Datshana P. Naidoo

Telomeres and atherosclerosis : review article

Abstract In humans and other multicellular organisms that have an extended lifespan, the leading causes of death are atherosclerotic cardiovascular disease and cancer. Experimental and clinical evidence indicates that these age-related disorders are linked through dysregulation of telomere homeostasis. Telomeres are DNA protein structures located at the terminal end of chromosomes and shorten with each cycle of cell replication, thereby reflecting the biological age of an organism. Critically shortened telomeres provoke cellular senescence and apoptosis, impairing the function and viability of a cell. The endothelial cells within atherosclerotic plaques have been shown to display features of cellular senescence. Studies have consistently demonstrated an association between shortened telomere length and coronary artery disease (CAD). Several of the CAD risk factors and particularly type 2 diabetes are linked to telomere shortening and cellular senescence. Our interest in telomere biology was prompted by the high incidence of premature CAD and diabetes in a subset of our population, and the hypothesis that these conditions are premature-ageing syndromes. The assessment of telomere length may serve as a better predictor of cardiovascular risk and mortality than currently available risk markers, and anti-senescence therapy targeting the telomere complex is emerging as a new strategy in the treatment of atherosclerosis. We review the evidence linking telomere biology to atherosclerosis and discuss methods to preserve telomere length.

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

BackgroundAll 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.MethodsWe 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.ResultsSpearman 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.ConclusionsWe 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.

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 (Cohens 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.

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.

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

Abstract 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.

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.

Are Common Polymorphisms of the Lipoprotein Lipase and Human Paraoxonase-1 Genes Associated with the Metabolic Syndrome in South African Asian Indians?

A cross-sectional study was performed to determine the possible contribution of the Human Paraoxonase-1 (PON1) and Lipoprotein Lipase (LPL) polymorphisms to the risk of the metabolic syndrome (MetS) in 817 participants of South African Asian Indian ancestry. Demographic and anthropometric data, including fasting blood for analysis of glycaemic and lipid parameters was collected. DNA was isolated from peripheral blood and allelic polymorphisms at positions Q192R, L55M in the PON1 gene and S447X and N291S in the LPL gene were studied using real-time PCR. Melting curve analysis was used to identify homozygotes and heterozygotes. The MetS was classified using the harmonised criteria. The prevalence of the MetS was 47.99%, with the main drivers being the increased waist circumference (96.6%), raised blood pressure (76.8%) and raised triglyceride levels (72.4%). There was no significant difference (p=n/s) in the distribution of the genotypes as well as their alleles in subjects with and without MetS. Increased levels of triglycerides was found in subjects with the MetS who had the QQ (p=0.007; OR=1.19; 95%CI=1.04; 1.36) and QR (p=0.018; OR=1.73; 95% CI=1.12; 2.67) genotypes of the Q192R polymorphisms. Subjects who had both the SX genotype (S447X polymorphism) and the LM genotype (L55M polymorphism) were more likely to have the MetS than those without (p=0.016; OR 2.19; 95% CI: 1.17, 4.06). Interactions involving the PON 1 gene may predispose to the MetS and to its component risk factors such as hypertriglyceridemia in this population. Environmental factors, such as lifestyle behaviour patterns appear to be the main driver contributing to obesity-related MetS.

Management of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a potentially lethal disease mainly affecting young females. Although the precise mechanism of PAH is unknown, the past decade has seen the advent of many new classes of drugs with improvement in the overall prognosis of the disease. Unfortunately the therapeutic options for PAH in South Africa are severely limited. The Working Group on PAH is a joint effort by the South African Heart Association and the South African Thoracic Society tasked with improving the recognition and management of patients with PAH. This article provides a brief summary of the disease and the recommendations of the first meeting of the Working Group.

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.

The implications of HIV infection on the management of valvular heart disease in Southern Africa

There is very limited information on the disease profile and treatment approaches in HIV patients with valvular heart disease (VHD) in developing countries. HIV infection impacts on patients with VHD in three settings: HIV/Aids as a comorbid disease in patients with underlying valve disease, infective endocarditis secondary to immunosuppression, and non-infective valve involvement from myocardial failure or from marantic endocarditis. The clinical presentation of infective endocarditis does not differ between HIV and non-HIV patients, with the exception that intravenous drug abuse is a common cause in specific populations. While peri-operative mortality and morbidity is high in acute infective endocarditis, surgical interventions do not increase the postoperative risk for complications or death and should therefore not be withheld. There is also little evidence to suggest that HIV or antiretroviral drugs increase the rate of cardiac-related pregnancy complications or that pregnancy may alter the course of HIV infection. Since antiretroviral therapy has been associated with considerable improvement in clinical status prior to surgery, as well as in long term outcomes, all patients with valve disease in whom intervention is likely should undergo HIV testing and staging so that highly active antiretroviral treatment (HAART) may be instituted timeously. Conclusion: The high prevalence of HIV in our population makes consideration of this comorbidity an essential facet in the routine evaluation and management of patients with VHD. There is solid evidence that these patients do no worse than non-HIV patients undergoing medical treatment or percutaneous/surgical intervention - open-heart surgery may be offered safely to patients with HIV if proper precautions are taken.