Position statement from the Indian Society of Gastroenterology, Cardiological Society of India, Indian Academy of Neurology and Vascular Society of India on gastrointestinal bleeding and endoscopic procedures in patients on antiplatelet and/or anticoagulant therapy.

Antiplatelet and/or anticoagulant agents (collectively known as antithrombotic agents) are used to reduce the risk of thromboembolic events in patients with conditions such as atrial fibrillation, acute coronary syndrome, recurrent stroke prevention, deep vein thrombosis, hypercoagulable states and endoprostheses. Antithrombotic-associated gastrointestinal (GI) bleeding is an increasing burden due to the growing population of advanced age with multiple comorbidities and the expanding indications for the use of antiplatelet agents and anticoagulants. GI bleeding in antithrombotic users is associated with an increase in short-term and long-term mortality. In addition, in recent decades, there has been an exponential increase in the use of diagnostic and therapeutic GI endoscopic procedures. Since endoscopic procedures hold an inherent risk of bleeding that depends on the type of endoscopy and patients' comorbidities, in patients already on antithrombotic therapies, the risk of procedure-related bleeding is further increased. Interrupting or modifying doses of these agents prior to any invasive procedures put these patients at increased risk of thromboembolic events. Although many international GI societies have published guidelines for the management of antithrombotic agents during an event of GI bleeding and during urgent and elective endoscopic procedures, no Indian guidelines exist that cater to Indian gastroenterologists and their patients. In this regard, the Indian Society of Gastroenterology (ISG), in association with the Cardiological Society of India (CSI), Indian Academy of Neurology (IAN) and Vascular Society of India (VSI), have developed a "Guidance Document" for the management of antithrombotic agents during an event of GI bleeding and during urgent and elective endoscopic procedures.

A common Matrix metalloproteinase 8 promoter haplotype enhances the risk for hypertension via diminished interactions with nuclear factor kappa B.

OBJECTIVES: Matrix metalloproteinase 8 (MMP8) has a prominent role in collagen turnover in blood vessels and vascular remodeling. The contribution of regulatory single nucleotide polymorphisms in MMP8 to cardiovascular diseases is unclear. We aimed to delineate the influence of MMP8 promoter variations on hypertension. METHODS: A case-control study in unrelated individuals ( n  = 2565) was carried out. Resequencing of the MMP8 proximal promoter, linkage disequilibrium analysis, genotyping of variants and regression analyses were performed. MMP8 promoter-reporter constructs were generated and expressed in human vascular endothelial cells under various conditions. RESULTS: We identified four single nucleotide polymorphisms (SNPs) in the promoter region of MMP8 : -1089A/G (rs17099452), -815G/T (rs17099451), -795C/T (rs11225395), -763A/T (rs35308160); these SNPs form three major haplotypes. Hap3 (viz., GTTT haplotype) carriers showed significant associations with hypertension in two geographically distinct human populations (e.g., Chennai: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.16-1.86, P  = 2 × 10 -3 ; Chandigarh: OR = 1.85, 95% CI = 1.21-2.81, P  = 4 × 10 -3 ). Hap3 carriers also displayed elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure levels. Hap3 promoter-reporter construct showed lower promoter activity than the wild-type (Hap1) construct. In silico analysis and molecular dynamics studies predicted diminished binding of the transcription factor nuclear factor kappa B (NF-κB) to the functional -815T allele of Hap3 compared to the -815G wild-type allele; this prediction was validated by in-vitro experiments. Hap3 displayed impaired response to tumor necrosis factor-alpha treatment, possibly due to weaker binding of NF-κB. Notably, MMP8 promoter haplotypes were identified as independent predictors of plasma MMP8 and endothelial dysfunction markers (von Willebrand factor and endothelin-1) levels. CONCLUSION: MMP8 promoter GTTT haplotype has a functional role in reducing MMP8 expression during inflammation via diminished interaction with NF-κB and in enhancing the risk of hypertension.

Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders.

Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations.

Acute ST-Elevation Myocardial Infarction in the Young Compared With Older Patients in the Tamil Nadu STEMI Program.

OBJECTIVE: To compare the clinical presentation, risk factors and outcomes of young patients (≤45 years) presenting with ST segment-elevation myocardial infarction (STEMI) with older STEMI patients in the Tamil Nadu STEMI program (TN-STEMI). METHODS: A total of 2,420 patients were enrolled in the TN-STEMI program, which is a pre-implementation and post-implementation quality of care study. The cohort of patients was divided into young STEMI patients (≤45 years) and compared with those aged >45 years. RESULTS: A total of 591(24.4%) patients in this cohort were aged ≤45 years; 92.5% of the young STEMI were males. Smoking was the most common risk factor and its use was significantly more in younger myocardial infarction (MI) patients than in older patients (57% vs 31%; p<0.001). Compared with their older counterparts, younger patients had a lower prevalence of hypertension (14.2% vs 28.3%; p<0.001) and diabetes mellitus (13.2% vs 29.7%; p<0.001). Total ischaemic time was shorter for younger patients (235 vs 255 mins; p=0.03). Young STEMI patients more frequently presented with single vessel disease and the left anterior descending coronary artery was the most common infarct-related artery; they also had a higher thrombus load. Young MI patients had reduced mortality, both in-hospital (3.4% vs 6.4%; p=0.005) and at one year (7.6% vs 17.6%; p<0.001). Younger male STEMI patients also showed lower mortality than younger female patients. CONCLUSIONS: Young STEMI patients compared with older STEMI patients had lower prevalence of traditional risk factors, shorter ischaemic time and reduced mortality. Young female STEMI patients had higher mortality than young male STEMI patients.

A haplotype variant of the human chromogranin A gene (CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders.

The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the CHGA promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the CHGA promoter in an Indian population (n = 769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G, G-513A, G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the CHGA promoter haplotype 2 under basal and pathophysiological conditions (viz. inflammation and hypoxia). Consistent with the higher in vitro CHGA promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels, plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the CHGA promoter haplotype 2 (occurring in a large proportion of the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders.

Post-Transcriptional Regulation of Renalase Gene by miR-29 and miR-146 MicroRNAs: Implications for Cardiometabolic Disorders.

Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3'-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (~1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (~2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3'-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3'-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈ 58,000-96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits.

Risk scoring system to predict contrast induced nephropathy following percutaneous coronary intervention.

BACKGROUND: Contrast induced nephropathy (CIN) is associated with significant morbidity and mortality after percutaneous coronary intervention (PCI). The aim of this study is to evaluate the collective probability of CIN in Indian population by developing a scoring system of several identified risk factors in patients undergoing PCI. METHODS: This is a prospective single center study of 1200 consecutive patients who underwent PCI from 2008 to 2011. Patients were randomized in 3:1 ratio into development (n = 900) and validation (n = 300) groups. CIN was defined as an increase of ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 hours after PCI when compared to baseline value. Seven independent predictors of CIN were identified using logistic regression analysis - amount of contrast, diabetes with microangiopathy, hypotension, peripheral vascular disease, albuminuria, glomerular filtration rate (GFR) and anemia. A formula was then developed to identify the probability of CIN using the logistic regression equation. RESULTS: The mean (±SD) age was 57.3 (±10.2) years. 83.6% were males. The total incidence of CIN was 9.7% in the development group. The total risk of renal replacement therapy in the study group is 1.1%. Mortality is 0.5%. The risk scoring model correlated well in the validation group (incidence of CIN was 8.7%, sensitivity 92.3%, specificity 82.1%, c statistic 0.95). CONCLUSION: A simple risk scoring equation can be employed to predict the probability of CIN following PCI, applying it to each individual. More vigilant preventive measures can be applied to the high risk candidates.

Three-year data from the XIENCE V INDIA study: safety and efficacy of XIENCE V in 1000 real world Indian patients.

BACKGROUND: Cardiovascular disease in Asia has reached epidemic proportions in recent years. Use of drug eluting stents in Asians has rapidly expanded with varying penetration rates across different countries. The XIENCE V INDIA Study included 'real world' patients who underwent XIENCE V stent implantation to assess short and intermediate term outcomes in Indian patients with diverse risk factors. OBJECTIVE: To evaluate 3-year clinical outcomes in a cohort of 'real world' Indian patients with CAD being treated with XIENCE V Everolimus Eluting Coronary Stent System. METHODS: 1000 patients were enrolled from 18 sites in India between June 2008 and March 2009. Patients were included if their index procedures were completed using only XIENCE V. There were no clinical or angiographic exclusions. An independent Clinical Events Committee adjudicated all endpoint-related events. The primary endpoint was stent thrombosis rate annually through to 3 years as defined by the Academic Research Consortium criteria. The co-primary endpoint was the composite rate of cardiac death and myocardial infarction at 1 year. RESULTS: At 1-year the primary endpoint of definite/probable stent thrombosis rate was 0.51%. No additional very late stent thrombosis was reported through a 3-year follow up. The composite endpoint of cardiac death and any myocardial infarction was 1.9%, 2.7% and 3.1% at 1, 2 and 3 years respectively. CONCLUSION: Despite the high risk population of coronary artery disease, the use of XIENCE V in 'real world' Indian patients was associated with very low clinical event rates upto three years of follow up.

Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation.

Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST also triggers glycogenolysis in liver and reduces glucose uptake in adipocytes and hepatocytes. Here, we probed for genetic variations in PST sequence and identified two variants within its functionally important carboxyl terminus domain: E287K and G297S. To understand functional implications of these amino acid substitutions, we tested the effects of wild-type (PST-WT), PST-287K, and PST-297S peptides on various cellular processes/events. The rank order of efficacy to inhibit insulin-stimulated glucose uptake was: PST-297S > PST-287K > PST-WT. The PST peptides also displayed the same order of efficacy for enhancing intracellular nitric oxide and Ca(2+) levels in various cell types. In addition, PST peptides activated gluconeogenic genes in the following order: PST-297S ≈ PST-287K > PST-WT. Consistent with these in vitro results, the common PST variant allele Ser-297 was associated with significantly higher (by ∼17 mg/dl, as compared with the wild-type Gly-297 allele) plasma glucose level in our study population (n = 410). Molecular modeling and molecular dynamics simulations predicted the following rank order of α-helical content: PST-297S > PST-287K > PST-WT. Corroboratively, circular dichroism analysis of PST peptides revealed significant differences in global structures (e.g. the order of propensity to form α-helix was: PST-297S ≈ PST-287K > PST-WT). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in ∼300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis.

Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits.

Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca(2+) rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of α-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction (up to ∼2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders.

Evaluation of the XIENCE V everolimus eluting coronary stent system in the Asian population of the SPIRIT V single arm study. 2-year clinical follow-up data.

BACKGROUND: Asian patients have a uniquely high risk for heart disease compared to other ethnicities. Past drug eluting stent trials have examined mainly populations of European heritage. As a significant proportion of the real world population in the SPIRIT V single arm study is Asian, the study provides insight into how this population responds to stenting with the XIENCE V Everolimus Eluting Coronary Stent (EES). METHODS AND RESULTS: 2,700 patients were enrolled at 93 sites in Europe, Asia Pacific and Canada between November 2006 and November 2007. 698 (26%) patients were recruited from Asian sites in India, China, Hong Kong, Malaysia, Singapore and Thailand. De novo coronary artery lesions of all patients were to be treated with up to 4 planned EES. Up to 2 year follow-up, major adverse cardiac events, myocardial infarction and target lesion revascularization rates were lower in the Asian subgroup than in the non-Asian subgroup. These results were mainly driven by better clinical outcomes in the Indian population. All populations showed similar low stent thrombosis rates. CONCLUSION: These findings demonstrate the safety and efficacy of the EES when used in a real-world Asian population, known to be at higher risk for heart disease.

An unusual combination of coronary arterial and systemic venous anomalies-clinical implications.

A 57-year-old male underwent coronary angiography for exertional angina which showed two left anterior descending coronary arteries (LAD)--a short LAD from the left coronary sinus terminating in the proximal Anterior Inter-Ventricular Sulcus (AIVS), a long LAD from the proximal right coronary artery entering the distal AIVS and an anomalous left circumflex artery from the right coronary sinus. In addition, he also had absent right superior vena cava and a persistent left superior vena cava entering the coronary sinus.

Accuracy of 64-slice coronary CT angiography in predicting percentage diameter stenosis.

OBJECTIVE: Aim of our study was to evaluate the diagnostic accuracy of 64-slice CT coronary angiogram in measuring the percentage diameter stenosis compared to invasive angiography. METHODS AND RESULTS: 100 consecutive patients with more than 50% stenosis in at least one major coronary artery measured by 64-slice CT angiogram were included in the study. Patients with atrial fibrillation, history of allergy to contrast agent, acute coronary syndrome, renal insufficiency, history of previous coronary bypass surgery or percutaneous transluminal coronary stent, heart rate more than 70 per minute at the time of scan in spite of beta-blocker therapy, and calcium score >2000 Agaston units were not included in the study. 15-segment American Heart Association classification was used, and segments were compared using qualitative angiography. 192 segments (12.80%) could not be assessed due to poor image quality. The major cause for poor image quality was dense calcification precluding the luminal assessment (60.42%). Comparing the maximal percentage diameter stenosis by 64-slice CT versus invasive angiogram, the Spearman correlation coefficient between the two modalities was 0.788 and p value was <0.001. Bland-Altman analysis showed a mean difference in percentage stenosis of 2.1 +/- 16.22%. A total of 91.97% (401 of 436) of segments were within 1.96 standard deviations. CONCLUSION: This study shows that 64-slice CT coronary angiogram is accurate in detecting percentage diameter stenosis compared to coronary angiogram if the image quality is good. Calcifications and motion artifacts are the main culprits of poor image quality.

Carotid artery stenting prior to coronary artery bypass graft surgery inpatients with left-main-coronary-artery disease.

Patients with concomitant carotid and left main or left main equivalent coronary artery disease are at high risk of both cardiac and cerebrovascular complications when they undergo revascularization procedures. Here, we present case reports of three patients who successfully underwent elective carotid stenting prior to coronary artery bypass surgery. Any sort of intervention in these patients is fraught with high risk due to the severity of their carotid and coronary artery disease.

A case of lipomatous hypertrophy of right ventricle.

Lipomatous hypertrophy is a condition that is being increasingly diagnosed with the advent of newer modalities. A middle aged lady was referred to us with recent onset dyspnea and palpitations. Echocardiography revealed diffuse thickening of the right ventricular free wall and outflow tract. Endomyocardial biopsy revealed this as a lipomatous hypertrophy involving the right ventricle. This is the first reported case of lipomatous hypertrophy involving the right ventricle.