Himanshu Rai

Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review.

Several association studies of endothelial nitric oxide synthase (NOS3) gene polymorphisms with respect to coronary artery disease (CAD) have been published in the past two decades. However, their association with the disease, especially among different ethnic subgroups, still remains controversial. This prompted us to conduct a systematic review and an updated structured meta-analysis, which is the largest so far (89 articles, 132 separate studies, and a sample size of 69,235), examining association of three polymorphic forms of the NOS3 gene (i.e. Glu298Asp, T786-C and 27bp VNTR b/a) with CAD. In a subgroup analysis, we tested their association separately among published studies originating predominantly from European, Middle Eastern, Asian, Asian-Indian and African ancestries. The pooled analysis confirmed the association of all the three selected SNP with CAD in three different genetic models transcending all ancestries worldwide. The Glu298Asp polymorphism showed strongest association (OR range = 1.28–1.52, and P<0.00001 for all comparisons), followed by T786-C (OR range = 1.34–1.42, and P<0.00001 for all comparisons) and 4b/a, (OR range = 1.19–1.41, and P≤0.002 for all comparisons) in our pooled analysis. Subgroup analysis revealed that Glu298Asp (OR range = 1.54–1.87, and P<0.004 for all comparisons) and 4b/a (OR range = 1.71–3.02, and P<0.00001 for all comparisons) have highest degree of association amongst the Middle Easterners. On the other hand, T786-C and its minor allele seem to carry a highest risk for CAD among subjects of Asian ancestry (OR range = 1.61–1.90, and P≤0.01 for all comparisons).

Lack of association between Glu298Asp polymorphism and coronary artery disease in North Indians

Nitric Oxide (NO) is an important molecule carrying number of different functions in humans. Published studies suggest that it may inhibit several key steps involved in the pathogenesis of atherosclerosis. Inhibition or reduction of NO due to Glu298Asp polymorphism may accelerate atherosclerosis. The aim of this study was to determine whether Glu298Asp polymorphism is implicated in the pathogenesis of coronary artery disease (CAD) among North Indian population from the state of Uttar Pradesh, India. We selected 253 CAD patients and 174 healthy, normotensive, non-diabetic controls, which were matched for gender and ethnicity. The Glu298Asp (rs1799983) variant was detected by genotyping subjects, using a polymerase chain reaction followed by restriction fragment length polymorphism. There was no significant difference found in the genotypic and allelic frequencies between patients and controls. Our study indicated that Glu298Asp polymorphism does not play any critical role in the pathogenesis of CAD, at least in North Indian population.

Interleukin-1 Gene Cluster Polymorphisms and Their Association with Coronary Artery Disease: Separate Evidences from the Largest Case-Control Study amongst North Indians and an Updated Meta-Analysis

Several researchers have reported significant association of numerous single nucleotide polymorphisms (SNPs) residing in the interleukin-1 (IL-1) gene cluster with coronary artery disease (CAD). However, their association status amongst North Indian ancestry (NIA) have never been systematically assessed. Despite a published meta-analysis on this subject, their association status worldwide as well as amongst different major ancestral subgroups still remains unclear. We therefore decided to prospectively test the association of 11 IL-1 gene cluster SNPs with CAD, vide a case-control study amongst a cohort of NIA and attempted to validate our results with the help of an updated meta-analysis of all relevant published association studies. Included studies were segregated into ancestral subgroups and association statuses for each subgroup were determined. A total of 323 cases and 400 healthy, age and sex matched controls belonging to NIA were prospectively enrolled and subsequently genotyped for 11 selected IL-1 gene cluster SNPs. Although results for none of the evaluated IL-1 gene cluster SNPs reached the adjusted level of significance (p<0.0045), clear trends of association were seen for IL1B -511 C>T and IL1RN 86bp VNTR in several of the constructed genetic models (p range = 0.01–0.044 and 0.005–0.034 respectively). The presence of >1, ‘T’ (minor) allele of IL1B -511 C>T in a genotype seemed to provide protection against CAD (OR = 0.62, p = 0.044), while the presence of >1, ‘C’ (major) allele seemed to increase the risk of CAD (OR = 1.36, p = 0.041). The minor allele (allele 2) of IL1RN 86bp VNTR and its homozygous genotype (2/2 genotype) also seemed to carry an increased risk for CAD (OR = 1.62, p = 0.005 and OR = 2.25, p = 0.031 respectively). On the other hand, several haplotype combinations constructed out of IL1B and IL1RN gene variants clearly showed statistically significant associations with CAD (p<0.0045). Our meta-analysis was conducted for 8 previously assessed IL-1 SNPs. We included 53 different studies which involved a total sample of 26,210 (13,982 cases and 12,228 controls). Our pooled results concurred with the findings of our case-control study and was not able to deduce any statistically significant associations for any of the 8 studied SNPs (p>0.05). Subgroup analysis, however, yielded interesting results, where significant differences in association statuses were seen for IL1A +4845 G>T, IL1B -511 C>T, IL1RN 86bp VNTR and IL1RN +8006 T>C for select ancestral subgroups. The hints of associations deduced for subjects belonging to NIA in our case-control study for both IL1B -511 C>T and IL1RN 86bp VNTR were duly validated vide significant p values seen for NIA in all three genetic models (OR range = 0.62–0.76, p range = 0.01–0.04 and OR range = 1.51–2.25, p range = 0.004–0.04 respectively). On the other hand, Mixed Ancestry (MA) subgroup carrying IL1B -511 C>T, IL1RN 86bp VNTR or IL1RN +8006 T>C polymorphisms seemed to enjoy significant protection against CAD. A few other ancestral subgroups also demonstrated significant associations for a few of the studied SNPs vide one of the three genetic models. Clinical interpretation of derived results is however recommended.

Association of V249I and T280M Polymorphisms in the Chemokine Receptor CX3CR1 Gene with Early Onset of Coronary Artery Disease Among North Indians

AIM Monocytes play a critical role in atherosclerosis. CX3CR1 is expressed on monocytes and acts as either a monocyte chemokine receptor or an adhesion molecule. Two common variants of CX3CR1, V249I and T280M, reportedly decrease the coronary artery risk. RESULTS We have examined the CX3CR1 genotype in 152 early-onset coronary artery disease (CAD) patients (age ≤ 45 years) and in 156 late-onset CAD patients (age ≥ 55 years) and in 300 healthy controls. Homozygous alleles CX3CR1-V249 and T280 were found associated with early onset of CAD (odds ratio [OR] 2.7, p<0.0001 and OR 2.76, p<0.0001, respectively), while alleles CX3CR1-I249 and M280 were found to be protective against early onset of disease (OR 0.36, p<0.0001 and OR 0.35, p<0.0001, respectively). A significant protective effect of the I(249)M(280) haplotype was observed in the early-onset CAD population (OR=0.40, 95% confidence interval [CI]=0.19-0.86, p=0.02), while the haplotype V(249)T(280) was associated with early onset of disease (OR=1.53, 95% CI=1.05-2.23, p=0.02). OBSERVATION It might be possible that the risk of early onset of CAD is associated with a genetic variation in chemokine receptor CX3CR1.

Differential Release Kinetics of Cardiac Biomarkers in Patients Undergoing Valve Replacement Surgery.

Differential release kinetics of cardiac biomarkers including brain natriuretic peptide (BNP), Troponin‐I, and CK‐MB following valve replacement (VR) are not well characterized.

Association of serum lipids and coronary artery disease with polymorphisms in the apolipoprotein AI-CIII-AIV gene cluster

Abstract Genetic variants are considered as one of the main determinants of the concentration of serum lipids and coronary artery disease (CAD). Polymorphisms in the Apolipoprotein (Apo) AI-CIII-AIV gene cluster has been known to affect the concentrations of various lipid sub-fractions and the risk of CAD. The present study assessed associations between polymorphisms of the Apo AI-CIII-AIV gene cluster, [ApoA-I,-75G > A, (rs1799837); ApoC-III 3238C > G, (SstI), (rs5128) and ApoA-IV, Thr347Ser(347A > T), (rs675)] with serum lipids and their contributions to CAD in North Indian population. We recruited age, sex matched, 200 CAD patients and 200 healthy controls and tested them for fasting levels of serum lipids. We genotyped selected polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. There were no statistically significant association of selected polymorphisms (or their combinations) with CAD even after employing additive, dominant and recessive models. However there was significant association of selected polymorphisms with various lipid traits amongst the control cohort (p < 0.05). Mean levels of high density lipoprotein cholesterol and triglycerides were found to be significantly higher among controls carrying at least one mutant allele at ApoA1-75G > A (p = 0.019) and ApoCIII SstI (p < 0.001) polymorphism respectively. Our study observed that the selected polymorphisms in the ApoAI-CIII-AIV gene cluster although significantly affect various lipid traits but this affect does not seem to translate into association with CAD, at least among North Indian population.

Differential release kinetics of cardiac biomarkers in off-pump coronary bypass

Background Differential release kinetics of the cardiac biomarkers (B-type natriuretic peptide, troponin I, and creatine kinase-MB) following off-pump coronary artery bypass are not well characterized. Methods Biomarker levels were assessed at 6, 24, 48 h, and 1 month preoperatively, in 80 patients who underwent off-pump coronary artery bypass. Results All biomarkers increased within 6 h of surgery. Peak B-type natriuretic peptide levels occurred at 24–48 h in 96% of patients, but only two-thirds had peak troponin I and creatine kinase-MB levels at this time, reflecting different release patterns. Levels of all biomarkers declined within 48 h, but 42% of patients still had B-type natriuretic peptide >100 pg·mL−1 at 1 month. Those with baseline B-type natriuretic peptide > 100 pg·mL−1 had a lower left ventricular ejection fraction (43.6% vs. 55.6%, p < 0.01) and longer inotropic (43.8 vs. 31.4 h, p = 0.03) and ventilator support (34 vs. 25.5 h, p = 0.04) than those with lower levels. B-type natriuretic peptide levels correlated positively with angiographic Syntax score (p = 0.02) and negatively with left ventricular ejection fraction (p < 0.001). Only baseline B-type natriuretic peptide predicted the durations of inotropic support (p = 0.01) and ventilation (p = 0.02). Postoperative B-type natriuretic peptide at 6, 24, and 48 h and delta B-type natriuretic peptide were significant predictors of mean ventilation time. Conclusion Even in patients undergoing off-pump surgery, there is significant natriuretic peptide and myocardial enzyme release. Only B-type natriuretic peptide levels had an association with postoperative variables.

Long-term clinical impact of polymer-free sirolimus-eluting stents in unselected patients.

ObjectivesThe long-term clinical impact of polymer-free sirolimus-eluting stents (PF-SES) in unselected patients undergoing percutaneous coronary intervention (PCI) still remains poorly investigated. We studied the long-term clinical impact of PF-SES in a large cohort of unselected patients receiving PCI therapy at two tertiary care centers in India. MethodsA total of 3213 patients received PCI with drug-eluting stents during the period from December 2004 to September 2011. Among these, those receiving PF-SES implantation were retrospectively included in this registry. The primary endpoint in our study was the occurrence of major adverse cardiac events (MACE), defined as the composite of death/myocardial infarction (MI) and target lesion revascularization, whereas the main secondary endpoints were cardiac death/MI and definite/probable stent thrombosis. ResultsA total of 1213 patients (83.8% men, 31.8% diabetics) with 1658 lesions (52.5% B2/C, according to the American College of Cardiology/American Heart Association classification) were studied. After a median follow-up of 1160 days, MACE occurred in 10.0% of patients, whereas the rates of cardiac death/MI and definite/probable ST were found to be 5.4 and 1.9%, respectively. The incidence of MACE was more common in patients aged at least 65 years [hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.13–2.52, P=0.01] and diabetics (HR=1.71, 95% CI=1.18–2.47, P=0.004). The incidence of cardiac death/MI was more common in patients aged at least 65 years (HR=2.21, 95% CI=1.32–3.70, P=0.003). The baseline risk profile did not impact the occurrence of target lesion revascularization. ConclusionIn this large cohort of unselected PCI patients treated in India, PF-SES shows a sustained safety and efficacy at long-term follow-up.