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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.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.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.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.

Introduction Atrio-ventricular (AV) conduction abnormalities and subsequent permanent pacemaker (PPM) implantation frequently complicate Transcatheter Aortic Valve Replacement(TAVR). Current guidelines are still unclear in certain clinical scenarios. Methods and Results A 78 year-old with pre-existing Left Bundle Branch Block and 1 degree AV block underwent TAVR complicated by transient complete heart block with no further prolongation of preexisting conduction. Electrophysiology study (otherwise not indicated based on guidelines), 3 days post-procedure revealed evidence of significant infra Hisian disease requiring PPM. Conclusion No specific guidelines are available at this stage and thus our report highlights need for further research into this patient subset.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Institute of Cardiovascular disease, Madras Medical Mission Background Type 2 Diabetes (DM) is a pro-inflammatory state in the pathogenesis of Atherosclerosis with the presence of many active proteins, of which CyclophilinA (CypA) has been shown to have a positive correlation with the presence and severity of vascular diseases. As Cyp A is proven to be secreted in varying levels from cells, in response to inflammatory stimuli, viz., hypoxia, infection, and oxidative stress, it is found ideal, to study it further as one of a reliable pro-inflammatory biomarker responsible for the progression of Coronary Artery Disease (CAD) in early DM. Purpose A prospective cross-sectional study was conducted to quantify CypA in the early phase of DM before the onset of CAD, in comparison to non-diabetic volunteers and to review it as one of the pro-inflammatory biomarkers of CAD, in association with hsCRP and other proven biomarkers (Insulin, Lipid profile, HBA1C, and Glucose). Methods The study subject comprised 299 patients with DM and 50 healthy volunteers. History of duration of DM and other co-morbidities was obtained. A comprehensive clinical examination and non-invasive evaluation of atherosclerotic vascular disease were done to rule out CAD. CypA was analyzed by ELISA kit in serum. P-value of Results The average age group of study population is 51­ with an SD of 9.4(Male 206; Female 143). The observed range of CypA in our study is 50–1974 ng/ml, which is much higher than the values obtained in other studies (2–200 ng/ml). An increased level of CYP A is seen in DM than control group with a significant P Value of 5 years of DM (one-way ANOVA). Review of hsCRP shows statistically different levels between DM and the control group (p=0.012). Scatter plots of CypA and hsCRP concentration showed values within 500 ng/ml of CypA distributed in the mid to average risk category of hsCRP ( Conclusion In our study CypA level is increased in the early stage of DM when compared with non-Diabetes. The range obtained is higher than the previous study values. CypA value of

The 143 low- and middle-income countries (LMICs) of the world constitute 80% of the world’s population or roughly 5.86 billion people with much variation in geography, culture, literacy, financial resources, access to health care, insurance penetration, and healthcare regulation. Unfortunately, their burden of cardiovascular disease in general and acute ST-segment–elevation myocardial infarction (STEMI) in particular is increasing at an unprecedented rate. Compounding the problem, outcomes remain suboptimal because of a lack of awareness and a severe paucity of resources. Guideline-based treatment has dramatically improved the outcomes of STEMI in high-income countries. However, no such focused recommendations exist for LMICs, and the unique challenges in LMICs make directly implementing Western guidelines unfeasible. Thus, structured solutions tailored to their individual, local needs, and resources are a vital need. With this in mind, a multicountry collaboration of investigators interested in LMIC STEMI care have tried to create a consensus document that extracts transferable elements from Western guidelines and couples them with local realities gathered from expert experience. It outlines general operating principles for LMICs focused best practices and is intended to create the broad outlines of implementable, resource-appropriate paradigms for management of STEMI in LMICs. Although this document is focused primarily on governments and organizations involved with improvement in STEMI care in LMICs, it also provides some specific targeted information for the frontline clinicians to allow standardized care pathways and improved outcomes.

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous 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 diseases states in Indian populations (n≈4300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure and catecholamines in Gly/Ser subjects as compared to 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, greater inhibition of insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT). Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor (IR) than PST-WT, 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 IR. 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.

ST elevation myocardial infarction (STEMI) represents a large proportion of the clinical presentation of coronary artery disease in Indian people. Owing to multiple factors contributing to the sex difference, women with STEMI are thought to have a higher risk of adverse outcomes than men. The aim of this study was to evaluate sex-related differences in the clinical characteristics and prognosis of patients with STEMI within a system of care.This study was a subgroup analysis of the Tamil Nadu-STEMI (TN-STEMI) program, a multicentre, prospective, observational study of a quality-improvement program studying patients with STEMI at four hub-and-spoke clusters in the southern state of Tamil Nadu, India. In total, 2,420 patients were enrolled between 2012 and 2014, and the data from all four clusters, pre- and postimplementation of integrated STEMI systems, were combined for this analysis, with a 1-year follow-up.The mean ± SD age of presentation of female patients (16%) was significantly later (60.1±10.9 years) compared with males (84%; 53.7±12 years). Diabetes was more prevalent in women (35.2% vs 23.8%; p0.001), as was hypertension (35.2% vs 22.9%; p0.001). Symptom to first medical contact in female patients was significantly delayed compared with males (193 mins vs 170 mins; p≤0.009). Women had higher mortality, both in hospital (10.4% vs 4.8%; p≤0.001) and at 1 year (26.7% vs 13%; p≤0.001). This pattern was persistent, even in the younger STEMI (45 years) population (in-hospital: 9.1% vs 3% [p≤0.05]; at 1 year: 18.2% vs 3% [p≤ 0.05]). In the regression model, females had a 1.8 times increased likelihood (p0.04) of mortality after adjusting for confounders.Among patients with STEMI, women have an unfavourable risk profile and adverse short- and long-term prognoses when compared to men.