Michiel Rienstra

Worldwide Epidemiology of Atrial Fibrillation A Global Burden of Disease 2010 Study

Background— The global burden of atrial fibrillation (AF) is unknown. Methods and Results— We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5–22.2 million] and 12.6 million women [95% UI, 12.0–13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8–19.3) in men and 18.9% (95% UI, 15.8–23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8–612.7) and 359.9 in women (95% UI, 334.7–392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2–78.5) and 43.8 in women (95% UI, 35.9–55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4–636.7) in men and 373.1 (95% UI, 347.9–402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2–95.4) in men and 59.5 (95% UI, 49.9–74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0–2.2) and 1.9-fold (95% UI, 1.8–2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. Conclusions— These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies.

Meta-analysis identifies six new susceptibility loci for atrial fibrillation

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation

CONTEXT Although the heritability of atrial fibrillation (AF) is established, the contribution of familial AF to predicting new-onset AF remains unknown. OBJECTIVE To determine whether familial occurrence of AF is associated with new-onset AF beyond established risk factors. DESIGN, SETTING, AND PARTICIPANTS The Framingham Heart Study, a prospective community-based cohort study started in 1948. Original and Offspring Cohort participants were aged at least 30 years, were free of AF at the baseline examination, and had at least 1 parent or sibling enrolled in the study. The 4421 participants in this analysis (mean age, 54 [SD, 13] years; 54% women) were followed up through December 31, 2007. MAIN OUTCOME MEASURES Incremental predictive value of incorporating different features of familial AF (any familial AF, premature familial AF [onset ≤65 years old], number of affected relatives, and youngest age of onset in a relative) into a risk model for new-onset AF. RESULTS Across 11,971 examinations during the period 1968-2007, 440 participants developed AF. Familial AF occurred among 1185 participants (26.8%) and premature familial AF occurred among 351 participants (7.9%). Atrial fibrillation occurred more frequently among participants with familial AF than without familial AF (unadjusted absolute event rates of 5.8% and 3.1%, respectively). The association was not attenuated by adjustment for AF risk factors (multivariable-adjusted hazard ratio, 1.40; 95% confidence interval [CI], 1.13-1.74) or reported AF-related genetic variants. Among the different features of familial AF examined, premature familial AF was associated with improved discrimination beyond traditional risk factors to the greatest extent (traditional risk factors, C statistic, 0.842 [95% CI, 0.826-0.858]; premature familial AF, C statistic, 0.846 [95% CI, 0.831-0.862]; P = .004). Modest changes in integrated discrimination improvement were observed with premature familial AF (2.1%). Net reclassification improvement (assessed using 8-year risk thresholds of <5%, 5%-10%, and >10%) did not change significantly with premature familial AF (index statistic, 0.011; 95% CI, -0.021 to 0.042; P = .51), although categoryless net reclassification was improved (index statistic, 0.127; 95% CI, 0.064-0.189; P = .009). CONCLUSIONS In this cohort, familial AF was associated with an increased risk of AF that was not attenuated by adjustment for AF risk factors including genetic variants. Assessment of premature familial AF was associated with a very slight increase in predictive accuracy compared with traditional risk factors.

Atrial Fibrillation Current Knowledge and Future Directions in Epidemiology and Genomics

Atrial fibrillation (AF) is of public health importance and profoundly increases morbidity, mortality and health-related expenditures. Morbidities include the increased risks of cardiovascular outcomes such as heart failure and stroke, and the deleterious effects on quality of life, functional status and cognition. The clinical epidemiology of AF, its risk factors and outcomes, have been extensively investigated. Genetic advances over the last decade have facilitated the identification of mutations and common polymorphisms associated with AF. Metabolomics, proteomics and other “omics” technologies have only recently been applied to the study of AF, and have not yet been systematically investigated. Systems biology approaches, while still in their infancy, offer the promise of providing novel insights into pathways influencing AF risk. In the present review, we address the current state of the epidemiology and genomics of AF. We seek to emphasize how epidemiology and “omic” advances will contribute towards a systems biology approach that will help to unravel the pathogenesis, risk stratification, and novel targets for AF therapies. Our purpose is to articulate questions and challenges that hinge on integrating novel scientific advances in the epidemiology and genomics of AF. As a reference we have provided a glossary in the inset box.

Cardiovascular Epigenetics Basic Concepts and Results From Animal and Human Studies

Epigenomic mechanisms, such as DNA methylation and histone modifications, represent a critical link between genomic coding and phenotype expression that is influenced by both underlying genetic and environmental factors. Animal models indicate that epigenomic mechanisms have fundamental roles in the development of inflammation, obesity, diabetes, atherosclerotic lesions, and cardiovascular disease. Aberrant DNA methylation and histone modifications have been found in pathology investigations of atherosclerotic lesions. In the present article, we propose an overview of the major milestones in epigenetics, as well as of recent development and technologies for epigenomic research. We review recent findings demonstrating the links of individual characteristics, risk factors, and biomarkers with epigenetic signatures. We present available evidence from human studies that have investigated the relation of epigenetic mechanisms with subclinical and clinical cardiovascular disease. Also, we provide a list of online resources that can help retrieve additional information and facilitate further work in epigenomics. Finally, we discuss open questions for future research in cardiovascular epigenomics, including issues related to the analysis of surrogate and cardiovascular tissues, conduction and analysis of genome-wide epigenetic studies, integration of genomic and transcriptomic data in epigenomic investigations, and perspectives for epigenomics in preventive cardiovascular medicine and pharmacology.

Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction

Atrial fibrillation (AF) is common in heart failure (HF), but few data regarding the prognostic relevance of AF are available in HF patients with preserved left ventricular ejection fraction (HF‐PEF). We aimed to study the clinical impact of AF vs. sinus rhythm (SR) in stabilized HF patients with reduced left ventricular ejection fraction (HF‐REF) and in those with preserved left ventricular ejection fraction (HF‐PEF).

Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT.

Background ASSERT demonstrated that subclinical atrial fibrillation (SCAF) is common in pacemaker patients without prior AF and is associated with increased risk of ischemic stroke or systemic embolism. SCAF episodes vary in duration and little is known about the incidence of different durations of SCAF, or their prognosis. Methods and results ASSERT followed 2580 patients receiving a pacemaker or ICD, aged >65 years with hypertension, without prior AF. The effect of SCAF duration on subsequent risk of ischemic stroke or embolism was evaluated with time-dependent covariate Cox models. Patients in whom the longest SCAF was ⩽6 min were excluded from the analysis (n=125). Among 2455 patients during mean follow-up of 2.5 years, the longest single episode of SCAF lasted >6 min to 6 h in 462 patients (18.8%), >6–24 h in 169 (6.9%), and >24 h in 262 (10.7%). SCAF duration >24 h was associated with a significant increased risk of subsequent stroke or systemic embolism (adjusted hazard ratio [HR] 3.24, 95% confidence interval [CI] 1.51–6.95, P=0.003). The risk of ischemic stroke or systemic embolism in patients with SCAF between 6 min and 24 h was not significantly different from patients without SCAF. Conclusions SCAF >24 h is associated with an increased risk of ischemic stroke or systemic embolism.

Screening for Atrial Fibrillation A Report of the AF-SCREEN International Collaboration

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Incidence of Atrial Fibrillation and Relationship With Cardiovascular Events, Heart Failure, and Mortality: A Community-Based Study From the Netherlands

BACKGROUND Important improvements have been made in treatment of diseases associated with atrial fibrillation (AF), such as hypertension, myocardial infarction, and heart failure. Incidence rates and risk factors may have changed with the aging of the population and changing lifestyles. Currently, the risk for AF is only partially explained, possibly because of differences between older cohorts and contemporary populations. OBJECTIVES This study investigated the incidence of AF in a contemporary cohort in the Netherlands, together with comorbidities associated with AF and associations of AF with cardiovascular outcomes. METHODS Incident AF was ascertained for hospital and study electrocardiograms in 8,265 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study in Groningen, the Netherlands. RESULTS During 9.7 ± 2.3 years of follow-up, 265 participants developed AF, with a resulting overall AF incidence of 3.3 per 1,000 person-years. Advancing age, male sex, antihypertensive drug use, higher body mass index, previous myocardial infarction, and previous stroke were associated with AF. After multivariable adjustment, AF was associated with cardiovascular events (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.06 to 4.75; p = 0.035), heart failure with either reduced or preserved ejection fraction (HR: 4.52; 95% CI: 2.02 to 10.09; p < 0.001), and all-cause mortality (HR: 3.02; 95% CI: 1.73 to 5.27; p < 0.001). CONCLUSIONS The incidence of AF in the present cohort was comparable to that shown in data of older studies. Obesity has become a major risk factor for incident AF. Although overall cardiovascular event rates were lower in the present study, the present study confirms the association of incident AF with such events.

An Update on the Prognosis of Patients With Atrial Fibrillation

Atrial fibrillation (AF) is a highly prevalent and costly health problem, with an estimated incidence of 28 per 1000 person-years in the United States and an incremental national cost of