sabinet e-publications. PubMed Central is therefore an additional repository of your full-text article. This ensures a long existence for your research and availability for generations to come. The further value of PMC lies in its capacity to store and cross reference data from diverse sources using a common format within a single repository. With PMC, a user can quickly search the entire collection of full-text articles and locate all relevant material. PMC also allows for the integration of its literature with a variety of other information resources that can enhance the research and knowledge fields of scientists, clinicians and others. We are offering authors from our 2012 published articles first opportunity to use this service at an initial fee of 80 US dollars.
Our authors will also be pleased to note that PubMed will now index our electronic journal. This allows us to publish more articles as we are not restricted by print dynamics. Since listing in Index Medicus, PubMed in 2007 as the Cardiovascular Journal of Africa, 590 peer-reviewed articles have been published and are freely available as linked full text. Authors and reviewers deserve our gratitude as their efforts help to record the development of cardiovascular research across our continent. The Cardiovascular Journal of Africa receives articles from across the world, but gives priority to articles from Africa. In order to assist Francophone Africa, we are enlisting French reviewers with competency in cardiovascular medicine. We need to expand this list, so if you are able to assist in reviewing, please contact our development editor, Glenda Hardy on Glenda@clinicscardive.com or go online to www.cvja.co.za and register as a reviewer. The Cardiovascular Journal of Africa will be present at the forthcoming PASCAR conference in Dakar, Senegal, 15–20 May 2013. We look forward to seeing you there, and of course, also at the 6th World Congress of Paediatric Cardiology and Cardiac Surgery, 17–22 February 2013 in Cape Town.
Andries Brink Editor-in-chief
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Cardiovascular Topics Management of acute coronary syndrome in South Africa: insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry COLIN SCHAMROTH, ACCESS South Africa investigators
Abstract Background: The burden of cardiovascular diseases is predicted to escalate in developing countries. While many studies have reported the descriptive epidemiology, practice patterns and outcomes of patients hospitalised with acute coronary syndromes (ACS), these have largely been confined to the developed nations. Methods: In this prospective, observational registry, 12 068 adults hospitalised with a diagnosis of ACS were enrolled between January 2007 and January 2008 at 134 sites in 19 countries in Africa, Latin America and the Middle East. Data on patient characteristics, treatment and outcomes were collected. Results: Of the 642 patients from South Africa in the registry, 615 had a confirmed ACS diagnosis and form the basis of this report; 41% had a discharge diagnosis of ST-segment elevation myocardial infarction (STEMI) and 59% a diagnosis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS), including 32% with non-ST-segment elevation myocardial infarction (NSTEMI) and 27% with unstable angina (UA). During hospitalisation, most patients received aspirin (94%) and a lipid-lowering medication (91%); 69% received a beta-blocker, and 66% an ACE inhibitor/angiotensin receptor blocker. Thrombolytic therapy was used in only 18% of subjects (36% of STEMI patients and 5.5% of NSTE-ACS patients). Angiography was undertaken in 93% of patients (61.3% on the first day), of whom 53% had a percutaneous coronary intervention (PCI) and 14% were referred for coronary artery bypass surgery. Drugeluting stents were used in 57.9% of cases. Clopidogrel was prescribed at discharge from hospital in 62.2% of patients. All-cause death at 12 months was 5.7%, and was higher in patients with STEMI versus non-ST-elevation ACS (6.7 vs 5.0%, p < 0.0001). Clinical factors associated with higher risk of death at 12 months included age ≥ 70 years, presence of diabetes mellitus on admission, and a history of stroke/ transient ischaemic attack (TIA). Milpark Hospital, Johannesburg, South Africa
COLIN SCHAMROTH, MB BCh (Wits), FCP (SA), MMed (Wits), cscham@global.co.za
Conclusions: In this observational study of ACS patients, the use of evidence-based pharmacological therapies for ACS was quite high. Interventional rates were high compared to international standards, and in particular the use of drug-eluting stents, yet the clinical outcomes (mortality, re-admission rates and severe bleeding episodes at one year) were favourable, with low rates compared with other studies. Keywords: acute coronary syndrome, myocardial infarction, unstable angina, registry, death Submitted 20/1/12, accepted 1/3/12 Published online 13/3/12 Cardiovasc J Afr 2012; 23: 365–370
www.cvja.co.za
DOI: 10.5830/CVJA-2012-017
Knowledge on the prevention and treatment of cardiovascular diseases derives from randomised, controlled clinical trials and observational studies. Registries of treatment patterns of particular disease processes have shaped and influenced treatment practices. These observational studies have also helped map out differences in the populations studied, whether this be geographical or ethnic. Current data derive almost exclusively from the developed world populations, and whether these data are applicable to population groups outside of the developed world is unknown.1-6 Knowledge on treatment trends and practices from the developing world is scanty or entirely absent. While studies such as the INTERHEART have demonstrated that the risk factors for the development of acute myocardial infarction are similar across population groups, the patterns of treatment of ischaemic heart disease among different population groups in underdeveloped nations remains unknown.7 Cardiovascular disease mortality and associated major risk factors (elevated blood pressure, raised cholesterol levels, cigarette smoking, diabetes mellitus, physical inactivity and high-fat diet) vary widely from country to country, but it is predicted that within the next decade, the major burden of cardiovascular diseases will shift to the developing countries.8 There is therefore a need to establish registries in developing countries to increase awareness of the cardiovascular disease burden and establish appropriate preventive and management strategies. To date there are no published registries on the
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management and outcomes of patients admitted to hospital for acute coronary syndromes in South Africa. The aim of the multinational observational ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry was to gain insights into the descriptive epidemiology, current practice patterns, and one-year outcomes of patients hospitalised with acute coronary syndrome (ACS), whether this be unstable angina (UA)/non-STsegment elevation acute coronary syndrome (NSTE-ACS) or ST-segment elevation myocardial infarction (STEMI), in developing countries in Africa, Latin America and the Middle East, excluding countries from Europe and North America. The complete ACCESS study design, methods and results have previously been published.9 The following report is of the data applicable to the South African patient cohort, and how these compare with the data from the ACCESS study as a whole.
Methods ACCESS was a prospective, observational, multinational registry in patients hospitalised for an acute coronary event. Patients were enrolled at 134 sites in 19 countries in North Africa (Algeria, Morocco, Tunisia), South Africa, Latin America (Argentina, Brazil, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Venezuela) and the Middle East (Egypt, Iran, Jordan, Kuwait, Lebanon, Saudi Arabia, United Arab Emirates). The ACCESS registry was conducted in accordance with the Guidelines for Good Clinical Practice and under the leadership of a scientific advisory board (the ACCESS steering committee). Each participating country had the responsibility of ensuring locally that all necessary regulatory submissions were performed in accordance with local regulations, including data-protection regulations. Local institutional review boards or independent ethics committees approved the study and all patients provided informed consent to participate. Selection of physicians was determined at the country level; 29 sites participated in South Africa. The aim was to enroll approximately 25 patients per site. Patients aged 21 years and older who were admitted alive to hospital with an ACS and provided signed, informed consent were eligible to participate in this all-comers registry. Patients with symptoms precipitated by a secondary co-morbidity (e.g. anaemia, heart failure or non-cardiac trauma) and patients participating in concomitant clinical trials were excluded from the study. Eligible patients who agreed to participate were recruited consecutively to avoid patient selection bias. To be enrolled, patients had to present with ischaemic symptoms of ACS within 24 hours of hospital presentation and have at least one of the following: (1) electrocardiographic changes [transient ST-segment elevation ≥ 1 mm, ST-segment depression ≥ 1 mm, new T-wave inversion ≥ 1 mm, pseudo-normalisation of previously inverted T waves, new Q waves (one-third of the height of the R wave or > 0.04 s), new R wave > S wave in lead V1, or new left bundle branch block]; (2) documentation of coronary artery disease [history of myocardial infarction (MI), angina, congestive heart failure believed to be due to ischaemia or resuscitated sudden cardiac death, history of or new positive stress test with imaging, previous or new cardiac catheterisation documenting coronary artery disease, prior or new percutaneous coronary intervention (PCI) or coronary artery bypass surgery
(CABG)]; and (3) an increase in a cardiac biochemical marker of myocardial necrosis (troponin or CK-MB). The data were recorded prospectively on admission to hospital (baseline), at discharge, and at 6 ± 1 months’ and 12 ± 1 months’ follow-up visits. Data were collected via telephonic interviews for patients who did not attend the follow-up appointments. In each country, 10% of sites that enrolled at least one patient were randomly selected to undergo a site visit and data audit. At each of these sites, 100% of case report forms for all enrolled patients were monitored for source documentation and accuracy. The primary endpoint was all-cause death at one year from initial hospitalisation. Secondary endpoints (one year from initial hospitalisation) included cardiovascular death, cardiovascular death and non-fatal MI, non-fatal stroke, non-fatal MI, the combined endpoint of cardiovascular death, stroke or myocardial infarction and re-hospitalisation for ischaemic events, the composite endpoint in each country, and bleeding episodes. All-cause death at 30 days was also recorded.
Results Recruitment of patients took place between January 2007 and January 2008. Of the 39 participating doctors in the 29 South African recruiting sites, 26 identified themselves as cardiologists, of whom 10 (38.5%) were interventional cardiologists. All major geographic areas in South Africa were involved in recruitment of registry patients. A list of the participating doctors is given at the end of the article. A total of 642 patients were enrolled in South Africa, 5.3% of the 12 068 enrolled in the entire ACCESS registry. In the Patients enrolled (n = 642) Exclusions: Other cardiac diagnosis (n = 16) Non-cardiac diagnosis (n = 11) ACS patients (n = 615)
NSTE-ACS (n = 362) Exclusions: Died (n = 18) Lost to followup (n = 16)
STEMI (n = 253) Exclusions: Died (n = 17) Lost to followup (n = 16)
Patients with one-year follow up (n = 548) NSTE-ACS (n = 328)
Fig. 1. Study flow chart.
STEMI (n = 220)
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total ACCESS study, 11 731 patients were confirmed as having an ACS. A flow chart of the study patients is given in Fig. 1. In South Africa, of the 642 total patients, 615 patients were confirmed as having an ACS and form the basis of this report. Completed data at the one-year follow up was available on 548 (89.1%) patients; 35(5.7%) had died and 32 (5.2%) were lost to follow up. Diagnosis at discharge (end of hospital stay) was STEMI in 41.1% and NSTE-ACS in 58.9%, including non-ST-segment elevation MI in 32.4% and unstable angina (no biomarker elevation) in 26.4%. Four patients enrolled in the survey had a ‘discharge’ diagnosis of death, indicating a 0.65% in-hospital mortality rate. In the entire ACCESS study, overall the in-hospital death rate was 2.6%. Within the South African cohort, 60.7% were Caucasian, 22.8% Asian, 10.7% of mixed ancestry and 5.9% of African ancestry. The population was predominantly male (75.9%) with a mean age of 58.0 ± 12.1 years. STEMI patients were younger than NSTE-ACS patients (mean age 54.5 vs 60.5 years). Selected patient baseline characteristics are shown in Table 1; 46.7% of patients had a history of angina, 29% a previous MI, and 6% a history of either cerebro- or peripheral vascular disease. Fifty-two per cent of patients gave a family history of cardiovascular disease, far higher than the 31% of the entire ACCESS cohort, and more patients had dyslipidaemia (56 vs 40% for the entire ACCESS population). More patients had had a prior CABG (10 vs 5%), previous PCI (19 vs 12%) and positive current smoking status (44 vs 39%). However there were fewer patients with pre-existing diabetes mellitus (24 vs 35%), but equal numbers of hypertensive subjects (56 vs 55%). Diabetic patients tended to be poorly controlled with a glycosylated
TABLE I. PATIENT BASELINE CHARACTERISTICS: SOUTH AFRICAN COHORT ACCORDING TO DISCHARGE DIAGNOSIS AND OVERALL, AND COMPLETE ACCESS STUDY OVERALL South Africa ACCESS NSTE-ACS STEMI All All Discharge diagnosis (n = 362) (n = 253) (n = 615) (n = 12 068) Myocardial infarction 119 (32.9) 62 (24.5) 181 (29.4) 2588 (21.4) Stroke/TIA 6 (1.7) 4 (1.6) 10 (1.6) 493 (4) Angina 216 (59.7) 71 (28.1) 287 (46.7) 5293 (43.8 Family history of cardiovascular disease 194 (53.6) 126 (49.8) 320 (52) 3728 (30.8) Congestive heart failure 27 (7.5) 9 (3.6) 36 (5.9) 640 (5.3) Peripheral arterial disease 18 (5) 8 (3.2) 26 (4.2) 541 (4.4) Prior PCI 85 (23.5) 32 (12.6) 117 (19) 1483 (12.2) 75 (88.2) 26 (81.3) 101 (86.3) N/A Prior PCI: S tent no stent 10 (11.8) 6 (18.7) 16 (13.7) N/A Prior CABG 57 (15.7) 6 (2.4) 63 (10.2) 602 (4.9) Diabetes 97 (26.8) 50 (19.8) 147 (23.9) 4208 (34.8) Hypertension 238 (65.7) 104 (41.1) 342 (55.6) 6655 (55.1) Dyslipidaemia 228 (63.0) 117 (46.2) 345 (56.1) 4864 (40.3) Current smoking 133 (37.0) 135 (53.6) 268 (43.9) 4730 (39.1) Body mass index 28.7 28.1 28.4 27.0 (kg/m2) PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft. Unless otherwise indicated, results are reported as number (percent); ACCESS includes South Africa.
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haemoglobin (HbA1c) level on admission of > 8.0% in 37.3% of patients. Diabetic patients with STEMI were more likely to have an HbA1c level > 8.0% than those with NSTE-ACS (46.7 vs 31.1%). Forty-nine per cent of patients admitted either moderate or heavy alcohol consumption. Patients were predominantly overweight [body mass index (BMI) 28.4 ± 5.2 kg/m2], with only 25% of patients having a BMI below 25 kg/m2. Women with STEMI had a larger waist circumference than the women with NSTE-ACS (98.6 ± 13.6 vs 95.1 ± 14.0 cm), while men with STEMI had smaller waist circumferences than those presenting with NSTE-ACS (99.9 ± 12.6 cm vs 103.1 ± 12.5 cm). Patients presenting with STEMI arrived at hospital sooner after onset of symptoms than the NSTE-ACS patients [median (Q1; Q3) 3.6 (1.6; 9.5) vs 7.4 (2.5; 25.7) hours], with 64.4% of STEMI patients arriving within six hours and 85.3% of the group within 12 hours of the onset of symptoms. This was despite 63.8% of patients living within a 30-minute drive from the admitting hospital. In the complete ACCESS database, the median delay from onset of symptoms to arrival in hospital was 4.0 (1.8; 12.6) hours for STEMI patients and 6.0 (2.0; 19.0) hours for NSTE-ACS patients. Patients with a discharge diagnosis of STEMI were more likely to have ischaemic symptoms (91.7 vs 69.6%), ECG changes suggestive of ischaemia (97.2 vs 59.7%) and elevated cardiac biomarkers (67.2 vs 53.3%) than patients with a discharge diagnosis of NSTE-ACS. Left bundle branch block was noted in 2.9% of patients overall (3.9% of NSTE-ACS and 1.6% of STEMI). Prior to hospitalisation, treatment with aspirin was commenced in 43.1% of patients, clopidogrel in 1.6%, unfractionated heparin (UFH) in 2.3% and low-molecular weight heparin (LMWH) in 1.5%. No form of thrombolytic therapy was administered pre-hospitalisation. Selected interventions and in-hospital treatments are shown in Table 2. Only 18% of patients received a thrombolytic on admission (36.0% of the STEMI patients and 5.5% of the NSTE-ACS patients). Less than 1% of patients were considered to have a contraindication to the use of a thrombolytic agent. TABLE 2. SELECTED IN-HOSPITAL INTERVENTIONS AND DRUG TREATMENTS: SOUTH AFRICAN COHORT ACCORDING TO DISCHARGE DIAGNOSIS AND OVERALL, AND COMPLETE ACCESS STUDY OVERALL South Africa ACCESS In-hospital interventions and drug NSTE-ACS STEMI All All treatments (n = 362) (n = 253) (n = 615) (n = 11731) Thrombolytics 20 (5.5) 91 (36) 111 (18) 2127 (18.1) Angiography 344 (95) 228 (90.1) 572 (93) 6787 (57.8) PCI 179 (49.4) 151 (59.7) 330 (53.7) 4141 (35.2) CABG 70 (19.3) 20 (7.9) 90 (14.6) 668 (5.6) Stent (% of PCI) 172 (96.1) 139 (92.1) 311 (94.2) 3900 (33.2) Drug-eluting stent (% of total stent usage) 108 (62.8) 72 (51.8) 180 (57.9) 1713 (43.9) Aspirin 331 (91.4) 247 (97.6) 578 (94) 10920 (93) Unfractionated heparin 131 (36.2) 113 (44.7) 244 (39.7) 4636 (39.5) LMWH 264 (72.9) 188 (74.3) 452 (73.5) (7144) 60.8) PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; LMWH: low-molecular weight heparin. Unless otherwise indicated, results are reported as number (percent); ACCESS includes South Africa.
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Streptokinase was the thrombolytic agent of choice in 54.5%, TNK-tPA in 30.3%, t-PA in 10.1% and r-PA in 5.1% of patients. The thrombolytic therapy was administered in association with LMWH in 36% and UFH in 26% of subjects. In 11% of patients, glycoprotein IIb/IIIa inhibitors were given on the same day as the thrombolytic therapy. This may reflect usage due to failed reperfusion and patients being referred for urgent rescue PCI. Overall, 93% of patients underwent angiography (90.1% of STEMI and 95.0% of NSTE-ACS patients). Fifty-three per cent went on to have PCI (59.7% of STEMI and 49.4% of NSTEACS patients), while 14.6% were referred for CABG (7.9% of STEMI and 19.3% of NSTE-ACS subjects). Of the patients referred for PCI, 94.2% had at least one stent inserted (92.1% of STEMI and 96.1% of NSTE-ACS patients), and in 57.9% of cases (51.8% of STEMI and 62.8% of NSTE-ACS patients), this was a drug-eluting stent. PCI was performed within 24 hours of hospitalisation in 61.3% of cases. There were 88 patients (34.8%) who received thrombolytic therapy but who did not exhibit reperfusion and were taken for PCI on the first day of hospitalisation. Most patients (94% of STEMI and NSTE-ACS subjects) received aspirin, 29.3% received a glycoprotein IIb/IIIa inhibitor, 58.7% a thienopyridine loading dose, and 65.9% a thienopyridine maintenance dose. All thienopyridine use was clopidogrel. UFH heparin was used in 39.7% of patients, and LMWH in 63.4%. The LMWH was almost exclusively enoxaparin. During hospitalisation, 560 (91.1%) patients received a statin, 13.2% a calcium channel blocker (CCB), 69.9% a beta-blocker (BB), 61.1% an angiotensin converting enzyme inhibitor (ACEI) and 5.2% an angiotensin II receptor blocker (ARB). In-hospital bleeding was reported in 21 patients (3.4%); 12 (4.7%) with STEMI and nine (2.5%) with NSTE-ACS.
Post-hospital management and follow up Ninety-two per cent of patients were discharged from hospital on aspirin, 62.2% on clopidogrel, 93.3% on a statin, 13.6% on a CCB, 67.4% on a beta-blocker, 61.4% on an ACE inhibitor, and 5.9% on an ARB (Table 3). The rates of use of these drugs were higher among patients with STEMI than in those with NSTEACS, with the exception of the use of ARBs.
TABLE 3. SELECTED DRUG TREATMENTS AT DISCHARGE: SOUTH AFRICAN COHORT ACCORDING TO DISCHARGE DIAGNOSIS AND OVERALL, AND COMPLETE ACCESS STUDY OVERALL South Africa ACCESS Discharge drug NSTE-ACS STEMI All All treatments (n = 360) (n = 251) (n = 611) (n = 11 427) Aspirin 333 (92.5) 233 (92.8) 566 (92.6) 90.1 Thienopyridine 208 (57.8) 172 (68.5) 380 (62.2) 76.1 Statin 330 (91.7) 240 (95.6) 570 (93.3) 89.2 Calcium channel 65 (18.1) 18 (7.2) 83 (13.6) 16.5 blockers Beta-blocker 222 (61.7) 190 (75.7) 412 (67.4) 75.8 ACE inhibitor 195 (54.2) 180 (71.7) 375 (61.4) 64.3 ARB 26 (7.2) 10 (4) 36 (5.9) 11.3 ARB: angiotensin receptor blocker Unless otherwise indicated result are reported as number (percent); ACCESS includes South Africa.
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Follow-up information was obtained telephonically in 58% of cases. At 12 months, 91 (15.6%) patients had had at least one further cardiac-related hospitalisation (41 for STEMI and 50 for NSTE-ACS patients). Unstable angina (i.e. no cardiac biomarker elevation) was the reason for re-hospitalisation in 49 (8.6%) cases and occurred 166 days (mean) after the index hospitalisation. Only four patients were re-admitted for NSTEACS and six for STEMI, 253 and 116 days (mean) after the index hospitalisation, respectively. Six patients reported stroke or TIA following hospitalisation and there were 14 re-admissions for heart failure. Bleeding episodes after discharge from hospital for the primary event occurred in 10 (1.8%) of the subjects, five (2.2%) in STEMI and five (1.5%) in NSTE-ACS patients. At one year, 80.2% of patients were still taking aspirin, 77.3% statin,19% clopidogrel, 10.3% CCB, 53.8% beta-blockers, 46% ACE inhibitors, and 3.8% ARB. Thirty-day death rates were 2.4% for STEMI and 1.7% for NSTE-ACS patients. Thirty-five patients (5.7%) had died by one year (± 35 days). The one-year mortality rate for patients admitted for STEMI was 6.7% and for NSTE-ACS, 5.0%. Causes of death were fatal MI (eight patients), fatal stroke (two), other cardiovascular including sudden death (12), non-cardiovascular (six), and unknown (seven). Predictors of the primary endpoint outcome (all-cause death at one year) were age ≥ 70 years (p = 0.0049), history of stroke/TIA (p = 0.0396), and diabetes (p = 0.0439).
Discussion This registry is the first in South Africa to document the demographics and management strategies used in patients admitted to hospital with a diagnosis of acute coronary syndrome. Patients with pre-existing risk factors of hypertension, diabetes and/or dyslipidaemia were more likely to present with NSTEACS, while smokers were more likely to present with STEMI. STEMI patients were also younger than NSTE-ACS patients. Although age ≥ 70 years was a predictor of one-year mortality, the mortality rates in the two groups were similar. Thrombolysis was performed in a minority of patients despite a lack of contraindications. This may reflect the availability of urgent angiography at most of the enrolling centres. Almost all patients were referred for angiography with high intervention rates. There was a preference for the use of drug-eluting stents as opposed to bare metal stents. Revascularisation rates were high and certainly higher than the overall ACCESS data (68.5 vs 40.8%), but were similar for NSTE-ACS and STEMI (68.75 and 68.6%) patients. Therefore, approximately one-third of all patients were being treated conservatively/medically only. The use of appropriate ancillary drug therapy in hospital and on discharge was in line with other registries; more than 90% receiving a statin, 70% a beta-blocker and 70% some form of RAAS blockade. As to be expected, the use of calcium channel blockers was low (13%). Use of anti-thrombotic therapy was also in keeping with guidelines; 94% receiving aspirin, two-thirds clopidogrel, and 65% heparin (with LMWH being used more commonly). However, the use of a thienopyridine at discharge was lower in the South African cohort (62.2%) compared with the ACCESS population (76.1%), despite a higher intervention rate and usage of stents, and in particular, drug-eluting stents. One has
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to assume that patients receiving a stent were discharged on a thienopyridine. This therefore leaves the suggestion that patients being referred for surgery or undergoing angiography without a PCI are not receiving a thienopyridine at discharge despite the diagnosis of an acute coronary syndrome. This is particularly worrying for those patients without STEMI, in whom there are clear guidelines for the prescription of a thienopyridine.10
always of concern. However this was less than that of the overall ACCESS registry data (8.4%) and is probably acceptable for a registry, as opposed to a trial. The data for the registry were compiled between January 2007 and January 2008. Subsequent to this, guidelines have changed and with this, changes in treatment protocols and prescription habits may also have occurred. Therefore some data may be out dated, but are nevertheless still relevant.
ACS registry populations
Conclusions
In terms of ACS types, patients enrolled in the ACCESS South Africa study were broadly similar to those in other observational studies conducted in Western populations. Just over half (56%) of the patients were diagnosed with NSTE-ACS and 39% with STEMI. In the second Euro-Heart Survey of Acute Coronary Syndromes (EHS-ACS-II) conducted in 2004, which included 6 385 patients from 32 European countries, the ACS population comprised almost equal proportions with NSTE-ACS and STEMI (48 and 47%, respectively) patients.11 In the GRACE study, which enrolled patients in 14 countries in Europe, North and South America, and Australia and New Zealand between 1999 and 2007,12-14 the proportion of patients with STEMI ranged from 30–40%, and 60–70% were diagnosed with NSTE-ACS. Patients enrolled in ACCESS South Africa were younger than those enrolled in other Western observational studies (58 vs 63–66 years),11,15 and there were more men (75 vs 64–72%).11,15,16 Current smoking (43.9%) and diabetes were also common (23.9%). The actual prevalence of diabetes may have been even higher, as the diagnosis was based on a prior history and did not include admission hyperglycaemia and the subsequent diagnosis of diabetes. When compared with the CREATE registry conducted exclusively in India and involving over 20 000 patients with an ACS, ACCESS South Africa had a higher percentage of patients aged 70 years and older (17.7 vs 13%), an equivalent percentage of male patients (75 vs 76%), and a much lower percentage with STEMI (39.4 vs 61%).17
In this study of ACS patients in South Africa, management tended to be aggressive, with high percentages of patients receiving angiography and an invasive treatment strategy. Drug usage was comparable to that in other countries and registries. Although this invasive approach may seem to be potentially costly, the 12-month death rate compared very favourably with other observational reports, and re-admission rates for bleeding and recurrent ischaemic events were low, suggesting that the cost may be justified and even economical in the long term. The use of evidence-based medications and interventions is in line with practices in the developed world. There is however still room for improvement. The drop-off in drug usage over time is of concern, particularly the finding that only 77% of patients were still on a statin at one year. Also the discharge prescription of thienopyridines was relatively low, particularly given the nature of the population studied. Increased efforts need to be directed at proven secondary prevention treatment strategies. This study was by no means complete or exhaustive, but serves as a template for practitioners and healthcare funders to take cognisance of the findings, make amendments to existing treatment protocols, and endeavour to improve drug utilisation and ultimately patient outcomes.
Limitations
ACCESS South Africa investigators: Colin Schamroth (national coordinator), Clive Corbett, Matthew Krausey, Goran Ignjatovic, David Kettles, Hennie Theron, Cobus Steyn, Braam Barnard, Iftikhar Ebrahim, Roland Zeelie, Victor Singh, Pule Mutati, Agostinho da Silva, Tjaart Venter, Ilse Kapp, Pieter Blomerus, Graham Cassel, Anthony Dalby, Juan Deseta, Nalin Patel, Nico van der Merwe, Fazul Tayob, Pule Mutati, Agostinho da Silva, Guy Letcher, Shirley Middlemost, Mohammed Essop, Theema Nunkoon, A Pappachan, Anthony Becker, Yasmin Bera, Christos Zambakides, Leonard Steingo, John Benjamin, Patrick Commerford, Jeffrey King, Sajidah Khan, Adriaan Snyders, Mohamed Khan.
The ACCESS South Africa study was an observational study and had all the limitations that such a study inherently has. The enrolling centres were all located in urban areas and were largely those that provided tertiary care (i.e. they had facilities for angiography and interventional therapy). Almost all enrolling centres were from the private healthcare sector. Patients were therefore mostly those that had access to private healthcare funding. These factors may all have influenced the population of patients studied. Patients enrolled had to be alive upon admission and provide consent. This therefore excluded ACS patients who died prior to hospitalisation or within a short time of arrival. It therefore represents more the demographics of survivors of the acute phase of ACS. As in all observational studies, the data were non-randomised and treatment protocols were non-standardised. Although the study called for recruitment of consecutive patients, it cannot be verified to what extend this aspect was complied with, and hence patient selection bias may also have been present. The number of patients lost to follow up (5.2%) is
The ACCESS registry was sponsored by Sanofi-aventis, Paris, France. ACCESS steering committee members: Gilles Montalescot (principal investigator) (France), Norka Antepara (Venezuela), Alvaro Escobar (Colombia), Samir Alam (Lebanon), Alain Leizorovicz (France), Carlos Martinez (Mexico), Jose Nicolau (Brazil), and Mohamed Sobhy (Egypt).
References 1.
2.
3.
Kumar A, Fonarow GC, Eagle KA, Hirsch AT, Califf RM, Alberts MJ, et al. Regional and practice variation in adherence to guideline recommendations for secondary and primary prevention among out-patients with atherothrombosis or risk factors in the United States: a report from the REACH Registry. Crit Path Cardiol 2009; 8(3): 104–11. Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, LopezSendon J. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 2002; 359(9304): 373–377. Fox KA, Goodman SG, Anderson FA (Jr), Granger CB, Moscucci
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M, Flather MD, et al. From guidelines to clinical practice: the impact of hospital and geographical characteristics on temporal trends in the management of acute coronary syndromes. The Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003; 24(15): 1414–1424. 4. Patel MR, Chen AY, Roe MT, Ohman EM, Newby LK, Harrington RA, et al. A comparison of acute coronary syndrome care at academic and nonacademic hospitals. Am J Med 2007; 120(1): 40–46. 5. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil 2009; 16(2): 121–137. 6. Hasdai D, Behar S, Wallentin L, Danchin N, Gitt AK, Boersma E, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23(15): 1190–1201. 7. Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART study investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937–952. 8. Waxman A. Prevention of chronic diseases: WHO global strategy on diet, physical activity and health. Food Nutr Bull 2003; 24(3): 281–284. 9. The ACCESS investigators. Management of acute coronary syndromes in developing countries: ACute Coronary Events – a multinational Survey of current management Strategies. Am Heart J 2011; 162: 852–859. e22. 10. The Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-Segment elevations. N Engl J Med 2001; 345: 494–502.
11. Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, Filippatos G, et al. The second Euro Heart Survey on acute coronary syndromes: Characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J 2006; 27(19): 2285–2293. 12. Fox KA, Goodman SG, Klein W, Brieger D, Steg PG, Dabbous O, et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002; 23(15): 1177–1189. 13. Budaj A, Brieger D, Steg PG, Goodman SG, Dabbous OH, Fox KA, et al. Global patterns of use of antithrombotic and antiplatelet therapies in patients with acute coronary syndromes: insights from the Global Registry of Acute Coronary Events (GRACE). Am Heart J 2003; 146(6): 999–1006. 14. Steg PG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002; 90(4): 358–363. 15. Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. J Am Med Assoc 2004; 291(22): 2727–2733. 16. Ohman EM, Roe MT, Smith SC (Jr), Brindis RG, Christenson RH, Harrington RA, et al. Care of non-ST-segment elevation patients: insights from the CRUSADE national quality improvement initiative. Am Heart J 2004; 148(5 Suppl): S34–39. 17. Xavier D, Pais P, Devereaux PJ, Xie C, Prabhakaran D, Reddy KS, et al. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 2008; 371(9622): 1435–1442.
DAKAR
Contact : BP : 6003 Dakar Tél : (221) 33 821 55 21 (221) 33 889 38 00 Poste : 3900 Fax : (221) 33 822 47 46 Mail: cardiodantec@orange.sn
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www.pascar.co.za www.sosecar.org
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Social drift of cardiovascular disease risk factors in Africans from the North West Province of South Africa: the PURE study PT PISA, R BEHANAN, HH VORSTER, A KRUGER
Abstract Objective: This study examined whether the association between socio-economic status (SES) and cardiovascular disease (CVD) risk factors in black South Africans from the North West Province had shifted from the more affluent groups with higher SES to the less affluent, lower SES groups over a period of nine years. Method: Cross-sectional baseline data of 2 010 urban and rural subjects (35 years and older) participating in the Prospective Urban and Rural (PURE) study and collected in 2005 were analysed to examine the relationship of level of education, employment and urban or rural residence with dietary intakes and other CVD risk factors. These relationships were compared to those found nine years earlier in the Transition and Health during the Urbanisation of South Africans (THUSA) study conducted in the same area. Results: The results showed that urban women had higher body mass index (BMI), serum triglyceride and fasting glucose levels compared to rural women and that both urban men and women had higher blood pressures and followed a more Westernised diet. However, rural men and women had higher plasma fibrinogen levels. The more highly educated subjects (which included both urban and rural subjects) were younger than those with no or only primary school education. Few of the risk factors differed significantly between education groups, except that more highly educated men and women had lower BMIs, and women had lower blood pressure and triglyceride levels. These women also followed a more prudent diet than those with only primary school education. Employed men and women had higher BMIs, higher energy intakes but lower plasma fibrinogen levels, and employed women had lower triglyceride levels. No significant differences in total serum cholesterol values were observed. Conclusion: These results suggest a drift of CVD risk factors from groups with higher SES to groups with a lower SES from 1996 to 2005, indicating that interventions to prevent CVD should also be targeted at Africans living in rural areas, those with low educational levels, and the unemployed.
Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa PT PISA, PhD, pisap@fellows.iarc.fr R BEHANAN, BSc HH VORSTER, DSc
Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, Potchefstroom, South Africa A KRUGER, PhD
Keywords: CVD risk factors, social drift phenomenon, socioeconomic status, dietary intakes, PURE baseline study, North West Province, South Africa, serum lipids Submitted 4/4/11, accepted 5/3/12 Cardiovasc J Afr 2012; 23: 371â&#x20AC;&#x201C;378
www.cvja.co.za
DOI: 10.5830/CVJA-2012-018
The escalating global burden of cardiovascular disease (CVD) is related to the rapid health transition that developing countries are experiencing.1 Adoption of high-energy, high-fat, Westernised diets and diminished physical activity contribute to the accelerating epidemic of CVD.2 South Africa, an emerging economy, is currently undergoing a health transition, characterised by the triple burden of disease consisting of a high prevalence of under-nutrition-related infectious diseases, the emergence of non-communicable chronic diseases (NCDs), and the human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) pandemic.3 The rate of urbanisation in the North West province of South Africa has dramatically increased, characterised by high rates of rural-to-urban migration, increased numbers of industrial companies, improved economic activity and an increased population in urban settings. Concurrently these economic changes have led to changes in the quality of food intake, from the traditional prudent dietary patterns and nutrient intake to modern, imprudent fast foods, which seem to play a major role in increasing the rate of NCDs. The THUSA study, conducted from 1996 to 1998 in the North West Province of South Africa, indicated that Africans with a higher socio-economic status (SES) had higher risk factors for CVD than those with a lower SES.4 Many studies have shown that in developing countries, during the early phases of the health transition, the NCD/CVD burden is usually higher in the higher SES class.2,5,6 In developed countries, the burden has shifted to the poor.7-11 This phenomenon of a shift of the burden of CVD in a population from the rich to the poor can be seen as a social drift in CVD risk. However, some studies found that the usual pattern is not always followed. In certain developing countries, higher CVD risk factors were seen in lower SES groups.12-15 A study from a developed country16 showed that higher CVD risk factors were found in higher SES groups. These studies illustrate a dynamic drift of the burden of CVD risk factors between groups of different SES within countries. As mentioned above, the health transition in developing countries is closely related to the transition from prudent, low-energy, low-fat diets traditionally followed in rural areas to the more Westernised high-energy, high-fat diets3 followed in urban areas. There is convincing evidence that this Westernised dietary pattern increases the risk of CVD and other NCDs
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through a variety of mechanisms.17 Diet can, therefore, be seen as a risk factor for CVD and dietary recommendations create the cornerstone in prevention of CVD.17 To be effective and successful, any dietary intervention programme should be focused, using dietary messages, educational material and nutritional advice targeted at specific groups.18 It is therefore important for prevention of CVD to know which groups within a population have a high risk for CVD and which risk factors should be targeted with dietary interventions. In this study of an African population undergoing a nutritional transition in the North West Province of South Africa, we explored the associations between SES (measured by level of urbanisation, education and employment) and CVD risk factors (including diet and nutrient intakes) that were prevalent in 2005 when the baseline PURE data were collected. PURE is an acronym for the 12-year Prospective Urban and Rural Epidemiological study, which is investigating the health transition in urban and rural Africans between 2005 and 2017. The objective of this study was to assess whether social drift in CVD risk has taken place over a period of nine years in Africans of the North West Province, by comparing the findings of the baseline PURE study data to those reported for the THUSA study,4 which was collected from 1996 to 1998.
Methods This analysis is based on cross-sectional data collected at baseline in 2005 as part of the North West Province, South Africa leg of the international 12-year PURE study. The PURE study is investigating the effects of the health and nutritional transitions, and specifically of NCDs or chronic diseases of lifestyle in urban and rural subjects. Migration stability was the main selection criterion within the chosen rural and urban communities. Four different areas of residence were used in the subject recruitment for the PURE study. Community A, a rural community, was located 450 km west of Potchefstroom on the highway to Botswana. Community B, a deep rural community 35 km east of A, was only accessible via a gravel road. Communities C and D were urban communities; C was the established Ikageng township, part of the greater Potchefstroom, and D was the informal settlements surrounding community C. A random household census regarding number of people, their ages and health profiles was done in 6 000 houses (1 500 in each community). Every head of a household gave signed consent to fill in the census questionnaire (see appendix on CVJA website under journal archives). If a person refused or was not at home, the next house was taken and a non-complier questionnaire was filled in. From the data obtained, a paper selection of possible subjects with no reported NCDs, tuberculosis or diagnosed HIV was made. A total of 2 010 apparently healthy African volunteers, 35 years and older, were then recruited. Participants were fasted (10–12 hours) for the baseline blood sampling and other measurements. Trained field workers assisted in providing information to the participants in their language of choice. Participants received feedback regarding their blood pressure, fasting glucose concentrations and HIV status, and were referred to the nearest clinic or hospital where necessary. Travelling expenses of participants were covered. Ethical approval was obtained from the Ethics Committee
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of the North-West University, Potchefstroom, South Africa (ethics number: 04M10) and signed informed consent forms were received from all participants. Subjects were provided with background information on the study and its purpose, and they were informed that participation was voluntary and they could withdraw at any time. Permission to conduct the study was also obtained from the North West Department of Health, tribal chiefs, and the local government authorities of each selected site. Structured, validated demographic, socio-economic and lifestyle questionnaires were administered by trained field workers during home visits in the language preferred by the participants. The questionnaires used were adapted from those used by all countries participating in the PURE study. A quantitative food frequency questionnaire (QFFQ), validated for this population,19 was administered by trained field workers using food models and food photographs of different portion sizes to assess habitual dietary intakes. The food data were converted to nutrient intakes using the South African food composition tables and computer program of the South African Medical Research Council.20 Anthropometric measurements were done by trained biokineticists. Height was measured to the nearest 0.5 cm with a stadiometer (Invicta, IP 1465, UK) and weight was determined on a portable electronic scale to the nearest 0.01 kg (Precision Health Scale, A & D company, Japan). All the measurements were done according to the guidelines adopted at the National Institute of Health-sponsored Arlie Conference.21 Body circumferences of participants were measured in light underwear with calibrated instruments (Holtain – unstretchable metal tape; John Bull – calipers). Body mass index was calculated by dividing weight in kilograms by height in square metres. Every participant who signed an informed consent form was tested for HIV infection, but was given the choice of knowing his/her status. Whole blood was used for the determination of HIV status, making use of the First Response (PMC Medical, India) rapid HIV card test. If tested positive, the test was repeated with the Pareeshak (BHAT Bio-tech India) card test. Pre-test counselling was done in groups of 10 persons before the blood sample was taken, and post-test counselling was individualised, according to the protocol of the National Department of Health of South Africa. A disposable needle was used to draw blood from the antecubital vein in the right arm of the participants. For plasma, each collection tube was filled to its capacity to ensure optimal blood:anticoagulant ratios. The tubes were inverted five times to ensure thorough mixing of the contents of the tube. The tubes were placed in ice boxes after labelling. A new sterile transfer pipette was used to aliquot blood cell, serum and plasma samples for analysis. Serum was prepared by allowing blood to clot at room temperature for 30 min; it was then centrifuged at 2 000 × g for 15 min at 10ºC. Blood was centrifuged within two hours of collection, separated and stored at –70ºC. Plasma samples were collected in ethylenediamine tetra acetic acid (EDTA) tubes, centrifuged at 2 000 × g for 15 min at 4ºC and transferred to cryo-tubes for storage at –70ºC. Both systolic and diastolic blood pressures were obtained using an OMRON automatic digital blood pressure monitor (Omron HEM-757). Subjects did not smoke, eat, exercise or do any intense activities for 30 min before taking the measurements, and they were rested and calmed for 10 min before doing the
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readings. Blood pressure measurements were performed twice, 5 min apart. Subjects were seated upright and relaxed with the arm supported at heart level and measurements were taken using the brachial artery. Blood glucose level was measured using Vitros DT6011 Chemistry Analyser, an Ortho-Clinical Diagnostics tool (Rochester, New York, USA). Quantitative determination of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), C-reactive protein and triglyceride (TG) levels were done by sequential multiple analyser computer (SMAC) using the Konelab20iTM auto-analyser. Plasma fibrinogen level was measured using a modified Clauss method (Multi fibrin U-test, Dade Behring, Deerfield Illinois, USA) on the Dade Behring BCS coagulation analyser.
Statistical analysis The SPSS package (version 17.0, SPSS Inc) was used to analyse the data. Means and 95% confidence intervals (CI) of CVD risk and dietary factors were calculated. Participants of both genders were divided into different groups, according to urbanisation, education and employment levels, and compared. Estimated significant differences between rural and urban participants were determined with analysis of variance using the general linear model (GLM) multivariate procedure. Univariate analysis was used to further explore the influence of education on CVD risk factors and dietary intakes. Employment was used as a proxy for income, and pairwise comparisons using GLM multivariate procedure was done for comparing the three groups (not answered, employed and not employed). Tests were considered significant at p < 0.05.
Results The total energy as well as macronutrient intakes and some selected micronutrient levels are shown in Table 1. This shows that mean total energy intakes of urban men and women were significantly higher than those of rural men and women. It can therefore be expected that other nutrient intakes would also be higher in urban subjects because more food was consumed.
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However, if differences in the percentages of energy contributed by the different macronutrients are compared, it is clear that not only total amounts of food, but also types of foods and, therefore, dietary patterns differed between urban and rural subjects. In urban men, the contributions of total protein, animal protein, total fat, saturated fat, and total carbohydrates to total energy were 12.5, 5.6, 25.3, 6.3 and 56.5%, respectively. In rural men the corresponding figures were 10.8, 3.2, 17.7, 3.9 and 63.1%. The same pattern was observed when urban and rural women were compared. In rural subjects, animal protein formed about a third of the total protein, while in urban subjects of both genders, about half of the total protein was from animal sources. Total and saturated fat intakes were twice as high in urban as in rural men and women. Percentage of total energy obtained from fat increased from rural values of 17.7 and 20.3% to urban values of 25.3 and 28.3% for men and women, respectively. This was a major shift from a low-fat, prudent diet followed in the rural areas to a higher-fat, more Westernised type of diet in the urban areas. Mean intakes of total dietary fibre were significantly higher in urban men and women compared to their rural counterparts. The percentage increases in energy intake from rural to urban men and women were 44 and 48%, while that of dietary fibre were 44 and 33% (percentages not shown in Table 1). Mean intakes of selected key micronutrients (iron, calcium and vitamin C) were substantially and significantly higher in urban than rural subjects. For calcium and vitamin C, it was more than double that of rural groups. In Table 2 the mean levels of CVD risk factors of urban men and women are compared to that of their rural counterparts. Rural women were slightly but significantly younger than urban women. There were no significant differences in total and highdensity lipoprotein (HDL) cholesterol levels, but urban women had significantly higher triglyceride levels than rural women. Their mean fasting glucose value was also significantly higher. Urban men and women had significantly higher blood pressures, and urban women had significantly higher mean BMI than rural women, although the rural women also had a mean BMI in the overweight range. Rural men and women had significantly higher plasma fibrinogen levels. There were
TABLE 1. MEAN (95% CI) OF ENERGY AND SELECTED NUTRIENT INTAKES Men Women Nutrients Urban (n = 399) Rural (n =347) Urban (n = 605) Rural (n = 659) Total energy (TE) (kJ) 10054.2 (9681.9–10426.4)a 6973.3 (6568.7–7377.8)a 9008.3 (8746.0-9269.6)b 6107.3 (5854.8–6359.8)b Total protein (g) 74.1 (71.3–76.8)a 44.4 (41.4–47.4)a 65.54 (63.7–67.4)b 39.50 (37.7–41.3)b [% of TE] [12.5] [10.8] [12.4] [11.0] 13.3 (11.6–14.96)a 31.2 (30.1–32.2)b 12.8 (11.8–13.8)b Animal protein (g ) 33.4 (31.9–35.0)a [5.6] [3.2] [5.9] [3.6] [% of TE] 32.4 (29.4–35.3)a 67.2 (65.1–69.4)b 32.6 (30.5–34.7)b Total fat (g) 67.1 (64.3–69.8)a [25.3] [17.7] [28.3] [20.3] [% of TE] 7.2 (6.3–8.0)a 17.2 (16.6–17.8)b 7.3 (6.7–7.8)b Saturated fat (g ) 16.6 (15.9–17.4)a [6.3] [3.9] [7.3] [4.5] [% of TE] 258.9 (244.7–273.1)a 293.7 (284.7–302.8)b 235.9 (227.1–244.6)b Total carbohydrates (g ) 334.3 (321.3–347.4)a [56.5] [63.1] [55.4] [65.7] [% of TE] 18.5 (17.3–19.7)a 22.7 (22.0–23.4)b 17.1 (16.4–17.8)b Dietary fibre (g) 26.7 (25.6–27.8)a Iron (g) 16.7 (16.0–17.4)a 12.4 (11.6–13.1)a 14.1 (13.6–14.6)b 11.1 (10.6–11.5)b a a b Calcium (g) 452.0 (429.3–474.6) 247.9 (223.2–272.5) 450.9 (434.5–467.3) 211.4 (195.5–227.2)b a a b Vitamin C (g ) 42.5 (39.1–45.8) 12.6 (9.0–16.2) 46.9 (44.0–49.8) 15.7 (12.9–18.5)b a,b Means with the same symbol differ significantly (p < 0.05); significant differences based on GLM, analysis of variance (ANOVA)
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TABLE 2. MEAN (95% CI) CARDIOVASCULAR DISEASE RISK FACTORS (EXCLUDING DIET) OF URBAN AND RURAL SUBJECTS Men Women Risk factor (means and 95% CI) Urban Rural Urban Rural Number (n) 399 347 605 659 47.5 (46.7–48.3)a Age (years) 50.4 (49. 3–51.6) 49.4 (48.3 – 50.6) 50.8 (49.8–51.7)a High-density lipoprotein cholesterol (mmol/l) 1.62 (1.55–1.69) 1.54 (1.47–1.61) 1.46 (1.40–1.51) 1.51 (1.46–1.56) Total cholesterol (mmol/l) 4.88 (4.73–5.02) 4.72 (4.58–4.87) 5.20 (5.07–5.32) 5.11 (5.0–5.22) 4.94 (4.80–5.07)a Fasting glucose (mmol/l) 4.93 (4.76–5.10) 4.81 (4.64–4.99) 5.19 (5.04–5.33)a a Triglyceride (mmol/l) 1.27 (1.18–1.36) 1.15 (1.06–1.24) 1.47 (1.40–1.53) 1.25 (1.19–1.31)a Systolic blood pressure (mmHg) 137.5 (134.0–140.0)a 132.2 (129.6–134.7)a 136.7 (134.5–138.8)b 127.8 (125.8–129.7)b Diastolic blood pressure (mmHg) 87.9 (86.4–89.5)a 84.9 (83.3–86.5)a 89.5 (88.2–90.8)b 86.4 (85.3–87.5)b Body mass index (kg/m²) 20.9 (20.5–21.4) 20.7 (20.2–21.1) 27.8 (27.2–28.5)a 25.9 (25.4–26.5)a Fibrinogen (g/l) 3.17 (2.95–3.39)a 3.50 (3.28–3.73)a 3.74 (3.55–3.93)b 4.04 (3.87–4.21)b C-reactive protein (mg/l) 7.87 (6.50–9.23) 8.56 (7.10–10.0) 9.17 (8.18–10.16) 8.09 (7.14–9.04) 6.6 (5.0–8.1)b Alcohol consumption g/day 17.8 (15.0–20.7) 20.0 (117.0–23.1) 9.0 (7.3–10.5)b a,b Means with the same symbol differ significantly (p < 0.05); significant differences based on GLM, analysis of variance (ANOVA).
no significant differences in C-reactive protein (CRP) between urban and rural groups. Both rural and urban men reported high alcohol intakes (17.8 and 20.0 g/day, respectively). Women took less alcohol, but urban women had significantly higher intakes, namely 9.0 versus 6.6 g/day reported by rural women. Table 3 shows the mean values of CVD risk factors of men with different reported education levels, while Table 4 gives the same data for women. The values of the 21 men and 37 women who did not answer the questions on education are also shown. In both men and women, the mean age of those with higher education (secondary school and/or additional education) was significantly lower. There were more educated individuals in the urban areas compared to rural areas. However, 52 men and 136 women residing in rural areas also completed secondary schooling and/or additional tertiary education. Tables 3 and 4 further indicate that the serum lipids, glucose
and fibrinogen levels did not differ significantly between subjects with different levels of education. In men there were also no differences in blood pressure, but women with higher education had significantly lower systolic and diastolic blood pressures. These women also had lower serum triglyceride levels. The BMI of men and women were significantly higher in those subjects who had primary and secondary schooling compared to those without any schooling. The same pattern was observed in the dietary intakes, with sustained increases in energy, fat and protein intake and decreases in carbohydrate intake in men and women with primary education compared to those with no education. This change to a more Westernised diet was sustained in men with secondary education. However, women with secondary education reported a more prudent diet with lower energy, protein and alcohol intakes than those with primary education.
TABLE 3. MEAN (95% CI) OF SELECTED CARDIOVASCULAR DISEASE RISK FACTORS IN MEN WITH DIFFERENT EDUCATION LEVELS Risk factor: mean (95% CI) Not answered None Primary Secondary school and higher Number of subjects 21 270 297 158 Age in years 48.2 (43.3–53.0) 52.5 (51.2–53.9) 49.4 (48.0–50.7) 45.5 (43.7–47.3)* Number of urban subjects 9 90 194 106 Number of rural subjects 12 180 103 52 High-density lipoprotein cholesterol (mmol/l) 1.42 (1.11–1.74) 1.68 (1.56–1.73) 1.54 (1.45–1.62) 1.58 (1.46–1.70) Total cholesterol (mmol/l) 4.62 (3.98–5.25) 4.78 (4.60–4.96) 4.79 (4.62–4.97) 4.89 (4.66–5.13) Fasting glucose (mmol/l) 4.77 (4.00–5.54) 4.78 (4.56–4.99) 4.93 (4.72–5.15) 4.84 (4.55–5.12) Triglyceride (mmol/l) 1.15 (0.76–1.54) 1.14 (1.03–1.25) 1.25 (1.14–1.35) 1.27 (1.2–1.41) C-reactive protein (mg/l) 9.55 (3.73–15.37) 9.30 (7.66–10.94) 8.23 (6.65–9.81) 6.02 (3.88–8.17) Systolic blood pressure (mmHg) 132.1 (121.2–143.0) 132.9 (29.9–136.0) 136.7 (133.6–139.7) 133.5 (129.4–137.5) Diastolic blood pressure (mmHg) 86.9 (80.1–93.8) 84.4 (82.4–86.3) 87.4 (85.5–89.3) 86.7 (84.1–89.2) Body mass index (kg/m²) 22.5 (20.6–24.3) 20.0 (19.5–20.5) 21.0 (20.5–21.6) 21.7 (21.0–22.4)* Fibrinogen (g/l) 3.14 (2.16–4.11) 3.65 (3.78–3.92) 3.17 (2.90–3.44) 3.05 (2.65–3.41) Total energy (TE) (KJ) 7963 (625–9667) 7626 (7141–8112) 9015 (8555–9474) 9390 (8676–10105)* Total fat (g) (% of TE) 49.4 (23.6%) 40.7 (20.3%) 52.9 (22.3%) 60.4 (24.4%)* Total protein (g) (% of TE) 53.9 (11.5%) 51.6 (11.5%) 63.4 (12.0%) 67.9 (12.3%)* Total carbohydrates (g) (% of TE) 282.3 (60.3%) 273.9 (61.6%) 315.2 (59.4%) 307.7 (55.7%)* Total fibre (g) 20.0 (15.1–25.0) 20.4 (19.0–21.8) 24.7 (23.3–26.0) 23.4 (21.4–25.4)* Alcohol consumption (g/day) 12.1 (–0.01–24.3) 17.7 (14.2–21.1) 18.8 (15.5–22.1) 22.0 (17.5–26.5) *Significant difference across different education levels (p < 0.05); significance differences based on GLM, analysis of variance (ANOVA).
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TABLE 4. MEAN (95% CI) OF SELECTED CARDIOVASCULAR DISEASE RISK FACTORS IN WOMEN WITH DIFFERENT EDUCATION LEVELS Risk factor: mean (95% CI) Not answered None Primary Secondary school and higher Number of subjects 37 420 531 276 Number of urban subjects 16 112 337 139 Number of rural subjects 21 308 194 136 Age (years) 47.0 (43.3–50.7) 50.2 (49.1–51.3) 50.7 (49.7–51.7) 44.0 (42.6-45.3)* High-density lipoprotein cholesterol (mmol/l) 1.36 (1.12–1.59) 1.55 (1.48–1.61) 1.49 (1.43–1.55) 1.43 (1.34–1.52) Total cholesterol (mmol/l) 5.50 (4.98–6.01) 5.20 (5.05–5.35) 5.19 (5.05–5.33) 4.99 (4.80–5.18) Fasting glucose (mmol/l) 5.29 (4.73–5.84) 5.04 (4.88–5.21) 4.94 (4.78–5.07) 4.88 (4.67–5.08) C-reactive protein (mg/l) 10.01 (6.04–14.00) 8.80 (7.61–10.00) 8.67 (7.61–9.73) 8.01 (6.53–9.48) Triglyceride (mmol/l) 1.38 (1.11–1.65) 1.40 (1.31–1.49) 1.36 (1.28–1.43) 1.22 (1.12–1.32)* Systolic blood pressure (mmHg) 130.6 (121.9–139.4) 130.4 (127.8–133.0) 134.5 (132.1–136.9) 126.9 (123.7-130.1)* Diastolic blood pressure (mmHg) 89.5 (84.3–94.7) 86.7 (85.2–88.2) 89.4 (88.0–90.9) 85.7 (83.7–87.6)* Body mass index (kg/m²) 28.6 (26.0–31) 25.2 (24.4–26.0) 27.6 (26.9–28.3) 27.4 (26.5–28.4)* Fibrinogen (g/l) 4.51 (3.69–5.32) 3.98 (3.74–4.22) 3.96 (3.73–4.18) 3.71 (3.41–4.01) Total energy (TE) (kJ) 7115 (5985–8245) 6677 (6337–7017) 7997 (7693–8300) 7419 (6960–7877)* Total fat (g) (% of TE) 45.1 (24.1%) 38.0 (21.6%) 55.4 (26.3%) 50.2 (25.7%)* Total protein (g) (% of TE) 48.3 (11.5%) 44.6 (11.4%) 56.4 (12.0%) 52.1 (11.9%)* Total carbohydrates (g) (% of TE) 259.0 (61.9%) 245.3 (62.5%) 274.6 (58.4%) 261.2 (59.8%) Total fibre (g) 18.1 (15.1–21.1) 18.2 (18.2–19.1) 21.0 (20.2–21.8) 19.3 (18.1–20.5)* Alcohol consumption (g/day) 4.3 (–2.2–10.9) 10.4 (8.4–12.3) 7.2 (5.5–8.9) 4.9 (2.5–7.4)* *Significant difference across different education levels population (p < 0.05); significant differences based on GLM, analysis of variance (ANOVA).
Table 5 compares the CVD risk factors of employed with unemployed men and women. Very few of the rural subjects were employed (15 men and 19 women) while 95 men and 95 women of the urban subjects were employed. Of the total sample of 679 men for whom employment data were available, 84.2% was unemployed, and of the 1 136 women who reported employment status, 90% was unemployed. The employed men and women were significantly younger
than the unemployed subjects. The employed men and women had a significantly higher mean BMI and energy intakes but lower HDL cholesterol (women), triglyceride (women), and fibrinogen (men and women) levels. Both the employed and unemployed women had mean BMIs in the overweight range. The diet of the employed showed all the characteristics of the higher-fat, more Westernised diet seen in the urban and more educated groups
TABLE 5. MEAN (95% CI) CARDIOVASCULAR DISEASE RISK FACTORS OF EMLOYED AND UNEMPLOYED MEN AND WOMEN Men Risk factor: means (95% CI)
Women
Not Answered
Employed
Unemployed
Not Answered
Employed
Unemployed
Total numbers
49
110
587
128
114
1022
Number of urban subjects
47
95
257
120
9
2
15
330
8
19
632
Age (years)
Number of rural subjects
52.8 (49.3–56.3)
44.6 (42.4–46.8)a
50.4 (49.5–51.4)b
50.3 (48.1–52.5)
45.6 (43.4–47.8)a
49.1 (48.4–49.9)b
High-density lipoprotein cholesterol (mmol/l)
1.46 (1.24–1.69)
1.53 (1.40–1.66)
1.60 (1.54–1.66)
1.19 (1.06–1.32)
1.43 (1.29–1.56)a
1.53 (1.49–1.56)a
Total cholesterol (mmol/l)
4.62 (4.17–5.07)
4.89 (4.61–5.18)
4.80 (4.68–4.92)
4.93 (4.64–5.210
4.92 (4.62–5.22)
5.20 (5.12–5.30)
Fasting glucose (mmol/l)
5.45 (4.89–6.00)
4.67 (4.31–5.00)a
4.84 (4.70–4.99)a
5.34 (5.03–5.67)
4.67 (4.35–5.00)a
4.96 (4.85–5.07)a
C-reactive protein (mg/l)
7.43 (3.04–11.81)
5.81 (3.04–8.58)
8.29 (7.12–9.47)
9.44 (7.04–11.84)
6.05 (3.56–8.54)
8.41 (7.61–9.23)
Triglyceride
1.30 (1.01–1.57)
1.31 (1.13–1.49)
1.18 (1.11–1.26)
1.56 (1.40–1.710
1.16 (0.99–1.31)a
1.33 (1.28–1.38)a
Systolic blood pressure (mmHg)
138.4 (130.5–146.2) 134.1 (129.2–139.1) 134.2 (132.1–136.3) 133.0 (128.0–138.0)
130.9 (125.7–136.1) 131.1 (129.4–132.8)
Diastolic blood pressure (mmHg)
88.8 (83.8-93.7)
85.8 (82.6-88.9)
86.0 (84.6-87.3)
86.9 (83.9–89.9)
87.8 (84.8-90.9)
87.7 (86.7–88.7)
Body mass index (kg/m²)
21.5 (20.1–22.8)
22.1 (21.3–23.0)a
20.6 (20.2–20.9)a
28.1 (26.6–29.6)
27.9 (26.3–29.4)b
26.5 (26.0–27.0)b
Fibrinogen (g/l)
2.17 (1.48–2.87)
2.98 (2.55–3.42)a
3.47 (3.28–3.65)a
3.62 (3.16–4.09)
3.51 (3.03–3.98)b
4.01 (3.85–4.16)b
Total energy (TE) (kJ)
7626.5 (6248.4– 9004.6)
10217.5 (9348.5– 11086.4)a
8385.7 (8016.6– 8754.8)a
6318.0 (5612.3– 7023.6)
8495.5 (7764.2– 9226.9)b
7174.6 (6938.3– 7410.9)b
Total fat (g) (% TE)
51.7 (25.8)
67.9 (25.3)a
46.4 (21.0)a
45.1 (27.1)
63.9 (28.6)b
44.0 (23.3)b
Total protein (g) (% TE)
53.5 (11.9)
74.8 (12.4)a
57.8 (11.7)a
44.9 (12.1)
63.6 (12.7)b
48.6 (11.5)b
Total carbohydrates (g) (% TE)
245.8 (54.8)
342.7 (57.0)a
295.4 (60.0)a
214.4 (57.7)
279.9 (56.0)b
259.5 (61.5)b
Total dietary fibre (g)
19.4 (15.5–23.3)
25.4 (22.9–27.9)a
22.3 (21.2–23.3)a
15.4 (13.6–17.20)
21.0 (19.1–22.9)b
19.4 (18.8–20.0)b
Alcohol consumption (g/day)
17.6 (7.6–27.6)
17.7 (11.4–24.0)
20.7 (18.0–23.4)
4.7 (0.5–9.0)
4.0 (–3.9–8.3)
8.2 (6.8–9.6)
Means with the same symbol for a specific variable indicate significant differences (p < 0.05); significant differences based on GLM analysis of variance (ANOVA).
a,b
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Discussion The purpose of this study was to establish the association between SES and CVD risk factors (including dietary intakes) in an African population in the North West province of South Africa. SES was differentiated by use of residential strata (urban or rural), employed or not employed, and education levels (none, primary schooling, or secondary schooling and/or higher education/training). The salient results are summarised briefly and discussed, after which a possible socio-economic drift in the CVD risk factors is critically evaluated. It should be noted that in the North West province of South Africa, a region taken over by rural-to-urban migration, the majority of those moving are in search of a better life in the cities, where they can possibly get jobs and help those that have stayed behind in the rural setting, usually children, women and the elderly. Using this as the trend in the North West province, oneâ&#x20AC;&#x2122;s setting can be used as a proxy for socio-economic status. Although this might not hold true for everyone, it does for more than 80% of the population, as seen in our 1996 to 1998 results from the THUSA study.4 It appears that more processed foods are reaching rural areas, unlike in earlier years.
Dietary intakes The increased intakes in total energy, fat and protein, characterised by increases in animal protein and saturated fat, with a concomitant decrease in total carbohydrates taken in during urbanisation confirm the changes in dietary patterns observed during the nutritional transition in other developing countries,22 as well as in South Africa.3 The observed increases in dietary fibre and micronutrient intake in the urban subjects are probably related to the increased energy and thus food intake. The increases were less than expected for dietary fibre in women, which shows change in the types of foods consumed. Although the mean increases in selected micronutrients were substantial, they did not reach recommended values, a phenomenon also observed in other urban black South Africans.23 The observation that intakes of macronutrients by the more highly educated women compared to those with little or no education were actually more prudent (lower in energy and fat) suggests that the nutritional transition may have reached a point in these women where healthier diets are now being followed.
CVD risk factors The only significant difference between rural and urban subjects regarding serum lipid levels was the increased triglyceride levels in urban women. The same group was significantly older than the rural women, had a higher fasting mean glucose level, and higher BMI. It is therefore possible that the higher triglyceride and glucose levels in urban women could be related to the older age and higher BMI, both known to influence these variables.17 Both urban men and women had higher mean blood pressures, while the rural subjects had higher mean plasma fibrinogen levels. Plasma fibrinogen is accepted as a risk factor for CVD.24 In addition, fibrinogen is an acute-phase reactant.25 The higher fibrinogen levels in the rural subjects could therefore also reflect chronic (perhaps low-grade) infection despite the fact that apparently healthy subjects were recruited for the PURE study. However, the mean values of the highly sensitive C-reactive
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protein did not differ significantly between urban and rural men and women. In the THUSA study,26 urban subjects tended to have higher plasma fibrinogen levels, although values were also raised in rural subjects, especially in those living on commercial farms.
Effects of educational level The salient observations regarding the effects of educational level on CVD risk factors were that with increased education there were increases in BMI and in energy and macronutrient intakes of both men and women when those with primary education were compared to those with no education. This change to a Westernised diet was sustained in men with secondary education but not in women. The other CVD risk factors did not show significant differences in uneducated and educated subjects, except for lower serum triglyceride levels and blood pressures in the more educated women. However, these women were also slightly but significantly younger than the uneducated women and it seems that they followed a more prudent diet than women with only primary schooling. The diet of the educated subjects resembled that of the urban subjects, indicative of the changes observed in the nutritional transition, with indications that in the highly educated women, energy and macronutrient intakes were changing back to more prudent intakes.
Effects of employment Of the 1 833 subjects for whom data on employment were available, 84.2% of the men and 90.0% of the women were unemployed, which may indicate a bias in the sample selection. This bias could be the result of recruiting volunteers who were available for a very long weekday of measurements, for which employed people would have to take leave. The official figure of the unemployment rate in South Africa between 2000 and 2006 averaged at 26.38%, with the highest in March 2003, at 31%.27 However, the PURE questionnaires used to assess employment status have a category described as homemaker, which is interpreted as unemployment. It is possible that employed domestic workers, especially in the urban areas, indicated this category, which may be partially responsible for the high unemployment figure. The employed subjects were significantly younger than the unemployed. This may explain why, despite the higher fat intake and more Westernised diet, the employed men and women had significantly lower fasting glucose and triglyceride (women) levels.
Is there a social drift in CVD risk factors in this population? To evaluate this question, one should consider the limitations of the study. Firstly, as already mentioned, the reported employment rates may suggest that the sample was biased. However, potential bias would be similar for all four sites where subjects were recruited. A second limitation was the absence of reliable data on personal income. In many African families, household income from different sources is shared by a varying number of extended family members.28 As proxy for socio-economic status, educational level, employment and residing in urban or rural areas were used. The data showed that many subjects with higher education were
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employed in the rural areas. None of these three variables is an ideal, independent indicator of SES, but it was assumed that each could be used to distinguish between higher and lower socioeconomic groups. Nevertheless, the data should be interpreted with care. Patterns of dietary intakes and risk factors for CVD emerged, regardless of which indicator of socio-economic status was used, with agreement between results of being urban, highly educated and employed. However, as indicated above, there were also some exceptions, which could be explained. The analysis of the relationships between socio-economic position and CVD risk factors in the participants of the THUSA study4 showed that nine years earlier, most (but not all) of the CVD risk factors were significantly higher in the subjects from the higher socio-economic group. The major difference between the THUSA study results and the PURE study results reported here was that total serum cholesterol levels did not differ between the higher and lower socio-economic groups, and that increased plasma fibrinogen levels were higher in subjects from the lower socio-economic groups in the PURE subjects. Although blood pressures were higher in urban subjects, in those groups with higher educational levels or employed, blood pressures did not differ significantly or were even lower than in those with lower educational levels or unemployed. These results suggest a drift of CVD risk factors (lipids and fibrinogen) from participants with high SES to those with lower SES. The changes in dietary intakes are intriguing. The typical increases in energy and fat intake associated with urbanisation were seen in the PURE subjects (Table 1). However, in women with the highest educational level, there were significant decreases in total energy and fat intake, suggesting that these women were now following a more prudent diet. As for urban participants, men with higher educational levels and employed men and women still had higher energy and fat intakes, reflected in higher BMIs and serum triglyceride levels. This raises the question whether diet was in anyway responsible for the drift of the CVD risk factors. It seems that the contribution of low intake of macronutrients should also be considered. It has been mentioned that although micronutrient intake of the urban subjects increased, recommended values were not reached. James and co-workers26 showed in the THUSA study that low micronutrient status was associated with increased plasma fibrinogen levels. Also, it is known that several antioxidant micronutrients protect against CVD and other NCDs.17 It is therefore reasonable to suggest that not only a prudent diet regarding macronutrients, but also an adequate diet regarding micronutrients is a prerequisite for dietary protection against CVD. The intakes of dietary fibre in all groups were low (see Table 1). High intake of dietary fibre (from whole grains, fruit and vegetables) is known to protect against CVD.29 Physical activity is a key determinant of CVD risk and should always be taken into account. In this study it was not reported, as the focus of this study was to observe whether a shift had occurred prior to the results we published on the THUSA study.4 Different demographics, including racial and religious heterogeneity of populations, may have an impact on dietary patterns. Since this epidemiological survey was composed of 2 010 black Africans undergoing transition and predominantly Christian, we state that religion did confound our results or act
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as modifier effectors to these associations. These are baseline results from a prospective epidemiological study that is on-going. Therefore findings reported here give us an insight into the associations between SES and specific CVD risk factors. These observations have limitations in that they were carried out at one point in time and give no indication of the sequence of events – whether exposure occurred before, during or after the onset of the outcome. This being so, it is impossible to infer causality. After subsequent follow ups (prospective), one of the advantages of such a study is that it can help determine and observe risk factors in those participants previously free of risk factors. Because the studies are longitudinal over time, and the collection of results is at regular intervals, recall error is minimised.
Conclusions South Africa is undergoing political changes which have led to rapid economic development and urbanisation of its African people. This has led to an increase in rural–urban migration, thus exposing the ‘once-protected’ black rural population to more Westernised dietary habits. These ultimately lead to the observed increase in incidence of NCDs in this population.30 The results of this study showed that urban, educated and employed subjects had high levels of several dietary and biochemical risk factors for CVD. However, the results also indicated that many people living in the rural areas of the North West province and those who had lower educational levels and were unemployed also had an increased risk of CVD despite still following a prudent but micronutrient-deficient diet. It was therefore concluded that the burden of CVD is shifting from the more affluent groups with higher SES to the poor. At this time, it seems that many of the risk factors of CVD are prevalent in all SES groups of black South Africans. It is therefore recommended that intervention programmes to prevent CVD and other NCDs should be targeted at all SES groups. Furthermore, efforts to improve dietary and nutrient intakes should not only focus on steering the nutritional transition into consumption of a more prudent, low-energy, low-fat diet, but should also ensure that sufficient micronutrients are taken in by emphasising the importance of a varied diet with sufficient amounts of nutrient-dense foods.
References 1.
2.
3. 4.
5.
6.
Torun B, Stein AD, Schroeder D, Grajeda R, Conslisk A, Rodriguez M, et al. Rural-to-urban migration and cardiovascular disease risk factors in young Guatemalan adults. Int J Epidemiol 2002; 31: 218–226. Reddy KKR, Rao AP, Reddy TPK. Socioeconomic status and the prevalence of coronary heart disease risk factors. Asia Pac J Clin Nutr 2002; 11(2): 98–103. Vorster HH. The emergence of cardiovascular disease during urbanization of Africans. Public Health Nutr 2002; 5(1A): 239–243. Vorster HH, Kruger A, Venter CS, Margetts BM, Macintyre UE. Cardiovascular disease risk factors and socio-economic position of Africans in transition: the THUSA study. Cardio J Afr 2007; 18(5): 282–289. Gilberts ECAM, Arnold MJCWJ, Grobbee DE. Hypertension and determinants of blood pressure with special reference to socioeconomic status in a rural South Indian community. J Epidemiol Comm Heal 1994; 48: 258–261. Gupta R, Gupta VP, Ahlwalia NS. Educational status, coronary heart
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disease, and coronary risk factor prevalence in a rural population of India. Brit Med J 1994; 309: 1332–1335. Iribarren C, Luepker RV, McGovern PG, Arnett DK, Blackburn H. Twelve- year Trends in Cardiovascular Disease Risk factors in the Minnesota Heart survey. Arch Int Med 1997; 157: 873–880. Nishi N, Makino K, Fukuda H, Tatara K. Effects of socioeconomic indicators on coronary risk factors, self-rated health and psychological well-being among urban Japanese civil servants. Soc Sci Med 2004; 58: 1159–1170. Ishizaki M, Martikainen P, Nakagawa H, Marmot M. The relationship between employment grade and plasma fibrinogen level among Japanese male employees. Atherosclerosis 2000; 151: 415–421. Panagiotakos DB, Pitsavos C, Chrysohoou C, Vlismas K, Skoumas Y, Palliou K, et al. Dietary habits mediate the relationship between socioeconomic status and CVD factors among healthy adults: the ATTICA study. Public Health Nutr 2008; 11(12): 1342–1349. Schroder H, Rohlfs I, Schmelz EM, Marrugat J. Relationship of socioeconomic status with cardiovascular risk factors and lifestyle in Mediterranean population. Eur J Nutr 2004; 43: 77–85. Roohafza HR, Sadeghi M, Kelishadi R. Cardiovascular risk factors in Iranian adults according to educational levels: Ishafan Healthy Heart Program. Asia Pac J Public heal 2005; 17(1): 9–14. Bobak MM, Hertzman C, Skodovak Z, Marmot M. Socioeconomic status and cardiovascular risk factors in the Czech Republic. Int J Epidemiol 1999; 28: 46–52. Reddy KS, Prabhakaran D, Jeemon P, Thankappan KR, Joshi P, Chaturvedi V, et al. Educational status and cardiovascular risk profile in Indians. Proc Nat Acad Sci 2007; 104(41): 16263–16268. Yu Z, Nissinen A, Vartianen E, Song G, Guo Z, Zheng G, et al. Associations between socioeconomic status and cardiovascular risk factors in an urban population in China. Bullen Wor Heal Org 2000; 78: 1296–1305. Yarnell J, Mccrum E, Arveiler D, Haas B, Dallongeville J, Montay E M, et al. Education, socioeconomic and lifestyle factors, and risk of coronary heart disease: the PRIME study. Int J Epidemiol 2005; 34: 268–275. Joint World health Organization (WHO)/Food and Agriculture Organization (FAO) expert Consultation. Diet, nutrition and the prevention of chronic diseases; WHO: Geneva, Switzerland, 2003.
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18. Jennings J, Drillepsie S, Mason J, Ltfi M, scialfa T. Managing successful nutrition programmes – Nutrition policy discussion paper no 8; A report based on an ACC/SCN workshop at the 14th IUNS Congress, Seoul: Korea, 1989. 19. MacIntyre UE, Venter CS, Vorster HH, Steyn HS. A combination of statistical methods for the analysis of the relative validation data of the quantitative food frequency questionnaire used in the THUSA study. Public Health Nutr 2000; 4(1): 45–51. 20. Wolmarans P, Danster N, Dalton A, Rossouw K, Schonfeldt H (eds). Condensed Food Composition Tables for South Africa. South African Medical Research Council, Parow Valley, Cape Town, 2010. 21. Lohman TG, Roche AF, Martorell R. Anthropometric standardization Reference Manual. Eds Human Kinetic Books: Champaign, Illinois. 1988. 22. Popkin BM. An overview on the nutrition transition and its health implications: The Bellagio meeting. Public Health Nutr 2002; 5: 93–103. 23. Vorster HH, Oosthuizen W, Jerling JC, Veldman FJ, Burger HM. The Nutritional Status of South Africans. A Review of the Literature from 1975–1996. Durban: Health Systems Trust, 1997; 1: 1–22; 2: 1–122. 24. Meade TW, Mellows S, Brozovic M, Miler GJ, Chakrabarti RR, North WR, et al. Haemostatic function and ischemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533–537. 25. Castell JV, Gomez-Iechon MJ, Dabid M, Fabra R, Trullenque R, Heiarich PC. Acute phase response of human hepatocytes: regulation of acute phase protein synthesis by interleukin 6. Hepatology 1990; 12(5): 1179–1186. 26. James S, Vorster HH, Venter CS, Kruger HS, Nell TA, Veldman FJ, et al. Nutritional status influences plasma fibrinogen concentration: evidence from the THUSA survey. Thrombosis Res 2000; 98: 383–394. 27. StatsSouth Africa, http://www.stassa.gov.za//accessed: 2011. 28. Lemke S, Jansen van Rensburg F, Vorster HH, Ziche J. Interdisciplinary research on food security in Africa households: exploratory directives. J Soc Sci 1999; 31(4): 255–264. 29. Rosamond WD. Dietary fiber and prevention of cardiovascular disease. J Am Coll Cardiol 2002; 39: 57–59. 30. Pisa, PT, Vorster HH, Chizura N. Cardiovascular disease and nutrition: the use of food based dietary guidelines to prevent CVD in Africa. S Afr Heart J 2011; 8: 38–47.
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Appendix PURE Quantitative Food Frequency Questionnaire Subject ID _______________________________________ Subject initials ������������������������
Centre #
Community #
Household #
Subject #
F
M
L
Today’s date Year
Month
Day
1. Name: ������������������������������������������������������������������������������ 2. Not applicable in South Africa ���������������������������������������������������������� 3. National identity # or equivalent
N/A
4. Date of Birth OR Age
Year
Month
Female
Male
Day
Years
5. Sex
Please think carefully about the food and drink you have consumed during the past month (four weeks). I will go through a list of foods and drinks with you and I would like you to tell me: • If you eat the food • How the food is prepared • How much of the food you eat at a time • How many times a day you eat it and if you do not eat it every day, how many times a week or a month you eat it. To help you to describe the amount of a food you eat, I will show you pictures of different amounts of the food. Please say which picture is the closest to the amount you eat, or if it is smaller, between the sizes or bigger than the pictures. There are no right or wrong answers. Everything you tell me is confidential. Only your subject number appears on the form. Is there anything you want to ask now? Are you willing to go on with the questions?
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FOOD FREQUENCY QUESTIONNAIRE INSTRUCTIONS: Circle the subject’s answer. Fill in the amount and times eaten in the appropriate columns.
I shall now ask you about the type and the amount of food you have been eating in the last few months. Please tell if you eat the food, how much you eat and how often you eat it. We shall start with maize meal porridge. TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
AMOUNT/ DAY
PORRIDGE AND BREAKFAST CEREALS AND OTHER STARCH Maize-meal porridge
Stiff (pap)
3400
Maize-meal porridge
Soft (slappap)
3399
Maize-meal porridge
Crumbly (phutu)
3401
Mabella
Stiff
3437
Mabella
Soft
Ting
Oats Other cooked porridge
3239 Type: ������������������������ Brand name of cereals at home now:
Breakfast cereals
���������������������������� ���������������������������� ����������������������������
Do you pour milk on your porridge or cereal? 1 Yes 2
No
If yes, what type of milk (whole fresh, sour, 1%, fat free, milk blend, etc) ������������������������������������������������������������������
If yes, how much milk
Do you put sugar on your porridge or cereal? 1 Yes 2
No 3989
If yes, how much sugar
3989 3989
Samp
Bought/Self ground
Samp and beans
Give ratio of samp:beans
Samp and peanuts
Give ratio of samp:peanuts
Rice
Pasta
3250 3402 (1:1) 3250 (samp)
White
3247
Brown
3315
Maize rice
3250
Macaroni Spaghetti Other specify: �����������������
3262
Home-made: specify topping ���������������������������� Pizza
3353 (base+ch)
���������������������������� Bought: specify topping ���������������������������� ����������������������������
You are being very helpful. Can I now ask you about meat?
3353 (base+ch)
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
AMOUNT/ DAY
CHICKEN, MEAT, FISH How many times do you eat meat (beef, mutton, pork, chicken, fish) per week? _______________________________________________ Boiled
2926
Fried: in batter/crumbs e.g. Kentucky
3018
Fried: not coated Chicken (codes with skin)
Bought: Chicken Licken
2925
Bought: Nando’s Roasted/grilled
2925
Other: ����������������������� Do you eat chicken skin? 1
Always
2
Sometimes
3
Never
Chicken bones stew Chicken feet
2997
Chicken offal Red meat
How do you like meat? With fat Fat trimmed Fried
Red meat
Stewed Mince with tomato and onion
2987
Other: Intestines: boiled nothing added
3003
Stewed with vegetables
Beef offal
Liver
2920
Kidney
2923
Other: specify ���������������������������� ���������������������������� Boiled Goat meat
4281
Stewed with vegetables Grilled/roasted
4281
What type of vegetables is usually put into meat stews? ������������������������������������������������������������������������������� Wors/sausage
2931
Bacon
2906
Cold meats
Polony
2919
Ham
2967
Vienna
2936
Other: specify ���������������������������� Bully Beef Canned meat
Other: specify ����������������������������
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TIMES EATEN FOOD
Meat pie
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
Beef
2939
Steak and kidney
2957
Cornish
2953
Chicken
2954
Other Hamburger Dried beans/peas/lentils
Bought Soup
3145
Salad Brands at home now:
Soya products e.g. Toppers
����������������������������
3196 (Toppers)
���������������������������� Pilchards in tomato/chilli/brine
Fried fish
Whole Mashed with fried onion With batter/crumbs Without batter/crumbs Tuna
Other canned fish
3102
3056 (oil)
Pickled fish Other: specify ����������������������������
Fish cakes Fish fingers
Eggs
Bought: fried
3080
Home-made with potato
3098
Bought
3081
Boiled/poached
2867
Scrambled: milk + fat Fried: fat
VEGETABLES AND FRUIT How do you cook cabbage? Boiled, nothing added
3756
Boiled with potato and onion and fat Cabbage
Fried, nothing added Fried in ���������������������� Boiled, then fried with potato, onion Other: Don’t know How do you cook spinach? Boiled, nothing added
Spinach/morogo/beetroot leaves/Other green leafy
Boiled with fat added Type of fat �������������������� With onion, tomato, potato With peanuts Other: Don’t know
3913
AMOUNT/ DAY
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
Home made with fat Type of fat �������������������� Tomato and onion gravy
Without fat
3925
Canned
4192
How do you cook pumpkin? Boiled, nothing added
Pumpkin (yellow)
4164
Cooked in fat and sugar Fat �������������������������� Boiled, little sugar and fat ���������������������������� Other Don’t know How do you cook carrots? Boiled, nothing added
3757
Boiled, sugar and fat Fat �������������������������� Carrots
With potato and onion: fat Raw, salad
3709
Chakalaka Other Don’t know How do you eat mealies?
Mealies/ Sweet corn
Beetroot
On cob – fat added Fat �������������������������� On cob – no fat added
3725
Creamed sweet corn/ canned
3726
Whole kernel/canned
3942
Salad
3699
Boiled, nothing added
3698
How do you cook potatoes?
Potatoes
Boiled/baked with skin
4155
Boiled/baked without skin
3737
Mashed Roasted Fat ______________________ French fries (chips)
3740
How do you cook sweet potatoes?
Sweet potatoes
Boiled/baked with skin
3748
Boiled/baked without skin
3903
Mashed Other: ���������������������������� Don’t know
AMOUNT/ DAY
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
Salad vegetables
DESCRIPTION
Per day
AMOUNT
Per week
Per month
Seldom/ never
CODE
Mixed salad: tomato, lettuce and cucumber
3921
Raw tomato
3750
Other salad vegetables: ���������������������������� ����������������������������
Other vegetables, specify + preparation Do you like fruit? 1 Yes 2
���������������������������� ���������������������������� No
Apples
3592
Pears
3582
Oranges
3560
Naartjies
3558
Grapes
3550
Peaches
Apricots
Fresh
3565
Canned
3567
Fresh
3534
Canned
3535
Mangoes Guavas
3556 Fresh
3551
Canned
3553
Avocado Wild fruit/berries Dried fruit Other fruit
3656 Specify type: ������������������ Types: ���������������������������� ����������������������������
If subject eats canned fruit: Do you have custard with the canned fruit? 1 Yes 2 Custard
No
Home-made: milk Commercial e.g. Ultramel
2716
BREAD AND BREAD SPREADS Bread/bread rolls
White
3210
Brown
3211
Whole-wheat
3212
Do you spread anything on the bread? 1
Always
2
Sometimes
3
Never
What brand do you have at home now? Margarine Don’t know ������������������� Peanut butter
3485
AMOUNT/ DAY
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
Jam/syrup/honey
3985
Marmite/Fray bentos/Oxo
4058
Fish/meat paste
3109 Type:
Cheese
���������������������������� ����������������������������
Achaar Specify: Other spreads
���������������������������� ����������������������������
Dumpling Vetkoek
White flour
3257
Whole-wheat flour
3324
Provita, crackers, etc
3235 Mayonnaise
Mayonnaise/salad dressing
3488
Other: specify ����������������������������
DRINKS Tea
English (normal)
4038
Rooibos
4054
Coffee Sugar/cup tea or coffee
4037 Tea:
3989
Coffee:
3989
What type of milk do you use in tea and coffee? Fresh/long-life: whole/full
2718
Fresh/long-life: 2%/low fat
2772
Fresh/long-life: fat-free
2775
Whole-milk powder Brand: ���������������������������� Low-fat milk powder Brand: ���������������������������� Milk/cup tea or coffee
Skimmed milk powder Brand: ���������������������������� Milk blend, Brand: ����������������������������
2721 (powder) 2825 (powder) 2825 (powder) 2770 (powder)
Whitener: type ���������������������������� Condensed milk
2714
Evaporated milk
2715
None
AMOUNT/ DAY
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TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
What type of milk do you drink milk as such?
Milk as such
Fresh/long-life: whole/full
2718
Fresh/long-life: 2%/low fat
2772
Fresh/long life: fat free
2775
Condensed milk
2714
Sour/maas
2787
Other: ����������������������� Nestlé: ���������������������������� Milo: Milk drinks
���������������������������� Flavoured milk: ���������������������������� Other: ������������������������
Yoghurt
Drinking yoghurt
2756
Thick yoghurt
2734
Low-fat sweetened with fruit
2732
Sweet O
4027
Six O Squash
Oros/Lecol – with sugar
3982
– artificially sweetened
3990
KoolAid
4027
Other: �����������������������
Fruit juice
Fresh/Liquifruit/Ceres
2866
Tropica (dairy–fruit juice mix)
2791
Other: ������������������������ ����������������������������
Fizzy drinks Coke, Fanta, etc
Sweetened
3981
Diet
Maueu/Motogo
4056
Home brew Tlokwe
4039
Beer
4031
Spirits
4035
Wine: red
4033
Wine: white
4033
Other: specify
���������������������������� ����������������������������
AMOUNT/ DAY
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
SNACKS AND SWEETS Potato crisps Peanuts
3417 Raw
4285
Roasted
3458
Cheese curls, Niknaks, etc
3267
Raisins
3552
Peanuts and raisins Name: Chocolates
���������������������������� ����������������������������
Candies
Sugus, gums, hard sweets, etc
4000
Sweets
Toffees, fudge, caramels
3991
Type: Biscuits/cookies
���������������������������� ���������������������������� Type:
Cakes and tarts
���������������������������� ����������������������������
Scones Type: Rusks
���������������������������� ����������������������������
Savouries
Sausage rolls
2939
Samoosas: meat filling
3355
Samoosas: vegetable filling
3414
Biscuits e.g. bacon kips Other specify: ���������������������������� ����������������������������
Jelly
3983
Baked pudding
Type: ������������������������
Instant pudding
Milk type: ���������������������
Ice cream
3483
Sorbet
3491 ����������������������������
Other specify
���������������������������� ����������������������������
AMOUNT/ DAY
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 7, August 2012
TIMES EATEN FOOD
DESCRIPTION
AMOUNT
Per day
Per week
Per month
Seldom/ never
CODE
SAUCES, GRAVIES AND CONDIMENTS Tomato sauce/ Worcester sauce
3139
Chutney
3168
Pickles
3866
Packet soups
3165
Other:
���������������������������� ����������������������������
WILD BIRDS, ANIMALS OR INSECTS (hunted in rural areas or on farms) Wild fruit
MISCELLANEOUS: Please mention any other foods used more than once/twice a week which we have talked about:
INDIGENOUS/TRADITIONAL FOODS/PLANTS/ANIMALS Please tell me if you use any indigenous plants OR other indigenous foods like mopani worms, locusts etc to eat Specify
AMOUNT/ DAY
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Target-organ damage and cardiovascular complications in hypertensive Nigerian Yoruba adults: a cross-sectional study OO OLADAPO, L SALAKO, L SADIQ, K SHOYINKA, K ADEDAPO, AO FALASE
Abstract Background: Hypertension is a major challenge to public health as it is frequently associated with sudden death due to the silent nature of the condition. By the time of diagnosis, some patients would have developed target-organ damage (TOD) and associated clinical conditions (ACC) due to low levels of detection, treatment and control. TOD and ACC are easy to evaluate in a primary healthcare (PHC) setting and offer valuable information for stratifying cardiovascular risks in the patient. The aim of this study was to evaluate the prevalence and correlates of TOD and established cardiovascular disease (CVD) in hypertensive Nigerian adults. Methods: A cross-sectional study was conducted on 2 000 healthy Yoruba adults between 18 and 64 years who lived in a rural community in south-western Nigeria. Participants diagnosed to have hypertension were examined for TOD and ACC by the presence of electrocardiographically determined left ventricular hypertrophy (LVH), microalbuminuria or proteinuria, retinopathy, or history of myocardial infarction and stroke. Results: A total of 415 hypertensive participants were examined and of these, 179 (43.1%) had evidence of TOD and 45 (10.8%) had established CVD. TOD was associated with significantly higher systolic (SBP) and diastolic blood pressure (DBP). The prevalence of LVH was 27.9%, atrial fibrillation 16.4%, microalbuminuria 12.3%, proteinuria 15.2%, hypertensive retinopathy 2.2%, stroke 6.3%, congestive heart failure (CHF) 4.6%, ischaemic heart disease 1.7%, and peripheral vascular disease 3.6%. Compared with those with
Department of Medicine, Cardiovascular Unit, University College Hospital, and Department of Anatomy, College of Medicine, University of Ibadan, Nigeria
OO OLADAPO, MB BS, MSc, FWACP, lolaoladapo@comui.edu.ng
University of Ibadan, Nigeria L SALAKO, DSc
Country office, World Health Organisation, Lagos Nigeria L SADIQ, MSc
Primary Health Egbeda Local Government, Oyo State, Nigeria K SHOYINKA, MB BS
Department of Chemical Pathology, College of Medicine, University of Ibadan, Nigeria K ADEDAPO, MB BS
Department of Medicine, Cardiovascular Unit, University College Hospital, College of Medicine, University of Ibadan, Nigeria AO FALASE, MB BS, MD
normal blood pressure (BP), the multivariate adjusted odds ratios (95% confidence interval) of developing TOD was 3.61 (0.59–8.73) for those with newly diagnosed hypertension; 4.76 (1.30–13.06) for those with BP ≥ 180/110 mmHg; and 1.85 (0.74–8.59) for those with diabetes mellitus. Conclusions: This study provides new data on TOD and its correlates in a nationally representative sample of hypertensive adults in Nigeria. In this low-resource setting, attempts should be made to detect hypertensive patients early within the community and manage them appropriately before irreversible organ damage and complications set in. The methods used in this study are simple and adaptable at the primary healthcare level for planning prevention and intervention programmes. Keywords: target-organ damage, left ventricular hypertrophy, microalbuminuria, retinopathy, established cardiovascular disease, hypertension, Nigeria Submitted 3/4/11, accepted 6/3/12 Cardiovasc J Afr 2012; 23: 379–384
www.cvja.co.za
DOI: 10.5830/CVJA-2012-021
Hypertension is often asymptomatic and recording blood pressure is opportunistic. Many of these patients are unaware of their condition and therefore remain untreated. Untreated or poorly controlled hypertension and left ventricular hypertrophy (LVH) are risk factors for cardiovascular diseases (CVD),1 a major cause of morbidity and mortality, and sudden death.2 The lack of awareness of the disease results in worse outcomes. A number of hypertensives may present for the first time with target-organ damage (TOD) involving various organs. Therefore at initial diagnosis, they already have hypertensive heart disease (HHD); some with LVH, while some have frank congestive heart failure (CHF). CHF is a lethal disease with a poor prognosis and reduced life expectancy.3 It imposes a large health, economic and social burden on the patient, his/her family and the community at large, and it usually affects males and females in their productive middle years. Major TOD of hypertension such as LVH,4 diastolic dysfunction,5 CHF,6 ischaemic heart disease (IHD),7 stroke8 and renal failure9 have been documented by various workers in Nigeria and these were mostly hospital-based studies. Autopsy studies confirmed that the commonest cause of sudden, unexpected death in Nigerians is hypertension.10,11 In Nigeria, little is known about the experiences of caregivers and care-seeking practices with regard to hypertension and factors influencing late presentation with TOD. Some of the undiagnosed hypertensives are detected incidentally during the course of management for other clinical conditions or during catastrophic events. The challenge to the physician therefore is
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early detection and treatment of hypertension before progression to complications of TOD, which portends a poor prognosis. There are few studies on target-organ involvement in hypertensive Nigerian patients at the secondary and tertiary level of care,12-14 but few or none in the general population and in the primary-care setting. The aim of our study was to evaluate the prevalence of TOD and established CVD in a hypertensive adult Nigerian population, using methods that could easily be adopted at the primary health centre (PHCs) level. This would be helpful to the health planners for formulation and implementation of preventative strategies.
Methods This work was part of a community-based, descriptive, non-interventional, cross-sectional survey of cardiometabolic risk factors, conducted from December 2002 to November 2005 in the Egbeda local government area (ELGA), a rural community in south-western Nigeria, with a population of 128 000. The local governments are serviced by PHCs which are meant to serve as the initial point of care for the majority of patients in Nigeria. The study protocol was evaluated and approved by the Ethics of Human Research Committee of the State Ministry of Health. Individual consent was obtained verbally and where possible by written consent. Four hundred and fifteen confirmed hypertensive adults (184 males and 231 females) above 18 years of age who participated in the cross-sectional, community-based survey formed the population for this study. Socio-demographic and anthropometric data were collected for each subject. Self-reported and patient clinical records of established CVD and complications such as heart failure, stroke, myocardial infarction, angina, peripheral vascular disease and kidney disease were recorded. Clinic blood pressure (BP) was measured by trained health workers in each PHC, according to guidelines of the International Society of Hypertension (ISH)/World Health Organisation (WHO) 1999 and the JNC-7.15,16 Measurements were taken using a standard mercury Accoson sphygmomanometer (Accoson works, Vale Road, London N4 1PS) with appropriate cuff size. Three BP measurements were taken using the subject’s right arm with the subject in the sitting position after five minutes of rest, with one minute between measurements. The mean of three measurements was used as the final value. Participants with an elevated BP measurement were invited to attend a second clinic visit after one to two weeks to have their BP measured again. The average BP of the second visit was used as a criterion for the diagnosis and control of hypertension. In addition, all treated hypertensive patients were asked to return for a second visit after one to two weeks to have their BP measured. Hypertension was defined as systolic blood pressure (SBP) ≤ 140 mmHg, diastolic blood pressure (DBP) ≤ 90 mm Hg, or current treatment with antihypertensive drugs in subjects with a history of hypertension.16,17 Awareness of hypertension meant a previous diagnosis of hypertension or high blood pressure. Controlled hypertension was defined as treated hypertension with SBP < 140 mmHg and DBP < 90 mmHg at the second clinic visit. Each subject underwent further physical examination to determine clinical features of LVH, CHF, stroke, renal failure, and fundoscopy for hypertensive retinopathy. Hypertensive cardiac
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damage was defined by the presence of electrocardiographic (ECG) LVH based on the voltage criteria of Araoye18 in black hypertensives. LVH was determined as follows: the sum of SV2 + RV6 in males of ≥ 40 mm and females of ≥ 35 mm and RI ≥ 12 mm. These criteria have been shown to correlate better with echocardiograhic LVH in Nigerians.19 Hypertensive eye damage was diagnosed based on the Keith-Wagener classification of hypertensive retinopathy and the patients were divided into four grades.20 Renal damage was diagnosed based on the presence of microalbuminuria as determined by spot urine albumin-tocreatinine ratio [ACR (mg/g)]. In males, ACR < 2.5 mg/g is normal, 2.5–25 mg/g defines microalbuminuria and > 25 mg/g indicates gross proteinuria. In females, ACR < 3.0 mg/g is normal, 3.0–30 mg/g defines microalbuminuria, and > 30 mg/g indicates gross proteinuria.21-24 Venous blood samples were obtained via the ante-cubital vein for biochemical assessment, including fasting serum total cholesterol, high-density lipoprotein cholesterol (HDL-C) and fasting blood glucose levels.
Statistical analysis The data obtained were analysed using SPSS version 13.0 software (SPSS Inc, Chicago, Illinois, USA). Descriptive analysis of the variables was performed to process the data as tables. Continuous variables were described by calculating the means and standard deviation (SD). Categorical variables were described using frequency tables.
Results A total of 415 subjects consisting of 184 men (44.3%) and 231 women (55.7%) participated in the study. The baseline characteristics of the subjects are shown in Table 1. The females were significantly older [50.4 (± 13.2) years] than the males [46.9 (± 16.7) years] (p < 0.001). SBP and DBP did not vary significantly according to gender. The detection and treatment rate of hypertension was low in the studied population. Only 14.2% of the subjects had self-reported hypertension and of these, only 18.6% had been on medications in the past three months; of whom only 27.3% had controlled blood pressure. This means that only 5.1% of subjects who had self-reported hypertension had controlled BP at the time of the study. The antihypertensive drugs used either alone or in combination included centrally acting alpha-adrenergic agonists such as α-methyl DOPA and Brinerdin (74.3%), thiazide diuretics (86.1%), calcium channel blockers (15.6%) and ACE inhibitors (1.7%). Some of the subjects who self-reported hypertension were on benzodiazepines prescribed as antihypertensives by their general practitioner. The prevalence of diabetes among the participants was 9.6% (7.1% in men and 11.7% in women). The prevalence of smoking in the study population was 5.1% and all the cigarette smokers were men. Table 2 shows the prevalence of hypertensive TOD among the subjects studied. Overall, 179 (43.1%) of the subjects, 83 (20.0%) men and 96 (23.1%) women, had evidence of TOD. The age difference between those subjects with (47.4 ± 11.5 years) and without (45.9 ± 13.2 years) TOD was not statistically significant (p = 0.12). The blood pressure of subjects in relation
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TABLE 3. BLOOD PRESSURE RANGES OF SUBJECTS IN RELATION TO TARGET-ORGAN DAMAGE
Table 1. Characteristics of the subjects included in the study Males (n = 184) Mean (SD)
Females (n = 231) Mean (SD)
Total (n = 415) Mean (SD)
Age (years)
43.4 (± 20.2)
50.4 (±13.2)
46.9 (± 16.7)
BMI (kg/m2)
25.1 (± 4.8)
28.7 (± 6.5)
26.9 (± 5.7)
Waist circumference (cm)
86.5 (± 14.7)
92.6 (± 13.3) 89.5 (± 14.0)
SBP (mmHg) DBP (mmHg)
159.4 (± 25.5) 156.9 (± 24.2) 158.2 (± 24.9) 98.7 (± 13.6)
94.9 (± 17.5) 96.8 (± 15.4)
Level of education None Primary
(28) 15.2%
(59) 25.5%
(87) 21.0%
(101) 54.9%
(136) 58.9%
(237) 57.1%
Secondary
(43) 23.4%
(31) 13.4%
(74) 17.8%
Tertiary
(12) 6.5%
(5) 2.2%
(17) 4.1%
Current cigarette smoker
(21) 11.4%
(0) 0.0%
(21) 5.1%
(0) 0.0%
(3) 1.3%
(3) 0.7%
(13) 7.1%
(27) 11.7%
(40) 9.6%
Current tobacco use* Diabetes Hypercholesterolaemia Hypertension (≥ 140/90 mmHg) Newly diagnosed Self-reported
(19) 10.3%
(22) 9.5%
(41) 9.9%
(163) 88.6%
(193) 83.5%
(356) 85.8%
(21) 11.4%
(38) 16.5%
(59) 14.2%
eceiving treatment in past R 3 months
(4) 19.0%
(7) 18.4%
(11) 18.6%
BP control
(1) 25.0%
(2) 28.6%
(3) 27.3%
*Tobacco use (chewing/snuffing).
to TOD is shown in Table 3. Subjects with TOD had significantly higher (p < 0.001) mean SBP (167.1 ± 15.6 mmHg) than those without TOD (156.3 ± 18.7 mmHg). Mean DBP was also significantly higher (p < 0.001) in those with TOD (102.3 ± 9.5 mmHg) than those without (95.8 ± 13.5 mmHg). The prevalence of LVH was 27.9% and atrial fibrillation was 16.4%. Subjects with LVH had significantly higher (p < 0.001) SBP (161.7 ± 18.9 mmHg) compared to those without LVH (153.3 ± 16.2 mmHg) and their DBP was also significantly higher (p < 0.001) at 99.4 ± 9.5 mmHg, compared with 91.5 ± 10.1 mmHg. Grade 3 hypertensive retinopathy was present in 2.2% of the TABLE 2. PREVALENCE OF HYPERTENSIVE TARGET ORGAN DAMAGE AMONG PARTICIPANTS Target-organ damage Number (n = 415) Prevalence (%) Heart LVH 116 27.9 LAE 91 21.9 Atrial fibrillation 68 16.4 Old infarcts/ischaemic changes 51 12.3 Retinopathy grade 0 83 20.0 grade 1 167 40.2 grade 2 156 37.6 grade 3 9 2.2 grade 4 0 0.0 Renal damage* Microalbuminuria 51 12.3 Gross proteinuria 63 15.2 LVH = left ventricular hypertrophy; LAE = left atrial enlargement; *Men, microalbuminuria = albumin-creatinine ratio (ACR) 2.5–25 mg/g and gross proteinuria is ACR > 25 mg/g; women, microalbuminuria = ACR 3.0–30 mg/g and gross proteinuria is ACR > 30 mg/g.
Target organ ECG abnormalities’ Present Absent Retinopathy Present Absent Renal damage Present Absent
Blood pressure (mmHg) SBP (± SD) DBP (± SD) p-value 161.7 ± 18.9 153.3 ± 16.2
99.4 ± 9.5 91.5 ± 10.1
< 0.001
155.6 ± 15.4 152.8 ± 18.2
93.7 ± 12.1 95.2 ± 13.0
0.52
163.5 ± 17.6 150.0 ± 16.2
101.6 ± 9.5 90.9 ± 9.5
0.001
study population, and the commonest retinopathy was grade 1 (40.2%), followed by grade 2 (37.6%). Microalbuminuria was present in 12.3% and gross proteinuria in 15.2%. The established CVD found in the subjects is shown in Table 4. History of stroke was found in 6.3% and CHF in 4.6% of the participants. Ischaemic changes and evidence of old myocardial infarcts were seen on ECG in 12.3% of the participants. However, only 0.5% gave a history of myocardial infarction and 1.2% gave a history of angina. Peripheral vascular disease was found in 3.6% of the subjects, of whom 73.3% (11/15) were diabetic. Overall, 45 (10.8%) subjects had established CVD. The results of multiple regression analyses after adjusting for potentially confounding variables are presented in Table 5, showing the association between TOD and selected variables. The odds of developing TOD were increased by new diagnosis of hypertension, systolic blood pressure ≥ 180 mmHg/diastolic blood pressure ≥ 110 mmHg, and diabetes mellitus.
Discussion The main findings of this study were the following: (1) The presence of TOD was frequent in this rural adult population; (2) The peak age for incidence of TOD was around 47 to 50 years, that is middle age; (3) TOD was related to the presence of newly diagnosed hypertension, stage 3 SBP and DBP, and diabetes mellitus; (4) The presence of established CVD was relatively frequent in this population; (5) There was a low detection rate, treatment and control of hypertension; (6) Atrial fibrillation was found in 16.4% of the population and this may have increased the risk of stroke as no patients were on treatment; (7) In spite of the low levels of angina and myocardial infarction, ischaemic changes and evidence of old infarcts were found in the ECGs of 12.3% of the population studied. The present study contributes to our knowledge on TOD in Nigerian hypertensives in several ways. First, our study demonstrates an incidence rate of TOD of 43.1% and established TABLE 4. PREVALENCE OF ESTABLISHED CARDIOVASCULAR DISEASE AMONG PARTICIPANTS CV complications Stroke Myocardial infarction Angina Congestive heart failure Peripheral vascular disease
Number (n = 415) 26 2 5 19 15
Prevalence (%) 6.3 0.5 1.2 4.6 3.6
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TABLE 5. ASSOCIATION BETWEEN HYPERTENSIVE TARGET-ORGAN DAMAGE AND SELECTED VARIABLES OR* (95% CI) for Detection of hypertension target-organ damage Self-reported 1.00 Newly diagnosed 3.61 (0.59–8.73) BMI 1.00 ≤ 24.9 kg/m2 0.95 (0.28–3.26) 25.0–29.9 kg/m2 1.44 (0.45–5.74) ≥ 30.0 kg/m2 Hypertension classification BP < 140/90 mmHg 1.00 SBP 140–159 mmHg/DBP 90–99 mmHg 1.34 (0.23–2.95) SBP 160–179 mmHg/DBP 100–109 mmHg 1.29 (0.20–4.95) SBP > 180 mmHg/DBP > 110 mmHg 4.76 (1.30–13.06) Diabetes mellitus No diabetes 1.00 Diabetes 1.85 (0.74–8.59) *OR (odds ratio) adjusted for age, gender, smoking, level of education, blood pressure control. BMI = body mass index.
CVD of 10.8% among a nationally representative sample of the adult population of hypertensive Nigerians. Most studies of this nature have been conducted in hypertensive Nigerian patients attending healthcare facilities. The relatively high prevalence of TOD among the community of rural-dwelling adults is worrisome as it approaches previously reported hospital-based values of 53.3%13 and 60.1%.12 Blacks have been shown to have more severe forms of hypertension with greater risk of TOD.25,26 This may be due to the fact that 85.8% of the subjects were newly diagnosed hypertensives. Some of the subjects had had their blood pressure measured for the first time during the study. Of those who had had previous blood pressure measurements, the definition of hypertension by their attending medical team was 160/95 mmHg. These physicians had failed to commence appropriate management even at this level. Furthermore, only 18.6% of the self-reported hypertensives were on any form of treatment, which was mostly suboptimal. Of these, only 27.3% had their blood pressure controlled. There is an urgent need for training and retraining of both the care givers and care seekers at the community and PHC levels in order to reduce the burden of CVD in the population. The prevalence of ECG-LVH was nearly 28%, based on Araoye’s criteria,18 indicating that these individuals had more severe LVH with a possibly worse prognosis. This may have been due to a long duration of undiagnosed hypertension in the subjects. LVH has been associated with increased incidence of CHF, coronary artery disease, stroke, arrhythmias and sudden death.27 In those receiving treatment for hypertension, the antihypertensives being used were inadequate to regress their LVH. LVH places the subjects at risk of developing adverse cardiovascular events. The percentage of subjects with LVH was lower than the 31.0%12 and 43.3%13 obtained in previous studies, although these were hospital based in urban settings. Another study in hypertensive urban civil servants in Ghana found a prevalence of 33.3%.28 Left atrial enlargement (LAE) was present on the ECGs of 21.9% of the subjects and atrial fibrillation in 16.4%. These are known risk factors for thrombo-embolic strokes and in
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the presence of hypertension, they may worsen the prognosis. Hypertension, a major risk factor for stroke in sub-Saharan Africa, including Nigeria, has been reported to occur in 33 to 62% of those with cerebral infarction and 60 to 92% of those with cerebral haemorrhage.29 The relatively high prevalence of stroke in our study population was 6.3% and this was comparable to a hospitalbased report of 8.9%12 but much higher than the 0.8% reported in a similar setting.13 In sub-Saharan Africa, stroke is a major CVD of public health concern, with high morbidity and mortality, affecting people in the prime of their lives.30,31 It also imposes a high economic burden on the healthcare systems, which this low-income country cannot afford. Kidney damage was found in 27.5% of the subjects and of these, 12.3% had microalbuminuria, while 15.2% had gross proteinuria. There is disparity between our findings and a previous study that reported microalbuminuria in 37% and overt proteinuria in 2% of newly diagnosed Nigerian hypertensives.32 Microalbuminuria is a sensitive marker for renal damage in hypertension.16 In our study, subjects who had ECG abnormalities and evidence of kidney damage had statistically significantly (p < 0.001) higher SBP and DBP compared with subjects who had neither TOD. In a study on TOD in hypertensive Ghanaian civil servants,28 trace proteins were found in 8.8%, proteinuria in 13.4% and chronic kidney disease in 4% of the participants. The high rate of proteinuria in our study population was a cause of concern as efforts in the primary prevention of chronic kidney disease should be intensified in this low-resource setting. Failure to do so will increase the economic burden on the fragile healthcare system. Based on the fact that grades 3 and 4 hypertensive retinopathy are used as evidence for TOD,31 the prevalence of hypertensive retinopathy in our study was 2.2% and was comparable to the prevalence reported in studies in sub-Saharan Africa.28,32,33 These studies reported a rarity of hypertensive retinopathy in this region, unlike the high prevalence in economically more advanced nations.34 About 78% of our subjects had either grade 1 or grade 2 retinopathy. Of the participants in this study, 10.8% had established CVD. Of these, 6.3% had stroke, 4.6% had CHF, 3.6% had peripheral vascular disease and 1.7% had ischaemic heart disease. Hypertension plays a significant role in the causation of CHF in Nigeria.12 Heart failure is another complication which would impose a social and economic burden on the populace. This underscores the importance of establishing intervention programmes for primary prevention, early detection and appropriate management of hypertension in this rural population. Although the prevalence of ischaemic heart disease was low in this study, its presence in the population may be significant, with epidemiological transition occurring at a rate faster than previously thought. The odds of developing TOD were highest in participants with blood pressure ≥ 180/110 mmHg, followed by newly diagnosed hypertensives and those with diabetes. Previous studies have shown a more positive correlation of hypertensive TOD with SBP than with DBP.12,35 Since hypertension is a silent disease, there is a need to create awareness to encourage opportunistic screening. Patients should be encouraged to adopt healthy lifestyles for the primary prevention of CVD as they
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may be unwilling to commence taking drugs, which may have side effects. This is particularly so when they do not have any symptoms. Of the few patients who were on antihypertensives, the drugs most frequently used were centrally acting ones such as α-methyl DOPA, or inappropriate ones such as benzodiazepines (valium, lexotan). Invariably, patients on such treatments will have uncontrolled BP and are likely to have more TOD and established CVD, with worse outcomes. Newly diagnosed hypertensives should have their cardiovascular risks fully assessed and appropriately managed. Since stage 3 hypertension was associated with significantly increased odds of developing TOD, efforts should be made to aggressively lower and control BP in such individuals. Our study had some limitations. The investigations did not include echocardiography for assessment of LVH, which is more sensitive than ECG. However, we used locally validated Araoye’s criteria to determine LVH with ECG, as this was likely to give us a more accurate diagnosis.18,19 The duration of hypertension could not be ascertained in most of our subjects as many had not had their BP checked until the time of the study. Therefore, we could not control for the duration of hypertension, which is a confounder in this type of study.
Conclusion This study showed a high level of TOD and established CVD in this rural population of hypertensives. Our findings strongly suggest that the epidemiological transition from communicable to non-communicable diseases is occurring at a faster rate than previously envisaged. In this low-resource setting, there is an urgent need for primordial and primary prevention of hypertension and its complications. Once detected, BP should be properly controlled with appropriate medications. To this effect, both the populace and health practitioners should receive health education and health promotion to reduce the burden of disease.
9. 10.
11. 12.
13.
14.
15. 16.
17.
18. 19.
20.
21.
22. We are grateful to the authorities of the ELGA, the gatekeepers/key opinion leaders and the participants who gave their time, support and enthusiasm in making this study a success. The study was funded in part by the country office of the WHO.
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William Nelson ECG quiz Question This is the ECG of an 83-year-old woman. What is bi-level AV block? What is leapfrog Wenckebach?
The answer will be provided on page 409.
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Prevalence of cardiac dyssynchrony and correlation with atrio-ventricular block and QRS width in dilated cardiomyopathy: an echocardiographic study JB ANZOUAN-KACOU, MP NCHO-MOTTOH, C KONIN, AR N’GUETTA, KA EKOU, BJ KOFFI, KE SOYA, ME TANO, R ABOUO-N’DORI
Abstract Introduction: Cardiac dyssynchrony causes disorganised cardiac contraction, delayed wall contraction and reduced pumping efficiency. We aimed to assess the prevalence of different types of dyssynchrony in patients with dilated cardiomyopathy (DCM), and to establish the correlation between atrio-ventricular block and atrio-ventricular dyssynchrony (AVD), and between impaired intra-ventricular conduction and the existence of inter-ventricular dyssynchrony (interVD) and intra-left ventricular dyssynchrony (intra-LVD). Methods: We included 40 patients in New York Heart Association stage III or IV, admitted consecutively with DCM with severe left ventricular dysfunction (left ventricular enddiastolic diameter ≥ 60 mm and/or ≥ 30 mm/m²) and left ventricular ejection fraction < 35%. Electrocardiographic and echocardiographic data were evaluated in all patients. Patients were divided into two groups: group 1: eight patients, with a QRS duration ≥ 120 ms, and all presented with left bundle branch block; group 2: 32 patients with a narrow QRS < 120 ms. Results: Overall, the mean age was 54.7 ± 16.8 years and patients in group 1 were older (67.2 ± 13.6 vs 51.5 ± 15.8 years, p = 0.01). The prevalence of atrio-ventricular dyssynchrony (AVD), inter-VD and intra-LVD was respectively 40, 47.5 and 70%. Two patients (5%) did not exhibit dyssynchrony. AVD was present with a similar frequency in the two groups (37.5% in group 1 vs 40.6% in group 2, p = 0.8). There was no correlation of the magnitude of AVD with the duration of the PR interval (from the beginning of the P wave to the beginning of the QRS complex) (r2 = 0.02, p = 0.37) or the QRS width (r² = 0.01, p = 0.38). A greater proportion of patients with inter-VD was observed in group 1 (87.5 vs 60%, p = 0.03). There was a trend towards a more important inter-ventricular mechanical delay according to QRS width (r2 = 0.009, p = 0.06). The proportion of intra-LVD was similar in all groups, with a high prevalence (87.5% in group 1 and 65.6% in group 2, p = 0.39). Conclusion: The assessment of cardiac dyssynchrony is possible in our country. Intra-ventricular mechanical Institute of Cardiology of Abidjan, Abidjan, Ivory Coast JB ANZOUAN-KACOU, MD, jb_anzouan@yahoo.fr MP NCHO-MOTTOH, MD C KONIN, MD AR N’GUETTA, MD KA EKOU, MD BJ KOFFI, MD KE SOYA ME TANO, MD R ABOUO-N’DORI, MD, PhD
dyssynchrony had a high prevalence in patients with DCM, irrespective of the QRS width. These data emphasise the usefulness of echocardiography in the screening of patients. Keywords: heart failure, cardiomyopathy, dyssynchrony, echocardiography, Africa Submitted 3/4/11, accepted 28/3/12 Cardiovasc J Afr 2012; 23: 385–388
www.cvja.co.za
DOI: 10.5830/CVJA-2012-032
In dilated cardiomyopathy (DCM), alterations in cardiac structure and function result in regions of early and late contraction, known as dyssynchrony.1 This dyssynchrony disorganises cardiac contraction, delays wall contraction and reduces pumping efficiency.1,2 Morbidity and mortality rates are higher in patients with severe left ventricular systolic dysfunction and ECG-derived prolonged QRS interval than in those with normal QRS duration.3 Three types of dyssynchrony may occur: atrio-ventricular dyssynchrony (AVD) with a discordance of contraction between the atria and ventricles, inter-ventricular dyssynchrony (interVD) with a discordance between the time of left and right ventricle contractions, and intra-left ventricular dyssynchrony (intra-LVD) with a discordance in the contraction of the walls of the left ventricle. A large number of studies have used echocardiography to assess dyssynchrony.1,4 Intra-LVD appears to be the principal factor associated with contractile impairment and is affected by cardiac resynchronisation therapy (CRT). CRT has been proven to reduce symptoms and hospitalisation for heart failure, and to improve quality of life, exercise capacity and the overall prognosis.1,4,5 In this study, we aimed to assess the prevalence of different types of dyssynchrony in patients with dilated cardiomyopathy, and to establish the correlation between atrio-ventricular block and AVD, and between impaired intra-ventricular conduction and the existence of inter-VD and intra-LVD.
Methods This prospective study was conducted at the Institute of Cardiology of Abidjan (ICA) from June to December 2009. We included patients in New York Heart Association (NYHA) stage III or IV, admitted consecutively with the following features: dilated cardiomyopathy with severe left ventricular dysfunction (left ventricular end-diastolic diameter > 60 mm and/or 30 mm/m²) as measured by M-mode echocardiography, and an ejection fraction < 35%, (by Simpson’s method). A total of 40 patients were included. We excluded patients with non-sinus rhythm or valvular heart disease.
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Clinical and echocardiographic characteristics of the patients are shown in Table 1. All patients underwent a standard 12-lead electrocardiogram and an ultrasound examination, which included a specific evaluation of atrio-ventricular, interventricular and intra-ventricular dyssynchrony. Examinations (M mode, two dimensional and Doppler evaluation) were performed using ultrasonographic equipment (General Electric VIVID 7 PRO). According to QRS duration, the patients were divided into two groups. Group 1 included eight patients with a QRS duration ≥ 120 ms and all presented with a left bundle branch block (LBBB). Group 2 included 32 patients with a narrow QRS < 120 ms. Assessment of AVD: parameters collected included the duration of transmitral pulsed Doppler flow (LVFT) and the length of the cardiac cycle (RR). The mean left ventricular filling time to cardiac cycle (LVFT/RR × 100 < 40%) defined atrioventricular dyssynchrony. Assessment of inter-VD: the pulmonary pre-ejection time (PPET) was measured from the beginning of the QRS complex to the beginning of the pulmonary flow velocity curve, recorded by pulse-wave (PW) Doppler in the left parasternal short-axis view. The aortic pre-ejection time (APET) was measured from the beginning of the QRS complex to the beginning of the aortic flow velocity curve, recorded by PW Doppler in the apical five-chamber view. The difference between the two values determined the inter-ventricular mechanical delay (IVMD); an IVMD > 40 ms was considered as the cut-off value for interventricular dyssynchrony. Assessment of intra-LVD: we determined by pulsed tissue Doppler the electrosystolic delay (ESD) from the onset of the QRS complex to the positive peak systolic (Sa) velocity for four basal segments (septal, lateral, inferior and anterior). Intra-LVD
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was considered to be present if one or more absolute differences (ΔS) > 40 ms were found between two segments.
Statistical analysis Data were collected and analysed with the software EPI INFO version 6.04 and Microsoft Excell 2010. Continuous variables were presented as mean ± standard deviation. Statistical analysis was performed with Fischer’s exact test for a significance level of 5% for the comparison of proportions. Comparisons between frequencies in the two groups were performed using the Chi-square test. Correlations between electrocardiographic and echocardiographic parameters were explored using Pearson’s correlation.
Results Overall, the mean age was 54.7 ± 168 years, and patients with QRS ≥ 120 ms were older than those with narrow QRS (67.2 ± 13.6 vs 51.5 ± 15.8 ms, p = 0.01) (Table 1). Most patients were male (57.5%). Systolic and diastolic left ventricular dysfunction, left ventricular end-diastolic dysfunction (LVEDD), systolic right ventricular dysfunction, and degree of mitral regurgitation were similar in the two groups. AVD was present in 16 patients (40%), inter-VD in 19 patients (47.5%) and intra-LVD in 28 patients (70%). Two patients (5%) did not exhibit dyssynchrony. AVD alone was present in two patients (5%), inter-VD alone in five patients (12.5%) and intra-LVD alone in 10 patients (25%). Four patients (10%) had at the same time AVD, inter-VD and intra-LVD. AVD was present with a similar frequency in the two groups (37.5% in group 1 vs 40.6% in group 2, p = 0.8) and the duration of LV filling time to cardiac cycle showed no difference between the two groups (Table 1). In the sub-group of 16 patients with AVD, the mean left
TABLE 1. CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF THE PATIENTS All patients Group 1 (QRS ≥ 120 ms) Group 2 (QRS < 120 ms) p-value (n = 40) (n = 8 patients) (n = 32 patients) (group 1 vs group 2) 0.01 Age (years) 54.7 ± 16.8 67.2 ± 13.6 51.5 ± 15.8 Males (n, %) 23 (57.5) 5 (62.5) 18 (56.3) 0.9 NYHA class III (n, %) 26 (65) 6 (75) 20 (62.5) 0.8 NYHA class IV (n, %) 14 (35%) 2 (25) 12 (37.5) 0.8 0.03 QRS width (ms) 100 ± 32.9 157.5 ± 29.1 85.6 ± 10.4 PR interval (ms) 180.7 ± 31.4 180 ± 4 180.9 ± 29.2 0.94 LVEF (%) 29 ± 5 31.3 ± 3.3 28 ± 5 0.14 LVEDD (mm) 66.7 ± 6.6 67.9 ± 6.1 66.4 ± 6.8 0.58 LVESD (mm) 57.7 ± 6.2 58.8 ± 5.2 57.3 ± 6.5 0.55 E/A 1.5 ± 1.1 1.7 ± 1 1.9 ± 0.9 0.64 DT (ms) 116 ± 5 125.3 ± 42.7 114.3 ± 52.3 0.6 Mitral regurgitation (degree) 1.5 ± 0.5 1.6 ± 0.5 1.5 ± 0.5 0.64 PASP (mmHg) 42.9 ± 9 43.3 ± 17.5 42.8 ± 15.3 0.93 SDTI 11.4 ± 2.5 11.6 ± 1.2 11.4 ± 2.7 0.58 LVFT/RR (%) 40.3 ± 8.3 42.3 ± 11.8 39.8 ± 7.3 0.45 0.01 IVMD (ms) 38.6 ± 19.3 54.4 ± 10.8 36.2 ± 18.7 ESD (ms) 66.5 ± 46.9 75.6 ± 28.9 64.2 ± 50.6 0.54 NYHA: New York Heart Association; LVEF: left ventricular ejection fraction; LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end-systolic diameter; PASP: pulmonary artery systolic pressure; E/A: ratio of E wave (early filling) and A wave (atrial contraction) of mitral valve inflow in pulsed Doppler; DT: deceleration time of early filling velocity; SDTI: right ventricular S peak in tissue Doppler imaging; LVFT/RR: left ventricular filling time to cardiac cycle; IVMD: inter-ventricular mechanical delay; ESD: electrosystolic delay; the bold emphasis marks the significant differences with p-value < 0.05.
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ventricular filling time to cardiac cycle was 32.6 ± 3.9%. Six patients had a first-degree atrio-ventricular block (AVB1). There was no relationship between the existence of an AVB1 and AVD (Table 2). There was no correlation between the magnitude of AVD and the duration of the PR interval (from the beginning of the P wave to the beginning of the QRS complex) (r² = 0.02, p = 0.37) or the QRS width (r² = 0.01, p = 0.38). Mean IVMD was 38.6 ± 19.3 ms. The IVMD was significantly higher in patients from group 1 than in group 2 (54.4 ± 10.8 vs 36.2 ± 18.7 ms, p = 0.01) (Table 1). Inter-VD was present in 19 patients (47.5%) with a mean IVMD of 55.8 ± 10.6 ms. A greater proportion of patients with inter-VD was observed in group 1 (QRS ≥ 120 ms) compared to those in group 2 (87.5 vs 60%, p = 0.03). There was a trend of increasing importance of IVMD according to QRS width (r² = 0.09, p = 0.06). The mean ΔS was 66.5 ± 46.9 ms. The ESD was similar in the two groups. Intra-LVD was present in 28 patients (70%) with a mean ΔS of 84.8 ± 46.2 ms. The proportion of intra-LVD was similar in all groups, 87.5% in group 1 and 65.6% in group 2 (Table 3). In patients with intra-LVD, seven had an ESD ≥ 100 ms (17.5% of the total population and 25% of the patients with intra-LVD). Three of these seven patients had a QRS duration ≥ 120 ms.
Discussion The study shows that in dilated cardiomyopathy, NYHA III to IV, cardiac dyssynchrony is common, regardless of QRS duration. Only two patients (5%) did not exhibit dyssynchrony. Intra-LVD seemed to be the most frequent type of mechanical dyssynchrony. The prevalence of AVD was 40%. There was no increase in this prevalence in the presence of AVB1. Jurcut et al.6 found the prevalence of AVD was 45% among 58 patients hospitalised for DCM of different aetiologies. Abnormal conduction of the atrio-ventricular node resulted in delay between the atrial and ventricular contractions. Too much delay means that the valve leaflets are open in the mid-plane position as ventricular systole starts, resulting in pre-systolic mitral and tricuspid regurgitation. Prolonged atrio-ventricular delay also means that the diastolic filling period is abbreviated, limiting diastolic volume.7 In the CARE-HF study,8 prolonged PR interval and right bundle branch block (RBBB) were predictors of favourable outcome in patients with NYHA stage TABLE 2. RELATIONSHIP BETWEEN FIRST-DEGREE ATRIOVENTRICULAR BLOCK AND ATRIOVENTRICULAR DYSSYNCHRONY (p = 0.85)
Patients with AVD Patients without AVD Total
Patients with AVB1 4 2 6
Patients without AVB1 12 22 34
Total 16 24 40
TABLE 3. RELATIONSHIP BETWEEN QRS DURATION AND INTRAVENTRICULAR DYSSYNCHRONY (p = 0.39)
Patients with intra-LVD Patients without intra-LVD Total
Group 1 Group 2 (QRS ≥ 120 ms) (QRS < 120 ms) 7 21 1 11 8 32
Total 28 12 40
III to IV heart failure. The prevalence of inter-VD was 47.5% in our study. Schuster et al. reported a prevalence of 45% for inter-VD in DCM.9 This prevalence was higher than in others series. Bader10 reported a prevalence of 23% in a population optimally treated for stable heart failure. This difference may be explained by the stage of heart failure. In the CARE-HF study, the prevalence of inter-VD among patients recruited by the conventional criteria of cardiac resynchronisation therapy was 62%.8 In our study the exclusive cause of wide QRS was LBBB. A number of patients (12) in our study population with normal QRS duration showed inter-VD. A greater proportion of patients with inter-VD was observed in group 1 (QRS ≥ 120 ms) compared to patients in group 2 (p = 0.03) (Table 4). This is in accordance with other series of patients.6,8,10,11 The IVMD was not significantly related to QRS duration even if there was a trend of increasing importance of IVMD according to QRS width (p = 0.06). Data in the literature showed a good correlation between the IVMD and the width of the QRS.6,10-12 This correlation improved slightly when patients with pulmonary hypertension or right ventricular dysfunction were excluded.12 We have shown a prevalence of 70% of intra-LVD, which seemed to be the most frequent type of mechanical dyssynchrony, irrespective of the QRS width (Table 3). Similar results were observed in other studies.6,10 Hospitalisation for heart failure is a predictor of the existence of left ventricular dyssynchrony and is significantly correlated with a high risk of early cardiac decompensation.10 There was a substantial proportion of patients with normal QRS duration who also showed intra-LVD (21/32) (Table 3). These findings point to the fact that the QRS width is not an accurate predictor of mechanical dyssynchrony. Inter-VD is the principal factor associated with contractile impairment and is affected by CRT.1 The evaluation of dyssynchrony is done with CRT. We noted that 21 patients with narrow QRS presented with intra-LVD. They could potentially have benefitted from CRT but if we rely on conventional criteria,13 these patients would have been excluded because they did not exhibit electrical dyssynchrony (defined by a QRS duration > 120 ms). Perez de Isla et al.14 noted that 38.4% of patients with QRS < 120 ms presented with intra-LVD. Ghio et al.12 found 29.5% of patients with QRS < 120 ms had left ventricular dyssynchrony. This prevalence was 72% in the study by Jurcut et al.6 In our study, in patients with intra-LVD, seven had an ESD ≥ 100 ms. Three of these seven had a QRS duration ≥ 120 ms. This cut-off value of 100 ms is an indicator of a good response to CRT.1 Improvement of left ventricular function after CRT is predicted by tissue Doppler imaging echocardiography. Penicka et al.,15 using a composite index of inter-VD and intra-LVD longer than 100 ms, achieved 88% accuracy in identifying patients who responded to CRT. There were some study limitations. This study was performed TABLE 4. RELATIONSHIP BETWEEN QRS DURATION AND INTERVENTRICULAR DYSSYNCHRONY (p = 0.03)
Patients with inter-VD Patients without inter-VD Total
Group 1 (QRS ≥ 120 ms) 7 1 8
Group 2 (QRS < 120 ms) 12 20 32
Total 19 21 40
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on a consecutive sample of patients (40) who presented in our department with DCM in NYHA stage III to IV during a sevenmonth period. A larger study population would bring more significance to the present data. We were not able to determine the aetiology of the DCM in some patients.
6.
7.
Conclusion The assessment of cardiac dyssynchrony is possible in our country but it remains largely untapped due to the low availability of the techniques and the inaccessibility of CRT. Intra-ventricular mechanical dyssynchrony has a high prevalence in patients with DCM, irrespective of the QRS width. A substantial proportion of patients with DCM and narrow QRS exhibiting intra-LVD may benefit from CRT. These data emphasise the value of echocardiography in the screening of patients.
References 1.
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Gorcsan III J, Abraham T, Agler AD, Bax JJ, Derumeaux G, Richard A. et al. ASE Expert Consensus Statement. Echocardiography for Cardiac Resynchronization Therapy: Recommendations for Performance and Reporting – A report from the American Society of Echocardiography Dyssynchrony Writing Group Endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008; 21: 191–213. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation 1989; 79: 845–853. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. Department of veterans Affairs Survival Trial of Antiarrhytmic Therapy in Congestive Heart Failure. QRS duration and mortality in patients. Am Heart J 2002; 143: 1085–1091. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, de Marco T, Carson P, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140–2150. Focused Update of ESC Guidelines on device therapy in heart failure 2010. An update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guide-
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lines for cardiac and resynchronization therapy. Eur Heart J 2010; 31: 2677–2687. Jurcut R, Pop I, Calin C, Coman IM, Ciudin R, Ginghina C. Utility of QRS width and echocardiography parameters in an integrative algorithm for selecting heart failure patients with cardiac dyssynchrony. Eur J Intern Med 2009; 20: 213–220. Kass DA. Ventricular dyssynchrony and mechanisms of resynchronization therapy. Eur Heart J 2002; 4(Suppl D): 23–30. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the Cardiac REsynchronizationHeart Failure (CARE-HF) trial extension phase]. Eur Heart J 2006; 27: 1928–1932. Schuster I, Habib G, Jego C, Thuny F, Avierinos JF, Derumeaux G, et al. Diastolic asynchrony is more frequent than systolic asynchrony in dilated cardiomyopathy and is less improved by cardiac resynchronization therapy. J Am Coll Cardiol 2005; 46: 2250–2257. Bader H, Garrigue S, Lafitte S, Reuter S, Jaïs P, Haïssaguerre M, et al. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol 2004; 43: 248–256 Ghio S, Freemantle N, Serio A, Magrini G, Scelsi L, Pasotti M, et al. Baseline echocardiographic characteristics of heart failure patients enrolled in a large European multicentre trial (CArdiac REsynchronisation Heart Failure study). Eur J Echocardiogr 2006; 7: 373–378. Ghio S, Constantin C, Klersy C, Serio A, Fontana A, Campana C, et al. Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur Heart J 2004; 25: 571–578. The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Guidelines for cardiac pacing and cardiac resynchronization therapy Europace 2007; 10: 959–998. Perez de Isla L, Florit J, Garcia-Fernandez MA, Evangelista A, Zamorano J. Prevalence of echocardiographically detected ventricular asynchrony in patients with left ventricular systolic dysfunction. J Am Soc Echocardiogr 2005; 18: 850–859. Penicka M, Bartunek J, De Bruyne B, Vanderheyden M, Goethals M, De Zutter M, et al. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004; 109: 978–983.
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Different lipid profiles according to ethnicity in the Heart of Soweto study cohort of de novo presentations of heart disease KAREN SLIWA, JASMINE G LYONS, MELINDA J CARRINGTON, SANDRINE LECOUR, A DAVID MARAIS, FREDERICK J RAAL, SIMON STEWART
Abstract Background: Historically, sub-Saharan Africa has reported low levels of atherosclerotic cardiovascular disease (CVD). However as these populations undergo epidemiological transition, this may change. Methods: This was an observational cohort study performed at Chris Hani Baragwanath Hospital in Soweto, South Africa. As part of the Heart of Soweto study, a clinical registry captured detailed clinical data on all de novo cases of structural and functional heart disease presenting to the Cardiology unit during the period 2006 to 2008. We examined fasting lipid profiles in 2 182 patients (of 5 328 total cases) according to self-reported ethnicity. The study cohort comprised 1 823 patients of African descent (61% female, aged 56 ± 16 years), 142 white Europeans (36% female, aged 57 ± 13 years), 133 Indians (51% female, aged 59 ± 12 years) and 87 of mixed ancestry (40% female, aged 56 ± 12 years). Results: Consistent with different patterns in heart disease aetiology, there were clear differences in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides across ethnicities (p < 0.001): patients of African descent had the lowest TC and LDL-C levels and Indians the highest. However, there were no significant differences in high-density lipoprotein cholesterol (HDL-C) levels between ethnicities (p = 0.20). Adjusting for age, gender and body
Hatter Institute for Cardiovascular Research in Africa and IIDMM, Faculty of Health Sciences, University of Cape Town, South Africa KAREN SLIWA, MD, PhD SANDRINE LECOUR, Pharm D, PhD
Soweto Cardiovascular Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa KAREN SLIWA, MD, PhD MELINDA J CARRINGTON, PhD SIMON STEWART, PhD
Baker IDI Heart and Diabetes Institute, Melbourne, Australia JASMINE G LYONS, BA, BSc (Hons) MELINDA J CARRINGTON, PhD SIMON STEWART, PhD, simon.stewart@bakeridi.edu.au
Department of Internal Medicine, Groote Schuur Hospital, Observatory, Cape Town, South Africa A DAVID MARAIS, FCPSA
Carbohydrate and Lipid Metabolism Research Unit, University of the Witwatersrand, Johannesburg, South Africa FREDERICK J RAAL, MD, PhD
mass index, patients of African descent were significantly less likely to record a TC of > 4.5 mmol/l (OR 0.33, 95% CI: 0.25–0.41) compared to all ethnic groups (all p < 0.001). Conclusions: These data confirm important blood lipid differentials according to ethnicity in patients diagnosed with heart disease in Soweto, South Africa. Such disparities in CVD risk factors may justify the use of specialised prevention and management protocols. Keywords: Africa, heart disease, lipids, ethnicity/race, epidemiologic transition Submitted 3/2/12, accepted 2/5/12 Cardiovasc J Afr 2012; 23: 389–395
www.cvja.co.za
DOI: 10.5830/CVJA-2012-036
The historical distribution of risk and communicable versus non-communicable forms of cardiovascular disease (CVD), particularly its major component heart disease, reflects the influence of cultural and ethnic factors.1 Historically, low levels of atherosclerotic CVD in populations of African descent were, in part, attributed to low levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) and high levels of high-density lipoprotein (HDL-C).2,3 Indeed, it appears a great deal of the burden of CVD in those of African descent can be attributed to hypertension, rather than dyslipidaemia.4 However, other ethnic groups, such as South Asians, have been shown to be more prone to the high levels of TC and TG and low HDL-C dyslipidaemia, associated with atherosclerotic forms of CVD.5 While a significant proportion of the excess risk of CVD in certain ethnic groups can be explained by environmental, nutritional and lifestyle factors, they do not fully account for such disparities. In order to apply appropriate CVD preventative and management strategies, it is crucial to understand the underlying processes that vary between ethnic groups, especially in settings where the burden of CVD is rapidly increasing. In sub-Saharan African communities, such as the urban enclave of Soweto, South Africa, there is clear evidence that the historical balance between communicable and non-communicable forms of heart disease is in epidemiological transition.6 The Heart of Soweto study of more than 5 000 de novo presentations of heart disease to the Baragwanath Hospital involved patients from an eclectic mix of cultural and ethnic backgrounds and the pattern of heart disease differed accordingly. We sought to determine if there were differences in the lipid profiles (and other major CVD risk factors) of patients with de novo presentations of heart disease in Soweto, South Africa according to ethnicity and whether these were independent of socio-economic profile.
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As described in detail previously, the 3 500-bed Chris Hani Baragwanath Hospital (case load of > 125 000 in-patients per annum) services the tertiary care needs of Soweto (population of 1.1 million) and surrounding communities. All cases of suspected heart disease are referred to the Hospital’s Cardiology unit for advanced diagnostic testing and gold-standard treatments. This prospective clinical registry of all de novo presentations (2006–2008) as part of the Heart of Soweto study7 represents sub-Saharan Africa’s largest and most detailed study of advanced forms of heart disease to date.6,7 The Heart of Soweto cohort of de novo case presentations comprised 5 328 patients. Of these, 2 185 (40%) patients simultaneously had a fasting serum TC level performed (as analysed by on-site routine chemistry laboratory). Of these, there were 1 964 cases with recorded LDL-C levels (90%), 1 996 with HDL-C levels (91%) and 1 969 with TG levels (90%). Complete lipid profiles were available for 1 945 cases (89%). None of the patients were on lipid-lowering agents at the time of presentation, as this medication would only be prescribed at the tertiary institution at the time of the study. Overall, 518 of 5 328 de novo cases of heart disease were identified as HIV positive (9.7%) with 54% of these prescribed highly active anti-retroviral therapies on presentation.8 In this sub-study, 116 participants (5.3%) were confirmed HIV positive. Some of the patients had been placed on anti-hypertensive medication prior to their first assessment at the cardiac clinic at Baragwanath Hospital. The study was approved by the University of the Witwatersrand Ethical Committee and conforms to the principles outlined in the Declaration of Helsinki. A complete list of study data captured by the registry, comprising basic socio-demographic (including self-reported ethnicity, years of education, and determination of birthplace as Soweto) and advanced clinical profiling has been described previously.6,7 The registry captured all advanced clinical investigative procedures (e.g. coronary angiography, which was undertaken in all people diagnosed with coronary artery disease). Echocardiography (performed on all patients) criteria used in the study have been described in detail previously.6,7 6,7
Risk factor definition Previous reports provide a range of thresholds for dyslipidaemia in African populations (e.g. a TC level from > 3.8 mmol/l9 to > 5.2 mmol/l).10 In this study, optimum lipid levels and treatment goals for patients with established CVD and associated conditions were defined according to European guidelines on cardiovascular disease prevention in clinical practice,11 as adopted by the Lipid and Atherosclerosis Society of South Africa and the South African Heart Association:12 high TC: > 4.5 mmol/l, high TGs: > 1.7 mmol/l and low HDL-C: < 1.0 mmol/l for males and < 1.2 mmol/l for females. Importantly, these guidelines echo the recommended LDL-C level of > 2.5 mmol/l as set by NCEP ATP III.13 Other risk factors for cardiovascular disease were measured, as previously described, on a clinical basis.7 As described in a previous report, hypertensive patients were identified on the basis of a documented blood pressure (BP) of ≥ 140/90 mmHg and/ or prescribed antihypertensive treatment. In both the cardiology unit and primary care clinics, BP was assessed following five minutes’ rest; seated systolic (SBP) and diastolic (DBP)
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blood pressure (in mmHg) and heart rate (beats per minute) measurements were performed using an appropriately sized arm cuff via a calibrated Dynamap (Critikon, Johannesburg, South Africa) monitor. The mean of three successive readings, each separated by two minutes’ rest, was taken. Anthropometric measurements were available for calculation of body mass index (BMI, kg/m2) in 1 593 (73%) cases, the low reporting rate restricted to ambulatory patients. Obesity was defined as BMI ≥ 30 kg/m2. Serum C-reactive protein (CRP) was measured in a sub-set of 664 patients (30% of all cases) if clinically indicated (e.g. suspected infection). Patients were stratified into risk tertiles.14 However, as levels of < 1.0 mg/l were not reported, we have used patients with a CRP of 1.0 mg/l (n = 40) as our ‘low-risk’ reference group for this parameter. This group was then compared to medium (1.1–3.0 mg/l, n = 50) and high (> 3.0 mg/l, n = 567) CRP risk categories. Due to incomplete data to formally assess the presence of familial hypercholesterolaemia (FH) according to the Dutch Lipid Clinic Network criteria,15 we examined the proportion of patients with an LDL-C ≥ 4.9 mmol/l and/or TC ≥ 7.5 mmol/l to determine potential cases of FH.
Statistical analyses Normally distributed continuous data are presented as the mean ± standard deviation, and non-Gaussian distributed variables as the median (inter-quartile range). Categorical data are presented as percentages with 95% confidence intervals (CI) where appropriate. For group comparisons, we initially used Chi square (χ2) analysis with calculation of odds ratios (OR) and 95% CI (where appropriate) for discrete variables, and one-way analysis of variance (ANOVA) for normally distributed continuous variables, and Kruskal-Wallis test for non-parametric continuous variables, with Tukey’s post hoc tests. Multiple logistic regression analyses (entry model) were used to derive age-, gender- and BMI-adjusted ORs for the risk of presenting with dyslipidaemia. Owing to the lower sample sizes of white Europeans, mixedancestry patients and Indians, these data were pooled when calculating ORs, relative to individuals of African descent. Significance was accepted at the two-sided level of p < 0.05 and p < 0.01 (Bonferroni correction) for ANOVA and KruskalWallis analyses.
Results Table 1 shows the socio-demographic and clinical profiles of this cohort according to ethnicity. While there were no differences in mean age across ethnicities, there were significant differences in the proportion of females; ranging from 61% in those of African descent to 36% in white Europeans. Overall, compared to all other ethnicities, African patients were more likely to be obese (OR 1.56, 95% CI: 1.15–2.13, p < 0.01 in age- and genderadjusted model) and have fewer than six years’ education (OR 1.72, 95% CI: 1.28–2.31, p < 0.0001). White European patients recorded the lowest prevalence of poor education (23%) but higher rates of smoking; when compared to patients of African descent, white Europeans were three-fold more likely to be current smokers (OR 3.4, 95% CI: 1.86–5.64, p < 0.001). Patients of mixed ancestry were twice as likely to be current smokers than patients of African descent (OR
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TABLE 1. CLINICAL AND DEMOGRAPHIC PROFILE ACCORDING TO ETHNICITY African descent (n = 1823)
White European (n = 142)
Mixed ancestry (n = 87)
Indian (n = 133)
p-value Demographic profile Mean age (years) 56.2 ± 15.8 57.3 ± 12.7 55.7 ± 12.1 58.6 ± 11.9 0.29 Female 1104 (61%) 51 (36%) 35 (40%) 68 (51%) < 0.001 < 6 years’ formal education 856 (47%) 33 (23%) 31 (36%) 71 (53%) < 0.001 Soweto origin 856 (47%) 2 (1%) 2 (2%) 0 (0%) < 0.001 Clinical presentation Total cholesterol (mmol/l) 4.1 ± 1.3 4.6 ± 1.3*** 4.8 ± 1.3*** 5.0 ± 1.1***^ < 0.001 Low-density lipoprotein cholesterol (mmol/l) 2.4 ± 1.0 2.7 ± 1.0* 2.8 ± 1.1* 3.0 ± 1.0*** < 0.001 High-density lipoprotein cholesterol (mmol/l) 1.2 ± 0.5 1.2 ± 0.5 1.2 ± 0.5 1.2 ± 0.4 0.24 < 0.001 Median triglycerides (mmol/l) 1.1 (0.8–1.6) 1.4 (1.0–2.1) *** 1.4 (0.9–1.9)** 1.8 (1.2–2.7) ***^# Median serum CRP (n = 664, mg/l) 16.6 (6.2–83.9) 27.0 (8.0–98.0) 25.0 (6.3–50.2) 7.9 (2.7–27.0) 0.03 Systolic blood pressure (mmHg) 136.6 ± 28.2 130.1 ± 27.1* 133.7 ± 25.9 133.8 ± 24.0 0.05 Diastolic blood pressure (mmHg) 77.8 ± 15.4 72.8 ± 12.8 * 75.8 ± 15.0 73.7 ± 12.2* < 0.001 29.7 ± 7.5 29.7 ± 9.8 25.6 ± 7.1*^^ 28.2 ± 5.7 < 0.001 Body mass index (n = 1593, kg/m2) Prevalence of dyslipidaemia High total cholesterol (mmol/l) 715 (39%) 76 (54%) 52 (60%) 93 (70%) < 0.001 High low-density lipoprotein cholesterol (mmol/l) 718 (44%) 68 (55%) 47 (60%) 85 (72%) < 0.001 High triglycerides (mmol/l) 386 (23%) 44 (36%) 33 (41%) 66 (56%) < 0.001 Low high-density lipoprotein cholesterol (mmol/l) 1044 (63%) 86 (66%) 47 (57%) 74 (62%) 0.58 Prevalence of other risk factors 579 (43%) 31 (37%) 12 (19%) 29 (30%) < 0.001 Obese (> 30 kg/m2) Type 2 diabetes 164 (9%) 9 (6%) 6 (7%) 18 (14%) 0.34 Current smoker 833 (46%) 104 (73%) 63 (72%) 57 (43%) < 0.001 Family history of CVD 765 (42%) 71 (50%) 34 (39%) 88 (66%) < 0.001 Primary diagnosis Hypertension 380 (21%) 15 (11%) 23 (26%) 33 (25%) 0.42 Hypertensive heart failure 525 (29%) 14 (10%) 14 (16%) 22 (17%) < 0.001 Coronary artery disease 179 (10%) 74 (52%) 23 (26%) 61 (46%) < 0.001 CRP = C-reactive protein; CVD = cardiovascular disease; median (interquartile range); Kruskal-Wallis test performed. Tukey’s post-hoc tests: *p < 0.05; **p < 0.01; ***p < 0.001 compared to African descent. ^p < 0.05; ^^p < 0.01 compared to white Europeans; ##p < 0.01 compared to mixed ancestry.
1.91, 95% CI: 1.08–3.36, p = 0.03). Indian patients were most likely to report a family history of heart disease (66% of patients, OR 3.96, 95% CI: 2.46–6.37, p < 0.001 compared to African descent). There were no significant differences between ethnicities in diabetes co-morbidity, despite a relatively high prevalence in Indian patients (14% compared to 9% in all other ethnic groups; p = 0.08). African patients were significantly more likely to be diagnosed with hypertensive heart failure (HT-HF) (OR 2.14, 95% CI: 1.48–3.11) and least likely to be diagnosed with coronary artery disease (CAD) (OR 0.16, 95% CI: 0.12–0.22, p < 0.001 for both). Despite representing only 12% of patients in this sub-study, white Europeans and Indian patients accounted for 40% of all primary diagnoses of CAD.
Lipid profiles There were significant (unadjusted) differences in lipid profiles across ethnicities with increasing gradients in TC, LDL-C and TG levels (all p < 0.001), however there were no differences observed between ethnicities in HDL-C values (p = 0.24) (Fig. 1). Overall, females had higher HDL-C values than males: 1.21 ± 0.50 vs 1.09 ± 0.50 mmol/l (p < 0.0001). While females had higher HDL-C levels than males in the African (p < 0.001),
white European (p = 0.04) and Indian (p = 0.01) groups, there was no difference in HDL-C levels in those of mixed ancestry: 1.33 ± 0.42 mmol/l in females vs 1.19 ± 0.60 mmol/l in males (p = 0.23). When compared to other ethnicities (pooled analyses), patients of African descent had significantly lower TC, LDL-C and TG levels (p < 0.01 for all comparisons). African patients were significantly less likely to have high TC (OR 0.33, 95% CI: 0.25–0.44), high LDL-C (OR 0.34; 95% CI: 0.25–0.47) and high TG levels (OR 0.37, 95% CI: 0.27–0.50) compared to other ethnicities (all p < 0.001). In gender- and age-adjusted linear regression models, BMI was positively but modestly associated with TC, LDL-C and TG levels (all p < 0.01). The estimated mean increase in TC level was 0.09 mmol/l (95% CI: 0.01–0.85; p < 0.0001) for a 5-kg/ m2 increase in BMI, while LDL-C increased 0.05 mmol/l for the same change in BMI (95% CI: 0.03–0.1, p = 0.002). There was also a positive association between TG values and BMI; a 5-kg/m2 increase in BMI was associated with a mean 0.07-mmol/l increase in TG level (95% CI: 0.04–0.1, p < 0.001). There was no association between BMI and HDL-C level (p = 0.8). Table 2 shows the independent predictors of dyslipidaemia in this cohort. Female gender was a positive predictor for high TC levels and females were less likely to have a low HDL-C value.
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200
250
200
Frequency
Frequency
150
100
African descent
150
100
African descent
White European
50
White European
50
Mixed ancestry
Mixed ancestry
Indian 0
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1.0
3.0
5.0
7.0
9.0
0
11.0
Indian .00
Plasma cholesterol (mmol/l)
2.00
4.00
6.00
8.00
Plasma LDL (mmol/l)
300
Frequency
Frequency
300
200
100
200
African descent
100
African descent
White European
White European
Mixed ancestry
Mixed ancestry 0
Indian .00
1.00
2.00
3.00
4.00
Plasma HDL (mmol/l)
0
Indian .01
2.01
4.01
6.01
Plasma triglycerides (mmol/l)
Fig. 1. Frequency distribution of lipid levels according to ethnicity. Lipid levels (mmol/l): mean (± standard deviation) in A, B and C. Median (inter-quartile range) for triglycerides (D). TC = total cholesterol; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.
Patients with poor education (< six years of formal education) were more likely to have lower lipid levels. The effect of urban upbringing versus migration (typically rural to urban) on dyslipidaemia in this cohort was not apparent; Soweto origin was not related to high TC and LDL-C or low HDL-C levels. However the effect of ethnicity on dyslipidaemia was apparent: compared to patients of African descent, white European, mixedancestry and Indian patients were two-, three- and four-fold more likely to have high TC levels, respectively. These lipid gradients, ranked across ethnicities, persisted for high LDL-C and high TG levels in age-, gender- and BMI-adjusted models; white European (OR 1.58, 95% CI: 0.92–2.69; p = 0.10), mixed-ancestry (OR 2.57, 95% CI: 1.50–4.39; p = 0.001) and Indian (OR 4.33 95% CI: 2.75–6.83; p < 0.0001) patients were
all more likely to have high TG levels compared to patients of African descent. Ethnicity was not associated with low HDL-C levels (Table 2). While current smokers were 1.5-fold more likely to have low HDL-C levels (OR 1.47, 95% CI: 1.17–1.85, p = 0.001), diabetes co-morbidity was not associated with low HDL-C (p = 0.3). CRP was only measured in a limited number of patients. However, subgroup analysis showed that serum CRP was strongly associated with low HDL-C: in age- and genderadjusted models, patients in the medium- (OR 3.17, 95% CI: 1.10–9.12; p = 0.03) and high-risk CRP groups (OR 5.58, 95% CI: 2.34–13.31; p < 0.001) were more likely to have low HDL-C levels compared to the low-risk reference group (i.e. those with a CRP of 1.0 mg/l). There was no association between
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TABLE 2. INDEPENDENT CORRELATES OF HIGH SERUM TOTAL CHOLESTEROL, HIGH LOW-DENSITY LIPOPROTEIN AND LOW HIGH-DENSITY LIPOPROTEIN CHOLESTEROL High TC Odds Ratio 95% CI
High LDL-C Odds Ratio 95% CI
Low HDL-C Odds Ratio 95% CI
Socio-demographic profile Female gender 1.39 1.12–1.72* 1.26 0.98–1.62 0.59 0.46–0.74** Age 1.00 1.00–1.01 1.00 1.00–1.01 0.99 0.98–0.99** < 6 years’ formal education 0.68 0.56–0.84** 0.74 0.59–0.92* 1.56 1.24–1.96** Soweto origin 0.83 0.67–1.02 0.86 0.69–1.07 0.93 0.74–1.15 Diabetes comorbidity 1.0 0.72–1.38 0.99 0.70–1.40 1.23 0.86–1.77 Current smoker 0.72 0.58–0.89** 0.68 0.54–0.85** 1.47 1.17–1.85** Ethnicity African ancestry (reference) 1.0 – 1.0 – 1.0 – White European 2.17 1.36–3.46* 2.10 1.27–3.47* 1.01 0.61–1.68 Mixed ancestry 3.04 1.79–5.15** 2.44 1.41–4.22* 0.71 0.42–1.20 Indian 4.15 2.61–6.60** 4.66 2.72–7.97** 1.00 0.63–1.59 TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; CI = confidence intervals. Age-, gender- and body mass index-adjusted analysis: *p < 0.01; **p < 0.001.
CRP and high TC, LDL-C or TG levels. Overall, 43 patients (2.2% of cohort with LDL-C levels measured) recorded an LDL-C ≥ 4.9 mmol/l, and 32 patients (1.8% with TC levels measured) had TC ≥ 7.5 mmol/l. A total of 56 patients (2.6%), comprising 43 of African descent (2.4% of ethnic group), six white Europeans (4.2%), three of mixed ancestry (3.4%) and four Indians (3.0%) had either elevated LDL-C or TC levels, suggestive of FH.
Discussion This study provides important insights into the lipid profiles according to ethnicity of more than 2 000 de novo cases of heart disease in Soweto, South Africa. We found significant gradients in lipid levels on this basis. Patients of African descent had the lowest, and Indians the highest TC, LDL-C and TG levels. These gradients in TC and LDL-C levels were particularly distinct in their magnitude and may represent clinically important differences for the development of atherosclerosis (see below). However, HDL-C levels did not differ across ethnic groups. Therefore the assumed protective role of HDL-C in the African population was not evident beyond cases of CAD (where African patients were under-represented). Overall, there were important differences in the risk factor and clinical profile of cases according to ethnicity. Irrespective of the relatively low levels of TC, low HDL-C was widespread, affecting nearly two-thirds (63%) of this cohort. This was surprising when considering the proportion affected with high TC (43%), LDL-C (47%) and TG (27%) levels. As a strong, independent predictor of CVD,16 this phenomenon of low HDL-C levels represents a potentially important therapeutic target for truncating an increasing burden of atherosclerotic disease in urban, sub-Saharan African communities. It is possible that an acute-phase response could lower HDL-C levels in most instances and may account for the reciprocal relationship found between CRP and HDL-C. Our observations in respect of ethnic differentials in lipid profiles are broadly consistent with prior studies in the region.9,17-20 Previous research has shown that those of African descent display an athero-protective lipid profile compared to white Europeans and Indians.5 Similarly, the INTERHEART Africa
case–control study (which investigated risk factors associated with first-time myocardial infarction) showed no difference in HDL-C levels between those of African descent, mixed-ancestry and European/other African groups.18 However, fewer than 200 cases were of African descent. Norman and colleagues reported in 2000 that cholesterolattributable mortality rates were highest in the Indian population of South Africa (at 22.2%), followed by white European (20.5%) and mixed-ancestry (8.8%) populations.9 By comparison, mortality attributable to ‘sub-optimal’ lipid levels (defined as TC ≥ 3.8 mmol/l) in those of African descent was only 1.8%, which reflected low TC levels compared to other ethnicities.9 Nonetheless, varied reports show that dramatic increases in mean TC levels have occurred in the past four decades,19,20 while HDL-C levels have decreased,21,22 both of which may be contributing to the increase in CAD prevalence over a similar time period.2 It is likely that the continued influences of epidemiological transition (giving rise to extensive urbanisation, Western diet and sedentary lifestyle) will continue to fuel these patterns.23 The prevalence of FH in African populations is unknown but is probably about 1:500, as has been reported in most other populations studied worldwide. South Africa has several communities in which there are founder effects that increase the prevalence of FH, including the Afrikaner, Jewish and Indian communities. Several LDL-C receptor errors have been identified in patients of mixed ancestry.24 In this cohort, genetic disorders such as FH were unlikely to be a major contributor to de novo presentations of heart disease, given the small number of probable/possible cases of the same (2.3%). Mixed hyperlipidaemia that could relate to an uncommon mutation in apoE in those of African descent was also not suspected. Examining the potential impact of migration on CVD and its risk factors may be helpful in understanding ethnic differences in the relative incidence of CVD in different African populations.25 In our multivariate analyses, urban (Soweto) origin was not associated with high TC or LDL-C, or low HDL-C levels. This was similar to a study on adults of the Cape Peninsula,26 in which measures of urbanisation had no effect on TC levels per se; rather, it was clusters of risk factors that corresponded with increased time residing in an urban setting.
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We identified more than six years of formal education as being independently predictive of high TC and LDL-C, and low HDL-C levels, which corresponds to other findings from the Heart of Soweto study.6 These results may indicate a progression in income/socio-economic status, enabling greater access to a Western diet and increased tendency for sedentary behaviour,27 especially in women.23 However, we have shown that the ethnicbased patterns of dyslipidaemia presented in this report persisted even after controlling for BMI. This important finding alludes to the influence of other factors that contribute to the presentation of heart disease and its risk factors. Other factors, such as very low TG levels,3 and novel factors unrelated to dyslipidaemia (such as more effective homocysteine metabolism),28 may confer relative protection against atherosclerotic heart disease in African populations. Patterns of hypertension and obesity, which persist even in migrated African populations,3 may suggest predisposing factors. However, the case for attributing genetic susceptibility to heart disease solely on the basis of ‘race/ethnicity’ is proving increasingly futile.29 In this study, we could clearly discount monogenic disorders of lipoproteins as the cause of lipid differentials across ethnicities, as they were uncommon. We have seen features of dyslipidaemia change in these populations over time,20-22 especially with regard to HDL-C levels. It is more likely that risk factors that can influence lipids, particularly obesity and its antecedents (poor diet and lack of physical activity),23 are driving the patterns of dyslipidaemia reported here. Relying on genetic susceptibility to explain ethnic differences in lipids, without recognising the role of gene–environment interaction in CVD risk will only prove counterproductive in addressing current prevention and management of CVD. Given that dyslipidaemia does not occur in isolation, future work should focus on likely contributors to these trends, irrespective of ethnicity. Insulin resistance or the metabolic syndrome dyslipidaemia is strongly associated with atherosclerotic CVD and may play a role in the consistently low HDL-C levels across ethnic groups, as reported here. In Indian patients, the prevalence of diabetes was 18%, which may contribute to the high rates of CAD in this group (half of primary diagnoses in those of Indian ethnicity), an association that has been shown previously.5 Despite a lower prevalence of diabetes in other ethnicities, overall high obesity rates in this cohort will likely contribute to an increased prevalence of both insulin resistance and diabetes in coming generations.23,30 Additionally, we found an inverse association between the inflammatory marker CRP and HDL-C levels in those whom the inflammatory marker was measured. Despite the subset representing only 30% of those with a reported lipid profile, the negative association was striking and may indicate enhanced CVD risk beyond other clinical risk factors.14 Therefore, the possible contribution of chronic, low-grade inflammation to dyslipidaemia warrants additional investigation, as it is associated with both chronic infection and atherosclerotic CVD.14 There are a number of limitations that require consideration. Clinical data (other than routine echocardiography and 12-lead ECG) were obtained according to clinical presentation and only those with suspected atherosclerotic disease had lipid levels measured. Systematic bias, therefore, needs to be carefully considered before attributing broad patterns in lipid profiles
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according to ethnicity and may overestimate the utility of measuring/treating dyslipidaemia within the wider community. Adiposity (BMI), a major confounder of both dyslipidaemia and heart disease, was recorded in 73% of patients in this cohort. However, its inclusion in the regression analyses did not alter the significant findings. Central obesity measurements (e.g. waistto-hip ratio) may have offered greater delineation of CVD risk, given its strong association with low HDL-C levels, particularly in women of African descent,10 however this was an impractical variable to obtain consistently, given the nature of the study setting. CRP was only measured in around one-third of selected cases and related data require careful interpretation.
Conclusion Differences in CVD risk factors, especially lipid profiles, were apparent in the ethnically diverse enclave of Soweto in South Africa. We have shown that while dyslipidaemia is an important risk factor in heart disease presentation, overall, disparities exist in the extent of lipid abnormalities. Significantly, low HDL-C levels persisted in all ethnicities. These trends have important public health and clinical implications that require further consideration. While there are inherent limitations in the interpretation of racial and ethnic comparisons, irrespective of the healthcare setting, rational approaches to secondary prevention of heart disease may require a diversity of strategies because of these ethnic differences. We thank all the doctors, nurses and patients who participated in the registry; and Elisabeth Tshele, Bridget Phooko, Maureen Kubheka and Phutuma Mathusi who contributed to the meticulous collection and management of clinical data. The Heart of Soweto registry was supported by the University of the Witwatersrand and unconditional research grants from Adcock-Ingram, the Medtronic Foundation USA, Servier, Bayer Health Care and BHP Billiton. SS, MJC and JGL are supported by the National Health and Medical Research Council of Australia. JGL is supported by the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand. This work was supported by the Victorian Government’s OIS Program.
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Effect of perindopril on pulse-wave velocity and endothelin-1 in black hypertensive patients ELZBIETA OSUCH, WILLEM J DU PLOOY, SANDRA H DU PLOOY, LINDE H BÖHMER
Abstract Introduction: We investigated the effect of perindopril on pulse-wave velocity (as indicator of arterial elasticity) and endothelin-1 (ET-1) levels in black hypertensive patients. Methods: Forty-four newly diagnosed hypertensive patients who received 4 mg perindopril daily were monitored for nine months. Pulse-wave velocity (PWV) was measured noninvasively along the carotid–femoral arterial segment (high elastic content) and the brachial–ulnar segment (low elastic content). Results: There was a significant increase in arterial elasticity, as indicated by a slower PWV in the carotid–femoral segment of the treatment group, from 11.6 to 7.5 m/s after nine months. The PWV of the treatment group (7.5 m/s) after nine months was lower than that of the healthy volunteer group (8.2 m/s) but it was not statistically significant. No correlation between ET-1 and PWV could be found. Conclusion: In addition to its blood pressure-lowering effect, our study confirmed the improvement in arterial elasticity in patients on perindopril therapy, without involvement of ET-1. Keywords: arterial elasticity, pulse-wave velocity, perindopril, endothelin-1, hypertension Submitted 20/1/12, accepted 3/5/12 Cardiovasc J Afr 2012; 23: 396–399
www.cvja.co.za
DOI: 10.5830/CVJA-2012-043
Pulse-wave velocity (PWV) has become the standard for measuring arterial elasticity or stiffness.1,2 A higher PWV indicates decreased elasticity. The elasticity of the larger arteries ensures a dampening of the pulse wave and it is stored as recoil energy to ensure continuous blood flow, with better perfusion.3 PWV was found to be higher in patients with sustained essential hypertension compared to normotensives subjects.4 Decreased arterial elasticity and endothelial dysfunction are associated with end-organ damage and, together with pulse pressure, are independent predictors of cardiovascular risk in hypertensive patients.5-7 Therefore, besides lowering blood pressure, structural and functional vascular properties have become important.1,8 Department of Pharmacology and Therapeutics, School of Medicine, MEDUNSA Campus, University of Limpopo, South Africa
ELZBIETA OSUCH, MB ChB, PhD (Pharmacol), MSc (Med) (Pharmacol), Dip Fam Med WILLEM J DU PLOOY, PhD, FCP (ACCP), BSc (Hons) (Pharmacol), Dip Intl Bio-ethics, wim.duplooy@ul.ac.za
Department of Physiology, School of Medicine, MEDUNSA Campus, University of Limpopo, South Africa SANDRA H DU PLOOY, MSc LINDE H BÖHMER, PhD
Only a few studies, however, have reported the effect of different drug therapies on abnormal arterial elasticity. The methods differed widely and the patient numbers varied between 10 and 20.9,10 In the Complior® study, 4 mg perindopril daily over six months showed an improvement in arterial elasticity.11 In patients with congestive heart failure it has been shown that captopril decreased endothelin production.12 It has also been shown that increased endothelin-1 (ET-1) was associated with decreased arterial elasticity in hypertensive patients.13 In this study we investigated the effect of a nine-month treatment of the angiotensin converting enzyme inhibitor (ACEI) perindopril on arterial elasticity, brachial pulse pressure and the role of ET-1 in black hypertensive patients.
Methods Newly diagnosed hypertensive patients with a diastolic pressure of > 85 mmHg and/or a systolic pressure of > 135 mmHg were enrolled in the study. Only treatment-naïve patients were admitted into the trial, after informed consent was obtained. Patients with secondary hypertension or any concomitant disease were excluded from the study. Those who needed any treatment other than 4 mg of perindopril to control their hypertension were excluded. Patients who were on any chronic or acute medication were also excluded. Forty-four patients received 4 mg of perindopril daily for a period of nine months. Fifty-one healthy volunteers served as a reference group. PWV was used as a surrogate indicator of arterial elasticity and was measured non-invasively using a Powerlab 4 SP system (AD Instruments Pty, Ltd, Australia) and connected to a desktop computer. PWV was measured along two segments of the arterial tree, the carotid–femoral segment (representing an arterial segment with a high elastic content) and the brachial–ulnar segment (representing an arterial segment with little elastic content). The carotid–femoral PWV was calculated from the time delay (∆t) between the recorded proximal (carotid) and distal (femoral) beginning of the upstroke of the wave, and the distance (∆d) separating the two respective transducers, according to the equation: ∆d ∆t
speed (v) = ___ Peripheral pulses were detected by miniature infrared plethysmo-Doppler sensors. The same operator placed the sensors, to limit bias. Each recording lasted for 15 seconds and the average of five consecutive pulses was used. Baseline values for volunteers and patients were recorded on three occasions prior to commencement of the study. Blood pressure was measured using calibrated non-invasive blood pressure (NIBP) equipment (Welch Allyn, Model 5200103A). Other parameters and measurements included pulse pressure, body mass index (BMI) and lead II of an ECG.
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Endothelin-1 was measured using an 125I immuno-assay radioactive ligand system (Amersham Biosciences International, South Africa, Cat no RPA 555). Briefly, the assay is based on the competition between unlabelled ET-1 and a fixed quantity of 125 I-labelled ET-3 (synthetic) for a limited number of binding sites on an ET-1-specific antibody. With fixed amounts of antibody and radioactive ligand, the amount of radioactive ligand bound by the antibody is inversely proportional to the concentration of the added non-radioactive ligand. The antibody-bound ET-1 is then reacted with a second antibody that is bound to magnetisable polymer particles. Separation of the antibody-bound fraction is effected by centrifugation of the suspension and decantation of the supernatant. Measurement of the radioactivity in the pellet enables the amount of labelled ET-3 in the bound fraction to be calculated. The concentration of the unlabelled ET-1 in the sample was determined from a standard curve. All samples were done in triplicate. Venous blood (5 ml) was collected into heparinised tubes and centrifuged immediately at 2 000 × g for 10 minutes at 4°C to remove the cells, after which the plasma was stored at –70°C for later analysis. Samples were then prepared and analysed according to the manufacturer’s instructions. Blood was also collected for routine blood analysis, including renin, aldosterone, cholesterol, glucose and electrolyte levels, and liver function. In the hypertensive patients all measurements were done and blood samples collected at baseline (before therapy), and after one, three, six and nine months of therapy.
Statistical analysis Analysis of variance (applying the Bonferroni principle) was used to determine intra-group variations at the different intervals. Comparisons between the control (healthy volunteers) and the experimental group (treatment-naïve patients) were done using the Mann-Whitney rank sum test. A p-value of < 0.05 was considered significant. Pearson’s coefficient was used to determine correlations between PWV, ET-1 levels and the other parameters. Descriptive statistics were given as median (1st quartile–3rd quartile). The study was approved by the Medunsa Research Ethics Committee of the University of Limpopo, IRB 00005122.
Results Of the 44 newly diagnosed hypertensive patients, 14 were male
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and 30 female, aged 50.4 ± 7.6 years, whereas in the control group, 19 were male and 32 female, aged 43.2 ± 8.3 years. The BMI at the beginning of the study period was 28 ± 6.9 kg/m2 for the control group and 31.5 ± 6.9 kg/m2 for the patient group. Five patients were regarded as lost to follow up, of whom three did not respond to perindopril alone and were give 2.5 mg indapamide, and three patients developed a dry cough. Thirty-nine patients completed the nine-month period on 4 mg perindopril. There was a significant decrease in systolic, diastolic and mean arterial pressure in the treatment group at each visit compared to baseline, but pulse pressure did not change. Values never reached the same level as those of the control group (Table 1). There was a significant continuous reduction in PWV that could indicate an increase in arterial elasticity in the carotid– femoral segment of the treatment group, from a median of 11.6 to 7.5 m/s over the nine-month period. The PWV of the treatment group (median 7.5 m/s) after nine months was lower than that of the healthy volunteer group (median 8.2 m/s) but was not statistically significant (Table 2). Although the absolute values of the PWV in the brachial– ulnar segment of the treatment group decreased over time, it was not significant. After the nine-month treatment, the average value was lower than that of the healthy volunteer group. The median PWV in the brachial–ulnar segment at all treatment intervals was lower than that of the carotid–femoral segment (Table 2). All values are given as median (1st–3rd quartile). ET-1 levels in the treatment group first increased from 6.15 (3.5–7.89) pmol/l at baseline to reach a maximum of 8.15 (5.32–9.63) pmol/l after six months but it was not significant. They then decreased to 4.53 (3.68–9.2) pmol/l after nine months. The ET-1 levels of the treatment group after nine months were lower than those of the healthy volunteer group but it was not significant. The baseline level of ET-1 in the treatment group was significantly higher [6.15 (3.5–7.89) pmol/l] than that of the healthy volunteer group [4.69 (3.0–5.4) pmol/l] (Table 2). Neither BMI nor other routine blood tests changed during the nine-month study period.
Discussion In this study we investigated the effect of a nine-month treatment with the ACE inhibitor perindopril on PWV and the role of ET-1 in black hypertensive patients. PWV was used as a surrogate to
TABLE 1. EFFECT OF PERINDOPRIL 4 MG DAILY ON BLOOD PRESSURE IN BLACK HYPERTENSIVE PATIENTS AFTER A NINE-MONTH TREATMENT COMPARED TO HEALTHY VOLUNTEERS Patients (n = 39) Control (n = 51) M0 M1 M3 M6 M9 116** 149 145* 137* 134* 136* (109–127) (140–154) (135–150) (130–150) (130–146) (127–149) DBP (mmHg) 73** 90 90 85 83* 81* (65–80) (85–96) (85–100) (80–93) (77–90) (75–87) MAP (mmHg) 88 110 105 99.4 96.6* 97.6* (79–96) (106–113) (92–113) (88–108.2) (85.91–105.4) (83.9–104.6) PP (mmHg) 47 55 55 50 50 56 (39–53) (50–63) (45–60) (43–55) (47–60) (49–63) Values are median IQF 25–75% (1st–3rd). SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, PP: pulse pressure. *Compared to baseline M0, (M1, M3, M6, M9) after one, three, six and nine months of therapy (p < 0.05 Mann-Whitney rank sum test). **Comparison between healthy volunteers (control) and baseline (M0) of patients before treatment. (p < 0.05 Mann-Whitney rank sum test).
Variable median (IQF 1–3) SBP (mmHg)
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TABLE 2. EFFECT OF PERINDOPRIL 4 MG DAILY ON PWV AND ET-1 IN BLACK HYPERTENSIVE PATIENTS AFTER A NINE-MONTH TREATMENT COMPARED TO HEALTHY VOLUNTEERS Patients (n = 39) Control (n = 51) M0 M1 M3 M6 M9 8.2** 11.6 9.3 7.96 9.6 7.5* (7.0–10.7) (7.1–14.0) (6.9–11.5) (7.4–10.8) (7.5–10.0) (6.3–10.5) Brachial–ulnar PWV (m/s) 6.4 ns 6.4 6.4 6.8 7.2 6.1 (4.4–9.8) (5.4–9.5) (5.3–10.1) (4.6–8.5) (4.4–8.8) (5.0–8.4) ET-1 (pmol/l) 4.69** 6.15 7.55 7.96 8.15 4.53 (3.0–5.4) (3.5–7.89) (4.66–9.42) (6.36–8.87) (5.32–9.63) (3.68–9.25) Values are median IQF 25–75% (1st–3rd). *Compared to baseline M0, M1, M3, M6 M9 after one, three, six and nine months of therapy (p < 0.05 Mann-Whitney rank sum test). **Comparison between healthy volunteers (control) and baseline (M0) of patients before treatment. (p < 0.05 Mann-Whitney rank sum test).
Variable median (IQF 1–3) Carotid–femoral PWV (m/s)
indicate arterial elasticity, which includes structure, elastin and collagen. It has been shown that β-adrenergic blocking agents, diuretics, and some direct vasodilators such as hydralazine and dihydralazine, only lowered blood pressure but had no effect on vascular elasticity, whereas the ACE inhibitors, calcium channel blockers in general and nitroprusside, in addition to their blood pressure-lowering properties, also improved arterial elasticity.10,14 In a six-month study it was shown that perindopril improved arterial elasticity in hypertensive patients independent of its blood pressure-lowering properties.11 In a number of studies, possible mechanisms were investigated. It was suggested that vascular collagen metabolism plays a role. However, no correlation could be found between matrix metalloproteinase (MMP)-1, the tissue inhibitor of MMP-1 (TIMMP-1), PWV and blood pressure in patients who received perindopril for six months.15 A more recent study showed that ET-1 contributed to a decreased arterial compliance in hypertension through inhibition of collagen degradation.13 Furthermore, it has been shown that captopril therapy in congestive heart failure decreased endothelin production.12 However, in our study, no correlation could be found between ET-1 levels and arterial elasticity in any arterial segment or at any of the measured intervals. This was in contrast to a study done in endurance-trained men, where a linear correlation between ET-1 and aortic PWV was found.16 The segment in which the arterial elasticity is measured is important. In a previous study it was found that perindopril had a smaller effect on the elasticity in the carotid artery than the femoral artery.17 In contrast to our study where the arterial elasticity in the brachial–ulnar segment was not affected by perindopril, another study showed an improvement in brachial elasticity.18
References
Conclusion
14.
In addition to its blood pressure-lowering effect, our study confirms the improvement in arterial elasticity in the carotid– femoral segment but not the brachial–ulnar segment in patients on perindopril therapy. Furthermore, we have shown that ET-1 was not correlated to arterial elasticity in patients receiving perindopril. As referenced by Milan et al., the European Society of Hypertension has now included in their guidelines the improvement of arterial elasticity as one of the therapeutic aims in the treatment of hypertension.19
1. 2. 3. 4.
5.
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12. 13.
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Raij L, Gonzalez-Ochoa AM. Vascular compliance in blood pressure. Curr Opin Nephrol Hypertens 2011; 5: 457–464. PMID: 21738031. Cavalcante JL, Lima JA, Redheul A et al. J Am Coll Cardiol 2011; 57: 1511–1522. PMID 21453829. Belz GG. Elastic properties and windkessel function of the human aorta. Cardiovasc Drugs Therapy 1995; 9: 73–83. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study. J Am Coll Cardiol 1989; 13: 399–405. Asmar R, Rudnichi A, Blacher J, London GM. Pulse pressure and aortic pulse wave are risk markers of cardiovascular risk in hypertensive populations. Am J Hypertension 2001; 14: 91–97. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37: 1236–1241. McNiery CM, Wallace S, Mackenzie IS, McDonnel B, Yasmin, Newby D, et al. Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 2006; 48: 602–608. Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens 2001: 10: 257–261. Cohn JN. Arterial compliance to stratify cardiovascular risk: More precision in therapeutic decision making. Am J Hypertension 2001; 14: 2–35. Glasser SP, Arnett DK, McVeigh E, Finkelstein SM, Bank AK, Morgan DJ, Cohn JN. The importance of arterial compliance in cardiovascular drug therapy. J Clin Pharmacol 1998; 38: 202–212. Asmar R, Topouchian J, Pannier B, Benetos A, Safar M. Pulse wave velocity as endpoint in large scale intervention trial. The Complior Study. J Hypertension 2001; 19: 813–818. Mazurek W, Halawa B. Does captopril decrease endothelial production of endothelin? Pol Markuriusz Lek 1997; 15: 105–108. PMID 9461703 Ergul A, Jupin D, Johnson MH, Prisant LM. Elevated endothelin-1 levels are associated with decreased arterial elasticity in hypertensive patients. J Clin Hypertens 2006; 8: 549–554. Kool MJ, Lustermans FA, Breed JG, Struijker Bodier HA, Hoeks AP, Reneman RS, Van Bortel LM. The influence of perindopril and the diuretic combination amiloride+hydrochlorothiaziede on the vessel wall properties of large arteries in hypertensive patients. J Hypertension 1995; 13: 839–848. Lacourciere Y, Beliveau R, Conter HS, Burgess ED, Lepage S, Pesant Y, et al. Effects of perindopril on elastic and structural properties of large arteries in essential hypertension. Can J Cardiol 2004; 20: 795–799. Otsuki T, Maeda S, Iemitsu M, Saito Y, Tanimura Y, Ajisaka R, Miyauchi T. Vascular endothelium-derived factors and arterial stiffness in strength-and endurance-trained men. Am J Physiol Heart Circ Physiol 2007; 292: H786–H791.
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17. Van Bortel LM, Kool MJ, Boudier HA, Struijker Boudier HA. Effects of antihypertensive agents on local arterial distensibility and compliance. Hypertension 1995; 26: 531–534. 18. Asmar RG, Journo HJ, Lacolley PJ, Santoni JP, Billaud E, Levy BI, Safar ME. Treatment for one year with perindopril: effect on cardiac
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mass and arterial compliance in essential hypertension. J Hypertens Suppl 1988; 6: S33–S39. 19. Milan A, Tosello F, Fbbri A, Vairo A et al. Arterial stiffness: from physiology to clinical implications. High Blood pressure Cardiovasc Prev 2011, 18: 1–12. PMID 21612307.
17-22 FEBRUARY 2013 CAPE TOWN, SOUTH AFRICA
COME TO CAPE TOWN...
6th
Paediatric Cardiology & Cardiac Surgery
Conference Secretariat Contact the conference secretariat or visit www.pccs2013.co.za Event Dynamics P.O Box 6761, Roggebaai, 8012, South Africa Telephone: +27(0) 21 408 9796 Fax: +27(0) 21 408 9954 E-mail: info@pccs2013.co.za
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A trendy, sophisticated, multi-cultural city at the foot of Africa in a diverse and beautiful natural environment. Cape Town is a destination with irresistable appeal. South Africa has a compelling history and with its abundance of game reserves offers visitors a uniquely different cultural and tourist experience. The most distinguished international faculty available makes the “6th World Congress” an attractive, interactive and unique meeting place for clinicians, scientists health care managers and policy developers from all across our world.
PROGRAMME TRACKS •Surgery, anaesthesia and intensive care •Catheter interventions from fetus to adult •Health systems and heart disease •Adults with congenital and acquired heart disease •Cardiology and the imaging revolution
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The effect of the metabolic syndrome on the risk and outcome of coronary artery bypass graft surgery MARIUS J SWART, WIHAN H DE JAGER, JOHANN T KEMP, PAUL J NEL, SAREL L VAN STADEN, GINA JOUBERT
Abstract Background: The individual components of the metabolic syndrome are risk factors for coronary artery disease. The underlying pathophysiology of a low-grade inflammatory process postulates that the metabolic syndrome could compromise a procedure such as coronary artery bypass graft surgery (CABG) done on cardiopulmonary bypass (CPB). Methods: From a single institution, 370 patients with the metabolic syndrome (IDF and ATP III criteria) and 503 patients without the metabolic syndrome were identified. The influence of the metabolic syndrome on the pre-operative core risk factors for CABG mortality as well as its effect on the mortality and major morbidity post surgery were investigated. Results: Patients with the metabolic syndrome were operated on less urgently than those without the metabolic syndrome. The EuroSCORE was also lower in those with the metabolic syndrome. Patients with the metabolic syndrome required fewer units of homologous red blood cells, but stayed statistically longer in hospital. Conclusions: In this surgical population the metabolic syndrome had no detrimental clinical effect on either the pre-operative risk factors or the outcome after CABG. Keywords: CABG, metabolic syndrome Submitted 14/6/11, accepted 4/7/12 Cardiovasc J Afr 2012; 23: 400–404
www.cvja.co.za
DOI: 10.5830/CVJA-2012-055
Major surgery such as coronary artery bypass graft surgery (CABG) has the risk of mortality and morbidity. Co-morbidities will contribute to this potential risk of complications. In the wellknown Parsonnet risk model for mortality from the late eighties, obesity, hypertension and diabetes mellitus were all risk factors for mortality.1 Opposed to that, none of these risk factors were considered important in the EuroSCORE, which was developed
Mediclinic Bloemfontein, South Africa
MARIUS J SWART, MB ChB, FCS (SA), mjswart@ktc.bfnmcc.co.za
School of Medicine, University of the Free State, Bloemfontein, South Africa WIHAN H DE JAGER JOHANN T KEMP PAUL J NEL SAREL L VAN STADEN
Department of Biostatistics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa GINA JOUBERT, MSc
a decade later, from 19 000 patients in Europe who had had a CABG.2 In a recent study of 10 000 patients, obesity was not a risk factor for immediate mortality after CABG.3 Large studies are required to have the power to reach statistical significance and to demonstrate the influence of such co-morbidities. Combining 146 000 patients from various hospitals showed a mortality of 3.7% for patients with diabetes mellitus and 2.7% for those without diabetes mellitus.4 According to the Society of Thoracic Surgeons’ database, the odds ratio for mortality for patients with diabetes mellitus and hypertension is 1.3 and 1.2, respectively, compared to a redo CABG with an odds ratio of 3.1.5 A combination of these risk factors could strengthen their individual statistical power. A triad of obesity (in particular central obesity), hypertension and diabetes mellitus fulfils the criteria for the metabolic syndrome. Dyslipidaemia is the fourth factor for diagnosing the metabolic syndrome. In 1988 Gerald Reaven attributed the irregularities associated with the metabolic syndrome to insulin resistance.6 Abdominal fat functions as an endocrine organ that secretes pro-inflammatory adipokines, which could be the underlying pathophysiology for insulin resistance.7 C-reactive protein (CRP) is a marker of subclinical inflammation and a predictor of coronary incidents.8 Furthermore, central obesity leads to an increase in CRP. In fact, as the various components of the metabolic syndrome are added, the CRP increasingly rises.9 If a patient has an underlying inflammatory condition, as with the metabolic syndrome, and is subjected to a further inflammatory insult during cardiopulmonary bypass, it is postulated that the risk for mortality and morbidity could be higher. This was confirmed by a study in 2007. The prevalence of the metabolic syndrome among these 5 300 patients was 46%. The relative risk for mortality for patients with the metabolic syndrome was 3.04 (95% CI: 1.73–5.32; p = 0.0001). Obesity and diabetes mellitus, as single risk factors, could not be established as independent hazards for mortality.10 Morbidity was also more prominent among patients with the metabolic syndrome. A year later another study came to a different conclusion. The metabolic syndrome had no impact on survival after treatment. These patients were treated with medication (n = 516), by percutaneous coronary intervention (n = 1 274), and CABG (n = 1 096).11 The prevalence of the metabolic syndrome is high. Among United States adults older than 20 years it is 24%, increasing with age to 40% among 60-year-olds.12 But it is not only a problem of the West. China experiences an epidemic of obesity, with the metabolic syndrome present in 13% of adults.13 In South Africa the prevalence is unknown, but from a study done in the Free State province among blacks, it could be as high as 31%, using the WHO criteria.14
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A study was therefore undertaken to investigate the consequences of the metabolic syndrome on a local population of CABG patients. This was done to establish its effect on the pre-operative risk factors for mortality as well as on the outcome after CABG.
Methods The study was an analytical cohort study. The target population was all patients who had had a CABG done by one surgeon (MJS) at the Mediclinic Bloemfontein between November 2000 and October 2010. The metabolic syndrome was defined according to the criteria set by the International Diabetes Federation (IDF) in 2005.15 When the body mass index (BMI) was < 30 kg/m2 but hypertension, diabetes mellitus and dyslipidaemia were present, the definition from the National Cholesterol Education Programme Adult Treatment Panel (ATP III) in 2001 was used16 (Table 1). Central obesity was assumed with a BMI ≥ 30 kg/m2, which is acceptable according to IDF criteria. To ascertain the effect of the metabolic syndrome on the pre-operative risk factors for mortality after CABG, the seven core risk factors from a previous study were used and adapted.17 These risk factors were older age, female gender, re-operation, left ventricular ejection fraction ≤ 40%, critical left main stem disease, number of bypasses as an indication of disease severity, and urgency of operation. In this study, urgency was assumed when the operation was done from the coronary care unit with or without an intra-aortic balloon pump (IABP). These patients included those admitted with unstable angina and acute myocardial infarction. Further information that was gathered included the older additive EuroSCORE for each patient and renal function according to the shortened Modification of Diet in Renal Disease formula (sMDRD).18 Patients with chronic kidney disease grade III were also documented. Postoperative data that were evaluated were the Society of Thoracic Surgeons’ major negative outcomes: re-exploration, permanent stroke, renal impairment (new dialysis or 50% rise in serum creatinine level from pre-operative value), mechanical ventilation longer than 48 hours, and deep sternal infection, but for this study rewiring of the sternum for dehiscence was considered deep sternal infection.19 Patients who were discharged, TABLE 1. CRITERIA FOR THE METABOLIC SYNDROME ATP III (2001) Three or more: 1. Abdominal obesity: waist circumference ≥ 94–102 cm (males) ≥ 80–88 cm (females) 2. Triglycerides: ≥ 1.7 mmol/l 3. HDL-C: < 1.03 mmol/l (males) < 1.29 mmol/l (females) 4. Hypertension: systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg 5. Fasting blood glucose: ≥ 6.1 mmol/l
IDF (2005) Central obesity Waist circumference, ethnicity specific plus any two: 1. Triglycerides: ≥ 1.7 mmol/l or specific treatment 2. HDL-C: < 1.03 mmol/l (males) < 1.29 mmol/l (females) or specific treatment 3. Hypertension: systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg or specific treatment 4. Fasting plasma glucose: ≥ 5.6 mmol/l or previously diagnosed type 2 diabetes HDL-C: high-density lipoprotein cholesterol.
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but re-admitted within six weeks for sternal rewiring were considered part of the study. Other information obtained from patient records included the mediastinal drainage, homologous red blood cell transfusion, in-hospital mortality, and length of stay (LOS). Patients were excluded from this study if it was not possible to make a diagnosis of the metabolic syndrome. Those patients who had a major procedure combined with the CABG, patients who were on pre-operative dialysis, and those who died on the operating table were also excluded. The study group was divided between patients with the metabolic syndrome and those without the metabolic syndrome. A group without central obesity, hypertension or diabetes mellitus was also identified.
Statistical analysis All the data were analysed by the Department of Biostatistics at the University of the Free State. Numerical data are expressed as means and ranges. Categorical variables are indicated in percentages. Differences were assessed using chi-square tests, Fisher exact tests, t-test or Kruskall-Wallis tests depending on the data type. This study was approved by the Ethics Committee of the Faculty of Health Sciences at the University of the Free State, Bloemfontein. All data were treated anonymously.
Results
The initial study population was 1 475 patients. Unfortunately 495 patients had insufficient information to diagnose them with the metabolic syndrome or definitely exclude the metabolic syndrome. Ninety-three patients had another major cardiac procedure with the CABG and were not considered for the study. Three patients had an associated malignant resection at the time of cardiac surgery. Seven patients who had been on renal dialysis before the surgery were excluded, as were the four patients who died in theatre and could not be evaluated postoperatively. From the remaining patients, 370 had the metabolic syndrome (322 according to the IDF criteria) and 503 patients did not meet the criteria. The prevalence of the metabolic syndrome among this study group was 42%. Of the group without the metabolic syndrome, 319 had no central obesity, hypertension or diabetes mellitus. On the other hand, 169 patients from the non-metabolic syndrome group had at least one of these three criteria and 15 had two criteria of the metabolic syndrome. However, three criteria are needed to diagnose the metabolic syndrome. Table 2 summarises the results for the two groups, patients with the metabolic syndrome and those without the metabolic syndrome. The gender distribution was equal between the groups. Although the metabolic syndrome patients were slightly younger (median 59 years) than the non-metabolic syndrome group (median 61 years), this did not reach statistical significance. As far as the other risk factors for mortality after CABG are concerned, there was no difference with regard to redo CABG, poor ventricular function, main stem lesion and number of bypasses. However, the metabolic syndrome group was operated on less urgently, as 67.6% were operated from the coronary care unit compared to 75.7% of the non-metabolic syndrome group (p = 0.0076). The mean EuroSCORE also differed statistically (p = 0.0494). The metabolic syndrome group had a mean EuroSCORE of 3.26 (median 3) and the non-metabolic syndrome group 3.61 (median 3). The mean sMDRD was 76.2 and 76.1 ml/min for
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the two groups, respectively. The percentage of patients who had advanced to stage III chronic disease was almost the same (18.6 vs 17.9%). Postoperatively, the mortality was similar for the two groups, with 1.9% of patients with the metabolic syndrome and 1.6% without the metabolic syndrome who died during their hospital stay. The re-exploration rate, percentages of patients with a permanent stroke, those with renal impairment, those with long mechanical ventilation periods, and patients who required rewiring of a dehisced sternum were similar in the two groups. Even if the total number of patients with morbidities were compared (15.9 vs 12.3%; p = 0.1271) the outcome was still matching. The mean mediastinal drainage was almost the same in the two groups (624 and 670 ml, respectively). Homologous blood transfusion was less in the metabolic syndrome group, with a mean of 0.4 units per patient compared to the 0.73 units per patient from the non-metabolic syndrome group (p = 0.0012). Patients from the metabolic syndrome group stayed a mean of 5.9 days (median 5) and those from the non-metabolic syndrome group 5.8 days (median 5). This difference reached a p-value of < 0.0001 and therefore the metabolic syndrome patients had a more prolonged hospital stay.
Discussion The metabolic syndrome increases the risk of developing coronary heart disease. In the Atherosclerosis Risk in Communities study, 23% of the 12 000 patients had the metabolic syndrome without diabetes mellitus and existing cardiovascular disease. Over an average of 11 years, the men were 1.5 times and women twice as likely to develop coronary artery disease.20
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The impact of the metabolic syndrome on the population was also addressed by Shaista Malik. In a cohort of 6 255 adult patients representing 16 million North Americans, 26% had the metabolic syndrome. The metabolic syndrome strongly predicted coronary heart disease, cardiovascular disease and all-cause mortality and more so than the individual components of the syndrome.21 For this study both the ATP III and IDF (2005) criteria were used. Since the completion of this series, the IDF has adapted its criteria. Central obesity is no longer an obligatory component, but it is one of five criteria, of which three constitute diagnosis of the metabolic syndrome.22 Central obesity is defined by waist circumference, but this is gender and ethnicity specific. Waist circumference was not available in our population but body weight and height were, from which the BMI could be derived. With a BMI of ≥ 30 kg/m2, 85% of men would have had a waist circumference of at least 102 cm and 98% of women a waist circumference of 88 cm and more.23 Patients without the metabolic syndrome might still have some of the components of the metabolic syndrome, of which each one is a risk factor for coronary artery disease. In the Framingham Heart study it was the triad of central obesity, hypertension and diabetes mellitus which had the highest risk for cardiovascular disease and mortality.24 Of those patients without the metabolic syndrome, 319 could be identified without a BMI ≥ 30 kg/m2, hypertension or diabetes mellitus. However, they could still have had dyslipidaemia. Even so, in this so-called ‘clean’ group, underlying undiagnosed diabetes mellitus could have been present. In a study on the diagnostic value of haemoglobin A1c and fasting plasma glucose levels in CABG patients with undiagnosed diabetes mellitus, 60% of patients who were initially admitted
TABLE 2: RESULTS OF THE METABOLIC SYNDROME AND NON-METABOLIC SYNDROME PATIENTS Age (mean) Gender, male:female Re-operation LVEF ≤ 40% Main stem Bypasses (mean number) Urgency EuroSCORE (mean) sMDRD ml/min (mean) CKD III
Metabolic syndrome (n = 370) 59.2 59 median 292:78 21.1% female 42 11.4% 22 5.9% 72 19.5% 2.63 3 median 250 67.6%
Non-metabolic syndrome (n = 503) 60.4 61 median 390:113 22.5% female 52 10.3% 22 4.4% 90 17.9% 2.71 3 median 381 75.7%
p-value 0.0811 0.6250 0.6331 0.2940 0.5562 0.2318 0.0076
3 median
0.0494
18.6%
3.61 76.1 90
17.9%
0.9960 0.7749
1.4% 0.8% 11.4% 2.7% 1.6% 15.9%
15 3 42 8 5 62
3.0% 0.6% 8.3% 1.6% 1.0% 12.3%
0.1115 0.7023 0.1017 0.2531 0.5418 0.1271
1.9% 16.5%
8 64
1.6% 12.7%
0.7348 0.0938
3.26 76.2 69
3 median
Re-exploration Permanent stroke Renal impairment Ventilation > 48 hours Re-sternal wiring Total number of patients with any of the above 5
5 3 42 10 6 59
Mortality Mortality + morbidity
7 58
Mediastinal drainage (ml) (mean) 624 670 0.3420 0.0012 RBC (units/patient) (mean) 0.4 0 median 0.73 0 median LOS days (mean) 5.9 5 median 5.8 5 median < 0.0001 LVEF: left ventricular ejection fraction; sMDRD: shortened Modified Diet in Renal Disease; CKD III: chronic kidney disease grade III; LOS: length of stay; RBC: red blood cells.
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without diabetes mellitus were found to have diabetes one month after surgery.25 A pure non-metabolic syndrome group of patients is therefore hard to identify in sufficient numbers among patients with coronary artery disease. In our study, the prevalence of 42% of patients with the metabolic syndrome correlates with others studies where the metabolic syndrome and CABG were investigated (46, 47, 51%).10, 29,30 However, in an overview of the metabolic syndrome in young South African Asian patients with myocardial infarction, the prevalence of the metabolic syndrome, depending on the definition, was as high as 69%.26 The perception was that patients with the metabolic syndrome might be younger. The median age difference was in fact two years, but this did not reach statistical significance. However the difference in the EuroSCORE was important. Age older than 60 years adds one percentage point to the EuroSCORE and this age difference below and above the age of 60 years probably contributed to the difference in EuroSCORE. The metabolic syndrome made no impact on the pre-operative critical core risk factors for mortality after CABG; in fact it was patients without the metabolic syndrome who were operated on more urgently than patients with the metabolic syndrome. A possible explanation for this observation might be that patients with the metabolic syndrome have underlying risk factors for coronary artery disease such as hypertension, diabetes mellitus and dyslipidaemia and therefore are better followed up and intervention occurs sooner on a more elective basis. The lack of effect of the metabolic syndrome on renal function pre-operatively was surprising. The postoperative outcome demonstrated hardly any difference between the two groups. The percentage of explorations for excessive mediastinal drainage was more than double in the non-metabolic syndrome group (3.0 vs 1.4%), but this did not reach statistical significance. In a study on the effect of obesity on the outcome after CABG, the rate of re-operation because of bleeding was double (p < 0.001) in the non-obese patients.27 The difference in actual volume of drainage was also not important. A significant difference between the two groups was indeed observed in the number of units of homologous red blood cells transfused. Patients with the metabolic syndrome have higher BMI and therefore a higher blood volume and better reserves for loss of blood. It is also postulated that patients with the metabolic syndrome have less fibrinolytic activity and are more prone to hypercoagulability.28 This study could not demonstrate a difference between the two groups in the percentage of patients with stroke and renal impairment after CABG. A Japanese study showed that on multivariate analysis, the metabolic syndrome had odds ratios of 2.47 (95% CI: 1.22–4.99; p = 0.012) for postoperative stroke and 3.81 (95% CI: 1.42–10.3; p = 0.008) for postoperative renal failure.29 The group of 319 patients without central obesity, hypertension or diabetes mellitus had less acute renal impairment after CABG (5.3 vs 11.4% with the metabolic syndrome; p = 0.0035). If the metabolic syndrome group was compared with this ‘clean’ group, the occurrence of mortality plus major morbidity was significantly different (15.7 vs 9.1 %; p = 0.0095), but it is probably the renal outcome that drove this finding. As far as the metabolic syndrome and non-metabolic syndrome per definition is concerned, this study could not show an effect of the metabolic syndrome on mortality and major morbidity.
403
The length of hospital stay was statistically longer in patients with the metabolic syndrome although the median stay was similar. This is explained by the fact that the group without the metabolic syndrome had more patients staying four days or less, than the group with the metabolic syndrome (41 vs 27%). Although statistically important, the clinical effect of 0.1 day (difference in mean) longer or shorter stay is negligible. In another smaller study (657 patients) than this one, the hospital stay was also longer for patients with the metabolic syndrome (8.3 vs 6.6 days; p = 0.003). In addition, this smaller study also found no difference for morbidity, although female patients with the metabolic syndrome had a higher mortality rate.30
Conclusions This study confirmed the high prevalence of the metabolic syndrome among patients who undergo CABG. It failed to demonstrate an effect of the metabolic syndrome on the pre-operative risk factors for CABG mortality. In fact, patients with the metabolic syndrome were operated on more electively than those without the metabolic syndrome. The only negative outcome in patients with the metabolic syndrome was their longer stay, although not clinically important. The ‘benefit’ of having the metabolic syndrome was the lower risk for homologous blood transfusion after surgery. This study can contribute numbers for future analysis of the influence of the metabolic syndrome in patients undergoing CABG. Until then, Simons et al. might be correct that the metabolic syndrome as they see it should only been regarded as an educational tool and has limited practical value for diagnosis or management.31
References 1.
Parsonet V, Dean D, Bernstein AD. A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989; 79(suppl I): I-3–I–12. 2. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16: 9– 13. 3. Van Straten AHM, Bramer S, Soliman Hamad MA, et al. Effect of body mass index on early and late mortality after coronary artery bypass grafting. Ann Thorac Surg 2010; 89: 30–37. 4. Carson JL, Scholz PM, Chen AY, Peterson ED, Gold J, Schneider SH. Diabetes mellitus increases short-term mortality and morbidity in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol 2002; 40: 418–423. 5. Grover FL. The Society of Thoracic Surgeons National Database: Current status and future directions. Ann Thorac Surg 1999; 68: 367–373. 6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607. 7. Bruce KD, Byrne CD. The metabolic syndrome: common origins of a multifactorial disorder. Postgrad Med J 2009; 85: 614–621. 8. Festa A, D’Agostino R, Howard G, Mykkänen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the Insulin Resistance Syndrome. Circulation 2000; 102: 42–47. 9. Santos A-C, Lopes C, Guimarães JT, Barros H. Central obesity as a major determinant of increased high-sensitivity C-reactive protein in metabolic syndrome. Intl J Obesity 2005; 29: 1452–1456. 10. Echahidi N, Pibarot P, Després J-P, et al. Metabolic syndrome increases operative mortality in patients undergoing CABG. J Am Coll Cardiol 2007; 50: 843–851.
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11. Shah B, Kumar N, Garg P, et al. Metabolic syndrome does not impact survival in patients treated for coronary artery disease. Coron Artery Dis 2008; 19: 71–77. 12. Domanski M. The metabolic syndrome. Clinical research: Atherosclerotic risk factors: Editorial comment J Am Coll Cardiol 2004; 43: 1396–1398. 13. Cheng TO. Metabolic syndrome in China. Circulation 2004; 109: e180. 14. Mollentze WF. Epidemiological aspects in South Africa. S Afr J Diabetes Vasc Dis 2004; 1: 55–56. 15. Zimmet P, Alberti G, Shaw J. A new IDF worldwide definition of the metabolic syndrome: The rationale and the results. Diabetes Voice 2005; 50: 31–33. 16. 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 (ATPIII). J Am Med Assoc 2001; 285: 2486–2497. 17. Jones RH, Hannan EL, KE Hammermeister, et al. Identification of preoperative variables needed for risk adjustment of short-term mortality after coronary artery bypass graft surgery. J Am Coll Cardiol 1996; 28: 1478–1487. 18. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 1999: 130: 461–470. 19. Shoyer ALW, Coombs LP, Peterson ED, et al. The Society of Thoracic Surgeons: 30 day operative mortality and morbidity risk models. Ann Thorac Surg 2003; 75: 1856–1865. 20. McNeill AM, Rosamond WD, Girmin CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities Study. Diabetes Care 2005; 28: 385–390. 21. Malik S, Wong ND, Franklin SS, et al. Impact of metabolic syndrome on mortality from coronary heart disease, cardiovascular disease and all causes in United States adults. Circulation 2004; 110: 1245–1250.
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22. Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the Metabolic Syndrome: A joint interim statement of the Internatinal Diabetes Federation Task Force on epidemiology and prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; Internatiol Atherosclerosis Society; and International Association for the study of Obesity. Circulatiom 2009; 120: 1640–1645. 23. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk. Arch Intern Med 2002; 162: 2074–2079. 24. Franco OH, Massaro JM, Civil J, Cobain MR, O’Malley B, D’Agostino RB. Trajectories of entering the metabolic syndrome: The Framingham Heart Study. Circulation 2009; 120: 1943–1950. 25. Tekumit H, Cenal AR, Polat A, Uzun K, Tataroglu C, Akinci E. Diagnostic value of hemoglobin A1c and fasting plasma glucose in coronary artery bypass grafting patients with undiagnosed diabetes mellitus. Ann Thorac Surg 2010; 89: 1482–1489. 26. Ranjith N, Pegoraro RJ, Naidoo DP, Esterhuizen TM. Metabolic syndrome in young Asian Indian patients with myocardial infartion. Cardiovasc J Afr 2007; 18: 228–233. 27. Engel AM, McDonough S, Smith JM. Does an obese body mass index affect hospital outcomes after coronary artery bypass graft surgery? Ann Thorac Surg 2009; 88: 1793–1800. 28. Anand SS, Qilong Y, Gerstein H, et al. Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease. Circulation 2003; 108: 420–425. 29. Kajimoto K, Miyauchi K, Kasai T, et al. Metabolic syndrome is an independent risk factor for stroke and acute renal failure after coronary artery bypass grafting. J Thorac and Cardiovasc Surg 2009; 137: 658–663. 30. Brackbill ML, Sytsma CS, Sykes K. Perioperative outcomes of coronary artery bypass grafting: Effects of metabolic syndrome and patient’s sex. Am J Crit Care 2009; 18: 468–473. 31. Simmons RK, Alberti KGMM, Gale EAM, et al. The metabolic syndrome: Useful concept or clinical tool? Diabetologia 2010; 53: 600–605.
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Review Article The promise of computer-assisted auscultation in screening for structural heart disease and clinical teaching L ZÜHLKE, L MYER, BM MAYOSI
Abstract Cardiac auscultation has been the central clinical tool for the diagnosis of valvular and other structural heart diseases for over a century. Physicians acquire competence in this technique through considerable training and experience. In Africa, however, we face a shortage of physicians and have the lowest health personnel-to-population ratio in the world. One of the proposed solutions for tackling this crisis is the adoption of health technologies and product innovations to support different cadres of health workers as part of task shifting. Computer-assisted auscultation (CAA) uses a digital stethoscope combined with acoustic neural networking to provide a visual display of heart sounds and murmurs, and analyses the recordings to distinguish between innocent and pathological murmurs. In so doing, CAA may serve as an objective tool for the screening of structural heart disease and facilitate the teaching of cardiac auscultation. This article reviews potential clinical applications of CAA. Keywords: auscultation, screening for cardiac disease, clinical teaching, primary healthcare Submitted 10/11/11, accepted 3/2/12 Published online 23/2/12 Cardiovasc J Afr 2012; 23: 405–408
www.cvja.co.za
DOI: 10.5830/CVJA-2012-007
Prior to the development of echocardiography and other imaging modalities, the stethoscope was the central investigative tool for the diagnosis of structural heart disease. While the stethoscope is relatively inexpensive and widely available, it remains a qualitative and subjective method of School of Adolescent and Child Health, Red Cross War Memorial Children’s Hospital, and Department of Medicine, University of Cape Town, Cape Town, South Africa L ZÜHLKE, MB ChB, DCH, FCPaed (SA), Cert Cardiology (Paed), MPH, Liesl.zuhlke@uct.ac.za
School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa L MYER, PhD, MB ChB, MPhil, MA, BA
Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa BM MAYOSI, DPhil, FCP (SA)
evaluating heart sounds, murmurs and other cardiac noises. The development of the digital stethoscope with additional analysis software promises to transform the stethoscope into a tool for quantitative and objective clinical evaluation of the heart. Such a tool may improve the assessment of innocent murmurs, reduce observer variation due to human acoustic abilities, and facilitate the teaching of cardiac auscultation.
The assessment of innocent murmurs Up to 80% of paediatric patients have a cardiac murmur, although less than 1% will eventually have a pathological condition underlying the murmur.1 Praecordial murmurs are also common among young adults, occurring in between 29 and 52% of the general population.2 The ability to distinguish between an innocent and a pathological murmur is therefore a fundamental clinical skill that should be imparted to doctors and other healthcare professionals involved in the screening and diagnosis of heart disease. The innocent murmur is, however, the most frequently misdiagnosed condition when testing auscultation skills of medical practitioners.3 As a consequence, large numbers of patients with an innocent murmur are inappropriately referred for echocardiography, which has serious economic implications, in addition to causing undue concern among healthy individuals and their families.4 Echocardiography is the first-line imaging modality for the confirmation of a diagnosis of structural heart disease.5 The American Heart Association and American College of Cardiology define a class 1 recommendation for echocardiography as: ‘where clinical features indicate at least a moderate probability that a murmur reflects structural heart disease’.6 These guidelines discourage the indiscriminate use of echocardiography as a screening tool due to the cost and the potential for overdiagnosis of disease. Despite this, patients are still referred inappropriately for echocardiography for the evaluation of innocent murmurs. In a retrospective review of 3 460 adult referrals for echocardiogram with the coding ‘murmur’ as the primary reason for referral, less than 50% had significant valvular disease.7 A study in Norway showed that only 10% of children referred to a cardiac centre for investigation of a cardiac murmur were subsequently found to have a congenital cardiac lesion.8 The majority of these children (71%) were referred by general practitioners, though in only 17% was a diagnosis made by the referring physician. There is therefore a major need to improve the ability of
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medical practitioners to identify murmurs that have a high probability of structural heart disease. CAA promises to address this need by providing a decision support tool on the likelihood of the presence of pathological murmur.
CAA as a teaching aid for cardiac auscultation In the past decade, numerous reports have expressed concern over the training of healthcare professionals in cardiac auscultation.3,9,10 Despite the fact that directors of USA-based medical school programmes interviewed considered auscultation an important clinical skill, only 27% of internal medicine and 37% of cardiology programmes offered any structured teaching of auscultation.10 A multi-centre study testing medical students, trainees, physicians and teaching faculty more comprehensively demonstrated low ability to recognise systolic and diastolic murmurs.11 These studies indicate the need for more directed teaching of cardiac auscultation. The ability of a digital stethoscope to record sounds, replay them at different speeds, provide a visual display and develop a database of heart sounds for on-going review creates a unique vehicle for teaching auscultation and is a major incentive for the addition of CAA into current teaching programmes.
The development of computer-assisted auscultation The pursuit of a quantitative and objective stethoscope has occupied investigators for decades, and electronic stethoscopes have been available commercially for some time.12 Early criticisms related to difficulty of use, distortion of sound and cumbersome designs. However, over the past decade, rapid advances have been made not only in the electronic stethoscopes themselves, but also in the associated computer analysis.13 The CAA provides a spectral and temporal analysis of heart sounds and a graphic display of the energy profiles relating to systolic and diastolic murmurs (Fig. 1).14 The quantitative measurement of the intensity of the heart sounds and murmurs in the spectral display, which is recorded simultaneously with the waveform of the sounds, allows objective classification into normal and abnormal sounds (Fig. 2).15 Signals obtained electronically may be subjected to objective visual and numerical analysis, transmitted to distant sites, and stored for medical and research purposes. The Food and Drug Administration (FDA) has approved the first CAA system as an aide to the physician for the
Auscultation sequence
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detection of abnormal heart murmurs. Using this software, the sensitivity for detection of murmurs increased from 77 to 89%, while the referral sensitivity increased from 87 to 93% among primary-care physicians.16 Another decision support system, aimed at the paediatric population and utilising novel signalprocessing techniques, recently reported a specificity of 94% and a sensitivity of 91% for the detection of murmurs associated with structural heart disease.17,18
Opportunities for clinical application CAA is a promising decision support tool for the identification of pathological murmurs and appropriate referral of cases for further investigation. Primary-care physicians assessing asymptomatic patients with heart murmurs were able to increase the sensitivity of pathological murmurs detected with the use of CAA from 77 to 89%, while referral sensitivity increased from 87 to 93%, and specificity increased from 64 to 79%.16 The clinical utility of the digital stethoscope and associated software in detecting cardiac disease has great potential (Table 1). A recent article described an autonomous auscultation system which could be used to screen for cardiovascular disease in the rural areas of Africa.19 The performance of the system was impressive, with a sensitivity of 82% and a specificity of 88% for the identification of pathological murmurs, demonstrating its potential benefit as a screening tool in a rural healthcare environment. The need for a method to detect athletes at risk of sudden cardiac death due to hypertrophic obstructive cardiomyopathy led to a pilot study examining the level of agreement between auscultation by a cardiologist and the results of CAA.20 This study was able to identify ejection systolic murmurs that are louder in standing than in reclining positions: a cardinal sign of hypertrophic obstructive cardiomyopathy. The third heart sound is an early abnormality in adult patients with heart failure. It is frequently missed in a cursory examination of the heart, but is easily recorded by means of CAA.21 The most common cause of acquired heart disease in the world, rheumatic heart disease, has long been neglected due to its waning incidence in the developed world.22 A landmark study in Mozambique and Cambodia, however,
Patient information Visual display of heart sounds and murmurs ECG
Fig 1. The computer interface, as displayed on a laptop computer, depicts the areas of auscultation, visual display of heart sounds and murmurs, as well as ECG. (Reproduced with the permission of Mr Thys Cronje.)
Fig 2. In this display, analysis has determined that pathological murmurs were detected in the tricuspid, aortic and pulmonary areas. The computer interface also displays the level of confidence (90%) and the heart rate. (Reproduced with the permission of Mr Thys Cronje.)
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TABLE 1. CLINICAL USES FOR CAA Screening for structural heart disease Clinical teaching of cardiac auscultation
Task shifting and telemedicine
Screening for structural heart disease at primary healthcare level can be improved by the additional of an objective tool to aid referral decision making. Areas where this could potentially be of application include pre-athletic screening, antenatal screening of pregnant women, and screening for heart failure and early rheumatic heart disease in asymptomatic people. CAA may aid in more directed teaching in cardiac auscultation. This includes specific training in auscultation sequence, length of auscultation at each site, as well in the creation of data banks of auscultation recordings. Sounds can be relayed to multiple listeners simultaneously, replayed at different speeds and a visual display can improve retention of information. CAA can also be incorporated into distance-learning programmes. The global shortage of trained medical specialists requires the training of a new cadre of mid-level and community health workers who may benefit from the use of CAA as a decision support tool in screening for structural heart disease. Telemedicine may be used to link these cadres of health workers, who are often in remote areas, to clinicians and secondary and tertiary centres.
demonstrated an almost 10-fold under-appreciation of affected patients, using conventional auscultation compared to portable echocardiography.23 It is currently being investigated whether CAA improves the early identification of pathological heart sounds in patients with rheumatic heart disease.24 Co-existing cardiovascular disease during pregnancy is a leading cause of maternal mortality and contributes to significant morbidity.25 Early identification of women with cardiac disease is essential to managing the effects of cardiac disease during and after pregnancy. Certain conditions such as rheumatic mitral stenosis are poorly tolerated in pregnancy. It is likely that mitral stenosis and other structural heart diseases would be identified during routine antenatal screening of pregnant women in primary healthcare clinics if CAA was used as a decision support tool for nurses and doctors in the antenatal clinic.
may improve the chances of adoption of this new technology.33 Firstly, successful CAA systems must have a clearly defined indication: screening, diagnosis, and/or teaching. In addition, ease of use by personnel is of particular importance. Data must be analysed in real-time and be stored in a format which can be integrated into clinical records. From a technical standpoint, standardised data sets would be of great benefit and need to be highly sensitive and specific. Finally, single-praecordial-site CAA does not approximate the clinical routine of auscultation in different sites, use of diaphragm, bell and adjunct manoeuvres to comprehensively examine the heart. A new recording device using a multiplepraecordial-site approach, simultaneously acquiring six auscultation sites, a single-channel ECG and a respiratory recording, is under development.
The use of CAA in task shifting and telemedicine
Conclusion
A recent World Health Organisation report outlined the crisis in human resources in healthcare, and focused on the particular shortage of trained specialists in sub-Saharan Africa.26 This shortage has resulted in the shifting of tasks normally performed by specialists, to mid-level and community health workers.27 The use of technology to support community health workers has been recommended, as many other areas of medicine have benefitted by incorporating technology to identify disease in remote areas of the world.28,29 A key issue regarding the health worker shortage in sub-Saharan Africa is insufficient training opportunities. Two-thirds of sub-Saharan African countries have only one medical school, and 11 sub-Saharan African countries have no medical school at all.30 One of the solutions is the introduction of distance learning and open-access teaching materials.31 The ability of the digital stethoscope to transmit banks of recorded data for remote teaching suggests its utility for such a programme. The computer interface also serves as a reminder to students of the correct auscultation method (in terms of placement and length of auscultation). Another use of CAA is in the field of telemedicine. Recording heart sounds using a digital stethoscope and transmitting the sound data for remote assessment by a cardiologist was demonstrated to have a sensitivity and specificity of 90 and 98%, respectively, for the detection of pathological murmurs, with low inter-observer and intra-observer variability.32
Heart disease is a major cause of morbidity and mortality in all age groups worldwide. For decades, conventional auscultation has been the mainstay for screening and diagnosis of structural heart disease. However, the inherent limitations of the standard stethoscope have resulted in declining reliance on auscultation findings and the inappropriate referral for echocardiography of large numbers of patients with innocent murmurs. CAA provides objectivity to a traditionally subjective clinical skill. As an objective diagnostic support tool, it may improve the number of appropriate cases of murmur that are referred for echocardiography from primary care. Furthermore, CAA can provide a new platform for teaching cardiac auscultation to health science students and physicians. Finally, CAA may provide a decision support tool for mid-level and community health workers, with linkage to central expertise and training through telemedicine.
Challenges and further development Despite the potential of CAA, it has yet to be adopted into mainstream clinical practice. There are several factors which
We thank Mr Thys Cronje for the photographs. As a Fogarty International Clinical Research Fellow, Dr Zühlke is supported by the National Institutes of Health, Office of the Director, Fogarty International Centre, Office of AIDS Research, National Cancer Centre, National Eye Institute, National Heart, Blood and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases Health, and NIH Office of Women’s Health and Research through the International Clinical Research Scholars and Fellows Programme at Vanderbilt University (R24 TW007988) and the American Relief and Recovery Act.
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474–478. Etchells E, Bell C, Robb K. Does this patient have an abnormal systolic murmur? J Am Med Assoc 1997; 277(7): 564–571. Gaskin PR, Owens SE, Talner NS, Sanders SP, Li JS. Clinical auscultation skills in pediatric residents. Pediatrics 2000; 105(6): 1184–1187. McCrindle BW, Shaffer KM, Kan JS, Zahka KG, Rowe SA, Kidd L. An evaluation of parental concerns and misperceptions about heart murmurs. Clin Pediatr (Phila) 1995; 34(1): 25–31. Dolara A. The decline of cardiac auscultation: ‘the ball of the match point is poised on the net’. J Cardiovasc Med (Hagerstown) 2008; 9(11): 1173–1174. Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Jr, Faxon DP, Freed MD, et al. 2008 focused update incorporated into the ACC/ AHA 2006 guidelines for the management 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 Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008; 52(13): e1–142. Movahed MR, Ebrahimi R. The prevalence of valvular abnormalities in patients who were referred for echocardiographic examination with a primary diagnosis of “heart murmur”. Echocardiography 2007; 24(5): 447–451. Norgard G, Greve G, Rosland GA, Berg A. [Referral practice and clinical assessment of heart murmurs in children]. Tidsskr Nor Laegeforen 2005; 125(8): 996–998. Shindler DM. Practical cardiac auscultation. Crit Care Nurs Q 2007; 30(2): 166–180. Mangione S, Nieman LZ. Cardiac auscultatory skills of internal medicine and family practice trainees. A comparison of diagnostic proficiency. J Am Med Assoc 1997; 278(9): 717–722. Vukanovic-Criley JM CS, Warde CM , Boker JR , Guevara-Matheus L , Churchill WH , Nelson WP , Criley JM. Competency in cardiac examination skills in medical students, trainees, physicians, and faculty: a multicenter study. Arch Intern Med 2006; 166(6): 610–616. Belmont JM, Mattioli LF, Goertz KK, Ardinger RH, Jr, Thomas CM. Evaluation of remote stethoscopy for pediatric telecardiology. Telemed J 1995; 1(2): 133–149. Tavel ME. Cardiac auscultation: a glorious past – and it does have a future! Circulation 2006; 113(9): 1255–1259. Gamero LG WR. Detection of the first and second heart sound using probabilistic models. 25th A Int Conf IEEE EMBS, Cancun, Mexico 2003; 25: 2877–2880. Noponen AL, Lukkarinen S, Angerla A, Sepponen R. Phonospectrographic analysis of heart murmur in children. BMC Pediatr 2007; 7: 23. Watrous RL, Thompson WR, Ackerman SJ. The impact of computerassisted auscultation on physician referrals of asymptomatic patients with heart murmurs. Clin Cardiol 2008; 31(2): 79–83.
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17. Fourie P. Development of a hand-held device for automated paediatric cardiac auscultation. S Afr Heart J 2009; 6(4): 263. 18. Pretorius E, Cronje ML, Strydom O. Development of a pediatric cardiac computer aided auscultation decision support system. Conf Proc IEEE Eng Med Biol Soc 2010; 1: 6078–6082. 19. Botha JS, Scheffer C, Lubbe WW, Doubell AF. Autonomous auscultation of the human heart employing a precordial electro-phonocardiogram and ensemble empirical mode decomposition. Australas Phys Eng Sci Med 2010; 33(2): 171–183. 20. Watrous RL, Bedynek J, Oskiper T, Grove DM. Computer-assisted detection of systolic murmurs associated with hypertrophic cardiomyopathy: a pilot study. Tex Heart Inst J 2004; 31(4): 368–375. 21. Hult P, Fjallbrant T, Wranne B, Ask P. Detection of the third heart sound using a tailored wavelet approach. Med Biol Eng Comput 2004; 42(2): 253–258. 22. Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM. Rheumatic fever: neglected again. Science 2009; 324(5923): 37. 23. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007; 357(5): 470–476. 24. Engel M, Zühlke L, Robertson KA. ASAP programme: Rheumatic fever and rheumatic heart disease: Where are we now in South Africa? S Afr Heart J 2009; 6: 270–273. 25. Diao M, Kane A, Ndiaye MB, Mbaye A, Bodian M, Dia MM, et al. Pregnancy in women with heart disease in sub-Saharan Africa. Arch Cardiovasc Dis 2011; 104(6-7): 370–374. 26. World Health Organization. The World Health Report 2006: Working together for Health. Geneva: WHO ISBN 92 4 156317 6 (NLM classification: WA 5300), 2006: 8. 27. Fulton BD, Scheffler RM, Sparkes SP, Auh EY, Vujicic M, Soucat A. Health workforce skill mix and task shifting in low income countries: a review of recent evidence. Hum Resour Hlth 2011; 9(1): 1. 28. Sinha SR, Barry M. Health technologies and innovation in the global health arena. N Engl J Med 2011; 365(9): 779–782. 29. Selke HM, Kimaiyo S, Sidle JE, Vedanthan R, Tierney WM, Shen C, et al. Task-shifting of antiretroviral delivery from health care workers to persons living with HIV/AIDS: clinical outcomes of a communitybased program in Kenya. J Acquir Immune Defic Syndr 2010; 55(4): 483–490. 30. Anyangwe SC, Mtonga C. Inequities in the global health workforce: the greatest impediment to health in sub-Saharan Africa. Int J Environ Res Publ Hth 2007; 4(2): 93–100. 31. Chapman C, White CB, Engleberg C, Fantone JC, Cinti SK. Developing a fully online course for senior medical students. Med Educ Online 2011; 16. 32. Dahl LB, Hasvold P, Arild E, Hasvold T. Heart murmurs recorded by a sensor based electronic stethoscope and e-mailed for remote assessment. Arch Dis Child 2002; 87(4): 297–301; discussion 297–301. 33. Mahnke C. Automated heartsound analysis/computer-aided auscultation: a cardiologist’s perspective and suggestions for future development. Conf Proc IEEE Eng Med Biol Soc 2009: 3115–3118.
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William Nelson ECG quiz Answer
This elderly woman has atrial tachycardia with AV block due to digitalis excess. We’ve seen a number of examples in the past of bi-level AV block – the concept being that alternating impulses are blocked ‘high’ in the AV junction and the potentially conductible stimuli can block it at a (functionally) lower level. The ladder diagram is my answer for this puzzler. There is some irregularity of the P–P cycle with an average rate of 187 per min. Clearly, many P waves are not conducted. I interpret this to represent 2:1 transmission with alternating impulses blocked ‘high’ and the potentially conductible stimuli showing gradual prolongation (Wenckebach block) until the stimulus encounters refractoriness and is not conducted. This resulting pause permits the next P wave, which previously had not been conductible, to now become the affective stimulus – leapfrog Wenckebach. Is the concept clear? Any disagreements?
SUBSCRIBE to CVJAfrica & SAJDVD Fully searchable data set of CVJAfrica (2001-2012) & SAJDVD (2004-2012). You can subscribe to both these journals online.
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South African Heart Association Congress The Cardiovascular Journal of Africa recently attended the 13th annual SA Heart congress, which was held at Sun City from 19–22 July. Below are photos of some of the delegates and exhibitors.
The Cardiovascular Journal of Africa’s independent panel awarded the best scientific article published in 2011 to Carla Fourie from North-West University at the gala dinner for her article ‘Is HIV-1 infection associated with endothelial dysfunction in a population of African ancestry in South Africa?’ Prof Lionel Opie, of UCT presented the award on behalf of the Journal.
Dr Graham Cassel, Johannesburg (left) and Prof B Gersh take a break between presentations.
Lesego Parkies and Dr Naren Jairam from Bayer (SA) with their campaign poster Sign Against Stroke, a global patient awareness campaign to treat atrial fibrillation comprehensively in order to reduce incidence of stroke.
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Dr Paresh Patel (Nairobi, Kenya), Zanele Ngema (Astrazeneca, SA) and Dr Dixon (Zimbabwe). SA Heart was well attended by delegates from Africa.
Talking to Torque Medical. Craig Goodburn with Sister Doris Mmethi (Heart Hospital, Cath Lab, Pretoria) at the Torque Medical stand.
Jan van der Merwe (Boehringer-Ingelheim), Prof Pat Commerford (UCT) and Mark Savary (BoehringerIngelheim).
Dr Jan Szczygielski (Germiston Hospital) and Portia Nhlabathi (Servier) enjoying a chat at the well-staffed Servier stand.
The Boston scientific team was well represented at SA Heart.
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Conference Reports SA Heart Conference 2012 Treating angina pectoris with If channel blockade: evaluating treatment with a newer agent The medical treatment of angina has become the poor relative in coronary artery disease (CAD) management, having been largely overshadowed by percutaneous coronary intervention and bypass surgery. Nonetheless, in angina patients with minor coronary involvement, in the very elderly, in patients with substantial comorbidity, and in those not wishing to have an intervention, so-called ‘conservative’ medical therapy is appropriate. This view was expressed by Dr Tony Dalby, Milpark Hospital cardiologist, at a Servier-sponsored breakfast symposium at the recent SA Heart Association Congress. ‘While the application of percutaneous intervention varies according to the acumen of the interventionalist, there remains a group of patients who would be better treated with medical management. The frequency of angina seen in patients treated in specialist practice has been significantly reduced by coronary intervention and coronary bypass surgery,
and possibly by the more effective application of preventive therapies such as statins and ACE inhibitors. However, angina remains a relevant clinical problem. It has been reported that in patients treated for chronic CAD, 38% will experience angina, 14% will have exercise-induced ischaemia, and in 4% the two conditions will overlap. In primary care, almost one in three patients with coronary artery disease had anginal events at least once a week.1 ‘The prognostic impact of angina is also not insignificant. In a small study of self-reported angina and treadmillinduced ischaemia among outpatients with stable CAD, myocardial infarction or death from coronary heart disease (CHD) occurred in 7% of patients with angina alone, rising to 23% in patients with both angina and ischaemia’, Dr Dalby noted.2 ‘The much-debated COURAGE trial3 showed that optimal medical therapy achieved better results in the first three years when compared to percutaneous revascularisation, after which no
Chronic stable angina pectoris (with/without LVD) Aspirin 75–150 mg daily unless contraindicated* Sublingual nitrate to alleviate acute attacks Beta-blocker for prevention of acute attacks Symptoms controlled Yes
No
Symptoms controlled Yes
Contraindication or intolerance to beta-blocker Add or substitute calcium channel blocker (DHP if LVD) and/or long-acting nitrate
No
Symptoms controlled Yes
No
Continue treatment
Consider revascularisation
Add or substitute ivabradine if heart rate > 60/min
* Use clopidogrel if allergic to aspirin
Fig. 1. Proposed algorithm for treatment of angina.
difference in outcome was observed’, Dr Dalby pointed out. ‘So clearly, optimal medical therapy is an appropriate option.’ He noted that whereas the primary focus of the If channel blocker ivabradbine’s use recently has been on heart failure and left ventricular dysfunction, its value as an effective anti-anginal agent has been underplayed. The role of heart rate increase over 70 beats/min as a significant contributor to cardiovascular events has been well established and is now an accepted fact. ‘When we compare ivabradine to β-blockers, which are currently our standard to achieve reduction of heart rate and ameliorate angina symptoms, it is clear that they are distinctly different drug types. Both drugs have heart rate reduction and anti-remodelling effects but ivabradine, working solely on the sinus node, when compared to beta-blockade in experimental animal models, preserves ventricular relaxation and contractility, preserves coronary vasodilatation during exercise, thereby reducing coronary resistance, and preserves cardiac output. Ivabradine does not increase airways resistance, cause hypoglycaemia or induce fatigue and is in fact extremely well tolerated.’ When ivabradine was compared to the calcium channel blocker amlodipine, it had a similar efficacy in improving exercise tolerance, a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) and similar safety.4 The angina efficacy of ivabradine has also been well established in everyday clinical practice. In the multicentre REDUCTION study of 5 000 patients, ivabradine lowered heart rate from 70 to less than 60 beats/min, concomitantly reducing angina attacks from an average of 2.5 to one per week.5 It also reduced nitrate use and was well tolerated by 98% of patients. ‘This is not surprising as we know that the angina event is preceded by an increased heart rate and
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S L O W the beat
Improve the outcome
Coralan® specifically reduces heart rate without affecting cardiac contraction 1, conduction 2 or blood pressure 3
Coralan® has powerful anti-anginal and anti-ischaemic efficacy 3
For full prescribing information, refer to package inser t approved by medicines regulator y authorit y. S3 CORALAN ® 5 mg Tablets. Ivabradine 5 mg. Reg. No. A39/7.1.4/0410 S3 CORALAN ® 7,5 mg Tablets. Ivabradine 7,5 mg. Reg. No. A39/7.1.4/4011
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. TEL: +27(0) 861 70 0 90 0. FA X: +27(0)11 525 3401. R e f e r e n c e s: 1. Vi l a i n e J P e t a l. J C a rd i ova s c P h a rm a c o l 2 0 0 3;42:68 8 - 696 . 2 . C a m m A e t a l. D ru g s R &D 20 03;4:83 - 89. 3. Borer J et al. Circulation 20 03;107:817- 823. 4. Swedberg K et al. Lancet 2010;376: 875 - 885.
Coralan ® improves outcomes in heart failure patients with a heart rate above 70bpm - SHIFT 4
100%
Baseline AF Symptoms
AF Symptoms at Six Months
Cryo = 163, AF Drug = 82
Cryo = 163, AF Drug = 54, censored at crossover 100%
80%
80% Cryoablation Group
60%
AF Drug Group
Cryoablation Group
60%
40%
40%
20%
20%
0%
All Palpitations Symptoms
Fatigue
Rapid Heartbeat
Dyspnea
P = NS, all comparisons
Dizziness
Syncope
0%
AF Drug Group
All Palpitations Symptoms
Fatigue
Rapid Heartbeat
Dyspnea
Dizziness
P < 0.001, except for syncope P = 0.049
Syncope
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increased oxygen demand for some 20 minutes before eventuating in the briefer experience of angina’, Dr Dalby said. The safety of combining ivabradine with beta-blockade has been demonstrated. The combination has been shown to increase exercise time on the treadmill.6 Importantly, a sub-study of the BEAUTIfUL trial7 suggested that ivabradine was safe and effective in angina patients with left ventricular dysfunction, Dr Dalby added. ‘I am not proposing that ivabradine should replace β-blockade in angina but that it be employed as a useful alternative therapy when the patient is intolerant of beta-blockade, or as an add-on to standard anti-anginal therapies when the symptoms cannot be controlled adequately.’ Dr Dalby concluded with a personal proposal
to include ivabradine in a South African guideline, based upon similar proposals from the European Society (Fig. 1).
4.
J Aalbers 1.
2.
3.
Bethan JF, Weekes AJ, Morgan C, Tavella R, Spertus JA. The prevalence of weekly angina among patients with chronic stable angina in primary care practices (CADENCE) study. Arch Intern Med 2009; 169(16): 1491–1499. Gehi AK, Ali S, Na B, Schiller NB, et al. Inducible ischemia and the risk of recurrent cardiovascular events in outpatients with stable CAD – the heart and soul study. Arch Intern Med 2008; 168(13): 1423–1428. Maron DJ, Boden WE, O’Rourke RA, et al, COURAGE Trial Research Group. Intensive multi-factorial intervention for stable CAD: optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. J Am Coll Cardiol 2010;
5.
6.
7.
55(13): 1348–1358. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficiacy and safety of ivabradine compared with amlodipine in patients with stable effort angina: a 3-month randomized, double blind, multicentre, non-inferiority trial. Drugs 2007; 67: 393. Koster R, Kaehler J, Meinertz T; Reduction study group. Treatment of stable angina pectoris by ivabradine in everyday practice: the REDUCTION study. Am Heart J 2009; 158(4): e51–e57. Amasova E, Andrejev E, Zaderey I, et al. Efficacy of ivabradine in combination with beta-blocker versus uptitration of beta-blocker in patients with stable angina. Cardiovasc Drugs Ther 2011; 25(6): 531–537. Tendera M, Talajic M, Robertson M, Tardif JC, et al. Safely of ivabradine in patients with CAD and LV systolic dysfunction (from the BEAUTIfUL Holter substudy). Am J Cardiol 2011; 107(6): 805–811.
Catheter ablation of atrial fibrillation: evidence shows significant benefit and reduced progression of disease
1s td ia gn os ed
Catheter ablation for patients with paroxysmal atrial fibrillation (PAF) and long-standing atrial fibrillation (LS-AF) delays progression of the disease, with improved results if patients are treated early and aggressively. Presenting the evidence for this approach, Dr R Tilz, representing Prof K Kuck of St Georg Hospital, Hamburg, Germany, noted that clinicians should consider AF ablation earlier and not wait too long. ‘We should aim to intervene with ablation after the first recurrence of AF after anti-arrhythmic therapy. Multiple cardioversions are also no longer the norm in Germany, as education of physicians and referring cardiologists has led to acceptance of the approach that catheter
paroxysmal
ablation should not be the last option, it should be an early option’, Dr Tilz noted. Technological advances have also supported the use of ablation with new rotor-guided cryo-ablation and forcesensing catheters, combined with threedimensional visualisation, allowing individual laboratories to achieve consistent and reproducible results. ‘There are several revolutionary technologies that are en route and the cutting edge of anti-arrhythmic intervention is very fast paced’, Dr Tilz said. The natural progression of AF from paroxysmal AF to persistent and permanent AF is well documented and annual progression is 10–15% per year, with 77% of patients developing
permanent AF within 14 years without catheter ablation (Fig. 1). ‘Atrial fibrillation is a very complex disease and there are many contributors to its initiation and maintenance. While age and genetic predisposition are not treatable, factors such as atrial and pulmonary vein stretch due to hypertension and obesity, and endocrine factors such as diabetes and hyperthyroidism are treatable and can help to reduce AF prevalence.’ AF is relatively rare in the under 50-year-old, with a prevalence of one in 1 000 women and double that among men. The prevalence rises to about 10% in over 85-year-olds. The benefit of catheter ablation at the onset of PAF, thereby preventing TABLE 1. INDEPENDENT PREDICTORS OF AF PROGRESSION
persistent
Time
permanent
Fig. 1. Natural time course of atrial fibrillation. Amended from Kirchhof P, et al. Europace 2009; 11: 860–885.
History of heart failure Hypertension Chronic obstructive lung disease History of stroke/TIA Age > 75 years Amended from reference 2.
OR 2.22 1.52 1.51
SCORE 2 1 1
2.02 1.52
2 1
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progression to persistent forms of AF has been shown in a number of studies, including a series of 350 consecutive patients (mainly men, age 57 ± 12 years) where 75% were AF free at the end of the first year1 without anti-arrhythmic drug therapy. These patients were then followed over a five-year period. The recurrence rate was 5.8% at two years and 25.5% at five years. The presence of hypertension and hyperlipidaemia was associated with a higher risk of recurrence. From this risk evaluation,2 the HATCH score was developed to help identify patients at risk of progression from PAF to AF. Patients with hypertension, older patients having had a prior stroke or transient ischaemic attack (two points), chronic obstructive pulmonary disease and heart failure (two points) were found to be more likely to progress to persistent forms of AF (Table 1). ‘Catheter ablation is also superior to anti-arrhythmic drugs and results are nicely consistent across clinical trials’, Dr Tilz noted. More than one ablation procedure is necessary to address the decline in AF control over time. In a recently published study,3 which included patients with PAF,
persistent and long-standing persistent AF, success rates after a single catheter ablation procedure were 40, 37 and 29% at one, two and five years, respectively, with most recurrences during the first six months. In all, 175 procedures were performed in the 100 patients, with a mean of two per patient, achieving much higher arrhythmia-free survival of 87, 81 and 63% at one, two and five years, respectively. ‘Using our preferred technique of circumferential PV isolation, guided by three-dimensional mapping and double lasso, our centre has achieved an 80% success rate following 1.5 procedures and a 46% success rate after a single procedure in a rather healthy patient population with PAF and normal left ventricular ejection factions’, Dr Tilz said. ‘The challenge to our team and the electrophysiologist generally, is to achieve permanent PV insulation over time. We treat aggressively and early. In this way, progression after catheter ablation is extremely low and in this study, only four patients (2.4%) developed chronic AF.’ Referring to recent USA data using radiofrequency catheter (RFA) ablation in a large cohort of older patients (mean
HEALTHCARE
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age 58 ± 10 years), catheter ablation limited progression to 0.6% per year compared to 9% per year reported in pharmacologically treated patients.4 ‘These and other studies allow us to conclude that catheter ablation can reduce progression to persistent AF’, Dr Tilz said. He recommends, however, that all patients continue with anti-coagulation whether ablation is successful or not. J Aalbers 1.
2.
3.
4.
Shah AN, Mittal S, SIchrovsky TC, Cotiga D, et al. Long-term outcome following successful pulmonary vein isolation: pattern and prediction of very late recurrence. J Cardiovasc Electrophysiol 2008; 19: 661–667. De Vos CB, Pisters R, Nieuwlaat R, Prins MH, et al. Progression from Paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol 2010; 55(8): 725–731. Weersasooriya R, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011; 57(2): 160–168. Jongnarangsin K, Suwanagool A, Chugh A, Crawford T, et al. Effect of catheter ablation on progression of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2012; 23(1): 9–14.
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e1
Case Report Severe cardiac failure due to rapidly progressive rheumatoid arthritis-associated valvulopathy JASON M TARKIN, NEARCHOS HADJILOIZOU, HENRY OLUWASEFUNMI SAVAGE, SANJAY K PRASAD, MARY N SHEPPARD, NEIL E MOAT, SAM KADDOURA
Abstract Cardiac failure due to rapidly progressive valve disease is a rare complication of rheumatoid arthritis (RA) that can be challenging to manage. A patient with severe heart failure secondary to RA who, after failing to respond to medical therapy, underwent high-risk valve surgery and did remarkably well, with dramatic symptomatic improvement and essentially normalised left ventricular size and function as seen on follow-up echocardiography. Keywords: cardiac failure, rheumatoid arthritis, valvular heart disease Submitted 14/6/11, accepted 23/2/12 Cardiovasc J Afr 2012; 23: e1–e3
www.cvja.co.za
DOI: 10.5830/CVJA-2012-012
Cardiovascular involvement is present in up to 70% of patients with rheumatoid arthritis (RA) at autopsy.1,2 Pericardial disease is the commonest cardiac manifestation, occurring in 30 to 50% of patients.1-3 Less frequently, myocarditis, cardiomyopathy, conduction defects, coronary artery vasculitis, aortitis and valvular heart disease can occur.1,2 In post-mortem studies, RA-associated cardiomyopathy was found in three to 30% of patients, and evidence of coronary artery vasculitis in up to 20%.3 The risk of developing congestive heart failure is twice as high in patients with RA, and higher rates of premature coronary artery disease are also seen.2,3 Mitral regurgitation (MR) has been reported in 30 to 80% of patients with RA, and aortic regurgitation (AR) in nine to 33%.3 Pathological mechanisms underlying cardiovascular manifestations in RA are multifactorial and include chronic inflammation, fibrosis, rheumatoid nodules and amyloid deposition. Chelsea and Westminster Hospital, Fulham Road; Royal Brompton Hospital, Sydney Street; Imperial College School of Medicine, London, UK JASON M TARKIN, MB BS NEARCHOS HADJILOIZOU, MB BS, MRCP SAM KADDOURA, BSc (Hons), BM BCh, DIC, PhD, FRCP, FESC, FACC, Sam.Kaddoura@chelwest.nhs.uk
Royal Brompton Hospital, Sydney Street; Imperial College School of Medicine, London, UK HENRY OLUWASEFUNMI SAVAGE, MB BS, MRCP SANJAY K PRASAD, MD, FRCP MARY N SHEPPARD, MD, FRC Path NEIL E MOAT, MS, FRCS
Medical treatments for RA may improve cardiovascular disease via their anti-inflammatory properties. Long-term treatment with methotrexate has been associated with reduced cardiovascular mortality, and disease-modifying anti-rheumatic drugs may also reduce hospitalisation for congestive heart failure in RA.4 However, this benefit remains unclear and several therapies, such as corticosteroids and non-steroidal antiinflammatory drugs can lead to increased cardiovascular risk.4
Case report A 52-year-old man from Ethiopia was admitted with worsening heart failure despite maximum medical therapy. He had a fivemonth history of worsening shortness of breath, orthopnoea and decreased exercise tolerance (NYHA III–IV), with two previous hospital admissions during this period. Past medical history included pulmonary sarcoidosis that had been treated with steroids and seropositive erosive RA with multiple joint involvement and typical rheumatoid nodules on his elbows. Current medications were perindopril 8 mg once daily, furosemide 40 mg twice daily, spironolactone 25 mg once daily, and long-term methotrexate therapy. On examination, blood pressure was 111/64 mmHg and heart rate 91 beats per min. Heart sounds I and II were audible, with an early diastolic murmur and a loud pan-systolic murmur heard. There was evidence of decompensated congestive cardiac failure with raised jugular venous pressure, bi-basal coarse crackles and marked peripheral oedema. Electrocardiogram showed sinus rhythm with non-specific T-wave changes. Chest radiograph showed pulmonary oedema, bilateral pleural effusions and increased cardiothoracic ratio. Echocardiography showed grossly dilated left and right ventricles [LV end-diastolic diameter (LVEDD) 6.5 cm], with severely impaired systolic function, bi-atrial dilatation (left atrium 6.1 cm), and no evidence of LV hypertrophy. There was severe, broad AR due to failure of co-aptation of the aortic valve cusps (aortic root 2.5 cm), occupying almost the entire left ventricular outflow tract with flow reversal in the descending and abdominal aorta. Left ventricular ejection fraction was 35 to 45% in the context of severe AR. Severe, eccentric MR and severe tricuspid regurgitation (TR) were also seen. Pulmonary artery pressure was elevated at 70 mmHg + right atrial pressure. All three valves appeared thickened (Figs 1A–D). Chest computed tomography confirmed pulmonary oedema with no evidence of parenchymal sarcoidosis. Coronary angiography showed unobstructed coronary arteries and catheterisation showed raised pulmonary artery pressures with
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Fig. 1. Echocardiography: four-chamber view showing bi-atrial and bi-ventricular dilatation and thickening of the mitral valve and tricuspid valve leaflets (A), short-axis view showing thickening of the aortic valve leaflets with a mal-coaptation defect between the left coronary cusp and non-coronary cusp (B), M-mode with colour flow across the aortic valve showing a non-dilated aortic valve root with severe broad aortic regurgitation (C), and three-chamber view with colour flow showing severe eccentric mitral regurgitation (D).
a mean of 53 mmHg. Cardiac magnetic resonance imaging (MRI) showed diffuse circumferential mid-wall and epicardial enhancement in the late phase following gadolinium contrast, in keeping with extensive myocardial fibrosis. There was no evidence of active inflammation, oedema or infarction (Fig. 2). His condition was extremely debilitating and his prognosis was poor. After extensive discussions between the patient, his cardiologist, the heart failure team and the cardiac surgeon, it was felt the only route to improve his quality of life was to undergo valve surgery despite the increased risk of mortality. Aortic valve replacement with mitral and tricuspid valve repair was undertaken after the patient recovered from his acute admission. Intra-operative transoesophageal echocardiography confirmed the presence of torrential AR, with severe MR and TR due to marked annular dilatation. Severe biventricular dilatation with extremely poor function was also confirmed. A size 28-mm Edwards Physio mitral and a size 32-mm rigid tricuspid ring were implanted. The aortic valve was replaced with a 19-mm Edwards Magna-Ease valve. He made a good post-operative recovery, and his symptoms have since improved dramatically. The excised native aortic valve leaflets were thickened with retracted cusps (Fig. 3A). Microscopically, there was a fibrosed inflamed aortic valve with dense fibroelastic tissue,
Fig. 2. Cardiac MRI in late phase after gadolinium contrast showing diffuse, circumferential mid-wall and epicardial enhancement consistent with extensive myocardial fibrosis.
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Fig. 3. Macroscopic view of the aortic valve showing thickened and retracted valve cusps (A). Histology slides showing lymphocyte infiltration and new vessel formation (B), and fibroelastic tissue (C).
neovascularisation and focal lymphocyte infiltration (Fig. 3B, C). There was no evidence of sarcoidosis in the valve or surrounding lymph node. No rheumatoid nodules, granuloma or calcification were seen. These findings supported the diagnosis of valvular heart disease secondary to RA. Post-operative echocardiography showed a well-seated prosthetic aortic valve with no AR, mild MR, no TR, and no pericardial collection. At one month, the LVEDD was improved to 6.0 cm. Echocardiography 10 months post surgery showed a well functioning aortic prosthetic valve with a significant reduction in LVEDD from 6.5 cm to 4.6 cm. Mitral and tricuspid valve function was improved, with no regurgitation seen 10 months post repair.
non-granulomatous valve disease has also been described in RA.2 This was the diagnosis in our patient.
Discussion
1.
Pre-operative non-invasive cardiac imaging supported a diagnosis of severe valvular heart disease due to RA, and aggressive steps were taken to treat his heart failure. Valve thickening was seen on echocardiography, which is a distinctive feature that provides evidence of valve involvement in RA.5 Myocardial fibrosis demonstrated on cardiac MRI gave further support to this diagnosis. The pattern of delayed enhancement helped to distinguish from other causes of myocardial fibrosis, including sarcoidosis and ischaemic cardiomyopathy. Most patients with RA-associated valvular heart disease have mild valvular insufficiency due to a slowly progressive granulomatous valvulitis.2 Rapidly progressive, severe
Conclusion This case report highlights potential difficulties in the management of patients with severe heart failure due to rheumatoid arthritis. Early surgical intervention is often the best treatment option in this setting, as severe left ventricular failure is unlikely to respond to medical treatment alone and valve replacement surgery can improve left ventricular function and prolong survival.6
References 2.
3. 4.
5.
6.
Lebowitz W. The heart in rheumatoid arthritis. Ann Intern Med 1063; 58: 102–123. Libby P, Bonow RO, Zipes DP, Mann DL. Rheumatic diseases and the cardiovascular system. In: Braunwald’s Heart Disease. 8th edn. Philadelphia: Saunders Elsevier 2007; 2094–2096. Voskuyl AE. The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology 2006; 45: iv4–iv7. Kaplan MJ. Cardiovascular complications of rheumatoid arthritis – assessment, prevention and treatment. Rheum Dis Clin North Am 2010; 36(2): 405–426. Roldan CA, DeLong C, Qualls CR, Crawford MH. Characterization of valvular heart disease in rheumatoid arthritis by transoesophageal echocardiography and clinical correlates. Am J Cardiol 2007; 100: 496–502. Levine AJ, Dimitri WR, Bonser RS. Aortic regurgitation in rheumatoid arthritis necessitating aortic valve replacement. Eur J Cardiothorac Surg 1999; 213–214.
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Case Report HIV infection, pulmonary arterial hypertension and pregnancy: a fatal triad MYAT TUN LIN NYO, LEANN SCHOEMAN, RAVEENDRA SOOKHAYI, BONGANI M MAYOSI
Abstract A 30-year-old pregnant HIV-seropositive woman presented with symptoms and signs suggestive of severe pulmonary arterial hypertension, with a fatal outcome. Histological features of pulmonary arterial hypertension were present at post mortem. This is the first report of histologically confirmed HIV-associated pulmonary arterial hypertension associated with pregnancy in Africa. Keywords: HIV infection, pulmonary arterial hypertension, pregnancy Submitted 25/10/11, accepted 5/3/12 Published online 29/5/12 Cardiovasc J Afr; 2012; 23: e4–e6
www.cvja.co.za
DOI: 10.5830/CVJA-2012-020
Case report A 30-year-old black African woman presented at 32 weeks of pregnancy (gravidity 2 and parity 1) complaining of shortness of breath, orthopnoea and a dry cough for a period of two months. She was known to be human immunodeficiency virus (HIV) seropositive with a CD4 cell count of 252 cells per μl, for which she was taking zidovudine. She had no history of hypertension, heart or lung disease. On admission, her blood pressure was 120/80 mmHg, pulse 110 beats per minute and respiratory rate 30 breaths per minute. She had a raised jugular venous pressure, praecordial signs of pulmonary hypertension (i.e. systolic right parasternal lift, and loud pulmonary component of the second heart sound) with tricuspid incompetence and pulsatile hepatomegaly.
Examination of the chest was normal. The chest radiograph revealed cardiomegaly with a right ventricular configuration and clear lung fields, while the ECG displayed sinus tachycardia, right-axis deviation, right ventricular hypertrophy and T-wave inversion in leads V1–4 (Fig. 1). Portable echocardiography showed a dilated right atrium and right ventricle with no structural valvular lesions. A full echocardiographic study with estimation of pulmonary arterial pressure by Doppler was not performed because the patient was too ill to be transported to the cardiac clinic echocardiography laboratory. Small wedge- and crescent-shaped sub-segmental perfusion defects were reported in both right and left upper lobes on radionuclide lung perfusion scan. A diagnosis of pulmonary embolism with pulmonary hypertension was made and she was treated with a continuous infusion of unfractionated heparin. She remained tachypnoeic despite therapeutic anticoagulation over the ensuing six days. On the seventh day, she became hypotensive, requiring intravenous inotropic support with adrenaline infusion. Intra-uterine foetal death was diagnosed at this stage. Labour was induced, and she delivered a stillborn infant six hours later. An hour after delivery she suffered a cardiac arrest and all resuscitation efforts were unsuccessful. Post mortem examination excluded major pulmonary embolism, pulmonary infarcts or pneumothorax. No deep-vein thromboses were present in the calves or pelvic venous plexus. The diagnostic finding was plexiform lesions of the pulmonary vasculature indicative of advanced HIV-associated pulmonary arterial hypertension (PAH) (Fig. 2A–D). Right ventricular hypertrophy was present, in keeping with cor pulmonale.
Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
MYAT TUN LIN NYO, FCP (SA) BONGANI M MAYOSI, DPhil, FCP (SA), bongani.mayosi@uct.ac.za
Department of Obstetrics and Gynaecology, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa LEANN SCHOEMAN, FCOG (SA)
Division of Anatomical Pathology, Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa RAVEENDRA SOOKHAYI, MB BCh
Fig. 1. Sinus tachycardia, right-axis deviation, right ventricular hypertrophy and T-wave inversion in leads V1 –4.
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Fig. 2. A: A plexogenic lesion arising from a larger artery (a). The artery is characterised by a thick muscular coat and association with a bronchus is not seen in this picture (M – media). B: A plexogenic lesion arising from an artery (a). An abnormal thin-walled vessel adjacent to the artery (b). Alveolar spaces (c). C: A plexiform lesion showing a collection of thin-walled vessels (a). The edge of an artery (b). Congested alveolar spaces (c). D: Verhoef elastic van Gieson (VEVG): note the deficient internal elastic lamina and fibro-intimal proliferation (double arrow).
Discussion To the best of our knowledge, this is the first confirmed case report of PAH associated with HIV in pregnancy in Africa. PAH has been reported in approximately 1/200 patients infected with HIV, compared to a prevalence of 1/200 000 in the general population.1,2 The typical histopathological findings in HIV-associated PAH are plexogenic pulmonary arteriopathy, thrombotic pulmonary arteriopathy and pulmonary venoocclusive disease.3 Pulmonary vessel endothelial cell proliferation and vasoconstriction triggered by pleomorphic cytokines (e.g. endothelin-1, interleukin-6 and tumour necrosis factor-α) released by HIV-infected pulmonary macrophages and dendritic cells are thought to play a central role in the pathogenesis of HIV-associated PAH, which has no apparent association with CD4 cell count or viral load.3,4 There is also evidence that individual antiretroviral drugs (i.e. ritonavir, indinavir, lamivudine, didanosine, abacavir and zidovudine) and a combination of three drugs (indinavir, didanosine and stavudine) at their therapeutic plasma concentrations may cause endothelial
dysfunction through endothelial nitric oxide synthase downregulation and superoxide anion production in porcine pulmonary artery rings and human pulmonary artery endothelial cells.5 It is therefore possible that both the HIV infection and treatment with zidovudine may have contributed to the pathogenesis of PAH in this patient. Clinical symptoms of HIV-associated PAH are dyspnoea, dry cough, angina, near syncope or syncope and oedema. Clinical signs are those of pulmonary hypertension and right heart failure. The haemodynamic stress of pregnancy, labour, delivery and the postpartum period are known to be potentially devastating in patients with PAH in general, resulting in a maternal mortality of 30–50%, despite modern treatment modalities.6 The majority of maternal deaths in PAH patients occur either during labour and delivery or within one month postpartum. Cardiovascular collapse is attributed to a mismatch between the physiological limitations of PAH and the changes that occur with pregnancy and delivery.6 To the best of our knowledge, there are no outcome studies in patients with the triad of pregnancy, PAH and HIV infection. While there are a number of treatment options for PAH
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associated with HIV, there is no consensus on the management of PAH in pregancy.4,6 Although highly active antiretroviral therapy has resulted in modest improvement in pulmonary pressures in some series,7 HIV-associated PAH, as with other forms of PAH, generally requires treatment with medications targeting the pulmonary vasculature, such as bosentan, prastacyclin and sildenafil.4 However, in pregnancy, only prostanoid therapy is recommended, while endothelin receptor agonists are contraindicated because of teratogenic effects.6 Several case reports have described improved maternal and foetal outcomes, likely due to the advent of the new advanced pulmonary hypertension therapies, earlier diagnosis of PAH, and the adoption of a multidisciplinary approach to treatment.6
needed to establish the clinical epidemiology and appropriate management of PAH in pregnant patients living with HIV.2
References 1. 2.
3. 4. 5.
Conclusion There are at least three major implications of this report. First, it raises the question of antenatal screening of HIV-positive patients for PAH using echocardiography and new biomarkers of myocardial dysfunction, such as serum brain natriuretic peptide (BNP) level,8 given the association of PAH with HIV infection. Second, the diagnosis of PAH ought to be considered in all pregnant HIV-positive patients with shortness of breath, signs of right heart failure and clinically normal lungs. Early detection of PAH associated with HIV in pregnancy by echocardiography may lead to the institution of life-saving therapy.6 Finally, research is
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Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 2001; 100: 1268–1271. Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection of cardiovascular disease in Africa. Circulation 2005; 112: 3602–3607. Barbaro G. Pathogenesis of HIV-associated heart disease, AIDS 2003; 17: S12–S20. Chin KM, Rubin LJ. Pulmonary arterial hypertension, J Am Coll Cardiol 2008; 51: 1527–1538. Wang X, Chai H, Lin PH, Yao Q, Chen C. Roles and mechanisms of human immunodeficiency virus protease inhibitor ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells. Am J Pathol 2009; 174: 771–781. Smith J, Mueller J, Daniels C. Pulmonary arterial hypertension in the setting of pregnancy: a case series and standard treatment approach. Lung 2011: 1–6. DOI 10.1007/s00408-011-9345-9. Zuber JP, Calmy A, Evison JM, et al. Pulmonary arterial hypertension related to HIV infection: improved haemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 2004; 38: 1178–1185. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, et al. Predicting survival in pulmonary arterial hypertension. Circulation 2010; 112: 164–172.
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Case Report Triple papillary fibroelastomas in an asymptomatic patient D KIREYEV, MH ASHRAF, MF WILSON
Abstract Papillary fibroelastoma is the third most common type of primary cardiac tumour. Even though the majority of patients with these tumours are asymptomatic, they may present with embolic phenomena, syncope and death. This report describes a patient with papillary fibroelastomas affecting all three cusps of the aortic valve, with accompanying transoesophageal echocardiography and images of surgical specimens of the tumours. Keywords: cardiac tumours, aortic valve, papillary fibroelastoma, echocardiography, surgical specimen Submitted 15/3/11, accepted 6/312 Cardiovasc J Afr 2012; 23: e7–e9
Due to the increasing size of the mass and the risk of an embolic event, the patient was referred for surgery. Instead of a conventional coronary angiogram, where there was a potential for embolisation of the tumour, the patient underwent a pre-operative cardiac computed tomography (CT) angiogram using 64-slice MDCT with intravenous contrast. It showed a left ventricular ejection fraction (LVEF) of 71%, calcium score of 679 Agatston units, moderate right coronary artery calcification (606 Agatston units) and mild stenosis in the left circumflex coronary artery after the first obtuse marginal branch. Review of the valvular structures showed a mass associated with the left coronary cusp of the aortic valve (Fig. 3).
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DOI: 10.5830/CVJA-2012-024
Primary tumours of the heart are extremely rare, with an incidence of 0.002 to 0.1%.1,2 After cardiac myxomas and lipomas, papillary fibroelastomas are the third most common type of primary cardiac tumour.3,4 Even though they are often asymptomatic, they may manifest as emboli, with life-threatening consequences.
Case report An 81-year-old woman with a history of atrial fibrillation was found to have a small fibroelastoma attached to the aortic valve during a routine transthoracic echocardiogram one year prior to admission. Recent echocardiography revealed a significant increase in size of the tumour. The patient was referred for a transoesophageal echocardiogram (TEE) for further evaluation of the tumour. TEE showed preserved ejection fraction, mild aortic, mitral and tricuspid regurgitation, and a 6 × 7-mm mobile mass attached to the left coronary cusp of the aortic valve, which was consistent with fibroelastoma (Figs 1, 2).
Fig. 1. Transoesophageal echocardiogram of the fibroelastomas with the aortic valve closed.
Department of Cardiology, State University of New York, Buffalo NY, USA D KIREYEV, MD, dkireyev@cha.harvard.edu
Department of Cardiothoracic Surgery, Kaleida Health, Buffalo NY, USA MH ASHRAF, MD
Department of Cardiology, Kaleida Health, Buffalo NY, USA MF WILSON, MD
Fig. 2. Transoesophageal echocardiogram of the fibroelastomas with the aortic valve open.
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Fig. 3. Soft tissue mass associated with the left coronary cusp of the aortic valve on CT scan.
The patient was taken to the operating room for removal of the fibroelastoma. The chest was opened using a minimally invasive technique at the level of the third intercostal space. The aorta was opened 4 cm above the origin of the right coronary artery. Intra-operative examination of the valve showed a 1-cm fibroelastoma attached to the edge of the left coronary cusp. Two small fibroelastomas were noted attached to the right coronary and non-coronary cusps. All three lesions were excised without damage to the aortic valve cusps (Fig. 4). Postoperative TEE showed no decline in LVEF and absence of aortic regurgitation. The patient tolerated the procedure well and had an uneventful recovery. The pathological specimen showed multiple irregular fragments of tan-white soft tissue with fine papillary excrescencies. Special stains for connective tissue (Masson) and elastic tissue were positive, confirming that the specimen was a fibroelastoma.
Discussion Papillary fibroelastomas are extremely rare primary cardiac tumours. They usually originate from the valves. The tumours most commonly involve aortic, mitral, tricuspid and pulmonary valves (in order of decreasing frequency).5 However, they can also affect other endothelial surfaces of the heart and Eustachian valves. Papillary fibroelastomas are small avascular tumours derived from endocardial elements and resemble sea anemones due to their multiple fronds.4,6 The majority of tumours are asymptomatic. Given the widespread use of echocardiography, the tumours are sometimes found during routine transthoracic echocardiograms, as in our case. Transoesophageal echocardiography is used for more precise evaluation of the tumour. However, smaller tumours could be missed even by this technique. Tumour attachment to the endocardium via a pedicle, its high mobility, speckled appearance with central echolucency, and shimmer at the tumourâ&#x20AC;&#x201C;blood interface are some of the
Fig. 4. Surgical specimen of the fibroelastomas after resection.
features which help echocardiographic diagnosis.7 The evolution of coronary computed tomography angiography and cardiac magnetic resonance imaging may provide additional diagnostic tools for identifying the tumours earlier. Papillary fibroelastomas can manifest as an embolic phenomenon in the form of transient ischaemic attack, stroke, angina, myocardial infarction, pulmonary embolism, retinal embolism, syncope and death.5,7 Even though treatment with antiplatelet medications and anticoagulation with warfarin are some of the treatment options, it has been suggested that a surgical approach should be strongly considered, even in asymptomatic patients, given the severity of the potential complications.4,7
Conclusion Due to the rarity of the tumour and the lack of large randomised trials, the surgical recommendation is based on isolated case reports and professional consensus. Valve repair and replacement carries significant short- and long-term complications including increased risk of endocarditis, embolic phenomena, deterioration and malfunction of the prosthesis. In our case, the surgery was performed using a minimally invasive approach with a valvesparing technique, decreasing the chance of both short- and long-term complications and facilitating earlier recovery of the patient.
References 1.
Lam KY, Dickens P, Chan ACL. Tumors of the heart: A 20 year experience with review of 12,485 consecutive autopsies. Arch Pathol Med 1993; 117: 1027â&#x20AC;&#x201C;1031.
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Basso C, Valente M, Poletti A, et al. Surgical pathology of primary cardiac and pericardial tumors. Eur J Cardiothorac Surg 1997; 12(5): 730–737. Baba Y, Tsuboi Y, Sakiyama K, et al. Cardiac papillary fibroelastoma as a cause of recurrent ischemic strokes; the diagnostic value of serial transesophageal echocardiography. Cerebrovasc Dis 2002; 14(3): 256–259. Grinda J-M, Couetil JP, Chauvaud S, et al. Cardiac valve papillary fibroelastoma: surgical excision for revealed or potential embolization. J Thorac Cardiovasc Surg 1999; 117: 106–110.
5.
6. 7.
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Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J 2003;146(3): 404–410. Abu Nassar SG, Parker JC Jr. Incidental papillary endocardial tumor: its potential significance. Arch Pathol 1971; 92: 370–376. Klarich KW, Enriquez-Sarano M, Gura GM, et al. Papillary fibroelastoma: echocardiographic characteristics for diagnosis and pathologic correlation. J Am Coll Cardiol 1997; 30(3): 784–790.
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Case Report Cardiac mass in a patient with sigmoid adenocarcinoma: a metastasis? HARRIS A NGOW, WMN WAN KHAIRINA
Abstract
Case report
Cardiac metastasis from a bowel malignancy seldom occurs and there is a limited number of case reports published on this subject. Although colorectal cancer is the third commonest malignancy in Malaysia, the incidence of cardiac metastasis has never been reported. We report a case of an elderly man with recently diagnosed adenocarcinoma of the sigmoid colon, who presented with congestive cardiac failure secondary to mechanical obstruction by a right atrial mass. The intractable shock led to his sudden death before any intervention could be planned. If an intra-cavity cardiac mass is detected in a patient with an underlying metastatic malignancy, cardiac metastasis should be suspected. However, primary cardiac tumour or thrombus could also be the differential diagnosis. In our case, the definitive cardiac pathology remained unsolved as an autopsy was refused.
A 59-year-old Chinese man was referred for progressive dyspnoea of three weeks’ duration. This was associated with orthopnoea, paroxysmal nocturnal dyspnoea and bilateral leg swelling. He also complained of reduced effort tolerance and progressive abdominal distension in the two weeks prior to admission. He had had altered bowel habits of one-month duration with diarrhoea and haematochezia. His appetite had been poor and he had had significant weight loss of 6 kg within one month. There was no significant past medical history. He did not smoke or consume alcohol. There was no family history of bowel malignancy or other tumours. He also denied a history of blood transfusion or risky behaviour. At presentation he was wasted and cachexic. The sclera were yellow with pale conjunctiva. His blood pressure was 110/70 mmHg. The pulse rate was 82 beat per minute and he was afebrile. There was no palpable lymphadenopathy. Chest examination showed reduced breath sounds with dullness bibasally. The precordium revealed normal heart sounds with no added sound or murmur. Abdominal examination revealed a distended abdomen with ascites. There was hepatomegaly with mild tenderness. The haemoglobin count was 10.4 g/dl, platelet count was 196 × 109/l, and total white cell count was 11.3 × 109/l. The liverfunction test showed a cholestatic picture with total bilirubin of 161.7 µmol/l (direct bilirubin 77.8 µmol/l and indirect bilirubin 83.9 µmol/l). Serum albumin was 22.9 g/l, and serum transaminases and alkaline phosphatase were normal. The INR was 1.4. Tumour markers including carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) were elevated at 13.4 ng/ml and 40.9 U/ml, respectively. The chest X-ray revealed a cannon-ball appearance. Abdominal ultrasound revealed coarse liver echotexture with gross ascites. Echogenic focal liver lesions were noted. Computed tomography of the chest, abdomen and pelvis revealed extensive lung nodules of varying sizes in both lung fields. Minimal pleural effusion was noted with multiple pretracheal, precarinal and subcarinal lymphadenopathy. The liver was enlarged with multiple liver nodules. Gross ascites was noted. A colonoscopy revealed a tumour at the sigmoid colon about 20 cm from the anal verge. The histopathological examination showed a dysplastic adenomatous polyp with features of invasive adenocarcinoma (Fig. 1). An echocardiogram showed a large homogeneous mobile mass at the right atrium measuring 5 × 6 cm (Fig. 2). While waiting for a decision on further management, the patient had cardio-respiratory arrest in the ward and died. This
Keywords: colorectal adenocarcinoma, cardiac tumour, metastasis, echocardiography Submitted 28/9/10, accepted 13/3/12 Cardiovasc J Afr 2012; 23: e10–e12
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DOI: 10.5830/CVJA-2012-027
Colorectal cancer is the third most common malignancy in Malaysia.1 The estimated prevalence is about eight per 100 000 population per year. It is also the third most common cause of mortality in Malaysia. Cardiac metastasis from colorectal adenocarcinoma is rare and usually a sign of extensive disease. The reported incidence in Malaysia is unknown. In the literature there are only a few cases reported thus far. In reported autopsy series of all cause of deaths, cardiac metastases appear in 1% of all cases.2 In autopsies of patients diagnosed with cancer, the incidence ranges from 1.6 to 15.4%.3-5 In colorectal cancer, the incidence of cardiac metastasis was 1.4 to 7.2% in autopsy studies.6 We report a case of a single cardiac mass in the right atrium from a patient with recently diagnosed sigmoid colon adenocarcinoma.
Department of Medicine, International Islamic University Malaysia, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia HARRIS A NGOW, MD, MMed (Int Med), harrisngow@gmail.com
Paediatric Department, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia WMN WAN KHAIRINA, MB BS, MMed (Paed)
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Fig. 1. A section of the sigmoid colon biopsy which showed the moderately differentiated adenocarcinoma x 40 magnification.
case illustrates a classic colonic adenocarcinoma with distant metastases. The cardiac mass was most likely a metastatic tumour.
Discussion The most common sites of colorectal carcinoma metastases are the liver and lungs. Cardiac metastases from primary colorectal carcinomas are extremely rare. Tumours that more often metastasise to the heart are carcinomas of the lung and breast, mesotheliomas, melanomas and lymphomas.7 Klatt and Heitz studied a total of 1 029 autopsies from patients diagnosed with malignancies.4 They found cardiac involvement in 10.4% of all cases; 36.4% of them originated from adenocarcinoma of the lung, gastrointestinal tract, female genitourinary tract, breast or pancreas.4 The incidence was similar to that of an earlier study by Goudie et al., which reported 10% of cardiac metastases in autopsies of cancer-related deaths.5 Right-sided cardiac involvement, especially in the right ventricle, is more common than in the left chambers.8 The reason for this has not been well established. In this patient a mass, which was most likely the metastasis, was found in the right atrium causing obstruction to the right ventricular inflow. In clinical practice, the most frequent form of cardiac metastasis is pericardial seeding, which may lead to pericardial tamponade. Metastasis to the endocardium is infrequent.9 This however may cause haemodynamic embarrassment, resulting in heart failure, as seen in our case. Generally, when the endomyocardium is involved, pericardial effusion is seen. However, in our case, pericardial effusion was not present. Two-dimensional echocardiography is the initial investigative modality for the detection of intra-cardiac mass as well as pericardial effusion, as it has high sensitivity and specificity.10 Nowadays additional cardiac computed tomography and magnetic resonance imaging are necessary to give adequate radiological assessment. These modalities may help to differentiate the intracavity mass from organised thrombus surrounding the mass. In addition, information from Doppler echocardiography, magnetic resonance imaging or thoracic radionuclide scanning may aid in differentiating a thrombus from a solitary intra-cardiac mass. These modalities may assist in detecting the presence or absence
Fig. 2. Two dimensional transthoracic echocardiogram showing the solitary homogenous mass in the right atrium with obstruction of the right ventricular inlet. (White arrows delineate the margins of the mass.)
of haemosiderin deposits in the mass, thereby differentiating an intra-cardiac mass from a thrombus. Cardiac magnetic resonance imaging shows in detail the location, insertion site and size of the tumour which will facilitate surgical resection. Tissue characterisation and signs of neovascularisation provide crucial information to differentiate between a tumour and thrombus if uncertainty arises after echocardiography. Multi-detector cardiac computed tomography or coronary angiography are the investigations of choice to identify concomitant coronary artery disease or anomalies prior to surgery. In our case, the concurrent findings of extensive sigmoid colon carcinoma and an infiltrative mass in the right atrium made metastatic intra-cardiac metastasis the most likely diagnosis. However, the lack of evidence due to unavailability of histopathological analysis made this conclusion uncertain. Although double pathology is rare, other differential diagnoses such as myxoma, thrombus or other primary cardiac tumour should still be entertained. The advancement in anti-cancer treatments and progress in diagnostic modalities have generally improved the survival rate of cancer patients. Therefore the frequency of intra-cardiac involvement would be expected to be higher. The possibility of developing metastatic disease in an infrequent site may also be increasingly seen in clinical practice. Early diagnosis and curative surgical resection may prevent progression and sudden cardiac death. In a patient with symptoms and signs of valvular obstruction such as in this patient, surgical intervention may be indicated. This may help to relieve the obstructive symptoms and lead to prolongation of life expectancy in such a patient. A palliative symptomatic approach may be adopted to obviate the mortality risk in patients such as ours.11,12 Our patient had unfortunately succumbed before any intervention could be carried out. Koizumi et al. reported a case of obstructive cardiac metastasis
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which had been successfully treated with surgical extirpation.13 Unfortunately, as seen in other reported cases, most cardiac metastases implied poor prognosis, with death occurring even after resection due to the invasive nature of the metastases.7,10,14
6.
7.
Conclusion Cardiac metastasis is possible in any extensive malignancy. The finding of an intracardiac mass should raise the suspicion of a secondary metastasis related to the primary malignancy. With improved diagnostic tools, the incidence of cardiac metastases is expected to increase, however, the prognosis is usually poor.
8. 9. 10. 11.
References 1. 2. 3.
4. 5.
Wendy L, Radzi M. New registry: National Cancer Patient Registry – Colorectal Cancer. MJM Patient Registry 2011; 63(Suppl): 57–58. Debourdeau P, Gigorov J, Texeira L, Aletti M, Zammit G. Malignant cardiac tumours. Bull Cancer 2004; 91; 156–146. Mukai K, Shinkai T, Tominaga K, Shimosato Y. The incidence of secondary tumours of the heart and pericardium: a 10 year study. Jpn J Clin Oncol 1988; 18: 195–201. Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990: 65; 1456–1459. Goudie RB. Secondary tumours of the heart and pericardium. Br Heart
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J 1955; 17; 183–188. Choi PW, Kim CN, Chang SH, Chang WI, Kim CY, Choi HM. Cardiac metastasis from colorectal cancer: A case report. World J Gastroenterol 2009; 15: 2675–2678. Oneglia C, Negri A, Bonora-Ottoni D, Gambarotti M, Bisleri G, Rusconi C, Muneretto C. Congestive heart failure secondary to right ventricular metastasis of colon cancer. A case report and review of the literature. Ital Heart J 2005; 6: 778–781. Prichard RW. Tumours of the heart. Arch Path 1951; 51: 98–128. Lord RV, Tie H, Tran D, Thorburn GW. Cardiac metastasis from a rectal adenocarcinoma. Clin Cardiol 1999: 22(11); 749. Tatli S, Lipton MJ. CT for intracardiac thrombi and tumours. Int J Cardiovasc Imaging 2005; 21(19): 115–151. Parravicini R, Fahim NA, Cocconcelli F, et al. Cardiac metastasis of rectal adenocarcinoma. Surgical treatment. Tex Heart Inst J 1995; 20(4); 296–298. Testempassi F, Takeuchi H, Fukuda Y, Harada J, Tada S. Cardiac metastasis of colon adenocarcinoma diagnosed by magnetic resonance imaging. Acta Cardiol 1994; 49(2): 191–196. Koizumi J, Agematsu K, Ohkado A, Shiikawa A, Uchida T. Solitary cardiac metastasis of rectal adenocarcinoma. Jpn J Thorac Cardiovasc Surg 2003; 51: 330–332. Yasuda N, Ishiki R, Agetsuma H. Single large metastatic tumour growing progressively and occupying right ventricular cavity. Heart 2002; 87: 528.
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Case Report Isolated lower limb ischaemia as an unusual presenting symptom of aortic dissection CHIH-HSIEN LEE, CHENG-HSI CHANG, YI-TING TSAI, CHING-WEN WU
Abstract Acute aortic dissection is not common but usually presents with a severe, sharp chest pain and high blood pressure. Widening of the mediastinum is usually also evident on chest X-ray. Although acute onset of severe chest or back pain is the most common presenting symptom, some patients may present with atypical symptoms and signs. Establishing a diagnosis of aortic dissection can be difficult in the presence of atypical symptoms, especially in the absence of pain. Such presentation of aortic dissection is easily ignored. We report a case of painless aortic dissection with normal blood pressure, which resulted in acute isolated lower limb ischaemia at presentation. Atypical presentation of isolated limb arterial occlusions in an older patient without the classic symptoms are seldom reported as aortic dissection. However, aortic dissection should be included in the differential diagnosis of patients with arterial occlusive disease without chest pain and with normal blood pressure. Keywords: aortic dissection, lower limb ischaemia Submitted 20/11/11, accepted 15/3/12 Published online 11/4/12 Cardiovasc J Afr 2012; 23: e13–e14
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DOI: 10.5830/CVJA-2012-029
Aortic dissection is a catastrophic disease with variable presentation. Pain is the most prominent initial symptom and severe chest pain is the major complaint in 80 to 95% of patients.1 However, approximately 6.4 to 14% of aortic dissection patients presented with painless aortic dissection.2-4 Isolated lower extremity ischaemia is an unusual presentation in aortic
dissection. Herein, we report a patient who presented with right lower extremity ischaemia with neither chest pain nor abdominal discomfort.
Case report A 62-year-old man with no previous history, suffered from sudden-onset parethesia of the right lower limb and chest tightness without pain. Because of his persistent symptoms, the patient presented at our hospital for evaluation and treatment. On initial evaluation, the patient had a right-side blood pressure of 108/79 mmHg, and left-side blood pressure of 100/70 mmHg. His oral temperature was 36.8°C, pulse rate was 60 beats/min and respiratory rate was 20/min. Physical examination revealed neither cardiac murmur nor abnormal breathing sounds. The muscle power of the right lower limb was reduced, with diminished pulse at the right femoral artery. Laboratory tests showed a white blood cell count of 10.53 × 103/ml, haemoglobin concentration of 14.4 g/dl, blood urea nitrogen concentration of 24 mg/dl, blood creatinine concentration of 1.3 mg/dl, sodium concentration of 141 mEq/l, and potassium concentration of 2.7 mEq/l. The liver function tests were normal and other observations were unremarkable. The ECG showed sinus rhythm. A chest CT scan revealed an intimal flap and we found Stanford type B aortic dissection (Fig. 1). The diagnosis of the acute dissection was confirmed and the patient received a sternotomy with elephant trunk. At one-year follow up he was fine.
Discussion Acute onset of severe chest or back pain characterised as ‘ripping’ or ‘tearing’ is the most common presenting symptom of aortic dissection, which typically originates from a primary
Internal Medicine – Acute Illness, Department of Internal Medicine, Tungs’ Taichung MetroHarbor Hospital, Taiwan CHIH-HSIEN LEE, MD
Department of Cardiac Surgery, Tungs’ Taichung MetroHarbor Hospital, Taiwan CHENG-HSI CHANG, MD CHING-WEN WU, MD, jamesolee@yahoo.com.tw
Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taiwan CHIH-HSIEN LEE, MD YI-TING TSAI, MD
Fig. 1. CT scan showing an intimal flap and Stanford type B aortic dissection.
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intimal tear causing separation of the aortic wall components, and collection of blood between the wall layers. Some patients with acute aortic dissection do not present with typical chest or back pain. The incidence of absence of pain in aortic dissection varied in different series in the literature but approximately 6.4 to 14% of aortic dissection patients presented with painless aortic dissection.2-4 As chest or back pain is by far the most characteristic presentation, its absence usually diverts our attention from a diagnosis of aortic dissection. Aortic dissection presenting with isolated ischaemia of the leg is rare, occurring in about 10% of patients, but is has been well described.2,3 Because isolated lower extremity ischaemia without chest pain and other classic symptoms of aortic dissection is rare, it is frequently misdiagnosed. In our patient, the isolated lower limb symptoms masked the oppressive feelings of the dissection. The absence of other finding, such as mediastinal widening and predisposing risk factors further hampered a correct diagnosis. If painless aortic dissection occurs in an older patient, as with our patient, there is often no indication, and early diagnosis is difficult. A delayed or missed diagnosis usually portends a poor outcome. Obstruction of any arterial branch may lead to ischaemia of several organs or extremities and produce a variety of symptoms in addition to the characteristic pain originating from the intimal tear of the aorta. Although chest radiography is helpful in providing important clues in suspected cases of aortic dissection, it is rarely diagnostic.2 Findings such as aortic knob abnormalities, mediastinal widening, irregular aortic contour, displacement of intimal calcification and pleural effusion are indicative. Normal chest radiographs are found in 10 to 20% of proven aortic dissections.1,2 We therefore recommend including aortic dissection in the differential diagnosis of limb ischaemia. In our patient, the development of acute isolated lower limb ischaemia was so
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severe that the differential diagnosis should have been limited to vascular insult. If a patient has no history of bleeding diathesis or any cancer, aortic dissection should be strongly considered. Aortic dissection should be presumed to be the cause of acute isolated lower limb ischaemia despite angiography not having been done. Our case presentation is intended to illustrate a category of patients with aortic dissection that may easily be overlooked and therefore untreated. Given the potential lethal nature of acute aortic dissection, appropriate diagnostic evaluation, such as echocardiography, CT scan or MRI are warranted for patients presenting with acute isolated limb ischaemia, particularly if predisposing risk factors or suggestive signs of aortic dissection are present.1
Conclusion When patients present with or develop signs and symptoms of isolated limb ischaemic injury without obvious cause, aortic dissection should be considered, even without the presence of characteristic pain. The diagnosis can be challenging in patients with painless aortic dissection.
References 1. 2.
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Crawford ES. The diagnosis and management of aortic dissection. J Am Med Assoc 1990; 246: 2537–2541. Ying CH, Pao YL, Joseph HL. Aortic dissection presenting as isolated lower extremity ischemia – a case report. Acta Cardiol Sin 2002; 18: 79–82. Chih CW, Tsui LH. Acute paraplegia in a patient with painless aortic dissection – a case report. Acta Cardio Sin 2001; 17: 245–249. Demircan A, Aksay E, Ergin M, Bildik F, Keles A, Aygencel G. Painless aortic dissection presenting with acute ischemic stroke and multiple organ failure. Emerg Med Australas 2011; 23: 215–216.
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