Doctoral Degrees (Cardiology)

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    Genetic contribution to the risk for metabolic syndrome : an investigation of candidate gene polymorphisms related to lipid and carbohydrate metabolism.
    (2015) Maistry, Tanya.; Gordon, Michelle Lucille.; Naidoo, Datshana Prakesh.
    Abstract available in PDF file.
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    The echocardiographic manifestations of an urban, working class community with a high cardiovascular risk profile.
    (2013) Prakaschandra, Dorcas Rosaley.; Naidoo, Datshana Prakesh.; Gordon, Michelle Lucille.
    The metabolic syndrome (MS), consequent upon the pandemic of obesity and diabetes, is associated with an increased risk for cardiovascular (CV) disease. Development of sub-clinical cardiac structural and functional changes associated with CV disease risk factors may be detected on echocardiography. The extent to which these structural changes and CV risk factors are dependent on genetic factors is not clearly established. This project was designed to investigate the relationship between CV disease risk factors, cardiac structural and functional changes and underlying genetic abnormalities. Specifically, the risk factor profile and the presence of the MS were determined. This was then correlated with the echocardiographic findings and gene polymorphisms. Method: A randomly selected cohort of 1428 subjects from the Phoenix community was studied. Demographic data was collected using the WHO STEPS instrument. Blood samples for biochemistry and genetic analysis, together with anthropometric measurements, were collected. Blood pressure and echocardiography was performed on all subjects. The metabolic syndrome was classified according to the National Cholesterol Education Panel (NECP) Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) criteria. The Lipoprotein Lipase and Human Paraoxonase-1 genes were genotyped on a Light Cycler 480 Real-Time PCR instrument, using allele-specific probes and sequencing. Results: There was a high prevalence of CV risk factors in this sample; particularly increased waist circumference (79%), obesity (64%) insulin resistance (58%) and hypertension (50%) across the age groups. This translated into a high prevalence of MS (38% using NCEP ATPIII and 46% using IDF criteria). There were significant echocardiographic differences between subjects with and without MS for chamber dimensions (p<0.001), left ventricular wall thickness (p<0.001) and mass (p<0.001), diastolic indices (E-wave {p<0.001}, trans-mitral ratio {p=0.017}) and sub-epicardial adipose tissue (SEAT) thickness (p<0.001). Stepwise multivariate analysis identified age (95% CI 0.975; 0.998), gender (95%CI 0.48; 0.9) and hypertension (95% CI 0.53; 0.99) as independent risk factors for diastolic abnormalities. Logistic regression identified age as the most significant contributor to diastolic abnormalities (OR=1.02; 95%CI 1.009; 1.03; Wald=13.4), followed by the waist circumference (OR=1.025; 95%CI 1.014; 1.037) and BMI (OR=1.075; 95% CI 1.035; 1.117). Genetic analysis showed significant associations between the heterozygous variant of Q192R genotype (PON-1 gene) and elevated HDL levels and also between this variant and obese women (p= <0.05). Conclusion: The high prevalence of CV risk factors and MS in this community has reached epidemic proportions. Although the MS was associated with significant remodelling of cardiac structure, alteration of diastolic indices and increased sub-epicardial adipose tissue thickness, BMI and waist circumference were stronger promoters of altered cardiac physiology. This augurs poorly for this population group unless intervention is introduced to address the markedly high prevalence of these culprit drivers.
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    The role of genetic factors in early onset coronary heart disease in the Natal Indian.
    (2000) Naidoo, Datshana Prakesh.; Chetty, R.; Sharma, Arya.
    Objective: To determine the role of candidate gene polymorphisms in patients who sustained myocardial infarction at a young age and examine their relationship, if any, to risk factors. Since angiotensin II is known to play a pathophysiological role at the myocardial and vascular level, the genes to be studied are those regulating the renin angiotensin system and tissue metabolism. Design: The risk factors and genetic profile is described in 117 young Indians with myocardial infarction recruited over a period of thirty months (Dec 1997 - Jun 1999). Controls comprised 80 normal subjects with no clinical evidence of coronary heart disease (CHD) and with a normal effort response. The key features of this study are the selection of young subjects with myocardial infarction, (mean age 43 ± 6.8 years) in whom the possibility of a genetic basis for the disease was felt to be more likely since the confounding effect of age as a risk factor was reduced. Setting: Patients recruited 3 -12 months after myocardial infarction from Addington Hospital, Durban. This hospital subserves the Indian community in the north of Durban. The majority of patients were from the Phoenix settlement area. Results: 1. The clinical profile of the young Indian with myocardial infarction is a young man, slightly overweight with a high prevalence of risk factors, particularly smoking and diabetes, coupled with sedentary behaviour and risk-prone dietary patterns characterised by high red meat intake and low fruit and vegetable consumption, resulting in increased BMI and W/H ratios. 2. There were no differences in the patterns of gene polymorphism in the reninangiotensin system between the study and control groups. This finding extended across all candidate gene loci studied i.e. those involving aldosterone, G-protein, TGF-B and homocysteine metabolism. Serum triglycerides, haemoglobin AlC and urine microalbumin levels were elevated in the probands together with low HDL-C levels (p = 0.001). 3. A striking finding of this study was the substantial proportion of patients found to have diabetes mellitus, totalling 47% of the proband group. Of the 53 diabetic patients, (45 males and 8 females) four (3 males, 1 female) had impaired glucose tolerance. Cigarette smoking, a positive family history of hypertension/diabetes and a family history for premature CHD emerged as important risk predictors for MI. Conclusion: This study, the first to report candidate gene polymorphisms in young Indians with coronary heart disease, has shown no obvious association between the genetic loci studied and acute myocardial infarction. Instead a high prevalence of risk factors, particularly smoking and diabetes mellitus, coupled with coronary-prone behavioural patterns was observed. In the light of these findings, genome-wide screening of unaffected siblings of subjects with early onset CHD cannot be recommended in this population until common polymorphisms can be clearly identified as risk factors. Indeed this study again supports the dire need for early, school level, education in behavioural lifestyle patterns and disease predisposition. The Indian community is a very high-risk group who should be targeted, not for secondary, but for primordial disease prevention measures. The study does not rule out the role of other candidate gene polymorphisms in the pathogenesis of CHD in these subjects. The high prevalence of diabetes and insulin resistance suggests that studies of genes regulating glucose and lipid metabolism should be pursued. Such candidate genes should include genes for lipoprotein lipase and paraoxonase polymorphisms which may explain the dyslipidaemia patterns in this group.