Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study)

Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new-onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography-tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new-onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 +/- 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF

Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study

OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years. CONCLUSIONS: Regardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three a third in individuals with at least one elevated risk factor

Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study)

Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new-onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography–tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new-onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 ± 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF

Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005–2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 × 10−279). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis

Relations of Liver Fat With Prevalent and Incident Atrial Fibrillation in the Framingham Heart Study

Background: Obesity is an important risk factor for nonalcoholic fatty liver disease and atrial fibrillation (AF). Less is known about the relations between nonalcoholic fatty liver disease and AF. We sought to evaluate the association between fatty liver and prevalent and incident AF in the community. Methods and Results: We examined Framingham Heart Study participants who underwent a study‐directed computed tomography scan, had hepatic steatosis (HS) evaluated, and did not report heavy alcohol use between 2002 and 2005. We evaluated cross‐sectional associations between liver fat and prevalent AF with logistic regression models. We assessed the relations between liver fat and incident AF during 12‐year follow‐up with Cox proportional hazards models. Of 2122 participants (53% women; mean age, 59.0±9.6 years), 20% had HS. AF prevalence (n=62) among individuals with HS was 4% compared to 3% among those without HS. There was no significant association between HS (measured as continuous or dichotomous variables) and prevalent AF in age‐ and sex‐adjusted or multivariable‐adjusted models. Incidence of AF (n=153) among participants with and without HS was 8.7 cases and 7.8 cases per 1000 person‐years, respectively. In age‐ and sex‐adjusted and multivariable‐adjusted models, there were no significant associations between continuous or dichotomous measures of HS and incident AF. Conclusions: In our community‐based, longitudinal cohort study, liver fat by computed tomography scan was not significantly associated with increased prevalence or incidence of AF over 12 years of follow‐up

Anticoagulation reversal in vitamin K antagonist–associated intracerebral hemorrhage: a systematic review

The effect of rapid anticoagulation reversal on mortality and functional outcome in vitamin K antagonist–associated intracerebral hemorrhage (VKA–ICH) is uncertain. Given the approval of idarucizumab for dabigatran reversal and pending approval for andexanet alfa for reversal of factor Xa inhibitors, a systematic appraisal of the effectiveness of reversal for VKA–ICH would provide a bench mark for current practice. We performed PubMed searches and reviewed current guidelines. Using pre-specified inclusion and exclusion criteria, studies were reviewed by two physicians independently. Data elements abstracted included study design, sample size, inclusion and exclusion criteria; patient characteristics at presentation; time to presentation and therapy; dose and timing of warfarin reversal agents; functional outcome and mortality. Studies were assessed for risk of bias. Twenty-one studies met the selection criteria. The overall quality of the studies was poor with small sample size for the majority and all studies being either case series or retrospective observational in design. Inclusion criteria were not uniform. Interpretation of the effectiveness of vitamin K antagonist reversal on functional outcome was not feasible due to lack of standard protocols in the management of VKA–ICH including choice, dose, and timing of reversal agent, timing of subsequent INR monitoring, and decision for repeat imaging. Confounding by indication, lack of universal reporting of functional outcome, and use of varied scales for the endpoint further limited a summary interpretation. Despite availability of reversal agents, mortality and morbidity remain high following VKA–ICH. Evidence for improvement in neurological outcome is limited

Neck Circumference and Risk of Incident Atrial Fibrillation in the Framingham Heart Study

Background Increased neck circumference, a proxy for upper‐body subcutaneous fat, is associated with cardiovascular risk and metabolic risk factors, accounting for body mass index (BMI) and waist circumference. The association between neck circumference and incident atrial fibrillation (AF) is unclear. The aim of current study was to evaluate the association between neck circumference and incident AF. Methods and Results We selected participants from the Framingham Heart Study aged ≥55 years without diagnosed AF and with available neck circumference, BMI, and waist circumference measurements. We defined high neck circumference as ≥14 inches in women and ≥17 inches in men on the basis of the Contal and O’Quigley changepoint method. We used Fine‐Gray models to estimate subdistribution hazards ratios (sHRs) for the association between neck circumference and incident AF accounting for the competing risk of death. We adjusted models for clinical risk factors. We then additionally adjusted separately for BMI, waist circumference, and height/weight. The study sample included 4093 participants (mean age 64±7 years, 55% female). During 11.2±5.7 mean years of follow‐up, incident AF occurred in 571 participants. High neck circumference was associated with incident AF (sHR for high versus low: 1.58; 95% CI, 1.32–1.90, P<0.0001). The association remained significant after adjustment for BMI (sHR, 1.51; 95% CI, 1.21–1.89; P=0.0003), waist circumference (sHR, 1.47; 95% CI, 1.18–1.83; P<0.0001), and height/weight (sHR, 1.37; 95% CI, 1.09–1.72; P=0.007). Conclusions High neck circumference was associated with incident AF adjusting for traditional adiposity measures such as BMI and waist circumference