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.

Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study.

BACKGROUND: The Heart of Soweto Study aims to increase our understanding of the characteristics and burden imposed by heart disease in an urban African community in probable epidemiological transition. We aimed to investigate the clinical range of disorders related to cardiovascular disease in patients presenting for the first time to a tertiary-care centre. METHODS: From Jan 1 to Dec 31, 2006, we recorded data for 4162 patients with confirmed cases of cardiovascular disease (1593 newly diagnosed and 2569 previously diagnosed and under treatment) who attended the cardiology unit at the Chris Hani Baragwanath Hospital in Soweto, South Africa. We developed a prospectively designed registry and gathered detailed clinical data relating to the presentation, investigations, and treatment of all 1593 patients with newly diagnosed cardiovascular disease. FINDINGS: Most patients were black Africans (n=1359 [85%]), and the study population contained more women (n=939 [59%]) than men. Women were slightly younger than were men (mean 53 [SD 16] years vs 55 [15] years; p=0.031), with 399 (25%) patients younger than 40 years. Heart failure was the most common primary diagnosis (704 cases, 44% of total). Moderate to severe systolic dysfunction was evident in 415 (53%) of 844 identified cases of heart failure, 577 (68%) of which were attributable to dilated cardiomyopathy or hypertensive heart disease, or both. Black Africans were more likely to be diagnosed with heart failure than were the rest of the cohort (739 [54%] vs 105 [45%]; odds ratio [OR] 1.46, 95% CI 1.11-1.94; p=0.009) but were less likely to be diagnosed with coronary artery disease (77 [6%] vs 88 [38%]; OR 0.10, 0.07-0.14; p<0.0001). Prevalence of cardiovascular risk factors was very high, with 897 (56%) patients diagnosed with hypertension (190 [44%] of whom were also obese). Only 209 (13%) patients had no identifiable risk factors, whereas 933 (59%) had several risk factors. INTERPRETATION: We noted many threats to the present and future cardiac health of Soweto, including a high prevalence of modifiable risk factors for atherosclerotic disease and a combination of infectious and non-communicable forms of heart disease, with late clinical presentations. Overall, our findings provide strong evidence that epidemiological transition in Soweto, South Africa has broadened the complexity and spectrum of heart disease in this community. This registry will enable continued monitoring of the range of heart disease.

Mapping the emergence of heart disease in a black, urban population in Africa: the Heart of Soweto Study.

BACKGROUND: There is increasing evidence that many populations in the developing world are in "epidemiologic transition" with the subsequent emergence of more "affluent" disease states. The "Heart of Soweto Study" will systematically investigate the emergence of heart disease (HD) in a large urban population in South Africa. METHODS: Part of the conurbation of Johannesburg, South Africa, Soweto is a predominantly Black African community of 1 million individuals. During an initial two year period, all individuals presenting to the local Baragwanath Hospital (3500 beds) with any form of HD will be studied. Demographic and diagnostic coding data in those with pre-established HD will form an abbreviated clinical registry of >12,000 "prevalent" cases. Similarly, socio-demographic, clinical and diagnostic data (e.g. echocardiography and ECG) in newly diagnosed patients will form a more detailed clinical registry of >5000 "incident" cases. Sub-studies of the relationship between HIV status and HD and the optimal management of chronic heart failure will also be performed. RESULTS: These data will provide a unique insight into the causes and consequences of a broad spectrum of HD-related conditions in a "developing world" community in epidemiologic transition. Initially documented population rates, in addition to detailed examinations of the underlying risk factors and causes of HD-related morbidity/mortality will provide an important platform for future stages of the study: a community-based, population screening program and culturally specific primary and secondary programs of care. CONCLUSION: There is an urgent need to systematically track the emergence of HD in the developing world. Initially involving more than 15,000 individuals, the unique Heart of Soweto Study has the potential to provide a wealth of information in this regard.

A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa.

BACKGROUND: Cardiovascular diseases (CVDs) are becoming increasingly significant in sub-Saharan Africa (SSA). Reliable measures of the contribution of major determinants are essential for informing health services and policy solutions. OBJECTIVE: To perform a systematic review of all longitudinal studies of CVDs and related risk factors that have been conducted in SSA. DATA SOURCE: We searched electronic databases from 1966 to October 2009. Published studies were retrieved from PubMed and Africa EBSCO. Reference lists of identified articles were scanned for additional publications. STUDY SELECTION: Any longitudinal study with data collection at baseline on major cardiovascular risk factors or CVD, including 30 or more participants, and with at least six months of follow up were included. DATA EXTRACTION: Data were extracted on the country of study, year of inception, baseline evaluation, primary focus of the study, outcomes, and number of participants at baseline and final evaluation. RESULTS: Eighty-one publications relating to 41 studies from 11 SSA countries with a wide range of participants were included. Twenty-two were historical/prospective hospitalbased studies. These studies focused on risk factors, particularly diabetes mellitus and hypertension, or CVD including stroke, heart failure and rheumatic heart disease. The rate of participants followed through the whole duration of studies was 72% (64-80%), with a significant heterogeneity between studies (for heterogeneity, p < 0.001). Outcomes monitored during follow up included trajectories of risk markers and mortality. CONCLUSIONS: Well-designed prospective cohort studies are needed to inform and update our knowledge regarding the epidemiology CVDs and their interactions with known risk factors in the context of common infectious diseases in this region.

Comparison between surrogate indices of insulin sensitivity and resistance, and the hyperinsulinaemic euglycaemic glucose clamp in urban South African blacks with and without coronary artery disease.

Coronary artery disease (CAD) and diabetes mellitus (DM) are increasing in urban black South Africans during their transition from a rural to a western lifestyle. Insulin resistance is associated with CAD and DM. Fasting-based indices [homeostasis model assessment of insulin resistance (HOMA IR), log HOMA IR, and quantitative insulin sensitivity check index (QUICKI)] were calculated and their correlations with the glucose disposal rate (M) obtained from the hyperinsulinaemic euglycaemic glucose clamp were compared in 40 patients with CAD and 20 patients without CAD. Normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and DM were categorised using the oral glucose tolerance test. M and QUICKI were lower in patients with CAD (p<0.0001 and p<0.02); HOMA IR and log HOMA IR were higher (p<0.02). M and QUICKI decreased and HOMA IR and log HOMA IR increased progressively across the NGT, IGT and DM categories in patients with and without CAD. Glucose concentrations increased across the glucose tolerance categories in patients with CAD (p<0.001) and without CAD (p<0.01). Linear regression analysis revealed significant correlations between M and log HOMA IR (r=-0.3412; p<0.02) and QUICKI (r=0.4078; p<0.003), and between waist circumference (WC) and log HOMA IR (r=0.4637) and QUICKI (r=-0.4680) both p<0.001. We concluded that patients with CAD were more insulin resistant than patients without CAD. As glucose tolerance declined, insulin resistance worsened. Log HOMA IR and QUICKI were comparable to the hyperinsulinaemic euglycaemic glucose clamp and these surrogate indices provided a valid method to estimate insulin sensitivity/resistance in our patients.

Postprandial hyperglycemia in urban South African blacks with and without coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is increasing in urban black South Africans during their transition from a rural to a western lifestyle. This study assessed postprandial hyperglycemia, which a risk factor for CAD, in blacks with and without CAD. METHODS: Fasting lipid levels and postprandial glucometabolic profiles were measured in 40 patients and 20 controls. Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM) were categorized according to American Diabetes Association criteria. Postprandial hyperglycemia was assessed by the oral glucose tolerance test (OGTT) and area under curve (AUC) analysis. Insulin resistance was evaluated by hyperinsulinemic euglycemic clamp (insulin-mediated glucose disposal, M-value). RESULTS: Glucose AUC was higher in patients than controls (p < 0.0001). Highest correlations were between AUC and 0-minute glucose (r = 0.7847; p < 0.0001), and 120-minute glucose (r = 0.9187; p < 0.0001). Patients had higher fasting and postprandial glucose responses (p < 0.05). Glucose concentrations increased among NGT, IGT, and DM categories in patients (p < 0.001) and controls (p < 0.01). Abnormal glucose tolerance was more prevalent in patients (50%) than controls (40%). M-values were lower in patients (p < 0.0001) and decreased between categories, significantly in DM patients (p < 0.02). More patients (70%) than controls (13%) had low M-values (p < 0.001). CONCLUSIONS: Postprandial hyperglycemia was common in black CAD patients and glucose concentrations at 0 minute and 120 minutes were the strongest determinants. As glucose tolerance declined, glycemic control deteriorated and insulin resistance worsened. Abnormal glucose tolerance and insulin resistance were more prevalent in patients with CAD.

Carotid intima-media thickness is a predictor of coronary artery disease in South African black patients.

BACKGROUND: Several studies have shown that increased carotid intima-media thickness (CIMT) confers risk of future coronary artery disease (CAD) and stroke. The present study aimed at investigating whether CIMT is a predictor of CAD in South African black patients. METHODS AND RESULTS: This was a prospective study of 53 patients, 41 men and 12 women, with ages ranging from 30 to 70 years. All patients had undergone coronary angiography for suspected CAD. B-mode ultrasound measurement of the carotid intima-media thickness was carried out in all patients, the operator being blinded to the coronary angiography findings. Twenty-nine of the 38 (76%) subjects with established CAD had increased CIMT, with an average mean CIMT of 1.13 mm. Single-vessel disease was present in 12 people, double-vessel disease in 11 and triple-vessel disease in 12. There was a significant positive linear trend between CIMT and the number of involved coronary vessels (p < 0.0001, r = 0.44). CONCLUSIONS: Increased CIMT correlated with evidence of angiographically proven CAD. The median percentile scores showed a progressive increase as the number of vessels involved increased. CIMT could be useful as a screening tool for the presence of CAD in the South African black population.

Leptin, adiponectin, and high-sensitivity C-reactive protein in relation to the metabolic syndrome in urban South African blacks with and without coronary artery disease.

BACKGROUND: Metabolic syndrome and coronary artery disease (CAD) are increasing in urban black South Africans during their transition from a rural to a western lifestyle. Inflammation is frequently associated with metabolic syndrome and CAD. This study evaluated markers of inflammation in black CAD patients, some of whom had metabolic syndrome. METHODS: Metabolic syndrome was defined according to International Diabetes Federation criteria. Inflammatory markers leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) were measured in 40 patients and 20 control subjects. RESULTS: Metabolic syndrome was present in 23 patients and absent in 17 patients. Leptin was the only significantly higher marker in patients with metabolic syndrome compared to patients without metabolic syndrome (P < 0.01). Leptin was higher in women than men (P < 0.01) and higher in both genders with metabolic syndrome (P < 0.03 and P < 0.04, respectively). Leptin levels rose significantly with increasing metabolic syndrome criteria (P < 0.05). hs-CRP concentrations were elevated in both patient groups. Positive correlations were found between leptin and body mass index (BMI) (r = 0.7107; P < 0.0001), waist circumference (WC) (r = 0.4981; P <0.002), and hs-CRP (r = 0.3886; P < 0.02). CONCLUSIONS: Leptin differentiated between CAD patients with and without metabolic syndrome and determined metabolic syndrome status in women and men. Leptin was the only marker that increased with additional metabolic syndrome criteria. Elevated hs-CRP concentrations may indicate a low-grade inflammatory state in CAD patients. Association of leptin with BMI, WC, and hs-CRP revealed a close link with metabolic syndrome, obesity, and inflammation in urban black South African CAD patients.

A time bomb of cardiovascular risk factors in South Africa: results from the Heart of Soweto Study "Heart Awareness Days".

BACKGROUND: There is strong anecdotal evidence that many urban communities in Sub-Saharan Africa are in epidemiologic transition with the subsequent emergence of more affluent causes of heart disease. However, data to describe the risk factor profile of affected communities is limited. METHODS: During 9 community screening days undertaken in the predominantly Black African community of Soweto, South Africa (population 1 to 1.5 million) in 2006-2007, we examined the cardiovascular risk factor profile of volunteers. Screening comprised a combination of self-reported history and a clinical assessment that included calculation of body mass index (BMI), blood pressure and random blood glucose and total cholesterol levels. RESULTS: In total, we screened a total of 1691 subjects (representing almost 0.2% of the total population). The majority (99%) were Black African, there were more women (65%) than men and the mean age was 46+/-14 years. Overall, 78% of subjects were found to have >or=1 major risk factor for heart disease. By far the most prevalent risk factor overall was obesity (43%) with significantly more obese women than men (23% versus 55%: OR 1.76 95% CI 1.62 to 1.91: p<0.001). A further 33% of subjects had high blood pressures (systolic or diastolic) and 13% an elevated (non-fasting) total blood cholesterol level: no statistically significant differences between the sexes were found. There was a positive correlation between increasing BMI and other risk factors including elevated systolic (r(2)=0.046, p<0.001) and diastolic blood pressure (r(2)=0.032, p<0.001) with overweight subjects three times more likely to have concurrent hypercholesterolemia (OR 3.3, 95% CI 2.1 to 5.3: p<0.01). CONCLUSIONS: These unique pilot data strongly suggest a high prevalence of related risk factors for heart disease in this urban black African population in epidemiologic transition. Further research is needed to confirm our findings and to determine their true causes and potential consequences.