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.

Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes.

BACKGROUND: The choice of drug-eluting stent in the treatment of patients with diabetes mellitus and coronary artery disease who are undergoing percutaneous coronary intervention (PCI) has been debated. Previous studies comparing paclitaxel-eluting stents with stents eluting rapamycin (now called sirolimus) or its analogues (everolimus or zotarolimus) have produced contradictory results, ranging from equivalence between stent types to superiority of everolimus-eluting stents. METHODS: We randomly assigned 1830 patients with diabetes mellitus and coronary artery disease who were undergoing PCI to receive either a paclitaxel-eluting stent or an everolimus-eluting stent. We used a noninferiority trial design with a noninferiority margin of 4 percentage points for the upper boundary of the 95% confidence interval of the risk difference. The primary end point was target-vessel failure, which was defined as a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization at the 1-year follow-up. RESULTS: At 1 year, paclitaxel-eluting stents did not meet the criterion for noninferiority to everolimus-eluting stents with respect to the primary end point (rate of target-vessel failure, 5.6% vs. 2.9%; risk difference, 2.7 percentage points [95% confidence interval, 0.8 to 4.5]; relative risk, 1.89 [95% confidence interval, 1.20 to 2.99]; P=0.38 for noninferiority). There was a significantly higher 1-year rate in the paclitaxel-eluting stent group than in the everolimus-eluting stent group of target-vessel failure (P=0.005), spontaneous myocardial infarction (3.2% vs. 1.2%, P=0.004), stent thrombosis (2.1% vs. 0.4%, P=0.002), target-vessel revascularization (3.4% vs. 1.2%, P=0.002), and target-lesion revascularization (3.4% vs. 1.2%, P=0.002). CONCLUSIONS: In patients with diabetes mellitus and coronary artery disease undergoing PCI, paclitaxel-eluting stents were not shown to be noninferior to everolimus-eluting stents, and they resulted in higher rates of target-vessel failure, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. (Funded by Boston Scientific; TUXEDO-India Clinical Trials Registry-India number, CTRI/2011/06/001830).

ENPP1 121Q functional variant enhances susceptibility to coronary artery disease in South Indian patients with type 2 diabetes mellitus.

Insulin resistance is associated with endothelial dysfunction and ensuing cardiovascular diseases in type 2 diabetes mellitus (T2DM) patients. ENPP1 is a key modulator of insulin signaling and its polymorphism, K121Q, increases the potency to competitively inhibit insulin receptor binding. We investigated the association of ENPP1 121Q variant with coronary artery disease (CAD) in patients with and without T2DM in South Indian population. Our study was conducted in 913 subjects: 198 patients with CAD, 284 patients in whom T2DM and CAD co-exists, 160 patients with T2DM and no CAD history, and 271 healthy volunteers. Genotyping was performed using PCR-RFLP and PCR-DNA sequencing. Genotype frequency of ENPP1 121Q was higher in disease groups compared to healthy subjects (p < 0.05). T2DM patients who carried polymorphic AC/CC genotypes were at 12.8-fold enhanced risk to CAD (95% CI 4.97-37.18, p < 0.01). Moreover we observed that 121Q, both in heterozygous and homozygous polymorphic states, was a risk factor for CAD without diabetes (OR 4.15, p < 0.01). 121Q variant was associated with T2DM patients with no CAD history too, but the risk was statistically insignificant after multivariate logistic regression analysis (OR 2.32, p > 0.05). We conclude that ENPP1 121Q variant is associated with increased risk for CAD in patients with T2DM in South Indian population. We also report that 121Q variant of ENPP1 was an independent risk factor for CAD irrespective of diabetic milieu. Factors which enhance insulin resistance increase the risk for onset and progression of coronary atherosclerosis irrespective of a diabetic background.

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.

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.

Longitudinal deformation - price we pay for better deliverability of coronary stent platforms.

Coronary stents, especially drug eluting stents (DES), have revolutionized the practice of interventional cardiology. Newer stents are manufactured by altering basic design characteristics to tackle complex coronary morphologies more effectively. Alteration in one particular attribute might affect other attributes adversely. Even though, reduction in the number and alteration of the orientation of the connectors improves the stent flexibility and deliverability, it adversely decreases the axial strength of the stent with resulting longitudinal stent deformation. A 67 year old female underwent percutaneous coronary intervention for a mid left anterior descending artery stenosis with a 2.75 × 16 mm Promus Element stent (Boston Scientific, Natick, Massachusetts). The stent got longitudinally distorted during post-stent balloon dilatation which was effectively managed with further dilatation with non-compliant balloon.

Door-to-balloon: where do we lose time? Single centre experience in India.

BACKGROUND/AIMS: To assess the factors causing delay in attaining DTB time of <90 min. METHODS: Eighty-five patients who underwent primary PCI from August 2008 to July 2009 were studied. From door-to-balloon, time was divided into 6 stages; any reason for delay was studied. RESULTS: The mean DTB time was 80.5 min (SD = 34.4, median time 75 min, range 30-195). DTB time was <90 min in 76.5%, and DTB time >90 min occurred in 23.5%. Mean door to ECG - 6.5 min (SD = 2.7), mean time for the decision of PCI - 7.5 min (SD = 10.5), mean time taken for the patient's consent - 19.6 min (SD = 17.6), for STEMI team activation - 6.7 min (SD = 7.6), average time for financial process - 39.2 min (SD = 22.9). Average time for sheath to balloon - 5.2 min (SD = 1.7). Hospital related delay occurred in 5%, patient related delay in 80%, both together in 15%. 89.5% of patient related delay was due to delay in giving consent and financial reasons. There was no statistically significant delay for patients presented at morning or night and during the weekdays or weekend. Total mortality was 4.7%. Mortality among <90 min was 3.1%, mortality among >90 min was 10% ('p' = 0.2). CONCLUSIONS: With effective hospital strategies, the DTB time of 90 min can be achieved in majority of patients. The chief delay in DTB time in this study was due to a delay in obtaining consent and financial reasons.

Concurrent endovascular repair of extensive thoracic aortic and infra-renal aorto-iliac aneurysms.

A 60 year-old woman presented with large extensive aneurysms in the thoracic aorta and infra-renal abdominal aorta with a normal segment of visceral aorta in between; the entire right common iliac artery was also aneurysmal. Concurrent endovascular repair of all aneurysmal regions was successfully performed using a left common iliac artery conduit to access the aorta, and multiple stent-grafts; a chimney graft preserved blood flow into the left subclavian artery. There were no features of spinal cord ischaemia despite coil embolisation of the right hypogastric artery. CT angiogram at six months showed patent stent-grafts with no endoleaks. The patient continued to do well at one-year clinical follow-up. Concurrent endovascular repair of thoracic and abdominal aortic aneurysms can be safely and successfully performed when anatomically feasible, and is an attractive alternative to staged or hybrid repair.

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.

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.

Managing complications in acute myocardial infarction.

Acute myocardial infarction (AMI) due to coronary artery disease is a leading cause of death in both the developed and developing countries. The advent of coronary care units and early reperfusion therapy (Thrombolytic and Percutaneous Coronary Intervention) has substantially decreased in-hospital mortality rates and has improved the outcome in survivors of the acute phase of MI. Complications of AMI include mechanical, arrhythmic, ischemic, and inflammatory (early pericarditis and post-MI syndrome) sequelae, as well as left ventricular mural thrombus. In addition to these broad categories, right ventricular (RV) infarction and cardiogenic shock are other common complications of AMI. The onset of each of these complications usually results in explicit symptoms and physical manifestations. Thus, a basic knowledge of the complications that occur in the postinfarction period and the clinical syndromes associated with each, will allow the physician to evaluate and treat the complication appropriately.

Prognostic significance of Troponin I in patients undergoing primary percutaneous coronary intervention.

This observational study investigates the prognostic significance of troponin I in patients undergoing primary percutaneous intervention (pPCI). Sequential cardiac biomarker sampling of the enrolled patients (n = 167) was performed on admission and at 6,12,24 and 48 h. Clinical characteristics, major adverse cardiac and cerebrovascular events (MACCE) (death, reinfarction, stroke and new or worsening heart failure) and left ventricular ejection fraction (LVEF) were noted on admission and 30 day follow-up. A 24-h troponin I level >60 ng/ml predicted MACCE (OR 4.06, p = 0.023; adjusted OR 5.09, p = 0.034) and less than 10% improvement in LVEF on follow-up (OR 2.49, p = 0.007). Thus, in patients undergoing pPCI, 24-h cardiac Troponin I is a good non-invasive surrogate to predict MACCE and improvement in LVEF.

Fibrinolytic Strategy for ST-Segment-Elevation Myocardial Infarction: A Contemporary Review in Context of the COVID-19 Pandemic.

The ongoing coronavirus disease 2019 pandemic has resulted in additional challenges for systems designed to perform expeditious primary percutaneous coronary intervention for patients presenting with ST-segment-elevation myocardial infarction. There are 2 important considerations: the guideline-recommended time goals were difficult to achieve for many patients in high-income countries even before the pandemic, and there is a steep increase in mortality when primary percutaneous coronary intervention cannot be delivered in a timely fashion. Although the use of fibrinolytic therapy has progressively decreased over the last several decades in high-income countries, in circumstances when delays in timely delivery of primary percutaneous coronary intervention are expected, a modern fibrinolytic-based pharmacoinvasive strategy may need to be considered. The purpose of this review is to systematically discuss the contemporary role of an evidence-based fibrinolytic reperfusion strategy as part of a pharmacoinvasive approach, in the context of the emerging coronavirus disease 2019 pandemic.

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population. OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPSCAD for South Asians. METHODS: This GPSCAD was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPSCAD reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPSCAD reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India. RESULTS: The GPSCAD, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPSCAD distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each). CONCLUSIONS: The new GPSCAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

A Common Tag Nucleotide Variant in MMP7 Promoter Increases Risk for Hypertension via Enhanced Interactions With CREB (Cyclic AMP Response Element-Binding Protein) Transcription Factor.

MMP (matrix metalloproteinase)-7-a potent extracellular matrix degrading enzyme-is emerging as a new regulator of cardiovascular diseases. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we probed for the association of a tag single-nucleotide polymorphism in the MMP7 promoter (-181A/G; rs11568818) with hypertension in an urban South Indian population (n=1501). The heterozygous AG genotype significantly increased risk for hypertension as compared with the wild-type AA genotype (odds ratio, 1.60 [95% CI, 1.25-2.06]; P=2.4×10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than wild-type AA individuals. The study was replicated in a North Indian population (n=949) (odds ratio, 1.52 [95% CI, 1.11-2.09]; P=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the CREB (cyclic AMP response element-binding protein) to the -181G promoter. In corroboration, overexpression/downregulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. The -181G promoter also displayed enhanced responses to hypoxia and epinephrine treatment. The higher promoter activity of -181G allele translated to increased MMP7 protein level, and MMP7-181AG heterozygous individuals displayed elevated plasma MMP7 levels, which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter polymorphism increased MMP7 expression under pathophysiological conditions (hypoxic stress and catecholamine excess) via increased interactions with CREB and enhanced the risk for hypertension in its carriers.

Consensus document for invasive coronary physiologic assessment in Asia-Pacific countries.

BACKGROUND: Currently, invasive physiologic assessment such as fractional flow reserve is widely used worldwide with different adoption rates around the globe. Patient characteristics and physician preferences often differ in the Asia-Pacific (APAC) region with respect to treatment strategy, techniques, lesion complexity, access to coronary physiology and imaging devices, as well as patient management. Thus, there is a need to construct a consensus document on recommendations for use of physiology-guided percutaneous coronary intervention (PCI) in APAC populations. This document serves as an overview of recommendations describing the best practices for APAC populations to achieve more consistent and optimal clinical outcomes. METHODS AND RESULTS: A comprehensive multiple-choice questionnaire was provided to 20 interven- tional cardiologists from 10 countries in the APAC region. Clinical evidence, tips and techniques, and clinical situations for the use of physiology-guided PCI in APAC were reviewed and used to propose key recommendations. There are suggestions to continue to develop evidence for lesion and patient types that will benefit from physiology, develop directions for future research in health economics and local data, develop appropriate use criteria in different countries, and emphasize the importance of education of all stakeholders. A consensus recommendation to enhance the penetration of invasive physiology-based therapy was to adopt the 5E approach: Evidence, Education, Expand hardware, Economics and Expert consensus. CONCLUSIONS: This consensus document and recommendations support interventional fellows and cardiologists, hospital administrators, patients, and medical device companies to build confidence and encourage wider implementation of invasive coronary physiology-guided therapy in the APAC region.