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Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
OBJECTIVES - We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.
METHODS - We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.
RESULTS - Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus () that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.
CONCLUSIONS - Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
BACKGROUND - There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV.
METHODS - Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence.
RESULTS - Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome.
CONCLUSIONS - Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.
BACKGROUND AND OBJECTIVES - The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.
RESULTS - In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.
CONCLUSIONS - In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.
Copyright © 2017 by the American Society of Nephrology.
We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (=0.34; <0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit-SBP ≥128 mm Hg (top 2 quartiles) had >2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42-5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.
© 2017 American Heart Association, Inc.
BACKGROUND - Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort.
METHODS - We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC.
RESULTS - Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/μL: ref; 350-499 cells/μL: aIRR = 1.32 (0.98 to 1.77); 200-349 cells/μL: aIRR = 1.37 (1.01 to 1.86); 100-199 cells/μL: aIRR = 1.60 (1.09 to 2.34); <100 cells/μL: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded.
CONCLUSIONS - The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.
Clinical evidence has indicated an increased myocardial infarction (MI) morbidity and mortality after exposure to air pollution (particulate matter<2.5 μm, PM2.5). However, the mechanisms by which PM2.5 aggravates MI remain unknown. Present study was to explore the adverse effect of PM2.5 on myocardium after MI and the potential mechanisms. Male mice with MI surgery were treated with PM2.5 by intranasal instillation. Neonatal mice ventricular myocytes (NMVMs) subjected to hypoxia were also incubated with PM2.5 to determine the role of PM2.5 in vitro. Exposure to PM2.5 significantly impaired the cardiac function and increased the infarct size in MI mice. TUNEL assay, flow cytometry and western blotting of Caspase 3, Bax and BCl-2 indicated that PM2.5 exposure could cause cellular apoptosis in vivo and in vitro. Besides, PM2.5 activated NFκB pathway and increased gene expression of IL-1β and IL-6 in NMVMs with hypoxia, which could be effectively reversed by SN-50-induced blockade of NFκB translocation to the nucleus. In summary, air pollution induces myocardium apoptosis and then impairs cardiac function and aggravates MI via NFκB activation.
Copyright © 2017 Elsevier Inc. All rights reserved.
BACKGROUND - The optimal revascularization technique in patients with left main coronary artery disease (CAD) remains controversial. We aimed to compare the long-term performance of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery in treatment of left main CAD.
METHODS - PubMed, EMBASE, and the Cochrane Library were searched until November 16, 2016.
RESULTS - Six randomized controlled trials and 22 matched observational studies including 22,487 patients and 90,167 patient-years of follow-up were included. PCI was associated with an overall higher risk for the major adverse cardiac and cerebrovascular events (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.14-1.77), mainly driven by higher rates of myocardial infarction (HR, 1.69; 95% CI, 1.22-2.34) and revascularization (HR, 2.80; 95% CI, 1.86-4.22). The overall risks for all-cause death (HR, 1.05; 95% CI, 0.93-1.20), cardiac death (HR, 1.05; 95% CI, 0.69-1.59), stroke (HR, 0.64; 95% CI, 0.33-1.24), and the composite safety endpoint of death, myocardial infarction, or stroke (HR, 1.06; 95% CI, 0.97-1.16) were similar between PCI and CABG. Stratified analysis based on stent types showed that the increased risk for myocardial infarction associated with PCI was only evident in patients with bare-metal stents or early-generation drug-eluting stents (DES), but not newer-generation DES. Stratified analyses based on study designs showed largely similar findings with the overall analyses, except for a significantly higher incidence of myocardial infarction in adjusted studies (HR, 2.01; 95% CI, 1.64-2.45) but a trend toward higher incidence in randomized trials (HR, 1.39; 95% CI, 0.85-2.27) associated with PCI.
CONCLUSIONS - Compared with CABG, PCI with newer-generation DES might be a safe alternative revascularization strategy for treatment of left main CAD, but is associated with more repeat revascularization.
Various stem cells have been explored for the purpose of cardiac repair. However, any individual stem cell population has not been considered as the ideal source. Recently, trophoblast stem cells (TSCs), a newly described stem cell type, have demonstrated extensive plasticity. The present study evaluated the therapeutic effect of TSCs transplantation for heart regeneration in a mouse model of myocardial infarction (MI) and made a direct comparison with the most commonly used mesenchymal stem cells (MSCs). Transplantation of TSCs and MSCs led to a remarkably improved cardiac function in contrast with the PBS control, but only the TSCs exhibited the potential of differentiation into cardiomyocytes in vivo. In addition, a significantly high proliferation level of both transplanted stem cells and resident cardiomyocytes was observed in the TSCs group. These findings primary revealed the therapeutic potential of TSCs in transplantation therapy for MI.
BACKGROUND - Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.
METHODS AND RESULTS - RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.
CONCLUSIONS - expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
© 2017 American Heart Association, Inc.