Association of Promoter Methylation and Expression of Inflammatory Genes IL-6 and TNF-α with the Risk of Coronary Artery Disease in Diabetic and Obese Subjects among Asian Indians.

The inflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are considered as the most important contributors to the endothelial dysfunction in subjects with type 2 diabetes mellitus (T2DM) and obesity. The hypomethylation of CpG sites in the promoter region of the IL-6 and TNF-α have shown to be associated with the increased expression of IL-6 and TNF-α. However, there are no studies on the methylation and expression of IL-6 and TNF-α with the risk of coronary artery disease (CAD) in subjects with T2DM and obesity in Asian Indians. Hence, the present study was aimed to investigate whether the IL-6, TNF-α promoter methylation and expression in blood leukocyte DNA is associated with the risk of CAD in diabetic and obese subjects in Asian Indians. For this study, we recruited 574 subjects which includes, 207 angiographically confirmed CAD patients, 100 T2DM patients, 82 obese subjects and 185 healthy controls. The methylation status of IL-6 and TNF-α gene loci was determined by methylation specific PCR (MPCR) and gene expression was determined by qPCR. We found significant hypomethylation of IL-6 in CAD and T2DM subjects (OR 1.98 95% CI: 1.32-2.97, p = 0.001, OR: 2.23 95% CI:1.34-3.76, p = 0.001, respectively). Further, a significant increase in the expression of IL-6 in CAD and T2DM subjects (fold change: 26.39 & 14.7, p = 0.0001) compared to the control subjects was observed. A significant increase in the hypomethylation of TNF-α in CAD, T2DM and obese subjects was observed as compared to the control (OR: 2.04 95% CI: 1.36-3.05, p = 0.0005, OR: 1.81 95% CI 1.10-2.96, p = 0.01, and OR: 2.1 95% CI 1.24-3.57, p = 0.007, respectively).We also found an increased expression of TNF-α in CAD, T2DM and obese subjects as compared to controls. In addition, presence of low folate, and hyperhomocysteinemia was observed in the present study, may be the contributing factors for the hypomethylation of IL-6 and TNF-α and oxidative stress. In conclusion, increased expression of IL-6 and TNF-α due to hypomethylation in T2DM and obese individuals may contribute to CAD risk in these subjects. The presence of hyperhomocysteinemia and increased oxidative risk may enhance the CAD risk further.

Probing the epigenetic signatures in subjects with coronary artery disease.

Depletion of S-adenosyl methionine and 5-methyltetrahydrofolate; and elevation of total plasma homocysteine were documented in CAD patients, which might modulate the gene-specific methylation status and alter their expression. In this study, we have aimed to delineate CAD-specific epigenetic signatures by investigating the methylation and expression of 11 candidate genes i.e. ABCG1, LIPC, PLTP, IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66 and TGFBR3. The methylation-specific PCR and qRT-PCR were used to assess the methylation status and the expression of candidate genes, respectively. CAD patients showed the upregulation of IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66, and TGFBR3. Hypomethylation of CDKN2A loci was shown to increase risk for CAD by 1.79-folds (95% CI 1.22-2.63). Classification and regression tree (CART) model of gene expression showed increased risk for CAD with F2RL3 > 3.4-fold, while demonstrating risk reduction with F2RL3 < 3.4-fold and IL-6 < 7.7-folds. This CAD prediction model showed the excellent sensitivity (0.98, 95% CI 0.88-1.00), specificity (0.91, 95% CI 0.86-0.92), positive predictive value (0.82, 95% CI 0.75-0.84), and negative predictive value (0.99, 95% CI 0.94-1.00) with an overall accuracy of 92.8% (95% CI 87.0-94.1%). Folate and B12 deficiencies were observed in CAD cases, which were shown to contribute to hypomethylation and upregulation of the prime candidate genes i.e. CDKN2A and F2RL3. Early onset diabetes was associated with IL-6 and TNF-α hypomethylation and upregulation of CDKN2A. The expression of F2RL3 and IL-6 (or) hypomethylation status at CDKN2A locus are potential biomarkers in CAD risk prediction. Early epigenetic imprints of CAD were observed in early onset diabetes. Folate and B12 deficiencies are the contributing factors to these changes in CAD-specific epigenetic signatures.

Relationship of echocardiographic left ventricular dyssynchrony with QRS width on surface electrocardiogram in patients with systolic heart failure: An observational study.

This study aimed to evaluate left ventricular dyssynchrony with QRS width on ECG in patients with systolic heart failure. 100 study patients were classified into two groups. Narrow QRS group-N- QRS (80-119 msec) and Wide QRS group-W- QRS (120-160 msec). Out of each 50 patients in W- QRS group, 38(76%) had LV dyssynchrony and 18 (36%) in N- QRS group had ventricular dyssynchrony. Dyssynchrony in narrow QRS patients with heart failure also needs attention as a therapeutic target in future studies.

Clinical picture of arrhythmogenic right ventricular dysplasia / cardiomyopathy patients from Indian origin.

OBJECTIVE: Among the inherited cardiomyopathies, Arrhythmogenic right ventricular dysplasia/cardiomyopathy is unique with a peculiar pathology of fibro-fatty replacement. Studies have been carried out all over the world and several groups have reported clinical heterogeneity in manifestation of ARVD/C related symptoms. Present study is an attempt to identify the clinical profile of ARVD/C patients from Asian Indian origin. METHODS: 31 patients in the span of three years were diagnosed with ARVD/C. Diagnosis was based on proposed task force criteria. RESULTS: The mean age at diagnosis was 32.9 +/- 16.4 years with slight tilt in male to female ratio (1.46). About 80% cases had palpitations, syncope in 45.16% and dyspnea in 22.5%, whereas 16% of patients were asymptomatic. About 50% of patients revealed a family history of confirmed ARVD/C or sudden death of a family member without any known cause. ECG showed T-wave inversion in about 60% cases, prolongation of QRS was observed in 20% cases. RV dilatation was observed in 80% of patients and 66.7% showed systolic dysfunction. RV free wall motion abnormalities were found in 33% patients. Most of the early onset cases with less than 30 years of age showed family history indicative of ARVD/C. Familial study in three patients indicated early onset of condition in younger generations in two families. CONCLUSIONS: ARVD/C in India shows relatively early age at onset when compared with other Asian populations with more than half of patients showing the disease below the age of 30 years. History in most of the early onset cases revealed family history indicating strong genetic influence.

A Prospective Study on Prevalence and Causes of Anaemia in Patients with Acute Coronary Syndrome.

INTRODUCTION: Anaemia is a contributor for adverse prognosis in Acute Coronary Syndrome (ACS), but the epidemiology and causes of anaemia in such patients is not defined. AIM: To study the prevalence and aetiology of anaemia in hospitalized patients with ACS. MATERIALS AND METHODS: All consecutive patients admitted with ACS from January to March, 2010 were included. Their clinical information was recorded. RESULTS: Of 130 (87 males) consecutive admissions for ACS, 47.7% had unstable angina, 10% had Non ST-Elevation Myocardial Infarction (NSTEMI) and 42.3% had ST-Elevation Myocardial Infarction (STEMI). Overall prevalence of anaemia (haemoglobin <130 g/l in men and <120 g/l in women) was 51.5% (n=67) and was more prevalent in women (n=30, 69.8%) than men (n=37, 42.5%). Moderate to severe anaemia was more in women (34.9%) compared to men (20.8%). Anaemia was more common in unstable angina patients (58.2%) than in NSTEMI (11.9%) or STEMI (29.9%) patients (p=0.013). Aspirin (p<0.01) and/or clopidogrel intake (p<0.01) and raised serum creatinine (p<0.01) were more often in anaemic patients. Heart failure (p<0.01) and triple vessel disease (p<0.05) were associated with anaemia. Multivariate predictors of duration of hospital stay were haemoglobin (p<0.05) at admission and revascularisation procedure (p=0.01) during hospital stay. The most common cause of anaemia was iron deficiency (29.9%). CONCLUSION: Anaemia was common in our patients admitted with ACS. Female gender, antiplatelet drug intake and raised creatinine were associated with anaemia, which in turn was associated with adverse in-hospital outcomes. The impact of correcting anaemia on outcomes in ACS needs long term prospective study.

Adrenal and extra-adrenal pheochromocytomas presenting as life-threatening ventricular arrhythmias: Report of three cases.

Pheochromocytoma patients can rarely have prolonged QT interval in the ECG. We report three cases of pheochromocytoma in females presenting with ventricular arrhythmia; two had torsades de pointes and a third patient had frequent VPCs and nonsustained ventricular tachycardia. All the patients were treated with surgical removal of the tumor with complete relief of symptoms and normalization of QT interval.