Background Abnormalities in left atrial (LA) function often occur before LA structural changes and clinically identified atrial fibrillation (AF). Little is known about the relationship between LA ...strain and the risk of subclinical atrial arrhythmias detected from extended ambulatory cardiac monitoring. Methods and Results A total of 1441 participants of MESA (Multi-Ethnic Study of Atherosclerosis) completed speckle-tracking echocardiography and cardiac monitoring during 2016 to 2018 (mean age, 73 years); participants in AF during echocardiography or during the entire cardiac monitoring period were excluded. Absolute values of LA reservoir, booster pump, and conduit strains were measured. We evaluated associations of LA strain with monitor-detected AF, premature atrial contractions, and supraventricular tachycardia. Primary analyses adjusted for demographic variables, blood pressure, diabetes, smoking, and clinical cardiovascular disease. Cardiac monitoring (median, 14 days) detected AF in 3%. Each SD (4.0%) lower (worse) LA booster pump strain was associated with 84% higher risk of monitor-detected AF (95% CI, 30%-162%), 39% higher premature atrial contraction frequency (95% CI, 27%-53%), and 19% higher supraventricular tachycardia frequency (95% CI, 10%-29%). Additional adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), LA volume index, tissue Doppler a' peak velocity, left ventricular ejection fraction, and global longitudinal strain had little impact on associations. Findings were similar for LA reservoir strain and null for LA conduit strain. Conclusions In a multiethnic community-based cohort, impaired LA strain was an important correlate of subclinical atrial arrhythmias, even after adjustment for conventional measures of LA structure and function.
Understanding venous thromboembolism (VTE) recurrence risk is central to determining the appropriate treatment course. Whether this risk varies after discontinuing anticoagulation or overall by type ...of incident event (pulmonary embolism PE vs deep vein thrombosis DVT) and by the detailed location of the DVT needs further clarification.
In this population-based inception cohort of incident VTE cases with follow-up by electronic health record review, incident DVT was categorized as distal, popliteal, or iliofemoral. We used the Fine-Gray regression model to describe the predictive association of the thrombus location with the risk of recurrence before death.
Among 2766 participants with an incident event from 2002 to 2010, 1713 (62%) ceased anticoagulation and were followed for recurrent events; 301 events were observed during the 4.5 years of follow-up. Relative to participants with an incident thrombus in an iliofemoral location and no PE, those with a thrombus in a popliteal location and no PE had a similar risk of recurrence (adjusted subdistribution hazard ratio aSHR, 0.82 95% confidence interval (CI), 0.57-1.19), while those with a thrombus in a distal location and no PE and those with a thrombus that included a PE had lower risk of recurrence: aSHR, 0.34 (95% CI, 0.20-0.57); and aSHR, 0.58 (95% CI 0.45-0.76), respectively.
The findings of this population-based inception cohort confirm that the risk of recurrent VTE after discontinuing anticoagulants is similar after iliofemoral and popliteal DVT but is lower after distal DVT. Recurrence may be lower after PE than proximal DVT.
DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across ...multiple prospective cohorts.
Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
BACKGROUND:DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident ...CHD across multiple prospective cohorts.
METHODS:Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
RESULTS:Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
CONCLUSION:Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
Highlights ► We study the influence of 27 candidate genes on statin effectiveness. ► We use myocardial infarction as the primary treatment outcome. ► The interaction with statins is most significant ...for SCARB1 rs4765615. ► None of the ten associated SNPs reach statistical significance in the replication study. ► PCSK9 670G carriers respond better to statins in UCP (significant) and HVH (not significant).
BACKGROUND
Diabetes may be an independent risk factor for atrial fibrillation. However, results from prior studies are in conflict, and no study has examined diabetes duration or glycemic control.
...OBJECTIVE
To examine the association of diabetes with risk of atrial fibrillation and to describe risk according to diabetes duration and glycemic control.
DESIGN
A population-based case-control study.
PARTICIPANTS
Within a large, integrated healthcare delivery system, we identified 1,410 people with newly-recognized atrial fibrillation from ICD-9 codes and validated cases by review of medical records. 2,203 controls without atrial fibrillation were selected from enrollment lists, stratified on age, sex, hypertension, and calendar year.
MAIN MEASURES
Information on atrial fibrillation, diabetes and other characteristics came from medical records. Diabetes was defined based on physician diagnoses recorded in the medical record, and pharmacologically treated diabetes was defined as receiving antihyperglycemic medications. Information about hemoglobin A1c levels came from computerized laboratory data.
KEY RESULTS
Among people with atrial fibrillation, 252/1410 (17.9%) had pharmacologically treated diabetes compared to 311/2203 (14.1%) of controls. The adjusted OR for atrial fibrillation was 1.40 (95% CI 1.15-1.71) for people with treated diabetes compared to those without diabetes. Among those with treated diabetes, the risk of developing atrial fibrillation was 3% higher for each additional year of diabetes duration (95% CI 1-6%). Compared to people without diabetes, the adjusted OR for people with treated diabetes with average hemoglobin A1c ≤7 was 1.06 (95% CI 0.74-1.51); for A1c >7 but ≤8, 1.48 (1.09-2.01); for A1c >8 but ≤9, 1.46 (1.02-2.08); and for A1c >9, 1.96 (1.22–3.14).
CONCLUSIONS
Diabetes was associated with higher risk of developing atrial fibrillation, and risk was higher with longer duration of treated diabetes and worse glycemic control. Future research should identify and test approaches to reduce the risk of atrial fibrillation in people with diabetes.
In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The ...PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
IMPORTANCE Little is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat ...menopausal symptoms. OBJECTIVE To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs—conjugated equine estrogens (CEEs) and estradiol. DESIGN, SETTING, AND PARTICIPANTS Population-based, case-control study from January 1, 2003, to December 31, 2009, comparing cardiovascular event risk associated with current CEEs and estradiol use in a large health maintenance organization in which the preferred formulary estrogen changed from CEEs to estradiol during the course of data collection. Participants were 384 postmenopausal women aged 30 to 79 years using oral hormone therapy. MAIN OUTCOMES AND MEASURES Incident venous thrombosis was the primary clinical outcome, and incident myocardial infarction and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, the endogenous thrombin potential–based normalized activated protein C sensitivity ratio, was measured in plasma of controls. RESULTS We studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02-4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91-3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55-2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential–based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity. CONCLUSIONS AND RELEVANCE In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.
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