Candidate gene polymorphisms related to lipid metabolism in Asian Indians living in Durban, South Africa.

BACKGROUND & OBJECTIVES: Asian Indians have been shown to have a high prevalence of metabolic syndrome (MetS), related to insulin resistance and possibly genetic factors. The aim of this study was to determine the genetic patterns associated with MetS in Asian Indians living in Durban, South Africa. METHODS: Nine hundred and ninety nine participants from the Phoenix Lifestyle Project underwent clinical, biochemical and genetic assessment. MetS was diagnosed according to the harmonized definition. The apolipoprotein A5 Q139X, lipoprotein lipase (LPL) Hinf I, human paraoxonase 1 (PON1) 192Arg/Gln, cholesteryl ester transfer protein (CETP) Taq1B, adiponectin 45T>G and leptin (LEP) 25CAG were genotyped by real-time polymerase chain reaction in participants with and without MetS. Univariate-unadjusted and multivariate-adjusted relations were conducted for all analyses. RESULTS: The prevalence of MetS was high (49.0%). More females had MetS than males (51.0 vs 42.8%). There was no significant difference in the distribution of genotypes between participants with MetS and those without. Males with the MetS who had the adiponectin TG genotype and human paraoxonase 1 AA genotype were more likely to have reduced high-density lipoprotein cholesterol (HDL-C) (P=0.001) and higher systolic blood pressure (P=0.018), respectively. INTERPRETATION & CONCLUSIONS: About half of the Asian Indians living in Phoenix had MetS. No association between the polymorphisms studied and the risk for MetS was observed. The adiponectin TG genotype may be associated with reduced HDL-C and the human paraoxonase 1 AA genotype with hypertension in males. This suggested that lifestyle factors were the major determinant for MetS in this ethnic group and the genetic risk might be related to its component risk factors than to MetS as an entity.

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Comparative assessment of absolute cardiovascular disease risk characterization from non-laboratory-based risk assessment in South African populations.

BACKGROUND: All rigorous primary cardiovascular disease (CVD) prevention guidelines recommend absolute CVD risk scores to identify high- and low-risk patients, but laboratory testing can be impractical in low- and middle-income countries. The purpose of this study was to compare the ranking performance of a simple, non-laboratory-based risk score to laboratory-based scores in various South African populations. METHODS: We calculated and compared 10-year CVD (or coronary heart disease (CHD)) risk for 14,772 adults from thirteen cross-sectional South African populations (data collected from 1987 to 2009). Risk characterization performance for the non-laboratory-based score was assessed by comparing rankings of risk with six laboratory-based scores (three versions of Framingham risk, SCORE for high- and low-risk countries, and CUORE) using Spearman rank correlation and percent of population equivalently characterized as 'high' or 'low' risk. Total 10-year non-laboratory-based risk of CVD death was also calculated for a representative cross-section from the 1998 South African Demographic Health Survey (DHS, n = 9,379) to estimate the national burden of CVD mortality risk. RESULTS: Spearman correlation coefficients for the non-laboratory-based score with the laboratory-based scores ranged from 0.88 to 0.986. Using conventional thresholds for CVD risk (10% to 20% 10-year CVD risk), 90% to 92% of men and 94% to 97% of women were equivalently characterized as 'high' or 'low' risk using the non-laboratory-based and Framingham (2008) CVD risk score. These results were robust across the six risk scores evaluated and the thirteen cross-sectional datasets, with few exceptions (lower agreement between the non-laboratory-based and Framingham (1991) CHD risk scores). Approximately 18% of adults in the DHS population were characterized as 'high CVD risk' (10-year CVD death risk >20%) using the non-laboratory-based score. CONCLUSIONS: We found a high level of correlation between a simple, non-laboratory-based CVD risk score and commonly-used laboratory-based risk scores. The burden of CVD mortality risk was high for men and women in South Africa. The policy and clinical implications are that fast, low-cost screening tools can lead to similar risk assessment results compared to time- and resource-intensive approaches. Until setting-specific cohort studies can derive and validate country-specific risk scores, non-laboratory-based CVD risk assessment could be an effective and efficient primary CVD screening approach in South Africa.

Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis.

BACKGROUND: In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES: The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN: The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 × 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS: IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.

The association between the hypertriglyceridaemia waist phenotype, cardiovascular risk factors and the metabolic syndrome in South African Asian-Indians.

BACKGROUND AND AIMS: The combination of high triglycerides and increased waist circumference (HTGW) has not been examined as a predictor of cardiometabolic abnormalities or the metabolic syndrome (MetS) in high-risk Asian populations. This study examines the so-called hypertriglyceridemia waist (HTGW) phenotype, (high serum triglycerides [Tg]) and increased waist circumference (WC) as a predictor of cardiometabolic abnormalities in a high-risk Asian population. METHODS: Data from the Phoenix Lifestyle Project, a cross-sectional study of 1349 South Asian Indians (15-65 years; 379 men; 970 women) in Durban, KwaZulu-Natal, were reclassified into different waist and Tg phenotypes using the demographic, anthropometric, and biochemical parameters. The HTGW phenotype was defined as WC ≥ 90 cm for men; ≥80 cm for women & TG ≥ 1.7 mmol/L. The MetS was determined using the harmonised criteria. Stepwise logistic regression was used to determine the strength of each phenotype as a predictor of the MetS. RESULTS: The HTGW phenotype was recorded in 35.4% of participants, predominantly women (36.1%) and 8.2% smokers. Metabolic derangements and cardiovascular risk factors increased significantly in those with HTGW phenotype. After adjustment, multivariate logistic regression showed that the association between elevated total serum cholesterol, LDL, lowered HDL, diabetes and hypertension with HTGW persisted. The odds for participants with the HTGW phenotype developing the MetS was 19.7 (95% CI 13.9; 27.9). The degree of concordance between the HTGW was highest with the IDF and harmonised criteria for MetS. CONCLUSION: The HTGW phenotype was associated with a significantly higher risk of developing additional lipid derangements, hypertension, diabetes and the MetS.

Association of cardio-metabolic risk factors with elevated basal heart rate in South African Asian Indians.

BACKGROUND: The aim of this study was to determine the association of increasing basal heart rate (BHR) with cardio-metabolic risk in a community sample of Asian Indians from South Africa, due to lack of population-based data on the interaction between heart rate and cardiovascular factors. METHODS: Data drawn from 1349 randomly selected participants was collected using the WHO STEPS questionnaire. Anthropometry, blood pressure, physical examination and laboratory analyses of venous blood samples and definition of cardiometabolic derangements were performed according to established guidelines. BHR classified into three categories, i.e., <60 bpm; 60-89 bpm and ≥90 bpm. Stepwise backward regression models were constructed for determination of association between increasing BHR and cardiometabolic parameters. A ROC was constructed to determine the AUC and to determine their sensitivity and specificity for discriminating increasing BHR levels. RESULTS: In 379 men (mean age 42±15 years; mean HR 79±13 bpm) and 970 women (mean age 46±12 years; mean HR 87±7.8 bpm), with BHR significantly higher in women (P<0.0001). The distribution of HR was: <60 bpm (2.7%); HR 60-89 bmp (75.8%); HR≥90 bpm (20.1%). In the adjusted logistic regression model fasting plasma glucose (P=0.02; OR 95% CI: 1.18 [1.02-1.4]); age (P=0.01 OR 95% CI: 0.97 [0.96-0.99]); systolic blood pressure (P<0.001 OR 95% CI: 0.95 [0.9-0.97]), and diastolic blood pressure (P≤0.001 OR 95% CI: 1.1 [1.06-1.1]) emerged as independently associated with increasing BHR. The highest AUC for discriminating increasing BHR was for mean diastolic blood pressure (AUC=0.618; P<0.001), and fasting blood glucose (AUC=0.595; P<0.0001). CONCLUSIONS: Increasing BHR was independently associated with derangements in fasting blood glucose and blood pressure.

Does acid reflux precipitate ischaemia in subjects with acute coronary syndrome?

AIM: It has been postulated that gastro-oesophageal reflux disease (GORD) may trigger coronary ischaemia through viscerocardiac reflex vasoconstriction in subjects with ischaemic heart disease (IHD). Our aim was to estimate the prevalence of GORD in subjects with IHD who present with acute coronary syndrome (ACS) and to determine whether GORD may serve as a trigger for ischaemic events. METHODS: Twenty patients with isolated reflux oesophagitis and 39 with acute coronary syndrome (ACS with concomitant GORD) were studied. Twenty-two subjects comprising normal volunteers and those who were admitted for minor surgical trauma were used as normal controls. All subjects underwent oesophago-gastroduodenal endoscopy (EGD) and acid instillation with hydrochloric acid (0.1 M), as well as nuclear imaging (sestaMIBI) with technetium99. Ischaemia was detected by ST depression using ECG monitoring for one hour during and immediately after EGD. RESULTS: Of the 111 subjects with ACS, 39 (35.1%) had erosive GORD and comprised the study group. Subjects with ACS had more incidence of diabetes (p = 0.001), hypertension (p = 0.002), a history of smoking (p = 0.006) and elevated serum triglyceride levels (p = 0.008) compared to the GORD group. Risk-factor clustering in the form of the metabolic syndrome was more common in ACS subjects (44 vs 5%; p = 0.008). ST depression was documented in 8/39 (20.5%) patients in the ACS group and 5/20 (25%) in the GORD group (p = 0.958). Reversible perfusion defects on sestaMIBI scan were seen in 35.6% of the ACS subjects. CONCLUSIONS: Although GORD is common in subjects with ACS, we have not been able to show that GORD may serve as a trigger for ischaemia in these subjects.

The Association of Epicardial Adipose Tissue and the Metabolic Syndrome in Community Participants in South Africa.

BACKGROUND: We sought to determine the association of echocardiographically derived epicardial adipose tissue (EAT) thickness, which is a component of visceral adipose tissue, with the metabolic syndrome (MetS) in a cohort of randomly selected community participants. METHODS: South African-Asian Indians aged 15-64 years were recruited over a 2-year period after informed consent was obtained. All participants who had complete measurements done for biochemistry and echocardiography (using established criteria), were dichotomized into the MetS or non-MetS groups defined according to the harmonized criteria. RESULTS: Of the 953 (232 men and 721 women) participants recruited, 47.1% (448) were classified with the MetS. These participants had larger waist circumference and body mass index (P < 0.001), with larger LA volumes and diameter, thicker ventricular walls, higher left ventricular mass, relative wall thickness, and EAT (P < 0.001). There was a corresponding increase in EAT thickness with increasing number of MetS risk factors at the transition from 0 MetS factors to 1 (95% confidence interval [CI] -0.8; -0.2) and from 2 to 3 MetS factors (95% CI -0.9; -0.4). The AUC of the receiver operator curve was highest for triglycerides (0.845), followed by fasting plasma glucose (0.795) and then EAT (0.789). An EAT value of <3.6 mm predicted the presence of the MetS with a 78% sensitivity and 70% specificity. Using backward stepwise logistic regression, the most significant independent determinants of the MetS after adjusting for age, gender, and type 2 diabetes mellitus, was fasting plasma glucose (odds ratio [OR] = 1.2), triglycerides (OR = 7.1), and EAT (OR = 2.3). CONCLUSION: Although EAT is associated with the MetS, and can identify individuals at increased cardiometabolic risk, it has a limited additional role compared to current risk markers.

Increased waist circumference is the main driver for the development of the metabolic syndrome in South African Asian Indians.

There is no current evidence available on the prevalence of metabolic syndrome (MetS) in South African Asian Indians, who are at high risk for cardiovascular disease. The aim of our study was to determine the prevalence of the MetS in this group, between males and females, as well as in the different age-groups, using the harmonised criteria and determined the main components driving the development of MetS. DESIGN AND METHODS: This cross-sectional study recruited randomly selected community participants between the ages of 15 and 65 years, in the community of Phoenix, in KwaZulu-Natal. All subjects had anthropometric variables and blood pressure measured, as well as blood drawn for blood glucose and lipids after overnight fasting. The MetS was determined using the harmonised criteria. RESULTS: There were 1378 subjects sampled, mean age 45.5±13years and 1001 (72.6%) women. The age standardised prevalence for MetS was 39.9% and significantly higher (p<0.001) in women (49.9% versus 35.0% in men). The MetS was identified in 6.9% of young adults (15-24 years), with a four-fold increase in the 25-34year olds, and 60.1% in the 55-64year old group. Clustering of MetS components was present in all age-groups, but increased with advancing age. The independent contributors to the MetS were increased waist circumference, raised triglycerides and obesity. This study highlights the high prevalence of MetS in this ethnic group and the emergence of MetS in our younger subjects. Urgent population-based awareness campaigns, focussing on correcting unhealthy lifestyle behaviours should begin in childhood.

Relationship of Body Anthropometry with Cardiovascular Risk Factors in a Random Community Sample: The Phoenix Lifestyle Project.

BACKGROUND: We studied the prevalence of metabolic syndrome (MetS) among Indians from a low-income community and evaluated the relationship between physical behavior patterns and anthropometric measures and the presence of MetS. METHODS: The modified WHO STEPS questionnaire was used to collect data from a randomized sample of 1154 subjects from the Indian community of Phoenix, Durban. MetS was classified according to the harmonized criteria. RESULTS: The median age of the sample was 47 (37-55) years, and 72% were predominantly females. There was a high prevalence of elevated body mass index (BMI) in 757 subjects (66%), which increased to 901 subjects (82%) when the ethnic-specific Asian cutoff (BMI ≥ 23) was applied. Overall increase in waist circumferences was noted from 60% to 79% when ethnic cutoffs were applied. Vigorous exercise was associated with a significant decrease in waist and BMI measurements (P < 0.0001). The prevalence of MetS increased from 30% and 57% (NCEP) to 45% and 60% in males and females, respectively, when the harmonized criteria (IDF and WHO) were applied. Fasting insulin and total cholesterol emerged as independent determinants of MetS for both genders. Neck circumference and HbA1c were also significant predictors of MetS in males. In females, midarm circumference (IDF/WHO) and HbA1c (modified NCEP) emerged as additional predictors of MetS. CONCLUSION: There was a high prevalence of obesity and MetS in this sample, related to sedentary behavior patterns. Neck and arm circumferences as well as total cholesterol may also serve as screening measures to increase the detection rate of MetS.

HIV-associated large-vessel vasculopathy: a review of the current and emerging clinicopathological spectrum in vascular surgical practice.

An established relationship exists between human immunodeficiency virus (HIV) and the vascular system, which is characterised by clinical expressions of aneurysmal and occlusive disease that emanate from a common pathological process. The exact pathogenesis is currently unknown; attempts to implicate opportunistic pathogens have been futile. Theories converge on leucocytoclastic vasculitis with the vaso vasora as the vasculopathic epicentre. It is thought that the virus itself or viral proteins trigger the release of inflammatory mediators that cause endothelial dysfunction and smooth muscle proliferation leading to vascular injury and thrombosis. The beneficial effects of highly active anti-retroviral therapy alter the natural history of the disease profile and promote longevity but are negated by cardiovascular complications. Atherosclerosis is an emerging challenge. Presently patients are managed by standard surgical protocols because of non-existent universal surgical interventional guidelines. Clinical response to treatment is variable and often compounded by complications of graft occlusion, sepsis and poor wound healing. The clinical, imaging and pathological observations position HIV-associated large-vessel vasculopathy as a unique entity. This review highlights the spectrum of HIV-associated large-vessel aneurysmal, occlusive and atherosclerotic disease in vascular surgical practice.

Myocardial perfusion imaging for evaluation of suspected ischemia and its relationship with glycemic control in South African subjects with diabetes mellitus.

BACKGROUND: The relationship between myocardial perfusion imaging (MPI) abnormalities, diabetes mellitus, and glucose control in South African populations is unknown. It was hypothesized that in subjects undergoing MPI for suspected coronary artery disease (CAD), those with diabetes would have more extensive perfusion defects and that diabetes control would influence MPI abnormalities. The aim of this study was to examine the relationship between the severity of CAD diagnosed with MPI in subjects with and without diabetes and to determine the relationship between diabetes control and extent of CAD. METHODS: This study was a retrospective chart review of 340 subjects in whom MPI scans were performed over a 12-month period. RESULTS: Subjects with diabetes had a higher prevalence of abnormal MPI, with more extensive ischemia, compared with subjects without diabetes (85.6% versus 68%; odds ratio 2.81, P<0.01). Glycated hemoglobin ≥7.0% was associated with a higher risk of abnormal MPI, with more extensive ischemia, compared with subjects having diabetes and glycated hemoglobin <7.0% (odds ratio 2.46, P=0.03) and those without diabetes (odds ratio 4.55, P=0.0001). CONCLUSION: Subjects with diabetes have more extensive myocardial ischemia when compared with subjects without diabetes. Furthermore, poorer diabetes control is associated with more abnormalities on MPI scanning.

Genetic variants associated with insulin resistance and metabolic syndrome in young Asian Indians with myocardial infarction.

BACKGROUND: The objective of this study was to assess whether an association exists between the metabolic syndrome and polymorphisms in genes involved in insulin resistance in young Asian Indian patients presenting with acute myocardial infarction (AMI). METHODS: The study population comprised 467 patients who were 45 years or younger. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) definitions were used to assess the prevalence of metabolic syndrome. We examined the genotype and allele frequencies of the IRS-I G972R, PPAR-gamma P12A, KCNJ11 E23K, and TNF-alpha -308G/A polymorphisms in relation to the metabolic syndrome determined by both definitions. RESULTS: The metabolic syndrome as defined by the NCEP ATP III criteria was found in 282 (60.4%) patients, and in 278 (59.5%) patients according to the IDF criteria. This gave only a moderate level of agreement of 79% between the two definitions (Cohen's kappa = 0.554). No association was found between the IRS-I G972R, PPAR-gamma P12A, and KCNJ11 E23K, or TNF-alpha -308G/A polymorphic variants and the metabolic syndrome, or its components, for either definition. CONCLUSION: Although the metabolic syndrome is a common finding in young Asian Indian patients with AMI, there was only a moderate level of agreement between the NCEP ATP III and IDF definitions of the syndrome. Our findings do not support a role for any of the polymorphic variant alleles in the four insulin resistance-related genes examined in the etiology of insulin resistance and reinforces the notion of a multifactorial etiology for the metabolic syndrome.

The role of echocardiography and its comparison with NT-proBNP measurements in patients with acute myocardial infarction.

BACKGROUND: This study investigated the use of echocardiography in the early detection of regional wall motion abnormalities (RWMA) in patients presenting with acute myocardial infarction (AMI). The relationship between RWMA and mechanical complications, as assessed by two-dimensional echocardiography, and admission levels of amino terminal fragment of pro-brain natriuretic peptide (NT- proBNP) was also examined. MATERIAL/METHODS: The study population comprised 226 patients admitted to hospital with a diagnosis of AMI. Echocardiography and NT-proBNP measurements were performed on all patients. RESULTS: Sixty-eight percent of the patients with AMI were found to have RWMA on echocardiography. Significantly more patients had RWMA within any given range of ejection fraction (EF) (p<0.001), but this difference was most pronounced in those with left ventricular (LV) dysfunction. Mitral regurgitation was the most common complication (48%) seen on echocardiography. The majority of patients (84%) had elevated NT-proBNP levels on admission; this was evident in all categories of EF (p=0.003). In those with normal EF on echocardiography (58%), more patients had elevated levels regardless of the presence of RWMA. CONCLUSIONS: This study showed that echocardiography is useful in the detection of RWMA in the early stages of AMI. No significant relationship was demonstrated between NT-proBNP levels and RWMA in patients with normal or abnormal LV function. Admission plasma NT-proBNP may, however, be considered as an additional marker in the diagnosis of AMI, especially in those without RWMA.